JP2024503114A - Combination of antidepressants and dextromethorphan for neuropsychiatric disorders - Google Patents

Abstract

Dosage forms, drug delivery systems and methods for sustained release or improved therapeutic efficacy of dextromethorphan are disclosed. Generally, antidepressants are administered orally to humans who are or are being treated with dextromethorphan. [Selection diagram] None

Description

(Cross reference to related applications)
This application claims priority to U.S. Provisional Patent Application No. 63/138,757, filed January 18, 2021, and is incorporated herein by reference in its entirety.

Antidepressant compounds can be used to improve the therapeutic properties of dextromethorphan, for example in the treatment of neurological and/or psychiatric disorders.

Some embodiments include a method of treating a neurological or psychiatric disease comprising administering to a human in need of treatment a combination of an antidepressant compound and dextromethorphan, wherein the human receives a combination of an antidepressant compound and dextromethorphan. Metabolism is accelerated.

FIG. 1 is a plot of mean plasma concentration of dextromethorphan over time after administration on day 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 2 shows the mean AUC _0-12 for dextromethorphan on day 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 3 shows the mean AUC _0-24 for dextromethorphan on day 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 4 shows the mean AUC _0-inf of dextromethorphan on day 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 5 shows the fold change in AUC of dextromethorphan on day 8 for subject administration of dextromethorphan alone compared to dextromethorphan and bupropion. FIG. 6 shows the mean AUC _0-12 of dextromethorphan on days 1 and 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 7 shows mean dextromethorphan in plasma concentrations for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 8 shows the mean dextromethorphan maximum plasma concentrations on days 1 and 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 9 shows a plot of mean plasma concentration of dextrorphan over time after administration on day 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 10 shows the mean dextrorphan maximum plasma concentrations after administration on days 1 and 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. FIG. 11 shows the mean AUC _0-12 of dextrorphan on days 1 and 8 for subject administration of dextromethorphan alone or dextromethorphan and bupropion. Figure 12 shows the effect of various antidepressant compounds on inhibition of dextromethorphan metabolism in human liver microsomes. FIG. 13 is a plot of mean MADRS total score change from baseline over time during a 6-week treatment period for subjects receiving bupropion alone or the combination of dextromethorphan and bupropion. FIG. 14 shows the percentage of subjects who achieved remission (MADRS≦10) over time during the 6-week treatment period for subjects receiving bupropion alone or the combination of dextromethorphan and bupropion. . FIG. 15 is a plot showing the decrease in MADRS total score over time for the subjects described in Example 6. FIG. 16 is a plot of percentage of responders over time for the subjects described in Example 6. FIG. 17 is a plot of the percentage of subjects in remission over time for the subjects described in Example 6.

Some embodiments include a method of treating a neurological and/or psychiatric disease comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant.

Some embodiments include methods of enhancing the therapeutic properties of dextromethorphan in the treatment of neurological diseases, including co-administering dextromethorphan and an antidepressant.

Some embodiments include a method of increasing dextromethorphan plasma concentrations in a human with an increased metabolism of dextromethorphan, comprising co-administering an antidepressant compound and dextromethorphan to the human.

Some embodiments include a method of inhibiting a metabolite of dextromethorphan, comprising administering an antidepressant compound to a human, wherein the human is an extensive metabolizer of dextromethorphan; is present in the human body at the same time as antidepressants.

Some embodiments include methods of increasing the metabolite lifetime of dextromethorphan, including methods of increasing the elimination half-life (T _1/2 ) of dextromethorphan. These embodiments can include administering an antidepressant compound to a human, the human is an extensive metabolizer of dextromethorphan, and dextromethorphan is administered to the human concurrently with the antidepressant compound. Exists in the body.

Some embodiments include a method of correcting a high metabolite of dextromethorphan, comprising administering an antidepressant compound to a human in need of correction, such as a human in need of treatment for pain. .

Some embodiments include administering an antidepressant compound in combination with administration of dextromethorphan to a human in need of treatment for a neurological and/or psychiatric disorder. Includes methods of improving the therapeutic properties of dextromethorphan in therapy.

Some embodiments provide a method of treating a neurological and/or psychiatric disorder comprising administering an antidepressant compound and dextromethorphan in combination to a human in need of treatment for the neurological and/or psychiatric disorder. include.

Co-administration of dextromethorphan with an antidepressant compound for 1 day, or 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 30 days, 35 days, 40 days, Occurs one or more times consecutively for a period of 45 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 100 days, or more. In some embodiments, co-administration is at least daily for at least two consecutive days.

In some embodiments, the antidepressant compound and dextromethorphan are co-administered for 1, 2, 3, 4, 5, 6, or 7 days prior to twice daily co-administration. It may be performed once a day.

Dextromethorphan contains the following structure.

Dextromethorphan is used as a cough suppressant. According to the FDA's labeling requirements for dextromethorphan products under the OTC monograph [21CFR341.74], dextromethorphan can be administered six times a day (every 4 hours), four times a day (every 6 hours), or should be administered three times a day (every 8 hours). The OTC monograph [21CFR341.74] also states, ``Dosage is the same as for dextromethorphan hydrobromide...Oral administration is 10 to 20 milligrams every 4 hours, 30 milligrams every 6 to 8 hours, 24 Do not exceed 120 milligrams per hour or as directed by your physician."

Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are extensive metabolizers. Humans are 1) high dextromethorphan metabolizers - humans who rapidly metabolize dextromethorphan, 2) poor dextromethorphan metabolizers - humans who only slightly metabolize dextromethorphan, or 3) dextromethorphan. Intermediate metabolizer - may be a human whose metabolism of dextromethorphan lies somewhere between extensive and poor metabolizers. Rapid metabolizers of dextromethorphan can also be ultra-rapid metabolizers. Extensive dextromethorphan metabolizers represent a significant portion of the population. For example, dextromethorphan can be metabolized to dextrorphan.

When given the same oral dose of dextromethorphan, plasma concentrations of dextromethorphan are significantly higher in poor or intermediate metabolizers compared to extensive metabolizers of dextromethorphan. Low plasma concentrations of dextromethorphan may limit its clinical utility as a single agent for extensive metabolizers and in some cases intermediate metabolism of dextromethorphan. Therapeutically active compounds, including some antidepressants, can inhibit the metabolism of dextromethorphan and increase the plasma concentration of dextromethorphan, thereby enhancing its therapeutic efficacy. Similarly, antidepressants can be administered once a day instead of twice a day, once a day instead of three times a day, and once a day instead of four times a day, without losing therapeutic efficacy. Dextrorphan may be given less frequently, such as twice a day instead of three times a day, or twice a day instead of four times a day, or in lower amounts.

Co-administration of dextromethorphan or dextrorphan with an antidepressant may enhance the mechanism of action or pharmacological properties of dextromethorphan and dextrorphan. Mechanisms of action of dextromethorphan and dextrorphan may include sigma-1 agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition and mu receptor potentiation.

Some embodiments agonize, antagonize, or modulate the sigma-1 receptor, or the NMDA receptor, block calcium channels, bind to muscarinic receptors, and inhibit the serotonin transporter (5HTT). or the co-administration of dextromethorphan or dextrorphan with antidepressants to inhibit mu receptors or enhance mu receptors.

The pharmacological properties of dextromethorphan and dextrorphan include NMDA high-affinity cytoactivity, NMDR-2A activity, and functional NMDR-2B receptor antagonism, sigma-1 stimulation, and putative mTOR activation (sigma-1). 1 stimulation, mu enhancement, beta-adrenergic receptor stimulation, and 5HTT inhibition), putative AMPA receptor transport (via mTOR activation, PCP antagonism, sigma-1 stimulation, beta stimulation, mu enhancement, and 5HTT inhibition), and Neuronal survival via dendrite formation, spindle formation, synapse formation, NMDA antagonism and sigma-1 and mTOR signaling may be included. Some embodiments include NMDA high affinity sites, NMDR-2A, functional NMDR-2B receptors, sigma-1 receptors, putative mTOR receptors (stimulation of sigma-1, enhancement of mu receptors, beta-adrenergic or putative AMPA receptors (e.g., activation of mTOR, antagonism of PCP activity, stimulation of sigma-1 receptors, stimulation of beta-adrenergic receptors, mu receptors) activating, antagonizing, stimulating, activating, inhibiting, affecting the transport of, or inhibiting 5HTT) Including co-administration of dextromethorphan or dextrorphan with antidepressants to modulate. Some embodiments include the combination of dextromethorphan or dextrorphan with an antidepressant to cause, increase, reduce, or modulate dendrite formation, spindle formation, or synapse formation. Including co-administration. Some embodiments include dextromethorphan or dextrorphan to cause, increase, reduce, or modulate neuronal survival through NMDA antagonism and/or sigma-1 and/or mTOR signaling; Including co-administration with depressants.

The pharmacological properties of dextromethorphan and dextrorphan may include 5HTT and norepinephrine transporter inhibition, sigma-1 stimulation, NMDA and PCP antagonism, and stimulation of serotonin 5HT1b/d receptors, if present. Some embodiments bind to, agonize, antagonize, stimulate, and activate 5HTT and/or norepinephrine transporters, sigma-1 receptors, NMDA and/or PCP receptors. , the combination of dextromethorphan or dextrorphan with antidepressants to inhibit it, affect its transport, or modulate it, and/or stimulate serotonin 5HT1b/d receptors. Including administration.

Additional properties of dextromethorphan and dextrophan include antagonism of presynaptic alpha-2 adrenergic receptors if present or postsynaptic alpha-2 stimulation, beta stimulation and possible muscarinic and mu antagonism. obtain. Some embodiments bind to, agonize or antagonize presynaptic alpha-2 adrenergic receptors, postsynaptic alpha-2 receptors, beta adrenergic receptors, muscarinic receptors, or mu receptors; Including the co-administration of dextromethorphan or dextrorphan with antidepressants to stimulate it, activate it, inhibit it, affect its transport and modulate it. Dextromethorphan and dextrorphan can be glial cell modulating agents. Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant to modulate glial cells.

Pain or other neurological and/or psychiatric disorders can be treated with a therapeutically effective amount of dextrorphan, e.g., by increasing dextromethorphan plasma concentrations or increasing the bioavailability of dextromethorphan. Treatment may include administering an effective amount of an antidepressant compound to a person in need of treatment for pain or other neurological disorders.

Examples of neurological disorders that can be treated or treated with increased efficacy by increased dextromethorphan concentrations, such as can be obtained by combining dextrorphan with antidepressants, include, but are not limited to, affective disorders. , including mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, seizure disorders, and headaches.

Affective disorders that may be treated by elevated dextromethorphan concentrations or by the combination of dextromethorphan and antidepressants include, but are not limited to, depression, major depression, treatment-resistant depression, and treatment-resistant depression. Bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthmia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression , atypical depression, mania, anxiety disorders, attention-deficit disorder (ADD), attention-deficit disorder/hyperactivity (ADDH), including hyperactivity, attention-deficit/hyperactivity disorder (AD/HD), bipolar and manic states, including obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychosexual dysfunction, pseudoaffects, and emotional instability.

Depression can be manifested by symptoms of depression. These symptoms include mood changes, intense feelings of sadness, despair, decreased mental function, decreased concentration, pessimistic worry, impatience, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, Psychological changes such as suicidal thoughts or attempts and/or self-deprecation may be included. Physical symptoms of depression include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and sex drive, fatigue, restlessness, aches, pains, headaches, cramps, indigestion, and/or Abnormalities in the circadian rhythm of hormone secretion may be involved.

For some patients, even with drug therapy such as antidepressants, the therapeutic effect is insufficient or no therapeutic effect is obtained at all. Treatment-resistant depression (TRD), or refractory depression, is a condition commonly associated with patients who have failed treatment with at least two antidepressants. Part of the diagnosis of TRD is that, for example, in a current depressive episode, antidepressants, given in sufficient amounts and over a sufficient time course, do not have sufficient therapeutic effect. TRD may be more difficult to treat because of the coexistence of other medical or psychological conditions, such as drug/alcohol abuse or eating disorders, or because TRD is misdiagnosed. Some patients with TRD have had an inadequate response to one, two, three, or more attempts at appropriate antidepressant treatment, or have had one, two, three, or more prior antidepressant treatments. There are some patients who have failed drug treatment or have not received an adequate response. In some embodiments, the patient receiving treatment for treatment-resistant depression is receiving at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antidepressant treatments. treatment has failed.

Indicators of treatment efficacy that can be improved by treatment with dextromethorphan in combination with antidepressants include, but are not limited to, the Montgomery-Asberg Depression Rating Scale (MADRS), quality of life; Enjoyment and Satisfaction Questionnaire Short Form, Impairment Scope Tool, Sheehan Disability Scale, Patient Rated Side Effect Inventory (PRISE), Columbia Suicide Severity Rating Scale (C-SSRS), Brief Depressive Symptom Scale - Self-Report (QIDS-SR) ), Clinical Global Impressions (CGI) scale, Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), Hamilton Depression Rating Scale 17-item version (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire ( MGF ATRQ), Brief Depressive Symptom Scale 16-Item Version - Self-Report (QIDS-SR16), Sheehan Disability Scale (SDS), Clinical Global Impression Severity (CGI-S), Clinical Global Impression Change Scale (CGI-C), Euro QOL 5 items 5 levels (EQ-5D-5L), Patient Global Impression of Change (PGIC), Generalized Anxiety Disorder 7 items (GAD-7), Clinical Global Impression Improvement Index (CGI-I), Sheehan Disorder Scale (SDS) ), Brief Depressive Symptom Scale 16-Item Version - Self-Report (QIDS-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Function Questionnaire (CPFQ), CPFQ - Cognitive Subscale (4 to 7 items) ), Brief Psychiatric Rating Scale (BPRS), Digit Symptom Substitution Test (DSST), Ray Auditory Verbal Learning Task (RAVLT), Trail Making Test (TMT), Stroop Color Naming Test (STROOP), Simple Reaction Time (SRT), etc. ), selective reaction time (CRT), etc. In some embodiments, treating a person with a combination of dextromethorphan and an antidepressant increases the person's score by at least about 10 on one of the above assessments compared to baseline or placebo. %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 5-15 %, about 15-25%, about 25-35%, about 35-45%, about 45-55%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, It may be improved (eg, reduced) by about 90-100%. In some embodiments, the improvement is compared to a baseline. In some embodiments, the improvement is compared to a placebo.

Administration of a combination of an antidepressant and dextromethorphan may result in rapid therapeutic effects, such as within about 1 week, within about 2 weeks, within about 3 weeks, or within about 4 weeks after initiation of treatment. There is.

In some embodiments, the enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan and an antidepressant, is increased over 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours. Start of action within , 5 hours, 6 hours, 6-8 hours, 8-12 hours, 12 hours, 1 day, 1-7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks there's a possibility that.

Patients who may benefit from the treatments described herein include those who are less than about 18 years old, about 0-5 years old, about 5-10 years old, about 10-12 years old, or about 12-18 years old. Pediatric patients, about 18 to 70 years old, about 18 to 65 years old, about 18 to 30 years old, about 10 to 20 years old, about 20 to 30 years old, about 30 to 40 years old, about 40 to 50 years old, about 50 to Adult patients, such as patients 60 years old, about 60-70 years old, about 70-80 years old, about 80-90 years old, about 30-50 years old, about 50-65 years old, over 65 years old, 65-75 years old, Includes elderly patients, such as patients who are about 75 to 90 years old, or over 90 years old, and patients who are about 41 years old or older.

In some embodiments, a human being treated with a combination of dextromethorphan and an antidepressant, e.g., for a type of depression, is treated with a combination of dextromethorphan and an antidepressant prior to treatment (e.g., on the same day as starting treatment, but Before the start of treatment or before treatment 0-1 week, 0-2 weeks, 0-3 weeks, 0-4 weeks, 0-2 months, 0-3 months, 0-4 months, 0-5 months Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Clinical Trials Version SCID-5-CT diagnosis of major depressive disorder is selected. In some embodiments, the human currently meets DSM-5 criteria for MDD without psychotic features based on SCID-5-CT.

In some embodiments, a human being treated with a combination of dextromethorphan and an antidepressant is treated for about 8 weeks to about 24 months, about 1 to 6 months, about 6 to about 6 months, depending on the type of depression, for example. 12 months, about 1 to 2 years, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 2 years, about 1 to 12 weeks, about 3 to 6 months, about 6 to 9 months, about 9 to 12 months, about 12 Suffering from an ongoing major depressive episode for up to 18 months, about 18 to 24 months, about 2 to 4 years, about 4 to 6 years, about 6 to 10 years, about 10 to 20 years, or longer; Or choose to suffer.

In some embodiments, a human being treated with a combination of dextromethorphan and an antidepressant receives, e.g., at least 1, at least about 2, at least having, or selected to have, major depressive episodes including about 3, at least about 4, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 20, at least about 20, at least about 30 or more major depressive episodes, such as at least about 10, at least about 40, at least about 40, at least about 40, at least about 30, or more major depressive episodes, such as at least about 15; at least about 15, at least about 40, at least about 40, at least about 30, or more. at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, about 1-5, about 5-10, about 10-20, about 20-30, about 30 ~40, about 40-50, about 50-60, about 60-70, about 70-80, about 80-90, about 90-100, or about 1-100, including about 4-7 lifetime depressive episodes or more than one lifetime depressive episode, such as a major depressive episode.

In some embodiments, a previous antidepressant in a current depressive episode (e.g., current major depressive episode), e.g., for the type of depression treated with a combination of dextromethorphan and an antidepressant. have or are selected to have an inadequate response to one or more previous antidepressant therapies, including drug therapy, e.g., 1, 2, 3, 4, 5 or more prior antidepressant therapies. Ru.

In some embodiments, a human being treated with a combination of dextromethorphan and an antidepressant may receive two or more background antidepressant treatments for at least 8 weeks and at an appropriate dose, e.g., due to the type of depression. Selected to have received or have been on a stable dose for at least 4 weeks prior to entering the double-blind treatment period. In some embodiments, antidepressant therapy is continued in conjunction with treatment with a combination of antidepressant and dextromethorphan.

In some embodiments, the human being treated with a combination of dextromethorphan and an antidepressant, for example for a type of depression, is or is selected to be male. In some embodiments, the human being treated with a combination of dextromethorphan and an antidepressant, for example for a type of depression, is or is selected to be female.

In some embodiments, a human being treated with a combination of dextromethorphan and an antidepressant, e.g., for a type of depression, is treated with a combination of dextromethorphan and an antidepressant prior to treatment (e.g., on the same day as starting treatment, but Before the start of treatment or before treatment 0-1 week, 0-2 weeks, 0-3 weeks, 0-4 weeks, 0-2 months, 0-3 months, 0-4 months, 0-5 months , at any time within a period of 0 to 6 months or longer), has a body mass index of about 18 to 40 kg/m ² , about 18.5 kg/m ² , less than about 18.5 kg/m ² , about 19 kg/m ² , about 19 to 24.9 kg/m ² , about 25 kg/m ² , about 25 to 29 kg/m ² , about 29 kg/m ² , more than about 29 kg/m ² , about 18 to 22 kg/m ² , about 22 to 24kg/m ² , approximately 24-26kg/m ² , approximately 26-28kg/m ² , approximately 28-30kg/m ² , approximately 30-32kg/m ² , approximately 32-34kg/m ² , approximately 34-36kg/m 2 m ² , about 36-38 kg/m ² , about 38-40 kg/m ² , about 18-26 kg/m ² , about 26-34 kg/m ² , or about 34-40 kg/m ² , or It is chosen to have.

The therapeutic effect may be observed at any appropriate time, such as week 1, week 1-2, week 1-3, week 1-4, week 1-6, week 4-6, week 6-8. week, 8th to 12th week, 12th to 16th week, end of 1st week, start of 2nd week, during or at the end of 2nd week, start of 3rd week, 3rd week During the week or at the end of the third week, at the start of the fourth week, during or at the end of the fourth week, at the beginning of the fifth week, during or at the end of the fifth week , at the beginning of the 6th week, during or at the end of the 6th week, at the beginning of the 7th week, during or at the end of the 7th week, at the beginning of the 8th week, at the 8th week. During the week or at the end of the 8th week, at the start of the 9th week, during or at the end of the 9th week, at the beginning of the 10th week, during the 10th week or at the end of the 10th week , at the beginning of the 11th week, during or at the end of the 11th week, at the beginning of the 12th week, during or at the end of the 12th week, at the beginning of the 13th week, at the 13th week. during or at the end of the 13th week, at the start of the 14th week, during or at the end of the 14th week, at the beginning of the 15th week, during the 15th week, or at the end of the 15th week. The assessment can be made at the beginning of week 16, during week 16, or at the end of week 16, or at any other time.

In some embodiments, the combination of dextromethorphan and an antidepressant is a novel oral NMDA receptor antagonist with multimodal activity for the treatment of central nervous system (CNS) disorders. Dextromethorphan, also known as a glutamate receptor modulator, is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with a novel mechanism of action distinct from currently available depression treatments. It acts on

Dextromethorphan is also a sigma-1 receptor agonist, a nicotinic acetylcholine receptor antagonist, and a serotonin and norepinephrine transporter inhibitor. Antidepressants can increase the bioavailability of dextromethorphan.

In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat nicotine addiction. In some embodiments, the combination of dextromethorphan and antidepressant may be administered to a human once daily or twice daily. In some embodiments, the combination of dextromethorphan and antidepressant may be administered twice daily to a human. In some embodiments, the combination of dextromethorphan and an antidepressant is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 1 month, at least 2 months. , once daily or twice daily for at least 3 months, at least 4 months, at least 5 months, at least 6 months, about 6 to 12 months, about 1 year, about 2 years or longer. Can be done. In some embodiments, the combination of dextromethorphan and antidepressant may be administered to a human twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, or longer.

In some embodiments, the smoker may be, or may be selected to be, an ad-lib smoker. In some embodiments, prior to administration of the combination of dextromethorphan and antidepressant, the smoker smokes an average of about 10, about 10-15, about 10-17, about 10-20, About 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 20-25, about 25-30, about 30-40, about 40-50 , or more cigarettes, or may choose to smoke.

In some embodiments, a combination of dextromethorphan and an antidepressant can be used to treat nicotine addiction, where the combination is about 30-100 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 35 mg, about 45 mg, about 55 mg, about 65 mg, about 75 mg, about 85 mg, about 90 mg or about 95 mg of dext Contains lomethorphan in free base or salt form. In some embodiments, dextromethorphan is in the form of an HBr salt.

In some embodiments, administration of a combination of dextromethorphan and an antidepressant to a human is measured using the number of cigarettes smoked per day as assessed via a daily smoking diary. resulting in a reduction in smoking intensity.

Administration of the combination of dextromethorphan and antidepressants to humans may be administered in some instances, for example, for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, reduce the average number of cigarettes smoked per day by at least 5% compared to antidepressants alone over a period of weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 6 months, or longer; at least 10%, at least 15%, at least 20%, at least 25%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, 10-20% , about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-80%, about 80-100%, about 20%, about 25% larger, about 30%, or about a 50% reduction.

Administration of a combination of dextromethorphan and antidepressants to humans who smoke cigarettes has been shown to be effective for some smokers at least 1, at least 2, at least 3, at least 4, at least 5, at least 5 cigarettes per day. 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, about 8-9, about 8-10, about 10-15, about 15-20 , may result in an average reduction of about 25 or more cigarettes.

Administration of a combination of dextromethorphan and an antidepressant to humans who smoke cigarettes significantly lowers exhaled carbon monoxide, a biochemical marker of smoking intensity, compared to those treated with antidepressants alone. For example, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65% , may be increased by at least 70%, about 35%, about 50%, about 60%, about 60-80%, about 80-90%, about 90-100%. In some embodiments, a smoker has lower exhaled carbon monoxide levels, a biochemical marker of smoking intensity, compared to taking an antidepressant alone or at baseline or at the beginning of a combination drug. It can be reduced by more than 50% compared to just before receiving the dose.

Forgetting to take a combination of dextromethorphan and antidepressants can increase smoking activity. For example, smokers who missed one or more doses of a dextromethorphan and antidepressant combination were more likely to smoke at least one or about You may smoke 1-2 or more cigarettes, and the day after you forget to take your dose, you are likely to smoke at least 1, at least 2, about 1-2, or about 2-3 or more cigarettes. be.

In some embodiments, enhancing the bioavailability of dextromethorphan or the combination of dextromethorphan and an antidepressant for the treatment of any of the conditions described herein, including TRD. May be used as adjunctive therapy. For example, adjunctive therapy may be used in combination with another antidepressant, such as clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline. , phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindanamine, benactidine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, niaramide, iproniazid, iproclozide, troxatone, butryptyline, dosulepine, dibenzepine, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, or metabolites of these compounds or Included are prodrugs or pharmaceutically acceptable salts of these compounds.

A combination of dextromethorphan and an antidepressant may be utilized to treat persons suffering from TRD, and for some individuals at least about 5%, at least about 10%, at least about 20%, at least about A reduction in depressive symptoms by 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any value thereof. Other reductions within the range bounded by .

Anxiety disorders including, but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD) , mania, manic depression, hypomania, unipolar depression, depression, stress disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophrenic tendency, A combination of dextromethorphan and an antidepressant may be used to treat people suffering from mental disorders, including aggression, agitation in Alzheimer's disease, and agitation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by a decline in cognitive function and behavioral and psychological symptoms including agitation. AD is the most common form of dementia, affecting an estimated 6 million people in the United States, and that number is projected to increase to approximately 14 million by 2050. Agitation in Alzheimer's disease occurs as the disease progresses. Agitation is reported in up to 70% of AD patients and is characterized by emotional distress, aggressive behavior, destructive irritability, and inability to control. Agitation may manifest as inappropriate verbal, emotional, and/or physical behavior. Inappropriate behavior includes, but is not limited to, incoherent babbling, inappropriate emotional responses, demands for attention, threats, irritability, frustration, screaming, repetitive questions, and mood swings. , swearing, verbal abuse, physical outbursts, emotional distress, restlessness, splintering, sleep disturbances, delusions, hallucinations, wandering, wandering, searching, rummaging, repetitive body movements, hoarding, shadowing, hitting, scratching, May include biting, combativeness, hyperactivity, and/or kicking. Management of agitation is a priority in AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, early nursing home admission, and increased mortality. There are currently no FDA-approved treatments for the treatment of agitation in AD patients.

A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from agitation in Alzheimer's disease, in some embodiments at least about 5%, at least about 10%, at least about 20% %, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100% reduction in symptoms associated with agitation or may result in a reduction in symptoms associated with agitation within the range delimited by any of these values.

Combinations of dextromethorphan with antidepressants may include, but are not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, and antidepressants. Contains anxiety and sleeping pills, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction is also used to treat people suffering from substance addiction and/or abuse, including all known forms of nicotine addiction such as cigarette, cigar and/or pipe smoking, as well as chewing tobacco addiction. good.

The combination of dextromethorphan and antidepressants may be used to treat, but is not limited to, senile dementia, Alzheimer's disease, memory loss, amnesia/amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention, Used to treat people with brain dysfunction including speech disorders, speech spasms, disorders including Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome, and intellectual disabilities such as schizophrenia may be done. Brain dysfunction also includes, but is not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, etc., and the symptoms include impaired consciousness, senile dementia, coma, and caution. including disorders caused by cerebrovascular disease, including those of symptoms such as a decline in cerebrovascular disease, and language impairment.

Movement disorders that may be treated by the combination of dextromethorphan and antidepressants include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballism, hemiballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless leg syndrome (RLS), tremor, essential tremor , and Tourette's syndrome, and Wilson's disease.

Dementias that can be treated with a combination of dextromethorphan and antidepressants include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia , Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

Motor neuron diseases that can be treated with a combination of dextromethorphan and antidepressants include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive Includes sexual muscular atrophy, postpolio syndrome (PPS), spinal muscular atrophy (SMA), spinal muscular atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

Neurodegenerative diseases that can be treated by the combination of dextromethorphan and antidepressants include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy ( SMA), medullary muscular atrophy, Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), Systematic atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) , muscular dystrophy, Charcot-Marie-Tooth (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia. .

Seizure disorders that may be treated by the combination of dextromethorphan and antidepressants include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures, simple partial seizures, Jacksonian seizures, complex partial seizures, and persistent partial seizures. generalized seizures, including but not limited to focal seizures, including but not limited to epilepsy, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; Including status epilepticus.

Types of headaches that can be treated by the combination of dextromethorphan and antidepressants, such as prodrugs, include, but are not limited to, migraine, tension, and cluster headaches.

Other neurological disorders that may be treated with a combination of dextromethorphan and antidepressants include Rett syndrome, autism, tinnitus, disturbed consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy, Vocal disorders due to uncontrolled laryngeal muscle spasms, including but not limited to transducer spasm dysphonia, adductor spasm dysphonia, muscle tone dysphonia, and vocal tremor, diabetic neuropathy, methotrexate neurotoxicity chemotherapy-induced neurotoxicity, such as incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence, and erectile dysfunction.

In some embodiments, the combination of dextromethorphan and an antidepressant is used to treat pain, joint pain, pain associated with sickle cell disease, affective dysregulation, depression (including treatment-resistant depression), It can be used to treat disorders related to memory and dementia, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

In some embodiments, a combination of dextromethorphan and an antidepressant can be used to treat treatment-refractory depression.

In some embodiments, a combination of dextromethorphan and an antidepressant can be used to treat allodynia.

In some embodiments, a combination of dextromethorphan and an antidepressant can be used to treat treatment-refractory hyperalgesia.

In some embodiments, a combination of dextromethorphan and an antidepressant can be used to treat dermatitis.

The pain-relieving properties of dextrorphan can be enhanced by a method that involves co-administering dextromethorphan and an antidepressant to humans.

The pain-relieving properties of antidepressants can be enhanced by a method that involves co-administering dextromethorphan and an antidepressant.

In some embodiments, ketamine or other NMDA receptor antagonists may be administered with an antidepressant.

These methods can be used to treat any type of pain, including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritic pain, complex regional pain syndrome, etc. It can be used to treat or provide relief from pain.

In some embodiments, co-administration of dextromethorphan and an antidepressant may be used to treat or reduce inflammation or inflammatory conditions, such as Crohn's disease, including pain associated with inflammation.

In some embodiments, co-administration of dextromethorphan and antidepressants can be used to treat psoriasis, cancer, viral infections, or as an adjuvant treatment for multiple myeloma.

Examples of musculoskeletal pain are low back pain (i.e. lumbosacral pain), primary dysmenorrhea, and pain associated with rheumatoid arthritis, axial spondyloarthritis, including juvenile rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. including joint pain, pain associated with vertebral crush fractures, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of the bone, temporary osteoporosis, temporary osteoporosis of the hip, etc.

In some embodiments, the combination of dextromethorphan and an antidepressant is used to treat low back pain, pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatoid arthritis, periarticular disorders, axonal spondyloarthropathies including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, temporary hip osteoarthritis, vertebral compression fractures ( It can be administered orally to alleviate musculoskeletal pain, including vertebral crush fractures), osteoporosis, and the like.

In some embodiments, a combination of dextromethorphan and an antidepressant may be administered to alleviate inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndrome.

Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis pain include osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (nonrheumatoid) arthropathy, nonrheumatoid arthritis, periarticular disorders, Charcot's These include neuropathic arthropathy involving the feet, axonal spondyloarthropathy including ankylosing spondylitis, and pain associated with SAPHO syndrome.

In some embodiments, a combination of dextrorphan and an antidepressant may be used to treat chronic musculoskeletal pain.

In some embodiments, the combination of dextromethorphan and an antidepressant is associated with complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or It may be administered to alleviate other types of complex regional pain syndromes such as CRPS. CRPS is a type of inflammatory pain. CRPS may also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the extremities that may be accompanied by edema, autonomic, motor and sensory changes.

In some embodiments, a combination of dextromethorphan and an antidepressant can be administered orally to alleviate neuropathic pain.

Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom pain, central pain, and the like. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, radiation therapy- or chemotherapy-related neuropathy, and the like.

In some embodiments, a combination of dextromethorphan and an antidepressant can be administered orally to alleviate fibromyalgia.

The term "treat" or "therapy" refers to the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or that otherwise affects the structure or any function of the body of humans or other animals. Including any activity that gives.

Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. Dextromethorphan and the antidepressant compound may be administered in separate compositions or dosage forms. In some embodiments, the dextromethorphan and antidepressant compound may be administered in a single dosage form.

Antidepressant compositions that may be co-administered with dextrorphan include, but are not limited to, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-clomipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine. , isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindanamine, benactidine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnaci Plan, tesofensine, brasofensine, moclobemide, rasagiline, niaramide, iproniazid, iproclozide, troxatone, butryptyline, dosulepine, dibenzepine, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, etc., or these Includes any metabolite or prodrug of the compounds, or any pharmaceutically acceptable salt of these compounds.

In some embodiments, the antidepressant is citaloprom (Celexa, Cipramil), escitaloprom (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox, Faverin), paroxetine (Paxil, Seroxat), sertraline (Zoloft). Selective serotonin reuptake inhibitors such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), venlafaxine (Effexor), etc. ), serotonin norepinephrine reuptake inhibitors (SNRIs); serotonin modulators and stimulants (SMSs), such as vilazodone (Viibryd), vortioxetine (Trintellix), etc.; nefazodone (Dutonin, Nefadar, Serzone), trazodone (Desyrel), etc.; ), norepinephrine reuptake inhibitors (NRIs) such as atomoxetine (Strattera), reboxetine (Edronax), teniroxazine (Lucelan, Metatone), viloxazine (Vivalan), etc.; amitriptyline ( Elavil, Endep), Amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepine (Noveril, Victoril), Dimethacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan) , imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitrasen (Dixeran, Melixeran, Trausabun), nitroxazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxyputyline (Agedal, Elronon, Nogedal), opipramol (Insidon), pipofezine ( Tricyclic antidepressants (TCAs) such as Azafen/Azaphen), protriptyline (Vivactil), trimipramine (Surmontil), etc.; amoxapine (Asendin), maprotiline (Ludiomil), mianserin (Tolvon), mirtazapine (Remeron), Tetracyclic antidepressants (TeCA) such as setiptiline (Tecipul); isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl, Zelapar, Emsam), caroxazone (Surodil) , Timostenil), metralindole (Inkazan), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), troxatone (Humoryl), eprobemide (Befol), minaprine (Brantur, Cantor), bifemeran (Alnert, Celeport) Oxidase inhibitors (MAOIs); agomelatine (Valdoxan), esketamine (Spravato), ketamine (Ketalar), tandospirone (Sediel), tianeptine (Stablon, Coaxil), α-methyltryptamine [αMT] (Indopan), etryptamine [α - Ethyltryptamine (αET)] (Monase), inderoxazine (Elen, Noin), medifoxamine (Credial, Gerdaxyl), oxaflozan (Conflictan), pivagabine (Tonerg), ademethionine [S-adenosyl-L-methionine (SAMe) ] (Heptral, Transmetil, Samyl), hypericum perforatum [St. , Triptum), rubidium chloride [RbCl] (Rubinorm), tryptophan (Tryptan, Optimax, Aminomine), magnesium, acetylcarnitine, saffron, amisulpride (Solian), aripiprazole (Abilify), brexpiprazole (Rexulti), lurasidone (Latuda) , olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), buspirone (Buspar), lithium (Eskalith, Lithobid), modafinil, thyroxine (T4), triiodothyronine (T3), minocycline, amitriptyline/chlordiazepoxide, amitriptyline /Perphenazine (Etafron), Flupenthixol/Melitrasen (Deanxit), Olanzapine/Fluoxetine (Symbyax), Tranylcypromine/Trifluoperazine (Parstelin, Parmodalin, Jatrosom N, Stelapar), 4-chlorokynurenine, AGN-241751 , apimostinel (NRX-1074), alketamine (PCN-101, HR-071603), dextromethadone (REL-1017), EVT-101 (ENS-101), ketamine (Ketalar), risrenemdaz (CERC-301, MK- 0657), other types of glutamatergic drugs such as Basimglurant (RG-7090); AN-788 (NSD-788), Tordesvenlafaxine ( monoaminergic drugs such as monoamine reuptake inhibitors including ansofaxine; LY03005, LPM570065), PDC-1421 (BLI-1005), etc.; Uptake inhibition and receptor modulators; monoamine receptor modulators including gepirone (TGFK07AD; Travivo), pimavanserin (Nuplazid; ACP-103; BVF-048), psilocybin, etc.; briraloxazine (RP-5063, RP-5000), lumateperone Atypical antipsychotics such as (ITI-007); Ademethionine (SAMe; MSI-190, MSI-195, Strada); GABAA receptor positive such as ganaxolone (CCD-1042) and Zuranolone (SAGE-217) Neurosteroids such as modulators, 3β-methoxypregnenolone (MAP-4343), PH-10-vomeroferrine, etc.; Atikaplant (JNJ-67953964, CERC-501, LY-2456302), BTRX- Opioid agonists such as κ-opioid receptor antagonists including 335140 (BTRX-140), buprenorphine/samidrphan (ALKS-5461), and other opioid agonists such as BTRX-246040 (BTRX-140) Drugs: Hydroxynorketamine ((2R,6R)-HNK), JNJ-39393406, JNJ-54175446, JNJ-61393215 (JNJ-3215, JNJ-61393215; Orexin-1), NNI-351, NSI-189, NV- 5138, onabotulinumtoxinA (Botox), pramipexole (CTC-501, CTC-413), celtrexant (MIN-202, JNJ-42847922, JNJ-922), sirukumab (CNTO-136), SUVN- 911, TS-121, etc.; tramadol (ETS6103; Viotra); cycloserine/lurasidone; 7,8-dihydroxyflavone (7,8-DHF), minocycline, nitrous oxide, pramipexole, R13, etc.

In some embodiments, about 40-120 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80- 90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mgmg, about 300-350mg, about 350- 400 mg, about 400-450 mg, or about 450-500 mg of levomilnacipran (Fetzima) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein) (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.5-1.4 mg/kg (for children), about 40-100 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50- 60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200- 250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg atomoxetine (Strattera) and about 30-60 mg, about 40-50 mg, or about 60-120 mg Dextromethorphan (or in other amounts described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease ( (e.g., orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of tenyloxazine (Lucelan, Metatone) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 5-20 mg, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg , about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg , about 300-350 mg, about 350-400 mg, about 400-450 mg, or about 450-500 mg of viloxazine (Vivalan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan ( or in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. be done.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of amitriptyline oxide (Amioxid, Ambivalon, Equilibrin) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan ( or in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. be done.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of dimethacrine (Istonil) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of melitrasen (Dixeran, Melixeran, Trausabun) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of nitroxazepine (Sintamil) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of noxyputyline (Agedal, Elronon, Nogedal) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of pipofezine (Azafen/Azaphen) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of setiptiline (Tecipul) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of caroxazone (Surodil, Timostenil) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of metralindole (Inkazan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of Pirazidol and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of eprobemide (Befol) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein). (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of minaprine (Brantur, Cantor) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of bifemelan (Alnert, Celeport) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of agomelatine (Valdoxan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of esketamine (Spravato) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of tandospirone (Sediel) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of tianeptine (Stablon, Coaxil) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of α-methyltryptamine [αMT] (Indopan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan. (or in other amounts described herein) once or twice daily in humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of etryptamine [α-ethyltryptamine (αET)] (Monase), and about 30-60 mg, about 40-50 mg, or about 60-120 mg. of dextromethorphan (or in other amounts as described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease; (e.g., orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of inderoxazine (Elen, Noin), medifoxamine (Credial, Gerdaxyl) and about 30-60 mg, about 40-50 mg, or about 60-120 mg. Dextromethorphan (or in other amounts described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease ( (e.g., orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of oxaflozan (Conflictan) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of pivagabine (Tonerg) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of ademethionine [S-adenosyl-L-methionine (SAMe)] (Heptral, Transmetil, Samyl), and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or in other amounts as described herein) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. administered to humans (e.g., orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg hypericum perforatum [St. John's wort (SJW)] (Jarsin, Kira, Movina) and about 30-60 mg, about 40- 50 mg, or about 60-120 mg of dextromethorphan (or in other amounts described herein) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Administered (eg, orally) to humans for treatment.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of oxytriptan [5-hydroxytryptophan (5-HTP)] (Cincofarm, Levothym, Triptum), about 30 mg of rubidium chloride [RbCl] (Rubinorm); ~60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in other amounts described herein) once or twice daily to treat agitation associated with depression or Alzheimer's disease. administered (e.g., orally) to humans to treat neuropsychiatric conditions such as

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of tryptophan (Tryptan, Optimax, Aminomine) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of magnesium, acetylcarnitine, saffron, amisulpride (Solian) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan. (or in other amounts described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. ) administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of aripiprazole (Abilify) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of brexpiprazole (Rexulti) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of lurasidone (Latuda) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of olanzapine (Zyprexa) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of quetiapine (Seroquel) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein). (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of risperidone (Risperdal) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein). (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of buspirone (Buspar) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of lithium (Eskalith, Lithobid) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of modafinil; and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (in other amounts) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of thyroxine (T4) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of triiodothyronine (T3) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as specified in the specification) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. .

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of minocycline and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as otherwise described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of amitriptyline/chlordiazepoxide and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of amitriptyline/perphenazine (Etafron) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as specified in the specification) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. .

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of flupenthixol/melitracene (Deanxit) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan ( or in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. be done.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of olanzapine/fluoxetine (Symbyax) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of tranylcypromine/trifluoperazine (Parstelin, Parmodalin, Jatrosom N, Stelapar) and about 30-60 mg, about 40-50 mg, or about 60-500 mg. 120 mg of dextromethorphan (or in other amounts as described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. , administered (eg, orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of 4-chlorokynurenine and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of AGN-241751 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of apimostinel (NRX-1074) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of alketamine (PCN-101, HR-071603) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan. (or in other amounts described herein) once or twice daily in humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of dextromethadone (REL-1017) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of Rislenemdaz (CERC-301, MK-0657) and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan. (or in other amounts described herein) once or twice daily in humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of basimglurant (RG-7090) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of AN-788 (NSD-788) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of toldesvenlafaxine (ansofaxine; LY03005, LPM570065) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan. (or in other amounts described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. ) to be administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of PDC-1421 (BLI-1005) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of MIN-117 (WF-516) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of TGBA01AD (FKB01MD) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (in other amounts as indicated) once or twice daily to humans (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of gepirone (TGFK07AD; Travivo) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of pimavanserin (Nuplazid; ACP-103; BVF-048) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextrose. lomethorphan (or in other amounts described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease (e.g. , orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of psilocybin and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as otherwise described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of briraloxazine (RP-5063, RP-5000) and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan. (or in other amounts described herein) once or twice daily in humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of lumateperone (ITI-007) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg ademethionine (SAMe; MS-190, MSI-195, Strada) and about 30-60 mg, about 40-50 mg, or about 60-120 mg. Dextromethorphan (or in other amounts described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease ( (e.g., orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of ganaxolone (CCD-1042) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of Zuranolone (SAGE-217) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of 3β-methoxypregnenolone (MAP-4343) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan ( or in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. be done.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of pH-10-vomeroferrine and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or herein (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of Atica Plant (JNJ-67953964, CERC-501, LY-2456302) and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg. Dextromethorphan (or in other amounts described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease ( (e.g., orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of BTRX-335140 (BTRX-140) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of buprenorphine/sadorphan (ALKS-5461), BTRX-246040 (LY-2940094) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in other amounts as described herein) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Administered (eg, orally) to humans.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg hydroxynorketamine ((2R,6R)-HNK) and about 30-60 mg, about 40-50 mg, or about 60-120 mg dextromethorphan. (or in other amounts described herein) once or twice daily to humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease (e.g., oral administration). ) to be administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of JNJ-39393406 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of JNJ-54175446 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of JNJ-61393215 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg (JNJ-3215, JNJ-61393215; Orexin-1) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextrome turfan (or in other amounts described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease (e.g. orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of NNI-351 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of NSI-189 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of NV-5138 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg onabotulinumtoxin A (Botox) and about 30-60 mg, about 40-50 mg, or about 60-120 mg dextromethorphan. (or in other amounts described herein) once or twice daily to humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease (e.g., oral administration). ) to be administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of pramipexole (CTC-501, CTC-413) and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan. (or in other amounts described herein) once or twice daily in humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. administered.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of celtrexant (MIN-202, JNJ-42847922, JNJ-922) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or in other amounts as described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease; (e.g., orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of circumab (CNTO-136) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of SUVN-911 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of TS-121 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of tramadol (ETS6103; Viotra) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) to treat neuropsychiatric symptoms, such as depression or agitation associated with Alzheimer's disease, once or twice daily (in other amounts as described in the literature).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of cycloserine/lurasidone and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of 7,8-dihydroxyflavone (7,8-DHF) and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextrome. turfan (or in other amounts described herein) once or twice daily in humans to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease (e.g. orally).

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of minocycline and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as otherwise described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of nitrous oxide and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of pramipexole and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as otherwise described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 0.01-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg , about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg , about 350-400 mg, about 400-450 mg, or about 450-500 mg of R13 and about 30-60 mg, about 40-50 mg, or about 60-120 mg of dextromethorphan (or as otherwise described herein). (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 10-60 mg or about 20-30 mg of agomelatine and about 30-60 mg or about 40-50 mg of dextromethorphan (or in other amounts described herein) are 1 It is administered (eg, orally) to humans once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 2-10 mg or about 3-5 mg of reboxetine and about 30-60 mg or about 40-50 mg of dextromethorphan (or in other amounts described herein) are 1 It is administered (eg, orally) to humans once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 2-10 mg or about 3-5 mg of esreboxetine and about 30-60 mg or about 40-50 mg of dextromethorphan (or in other amounts described herein) are 1 It is administered (eg, orally) to humans once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 2-40 mg, about 4-6 mg, about 8-12 mg or about 16-24 mg of vortioxetine and about 30-60 mg or about 40-50 mg of dextromethorphan (or as described herein) (eg, orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease, once or twice daily.

In some embodiments, about 10-240 mg or about 20-120 mg of levomilnacipran and about 30-60 mg or about 40-50 mg of dextromethorphan (or in other amounts described herein) ) is administered (eg, orally) to humans once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 5-80 mg, about 10-30 mg, or about 20-40 mg of vilazodone and about 30-60 mg, or about 40-50 mg of dextromethorphan (or other described herein) (eg, orally) once or twice daily to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease.

In some embodiments, about 15-120 μg/kg/hour of brexanolone is administered over a 60-hour period (e.g., by intravenous injection) and about 60-120 mg or about 80-100 mg of dextromethorphan (or (in other amounts as described herein) once or twice daily to humans (e.g., orally) to treat neuropsychiatric symptoms such as depression or agitation associated with Alzheimer's disease. Ru.

The combination of dextromethorphan and an antidepressant may provide greater efficacy, such as greater pain relief, than would be achieved by administering either component. In hypermetabolizers, dextromethorphan can be rapidly and extensively metabolized, resulting in low systemic exposure even at high doses. Antidepressants are inhibitors of dextromethorphan metabolism.

As mentioned above, this inhibition can increase plasma concentrations of dextromethorphan, resulting in additive or synergistic effects such as alleviation of neurological disorders, including pain, depression, smoking cessation, and the like. Therefore, although inhibition of dextromethorphan metabolism is only one of the many potential benefits of the combination, co-administration of dextromethorphan and antidepressants may be useful for many individuals. Efficacy may be enhanced. Co-administration of dextromethorphan and antidepressants can enhance the analgesic properties of antidepressants for many individuals. Co-administration of dextromethorphan and an antidepressant may also enhance the antidepressant properties of the antidepressant for many individuals, including faster onset of action.

Another potential advantage of co-administration of dextromethorphan and antidepressants is that it may be useful in reducing the likelihood of adverse events such as somnolence associated with treatment with dextromethorphan. This may be useful, for example, in human patients who are at risk of experiencing adverse events as a result of being treated with dextromethorphan.

Another potential benefit of co-administration of dextromethorphan and antidepressants is that it may be useful to reduce the likelihood of adverse events, such as seizures, associated with treatment with antidepressants. . This may be useful, for example, in human patients who are at risk of experiencing adverse events as a result of being treated with antidepressants.

For antidepressants, co-administration may reduce central nervous system adverse events, gastrointestinal events, or other types of adverse events associated with antidepressants. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, light-headedness, tremors, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or agitation, tinnitus, drowsiness, dizziness, sedation, somnolence, confusion, disorientation, malaise, loss of coordination, fatigue, euphoria, irritability, insomnia, disturbed sleep, seizures, excitement, nervousness, hysteria, hallucinations, delusions, These include paranoia, headaches and/or migraines, and extrapyramidal symptoms such as oculomotor crises, torticollis, hyperexcitability, increased muscle tone, ataxia and/or tongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, indigestion, diarrhea, bloating, flatulence, peptic ulcers with bleeding, loose stools, constipation, stomach pain, heartburn, gas, and loss of appetite. , including stomach bloating, indigestion, bloating, acidity, dry mouth, gastrointestinal disorders, and stomach pain.

Co-administration of dextromethorphan and an antidepressant does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds can be administered in a single dosage form, or they can be administered in two separate dosage forms. Additionally, the two compounds can be administered simultaneously, although this is not required. The compounds may be given at different times so long as they are both in the human body at the same time at least part of the time that the co-administration treatment is being carried out.

The side effects of antidepressants may be reduced by administering the antidepressant with dextromethorphan. Examples of side effects that may be reduced include, but are not limited to, abnormal sensations of rotation and movement, agitation, arm weakness, bloating, blurred vision, burning sensation in the eyes, ringing in the ears, and changes in vital signs. , heart rate, breathing rate, body temperature, and blood pressure), cold sensation, constipation, difficulty concentrating, difficulty sleeping, difficulty falling asleep, difficulty urinating, difficulty defecating, ear discomfort, eye discomfort, stomach discomfort, dizziness. , dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feverishness, heavy head, more excitability than usual, feeling more tired than usual, feeling tired, trembling of hands, feeling of weakness in hands. , headache, heartburn, hot flashes, increased blood pressure, skin sensitivity, skin sensitivity on the head and face, involuntary muscle contractions, involuntary muscle contractions throughout the body, knee pain, beriberi, light-headedness, loose stools, loss of appetite, lower back pain, menstrual abnormalities, Metallic taste, increased saliva production, dry mucous membranes, stuffy nose, nausea, runny nose, slight pressure in the eyes, shaking when stretching or yawning, skin sensitivity, skin sensitivity on the arms, face and/or head. , sleep disturbances, loose stools, stomach pain, stomach discomfort, sweaty hands and/or feet, throat irritation, sore throat, ringing in the ears, tremors, and/or weakness. These side effects may also be referenced or grouped according to corresponding terms, equivalent terms, or other related terms listed in the Medical Regulatory Terminology (MedRA).

In some embodiments, co-administration consisting of a combination of dextrorphan and an antidepressant results in both the antidepressant and dextromethorphan contributing pain relief properties. For example, the combination may improve pain relief properties, including potentially faster onset of action, compared to antidepressants alone or compared to dextromethorphan alone.

In some embodiments, the combination is at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50% as compared to the antidepressant alone. , at least about 100%, up to about 500%, or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100 % to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to any amount of pain relief in the range bounded by about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any value thereof; Any amount of pain relief between any value may improve the pain relief properties.

In some embodiments, the combination is at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50% compared to dextrorphan alone. , at least about 100%, up to about 500%, or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100 % to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to any amount of pain relief in the range bounded by about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any value thereof; Any amount of pain relief between any value may improve the pain relief properties.

Unless otherwise specified, references to compounds described herein, by structure, name, or any other means, such as dextromethorphan or antidepressants, refer to pharmaceutically acceptable salts, Alternative solid forms such as polymorphs, solvates, hydrates, tautomers, deuterium-modified forms such as deuterium-modified dextromethorphan, under the conditions under which the compounds are used as described herein. Includes any chemical species that can be rapidly converted to a compound described herein.

In some embodiments, an excess amount of one stereoisomer of the antidepressant can be administered. In other embodiments, an excess of the S-enantiomer of the antidepressant (e.g., at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or an optically pure S-enantiomer), or an excess of the R-enantiomer (e.g., at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or optically pure R-enantiomer) can be administered.

In some embodiments, both the dextromethorphan and the antidepressant are formulated to be immediate release. In some embodiments, both the dextromethorphan and the antidepressant are formulated to be sustained release. In some embodiments, the dextromethorphan is formulated to be immediate release and the antidepressant is formulated to be sustained release. In some embodiments, the dextromethorphan is formulated to be sustained release and the antidepressant is formulated to be immediate release.

Examples of deuterated dextromethorphan include, but are not limited to:

Contains d6-dextromethorphan.

The dosage form or composition can be a combination or mixture of dextromethorphan and an antidepressant, alone or in a vehicle. For example, dextromethorphan and an antidepressant can be dispersed in each other or together in a vehicle. A dispersion comprises a mixture of solid materials, where the small individual particles are essentially one compound, such as can occur when two powders of two different drugs are combined with a solid vehicle material. The small particles are dispersed among each other and the formulation is carried out in solid form. In some embodiments, the dextromethorphan and antidepressant can be substantially uniformly dispersed within the composition or dosage form. Alternatively, the dextromethorphan and antidepressant may be in separate domains or phases within the composition or dosage form. For example, one drug can be in the coating and the other drug can be in the core within the coating. For example, one drug can be formulated for sustained release and the other drug can be formulated for immediate release.

Some embodiments include administration of a tablet comprising an antidepressant in a dosage form that provides sustained release and dextromethorphan in a dosage form that provides immediate release. Although there are various ways in which sustained release of antidepressants can be achieved, in some embodiments, antidepressants are combined with hydroxypropyl methylcellulose. For example, antidepressant particles can be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (eg, METHOCEL®) to form a blended powder mixture. It may be combined with immediate release dextromethorphan in a single tablet.

Dextromethorphan and/or antidepressants (all referred to herein collectively as "therapeutic compounds" for convenience) may be administered according to selected routes of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005. may be combined with a selected pharmaceutical carrier. The relative proportions of active ingredient and carrier can be determined by, for example, the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice.

The therapeutic compound may be administered by any means that brings the active agent into contact with the desired site or site(s) of action within the patient's body. The compounds can be administered by any conventional means that can be used in conjunction with pharmaceuticals, either as individual therapeutic agents or as a combination of therapeutic agents. For example, they may be administered as the only active agent in a pharmaceutical composition, or they may be used in combination with other therapeutically active ingredients.

The therapeutic compounds may be administered to human patients in a variety of forms compatible with the chosen route of administration, eg, orally or parenterally. In this regard, parenteral administration includes administration by the following routes: i.e. intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transdermal, ocular, transepithelial including sublingual and buccal, insufflation, aerosol and rectal systemic ophthalmic, cutaneous, ophthalmic, rectal and nasal inhalation. Local administration including

The amount of dextromethorphan in the therapeutic composition can vary. For example, some liquid compositions include about 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 0.5 % (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) ) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v) , or from about 40% (w/v) to about 50% (w/v) dextromethorphan.

Some liquid dosage forms include about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 55 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg from about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any of these values. and any amount of dextromethorphan between.

Some solid compositions have at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w) w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60 % (w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) dextromethorphan. .

Some solid dosage forms are about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg , about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in the range bounded by any of these values, or any amount of dextromethorphan between any of these values. may include amounts.

In some embodiments, the amount of dextromethorphan is about 0.1 mg/kg to about 20 mg/kg, about 0.75 mg/kg to about 7.5 mg/kg, about 0.1 mg based on the weight of the patient. /kg to about 5 mg/kg, about 0.1 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 0.9 mg/kg, about 0.3 mg/kg to about 1 mg/kg, about 0.6 mg /kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.8 mg/kg, about 0.75 mg/kg, about 0.4 mg/kg to about 1.5 mg/kg, about 1 mg/kg to About 2 mg/kg, about 10 mg/kg to about 20 mg/kg, about 12 mg/kg to about 17 mg/kg, about 15 mg/kg to about 20 mg/kg, about 1 mg/kg, about 1 mg/kg to about 10 mg/kg. Any value in or between these ranges.

The amount of antidepressant in the therapeutic composition can vary. If increasing the plasma concentration of dextromethorphan is desired, the antidepressant should be administered in an amount that increases the plasma concentration of dextromethorphan. For example, the antidepressant may be administered on day 8, 9, or 10 at least about twice, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times It can be administered in an amount that results in plasma concentrations of turphan.

In some embodiments, the antidepressant is at least about twice the plasma concentration of the same amount of dextromethorphan administered without the antidepressant on day 8, day 9, or day 10. about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times An amount of dextromethorphan can be administered to a human that results in a mean plasma concentration in the human for a certain 12 hour area under the curve from the time of administration (AUC _0-12 ) or 12 hours after administration (C _mean ).

In some embodiments, the antidepressant is at least about 2 times, at least about 5 times, at least about 10 times the plasma concentration of the same amount of antidepressant on day 8, day 9, or day 10. , at least about 15 times, at least about 20 times, at least about 30 times, or at _least about 40 times.

Due to co-administration of antidepressants, increases in dextromethorphan plasma concentrations were observed on the first day when antidepressants were administered compared to the same amount of dextromethorphan administered without antidepressants. can occur. For example, the dextromethorphan plasma concentration on the first day the antidepressant is administered is at least about 1.5 times, at least about 2 times the level that could be achieved with the same amount of dextromethorphan administered without the antidepressant. at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times. could be.

In some embodiments, for example, by co-administering dextromethorphan and an antidepressant, the dextromethorphan plasma concentration is increased on day 1. The dextromethorphan AUC is the same without the antidepressant. The AUC may be at least twice the AUC that can be achieved by administering the amount of dextromethorphan.

In some embodiments, the dextromethorphan AUC _0-12 on the first day that the dextromethorphan plasma concentration is increased, for example by co-administering dextromethorphan with an antidepressant, is at least about 15 ng·hr at least about 17 ng·hr/mL, at least about 19 ng·hr/mL, at least about 20 ng·hr/mL, at least about 22 ng·hr/mL, at least about 23 ng·hr/mL, at least about 24 ng·hr/mL , at least about 25 ng·hr/mL, at least about 26 ng·hr/mL, at least about 27 ng·hr/mL, at least about 28 ng·hr/mL, at least about 29 ng·hr/mL, at least about 30 ng·hr/mL, at least about 31 ng·hr/mL, at least about 32 ng·hr/mL, at least about 33 ng·hr/mL, at least about 34 ng·hr/mL, at least about 35 ng·hr/mL, at least about 36 ng·hr/mL, at least about 37 ng - at least about 38 ng-hour/mL, at least about 39 ng-hour/mL, at least about 40 ng-hour/mL, at least about 41 ng-hour/mL, at least about 42 ng-hour/mL, at least about 43 ng-hour at least about 44 ng·hr/mL, at least about 45 ng·hr/mL, at least about 46 ng·hr/mL, at least about 47 ng·hr/mL, at least about 48 ng·hr/mL, at least about 49 ng·hr/mL , at least about 50 ng·hr/mL, at least about 51 ng·hr/mL, at least about 52 ng·hr/mL, at least about 53 ng·hr/mL, at least about 54 ng·hr/mL, at least about 55 ng·hr/mL, at least It can be about 56 ng·hr/mL, at least about 56.7 ng·hr/mL, and up to 10,000 ng·hr/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 8 by co-administering dextromethorphan with an antidepressant, for example, the dextromethorphan AUC _0-12 is at least about 40 ng·hr. at least about 50 ng·hr/mL, at least about 60 ng·hr/mL, at least about 70 ng·hr/mL, at least about 80 ng·hr/mL, at least about 90 ng·hr/mL, at least about 100 ng·hr/mL , at least about 150 ng·hr/mL, at least about 200 ng·hr/mL, at least about 250 ng·hr/mL, at least about 300 ng·hr/mL, at least about 350 ng·hr/mL, at least about 400 ng·hr/mL, at least about 450 ng·hr/mL, at least about 500 ng·hr/mL, at least about 550 ng·hr/mL, about 500 ng·hr/mL to about 600 ng·hr/mL, about 500 ng·hr/mL to about 550 ng·hr/mL , about 500 ng·hr/mL to about 525 ng·hr/mL, about 525 ng·hr/mL to about 600 ng·hr/mL, at least about 600 ng·hr/mL, at least about 650 ng·hr/mL, at least about 700 ng·hr /mL, at least about 750 ng·hr/mL, at least about 800 ng·hr/mL, about 800 ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL 875 ng/mL to approximately 900 ng/hour/mL, approximately 900 ng/mL to approximately 1000 ng/mL, approximately 1000 ng/mL to approximately 1100 ng/mL /mL, approximately 1100ng・hour/mL to approximately 1200ng・hour/mL, approximately 1200ng・hour/mL to approximately 1300ng・hour/mL, approximately 1300ng・hour/mL to approximately 1400ng・hour/mL, approximately 1400ng・hour/ mL ~ approx. 1500 ng/hr/mL, approx. 1500 ng/hr/mL ~ approx. 1600 ng/hr/mL, approx. 1600 ng/hr/mL ~ approx. 1700 ng/hr/mL, approx. 1700 ng/hr/mL ~ approx. 1800 ng/hr/mL , about 1800 ng·hr/mL to about 2000 ng·hr/mL, at least about 850 ng·hr/mL, at least about 900 ng·hr/mL, at least about 950 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1050 ng - at least about 1100 ng-hour/mL, at least about 1150 ng-hour/mL, at least about 1200 ng-hour/mL, at least about 1250 ng-hour/mL, at least about 1300 ng-hour/mL, at least about 1350 ng-hour /mL, at least about 1400 ng·hr/mL, at least about 1450 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1550 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1625 ng·hr/mL , at least about 1650 ng·hr/mL, at least about 1675 ng·hr/mL, or at least about 1686.3 ng·hr/mL, and in some embodiments up to about 50,000 ng·hr/mL. .

In some embodiments, the dextromethorphan plasma concentration is increased at day 8 by co-administering dextromethorphan with an antidepressant, for example, the dextromethorphan AUC _0-24 is at least about 50 ng·hr at least about 75 ng·hr/mL, at least about 100 ng·hr/mL, at least about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about 500 ng·hr/mL , at least about 600 ng·hr/mL, at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800 ng - at least about 1900 ng-hour/mL, at least about 2000 ng-hour/mL, at least about 2100 ng-hour/mL, at least about 2200 ng-hour/mL, at least about 2300 ng-hour/mL, at least about 2400 ng-hour /mL, at least about 2500 ng·hr/mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, at least about 1850 ng·hr/mL, at least about 2900 ng·hr/mL , at least about 2950 ng·hr/mL, or at least about 2975.3 ng·hr/mL, and in some embodiments up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC _0-inf on day 8 where the dextromethorphan plasma concentration is increased, for example by co-administering dextromethorphan with an antidepressant, is at least about 75 ng·hr. at least about 100 ng·hr/mL, at least about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about 500 ng·hr/mL, at least about 600 ng·hr/mL , at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800 ng·hr/mL, at least about 1900 ng - at least about 2000 ng.hr/mL, at least about 2100 ng.hr/mL, at least about 2200 ng.hr/mL, at least about 2300 ng.hr/mL, at least about 2400 ng.hr/mL, at least about 2500 ng.hr. /mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, at least about 2900 ng·hr/mL, at least about 3000 ng·hr/mL, at least about 3100 ng·hr/mL , at least about 3200 ng·hr/mL, at least about 3300 ng·hr/mL, at least about 3400 ng·hr/mL, at least about 3500 ng·hr/mL, at least about 3600 ng·hr/mL, at least about 3700 ng·hr/mL, at least about 3800 ng·hr/mL, at least about 3900 ng·hr/mL, at least about 4000 ng·hr/mL, at least about 4100 ng·hr/mL, at least about 4200 ng·hr/mL, at least about 4300 ng·hr/mL, at least about 4400 ng - at least about 4500 ng-hour/mL, at least about 4600 ng-hour/mL, at least about 4700 ng-hour/mL, at least about 4800 ng-hour/mL, at least about 4900 ng-hour/mL, at least about 5000 ng-hour /mL, at least about 5100 ng·hr/mL, at least about 5200 ng·hr/mL, at least about 5300 ng·hr/mL, at least about 5400 ng·hr/mL, at least about 5500 ng·hr/mL, at least about 5600 ng·hr/mL , at least about 5700 ng·hr/mL, at least about 5800 ng·hr/mL, at least about 5900 ng·hr/mL, at least about 6000 ng·hr/mL, at least about 6100 ng·hr/mL, at least about 6200 ng·hr/mL, at least about 6300 ng·hr/mL, at least about 6400 ng·hr/mL, at least about 6500 ng·hr/mL, at least about 6600 ng·hr/mL, at least about 6700 ng·hr/mL, at least about 6800 ng·hr/mL, at least about 6900 ng - at least about 7000 ng.hr/mL, at least about 7100 ng.hr/mL, at least about 7150 ng.hr/mL, at least about 7200 ng.hr/mL, or at least about 7237.3 ng.hr/mL. , in some embodiments, can be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 9 by co-administering dextromethorphan with an antidepressant, for example, the dextromethorphan AUC _0-12 is at least about 40 ng·hr at least about 50 ng·hr/mL, at least about 60 ng·hr/mL, at least about 70 ng·hr/mL, at least about 80 ng·hr/mL, at least about 90 ng·hr/mL, at least about 100 ng·hr/mL, at least about 150 ng·hr/mL, at least about 200 ng·hr/mL, at least about 250 ng·hr/mL, at least about 300 ng·hr/mL, at least about 350 ng·hr/mL, at least about 400 ng·hr/mL, at least about 450 ng·hr/mL, at least about 500 ng·hr/mL, at least about 550 ng·hr/mL, about 500 ng·hr/mL to about 600 ng·hr/mL, about 500 ng·hr/mL to about 550 ng·hr/mL, about 500 ng·hr/mL to about 525 ng·hr/mL, about 525 ng·hr/mL to about 600 ng·hr/mL, at least about 600 ng·hr/mL, at least about 650 ng·hr/mL, at least about 700 ng·hr/mL mL, at least about 750 ng·hr/mL, at least about 800 ng·hr/mL, about 800 ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr /mL ~ approx. 875 ng/hr/mL, approx. 875 ng/hr/mL ~ approx. 900 ng/hr/mL, approx. 900 ng/hr/mL ~ approx. 1,000 ng/hr/mL, approx. 1,000 ng/hr/mL ~ approx. 1,100ng・hour/mL, about 1,100ng・hour/mL to about 1,200ng・hour/mL, about 1,200ng・hour/mL to about 1,300ng・hour/mL, about 1,300ng・hour /mL ~ approx. 1,400 ng/hr/mL, approx. 1,400 ng/hr/mL ~ approx. 1,500 ng/hr/mL, approx. 1,500 ng/hr/mL ~ approx. 1,600 ng/hr/mL, approx. 1 , 600ng・hour/mL to about 1,700ng・hour/mL, about 1,700ng・hour/mL to about 1,800ng・hour/mL, about 1,800ng・hour/mL to about 2,000ng・hour/ mL, at least about 850 ng·hr/mL, at least about 900 ng·hr/mL, at least about 950 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1050 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1150 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1250 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1350 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1450 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1550 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1625 ng·hr/mL, at least about 1650 ng·hr/mL, at least about 1675 ng·hr/mL. hr/mL, or at least about 1686.3 ng·hr/mL, and in some embodiments up to about 50,000 ng·hr/mL.

In some embodiments, the dextromethorphan plasma concentration is increased at day 9 by co-administering dextromethorphan with an antidepressant, for example, the dextromethorphan AUC _0-24 is at least about 50 ng·hr /mL, at least about 75 ng·hr/mL, at least about 100 ng·hr/mL, at least about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about 500 ng·hr/mL , at least about 600 ng·hr/mL, at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800 ng - at least about 1900 ng-hour/mL, at least about 2000 ng-hour/mL, at least about 2100 ng-hour/mL, at least about 2200 ng-hour/mL, at least about 2300 ng-hour/mL, at least about 2400 ng-hour /mL, at least about 2500 ng·hr/mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, at least about 1850 ng·hr/mL, at least about 2900 ng·hr/mL , at least about 2950 ng·hr/mL, or at least about 2975.3 ng·hr/mL, and in some embodiments up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC _0-inf on day 9 where the dextromethorphan plasma concentration is increased, for example by co-administering dextromethorphan with an antidepressant, is at least about 75 ng·hr. at least about 100 ng·hr/mL, at least about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about 500 ng·hr/mL, at least about 600 ng·hr/mL , at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800 ng·hr/mL, at least about 1900 ng - at least about 2000 ng.hr/mL, at least about 2100 ng.hr/mL, at least about 2200 ng.hr/mL, at least about 2300 ng.hr/mL, at least about 2400 ng.hr/mL, at least about 2500 ng.hr. /mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, at least about 2900 ng·hr/mL, at least about 3000 ng·hr/mL, at least about 3100 ng·hr/mL , at least about 3200 ng·hr/mL, at least about 3300 ng·hr/mL, at least about 3400 ng·hr/mL, at least about 3500 ng·hr/mL, at least about 3600 ng·hr/mL, at least about 3700 ng·hr/mL, at least about 3800 ng·hr/mL, at least about 3900 ng·hr/mL, at least about 4000 ng·hr/mL, at least about 4100 ng·hr/mL, at least about 4200 ng·hr/mL, at least about 4300 ng·hr/mL, at least about 4400 ng - at least about 4500 ng-hour/mL, at least about 4600 ng-hour/mL, at least about 4700 ng-hour/mL, at least about 4800 ng-hour/mL, at least about 4900 ng-hour/mL, at least about 5000 ng-hour /mL, at least about 5100 ng·hr/mL, at least about 5200 ng·hr/mL, at least about 5300 ng·hr/mL, at least about 5400 ng·hr/mL, at least about 5500 ng·hr/mL, at least about 5600 ng·hr/mL , at least about 5700 ng·hr/mL, at least about 5800 ng·hr/mL, at least about 5900 ng·hr/mL, at least about 6000 ng·hr/mL, at least about 6100 ng·hr/mL, at least about 6200 ng·hr/mL, at least about 6300 ng·hr/mL, at least about 6400 ng·hr/mL, at least about 6500 ng·hr/mL, at least about 6600 ng·hr/mL, at least about 6700 ng·hr/mL, at least about 6800 ng·hr/mL, at least about 6900 ng - at least about 7000 ng.hr/mL, at least about 7100 ng.hr/mL, at least about 7150 ng.hr/mL, at least about 7200 ng.hr/mL, or at least about 7237.3 ng.hr/mL. , in some embodiments, can be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 10 by co-administering dextromethorphan with an antidepressant, for example, the dextromethorphan AUC _0-12 is at least about 40 ng·hr at least about 50 ng·hr/mL, at least about 60 ng·hr/mL, at least about 70 ng·hr/mL, at least about 80 ng·hr/mL, at least about 90 ng·hr/mL, at least about 100 ng·hr/mL , at least about 150 ng·hr/mL, at least about 200 ng·hr/mL, at least about 250 ng·hr/mL, at least about 300 ng·hr/mL, at least about 350 ng·hr/mL, at least about 400 ng·hr/mL, at least about 450 ng·hr/mL, at least about 500 ng·hr/mL, at least about 550 ng·hr/mL, about 500 ng·hr/mL to about 600 ng·hr/mL, about 500 ng·hr/mL to about 550 ng·hr/mL , about 500 ng·hr/mL to about 525 ng·hr/mL, about 525 ng·hr/mL to about 600 ng·hr/mL, at least about 600 ng·hr/mL, at least about 650 ng·hr/mL, at least about 700 ng·hr /mL, at least about 750 ng·hr/mL, at least about 800 ng·hr/mL, about 800 ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL time/mL ~ approx. 875 ng/hr/mL, approx. 875 ng/hr/mL ~ approx. 900 ng/hr/mL, approx. 900 ng/hr/mL ~ approx. 1,000 ng/hr/mL, approx. 1,000 ng/hr/mL Approximately 1,100ng・hour/mL, approximately 1,100ng・hour/mL to approximately 1,200ng・hour/mL, approximately 1,200ng・hour/mL to approximately 1,300ng・hour/mL, approximately 1,300ng・hour/mL 1,400 ng/mL to approximately 1,500 ng/hour/mL, approximately 1,500 ng/mL to approximately 1,600 ng/hour/mL, approx. 1,600ng・hour/mL to about 1,700ng・hour/mL, about 1,700ng・hour/mL to about 1,800ng・hour/mL, about 1,800ng・hour/mL to about 2,000ng・hour /mL, at least about 850 ng·hr/mL, at least about 900 ng·hr/mL, at least about 950 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1050 ng·hr/mL, at least about 1100 ng·hr/mL , at least about 1150 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1250 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1350 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1450 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1550 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1625 ng·hr/mL, at least about 1650 ng·hr/mL, at least about 1675 ng·hr/mL, or at least about 1686.3 ng·hr/mL, and in some embodiments up to about 50,000 ng·hr/mL.

In some embodiments, the dextromethorphan plasma concentration is increased at day 10 by co-administering dextromethorphan with an antidepressant, for example, the dextromethorphan AUC _0-24 is at least about 50 ng·hr /mL, at least about 75 ng·hr/mL, at least about 100 ng·hr/mL, at least about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about 500 ng·hr/mL , at least about 600 ng·hr/mL, at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800 ng - at least about 1900 ng-hour/mL, at least about 2000 ng-hour/mL, at least about 2100 ng-hour/mL, at least about 2200 ng-hour/mL, at least about 2300 ng-hour/mL, at least about 2400 ng-hour /mL, at least about 2500 ng·hr/mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, at least about 1850 ng·hr/mL, at least about 2900 ng·hr/mL , at least about 2950 ng·hr/mL, or at least about 2975.3 ng·hr/mL, and in some embodiments up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC _0-inf on day 10 when the dextromethorphan plasma concentration is increased, for example, by co-administering dextromethorphan with an antidepressant, is at least about 75 ng·hr at least about 100 ng·hr/mL, at least about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about 500 ng·hr/mL, at least about 600 ng·hr/mL , at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800 ng·hr/mL, at least about 1900 ng - at least about 2000 ng.hr/mL, at least about 2100 ng.hr/mL, at least about 2200 ng.hr/mL, at least about 2300 ng.hr/mL, at least about 2400 ng.hr/mL, at least about 2500 ng.hr. /mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, at least about 2900 ng·hr/mL, at least about 3000 ng·hr/mL, at least about 3100 ng·hr/mL , at least about 3200 ng·hr/mL, at least about 3300 ng·hr/mL, at least about 3400 ng·hr/mL, at least about 3500 ng·hr/mL, at least about 3600 ng·hr/mL, at least about 3700 ng·hr/mL, at least about 3800 ng·hr/mL, at least about 3900 ng·hr/mL, at least about 4000 ng·hr/mL, at least about 4100 ng·hr/mL, at least about 4200 ng·hr/mL, at least about 4300 ng·hr/mL, at least about 4400 ng - at least about 4500 ng-hour/mL, at least about 4600 ng-hour/mL, at least about 4700 ng-hour/mL, at least about 4800 ng-hour/mL, at least about 4900 ng-hour/mL, at least about 5000 ng-hour /mL, at least about 5100 ng·hr/mL, at least about 5200 ng·hr/mL, at least about 5300 ng·hr/mL, at least about 5400 ng·hr/mL, at least about 5500 ng·hr/mL, at least about 5600 ng·hr/mL , at least about 5700 ng·hr/mL, at least about 5800 ng·hr/mL, at least about 5900 ng·hr/mL, at least about 6000 ng·hr/mL, at least about 6100 ng·hr/mL, at least about 6200 ng·hr/mL, at least about 6300 ng·hr/mL, at least about 6400 ng·hr/mL, at least about 6500 ng·hr/mL, at least about 6600 ng·hr/mL, at least about 6700 ng·hr/mL, at least about 6800 ng·hr/mL, at least about 6900 ng - at least about 7000 ng.hr/mL, at least about 7100 ng.hr/mL, at least about 7150 ng.hr/mL, at least about 7200 ng.hr/mL, or at least about 7237.3 ng.hr/mL. , in some embodiments, can be up to about 100,000 ng·hr/mL.

In some embodiments, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan plasma concentration is increased so that the dextromethorphan C _maximum on the first day is the same without the antidepressant. C _maximum that can be achieved with administration of an amount of dextromethorphan.

In some embodiments, the dextromethorphan C _maximum on the first day that dextromethorphan plasma concentrations are increased, e.g., by co-administering dextromethorphan with an antidepressant, is at least about 1.0 ng/mL; at least about 1.5 ng/mL, at least about 2.0 ng/mL, at least about 2.5 ng/mL, at least about 3.0 ng/mL, at least about 3.1 ng/mL, at least about 3.2 ng/mL, at least about 3.3 ng/mL, at least about 3.4 ng/mL, at least about 3.5 ng/mL, at least about 3.6 ng/mL, at least about 3.7 ng/mL, at least about 3.8 ng/mL, at least about 3. 9 ng/mL, at least about 4.0 ng/mL, at least about 4.1 ng/mL, at least about 4.2 ng/mL, at least about 4.3 ng/mL, at least about 4.4 ng/mL, at least about 4.5 ng/mL mL, at least about 4.6 ng/mL, at least about 4.7 ng/mL, at least about 4.8 ng/mL, at least about 4.9 ng/mL, at least about 5.0 ng/mL, at least about 5.1 ng/mL, at least about 5.2 ng/mL, at least about 5.3 ng/mL, at least about 5.4 ng/mL, at least about 5.5 ng/mL, at least about 5.6 ng/mL, at least about 5.7 ng/mL, at least about 5.7 ng/mL, at least about 5.8 ng/mL, at least about 5.9 ng/mL, at least about 6.0 ng/mL, at least about 6.1 ng/mL, at least about 6.2 ng/mL, at least about 6. 3ng/mL, at least about 6.4ng/mL, at least about 6.5ng/mL, at least about 6.6ng/mL, at least about 6.7ng/mL, at least about 6.8ng/mL, at least about 6.9ng/mL mL, at least about 7.0 ng/mL, at least about 7.1 ng/mL, at least about 7.2 ng/mL, at least about 7.3 ng/mL, at least about 7.4 ng/mL, at least about 7.5 ng/mL, at least about 7.6 ng/mL, at least about 7.7 ng/mL, at least about 7.8 ng/mL, at least about 7.9 ng/mL, at least about 8.0 ng/mL, at least about 8.1 ng/mL, at least about 8.2 ng/mL, at least about 8.3 ng/mL, at least about 8.4 ng/mL, at least about 8.5 ng/mL, at least about 8.6 ng/mL, or at least about 8.7 ng/mL; In some embodiments, it can be up to about 1000 ng·hr/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 8 by co-administering dextromethorphan with an antidepressant, for example, the dextromethorphan C _maximum is about 50 ng/mL to about 60 ng. /mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng /mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng /mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng /mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, about 170ng/mL to about 200ng /mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL. /mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL , at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, at least about 145 ng /mL, at least about 150 ng/mL, at least about 155 ng/mL, or at least about 158.1 ng/mL, and in some embodiments up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 9, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _maximum is about 50 ng/mL to about 60 ng. /mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng /mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng /mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng /mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, about 170ng/mL to about 200ng /mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL. /mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL , at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, at least about 145 ng /mL, at least about 150 ng/mL, at least about 155 ng/mL, or at least about 158.1 ng/mL, and in some embodiments up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 10, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _maximum is about 50 ng/mL to about 60 ng. /mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng /mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng /mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng /mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, about 170ng/mL to about 200ng /mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL. /mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL , at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, at least about 145 ng /mL, at least about 150 ng/mL, at least about 155 ng/mL, or at least about 158.1 ng/mL, and in some embodiments up to about 10,000 ng/mL.

In some embodiments, the antidepressant is at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng over a period of time between two separate and consecutive administrations of dextromethorphan. /mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL. , at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng /mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5 ng/mL, about 20 ng/mL. /mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng /mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng /mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng /mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng /mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, and in some embodiments up to about 10,000 ng/mL. Administered in an amount that produces _{an average} . For example, if dextromethorphan is administered at 8:00 am and 8:00 pm on day 1, and dextromethorphan is not administered after 8:00 am and before 8:00 pm on day 1, two separate doses of dextromethorphan And the period between consecutive administrations is from just after 8:00 a.m. to just before 8:00 p.m. on the first day.

In some embodiments, the dextromethorphan plasma concentration is increased on day 8, such as by co-administering dextromethorphan with an antidepressant, and _{the mean} dextromethorphan C is at least about 4.0 ng/mL. , at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng /mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL , at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng /mL, or at least about 140.5 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL. mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, some embodiments up to about 10,000 ng/mL. The above C _mean values are calculated for the period between two separate and consecutive doses of dextromethorphan, or if dextromethorphan is administered only once on day 8, the C _mean It may be for the next 12 hours.

In some embodiments, the dextromethorphan plasma concentration is increased on day 9, such as by co-administering dextromethorphan with an antidepressant, and _{the mean} dextromethorphan C is at least about 4.0 ng/mL. , at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng /mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL , at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng /mL, or at least about 140.5 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL. /mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng /mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng /mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng /mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, in some implementations. In form, it can be up to about 10,000 ng/mL. The above C- _means are calculated for the period between two separate and consecutive doses of dextromethorphan, or if dextromethorphan is administered only once on day 9, the C _-means are calculated from the first dose of dextromethorphan. It may be for the next 12 hours.

In some embodiments, the dextromethorphan C _average on day 10 when the dextromethorphan plasma concentration is increased is at least about 4.0 ng/mL, for example, by co-administering dextromethorphan with an antidepressant. , at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng /mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL , at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 135 ng/mL, at least about 140 ng /mL, or at least about 140.5 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55 ng/mL. mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL to about 200 ng/mL, some embodiments up to about 10,000 ng/mL. The above C- _means are calculated for the period between two separate and consecutive doses of dextromethorphan, or if dextromethorphan is administered only once on day 10, the C _-means are calculated from the first dose of dextromethorphan. It may be for the next 12 hours.

The fluctuation index value FI (%) of dextromethorphan can be determined by the formula.

In some embodiments, the dextromethorphan FI (%) on day 8 where the plasma concentration of dextromethorphan was increased, e.g., by co-administering dextromethorphan with the antidepressant. at least 1.5-fold or at least 2-fold compared to 8 days of administration of dextromethorphan without increasing plasma concentrations as by co-administration with dextromethorphan.

In some embodiments, the dextromethorphan FI (%) on day 9 where the plasma concentration of dextromethorphan was increased, e.g., by co-administering dextromethorphan with the antidepressant. Co-administration with dextromethorphan results in a decrease of at least 1.5-fold or at least 2-fold compared to administration of dextromethorphan for 9 days without increasing plasma concentrations.

In some embodiments, the dextromethorphan FI (%) on day 10 where the plasma concentration of dextromethorphan was increased, for example, by co-administering dextromethorphan with the antidepressant. at least 1.5-fold or at least 2-fold compared to administration of dextromethorphan for 10 days without increasing plasma concentrations as by co-administering with dextromethorphan.

In some embodiments, the dextromethorphan FI (%) on day 8 where the plasma concentration of dextromethorphan is increased by co-administering dextromethorphan with an antidepressant is less than 100%, less than 50% less than, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within the range delimited by any of these values. .

In some embodiments, the dextromethorphan FI (%) on day 9 when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with an antidepressant, is less than 100%; less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within the range delimited by any of these values. It is.

In some embodiments, the dextromethorphan FI (%) on day 9 when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with an antidepressant, is less than 100%; less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within the range delimited by any of these values. It is.

In some embodiments, the dextromethorphan FI (%) on day 8 where the plasma concentration of dextromethorphan was increased, e.g., by co-administering dextromethorphan with the antidepressant. at least 1.5 times, at least 2 times, at least 3 times, at least 4 times as compared to 8 days of administration of dextromethorphan without increasing plasma concentrations, such as by co-administering with dextromethorphan. , at least 5 times, or at least 6 times.

In some embodiments, the dextromethorphan FI (%) on day 9 where the plasma concentration of dextromethorphan was increased, e.g., by co-administering dextromethorphan with the antidepressant. at least 1.5 times, at least 2 times, at least 3 times, at least 4 times as compared to 9 days of administration of dextromethorphan without increasing plasma concentrations, such as by co-administration with dextromethorphan. , at least 5 times, or at least 6 times.

In some embodiments, the dextromethorphan FI (%) on day 10 where the plasma concentration of dextromethorphan was increased, for example, by co-administering dextromethorphan with the antidepressant. at least 1.5 times, at least 2 times, at least 3 times, at least 4 times as compared to 10 days of administration of dextromethorphan without increasing plasma concentrations, such as by co-administration with dextromethorphan. , at least 5 times, or at least 6 times.

In some embodiments, the dextromethorphan FI (%) on day 8 when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with an antidepressant, is less than 100%; less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any FI (%) value within the range delimited by any of these values. It is.

In some embodiments, the dextromethorphan FI (%) on day 9 when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with an antidepressant, is less than 100%; less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any FI (%) value within the range delimited by any of these values. It is.

In some embodiments, the dextromethorphan FI (%) on day 9 when the plasma concentration of dextromethorphan is increased, e.g., by co-administering dextromethorphan with an antidepressant, is less than 100%; less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any FI (%) value within the range delimited by any of these values. It is.

In some embodiments, the dextromethorphan trough concentration (e.g., 12-hour post-dose plasma concentration; also referred to as the "C _minimum ") on the first day that the antidepressant and dextromethorphan are administered is It may be at least twice the trough level that can be achieved with the same amount of dextromethorphan administered without the depressant.

In some embodiments, the dextromethorphan C _minimum on the first day the dextromethorphan plasma concentration is increased, e.g., by co-administering dextromethorphan with an antidepressant, is at least about 0.8 ng/mL; at least about 0.9 ng/mL, at least about 1.0 ng/mL, at least about 1.1 ng/mL, at least about 1.2 ng/mL, at least about 1.3 ng/mL, at least about 1.4 ng/mL, at least about 1.5 ng/mL, at least about 1.6 ng/mL, at least about 1.7 ng/mL, at least about 1.8 ng/mL, at least about 1.9 ng/mL, at least about 2.0 ng/mL, at least about 2. 1 ng/mL, at least about 2.2 ng/mL, at least about 2.3 ng/mL, at least about 2.4 ng/mL, at least about 2.5 ng/mL, or at least about 2.5 ng/mL, about 100 ng /mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 5, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _minimum is at least about 1.5 ng/mL; at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL. mL, or at least about 80.9 ng/mL, and up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 6, e.g., by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _minimum is at least about 1.5 ng/mL; at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, or at least about 102.2 ng/mL, and up to about 10,000 ng/mL. .

In some embodiments, the dextromethorphan plasma concentration is increased on day 7, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _minimum is at least about 1.5 ng/mL; at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, or at least about 110.6 ng/mL. and up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 8, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _minimum is at least about 1.5 ng/mL; at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 119. 3ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 9, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _minimum is at least about 1.5 ng/mL; at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, or at least about 119 .3ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to About 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to It can be about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan plasma concentration is increased on day 10, for example, by co-administering dextromethorphan with an antidepressant, the dextromethorphan C _minimum is at least about 1.5 ng/mL; at least about 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, or at least about 119 .3ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to About 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to It can be about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and up to about 10,000 ng/mL.

In some embodiments, the antidepressant is administered on the first day of at least two days of treatment with dextromethorphan and the reduction in dextromethorphan plasma concentration is less than the same amount administered without the antidepressant. of dextromethorphan on the first day when antidepressants and dextromethorphan are co-administered. For example, the plasma concentration of dextromethorphan on day 1 may be reduced by at least 5% compared to the plasma concentration of dextromethorphan that can be achieved by administering the same amount of dextromethorphan without an antidepressant.

In some embodiments, the antidepressant is co-administered with dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, and on day 5 the dextromethorphan plasma concentration is This is higher than the dextromethorphan plasma concentration that can be achieved with the same dose administered for 5 consecutive days without antidepressants. For example, dextromethorphan plasma concentrations on day 5 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) of the same amount of dextromethorphan administered for 5 consecutive days without antidepressants It can be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times the level that can be achieved with administration of lometorphan.

In some embodiments, an antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 6 consecutive days, and the dextromethorphan plasma concentration on day 6 is This is higher than the dextromethorphan plasma concentration that can be achieved with the same amount of dextromethorphan administered for 6 consecutive days without a depressant. For example, dextromethorphan plasma concentrations on day 6 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours post-dose) are the same for the same amount of dextromethorphan administered for 6 consecutive days without antidepressants. It can be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times the level that can be achieved with administration of lometorphan. .

In some embodiments, an antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 7 consecutive days, and the dextromethorphan plasma concentration on day 7 is This is higher than the dextromethorphan plasma concentration that can be achieved with the same amount of dextromethorphan administered for 7 consecutive days without a depressant. For example, the 7-day dextromethorphan plasma concentration (e.g., at 0, 1, 3, 6, or 12 hours post-dose) for dextromethorphan administered for 7 consecutive days without antidepressants It can be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times the level that can be achieved with the same amount of administration. .

In some embodiments, the antidepressant and dextromethorphan are co-administered for at least 8 consecutive days, and on the 8th day, the dextromethorphan is administered at 0 hours, 1 hour, 3 hours, etc. after co-administration. at least 5 times, at least 10 times, at least 20 times, at least 30 times the plasma concentration that could be achieved by administering the same amount of dextromethorphan for 6 hours, or 12 hours, for 8 consecutive days without an antidepressant; have a plasma concentration of at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times.

In some embodiments, an antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 8 consecutive days, and the dextrorphan plasma concentration on day 8 is This is lower than the dextrorphan plasma concentration that can be achieved with the same amount of dextromethorphan administered for 8 consecutive days in the absence of depressants. For example, the 8-day dextrorphan plasma concentration (e.g., at 0, 1, 3, 6, or 12 hours postdose) for dextromethorphan administered for 8 consecutive days without antidepressants is It may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to dextrorphan plasma concentrations that can be achieved with the same amount of administration.

In some embodiments, the antidepressant and dextromethorphan are co-administered for at least 9 consecutive days, and on the 9th day, dextromethorphan is administered, e.g. at least 5 times, at least 10 times the plasma concentration that could be achieved with the administration of the same amount of dextromethorphan administered for 9 consecutive days without an antidepressant, at 1 hour, 3 hours, 6 hours, or 12 hours; have a plasma concentration of at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times.

In some embodiments, an antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 9 consecutive days, and the dextrorphan plasma concentration on day 9 is This is lower than the dextrorphan plasma concentration that can be achieved with the same amount of dextromethorphan administered for 9 consecutive days in the absence of depressants. For example, day 9 dextrorphan plasma concentrations (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) of dextromethorphan administered for 9 consecutive days without antidepressants It may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to dextrorphan plasma concentrations that can be achieved with the same amount of administration.

In some embodiments, the antidepressant and dextromethorphan are co-administered for at least 10 consecutive days, and on the 10th day, the dextromethorphan is at least 5 times, at least 10 times the plasma concentration that could be achieved with the administration of the same amount of dextromethorphan administered for 10 consecutive days without an antidepressant, at 1 hour, 3 hours, 6 hours, or 12 hours; having a plasma concentration of at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times.

In some embodiments, an antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 10 consecutive days, and the dextrorphan plasma concentration on day 10 is This is lower than the dextrorphan plasma concentration that can be achieved with the same amount of dextromethorphan administered for 10 consecutive days without depressants. For example, the 10-day dextrorphan plasma concentration (e.g., at 0, 1, 3, 6, or 12 hours post-dose) for dextromethorphan administered for 10 consecutive days without antidepressants. It may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to dextrorphan plasma concentrations that can be achieved with the same amount of administration.

For compositions containing dextromethorphan and antidepressants, some liquids may range from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) from about 5% (w/v), from about 5% (w/v) to about 7% (w/v), from about 5% (w/v) to about 15% (w/v), from about 7% ( w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), about 40% (w/v) to about 50% (w/v) /v) in combination with dextromethorphan and an antidepressant, or any amount in the range delimited by any of these values, or any amount between any of these values.

Some solid compositions have at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w) w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60 % (w/w), about 70% (w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) of the combined dextromethorphan and It may include an antidepressant, or any amount in the range delimited by any of these values, or any amount between any of these values.

A therapeutically effective amount of a therapeutic compound may vary depending on the situation. For example, the daily dose of dextromethorphan may be about 0.1 mg to about 1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg, about 60 mg to about 700 mg, about 100 mg to about 400 mg, in some examples. about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg from about 60 mg, from about 20 mg to about 60 mg, from about 60 mg to about 100 mg, from about 100 mg to about 200 mg, from about 100 mg to about 140 mg, from about 160 mg to about 200 mg, from about 200 mg to about 300 mg, from about 220 mg to about 260 mg, from about 300 mg to about 400 mg, about 340 mg to about 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 360 mg, or by any value thereof. It can be a delimited range of daily doses, or any daily dose between any of these values. Dextromethorphan may be administered once daily, or twice daily or every 12 hours, three times daily, at approximately half, 1/3, 1/4, or 1/6 of the daily dose, respectively. It may be administered 4 times or 6 times a day.

In some embodiments, about 15 mg/day to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45 mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day. From about 100 mg/day to about 110 mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300 mg/day of dextromethorphan in humans in need thereof. administered.

Antidepressant compounds can be administered as needed to treat pain, depression or neurological conditions such as cough. In some embodiments, the antidepressant composition and dextromethorphan are present for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days, at least 14 days. days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 60 days, at least 90 days, at least 6 months, at least 9 months, at least 180 days, at least 365 days, at least 18 months, Administered at least once a day, such as once a day or twice a day, for at least 2 years or longer, up to 1 year, up to 18 months, up to 3 years, up to 5 years, or longer Ru.

In some embodiments, the co-administration of dextromethorphan and the antidepressant comprises about 1, 2, 3 doses once daily before co-administering the dextromethorphan and antidepressant twice daily. , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more days.

The therapeutic compounds can be formulated for oral administration, for example, with an inert diluent or an edible carrier. Alternatively, it may be enclosed within a hard or soft shell gelatin capsule, compressed into a tablet, or incorporated directly into a dietary food. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of orally ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Tablets, troches, pills, capsules, etc. may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, sucrose, Sweetening agents such as lactose or saccharin, or flavoring agents such as peppermint, oil of wintergreen or cherry flavor. When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings, for example, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amounts used.

Certain compositions or dosage forms may be liquid or may include a solid phase dispersed within a liquid.

Therapeutic compounds may be formulated for parenteral or intraperitoneal administration. Solutions of the active compound, such as the free base or pharmaceutically acceptable salt, can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also have the oil dispersed in or in glycerol, liquid polyethylene glycols, and mixtures thereof. Under normal conditions of storage and use, these formulations may contain a preservative to prevent the growth of microorganisms.

In some embodiments, the human or patient is, or is selected to be, Black or African American.

In some embodiments, the human or patient is or is selected to be Caucasian.

In some embodiments, the human or patient is or is selected to be of Asian descent.

In some embodiments, the human or patient is or is selected to be a Native Hawaiian or other Pacific Islander.

In some embodiments, the human or patient is, or is selected to be, Hispanic or Latino.

In some embodiments, the human or patient is, or is selected to be, a Native American or Alaska Native.

In some embodiments, the human or patient is not, or is selected to be of non-Hispanic or Latin American descent.

Particularly Contemplated Embodiments The following are examples of embodiments specifically contemplated by the inventors.
(Embodiment 1)
delivering enhanced plasma concentrations or bioavailability of dextromethorphan to a human in need of treatment, or a combination of a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound; A method of treating pain or neurological and/or psychiatric disorders comprising administering.
(Embodiment 2)
A method of treating pain comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan.
(Embodiment 3)
A method of enhancing the pain relief properties of dextromethorphan comprising co-administering dextromethorphan and an antidepressant compound.
(Embodiment 4)
A method of increasing dextromethorphan plasma concentrations in a human who is an extensive metabolizer of dextromethorphan, the method comprising co-administering an antidepressant compound to the human undergoing treatment comprising administration of dextromethorphan.
(Embodiment 5)
A method of inhibiting the metabolism of dextromethorphan comprising administering an antidepressant compound to a human, wherein the human is an extensive metabolizer of dextromethorphan, and the dextromethorphan is combined with the antidepressant compound. simultaneously present in said human body.
(Embodiment 6)
A method of increasing the metabolic lifespan of dextromethorphan comprising administering an antidepressant compound to a human, said human being an extensive metabolizer of dextromethorphan; simultaneously present in said human body.
(Embodiment 7)
A method of correcting the hypermetabolism of dextromethorphan comprising administering an antidepressant compound to a human in need thereof.
(Embodiment 8)
A method of improving the pain relief properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human in need of treatment for pain.
(Embodiment 9)
A method of improving the antitussive properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human in need of treatment for cough.
(Embodiment 10)
A method of treating cough comprising administering a combination of an antidepressant compound and dextromethorphan to a human in need thereof.
(Embodiment 11)
A method of improving the therapeutic properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human in need of treatment for a neurological and/or psychiatric disorder.
(Embodiment 12)
A method of treating a neurological and/or psychiatric disorder comprising administering a combination of an antidepressant compound and dextromethorphan to a human in need thereof.
(Embodiment 13)
13. The method of embodiment 12, wherein the human is an extensive metabolizer of dextromethorphan.
(Embodiment 14)
Any of the preceding embodiments, such as embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein the dextromethorphan and the antidepressant compound are administered in separate dosage forms. , 11, 12, or 13.
(Embodiment 15)
A pharmaceutical composition comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant compound, and a pharmaceutically acceptable excipient.
(Embodiment 16)
An oral dosage form comprising at least 20 mg of dextromethorphan and an effective amount of an antidepressant compound for inhibiting the metabolism of dextromethorphan in humans, a major metabolizer of dextromethorphan.
(Embodiment 17)
17. The oral dosage form of embodiment 16, wherein about 30 mg to about 350 mg dextromethorphan is present in the dosage form.
(Embodiment 18)
The method of any preceding embodiment, wherein dextromethorphan is administered to the human for the treatment of cough.
(Embodiment 19)
The method of any preceding embodiment, wherein the dextromethorphan is administered to the human at least once a day for at least 8 days, at least 9 days, or at least 10 days.
(Embodiment 20)
The antidepressant is administered in an amount that results in a plasma concentration of dextromethorphan in said human on day 8 that is at least 10 times the plasma concentration produced by the same amount of dextromethorphan administered without the antidepressant. A method as described in any preceding embodiment.
(Embodiment 21)
The method of any preceding embodiment, wherein the human is an extensive metabolizer of dextromethorphan.
(Embodiment 22)
The method of any preceding embodiment, wherein dextromethorphan is administered to the human for the treatment of pain.
(Embodiment 23)
The pain may be associated with any antecedent pain, including posterior pain, cancer pain, arthralgia, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain. A method as described in an embodiment, such as embodiment 22.
(Embodiment 24)
The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain.
(Embodiment 25)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises post-operative pain.
(Embodiment 26)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises cancer pain.
(Embodiment 27)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises joint pain.
(Embodiment 28)
23. The method of embodiment 22, wherein the pain comprises lumbosacral pain.
(Embodiment 29)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises musculoskeletal pain.
(Embodiment 30)
The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises neuropathic pain.
(Embodiment 31)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises nociceptive pain.
(Embodiment 32)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises chronic musculoskeletal pain.
(Embodiment 33)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with rheumatoid arthritis.
(Embodiment 34)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with juvenile rheumatoid arthritis.
(Embodiment 35)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with osteoarthritis.
(Embodiment 36)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with axial spondyloarthritis.
(Embodiment 37)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with ankylosing spondylitis.
(Embodiment 38)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with diabetic peripheral neuropathy.
(Embodiment 39)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with posterior neuralgia.
(Embodiment 40)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with trigeminal neuralgia.
(Embodiment 41)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with monoradiculopathy.
(Embodiment 42)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with phantom limb pain.
(Embodiment 43)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with central pain.
(Embodiment 44)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises cancer-related pain.
(Embodiment 45)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with lumbar nerve root compression.
(Embodiment 46)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with spinal cord injury.
(Embodiment 47)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with post-stroke pain.
(Embodiment 48)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with central multiple sclerosis pain.
(Embodiment 49)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with HIV-associated neuropathy.
(Embodiment 50)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with radiation therapy-associated neuropathy.
(Embodiment 51)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with chemotherapy-associated neuropathy.
(Embodiment 52)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain comprises toothache.
(Embodiment 53)
23. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with primary dysmenorrhea.
(Embodiment 54)
The method of any preceding embodiment, wherein 90 mg/day of dextromethorphan is administered to said human.
(Embodiment 55)
55. The method of any preceding embodiment, such as embodiment 54, wherein 45 mg of dextromethorphan is administered to said human twice a day.
(Embodiment 56)
The method of any preceding embodiment, wherein the antidepressant is administered in an amount that provides an AUC _0-12 of dextromethorphan that is at least about 40 ng·hr/mL.
(Embodiment 57)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan is at least about 50 ng·hr/mL.
(Embodiment 58)
The method of any preceding embodiment, wherein the human is in need of treatment with dextromethorphan.
(Embodiment 59)
The method of any preceding embodiment, such as embodiment 85, wherein the AUC _0-12 of the dextromethorphan on day 8, day 9, or day 10 is at least about 100 ng·hr/mL.
(Embodiment 60)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan on day 8, day 9, or day 10 is at least about 400 ng·hr/mL.
(Embodiment 61)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan on day 8, day 9, or day 10 is at least about 800 ng·hr/mL.
(Embodiment 62)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan on day 8, day 9, or day 10 is at least about 1500 ng·hr/mL.
(Embodiment 63)
The method of any preceding embodiment, wherein the AUC _0-24 of the dextromethorphan on day 8, day 9, or day 10 is at least about 100 ng·hr/mL.
(Embodiment 64)
The method of any preceding embodiment, wherein the AUC _0-24 of said dextromethorphan on day 8, day 9, or day 10 is at least about 1500 ng·hr/mL.
(Embodiment 65)
The method of any preceding embodiment, wherein the dextromethorphan AUC _0-24 on day 8, day 9, or day 10 is at least about 2900 ng·hr/mL.
(Embodiment 66)
The method of any preceding embodiment, wherein the AUC _0-inf of the dextromethorphan on day 8, day 9, or day 10 is at least about 100 ng·hr/mL.
(Actual form 67)
The method of any preceding embodiment, wherein the AUC _0-inf of the dextromethorphan on day 8, day 9, or day 10 is at least about 1500 ng·hr/mL.
(Embodiment 68)
The method of any preceding embodiment, wherein the AUC _0-inf of the dextromethorphan on day 8, day 9, or day 10 is at least about 3500 ng·hr/mL.
(Embodiment 69)
The method of any preceding embodiment, wherein the AUC _0-inf of the dextromethorphan on day 8, day 9, or day 10 is at least about 5000 ng·hr/mL.
(Embodiment 70)
The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in _{a Cmax} of dextromethorphan that is at least about 6 ng/mL.
(Embodiment 71)
71. The method of any preceding embodiment, such as embodiment 70, wherein the _Cmax of said dextromethorphan on day 8, day 9, or day 10 is at least about 10 ng/mL.
(Embodiment 72)
The method of any preceding embodiment, wherein _{the Cmax} of said dextromethorphan on day 8, day 9, or day 10 is at least about 20 ng/mL.
(Embodiment 73)
The method of any preceding embodiment, wherein _{the Cmax} of said dextromethorphan on day 8, day 9, or day 10 is at least about 60 ng/mL.
(Embodiment 74)
The method of any preceding embodiment, wherein the _Cmax of the dextromethorphan on day 8, day 9, or day 10 is at least about 120 ng/mL.
(Embodiment 75)
The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in a C _-mean of dextromethorphan that is at least about 5 ng/mL over a 12-hour period following a single administration.
(Embodiment 76)
The method of any preceding embodiment, wherein the C _mean of the dextromethorphan on day 8, day 9, or day 10 is at least about 20 ng/mL.
(Embodiment 77)
The method of any preceding embodiment, wherein the C _mean of the dextromethorphan on day 8, day 9, or day 10 is at least about 70 ng/mL.
(Embodiment 78)
The method of any preceding embodiment, wherein the C _mean of the dextromethorphan on day 8, day 9, or day 10 is at least about 120 ng/mL.
(Embodiment 79)
The method of any preceding embodiment, wherein the antidepressant is administered in an amount that provides an AUC _0-12 of dextromethorphan that is at least about 40 ng·hr/mL.
(Embodiment 80)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan is at least about 50 ng·hr/mL.
(Embodiment 81)
The method of any preceding embodiment, wherein the antidepressant is co-administered with dextromethorphan at least daily for at least two consecutive days.
(Embodiment 82)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan on day 8, day 9, or day 10 is at least about 100 ng·hr/mL.
(Embodiment 83)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan on day 8, day 9, or day 10 is at least about 800 ng·hr/mL.
(Embodiment 84)
The method of any preceding embodiment, wherein the AUC _0-12 of the dextromethorphan on day 8, day 9, or day 10 is at least about 1500 ng·hr/mL.
(Embodiment 85)
The method of any preceding embodiment, wherein the AUC _0-24 of the dextromethorphan on day 8, day 9, or day 10 is at least about 100 ng·hr/mL.
(Embodiment 86)
The method of any preceding embodiment, wherein the AUC _0-24 of said dextromethorphan on day 8, day 9, or day 10 is at least about 1500 ng·hr/mL.
(Embodiment 87)
The method of any preceding embodiment, wherein the AUC _0-inf of the dextromethorphan on day 8, day 9, or day 10 is at least about 100 ng·hr/mL.
(Embodiment 88)
The method of any preceding embodiment, wherein the AUC _0-inf of the dextromethorphan on day 8, day 9, or day 10 is at least about 3500 ng·hr/mL.
(Embodiment 89)
The method of any preceding embodiment, wherein the AUC _0-inf of the dextromethorphan on day 8, day 9, or day 10 is at least about 5000 ng·hr/mL.
(Embodiment 90)
The method of any preceding embodiment, wherein about 0.6 mg/kg to about 0.8 mg/kg of said dextromethorphan is administered orally once or twice daily.
(Embodiment 91)
The method of any preceding embodiment, wherein the human suffers from treatment-resistant depression.
(Embodiment 92)
The method of any preceding embodiment, wherein the dextromethorphan is administered orally in a dosage form that provides immediate release of the dextromethorphan.
(Embodiment 93)
The method of any preceding embodiment, wherein the antidepressant is administered orally in a dosage form that provides sustained release of the antidepressant.
(Embodiment 94)
A method as described in any preceding embodiment, wherein the antidepressant and the dextromethorphan are orally administered together in a single dosage form that is administered orally once or twice daily.
(Embodiment 95)
The method of any preceding embodiment, wherein the dextromethorphan and the antidepressant are administered orally for at least 5 weeks.
(Embodiment 96)
The method of any preceding embodiment, wherein the human is suffering from major depressive disorder.
(Embodiment 97)
A method as described in any preceding embodiment, wherein the antidepressant comprises an enantiomeric excess of the R-enantiomer.
(Embodiment 98)
The method of any preceding embodiment, wherein the antidepressant comprises an enantiomeric excess of the S-enantiomer.
(Embodiment 99)
The method of any preceding embodiment, wherein the dextromethorphan comprises deuterated dextromethorphan.
(Embodiment 100)
The method of any preceding embodiment, wherein the human is currently suffering from depression and has previously been unsuccessfully treated with at least two antidepressants.
(Embodiment 101)
A method for rapidly alleviating symptoms of depression comprising administering a combination of an antidepressant and dextromethorphan to a human in need once or twice a day. , experiencing a therapeutic effect within two weeks from the first day of administering the combination of an antidepressant and dextromethorphan.
(Embodiment 102)
The use of a combination of an antidepressant and dextromethorphan in the manufacture of a medicinal product for rapid relief of symptoms of depression, wherein the medicinal product is administered once or twice a day. Achieving therapeutic effect within two weeks from the first day of use.
(Embodiment 103)
A method or use thereof according to any preceding embodiment, wherein said human has previously had an inadequate response to at least one antidepressant therapy.
(Embodiment 104)
A method or use thereof according to any preceding embodiment, wherein said depression is major depressive disorder.
(Embodiment 105)
A method or use thereof according to any preceding embodiment, wherein said depression is treatment-resistant depression.
(Embodiment 106)
A method or use thereof according to any preceding embodiment, wherein the combination of said antidepressant and said dextromethorphan is administered once a day or twice a day for at least 30 days.
(Embodiment 107)
A method or use thereof according to any preceding embodiment, wherein the combination of said antidepressant and said dextromethorphan is administered once a day or twice a day for at least 42 days.
(Embodiment 108)
A method of treating nicotine addiction associated with tobacco smoking, the method comprising administering to a human suffering from nicotine addiction a combination of an antidepressant and dextromethorphan daily for at least 21 consecutive days, the human suffering from nicotine addiction A method of administering to said human a total amount of 80 mg to 140 mg of dextromethorphan daily, the method being more effective than administering the same amount of an antidepressant alone, the person being a cigarette smoker.
(Embodiment 109)
Humans who took the combination of antidepressant and dextromethorphan twice a day in two equal doses, but only took one of the two divided doses or did not take the drug combination. 109. The method of embodiment 108, wherein the intensity of nicotine self-intake is reduced on the day of administration or the next day compared to a human subject.
(Embodiment 110)
110. The method of embodiment 108 or 109, wherein the combination of an antidepressant and dextromethorphan is administered to said human daily for at least 42 consecutive days.
(Embodiment 111)
111. The method of embodiment 108, 109 or 110, wherein about 90 mg of dextromethorphan is administered to said human daily.
(Embodiment 112)
112. The method of any of embodiments 109-111, wherein about 40 mg to about 50 mg of dextromethorphan in each dose is administered to said human twice a day.
(Embodiment 113)
113. The method of any of embodiments 109-112, which is more effective than administering dextromethorphan alone to nicotine addicts.
(Embodiment 114)
114. The method of any of embodiments 109-113, wherein the antidepressant is deuterium enriched.
(Embodiment 115)
188. The method of embodiment 187, wherein the dextromethorphan is deuterium-enriched dextromethorphan.

(Example)
The efficacy of the combination of the antidepressants bupropion and dextromethorphan is demonstrated in several examples below. Example 2 shows that the results for bupropion are also observable with other antidepressants.

(Example 1)
As shown in Table 1 below, 15 human subjects were randomized into one of two treatment groups to receive dextromethorphan (DM) alone or DM in combination with bupropion.

All subjects were extensive metabolizers (including ultra-rapid) of dextromethorphan as determined by CYP2D6 genetic testing. Dextromethorphan is administered at 12 hour intervals from days 1 to 8, with the final dose on the morning of day 8. Bupropion is administered once daily at 12-hour intervals on days 1-3, with the final dose on the morning of day 8.

Plasma samples were taken for concentration analysis of dextromethorphan, total dextrorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8. Plasma samples for determination of dextromethorphan trough concentrations were obtained approximately 12 hours after administration on days 1, 5, 6, and 8.

Concentrations of dextromethorphan, total dextrorphan (unconjugated and glucuronide forms), bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were measured using LC-MS/MS. Pharmacokinetic parameters were calculated.

Phenotypic determination of dextromethorphan metabolic status was performed by Jurica et al. This was done by calculating the metabolic rate of dextromethorphan/dextrorphan as described in Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 486-490. Plasma concentrations of dextromethorphan and dextrorphan 3 hours after administration were used with a dextromethorphan/dextrorphan ratio of 0.3 or higher indicating a hypometabolizer phenotype.

(result)
As shown in Figure 1 and Table 2, plasma concentrations of dextromethorphan were significantly increased with bupropion administration.

As shown in Figures 2-4, the AUC of dextromethorphan was significantly increased upon administration of bupropion. As shown in Figure 5 and Table 2A, administration of bupropion with dextromethorphan resulted in significantly lower average dextromethorphan AUC _0-12 , AUC _0-24 , and and approximately 60-fold, 80-fold, and 175-fold increases in AUC _0-inf . As shown in Figure 6 and Table 2B, the increase in dextromethorphan AUC occurred as quickly as day 1 (approximately 3 times the increase in AUC _0-12 ).

As shown in Figure 7 and Tables 2A and 3, trough plasma concentrations of dextromethorphan (also referred to as "minimum mean plasma concentration" or "C _-minimum ") increased significantly with administration of bupropion. Administration of bupropion with dextromethorphan resulted in an approximately 105-fold increase in the mean trough plasma concentration of dextromethorphan on day 8 compared to administration of dextromethorphan alone.

As shown in Table 2A, the mean plasma concentration (C _mean ) of dextromethorphan on day 8 increased approximately 60-fold with bupropion administration compared to administration of dextromethorphan alone. The maximum mean plasma concentration ( _Cmax ) was also significantly increased, as shown in Figure 8 and Table 2A.

The _Tmax and elimination half-life (T _{1/2 el} ) of dextromethorphan were significantly increased with administration of bupropion on day 8. Administration of bupropion with dextromethorphan resulted in a mean T _max of 3.6 hours compared to 2.3 hours with dextromethorphan alone. Administration of bupropion with dextromethorphan resulted in a mean T _{1/2 el} of 27.7 hours compared to 6.6 hours for dextromethorphan alone.

As shown in Figure 9 and Table 4, plasma concentrations of dextrophan were significantly reduced with bupropion administration.

As shown in Figures 10-11, there was an approximately 78% decrease in mean dextrorphan C _max and an approximately 55% decrease in mean dextrorphan AUC _0-12 on day 8 with bupropion administration. .

Phenotyping of dextromethorphan metabolic status showed that subjects on either treatment did not have hypometabolism on day 1. However, at day 8, 100% of subjects treated with bupropion converted to poor metabolizer status compared to 0% of subjects treated with dextromethorphan alone. The mean plasma dextromethorphan/dextrophan metabolic rate increased from 0.01 on day 1 to 0.71 on day 8 with bupropion administration. The mean rate in the group receiving DM alone was 0.00 on day 1 and remained unchanged on day 8.

On day 8, mean plasma concentrations of bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were at least 10 ng/mL, 200 ng/mL, 20 ng/mL, and 100 ng/mL, respectively, after bupropion administration. .

As used in this section, the term "fold change" or "fold increase" refers to the ratio of the value of bupropion with dextromethorphan to the same value of dextromethorphan alone (i.e., value of bupropion with dextromethorphan divided by the same value of torphan).

(Example 2)
The ability of various antidepressant compounds to inhibit the metabolism of dextromethorphan was investigated using human liver microsomes. Each antidepressant compound was made in duplicate at 7 increasing concentrations (0.1-100 μM) at 37°C in the presence of dextromethorphan (5 μM) and incubated with human liver microsomes (0.5 mg/mL). . Assays were performed in the presence of 2mM NADPH in 100mM potassium phosphate (pH 7.4) containing 5mM magnesium chloride in a final volume of 200μL assay.

After optimal incubation at 37°C, the reaction was stopped by adding methanol containing internal standard for analytical quantification. Quenched samples were incubated at 4°C for 10 minutes and centrifuged at 4°C for 10 minutes. The supernatant was removed and metabolites of dextromethorphan (dextrorphan) were analyzed by LC-MS/MS. The degree of reduction in metabolite formation compared to the vehicle control is used to calculate the IC ₅₀ value (the test concentration that produces 50% inhibition of dextromethorphan metabolism) for each antidepressant compound, with lower IC ₅₀ values It was shown to be highly effective.

The results are summarized in Table 5 below and the corresponding efficacy is shown in Figure 12.

(Example 3)
(Phase 2 clinical trial design)
A Phase 2 clinical trial of the combination administration of dextromethorphan and bupropion (DM/BU) was conducted over a 6-week treatment period in 80 adult patients with a confirmed diagnosis of moderate-to-severe major depressive disorder (MDD). It was a randomized, double-blind, active-controlled, multicenter US study in which the drug was administered twice daily. The treatment groups (1:1 randomization) were 43 patients with DM/BU (dextromethorphan 45 mg/bupropion 105 mg) or 37 patients with active comparator bupropion (105 mg). Of these patients, 23% had previously received first-line treatment for depression. Extensive quality control measures were implemented in this clinical trial.

(Primary evaluation item)
Changes from baseline in Montgomery Asberg Depression Rating Scale (MADRS) total score over the 6-week treatment period were calculated at each time point and averaged.

FIG. 13 and Table A show changes over time in MADRS total scores during a 6-week treatment period for subjects administered bupropion (BU) or a combination of dextromethorphan and bupropion (DM/BU).

(Secondary evaluation item)
Table B shows secondary endpoints along with P values.

Figure 14 shows the percentage of subjects who achieved remission (as determined by MADRS≦10) during the 6-week treatment period for subjects treated with bupropion (BU) or the combination of dextromethorphan and bupropion (DM/BU) .

(safety)
Clinical trials showed that DM/BU administration was safe and well tolerated, with similar rates of adverse events in the DM/BU and bupropion treatment groups. No serious adverse events were observed. There was no significant difference between these two treatment groups in terms of discontinuation due to adverse events. The most commonly reported adverse events in the DM/BU treatment group were nausea, dizziness, dry mouth, decreased appetite, and anxiety. DM/BU was not associated with psychostimulant effects, weight gain, or worsening of sexual dysfunction.

(summary)
Statistically significant improvements were achieved in MADRS and secondary endpoints of DM/BU in MDD patients. Early and sustained separation from the active comparator, bupropion, was observed. The administration of DM/BU was safe and well tolerated, and no effects such as inducing psychotic symptoms, weight gain, or worsening of sexual dysfunction were observed.

Thus, DM/BU showed significant and rapid antidepressant effects and had a favorable safety profile in clinical trials targeting MDD.

(result)
Figures 13 and 14 show that 80 adult patients with depression were treated with a combination of 45 mg DM and 105 mg BU twice daily for 43 patients during a 6-week treatment period; It was created based on the results of a US clinical trial in which 105 mg of BU was administered alone to patients. Of these patients, 23% had previously received first-line treatment for depression.

As shown in Figure 13 and Table A, the MADRS total score (Depression Rating Scale) was significantly lower with the combination of DM and BU than with BU alone, even in the first week of treatment. At week 6, DM/BU combination administration reduced MADRS total score by approximately 42% compared to bupropion alone.

As shown in Figure 14, even as early as the second week of treatment, the combined administration of DM/BU resulted in a significantly higher remission rate, approximately 20% higher than the control BU alone (approximately 8 times). rate is high. At week 6 of treatment, the combination administration of DM/BU resulted in a significantly higher remission rate of approximately 30% compared to the control BU alone.

The clinical trials described above showed that administration of the combination of bupropion and dextromethorphan (DM/BU) would result in higher efficacy than would otherwise be achieved when bupropion was administered alone. . This clinical trial demonstrated that the combination of dextromethorphan and bupropion has an additive or synergistic effect in the treatment of depression.

(Example 4: Product kit)
In some embodiments, the product kit includes a combination of dextromethorphan and bupropion for treating depression, and the product kit includes about 30 mg to about 60 mg dextromethorphan and about 100 mg to about 200 mg bupropion. Once-daily or twice-daily administration of the dosage form provides greater efficacy in humans than administration of bupropion alone. In some embodiments, the product kit includes 45 mg dextromethorphan and 105 mg bupropion.

In some embodiments, the product kit is an oral sustained release delivery system for dextromethorphan in a dosage form comprising bupropion, dextromethorphan, and a water-soluble vehicle, the dosage form comprising about 30 mg to about 60 mg. When the dosage form contains dextromethorphan and about 100 mg to about 200 mg of bupropion and is used once or twice daily for at least 8 days, the elimination half-life (T _1/2 ) of dextromethorphan is at day 8. The elimination half-life is longer than that of dextromethorphan alone.

(Example 5)
Approximately 40 million American adults smoke cigarettes, and approximately 70% of them report wanting to quit. According to the Centers for Disease Control and Prevention, tobacco use causes approximately 500,000 premature deaths each year in the United States alone. Smoking is one of the largest causes of premature death worldwide, estimated to account for nearly 20% of all deaths in developed countries (Dani JA and Heinemann S (1996) Neuron 16:5, pp.905- 8). Direct medical costs and productivity losses as a result of smoking amount to nearly $300 billion per year in the United States alone. It is estimated that only 3% to 5% of smokers who attempt to quit without assistance are successful within 6 to 12 months, and relapse rates remain above 80% even with current treatments (Hughes JR, et al. (2004) Addiction 99:1, pp. 29-38). The vast majority of smokers who attempt to quit fail to quit, highlighting the need for new approaches. The combination of dextromethorphan and bupropion (DM/BU) has the potential to address this situation due to the novel mechanism of action of DM/BU.

The dextromethorphan component of DM/BU is a sigma-1 receptor agonist, nicotinic acetylcholine receptor antagonist, and serotonin and norepinephrine transport inhibitor. DM/BU's bupropion serves to increase the bioavailability of dextromethorphan, is a norepinephrine and dopamine reuptake inhibitor, and a nicotinic acetylcholine receptor antagonist. Both components of DM/BU are nicotinic acetylcholine receptor antagonists, and their mechanism of action is associated with nicotine dependence. Therefore, DM/BU may provide a new mechanism of action for smoking cessation treatment.

(Phase 2 clinical trial design)
This clinical trial was a phase 2, randomized, double-blind, active-controlled study to evaluate efficacy and safety in smoking cessation treatment for DM/BU. A total of 58 smokers were randomized in a 1:1 ratio to receive either DM/BU (dextromethorphan 45 mg/bupropion 105 mg) (n = 31) or the active comparator bupropion (105 mg) (n = 27). was administered twice a day and evaluated over a period of 3 weeks. The subjects who participated in this experiment were regular smokers who used 10 or more cigarettes per day. The average number of cigarettes smoked per day at baseline was 20 in the DM/BU treatment group and 17 in the bupropion treatment group.

(Primary evaluation item)
The primary endpoint was change in smoking intensity measured by number of cigarettes smoked per day as assessed by daily smoking diary.

Reduction in ad libitum smoking has been shown to correlate with smoking cessation and was therefore chosen as the primary endpoint of this study.

(safety)
Medication adherence was similar between study groups for both morning doses (97.1% for DM/BU and 96.6% for bupropion) and evening doses (76.3% for DM/BU and 79.4% for bupropion). there were. In this study, DM/BU was safe and well tolerated, and no serious adverse events were observed. The most commonly reported side effects were headache, dry mouth, and insomnia/vivid dreams, with similar incidence in both treatment groups.

(result)
Treatment with DM/BU reduced the average number of cigarettes smoked per day over a 3-week period by 25% compared to bupropion, a prespecified primary endpoint. 8.49 bottles, bupropion 6.79 bottles, p=0.0016).

Consistent with this finding, smokers receiving DM/BU had higher exhaled carbon monoxide levels of 50% compared to smokers treated with bupropion, a biochemical indicator of smoking intensity. % (52.0% for DM/BU and 30.4% for bupropion, p=0.15).

In addition, human subjects who took DM/BU as prescribed on a given day smoked fewer cigarettes on the day of DM/BU dosing compared to subjects who foregone one or both doses of DM/BU. smoked 1.0 fewer cigarettes (p=0.026), and smoked 1.2 fewer cigarettes the next day (p=0.008).

(summary)
Treatment with DM/BU achieved the prespecified primary endpoint in a Phase 2 study in smoking cessation. Treatment with DM/BU showed a statistically significant reduction in daily smoking (p=0.0016) compared to the active comparator, bupropion alone. The findings in this Phase 2 clinical trial are notable because DM/BU was compared to bupropion, which is approved as a smoking cessation treatment.

Furthermore, the improvements in DM/BU observed in this human trial to bupropion are similar in magnitude to the improvements versus placebo reported for the approved smoking cessation drug varenicline in similarly designed trials. That's worth noting. Varenicline is a prescription drug used to treat smoking addiction. This drug is the first nicotine receptor partial agonist to be approved. Specifically, varenicline is a partial agonist of the α4/β2 subtype of nicotinic acetylcholine receptors.

(Example 6)
A Phase 3, randomized, double-blind, multicenter, placebo-controlled clinical trial of combination treatment of dextromethorphan (DM) and bupropion (BU or BUP) in patients with major depressive disorder (MDD) was conducted in the United States. . A total of 327 patients with a confirmed diagnosis of moderate to severe MDD were randomly assigned in a 1:1 ratio to receive either dextromethorphan 45 mg/bupropion 105 mg (DM/BU) (n=163) or placebo (n=164). ) is administered once a day for the first three days (days 1, 2, and 3) and then twice a day (starting on day 4) for a total of 6 weeks.

Baseline inclusion criteria were men or women aged 18 to 65 years, meeting DSM-5 criteria for current MDD without psychotic features, and having a Montgomery-Osberg Depression Rating Scale (MADRS) total score of 25. Above, the CGI-S score is 4 or more. Exclusion criteria were electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or from schizophrenia, bipolar disorder, obsessive-compulsive disorder, and other common medical conditions during the current episode or in the past 6 months. Includes history of experimental central nervous system treatment for derived psychiatric symptoms.

The subject attributes and baseline characteristics of the patients are shown in Table 6 below.

Subject demographics and baseline characteristics were similar in both treatment groups. Study completion rates were over 75% in both groups.

The primary endpoint of the study was change from baseline in MADRS total score at week 6. Secondary endpoints were change in MADRS at week 1 and week 2, remission, response, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and patient general Including Impression-Improvement (PGI-I), MADRS-6, Sheehan Disability Scale (SDS), other quality of life measures, safety and tolerability. P values were calculated based on least squares mean estimates.

DM/BU met the primary endpoint and rapidly and significantly improved symptoms of depression. Specifically, DM/BU produced rapid, sustained, and statistically significant improvements in depressive symptoms as measured by the MADRS total score compared to placebo (p=0.002 for primary endpoint). DM/BU showed a highly statistically significant decrease in Montgomery-Osberg Depression Rating Scale (MADRS) total score compared to placebo at week 6 of treatment, with an average reduction from baseline of DM/BU. and 11.9 points for placebo (p=0.002).

Furthermore, statistically significant improvements were observed at week 1 or as early as 4 days after starting twice-daily dosing. As shown in Figure 15, a statistically significant improvement was observed in the first week for MADRS total score, with a decrease in MADRS total score of 7 points for DM/BU compared to 4.9 points for placebo. .3 points (key secondary endpoint, p=0.007), and statistical significance was maintained for this item at all subsequent time points (e.g., Weeks 2, 3, 4, 5, and 6). . In addition, patient general impression improvement level (PGI-I) (p = 0.008), clinical global impression severity level (CGI-S) (p = 0.0013), clinical general impression improvement level (CGI-I) (p = 0.035), Simple Depressive Symptom Scale 16-Item Version - Self-Report (QIDS-SR16) (p = 0.0016), Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) ( p=0.031) and other endpoints were also observed at week 1 and any time point thereafter (eg, weeks 2, 3, 4, 5, 6).

As shown in Figure 16, response, defined as an improvement of 50% or more in MADRS total score, was 54.0% for patients receiving DM/BU compared to 34.0% for patients receiving placebo. 0% were seen at week 6 (p<0.001).

As shown in Figure 17, the rate of remission from depression (defined as MADRS ≤10) was significantly lower at week 2 (p=0.013) and at each subsequent time point (e.g., week 3, 4, or 6). , was statistically significantly greater for DM/BU compared to placebo, being achieved by 39.5% of DM/BU patients compared to 17.3% of placebo patients at week 6 (p<0 .001).

DM/BU also significantly improved functional impairment as measured by the Sheehan Disability Scale (SDS) compared to placebo at week 2 (p=0.003) and at all subsequent time points (p=0.002 at week 6). It was also associated with a statistically significant reduction in comparison.

Clinical efficacy (defined as 50% or higher) in the following MADRS total scores (p<0.001), PGI-I (p=0.007), CGI-S (p=0.002), CGI-I (p = 0.016), QIDS-SR-16 (p = 0.001), Sheehan Disability Scale (SDS) (p = 0.002), and Q-LES-Q-SF (p = 0.011). In secondary endpoints, DM/BU demonstrated statistically significant improvements at week 6 compared to placebo, reflecting increasing treatment efficacy over time.

DM/BU was well tolerated in phase 3 clinical trials. The most commonly reported adverse events in the DM/BU treatment group were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. In the DM/BU treatment group, there was one serious adverse event that the investigator determined was not causally related to the study drug. The rate of treatment discontinuation due to adverse events was low in both treatment groups (6.2% in the DM/BU treatment group and 0.6% in the placebo group). Treatment with DM/BU was not associated with psychostimulant effects or weight gain.

Unless otherwise indicated, all numbers expressing quantities, quantities, percentages or other properties of ingredients used in the specification and claims refer in all cases to the exact value indicated and "about" should be understood as indicating both the values qualified by the term. Therefore, unless indicated to the contrary, the numerical parameters set forth herein and in the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At a minimum, each numerical parameter should be construed using at least the reported number of significant figures and ordinary rounding techniques, and not as an attempt to limit the application of the doctrine of equivalents to the claims. .

When used in the context of describing the present embodiments (particularly in the context of the appended claims), the terms "a", "an", "the" and similar referents are used unless indicated otherwise or in context. shall be construed to include both the singular and the plural unless clearly contradicted by. All methods described herein may be performed in any suitable order, unless indicated otherwise herein or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "etc.") are merely intended to better describe the present embodiments and to limit the scope of the claims. It is not limited. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more group members may be included in or deleted from a group for convenience and/or to expedite the process. In the event of such inclusion or deletion, the specification will be deemed to include the modified group and will therefore be deemed to satisfy the description requirements of all Markush groups used in the appended claims. It will be done.

Specific embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will be apparent to those skilled in the art upon reading the above description. The inventors expect those skilled in the art to make appropriate use of such variations, and the inventors expect that those skilled in the art will make appropriate use of such variations, and the inventors believe that the claimed embodiments are specifically described herein. It is intended to be implemented in other ways. Accordingly, the claims include all modifications and equivalents of the claimed subject matter as permitted by applicable law. Furthermore, unless indicated otherwise herein or clearly contradicted by context, any combination of the above elements in all possible variations is contemplated.

Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be used are within the scope of the claims. Thus, by way of example and not limitation, other embodiments may be utilized in accordance with the teachings herein. Therefore, the claims are not limited to the embodiments precisely as shown and described.

[Additional notes]
[Additional note 1]
comprising administering a combination of an antidepressant and dextromethorphan to a human in need of treatment;
The antidepressants include levomilnacipran, vilazodone, vortioxetine, atomoxetine, reboxetine, teniroxazine, viloxazine, amitriptyline oxide, dimethacrine, melitracene, nitroxazepine, noxiptyline, pipofedine, setiptyline, caroxazone, metralindole, pirlindole, eprobemide, minaprine, Bifemeran, agomelatine, esketamine, tandospirone, tianeptine, α-methyltryptamine, etryptamine, α-ethyltryptamine, inderoxazine, medifoxamine, oxafrosan, pivagabine, ademethionine, S-adenosyl-L-methionine, hypericum perforatum , oxytryptane, 5-hydroxytryptophan, rubidium chloride, tryptophan, magnesium, acetylcarnitine, saffron, amisulpride, aripiprazole, brexpiprazole, lurasidone, olanzapine, quetiapine, risperidone, buspirone, lithium, modafinil, thyroxine, triiodothyronine, Minocycline, combination of amitriptyline and chlordiazepoxide, combination of amitriptyline and perphenazine, combination of flupenthixol and melitracene, combination of olanzapine and fluoxetine, combination of tranylcypromine and trifluoperazine, 4-chlorokynurenine, AGN -241751, apimostinel, alketamine, dextromethadone, EVT-101, rislenemdaz, basimglurant, AN-788, tordesvenlafaxine, PDC-1421, MIN-117, TGBA01AD, gepirone, pimavanserin, psilocybin, briraloxazine, lumateperone, ademethionine, ganaxolone, zuranolone, 3β-methoxypregnenolone, PH-10-vomeropherine, aticaplant, BTRX-335140, combination of buprenorphine and samidrphan, BTRX-246040, hydroxynorketamine, JNJ-39393406, JNJ- 54175446, JNJ-61393215, NNI-351, NSI-189, NV-5138, onabotulinumtoxinA, pramipexole, celtrexant, circumab, SUVN-911, TS-121, tramadol, combination of cycloserine and lurasidone, 7,8-dihydroxyflavone (7,8-dhf), minocycline, nitrous oxide, pramipexole, R13, or combinations thereof,
A method for treating depression, characterized by:

[Additional note 2]
The antidepressant includes levomilnacipran.
The method according to appendix 1, characterized in that:

[Additional note 3]
The antidepressant includes vilazodone.
The method according to appendix 1, characterized in that:

[Additional note 4]
The antidepressant includes vortioxetine.
The method according to appendix 1, characterized in that:

[Additional note 5]
The antidepressant includes atomoxetine.
The method according to appendix 1, characterized in that:

[Additional note 6]
The antidepressant includes reboxetine.
The method according to appendix 1, characterized in that:

[Additional note 7]
The antidepressant includes tenyloxazine.
The method according to appendix 1, characterized in that:

[Additional note 8]
The antidepressant includes viloxazine.
The method according to appendix 1, characterized in that:

[Additional note 9]
The antidepressant includes amitriptyline oxide,
The method according to appendix 1, characterized in that:

[Additional note 10]
The antidepressant includes dimethacrine.
The method according to appendix 1, characterized in that:

[Additional note 11]
The antidepressant includes melitracene.
The method according to appendix 1, characterized in that:

[Additional note 12]
The antidepressant includes nitroxazepine.
The method according to appendix 1, characterized in that:

[Additional note 13]
The antidepressant includes noxyputyline.
The method according to appendix 1, characterized in that:

[Additional note 14]
The antidepressant includes pipofezine.
The method according to appendix 1, characterized in that:

[Additional note 15]
The antidepressant includes setiptiline.
The method according to appendix 1, characterized in that:

[Additional note 16]
The antidepressant includes caroxazone.
The method according to appendix 1, characterized in that:

[Additional note 17]
The antidepressant includes metralindole.
The method according to appendix 1, characterized in that:

[Additional note 18]
The antidepressant includes pirlindole,
The method according to appendix 1, characterized in that:

[Additional note 19]
The antidepressant includes eprobemide.
The method according to appendix 1, characterized in that:

[Additional note 20]
The antidepressant includes minaprine.
The method according to appendix 1, characterized in that:

[Additional note 21]
The antidepressant includes biphemeran.
The method according to appendix 1, characterized in that:

[Additional note 22]
The antidepressant includes agomelatine.
The method according to appendix 1, characterized in that:

[Additional note 23]
The antidepressant includes esketamine.
The method according to appendix 1, characterized in that:

[Additional note 24]
The antidepressant includes tandospirone.
The method according to appendix 1, characterized in that:

[Additional note 25]
The antidepressant includes tianeptine.
The method according to appendix 1, characterized in that:

[Additional note 26]
The antidepressant includes α-methyltryptamine.
The method according to appendix 1, characterized in that:

[Additional note 27]
The antidepressant includes etryptamine.
The method according to appendix 1, characterized in that:

[Additional note 28]
The antidepressant includes inderoxazine.
The method according to appendix 1, characterized in that:

[Additional note 29]
The antidepressant includes medifoxamine.
The method according to appendix 1, characterized in that:

[Additional note 30]
The antidepressant includes oxafrosan.
The method according to appendix 1, characterized in that:

[Additional note 31]
The antidepressant includes pivagabine.
The method according to appendix 1, characterized in that:

[Additional note 32]
The antidepressant includes ademethionine.
The method according to appendix 1, characterized in that:

[Additional note 33]
The antidepressant includes hypericum perforatum.
The method according to appendix 1, characterized in that:

[Additional note 34]
The antidepressant includes oxytriptan.
The method according to appendix 1, characterized in that:

[Additional note 35]
The antidepressant contains 5-hydroxytryptophan.
The method according to appendix 1, characterized in that:

[Appendix 36]
The antidepressant includes rubidium chloride.
The method according to appendix 1, characterized in that:

[Additional note 37]
The antidepressant contains tryptophan.
The method according to appendix 1, characterized in that:

[Appendix 38]
The antidepressant contains magnesium,
The method according to appendix 1, characterized in that:

[Appendix 39]
The antidepressant includes acetylcarnitine.
The method according to appendix 1, characterized in that:

[Additional note 40]
The antidepressant includes saffron.
The method according to appendix 1, characterized in that:

[Additional note 41]
The antidepressant includes amisulpride.
The method according to appendix 1, characterized in that:

[Additional note 42]
The antidepressant includes aripiprazole,
The method according to appendix 1, characterized in that:

[Additional note 43]
The antidepressant includes brexpiprazole.
The method according to appendix 1, characterized in that:

[Additional note 44]
The antidepressant includes lurasidone.
The method according to appendix 1, characterized in that:

[Additional note 45]
The antidepressant includes olanzapine.
The method according to appendix 1, characterized in that:

[Additional note 46]
The antidepressant includes quetiapine.
The method according to appendix 1, characterized in that:

[Additional note 47]
The antidepressant includes risperidone.
The method according to appendix 1, characterized in that:

[Additional note 48]
The antidepressant includes buspirone.
The method according to appendix 1, characterized in that:

[Additional note 49]
The antidepressant includes lithium,
The method according to appendix 1, characterized in that:

[Additional note 50]
The antidepressant includes modafinil,
The method according to appendix 1, characterized in that:

[Additional note 51]
The antidepressant includes thyroxine,
The method according to appendix 1, characterized in that:

[Additional note 52]
The antidepressant includes triiodothyronine,
The method according to appendix 1, characterized in that:

[Additional note 53]
The antidepressant includes minocycline.
The method according to appendix 1, characterized in that:

[Additional note 54]
The antidepressant includes a combination of amitriptyline and chlordiazepoxide.
The method according to appendix 1, characterized in that:

[Additional note 55]
The antidepressant includes a combination of amitriptyline and perphenazine.
The method according to appendix 1, characterized in that:

[Additional note 56]
The antidepressant includes a combination of flupenthixol and melitracene.
The method according to appendix 1, characterized in that:

[Additional note 57]
The antidepressant includes a combination of olanzapine and fluoxetine.
The method according to appendix 1, characterized in that:

[Additional note 58]
The antidepressant includes a combination of tranylcypromine and trifluoperazine.
The method according to appendix 1, characterized in that:

[Additional note 59]
The antidepressant includes 4-chlorokynurenine,
The method according to appendix 1, characterized in that:

[Additional note 60]
The antidepressant includes AGN-241751,
The method according to appendix 1, characterized in that:

[Additional note 61]
The antidepressant includes apimostinel.
The method according to appendix 1, characterized in that:

[Additional note 62]
The antidepressant includes alketamine.
The method according to appendix 1, characterized in that:

[Additional note 63]
The antidepressant includes dextromethadone.
The method according to appendix 1, characterized in that:

[Additional note 64]
The antidepressant includes EVT-101.
The method according to appendix 1, characterized in that:

[Additional note 65]
The antidepressant includes rislenemdaz.
The method according to appendix 1, characterized in that:

[Additional note 66]
The antidepressant includes basimglurant.
The method according to appendix 1, characterized in that:

[Additional note 67]
The antidepressant includes AN-788.
The method according to appendix 1, characterized in that:

[Additional note 68]
The antidepressant includes toldesvenlafaxine.
The method according to appendix 1, characterized in that:

[Additional note 69]
The antidepressant includes PDC-1421,
The method according to appendix 1, characterized in that:

[Additional note 70]
The antidepressant includes MIN-117.
The method according to appendix 1, characterized in that:

[Additional note 71]
The antidepressant includes TGBA01AD,
The method according to appendix 1, characterized in that:

[Additional note 72]
The antidepressant includes gepirone.
The method according to appendix 1, characterized in that:

[Additional note 73]
The antidepressant includes pimavanserin.
The method according to appendix 1, characterized in that:

[Additional note 74]
The antidepressant includes psilocybin.
The method according to appendix 1, characterized in that:

[Additional note 75]
The antidepressant includes briraloxazine.
The method according to appendix 1, characterized in that:

[Additional note 76]
The antidepressant includes lumateperone.
The method according to appendix 1, characterized in that:

[Additional note 77]
The antidepressant includes ademethionine.
The method according to appendix 1, characterized in that:

[Additional note 78]
The antidepressant includes ganaxolone.
The method according to appendix 1, characterized in that:

[Additional note 79]
The antidepressant includes zuranolone.
The method according to appendix 1, characterized in that:

[Additional note 80]
The antidepressant includes 3β-methoxypregnenolone.
The method according to appendix 1, characterized in that:

[Additional note 81]
The antidepressant includes PH-10-vomeroferrine.
The method according to appendix 1, characterized in that:

[Additional note 82]
The antidepressant includes atica plant.
The method according to appendix 1, characterized in that:

[Additional note 83]
The antidepressant includes BTRX-335140.
The method according to appendix 1, characterized in that:

[Additional note 84]
the antidepressant comprises a combination of buprenorphine and samidrphan;
The method according to appendix 1, characterized in that:

[Additional note 85]
The antidepressant includes hydroxynorketamine.
The method according to appendix 1, characterized in that:

[Additional note 86]
The antidepressant includes JNJ-39393406,
The method according to appendix 1, characterized in that:

[Additional note 87]
The antidepressant includes JNJ-54175446,
The method according to appendix 1, characterized in that:

[Additional note 88]
The antidepressant includes JNJ-61393215,
The method according to appendix 1, characterized in that:

[Additional note 89]
The antidepressant includes NNI-351.
The method according to appendix 1, characterized in that:

[Additional note 90]
The antidepressant includes NSI-189.
The method according to appendix 1, characterized in that:

[Additional note 91]
The antidepressant includes NV-5138.
The method according to appendix 1, characterized in that:

[Additional note 92]
The antidepressant includes onabotulinumtoxinA,
The method according to appendix 1, characterized in that:

[Additional note 93]
The antidepressant includes pramipexole.
The method according to appendix 1, characterized in that:

[Additional note 94]
The antidepressant includes celtrexant.
The method according to appendix 1, characterized in that:

[Appendix 95]
The antidepressant includes circumab,
The method according to appendix 1, characterized in that:

[Additional note 96]
The antidepressant includes SUVN-911.
The method according to appendix 1, characterized in that:

[Additional note 97]
The antidepressant includes TS-121.
The method according to appendix 1, characterized in that:

[Additional note 98]
The antidepressant includes tramadol.
The method according to appendix 1, characterized in that:

[Additional note 99]
The antidepressant includes a combination of cycloserine and lurasidone.
The method according to appendix 1, characterized in that:

[Additional note 100]
The antidepressant contains 7,8-dihydroxyflavone,
The method according to appendix 1, characterized in that:

[Additional note 101]
The antidepressant includes minocycline.
The method according to appendix 1, characterized in that:

[Additional note 102]
The antidepressant includes nitrous oxide.
The method according to appendix 1, characterized in that:

[Additional note 103]
The antidepressant includes pramipexole.
The method according to appendix 1, characterized in that:

[Additional note 104]
The antidepressant comprises R13.
The method according to appendix 1, characterized in that:

Claims (104)

comprising administering a combination of an antidepressant and dextromethorphan to a human in need of treatment;
The antidepressants include levomilnacipran, vilazodone, vortioxetine, atomoxetine, reboxetine, teniroxazine, viloxazine, amitriptyline oxide, dimethacrine, melitracene, nitroxazepine, noxiptyline, pipofedine, setiptyline, caroxazone, metralindole, pirlindole, eprobemide, minaprine, Bifemeran, agomelatine, esketamine, tandospirone, tianeptine, α-methyltryptamine, etryptamine, α-ethyltryptamine, inderoxazine, medifoxamine, oxafrosan, pivagabine, ademethionine, S-adenosyl-L-methionine, hypericum perforatum , oxytryptane, 5-hydroxytryptophan, rubidium chloride, tryptophan, magnesium, acetylcarnitine, saffron, amisulpride, aripiprazole, brexpiprazole, lurasidone, olanzapine, quetiapine, risperidone, buspirone, lithium, modafinil, thyroxine, triiodothyronine, Minocycline, combination of amitriptyline and chlordiazepoxide, combination of amitriptyline and perphenazine, combination of flupenthixol and melitracene, combination of olanzapine and fluoxetine, combination of tranylcypromine and trifluoperazine, 4-chlorokynurenine, AGN -241751, Apimostinel, Arketamine, Dextromethadone, EVT-101, Rislenemdaz, Basim Gullant, AN-788, Tordesvenlafaxine, PDC-1421, MIN-117, TGBA01AD, Gepirone, Pimavanserin, Psilocybin, Briraloxazine, lumateperone, ademethionine, ganaxolone, zuranolone, 3β-methoxypregnenolone, PH-10-vomeropherine, aticaplant, BTRX-335140, combination of buprenorphine and samidrphan, BTRX-246040, hydroxynorketamine, JNJ-39393406, JNJ- 54175446, JNJ-61393215, NNI-351, NSI-189, NV-5138, onabotulinumtoxinA, pramipexole, celtrexant, circumab, SUVN-911, TS-121, tramadol, combination of cycloserine and lurasidone, 7,8-dihydroxyflavone (7,8-dhf), minocycline, nitrous oxide, pramipexole, R13, or combinations thereof,
A method for treating depression, characterized by: The antidepressant includes levomilnacipran.
The method according to claim 1, characterized in that: The antidepressant includes vilazodone.
The method according to claim 1, characterized in that: The antidepressant includes vortioxetine.
The method according to claim 1, characterized in that: The antidepressant includes atomoxetine.
The method according to claim 1, characterized in that: The antidepressant includes reboxetine.
The method according to claim 1, characterized in that: The antidepressant includes tenyloxazine.
The method according to claim 1, characterized in that: The antidepressant includes viloxazine.
The method according to claim 1, characterized in that: The antidepressant includes amitriptyline oxide,
The method according to claim 1, characterized in that: The antidepressant includes dimethacrine.
The method according to claim 1, characterized in that: The antidepressant includes melitracene.
The method according to claim 1, characterized in that: The antidepressant includes nitroxazepine.
The method according to claim 1, characterized in that: The antidepressant includes noxyputyline.
The method according to claim 1, characterized in that: The antidepressant includes pipofezine.
The method according to claim 1, characterized in that: The antidepressant includes setiptiline.
The method according to claim 1, characterized in that: The antidepressant includes caroxazone.
The method according to claim 1, characterized in that: The antidepressant includes metralindole.
The method according to claim 1, characterized in that: The antidepressant includes pirlindole,
The method according to claim 1, characterized in that: The antidepressant includes eprobemide.
The method according to claim 1, characterized in that: The antidepressant includes minaprine.
The method according to claim 1, characterized in that: The antidepressant includes biphemeran.
The method according to claim 1, characterized in that: The antidepressant includes agomelatine.
The method according to claim 1, characterized in that: The antidepressant includes esketamine.
The method according to claim 1, characterized in that: The antidepressant includes tandospirone.
The method according to claim 1, characterized in that: The antidepressant includes tianeptine.
The method according to claim 1, characterized in that: The antidepressant includes α-methyltryptamine.
The method according to claim 1, characterized in that: The antidepressant includes etryptamine.
The method according to claim 1, characterized in that: The antidepressant includes inderoxazine.
The method according to claim 1, characterized in that: The antidepressant includes medifoxamine.
The method according to claim 1, characterized in that: The antidepressant includes oxafrosan.
The method according to claim 1, characterized in that: The antidepressant includes pivagabine.
The method according to claim 1, characterized in that: The antidepressant includes ademethionine.
The method according to claim 1, characterized in that: The antidepressant includes hypericum perforatum.
The method according to claim 1, characterized in that: The antidepressant includes oxytriptan.
The method according to claim 1, characterized in that: The antidepressant contains 5-hydroxytryptophan.
The method according to claim 1, characterized in that: The antidepressant includes rubidium chloride.
The method according to claim 1, characterized in that: The antidepressant contains tryptophan.
The method according to claim 1, characterized in that: The antidepressant contains magnesium,
The method according to claim 1, characterized in that: The antidepressant includes acetylcarnitine.
The method according to claim 1, characterized in that: The antidepressant includes saffron.
The method according to claim 1, characterized in that: The antidepressant includes amisulpride,
The method according to claim 1, characterized in that: The antidepressant includes aripiprazole.
The method according to claim 1, characterized in that: The antidepressant includes brexpiprazole.
The method according to claim 1, characterized in that: The antidepressant includes lurasidone.
The method according to claim 1, characterized in that: The antidepressant includes olanzapine.
The method according to claim 1, characterized in that: The antidepressant includes quetiapine.
The method according to claim 1, characterized in that: The antidepressant includes risperidone.
The method according to claim 1, characterized in that: The antidepressant includes buspirone.
The method according to claim 1, characterized in that: The antidepressant includes lithium,
The method according to claim 1, characterized in that: The antidepressant includes modafinil,
The method according to claim 1, characterized in that: The antidepressant includes thyroxine,
The method according to claim 1, characterized in that: The antidepressant includes triiodothyronine,
The method according to claim 1, characterized in that: The antidepressant includes minocycline.
The method according to claim 1, characterized in that: The antidepressant includes a combination of amitriptyline and chlordiazepoxide.
The method according to claim 1, characterized in that: The antidepressant includes a combination of amitriptyline and perphenazine.
The method according to claim 1, characterized in that: The antidepressant includes a combination of flupenthixol and melitracene.
The method according to claim 1, characterized in that: The antidepressant includes a combination of olanzapine and fluoxetine.
The method according to claim 1, characterized in that: The antidepressant includes a combination of tranylcypromine and trifluoperazine.
The method according to claim 1, characterized in that: The antidepressant includes 4-chlorokynurenine,
The method according to claim 1, characterized in that: The antidepressant includes AGN-241751,
The method according to claim 1, characterized in that: The antidepressant includes apimostinel.
The method according to claim 1, characterized in that: The antidepressant includes alketamine.
The method according to claim 1, characterized in that: The antidepressant includes dextromethadone.
The method according to claim 1, characterized in that: The antidepressant includes EVT-101.
The method according to claim 1, characterized in that: The antidepressant includes rislenemdaz.
The method according to claim 1, characterized in that: The antidepressant includes basimglurant.
The method according to claim 1, characterized in that: The antidepressant includes AN-788.
The method according to claim 1, characterized in that: The antidepressant includes toldesvenlafaxine.
The method according to claim 1, characterized in that: The antidepressant includes PDC-1421,
The method according to claim 1, characterized in that: The antidepressant includes MIN-117.
The method according to claim 1, characterized in that: The antidepressant includes TGBA01AD,
The method according to claim 1, characterized in that: The antidepressant includes gepirone.
The method according to claim 1, characterized in that: The antidepressant includes pimavanserin.
The method according to claim 1, characterized in that: The antidepressant includes psilocybin.
The method according to claim 1, characterized in that: The antidepressant includes briraloxazine.
The method according to claim 1, characterized in that: The antidepressant includes lumateperone.
The method according to claim 1, characterized in that: The antidepressant includes ademethionine.
The method according to claim 1, characterized in that: The antidepressant includes ganaxolone.
The method according to claim 1, characterized in that: The antidepressant includes zuranolone.
The method according to claim 1, characterized in that: The antidepressant includes 3β-methoxypregnenolone.
The method according to claim 1, characterized in that: The antidepressant includes PH-10-vomeroferrine.
The method according to claim 1, characterized in that: The antidepressant includes atica plant.
The method according to claim 1, characterized in that: The antidepressant includes BTRX-335140.
The method according to claim 1, characterized in that: the antidepressant comprises a combination of buprenorphine and samidrphan;
The method according to claim 1, characterized in that: The antidepressant includes hydroxynorketamine.
The method according to claim 1, characterized in that: The antidepressant includes JNJ-39393406,
The method according to claim 1, characterized in that: The antidepressant includes JNJ-54175446,
The method according to claim 1, characterized in that: The antidepressant includes JNJ-61393215,
The method according to claim 1, characterized in that: The antidepressant includes NNI-351.
The method according to claim 1, characterized in that: The antidepressant includes NSI-189.
The method according to claim 1, characterized in that: The antidepressant includes NV-5138.
The method according to claim 1, characterized in that: The antidepressant includes onabotulinumtoxinA,
The method according to claim 1, characterized in that: The antidepressant includes pramipexole.
The method according to claim 1, characterized in that: The antidepressant includes celtrexant.
The method according to claim 1, characterized in that: The antidepressant includes circumab,
The method according to claim 1, characterized in that: The antidepressant includes SUVN-911.
The method according to claim 1, characterized in that: The antidepressant includes TS-121.
The method according to claim 1, characterized in that: The antidepressant includes tramadol.
The method according to claim 1, characterized in that: The antidepressant includes a combination of cycloserine and lurasidone.
The method according to claim 1, characterized in that: The antidepressant contains 7,8-dihydroxyflavone,
The method according to claim 1, characterized in that: The antidepressant includes minocycline.
The method according to claim 1, characterized in that: The antidepressant includes nitrous oxide.
The method according to claim 1, characterized in that: The antidepressant includes pramipexole.
The method according to claim 1, characterized in that: The antidepressant comprises R13.
The method according to claim 1, characterized in that: