KR20230131927A - Combination of antidepressants and dextromethorphan for neuropsychiatric disorders - Google Patents

Abstract

Dosage forms, drug delivery systems, and methods related to sustained release or improved therapeutic effect of dextromethorphan are disclosed. Typically, antidepressants are administered orally to humans treated or undergoing treatment with dextromethorphan.

Description

Combination of antidepressants and dextromethorphan for neuropsychiatric disorders

Cross-reference to related applications

This application claims priority to U.S. Provisional Application No. 63/138,757, filed January 18, 2021, the entire contents of which are incorporated herein by reference.

summary

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

Some embodiments include methods of treating a neurological or psychiatric disorder comprising administering a combination of an antidepressant compound and dextromethorphan to a human in need thereof, wherein the human is a widespread metabolizer of dextromethorphan. (metabolizer).

Figure 1 is a plot of mean plasma concentrations of dextromethorphan over time after 8 days of dosing for subjects administered dextromethorphan alone or dextromethorphan plus bupropion.
Figure 2 depicts the mean AUC _0-12 of dextromethorphan at day 8 for subjects receiving dextromethorphan alone or dextromethorphan plus bupropion.
Figure 3 depicts the mean AUC of dextromethorphan _0-24 at day 8 for subjects receiving dextromethorphan alone or dextromethorphan plus bupropion.
Figure 4 depicts the mean AUC _0-inf of dextromethorphan at day 8 for subjects receiving dextromethorphan alone or dextromethorphan plus bupropion.
Figure 5 depicts the fold change in dextromethorphan AUC at day 8 for subjects receiving dextromethorphan alone compared to dextromethorphan and bupropion.
Figure 6 depicts the mean AUC _0-12 for dextromethorphan on days 1 and 8 for subjects receiving dextromethorphan alone or dextromethorphan plus bupropion.
Figure 7 depicts mean dextromethorphan trough plasma concentrations for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
Figure 8 depicts mean peak dextromethorphan plasma concentrations on days 1 and 8 for subjects receiving dextromethorphan alone or dextromethorphan plus bupropion.
Figure 9 is a plot of mean plasma concentrations of dextrorphan over time after 8 days of dosing for subjects administered dextromethorphan alone or dextromethorphan plus bupropion.
Figure 10 depicts mean dextrorphan peak plasma concentrations on days 1 and 8 for subjects administered dextromethorphan alone or dextromethorphan plus bupropion.
Figure 11 depicts the mean AUC _0-12 for dextrorphan on days 1 and 8 for subjects receiving dextromethorphan alone or dextromethorphan plus bupropion.
Figure 12 depicts the efficacy of various antidepressant compounds to inhibit the metabolism of dextromethorphan in human liver microsomes.
Figure 13 is a plot of mean MADRS total score change from baseline over time over a 6-week dosing period for subjects receiving bupropion alone or a combination of dextromethorphan and bupropion.
Figure 14 depicts the percentage of subjects achieving remission (MADRS ≤ 10) over time over a 6-week dosing period for subjects receiving bupropion alone or a combination of dextromethorphan and bupropion.
Figure 15 is a plot of MADRS total score decline over time for the subjects described in Example 6.
Figure 16 is a plot of percent responder over time for the subjects described in Example 6.
Figure 17 is a plot of the percent of subjects in remission over time for the subjects described in Example 6.

Some embodiments include methods of treating a neurological and/or psychiatric disorder 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 disorders comprising administering dextromethorphan in combination with an antidepressant.

Some embodiments include methods of increasing dextromethorphan plasma concentrations in a human, who is an extensive metabolizer of dextromethorphan, comprising coadministering the human with an antidepressant compound and dextromethorphan.

Some embodiments include methods of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound to a human, wherein the human is a widespread metabolizer of dextromethorphan, and wherein the dextromethorphan is It exists simultaneously in the human body as an antidepressant.

Some embodiments include methods of increasing the metabolic life of dextromethorphan, comprising increasing the elimination half-life (T _1/2 ) of dextromethorphan. These embodiments may include administering an antidepressant compound to a human, wherein humans are extensive metabolizers of dextromethorphan, and dextromethorphan is simultaneously present in the human body as an antidepressant compound.

Some embodiments include methods of correcting extensive metabolism of dextromethorphan comprising administering an antidepressant compound to a human in need thereof, such as a human in need of pain treatment.

Some embodiments provide dextromethorphan in the treatment of a neurological and/or mental disorder, comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human in need thereof. Methods for improving the therapeutic properties of tromethorphan are included.

Some embodiments include 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.

Co-administration of an antidepressant compound and dextromethorphan may be administered daily, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. , 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100 or more consecutive days. there is. In some embodiments, combined administration is performed at least daily for at least 2 consecutive days.

In some embodiments, co-administration of the antidepressant compound and dextromethorphan is once daily for 1, 2, 3, 4, 5, 6, or 7 days prior to co-administration twice daily. can do.

Dextromethorphan has the structure shown below.

Dextromethorphan is used as a cough suppressant. According to FDA's labeling requirements for dextromethorphan products under the OTC monograph [21CFR341.74], dextromethorphan is administered 6 times daily (every 4 hours), 4 times daily (every 6 hours), or 3 times daily. It should be administered twice (every 8 hours). The OTC monograph [21CFR341.74] also states that “the dosage is equivalent to dextromethorphan hydrobromide…[oral] dosage is 10 to 20 mg every 4 hours or 30 mg every 6 to 8 hours for 24 hours. “It should not exceed 120 mg, or follow the doctor’s instructions.”

Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are extensive metabolizers. Humans may be: 1) extensive metabolizers of dextromethorphan - people who rapidly metabolize dextromethorphan; 2) People with poor dextromethorphan metabolism - People with poor dextromethorphan metabolism; or 3) intermediate metabolizers of dextromethorphan - people whose metabolism of dextromethorphan is somewhere between extensive metabolizers and poor metabolizers. Extensive metabolizers may also be ultrarapid metabolizers. Extensive metabolizers of dextromethorphan make up a significant portion of the human population. For example, dextromethorphan can be metabolized to dextrorphan.

When administered the same oral dose of dextromethorphan, plasma concentrations of dextromethorphan are significantly higher in poor or intermediate metabolizers compared to extensive metabolizers of dextromethorphan. The low plasma concentrations of dextromethorphan may limit its clinical utility as a single agent for extensive and possibly intermediate metabolizers of dextromethorphan. Some therapeutically active compounds, including antidepressants, may inhibit the metabolism of dextromethorphan and increase the plasma concentration of dextromethorphan, thereby improving its therapeutic efficacy. Similarly, antidepressants include dextromethorphan once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, and twice a day instead of three times a day. , or may allow for less frequent dosing, such as twice a day instead of four times a day, or in lower doses without loss of therapeutic efficacy.

Coadministration of antidepressants with dextromethorphan or dextrorphan may improve the mechanism of action or pharmacological properties of dextromethorphan and dextrorphan. The mechanism 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 include administering an antidepressant in combination with dextromethorphan or dextrorphan to agonize, antagonize, or modulate the sigma-1 receptor, or NMDA receptor; Blocks calcium channels; Binds to muscarinic receptors; Inhibits the serotonin transporter (5HTT); or enhancing mu receptors.

Pharmacological properties of dextromethorphan and dextrorphan include NMDA high affinity site activity, NMDR-2A activity, and functional NMDR-2A receptor antagonism, sigma-1 stimulation, and putative mTOR activation (sigma-1 stimulation, mu potentiation, beta-adrenergic receptor stimulation, and 5HTT inhibition), putative AMPA receptor trafficking (by mTOR activation, PCT antagonism, sigma-1 stimulation, beta stimulation, mu potentiation, and 5HTT inhibition), and dendrite formation. , spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and sigma-1 and mTOR signaling. Some embodiments include administering an antidepressant in combination with dextromethorphan or dextrorphan to stimulate the NMDA high affinity site, NMDR-2A, functional NMDR-2B receptor, sigma-1 receptor, putative mTOR receptor (e.g., sigma-1 stimulation). , potentiating mu receptors, stimulating beta adrenergic receptors, or inhibiting 5HTT), or putatively on AMPA receptors (e.g. activating mTOR, antagonizing PCP activity, stimulating sigma-1 receptors, stimulating beta adrenergic receptors, potentiating mu receptors, or by inhibiting 5HTT). Some embodiments include administering an antidepressant in combination with dextromethorphan or dextrorphan to induce, increase, decrease, or otherwise modulate dendrite formation, spinogenesis, or synaptogenesis. Some embodiments include administering an antidepressant in combination with dextromethorphan or dextrorphan to induce, increase, decrease, or otherwise modulate neuronal survival by NMDA antagonism and/or sigma-1 and/or mTOR signaling. Includes.

Pharmacological properties of dextromethorphan and dextrorphan may include 5HTT and norepinephrine transporter inhibition, sigma-1 stimulation, NMDA and PCP antagonism, and possibly serotonin 5HT1b/d receptor stimulation. Some embodiments bind, agonize, antagonize, stimulate, activate, inhibit, affect trafficking of 5HTT and/or norepinephrine transporter, sigma-1 receptor, NMDA and/or PCP receptor and/or serotonin 5HT1b. Involves stimulating /d receptors.

Additional properties for dextromethorphan and dextrorphan may include possible presynaptic alpha-2 adrenergic receptor antagonism or postsynaptic alpha-2 stimulation, beta stimulation, and possible muscarinic and mu antagonism. Some embodiments bind to, act on, antagonize, stimulate, activate, inhibit, traffic to or affect presynaptic alpha-2 adrenergic receptors, postsynaptic alpha-2 receptors, beta adrenergic receptors, muscarinic receptors, or mu receptors. Control involves administering antidepressants in combination with dextromethorphan or dextrorphan. Dextromethorphan and dextrorphan may be glial cell modulators. Some embodiments include administering an antidepressant in combination with dextromethorphan or dextrorphan to modulate glial cells.

Pain or other neurological and/or psychiatric disorders can be treated with dextromethorphan, for example, by a method comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound to a person in need thereof. It can be treated by improving plasma concentrations or increasing dextromethorphan bioavailability.

Examples of neurological disorders that can be treated with improved efficacy by improved dextromethorphan concentrations, such as can be achieved with a combination of dextromethorphan and an antidepressant, include, but are not limited to: Emotional disorders disability, mental disorders, cerebral dysfunction, movement disorders, dementia, motor neurone disease, neurodegenerative diseases, seizure disorders, and headaches.

Affective disorders that can be treated by enhanced dextromethorphan concentrations or a combination of dextromethorphan and antidepressants include depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorder including cyclothymia, and seasonal affective disorder. Disorders, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), hyperactivity Attention deficit disorder (ADDH), and attention-deficit/hyperactivity disorder (AD/HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, and substance addiction or abuse. , nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Depression can manifest itself as depressive symptoms. These symptoms may include mood swings, extreme sadness, despair, mental slowness, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and/or self-deprecation. Changes may be included. Physical symptoms of depression include insomnia, loss of appetite, decreased appetite, weight loss, weight gain, decreased energy and libido, fatigue, anxiety, aches, pain, headaches, cramps, digestive problems, and/or abnormal hormonal circadian rhythms. This may be included.

Some patients may have an inadequate or no response to treatment, even after treatment with medications such as antidepressants. Treatment-resistant depression (TRD), or treatment-refractory depression, is a condition usually associated with patients who have failed treatment with at least two antidepressant medications. Part of the diagnosis for TRD is that the patient has had an inadequate response to antidepressant treatment, for example at an appropriate dose and after an appropriate course, in a current depressive episode. TRD may be more difficult to treat due to misdiagnosis of TRD or comorbidity with other medical or mental illnesses, such as drug/alcohol abuse or eating disorders. Some patients with TRD have had an inadequate response to 1, 2, 3, or more trials of appropriate antidepressant treatment, or have failed or had an inadequate response to 1, 2, 3, or more prior antidepressant treatments. In some embodiments, the patient receiving treatment for treatment-resistant depression has failed treatment with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antidepressant regimens.

Measures of treatment effectiveness that may be improved by treatment with a combination of dextromethorphan and an antidepressant include, but are not limited to: Montgomery-Asberg Depression Rating Scale (MADRS), enjoyment of quality of life, and Satisfaction Questionnaire Short Form, Functional Impairment Scope Instrument, Sheehan Disability Scale, Patient Rated Inventory of Side Effects (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS) , Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR), Clinical Global Impression (CGI) scale, Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ: Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, 17-item Hamilton Rating Scale for Depression (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ), 16-item measure of depressive symptoms. QIDS-SR16: Quick Inventory of Depressive Symptomatology - Self Report, Sheehan Disability Scale (SDS). Clinical Global Impression of Illness (CGI-S), Clinical Global Impression of Change (CGI-C), EuroQOL 5 Dimension 5 Scale (EQ-5D-5L) , Patient Global Impression of Change (PGIC), 7-item Generalized Anxiety Disorder (GAD-7), Clinical Global Impression - Improvement (CGI-I), Sheehan Disability Scale (SDS), and depressive symptoms. 16-Item Quick List - Self-Report (QIDS-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ-Cognitive Subscale (Items 4 to 7), Brief Psychiatric Inventory. Brief Psychiatric Rating Scale (BPRS), etc.; Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Task (RAVLT), Trail Making Test (TMT), Stroop Color Naming Test (STROOP) , Simple Reaction Time (SRT), Choice Reaction Time (CRT), etc. In some embodiments, treating a person with a combination of dextromethorphan and an antidepressant increases the individual's score on one of the above assessments by at least about 10%, at least about 20%, at least about 30%, At least about 40%, at least about 50%, about 10 to 20%, about 20 to 30%, about 30 to 40%, about 40 to 50%, about 5 to 15%, about 15 to 25%, about 25 to 35% %, about 35 to 45%, about 45 to 55%, about 50 to 60%, about 60 to 70%, about 70 to 80%, about 80 to 90%, about 90 to 100% improvement (e.g. reduction) You can do it. In some embodiments, the improvement is compared to baseline. In some embodiments, the improvement is compared to placebo.

Combination administration of an antidepressant and dextromethorphan may result in a rapid therapeutic effect, for example, within about 1 week, within about 2 weeks, within about 3 weeks, or within about 4 weeks after starting treatment.

In some embodiments, the enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan and an antidepressant, is 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 6 to 8 hours. It may have an onset of action within an hour, 8 to 12 hours, 12 hours, a day, 1 to 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks.

Patients who may benefit from the treatments described herein include those under about 18 years of age, about 0 to 5 years of age, about 5 to 10 years of age, about 10 to 12 years of age, or about 12 to 18 years of age. 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 adult patients, such as patients aged 50 to 60, approximately 60 to 70, approximately 70 to 80, approximately 80 to 90, approximately 30 to 50, or approximately 50 to 65; geriatric patients, such as patients over 65 years of age, about 65 to 75 years of age, about 75 to 90 years of age, or patients over 90 years of age; and patients approximately 41 years of age or older.

In some embodiments, a human being treated with a combination of dextromethorphan and an antidepressant may undergo treatment prior to treatment (e.g., on the day of starting treatment but before starting treatment, or prior to treatment, 0 to 1), e.g., for the type of depression. Within a week, within 0 to 2 weeks, within 0 to 3 weeks, within 0 to 4 weeks, within 0 to 2 months, within 0 to 3 months, within 0 to 4 months, within 0 to 5 months, within 0 to 6 months, or longer ), Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Edit (DSM-IV-TR), Constructed Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Clinical Trial Version SCID-5-CT Patients are selected for whether they have or have been diagnosed with major depressive disorder. In some embodiments, the human currently meets SCID-5-CT criteria, DSM-5 criteria for MDD without psychotic features.

In some embodiments, a human treated with a combination of dextromethorphan and an antidepressant can expect a treatment regimen of about 8 weeks to about 24 months, about 1 to 6 months, about 6 to 12 months, about a type of depression, e.g. 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 to 18 months, The patient is selected for having or is suffering from a major depressive episode that has lasted for 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.

In some embodiments, the human being treated with the combination of dextromethorphan and an antidepressant has at least 1, at least about 2, at least about 3, at least about 4, e.g., at least about 4 types of depression, e.g. at least about 5, at least about 10, at least about 15, 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, at least about 100, about 1 to 5, about 5 to 10, about 10 to 20, about 20 to 30, about 30 to 40, about 40 to 50, about 50 to 60 About 1 to 100 or more lifetime episodes, such as a major depressive episode, including about 60 to 70, about 70 to 80, about 80 to 90, about 90 to 100, or about 4 to 7 lifetime depressive episodes. Have a depressive episode, or be selected for having one.

In some embodiments, the human being treated with the combination of dextromethorphan and an antidepressant may have one or more prior antidepressant therapies, e.g., for the type of depression, including prior antidepressant therapy in a current depressive episode (e.g., current major depressive episode). The patient is selected for having or has had an inadequate response to antidepressant therapy, e.g., 1, 2, 3, 4, 5 or more prior antidepressant treatments.

In some embodiments, the human being treated with a combination of dextromethorphan and an antidepressant is treated, e.g., for the type of depression, at a dose appropriate for at least 8 weeks and stable for at least 4 weeks before entering a double-blind treatment period. The dose taken is selected for whether or not one has received background antidepressant therapy. In some embodiments, the antidepressant therapy is continued with treatment with a combination of an antidepressant and dextromethorphan.

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

In some embodiments, a human being treated with a combination of dextromethorphan and an antidepressant may be treated prior to treatment (e.g., on the day of starting treatment but prior to treatment, or within 0 to 1 week prior to treatment, e.g., for the type of depression). , within 0 to 2 weeks, within 0 to 3 weeks, within 0 to 4 weeks, within 0 to 2 months, within 0 to 3 months, within 0 to 4 months, within 0 to 5 months, within 0 to 6 months, or or more) about 18 to 40 kg/m2, about 18.5 kg/m2, less than 18.5 kg/m2, about 19 kg/m2, about 19 to 25 kg/m2, about 25 kg/m2, about 25 to 29 kg/m2 , about 29 kg/m2, 29 kg/m2 or more, about 18 to 22 kg/m2, about 22 to 24 kg/m2, about 24 to 26 kg/m2, about 26 to 28 kg/m2, about 28 to 30 kg /㎡, about 30 to 32 kg/㎡, about 32 to 34 kg/㎡, about 34 to 36 kg/㎡, about 36 to 38 kg/㎡, about 38 to 40 kg/㎡, about 18 to 26 kg/㎡ , having or having a body mass index of about 26 to 34 kg/m2, or about 34 to 40 kg/m2.

The treatment effect is during 1 week, 1st to 2nd week, 1st to 3rd week, 1st to 4th week, 1st to 6th week, 4th to 6th week, 6th to 8th week, 8th to 12th week, 12th to 16th week, end of 1st week. to; At the beginning, middle or end of the two weeks; At the beginning, middle or end of week 3; At the beginning, middle or end of the 4th week; At the beginning, middle or end of week 5; At the beginning, middle or end of the 6th week; At the beginning, middle or end of week 7; At the beginning, middle or end of the 8th week; At the beginning, middle or end of the 9th week; At the beginning, middle or end of week 10; At the beginning, middle or end of the 11th week; At the beginning, middle or end of the 12 weeks; At the beginning, middle or end of the 13th week; At the beginning, middle or end of 14 weeks; At the beginning, middle or end of 15 weeks; Assessments may be made at any appropriate time, such as at the beginning, middle or 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 combined activity for the treatment of central nervous system (CNS) disorders. Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, which has a novel mechanism of action that makes it different from currently available antidepressant medications.

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

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

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

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

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

In some cases, administering a combination of dextromethorphan and an antidepressant to humans may be administered over a period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks. Decrease the average number of cigarettes smoked per day by at least 5%, at least 10%, at least 15%, or at least 20% over a period of weeks, 11 weeks, 12 weeks, 3 months, 4 months, 6 months, or more compared to antidepressants alone , at least 25%, about 5 to 10%, about 10 to 15%, about 15 to 20%, about 20 to 25%, about 25 to 30%, about 10 to 20%, about 20 to 30%, about 30 to Resulting in a reduction of 40%, about 40 to 50%, about 50 to 60%, about 60 to 80%, about 80 to 100%, about 20%, greater than about 25%, about 30%, or about 50%.

When smokers are given a combination of dextromethorphan and an antidepressant, some smokers, on average, smoke at least 1 cigarette, at least 2 cigarettes, at least 3 cigarettes, at least 4 cigarettes, at least 5 cigarettes, at least 6 cigarettes per day. at least 7 cigarettes, at least 8 cigarettes, at least 9 cigarettes, at least 10 cigarettes, at least 15 cigarettes, at least 20 cigarettes, about 8 to 9 cigarettes, about 8 to 10 cigarettes, about 10 to 15 cigarettes, about 15 to 20 cigarettes, about 25 It may result in a decrease in cigarette smoking, or even more.

When smokers were given a combination of dextromethorphan and an antidepressant, the proportion of smokers who experienced a 50% or greater decrease in exhaled carbon monoxide levels, a biochemical marker of smoking intensity, compared to those treated with antidepressants alone. At least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, about 35%, about 50%, about 60%, about 60 It can be a larger percentage, such as from about 80%, about 80 to 90%, or about 90 to 100%. In some embodiments, a given smoker has a greater than 50% decrease in exhaled carbon monoxide levels, a biochemical marker of smoking intensity, compared to the result of administering the antidepressant alone, or compared to baseline or immediately prior to receiving the first dose of the combination. You can experience it.

Missing a combined dose of dextromethorphan and an antidepressant may increase smoking activity. For example, smokers who miss one or more doses of a combination of dextromethorphan and an antidepressant are more likely to smoke at least 1 cigarette or about 1 to 2 more cigarettes on each missed day compared to smokers who do not miss any doses of the combination. You may smoke at least 1 cigarette, at least 2 cigarettes, about 1 to 2 cigarettes, or about 2 to 3 more cigarettes the day after you miss your dose.

In some embodiments, the enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan and an antidepressant, can be used as adjunctive therapy for the treatment of any of the conditions cited herein, including TRD. For example, the above adjuvant therapies include clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, and trimipramine. Min, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactizine, escitalopram , fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nyalamide, ipronia. zide, iproclozide, toloxatone, buttriptyline, dosulepine, dibenzepine, iprindole, rofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, etc., or metabolites of any of these compounds, or It can be used in combination with other antidepressants, such as prodrugs, or pharmaceutically acceptable salts of any of these compounds.

A combination of dextromethorphan and an antidepressant may be used to treat people with TRD and, in some individuals, reduce depressive symptoms in at least about 5%, at least about 10%, at least about 20%, and at least about 30%. , a reduction of 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 reduction in a range limited to any of these values. may result in

The combination of dextromethorphan and antidepressants has been linked to phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); Mania, bipolar disorder, hypomania, unipolar depression, depression, stress disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, Alzheimer's disease aggression, agitation ), and can be used to treat people suffering from mental disorders, including, but not limited to, agitation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms, including agitation. AD is the most common form of dementia and affects approximately 6 million people in the United States, a number expected to increase to approximately 14 million by 2050. Fluctuations in Alzheimer's disease occur as the disease progresses. Agitation is reported in up to 70% of patients with Alzheimer's disease and is characterized by emotional distress, aggressive behavior, disruptive irritability, and disinhibition. Agitation may manifest itself as inappropriate verbal, emotional, and/or physical behavior. Inappropriate behavior may include incoherent babbling, inappropriate emotional responses, attention demands, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, violent language, physical outbursts, emotional distress, restlessness, nervousness, difficulty sleeping, May include delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, shadowing, hitting, scratching, biting, belligerence, hyperactivity and/or kicking. but is not limited to this. 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 placement, 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 the agitation of Alzheimer's disease, in some embodiments reducing the agitation-related symptoms in 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%, or any other range limited by these values. may result in a decrease.

The combination of dextromethorphan and antidepressants may be associated with drug dependence, cocaine addiction, psychostimulants (e.g. crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, and psychedelics. It can be used to treat individuals suffering from addiction and/or abuse of substances including, but not limited to, clidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as cigarette, cigar and/or pipe smoking, vaping, and chewing tobacco addiction.

The combination of dextromethorphan and antidepressants may cause senile dementia, Alzheimer's type dementia, amnesia, amnesia/amnesia syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, vocal spasms, Parkinson's disease, and Lennox-Gas. It can be used to treat people suffering from brain dysfunction including, but not limited to, Sat syndrome, autism, hyperkinesis syndrome, and schizophrenia. Brain dysfunction also includes disorders caused by cerebrovascular diseases, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, etc., where symptoms include impaired consciousness, senile dementia, and coma. conditions, including impaired attention, and language impairment.

Movement disorders that can be treated by the combination of dextromethorphan and antidepressants include akathisia, akathisia, related movements, athetosis, ataxia, ballistic chorea, hemichorea, bradykinesia, cerebral palsy, chorea, and Huntington's disease. , rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spastic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs 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 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, and Wernicke's disease. including, but not limited to, Korsakoff syndrome, and Pick's disease.

Motor neuron diseases that can be treated with a combination of dextromethorphan and antidepressants include amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, and post-polio syndrome (PPS). ), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sach disease, Sandoff disease, and hereditary spastic paraplegia.

Neurodegenerative diseases that can be treated with a combination of dextromethorphan and antidepressants include Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, and Friedreich's movement. Ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Schei-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Men Kissing disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paresis, neurofibromatosis, olivopontine cerebellar atrophy. or degeneration, striatal substantia nigra degeneration, Guillain-Barré syndrome, and spastic paraplegia.

Seizure disorders that can be treated with a combination of dextromethorphan and an antidepressant include epileptic seizures, non-epileptic seizures, epilepsy, and febrile seizures; Partial seizures, including but not limited to simple partial seizures, Jackson's seizures, complex partial seizures, and partial-onset epilepsy; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

Headache types that can be treated with a combination of dextromethorphan and an antidepressant include, but are not limited to, migraines, tension headaches, and cluster headaches.

Other neurological disorders that can be treated with the combination of dextromethorphan and antidepressants include Rett syndrome, autism, tinnitus, disorders of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; Voice disorders due to uncontrolled laryngeal muscle spasm, including but not limited to abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic dysphonia, and voice tremor; Diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; Urinary incontinence, including but not limited to stress incontinence, urge 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, emotional incontinence, depression (including treatment-resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, It may be used to treat amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, and cough (including chronic cough).

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

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

The pain-relieving properties of dextromethorphan can be enhanced by a method comprising co-administering dextromethorphan and an antidepressant to a human.

The pain-relieving properties of antidepressants can be enhanced by methods involving co-administering dextromethorphan with an antidepressant.

In some embodiments, ketamine or another NMDA receptor antagonist may be administered in combination with an antidepressant.

These methods can be used to treat or relieve 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. can be used for

In some embodiments, co-administration of dextromethorphan with 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, coadministration of dextromethorphan with an antidepressant may be used to treat psoriasis, cancer, viral infections, or as an adjuvant treatment for multiple myeloma.

Examples of musculoskeletal pain include low back pain (i.e., lumbosacral pain), primary dysmenorrhea, and arthritic pain, such as rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondyloarthritis, including ankylosing spondylitis, and pain associated with spinal crush fractures. , fibrous dysplasia, osteogenesis imperfecta, Paget's disease, transient osteoporosis, and transient hip osteoporosis.

In some embodiments, the combination of dextromethorphan and an antidepressant is used to treat back pain, and rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, and periarticular arthritis. It can be administered orally to relieve musculoskeletal pain, including pain associated with disease, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, spinal crush fractures, osteoporosis, etc.

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

Arthritis refers to an inflammatory joint disease that may be associated with pain. Examples of arthritic pain include osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathy, including Charcot foot, and spasticity. axial spondyloarthritis, including spondylitis, and pain associated with SAPHO syndrome.

In some embodiments, a combination of dextromethorphan and an antidepressant is used to treat chronic musculoskeletal pain.

In some embodiments, the combination of dextromethorphan and an antidepressant is used to treat complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or It may be administered to relieve other types of CRPS. CRPS is a type of inflammatory pain. CRPS can 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 swelling and changes in the autonomic, motor, and sensory systems.

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

Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, and central pain. 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, and radiation- or chemotherapy-related neuropathy.

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

The term "treat" or "therapy" means the diagnosis, cure, alleviation, treatment or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or function of the body of humans or other animals. Includes.

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 formulations. In some embodiments, dextromethorphan and the antidepressant compound can be administered in a single dosage form.

Antidepressant compounds that may be administered in combination with dextromethorphan include clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, and Triptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactizine , escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofencin, moclobemide, rasagiline, Nyalamide, iproniazid, iproclozide, toloxatone, buttriptyline, dosulepine, dibenzepine, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, etc., or any of these compounds Metabolites or prodrugs of any of these compounds, or pharmaceutically acceptable salts of any of these compounds are included.

In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor, such as citalopram (Celexa, Cipramil), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox, Faverin) ), paroxetine (Paxil, Seroxat), sertraline (Zoloft, Lustral), etc.; Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), venlafaxine (Effexor), etc.; Serotonin modulators and stimulants (SMS) such as vilazodone (Viibryd), vortioxetine (Trintellix), etc.; Serotonin antagonists and reuptake inhibitors (SARIs), such as nefazodone (Dutonin, Nefadar, Serzone), trazodone (Desyrel), norepinephrine reuptake inhibitors (NRIs), such as atomoxetine (Strattera), reboxetine (Edronax), tenyloxazine (Lucelan, Metatone), viloxazine (Vivalan), etc.; Tricyclic antidepressants (TCAs), such as amitriptyline (Elavil, Endep), amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), and dibenzepine. (Noveril, Victoril), dimethacrine (Istonil), dosulepine (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Lomont, Gamanil), melithracene (Dixeran, Melixeran) , Trausabun), nitroxazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxiptyline (Agedal, Elronon, Nogedal), opipramol (Insidon), pipofezine (Azafen/Azaphen), protriptyline (Vivactil), trimipramine (Surmontil), etc.; Tetracyclic antidepressants (TeCA), such as amoxapine (Asendin), maprotiline (Ludiomil), mianserin (Tolvon), mirtazapine (Remeron), setiptyline (Tecipul), etc.; Monoamine oxidase inhibitors (MAOIs), such as isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl, Zelapar, Emsam), and caroxazone (Surodil) , Timostenil), metralindol (Inkazan), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), toloxatone (Humoryl), eprobemide (Befol), minaprin (Brantur, Cantor), Bife Melan (Alnert, Celeport); Agomelatine (Valdoxan), esketamine (Spravato), ketamine (Ketalar), tandospirone (Sediel), tianeptine (Stablon, Coaxil), α-methyltryptamine [αMT] (Indopan), etriptamine [α -Ethyltryptamine (αET)] (Monase), indeloxazine (Elen, Noin), medipoxamine (Cledial, Gerdaxyl), oxaflozan (Conflictan), pivagabin (Tonerg), ademethionine [S-adeno Sil-L-methionine (SAMe)] (Heptral, Transmetil, Samyl), St. John's wort [Hypericum perforatum; St. St. John's Wort (SJW)] (Jarsin, Kira, Movina), oxytriptan [5-hydroxytryptophan (5-HTP)] (Cincofarm, Levothym, Triptum), rubidium chloride [RbCl] (Rubinorm), tryptan, Optimax, Aminomine), magnesium, acetylcarnitine, saffron, amisulprid (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, amitrip Tilin/perphenazine (Etafron), flupentixole/mellithracene (Deanxit), olanzapine/fluoxetine (Symbyax), tranylcypromine/trifluoperazine (Parsteline, Parmodalin, Jatrosom N, Stelapar), NMDA receptor Glutamate agents, including modulators, such as 4-chlorokynurenine, AGN-241751, afimostinel (NRX-1074), arketamine (PCN-101, HR-071603). Other types of glutamatergic drugs, such as dextromethadone (REL-1017), EVT-101 (ENS-101), ketamine (Ketalar), lislenemdaz (CERC-301, MK-0657), etc. Lant (RG-7090); Monoaminergic, such as monoamine reuptake inhibitors, including AN-788 (NSD-788), toludesvenlafaxine (ansofaxine; LY03005, LPM570065), PDC-1421 (BLI-1005), etc., MIN-117 (WF-516) ), monoamine reuptake inhibitors and receptor modulators such as TGBA01AD (FKB01MD); Monoamine receptor modulators including gepirone (TGFK07AD; Travivo), pimavanserin (Nuplazid; ACP-103; BVF-048), psilocybin, etc.; Atypical antipsychotics, including brillaroxazine (RP-5063, RP-5000), lumateperone (ITI-007), etc.; Ademethionine (SAMe; MSI-190, MSI-195, Strada); Neurosteroids such as GABA _A receptor positive modulators, including ganaxolone (CCD-1042), zuranolone (SAGE-217), 3β-methoxypregnenolone (MAP-4343), PH-10 - vomeroperin, etc. other neurosteroids; Opioids, such as κ-opioid receptor antagonists, including articarant (JNJ-67953964, CERC-501, LY-2456302), BTRX-335140 (BTRX-140), and buprenorphine/samidorphan (ALKS-5461) Second, other opioids such as BTRX-246040 (LY-2940094); Hydroxynorketamine ((2R,6R)-HNK), JNJ-39393406, JNJ-54175446, JNJ-61393215 (JNJ-3215, JNJ-61393215; Orexin-1), NNI-351, NSI-189, NV-5138 , OnabotulinumtoxinA (Botulinum Toxin A, Botox), Pramipexole (CTC-501, CTC-413), Celtorexant (MIN-202, JNJ-42847922, JNJ-922), Sirucumab (CNTO-136) , SUVN-911, TS-121, etc.; tramadol (ETS6103; Viotra); Cycloserine/Lurasidone; It may be 7,8-dihydroxyflavone (7,8-DHF), minocycline, nitrous oxide, pramipexole, R13, etc.

In some embodiments, about 40 to 120 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 70 mg. 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg , about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of levomilnacipran (Fetzima) and about 30 to 60 mg, about 40 to 50 mg. mg, or about 60 to 120 mg of dextromethorphan (or in other amounts described herein) once or twice daily in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. Administered (e.g. orally).

In some embodiments, about 0.5 to 1.4 mg/kg (for children), about 40 to 100 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 50 mg. 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg , about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of atomoxetine (Strattera) and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or another amount described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of tenyloxazine (Lucelan, Metatone) and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or another amount described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 5 to 20 mg, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 6 mg. 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg , about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of biloxazine. (Vivalan) 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) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (for example, orally) to treat.

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

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of melithracene (Dixeran, Melixeran, Trausabun) 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) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (for example, orally) to treat.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of nitroxazepine (Sintamil) 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) for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g. orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of noxiptyline (Agedal, Elronon, Nogedal) 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) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (for example, orally) to treat.

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

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

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

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

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

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of minaprine (Brantur, Cantor) , about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of biphemelan (Alnert, Celeport); , about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

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

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

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

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

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of etriptamine [α-ethyltripte] tamin (αET)] (Monase) 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) for the treatment of depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as.

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

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

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

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of St. John's wort [Hypericum perforatum; [St. St. John's Wort (SJW)] (Jarsin, Kira, Movina) 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) for the treatment of depression. or administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions, such as agitation associated with Alzheimer's disease.

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of tryptophan (Tryptan, Optimax, Aminomine) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

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

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

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

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

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

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

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

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

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of modafinil, and about 30 to 60 mg mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) per day in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered in one or two doses (e.g. orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of thyroxine (T4), and about 30 From about 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or in other amounts described herein) can be administered to humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g. orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of triiodothyronine (T3); , about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of minocycline, 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 daily in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice (e.g. orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of amitriptyline/chlordiazepoxide. 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) for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of amitriptyline/perphenazine ( Etafron) 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) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (for example, orally) to treat.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of flupentixole/mellithracene ( Deanxit) 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) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (for example, orally) to treat.

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of tranylcypromine/triflu. Operazine (Parstelin, Parmodalin, Jatrosom N, Stelapar) 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) may be used to treat depression or It is administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions, such as agitation associated with Alzheimer's disease.

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of AGN-241751, and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of Apimostinel (NRX-1074) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of dextromethadone (REL-1017) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of EVT-101 (ENS-101) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, 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) to treat neurological disorders such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g. orally) to treat psychotic conditions.

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of AN-788 (NSD-788) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of toludesvenlafaxine (Ansofaxine; LY03005) , LPM570065) 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) to treat neuropsychiatric disorders such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat the condition.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of PDC-1421 (BLI-1005) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of MIN-117 (WF-516) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of TGBA01AD (FKB01MD), and about 30 mg From about 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or in other amounts described herein) can be administered to humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g. orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of gepirone (TGFK07AD; Travivo); , about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of pimavanserin (Nuplazid; ACP- 103; BVF)-048) 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) for the treatment of depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat the same neuropsychiatric condition.

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of brillaroxazine (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) to treat neuropsychiatric disorders such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat a medical condition.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of lumateperone (ITI-007) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of Ganaxolone (CCD-1042) and , about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of zuranolone (SAGE-217); , about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of 3β-methoxypregnenolone ( MAP-4343) 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) to treat neuropsychiatric disorders such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat a medical condition.

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of articarant (JNJ-67953964, CERC-501, LY-2456302) 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) for the treatment of depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of BTRX-335140 (BTRX-140) 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) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. To do this, it is administered to humans once or twice a day (for example, orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of buprenorphine/samidorphan. (ALKS-5461) BTRX-246040 (LY-2940094) 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) for treating depression. or administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as agitation associated with Alzheimer's disease.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of hydroxynorketamine ((2R, 6R)-HNK) 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) to prevent neurological disorders such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g. orally) to treat psychotic conditions.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of JNJ-39393406, and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of JNJ-54175446, and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg (JNJ-3215, JNJ-61393215 ; orexin-1) 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) to treat neurological disorders such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g. orally) to treat psychotic conditions.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of NNI-351, and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of NSI-189, and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of NV-5138, and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, 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) to treat neuropsychiatric disorders such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat a medical condition.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of seltorexant (MIN-202, JNJ-42847922, JNJ-922) 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) for the treatment of depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of sirucumab (CNTO-136) , about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) for treating neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of SUVN-911, and about 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of TS-121, and about 30 to 500 mg. 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) may be administered in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice daily (e.g., orally).

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of cycloserine/lurasidone, About 30 to 60 mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or in other amounts described herein) for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g. orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of 7,8-dihydroxyflavone. (7,8-DHF) 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) for the treatment of depression or agitation associated with Alzheimer's disease. It is administered to humans once or twice daily (e.g., orally) to treat the same neuropsychiatric condition.

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of minocycline, 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 daily in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice (e.g. orally).

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of nitrous oxide, and about 30 to 60 mg mg, about 40 to 50 mg, or about 60 to 120 mg of dextromethorphan (or other amounts described herein) per day in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered in one or two doses (e.g. orally).

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

In some embodiments, about 0.01 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 7 mg. 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg , about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 250 mg, about 250 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 400 to 450 mg, or about 450 to 500 mg of R13, 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 daily in humans for the treatment of neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. It is administered once or twice (e.g. orally).

In some embodiments, the combination of about 10 to 60 mg or about 20 to 30 mg of agomelatine and about 30 to 60 mg or about 40 to 50 mg of dextromethorphan (or in other amounts described herein) It is administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease. The two compounds can be administered individually or in a single dosage form.

In some embodiments, the combination of about 2 to 10 mg or about 3 to 5 mg of reboxetine and about 30 to 60 mg or about 40 to 50 mg of dextromethorphan (or in other amounts described herein) is used to treat depression. or administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as agitation associated with Alzheimer's disease.

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

In some embodiments, about 2 to 40 mg, about 4 to 6 mg, about 8 to 12 mg, or about 16 to 24 mg of vortioxetine and about 30 to 60 mg or about 40 to 50 mg of dextromethor. A combination of tablets (or in other amounts described herein) is administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease.

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

In some embodiments, about 5 to 80 mg, about 10 to 30 mg, or about 20 to 40 mg of vilazodone and about 30 to 60 mg or about 40 to 50 mg of dextromethorphan (or Combinations (in different amounts) are administered to humans once or twice daily (e.g., orally) to treat neuropsychiatric conditions such as depression or agitation associated with Alzheimer's disease.

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

Combining an antidepressant and dextromethorphan may provide greater efficacy, such as greater pain relief, than can be achieved by administering each component alone. In extensive metabolizers, dextromethorphan can be metabolized rapidly and extensively, resulting in low systemic exposure even at high doses. The antidepressant is an inhibitor of dextromethorphan metabolism.

As described above, this inhibition may increase dextromethorphan plasma concentrations, resulting in additive or synergistic effects such as relief of neurological disorders including pain, depression, smoking cessation, etc. Accordingly, while inhibition of dextromethorphan metabolism is one of the numerous potential advantages of this combination, co-administration of dextromethorphan with an antidepressant may thereby enhance the efficacy of the antidepressant in many individuals. Coadministration of dextromethorphan and an antidepressant may enhance the analgesic properties of the antidepressant in many individuals. Co-administration of dextromethorphan and an antidepressant may also improve the antidepressant properties of the antidepressant in many individuals, including a faster onset of action.

Another potential advantage of coadministering dextromethorphan with an antidepressant is that it may be useful in reducing the likelihood of adverse reactions, such as drowsiness, associated with dextromethorphan treatment. This may be useful, for example, in human patients at risk of experiencing adverse events as a result of treatment with dextromethorphan.

Another potential advantage of coadministering dextromethorphan with an antidepressant is that it may be useful in reducing the likelihood of adverse reactions, such as seizures, associated with antidepressant treatment. This could be useful, for example, in human patients at risk of experiencing adverse reactions as a result of treatment with antidepressants.

With respect to antidepressants, coadministration with dextromethorphan may reduce central nervous system adverse reactions, gastrointestinal adverse reactions, or other types of adverse reactions associated with antidepressants. Central nervous system (CNS) adverse reactions include nervousness, dizziness, insomnia, light-headedness, tremors, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or excitement, tinnitus, drowsiness, dizziness, sedation, lethargy, and confusion. , disorientation, drowsiness, ataxia, fatigue, euphoria, nervousness, insomnia, sleep disturbances, convulsive seizures, excitement, catatonia, hysteria, hallucinations, delusions, paranoia, headaches and/or migraines, and ocular crises, torticollis, and hypersensitivity. Extrapyramidal symptoms include, but are not limited to, agitation, increased muscle tone, ataxia, and/or tongue protrusion.

Gastrointestinal adverse reactions include nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcer with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, stomach fullness, indigestion, These include, but are not limited to, bloating, hyperacidity, dry mouth, gastrointestinal upset, and stomach pain.

When dextromethorphan and an antidepressant are administered together, the two compounds do not necessarily have to be administered in the same dosage form. For example, the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. Additionally, both compounds can be administered simultaneously, but this is not necessary. The compounds may be given at different times as long as they are simultaneously present in the body for at least part of the time during which treatment by combination administration is carried out.

By administering antidepressants together with dextromethorphan, the side effects of antidepressants can be reduced. Examples of side effects that may be reduced include abnormal sensations of rotation and movement, agitation, arm weakness, bloating, blurred vision, burning eyes, ringing in the ears, and changes in vital signs (heart rate, respiratory rate, temperature, and blood pressure), feeling cold, constipation, difficulty concentrating, difficulty sleeping, difficulty falling asleep, difficulty urinating, difficulty bowel movement, discomfort in the ears, discomfort in the eyes, discomfort in the stomach, dizziness, dry lips. , dry mouth, dry throat, menstrual cramps, fatigue, feeling hot, feeling heavy-headed, feeling more agitated than usual, feeling more tired than usual, tiredness, hand tremors, hand weakness, headache, heartburn, hot flashes, blood pressure Elevation, increased skin sensitivity, increased skin sensitivity of the head and face, involuntary muscle contractions, involuntary muscle contractions throughout the body, knee pain, leg weakness, dizziness, loose stools, decreased appetite, back pain, menstrual irregularities, metallic taste, salivation more than usual. Excessive lice, dry mucous membranes, stuffy nose, nausea, runny nose, mild pressure in the eyes, shaking when stretching or yawning, skin sensitivity, skin sensitivity on the arms, face and/or head, trouble sleeping, loose stools, abdominal pain, stomach discomfort, hands and/ or sweating at the feet, throat irritation, throat pain, tinnitus, tremors and/or weakness. These side effects may be referenced or grouped according to their corresponding terms, equivalent terms, or other related terms in the Medical Dictionary for Regulatory Activities (MedRA).

In some embodiments, co-administration of a combination of an antidepressant and dextromethorphan causes both the antidepressant and dextromethorphan to contribute to the pain relief properties of the combination. For example, the combination may have improved pain relief properties compared to an antidepressant alone or dextromethorphan alone, including a potentially faster onset of action.

In some embodiments, the combination provides 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%, at least 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 about 170%, about 170% to about 180% , from about 180% to about 190%, from about 190% to about 200%, or a range limited by any of these values, or any amount of pain relief in a range between these values. You can.

In some embodiments, the combination provides 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%, at least 100%, compared to dextromethorphan alone. %, 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 about 170%, about 170% Improved pain relief in any amount ranging from about 180%, about 180% to about 190%, about 190% to about 200%, or a range limited by any of these values, or a range between these values. May have mitigating properties.

Unless otherwise indicated, reference by structure, name or other means to a compound herein, such as dextromethorphan or an antidepressant, includes pharmaceutically acceptable salts; Alternative solid forms such as polymorphs, solvates, hydrates, etc.; tautomer; deuterium modified compounds such as deuterium modified dextromethorphan; or any chemical species that can be rapidly converted to a compound described herein under the conditions under which the compound is used as described herein.

In some embodiments, more than one stereoisomer of the antidepressant may be administered. In other embodiments, the excess S-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 enantiomerically pure S-enantiomer) or an excess of 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 the mirror image Antidepressants of the isomerically pure R-enantiomer) may be administered.

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

Examples of deuterium modified dextromethorphan include, but are not limited to, those shown below.

The dosage form or composition may be a blend or mixture of dextromethorphan and an antidepressant alone or in a vehicle. For example, dextromethorphan and the antidepressant can be dispersed together or co-dispersed in the vehicle. A dispersion may comprise a mixture of solid substances in which the small individual particles are substantially one compound, but where the small particles are dispersed and blended together, such as may occur when two powders of two different drugs are blended with a solid vehicle material. It is made in solid form. In some embodiments, dextromethorphan and the antidepressant can be dispersed substantially uniformly within the composition or dosage form. Alternatively, dextromethorphan and the antidepressant may exist as separate regions or phases within the composition or dosage form. For example, one drug may be within the coating and another drug may be within the core within the coating. For example, one drug may be formulated for sustained release and another drug may be formulated for immediate release.

Some embodiments involve administration of tablets containing an antidepressant in a form that provides sustained release and dextromethorphan in a form that provides immediate release. There are many ways in which sustained release of an antidepressant can be achieved, but in some embodiments, the antidepressant is combined with hydroxypropyl methylcellulose. For example, particles of an antidepressant can be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., ^METHOCEL® ) to form a mixture of blended powders. It can be combined with immediate release dextromethorphan in a single tablet.

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

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

Therapeutic compounds can be administered to human patients in a variety of forms suitable for the chosen route of administration, for example orally or parenterally. In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial, including transdermal, ocular, sublingual and buccal; Topical, including eye, skin, ocular, rectal and nasal inhalation via inhalation, aerosol and rectal systemic.

The amount of dextromethorphan in the therapeutic composition may vary. For example, some liquid compositions have 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 about 40% (w/v) to about 50%. (w/v) dextromethorphan.

Some liquid dosage forms include from about 10 mg to about 500 mg, from about 30 mg to about 350 mg, from about 50 mg to about 200 mg, from about 50 mg to about 70 mg, from about 20 mg to about 50 mg, from about 30 mg to about 30 mg. 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 to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or It may contain about 180 mg of dextromethorphan, or any amount of dextromethorphan within a range limited by any of these values or within a range between 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). /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), 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) w), from about 70% (w/w) to about 80% (w/w), or from about 80% (w/w) to about 90% (w/w) of dextromethorphan. .

Some solid dosage forms include dosages of from about 10 mg to about 500 mg, from about 30 mg to about 350 mg, from about 20 mg to about 50 mg, from about 30 mg to about 60 mg, from about 40 mg to about 50 mg, from about 40 mg to about 40 mg. 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 It may contain any amount of dextromethorphan within a range limited by these values or in a range between these values.

In some embodiments, the amount of dextromethorphan is from about 0.1 mg/kg to about 20 mg/kg, from about 0.75 mg/kg to about 7.5 mg/kg, from about 0.1 mg/kg to about 5 mg/kg, based on the body weight of the patient. ㎎/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 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, or these It can be a range bounded by or any value in a range in between.

The amount of antidepressant in the therapeutic composition may vary. If the goal is to increase plasma concentrations of dextromethorphan, antidepressants should be administered in doses that increase plasma concentrations of dextromethorphan. For example, an antidepressant may cause the plasma concentration of dextromethorphan in a human to be at least about 2 times, and at least about 5 times, the plasma concentration of the same amount of dextromethorphan administered without the antidepressant on days 8, 9, or 10. 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 some embodiments, the antidepressant is administered on days 8, 9, or 10 at the area under the curve 12 hours from the time of dosing of dextromethorphan (AUC _0-12 ), or the average plasma concentration in humans 12 hours after dosing ( C _avg ) is at least about 2 times, 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 the plasma concentration of the same amount of dextromethorphan administered without the antidepressant, It can be administered to humans in an amount that is 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.

In some embodiments, the antidepressant is such that the maximum plasma concentration (C _max ) of dextromethorphan in a human on day 8, 9, or 10 is at least about 2 times, at least about 5 times the plasma concentration of the same amount of antidepressant, It can be administered to humans in an amount that is at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times.

When an antidepressant is administered in combination with dextromethorphan, higher dextromethorphan plasma concentrations may occur on the first day of antidepressant administration compared to when the same amount of dextromethorphan is administered without an antidepressant. For example, the plasma concentration of dextromethorphan on the first day of antidepressant administration is at least about 1.5 times, at least about 2 times, at least about 2.5 times, and at least about the concentration achieved by administering the same amount of dextromethorphan without the antidepressant. It can be 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.

In some embodiments, for example, on the first day that dextromethorphan plasma concentrations are improved by co-administration of an antidepressant and dextromethorphan, the dextromethorphan AUC is greater than that of the same amount of dextromethorphan without the antidepressant. It may be at least twice the AUC that will be achieved by administration.

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

In some embodiments, such as by co-administration of an antidepressant and dextromethorphan, the dextromethorphan AUC _0-12 on day 8 when the dextromethorphan plasma concentration is improved is at least about 40 ng·hr/ml. , at least about 50ng·hr/ml, at least about 60ng·hr/ml, at least about 70ng·hr/ml, at least about 80ng·hr/ml, at least about 90ng·hr/ml, at least about 100ng·hr/ml, at least About 150ng·hr/ml, at least about 200ng·hr/ml, at least about 250ng·hr/ml, at least about 300ng·hr/ml, at least about 350ng·hr/ml, at least about 400ng·hr/ml, at least about 450ng ㆍhr/ml, at least about 500ng·hr/ml, at least about 550ng·hr/ml, about 500ng·hr/ml to about 600ng·hr/ml, about 500ng·hr/ml to about 550ng·hr/ml, about 500ng·hr/ml to about 525ng·hr/ml, about 525ng·hr/ml to about 600ng·hr/ml, at least about 600ng·hr/ml, at least about 650ng·hr/ml, at least about 700ng·hr/ml , at least about 750ng·hr/ml, at least about 800ng·hr/ml, about 800ng·hr/ml to about 900ng·hr/ml, about 850ng·hr/ml to about 900ng·hr/ml, about 850ng·hr/ ㎖ to about 875ngㆍhr/㎖, about 875ngㆍhr/㎖ to about 900ngㆍhr/㎖, about 900ngㆍhr/㎖ to about 1,000ngㆍhr/㎖, about 1,000ngㆍhr/㎖ to about 1,100ngㆍ hr/ml, about 1,100ng·hr/ml to about 1,200ng·hr/ml, about 1,200ng·hr/ml to about 1,300ng·hr/ml, about 1,300ng·hr/ml to about 1,400ng·hr/ ㎖, about 1,400ng·hr/ml to about 1,500ng·hr/ml, about 1,500ng·hr/ml to about 1,600ng·hr/ml, about 1,600ng·hr/ml to about 1,700ng·hr/ml, About 1,700ng·hr/ml to about 1,800ng·hr/ml, about 1,800ng·hr/ml to about 2,000ng·hr/ml, at least about 850ng·hr/ml, at least about 900ng·hr/ml, at least about 950ng·hr/ml, at least about 1000ng·hr/ml, at least about 1050ng·hr/ml, at least about 1100ng·hr/ml, at least about 1150ng·hr/ml, at least about 1200ng·hr/ml, at least about 1250ng·hr hr/ml, at least about 1300ng·hr/ml, at least about 1350ng·hr/ml, at least about 1400ng·hr/ml, at least about 1450ng·hr/ml, at least about 1500ng·hr/ml, at least about 1550ng·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, in some embodiments It may be up to about 50,000 ng·hr/ml.

In some embodiments, e.g., by co-administration of an antidepressant and dextromethorphan, the dextromethorphan AUC _0-24 on day 8 when the dextromethorphan plasma concentration is improved is at least about 50 ng·hr/ml. , at least about 75ng·hr/ml, at least about 100ng·hr/ml, at least about 200ng·hr/ml, at least about 300ng·hr/ml, at least about 400ng·hr/ml, at least about 500ng·hr/ml, at least About 600ng·hr/ml, at least about 700ng·hr/ml, at least about 800ng·hr/ml, at least about 900ng·hr/ml, at least about 1000ng·hr/ml, at least about 1100ng·hr/ml, at least about 1200ng ㆍhr/ml, at least about 1300ng·hr/ml, at least about 1400ng·hr/ml, at least about 1500ng·hr/ml, at least about 1600ng·hr/ml, at least about 1700ng·hr/ml, at least about 1800ng·hr /ml, at least about 1900ng·hr/ml, at least about 2000ng·hr/ml, at least about 2100ng·hr/ml, at least about 2200ng·hr/ml, at least about 2300ng·hr/ml, at least about 2400ng·hr/ml , at least about 2500ng·hr/ml, at least about 2600ng·hr/ml, at least about 2700ng·hr/ml, at least about 2800ng·hr/ml, at least about 1850ng·hr/ml, at least about 2900ng·hr/ml, at least It may be 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, for example, by co-administration of an antidepressant and dextromethorphan, the dextromethorphan AUC _0-inf on day 8 when the dextromethorphan plasma concentration is improved is at least about 75 ng·hr/ml. , at least about 100ng·hr/ml, at least about 200ng·hr/ml, at least about 300ng·hr/ml, at least about 400ng·hr/ml, at least about 500ng·hr/ml, at least about 600ng·hr/ml, at least About 700ng·hr/ml, at least about 800ng·hr/ml, at least about 900ng·hr/ml, at least about 1000ng·hr/ml, at least about 1100ng·hr/ml, at least about 1200ng·hr/ml, at least about 1300ng ㆍhr/ml, at least about 1400ng·hr/ml, at least about 1500ng·hr/ml, at least about 1600ng·hr/ml, at least about 1700ng·hr/ml, at least about 1800ng·hr/ml, at least about 1900ng·hr /ml, at least about 2000ng·hr/ml, at least about 2100ng·hr/ml, at least about 2200ng·hr/ml, at least about 2300ng·hr/ml, at least about 2400ng·hr/ml, at least about 2500ng·hr/ml , at least about 2600ng·hr/ml, at least about 2700ng·hr/ml, at least about 2800ng·hr/ml, at least about 2900ng·hr/ml, at least about 3000ng·hr/ml, at least about 3100ng·hr/ml, at least About 3200ng·hr/ml, at least about 3300ng·hr/ml, at least about 3400ng·hr/ml, at least about 3500ng·hr/ml, at least about 3600ng·hr/ml, at least about 3700ng·hr/ml, at least about 3800ng ㆍhr/ml, at least about 3900ng·hr/ml, at least about 4000ng·hr/ml, at least about 4100ng·hr/ml, at least about 4200ng·hr/ml, at least about 4300ng·hr/ml, at least about 4400ng·hr /ml, at least about 4500ng·hr/ml, at least about 4600ng·hr/ml, at least about 4700ng·hr/ml, at least about 4800ng·hr/ml, at least about 4900ng·hr/ml, at least about 5000ng·hr/ml , at least about 5100ng·hr/ml, at least about 5200ng·hr/ml, at least about 5300ng·hr/ml, at least about 5400ng·hr/ml, at least about 5500ng·hr/ml, at least about 5600ng·hr/ml, at least About 5700ng·hr/ml, at least about 5800ng·hr/ml, at least about 5900ng·hr/ml, at least about 6000ng·hr/ml, at least about 6100ng·hr/ml, at least about 6200ng·hr/ml, at least about 6300ng ㆍhr/ml, at least about 6400ng·hr/ml, at least about 6500ng·hr/ml, at least about 6600ng·hr/ml, at least about 6700ng·hr/ml, at least about 6800ng·hr/ml, at least about 6900ng·hr /ml, at least about 7000ng·hr/ml, at least about 7100ng·hr/ml, at least about 7150ng·hr/ml, at least about 7200ng·hr/ml, or at least about 7237.3 ng·hr/ml, and in some embodiments In embodiments, it may be up to about 100,000 ng·hr/ml.

In some embodiments, for example, by co-administration of an antidepressant and dextromethorphan, the dextromethorphan AUC _0-12 on day 9 when the dextromethorphan plasma concentration is improved is at least about 40 ng·hr/ml. , at least about 50ng·hr/ml, at least about 60ng·hr/ml, at least about 70ng·hr/ml, at least about 80ng·hr/ml, at least about 90ng·hr/ml, at least about 100ng·hr/ml, at least About 150ng·hr/ml, at least about 200ng·hr/ml, at least about 250ng·hr/ml, at least about 300ng·hr/ml, at least about 350ng·hr/ml, at least about 400ng·hr/ml, at least about 450ng ㆍhr/ml, at least about 500ng·hr/ml, at least about 550ng·hr/ml, about 500ng·hr/ml to about 600ng·hr/ml, about 500ng·hr/ml to about 550ng·hr/ml, about 500ng·hr/ml to about 525ng·hr/ml, about 525ng·hr/ml to about 600ng·hr/ml, at least about 600ng·hr/ml, at least about 650ng·hr/ml, at least about 700ng·hr/ml , at least about 750ng·hr/ml, at least about 800ng·hr/ml, about 800ng·hr/ml to about 900ng·hr/ml, about 850ng·hr/ml to about 900ng·hr/ml, about 850ng·hr/ ㎖ to about 875ngㆍhr/㎖, about 875ngㆍhr/㎖ to about 900ngㆍhr/㎖, about 900ngㆍhr/㎖ to about 1,000ngㆍhr/㎖, about 1,000ngㆍhr/㎖ to about 1,100ngㆍ hr/ml, about 1,100ng·hr/ml to about 1,200ng·hr/ml, about 1,200ng·hr/ml to about 1,300ng·hr/ml, about 1,300ng·hr/ml to about 1,400ng·hr/ ㎖, about 1,400ng·hr/ml to about 1,500ng·hr/ml, about 1,500ng·hr/ml to about 1,600ng·hr/ml, about 1,600ng·hr/ml to about 1,700ng·hr/ml, About 1,700ng·hr/ml to about 1,800ng·hr/ml, about 1,800ng·hr/ml to about 2,000ng·hr/ml, at least about 850ng·hr/ml, at least about 900ng·hr/ml, at least about 950ng·hr/ml, at least about 1000ng·hr/ml, at least about 1050ng·hr/ml, at least about 1100ng·hr/ml, at least about 1150ng·hr/ml, at least about 1200ng·hr/ml, at least about 1250ng·hr hr/ml, at least about 1300ng·hr/ml, at least about 1350ng·hr/ml, at least about 1400ng·hr/ml, at least about 1450ng·hr/ml, at least about 1500ng·hr/ml, at least about 1550ng·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, in some embodiments It may be up to about 50,000 ng·hr/ml.

In some embodiments, for example, by co-administration of an antidepressant and dextromethorphan, the dextromethorphan plasma concentration is improved by day 9, where the dextromethorphan AUC _0-24 is at least about 50 ng·hr/ml. , at least about 75ng·hr/ml, at least about 100ng·hr/ml, at least about 200ng·hr/ml, at least about 300ng·hr/ml, at least about 400ng·hr/ml, at least about 500ng·hr/ml, at least About 600ng·hr/ml, at least about 700ng·hr/ml, at least about 800ng·hr/ml, at least about 900ng·hr/ml, at least about 1000ng·hr/ml, at least about 1100ng·hr/ml, at least about 1200ng ㆍhr/ml, at least about 1300ng·hr/ml, at least about 1400ng·hr/ml, at least about 1500ng·hr/ml, at least about 1600ng·hr/ml, at least about 1700ng·hr/ml, at least about 1800ng·hr /ml, at least about 1900ng·hr/ml, at least about 2000ng·hr/ml, at least about 2100ng·hr/ml, at least about 2200ng·hr/ml, at least about 2300ng·hr/ml, at least about 2400ng·hr/ml , at least about 2500ng·hr/ml, at least about 2600ng·hr/ml, at least about 2700ng·hr/ml, at least about 2800ng·hr/ml, at least about 1850ng·hr/ml, at least about 2900ng·hr/ml, at least It may be 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, such as by co-administration of an antidepressant and dextromethorphan, the dextromethorphan AUC _0-inf on day 9 when the dextromethorphan plasma concentration is improved is at least about 75 ng·hr/ml. , at least about 100ng·hr/ml, at least about 200ng·hr/ml, at least about 300ng·hr/ml, at least about 400ng·hr/ml, at least about 500ng·hr/ml, at least about 600ng·hr/ml, at least About 700ng·hr/ml, at least about 800ng·hr/ml, at least about 900ng·hr/ml, at least about 1000ng·hr/ml, at least about 1100ng·hr/ml, at least about 1200ng·hr/ml, at least about 1300ng ㆍhr/ml, at least about 1400ng·hr/ml, at least about 1500ng·hr/ml, at least about 1600ng·hr/ml, at least about 1700ng·hr/ml, at least about 1800ng·hr/ml, at least about 1900ng·hr /ml, at least about 2000ng·hr/ml, at least about 2100ng·hr/ml, at least about 2200ng·hr/ml, at least about 2300ng·hr/ml, at least about 2400ng·hr/ml, at least about 2500ng·hr/ml , at least about 2600ng·hr/ml, at least about 2700ng·hr/ml, at least about 2800ng·hr/ml, at least about 2900ng·hr/ml, at least about 3000ng·hr/ml, at least about 3100ng·hr/ml, at least About 3200ng·hr/ml, at least about 3300ng·hr/ml, at least about 3400ng·hr/ml, at least about 3500ng·hr/ml, at least about 3600ng·hr/ml, at least about 3700ng·hr/ml, at least about 3800ng ㆍhr/ml, at least about 3900ng·hr/ml, at least about 4000ng·hr/ml, at least about 4100ng·hr/ml, at least about 4200ng·hr/ml, at least about 4300ng·hr/ml, at least about 4400ng·hr /ml, at least about 4500ng·hr/ml, at least about 4600ng·hr/ml, at least about 4700ng·hr/ml, at least about 4800ng·hr/ml, at least about 4900ng·hr/ml, at least about 5000ng·hr/ml , at least about 5100ng·hr/ml, at least about 5200ng·hr/ml, at least about 5300ng·hr/ml, at least about 5400ng·hr/ml, at least about 5500ng·hr/ml, at least about 5600ng·hr/ml, at least About 5700ng·hr/ml, at least about 5800ng·hr/ml, at least about 5900ng·hr/ml, at least about 6000ng·hr/ml, at least about 6100ng·hr/ml, at least about 6200ng·hr/ml, at least about 6300ng ㆍhr/ml, at least about 6400ng·hr/ml, at least about 6500ng·hr/ml, at least about 6600ng·hr/ml, at least about 6700ng·hr/ml, at least about 6800ng·hr/ml, at least about 6900ng·hr /ml, at least about 7000ng·hr/ml, at least about 7100ng·hr/ml, at least about 7150ng·hr/ml, at least about 7200ng·hr/ml, or at least about 7237.3ng·hr/ml, and in some embodiments In embodiments, it may be up to about 100,000 ng·hr/ml.

In some embodiments, for example, by co-administration of an antidepressant and dextromethorphan, the dextromethorphan plasma concentration is improved by day 10, where the dextromethorphan AUC _0-12 is at least about 40 ng·hr/ml. , at least about 50ng·hr/ml, at least about 60ng·hr/ml, at least about 70ng·hr/ml, at least about 80ng·hr/ml, at least about 90ng·hr/ml, at least about 100ng·hr/ml, at least About 150ng·hr/ml, at least about 200ng·hr/ml, at least about 250ng·hr/ml, at least about 300ng·hr/ml, at least about 350ng·hr/ml, at least about 400ng·hr/ml, at least about 450ng ㆍhr/ml, at least about 500ng·hr/ml, at least about 550ng·hr/ml, about 500ng·hr/ml to about 600ng·hr/ml, about 500ng·hr/ml to about 550ng·hr/ml, about 500ng·hr/ml to about 525ng·hr/ml, about 525ng·hr/ml to about 600ng·hr/ml, at least about 600ng·hr/ml, at least about 650ng·hr/ml, at least about 700ng·hr/ml , at least about 750ng·hr/ml, at least about 800ng·hr/ml, about 800ng·hr/ml to about 900ng·hr/ml, about 850ng·hr/ml to about 900ng·hr/ml, about 850ng·hr/ ㎖ to about 875ngㆍhr/㎖, about 875ngㆍhr/㎖ to about 900ngㆍhr/㎖, about 900ngㆍhr/㎖ to about 1,000ngㆍhr/㎖, about 1,000ngㆍhr/㎖ to about 1,100ngㆍ hr/ml, about 1,100ng·hr/ml to about 1,200ng·hr/ml, about 1,200ng·hr/ml to about 1,300ng·hr/ml, about 1,300ng·hr/ml to about 1,400ng·hr/ ㎖, about 1,400ng·hr/ml to about 1,500ng·hr/ml, about 1,500ng·hr/ml to about 1,600ng·hr/ml, about 1,600ng·hr/ml to about 1,700ng·hr/ml, About 1,700ng·hr/ml to about 1,800ng·hr/ml, about 1,800ng·hr/ml to about 2,000ng·hr/ml, at least about 850ng·hr/ml, at least about 900ng·hr/ml, at least about 950ng·hr/ml, at least about 1000ng·hr/ml, at least about 1050ng·hr/ml, at least about 1100ng·hr/ml, at least about 1150ng·hr/ml, at least about 1200ng·hr/ml, at least about 1250ng·hr hr/ml, at least about 1300ng·hr/ml, at least about 1350ng·hr/ml, at least about 1400ng·hr/ml, at least about 1450ng·hr/ml, at least about 1500ng·hr/ml, at least about 1550ng·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, in some embodiments It may be up to about 50,000 ng·hr/ml.

In some embodiments, for example, by co-administration of an antidepressant and dextromethorphan, the dextromethorphan plasma concentration is improved by day 10, where the dextromethorphan AUC _0-24 is at least about 50 ng·hr/ml. , at least about 75ng·hr/ml, at least about 100ng·hr/ml, at least about 200ng·hr/ml, at least about 300ng·hr/ml, at least about 400ng·hr/ml, at least about 500ng·hr/ml, at least About 600ng·hr/ml, at least about 700ng·hr/ml, at least about 800ng·hr/ml, at least about 900ng·hr/ml, at least about 1000ng·hr/ml, at least about 1100ng·hr/ml, at least about 1200ng ㆍhr/ml, at least about 1300ng·hr/ml, at least about 1400ng·hr/ml, at least about 1500ng·hr/ml, at least about 1600ng·hr/ml, at least about 1700ng·hr/ml, at least about 1800ng·hr /ml, at least about 1900ng·hr/ml, at least about 2000ng·hr/ml, at least about 2100ng·hr/ml, at least about 2200ng·hr/ml, at least about 2300ng·hr/ml, at least about 2400ng·hr/ml , at least about 2500ng·hr/ml, at least about 2600ng·hr/ml, at least about 2700ng·hr/ml, at least about 2800ng·hr/ml, at least about 1850ng·hr/ml, at least about 2900ng·hr/ml, at least It may be 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, such as by co-administration of an antidepressant and dextromethorphan, the dextromethorphan AUC _0-inf on day 10 when the dextromethorphan plasma concentration is improved is at least about 75 ng·hr/ml. , at least about 100ng·hr/ml, at least about 200ng·hr/ml, at least about 300ng·hr/ml, at least about 400ng·hr/ml, at least about 500ng·hr/ml, at least about 600ng·hr/ml, at least About 700ng·hr/ml, at least about 800ng·hr/ml, at least about 900ng·hr/ml, at least about 1000ng·hr/ml, at least about 1100ng·hr/ml, at least about 1200ng·hr/ml, at least about 1300ng ㆍhr/ml, at least about 1400ng·hr/ml, at least about 1500ng·hr/ml, at least about 1600ng·hr/ml, at least about 1700ng·hr/ml, at least about 1800ng·hr/ml, at least about 1900ng·hr /ml, at least about 2000ng·hr/ml, at least about 2100ng·hr/ml, at least about 2200ng·hr/ml, at least about 2300ng·hr/ml, at least about 2400ng·hr/ml, at least about 2500ng·hr/ml , at least about 2600ng·hr/ml, at least about 2700ng·hr/ml, at least about 2800ng·hr/ml, at least about 2900ng·hr/ml, at least about 3000ng·hr/ml, at least about 3100ng·hr/ml, at least About 3200ng·hr/ml, at least about 3300ng·hr/ml, at least about 3400ng·hr/ml, at least about 3500ng·hr/ml, at least about 3600ng·hr/ml, at least about 3700ng·hr/ml, at least about 3800ng ㆍhr/ml, at least about 3900ng·hr/ml, at least about 4000ng·hr/ml, at least about 4100ng·hr/ml, at least about 4200ng·hr/ml, at least about 4300ng·hr/ml, at least about 4400ng·hr /ml, at least about 4500ng·hr/ml, at least about 4600ng·hr/ml, at least about 4700ng·hr/ml, at least about 4800ng·hr/ml, at least about 4900ng·hr/ml, at least about 5000ng·hr/ml , at least about 5100ng·hr/ml, at least about 5200ng·hr/ml, at least about 5300ng·hr/ml, at least about 5400ng·hr/ml, at least about 5500ng·hr/ml, at least about 5600ng·hr/ml, at least About 5700ng·hr/ml, at least about 5800ng·hr/ml, at least about 5900ng·hr/ml, at least about 6000ng·hr/ml, at least about 6100ng·hr/ml, at least about 6200ng·hr/ml, at least about 6300ng ㆍhr/ml, at least about 6400ng·hr/ml, at least about 6500ng·hr/ml, at least about 6600ng·hr/ml, at least about 6700ng·hr/ml, at least about 6800ng·hr/ml, at least about 6900ng·hr /ml, at least about 7000ng·hr/ml, at least about 7100ng·hr/ml, at least about 7150ng·hr/ml, at least about 7200ng·hr/ml, or at least about 7237.3ng·hr/ml, and in some embodiments In embodiments, it may be up to about 100,000 ng·hr/ml.

In some embodiments, on the first day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _max is equal to the same amount of dextromethorphan without the antidepressant. It may be at least twice the C _max that will be achieved by administering .

In some embodiments, on the first day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _max 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 /ml, at least about 3.5ng/ml, at least about 3.6ng/ml, at least about 3.7ng/ml, at least about 3.8ng/ml, at least about 3.9ng/ml, at least about 4.0ng/ml, at least about 4.1ng/ 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, 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 5.8 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 6.3 ng/mL, at least about 6.4 ng/mL, at least about 6.5 ng/mL, at least about 6.6 ng/mL, at least about 6.7 ng/mL, at least about 6.8 ng/mL, at least about 6.9 ng/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, and in some embodiments, up to about 1000 ng·hr/ml.

In some embodiments, on the eighth day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _max ranges from about 50 ng/ml to about 60 ng/ml. ㎖, about 50ng/㎖ to about 55ng/㎖, about 55ng/㎖ to about 60ng/㎖, about 80ng/㎖ to about 90ng/㎖, about 80ng/㎖ to about 85ng/㎖, about 85ng/㎖ to about 90ng/㎖ ㎖, about 90ng/㎖ to about 95ng/㎖, about 95ng/㎖ to about 100ng/㎖, about 100ng/㎖ to about 105ng/㎖, about 105ng/㎖ to about 110ng/㎖, about 110ng/㎖ to about 115ng/㎖ ㎖, about 115ng/㎖ to about 120ng/㎖, about 120ng/㎖ to about 130ng/㎖, about 130ng/㎖ to about 135ng/㎖, about 135ng/㎖ to about 140ng/㎖, about 140ng/㎖ to about 145ng/㎖ ㎖, about 145ng/㎖ to about 150ng/㎖, about 150ng/㎖ to about 155ng/㎖, about 155ng/㎖ to about 160ng/㎖, about 160ng/㎖ to about 170ng/㎖, about 170ng/㎖ 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, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml, at least about 50ng/ml, at least about 55ng/ml, at least about 60ng/ml, at least about 65ng/ml 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 It may be 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, on the ninth day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _max ranges from about 50 ng/ml to about 60 ng/ml. ㎖, about 50ng/㎖ to about 55ng/㎖, about 55ng/㎖ to about 60ng/㎖, about 80ng/㎖ to about 90ng/㎖, about 80ng/㎖ to about 85ng/㎖, about 85ng/㎖ to about 90ng/㎖ ㎖, about 90ng/㎖ to about 95ng/㎖, about 95ng/㎖ to about 100ng/㎖, about 100ng/㎖ to about 105ng/㎖, about 105ng/㎖ to about 110ng/㎖, about 110ng/㎖ 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/㎖ to about 150ng/㎖, about 150ng/㎖ to about 155ng/㎖, about 155ng/㎖ to about 160ng/㎖, about 160ng/㎖ to about 170ng/㎖, about 170ng/㎖ 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, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml, at least about 50ng/ml, at least about 55ng/ml, at least about 60ng/ml, at least about 65ng/ml 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 It may be 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, on the 10th day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _max ranges from about 50 ng/ml to about 60 ng/ml. ㎖, about 50ng/㎖ to about 55ng/㎖, about 55ng/㎖ to about 60ng/㎖, about 80ng/㎖ to about 90ng/㎖, about 80ng/㎖ to about 85ng/㎖, about 85ng/㎖ to about 90ng/㎖ ㎖, about 90ng/㎖ to about 95ng/㎖, about 95ng/㎖ to about 100ng/㎖, about 100ng/㎖ to about 105ng/㎖, about 105ng/㎖ to about 110ng/㎖, about 110ng/㎖ to about 115ng/㎖ ㎖, about 115ng/㎖ to about 120ng/㎖, about 120ng/㎖ to about 130ng/㎖, about 130ng/㎖ to about 135ng/㎖, about 135ng/㎖ to about 140ng/㎖, about 140ng/㎖ to about 145ng/㎖ ㎖, about 145ng/㎖ to about 150ng/㎖, about 150ng/㎖ to about 155ng/㎖, about 155ng/㎖ to about 160ng/㎖, about 160ng/㎖ to about 170ng/㎖, about 170ng/㎖ 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, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml, at least about 50ng/ml, at least about 55ng/ml, at least about 60ng/ml, at least about 65ng/ml 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 It may be 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 in combination with dextromethorphan is such that the C _avg of dextromethorphan is at least about 4.0 ng/ml, at least about 5.0 over the period between two separate and consecutive administrations of dextromethorphan. 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 /ml, at least about 110ng/ml, at least about 115ng/ml, at least about 120ng/ml, at least about 125ng/ml, at least about 130ng/ml, at least about 135ng/ml, at least about 140ng/ml, or at least about 140.5ng /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 155ng /ml, from about 155 ng/ml to about 160 ng/ml, from about 160 ng/ml to about 170 ng/ml, from about 170 ng/ml to about 200 ng/ml, and in some embodiments, up to about 10,000 ng/ml. It can be. 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, dextromethorphan The period between two separate consecutive doses of metorphan is from shortly after 8:00 a.m. to just before 8:00 p.m. on Day 1.

In some embodiments, on the eighth day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _avg 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 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, about 55 ng/ml 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 can be 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, and in some embodiments, up to about 10,000 ng/ml day. You can. The C _avg values given above may be for the period between two separate and consecutive doses of dextromethorphan, or, if dextromethorphan is administered only once every eight days, C _avg may be for the period between the first dose of dextromethorphan. This may be for 12 hours after the first dose.

In some embodiments, on the ninth day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _avg 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 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, about 55 ng/ml 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 can be 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, and in some embodiments, up to about 10,000 ng/ml day. You can. The C _avg values given above may be for the period between two separate and consecutive doses of dextromethorphan, or, if dextromethorphan is administered only once every 9 days, C _avg may be for the period between the first dose of dextromethorphan. This may be for 12 hours after the first dose.

In some embodiments, on the 10th day of enhanced dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _avg 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 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, about 55 ng/ml 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 can be 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, and in some embodiments, up to about 10,000 ng/ml day. You can. The C _avg values given above may be for the period between two separate and consecutive doses of dextromethorphan, or, if dextromethorphan is administered only once every 10 days, C _avg may be for the period between the first dose of dextromethorphan. This may be for 12 hours after the first dose.

The dextromethorphan fluctuation index value FI (%) can be determined by the following equation:

In some embodiments, on day 8 when the dextromethorphan plasma concentration is increased, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan FI (%) is equal to the ratio of dextromethorphan and the antidepressant. It is reduced by at least 1.5-fold or at least 2-fold compared to dextromethorphan administered for 8 days without an increase in plasma concentration, such as by co-administration of .

In some embodiments, on day 9, when the dextromethorphan plasma concentration is increased, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan FI (%) is equal to the ratio of dextromethorphan and the antidepressant. It is reduced by at least 1.5-fold or at least 2-fold compared to dextromethorphan administered for 9 days without an increase in plasma concentration, such as by co-administration of .

In some embodiments, the dextromethorphan FI (%) on day 10 of increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, is equal to or greater than the ratio of dextromethorphan and the antidepressant. Compared to dextromethorphan administered for 10 days without an increase in plasma concentration, such as by co-administration, it is reduced by at least 1.5-fold or at least 2-fold.

In some embodiments, the dextromethorphan FI(%) is less than 100%, less than 50%, on day 8 of increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant. , less than 40%, less than 30%, about 20 to 50%, about 20 to 40%, about 20 to 30%, or any FI(%) value in a range limited by any of these values.

In some embodiments, the dextromethorphan FI(%) is less than 100% and less than 50% on day 9 after the increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant. , less than 40%, less than 30%, about 20 to 50%, about 20 to 40%, about 20 to 30%, or any FI(%) value in a range limited by any of these values.

In some embodiments, the dextromethorphan FI(%) is less than 100% and less than 50% on day 9 after the increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant. , less than 40%, less than 30%, about 20 to 50%, about 20 to 40%, about 20 to 30%, or any FI(%) value in a range limited by any of these values.

In some embodiments, for example, when dextromethorphan plasma concentrations are improved by co-administration of dextromethorphan and an antidepressant, the dextrorphan FI (%) on day 8 is increased by co-administration of dextromethorphan with the antidepressant. As with co-administration, the plasma concentration decreases by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold compared to dextromethorphan administered for 8 days without an increase in plasma concentration.

In some embodiments, for example, when dextromethorphan plasma concentrations are improved by co-administration of dextromethorphan and an antidepressant, the dextrorphan FI (%) on day 9 is increased by co-administration of dextromethorphan with the antidepressant. As with co-administration, the plasma concentration decreases by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold compared to dextromethorphan administered for 9 days without an increase in plasma concentration.

In some embodiments, for example, when dextromethorphan plasma concentrations are improved by co-administration of dextromethorphan and an antidepressant, the dextrorphan FI (%) on day 10 is increased by co-administration of dextromethorphan with the antidepressant. As with co-administration, the plasma concentration decreases by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold compared to dextromethorphan administered for 10 days without an increase in plasma concentration.

In some embodiments, for example, by co-administration of dextromethorphan and an antidepressant, the dextromethorphan FI(%) on day 8 of increased dextromethorphan FI(%) is less than 100%, less than 70%. , any FI(%) value in a range limited by less than 60%, less than 50%, less than 40%, about 30 to 70%, about 30 to 60%, about 30 to 50%, or any of these values. You can.

In some embodiments, the dextromethorphan FI(%) is less than 100% and less than 70% on day 9 after the increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant. , any FI(%) value in a range limited by less than 60%, less than 50%, less than 40%, about 30 to 70%, about 30 to 60%, about 30 to 50%, or any of these values. You can.

In some embodiments, the dextromethorphan FI(%) is less than 100% and less than 70% on day 9 after the increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant. , less than 60%, less than 50%, about 30 to 70%, about 30 to 60%, about 30 to 50%, or any FI(%) value in a range limited by any of these values.

In some embodiments, the trough level of dextromethorphan on the first day that the antidepressant and dextromethorphan are administered (e.g., the plasma level 12 hours after administration; also referred to herein as “C _min ”) is equal to the same amount without the antidepressant. may be at least twice the trough level that would be achieved by administering dextromethorphan.

In some embodiments, on the first day of increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _min 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. /ml, at least about 1.7ng/ml, at least about 1.8ng/ml, at least about 1.9ng/ml, at least about 2.0ng/ml, at least about 2.1ng/ml, at least about 2.2ng/ml, at least about 2.3ng/ mL, at least about 2.4 ng/mL, at least about 2.5 ng/mL, or at least about 2.5 ng/mL, and may be up to about 100 ng/mL.

In some embodiments, for example, by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _min on day 5 of increased dextromethorphan C min 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 10ng/ml, at least about 15ng/ml, at least about 20ng/ml, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml 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, or at least about 80.9 ng/mL. It may be mL, and may be up to about 10,000 ng/mL.

In some embodiments, for example, by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _min on day 6 of increased dextromethorphan C min 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 10ng/ml, at least about 15ng/ml, at least about 20ng/ml, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml 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, It may be 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 may be up to about 10,000 ng/mL.

In some embodiments, for example, by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _min on day 7 of increased dextromethorphan C min 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 10ng/ml, at least about 15ng/ml, at least about 20ng/ml, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml 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, It can be at least about 90 ng/ml, at least about 95 ng/ml, at least about 100 ng/ml, at least 105 ng/ml, at least 110 ng/ml, or at least about 110.6 ng/ml, and can be up to about 10,000 ng/ml.

In some embodiments, on day 8, when the dextromethorphan plasma concentration is increased, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _min 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 10ng/ml, at least about 15ng/ml, at least about 20ng/ml, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml 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 105 ng/ml, at least 110 ng/ml, at least 115 ng/ml, at least 119.3 ng/ml, about 20 ng/ml to about 30 ng/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 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 about 155 ng/ml, about 155 ng/ml to about 160 ng/ml, about It may be from 160 ng/ml to about 170 ng/ml, or from about 170 ng/ml to about 200 ng/ml, and may be up to about 10,000 ng/ml.

In some embodiments, on day 9, when the dextromethorphan plasma concentration is increased, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _min 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 10ng/ml, at least about 15ng/ml, at least about 20ng/ml, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml 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 105 ng/ml, at least 110 ng/ml, at least 115 ng/ml, at least 119.3 ng/ml, about 20 ng/ml to about 30 ng/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 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 about 155 ng/ml, about 155 ng/ml to about 160 ng/ml, about It may be from 160 ng/ml to about 170 ng/ml, or from about 170 ng/ml to about 200 ng/ml, and may be up to about 10,000 ng/ml.

In some embodiments, on day 10 of increased dextromethorphan plasma concentration, e.g., by co-administration of dextromethorphan and an antidepressant, the dextromethorphan C _min 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 10ng/ml, at least about 15ng/ml, at least about 20ng/ml, at least about 25ng/ml, at least about 30ng/ml, at least about 35ng/ml, at least about 40ng/ml, at least about 45ng/ml 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 105 ng/ml, at least 110 ng/ml, at least 115 ng/ml, at least 119.3 ng/ml, about 20 ng/ml to about 30 ng/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 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 about 155 ng/ml, about 155 ng/ml to about 160 ng/ml, about It may be from 160 ng/ml to about 170 ng/ml, or from about 170 ng/ml to about 200 ng/ml, and may be 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, wherein the decrease in dextromethorphan plasma concentration is compared to the same amount of dextromethorphan without the antidepressant. It occurs on the first day of concurrent administration of and dextromethorphan. For example, the dextrorphan plasma concentration on the first day may be reduced by at least 5% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without the antidepressant.

In some embodiments, the antidepressant is administered in combination with dextromethorphan for at least 5 consecutive days to a human in need of treatment with dextromethorphan, wherein the dextromethorphan plasma concentration on the 5th consecutive day is This is higher than the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan for 5 days without antidepressant medication. For example, dextromethorphan plasma concentrations on day 5 (e.g., 0, 1, 3, 6, or 12 hours post-administration) will increase after 5 consecutive doses of the same amount of dextromethorphan without the antidepressant. The concentration may 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 concentration achieved when administered for one day.

In some embodiments, the antidepressant is administered in combination with dextromethorphan for at least 6 consecutive days to a human in need of treatment with dextromethorphan, wherein the dextromethorphan plasma concentration on the 6th consecutive day is This is higher than the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan for 6 days without antidepressant medication. For example, dextromethorphan plasma concentrations on day 6 (e.g., 0, 1, 3, 6, or 12 hours post-administration) would be greater than the 6 consecutive doses of the same amount of dextromethorphan without the antidepressant. The concentration may 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 concentration achieved when administered for one day.

In some embodiments, the antidepressant is administered in combination with dextromethorphan for at least 7 consecutive days to a human in need of treatment with dextromethorphan, wherein the dextromethorphan plasma concentration on day 7 is continuous. This is higher than the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan for 7 days without antidepressant medication. For example, dextromethorphan plasma concentrations on day 7 (e.g., 0, 1, 3, 6, or 12 hours post-dose) would be greater than those administered with the same amount of dextromethorphan continuously without the antidepressant. The concentration may 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 concentration achieved when administered for 7 days.

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

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, wherein the dextrorphan plasma concentration on day 8 is equal to or greater than 8 consecutive days. dextrorphan plasma concentrations are lower than those achieved by administering the same amount of dextromethorphan without an antidepressant. For example, dextromethorphan plasma concentrations on day 8 (e.g., 0, 1, 3, 6, or 12 hours after administration) would be greater than those administered with the same amount of dextromethorphan without the antidepressant for 8 consecutive days. When compared to the dextrorphan plasma concentration achieved when administered, it can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%.

In some embodiments, the antidepressant and dextromethorphan are coadministered for at least 9 consecutive days, wherein on day 9 dextromethorphan is administered, e.g., 0 hours after coadministration of the antidepressant with dextromethorphan. , at least 5 times, at least 10 times, at least 20 times, at least the plasma concentration achieved by administering the same amount of dextromethorphan without an antidepressant for 9 consecutive days at 1 hour, 3 hours, 6 hours, or 12 hours. It has a plasma concentration that is 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or up to about 1000-fold.

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, wherein the dextrorphan plasma concentration on day 9 is equal to or greater than 9 consecutive days. dextrorphan plasma concentrations are lower than those achieved by administering the same amount of dextromethorphan without an antidepressant. For example, dextromethorphan plasma concentrations on day 9 (e.g., 0, 1, 3, 6, or 12 hours post-administration) would be greater than those administered with the same amount of dextromethorphan for 9 consecutive days without the antidepressant. The dextrorphan plasma concentration may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the dextrorphan plasma concentration achieved when administered for a period of time.

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

In some embodiments, an antidepressant and dextromethorphan are administered in combination to a human in need of treatment with dextromethorphan for at least 10 consecutive days, wherein the dextrorphan plasma concentration on day 10 is equal to or greater than 10 consecutive days. dextrorphan plasma concentrations are lower than those achieved by administering the same amount of dextromethorphan without an antidepressant. For example, dextromethorphan plasma concentrations on day 10 (e.g., 0, 1, 3, 6, or 12 hours after administration) would be greater than the same dose of dextromethorphan for 10 consecutive days without the antidepressant. The dextrorphan plasma concentration may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the dextrorphan plasma concentration achieved when administered for a period of time.

For compositions comprising both dextromethorphan and an antidepressant, some of the liquid may contain 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) to about 5% (w) /v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (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), about 40% (w/v) to about 50% (w/v) of the combined dextromethorphan and an antidepressant, or a range limited by any such value, or an amount between 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). /w), at least about 80% (w/v), 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), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) about 60 % (w/w), about 70% (w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) combined dextromethorphan. and antidepressants, or a range limited by any such value, or an amount between such values.

The therapeutically effective amount of a therapeutic compound may vary depending on the situation. For example, the daily dose of dextromethorphan may in some cases be from 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, 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, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to 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, about 100 mg to about 140 mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about 220 mg to about 260 mg, 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 these values. The daily dose may be within the boundary range, or anywhere between these values. Dextromethorphan once daily; or may be administered twice a day or every 12 hours, three times a day, four times a day, or six times a day, respectively, in an amount of about half, one-third, one-quarter, or one-sixth of the daily dose. .

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. /day, about 60 mg/day to about 100 mg/day, about 80 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. A dose of dextromethorphan is administered to humans who need it.

Antidepressant compounds can be administered as needed to treat neurological conditions such as pain, depression, or cough. In some embodiments, the antidepressant compound and dextromethorphan are administered 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, or 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, at least 2 years, or It is administered at least once daily, such as once daily or twice daily, for longer, up to 1 year, up to 18 months, up to 2 years, up to 3 years, up to 5 years, or longer.

In some embodiments, the co-administration of the antidepressant and dextromethorphan is administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9 days prior to co-administration of the antidepressant and dextromethorphan twice daily. , can be done once a day for 10, 11, 12, 13, 14, 15, or more days.

Therapeutic compounds may be formulated for oral administration, for example with an inert diluent or edible carrier, enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into dietary foods. For oral therapeutic administration, the active compounds can be incorporated with excipients and used in the form of ingestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.

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, etc.; Lubricants such as magnesium stearate; Sweeteners such as sucrose, lactose, or saccharin; Or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain a liquid carrier in addition to substances of the above type. A variety of different materials may be present as coatings, for example tablets, pills or capsules may be coated with shellac, sugar or both. Syrups or elixirs may contain the active compounds, sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings such as cherry or orange flavor. It may be desirable for the substances of the dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts used.

Some compositions or dosage forms may be liquid or may include a solid phase dispersed in a liquid.

Therapeutic compounds may be formulated for parenteral or intraperitoneal administration. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also have oil dispersed or dispersed in glycerol, liquid polyethylene glycol, and mixtures thereof. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth.

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, Asian.

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 not to be, Hispanic or Latino.

Specifically, the contemplated embodiments

The following are examples of embodiments specifically contemplated by the inventor:

Embodiment 1. A method of treating pain or a neurological and/or psychiatric disorder comprising administering to a person in need thereof a therapeutically effective amount of a combination of dextromethorphan and an antidepressant compound.

Embodiment 2. A method of treating pain comprising administering a combination of an antidepressant compound and dextromethorphan to a human in need thereof.

Embodiment 3. A method of enhancing the pain relief properties of dextromethorphan comprising coadministering dextromethorphan and an antidepressant compound.

Embodiment 4. Increasing dextromethorphan plasma concentrations in humans who are extensive metabolizers of dextromethorphan, comprising co-administering an antidepressant compound to humans undergoing treatment comprising administration of dextromethorphan. method.

Embodiment 5. A method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound to a human, wherein the human is a widespread metabolizer of dextromethorphan, and wherein the dextromethorphan is a A method of inhibiting the metabolism of dextromethorphan, which exists simultaneously with antidepressant compounds in the body.

Embodiment 6. A method of increasing the metabolic lifespan of dextromethorphan, comprising administering an antidepressant compound to a human, wherein the human is a broad metabolizer of dextromethorphan, and the dextromethorphan is a human A method of increasing the metabolic lifespan of dextromethorphan, which is present simultaneously with the antidepressant compound in the body.

Embodiment 7. A method of correcting extensive metabolism 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 concurrently with administering dextromethorphan to a human in need thereof.

Embodiment 9. A method of improving the antitussive properties of dextromethorphan comprising administering an antidepressant compound concurrently with administering dextromethorphan to a human in need of cough treatment.

Embodiment 10. A method of treating cough comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan.

Embodiment 11. A method of improving the therapeutic properties of dextromethorphan comprising administering an antidepressant compound concurrently 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 to a human in need thereof a combination of an antidepressant compound and dextromethorphan.

Embodiment 13. The method of Embodiment 12, wherein the human is an extensive metabolizer of dextromethorphan.

Embodiment 14. The method of any preceding embodiment, such as Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein dextromethorphan and an antidepressant compound. is administered in a separate dosage form.

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 to inhibit the metabolism of dextromethorphan in humans who are extensive metabolizers of dextromethorphan.

Embodiment 17. The oral dosage form of Embodiment 16, wherein about 30 mg to about 350 mg of dextromethorphan is present in the dosage form.

Embodiment 18. The method of any of the preceding embodiments, wherein dextromethorphan is administered to a human for the treatment of cough.

Embodiment 19. The method of any of the preceding embodiments, wherein dextromethorphan is administered to the human at least daily for at least 8 days, at least 9 days, or at least 10 days.

Embodiment 20. The method of any of the preceding embodiments, wherein the antidepressant is administered in an amount such that the plasma concentration of dextromethorphan in the human on day 8 is at least 10 times the plasma concentration of the same amount of dextromethorphan administered without the antidepressant. How to become.

Embodiment 21. The method of any of the preceding embodiments, wherein the human is an extensive metabolizer of dextromethorphan.

Embodiment 22. The method of any of the preceding embodiments, wherein dextromethorphan is administered to a human for the treatment of pain.

Embodiment 23. The method of any of the preceding embodiments, such as Embodiment 22, wherein the pain is post-operative pain, cancer pain, arthritis pain, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain. How to include

Embodiment 24. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain.

Embodiment 25. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises postoperative pain.

Embodiment 26. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises cancer pain.

Embodiment 27. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises arthritic pain.

Embodiment 28. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises lumbosacral pain.

Embodiment 29. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises musculoskeletal pain.

Embodiment 30. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises neuropathic pain.

Embodiment 31. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises nociceptive pain.

Embodiment 32 The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises chronic musculoskeletal pain.

Embodiment 33. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with rheumatoid arthritis.

Embodiment 34. The method of any preceding embodiment, such as embodiment 22, wherein the pain is associated with juvenile rheumatoid arthritis.

Embodiment 35. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with osteoarthritis.

Embodiment 36. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with axial spondyloarthritis.

Embodiment 37. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with ankylosing spondylitis.

Embodiment 38. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with diabetic peripheral neuropathy.

Embodiment 39. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with postherpetic neuralgia.

Embodiment 40. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with trigeminal neuralgia.

Embodiment 41 The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with a monogenic myopathy.

Embodiment 42. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain relates to phantom limb pain.

Embodiment 43. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with central pain.

Embodiment 44. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with cancer-related pain.

Embodiment 45. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises lumbar nerve root compression.

Embodiment 46. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with spinal cord injury.

Embodiment 47. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with post-stroke pain.

Embodiment 48. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with central multiple sclerosis pain.

Embodiment 49. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with HIV-related neuropathy.

Embodiment 50. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with radiation therapy-related neuropathy.

Embodiment 51. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with chemotherapy-related neuropathy.

Embodiment 52. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain comprises toothache.

Embodiment 53. The method of any of the preceding embodiments, such as embodiment 22, wherein the pain is associated with primary dysmenorrhea.

Embodiment 54. The method of any of the preceding embodiments, wherein 90 mg/day of dextromethorphan is administered to the human.

Embodiment 55. The method of any of the preceding embodiments, such as Embodiment 54, wherein 45 mg of dextromethorphan is administered to the human twice daily.

Embodiment 56. The method of any of the preceding embodiments, wherein the antidepressant is administered in an amount such that the AUC _0-12 of dextromethorphan is at least about 40 ng·hr/ml.

Embodiment 57. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan is at least about 50 ng·hr/ml.

Embodiment 58. The method of any of the preceding embodiments, wherein the human is in need of treatment with dextromethorphan.

Embodiment 59. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan on days 8, 9, or 10 is at least about 100 ng·hr/ml.

Embodiment 60. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan on days 8, 9, or 10 is at least about 400 ng·hr/ml.

Embodiment 61. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan on days 8, 9, or 10 is at least about 800 ng·hr/ml.

Embodiment 62. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan on days 8, 9, or 10 is at least about 1500 ng·hr/ml.

Embodiment 63. The method of any of the preceding embodiments, wherein the AUC _0-24 of dextromethorphan on days 8, 9, or 10 is at least about 100 ng·hr/ml.

Embodiment 64. The method of any of the preceding embodiments, wherein the AUC _0-24 of dextromethorphan on days 8, 9, or 10 is at least about 1500 ng·hr/ml.

Embodiment 65. The method of any of the preceding embodiments, wherein the AUC _0-24 of dextromethorphan on days 8, 9, or 10 is at least about 2900 ng·hr/ml.

Embodiment 66. The method of any of the preceding embodiments, wherein the AUC _0-inf of dextromethorphan on day 8, day 9, or day 10 is at least about 100 ng·hr/ml.

Embodiment 67. The method of any of the preceding embodiments, wherein the AUC _0-inf of dextromethorphan on day 8, 9, or 10 is at least about 1500 ng·hr/ml.

Embodiment 68. The method of any of the preceding embodiments, wherein the AUC _0-inf of dextromethorphan on day 8, day 9, or day 10 is at least about 3500 ng·hr/ml.

Embodiment 69. The method of any of the preceding embodiments, wherein the AUC _0-inf of dextromethorphan on day 8, 9, or 10 is at least about 5000 ng·hr/ml.

Embodiment 70. The method of any of the preceding embodiments, wherein the antidepressant is administered in an amount such that the C _max of dextromethorphan is at least about 6 ng/ml.

Embodiment 71 The method of any of the preceding embodiments, such as Embodiment 70, wherein the C _max of dextromethorphan on day 8, 9, or 10 is at least about 10 ng/ml.

Embodiment 72. The method of any of the preceding embodiments, wherein the C _max of dextromethorphan on day 8, 9, or 10 is at least about 20 ng/ml.

Embodiment 73. The method of any of the preceding embodiments, wherein the C _max of dextromethorphan on day 8, 9, or 10 is at least about 60 ng/ml.

Embodiment 74. The method of any of the preceding embodiments, wherein the C _max of dextromethorphan on day 8, 9, or 10 is at least about 120 ng/ml.

Embodiment 75. The method of any of the preceding embodiments, wherein the antidepressant is administered in an amount such that the C _avg of dextromethorphan is at least about 5 ng/ml 12 hours after a single administration.

Embodiment 76. The method of any of the preceding embodiments, wherein the C _avg of dextromethorphan on day 8, 9, or 10 is at least about 20 ng/ml.

Embodiment 77. The method of any of the preceding embodiments, wherein the C _avg of dextromethorphan on day 8, 9, or 10 is at least about 70 ng/ml.

Embodiment 78. The method of any of the preceding embodiments, wherein the C _avg of dextromethorphan on day 8, 9, or 10 is at least about 120 ng/ml.

Embodiment 79. The method of any of the preceding embodiments, wherein the antidepressant is administered in an amount such that the AUC _0-12 of dextromethorphan is at least about 40 ng·hr/ml.

Embodiment 80. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan is at least about 50 ng·hr/ml.

Embodiment 81. The method of any of the preceding embodiments, wherein the antidepressant is administered in combination with dextromethorphan at least daily for at least two consecutive days.

Embodiment 82. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan on days 8, 9, or 10 is at least about 100 ng·hr/ml.

Embodiment 83. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan on days 8, 9, or 10 is at least about 800 ng·hr/ml.

Embodiment 84. The method of any of the preceding embodiments, wherein the AUC _0-12 of dextromethorphan on days 8, 9, or 10 is at least about 1500 ng·hr/ml.

Embodiment 85. The method of any of the preceding embodiments, wherein the AUC _0-24 of dextromethorphan on days 8, 9, or 10 is at least about 100 ng·hr/ml.

Embodiment 86. The method of any of the preceding embodiments, wherein the AUC _0-24 of dextromethorphan on days 8, 9, or 10 is at least about 1500 ng·hr/ml.

Embodiment 87. The method of any of the preceding embodiments, wherein the AUC _0-inf of dextromethorphan on day 8, 9, or 10 is at least about 100 ng·hr/ml.

Embodiment 88. The method of any of the preceding embodiments, wherein the AUC _0-inf of dextromethorphan on day 8, 9, or 10 is at least about 3500 ng·hr/ml.

Embodiment 89. The method of any of the preceding embodiments, wherein the AUC _0-inf of dextromethorphan on day 8, 9, or 10 is at least about 5000 ng·hr/ml.

Embodiment 90. The method of any of the preceding embodiments, wherein about 0.6 mg/kg to about 0.8 mg/kg of dextromethorphan is administered orally once or twice daily.

Embodiment 91. The method of any of the preceding embodiments, wherein the human suffers from treatment-resistant depression.

Embodiment 92. The method of any of the preceding embodiments, wherein dextromethorphan is administered orally in a dosage form that provides immediate release of dextromethorphan.

Embodiment 93. The method of any of the preceding embodiments, wherein the antidepressant is administered orally in a dosage form that provides sustained release of the antidepressant.

Embodiment 94. The method of any of the preceding embodiments, wherein the antidepressant and dextromethorphan are administered orally together in a single dosage form administered orally once or twice daily.

Embodiment 95. The method of any of the preceding embodiments, wherein dextromethorphan and the antidepressant are administered orally for at least 5 weeks.

Embodiment 96. The method of any of the preceding embodiments, wherein the human suffers from major depressive disorder.

Embodiment 97. The method of any of the preceding embodiments, wherein the antidepressant comprises an enantiomeric excess of the R-enantiomer.

Embodiment 98. The method of any of the preceding embodiments, wherein the antidepressant comprises an enantiomeric excess of the S-enantiomer.

Embodiment 99. The method of any of the preceding embodiments, wherein the dextromethorphan comprises deuterium-modified dextromethorphan.

Embodiment 100. The method of any of the preceding embodiments, wherein the human is currently suffering from depression and has been previously treated unsuccessfully with at least two antidepressants.

Embodiment 101. A method of rapidly alleviating symptoms of depression comprising administering a combination of an antidepressant and dextromethorphan to a human in need thereof once daily or twice daily, wherein the human is receiving treatment. The effects are experienced within two weeks of the first day of administration of the combination of an antidepressant and dextromethorphan.

Embodiment 102. Use of a combination of an antidepressant and dextromethorphan in the manufacture of a medicament for rapidly alleviating symptoms of depression, wherein the medicament achieves a therapeutic effect within 2 weeks from the first day on which the medicament is administered. Use for administration once a day or twice a day.

Embodiment 103. The method or use of any of the preceding embodiments, wherein the human has previously had an inadequate response to at least one antidepressant therapy.

Embodiment 104. The method or use of any of the preceding embodiments, wherein the depression is major depressive disorder.

Embodiment 105. The method or use of any of the preceding embodiments, wherein the depression is treatment-resistant depression.

Embodiment 106. The method or use of any of the preceding embodiments, wherein the combination of an antidepressant and dextromethorphan is administered once daily or twice daily for at least 30 days.

Embodiment 107. The method or use of any of the preceding embodiments, wherein the combination of an antidepressant and dextromethorphan is administered once daily or twice daily for at least 42 days.

Embodiment 108. A method of treating nicotine addiction associated with cigarette smoking comprising administering to a person suffering from nicotine addiction a combination of an antidepressant and dextromethorphan daily for at least 21 consecutive days, wherein the person is immediately ( ad-lib) A person is a cigarette smoker and a total amount of 80 mg to 140 mg of dextromethorphan is administered to the person every day, and this method is more effective than administering the same amount of antidepressant alone.

Embodiment 109. The method of Embodiment 108, wherein a person taking a combination of an antidepressant and dextromethorphan twice daily in two equal divided doses on the same day or in two divided doses the day after administration. Method that results in greater reductions in nicotine self-administration intensity than those who take only one dose or no combination medication.

Embodiment 110. The method of Embodiment 108 or 109, wherein the combination of an antidepressant and dextromethorphan is administered to the person daily for at least 42 consecutive days.

Embodiment 111. The method of Embodiments 108, 109, or 110, wherein about 90 mg of dextromethorphan is administered to the person daily.

Embodiment 112. The method of any one of Embodiments 109 to 111, wherein about 40 mg to about 50 mg of dextromethorphan in each dose is administered to the human twice daily.

Embodiment 113 The method of any of Embodiments 109 to 112, wherein the method is more effective than administering dextromethorphan alone to a nicotine addict.

Embodiment 114. The method of any one of Embodiments 109 to 113, wherein the antidepressant is deuterium enriched.

Embodiment 115. The method of embodiment 108, wherein the dextromethorphan is deuterium enriched.

Example

The combined effect of the antidepressants bupropion and dextromethorphan in humans is demonstrated in several examples below. Example 2 shows that the results for bupropion are likely to be observed with other antidepressants.

Example 1

As shown in Table 1 below, 15 human subjects were randomly assigned to one of two treatment groups receiving dextromethorphan (DM) alone or DM in combination with bupropion.

All subjects were extensive metabolizers, including ultra-rapid dextromethorphan metabolizers as determined by CYP2D6 genetic testing. Dextromethorphan was administered every 12 hours on days 1 to 8 and on the last morning of day 8. Bupropion was administered once daily on days 1 to 3 and then at 12-hour intervals on the final morning of day 8.

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

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

Phenotypic determination of dextromethorphan metabolizer status was performed as described in Jurica et al. This was performed by calculating the dextromethorphan/dextrorphan metabolic ratio as described in Journal of Clinical Pharmacy and Therapeutics , 2012, 37, 486-490. The plasma concentrations of dextromethorphan and dextrorphan 3 hours after administration were used, and a dextromethorphan/dextrorphan ratio of 0.3 or more indicates a poor metabolizer phenotype.

result

Plasma concentrations of dextromethorphan significantly increased with bupropion administration, as shown in Figure 1 and Table 2.

The AUC of dextromethorphan significantly increased with the administration of bupropion, as shown in Figures 2 to 4. As shown in Figure 5 and Table 2A, administration of bupropion with dextromethorphan resulted in mean dextromethorphan AUC _{of 0-12} , AUC _{of 0-24} , and AUC at day 8 compared to dextromethorphan alone. AUC _0-inf increased approximately 60-fold, 80-fold, and 175-fold, respectively. As shown in Figure 6 and Table 2B, the increase in dextromethorphan AUC occurred as early as day 1 (approximately 3-fold increase in AUC _0-12 ).

The trough plasma concentration of dextromethorphan (also referred to as “minimum mean plasma concentration” or “C _min ”) increased significantly with bupropion administration, as shown in Figure 7 and Tables 2A and 3. Administration of bupropion with dextromethorphan increased the mean trough plasma concentration of dextromethorphan by approximately 105-fold at day 8 compared to administration of dextromethorphan alone.

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

The T _max and elimination half-life (T _{1/2 el} ) of dextromethorphan were significantly increased by bupropion administration on day 8. An increase in T _{1/2 el} indicates an increase in the metabolic lifetime of dextromethorphan. Administration of dextromethorphan and bupropion had an average T _max of 3.6 hours, compared to 2.3 hours for administration of dextromethorphan alone. The average T _{1/2 el} for administration of bupropion and dextromethorphan was 27.7 hours compared to 6.6 hours for administration of dextromethorphan alone.

Plasma concentrations of dextrorphan were significantly reduced by bupropion administration, as shown in Figure 9 and Table 4.

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 of bupropion administration.

Phenotypic determination of dextromethorphan metabolizer status showed that there were no poor metabolizers in either treatment group on day 1. However, by day 8, 100% of subjects treated with bupropion converted to poor metabolizer status compared to 0% of subjects treated with dextromethorphan alone. The average plasma dextromethorphan/dextrorphan metabolic ratio increased from 0.01 on day 1 to 0.71 on day 8 with bupropion administration. The average ratio of the group administered DM alone was 0.00 on day 1 and did not change on day 8.

On day 8, the 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, following bupropion administration.

As used in this section, the terms “fold change” or “fold increase” refer to the ratio of the value for bupropion and dextromethorphan to the same value for dextromethorphan alone (i.e., the value of the plate divided by the same value of dextromethorphan alone).

Example 2

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

After optimal incubation at 37°C, the reaction was terminated by adding methanol containing internal standards 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 the metabolite of dextromethorphan (dextrorphan) was analyzed by LC-MS/MS. The reduction in metabolite formation compared to vehicle control was used to calculate the IC ₅₀ value (test concentration that inhibits dextromethorphan metabolism by 50%) for each antidepressant compound, with lower IC ₅₀ indicating greater efficacy. represents.

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

Example 3

Phase 2 clinical design:

A phase 2 clinical trial of dextromethorphan in combination with bupropion (DM/BU) was conducted in adults diagnosed with moderate to severe major depressive disorder (MDD) who received twice daily doses for a 6-week treatment period. This was a randomized, double-blind, active-controlled, multicenter, US clinical trial involving 80 patients. Dose groups (1:1 randomization) included DM/BU (45 mg dextromethorphan/105 mg bupropion) with 43 patients, or active comparator bupropion (105 mg) with 37 patients. Of these patients, 23% had previously received primary treatment for depression. There were extensive quality control measures in the clinical trial.

Primary endpoints:

Over the 6-week treatment period, the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score was calculated and averaged at each time point.

Figure 13 and Table A show the change in MADRS total score over time during the 6-week dosing period for subjects administered bupropion (BU) or dextromethorphan and bupropion (DM/BU).

Secondary endpoints:

Table B lists secondary endpoints with P-values.

*P-values are for DM/BU versus the active comparator bupropion (BU). Many secondary endpoints favored DM/BU.

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

safety:

Clinical studies have shown that DM/BU administration is safe and well tolerated, with similar rates of adverse reactions in the DM/BU and bupropion groups. No serious adverse reactions were observed. There was no significant difference between the two treatment groups in discontinuation due to adverse events. The most commonly reported adverse reactions in the DM/BU group were nausea, dizziness, dry mouth, decreased appetite, and anxiety. DM/BU was not associated with increased psychotic effects, weight gain, or sexual dysfunction.

summary:

Statistically significant improvements were achieved in MADRS and secondary efficacy endpoints for DM/BU in MDD patients. Early and sustained dissociation from the active comparator bupropion was observed. Administration of DM/BU was safe and well tolerated, without psychotic effects, weight gain, or increased sexual dysfunction.

Accordingly, DM/BU demonstrated significant and rapid antidepressant activity with a favorable safety profile in clinical trials in MDD.

result:

Figures 13 and 14 show 80 adult patients with depression, 43 patients treated with a combination of DM 45 mg and BU 105 mg, administered twice daily over a 6-week treatment period, and 43 patients treated with BU 105 mg. It was written based on the results of a US clinical trial targeting 37 patients. Of these patients, 23% had previously received primary treatment for depression.

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

As shown in Figure 14, even as early as the second week of treatment, the remission rate of the DM/BU combination was significantly higher (about 8 times) than the remission rate of the reference drug BU alone, and the remission rate was about 20% higher. At the 6th week of treatment, the remission rate of DM/BU combination was approximately 30% higher than that of the control drug BU alone.

The above clinical studies showed that combined administration of bupropion and dextromethorphan (DM/BU) provides greater efficacy than that achieved by administration of bupropion alone. This clinical study demonstrated that the combination of dextromethorphan and bupropion has additive or synergistic efficacy in the treatment of depression.

Example 4: Product Kit:

In some embodiments, the product kit comprises a combination of dextromethorphan and bupropion for the treatment of depression, wherein the product kit comprises about 30 mg to about 60 mg of dextromethorphan and about 100 mg to about 200 mg. of bupropion, wherein administration of the dosage form once daily or twice daily results in greater efficacy in humans than administration of bupropion alone. In some embodiments, the product kit contains 45 mg of dextromethorphan and 105 mg of bupropion.

In some embodiments, the product kit includes a dosage form containing bupropion; dextromethorphan; and a water-soluble vehicle, wherein the dosage form contains from about 30 mg to about 60 mg of dextromethorphan and from about 100 mg to about 200 mg of bupropion, and wherein the dosage form is administered at least once a day for at least 8 days. When used once or twice, the elimination half-life (T _1/2 ) of dextromethorphan increases compared to dextromethorphan administered alone on the 8th day.

Example 5:

Nearly 40 million American adults smoke, and about 70% of them report that they want to quit. According to the Centers for Disease Control and Prevention, smoking causes approximately 500,000 premature deaths each year in the United States alone. Smoking is the single largest cause of premature death worldwide, accounting for nearly 20% of all deaths in developed countries [Dani JA and Heinemann S (1996) Neuron 16:5, pp. 905-8]. Direct health care and lost productivity costs due to smoking total nearly $300 billion annually in the United States alone. It is estimated that only 3 to 5% of smokers who attempt to quit without assistance are successful over 6 to 12 months, and even with current treatments, relapse rates remain above 80% [Hughes JR, et al. (2004) Addiction 99:1, pp. 29-38]. As the majority of smokers who try to quit smoking fail, a new approach is needed. The combination of dextromethorphan and bupropion (DM/BU) has the potential to address this condition 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 inhibitor of the serotonin and norepinephrine transporters. The bupropion component of DM/BU acts 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, a mechanism involved in nicotine dependence. Therefore, DM/BU provides a potentially novel mechanism of action for smoking cessation treatment.

Phase 2 clinical design:

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

Primary endpoints:

The primary outcome measure was change in smoking intensity measured using the number of cigarettes smoked per day assessed through a daily smoking diary.

Reduction in extemporaneous smoking was chosen as the primary endpoint in this trial because it has been shown to be correlated with smoking cessation.

safety:

Medication compliance was similar between study groups for both the morning dose (97.1% for DM/BU and 96.6% for bupropion) and evening dose (76.3% for DM/BU and 79.4% for bupropion). In this study, DM/BU was safe and well tolerated without serious side effects. The most commonly reported adverse reactions were headache, dry mouth, and insomnia/vivid dreams, with similar rates in both treatment groups.

result:

Treatment with DM/BU reduced the prespecified primary endpoint, the average number of cigarettes smoked per day over 3 weeks, by more than 25% compared to bupropion (8.49 and 6.79 cigarettes per day for DM/BU and bupropion, respectively). mean decrease in cigarette smoking, p = 0.0016).

Consistent with these results, a greater proportion of smokers who received DM/BU experienced a greater than 50% reduction in exhaled carbon monoxide levels, a biochemical indicator of smoking intensity, compared with those treated with bupropion (DM/BU 52.0% for cases vs. 30.4% for bupropion, p = 0.15).

Additionally, human subjects who took DM/BU on pre-specified days smoked 1.0 fewer cigarettes on DM/BU drug days compared to those who missed one or both doses of DM/BU (p=0.026). ), and smoked 1.2 less cigarettes the next day (p=0.008).

summary:

Treatment with DM/BU achieved the prespecified primary endpoint of the phase 2 smoking cessation trial. Treatment with DM/BU demonstrated a statistically significant reduction in daily smoking compared to the active comparator bupropion alone (p = 0.0016). The results of this phase 2 clinical trial are noteworthy because DM/BU was compared with bupropion, an approved smoking cessation treatment.

Additionally, it is worth noting that the improvement in DM/BU over bupropion observed in this clinical trial in humans was similar in magnitude to the improvement over placebo reported for varenicline, an approved smoking cessation treatment, in a study of similar design. There is. Varenicline is a prescription medication used to treat smoking addiction. This drug is the first approved nicotine receptor partial agonist. Specifically, varenicline is a partial agonist of the alpha4/beta2 subtype of nicotinic acetylcholine receptors.

Example 6

A phase 3, randomized, double-blind, multicenter, placebo-controlled clinical trial of dextromethorphan (DM) in combination with 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 45 mg dextromethorphan/105 mg bupropion (DM/BU) (n=163) or placebo (n=164). It was administered once a day for the first 3 days (day 1, 2, and 3) and twice a day thereafter (starting on day 4) for a total of 6 weeks.

Inclusion criteria are as follows: male or female, aged 18 to 65 years, meeting DSM-5 criteria for current MDD without psychotic features, with a MADRS total score of at least 25, and a CGI-S score of at least 4. . Exclusion criteria were: electroconvulsive therapy, vagal stimulation, transcranial magnetic stimulation, psychiatric symptoms secondary to schizophrenia, bipolar disorder, obsessive-compulsive disorder, and other general medical conditions during the current episode or in the past 6 months; or history of any empiric central nervous system treatment.

Patient demographics and baseline characteristics are shown in Table 6 below:

Unless otherwise specified, data are means (SD).

Abbreviations: BMI = body mass index; BU = bupropion; CGI-S = Clinical Global Impression - Severity; DM = dextromethorphan; MADRS = Montgomery-Asberg Depression Rating Scale

Demographic and baseline characteristics were similar in both treatment groups. Study completion rate was greater than 75% in both treatment groups.

The primary endpoint of the study was change from baseline in MADRS total score at week 6. Secondary endpoints were MADRS change at weeks 1 and 2, remission, response, clinical global impression-improvement (CGI-I), clinical global impression-severity (CGI-S), and global patient impression-improvement ( PGI-I), MADRS-6, Sheehan Disability Scale (SDS), other quality of life scales, safety and tolerability. P-values were calculated based on least squares mean estimates.

DM/BU met its primary endpoint and rapidly and significantly improved depression symptoms. Specifically, DM/BU demonstrated rapid, sustained, and statistically significant improvement in depressive symptoms as measured by the MADRS total score compared to placebo (p=0.002 for the primary endpoint). DM/BU demonstrated a statistically significant reduction in Montgomery-Asberg Depression Rating Scale (MADRS) total score compared to placebo at week 6, with an average decrease of 16.6 points from baseline for DM/BU and 11.9 points for placebo. (p=0.002).

Additionally, statistically significant improvement was observed in the first week or just 4 days after starting twice-daily dosing. As shown in Figure 15, a statistically significant improvement was observed in the MADRS total score at week 1, with a 7.3-point decrease in MADRS total score for DM/BU versus a 4.9-point decrease for placebo (key secondary endpoint, p =0.007), and statistical significance was maintained for this measure at all subsequent time points (e.g., weeks 2, 3, 4, 5, or 6). Global Patient Impression-Improvement (PGI-I) (p=0.008); Clinical Global Impression-Severity (CGI-S) (p=0.013); Clinical Global Impression-Improvement (CGI-I) (p=0.035); Quick Inventory of Self-Assessment of Depressive Symptoms (QIDS-SR-16) (p=0.016); Statistically significant improvement on the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) (p=0.031); and other endpoints were also observed at week 1 and at all subsequent time points (e.g., week 2, week 3, week 4, week 5, or week 6).

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

As shown in Figure 17, depression remission rates (defined as MADRS ≤10) were significantly higher for DM/BU compared to placebo at week 2 (p=0.013) and at all time points thereafter (e.g., weeks 3, 4, or 6). It was statistically significantly greater, achieved by 39.5% of DM/BU patients compared to 17.3% of placebo patients at week 6 (p<0.001).

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

DM/BU demonstrated statistically significant improvements at week 6 compared to placebo in all secondary endpoints, including: clinical response on MADRS total score ( defined as ≥50%) (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).

DM/BU was well tolerated in phase 3 clinical trials. The most commonly reported adverse reactions in the DM/BU group were dizziness, nausea, headache, diarrhea, drowsiness, and dry mouth. There was one serious adverse event in the DM/BU arm that the investigator considered to be unrelated to the study drug. Discontinuation rates due to adverse events were low in both treatment groups (6.2% for DM/BU and 0.6% for placebo). DM/BU treatment was not associated with psychotic effects or weight gain.

Unless otherwise indicated, all numbers referring to quantities of ingredients, properties (e.g., amounts, percentages, etc.) used in the specification and claims represent in all cases both the exact value indicated and as modified by the term “about.” It should be understood as Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the desired properties to be achieved. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant figures and by applying ordinary rounding techniques.

As used in the context of describing embodiments (and especially in the context of the following claims), the terms "a", "an", "the" and similar referents are singular, unless otherwise indicated herein or clearly dictated by the context. It should be interpreted to include both and plural. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., “such as”) provided herein is merely to better describe the embodiments and does not limit the scope of any claims. No language in the specification should be construed as indicating any non-claimed element essential to carrying out the claims.

Groupings of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member may be referenced and claimed individually or in combination with other members of the group or other elements identified herein. For convenience and/or expedited prosecution, one or more group members may be included in or excluded from the group. In the event of such inclusion or omission, the specification is deemed to include the group as modified and, when used in the appended claims, fulfills the written description of all Markush groups.

Specific embodiments are described herein that include the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations to these described embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventor intends the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Additionally, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

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

Claims (104)

A method of treating depression comprising administering to a human in need thereof a combination of an antidepressant and dextromethorphan, wherein the antidepressant is levomilnacipran, vilazodone, vortioxetine, atomoxetine, reboxetine, teniloc. Photo, biloxazine, amitriptyline oxide, dimethacrine, melithracene, nitroxazepine, noxiptyline, pipopezine, setiptyline, caroxazone, metralindole, pyrlindole, eprobemide, minaprine , biphemelan, agomelatine, esketamine, tandospirone, tianeptine, α-methyltryptamine, etriptamine, α-ethyltryptamine, indeloxazine, medifoxamine, oxaflozan, pivagabin, Ademethionine, S-adenosyl-L-methionine, St. John's wort ( hypericum perforatum ), oxytriptan, 5-hydroxytryptophan, rubidium chloride, tryptophan, magnesium, acetylcarnitine, saffron, amisulpride, aripiprazole, brexpi Prazole, lurasidone, olanzapine, quetiapine, risperidone, buspirone, lithium, modafinil, thyroxine, triiodothyronine, minocycline, combination of amitriptyline and chlordiazepoxide, amitriptyline and Perfena. Combination of gin, flupentixol and melithracene, combination of olanzapine and fluoxetine, combination of tranylcypromine and trifluoperazine, 4-chlorokynurenine, AGN-241751, afimostinel, arketamine, dextromethadone, EVT-101, rislenemdaz, basimglurant, AN-788, toludesvenlafaxine, PDC-1421, MIN-117, TGBA01AD, gepirone, pimavanserin, psilocybin, brillaroxazine, lumateperone , ademethionine, ganaxolone, zuranolone, 3β-methoxypregnenolone, PH-10 - vomeroperin, articarant, BTRX-335140, combination of buprenorphine and samidorphan, BTRX-246040, Hyde Roxynorketamine, JNJ-39393406, JNJ-54175446, JNJ-61393215, NNI-351, NSI-189, NV-5138, Onabotulinumtoxin A, Pramipexole, Seltorexant, Sirucumab, SUVN-911, TS- 121, tramadol, a combination of cycloserine and lurasidone, 7,8-dihydroxyflavone (7,8-dhf), minocycline, nitrous oxide, pramipexole, R13, or a combination thereof, How to treat depression. The method of claim 1, wherein the antidepressant comprises levomilnacipran. The method of claim 1, wherein the antidepressant comprises vilazodone. 2. The method of claim 1, wherein the antidepressant comprises vortioxetine. The method of claim 1, wherein the antidepressant comprises atomoxetine. 2. The method of claim 1, wherein the antidepressant comprises reboxetine. 2. The method of claim 1, wherein the antidepressant comprises teniloxazine. 2. The method of claim 1, wherein the antidepressant comprises biloxazine. The method of claim 1, wherein the antidepressant comprises amitriptyline oxide. 2. The method of claim 1, wherein the antidepressant comprises dimethacrine. The method of claim 1, wherein the antidepressant comprises melithracene. 2. The method of claim 1, wherein the antidepressant comprises nitroxazepine. The method of claim 1, wherein the antidepressant comprises noxyptyline. The method of claim 1, wherein the antidepressant comprises pipopezine. The method of claim 1, wherein the antidepressant comprises setiptyline. 2. The method of claim 1, wherein the antidepressant comprises caroxazone. The method of claim 1, wherein the antidepressant comprises metralindole. The method of claim 1, wherein the antidepressant comprises pirlindole. The method of claim 1, wherein the antidepressant comprises eprobemide. The method of claim 1, wherein the antidepressant comprises minaprine. The method of claim 1, wherein the antidepressant comprises biphemelan. The method of claim 1, wherein the antidepressant comprises agomelatine. 2. The method of claim 1, wherein the antidepressant comprises esketamine. 2. The method of claim 1, wherein the antidepressant comprises tandospirone. 2. The method of claim 1, wherein the antidepressant comprises tianeptine. 2. The method of claim 1, wherein the antidepressant comprises α-methyltryptamine. The method of claim 1, wherein the antidepressant comprises etriptamine. The method of claim 1, wherein the antidepressant comprises indeloxazine. The method of claim 1, wherein the antidepressant comprises medifoxamine. 2. The method of claim 1, wherein the antidepressant comprises oxaflozan. The method of claim 1, wherein the antidepressant comprises pivagabine. 2. The method of claim 1, wherein the antidepressant comprises ademethionine. The method of claim 1, wherein the antidepressant comprises St. John's wort. 2. The method of claim 1, wherein the antidepressant comprises oxytriptan. 2. The method of claim 1, wherein the antidepressant comprises 5-hydroxytryptophan. The method of claim 1, wherein the antidepressant comprises rubidium chloride. The method of claim 1, wherein the antidepressant comprises tryptophan. 2. The method of claim 1, wherein the antidepressant comprises magnesium. The method of claim 1, wherein the antidepressant comprises acetylcarnitine. 2. The method of claim 1, wherein the antidepressant comprises saffron. 2. The method of claim 1, wherein the antidepressant comprises amisulpride. The method of claim 1, wherein the antidepressant comprises aripiprazole. The method of claim 1, wherein the antidepressant comprises brexpiprazole. The method of claim 1, wherein the antidepressant comprises lurasidone. 2. The method of claim 1, wherein the antidepressant comprises olanzapine. The method of claim 1, wherein the antidepressant comprises quetiapine. 2. The method of claim 1, wherein the antidepressant comprises risperidone. 2. The method of claim 1, wherein the antidepressant comprises buspirone. The method of claim 1, wherein the antidepressant comprises lithium. The method of claim 1, wherein the antidepressant comprises modafinil. The method of claim 1, wherein the antidepressant comprises thyroxine. The method of claim 1, wherein the antidepressant comprises triiodothyronine. 2. The method of claim 1, wherein the antidepressant comprises minocycline. The method of claim 1, wherein the antidepressant comprises a combination of amitriptyline and chlordiazepoxide. 2. The method of claim 1, wherein the antidepressant comprises a combination of amitriptyline and perphenazine. The method of claim 1, wherein the antidepressant comprises a combination of flupentixol and melithracene. 2. The method of claim 1, wherein the antidepressant comprises a combination of olanzapine and fluoxetine. 2. The method of claim 1, wherein the antidepressant comprises a combination of tranylcypromine and trifluoperazine. The method of claim 1, wherein the antidepressant comprises 4-chlorokynurenine. The method of claim 1, wherein the antidepressant comprises AGN-241751. The method of claim 1, wherein the antidepressant comprises afimostinel. 2. The method of claim 1, wherein the antidepressant comprises arketamine. 2. The method of claim 1, wherein the antidepressant comprises dextromethadone. The method of claim 1, wherein the antidepressant comprises EVT-101. The method of claim 1, wherein the antidepressant comprises lislenemdaz. 2. The method of claim 1, wherein the antidepressant comprises basimglurant. The method of claim 1, wherein the antidepressant comprises AN-788. 2. The method of claim 1, wherein the antidepressant comprises toludesvenlafaxine. The method of claim 1, wherein the antidepressant comprises PDC-1421. 2. The method of claim 1, wherein the antidepressant comprises MIN-117. The method of claim 1, wherein the antidepressant comprises TGBA01AD. The method of claim 1, wherein the antidepressant comprises gepirone. The method of claim 1, wherein the antidepressant comprises pimavanserin. The method of claim 1, wherein the antidepressant comprises psilocybin. 2. The method of claim 1, wherein the antidepressant comprises brillaroxazine. The method of claim 1, wherein the antidepressant comprises lumateperone. 2. The method of claim 1, wherein the antidepressant comprises ademethionine. 2. The method of claim 1, wherein the antidepressant comprises ganaxolone. The method of claim 1, wherein the antidepressant comprises zuranolone. 2. The method of claim 1, wherein the antidepressant comprises 3β-methoxypregnenolone. 2. The method of claim 1, wherein the antidepressant comprises PH-10 - vomeroperine. 2. The method of claim 1, wherein the antidepressant comprises aticarant. The method of claim 1, wherein the antidepressant comprises BTRX-335140. 2. The method of claim 1, wherein the antidepressant comprises a combination of buprenorphine and samidorphan. 2. The method of claim 1, wherein the antidepressant comprises hydroxynorketamine. The method of claim 1, wherein the antidepressant comprises JNJ-39393406. The method of claim 1, wherein the antidepressant comprises JNJ-54175446. The method of claim 1, wherein the antidepressant comprises JNJ-61393215. The method of claim 1, wherein the antidepressant comprises NNI-351. The method of claim 1, wherein the antidepressant comprises NSI-189. The method of claim 1, wherein the antidepressant comprises NV-5138. 2. The method of claim 1, wherein the antidepressant comprises onabotulinumtoxin A. 2. The method of claim 1, wherein the antidepressant comprises pramipexole. The method of claim 1, wherein the antidepressant comprises seltorexant. The method of claim 1, wherein the antidepressant comprises sirucumab. The method of claim 1, wherein the antidepressant comprises SUVN-911. 2. The method of claim 1, wherein the antidepressant comprises TS-121. 2. The method of claim 1, wherein the antidepressant comprises tramadol. The method of claim 1, wherein the antidepressant comprises a combination of cycloserine and lurasidone. 2. The method of claim 1, wherein the antidepressant comprises 7,8-dihydroxyflavone. 2. The method of claim 1, wherein the antidepressant comprises minocycline. The method of claim 1, wherein the antidepressant comprises nitrous oxide. The method of claim 1, wherein the antidepressant comprises pramipexole. 2. The method of claim 1, wherein the antidepressant comprises R13.