CN117615757A - Compositions and methods for treating depression - Google Patents

Abstract

The present disclosure provides methods for treating major depressive disorder in a human patient suffering from moderate or severe anorgasmia. The methods comprise administering to the patient in need thereof an effective amount of alteplerian (atetopiramate) or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is under-responsive to other antidepressant therapies prior to treatment with atenolol. In other embodiments, the other antidepressant therapy comprises a selective 5-hydroxytryptamine reuptake inhibitor SSRI, a 5-hydroxytryptamine-norepinephrine reuptake inhibitor SNRI, or a combination thereof.

Description

Compositions and methods for treating depression

Technical Field

The present disclosure relates to methods for treating depression using atetopiramate (atetopiramate).

Background

Kappa Opioid Receptors (KORs) and their natural ligand dynorphins are located in areas of the brain that affect rewards and stress, and can play a key role in mood, stress, and addictive disorders. Chronic stress, substance abuse and acute withdrawal lead to increased dynorphin expression, activating KOR and subsequent downstream signaling pathways to inhibit mesencephalon marginal dopamine surge, leading to negative emotional states. Behavioral pharmacology of KOR antagonism has been tested in animal models of hedonia, depression and anxiety and found to have a meaningful effect, which translates into therapeutic benefit for humans. KOR antagonists may be effective in treating patients with mood disorders by modulating the negative mood states associated with stress responses.

A lack of hedonia is one of the core symptoms of depression. About 90% of patients with Major Depressive Disorder (MDD) have at least mild symptoms of lack of hedonia. Only about 50% of MDD patients show a meaningful response (> 50% improvement over first-line antidepressant treatment), and therefore many patients still suffer from substantial sustained damage. Although treatment strategies such as replacement of antidepressants and treatment with concomitant medications may improve response, almost 40% of patients still have symptoms and complete relief cannot be achieved.

What is needed is a treatment for patients suffering from depression and lack of pleasure.

U.S. Pat. No. 7,709,522 B2 describes a selective kappa opioid receptor antagonist, 3-fluoro-4- [4- [2- (3, 5-dimethylphenyl) pyrrolidin-1-yl-methyl ] phenoxy ] benzamide.

Krystal et al, (2020) 'A randomized proof-of-mechanism trial applying the' fast-fail 'approach to evaluating kappa-opioid antagonism as a treatment for anhedonia' Nature Medicine, volume 26, phase 5, pages 760-768 report the results of a multicenter, 8 week, double-blind, placebo-controlled, randomized trial using the selective kappa-opioid receptor antagonist JNJ-67953964 for patients with anorgasmia and mood or anxiety disorders.

Urbano et al, (2014) "Antagonists of the kappa opioid receptor", bioorganic & Medicinal Chemistry Letters, volume 24, 9, pages 2021-2032 describe OPRK antagonist LY2456302, which is undergoing phase II clinical trials for enhancing antidepressant therapy in refractory depression.

Underraga et al, (2012) "random, placebo-Controlled Trials of Antidepressants for Acute Major Depression: third-Year Meta-analytical Review", neuropyschopharmacology, volume 37, page 4, describes a Meta-analysis Review of Placebo-controlled trials of acute, monophasic, major depressive episodes reported in the past three decades to compare individual antidepressant and class efficacy (drug-Placebo RD), and consider factors related to the Year of reporting by bivariate and multivariate regression modeling.

Summary of the inventionsummary

In some aspects, the disclosure relates to methods for treating major depressive disorder in a human patient suffering from a lack of pleasure, comprising administering to a patient in need thereof an effective amount of altaicaropram or a pharmaceutically acceptable salt thereof. In another aspect, methods for treating Major Depressive Disorder (MDD) in a human patient are provided, comprising administering to a patient in need thereof an effective amount of alteplercanium or a pharmaceutically acceptable salt thereof, consisting of, or consisting essentially of, the steps, wherein the patient has a lack of hedonia. In certain embodiments, the patient is under-responsive to other antidepressant therapies prior to treatment with atenolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the other antidepressant therapy comprises one or more antidepressants. In certain embodiments, prior to treatment with atenolol or a pharmaceutically acceptable salt thereof, the patient is under-responsive to other antidepressant therapies, including, for example, under-responsive to selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs), or a combination thereof. In certain embodiments, the one or more antidepressants comprise a selective 5-hydroxytryptamine reuptake inhibitor (SSRI). In certain embodiments, the one or more antidepressants comprise a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI) treatment. In certain embodiments, methods for treating Major Depressive Disorder (MDD) in a human patient are provided, comprising administering to a patient in need thereof an effective amount of alteplercanium or a pharmaceutically acceptable salt thereof, consisting of, or consisting essentially of, wherein the patient suffers from a lack of hedonia, and wherein the patient is under-responsive to selective 5-hydroxytryptamine reuptake inhibitor (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof. Also described herein is an actecapram or a pharmaceutically acceptable salt thereof for use in the treatment of Major Depressive Disorder (MDD) in a human patient, the treatment comprising administering to a patient in need thereof an effective amount of actecapram or a pharmaceutically acceptable salt thereof, consisting of or consisting essentially of the steps, wherein the patient suffers from a lack of hedonia, and wherein the patient is under-responsive to a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof. In certain embodiments, the patient has a sneezing-hamilton fast induction scale (SHAPS) score of 20 or more. In certain embodiments, the patient suffers from moderate or severe anorgasmia. In certain embodiments, the patient has a SHAPS score of 38 or greater.

In other aspects, the methods comprise adjunctive therapy with an effective amount of one or more antidepressants. The one or more antidepressants may include, for example, a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

In a further aspect, the present disclosure relates to an actalapril, or a pharmaceutically acceptable salt thereof, for use in a method of treating major depressive disorder in a human patient suffering from a lack of pleasure, the method comprising administering to the patient in need thereof an effective amount of actalapril, or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient has a sneezing-hamilton fast induction scale (SHAPS) score of 20 or more. In certain embodiments, the patient suffers from moderate or severe anorgasmia. In certain embodiments, the patient has a total SHAPS score of 32 or greater. In certain embodiments, the patient has a SHAPS score of 38 or greater.

In still other aspects, the present disclosure is also directed to actecapram or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder in a human patient suffering from a lack of hedonia, the treatment particularly comprising administering an effective amount of actecapram or a pharmaceutically acceptable salt thereof. Also described is actecapram or a pharmaceutically acceptable salt thereof for use in the treatment of Major Depressive Disorder (MDD) in a human patient, the treatment comprising administering to a patient in need thereof an effective amount of actecapram or a pharmaceutically acceptable salt thereof, consisting of or consisting essentially of the steps, wherein the patient has a lack of hedonia. In certain embodiments, the patient has a sneezing-hamilton fast induction scale (SHAPS) score of 20 or more at baseline. In certain embodiments, the patient suffers from moderate or severe anorgasmia. In certain embodiments, the patient has a total SHAPS score of 32 or greater. In certain embodiments, the patient has a SHAPS score of 38 or greater at baseline.

In yet a further aspect, the present disclosure also relates to the use of alteplercanium or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating major depressive disorder in a human patient suffering from a lack of hedonia, in particular wherein the treatment comprises administering an effective amount of alteplercanium or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient has a sneezing-hamilton fast induction scale (SHAPS) score of 20 or more. In certain embodiments, the patient suffers from moderate or severe anorgasmia. In certain embodiments, the patient has a total SHAPS score of 32 or greater. In certain embodiments, the patient has a SHAPS score of 38 or greater.

In other aspects, the present disclosure also relates to a package or pharmaceutical product comprising actalapril or a pharmaceutically acceptable salt thereof and instructions for treating major depressive disorder in a human patient suffering from a lack of hedonia, in particular, wherein the treatment comprises administering an effective amount of actalapril or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient has a sneezing-hamilton fast induction scale (SHAPS) score of 20 or more. In certain embodiments, the patient has a measured total SHAPS score of 32 or more. In certain embodiments, the patient suffers from moderate or severe anorgasmia. In certain embodiments, the patient has a SHAPS score of 38 or greater.

Drawings

FIG. 1 is a test design of example 1.

Fig. 2 is a line graph showing the total score of MADRS (montgomery-asberg depression rating scale): the mean least squares mean of the enrichment intent-to-treat (eITT) analysis set over the treatment period varied (. + -. SE) from baseline.

Fig. 3 is a graph showing the total score change for MADRS at week 6 of treatment for enriched and whole populations: MMRM results-estimated LS mean and comparison with placebo.

Fig. 4 is a line graph showing the total score of SHAPS (sneezing-hamilton fast induction scale): changes (±se) from baseline in the least squares mean of the eITT analysis set during the treatment period.

Fig. 5 is a graph showing the total score change of SHAPS at week 6 of treatment for the enriched and whole populations: MMRM (mixed effect model of repeated measurements) results-estimated LS mean and comparison with placebo.

Fig. 6 is a line graph showing MADRS total score: mean value (±se) of eITT analysis set over time.

Fig. 7A is a line graph showing MADRS total score: mean value over time (±se) of the full intent-to-treat (fttt) analysis set. Fig. 7B is an excerpt from week 0 to week 6 of the treatment of fig. 7A.

Fig. 8 is a line graph showing MADRS total score: eITT analysis sets the percentage of subjects with remission of depression symptoms (total score. Ltoreq.10) during the treatment period.

Fig. 9 is a line graph showing MADRS total score: the fITT analysis sets the percentage of subjects (total score. Ltoreq.10) with remission of the depressive symptoms during the treatment period.

Fig. 10 is a line graph showing MADRS total score: eITT analysis of the percentage of responders (30% improvement over baseline) during the treatment period.

Fig. 11 is a line graph showing MADRS total score: the fITT analysis sets the percentage of responders (30% improvement over baseline) during the treatment period.

Fig. 12 is a line graph showing MADRS total score: eITT analysis of the percentage of responders (50% improvement over baseline) during the treatment period.

Fig. 13 is a line graph showing MADRS total score: the fITT analysis sets the percentage of responders (50% improvement over baseline) during the treatment period.

Fig. 14 is a line graph showing the SHAPS total score: mean value (±se) of eITT analysis set over time.

Fig. 15 is a line graph showing the SHAPS total score: mean value (±se) of the fttt analysis set over time.

Fig. 16 shows the change from baseline in MADRS according to severity of hedonic deficit.

FIG. 17A is a line graph showing the change from baseline in MADRS in patients with high hedonia (i.e., SHAPS. Gtoreq.38). Fig. 17B is a line graph showing the change from baseline in MADRS for patients with low hedonia (i.e., SHAPS < 38).

Fig. 18 is a bar graph showing a comparison of MADRS for patients with low and high hedonia.

Fig. 19 is a line graph showing the change in ASEX total score mean from baseline.

Fig. 20 is a bar graph showing the change of the general score average value of the ASEX term level change from the baseline.

FIG. 21 is a study protocol of example 2. All patients will continue to take the antidepressant SSRI/SNRI orally throughout the study. About another 34 geriatric participants will be randomized.

FIG. 22 is a study protocol of example 3. All patients will continue to take the antidepressant SSRI/SNRI orally throughout the study. Approximately 68 other geriatric participants will be randomized.

Fig. 23 is a bar chart showing the SHAPS item: variation of the mean LS from baseline according to baseline SHAPS total score for the f itt analysis set at week 6. In this figure, bars alternate from top to bottom to represent placebo or alteplerian. For example, the first refers to atecarbopol, the second refers to placebo, the third refers to atecarbopol, and so on.

Fig. 24 is a graph showing MADRS total score: the fITT analysis set at week 6 was poor (60%) on LS mean for the different subgroups. In this chart, <17 indicates mild severity; 18 to 24 indicate mild to moderate severity and 25 to 30 represent moderate to severe.

Detailed Description

All individual features mentioned herein (e.g., specific embodiments or specific preferred features) can be considered alone or in combination with any other features mentioned herein (including specific embodiments or preferred features); thus, preferred features can be used in combination with other preferred features or independently thereof (and similarly in combination with particular embodiments).

In one aspect of the invention, there are provided methods for treating Major Depressive Disorder (MDD) in a human patient, comprising administering to a patient in need thereof an effective amount of alteplerian or a pharmaceutically acceptable salt thereof, consisting of or consisting essentially of the steps, wherein the patient has a lack of hedonia. In another aspect of the invention, methods are provided for treating Major Depressive Disorder (MDD) in a human patient, comprising administering to a patient in need thereof an effective amount of alteplerian or a pharmaceutically acceptable salt thereof, consisting of or consisting essentially of the steps, wherein the patient suffers from a lack of hedonia, and wherein the patient is under-responsive to selective 5-hydroxytryptamine reuptake inhibitor (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

Also described herein is an actecapram or a pharmaceutically acceptable salt thereof for use in the treatment of Major Depressive Disorder (MDD) in a human patient, the treatment comprising administering to the patient in need thereof an effective amount of actecapram or a pharmaceutically acceptable salt thereof, consisting of or consisting essentially of the steps, wherein the patient has a lack of hedonia. Also described herein is an actecapram or a pharmaceutically acceptable salt thereof for use in the treatment of Major Depressive Disorder (MDD) in a human patient, the treatment comprising administering to a patient in need thereof an effective amount of actecapram or a pharmaceutically acceptable salt thereof, consisting of or consisting essentially of the steps, wherein the patient suffers from a lack of hedonia, and wherein the patient is under-responsive to a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

In one aspect of the invention, methods are provided for treating patients suffering from a more severe type of depression (i.e., major depressive disorder) and experiencing a lack of hedonia, particularly moderate to severe hedonia.

In an embodiment of any of the foregoing methods of treatment, the patient is under-responsive to other antidepressant medications prior to treatment with atetopiramate or a pharmaceutically acceptable salt thereof. In certain embodiments, the other antidepressant therapy comprises one or more antidepressants. In certain embodiments, the one or more antidepressants comprise a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof. In certain embodiments, the one or more antidepressants comprise a selective 5-hydroxytryptamine reuptake inhibitor (SSRI). In certain embodiments, the one or more antidepressants comprise a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI) treatment. In certain embodiments, the one or more antidepressants comprise a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI) treatment.

For each of the therapeutic methods described herein, it will be understood that the therapeutic method may also be defined as a method for preparing a medicament for treating the indication, or alternatively, actalapram for treating the indication.

MDD alone is difficult to treat and treatment of patients with a lack of pleasure is even more problematic because of their impaired ability to measure pleasure. Thus, these patients often are not properly treated due to ineffective medication, repeated and unnecessary medical appointments, lack of patient compliance, patient frustration in general, and the like. In addition, antidepressants are known to have various side effects such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive disorders, and the like. Thus, the patient may choose to refrain or stop taking antidepressants to avoid or prevent any side effects.

The methods described herein are effective in controlling depression and lack of hedonia in a patient using actalapril. Ideally, these methods successfully allow patients to control their depression while reducing a lack of pleasure. In certain embodiments, the patient treated according to the method suffers from moderate to severe anorgasmia. As used herein, the term "lack of pleasure" refers to a lack or decrease in the ability to experience pleasure in daily activities. The term lack of hedonia includes a lack of hedonia in sensory experience (i.e., touch, taste, smell) and social interactions. In some embodiments, the lack of pleasure and depressed mood are diagnostic criteria for major depressive episodes as part of MDD. The lack of pleasure also presents a drawback of one or more components of reward-related behavior (also known as a pleasure cycle, such as want, like, and learn). The pleasure cycle can be divided into three phases: a desire phase (mainly intended), a completion phase (mainly like), a satisfaction phase (mainly learning). The urge phase is characterized by an initial energy expenditure to obtain rewards; the finishing stage is to enjoy rewards; while the satisfaction stage is characterized by learning and feedback integration.

To evaluate the potential impact on a lack of hedonia, a hedonia scale may be used. For example, the sneezin-hamilton hedonic scale (SHAPS) analysis is an effective scale for measuring hedonic deficits. SHAPS is a scale of the completion of subjects who score whether they experience a sense of pleasure when they perform a series of activities or experiences. SHAPS is a self-reporting 14-item tool developed for assessing hedonic capacity. Subjects scored whether they experienced a sense of pleasure while performing a series of activities or experiences. The subject may rate the answer as 1 to 4, where 1 indicates "full consent," 2 indicates "consent," 3 indicates "disagreement," and 4 indicates "full disagreement. The subject's answers are summed to provide a total score ranging from 14 to 56. A higher total SHAPS score indicates a higher level of current lack of hedonia. The physician/clinical judgment can be used to assess lack of hedonia alone or in combination with a hedonic deficit scale. Another scale for measuring hedonic deficits is the dimensional hedonic deficits rating scale (DARS).

In some embodiments, the patient suffers from a lack of pleasure. In some embodiments, the patient suffers from a moderate lack of hedonia. In other embodiments, the patient suffers from severe anorgasmia. The assessment of moderate or severe anorgasmia is typically determined by a physician/clinical judgment and/or by one or more tests that provide insight into whether the patient has a anorgasmia. For example, the severity of a lack of pleasure may be determined using the SHAPS method. In some embodiments, a patient with moderate or severe anorgasmia is considered to have a high level of anorgasmia. For example, patients with SHAPS scores of 38 or higher are considered to have moderate to severe lack of hedonia, which can be considered to be a high level of hedonia (which can also be described as "pronounced" hedonia). In some embodiments, a high level of lack of hedonia is reflected in a SHAPS score of at least about 40, about 42, about 44, about 46, about 48, about 50, about 52, about 54, about 56, about 58, or more. Patients with mild or no anorgasmia are considered to have a low level of anorgasmia, as assessed by a physician/clinical judgment and/or one or more tests. For example, patients with SHAPS scores below 38 are considered to have low hedonic deficits. In certain embodiments, a patient with a mild hedonic deficit may have a SHAPS score of 20 to less than 38, for example, a SHAPS score of 20 to about 36, about 22 to about 36, about 24 to about 36, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 30 to about 36, about 32 to about 36, about 34 to about 36, about 20 to about 34, about 22 to about 34, about 24 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 34, about 30 to about 32, or about 32 to about 34. In general, a shas score below 20 may be considered to correspond to normal hedonic function (e.g., as indicated in the examples, "lack of pleasure" may be characterized as a patient with a shas score below 20), and for purposes of this disclosure it will fall into a low category of lack of pleasure, such as a shas score below 38.

In all aspects of the disclosure, a patient with Major Depressive Disorder (MDD) may have a shas score of 20 or more. In some embodiments, a patient with MDD may have a SHAPS score at baseline of 22 or higher, 24 or higher, 26 or higher, 28 or higher, 30 or higher, 32 or higher, 34 or higher, 36 or higher, or 38 or higher. In some embodiments, the patient's SHAPS score is assessed at baseline (e.g., 1 day prior to administration of atetopiramate).

In some embodiments, the patient's lack of hedonia decreases from a high level of hedonia to a low level of hedonia. In still other embodiments, the lack of hedonia in the patient is reduced by at least 40% after treatment with atenolol, as measured by the change in the total score of the lack of hedonia scale from baseline. In still other embodiments, the lack of hedonia in the patient is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% after treatment with atenolol, as measured by the change in the total score of the lack of hedonia scale from baseline. In still other embodiments, the lack of hedonia in the patient is reduced by about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 40% to about 70%, about 50% to about 70%, about 60% to about 70%, about 40% to about 60%, about 50% to about 60%, or about 50% to about 60% after treatment with alteplerian, as measured by the change in the total score of the lack of hedonia scale from baseline. In other embodiments, the patient's lack of hedonia is improved, i.e., reduced by 100%, as measured by the change from baseline in the total score of the lack of hedonia scale, following treatment with atenolol.

After initiation of treatment with atenolol, a reduction in hedonia can be measured relative to a hedonia (i.e., baseline hedonia measurement) of the patient measured prior to treatment with atenolol. In this way, the treating clinician can calculate the change in hedonia from baseline to a measure of real-time hedonia at any point in time after treatment with atenolol. Thus, standard methods of measuring a lack of hedonia, such as a lack of hedonia scale, e.g., SHAPS, may be used.

Desirably, a baseline lack of hedonia measurement is obtained no more than about 1 week prior to the onset of treatment with atenolol. In some embodiments, the baseline hedonic deficiency measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day prior to treatment with atetopiramate. In further embodiments, the baseline lack of hedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes prior to the initiation of treatment with atetopiramate.

The change in the lack of patient hedonia will depend on several factors including, but not limited to, the severity of the lack of hedonia, the patient's sensitivity to atecard blue, other agents being administered, and the like. In some embodiments, the lack of pleasure in the patient decreases after about 3 weeks of atenolol treatment. In other embodiments, the lack of pleasure in the patient decreases after about 3 weeks of atenolol treatment. In further embodiments, the lack of hedonia in the patient decreases after about 3 weeks to about 6 weeks of atenolol treatment, and in certain embodiments, until week 6 of atenolol treatment. In certain embodiments, the lack of hedonia in the patient is reduced by at least 40% after about 6 weeks of treatment with atenolol, as measured by the change from baseline in the total score of the lack of hedonia scale. In further embodiments, the patient's lack of hedonia decreases within about 3 weeks, and in some embodiments within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score of the lack of hedonia scale and/or the physician/clinical judgment.

It has been found that the methods described herein not only improve the symptoms of depression and lack of pleasure in patients, but also reduce the side effects of antidepressants. This may reduce absences (e.g., increase visit times or interactions with doctors), improve cognitive functions, improve health-related quality of life, increase interest and participation in daily activities, improve family and interpersonal relationships, improve work capacity at workplaces, reduce hospitalization, etc.

As used herein, unless otherwise indicated, the terms "subject" and "patient" refer to a human being who has been the subject of treatment, observation, or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the patient is an adult. As used herein, the term "adult" refers to a person aged about 18 years or older. In certain aspects, the patient is an elderly adult, i.e., greater than or equal to 65 years old.

As used herein, unless otherwise indicated, the terms "treatment", "treatment" and the like shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder, and include the administration of a compound described herein to prevent the onset of, alleviate the symptoms of, or one or more of the symptoms of, or complications, or eliminate the disease, condition, or disorder.

As used herein, the term "depression" (also referred to as depressive disorder) includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, post-partum depression, premenstrual anxiety disorder, contextual depression, anorgasmia, depression, middle aged depression, senile depression, bipolar depression, depression due to determinable sources of pressure, refractory depression, or combinations thereof. In certain embodiments, the depression is a major depressive disorder. In other embodiments, the major depressive disorder is accompanied by a depression feature or anxiety affliction. In further embodiments, the depression is a refractory depression. In other embodiments, the depression is major depressive disorder with suicidal ideation.

As known in the art, a patient is considered to have a major depressive disorder if the patient exhibits five or more symptoms that differ from the previous function within the same two week period; there must be a low mood and/or loss of interest/pleasure; the symptoms apparently attributed to another medical condition were excluded. See, e.g., table a.

In some embodiments, to diagnose MDD, the following criteria must also be met:

major depressive disorders may be classified as mild, moderate or severe. In some embodiments, the MDD is light. In other embodiments, the MDD is moderate. In further embodiments, the MDD is severe. As used herein, "mild MDD" applies to patients with little if any symptoms beyond those required to make a diagnosis, the intensity of the symptoms being painful but controllable, and the symptoms causing a mild impairment of social or professional function. Mild MDD may be single episode (ICD-10F32.0) or recurrent episode (ICD-10F33.0). "moderate MDD" is suitable for patients with a variety of symptoms, symptoms intensities, and/or dysfunctions that fall between those designated as "mild" and "severe". Moderate MDD may be a single episode (ICD-10F32.1) or recurrent episodes (ICD-10F33.1). "severe MDD" is applicable to patients where the number of symptoms is significantly more than that required to make a diagnosis, the intensity of the symptoms is severely painful and uncontrollable, and the symptoms significantly interfere with social and professional functions and require emergency symptom control. In some embodiments, the severe MDD may be a single episode (ICD-10F32.2) or recurrent episodes (ICD-10F33.2). In other embodiments, MDDs are classified according to the DSM-5 definition of Table B.

Several scales are known in the art that can be used to diagnose or monitor MDD patients. Examples of such scales include, but are not limited to, the Montgomery-Arabidopsis depression rating scale (MADRS), the clinical global impression-severity (CGI-S) scale, the major depressive disorder symptom scale (SMDDS), the treatment experience self-assessment (SATE) scale, and the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), i.e., MGH-ATRQ.

In some embodiments, MADRS is utilized to diagnose and/or monitor a patient. MADRS is a 10-term rating scale for antidepressant studies. It is performed by a clinician and is designed for MDD patients to measure the overall severity of depressive symptoms. The MADRS scale is a validated, reliable and accepted by regulatory health authorities as the primary scale for determining efficacy in major depressive states. In some embodiments, MADRS is performed using a Structured Interview Guide (SIGMA) for MADRS. The scale consisted of 10 entries, with each entry having a score ranging from 0 (the entry is absent or normal) to 6 (symptom severity or persistence), with a total possible score of 60. A higher score indicates a more severe condition. MADRS evaluate obvious sadness, reported sadness, mental stress, sleep, appetite, attention, burnout, insensitivity (level of interest), pessimistic ideas, and suicide ideas.

In other embodiments, CGI-S is used to diagnose and/or monitor depression in a patient. CGI-S is a scale that evaluates the severity of a disease in a subject at the time of evaluation relative to the past experience of a clinician with the same diagnosis and treatment improvement. CGI-S provides an overall generalized measure of the severity of a subject ' S disease as determined by a clinician, taking into account all available information, including knowledge of the subject ' S medical history, psychosocial condition, symptoms, behavior, and the effect of symptoms on the subject ' S ability to work. CGI-S rated the severity of the psychopathology on a scale of 0 to 7. The severity of mental illness in the subjects was assessed at the time of assessment according to the following: 0 = unevaluated; 1 = normal (no disease at all); 2 = borderline psychosis; 3 = mild illness; 4 = moderate illness; 5 = significant illness; 6 = severe illness; 7 = in the most ill patient.

In further embodiments, SMDDS is used to diagnose and/or monitor depression in a patient. SMDDS is a subjective assessment of the patient. SMDDS is a 16 item PRO metric. Each item was rated by the subject according to the 5-minute licker-in scale. The subject answers each question using a rating scale between 0 ("neither" nor "or" from none ") and 4 (" very "or" always "). The total score ranged from 0 to 60.SMDDS uses recall period and verbal rating for 7 days. A higher score indicates a more severe depressive symptom.

In yet other embodiments, SATE is used to diagnose and/or monitor depression in a patient. SATE is one to three questionnaires that are performed when the subject is unable to complete other evaluations (i.e., away from the clinical setting, such as at home). SATE is useful in assessing improvement or worsening of depression symptoms in subjects over a short period of time. For general depression assessment, the subject selects an option from improvement, no change, or exacerbation; for depression improvement, the subject selects one of slightly improved, greatly improved, while for depression exacerbation, the subject may choose to slightly exacerbate, severely exacerbate, extremely severely exacerbate. See table C.

MGH-ATRQ is a self-rating scale for determining treatment resistance in MDD patients. The questionnaire investigates the history of antidepressant treatment, and specific anchor points were used to define the adequacy of the dose and duration and extent of symptom improvement for each antidepressant trial. MGH-ATRQ allows for determination of therapeutic resistance to depression and is known to those skilled in the art.

In certain embodiments, the patient is under-responsive to other antidepressant therapies (i.e., antidepressants or treatments other than actalapram for the treatment of depression). As used herein, "hyporesponsive" refers to a reduction in the severity of depressive symptoms experienced by a patient from the beginning of treatment of less than about 50%. Often, the hyporeactivity occurs during the current/active onset of depression. In some embodiments, insufficient response refers to a reduction in the severity of symptoms of depression experienced by the patient from about 26% to less than about 50% from the beginning of the treatment. In other embodiments, insufficient response means a reduction in the severity of symptoms of depression experienced by a patient from the beginning of treatment of about 26% to about 49%, about 26% to about 45%, about 26% to about 40%, about 26% to about 35%, about 26% to about 30%, about 30% to about 49%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 49%, about 35% to about 45%, about 35% to about 40%, about 40% to about 49%, or about 40% to about 45%. Patient response may be measured by one or more scales described herein and/or by physician/clinical judgment. In some embodiments, the under-reaction is measured by MGH-ATRQ, MADRS, or SHAPS. In other embodiments, the underreaction is measured by MGH-ATRQ.

To the extent that the patient is said to be partially responsive to treatment, this means that some mild to moderate symptoms improve since the beginning of treatment, some of the initial symptoms remain present and plague the patient, and these persistent symptoms still affect behavior and function. For example, a patient's motivation, productivity, and interest in his usual activities may still be compromised.

Antidepressant therapy refers to any agent useful in the treatment of depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors, tricyclic, tetracyclic, acyclic, triazolopyridine, selective 5-hydroxytryptamine reuptake inhibitors (SSRI), 5-hydroxytryptamine receptor antagonists, 5-hydroxytryptamine noradrenergic reuptake inhibitors (SNRI), noradrenergic and specific 5-hydroxytryptamine agents, noradrenergic reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics). Examples of monoamine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, and the like. Examples of tricyclic drugs include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protyline, trimipramine, clomipramine, amoxapine, and the like. Examples of tetracyclic drugs include maprotiline and the like. Examples of acyclic classes include nomifensine and the like. Examples of triazolopyridines include trazodone and the like. Examples of SSRI include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, and the like. Examples of 5-hydroxytryptamine receptor antagonists include naftoprazone and the like. Examples of SNRI include venlafaxine, milnacipran, desvenlafaxine, duloxetine, levomilnacipran, and the like. Examples of noradrenergic and specific 5-hydroxytryptamine drugs include mirtazapine and the like. Examples of norepinephrine reuptake inhibitors include reboxetine, edestin Wo Xiting, and the like. (a) Examples of typical antipsychotics include phenothiazines (e.g., chlorpromazine, thiodazine, fluphenazine, perphenazine, trifluoperazine, levopromazine), thioxanthenes (e.g., thiothiothiothioxine, flupentixne), butyrenes (e.g., haloperidol), dibenzooxazepines (e.g., rosapine), indolinones (e.g., morpholone), substituted benzamides (e.g., sulpiride, amisulpride), and the like. Examples of atypical antipsychotics include paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, pirpirone, blonanserin, sertindole, ORG-5222, sonapizole, aripiprazole, nemorubide, SR-31742, CX-516, SC-111, NE-100, divalproex (mood stabilizer), and the like. In further embodiments, the antidepressant therapy comprises natural products such as kava, johnsona, etc., or dietary supplements such as s-adenosylmethionine, etc. In still other embodiments, the antidepressant therapy includes a neuropeptide, such as thyrotropin releasing hormone or the like, or a compound targeting a neuropeptide receptor, such as a neurokinin receptor antagonist or the like. In yet further embodiments, the antidepressant therapy is a hormone, such as triiodothyronine or the like. In other embodiments, the antidepressant therapy is an SSRI, an SNRI, or a combination thereof. Preferably, the antidepressant is an SSRI, i.e. escitalopram, sertraline, paroxetine, fluoxetine or citalopram. In other embodiments, the antidepressant is an SNRI, i.e., venlafaxine, duloxetine, vortioxetine, or desvenlafaxine. There are also non-pharmacological treatments such as psychotherapy and transcranial magnetic stimulation, which are also available and can be used as adjuvant therapy options.

The therapeutically effective amount/dose levels and dosage regimens for other antidepressant therapies can be readily determined by one of ordinary skill in the art. For example, approved therapeutic doses and regimens for pharmaceutical agents are well known and listed, for example, in packaging labels, standard dose guidelines, standard dose references such as Physician's desk Reference (Medical Economics Company or website http:///www.pdrel.com), or other sources.

In some embodiments, the other antidepressant therapy may include an antidepressant. In other embodiments, the other antidepressant therapy includes two or more antidepressants. In further embodiments, the other antidepressant therapy comprises two antidepressants. In still other embodiments, the other antidepressant therapy includes three antidepressants. The attending physician will be able to select the appropriate antidepressant therapy for use as described herein.

In certain embodiments, the patient is receiving treatment with other antidepressant therapy prior to receiving atetopiramate or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is receiving other antidepressant therapy, comprising an SSRI, an SNRI, or a combination thereof. In other embodiments, the patient stops treatment with other antidepressant medications before starting treatment with atetopiramate.

Adjunctive therapy comprising the use of an effective amount of one or more antidepressants is also contemplated in the methods described herein. As used herein, the terms "adjunctive therapy" and "adjunctive therapy" shall mean the treatment of a patient in need thereof by administration of actecapram or a pharmaceutically acceptable salt thereof (particularly actecapram) in combination with one or more antidepressants, wherein the actecapram and the antidepressants are administered simultaneously, sequentially, separately or in a single pharmaceutical formulation by any suitable means.

In some aspects, the atetopiramate is administered adjunctively with other antidepressants currently administered to the patient, including current antidepressants to which the patient is not responsive. In other embodiments, the atetopiramate is administered adjunctively with antidepressants that have not been previously administered to the patient. In still other embodiments, the atetopiramate is administered in a regimen with an antidepressant that was previously administered to the patient.

When the atenolol and other antidepressant are administered in separate dosage forms, the number of doses each active compound is administered per day may be the same or different, and more typically may be different. Antidepressants may be administered according to the prescription of the attending physician and/or according to his/her label, and atetopiramate administered as described herein. Typically, patients receive treatment with both an antidepressant and atetopiramate at the same time, both of which are administered by their prescribed dosing regimen. The atenolol and antidepressant may be administered according to a simultaneous or alternating regimen, at the same time or at different times during the course of treatment, simultaneously in separate or single forms.

The atenolol and the antidepressant may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral administration, intravenous administration (iv), intranasal administration (in), intramuscular administration (im), subcutaneous administration (sc), transdermal administration, buccal administration, and rectal administration. In some embodiments, the atetopiramate is administered orally.

There are several advantages to the treatment with atetopiramate described herein over prior art treatments. In some embodiments, the patient does not experience multiple of the side effects associated with other antidepressants (i.e., antidepressants other than atetopiramate). In certain aspects, the patient does not experience weight gain during treatment with atetopiramate. As used herein, the term "weight gain" refers to the increase in patient weight relative to the patient weight prior to administration of atecarbopram or the patient weight estimated at the time of initial administration of atecarbopram. In certain embodiments, the patient may actually see a decrease in overall body weight relative to the patient's body weight prior to taking the actalapril. In further embodiments, the patient's weight is stable, i.e., neither increased nor decreased. In certain embodiments, the patient does not experience clinically relevant weight gain, which is characterized by a weight gain of ≡7%.

This is in contrast to many other antidepressants, where weight gain (including clinically relevant weight gain) is a common but unfortunate side effect.

In certain embodiments, administration of the alteplercanin achieves a maximum plasma concentration (C) of the alteplercanin of about 20ng/mL to about 45ng/mL _max ). In further embodiments, administration of the alteplercanin achieves a maximum plasma concentration (C _max ). In yet other embodiments, the method comprisesAdministration of tekaplan achieves a maximum plasma concentration (C) of atekaplan of about 30ng/mL to about 35ng/mL _max )。

In a further aspect, the patient does not experience a decrease in sexual function during treatment with atetopiramate. As used herein, the term "reduced sexual function" refers to a reduction or attenuation of one or more components of the human sexual drive (i.e., sexual function). In some embodiments, the sexual function comprises one or more of sexual drive, sexual arousal, vaginal lubrication, erection, achievement of orgasm or orgasm satisfaction. In other embodiments, the sexual function comprises a sexual drive. In further embodiments, the sexual function comprises vaginal lubrication. In further embodiments, the sexual function comprises reaching orgasm. In yet other embodiments, the sexual function comprises orgasm satisfaction. Desirably, the patient's sexual function is assessed at the time of initial administration of atenolol. Thus, the sexual function of a patient when taking atetopiramate can be compared to the sexual function of a patient prior to administration of atetopiramate. Sexual function may be assessed using standard scales and techniques, such as the arizona experience scale (ASEX). ASEX was used to investigate whether atetoplan has a further positive or negative effect on sexual function. ASEX is a 5-term rating scale for patient performance that quantifies sexual drive, sexual arousal, vaginal lubrication or penile erection, ability to reach orgasm, and satisfaction. The scoring range is 5 to 30 and there are two different versions of the scale (male and female).

Other scales may be utilized to determine the effectiveness of the methods used herein in treating a patient. Examples include Cognitive and Physical Function Questionnaires (CPFQ), karlin card sleepiness scale (KSS), and temporal pleasure experience scale (TEPS). CPFQ is a short self-reporting scale that provides additional information about the impact of adjuvant therapy on various aspects of cognitive and executive functions including attention, memory and mental acuity. It has been reported that subjects with MDD often have difficulties in functioning in this regard. KSS is an assessment of subject reports used to rate sleepiness on a scale of 1 to 9, ranging from "extremely alert" (1) to "very drowsy," in an effort to stay awake and struggle with sleep "(9). TEPS includes 18 entries, a 2-component table designed to distinguish between expected and completed hedonia.

As used herein, unless otherwise indicated, the term "atecarbopol" refers to 3-fluoro-4-4-2- (3, 5-dimethylphenyl) pyrrolidin-1-yl-methylphenoxy-benzamide, the following compounds:

and are also known as JNJ-67953964, CERC-501 and LY-2456302. In some embodiments, "atecarbopram" refers to the (S) -enantiomer of atecarbopram, namely the following compound:

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Also known as (S) -alteplerian or (S) -3-fluoro-4-4-2- (3, 5-dimethylphenyl) pyrrolidin-1-yl-methylphenoxy-benzamide. In other embodiments, the actecapram used in the methods described herein is substantially free of the (R) -enantiomer, i.e., either (R) -actecapram or (R) -3-fluoro-4-4-2- (3, 5-dimethylphenyl) pyrrolidin-1-yl-methylphenoxy-benzamide having the structure:

in other embodiments, the alteplerian contains less than about 10% by weight of the (R) -enantiomer of alteplerian, based on the weight of the alteplerian. In further embodiments, the alteplerian contains less than about 10 wt.%, about 9 wt.%, about 8 wt.%, about 7 wt.%, about 6 wt.%, about 5 wt.%, about 4 wt.%, about 3 wt.%, about 2 wt.%, about 1 wt.%, about 0.5 wt.%, about 0.1 wt.%, about 0.005 wt.%, or about 0.001 wt.% of the (R) -enantiomer of the alteplerian, based on the weight of the alteplerian. In still other embodiments, the alteplerian contains from about 0.001% to about 10% by weight of the (R) -enantiomer of alteplerian, based on the weight of the alteplerian. In still further embodiments, the alteplerian comprises from about 0.001 wt.% to about 10 wt.%, from about 0.001 wt.% to about 5 wt.%, from about 0.001 wt.% to about 1 wt.%, from about 0.001 wt.% to about 0.5 wt.%, from about 0.001 wt.% to about 0.1 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.1 wt.% to about 1 wt.%, from about 0.1 wt.% to about 5 wt.%, or from about 0.5 wt.% to about 5 wt.% of the (R) -enantiomer of the alteplerian, based on the weight of the alteplerian.

Pharmaceutically acceptable salts of alteplercanium are also contemplated by the present invention and can be readily selected by one of skill in the art. By "pharmaceutically acceptable salt" is meant a salt of atetopiramate that is non-toxic, biologically tolerable or otherwise biologically suitable for administration to a subject. Generally, see g.s. Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J.Med. Chem.,2007,50:6665-72, s.m. berge, "Pharmaceutical Salts", J.pharm. Sci.,1977,66:1-19; and Handbook of Pharmaceutical Salts Properties, selection, and Use, stahl and Wermuth editions, wiley-VCH and VHCA, zurich,2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation or allergic response.

Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromate (such as hydrobromide), iodate (such as hydroiodide), acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ -hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

The methods described herein comprise administering to a patient an effective amount of alteplercanin or a pharmaceutically acceptable salt thereof. As used herein, the term "effective amount" means the amount of active compound or agent that elicits the biological or medicinal response in a human that is being sought by a researcher, doctor or other clinician, including alleviation of one or more of the symptoms of the disease or disorder being treated. In some embodiments, the atetopiramate is used in an effective amount as determined by the attending physician. In other embodiments, the other antidepressants are used alone or in combination with the antidepressant in an effective amount.

The amount of atenolol administered according to the methods described herein can be determined by one skilled in the art and is stated based on atenolol free base unless otherwise indicated. That is, the amount indicates the amount of the atticopram molecule administered in addition to, for example, a solvent (such as in a solvate) or a counterion (such as in a pharmaceutically acceptable salt). In some embodiments, the effective amount of atetopiramate is less than about 60mg. In other embodiments, the effective amount of atetopiramate is about 0.5mg, about 1mg, about 2mg, about 4mg, about 5mg, about 10mg, about 15mg, about 20mg, 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, or about 60mg. In a further embodiment of the present invention, an effective amount of atenolol is about 1mg to about 50mg, about 5mg to about 50mg, about 10mg to about 50mg, about 20mg to about 50mg, about 30mg to about 50mg, about 40mg to about 50mg, about 1mg to about 45mg, about 2mg to about 45mg, about 5mg to about 45mg, about 10mg to about 45mg, about 20mg to about 45mg, about 30mg to about 40mg, about 30mg to about 35mg, about 1mg to about 40mg, about 5mg to about 40mg, about 10mg to about 40mg, about 20mg to about 40mg, about 30mg to about 40mg, about 1mg to about 35mg, about 2mg to about 35mg about 5mg to about 35mg, about 10mg to about 35mg, about 20mg to about 35mg, about 25mg to about 35mg, about 30mg to about 35mg, about 1mg to about 30mg, about 2mg to about 30mg, about 5mg to about 30mg, about 10mg to about 30mg, about 20mg to about 30mg, about 25mg to about 30mg, about 1mg to about 20mg, about 2mg to about 20mg, about 5mg to about 20mg, about 10mg to about 20mg, about 15mg to about 20mg, about 1mg to about 15mg, about 2mg to about 15mg, about 5mg to about 15mg, about 10mg to about 15mg, about 1mg to about 10mg, about 2mg to about 10mg, or about 5mg to about 10mg. In yet other embodiments, the effective amount of atetopiramate is about 5mg to about 15mg. In yet other embodiments, the effective amount of atetopiramate is about 10mg. In yet other embodiments, the effective amount of atetopiramate is about 5mg.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Preferred pharmaceutical compositions contain, as the active ingredient, atenolol in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, in accordance with conventional pharmaceutical compounding techniques. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published under American Pharmaceutical Association and Pharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions are described in various publications, such as Pharmaceutical Dosage Forms: tables, second Edition, revised and Expanded, volumes 1-3, edited by Lieberman et al; pharmaceutical Dosage Forms: parenteral Medications, volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms Disperse Systems, volumes 1-2, edited by Lieberman et al; the above publications are published by Marcel Dekker, inc.

In certain embodiments, the pharmaceutical compositions for use herein further comprise one or more buffers, preservatives, penetrants, wetting agents, surfactants, solubilizers, thickeners, colorants, antioxidants, emulsifiers, isotonicity agents, suspending agents and/or viscosity increasing agents.

In some embodiments, the pharmaceutical composition further comprises one or more buffers and/or buffer systems (i.e., conjugate acid base pairs). As used herein, the term "buffer" shall refer to any solid or liquid composition (preferably an aqueous liquid composition) that, when added to an aqueous formulation, adjusts the pH of the formulation. Those skilled in the art will recognize that the buffer may adjust the pH of the aqueous formulation from any direction (toward a more acidic, more basic or more neutral pH). Preferably, the buffer is pharmaceutically acceptable. Suitable examples of buffers that may be used in the aqueous formulations described herein include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, and the like.

Optionally, the pharmaceutical compositions herein may contain a preservative. As used herein, unless otherwise indicated, the terms "antimicrobial preservative" and "preservative" refer to any substance added to a pharmaceutical composition to protect it from microbial degradation or microbial growth. In this regard, microbial growth generally plays a vital role, i.e., preservatives are used for the primary purpose of avoiding microbial contamination. It may also be desirable to avoid any influence of microorganisms on the active ingredient and excipient, respectively, i.e. to avoid microbial degradation. Representative examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexetidine, imidurea, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sorbic acid, and potassium sorbate.

As used herein, the terms "osmotic agent," "permeation enhancer," and "saturation agent" refer to any substance that increases or promotes the absorption and/or bioavailability of actecapram. Preferably, the osmotic agent increases or promotes the absorption and/or bioavailability of the atetopiramate after administration. Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid, lecithin, and the like; and chitosan (and salts), as well as surface active ingredients such as benzalkonium chloride, sodium lauryl sulfate, sodium docusate, polysorbate, laureth-9, oxitoxynol, sodium deoxycholate, polyarginine, and the like. Preferably, the penetrant is selected to meet one or more of the following general requirements:

the pharmaceutical compositions for use herein may also comprise one or more additional excipients, such as wetting agents, surfactant components, solubilizing agents, thickening agents, colorants, antioxidant components, and the like.

Examples of suitable antioxidant components (if used) include, but are not limited to, one or more of the following: a sulfite; ascorbic acid; ascorbates, such as sodium, calcium or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediamine tetraacetic acid or its sodium or calcium salt; tocopherols; gallic acid esters such as propyl gallate, octyl gallate or dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant component provides long term stability to the liquid composition.

Solubilizing agents and emulsifiers may be included to facilitate more uniform dispersion of the active ingredient or other excipients that are generally insoluble in the liquid carrier. Examples of suitable emulsifiers, if used, include, but are not limited to, for example, gelatin, cholesterol, gum arabic, tragacanth, pectin, methylcellulose, carbomers, and mixtures thereof. Examples of suitable solubilizing agents include polyethylene glycol, glycerol, D-mannitol, trehalose, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof. The solubilizing agent or emulsifier may be present in an amount sufficient to solubilize or disperse the active ingredient (i.e., atetopiramate) in the carrier.

Suitable isotonic agents, if used, may include sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose, and mixtures thereof.

Suspending agents or viscosity enhancers may also be added to the pharmaceutical compositions. Suitable examples include, but are not limited to, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, carbomers, pectins, sodium alginate, chitosan salts, gellan gum, poloxamers, polyvinylpyrrolidone, xanthan gum and the like.

Advantageously, the alteplerian may be administered once daily, or the total daily dose may be administered in divided doses of two, three or four times daily.

As described herein, in particular, patients are under-responsive to other antidepressant therapies prior to treatment with atetopiramate. Thus, in one particular embodiment, the present disclosure relates to atetopiramate, or a pharmaceutically acceptable salt thereof, for use as described herein, wherein the patient is under-responsive to other antidepressant therapies prior to treatment with atetopiramate. In another particular embodiment, the present disclosure also relates to the use of alteplercanin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament as described herein, wherein the patient is under-responsive to other antidepressant medications prior to treatment with alteplercanin. In another particular embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the patient is under-responsive to other antidepressant medications prior to treatment with atetopiramate. Such antidepressant therapy may be selected in particular from the group consisting of selective 5-hydroxytryptamine reuptake inhibitors (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRI) or combinations thereof.

As described herein, atetopiramate may be used as an adjunct therapy, or in other words, as an adjunct drug or in combination with one or more antidepressants, for example, the patient may have already or have also been administered one or more antidepressants. Thus, in another particular embodiment, the present disclosure relates to atetopiramate, or a pharmaceutically acceptable salt thereof, for use as described herein, comprising administering atetopiramate, or a pharmaceutically acceptable salt thereof, as an adjunctive therapy with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure relates to atetopiramate, or a pharmaceutically acceptable salt thereof, for use as described herein, comprising administering the atetopiramate, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure relates to atetopiramate, or a pharmaceutically acceptable salt thereof, for use as described herein, comprising administering the atetopiramate, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure also relates to the use of alteplercanium, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament as described herein, wherein the treatment comprises administering an effective amount of alteplercanium, or a pharmaceutically acceptable salt thereof, as an adjunctive treatment with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure also relates to the use of alteplercanium, or a pharmaceutically acceptable salt thereof, as described herein, wherein treating comprises administering an effective amount of alteplercanium, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure also relates to the use of alteplercanium, or a pharmaceutically acceptable salt thereof, as described herein, wherein treating comprises administering an effective amount of alteplercanium, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the treatment instructions direct the administration of an effective amount of alteplercanin or a pharmaceutically acceptable salt thereof as an adjunct treatment with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the treatment instructions direct the administration of an effective amount of alteplercanin or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In another particular embodiment, the present disclosure also relates to a package or medicament as described herein, wherein the treatment instructions direct the administration of an effective amount of alteplercanin or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more antidepressants. The one or more antidepressants may be selected from a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

As already described, the present disclosure relates to actecapram or a pharmaceutically acceptable salt thereof for use as described herein. In a particular embodiment, the atetopiramate is S-atetopiramate or a pharmaceutically acceptable salt thereof. In another embodiment of the present disclosure, the amount of acticaprin, particularly S-acticaprin, or a pharmaceutically acceptable salt thereof, used as described herein, administered should be from about 2mg to about 35mg, more particularly about 10mg, more particularly about 5mg. In yet another embodiment, the alteplercanium, particularly S-alteplercanium, or a pharmaceutically acceptable salt thereof, as used herein is administered orally. Furthermore, in another particular embodiment, the present disclosure relates to atetopiramate, in particular S-atetopiramate or a pharmaceutically acceptable salt thereof, for use as described herein, which is administered once daily. The present disclosure also relates to the use of alteplerian or a pharmaceutically acceptable salt thereof in the manufacture of a medicament as described herein. In a particular embodiment, the atetopiramate is S-atetopiramate or a pharmaceutically acceptable salt thereof. In another embodiment of the use described herein, the amount of actecapram administered should be from about 2mg to about 35mg, more particularly about 10mg, more particularly about 5mg. In yet another embodiment of the use, the atetopiramate should be administered orally. Furthermore, in another particular embodiment of the use, the atetopiramate, in particular S-atetopiramate or a pharmaceutically acceptable salt thereof, should be administered once daily. In another particular embodiment, the present disclosure also relates to a package or a pharmaceutical product as described herein, wherein the alteplerian, in particular S-alteplerian, or a pharmaceutically acceptable salt thereof. In another embodiment of a package or pharmaceutical product as described herein, the instructions for treatment direct the administration of about 2mg to about 35mg of atetopiramate, more particularly about 10mg of atetopiramate, more particularly about 5mg of atetopiramate. In yet another embodiment of the package or the pharmaceutical product as described herein, the treatment instructions direct the oral administration of the altaicaprlan, particularly S-altaicapramycin, or a pharmaceutically acceptable salt thereof. Furthermore, in another specific embodiment of the package or the pharmaceutical product as described herein, the treatment instructions direct the daily administration of the alteplerian, in particular S-alteplerian, or a pharmaceutically acceptable salt thereof.

Advantageously, administration of atetopiramate does not result in weight gain during treatment, including clinically relevant weight gain. Thus, in another particular embodiment, the present disclosure relates to atetopiramate, or a pharmaceutically acceptable salt thereof, for use as described herein, wherein the patient does not experience weight gain during treatment with atetopiramate. In another particular embodiment, the present disclosure relates to the use as defined herein, wherein the patient does not experience weight gain during treatment with atetopiramate. In another particular embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the patient does not experience weight gain during treatment with atetopiramate. In particular, the body weight of the patient may be assessed at the time of initial administration of atetopiramate.

It was also unexpectedly observed that, based on the evaluation at initial administration, the patient did not experience a decrease in sexual function during treatment with atetopland. Thus, in a further particular embodiment, the present disclosure relates to atetopiramate, or a pharmaceutically acceptable salt thereof, for use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with atetopiramate. In another particular embodiment, the disclosure relates to a use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with atetopiramate. In another particular embodiment, the present disclosure relates to a package or pharmaceutical product as described herein, wherein the patient does not experience a decrease in sexual function during treatment with atetopiramate. The term "sexual function" encompasses sexual drive, sexual arousal, vaginal lubrication, erection, attainment of orgasm or orgasm satisfaction. The satisfaction can be assessed by methods known to the skilled person, for example by applying the arizona experience scale (ASEX).

As already described, patients suffer from a lack of pleasure, in particular a moderate or severe lack of pleasure. The lack of hedonia may be measured by a lack of hedonia scale, such as the sneriant-hamilton hedonia scale (SHAPS). Thus, in one particular embodiment, the present disclosure relates to atetopland or a pharmaceutically acceptable salt thereof for use as described herein, wherein the patient's lack of hedonia is reduced by at least 40% after 6 weeks of treatment with atetopland, as measured by a change in the total score of the hedonia scale from baseline, more particularly, the patient's lack of hedonia is reduced within about 3 weeks to about 6 weeks, as measured by a change in the total score of the hedonia scale from baseline. In another particular embodiment, the hedonic deficit scale is the sneezing-hamilton hedonic scale (SHAPS). Thus, in one particular embodiment, the disclosure relates to a use as described herein, wherein the lack of hedonia in the patient is reduced by at least 40% after 6 weeks of treatment with atenolol, as measured by a change in the total score of the lack of hedonia scale from baseline, more particularly the lack of hedonia in the patient is reduced within about 3 weeks to about 6 weeks, as measured by a change in the total score of the lack of hedonia scale from baseline. In another particular embodiment, the present disclosure relates to a package or pharmaceutical product as described herein, wherein the lack of hedonia in the patient is reduced by at least 40% after 6 weeks of treatment with atectone, as measured by the change in the total score of the lack of hedonia scale from baseline, more particularly the lack of hedonia in the patient is reduced within about 3 weeks to about 6 weeks, as measured by the change in the total score of the lack of hedonia scale from baseline.

Aspects of the invention

Aspect 1: a method of treating major depressive disorder in a human patient suffering from a lack of pleasure, the method comprising administering to the patient in need thereof an effective amount of alteplercanium or a pharmaceutically acceptable salt thereof.

Aspect 2: the method of claim 1, wherein the patient is under-responsive to other antidepressant medications prior to treatment with atetopiramate.

Aspect 3: the method of claim 2, wherein the other antidepressant therapy comprises a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

Aspect 4: the method of any one of the preceding aspects, further comprising adjunctive therapy with an effective amount of one or more antidepressants.

Aspect 5: the method of claim 4, wherein the one or more antidepressants is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

Aspect 6: the method of any one of the preceding aspects, wherein the altaicaro pram is S-altaicaro pram or a pharmaceutically acceptable salt thereof.

Aspect 7: the method of any one of the preceding aspects, wherein the effective amount of alteplerian is from about 2mg to about 35mg.

Aspect 8: the method of aspect 7, wherein the effective amount of alteplercanin is about 10mg.

Aspect 9: the method of aspect 7, wherein the effective amount of alteplercanin is about 5mg.

Aspect 10: the method of any one of the preceding aspects, wherein the alteplerian is administered orally.

Aspect 11: the method of any one of the preceding aspects, wherein the alteplerian is administered once daily.

Aspect 12: the method of any one of the preceding aspects, wherein the patient has a schneider-hamilton hedonic scale (SHAPS) score of 20 or more.

Aspect 13: the method of any one of the preceding aspects, wherein the patient has a shas score of 22 or higher, 24 or higher, 26 or higher, 28 or higher, 30 or higher, 32 or higher, 34 or higher, 36 or higher, or 38 or higher.

Aspect 14: the method of any one of the preceding aspects, wherein the patient has a shas score of 38 or greater.

Aspect 15: the method of any one of aspects 1 to 11, wherein the patient has a moderate lack of hedonia.

Aspect 16: the method of any one of aspects 1 to 11, wherein the patient has severe anorgasmia.

The method of any one of the preceding aspects, wherein the treatment ameliorates depression and a lack of pleasure symptoms in the patient.

Aspect 17: the method of any one of the preceding aspects, wherein the patient does not experience weight gain during the treatment with atetopiramate.

Aspect 18: the method of aspect 17, wherein the body weight of the patient is assessed at the initial administration of the alteplerian.

Aspect 19: the method of any one of the preceding aspects, wherein the patient does not experience a decrease in sexual function during the treatment with atetopiramate.

Aspect 20: the method of aspect 19, wherein the sexual function of the patient is assessed at the initial administration of the alteplerian.

Aspect 21: the method of claim 19 or 20, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, attainment of orgasm, or orgasm satisfaction.

Aspect 22: the method of any one of aspects 19 to 21, wherein sexual function is assessed by the arizona sexual experience scale (ASEX).

Aspect 23: the method of any one of the preceding aspects, wherein the lack of hedonia in the patient is reduced by at least 40% after 6 weeks of the treatment with atetopiramate, as measured by the change from baseline in the total score of the lack of hedonia scale.

Aspect 24: the method of any one of the preceding aspects, wherein the lack of hedonia in the patient decreases within about 3 weeks to about 6 weeks, as measured by a change in the total score of the lack of hedonia scale from baseline.

Aspect 25: the method of aspects 23 or 24, wherein the hedonic deficit scale is the sneezing-hamilton hedonic scale (SHAPS).

Aspect 26: the method according to any one of the preceding aspects, wherein the administration of the alteplerian blue achieves a maximum plasma concentration (C) of alteplerian blue of about 20ng/mL to about 45ng/mL _max )。

Aspect 27: the method according to any one of the preceding aspects, wherein the administration of the alteplerian blue achieves a maximum plasma concentration (C) of alteplerian blue of about 25ng/mL to about 35ng/mL _max )。

Aspect 28: the method according to any one of the preceding aspects, wherein the administration of the alteplerian blue achieves a maximum plasma concentration (C) of alteplerian blue of about 30ng/mL to about 35ng/mL _max )。

Aspect 29: atetopiramate or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder in a human patient suffering from a lack of hedonia.

Aspect 30: the alteplerian or a pharmaceutically acceptable salt thereof for use according to aspect 29, wherein the treatment comprises administering an effective amount of alteplerian or a pharmaceutically acceptable salt thereof.

Aspect 31: the alteplerian or pharmaceutically acceptable salt thereof for use according to aspects 29 or 30, wherein the patient is under-responsive to other antidepressant therapies prior to treatment with alteplerian.

Aspect 32: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 31, wherein the other antidepressant therapy comprises a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

Aspect 33: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 32, further comprising adjunctive therapy with an effective amount of one or more antidepressants.

Aspect 34: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 33, wherein the one or more antidepressants is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

Aspect 35: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 34, wherein the alteplerian is S-alteplerian or a pharmaceutically acceptable salt thereof.

Aspect 36: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 35, wherein said effective amount of alteplerian is from about 2mg to about 35mg.

Aspect 37: the alteplerian or pharmaceutically acceptable salt thereof for use according to aspect 36, wherein said effective amount of alteplerian is about 10mg.

Aspect 38: the alteplerian or pharmaceutically acceptable salt thereof for use according to aspect 36, wherein said effective amount of alteplerian is about 5mg.

Aspect 39: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 38, wherein the alteplerian is administered orally.

Aspect 40: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 39, wherein said alteplerian is administered once daily.

Aspect 41: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 40, wherein the patient has a sneof schneider-hamilton rapid induction scale (SHAPS) score of 20 or more.

Aspect 42: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 40, wherein the patient has a shas score of 22 or higher, 24 or higher, 26 or higher, 28 or higher, 30 or higher, 32 or higher, 34 or higher, 36 or higher, or 38 or higher.

Aspect 43: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 40, wherein the patient has a shas score of 38 or higher.

Aspect 44: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 43, wherein the patient suffers from moderate anorgasmia.

Aspect 45: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 43, wherein the patient suffers from severe anorgasmia.

The alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 45, wherein said treatment ameliorates depression and anorgasmia symptoms in said patient.

Aspect 46: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 45, wherein said patient does not experience weight gain during said treatment with alteplerian.

Aspect 47: the alteplerian or a pharmaceutically acceptable salt thereof for use according to aspect 46, wherein the body weight of the patient is assessed at the initial administration of the alteplerian.

Aspect 48: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 47, wherein said patient does not experience a decrease in sexual function during said treatment with alteplerian.

Aspect 49: the alteplerian or a pharmaceutically acceptable salt thereof for use according to aspect 48, wherein the estimated patient's sexual function is assessed at the time of initial administration of the alteplerian.

Aspect 50: the alteplerian or pharmaceutically acceptable salt thereof for use according to aspects 48 or 49, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, attainment of orgasm or orgasm satisfaction.

Aspect 51: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 48 to 50, wherein sexual function is assessed by the arizona sexual experience scale (ASEX).

Aspect 52: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 51, wherein said lack of hedonic effect in said patient is reduced by at least 40% after 6 weeks of said treatment with alteplerian, as measured by the change in total score of the lack of hedonic effect scale from baseline.

Aspect 53: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 52, wherein said lack of hedonia in said patient decreases within about 3 weeks to about 6 weeks as measured by a change in the total score of the lack of hedonia scale from baseline.

Aspect 54: the alteplerian or pharmaceutically acceptable salt thereof for use according to aspects 52 or 53, wherein said hedonic deficit scale is said sneezin-hamilton hedonic scale (SHAPS).

Aspect 55: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 54, wherein the alteplerian achieves a maximum plasma concentration (C _max )。

Aspect 56: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 55, wherein the alteplerian achieves a maximum plasma concentration (C _max )。

Aspect 57: the alteplerian or pharmaceutically acceptable salt thereof for use according to any one of aspects 29 to 56, wherein the alteplerian achieves a maximum plasma concentration (C _max )。

Aspect 58: use of alteplerian or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of major depressive disorder in a human patient suffering from a lack of hedonia.

Aspect 59: the use of aspect 58, wherein the treatment comprises administering an effective amount of alteplerian or a pharmaceutically acceptable salt thereof.

Aspect 60: the use of aspects 58 or 59, wherein the patient is under-responsive to other antidepressant therapy prior to treatment with atetopiramate.

Aspect 61: the use of any one of aspects 58 to 60, wherein the other antidepressant therapy comprises a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

Aspect 62: the use of any one of aspects 58 to 61, further comprising adjunctive therapy with an effective amount of one or more antidepressants.

Aspect 63: the use of any one of aspects 58-62, wherein the one or more antidepressants is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

Aspect 64: the use of any one of aspects 58 to 63, wherein the alteplercanin is S-alteplercanin or a pharmaceutically acceptable salt thereof.

Aspect 65: the use of any one of aspects 58 to 64, wherein the amount of alteplercanium is from about 2mg to about 35mg.

Aspect 66: the use according to aspect 65, wherein the amount of alteplercanin is about 10mg.

Aspect 67: the use according to aspect 65, wherein the amount of alteplercanin is about 5mg.

Aspect 68: the use of any one of aspects 58 to 67, wherein the alteplerian is administered orally.

Aspect 69: the use of any one of aspects 58 to 68, wherein the alteplerian is administered once daily.

Aspect 70: the use of any one of aspects 58 to 69, wherein the patient has a schneider-hamilton hedonic scale (SHAPS) score of 20 or more.

Aspect 71: the use of any one of aspects 58 to 69, wherein the patient has a shas score of 22 or higher, 24 or higher, 26 or higher, 28 or higher, 30 or higher, 32 or higher, 34 or higher, 36 or higher, or 38 or higher.

Aspect 72: the use of any one of aspects 58 to 69, wherein the patient has a shas score of 38 or higher.

Aspect 73: the use of any one of aspects 58 to 72, wherein the patient has a moderate lack of hedonia.

Aspect 74: the use of any one of aspects 58 to 72, wherein the patient has severe anorgasmia.

The use of any one of aspects 58 to 72, wherein the treatment ameliorates depression and lack of pleasure symptoms in the patient. Aspect 75: the use of any one of aspects 58 to 74, wherein the patient does not experience weight gain during the treatment with alteplerian.

Aspect 76: the use of aspect 75, wherein the body weight of the patient is assessed at the initial administration of the alteplerian.

Aspect 77: the use of any one of aspects 58 to 76, wherein the patient does not experience a decrease in sexual function during the treatment with alteplerian.

Aspect 78: the use of aspect 77, wherein the sexual function of the patient is assessed at the initial administration of the alteplerian.

Aspect 79: the use of aspects 77 or 78, wherein said sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, attainment of orgasm or orgasm satisfaction.

Aspect 80: the use of any one of aspects 77 to 79, wherein sexual function is assessed by the arizona sexual experience scale (ASEX).

Aspect 81: the use of any one of aspects 58 to 80, wherein the lack of hedonia in the patient is reduced by at least 40% after 6 weeks of the treatment with atetopiramate, as measured by the change in total score of the lack of hedonia scale from baseline.

Aspect 82: the use of any one of aspects 58 to 81, wherein the lack of hedonia in the patient decreases within about 3 weeks to about 6 weeks, as measured by a change in the total score of the lack of hedonia scale from baseline.

Aspect 83: the use of aspects 81 or 82, wherein the hedonic deficit scale is the sneezing-hamilton hedonic scale (SHAPS).

Aspect 84: the use of any one of aspects 58 to 83, wherein the alteplercanium achieves a maximum plasma concentration (C) of alteplercanium from about 20ng/mL to about 45ng/mL _max )。

Aspect 85: the use of any one of aspects 58 to 84, wherein the alteplercanium achieves a maximum plasma concentration (C _max )。

Aspect 86: the use of any one of aspects 58 to 85, wherein the alteplercanium achieves a maximum plasma concentration (C) of alteplercanium from about 30ng/mL to about 35ng/mL _max )。

The following examples are presented to aid in the understanding of the invention and are not intended to, and should not be construed to, limit in any way the invention as set forth in the claims following the examples.

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Example 1

This is a multicenter, placebo-controlled, randomized, double-blind study directed to MDD subjects with inadequate response to SSRI/SNRI treatment. Evaluating atetopiramate as an adjuvant therapy; thus, the eligible subjects maintained their SSRI/SNRI treatment without any change throughout the study. At least 50% of enrolled subjects must suffer from a lack of pleasure (as measured by the total SHAPS score ≡20).

A. Purpose(s)

The main objective was to evaluate the efficacy of atetopland compared to placebo in alleviating symptoms of depression when administered as an adjunctive treatment to MDD subjects that are partially responsive to SSRI/SNRI treatment, as assessed by the change in MADRS from baseline in non-responders during the placebo-in period.

The secondary objectives are:

i. the efficacy of atetopiramate in alleviating symptoms of depression when administered as an adjunctive therapy to MDD subjects that are partially responsive to SSRI/SNRI treatment, as compared to placebo, is assessed by changes in MADRS from baseline in responders and non-responders during the placebo run in period.

Study-assisted alteplan treatment overall safety and tolerability in MDD subjects when used in combination with SSRI or SNRI.

Study of the effects of atenolol and placebo on depression-related anorgasmia as assessed by SHAPS.

The effect of atekaprin on symptoms of depression was studied using clinical global impression-severity (CGI-S), patient reported major depressive disorder symptoms scale (SMDDS), and treatment history self-assessment (SATE).

v.studyoftheeffectsofatenololonanxietysymptomatologyUsingHAM-A,anduseofHAM-A ₆ The component table investigated the effect of atetopland on the core symptoms of anxiety.

Plasma PK of atetopiramate in MDD subjects was assessed and its relationship to efficacy and safety parameters was explored.

Secondary exploratory purposes include:

i. CPFQ was used to explore the effects of atectalopram on various aspects of cognitive and executive function.

Exploring genetic/epigenetic variations that are associated with mood-related biomarkers (including but not limited to growth factors, HPA axis markers, immune system activation, metabolic markers) and possibly with clinical response, non-response, or safety and tolerability parameters of alteplerian.

B. Study design

For each subject, the study consisted of two phases: a screening phase of up to 5 weeks and a double blind treatment phase lasting 11 weeks. See fig. 1.

MDD subjects receiving licensed SSRI/SNRI treatment and having either an insufficient response or only partial response to the treatment were screened. The evaluations included MINI, antidepressant therapy history questionnaire (TRQ), and MADRS.

The treatment phase consisted of 3 time periods. The duration of the undisclosed placebo run-in period, after which the subjects entered a double blind treatment period during which they were randomly assigned to 10mg of atetopiramate (two 5mg capsules) or continued to take placebo for 6 weeks. Each capsule contained atticopram (5 mg), microcrystalline cellulose (94.95 mg) and magnesium stearate (0.05 mg) in a hard gelatin capsule. The subjects completed the treatment period, entered the withdrawal period and were treated with placebo for the remaining time of the treatment period. The total duration of each subject was about 16 weeks. A total of 11 visits, including screening, were scheduled. An overall flow chart is shown in fig. 1.

Subjects were screened for compliance with inclusion and exclusion criteria within 35 to 2 days prior to day 1. Structured interview guidelines for MADRS are used to assess symptoms of depression.

Double blind treatment stage

The duration of the double blind treatment phase was 11 weeks, divided into 3 time periods. The subjects received the drug after the visit was completed on day 1. The first dose was taken at home on day 2. All medications were taken on an empty stomach. At visit 3, 4 and 5, subjects were re-randomized to blinded subjects during placebo run-in. During the double blind phase, subjects were visited every 1 to 2 weeks to the outpatient center. See table 1.

Lead-in period: subjects who successfully completed the baseline visit at the clinical site/unit were treated with placebo for the duration of the entire lead-in period.

Treatment period: at the end of the lead-in period, placebo-lead responders and placebo-lead non-responders were randomized to receive either placebo or 10mg of atetoplan at a ratio of 1:1 for 6 weeks. The exact time of randomization, response criteria, and drug treatment allocation of each subject was not known to the subject.

Drug withdrawal period: subjects who completed the double blind treatment period before the end of week 11 entered a withdrawal period during which they were treated with placebo for the remainder of the treatment period.

C. Dosage and administration

The atetopiramate is provided in the form of 5mg capsules. Placebo is provided in matched capsules. All subjects took 2 capsules, QD. From day 2 to day 78, the capsules were taken daily with some water in a fasting state (fasted for at least 4 hours prior to dosing). The medicine is taken before breakfast. If the subject forgets to take the medicine before breakfast, the subject should take the medicine before the next meal, at the latest at dinner on the day. If the subject reminds after the evening meal, the dosage on the day is dispensed with, and the subject takes the dosage before the breakfast on the next day.

When the 11 th visit plan was performed after 3 days, the subjects continued to take the drug until the 11 th visit.

The capsule is swallowed whole granule without chewing, splitting, dissolving or grinding. After taking the medicine, the subject does not eat or drink for at least 30 minutes.

The first dose was administered on day 2 of the double blind phase in a fasting state. The dosage of the medicine is as follows:

10mg of atetopiram: 2-granule 5mg atticopram capsule

Placebo: 2 placebo capsules.

Based on the results of blind screening of the safety data, the drug dose was adjusted to 5mgQD as needed. When deciding to reduce the dose, this applies only to new subjects, and the dose of drug is:

5mg of atetopiram: 1 granule 5mg atetopiram capsule

Placebo: 1 placebo capsule.

As used herein, the enriched ITT analysis set (eITT) is defined as all participating lead placebo-non-responders randomized to the treatment period, who received at least one dose of study drug during the treatment period and who performed at least one post-baseline MADRS assessment during the treatment period. Similarly, the full ITT analysis set (fat) is defined as all participating subjects randomized into the treatment period, receiving at least one dose of study drug during the treatment period, and performing a post-treatment baseline assessment of at least one MADRS during the treatment period.

D. Clinical assessment

(i) Depression: montgomery-Absberger depression rating scale (MADRS), clinical global impression-severity (CGI-S), major depressive disorder symptom scale (SMDDS), and treatment experience self-assessment (SATE)

(ii) Lack of pleasure: scomultiple-Hamiltonian quick inductance scale (SHAPS)

(iii) Anxiety: structured interview guidelines (SIGH-A) and HAM-A6 for the Hamiltonian anxiety scale

(iv) Effect on cognition: cognitive and Physical Function Questionnaire (CPFQ)

(v) Security assessment

Standard safety assessments were performed including physical and neurological examinations, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis. Based on observations of GI disease in previous studies, a kit including PGI, PGII, G and HpIgG was added to a clinical laboratory test kit to detect gastric mucosal status.

(vi) Ideation of suicide: C-SSRS

(vii) Exploratory: CPFQ

(viii) Central sedation effect: carlin's card sleepiness scale

(ix) Sexual dysfunction: ASEX

E. Patient population

Of 184 subjects, 169 subjects were randomized into treatment period and included a safety population, while 166 subjects were considered a full ITT population. Of 166 subjects in the full ITT population, 121 subjects (73%) were placebo-introduced non-responders (enriched ITT population) and the remaining 45 subjects (27%) were placebo-introduced responders. Of 121 subjects in the enriched population, 112 subjects (92.6%) were white and 84 subjects (69.4%) were females. The average age was 41.6 years, ranging from 19 years to 64 years. All subjects had a lack of pleasure at the treatment baseline (defined as a total SHAPS score ≡20). A high level of lack of hedonia (defined as a total SHAPS score of > 38) was observed in 43.8% of the subjects. Generally, the treatment groups were similar in baseline characteristics. Subject demographics and safety analysis of eITT are provided in tables 2 and 3.

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E. Efficacy evaluation

At the end of the lead-in period, the subject's response status was assessed according to a double blind response criterion based on MADRS reduction relative to the lead-in baseline. During the treatment period, the placebo-introduced responders and the placebo-introduced non-responders were randomly assigned to either the atica or placebo at a 1:1 ratio. Randomization was stratified according to the status of the lead-in response (no responders had a <30% decrease in MADRS total score from baseline at the end of the lead-in period, and some had a 30% decrease or more from baseline at the end of the lead-in period) and absence/presence of a hedonic deficit (presence was defined as SHAPS total score 20 or more).

Duration of treatment: the study consisted of two time periods: a screening phase of up to 5 weeks and a double blind treatment phase of 11 weeks. The double blind treatment phase of the trial consisted of 3 time periods. The first period was placebo run in for 3 weeks, after which the subjects entered a treatment period during which they were randomly assigned to atetopland or continued to take placebo for 6 weeks. Subjects who successfully completed the treatment period were treated with placebo during the 2 week withdrawal period (i.e., period 3). The total duration of each subject was about 16 weeks.

Principal analysis set of efficacy: efficacy analysis was based on the eITT set, which was defined as all participating lead placebo non-responders randomized to treatment period, receiving at least one dose of drug and performing at least one post-baseline MADRS assessment during treatment period. The primary analysis set was used for all efficacy endpoints.

Secondary analysis set of efficacy: the secondary analysis set is the fITT set, which is defined as all participating subjects randomized into the treatment period, receiving at least one dose of drug and performing at least one post-baseline MADRS assessment during the treatment period. The secondary analysis set was used for all efficacy endpoints to examine effects in the general population, which may aid in subsequent studies in the design development plan.

Security analysis set: the safety analysis is based on a full safety analysis set defined as all participating subjects receiving at least one dose of the drug during the treatment period.

The efficacy endpoints of eITT and fITT are presented.

Significance level: analysis of the primary efficacy endpoint was performed at a significance level (unilateral) of 0.20. Analysis of secondary efficacy endpoints was performed at a level of significance of 0.20 (bilateral). No adjustments were made to the multiple comparisons.

F. Results

(i) The main end point is: total MADRS score for placebo-induced period non-responders at treatment week 6 relative to treatment base Line change

Enrichment of ITT analysis sets

The mean (SD) MADRS total score at treatment baseline was 29.0 (4.61), ranging from 19 to 41. See fig. 2. The mean change (SD) of the total MADRS score at week 6 of treatment with atetopiramate and placebo from the treatment baseline was-10.2 (8.44) and-8.2 (8.53), respectively. The observed effect amount was 0.23. See tables 4 to 6 and fig. 6.

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Based on a randomized effect in the subject; take country, treatment, time/treatment interactions as factors; and a significant positive efficacy signal of atetopland relative to placebo was detected at a single-sided 0.20 significance level with the baseline MADRS total score as a result of the MMRM model of continuous covariates. The estimated LS mean difference between atetopland and placebo at week 6 of treatment was-2.1, with an 80% unilateral CI upper limit of-1.09. The corresponding p value is 0.044. The therapeutic effect of the fITT population is greater than that of the eITT population: -3.1, 80% single-sided CI upper limit of-2.2 (p=0.002). The effective amounts were 0.36 and 0.23, respectively. See fig. 2 and 3.

Full ITT analysis set

The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86), ranging from 0 to 41. See fig. 7A and 7B. The mean change in total MADRS score at week 6 of treatment with fITT versus placebo was less than the eITT from treatment baseline of-9.7 (8.02) and-6.6 (8.57), respectively. The observed effect amount was 0.36. These results demonstrate the statistical advantage over placebo, with the greatest difference observed in effect persistence at week 6. See table 7.

Significant effects of atetoplan relative to placebo were also detected in the ftt population. The estimated LS mean difference between atetoplan and placebo at week 6 of treatment was-3.1, with an 80% unilateral CI upper limit of-2.21. The corresponding p value is 0.002. See tables 8 to 9 and fig. 3.

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Effect of covd-19 on primary efficacy assessment

All data collected prior to day 3, 15 of 2020 (estimated date of covd-19 block in most countries of the trial) were subjected to a complementary analysis using the same MMRM model as described for the primary analysis. At least one MADRS evaluation was excluded from the model for 17% of subjects in the fITT population and 19% of subjects in the eITT population due to the effect of COVID-19. The analysis results confirm the main efficacy analysis results in the eITT population and the fITT population. The estimated values of LS mean differences for eITT and fITT were-3.0 (80% single-sided CI upper limit of-1.88) and-3.4 (80% single-sided CI upper limit of-2.51), respectively.

(ii) Secondary endpoint

MADRS remission rate during treatment period

At week 6 of treatment, the percentage of subjects with atetopland and placebo MADRS relief (MADRS total score. Ltoreq.10) in the eITT population was 16.9% and 16.9%, respectively. The remission rates for the 6 th week of treatment with atetopland and placebo in the ftt population were 31.2% and 22.2%, respectively. For both populations (eITT and fITT), no significant treatment differences were detected at treatment week 6 using the chi-square test (bilateral p=0.999 and p=0.203, respectively). See fig. 8 and 9.

MADRS response rate during treatment period (improvement of at least 30%)

In the eITT population, the percentage of subjects with a total MADRS score improvement of > 30% at week 6 of treatment with atetopland and placebo was 57.6% and 45.8%, respectively. The response rates of the atica and placebo treatment at week 6 were 61.8% and 44.4%, respectively, in the fITT population. For both populations, the treatment differences at treatment week 6 were significant at 20% bilateral significance levels (chi square test: eITT p=0.197 and fITT p=0.029).

MADRS response rate during treatment period (improvement of at least 50%)

In the eITT population, the percentage of subjects with a total score improvement of 50% or more at week 6 of treatment with atetopland and placebo was 35.6% and 22.0%, respectively. The response rates of the atica and placebo treatment at week 6 were 38.2% and 23.5%, respectively, in the fITT population. For both populations, the treatment differences at treatment week 6 were significant at 20% bilateral significance levels (chi square test: eITT p=0.104, and fITT p=0.046). See table 10 and fig. 10-13.

Variation of total SHAPS score from treatment baseline to treatment week 6

Enrichment of ITT analysis sets

In the eITT population, a greater difference between atenolol and placebo at week 6 of treatment was observed in a subset of subjects with high level of anhedonia (baseline total shas score > 38) compared to subjects with low level of anhedonia (20. Ltoreq. Baseline total shas score < 38). The effective amounts were 0.38 and 0.11, respectively.

The average (SD) SHAPS total score at treatment baseline was 36.6 (5.45), ranging from 20 to 50. The mean change (SD) of total SHAPS scores at week 6 of treatment with atetopland and placebo from treatment baseline was-4.6 (6.23) and-4.2 (5.04), respectively. The observed effect amount was 0.07. See table 11 and fig. 14 and 23.

Changes in the SHAPS total score were analyzed using the same MMRM model as the MADRS total score. At week 6 of treatment, the estimated LS mean difference for 80% bilateral CI between atetoplan and placebo was-0.7 [ -1.81,0.41]. See fig. 4 and tables 12 and 13, and fig. 15. The corresponding p value is 0.419.

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At week 6 of treatment, the estimated LS mean difference for 80% bilateral CI between atetoplan and placebo was-0.8 [ -1.79,0.10]. The corresponding p value is 0.250. See fig. 4 and 5.

Full ITT analysis set

Similar trends were observed in the fttt population and the magnitude of the differences was greater than that observed in the eITT population. The effective amounts were 0.51 and 0.29, respectively. The average (SD) baseline shas total score at treatment baseline was 35.6 (5.67), ranging from 14 to 50. The mean change in total SHAPS score at week 6 of treatment with the ftt population relative to treatment baseline was similar to the change in eITT, 4.7 (5.91) and 4.2 (4.98), respectively. The observed effect amount was 0.08. See table 14.

MADRS total score change from baseline treatment to week 6 treatment based on the level of lack of pleasure at baseline

Enrichment of ITT analysis sets

In a subset of subjects (n=53) with high level of hedonia at the treatment baseline (shas total score ∈38), a larger difference between atetopand placebo at week 6 of treatment was observed compared to subjects (n=65) with low level of hedonia (20+.baseline shas total score < 38), respectively: [ -7.5,0.7]90% double sided CI, -3.4 and [ -4.2,2.5]90% double sided CI, -0.9 (Table 15). The observed effect amounts were 0.38 and 0.11, respectively.

Full ITT analysis set

Similar trends were observed in the fITT population. The magnitude of the difference is greater than in the eITT population: for high-grade subjects with lack of hedonia (n=63), at [ -8.4, -0.8]90% bilateral CI, they were-4.6, and for low-grade subjects with lack of hedonia (n=94), at [ -5.0,0.4]90% bilateral CI, they were-2.3. See table 16. The observed effect amounts were 0.51 and 0.29, respectively.

This data demonstrates that a division into high and low hedonia is beneficial for the treatment of MDD: the atetopiramate has higher therapeutic effect. Furthermore, the placebo response was lower in patients with high hedonic deficits than in patients with low hedonic deficits.

Changes in CGI-S score at treatment time relative to treatment baseline

Changes in SMDDS overall score at week 6 of treatment relative to treatment baseline

Number of subjects with SATE score at week 6 of treatment

Changes in HAM-A6 total score at week 6 of treatment relative to treatment baseline

These data demonstrate a greater improvement in HAMA6 scores for the atiand treated patients compared to placebo.

Variation of SIGH-A structured interview guideline score at week 6 of treatment from treatment baseline

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_max Maximum plasma concentration of atetopiramate (C)

C _max Defined as the maximum plasma concentration of alteplerian. The eITT population includes all participating lead placebo non-responders randomized into the treatment period, receiving at least one study drug and performing at least one post-baseline MADRS assessment during the treatment period. "N" (number of subjects analyzed) herein includes the number of subjects that the endpoint can evaluate. "n" (number of analyses) herein includes all subjects that are rated by the specified time point category.

(iii) Safety endpoint

Overall, in the full safety analysis set, 40/85 (47.1%) of subjects in the alteplerian group and 30/84 (35.7%) of subjects in the placebo group experienced at least one TEAE during the treatment period. See table 23.

The most common TEAE during the treatment period was experienced by headache (10/85 (i.e. 11.8%) of the subjects in the atticoplanan group and 6/84 (i.e. 7.1%) of the subjects in the placebo group) and diarrhea (7/85 (i.e. 8.2%) of the subjects in the atticoplanan group and 2/84 (i.e. 2.4%) of the subjects in the placebo group). See table 24.

A total of 2 subjects discontinued treatment during the treatment period due to treatment emergent adverse events: 1 subject in the attica 10 group discontinued treatment due to diarrhea, nausea, vomiting and headache, and another subject in the placebo group discontinued treatment due to acute calculous cholecystitis.

Overall, 17/169 subjects developed TEAE of particular interest during the treatment period: 13/85 (15.3%) of the subjects in the atticopram group and 4/84 (4.8%) of the subjects in the placebo group. The most common treatment emergent adverse events during the treatment phase are headache and diarrhea. The most common TEAE of particular interest during the treatment period was experienced by subjects with diarrhea and itching (in the atectaprine group, 5/85 (i.e. 5.9%) and in the placebo group, 0/84 subjects). The placebo group also experienced acute cholecystitis in 1 patient (1.19%) compared to 0 in the patients treated with atectapriand see table 25.

Two serious adverse events occurred. One subject of the placebo group experienced acute calculous cholecystitis during the treatment period and the other subject developed suicidal ideation during the lead-in period. Two subjects discontinued treatment due to these AEs.

Death was not reported.

(iv) Analysis of lack of pleasure

Patients in the larger fITT group maintained baseline levels of depression and lack of severity consistent with the eITT group. See tables 26-28.

The results demonstrate that the more patients with a lack of pleasure at baseline, the better the therapeutic effect. See fig. 16.

The results demonstrate that the more patients with a lack of pleasure at baseline, the better the therapeutic effect. See fig. 17A and 17B. In fig. 17A (i.e., the high-pleasure-deficient group), the placebo + oral antidepressant group exhibited less placebo response than the low-pleasure-deficient group in fig. 17B. Similarly, the therapeutic effect of the atenolol+oral antidepressant group in the high-hedonic deficient group is higher than in the low-hedonic deficient group. Overall, the effect amount was greater per single time point (from week 1) in the high-hedonic deficit group. At week 6, LSMD was more than twice that of the low-hedonic deficient group. Furthermore, when the symptom level is observed, the improvement of each item associated with a lack of pleasure and anxiety in the high-pleasure lack subgroup is greater than in the low-pleasure lack subgroup. See fig. 18.

(v) Weight change

At the time point of introduction of the baseline, the average body weight of placebo group subjects was 76.17kg, while the average body weight of the atetopiramate group subjects was 78.66kg. After 6 weeks of the double-blind treatment phase, the average body weight of the placebo group was 75.75kg, while the average body weight of the atetopiramate group was 78.57kg. This indicates that the body weights of the two groups remained relatively stable during the double blind treatment period of 6 weeks. This is unexpected because other adjunctive treatments of MDD can lead to average weight gain. See Thase M et al J Clin Psych.2015:76 (9), 1224-1231; thase, J Clin Psych.2015,76 (9): 1232-1240; el Khalili, int J Neuropyschopharmacol.2010, 13,917-932; marcus, J.Clin.Psychopharmacol.2008,28:156-165; berman, j.clin.psychiatyry 2007;68:843-853; berman, american College of Neuropsychopharmacology,2008,Annual Meeting Abstracts (scotts, arizona, 12 th to 11 th of 2008) ACNP,2008; earley, american College of Neuropsychopharmacology,2007,Annual Meeting Abstracts (bocarton, florida, 12 months 9 to 13 days 2007.) the tennessee nanshiville, ACNP,2007. See table 29.

(vi) Completion rate

Patients passing through the screening phase enter the lead-in phase, followed by the double blind phase. Patients who responded to placebo during the lead-in phase were marked as non-responders. Patients that did not respond to placebo were labeled as non-responders. The double-blind treatment phase continued for another 6 weeks after which the patient entered the withdrawal phase.

Of 121 subjects in the enriched population (60 in the atectapram group, 61 in the placebo group), 117 (96.7%) completed the study. The overall completion rate of the full ITT analysis set was 95%. In contrast, the completion rate of the adjuvant aripiprazole study was about 85% (Pae, CNS Drugs,2011;25, 109-127), and the completion rate of the adjuvant quetiapine was 45% to 62% (El Khalili as cited above). A total of 4 subjects (3.3%) discontinued the study: 2 placebo-treated subjects and 2 atetopland-treated subjects. See tables 30 and 31.

(vii) Sexual function

Sexual dysfunction is a common side effect of antidepressant therapy and can be very annoying to patients and their sexual partners. Major depression itself is associated with an increase in sexual dysfunction, and multiple ones of the drug treatments are known to further worsen sexual function. In a large survey of nearly 5000 patients in france, the prevalence of sexual dysfunction was estimated to be 65% in untreated MDD patients. The prevalence of sexual dysfunction increases to 71% in patients treated with antidepressant therapy.

Sexual pleasure is an important component of hedonic mood. The brain reward circuit is controlled by several zones: nucleus accumbens, ventral tegmental areas and amygdala. It is hypothesized that treatment with kappa opioid receptors may restore normal homeostasis in overactive patients. Treatment with atetopiramate may improve symptoms of lack of pleasure. Other symptoms associated with the reward circuit include: sexual pleasure, lack of interest, and lack of enjoyment.

The sexual function of the patient is measured using a standard, widely accepted rating scale ASEX. See table 32.

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The average change (SD) of ASEX total score from treatment baseline at week 6 of atetopland and placebo was-1.5 (4.02) score and-0.7 (2.98) score, respectively. A lower score on ASEX indicates improvement. The score drop was greater in the altepram group at week 6 compared to placebo. This is unexpected because adjuvant treatment with other agents is expected to worsen sexual function, i.e., the ASEX score increases over time. See fig. 19.

Patients receiving treatment with atetopiramate have a significant improvement in sexual function. The individual item level changes were also examined and the greatest change was found to occur in items related to the completed hedonic effect: orgasm is satisfied and orgasm and vaginal lubrication/erection is achieved. The majority of improvements can be seen in items 3, 4 and 5 of figure 20.

(viii) Takes effect

The efficacy of atetopiramate can be estimated from the study. Fig. 7B depicts least squares mean change from baseline. Significant therapeutic effects biased towards atetopaz were observed as early as week 3. In this regard, atetopiramate showed statistically better effects than placebo.

Example 2: single dose of actecapram as an adjunct antidepressant therapy

Study design: one was a 6 week, multicentric, double blind, randomized, placebo-controlled study aimed at assessing efficacy, safety and tolerability of atectalopram in adult and aged subjects (18 to 74 years) suffering from MDD and significant lack of hedonia (MDD anh+) and in current depressive episodes, who had inadequate response to SSRI or 5-hydroxytryptamine and SNRI. See fig. 21.

For all subjects, the study will consist of 3 phases: qualification screening phase (up to 4 weeks prior to administration of the first dose), double blind treatment phase for 6 weeks and follow-up for 1 to 2 weeks. Subjects completing the double blind phase may participate in an open-label long-term safety study.

Sample size and randomization: approximately 544 MDD subjects with significant hedonic deficit (mddanh+) and without significant hedonic deficit (MDDANH-) will be randomized to the auxiliary placebo or alteplan in a 1:1 ratio to obtain at least 314 adult subjects meeting the predefined criteria for mddanh+ to meet the conditions for inclusion in the primary analysis. Randomization will be stratified according to study site, age group (adult [ <65 years ], elderly [. Gtoreq.65 years ]), baseline hedonia, and baseline MADRS overall score. All subjects will continue to take baseline antidepressants (SSRI/SNRI) throughout the study.

Dosage and administration all eligible subjects will receive actalapram or placebo except for the baseline SSRI/SNRI that will continue to be taken throughout the study. The study medication will be taken daily.

Inclusion criteria:

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exclusion criteria:

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A. therapeutic purposes and endpoints

Assessment of primary and secondary (critical and other) endpoints will be performed against FAS, which includes MDD anh+ adult (non-geriatric) subjects taking at least 1 dose of study drug.

Primary endpoint: adjuvant therapy evaluating atetopiramate as antidepressant (SSRI or SNRI) for efficacy compared to placebo in improving symptoms of depression in adult subjects with MDD anh+ and insufficient response to current antidepressants, as assessed by the change from baseline in total MADRS score from day 1 (before randomization) to the end of the 6 week double blind treatment period (day 43):

change in MADRS total score from baseline to day 43

Critical secondary endpoint: efficacy of atetoplanine as an adjunct therapy to antidepressants in MDD anh+ adult subjects compared to placebo was evaluated based on the following patient reported lack of pleasure assessment:

the change in the dimensional hedonic deficit rating scale (DARS) total score from baseline to day 43.

Other secondary endpoints: atekaplan was evaluated as adjuvant therapy in MDD anh+ adult subjects based onEfficacy in the subjects compared to placebo:

the proportion of responders on day 43 (total MADRS score decrease. Gtoreq.50%).

Proportion of subjects with remission of depression symptoms (defined as total MADRS score at day 43. Ltoreq.12).

MADRS 6 change from baseline to day 43.

The PHQ-9 total score varied from baseline to day 43.

Changes in SHAPS total score from baseline to day 43.

Changes in anxiety symptoms from baseline to day 43 with GAD-7.

Exploratory property: the efficacy of atetopiramate as adjuvant therapy in MDD anh+ adult subjects and in all MDD subjects (adult subjects and geriatric subjects with MDD anh+ and MDD ANH-) compared to placebo was evaluated based on:

changes in total score of MADRS over time relative to baseline.

MADRS lack of change in term factor score over time from baseline.

Changes in patient reported lack of pleasure results (SHAPS, DARS) over time from baseline.

Changes in PHQ-9 total score over time relative to baseline.

Health related quality of life and change in health status from baseline to day 43 as assessed by the EQ-5D-5L questionnaire.

The change in SDS total score from baseline to day 43.

Changes in CGI-S score over time from baseline.

Anxiety symptoms with GAD-7 over time relative to baseline.

Changes in depression symptoms over time relative to baseline using PGI-S.

Changes in sexual function reported from baseline to day 43 using ASEX patients.

The efficacy of atetopiramate as an adjuvant therapy in MDDANH-adult subjects compared to placebo was evaluated based on:

changes in total score of MADRS over time relative to baseline.

Changes in DARS total score over time from baseline.

Safety purpose (all): the following safety endpoints will be assessed for adult and geriatric subjects, respectively; the safety analysis set for each age group will include all randomized subjects receiving at least one dose of study drug:

AE including AESI. An AE may be any adverse and unexpected sign (including abnormal findings), symptom, or disease that is temporally associated with the use of a pharmaceutical (investigational or non-investigational) product, whether or not associated with the pharmaceutical (investigational or non-investigational) product. TEAE is AE that occurs during the treatment phase from post-baseline exacerbation. The full safety analysis set includes all participating subjects who received at least 1 dose of study drug during the treatment period.

Vital signs

ECG, laboratory values

weight/BMI

Suicidal trend assessment using C-SSRS

Withdrawal symptom assessment Using PWC-20

B. Concomitant therapy and illicit therapy

Background therapy: all subjects will continue to take baseline antidepressants (SSRI/SNRI) throughout the study. The following antidepressants are allowed: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine and desvenlafaxine. During the study, the subject will continue to take only one of these allowable antidepressants (i.e., monotherapy) at a sufficient tolerating dose. No change in antidepressant or dose was allowed from screening until the end of the study.

Forbidden therapy: as indicated, the subject must not use the following drugs or dietary supplements prior to or during the study, unless for the treatment of AE or breakthrough symptoms, preferably at EOT visitAfter diagnosis:

MAOI within 4 weeks prior to screening until the first follow-up.

Antipsychotic drug from at least 14 days prior to day 1 until prior to the first follow-up.

Hypnotics or dietary supplements (from at least 7 days prior to day 1 until prior to the first follow-up) including, but not limited to, benzodiazepines, non-benzodiazepines hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and lamitinone), sedative antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin/agomelatine.

Subjects taking benzodiazepines and/or allowed non-benzodiazepines sleep medications during the screening phase may continue to take these medications (at doses equal to or less than 6 mg/day equivalent of lorazepam) during the double-blind treatment phase. During the double blind treatment phase, the dose was not allowed to increase by more than 6 mg/day equivalent of lorazepam, nor was the new benzodiazepine drug allowed.

non-SSRI/SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine and SAMe) from at least 7 days prior to day 1 until the first follow-up.

During the screening and double blind phases, any form of new or current psychotherapy is prohibited from changing.

Opioid and mood stabilizer (e.g., lithium and anticonvulsant) from at least 7 days prior to day 1 until prior to the first follow-up.

Stimulants (e.g., dextroamphetamine, methylphenidate, dextroamphetamine), oral systemic steroids, and appetite suppressants (ephedrine) and isosuprolide from at least 7 days prior to day 1 until before EOT.

Magnetic and electrical stimulation therapies: from screening to study end visit, electroconvulsive therapy, vagal nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation. TMS or DCS or electrical stimulation use prior to screening is not within the exclusion range.

T3, thyroid hormone or other thyroid function supplements for the treatment of depression.

These drugs are permissible when used to control pre-existing thyroid diseases/disorders.

Ketamine or esketamine (up to 2 doses allowed for lifetime before screening) within 5 years before and during the study.

Hallucinogens (e.g., siroccin).

Memantine.

Other study drugs within 30 days prior to and during the study.

Example 3: a randomized, double-blind, multi-center, placebo-controlled study aimed at evaluating as adjuvant therapy 5mg and 10mg of atica in a fixed dose with MDD and significant anorgasmia and current antidepressant medication Efficacy, safety and tolerability in adult and geriatric subjects with insufficient response

Study design: one was an 8 week, multicentric, double blind, randomized, placebo-controlled study aimed at assessing efficacy, safety and tolerability of atectalopram in adult and geriatric subjects (18 to 74 years) suffering from MDD and significant lack of hedonia and in current depressive episodes, with inadequate response to SSRI or SNRI. See fig. 22.

For all subjects, the study will consist of 3 phases:

Qualification screening stage (up to 4 weeks before administration of the first dose),

a double blind treatment phase for 8 weeks,

and a follow-up period of 1 week to 2 weeks.

Approximately 624 subjects (randomized to placebo, 5mg of atenolol and 10mg of atenolol in a 2:1:1 ratio) will participate in the study. The goal of this recruitment was to reach at least 556 adult subjects with MDD and significant hedonia and approximately 68 elderly subjects (65 years or more) with MDD and significant hedonia.

Subjects completing the double blind treatment phase may participate in an open label long-term safety study.

Sample size and randomization: about 624 adult subjects suffering from MDD and significant hedonia<65 years) and elderly subjects (. Gtoreq.65 years) will be randomized to a ratio of 2:1:1 to either a secondary placebo, 5mg of alteplercanium or 10mg of alteplercanium to obtain at least 556 adult subjects meeting predefined criteria for MDD and significant hedonia to meet the conditions for inclusion in the primary therapeutic efficacy analysis set. Randomization will be stratified according to study site, age group (adult, elderly) and baseline MADRS overall score. All subjects will continue to take baseline antidepressants (SSRI/SNRI) throughout the study.

Dosage and administration: all eligible subjects will receive 5mg of alteplerian, 10mg of alteplerian or placebo, except for the baseline SSRI/SNRI that will continue to be taken throughout the study. The study medication will be taken daily.

Inclusion criteria:

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exclusion criteria:

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A. therapeutic purposes and endpoints

Assessment of primary and secondary (critical and other) endpoints will be performed against a Full Analysis Set (FAS) comprising adult (non-geriatric) subjects with MDD and significant hedonic deficits who took at least 1 dose of study drug.

Primary endpoint: evaluation of efficacy of 2 fixed doses of atenolol (5 mg and 10 mg) as an adjunct therapy to antidepressants (SSRI or SNRI) in improving symptoms of depression compared to placebo in adult subjects with MDD and significant anorgasmia and inadequate response to current antidepressants (18 to 64 years)

Change in MADRS total score from baseline to day 43

Critical secondary endpoint: the efficacy of adjunctive therapy of atetoplan 10mg as an antidepressant in adult subjects with MDD and significant hedonic deficit compared to placebo was evaluated based on the following patient reported hedonic deficit evaluation results:

the change in the dimensional hedonic deficit rating scale (DARS) total score from baseline to day 43.

Other secondary endpoints: evaluation of efficacy of actalapril as an adjunct therapy to antidepressants (SSRI or SNRI) in adult subjects with MDD and significant hedonic deficit compared to placebo:

the proportion of responders (MADRS total score decrease. Gtoreq.50%) at day 43 and day 57.

Proportion of subjects with remission of depression symptoms (defined as total MADRS score at day 43 and day 57. Ltoreq.12).

MADRS-6 change from baseline to day 43 and day 57.

The change in total score from baseline to day 43 and day 57 for the 9 patient health questionnaires (PHQ-9).

Exploratory property: the efficacy of atenulan as an adjunct therapy in adult subjects with MDD and significant anorgasmia compared to placebo was evaluated based on:

changes in total score of MADRS over time relative to baseline.

MADRS lack of change in term factor score over time from baseline.

Changes in patient reported lack of pleasure results (SHAPS, DARS) over time from baseline.

Changes in PHQ-9 total score over time relative to baseline.

Health related quality of life and change in health status from baseline to day 43 as assessed by the EQ-5D-5L questionnaire.

Change in the total score of the haen disability scale (SDS) from baseline to day 43.

Changes in CGI-S score over time from baseline.

Anxiety symptoms with GAD-7 over time relative to baseline.

Changes in depression symptoms over time relative to baseline using PGI-S.

Changes in sexual function reported from baseline to day 43 using ASEX patients.

Safety purpose (all): the following safety endpoints will be assessed for adult and geriatric subjects, respectively; the safety analysis set for each age group will include all randomized subjects receiving at least one dose of study drug:

AE including AESI

Vital signs

·ECG

Laboratory values

weight/BMI

Suicidal trend assessment using C-SSRS

Withdrawal symptom assessment Using PWC-20

Other purposes (exploratory)：

Identify diagnostic biomarkers and study the changes in MDD-related biomarkers associated with clinical response to depression symptoms and lack of hedonia in actecapram monotherapy.

Identify genetic and other factors that may affect the Pharmacokinetics (PK), safety or tolerability of atetopiramate.

B. Concomitant therapyForbidden therapy

Background therapy: all subjects will continue to take baseline antidepressants (SSRI/SNRI) throughout the study. The following antidepressants are allowed: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine and desvenlafaxine. During the study, the subject will continue to take only one of these allowable antidepressants (i.e., monotherapy) at a sufficient tolerating dose. No change in antidepressant or dose was allowed from screening until the end of the study.

Forbidden therapy：

As indicated, the subject must not use the following drugs or dietary supplements prior to or during the study, unless for the treatment of AE or breakthrough symptoms, preferably after EOT visits:

MAOI within 4 weeks prior to screening until the first follow-up.

Antipsychotic drug from at least 14 days prior to day 1 until prior to the first follow-up.

Hypnotics or dietary supplements (from at least 7 days prior to day 1 until prior to the first follow-up) including, but not limited to, benzodiazepines, non-benzodiazepines hypnotics (e.g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and lamitinone), sedative antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin. Subjects taking benzodiazepines and/or allowed non-benzodiazepines sleep medications during the screening phase may continue to take these medications (at doses equal to or less than 6 mg/day equivalent of lorazepam) during the double-blind treatment phase. During the double blind treatment phase, the dose was not allowed to increase by more than 6 mg/day equivalent of lorazepam, nor was the new benzodiazepine drug allowed.

non-SSRI/SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine and SAMe) from at least 7 days prior to day 1 until the first follow-up.

During the screening and double blind phases of the present study, any form of new or current psychotherapy was prohibited from changing.

Opioid and mood stabilizer (e.g., lithium and anticonvulsant) from at least 7 days prior to day 1 until prior to the first follow-up.

Stimulants (e.g., dextroamphetamine, methylphenidate, dextroamphetamine), oral systemic steroids, and appetite suppressants (ephedrine) and isosuprolide from at least 7 days prior to day 1 until before EOT.

Magnetic and electrical stimulation therapies: from screening to study end visit, electroconvulsive therapy, vagal nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation. TMS or DCS or electrical stimulation use prior to screening is not within the exclusion range.

T3, thyroid hormone or other thyroid function supplements for the treatment of depression. These drugs are permissible when used to control pre-existing thyroid diseases/disorders.

Ketamine or esketamine (up to 2 doses allowed for lifetime before screening) within 5 years before and during the study.

Hallucinogens (e.g., siroccin).

Memantine.

Other study drugs within 30 days prior to and during the study.

Claims (30)

1. A method for treating major depressive disorder in a human patient suffering from a lack of pleasure, the method comprising administering to the patient in need thereof an effective amount of alteplercanium or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the patient is under-responsive to other antidepressant medications prior to treatment with atetopiramate.

3. The method of claim 2, wherein the other antidepressant therapy comprises a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

4. The method of any preceding claim, further comprising adjunctive therapy with an effective amount of one or more antidepressants.

5. The method of claim 4, wherein the one or more antidepressants is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

6. A process according to any preceding claim, wherein the altaicaprlan is S-altaicaprlan or a pharmaceutically acceptable salt thereof.

7. The method of any preceding claim, wherein the effective amount of alteplerian is from about 2mg to about 35mg.

8. The method of any preceding claim, wherein the effective amount of alteplerian is about 10mg.

9. The method of any preceding claim, wherein the alteplerian is administered orally.

10. The method of any preceding claim, wherein the alteplerian is administered once daily.

11. The method of any preceding claim, wherein the patient has a sneezing-hamilton fast induction scale (SHAPS) score of 20 or more.

12. The method of any preceding claim, wherein the patient has a shas score of 22 or higher, 24 or higher, 26 or higher, 28 or higher, 30 or higher, 32 or higher, 34 or higher, 36 or higher, or 38 or higher.

13. The method of any preceding claim, wherein the patient has a shas score of 38 or higher.

14. The method of any preceding claim, wherein the patient has moderate to severe anhedonia.

15. The method of claim 14, wherein the patient has a moderate lack of pleasure.

16. The method of claim 14, wherein the patient has severe anorgasmia.

17. The method of any preceding claim, wherein the patient does not experience weight gain during the treatment with atetopiramate.

18. The method of claim 17, wherein the body weight of the patient is assessed at the initial administration of the alteplerian.

19. The method of any preceding claim, wherein the patient does not experience a decrease in sexual function during the treatment with atetopiramate.

20. The method of claim 19, wherein the sexual function of the patient is assessed at the initial administration of the alteplan.

21. The method of claim 19 or claim 20, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, attainment of orgasm or orgasm satisfaction.

22. The method of any one of claims 19 to 21, wherein sexual function is assessed by the arizona sexual experience scale (ASEX).

23. The method of any preceding claim, wherein the lack of hedonia in the patient is reduced by at least 40% after 6 weeks of the treatment with atenolol, as measured by the change from baseline in the total score of the lack of hedonia scale.

24. The method of any preceding claim, wherein the lack of hedonia in the patient decreases within about 3 weeks to about 6 weeks as measured by a change in the total score of the lack of hedonia scale from baseline.

25. The method of claim 23 or claim 24, wherein the hedonic deficit scale is the schneider-hamilton hedonic scale (SHAPS).

26. The method of any preceding claim, wherein the administration of the alteplercanin achieves a maximum plasma concentration (C) of alteplercanin of about 20ng/mL to about 45ng/mL _max )。

27. The method of any preceding claim, wherein the administration of the alteplercanin achieves a maximum plasma concentration (C) of alteplercanin of about 25ng/mL to about 35ng/mL _max )。

28. The method of any preceding claim, wherein the administration of the alteplercanin achieves a maximum plasma concentration (C) of alteplercanin of about 30ng/mL to about 35ng/mL _max )。

29. Alteplerian or a pharmaceutically acceptable salt thereof for use in a method according to any one of claims 1 to 28.

30. Use of alteplerian or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in a method of treatment according to any one of claims 1 to 28.