Metabolic benefits of seltorexant on patient's weight and insulin sensitivity

Abstract

Methods of treating a patient with major depressive disorder (MDD) and insulin resistance are provided. Also provided are methods of treating a patient with MDD and stabilizing or decreasing body weight of the patient. The methods include administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

Description

METABOLIC BENEFITS OF SELTOREXANT ON PATIENT’S WEIGHT AND INSULIN SENSITIVITYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 63 / 698,386, filed September 24, 2024, the disclosure of which is incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure relates to methods for treating patients with major depressive disorder (MDD) and insulin resistance. The disclosure also relates to treating patients with MDD and stabilizing or decreasing the body weight of the patient.BACKGROUND

[0003] While suicide-related death contributes a significant impact on the premature mortality associated with major depressive disorder (MDD), the greatest causes of excess mortality are cardiovascular and metabolic diseases. MDD is associated with a 2- to 4-fold increased risk of death from cardiovascular disease (CVD) and a 2-fold increase in death from cerebrovascular disease, each driven largely by elevated risk of atherosclerotic vascular disease, especially secondary to Type-2 diabetes, metabolic syndrome, and chronic inflammation. Insulin resistance (IR) and increased body weight significantly elevate the risk of developing diabetes mellitus (DM) and CVD.

[0004] The most widely used adjunctive treatments for MDD are known to be associated with adverse metabolic effects that include hyperglycemia, dyslipidemia and body weight gain. There are currently no specific approved treatments tailored to individuals with MDDIS. Furthermore, there are no therapies available that provide these metabolic benefits for either the overall MDD or MDD with insomnia symptoms (MDDIS) populations.

[0005] Seltorexant (JNJ-42847922) is a potent and selective antagonist of the human orexin-2 receptor (0X2R) that is being developed for adjunctive treatment of MDD, including MDDIS. The mode of action through which seltorexant produces antidepressant effects is thought to be the attenuation of hyperarousal mediated via 0X2R activation. Relative to existing therapies, seltorexant uniquely increases sleep while preserving the normative sleep architecture. Moreover, preclinical evidence supports a role for the orexinsystem in modulating the stressed component of HPA axis function and other aspects of stress-responsiveness, and in depressed patients seltorexant reduces the waking cortisol response toward normative levels.

[0006] New therapies for treating patients for depression and regulating metabolic side effects of hyperglycemia, dyslipidemia and body weight gain therefrom are needed.SUMMARY

[0007] In some embodiments, the disclosure provides methods of treating a patient with major depressive disorder (MDD) and insulin resistance, comprising administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

[0008] In other embodiments, the disclosure provides methods of treating a patient with MDD and stabilizing or decreasing body weight of the patient, comprising administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

[0009] The general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as defined in the appended claims. Other aspects of the present disclosure will be apparent to those skilled in the art in view of the detailed description of the disclosure as provided herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The present disclosure may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part of this disclosure. The summary, as well as the following detailed description, is further understood when read in conjunction with the appended figures:

[0011] FIG. 1 is the study scheme for Example 2. In this figure, all participants will continue their baseline antidepressant during the entire study. Participants with MDDIS and MDD without IS will be randomized separately. *An extension of up to 2 weeks of the screening phase may be allowed (e.g., if needed to confirm eligibility criteria, for scheduling difficulties, or for tapering disallowed medication) with permission from the medical monitor. If there is an extension, screening visit 2 should still occur within 1-7 days prior toDay 1 / baseline. An interim analysis will be performed to evaluate futility. All participants who discontinue study drug in the DB treatment phase, will have an Early Withdrawal visit (Visit 8) and a Follow-up visit (Visit 10). Participants who discontinue study drug prior to Day 35 may continue after the Follow-up visit (Visit 10) with additional Follow up visits, every 2 weeks until Day 50-57. If a participant discontinues study drug before the end of the OL phase, an End-of-Phase / EW assessment must be performed and then FU assessments should be obtained 7 to 14 days after the EOPZEW visit.

[0012] FIG. 2 is the study scheme for Example 3. In this figure, all participants will continue their baseline antidepressant during the entire study. *An extension of up to 2 weeks of the screening phase may be allowed (e.g., if needed to confirm eligibility criteria or for scheduling difficulties) with permission from the medical monitor. If there is an extension, screening visit 2 should still occur within 2-5 days prior to Day 1 / baseline. All participants who discontinue study drug in the DB treatment phase (prior to visit 13), will have an Early Withdrawal visit (Visit 13) and a Follow-up visit (Visits 14 and 15). Participants who discontinue study drug prior to Day 182 may continue after the Follow-up visit (Visit 15) with additional follow-up visits every 4 weeks until Day 196.

[0013] FIG. 3 is a line graph of Weight: Analysis Under Estimand 1 : LS Mean (+ / - SE) of Change From Baseline Over Time (Line Plot): MMRM Observed Case Analysis - Double-blind Phase; FAS1 Analysis Set (Study 42847922MDD3005). In this figure, LS Mean and SE were based on a mixed model for repeated measures (MMRM) with treatment (Seltorexant 20 mg and Quetiapine XR), country, age group (adults < 65 years and elderly > 65 years), baseline rumination level (RRS total score < 54, > 54), time, and time-by- intervention interaction as factors and baseline weight as a covariate. Intercurrent events are handled by the following strategies: discontinuation of add-on study agent only: hypothetical; discontinuation of both add-on study agent and underlying antidepressant: hypothetical; switch of add-on study agent and / or underlying antidepressant: hypothetical. FAS1 analysis set includes all randomized participants who received at least 1 dose of study intervention and had baseline MADRS total score > 24.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0014] Unlike atypical antipsychotics approved as adjunctive therapies for MDD, seltorexant has a favorable metabolic profile and limited impact on weight. This significantdistinction addresses safety concerns and provides an effective treatment option for MDD patients with inadequate responses to standard therapies, particularly those with high insulin resistance and at high cardiometabolic risk.

[0015] Clinically significant elevation in insulin resistance (IR) is associated with an increased cardiometabolic risk. Reduction of IR results in cardiometabolic benefits, potentially reducing the risk of developing diabetes and cardiovascular diseases. Considering the existing adjunctive standard of care options available for MDD patients and the known cardiometabolic side effects of atypical antipsychotics used adjunctively, seltorexant has a significant advantage over existing standard of care options. The data suggest seltorexant differentiates from other adjunctive antidepressant treatments in the ability to lower IR in depressed patients presenting with clinically significant insulin resistance, as manifested by co-morbid diabetes, pre-diabetes, or obesity with elevated baseline HOMA-IR levels. The reduction in IR conceivably may reduce the elevated risk for cardiovascular disease, metabolic syndrome and Type-2 diabetes associated with MDD, potentially addressing the excess mortality rates in MDD, which are primarily attributable to these co-morbidities.Definitions

[0016] “Depression” includes major depressive disorder (MDD), persistent depressive disorder, seasonal affective disorder, psychotic depression, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, mid-life depression, late-life depression, depression due to identifiable stressors, treatment resistant depression, or combinations thereof. In certain embodiments, the depression is MDD.

[0017] The methods described herein are useful in the treatment of the core (or psychic) symptoms of depression. These “psychic symptoms” include depressed mood and / or loss of interest or pleasure in nearly all activities. Other examples include, irritable mood, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, and indecisiveness. In particular, core depressive symptoms include depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and general somatics (tiredness and pains). In general, the effect on the psychic symptoms are overall unrelated to the seltorexant’ s effect on sleep related items.

[0018] “Night” includes the period of time from sunset to sunrise, occurring once each twenty-four hours. In some embodiments, night refers to a timeframe in a twenty-four period in a day that precedes sleep by a subject.

[0019] The term “sleep onset” refers to the transition from wakefulness into nonrapid eye movement (NREM) sleep; and “sleep” generally refers to non-rapid eye movement (NREM) or rapid eye movement (REM) sleep. The term “awake” describes a reasonably alert state of consciousness characterized by alpha and beta waves as detected by electroencephalogram, voluntary rapid eye movements and / or eye blinks. In other embodiments, an awake state may be characterized as the absence of NREM or REM sleep.

[0020] “Insomnia symptoms” refer to symptoms arising from a diagnosis using criteria found in the American Psychiatric Association’s fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and the Third Edition of the World Health Organization’s International Classification of Sleep Disorders (ICSD-3). In some embodiments, an “insomnia symptom” includes difficulty initiating or maintaining sleep and waking too early and / or obtaining non-restorative sleep, where the sleep difficulty results in some form of daytime impairment. To the extent insomnia symptoms are to be categorized by severity, a diagnostic scale may be used. For example, The Insomnia Severity Index (ISI) is a 7-item questionnaire assessing the nature, severity, and impact of insomnia having a patient and a clinician version. The dimensions evaluated are: severity of sleep onset, sleep maintenance, early morning awakening problems; sleep dissatisfaction; interference of sleep problem with daytime functioning; noticeability of sleep problems by others; and distress caused by the sleep difficulties. A 5-point Likert scale (0-4) is used to rate each item, yielding a total score ranging from 0 to 28. The total score is interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).

[0021] Some of the quantitative expressions given herein are not qualified with “about.” It is understood that whether “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value.

[0022] As used herein, unless otherwise noted, “treating,” “treatment,” and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably 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 the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder. Similarly, “treatment” is used to encompass (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and / or (d) delay or avoidance of the development of the disorder or condition, or any combination thereof.

[0023] As used herein, unless otherwise noted, “subject” and “patient” may be used interchangeably and refer to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. In some embodiments, the subject or patient has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. One skilled in the art will further recognize that the methods of treatment are directed to subjects or patients in need of such treatment, prevention or dosing regimen, more particularly to subjects or patients diagnosed with or exhibiting at least one symptom of depression (preferably, meeting the criteria for major depressive disorder or episode) regardless of type or underlying cause. In some embodiments, the subject has MDD. In further embodiments, the subject has MDD with insomnia symptoms (MDDSI). In particular embodiments, the MDDIS patient is one having (i) a PROMIS-SD- 8a T-score of > 54, and (ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

[0024] One skilled in the art will recognize that wherein methods of prevention are described, a subject in need thereof (i.e., a subject in need of prevention) shall include any subject who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of having new episodes of depression (and therefore in need of secondary prevention or preventive treatment) as aconsequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.

[0025] Further, some of the quantitative expressions herein are recited as a range from about value X to about value Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about value X through about value Y, or any value or range of values therein.

[0026] As used herein, “including,” “containing,” and “comprising” are used herein in their open, non-limiting sense.Compounds

[0027] Seltorexant is an orexin-2 antagonist and may be used in the treatment of depression. Seltorexant, ie., [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4- c]pyrrol-2-yl]-(2-fluoro-6-[l,2,3]triazol-2-yl-phenyl)-methanone, is also known as MIN-202 and JNJ-42847922 and has the chemical structure below (i.e., the free base):

[0028] Seltorexant may be administered such that it has a time to maximal plasma concentration of less than about 3 hours, less than about 2 hours, and preferably less than about 1 hour, i.e., less than about 45 minutes, less than about 30 minutes, less than about 15 minutes, among others. In other embodiments, seltorexant has an elimination half-life of about 4 hours and typically less than about 4 hours. For example, seltorexant has a half-life of about 2 to about 3 hours, e.g., about 2 hours, about 2.1 hours, about 2.2 hours, about 2.3 hours, about 2.4 hours, about 2.5 hours, about 2.6 hours, about 2.7 hours, about 2.8 hours, or about 2.9 hours to about 3 hours. Given the short half-life, the amount of seltorexant remaining in the subject upon waking is typically below the threshold required for pharmacodynamic effect. In particular embodiments, the antidepressant effect from seltorexant is maintained when the patient is awake the next day.

[0029] Seltorexant also includes pharmaceutically acceptable salts thereof and methods of treatment using such salts. A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of seltorexant that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, Paulekuhn,“Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database,” J. Med. Chem., 2007, 50:6665-72, Berge, “Pharmaceutical Salts”, J Pharm Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.

[0030] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bi sulfates, sulfites, bi sulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, mal onates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. In some embodiments, the pharmaceutically acceptable salt of seltorexant is the HC1 salt, i.e., [5-(4,6-dimethyl-pyrimidin-2-yl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[l,2,3]triazol-2-yl-phenyl)-methanone hydrochloride.

[0031] The desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, e.g., treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid, glutaric acid, or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids, and any otheracid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0032] Additionally, seltorexant also includes hydrates, solvates, and polymorphs thereof, and mixtures thereof, even if such forms are not listed explicitly. Certain embodiments include hydrates of the pharmaceutical salt, including a hydrate of the HC1 salt of seltorexant.

[0033] Pharmaceutically acceptable prodrugs of seltorexant and treatment methods employing such pharmaceutically acceptable prodrugs are also contemplated. “Prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the seltorexant). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, e.g., in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.Methods

[0034] The disclosure provides methods for treating patients with major depressive disorder (MDD) and insulin resistance. The methods include administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof. The term “insulin resistance” as used herein refers to the ability of a patient’s cells to respond to insulin. Insulin resistance may be determined by those skill in the art using well accepted methods. In some embodiments, the Homeostatic Model Assessment for Insulin Resistance(HOMA-IR) index is utilized to calculate insulin resistance. HOMA-IR is calculated as:22.5By using this index, patients having a HOMA-IR value of less than 1.9 are considered to have “normal” insulin resistance. Patients having a HOMA-IR value of 1.9 to 2.9 are considered to have “early” insulin resistance. Patients having a HOMA-IR value greater than 2.9 are considered to have “high” insulin resistance.

[0035] In other embodiments, the Homeostatic Model Assessment for Beta cells(HOMA-B) index is utilized to provide a quantitative estimate of beta-cell function in the pancreas. HOMA-B is calculated as:By using this index, patients having a HOMA-B value of 167 to 175 are considered to have “normal” beta-cell function.

[0036] In some embodiments, a non-diabetic patient has a HbAlc of less than 5.7%. In other embodiments, a non-diabetic patient has a fasting glucose of less than 5.5 mmol / L (100 mg / dL mg / dL). In further embodiments, a non-diabetic patient has a non-fasting glucose of less than 7.8 mmol / L (140 mg / dL).

[0037] Patients being treated with seltorexant may be diabetic. The term “diabetic” is known in the art and may be determined using well-accepted techniques. In some embodiments, a diabetic patient has a hemoglobin Ale (HbAlc) of 6.5% or greater. In other embodiments, a diabetic patient has a fasting glucose of 7.0 mmol / L or greater (126 mg / dL) or greater). In further embodiments, a diabetic patient has a non-fasting glucose of 11.1 mmol / L or greater (200 mg / dL or greater). In yet other embodiments, a diabetic patient has a medical history of diabetes. Some patients treated according to the methods described herein may be “pre-diabetic”. In some embodiments, a pre-diabetic patient has a HbAlc of 5.7% to 6.5%. In other embodiments, a pre-diabetic patient has a fasting glucose of 5.6 mmol / L to 7.0 mmol / L (100 mg / dL to 125 mg / dL). In further embodiments, a pre-diabetic patient has a non-fasting glucose of 7.8 mmol / L to 11.0 mmol / L (140 mg / dL to 199 mg / dL).

[0038] The methods described herein permit the reduction of a patient’s insulin resistance, as compared to a baseline insulin resistance before seltorexant administration. In certain embodiments, the patient has a high baseline insulin resistance, as measured by HOMA-IR and / or HOMA-B as described herein. In other embodiments, the patient has an early baseline insulin resistance, as measured by HOMA-IR and / or HOMA-B. Desirably, the methods result in reducing a patient’s insulin resistance to a level that is considered normal, as measured by HOMA-IR and / or HOMA-B. In some embodiments, the methods result in reducing a patient’s insulin resistance from high insulin resistance to early insulin resistance, as measured by HOMA-IR and / or HOMA-B. In further embodiments, the methods result in reducing a patient’s insulin resistance from high insulin resistance to normal insulinresistance, as measured by HOMA-IR and / or HOMA-B. In other embodiments, the methods result in reducing a patient’s insulin resistance from early insulin resistance to normal insulin resistance, as measured by HOMA-IR and / or HOMA-B. In yet further embodiment, the methods do not result in a meaningful increase in insulin resistance, as measured by HOMA- IR and / or HOMA-B.

[0039] Patients being treated with seltorexant may be of varying weights. In some embodiments, the patient is considered to have a normal weight, i.e., a body mass index (BMI) of 25 or less. In other embodiments, the patient is considered overweight, i.e., a BMI of 25 to 30. In other embodiments, the patient is considered obese, i.e., a BMI over 30.

[0040] The disclosure also provides methods of treating a patient with major depressive disorder (MDD) and stabilizing or decreasing body weight of the patient. The methods include administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof. As used herein, stabilizing body weight of a patient refers to maintaining a consistent weight. By doing so, a patient’s body weight is stabilized if the patient’s body weight does not have large fluctuations, i.e., large amounts of body weight loss or gain, as compared to a baseline body weight before seltorexant administration. In some embodiments, the methods described herein permits patients to stabilize body weight, as compared to a baseline body weight before seltorexant administration. For example, 7% weight gain is considered the standard measure of clinically significant increase for antipsychotic medication. This amount of weight gain can lead to significant medical problems such as diabetes and increase the risk of cardiac disease. Weight gain is seen with the long-term use of antidepressant medications across classes and may be a contributor to increased medical risks in patients with MDD. Here, the disclosed methods result in a less than 7% weight gain relative to a baseline body weight before seltorexant administration.

[0041] For patients having a body weight baseline that is higher than recommended by a medical professional, the methods permit a reduction in the patient’s body weight. In some embodiments, the methods reduce the patient’s body weight to a normal weight.

[0042] The disclosure also relates to methods for stratifying human patients with MDD in order to identify a human patient with MDD with insomnia symptoms (MDDIS) where such patients can benefit from treatment with seltorexant. As disclosed herein, such patients can be identified through clinician-reported insomnia symptoms and / or patient reported sleep disturbances.

[0043] In certain embodiments, sleep disturbance is measured by a patient reported outcome (PRO) instrument due to its subjective nature. For example, the Patient Reported Outcomes Measurement Information System (PROMIS) captures self-reported, qualitative health aspects in the domains of physical, mental, and social health. PROMIS item banks and short forms are developed using state of the art psychometric techniques, such as Item Response Theory Models. The PROMIS Sleep Disturbance instruments are content valid measures of subjective sleep disturbance experiences.

[0044] In particular embodiments, the PROMIS Sleep Disturbance-Short Form 8a (PROMIS-SD-8a) is used to assess sleep disturbance. The recall period for all PROMIS-SD- 8a items is the “past 7 days.'' The first item, “Sleep quality” uses a 5-point response scale where l=Very good; 2 = Good; 3= Fair; 4=Poor; and 5=Very Poor. Items 2 through 8 also employ a 5-point response scale (l=Not at all; 2=A little bit; 3=Somewhat; 4=Quite a bit; 5 =Very Much) (see Fig.7). Items 2 “Sleep was refreshing" and 8 “Satisfied with sleep" are reverse coded so that higher ratings indicate poorer sleep quality. Responses to the 8 items are summed and then converted, using a provided conversion table (see Table 1 in Example 1), to a t-score metric ranging from 0 to 100 with a mean of 50 and a standard deviation (SD) of 10. Higher total PROMIS-SD-8a scores indicate poorer sleep disturbance.

[0045] Additionally, the stratification can include criteria involving clinician- reported outcome (ClinRO) measures of depression symptom severity to supplement the patient reported outcome (PRO) criteria due to its subjective nature. This ensures that high levels of sleep disturbance as reported by the patient are insufficient on their own to include the participant as part of the intended patient population. The PRO (e.g. provided in the PROMIS-SD-8a instrument) is indicative of the sleep disturbance experienced by the patient and provides a valuable insight into the patient’s distress associated with their sleep. Information obtained from the patient through a structured clinical interview is utilized by the clinician to confirm core diagnostic symptoms of insomnia. Incorporating both PRO and ClinRO in the approach provides a more nuanced assessment of the patient’s condition, making the overall assessment more robust and helping mitigate the effects of random fluctuations in PRO.

[0046] The HAM-D is a 17-item clinician-reported outcome (ClinRO) measure of depression symptom severity. The HAM-D includes insomnia items that are utilized in the present methods. As reflected in Table 2 of Example 1 (reproduced below), there are threeinsomnia items, referred to as early insomnia, middle insomnia, and late insomnia, each having responses with scores from 0 to 2.

[0047] The HAM-D is completed by clinicians through administration of a standardized interview. There may be slight variations to the item description within each concept depending on, e.g., the interview guide. For example, there is a HAM-D through administration of a semi-structured Clinical Interview Guide for the HAM-D17 (Bech, “The Bech, Hamilton and Zung scales for mood disorders: screening and listening,” Springer, Berlin 1996, second revised edition). In addition, there is a Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D; Williams, “A structured interview guide for the Hamilton Depression Rating Scale,” Arch Gen Psychiatry. 1988). Both interview guides include primary questions and follow-up probes for assessing early, middle, and late insomnia over the past week, and both can be used in the stratification and treatment methods disclosed herein. In preferred embodiments, the SIGH-D is used as it is deemed more rigorous and structured.

[0048] For purposes of this disclosure, reference is made to items 3, 4, and 5 for the concepts early insomnia (3), middle insomnia (4), and late insomnia (5) respectively. Items 3, 4, 5 typically are associated with the SIGH-D, whereas the same items under HAM-D are items 4, 5, and 6. However, regardless of the numbering, the three concepts: early insomnia, middle insomnia, and late insomnia are used for the disclosed stratification and treatment methods. And unless otherwise noted, reference to HAM-D and SIGH-D may be usedinterchangeably for purposes of the stratification and treatment methods disclosed herein. The SIGH-D scoring being most often used in clinical study because it has been validated.

[0049] The stratification criteria includes SIGH-D items 3, 4, and 5 to measure clinical manifestations of insomnia resulting in lost sleep time as well as the PROMIS-SD-8a. In particular embodiments, a MDDIS patient is one having (i) a PROMIS-SD-8a T-score of > 54, and (ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items. All other patients are stratified as MDD with no or mild IS (or non-MDDIS).

[0050] In another embodiment of the invention clinical practice health care providers may administer the PROMIS -SD-8 a and SIGH-D (or HAM-D) orally and / or using electronic questionnaires, preferably the SIGH-D instrument will be administered orally to depressed patients. In circumstances where the physician does not have the resources or time to formally administer the PROMIS-SD-8a and / or SIGH-D instruments, the health care provider should interview the patients to assess their sleep disturbance and insomnia. Health care providers should ask the patient about their sleep disturbances with clinical questions consistent with items on the PROMIS-SD-8a and independently assess whether the patient has insomnia and the patient’s level of insomnia (e.g. with questions 3, 4 and 5 provided above) to assess whether the patient has MDDIS.

[0051] In other embodiments, MDDIS can be assessed as MDD with IS as a) moderate to severe IS by a patient version ISI total score of >15 and b) a positive response for IS (MDD symptoms Item 4) on the Structured Clinical Interview for DSM-5 Axis I Disorders Clinical Trials Version (SCID-CT). In addition, the clinician version ISI total score >15 may also be assessed. In general, MDDIS is assessed and determined by a physician, clinician or other medical professional.

[0052] The compound is preferably administered once daily and is administered to the subject prior to sleep. For example, the compound is administered within about 2 hours of sleep, within about 1 hour, or within about 30 minutes before sleep. In other embodiments, the compound is administered at least about 4 hours before the subject wakes or intends to wake from sleep, including about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, or about 12 hours before the subject wakes or intends to wake from sleep. In certain embodiments, thecompound is administered at least 6 hours to about 12 hours before the subject wakes or intends to wake from sleep. In preferred embodiments, the compound is administered at night.

[0053] After administration of seltorexant, it undergoes at least one half-life before the subject wakes from sleep. In other embodiments, seltorexant undergoes at least two halflives, and preferably at least three half-lives before the subject wakes from sleep.

[0054] In certain embodiments, the patient had an inadequate response to other antidepressant other than seltorexant prior to treatment with seltorexant. “Inadequate response” as used herein refers to a patient experiencing a less than about 50% reduction in depressive symptom severity from the start of initiating treatment. Typically, the inadequate response is during a current / active episode of the depression. In some embodiments, an inadequate response refers to a patient experiencing about 26 to less than about 50% reduction in depressive symptom severity from the start of initiating treatment. In other embodiments, an inadequate response refers to a patient experiencing 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% reduction in depressive symptom severity from the start of initiating treatment. A patient’s response may be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, an inadequate response is measured by MGH-ATRQ, MADRS, or SHAPS.

[0055] Therapeutically effective amounts for seltorexant include amounts that elicit the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. Optimal dosages to be administered may be readily determined by those skilled in the art, and may vary with the mode of administration, the strength of the preparation and the advancement of the disease condition. Such factors including the particular patient being treated, including patient’s sex, age, weight, diet, time of administration and concomitant diseases, hepatic impairment, among others. Methods for dosing patients with hepatic impairment have been described in US Provisional Patent Application 63 / 524,198.

[0056] The effective amount of seltorexant may be described without reference to the weight of the subject. In some embodiments, about 10 mg to 40 mg of seltorexant is administered. In some embodiments, about 10 mg to 20 mg of seltorexant is administered. In further embodiments, about 10 mg of seltorexant is administered. In still other embodiments, about 20 mg of seltorexant is administered. All dosage amounts mentioned herein, unless otherwise indicated, refers to the free form (z.e., free base or free base equivalent, non-salt or non-hydrate form) of seltorexant. The amounts are recited as freeform equivalents, z.e., quantities as if the free form would be administered. If salts or solvates are administered the amounts need to be calculated in function of the molecular weight ratio between the salt or solvate and the free form.

[0057] Patients treated according to the methods described herein may be naive or have been treated with an antidepressant other than seltorexant. In some embodiments, the patient is treatment naive. In other embodiments, the patient was treated with an antidepressant other than seltorexant. Typically, such other antidepressants, e.g., SSRI / SNRI, are known to be associated with adverse metabolic effects that include hyperglycemia, dyslipidemia and body weight gain.

[0058] In certain embodiments, seltorexant is administered to a human patient for the treatment of MDD, e.g., MDDIS, where the patient had an inadequate response to other antidepressant therapy (z.e., antidepressant medication or treatment used to treat depression other than seltorexant), such as, e.g., selective serotonin reuptake inhibitor (SSRI) and / or serotonin-norepinephrine reuptake inhibitor (SNRI). More specifically, seltorexant, or the other compounds described herein, may be administered with a second pharmaceutically active agent to a human subject for the treatment of MDD, e.g., MDDIS, where the subject has an inadequate response to a SSRI and / or a SNRI. In some examples, the second pharmaceutically active agent is a SSRI or a SNRI.

[0059] The prevention and / or reduction of severity of depression may be observed qualitatively (e.g., by general patient evaluation by a clinician during visits to a clinic) or as a quantitative reduction in scores over a period of time (e.g., 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, etc.) determined using any suitable clinical scale (e.g., diagnostic questionnaires) for measuring severity of depression symptoms as would be understood by those of ordinary skill in the art, such as, e.g., Clinical Global Impression-Severity (CGI-S) scale, EuroQol; 5 dimension; 5 level (EQ-5D-5L), Patient Health Questionnaire-9 Item(PHQ-9), Sheehan Disability Scale (SDS), Inventory of Depressive Symptomatology- Clinician rated, 30-item scale (IDS-C30), Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton rating scale for depression (HAM-D or HDRS) Beck Scale for Depression, Quick Inventory of Depressive Symptomology (QIDS), 17-item Hamilton Depression Rating Scale (HDRS 17), Patient Health Questionnaire (PHQ-9),

[0060] As described herein, seltorexant may be administered as a monotherapy or may be administered in combination with additional active ingredients in the treatment of the above conditions, i.e., adjunctive treatment. The additional active ingredients may be administered simultaneously, separately, or sequentially. In some embodiments, the additional active ingredients are effective in the treatment of conditions, disorders, or diseases mediated by orexin activity, such as another orexin modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound herein), decrease one or more side effects, or decrease the required dose of the compound described herein or additional active agent. In certain embodiments, the additional active ingredient is an antidepressant. In other embodiments, the additional active ingredient is a monoaminergic antidepressant.

[0061] Accordingly, seltorexant may be used in combination with a second antidepressant. The second antidepressant may be a conventional drug used to combat depression such as N-methyl-D-aspartate receptor antagonists, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), corticotropin releasing factor (CRF) antagonists, alpha-adrenoreceptor antagonists and atypical antidepressants. In some embodiments, the N-methyl-D-aspartate (NMD A) receptor antagonist is ketamine including racemates esketamine, arketamine, or combinations thereof. In further embodiments, the norepinephrine reuptake inhibitor includes amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, reboxetine, or pharmaceutically acceptable salts thereof. In other embodiments, the selective serotonin reuptake inhibitor includes fluoxetine, fluvoxamine, paroxetine, sertraline, or pharmaceutically acceptable salts thereof. In further embodiments, the monoamine oxidase inhibitor includes isocarboxazid, phenelzine,tranylcypromine, selegiline and pharmaceutically acceptable salts thereof. In yet other embodiments, the reversible inhibitor of monoamine oxidase includes moclobemide or pharmaceutically acceptable salts thereof. In still further embodiments, the serotonin and noradrenaline reuptake inhibitor includes venlafaxine or pharmaceutically acceptable salts thereof. In other embodiments, the atypical antidepressant includes bupropion, lithium, nefazodone, trazodone, viloxazine, sibutramine, or pharmaceutically acceptable salts thereof. In yet further embodiments, the second antidepressant includes adinazolam, alaproclate, amineptine, amitriptyline / chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindole, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine, zometapine, or pharmaceutically acceptable salts thereof; or St. John's wort herb, Hypericum perforatum, or extracts thereof.

[0062] In certain embodiments, the patient to be treated meets DSM-5 diagnostic criteria for MDD and is treated in an outpatient setting. Typically, the depression is as least of moderate depression severity based on an industry accepted scale. For example, generally, a score of 17 on the HDRS-17 scale is recognized as a cutoff for moderate to severe depression. In another embodiment, MDD, e.g., MDDIS, patients with mild to severe depression symptoms may be treated for MDD, e.g., MDDIS, wherein mild depression is from 8 to 16 on the HDRS17; moderate is from 17-23 on the HDRS17 and severe is 24 and above on the HDRS17 scale. In other embodiments, the patient has a score of 0-7 and is classified as “not depressed.” In other embodiments, the patient with MDDIS is identified by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

[0063] Patients from 17 to 74 have been studied with seltorexant. Seltorexant, generally appears suitable for adults and adolescents. For example, adolescent patients from about 12 to about 17 years old with MDD, e.g., MDDIS, or from about 10 to about 17 yearsold with MDD, e.g., MDDIS, could be administer seltorexant. Typically the patient is from 18 to 74 years of age.Compositions

[0064] Seltorexant may be formulated as a pharmaceutical composition to administration to a subject. Accordingly, a pharmaceutical composition may comprise (a) an effective amount of seltorexant and (b) a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0065] Delivery forms of the pharmaceutical compositions containing one or more dosage units of seltorexant may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, ocular routes, or by inhalation.

[0066] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, or liquid preparations. In some embodiments, the compositions are formulated for intravenous infusion, topical administration, or oral administration. In certain embodiments, the compositions are formulated for immediate release.

[0067] For oral administration, seltorexant can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. In certain embodiments, seltorexant may be taken with food.

[0068] Oral tablets may include seltorexant mixed with pharmaceutically acceptable excipients such as inert fillers, diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, glidants and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, lactose monohydrate, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, hypromellose, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone, sodium starch glycolate,microcrystalline cellulose, crospovidone (cross-linked polyvinyl N-pyrrolidone or PVP), and alginic acid are suitable disintegrating agents. Binding agents may include hypromellose (hydroxypropyl methylcellulose or HPMC), starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. The glidant, if present, may be silica (SiCh) such as colloidal silica. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0069] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, seltorexant may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing seltorexant with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0070] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically-acceptable excipients such as suspending agents (e.g., sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0071] Seltorexant may also be administered by non-oral routes. For example, seltorexant may be formulated for rectal administration. For parenteral use, including intravenous, intramuscular, or intraperitoneal routes, seltorexant may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi -dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 pg / kg / minute of seltorexant, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0072] For topical administration, seltorexant may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering seltorexant may utilize a patch formulation to affect transdermal delivery.

[0073] Seltorexant may alternatively be administered by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.Aspects

[0074] Aspect 1. A method of treating a patient with major depressive disorder (MDD) and insulin resistance, comprising administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

[0075] Aspect 2. The method of Aspect 1, wherein the patient has MDD with insomnia symptoms (MDDIS).

[0076] Aspect 3. The method of Aspect 2, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and / or patient-reported sleep disturbance.

[0077] Aspect 4. The method of Aspect 2 or 3, wherein the patient with MDDIS is identified by the following criteria: a PROMIS-SD-8a T-score of > 54, and either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

[0078] Aspect 5. The method of any one of the preceding Aspects, wherein the insulin resistance is normal or early, prior to administering seltorexant.

[0079] Aspect 6. The method of Aspect 5, wherein the insulin resistance is normal, such as having a Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) value of less than 1.9.

[0080] Aspect 7. The method of Aspect 5, wherein the insulin resistance is early, such as having a HOMA-IR value of 1.9 to 2.9.

[0081] Aspect 8. The method of Aspect 5, wherein there is no increase in the insulin resistance after administering seltorexant.

[0082] Aspect 9. The method of any one of Aspects 1 to 4, wherein the insulin resistance is high prior to administering seltorexant.

[0083] Aspect 10. The method of Aspect 9, wherein the patient has a HOMA-IR value of greater than 2.9.

[0084] Aspect 11. The method of Aspect 10, wherein the insulin resistance is reduced after administering seltorexant.

[0085] Aspect 12. The method of Aspect 10, wherein the patient has a baseline insulin level and the insulin level of the patient is reduced after administering seltorexant.

[0086] Aspect 13. The method of any of one Aspect 1-12, wherein the patient is obese.

[0087] Aspect 14. The method of Aspect 13, wherein the patient has a body mass index (BMI) of over 30.

[0088] Aspect 15. The method of any one of Aspects 1-12, wherein the patient is pre-diabetic.

[0089] Aspect 16. The method of Aspect 15, wherein the patent has (i) a HbAlc of 5.7% to 6.5%, (ii) a fasting glucose of 5.6 mmol / L to 7.0 mmol / L, (iii) a non-fasting glucose of 7.8 mmol / L to 11.0 mmol / L or (iv) any combinations of (i)-(iii).

[0090] Aspect 17. The method of any one of Aspects 1-12, where the patient is diabetic.

[0091] Aspect 18. The method of Aspect 17, wherein the patient has (i) a hemoglobin Ale (HbAlc) of 6.5% or greater, (ii) a fasting glucose of 7.0 mmol / L, (iii) a nonfasting glucose of 11.1 mmol / L or greater, (iv) a medical history of diabetes, or (v) any combination of (i)-(iv).

[0092] Aspect 19. The method of any one of Aspects 1-18, wherein seltorexant is administered as a free base.

[0093] Aspect 20. The method of any one of Aspects 1-18, wherein a hydrochloride salt of seltorexant is administered.

[0094] Aspect 21. The method of Aspect 20, wherein a hydrate of the hydrochloride salt of seltorexant is administered.

[0095] Aspect 22. The method of any one of the preceding Aspects, wherein seltorexant is administered orally.

[0096] Aspect 23. The method of any one of the preceding Aspects, wherein seltorexant is administered once daily.

[0097] Aspect 24. The method of any one of the preceding Aspects, wherein seltorexant is administered prior to sleep.

[0098] Aspect 25. The method of any of one of the preceding Aspects, wherein seltorexant is administered at night.

[0099] Aspect 26. The method of Aspect 25, wherein antidepressant effect from seltorexant is maintained when the patient is awake the next day.

[0100] Aspect 27. The method of any one of the preceding Aspects, wherein seltorexant treats a psychic symptom of the depression.

[0101] Aspect 28. The method of any one of the preceding Aspects, wherein the patient had an inadequate response to an antidepressant other than seltorexant prior to treatment with seltorexant.

[0102] Aspect 29. The method of Aspect 28, wherein the antidepressant other than seltorexant is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

[0103] Aspect 30. The method of any one of the preceding Aspects, wherein seltorexant or a pharmaceutically acceptable salt thereof is adjunctively administered with a second pharmaceutically active agent.

[0104] Aspect 31. The method of Aspect 30, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

[0105] Aspect 32. The method of any one of the preceding Aspects, wherein about 20 mg of seltorexant is administered.

[0106] Aspect 33. A method of treating a patient with major depressive disorder (MDD) and stabilizing or decreasing body weight of the patient, comprising administering to the patient about 10 to about 20 mg of seltorexant or a pharmaceutically acceptable salt thereof.

[0107] Aspect 34. The method of Aspect 33, wherein the patient has MDD with insomnia symptoms (MDDIS).

[0108] Aspect 35. The method of Aspect 34, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

[0109] Aspect 36. The method of Aspect 34 or 35, wherein the patient with MDDIS is identified by the following criteria: a PROMIS-SD-8a T-score of > 54, andeither a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

[0110] Aspect 37. The method of any one of Aspects 33-36, wherein the patient has been treated with an antidepressant other than seltorexant.

[0111] Aspect 38. The method of Aspect 37, wherein the antidepressant other than seltorexant was a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

[0112] Aspect 39. The method of any one of Aspects 33-38, wherein the patient is pre-diabetic, diabetic, or obese.

[0113] Aspect 40. The method of Aspect 39, wherein the patient is diabetic.

[0114] Aspect 41. The method of Aspect 40, wherein the patient has (i) a hemoglobin Ale (HbAlc) of 6.5% or greater, (ii) a fasting glucose of 7.0 mmol / L, (iii) a nonfasting glucose of 11.1 mmol / L or greater, (iv) a medical history of diabetes, or (v) any combination of (i)-(iv).

[0115] Aspect 42. The method of Aspect 39, wherein the patient is pre-diabetic.

[0116] Aspect 43. The method of Aspect 42, wherein the patent has (i) a HbAlc of 5.7% to 6.5%, (ii) a fasting glucose of 5.6 mmol / L to 7.0 mmol / L, (iii) a non-fasting glucose of 7.8 mmol / L to 11.0 mmol / L or (iv) any combinations of (i)-(iii).

[0117] Aspect 44. The method of Aspect 39, wherein the patient is obese.

[0118] Aspect 45. The method of Aspect 44, wherein the patient has a body mass index (BMI) of over 30.

[0119] Aspect 46. The method of any one of Aspects 33-45, wherein there is a less than 7% weight gain relative to a baseline body weight before seltorexant administration

[0120] Aspect 47. The method of any one of Aspects 33-46, wherein seltorexant is administered as a free base.

[0121] Aspect 48. The method of any one of Aspects 33-46, wherein a hydrochloride salt of seltorexant is administered.

[0122] Aspect 49. The method of Aspect 48, wherein a hydrate of the hydrochloride salt of seltorexant is administered.

[0123] Aspect 50. The method of any one of the preceding Aspects, wherein seltorexant is administered orally.

[0124] Aspect 51. The method of any one of the preceding Aspects, wherein seltorexant is administered once daily.

[0125] Aspect 52. The method of any one of the preceding Aspects, wherein seltorexant is administered prior to sleep.

[0126] Aspect 53. The method of any of one of the preceding Aspects, wherein seltorexant is administered at night.

[0127] Aspect 54. The method of Aspect 53, wherein antidepressant effect from seltorexant is maintained when the patient is awake the next day.

[0128] Aspect 55. The method of any one of the preceding Aspects, wherein seltorexant treats a psychic symptom of the depression.

[0129] Aspect 56. The method of any one of the preceding Aspects, wherein the patient had an inadequate response to an antidepressant other than seltorexant prior to treatment with seltorexant.

[0130] Aspect 57. The method of Aspect 56, wherein the antidepressant other than seltorexant is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

[0131] Aspect 58. The method of any one of the preceding Aspects, wherein seltorexant or a pharmaceutically acceptable salt thereof is adjunctively administered with a second pharmaceutically active agent.

[0132] Aspect 59. The method of Aspect 58, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

[0133] Aspect 60. The method of any one of the preceding Aspects, wherein about 20 mg of seltorexant is administered.

[0134] Example 1: A Patient Stratification Approach

[0135] A. Measurement model: Sleep disturbance

[0136] Sleep disturbance is best measured by a patient reported outcome (PRO) instrument due to its subjective nature. The Patient Reported Outcomes Measurement Information System (PROMIS) captures self-reported, qualitative health aspects in the domains of physical, mental, and social health. PROMIS item banks and short forms are developed using state of the art psychometric techniques, such as Item Response Theory Models. The PROMIS Sleep Disturbance instruments are content valid measures of subjective sleep quality experiences. Here, the PROMIS Sleep Disturbance-Short Form 8a (PROMIS-SD-8a) was used to assess sleep disturbance. The recall period for all PROMIS- SD-8a items is the “past 7 days.’ The first item, “Sleep quality’ uses a 5-point response scale where l=Very good; 2 = Good; 3= Fair; 4=Poor; and 5=Very Poor. Items 2 through 8 also employ a 5-point response scale (l=Not at all; 2=A little bit; 3=Somewhat; 4=Quite a bit; 5 =Very Much) (see Fig. 7). Items 2 “Sleep was refreshing” and 8 “Satisfied with sleep” are reverse coded so that higher ratings indicate poorer sleep quality. Responses to the 8 items are summed and then converted, using the conversion of Table 1, to a t-score metric ranging from 0 to 100 with a mean of 50 and a standard deviation (SD) of 10. Higher total PROMIS- SD-8a scores indicate greater sleep disturbance.

[0137] B. Clinician-reported insomnia symptoms

[0138] Additionally, the stratification includes criteria involving clinician-reported outcome (ClinRO) measures of depression symptom severity to supplement the patient reported outcome (PRO) criteria due to its subjective nature. This ensures that high levels of sleep disturbance as reported by the patient are insufficient on their own to include the participant as part of the intended patient population. Information obtained from the patient through a structured clinical interview is utilized by the clinician to confirm core diagnostic symptoms of insomnia. Incorporating both PRO and ClinRO in the approach helps reduce thereliance on a single measure, making the overall assessment more robust and helping mitigate the effects of random fluctuations in PRO.

[0139] The HAM-D is a 17-item clinician-reported outcome (ClinRO) measure of depression symptom severity. The HAM-D insomnia items are shown in Table 2. There is a HAM-D through administration of a semi-structured Clinical Interview Guide for the HAM- D17 (Bech P. The Bech, Hamilton and Zung scales for mood disorders: screening and listening. Springer, Berlin 1996, second revised edition). In addition, there is a Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D; Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988). For purposes of this disclosure, reference is made to items 3 (early insomnia), 4 (middle insomnia), and 5 (late insomnia) which are associated with the SIGH-D.

[0140] SIGH-D items 3, 4, and 5 evaluate the three diagnostic symptoms of insomnia specified in the DSM-5 and ICD-11 : difficulty initiating sleep, difficulty maintaining sleep, and waking up too early and being unable to fall back asleep (Table 2). SIGH-D items / response categories:

[0141] C. Patient stratification Criteria

[0142] The stratification criteria includes SIGH-D items 3, 4, and 5 utilizing the standardized Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D) to measure clinical manifestations of insomnia resulting in lost sleep time as well as Patient Reported Outcome Measurement Information System-Sleep Disturbance Short Form 8a (PROMIS-SD-8a).

[0143] The patient stratification criteria using SIGH-D and PROMIS-SD-8a is shown in Table 3.

[0144] Example 2: MDD3001 Study

[0145] A. Objectives and Endpoints

[0146] For the following objectives and endpoints, MDDIS is defined as MDD with IS as a) moderate to severe IS by a patient version ISI total score of >15 at the end of screening and b) a positive response for IS (MDD symptoms Item 4) on the SCID-CT. In addition, the clinician version ISI total score >15 is also required since this version was used in the Phase 2 program. MDD without IS is defined as MDD with either the patient ISI (primary) or clinician ISI total score <15 or a negative response for IS (MDD symptoms Item 4) on the SCID-CT.Open-Label Treatment Phase

[0147] B. Study Design

[0148] (i) Overall Design

[0149] This is a multicenter, DB, randomized, parallel-group, placebo-controlled, 6-week study with seltorexant 20 mg followed by an OL treatment phase with seltorexant 20 mg for up to one year. The study will assess the efficacy (DB phase) and safety (DB and OL phases) of seltorexant as an adjunctive therapy in adult and elderly participants (18 to 74 years of age, inclusive) with MDDIS, as well as efficacy and safety (DB and OL phases) in all participants with MDD (with and without IS) who have had an inadequate response to current antidepressant therapy with an SSRI / SNRI. In addition, PK, pharmacogenomics, and biomarkers will also be evaluated.

[0150] A total of approximately 550 participants with MDD will be enrolled in this study; approximately 386 participants with MDDSI and 164 participants with MDD without IS will be enrolled. All participants who complete the DB phase will be offered to participate in the OL phase.

[0151] The planned study dose of seltorexant is 20 mg.

[0152] The study will consist of 4 phases: a screening phase (up to 30 days), a DB treatment phase (43 days), OL treatment phase (1-year), and a posttreatment follow-up phase (7 to 14 days after end of treatment).

[0153] Participants will continue to take their baseline SSRI / SNRI antidepressant (at the same dose, every day without change, and at approximately the same time of the day as prior to entering the study) throughout the study during screening through the follow-up phase.

[0154] (ii) Double-Blind Treatment Phase

[0155] Participants who meet all inclusion criteria and none of the exclusion criteria will be randomly assigned to receive placebo and seltorexant 20 mg in a 1 : 1 ratio for 6 weeks.

[0156] Participants should take their assigned study drug at home, once daily at bedtime, from Day 1 to Day 42. Participants for whom tolerability at the assigned dose is unacceptable should be withdrawn from the study drug, and the AE should be recorded as a reason for discontinuation. Throughout the study, participants will need to continue their baseline SSRI / SNRI antidepressant (at the same dose and taken around the same time of the day as prior to entering the study) on which they have had inadequate response at the time of screening. All participants who discontinue study drug in the DB treatment phase, will have an Early Withdrawal visit (Visit 8) and a Follow-up visit (Visit 10). Participants whodiscontinue study drug prior to Day 35 may continue after the Follow-up visit (Visit 10) with additional follow-up visits every 2 weeks until Day 50-57.

[0157] Efficacy and safety assessments, sparse PK sampling, biomarkers sampling, and other study procedures will be performed at each visit. If a participant withdraws from the study drug, the End-of-Phase / Early Withdrawal visit assessments (including MADRS) will be performed, preferably on the day after the last dose or as soon as the participant is available for the assessment by designees. Entry to the follow-up phase should not be conducted in participants who withdraw consent for further study assessments; however, they should complete the study assessments including DB End-of-Phase visit if they are willing to do so.

[0158] For participants continuing from DB to OL treatment phase, the DB End- of-Phase visit serves as the baseline visit for the OL treatment phase. The participant has up to 14 days to continue from the DB phase to the OL phase. If it has been more than 3 days since the DB End-of-Phase visit, baseline procedures for the OL phase need to be performed.

[0159] (iii) Open-label Treatment Phase

[0160] All eligible participants entering the OL treatment phase will be assigned to receive OL seltorexant treatment at a dose of 20 mg from OL baseline visit until the End-of- Phase / Early Withdrawal visit.

[0161] Efficacy and safety assessments, sparse PK sampling, biomarkers sampling, and other study procedures will be performed at each visit. If a participant withdraws from the study drug, rating of the MADRS, and the End-of-Phase / Early Withdrawal visit assessments will be performed, preferably on the day after the last dose or as soon as the participant is available for the assessment.

[0162] After the last dose of treatment in the OL phase, the participant should have the End-of-Phase visit, preferably the day after the last dose. After completion of this visit, the participant enters the follow-up phase. Entry to the follow-up phase should not be conducted in participants who withdraw consent from study assessments; however, they should complete the OL End-of-Phase visit if they are willing to do so.

[0163] (iv) Follow-Up / End of Study Visit

[0164] Completers of the OL phase and participants who discontinue early from the OL phase will enter the follow-up phase, however, for completers of the OL phase whomay continue the treatment with seltorexant after the study completion in another study / access program, the follow-up phase will not be mandatory.

[0165] Participants will return to the study center for a follow-up visit within 7 to 14 days after the last dose of study drug. At the follow-up visit, safety and efficacy assessments / procedures will be completed per. Participants who completed the DB phase but have chosen not to continue in the OL phase will have a follow-up visit as described above. Participants who choose to continue in the OL treatment phase will not complete the follow-up assessments after end of DB phase but will complete the follow-up assessments after completion of treatment with seltorexant in the OL treatment phase or after discontinuation from the treatment.

[0166] For participants who have completed the study (either at the end of OL phase or end of DB treatment for those not entering the OL phase), this follow-up visit is the last visit. All participants who discontinue study drug in the DB treatment phase, will have an Early Withdrawal visit (Visit 8) and a Follow-up visit (Visit 10). Participants who discontinue study drug prior to Day 35 may continue after the Follow-up visit (Visit 10) with additional Follow-up visits, every 2 weeks until Day 50-57.

[0167] At the start of the follow-up phase, further clinical / standard of care for the treatment of depression should be arranged.

[0168] The duration of participation in the study for an individual participant (including screening, DB treatment, OL treatment, and follow-up phases) will be up to 64 weeks. A diagram of the study design is provided in FIG. 1.

[0169] (v) Safety Evaluations

[0170] Standard safety evaluations including collection of AEs and concomitant medications, physical examination (including a brief neurological examination), body weight, BMI, waist circumference, vital signs, 12-lead ECG, urine drug screening, alcohol breath test, and clinical laboratory tests will be performed to monitor participant safety throughout the study. A serum or urine pregnancy test will be performed only for WOCBP. Additional serum and urine pregnancy tests and drug and alcohol tests may be conducted as needed.

[0171] (vi) End of Study and End of Treatment Definitions

[0172] A participant will be considered to have completed the DB treatment phase if he or she has completed the Day 43 visit of the DB treatment phase and has not discontinued study drug early during DB phase.

[0173] A participant will be considered to have completed the follow-up phase if he or she has completed assessments at all follow-up visits.

[0174] A participant will be considered to have completed OL treatment phase of the study if he or she has completed assessments at the Week 59 visit of the OL treatment phase.

[0175] Participants who discontinue study drug for any reason before completion of either treatment phase will not be considered to have completed the study.

[0176] The end of study is considered as the last study assessment completed for the last participant in the study.

[0177] C. Study Population

[0178] Screening for eligible participants will be performed within 30 days before administration of the study drug.

[0179] The inclusion and exclusion criteria for enrolling participants in this study are described. Waivers are not allowed.

[0180] (i) Inclusion Criteria

[0181] Each potential participant must satisfy all of the following criteria to be enrolled in the study:1. : Male or female, aged 18 to 74 years (inclusive). Participants should be at least18 years of age or older as per the legal age of consent in the jurisdiction in which the : study is taking place.2. : Meet DSM-5 diagnostic criteria for MDD, without psychotic features (DSM-5 296.22, i 296.23, 296.32, or 296.33), based upon clinical assessment and confirmed by the : SCID-CT diagnosed with first depressive episode prior to age 60. The length of the : current depressive episode must be <24 months prior to randomization.3. : Have had an inadequate response to at least 1 but no more than 2 antidepressants (see : the inclusion criterion 4 below), administered at an adequate dose and duration in the i current episode of depression. The current antidepressant cannot be the first : antidepressant treatment for the first lifetime episode of depression. An inadequate : response is defined as <50% reduction but with some improvement (i.e., improvement : >0%) in depressive symptom severity with residual symptoms present other than i insomnia, and overall good tolerability, as assessed by the MGH-ATRQ. An adequate : trial is defined as an antidepressant treatment for at least 6 weeks on a stable dose (andno greater than 18 months in the current episode) at or above the minimum therapeutic dose specified in the MGH-ATRQ, must include the participant’s current antidepressant treatment. Participants with no improvement on the current SSRI / SNRI should not be enrolled in the study. If the participant has received 2 SSRI / SNRI treatments of sufficient dose and duration in the current episode, and has shown <25% improvement to both, then the participant would not qualify based on exclusion criterion 9.Is receiving and tolerating well any one of the following SSRI or SNRI for depressive symptoms at screening, in any formulation and available in the participating country: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine at a stable dose (at therapeutic dose level) for at least 6 weeks, and for no greater than 18 months in the current episode. The SSRI / SNRI needs to be approved for the treatment of MDD according to the local label of the country where the clinical site is located. Participants using fluvoxamine as baseline SSRI and have normal renal and hepatic function may enter the study.Have a HDRS- 17 total score >20 at the first screening interview, must not demonstrate a clinically significant improvement (i.e., an improvement of >20% on their HDRS- 17 total score) from the first to the second independent HDRS-17 rating, and must have a HDRS-17 total score >18 at the second screening interview.BMI between 18 and 40 kg / m2, inclusive (BMI=weight / height2).Must be an outpatient at screening.Participant must be medically stable on the basis of the following performed at screening: physical examination (including a brief neurological examination), vital signs (including blood pressure), and 12-lead ECG performed at screening and baseline.Participant must be medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study.Must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and be willing to participate in the study. A woman of childbearing potential must have a negative highly sensitive serum (P- hCG) pregnancy test at screening and a negative urine pregnancy test predose on Day 1 of the DB phase prior to randomization. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies. a. Before entering the study, a woman must be either:• PostmenopausalA postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In women who are <40 years old and have amenorrhea, FSH should be performed to determine post-menopausal status, based on the reference range of central laboratory. In women who are >40 years old and have amenorrhea for less than 12 months, FSH test may be performed at to assist in determining their post-menopausal status. In women who are >40 years old and have amenorrhea for >12 months, FSH is not required.• Permanently sterilePermanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion / ligation procedures, and bilateral oophorectomy. No FSH testing is required. b. Of childbearing potential and• Practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly).Examples of highly effective contraceptives include:- User independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone- releasing system (IUS); vasectomized partner; sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needsto be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)- User-dependent methods: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectableTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies Agrees to remain on a highly effective method throughout the study and for at least 1 month after the last dose of study drug.: If the childbearing potential status changes after start of the study or the risk of : pregnancy changes (e.g., a woman who is not heterosexually active becomes active) : a female participant or female partner of a male participant must begin a highly : effective method of contraception, as described throughout the inclusion criteria. If : reproductive status is questionable, additional evaluation should be considered.13. A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the : purposes of assisted reproduction during the study and for a period of at least 1 month : after receiving the last dose of study drug.14. : During the study and for a minimum of 1 spermatogenesis cycle (defined as: approximately 3 months) after receiving the last dose of study drug, a man• who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (e.g., condom with spermicidal foam / gel / film / cream / suppository) and his female partner must use a highly effective method of contraception.• who is sexually active with a woman who is pregnant must use a condom.• must agree not to donate sperm.

[0182] (ii) Exclusion Criteria

[0183] Any potential participant who meets any of the following criteria will be excluded from participating in the study:Has a recent (last 3 months) history of, or current signs and symptoms of,- severe renal insufficiency (CrCl <30 mL / min);- clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic, hematologic, rheumatologic, immunologic or endocrine disorders.- uncontrolled Type 1 or Type 2 diabetes mellitus. Participants with Type 1 or Type 2 diabetes mellitus who are controlled (hemoglobin Ale <8.5% and glucose <150 mg / dL at screening) may be eligible to participate if otherwise medically healthy, and if on a stable regimen of glucose-lowering medications for at least 2 months prior to screening.Has a history of narcolepsy or seizures (except childhood seizures)Has clinically significant hepatic disease as defined by:- >2x ULN increase of AST or ALT at screening (one retest is permitted)- significant liver disease including cirrhosis, ascites, active hepatitis etc. (fatty liver disease and Gilbert’s syndrome will be allowed as long as it does not meet above criteria).Has taken a strong inhibitor of CYP3A4 or CYP2C9 or moderate / strong inducer of CYP3A4 or CYP2C9 or a dual inhibitor / inducer of CYP3A4 and CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study.Has taken a moderate inhibitor of CYP3A4 or CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study and has:- limited renal (CrCl <60 mL / min) or- hepatic disease (AST / ALT >1.5X ULN and bilirubin >1.5X ULN).Has current signs / symptoms of hypothyroidism or hyperthyroidism. For participants with a history of thyroid disease and for participants who, regardless of thyroid history have the TSH value out of range, a FT4 test will be conducted. If the FT4 value is abnormal and considered to be clinically significant the participant is not eligible.Participants with a pre-existing history of thyroid disease / disorder who are treated with thyroid hormones need to be on a stable dosage for 3 months prior to the start of the screening phase.Participants taking thyroid supplementation for antidepressant purposes are not allowed in the study.Has Cushing’s Disease, Addison’s Disease, primary amenorrhea, or other evidence of significant medical disorders of the HPA axis.Has a current or recent history of homicidal ideation or serious suicidal ideation within the past 3 months, corresponding to a positive response on item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) for ideation on the C-SSRS, or a history of suicidal behavior within the past 6 months, as validated by the C-SSRS at screening or Day 1. Participants with prior suicidal behavior in the past year, or prior serious suicidal ideation / plan within the past 6 months, should be carefully screened. For current suicidal ideation, only participants with non-serious items (1-3 of the suicidal ideation section of the C-SSRS) may be included.Has a history of treatment-resistant MDD, defined as a lack of response to 2 or more adequate antidepressant treatments in the current episode, as indicated by no or minimal (<25% improvement in symptoms) when treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at least 6 weeks).Has a history or evidence of clinically meaningful noncompliance with current antidepressant therapy.Has a primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, social anxiety disorder, or specific phobia which has been the primary focus of psychiatric treatment within the past 2 years. These are allowed as secondary diagnoses if MDD is the primary focus of treatment.Current active DSM-5 diagnosis of obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, bulimia nervosa or fibromyalgia. These disorders need to be in remission for at least 1 year for the participant to be enrolled.Has history or current diagnosis of a psychotic disorder, bipolar disorder, intellectual disability, autism spectrum disorder, borderline personality disorder, or somatoform disorders.Has any significant primary sleep disorder, including but not limited to obstructive sleep apnea, restless leg syndrome, or parasomnias. Patients with insomnia disorder are allowed.Has a history of moderate to severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening or positive test result(s) for alcohol and / or drugs of abuse (e.g., opiates (including methadone), cocaine, amphetamines, methamphetamines, cannabinoids, cannabidiol (CBD), barbiturates, 3, 4-Methylenedi oxymethamphetamine (MDMA)) at screening or at baseline.One retest during screening is allowed. Tobacco and caffeine use are not exclusionary. Taking at screening benzodiazepines at high dosages greater than the equivalent of 30 mg diazepam or 3 mg of lorazepam at long duration which might result in benzodiazepine withdrawal syndrome. Participants must have a negative benzodiazepine test at baseline and be free of signs of the benzodiazepine abstinence syndrome.Had a clinically significant acute illness within 7 days before the first dose of study drug.Has a known malignancy or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that is considered cured with minimal risk of recurrence). Has clinically significant ECG abnormalities at screening or Day 1 prior to randomization that may jeopardize the participants’ safety or the integrity of the study defined as:During screening and / or Day 1, QTcF: >450 msec (males); >470 msec (females). If the QTcF is prolonged on the initial ECG at a given time point, the average QTcF of 3 ECGs, recorded 4 minutes apart, must not be >450 msec for males and >470 msec for females.Evidence of 2nd and 3rd degree atrioventricular block.Features of new ischemia Other clinically important arrhythmia or cardiac abnormalitiesHas within the last 5 years received any prior antidepressant treatment with ketamine / esketamine, electroconvulsive therapy, vagal nerve stimulation, or a deep brain stimulation device. Participants who previously had taken up to 2 doses of ketamine / esketamine and did not continue (e.g., did not benefit from the treatment or experienced tolerability issues) can be considered for enrollment.

[0184] If a participant's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.

[0185] D. Study Intervention

[0186] (i) Study Interventions Administered

[0187] Seltorexant will be supplied as tablets of 20 mg. Placebo will be supplied as matching tablets.

[0188] During the DB phase, all participants should take their assigned study drug once daily at bedtime, with water, with or without a meal, from Day 1 to Day 42.

[0189] During the OL phase, participants will be supplied 20 mg tablets to be taken daily at bedtime from OL baseline until the End-of-Phase / Early Withdrawal visit.

[0190] (ii) SSRI / SNRI Antidepressant Administration

[0191] The baseline SSRI / SNRI antidepressant dose needs to be stable for at least 6 weeks (and no more than 18 months in the current episode) prior to screening. Participants will continue to take their baseline SSRI / SNRI antidepressant preferably at the same dose, without change, every day, at approximately the same time of the day as prior to entering the study, throughout the study, starting at screening and including the follow-up phase. Lack of adherence to the SSRI / SNRI may be a cause for screen failure or study drug discontinuation.

[0192] During the OL phase, participants need to remain on the SSRI / SNRI antidepressant throughout the entire study, unless significant tolerability issue occurs, in which case the oral SSRI / SNRI antidepressant may be discontinued and if appropriate, switched to a new SSRI / SNRI antidepressant. Only one switch of SSRI / SNRI may be made during the OL treatment phase.

[0193] (iii) Intervention After the End of the Study

[0194] Participants will be instructed that after completion of the DB treatment phase they may be eligible to participate in the OL treatment phase. Study drug will not be made available to them after they have completed the OL treatment phase or discontinued study drug treatment in either phase. Participants should return to their primary physician to determine standard of care.

[0195] For participants who complete the study or discontinue treatment early in the DB treatment phase, MDD treatment may be modified (including use of disallowedmedications) after the initial follow-up visit (7 to 14 days after End of the DB phase - Visit 10). If needed during the follow-up period, a disallowed medication may be started due to an AE or for breakthrough symptoms prior to the first follow-up visit. Concomitant medications and the indication for the use should be recorded at each Follow-up visit.

[0196] E. Study Assessments and Procedures

[0197] (i) Overview

[0198] The total blood volume to be collected from each participant will be approximately 160 mL during the Screening and DB phases and 200 mL during the OL phase with the total volume over the maximum 15-month study duration not to exceed 450 mL.

[0199] (ii) Order of Assessments

[0200] Safety assessments, such as vital signs and ECG, are recommended to be performed before blood is drawn and food is provided. On days when fasting laboratory blood samples are taken, it is recommended that efficacy assessments including PRO assessments should be administered after food is provided and participants feel comfortable without help or time pressure, and under quiet conditions. The PRO assessments will be completed by all participants where appropriate PROs and translations are available and approved. Participants should complete the PRO assessments. Study personnel will instruct participants how to self-complete the PRO assessment.

[0201] (iii) Efficacy Assessments

[0202] The following efficacy assessments will be performed at the timepoints. Screening and prebaseline HDRS-17 and ISI (clinician version) will be administered by independent central raters. The MADRS (SIGMA) and CGLS will be performed. It is recommended that the raters for the efficacy assessments (MADRS and CGLS) not be involved in study drug dosing, AE assessments, or other safety evaluations. The CSD, ISI (patient version), PROMIS-SD (Short Form 8a), PHQ-9, PGLS, PGLC, EQ-5D-5L, SDS, and RRS will be completed by the participants. Participants are recommended to wear an actigraphy device from beginning of screening to end of DB treatment (or early withdrawal).

[0203] (iv) Safety Assessments

[0204] The collection of AEs and concomitant medications will start after the informed consent has been signed and will continue until the follow-up visit at the timepoints.

[0205] The following safety assessments will be performed: physical examination, body weight, BMI, waist circumference, vital signs, 12-lead ECG, urine drug testing, alcohol breath test, pregnancy testing (serum pregnancy test at screening and urine pregnancy test thereafter for female participants of childbearing potential only), clinical laboratory tests (hematology, chemistry panel including fasting glucose, lipid panel, TSH, FT4, HbAlc, insulin, and urinalysis).

[0206] Additional blood and urine samples may be taken, or vital signs and ECGs recorded.

[0207] Menstrual cycles will be tracked in premenopausal women who are still having their menses during the study, using a participant diary and participant’s verbal report.

[0208] (v) Physical Examination

[0209] The physical examinations will include assessment of sensation, level of alertness, ataxia, tremor, and other routine components of a brief neurological examination. Height will be measured at screening only. Body weight and waist circumference will be measured at screening and throughout the study.

[0210] Body weight should be measured using a calibrated scale at each indicated visit. Participants should be weighed at approximately the same time of day on the same scale, wearing lightweight clothing without shoes; they will be instructed to empty their bladders before being weighed.

[0211] Waist circumference will be measured with the participant standing, wearing underwear, with or without a gown. The measurement will be performed at a level midway between the superior aspect of the iliac crests and the lower lateral margin of the ribs. The measurement need not be at the level of the umbilicus. The measuring tape will be kept horizontal.

[0212] (vi) Clinical Safety Laboratory Assessments

[0213] Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will be collected. Clinical laboratory assessments (including TSH, FT4, hematology, serum chemistry, HbAlc, lipid panel, and urinalysis) should be performed at approximately the same time under fasting conditions, except possibly at the screening visit. The clinical laboratory assessments, ECGs and vital signs should be done first and then food or coffee provided, before patient-reported outcomes and clinician rated observations are carried out.

[0214] F. Statistical Considerations

[0215] Statistical analysis will be performed.

[0216] (i) Sample Size Determination

[0217] Approximately 550 participants (randomized in 1 : 1 ratio to placebo and seltorexant 20 mg) are planned to be enrolled in the DB treatment phase (including approximately 386 participants with MDDIS and approximately 164 participants with MDD without IS). The enrollment is targeted to achieve approximately 374 participants eligible to be included in FAS1. Assuming treatment difference of 4.4 points in change from baseline in MADRS total score between seltorexant and placebo, SD of 12, 1 -sided significance level of 0.025 (equivalently, 2-sided 0.05), this sample size (i.e., 374 in FAS1) will provide approximately 90% power in a comparison between seltorexant and placebo in the primary efficacy analysis (in participants with MDDIS), accounting for a drop-out rate of approximately 15%. The assumed treatment difference and standard deviation used in this calculation are based on Phase 2 (42847922MDD2001) study results, as well as on clinical judgment.

[0218] (ii) Populations for Analyses

[0219] The following full analysis sets (FAS) will be defined.• FAS1 : defined as all participants who were randomly assigned to study drug and received at least 1 dose of study drug and had a baseline MADRS total score >24. FAS1 will be used for primary efficacy analysis for all submissions with the exception of the European Union (EU) dossier.• FAS2: defined as all participants who were randomly assigned to study drug and received at least 1 dose of study drug. FAS2 will be used for primary efficacy analysis for the EU dossier.• FAS1 WOIS: defined as all MDD participants without IS who were randomly assigned to study drug and received at least 1 dose of study drug and had a baseline MADRS total score >24. This analysis set will be used for other DB efficacy analyses for submissions other than the EU dossier.• FAS2 WOIS: defined as all MDD participants without IS who were randomly assigned to study drug and received at least 1 dose of study drug. This analysis set will be used for other DB efficacy analyses for the EU dossier.• FAS1 ALL: defined as all participants (MDD with and without IS) who were randomly assigned to study drug and received at least 1 dose of study drug and had a baseline MADRS total score >24. This analysis set will be used for other DB efficacy analyses for submissions other than the EU dossier.• FAS2 ALL: defined as all participants (MDD with and without IS) who were randomly assigned to study drug and received at least 1 dose of study drug. This analysis set will be used for other DB efficacy analyses for the EU dossier.

[0220] The analyses of primary and key secondary endpoints (and other efficacy analyses) will be based on FAS (FAS1 for the non-EU dossier, and FAS2 for the EU dossier). For the EU dossier, the primary analysis will be based on FAS2, and the FAS1 will be used for supplementary analyses; for the non-EU dossier, the primary analysis will be based on FAS1, and the FAS2 will be used for supplementary analyses.

[0221] For the OL phase, the efficacy analyses will be based on the OL full analysis set, which consists of all participants who received at least 1 dose of study drug during the OL phase.

[0222] The DB safety analyses will be based on the DB safety analysis set, which consists of all participants who were randomly assigned to study drug and received at least 1 dose of study drug during the DB phase.

[0223] For all participants who are randomly assigned to study drug, descriptive statistics (e.g., study completion / withdrawal information, demographic and baseline data) will be provided.

[0224] For the OL phase, safety analyses will be based on the OL safety analysis set, which consists of all participants who received at least 1 dose of study drug during the OL phase.

[0225] (iii) Statistical Analyses

[0226] (a) Efficacy Analyses

[0227] The analyses of primary and key secondary endpoints will be based on FAS1 and FAS2.

[0228] The primary efficacy endpoint is the change in MADRS total score from baseline to Day 43 in participants with MDDIS.

[0229] The first key secondary endpoint is the change in MADRS-WOSI from baseline to Day 43. The second key secondary endpoint is the change in PROMIS-SD T- score from baseline to Day 43.

[0230] There are two primary estimands defined for the primary efficacy endpoint:

[0231] Estimand 1:

[0232] Population: participants with MDDIS who have had an inadequate response to current antidepressant therapy with an SSRI / SNRI, as reflected by the inclusion / exclusion criteria (participants need to have a baseline MADRS total score >24 for this estimand).

[0233] Endpoint: change in MADRS total score from baseline to Day 43.

[0234] Intercurrent events and corresponding strategies:• Treatment discontinuation of add-on study drug only (Hypothetical strategy: as if the intercurrent event had not occurred)• Treatment discontinuation of both underlying antidepressant and add-on study drug (Hypothetical strategy: see above)• Switch of add-on treatment and / or underlying antidepressant (Hypothetical strategy: see above)

[0235] Summary measure: difference in treatment means.

[0236] Estimand 2:

[0100] Population: participants with MDDIS who have had an inadequate response to current antidepressant therapy with a SSRI / SNRI, as reflected by the inclusion / exclusion criteria.

[0101] Endpoint: change in MADRS total score from baseline to Day 43.

[0102] Intercurrent events and corresponding strategies:• Treatment discontinuation of add-on study drug only (Treatment policy strategy: all observed values of the endpoint are used regardless of whether or not the participant had experienced this intercurrent event)• Treatment discontinuation of both underlying antidepressant and add-on study drug (Hypothetical strategy: as if the intercurrent event had not occurred)• Switch of add-on treatment and / or underlying antidepressant (Hypothetical strategy: as if the participant had discontinued treatment instead of switching)

[0237] A supplementary estimand will be defined with the same components as Estimand 2, with the hypothetical strategy being replaced by a treatment policy strategy forthe intercurrent event of treatment discontinuation of both underlying antidepressant and addon study drug.

[0238] With the exception of the European Union (EU) dossier, the primary estimand is Estimand 1, and the supplementary estimand is Estimand 2. For the EU dossier, the primary estimand is Estimand 2, and the supplementary estimand is Estimand 1.

[0239] Under Estimand 2, MADRS will need to be collected after study drug discontinuation for participants who did not withdraw consent and will be included in the analyses when the treatment policy strategy is applied.

[0240] Main Analysis Under Estimand 1

[0241] The comparison between seltorexant and placebo will be performed using the appropriate contrasts in a MMRM with main comparison at Day 43. The MMRM will include country, age group (adults (<65 years) and elderly (>65 years)), baseline rumination level (RRS total score <54, >54), time, treatment (placebo and seltorexant), and treatment by time interaction as factors, and baseline MADRS total score as a covariate.

[0242] Sensitivity Analysis Under Estimand 1

[0243] For Estimand 1, delta adjustment with a tipping point will be conducted as a sensitivity analysis.

[0244] Main Analysis Under Estimand 2

[0245] The copy reference (CR) multiple imputation (MI) method will be performed. A mixed model (which will include country, age group (adults (<65 years) and elderly (>65 years)), baseline rumination level (RRS total score <54, >54), time, treatment (placebo and seltorexant), and treatment by time interaction as factors, and baseline MADRS total score as a covariate) will be applied to each imputed dataset (with the CR MI method), and the Rubin’s rule will be used to combine results from each imputed dataset.

[0246] Sensitivity Analysis Under Estimand 2

[0247] For Estimand 2, the Copy Increment from Reference (CIR) MI method will be performed as a sensitivity analysis.

[0248] Key Secondary Efficacy Endpoints

[0249] The same estimands (except the endpoint) and corresponding analyses as for the primary endpoint will be used for the key secondary endpoints.

[0250] Testing Procedure for Primary and Key Secondary Endpoints

[0251] The fixed sequence testing procedure will be applied to control the familywise error rate (FWER) at two-sided 0.05 level accounting for multiplicity due to the primary (MADRS total score) and key secondary efficacy endpoints (MADRS-WOSI and PROMIS-SD). The fixed sequence testing procedure will first test the primary endpoint at two-sided 0.05 level. If the hypothesis corresponding to the primary endpoint is rejected, then the first key secondary endpoint (MADRS-WOSI) will be tested at two-sided 0.05 level; if the hypothesis corresponding to the primary endpoint is not rejected, then the testing procedure will stop. If the hypothesis corresponding to MADRS-WOSI is rejected, then the second key secondary endpoint (PROMIS-SD) will be tested at two-sided 0.05 level; if the hypothesis corresponding to MADRS-WOSI is not rejected, then the testing procedure will stop.

[0252] Other Efficacy Endpoints

[0253] There is no multiplicity adjustment for other efficacy endpoints.

[0254] Efficacy Analyses in the OL Phase

[0255] For the OL treatment phase, efficacy analyses will be based on the OL full analysis set, which consists of all participants who received at least 1 dose of study drug during the OL phase. The efficacy outcomes in the OL phase will be summarized descriptively.

[0256] Safety Analyses

[0257] For the DB treatment phase, safety analyses will be based on the safety analysis set, which consists of all participants who were randomly assigned to study drug and received at least 1 dose of study drug during the DB phase.

[0258] For the OL treatment phase, safety analyses will be based on the OL safety analysis set, which consists of all participants who received at least 1 dose of study drug during the OL phase.

[0259] Clinical Laboratory Tests

[0260] Laboratory data will be summarized by type of laboratory test and treatment. Reference ranges and markedly abnormal results will be used in the summary of laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time point. A listing of participants with any markedly abnormal laboratory results will be provided.

[0261] Descriptive statistics of pulse, sitting blood pressure (systolic and diastolic), and temperature for observed values will be provided and changes from baseline will be summarized at each scheduled time point by treatment. The percentage of participants with values beyond clinically important limits will be summarized. Changes in body weight, waist circumference, and BMI will be summarized descriptively.

[0262] G. Post-Hoc Analysis

[0263] Analyses were conducted on the one-year OLE of this study of adjunctive seltorexant (20 mg) vs. placebo. Weight changes, insulin resistance (HOMA-IR), and insulin levels were analyzed using descriptive statistics. Weight changes were also analyzed using a MMRM.

[0264] Over 52-weeks of OLE treatment, patients who received seltorexant adjunctive to an SSRESNRI exhibited minimal weight gain (mean weight change = 1.5 kg), with no incremental weight gain compared with typical weight gain associated with SSRI / SNRI treatments (approximately 1.5 kg after one year of treatment. See, Petimar, Medication-Induced Weight Change Across Common Antidepressant Treatments: A Target Trial Emulation Study. Ann Intern Med. 2024 Aug;177(8):993-1003.

[0265] Analysis of metabolic parameters in this study revealed significant insulin resistance (HOMA-IR >2.9) at baseline in obese, pre-diabetic, and diabetic patients.

[0266] Throughout the study duration, obese patients, as well as those with either pre-diabetes or diabetes, and especially patients with diabetes, showed a clinically meaningful improvement in major metabolic parameters such as HOMA-IR and insulin levels by the end of the 52-week treatment (Table 4).

[0267] Similar to the data from MDD3005 (shown below), seltorexant demonstrated a clinically meaningful effect in reducing IR in participants with high IR at baseline (HOMA-IR >2.9) (Table 5).

[0268] Example 3: MDD3005 Study

[0269] A. Objectives and Endpoints

[0270] For the following objectives and endpoints, MDDIS is defined as MDD with IS as a) moderate to severe IS by a patient version ISI total score of >15 at the end of screening and b) a positive response for IS (MDD symptoms Item 4) on the Structured Clinical Interview for DSM-5 Axis I Disorders Clinical Trials Version (SCID-CT). In addition, the clinician version ISI total score >15 is also required since it was used in the Phase 2 program.

[0271] (i) Safety objectives:

[0272] To assess the safety and tolerability of seltorexant compared with quetiapine XR as adjunctive therapy to an SSRI / SNRI in participants with MDDIS using:• Laboratory values, including lipids and glucose, and ECG• Vital signs and physical examination, including weight, BMI, and waist circumference

[0273] (ii) Other Exploratory objectives:• To assess the the efficacy and safety of seltorexant compared with quetiapine XR as adjunctive therapy to an SSRI or SNRI in treatment response without clinically meaningful weight gain based on:- Difference in proportions of participants who metMADRS response criteria (>50% improvement in MADRS total score from baseline) and did not have weight increase of >7% at Week 26 for seltorexant vs quetiapine XR.

[0274] B. Study Design

[0275] (i) Overall Design

[0276] This is a multicenter, DB, randomized, parallel-group, and active- controlled, 26-week, study to assess the efficacy and safety of 20 mg seltorexant compared with flexibly dosed quetiapine XR (150 or 300 mg) as an adjunctive therapy in adult andelderly participants with MDDIS (18 to 74 years of age, inclusive), who have had an inadequate response to current antidepressant therapy with an SSRI / SNRI.

[0277] This study will enroll approximately 720 participants with MDDIS, to target approximately 678 participants in the full analysis set 1 (FAS1). The planned dose of seltorexant is 20 mg and quetiapine XR is 150 or 300 mg.

[0278] The study will consist of 3 phases: a screening phase (up to 30 days), a DB treatment phase (26 weeks), and a posttreatment follow-up phase (7-14 day after the end of DB treatment phase for all participants, and up to 196 days from baseline for participants who stop study treatment early).

[0279] Participants will continue to take their baseline SSRI / SNRI antidepressant (at the same dose, without change, and at approximately the same time as prior to entering the study) from screening through the first follow-up visit.

[0280] Double-blind Treatment Phase

[0281] Participants who meet all inclusion criteria and none of the exclusion criteria will be randomly assigned to receive a fixed dose of seltorexant (20 mg) or flexible dose of quetiapine XR (150 or 300 mg) in a 1 : 1 ratio.

[0282] Participants should take their assigned study drug at home, once daily at bedtime, starting from Day 1. All participants randomized to seltorexant will start with 20 mg once daily at night and remain on this dose throughout. Participants randomized to the quetiapine XR group, will receive 50 mg once daily for 2 days, followed by an increase to 150 mg once daily on Day 3, as per prescribing guidelines in the product label. After the initial dosing period, dose adjustments may be made starting at the Day 14 visit. Since treatment assignment is blinded, a participant on seltorexant will remain on 20 mg dose even if the dose is up titrated. The first dose adjustment of quetiapine XR must be upwards. Subsequent adjustments may be made upwards or downwards within the dose ranges (150 mg or 300 mg for quetiapine XR) if necessary, depending upon the participant’s clinical response and tolerability. Dose adjustments can only occur during clinic visits. If necessary, an unscheduled visit may be scheduled.

[0283] Participants for whom tolerability at the assigned dose is either unacceptable or cannot be appropriately managed should be withdrawn from the study drug, and any reported AE, if any, as a reason for discontinuation. Participants who discontinue early from treatment and do not withdraw consent, will have End-of-Treatment and Follow-up visits, and will be further assessed during additional Follow-up visits, every 4-weeks until Day 196.

[0284] Throughout the study, participants will need to continue their baseline SSRI / SNRI antidepressant (at the same dose and taken around the same time of the day as prior to entering the study) on which they have had inadequate response at the time of screening.

[0285] Efficacy and safety assessments, biomarkers sampling, and other study procedures will be performed at each visit. If a participant withdraws from the study drug, rating of the MADRS, and the end of study / early withdrawal visit assessments (including MADRS) will be performed, preferably on the day after the last dose or as soon as the participant is available for the assessment.

[0286] Entry to the follow-up phase should not be conducted in participants who withdraw consent for further study assessments; however, they should complete the DB end- of-phase visit if they are willing to do so.

[0287] Follow -Up / End of Study Visit

[0288] Participants who received at least 1 dose of study drug, except those who withdrew consent for the study or who are lost to follow-up, will return to the study center for a follow-up visit within 7 to 14 days after the last dose of study drug. At the follow-up visit, safety and efficacy assessments / procedures will be completed.

[0289] For participants who have discontinued study drugs and wish to stay in the study, they may continue in the follow-up phase after the first follow-up visit. These visits will occur every 4 weeks. The participant may stay in the follow-up phase for up to 196 days from DB baseline. After the first follow-up visit, further clinical / standard of care for the treatment of depression should be arranged. Participants who have withdrawn consent from assessments may not participate in the extended follow-up phase.

[0290] The duration of participation in the study for an individual participant (including screening, DB treatment, and follow-up phases) will be approximately 32 weeks.

[0291] A diagram of the study design is provided in FIG. 2.

[0292] Safety Evaluations

[0293] Standard safety evaluations including collection of AEs and concomitant medications, physical examination, body weight, BMI, waist circumference, vital signs, 12- lead ECG, urine drug screening, alcohol breath test, and clinical laboratory tests will beperformed to monitor participant safety throughout the study. A serum or urine pregnancy test will be performed only for WOCBP. Additional serum and urine pregnancy tests and drug and alcohol tests may be conducted as needed.

[0294] Since weight gain as well as other metabolic abnormalities is a known consequence of antidepressant treatment, weight as well as other metabolic measures (waist circumference, fasting glucose, triglycerides, HbAlc, insulin) will be collected throughout the study. Weight will also be assessed separately as a key secondary endpoint.

[0295] Weight Gain: A 7% weight gain is considered the standard measure of clinically significant increase for antipsychotic medication which included quetiapine XR and this amount of weight gain can lead to significant medical problems such as diabetes and increase the risk of cardiac disease.Error! Reference source not found- Weight gain is seen with the long-term use of antidepressant medications across classes and may be a contributor to increased medical risks in patients with MDD.

[0296] End of Study and End of Treatment Definitions

[0297] A participant will be considered to have completed the DB treatment phase if he or she has completed the Week 26 visit of the DB treatment phase and has not discontinued study drug prior to Week 26.

[0298] A participant will be considered to have completed the follow-up phase if he or she has completed assessments at all follow-up visits.

[0299] Participants who prematurely discontinue study drug for any reason before completion of the DB treatment phase will not be considered to have completed the study.

[0300] The end of study is considered as the last study assessment, completed for the last participant in the study.

[0301] C. Study Population

[0302] Screening for eligible participants will be performed within 30 days before administration of the study drug.

[0303] The inclusion and exclusion criteria for enrolling participants are described.

[0304] (i) Inclusion Criteria

[0305] Each potential participant must satisfy all of the following criteria to be enrolled in the study:Male, or female, aged 18 to 74 years (inclusive). Participants should be at least18 years of age or older as per the legal age of consent in the jurisdiction in which the study is taking place. Meet DSM-5 diagnostic criteria for MDD, without psychotic features (DSM-5 296.22,296.23, 296.32, or 296.33), based upon clinical assessment and confirmed by the SCID-CT diagnosed with first depressive episode prior to age 60. The length of the current depressive episode must be <24 months. The sleep item of the MDD symptoms (Item 4 of the SCID-CT) should be positive for IS prior to randomization. Have had an inadequate response to at least 1 but no more than 2 antidepressants (see the inclusion criterion 4 below), administered at an adequate dose and duration in the current episode of depression. The current antidepressant cannot be the first antidepressant treatment for the first lifetime episode of depression. An inadequate response is defined as <50% reduction but with some improvement (i.e., improvement >0%) in depressive symptom severity with residual symptoms present other than insomnia, and overall good tolerability, as assessed by the MGH-ATRQ. An adequate trial is defined as a stable antidepressant treatment for at least 6 weeks on a stable dose (and no greater than 18 months in the current episode) at or above the minimum therapeutic dose specified in the MGH-ATRQ and must include the participant’s current antidepressant treatment. Participants with no improvement on the current SSRI / SNRI should not be enrolled in the study. If a participant has received 2 SSRI / SNRI treatments of sufficient dose and duration in the current episode, and has shown <25% improvement to both, then the participant would not qualify based on exclusion criterion 9. Is receiving and tolerating well any one of the following SSRI or SNRI for depressive symptoms at screening, in any formulation and available in the participating country: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine at a stable dose (at or above therapeutic dose level) for at least 6 weeks, and for no greater than 18 months in the current episode. Participants using fluvoxamine as baseline SSRI and have normal renal and hepatic function may enter the study.Have a HDRS- 17 total score >20 at the first screening interview, must not demonstrate a clinically significant improvement (i.e., an improvement of >20% on their HDRS- 17 total score) from the first to the second independent HDRS- 17 rating, and must have a HDRS- 17 total score >18 at the second screening interview.Have a patient version ISI total score >15 as well as a clinician version of the ISI total score >15 at the second screening visit.BMI between 18 and 40 kg / m2, inclusive (BMI=weight / height2).Must be an outpatient at screening.Participant must be medically stable on the basis of the following: physical examination, vital signs (including blood pressure), and 12-lead ECG performed at screening and baseline. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined.Participant must be medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included if the abnormalities or deviations from normal are not clinically significant or to be appropriate and reasonable for the population under study.Must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and be willing to participate in the study.A woman of childbearing potential must have a negative highly sensitive serum (P- hCG) pregnancy test at screening and a negative urine pregnancy test predose on Day 1 of the DB phase prior to randomization.Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies. c. Before entering the study, a woman must be either:• PostmenopausalA postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In women who are <40 years old and have amenorrhea, FSH should be performed to determine post-menopausal status, based on the reference range of central laboratory. In women who are >40 years old and have amenorrhea for less than 12 months, FSH test may be performed to assist in determining their post-menopausal status. In womenwho are >40 years old and have amenorrhea for >12 months, FSH is not required.. Permanently sterilePermanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion / ligation procedures, and bilateral oophorectomy. No FSH testing is required. d. Of childbearing potential and• Practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly). The potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention should be determined.Examples of highly effective contraceptives include:- User independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone- releasing system (IUS); vasectomized partner; sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)- User-dependent methods: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectableTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies• Agrees to remain on a highly effective method throughout the study and for at least 1 month after the last dose of study drug.: If the childbearing potential status changes after start of the study or the risk of : pregnancy changes (e.g., a woman who is not heterosexually active becomes active) : a female participant or female partner of a male participant must begin a highly : effective method of contraception, as described throughout the inclusion criteria. If : reproductive status is questionable, additional evaluation should be considered.14. A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the : purposes of assisted reproduction during the study and for a period of at least 1 month : after receiving the last dose of study drug.15. i During the study and for a minimum of 1 spermatogenesis cycle (defined as: approximately 3 months) after receiving the last dose of study drug, a man• who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (e.g., condom with spermicidal foam / gel / film / cream / suppository) and his female partner must use a highly effective method of contraception.• who is sexually active with a woman who is pregnant must use a condom.• must agree not to donate sperm.

[0306] (ii) Exclusion Criteria

[0307] Any potential participant who meets any of the following criteria will be excluded from participating in the study:1. : Has a recent (last 3 months) history of, or current signs and symptoms of,- severe renal insufficiency (CrCl <30 mL / min);- clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic, hematologic, rheumatologic, immunologic or endocrine disorders.- uncontrolled Type 1 or Type 2 diabetes mellitus. Participants with Type 1 or Type 2 diabetes mellitus who are controlled (hemoglobin Ale <8.5% and glucose <150 mg / dL at screening) may be eligible to participate if otherwise medically healthy, and if on a stable regimen of glucose-lowering medications for at least 2 months prior to screening.2. : Has a history of narcolepsy or seizures (except childhood seizures)3. : Has clinically significant hepatic disease as defined by:- >2x ULN increase of AST or ALT at screening (one retest is permitted)- significant liver disease including cirrhosis, ascites, active hepatitis etc. (fatty liver disease and Gilbert’s syndrome will be allowed as long as it does not meet above criteria).Has taken a strong inhibitor of CYP3A4 or CYP2C9 or moderate / strong inducer of CYP3A4 or CYP2C9 or a dual inhibitor / inducer of CYP3A4 and CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study.Has taken a moderate inhibitor of CYP3A4 or CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study and has:- limited renal (CrCl <60 mL / min) or- hepatic disease (AST / ALT >1.5X ULN and bilirubin >1.5X ULN).Has current signs / symptoms of hypothyroidism or hyperthyroidism. For participants with a history of thyroid disease and for participants who, regardless of thyroid history have the TSH value out of range, a FT4 test will be conducted. If the FT4 value is abnormal and considered to be clinically significant the participant is not eligible. Participants with a pre-existing history of thyroid disease / disorder who are treated with thyroid hormones need to be on a stable dosage for 3 months prior to the start of the screening phase. Participants taking thyroid supplementation for antidepressant purposes are not allowed in the study.Has Cushing’s Disease, Addison’s Disease, primary amenorrhea, or other evidence of significant medical disorders of the HPA axis.Has a current or recent history of homicidal ideation or serious suicidal ideation within the past 3 months, corresponding to a positive response on item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) for ideation on the C-SSRS, or a history of suicidal behavior within the past 6 months, as validated by the C-SSRS at screening or Day 1. Participants with prior suicidal behavior in the past year, or prior serious suicidal ideation / plan within the past 6 months, should be carefully screened. For current suicidal ideation, only participants with non-serious items may be included.Has a history of treatment-resistant MDD, defined as a lack of response to 2 or more adequate antidepressant treatments in the current episode, as indicated by no orminimal (<25% improvement in symptoms) when treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at least 6 weeks).Has a history or evidence of clinically meaningful noncompliance with current antidepressant therapy.Has a primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, social anxiety disorder, or specific phobia which has been the primary focus of psychiatric treatment within the past 2 years. These are allowed as secondary diagnoses if MDD is the primary focus of treatment.Current active DSM-5 diagnosis of obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, bulimia nervosa or fibromyalgia. These disorders need to be in remission for at least 1 year for the participant to be enrolled.Has history or current diagnosis of a psychotic disorder, bipolar disorder, intellectual disability, autism spectrum disorder, borderline personality disorder, somatoform disorders.Has any significant primary sleep disorder, including but not limited to obstructive sleep apnea, restless leg syndrome, or parasomnias. Participants with insomnia disorder are allowed.Has a history of moderate to severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening or positive test result(s) for alcohol and / or drugs of abuse (e.g., opiates (including methadone), cocaine, amphetamines, methamphetamines, cannabinoids, cannabidiol (CBD), barbiturates, 3, 4-Methylenedi oxymethamphetamine (MDMA)) at screening or at baseline. One retest during screening is allowed. Tobacco and caffeine use are not exclusionary.Taking, at screening, benzodiazepines at high dosages greater than the equivalent of 30 mg diazepam or 3 mg of lorazepam at long duration which might result in benzodiazepine withdrawal syndrome. Participants must have a negative benzodiazepine test at baseline and be free of signs of the benzodiazepine abstinence syndrome.Had a clinically significant acute illness within 7 days before the first dose of study drug.Has a known malignancy or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that is considered cured with minimal risk of recurrence).Has clinically significant ECG abnormalities at screening or Day 1 prior to randomization that may jeopardize the participants’ safety or the integrity of the study, defined as:- During screening and / or Day 1, QTcF: >450 msec (males); >470 msec (females). If the QTcF is prolonged on the initial ECG at a given time point, the average QTcF of 3 ECGs, recorded 4 minutes apart, must not be >450 msec for males and >470 msec for females.- Evidence of 2nd and 3rd degree atrioventricular block.- Features of new ischemia- Other clinically important arrhythmia or cardiac abnormalitiesHas within the last 5 years received any prior antidepressant treatment with ketamine / esketamine, electroconvulsive therapy, vagal nerve stimulation, or a deep brain stimulation device. Participants who previously had taken up to 2 doses of ketamine / esketamine and did not continue (e.g., did not benefit from the treatment or experienced tolerability issues) can be considered for enrollment.Ongoing psychological treatments (e.g., Cognitive Behavior Therapy, Interpersonal Psychotherapy, Psychodynamic Psychotherapy etc.), initiated within 6 weeks prior to start of screening. A participant who has been receiving ongoing psychological treatment for a period of greater than 6 weeks is eligible, if the psychological treatment to be of stable duration and frequency.Has received experimental therapies (psychological, pharmacologic or noninvasive) within 30 days before screening or if greater than 2 experimental therapies in the past year Has known allergies, hypersensitivity, intolerance or any contraindication to seltorexant and local label for quetiapine XR or its excipients. Has had exposure to quetiapine >50 mg / day (immediate release or XR) in the current episode of MDD or >30-day total exposure to a dose of quetiapine >100 mg / day (immediate release or XR) in the last 3 years prior to screening (per patient report or

[0308] If a participant's clinical status changes after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.

[0309] D. Study Intervention

[0310] Study Interventions Administered

[0311] This study is planned to investigate a seltorexant dose of 20 mg compared with quetiapine XR 150-300 mg as an adjunctive treatment for MDDIS.

[0312] During the DB treatment phase, seltorexant (20 mg) and quetiapine (50 mg, 150 mg or 300 mg) will be supplied as over-encapsulated tablets. Placebo will be supplied as matching capsules containing microcrystalline cellulose.

[0313] All participants should take their assigned study drug once daily at bedtime, with water, with or without a meal.

[0314] The over-encapsulated tablets must be swallowed whole with water and not chewed, divided, dissolved or crushed. Pill counts of study drug will be performed at postrandomization visits during the treatment phase of the study.

[0315] If a scheduled (i.e., at bedtime) dose is missed, participants are advised not to take the dose in the morning and not to administer 2 doses at a time the next evening. The dose will be skipped.

[0316] Adult participants will take 1 capsule daily during the first week and 2 capsules daily from the second week onwards. During the first week, adult participants on seltorexant will take 1 over-encapsulated tablet of 20 mg seltorexant daily. Adult participants on quetiapine XR will take one over-encapsulated 50 mg tablet daily for the first 2 days, then continue to take 1 over-encapsulated 150 mg tablet daily. Elderly participants will take 1 or 2 capsules daily during the first week depending on their individual titration schedule and 2 capsules daily from the beginning of Week 2 onwards. Elderly participants on quetiapine XR will start with 1 over-encapsulated 50 mg tablet on Day 1-3 and take a second overencapsulated 50 mg tablet when the quetiapine XR daily dose can be increased according to the local prescribing label. A telephone call may be scheduled to assess patient’s tolerability before increasing dose. Elderly patients on seltorexant will start with 1 over-encapsulated tablet of 20 mg on Day 1 and a second capsule of placebo to match the blinded dose titration schedule of quetiapine XR.

[0317] During the second week and onwards, all participants on seltorexant will take 1 over-encapsulated tablet of 20 mg seltorexant and 1 capsule of placebo. Participants on the quetiapine XR lower dose will take 1 over-encapsulated tablet of quetiapine XR 150 mg and 1 capsule of placebo. Participants on the quetiapine XR higher dose will take 2 overencapsulated tablets of 150 mg quetiapine XR (Table 6).

[0318] All participants randomized to seltorexant will receive 20 mg. Adult participants randomized to quetiapine XR will receive 50 mg once daily for 2 days, followed by an increase to 150 mg once daily on Day 3, as per prescribing guidelines in the product label. Dose titration for elderly participants will be slower (doses can be increased by increments of 50 mg) and will be performed according to the local prescribing label. All participants will receive quetiapine XR 150 mg once daily by Day 8.

[0319] After the initial dosing period, dose adjustments may be made starting with the first scheduled clinic visit (Day 14), unless the local label is indicating otherwise. The first dose adjustment must be upwards. Subsequent adjustments may be made upwards or downwards within the study dose ranges (150 or 300 mg for participants randomized to quetiapine XR) if necessary. Adjustments of dose should only be made after a clinic visit (if needed may be an unscheduled visit) and assessment of efficacy and tolerability of the medication. Since the study is blinded, participants assigned to seltorexant will remain on 20 mg nightly even if the higher dose is used.

[0320] Participants for whom tolerability at the lowest dose is either unacceptable or cannot be appropriately managed should be withdrawn from the study, and the AE as a reason for discontinuation. For participants on the higher dose, if there is a lack of responseafter a clinically appropriate treatment time, discontinuation of the participant due to lack of efficacy should be considered.

[0321] (i) SSRI / SNRI Antidepressant Administration

[0322] The baseline SSRI / SNRI antidepressant dose needs to be stable for at least 6 weeks (and no more than 18 months in the current episode) prior to screening. Participants will continue to take their baseline SSRI / SNRI antidepressant preferably at the same dose, without change, every day, at approximately the same time of the day as prior to entering the study throughout the study, starting at screening and including the follow-up phase. Lack of adherence to the SSRI / SNRI may be a cause for screen failure or study drug discontinuation.

[0323] However, the dose of the antidepressant may be changed during the DB treatment phase (not during screening) due to tolerability concerns and proposed changes should be discussed.

[0324] (ii) Intervention After the End of the Study

[0325] Participants will be instructed that study drug will not be made available to them after they have completed the DB treatment phase or discontinued study drug treatment. Participants should return to their primary physician to determine standard of care.

[0326] For participants who discontinue the DB treatment early, MDD treatment may be modified (including use of disallowed medications) after the initial Follow-up visit (7-14 day after End-of-Phase visit) during the extended follow-up phase. If needed during the initial follow-up period, a disallowed medication may be started due to an AE or for breakthrough symptoms.

[0327] E. Study Assessments and Procedures

[0328] (i) Overview

[0329] The total blood volume to be collected from each participant will be approximately 150 mL but not to exceed 250 mL.

[0330] (ii) Efficacy Assessments

[0331] The following efficacy assessments will be performed at the timepoints indicated. Screening and prebaseline HDRS-17 and ISI (clinician version) will be administered by independent central raters. The MADRS (SIGMA), MADRS-WOSI, MADRS-6, CGLS, and weight assessment will be performed. It is recommended that the raters for the efficacy assessments not be involved in study drug dosing, AE assessments, or other safety evaluations. The SDS, CSD, ISI (patient version), PHQ-9, PROMIS-SD (ShortForm 8a), PROMIS-Fatigue, PGI-S, PGI-C, QLDS, EQ-5D-5L, and RRS will be completed by the participants. Response is considered a clinically relevant endpoint and for this study is considered a >50% improvement in MADRS total score compared to DB baseline. The primary endpoint is the response at Week 26. If a participant does not have a MADRS at Week 26, they are considered a non-responder.

[0332] (iii) Safety Assessments

[0333] The collection of AEs and concomitant medications will start after the informed consent has been signed and will continue through the follow-up visit.

[0334] The following safety assessments will be performed: physical examination, body weight, BMI, waist circumference, vital signs, 12-lead ECG, urine drug testing, alcohol breath test, pregnancy testing (serum pregnancy test at screening and urine pregnancy test thereafter for female participants of childbearing potential only), clinical laboratory tests (hematology, chemistry panel including fasting glucose, lipid panel, TSH, FT4, HbAlc, insulin, and urinalysis). Weight will also be assessed separately as a key secondary endpoint.

[1000] Weight

[0335] A 7% weight gain is considered the standard measure of increase for antipsychotic medication which included quetiapine XR and this amount of weight gain can lead to significant medical problems such as diabetes and increase the risk of cardiac disease. Weight gain is seen with the long-term use of antidepressant medications across classes and may be a contributor to increased medical risks in patients with MDD.

[0336] To minimize influence of external factors, body weight should be measured using a calibrated scale at each indicated visit. Participants should be weighed at approximately the same time of day on the same scale, wearing lightweight clothing without shoes; they will be instructed to empty their bladders before being weighed. The scale should be calibrated according to the manufacturers specifications and at the frequency recommended by the manufacturer before the first participant is weighed. Calibration must be documented.

[0337] Physical Examination

[0338] Physical examinations will include assessment of sensation, level of alertness, ataxia, tremor, and other routine components of a neurological examination. Height will be measured at screening only. Body weight and waist circumference will be measured at screening and throughout the study.

[0339] Waist circumference will be measured with the participant standing, wearing underwear, with or without a gown. The measurement will be performed at a level midway between the superior aspect of the iliac crests and the lower lateral margin of the ribs. The measurement need not be at the level of the umbilicus. The measuring tape will be kept horizontal.

[0340] Clinical Safety Laboratory Assessments

[0341] Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will be collected. Clinical laboratory assessments (including TSH, FT4, hematology, serum chemistry, HbAlc, lipid panel, and urinalysis) should be performed at approximately the same time under fasting conditions, except possibly at the screening visit. The clinical laboratory assessments, weight, ECGs and vital signs should be done first and then food or coffee provided, before patient-reported outcomes and clinician rated observations are carried out.

[0342] F. Statistical Considerations

[0343] A general description of the statistical methods to be used to analyze the efficacy and safety data is outlined below.

[0344] (i) Statistical Hypotheses

[0345] This study is designed to primarily show that seltorexant is superior to quetiapine XR as an adjunctive MDD treatment in achieving a response criterion (defined as >50% improvement in MADRS total score from baseline) at Week 26.

[0346] If pTand pc are the proportion of participants meeting response criteria at Week 26, for seltorexant and quetiapine XR respectively, then the primary hypothesis can be written as follows:Ho: PT- pc <0Hi: PT- pc >0

[0347] Superiority can be concluded if the two-sided p-value for the testing of the above hypothesis is less than 0.05.

[0348] In addition, this study has a key secondary hypothesis:• If gT and pcare the mean change in weight at Week 26 for seltorexant and quetiapine XR respectively, then the key secondary hypothesis can be written as follows:Ho: PT- pc >0Hi: | T - gc <0

[0349] (ii) Sample Size Determination

[0350] The enrollment will need to target a total of approximately 678 participants in the FASl. The randomization will be in a 1 : 1 ratio to seltorexant: quetiapine XR. The following assumptions were used in the sample size calculation, based on clinical interpretation of available data:• 31% response rate in the seltorexant group at end of the 26-week DB phase• 20.2% response rate in the quetiapine XR group at end of the 26-week DB phase• Participants who discontinue the DB treatment early are considered as nonresponders• Two-sided type I error level (alpha) of 0.05 (or equivalently, one-sided alpha of 0.025)• Power of 90% to reject a null hypothesis: response rate in the seltorexant group is less than or equal to response rate in the quetiapine XR group, using a testing method based on normal approximation to the binomial distribution.

[0351] The assumed Week 26 response rate in the quetiapine XR group is derived based on the Study 42847922MDD2002 Week 24 response rate, with an adjustment to reflect the general trend of decreased response rate over time (mainly driven by discontinuation over time). The assumed Week 26 response rate in the seltorexant group is derived, both based on the Study 42847922MDD2002 Week 24 response rate for 20 mg dose and based on the anticipated effect of seltorexant at Week 26 (minimum 10% difference between seltorexant and quetiapine XR).

[0352] (iii) Populations for Analyses

[0353] Two full analysis sets (FAS) will be defined.• FASl : defined as all participants who were randomly assigned to study drug and received at least 1 dose of study drug and had a baseline MADRS total score >24. FASl will be used for primary efficacy analysis, with the exception of the European Union (EU) dossier.• FAS2: defined as all participants who were randomly assigned to study drug and received at least 1 dose of study drug. FAS2 will be used for primary efficacy analysis for the EU dossier.

[0354] The analyses of primary and key secondary endpoints (and other efficacy analyses) will be based on the FAS (FAS1 for the non-EU dossier, and FAS2 for the EU dossier). For the EU dossier, the primary analysis will be based on FAS2, and the FAS1 will be used for supplementary analyses; for the non-EU dossier, the primary analysis will be based on FAS1, and the FAS2 will be used for supplementary analyses.

[0355] Safety analyses will be based on the safety analysis set, which consists of all participants who were randomly assigned to study drug and received at least 1 dose of study drug.

[0356] For all participants who are randomly assigned to study drug, descriptive statistics (e.g., study completion / withdrawal information, demographic and baseline data) will be provided.

[0357] (iv) Statistical Analyses

[0358] The analyses of primary and key secondary endpoints (and other efficacy analyses) will be based on the FAS (FAS1 for the non-EU dossier, and FAS2 for the EU dossier).

[0359] The primary endpoint is the proportion of participants who meet the response criteria (>50% improvement in MADRS total score from baseline) at Week 26. Participants who discontinue treatment prior to Week 26 will not be considered meeting the response criteria.

[0360] The key secondary endpoint is change in body weight from baseline at Week 26.

[0361] The estimand for the primary endpoint is defined by the following components:

[0362] Population: participants with MDDIS who have had an inadequate response to current antidepressant therapy with an SSRI / SNRI, as reflected by the inclusion / exclusion criteria (with the exception of the EU dossier, participants need to have a baseline MADRS total score >24for this estimand).

[0363] Endpoint: proportion of participants who meet response criteria (>50% improvement in MADRS total score from baseline) at Week 26. For calculating the proportion, the denominator is number of participants in the FAS within each treatment group. Note that participants who discontinue treatment prior to Week 26 will not be considered as meeting the response criteria.

[0364] Summary Measure: Difference in proportions between treatments. Note that for the primary endpoint, participants who discontinue study drug early will not be considered as responders, by definition of this endpoint, its corresponding main estimand does not have the components for intercurrent events and strategies.

[0365] Main Analysis for the Primary Endpoint of Response Rate: With the exception of the EU dossier, the stratified Cochran-Mantel-Haenszel (CMH) test adjusted for country, age group and baseline rumination level will be used for testing the proportion difference between treatment groups, for the primary endpoint of response rate.

[0366] For the EU dossier, the stratified CMH test adjusted for country, age group, baseline rumination level and baseline MADRS groups will be used for testing the proportion difference between treatment groups, for the primary endpoint of response rate.

[0367] The following estimands are defined for the key secondary endpoint: Estimand 1 using the FAS1 analysis set, and Estimand 2 using the FAS2 analysis set. For submissions other than the EU dossier, the primary estimand is Estimand 1, and the supplementary estimand is Estimand 2. For the EU dossier, the primary estimand is Estimand 2, and the supplementary estimand is Estimand 1.

[0368] The sections below describe the primary and sensitivity analyses performed for each primary and supplementary estimand.

[0369] Estimand 1:

[0370] Population: same as Estimand for the primary endpoint.

[0371] Endpoint: change from baseline to Week 26 in weight.

[0372] Intercurrent events and corresponding strategies:• Treatment discontinuation of add-on study drug only (Hypothetical strategy: as if the intercurrent event had not occurred)• Treatment discontinuation of both underlying antidepressant and add-on study drug (Hypothetical strategy: see above)• Switch of add-on treatment and / or underlying antidepressant (Hypothetical strategy: see above)

[0373] Summary Measure: Difference in treatment means

[0374] Estimand 2:

[0375] Has the same components as Estimand 1 for weight change, except for the study population and strategy for the intercurrent event of “Treatment discontinuation of addon study drug only” :• Population: Participants with MDDIS who have had an inadequate response to current antidepressant therapy with a SSRI / SNRI, as reflected by the inclusion / exclusion criteria (i.e., regardless of the baseline MADRS total score).• Treatment discontinuation of add-on study drug only (Treatment policy strategy: all observed values of the endpoint are used regardless of whether or not the participant had experienced this intercurrent event)

[0376] Main Analysis Under Estimand 1

[0377] Under Estimand 1 for weight change, the comparison between seltorexant and quetiapine in weight change will be performed using the appropriate contrasts in a MMRM, with main comparison at Week 26. The MMRM will include country, age group (adults (<65 years) and elderly (>65 years)), baseline rumination level (RRS total score <54, >54), time, treatment and treatment by time interaction as factors, and baseline weight as a covariate.

[0378] Sensitivity Analysis Under Estimand 1

[0379] For the weight change, delta adjustment with a tipping point will be conducted as a sensitivity analysis.

[0380] Main Analysis Under Estimand 2

[0381] Under Estimand 2, weight data collected after treatment discontinuation of add-on study drug only are planned to be included in the analyses, and the comparison between treatment groups will be performed using the appropriate contrast based on an analysis of covariance (ANCOVA) model using last observation carried forward (LOCF) data. The model will include factors for treatment, country, age group, baseline RRS group, baseline MADRS group, and baseline weight as a covariate.

[0382] Testing Procedure for Primary and Key Secondary Endpoints

[0383] The overall significance level for the analysis of primary and key secondary endpoints is two-sided 0.05. To control the overall type I error, the primary endpoint (i.e., response rate) analysis will be tested at two-sided 0.05 type I error level; after rejecting the primary null hypothesis, the key secondary endpoint (i.e., weight change) will be tested at a two-sided 0.05 type I error level.

[0384] Analyses for Additional Secondary Endpoints

[0385] Time to potentially treatment-related discontinuation of study drug will be estimated by the Kaplan-Meier method and summarized (number of discontinuations, number of censored participants, median, 25thand 75thpercentile, if estimable) by treatment group. Potentially non-treatment-related study drug discontinuations will be considered as censored. Treatment differences will be compared using a log-rank test. The estimate of the hazard ratio and its 95% confidence interval will be based on the Cox proportional hazards model with treatment as a factor.

[0386] Safety Analyses

[0387] Safety analyses will be based on the safety analysis set, which consists of all participants who were randomly assigned to study drug and received at least 1 dose of study drug.

[0388] Clinical Laboratory Tests

[0389] Laboratory data will be summarized by type of laboratory test and treatment. Reference ranges and markedly abnormal results will be used in the summary of laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time point. A listing of participants with any markedly abnormal laboratory results will be provided.

[0390] Vital Signs

[0391] Descriptive statistics of pulse, sitting blood pressure (systolic and diastolic), and temperature for observed values will be provided and changes from baseline will be summarized at each scheduled time point by treatment. The percentage of participants with values beyond clinically important limits will be summarized. Changes in body weight, BMI, and waist circumference will be summarized descriptively. Body weight will also be analyzed based on the FAS as the key secondary endpoint.

[0392] G. Post-Hoc Analysis

[0393] Analyses were conducted on the 26-week Ph3 differentiation study of seltorexant (20 mg) vs. the standard of care comparator quetiapine XR (150-300 mg) used adjunctively to SSRI / SNRI.

[0394] Weight changes, insulin resistance (HOMA-IR), and insulin levels were analyzed using descriptive statistics. Weight changes were also analyzed using a MMRM.

[0395] In this study, seltorexant showed numerically greater although not statistically superior efficacy compared to quetiapine as measured by the primary endpoint (proportion of responders (>50% improvement in MADRS total score from baseline) at week26).

[0396] Seltorexant showed a distinct advantage over quetiapine XR in the key secondary endpoint, causing less weight gain at week 26 (FIG. 1; nominal p-value <0.001). The results were consistent across subsets of participants with pre-diabetes, diabetes, and obesity at baseline, with the most notable differences in weight gain seen in participants with diabetes and obesity (Table 7). Overall, only 4.4% of seltorexant participants experienced>7% weight gain, compared to 18.3% of quetiapine XR participants.

[0397] Analysis of metabolic parameters in this study revealed significant insulin resistance (HOMA-IR >2.9) at baseline in obese, pre-diabetic, and diabetic patients.

[0398] In this study, seltorexant demonstrated a clinically meaningful improvement in insulin resistance (IR) and insulin levels at week 26, while quetiapine XR resulted in significantly worsened IR and increased insulin levels (Table 8). Seltorexant demonstrated a clinically meaningful effect in reducing IR in participants with high IR at baseline, with no impact on participants with normal or early IR.

[0399] In contrast, quetiapine XR did not have an impact on high IR but resulted in a clinically meaningful increase in IR in participants with normal and early IR at baseline (Table 9).

[0400] Example 4: Summary

[0401] The data of Examples 2 and 3 showed that higher IR is associated with greater cardiometabolic risk and reduction in IR is anticipated to yield cardiometabolic benefits including potentially reducing risk of developing diabetes and cardiovascular diseases. The recognized link between depression, immunometabolic parameters, IR, and overall cardiometabolic risk underscores the potential metabolic benefits of seltorexant as adjunctive therapy in long-term management of MDD.

[0402] Considering the existing adjunctive standard of care options available for MDD patients and the known cardiometabolic side effects of antipsychotics used adjunctively, seltorexant has a significant advantage over existing standard of care options, providing a safer treatment alternative for patients with MDD, especially those who are at higher cardiometabolic risk, with the potential to revert insulin resistance in this population and reduce the cardiovascular risk in a long term.

[0403] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

[0404] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the disclosure and that such changes and modifications can be made without departing from the spirit of the disclosure. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the disclosure.

Claims

What is claimed is:

1. Seltorexant or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder (MDD) and insulin resistance, wherein about 10 to about 20 mg of said seltorexant or pharmaceutically acceptable salt thereof is administered to a patient.

2. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim1, wherein the patient has MDD with insomnia symptoms (MDDIS).

3. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim2, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and / or patient-reported sleep disturbance.

4. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 2 or 3, wherein the patient with MDDIS is identified by the following criteria:(i) a PROMIS-SD-8a T-score of > 54, and(ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

5. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein the insulin resistance is normal or early, prior to administering said seltorexant or pharmaceutically acceptable salt thereof.

6. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 5, wherein the insulin resistance is normal, such as having a Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) value of less than 1.9.

7. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 5, wherein the insulin resistance is early, such as having a HOMA-IR value of 1.9 to 2.9.

8. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 5 to 7, wherein there is no increase in the insulin resistance after administering said seltorexant or pharmaceutically acceptable salt thereof.

9. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 4, wherein the insulin resistance is high prior to administering said seltorexant or pharmaceutically acceptable salt thereof.

10. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 9, wherein the patient has a HOMA-IR value of greater than 2.9.

11. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 9 or 10, wherein the insulin resistance is reduced after administering said seltorexant or pharmaceutically acceptable salt thereof.

12. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 9 to 11, wherein the patient has a baseline insulin level and the insulin level of the patient is reduced after administering said seltorexant or pharmaceutically acceptable salt thereof.

13. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-12, wherein the patient is obese.

14. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 13, wherein the patient has a body mass index (BMI) of over 30.

15. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-14, wherein the patient is pre-diabetic.

16. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 15, wherein the patent has (i) a HbAlc of 5.7% to 6.5%, (ii) a fasting glucose of 5.6 mmol / L to 7.0 mmol / L, (iii) a non-fasting glucose of 7.8 mmol / L to 11.0 mmol / L or (iv) any combinations of (i)-(iii).

17. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-14, where the patient is diabetic.

18. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 17, wherein the patient has (i) a hemoglobin Ale (HbAlc) of 6.5% or greater, (ii) afasting glucose of 7.0 mmol / L, (iii) a non-fasting glucose of 11.1 mmol / L or greater, (iv) a medical history of diabetes, or (v) any combination of (i)-(iv).

19. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-18, wherein seltorexant is administered as a free base.

20. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-18, wherein a hydrochloride salt of seltorexant is administered.

21. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 20, wherein a hydrate of the hydrochloride salt of seltorexant is administered.

22. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered orally.

23. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered once daily.

24. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered prior to sleep.

25. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered at night.

26. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 25, wherein antidepressant effect from said seltorexant or pharmaceutically acceptable salt thereof is maintained when the patient is awake the next day.

27. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof treats a psychic symptom of the depression.

28. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein the patient had an inadequate response to an antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof prior to treatment with said seltorexant or pharmaceutically acceptable salt thereof.

29. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 28, wherein the antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

30. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is adjunctively administered with a second pharmaceutically active agent.

31. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 30, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

32. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein about 20 mg of said seltorexant or pharmaceutically acceptable salt thereof is administered.

33. Seltorexant or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder (MDD) and stabilizing or decreasing body weight of the patient, wherein about 10 to about 20 mg of said seltorexant or pharmaceutically acceptable salt thereof is administered to a patient.

34. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim33, wherein the patient has MDD with insomnia symptoms (MDDIS).

35. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim34, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

36. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 34 or 35, wherein the patient with MDDIS is identified by the following criteria:(i) a PROMIS-SD-8a T-score of > 54, and(ii) either a score of 2 on any of SIGH-D items 3, 4, or 5 or a sum score of 3 or greater for these three items.

37. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 33-36, wherein the patient has been treated with an antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof.

38. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 37, wherein the antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof was a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

39. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 33-38, wherein the patient is pre-diabetic, diabetic, or obese.

40. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim39, wherein the patient is diabetic.

41. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim40, wherein the patient has (i) a hemoglobin Ale (HbAlc) of 6.5% or greater, (ii) a fasting glucose of 7.0 mmol / L, (iii) a non-fasting glucose of 11.1 mmol / L or greater, (iv) a medical history of diabetes, or (v) any combination of (i)-(iv).

42. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 39, wherein the patient is pre-diabetic.

43. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 42, wherein the patent has (i) a HbAlc of 5.7% to 6.5%, (ii) a fasting glucose of 5.6 mmol / L to 7.0 mmol / L, (iii) a non-fasting glucose of 7.8 mmol / L to 11.0 mmol / L or (iv) any combinations of (i)-(iii).

44. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 39, wherein the patient is obese.

45. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 44, wherein the patient has a body mass index (BMI) of over 30.

46. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 33-45, wherein there is a less than 7% weight gain relative to a baseline body weight before administration of said seltorexant or pharmaceutically acceptable salt thereof.

47. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 33-46, wherein seltorexant is administered as a free base.

48. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 33-46, wherein a hydrochloride salt of seltorexant is administered.

49. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 48, wherein a hydrate of the hydrochloride salt of seltorexant is administered.

50. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered orally.

51. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered once daily.

52. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered prior to sleep.

53. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is administered at night.

54. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 53, wherein antidepressant effect from said seltorexant or pharmaceutically acceptable salt thereof is maintained when the patient is awake the next day.

55. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof treats a psychic symptom of the depression.

56. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein the patient had an inadequate response to an antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof prior to treatment with said seltorexant or pharmaceutically acceptable salt thereof.

57. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 56, wherein the antidepressant other than seltorexant or a pharmaceutically acceptable salt thereof is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

58. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein said seltorexant or pharmaceutically acceptable salt thereof is adjunctively administered with a second pharmaceutically active agent.

59. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in claim 58, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

60. Seltorexant or a pharmaceutically acceptable salt thereof for use as claimed in any one of the preceding claims, wherein about 20 mg of said seltorexant or pharmaceutically acceptable salt thereof is administered.

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