Seltorexant for delaying relapse, or maintaining stable response or remission, in a patient having major depressive disorder with insomnia symptoms

Abstract

The disclosure provides methods of delaying relapse, or maintaining stable response or stable remission, in patients with major depressive disorder with insomnia symptoms (MDDIS).

Description

SELTOREXANT FOR DELAYING RELAPSE, OR MAINTAINING STABLE RESPONSE OR REMISSION, IN A PATIENT HAVING MAJOR DEPRESSIVE DISORDER WITH INSOMNIA SYMPTOMSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit to the priority of U.S. Provisional Patent Application No. 63 / 676,775, filed July 29, 2024, the contents of which are incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure provides methods of treating patients with major depressive disorder with insomnia symptoms (MDDIS) or with no or mild insomnia symptoms using seltorexant.BACKGROUND

[0003] Orexins (also known as hypocretins) are neuropeptides expressed by neurons in the perifornical area, the dorsomedial hypothalamus and the lateral hypothalamus (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al, 1998, Cell 92, 573-585). Orexinergic neurons project to many areas of the brain including other hypothalamic nuclei, the midline paraventricular thalamus, brain stem nuclei, the ventral tegmental area and nucleus accumbens shell. (Peyron et al., 1998, J. Neurosci. 18, 9996- 10016) Orexin neuropeptides, classified as either orexin-A or orexin-B, bind to the seven transmembrane G-protein coupled receptors orexin- 1 (OX1R) and orexin-2 (OX2R) (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al, 1998, Cell 92, 573-585). While orexin-A is non-selective for OX1R and OX2R, orexin-B shows higher affinity for OX2R (Sakaurai et al, 1998, Cell 92, 573-585). Orexin receptor antagonists are classified as single orexin receptor (SORAs) or dual receptor antagonists (DORAs).

[0004] Major depressive disorder (MDD) is a common, serious, recurrent mental disorder. MDD is the leading cause of disability, and its prevalence is rising. Current therapies, commonly used as first-line antidepressant treatment in patients with MDD, are sub-optimally effective in some patients who require adjunctive treatment, or who are otherwise poorly compliant because of their associated adverse events (AEs), such as weight gain and sexual side effects. Currently approved treatments are limited to the atypicalantipsychotic drug class, which also present considerable tolerability concerns (e.g., metabolic syndrome, akathisia, and extrapyramidal symptoms).

[0005] Major depressive disorder with moderate to severe insomnia symptoms (MDDIS) also presents as subset of MDD which is difficult to treat. Patients often relapse, thereby requiring immediate intervention. As a result, alternate methods of treating MDDIS patients are needed.SUMMARY

[0006] 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.

[0007] The disclosure provides methods for delaying relapse, or maintaining stable response or stable remission, in a patient having major depressive disorder with insomnia symptoms (MDDIS), wherein the patient is in stable response or stable remission following the administration of about 10 mg to about 20 mg of seltorexant during a treatment phase, comprising thereafter continuing to administer about 10 mg to about 20 mg of seltorexant to the patient during a maintenance phase. The delay in relapse is, for example, relative to a patient that is in stable response or stable remission following the administration of about 10 mg to about 20 mg of seltorexant during the treatment phase, but thereafter discontinues administration of seltorexant.

[0008] In particular embodiments, the disclosure is directed to methods for delaying relapse, or maintaining stable response or stable remission, in a patient having major depressive disorder with insomnia symptoms (MDDIS), wherein the patient is being treated with SSRI and / or SNRI antidepressant therapy, has an inadequate response to the SSRI and / or SNRI antidepressant therapy, and is in stable response or stable remission following adjunctive administration of 20 mg, orally, once daily of seltorexant during a treatment phase, comprising thereafter continuing to administer 20 mg, orally, once daily of seltorexant and the SSRI and / or SNRI antidepressant therapy to the patient during a maintenance phase. The delay in relapse is, for example, relative to a patient that is in stable response or stable remission following the adjunctive administration the SSRI and / or SNRI antidepressant therapy and the 20 mg, orally, once daily of seltorexant during the treatment phase, butthereafter continues the SSRI and / or SNRI antidepressant therapy without seltorexant during a maintenance phase.

[0009] 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.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 a schematic diagram of Part 1. In this figure, seltorexant 20 mg or placebo are given as adjunctive treatment to the participants’ current (background) SSRI / SNRI which is required to be maintained throughout the study. Participants who discontinue from Part 1 or complete Part 1 of the study and elect not to proceed to Part 2 will complete their end-of-treatment and follow-up visit as outlined. Only completers from Part 1 DB can roll over to Part 2.

[0012] FIG. 2 is a schematic diagram of Part 2. In this figure, seltorexant 20 mg or placebo are given as adjunctive treatment to the participants’ current (background) SSRI / SNRI which is required to be taken throughout the study. Only completers from Part 1 DB can roll over to Part 2. Some participants from Part 1 may not be allowed to roll over into Part 2. Cohort 2 consists of participants who enter directly into Part 2 of the study without participating in Part 1. An interim analysis may be conducted to evaluate the following options: (1) stop early due to superiority to placebo (b) continue the study with a re-estimated number of relapses.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTSDefinitions

[0013] In this disclosure, “depression” includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, mid-life depression, late-life depression, depression due to identifiable stressors, treatment resistantdepression, or combinations thereof. In certain embodiments, the depression is major depressive disorder.

[0014] 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 seltorexant’ s effect on sleep related items.

[0015] “Night” includes the period of time from sunset to sunrise, occurring once each twenty-four hours. Night can also refer to evening time. In some embodiments, night refers to a timeframe in a twenty -four period in a day that precedes sleep by a subject.

[0016] “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 symptoms” include 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).

[0017] Some of the quantitative expressions given herein are 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 tosuch 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.

[0018] 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.

[0019] 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 patient is an adult, e.g., 18 to 64 years inclusive. In other embodiments, the patient is an elderly adult of 65 years of age or older. In other embodiments, the patient is a juvenile patient of about 14 years of age to about 17 years of age.

[0020] The term “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. Similarly, the term “bedtime” refers to a timepoint when the patient attempts to fall asleep. In some embodiments, the term “bedtime” includes 30 minutes before the patient attempts to fall asleep. By falling asleep, it is meant that the patient takes active steps to fall asleep (e.g., turning out lights, positioning in a sleeping position (prone or upright), turning off electronic devices, etc.). In certain embodiments, bedtime is at night.

[0021] 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.

[0022] 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 further embodiments, the subject has MDD with insomnia symptoms (MDDIS). 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.

[0023] “Response” as used herein is defined as 50% or greater reduction from the baseline MADRS score at any time point of the treatment. “Stable response” as used herein is defined as 50% or greater reduction in the MADRS total score from baseline (day 1 of the treatment phase) for 3 consecutive biweekly assessments of the treatment phase following the patient having first achieved a substantially complete response during the treatment phase, but does not meet criteria for stable remission. In another embodiment, stable response is a 50% or greater reduction in the MADRS total score from baseline (day 1 of the treatment phase) for 4 consecutive weeks following the patient having first achieved a substantially complete response during the treatment phase, but does not meet criteria for stable remission. The term “substantially complete response” as used herein refers to a patient having a reduction of the MADRS score from baseline of at least a 50%. In certain embodiments, one excursion of a reduction of > 40% from baseline in the MADRS total score will be acceptable, provided that the subsequent MADRS total score confirms the response criteria. In other embodiments, after 6 weeks of steady improvement treatment, an additional 4 weeks improvement or not worsening could establish a stable response.

[0024] “Remission” as used herein is defined as MADRS total score of 10 points or less and a CGI-S score of 2 or less at any time point of the treatment phase. “Stable remission” as used herein is defined as MADRS total score of 10 or less and CGI-S score of 2 or less for at least 4 consecutive weeks following the patient having first achieved a substantially complete response during the treatment phase. In certain embodiments, one excursion from this definition up to the MADRS total score of 12 will be acceptable, provided that the subsequent MADRS total score confirms the remission criteria.

[0025] A “relapse” as used herein includes the appearance of new depressive symptoms or worsening of previously stable or improving MDD symptoms. In some embodiments, relapse is confirmed at least by one MADRS and CGI-S assessment. Other scale assessments should be conducted at the time of relapse, as needed. In some embodiments, a patient has relapsed when the MADRS total score is 22 or greater for 2 consecutive assessments separated by at least 7 days and both assessments showing at least 30% worsening from the MADRS total score reported at the baseline of the maintenance phase. In other embodiments, a patient has relapsed when there is a clinically meaningful worsening response defined as a 2-point or more increase in CGI-S depression score from the baseline of the maintenance phase and a score 4 or more in CGI-S depression. In other embodiments, a patient has relapsed when there is a clinically meaningful increase in suicidal ideation measured with C-SSRS (e.g., a score of 4 or 5 for suicidal ideation). In yet other embodiments, a patient has relapsed if the patient has an actual, aborted, or interrupted suicide attempt. In still further embodiments, a patient has relapsed if the patient is hospitalized for suicide prevention or worsening of depressive symptoms. In other embodiments, a patient has relapsed if the depressive syndrome returns with manifestation of core criterion symptoms and there is a need for alternative antidepressant treatment for this depressive episode as determined by a treating physician. In further embodiments, a patient has relapsed if there are any other clinically relevant events to be suggestive of a relapse of depressive illness.

[0026] 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 a consequence 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.

[0027] 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.

[0028] As used herein, “including,” “containing,” and “comprising” are used herein in their open, non-limiting sense.Compounds

[0029] Seltorexant is an orexin-2 antagonist and may be used in the treatment of depression. Seltorexant, 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, is also known as MIN-202 and JNJ-42847922 and has the chemical structure below:

[0030] 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.

[0031] 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, G.S. Paulekuhn, “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S.M. Berge, “PharmaceuticalSalts”, 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.

[0032] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, 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-l-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.

[0033] 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 other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0034] 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 HCL salt of seltorexant.

[0035] 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

[0036] The disclosure provides methods for delaying relapse, or maintaining stable response or stable remission, in a patient having major depressive disorder with insomnia symptoms (MDDIS), wherein the patient is in stable response or stable remission following the administration of about 10 mg to about 20 mg of seltorexant during a treatment phase, comprising thereafter continuing to administer about 10 mg to about 20 mg of seltorexant to the patient during a maintenance phase. The delay in relapse is, for example, relative to a patient that is in stable response or stable remission following the administration of about 10 mg to about 20 mg of seltorexant during a treatment phase, but thereafter discontinues administration of seltorexant.

[0037] In particular embodiments, the disclosure is directed to methods for delaying relapse, or maintaining stable response or stable remission, in a patient having major depressive disorder with insomnia symptoms (MDDIS), wherein the patient is being treated with SSRI and / or SNRI antidepressant therapy, has an inadequate response to the SSRI and / or SNRI antidepressant therapy, and is in stable response or stable remission following adjunctive administration of 20 mg, orally, once daily of seltorexant during a treatment phase, comprising thereafter continuing to administer 20 mg, orally, once daily of seltorexant and the SSRI and / or SNRI antidepressant therapy to the patient during a maintenance phase. Thedelay in relapse is, for example, relative to a patient that is in stable response or stable remission following the adjunctive administration the SSRI and / or SNRI antidepressant therapy and the 20 mg, orally, once daily of seltorexant during the treatment phase, but thereafter continues the SSRI and / or SNRI antidepressant therapy without seltorexant during a maintenance phase.

[0038] The disclosure provides 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 an orexin-2 receptor antagonist, such as seltorexant. As disclosed herein, such patients can be identified through clinician-reported insomnia symptoms and patient reported sleep disturbances.

[0039] 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.

[0040] 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.

[0041] 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. The PRO (e.g., provided in thePR0MIS-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.

[0042] 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 three insomnia items, referred to as early insomnia, middle insomnia, and late insomnia, each having responses with scores from 0 to 2.

[0043] 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 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 IB. 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 methodsdisclosed herein. In preferred embodiments, the SIGH-D is used as it is deemed more rigorous and structured.

[0044] 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 used interchangeably 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.

[0045] 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).

[0046] In another embodiment of the invention clinical practice health care providers may administer the PROMIS-SD-8a 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.

[0047] Seltorexant is preferably administered once daily. In certain embodiments, seltorexant is administered to the subject prior to sleep. For example, seltorexant is administered within about 2 hours of sleep, within about 1 hour, or within about 30 minutes before sleep. In other embodiments, seltorexant 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 8.5hours, 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, seltorexant is administered at least 6 hours to about 12 hours before the subject wakes or intends to wake from sleep. In preferred embodiments, seltorexant is administered at night.

[0048] 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.

[0049] 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.

[0050] The effective amount of seltorexant may be described without reference to the weight of the subject. In some embodiments, about 20 mg of seltorexant is administered. All dosage amounts mentioned herein, unless otherwise indicated, refers to the free form (i.e., free base or free base equivalent, non-salt or non-hydrate form) of seltorexant. The amounts are recited as free-form equivalents, i.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.

[0051] As noted above, methods of treating depression in a patient are described. The methods include administering seltorexant in one or two phases or more, e.g., a treatment phase and a maintenance phase. In some embodiments, the treatment phase comprises an induction phase and a stabilization phase. Accordingly, an effective amount of seltorexant, e.g., about 10 mg to about 20 mg, preferably 20 mg, is administered in each phase. In still other embodiments, seltorexant is adjunctive treatment to another antidepressant, e.g.,SSRI / SNRI antidepressants, for major depressive disorder during the treatment phase and the maintenance phase.

[0052] In some embodiments, the treatment phase is sufficiently long as to achieve a robust, stable reduction of depressive symptoms. The treatment phase may depend on factors including, without limitation, the particular patient and / or the patient's sex, age, weight, time of administration, administration frequency and concomitant diseases. The totality of the treatment phase may be a period of about 12 to about 16 weeks. In some embodiments, the treatment phase is about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks. In other embodiments, the treatment phase is about 12 to about 15 weeks, about 12 to about 14, about 12 to about 13 weeks, about 13 to about 16 weeks, about 13 to about 15 weeks, about 13 to about 14 weeks, about 14 to about 16 weeks, or about 14 to about 15 weeks. In other embodiments, before entering the treatment phase, certain patients are administered seltorexant for about 4 to about 6 weeks, preferably about 6 weeks. Such patients that tolerate the drug and that show improvement in depressive symptoms and / or no worsening of depressive symptoms, continue to the treatment phase.

[0053] In certain embodiments, the treatment phase comprises an induction phase. In some embodiments, the induction phase is sufficiently long as to achieve a substantially complete response. The induction phase may depend on factors including, without limitation, the particular patient and / or the patient's sex, age, weight, time of administration, administration frequency and concomitant diseases. The totality of the induction phase may be a period of about 4 to about 8 weeks, and typically a minimum of about 4 weeks. In some embodiments, the induction phase is about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks. In other embodiments, the induction phase is about 4 to about 7 weeks, about 4 to about 6 weeks, about 4 to about 5 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 5 to about 6 weeks, about 6 to about 8 weeks, about 6 to about 7 weeks, or about 7 to about 8 weeks.

[0054] After the induction phase, and typically after the patient has achieved a substantially complete response in the induction phase, the treatment phase further comprises a stabilization phase for patients demonstrating a response to seltorexant. In some embodiments, the stabilization phase is sufficiently long for the patient to achieve stable response or stable remission. In certain embodiments, the totality of the stabilization phase is about 4 weeks, and in other embodiments, the totality of the stabilization phase is about 8weeks. For example, the stabilization phase is phase is about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks. It is within the stabilization phase that stable response or stable remission is achieved before the patient continues to a maintenance phase.

[0055] For example, “stable response ” is a 50% or greater reduction in the MADRS total score from baseline (day 1 of the treatment phase) for 3 consecutive biweekly assessments of the stabilization phase, but does not meet criteria for stable remission. In another embodiment, stable response is a 50% or greater reduction in the MADRS total score from baseline (day 1 of the treatment phase) for 4 consecutive weeks of the stabilization phase, but does not meet criteria for stable remission. In certain embodiments, one excursion of a reduction of > 40% from baseline in the MADRS total score will be acceptable during the stabilization phase, provided that the subsequent MADRS total score confirms the response criteria. In other embodiments, after 6 weeks of steady improvement treatment, an additional 4 weeks improvement or not worsening could establish a stable response. “Stable remission” is a MADRS total score of 10 or less and CGI-S score of 2 or less for at least 4 consecutive weeks of the stabilization phase. In certain embodiments, one excursion up to the MADRS total score of 12 will be acceptable during the stabilization phase, provided that the subsequent MADRS total score confirms the remission criteria.

[0056] After the treatment phase (which can include an induction and a stabilization phase), patients who are in stable response or stable remission continue to a maintenance phase of variable duration. The maintenance phase is contemplated to be as long as the patient is receiving a benefit and / or not experiencing a worsening of depressive symptoms. In some embodiments, the maintenance phase will be about 4 weeks to about 52 weeks. In other embodiments, the maintenance phase is at least six months. In other embodiments, the maintenance phase is at least one year.

[0057] It is contemplated that the relapse rate during the maintenance phase for patients that are in stable response or stable remission at the start of the maintenance phase is about 15% to about 27% over a six month period, or over a 6 to 12 month period, or over a 6 to 9 month period, with seltorexant + oral AD, for example, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, or about 27%, compared to about 32% to about 42% over a six month period for patients that continue with oral AD alone during the maintenance phase, including about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about39%, about 40%, about 41%, or about 42%. For example, the relapse rate during the maintenance phase for patients that are in stable response or stable remission at the start of the maintenance phase is contemplated to be about 22% over a six month period with seltorexant + oral AD, compared to about 37% over a six month period for patients that continue with oral AD alone during the maintenance phase.

[0058] When needed and / or at timepoints disclosed herein, the patient’s response is assessed by one skilled in the art. In some embodiments, the patient’s response is assessed daily. In other embodiments, the patient’s response is assessed twice weekly. In further embodiments, the patient’s response is assessed every other day. In yet other embodiments, the patient’s response is assessed at the end of the induction phase. Typically, the patient’s response may be assessed using techniques and tests known to those skilled in the art. In some embodiments, the patient’s MADRS score is determined and used as the determination as to whether the induction phase has concluded.

[0059] In certain embodiments, seltorexant is administered to a human patient for the treatment of MDDIS, where the patient had an inadequate response to other antidepressant therapy (i.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 may be administered with a second pharmaceutically active agent to a human subject for the treatment of 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, or a combination thereof, including the same SSRI and / or SNRI that resulted in the inadequate response

[0060] Subjects have an inadequate response to a treatment when the treatment partially reduces severity of symptoms, but the subject continues to have symptoms. More specifically, an inadequate response may be defined as less than 50% reduction but with some improvement (that is, improvement greater than 0%) in symptom severity. For example, subjects have an inadequate response to a treatment for depression when the treatment partially reduces severity of depression symptoms, but the subject continues to have depression symptoms. Specifically, an inadequate response may be defined as less than 50% reduction but with some improvement (that is, improvement greater than 0%) in depressive symptom severity with residual symptoms other than insomnia present, andoverall good tolerability. The level of response to a treatment may be assessed by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH- ATRQ), which is a self-rated scale used to determine treatment resistance in MDD. A patient’s response may also be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, an inadequate response is measured by MADRS. In other embodiments, inadequate response is defined as < 50% improvement) taken for at least 6 weeks during the current episode as obtained in the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire).

[0061] 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 (HDRS17), Patient Health Questionnaire (PHQ-9),

[0062] As described herein, seltorexant 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.

[0063] 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 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, monirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, 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.

[0064] In those embodiments where the patient had an inadequate response to the second antidepressant, the dose / frequency of administration of the second antidepressant that resulted in the inadequate response is continued in combination with seltorexant. In certain embodiments, the dose of the second antidepressant may be changed during the maintenance phase as disclosed herein. Moreover, it also is desirable to take the second antidepressant at about the same time of day as prior to entering the treatment phase of seltorexant administration. It is preferred that the baseline second antidepressant medication and dose is stable for at least about 6 weeks prior to initiating treatment with seltorexant.

[0065] 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, MDDIS patients with mild to severe depression symptoms may be treated for 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.”

[0066] In certain embodiments, the patient does not have 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). Additionally, in other embodiments, the patent does not have 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. In other embodiments, the patient does not have any significant primary sleep disorder, including but not limited to obstructive sleep apnea, restless leg syndrome, or parasomnias.Compositions

[0067] Seltorexant may be formulated as a pharmaceutical composition to administration to a subject. Accordingly, a pharmaceutical composition may comprise (a) aneffective 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.

[0068] 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. Preferred administration is oral.

[0069] 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.

[0070] 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.

[0071] 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 besilica (SiCh) such as colloidal silica. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl di stearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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

[0077] Aspect 1 : A method of delaying relapse, or maintaining stable response or stable remission, in a patient having major depressive disorder with insomnia symptoms (MDDIS), wherein the patient is in stable response or stable remission following the administration of about 10 mg to about 20 mg of seltorexant during a treatment phase, comprising thereafter continuing to administer about 10 mg to about 20 mg of seltorexant to the patient during a maintenance phase.

[0078] Aspect 2: The method of aspect 1, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

[0079] Aspect 3 : The method of aspect 1 or 2, 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.

[0080] Aspect 4: The method of aspect 3, wherein seltorexant is administered as a free base during the treatment phase and the maintenance phase.

[0081] Aspect 5: The method of aspect 3, wherein a hydrochloride salt of seltorexant is administered during the treatment phase and the maintenance phase.

[0082] Aspect 6: The method of aspect 3, wherein a hydrate of the hydrochloride salt of seltorexant is administered during the treatment phase and the maintenance phase.

[0083] Aspect 7: The method of any one of aspects 1-6, wherein seltorexant is administered orally during the treatment phase and the maintenance phase.

[0084] Aspect 8: The method of any one of aspects 1-7, wherein seltorexant is administered once daily during the treatment phase and the maintenance phase.

[0085] Aspect 9: The method of any of aspects 1-8, wherein seltorexant is administered prior to sleep during the treatment phase and the maintenance phase.

[0086] Aspect 10: The method of any of aspects 1-9, wherein seltorexant is administered at night during the treatment phase and the maintenance phase.

[0087] Aspect 11 : The method of aspect 10, wherein antidepressant effect from seltorexant is maintained when the patient is awake the next day.

[0088] Aspect 12: The method of any one of aspects 1-11, wherein seltorexant treats a psychic symptom of the depression.

[0089] Aspect 13: The method of any of aspects 1-12, wherein the patient had an inadequate response to an antidepressant other than seltorexant prior to the treatment phase.

[0090] Aspect 14: The method of aspect 13, wherein the antidepressant other than seltorexant is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

[0091] Aspect 15: The method of any one of aspects 1-14, wherein seltorexant or a pharmaceutically acceptable salt thereof is adjunctively administered with a second pharmaceutically active agent during the treatment phase and the maintenance phase.

[0092] Aspect 16: The method of aspect 15, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or combination thereof.

[0093] Aspect 17: The method of any one of aspects 1-16 where the treatment phase is about 12 to about 16 weeks.

[0094] Aspect 18: The method of any one of aspects 1-17, wherein the maintenance phase is about 16 to about 52 weeks.

[0095] Aspect 19: The method of any of the aspects 1-17, wherein the maintenance phase is at least about six months.

[0096] Aspect 20: The method of any one of aspects 1-19, wherein about 20 mg of seltorexant is administered to the patient during the treatment phase and the maintenance phase.Examples

[0097] Example 1 : Patient Stratification Approach

[0098] A. Measurement model : Sleep disturbance

[0099] 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 scalewhere 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.

[0100] B. Clinician-reported insomnia symptoms

[0101] 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 the reliance on a single measure, making the overall assessment more robust and helping mitigate the effects of random fluctuations in PRO.

[0102] 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 20 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 IB. 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.

[0103] 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:

[0104] C Patient stratification Criteria

[0105] 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).

[0106] The patient stratification criteria using SIGH-D and PROMIS-SD-8a is shown in Table 3.

[0107] Example 2: Study 42847922MDD3004

[0108] A. Protocol Summary

[0109] The study will investigate 20 mg seltorexant as adjunctive treatment to SSRI / SNRI antidepressants for major depressive disorder (MDD) compared with placebo as adjunctive therapy in patients with a partial response to first line antidepressant therapy.

[0110] PART 1 : The hypothesis for Part 1 of this study is that adjunctive treatment with seltorexant is superior to placebo in treating depressive symptoms, as measured by change in MADRS total score from baseline to Day 43 in adult and elderly participants with major depressive disorder with insomnia symptoms (MDDIS) who have had an inadequate response to treatment with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

[0111] PART 2: The hypothesis for Part 2 of this study is that adjunctive treatment with seltorexant is superior to placebo in maintaining an effect / improvement in depressive symptoms (i.e., delaying relapse of depressive symptoms) after achieving a stable response (including those participants with a stable remission) after open-label (OL) treatment with seltorexant in adult and elderly participants with MDDIS who have had an inadequate response to treatment with an SSRI / SNRI.

[0112] B. Objectives and Endpoints

[0113] The primary and secondary objectives and endpoints are being investigated in participants with MDD who have moderate or severe insomnia symptoms (MDDIS). However, this study also includes participants with no or mild insomnia symptoms. The exploratory objectives of this study evaluate the effect of seltorexant in participants withMDD with no or mild IS, as well as in all participants (full population).

[0114] Additional exploratory objective - Part 1 only: To explore the effect of placebo response prognostic covariate on statistical power using a prognostic score generated from a model to be built and validated in historical clinical trials.

[0115] C Estimands

[0116] (i) PART I

[0117] There are 2 primary estimands defined for the primary efficacy endpoint:

[0118] (a) Estimand 1 :

[0119] Population: participants with MDDIS and an inadequate response to current antidepressant therapy with an SSRI / SNRI, as reflected by the inclusion / exclusion criteria (participants need to meet pre-specified stratification criteria as described in Example 1 for this estimand).

[0120] Endpoint: change in MADRS total score from baseline to Day 43.

[0121] 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 study drug and / or switch of underlying antidepressant (Hypothetical strategy: see above)

[0122] Summary measure: difference in treatment means.

[0123] (b) Estimand 2:

[0124] Population: participants with MDDIS and an inadequate response to current antidepressant therapy with an SSRI / SNRI, as reflected by the inclusion / exclusion criteria.

[0125] Endpoint: change in MADRS total score from baseline to Day 43.

[0126] 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 study drug and / or switch of underlying antidepressant (Hypothetical strategy: as if participants had discontinued treatment instead of switching)

[0127] A supplementary estimand will be defined with the same components as Estimand 2, with the hypothetical strategy being replaced by a treatment policy strategy for the intercurrent event of treatment discontinuation of both underlying antidepressant and addon study drug.

[0128] With the exception of 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.

[0129] Under Estimand 2, MADRS will need to be collected after study drug discontinuation for participants who did not withdraw consent and included in the analyses when the treatment policy strategy is applied.

[0130] (ii) Part 2

[0131] The primary efficacy estimand is defined by the following components:

[0132] Population: participants who are in stable response at the end of the stabilization phase

[0133] Endpoint: time from randomization to the first relapse event during the DB Maintenance Phase.

[0134] Intercurrent events and corresponding strategies:• Treatment discontinuation — Hypothetical Strategy: as if the intercurrent event had not occurred.• Switch of add-on treatment and / or underlying antidepressant - Hypothetical Strategy (as above).

[0135] Summary Measure: hazard ratio (seltorexant relative to placebo). This summary measure is not used for the primary hypothesis testing; log-rank test p-value will be used for the hypothesis testing.

[0136] D. Study Design

[0137] (i) Overall Design

[0138] This is a 2-part (Part 1 and Part 2, respectively) multicenter, multiphase study. Participants in the study will include those with MDD with inadequate response to SSRI / SNRI therapy and with MDDIS, as well as those with non-MDDIS. The MDDIS population will be the population of the primary efficacy analysis and will be defined by meeting the definition and severity of the major depressive episode as per the inclusion / exclusion criteria, as well as having moderate to severe insomnia symptoms defined in a blinded manner according to the stratification factor as described in Example 1.

[0139] (ii) Hypotheses and Study Design

[0140] (a) PART 1

[0141] The hypothesis for Part 1 of this study is that adjunctive treatment with seltorexant is superior to placebo in treating depressive symptoms, as measured by change in MADRS total score from baseline to Day 43 in adult and elderly participants with MDDIS who have had an inadequate response to treatment with a SSRVSNRI.

[0142] This part of the study consists of 3 phases: (a) Screening (up to 30 days), (b) DB treatment of 43 days, (c) a posttreatment FU phase (7-14 days after the DB treatment phase for those participants who do not proceed to Part 2 of the study). Part 1 of the study will be a short-term (6-week) multicenter, DB, randomized, parallel-group, placebo-controlled, study to assess the efficacy and safety of 20 mg seltorexant as adjunctive therapy in adult (18 to 64 years, inclusive) and elderly (65 to 74 years, inclusive) MDDparticipants with MDDIS and with no or mild IS, who have had an inadequate response to current antidepressant therapy (SSRI or SNRI).

[0143] Participants should take their assigned study drug at home, once daily at bedtime during each of the treatment phases. The assigned study drug will be the only augmentation to antidepressant treatment allowed during the study. Participants will continue to take their single baseline SSRI / SNRI antidepressant throughout the study starting at screening and including all the phases of the study (at the same dose, without change, and at approximately the same time of day as prior to entering the study). However, antidepressant treatment may be modified due to an AE during the Follow up phase.

[0144] If a participant will require any change in the dose or type of the background antidepressant, this should occur after completion of Part 1. If a change in the dose or type of antidepressant treatment is required prior to entry into Part 2, the participants impacted need to be re-screened as direct-entry participants in order to enter Part 2.

[0145] Approximately 600 participants with MDD (including approximately 480 participants with MDDIS and approximately 120 participants with non-MDDIS) will be enrolled in Part 1 of this study, to target approximately 466 participants in the full analysis set 1 (FAS1). Part 1 may enroll more than 600 participants to ensure that 480 participants with MDDIS (primary endpoint) are enrolled. Similarly, even if 480 participants with MDDIS are enrolled, recruitment may continue until approximately 600 participants have been enrolled.

[0146] All participants who complete Part 1, irrespective of their response to treatment, who meet eligibility criteria for Part 2, can enter Part 2. In addition, approximately 152 directly enrolled participants with MDD will enter Part 2.

[0147] (b) PART 2

[0148] The hypothesis for Part 2 of this study is that adjunctive treatment with seltorexant is superior to placebo in maintaining an effect / improvement in depressive symptoms (i.e., delaying relapse of depressive symptoms) after achieving a stable response (including those participants with a stable remission) after OL treatment with seltorexant in adult and elderly participants with MDDIS who have had an inadequate response to treatment with an SSRI / SNRI.

[0149] This will use a DB, randomized withdrawal design to assess whether 20 mg seltorexant compared with placebo as adjunctive treatment for MDDIS maintains an effect (improvement) in depressive symptoms (i.e., delays relapse) in adult and elderly participantswho have had an inadequate response to their current antidepressant (SSRI / SNRI) treatment and who have a stable response after OL treatment with 20 mg seltorexant.

[0150] In Part 2 open-label phases (Induction and Stabilization) all participants will receive seltorexant 20 mg in addition to their continuing background SSRI / SNRI treatment. Participants who achieve a stable response to seltorexant treatment will be evaluated for delay in relapse of depressive symptoms compared with placebo in the DB treatment maintenance phase.

[0151] Participants in Part 2 will be recruited from 2 sources:• Eligible completers of the DB Treatment Phase of Part 1 of this study (rollover participants)• Newly enrolled participants who have had an inadequate response to their current antidepressant (SSRI / SNRI) treatment (direct-entry participants).

[0152] Depending on the source of enrollment, Part 2 will consist of 4 Phases (for participants who are rollovers from Part 1) or 5 phases (participants who join Part 2 by direct entry). Part 2 will consist of the following phases:• Screening Phase (up to 30 days, direct-entry participants only; this does not apply to rollovers from Part 1)• OL Treatment Induction Phase (4-8 weeks)• OL Treatment Stabilization Phase (8 weeks)• DB Treatment Maintenance Phase (variable duration, until relapse or until study completion)• Follow-up Phase (7-14 days, after end of treatment)

[0153] Participants who are rolling over from Part 1 will not require additional screening for Part 2. For Part 1 DB completers continuing to Part 2 (i.e., Part 1 rollovers), the Part 1 End of DB visit serves as the baseline visit for the Part 2 OL Induction Phase. Rollover from Part 1 to Part 2 should occur on the same day; however, if needed up to 3 days to continue from Part 1 to Part 2 is allowed.

[0154] During the OL Induction Phase, all participants will receive seltorexant 20 mg once daily at bedtime as well as their background SSRI / SNRI antidepressant. The total length of the Induction Phase is 4-8 weeks. Participants who show response (defined as >50% improvement in MADRS total score from the Part 1 DB baseline for Part 1 rollovers, or from Part 2 OL baseline for Part 2 direct entry participants) after a minimum of 4 weeks of OLtreatment should proceed to the OL Stabilization Phase. The last day of the OL Induction Phase is the same as the first day of the OL Stabilization Phase. If the participant is not a responder by the end of an 8-week period of the OL Induction Phase, then the participant should be discontinued and have an End-of-Treatment / Early Withdrawal visit conducted and proceed to the Follow-up Phase.

[0155] During the OL Stabilization Phase, participants will continue to take seltorexant 20 mg once daily at bedtime as well as their background SSRI / SNRI antidepressant. The total length of the Stabilization Phase is 8 weeks. At the end of the Stabilization Phase, participants with a stable response are eligible to be randomized to the DB Maintenance Phase; all other participants will have an End-of-Treatment / Early Withdrawal visit conducted and proceed to the Follow-up Phase. For participants with a stable response at the end of this phase, the last visit of the OL Stabilization Phase will also serve as the baseline visit of the DB Maintenance Phase (i.e., DB Day 1).

[0156] In the DB Maintenance Phase, stable responder participants will be randomly assigned to receive placebo or seltorexant (20 mg) in a 1 : 1 ratio to be taken in addition to their background SSRI / SNRI. Approximately 325 stable responder participants (including approximately 260 participants with MDDIS and approximately 65 participants with non-MDDIS) are expected to be randomized into the DB Maintenance Phase. The study will be stopped once the required number of relapses in the participants with MDDIS are observed.

[0157] Once the required number of relapses is reached in the Part 2 Maintenance Phase, participants in Part 1 will be able to complete their treatment in the Part 1 DB phase and will do their EOT visit and will be directed to their follow up phase They will not be able to roll over into Part 2. Patients who are ongoing in treatment in Part 2 will proceed to their early withdrawal visit and follow up.

[0158] At the start of the follow-up phase, further clinical / standard of care for the treatment of depression will be arranged.

[0159] (iii) Response, Stable Response, Stable Remission and Relapse Criteria

[0160] (a) Response (Part 2, Induction Phase)

[0161] Response is defined as a > 50% reduction from the baseline MADRS score at any visit during the study. Baseline MADRS scores obtained at Baseline Part 1 (for Part 1participants only) or Baseline Part 2 (for Part 2 direct-entry participants only) will be used to define response status.

[0162] In Part 2 of the study, response to the treatment with seltorexant in the Induction Phase will be assessed by the site MADRS rater as the change vs. Baseline of Part 1 (for completers of Part 1) or Part 2 (for direct entry participants) at Week 5, Week 7 and Week 9 of the Induction phase (Visit 1.5, 1.6 and 1.7). Only participants who meet at least a 50% reduction from baseline in the MADRS total score at any of these visits (i.e., Visit 1.5, 1.6 or 1.7) will proceed to the Stabilization phase at the current visit, i.e., no further Induction phase visits should be completed. If the baseline MADRS score is an odd number, the percentage change in MADRS score corresponding to the 50% response rounded upwards to the next whole number will be acceptable to continue to the next phase of the study.

[0163] (b) Stable response (Part 2, Stabilization Phase)

[0164] Stable response is defined as a >50% reduction in the MADRS total score, as assessed by the site rater, for the last 3 consecutive visits (i.e., Visit 2.2. 2.3 and 2.4 at Week 5, 7 and 9, respectively) of the OL Stabilization Phase. One excursion of a reduction of > 40% from baseline in the MADRS total score will be acceptable at Week 7 (Visit 2.3), provided that the subsequent MADRS total score confirms the response criteria. If the participant missed any scheduled visits, unscheduled visits should be performed to confirm that response criteria were met for the last 3 consecutive visits of the OL Stabilization Phase. Only participants who meet stable response criteria will proceed to the DB Maintenance Phase.

[0165] The rationale for allowing one excursion in the assessment of stable response was done to account for inter- and intra-rater variability, and natural small fluctuations in depressive symptoms during the course of an episode and subsequent symptom improvement.

[0166] (b) Remission

[0167] Remission is defined as MADRS total score of <10 points and CGI-S < 2 at any visit during the study.

[0168] (c) Stable remission

[0169] Stable remission is defined as MADRS total score <10 and CGI-S < 2 for at least 4 consecutive weeks of the OL Stabilization Phase. One excursion from this definition up to the MADRS total score of 12 (at Visit 2.3, Week 7 of the OL Stabilization Phase) willbe acceptable, provided that the subsequent MADRS total score confirms the remission criteria.

[0170] (d) Relapse Criteria

[0171] A relapse manifests as the appearance of new depressive symptoms or worsening of previously stable or improving MDD symptoms. During Part 2, participants who previously achieved stable response and are now experiencing deterioration of depressive symptoms or new suicidal ideations must be assessed at unscheduled visit, preferably within 7 to 14 days, and the relapse should be confirmed at least by one MADRS and CGI-S assessment, where feasible. Other scale assessments should be conducted at the time of relapse, where feasible.

[0172] Relapse criteria will be evaluated in participants who previously achieved stable response in the DB maintenance phase. Occurrence of ANY of the following criteria will constitute a relapse:1. MADRS total score >22 for 2 consecutive assessments separated by at least 7 days and both assessments showing >30% worsening from the MADRS total score reported at the baseline of the DB Maintenance Phase. Participants who present with worsening of insomnia symptoms should manifest other core criterion symptoms of depression to be considered a relapse. The date of the second MADRS assessment will be used for the date of relapse.2. Clinically meaningful worsening response defined as >2-point increase in CGI- S depression score from the baseline of the DB Maintenance Phase and a score >4 in CGI-S depression.3. Clinically meaningful increase in suicidal ideation measured with C-SSRS (score of 4 or 5 for suicidal ideation since the last visit).4. The following events will also be considered to represent a relapse and be used for the date of relapse:• an actual, aborted, or interrupted suicide attempt.• hospitalization for suicide prevention or worsening of depressive symptoms.• the depressive syndrome returns with manifestation of core criterion symptoms and there is a need for alternative antidepressant treatment for this depressive episode.any other clinically relevant event to be suggestive of a relapse of depressive illness.

[0173] If the participant meets other relapse criteria and has not had 2 MADRS assessments done, an unscheduled visit should be planned within 7-14 days. During this visit, the MADRS, CGI-S and C-SSRS will be performed. Participants who meet relapse criteria in the DB maintenance phase will be considered as study completers and will have their End-of- Phase visit, and then enter the Follow-up phase.

[0174] The date of the event suggestive of a relapse of depressive illness will be used if the participant is not hospitalized.

[0175] If several relapse criteria are met, the date of the earliest event will be defined as the date of relapse for a participant.

[0176] (iv) End-of-Treatment / Early Withdrawal Visit and Follow-up Phase

[0177] Participants who complete Part 1 but do not wish to continue to Part 2 and participants who discontinue in the Induction or Stabilization phase of the study should have the End-of-Treatment / Early Withdrawal visit, preferably the day after the last dose. Every effort should be made to complete End-of-Treatment / Early Withdrawal visit as soon as possible after last dose of study drug. After completion of this visit, the participants will enter the Follow-up Phase where participants who had received at least 1 dose of the study drug and did not withdraw consent will have further assessments during FU. During the Follow up Phase, there will be a phone call the day after the End-of-Treatment / Early Withdrawal visit to assess for any clinical change in stopping the study drug and a visit 7-14 days after the End-of-Treatment / Early Withdrawal visit. For participants who have completed the study (either at the end of Part 2 or Part 1 completers not proceeding to Part 2), this Follow-up visit is the last visit.

[0178] All participants who discontinue study drug in Part 1, 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.

[0179] Participants who discontinue early from the Part 2 DB Maintenance Phase may continue with additional follow-up visits every 4 weeks until relapse or study termination, whichever occurs first. Relapse data should be collected during this period. Anunscheduled visit should be performed 7-14 days after an initial MADRS total score >22 to assess for relapse.

[0180] At the start of the follow-up phase, further clinical / standard of care for the treatment of depression will be arranged.

[0181] (v) Operationalization of the Transition from Part 1 to Part 2 of the Study

[0182] Upon completion of the DB treatment phase in Part 1 of the study, participants will have the opportunity to either rollover over into Part 2 or complete the trial at the end of Part 1. Participants ideally should enroll into Part 2 immediately; however, if this is not possible, they have up to 2 weeks to enroll into Part 2.

[0183] In addition, participants completing Part 1 must meet all of the inclusion criteria.

[0184] Participants who meet eligibility criteria to roll over to Part 2 as described must be willing to continue in the trial.

[0185] Participants rolling over from Part 1 to Part 2 of the trial will keep their same participant number as that assigned in Part 1.

[0186] A diagram of the study design is provided in FIG. 1.

[0187] (vi) Ending Study Participation Once the Required Number of Relapses have Occurred in Part 2

[0188] Participants Still in Part 1

[0189] Any participant still in Part 1 of the trial when the required number of relapses is reached by participants in Part 2 will continue in Part 1 of the study. In addition, the required number of participants for Part 1 must be achieved even if Part 2 has ended (i.e., when the required number of relapses have occurred). Participants upon completing DB treatment in Part 1 will have their end-of-treatment visit and will then proceed to the FU phase. These participants will not be allowed to roll over into Part 2 of the study.

[0190] Direct Entry Participants to Part 2

[0191] Direct entry participants who may be in the screening phase when the required number of relapses is reached by participants in Part 2 will be screen failed and will not proceed to the 4 to 8-week OL treatment induction phase.

[0192] Participants in Part 2

[0193] Participants who are in the OL induction phase, the OL treatment stabilization phase, the DB treatment maintenance phase will be discontinued, have an End- of-Treatment / Early Withdrawal visit conducted, then proceed to the FU Phase.

[0194] (vii) Scales to Assess MDD Diagnosis and Severity

[0195] MMSE (screening only): The Mini Mental State Examination (MMSE) test is a 30-item questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for dementia. The test is divided into 2 sections: the first section requires vocal responses and covers orientation, memory, and attention. The second section tests the ability to name, follow verbal and written commands, write a sentence spontaneously, and copy a complex polygon similar to a Bender-Gestalt Figure. The score ranges from 0 (minimum score) to 30 (maximum score) and it is calculated by the sum of the subitems scored 0 (incorrect answer) or 1 (correct answer).

[0196] MGH-ATRQ (Screening Only): The Massachusetts General Hospital- Antidepressant Treatment Response Questionnaire (MGH-ATRQ) is used to determine treatment response and resistance in MDD. The MGH-ATRQ evaluates the adequacy of duration and dose of all antidepressant medications used in the current MDE. The MGH- ATRQ will be completed by the clinician in collaboration with the participant to confirm the number of antidepressant treatment failures in the current MDE.

[0197] SCID-CT (screening only): The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide for making DSM-5 psychiatric diagnoses. It is administered by a clinician or trained rater who is familiar with the DSM-5 classification and diagnostic criteria as well as clinical diagnostics. In this study the insomnia disorder module of the SCID-CT will be included as a separate supplement.

[0198] SIGH-D (Screening only): The Structured Interview Guide (SIGH-D; Williams, 1988) of the 17-item Hamilton Depression Rating Scale (HRSDn) is among the most widely used and validated standardized clinician-administered depression assessment scales. It contains 17 items pertaining to symptoms of depression experienced over the past week. This assessment is used only during screening to validate the inclusion criterion of moderate-to-severe current depressive symptoms.

[0199] (viii) Efficacy Measures

[0200] (a) Primary Efficacy Measure

[0201] MADRS: The 10-item Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS scale is a validated, reliable scale and acceptable to regulatory health authorities as a primary scale to determine efficacy in major depression.

[0202] (b) Secondary / Exploratory Efficacy Measures

[0203] PROMIS-SD (Short Forms 4a, 8a, and 10a): The Patient-Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD) captures selfreported, qualitative health aspects in the domains of physical, mental, and social health. This measure has been developed using state of the art psychometric techniques such as Item Response Theory Models, and the PROMIS-SD has been shown to adequately represent sleep disturbance. This measure provides high total test information with high validity and reliability. Three short form versions of PROMIS-SD will be used in this study. These include the 4-item short form (4a), 8-item short form (8a), and a 10-item custom short form which includes the 8a items plus 2 additional items from the IRT-calibrated PROMIS-SD item bank. The 4a is a subset from the 8a and will be calculated from items completed on the more comprehensive form 8a.

[0204] MADRS-6 and MADRS-WOSI: The 6-item MADRS-6 is a clinician- administered scale designed to measure the core symptoms of depression severity and detects changes due to antidepressant treatment. It is a subset of the 10-item MADRS, as is the 9- item MADRS without the sleep item [MADRS-WOSI], which will also be utilized as a secondary / expl oratory efficacy measure.

[0205] PHQ-9: The Patient Health Questionnaire-9 (PHQ-9) is a 9-item patient- reported outcome measure to assess severity and impact of depressive symptoms.

[0206] SDS: The 5-item Sheehan Disability Scale (SDS), a patient-reported outcome measure, has been widely used and accepted for assessment of functional impairment and associated disability.

[0207] EQ-5D-5L: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS).

[0208] CGI-S: The single-item Clinical Global Impress! ons-Severity (CGI-S) provides an overall clinician-determined summary measure of the severity of the participant’sillness (i.e., depression) that considers all available information, including knowledge of the participant’s history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant’s ability to function.

[0209] PGI-C (depression): The Patient Global Impression of Change (PGI-C) for depression is a single patient-reported item that captures participants’ perceptions of improvement or deterioration in depression symptoms compared to when they started the study. The PGI-C (depression) item is:• Compared to when you started this study, how are your depression symptoms? Select one response. (Much better - Somewhat better - A little better - About the same - A little worse - Somewhat worse - Much worse)

[0210] PGI-S (insomnia symptoms): The Patient Global Impression of Severity for Insomnia Symptoms (PGI-S) are 3 patient-reported items that capture participants’ perceived severity of their insomnia symptoms over the past 7 days. The PGI-S (insomnia symptoms) items are:• In the past 7 days, how would you describe your difficulty falling asleep or staying asleep? (No difficulty falling asleep or staying asleep - Mild - Moderate - Severe - Very Severe)• Thinking about the past 7 days, please choose the response below that best describes the problem of not feeling rested the next day. (I did not have this problem - Mild - Moderate - Severe - Very Severe)• In the past 7 days, how would you describe your sleep problems? (No sleep problems - Mild - Moderate - Severe - Very severe)

[0211] PGI-C (insomnia symptoms): The Patient Global Impression of Change (PGI-C) for insomnia symptoms are three patient-reported item that capture participants’ perceptions of improvement or deterioration in insomnia symptoms or sleep disturbances compared to when they started the study. The PGI-C (insomnia symptoms) items are:• Compared to when you started this study, how would you describe your difficulty falling asleep or staying asleep? (Much better - Somewhat better - A little better - About the same - A little worse - Somewhat worse - Much worse)• Compared to when you started this study, how would you describe your experience of not feeling rested the next day? (Much better - Somewhatbetter - A little better - About the same - A little worse - Somewhat worse - Much worse)• Compared to when you started this study, how would you describe your sleep problems? (Much better - Somewhat better - A little better - About the same - A little worse - Somewhat worse - Much worse)

[0212] CSD: For the Consensus Sleep Diary (CSD) participants will be asked to provide answers to questions to determine their subjective experience of sleep. The CSD is the only sleep diary developed with rigorous methodology for patient-reported outcome development, including employing user / focus group feedback and expert feedback to establish construct validity. It has undergone psychometric testing, and its content validity has been confirmed by patient focus groups.

[0213] ISI: The ISI is a validated 7-item questionnaire assessing the nature, severity, and impact of insomnia. The clinician and patient-reported versions will be used in this study. Evaluation of sleep in this study is important as insomnia and other sleep problems are common in MDD and may contribute to the persistence of a depressive episode or may be a residual symptom of a current depressive episode, despite other symptoms of depression having responded to treatment.

[0214] (ix) Safety Evaluations

[0215] Standard safety evaluations including collection of AEs and concomitant medications, physical examination, body weight, ASEX, 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 participants of childbearing potential. Additional serum and urine pregnancy tests may be conducted.

[0216] Emergence of suicidal ideation will be assessed using the C-SSRS. The C- SSRS has been used frequently in clinical studies and it is a standard measure for suicidal ideation assessment; its use is in accordance with Food and Drug Administration (FDA) guidance.

[0217] In addition, potential withdrawal effects will be assessed by the clinician using the 20-item physician’s withdrawal checklist (PWC-20). The PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms.

[0218] (x) End of Study Definition

[0219] For Part 1, a participant will be considered to have completed the Part 1 DB treatment phase if they have completed the Day 43 visit of the DB treatment phase and have not discontinued study drug early during DB phase. A Part 1 participant will be considered to have completed the Part 1 follow-up phase if they have completed assessments at Follow-up visit 7-14 days after the EOT visit.

[0220] Part 2 of this study will be terminated after the required number of relapse events are obtained (target number, re-estimated event number depending on IA results, or earlier based on the results of the IA for efficacy).

[0221] For Part 2, completers are participants who are in the DB Maintenance Phase when the study is terminated and participants who have relapsed during the DB Maintenance Phase.

[0222] Participants who prematurely discontinue study drug in the DB Maintenance Phase for any reason other than a relapse or study termination will not be considered to have completed the study. Any Part 2 ongoing participant not in DB Maintenance Phase when the study is completed / terminated will be considered as a non-compl eter / EW .

[0223] The end of study is considered as the last study assessment for the last participant in the study.

[0224] E. Study Population

[0225] Screening for eligible participants will be typically performed within 30 days before administration of the study drug.

[0226] (i) Inclusion Criteria

[0227] Any potential participant who meets any of the following criteria will be included in the study.

[0228] (a) Participants in Part 1 and Direct Enrollers to Part 21. Participants aged 18 to 74 years (inclusive).Participants should be at least 18 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 based upon clinical assessment and confirmed by the SCID-CT diagnosed with first depressive episode prior to age 60.Have had an inadequate response to at least 1 but no more than 2 antidepressants, administered at an adequate dose and duration started 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, 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 at or above the minimum therapeutic dose specified in the MGH-ATRQ, and this 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 at least 2 prior antidepressant 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 8. Is receiving and tolerating well any one of the following SSRI or SNRI for depressive symptoms at screening, in any formulation and approved 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.The SSRI or SNRI need 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. Having a major depressive episode of at least moderate severity, as assessed with SIGH-D in a blinded manner at screening and must not demonstrate a clinically significant improvement from the beginning to end of screening. The assessment of depressive symptoms severity and their change over the screening period will be done by the centralized rater in a blinded manner. Body mass index (BMI) between 18 and 40 kg / m2, inclusive (BMI=weight / height2). Must be an outpatient at screening. Participant must be medically stable, based on 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. If there are anyabnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined. Participant must be medically stable based on 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 to be not clinically significant or to be appropriate and reasonable for the population under study. A participant of childbearing potential must have a negative highly sensitive serum P- HCG pregnancy test result at screening and negative urine pregnancy test result before the first treatment. Contraceptive use should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies.Before entering the study, a participant must be either: a. Not of childbearing potential, defined as: o PostmenopausalA postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In participants 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 participants 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 participants who are >40 years old and have amenorrhea for >12 months, FSH is not required. o Secondary amenorrhea due to permanent absence of reproductive potential. In such cases, no FSH testing is required. See, following, e.g. : o Has undergone a surgical procedure that precludes reproductive potential, including but not limited to a hysterectomy, or bilateral salpingectomy, or bilateral oophorectomy, or bilateral orchidectomy.• Participants presenting with secondary amenorrhea for at least 6 months (e.g., due to hypothalamic amenorrhea or hormonal imbalances because of conditions like polycystic ovarian syndrome or hypothyroidism) will be evaluated on a case-by-casebasis, after confirmation by a participant’s health care provider and discussion with the medical monitor.• b. Of childbearing potential and o 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); bilateral tubal ligation / occlusion; vasectomized partner.- User-dependent methods: 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 periodically evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant).Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, injectable, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable.Typical 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. o 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 participant of childbearing potential becomes sexually active with a partner where pregnancy can occur) the participant and / or their partner must begin a highly effective method of contraception, as described throughout theinclusion criteria. If reproductive status is questionable, additional evaluation should be considered.• The requirements for contraception as specified under this exclusion criterion, are not optional.12. A participant must agree not to donate gametes (ova, oocytes) 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.13. 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 participant who is capable of producing sperm and: a. is sexually active with a person of childbearing potential must agree to use a barrier method of contraception (e.g., condom with spermicidal foam / gel / film / cream / suppository) and their partner must use a highly effective method of contraception. b. is sexually active with a person who is pregnant must use a condom. c. Must agree not to donate sperm.

[0229] (b) Participants in Part 2

[0230] Participants Entering After Completing Part 1 (i.e., Rollover Participants)

[0231] Participant in this part of the study must meet all of the following criteria:15. Must have completed Part 1 DB treatment phase16. Can consistently tolerate study drug (at the end of Part 1), and there is no additional safety risk for the participant if they proceed to Part 2).17 Was able to consistently follow the study procedures in Part 1.18. Must be medically stable based on clinical laboratory tests. Laboratory abnormalities and AEs identified in Part 1 should be reviewed prior to entering Part 2.

[0232] Participants Directly Entering Part 2 (i.e., Direct Enrollers)

[0233] Participants who directly enter Part 2 without participating in Part 1 (i.e., direct enrollers) will need to meet all Inclusion criteria and not meet any exclusion criteria from Part 1 to be able to participate in Part 2.

[0234] (ii) Exclusion Criteria

[0235] (a) Participants in Part 1 and Part 2 Direct Enrollers

[0236] Any potential participant who meets any of the following criteria will be excluded from participating:1. Has a recent (last 3 months) history of, or current signs and symptoms of, severe renal insufficiency (creatinine clearance <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 [HbAlc] <8.5% and fasting glucose <150 mg / dL at screening) may be eligible to participate if otherwise medically healthy, and if on a stable regimen of glucose-lowering therapy (e.g., diet, lifestyle or medication), remaining on a stable regimen for at least 2 months prior to screening. One retest for fasting plasma glucose and / or HbAlc is permitted.2. Has a history of narcolepsy and seizures (except childhood seizures).3. Has clinically significant hepatic disease as defined by:>2x Upper Limit of Normal [ULN]) increase of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin > 2 x ULN at screening (one retest is permitted) significant liver disease including cirrhosis, ascites, active hepatitis etc. (fatty liver disease will be allowed if it meets first criteria).4. 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 thyroid-stimulating hormone (TSH) value out of range and not exceeding 2 x ULN, a free thyroxine (FT4) test will be conducted. If the FT4 value is abnormal and considered to be clinically significant (after discussion with the study responsible physician / scientist or designee) 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.5. Participants taking thyroid supplementation for antidepressant purposes.6. 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 clinically significant 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 a prior suicide attempt of any sort, or prior serious suicidal ideation / plan within the past 6 months, should be carefully screened for current suicidal ideation. 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 taken a strong inhibitor or a 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 CYP3 A4 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 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. 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 sleep disorder, including but not limited tountreated / uncontrolled obstructive sleep apnea, restless leg syndrome, or parasomnias. Participants with insomnia disorder or well-controlled obstructive sleep apnea 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. 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-Methylenedioxymethamphetamine [MDMA]) at screening or baseline. 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 that may jeopardize the participant’s safety or the integrity of the study, defined as:During screening and / or Day 1, a QT interval corrected according to Fridericia’s formula (QTcF): >450 msec (male assigned sex at birth); >470 msec (female assigned sex at birth)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 those assigned male at birth and >470 msec for those assigned female at birth:Evidence of 2ndand 3rddegree atrioventricular block.Features of new ischemiaOther clinically important arrhythmia or cardiac abnormalities Has within the last 5 years received any prior antidepressant treatment withelectroconvulsive therapy, vagal nerve stimulation, or a deep brain stimulation device. Use of ketamine / esketamine in the current depressive episode (up to 2 doses are allowed). Recently started 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 known allergies, hypersensitivity, intolerance, or any contraindication to seltorexant or its excipients. Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an equivalent amount of blood within 30 days before the first dose of study drug. Has cognitive impairment that would render the informed consent invalid or limit the ability of the participant to comply with the study requirements. Participant has neurodegenerative disorder (e.g., Alzheimer’s disease, vascular dementia, Parkinson’s disease with clinical evidence of cognitive impairment) or evidence of mild cognitive impairment (MCI). Participants of age >65 years: has a MMSE <25 or <23 for those participants with less than high school equivalent education. Has any condition for which participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Has taken any disallowed therapies, Prior and Concomitant Therapy For those of childbearing potential: Is pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or within 1 month after the last dose of study drug. For those capable of producing sperm: Plans to conceive a child while enrolled in this study or within 3 months after the last dose of study drug. Has had major surgery, (e.g., requiring general anesthesia) within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.Participants with planned surgical procedures to be conducted under local anesthesia may participate.

[0237] The participants’ final eligibility will be based in part on an assessment of their SIGH-D depressive symptom severity score evaluated by using a blinded algorithm (blinded to the site and to the centralized rater) prior to Day 1.

[0238] General principles of the pre-defined algorithm are:• Exclusion of participants with depression symptom scores of mild severity, below the blinded SIGH-D cut-off;• Exclusion of participants who significantly improved on depressive symptoms during the screening period.

[0239] (iii) Lifestyle Considerations

[0240] Potential participants are recommended to follow the following lifestyle restrictions during the study to be eligible for participation:1. The use of limited amounts of alcohol,Participants whose sex assigned at birth is male: up to 2 drinks daily on average over a week (2 glasses wine [12%, 5 fluid ounces {148 mL) each], 2 regular beers [5%, 12 fluid ounces {355 mL} each], or 2 shots liquor [40%, 1.5 ounces {44 mL} each]), will be allowed during the study.Participants whose sex assigned at birth is female, and elderly: up to 1 drink daily on average over a week (1 glass wine [12%, 5 fluid ounces {148 mL}], 1 regular beer [5%, 12 fluid ounces {355 mL}], or 1 shot liquor [40%, 1.5 ounces {44 mL}]), will be allowed during the study.Alcohol should not be consumed on the day of a study visit prior to assessments.2. Participants will be advised not to donate blood during the study.3. Participants should be cautioned not to drive a car or operate machinery or engage in any potentially hazardous activities if they have had insufficient sleep following administration of the study drug or at any time during the study if the participant feels that their baseline competency is impaired, such as feeling sedated.

[0241] F. Study Intervention and Concomitant Therapy

[0242] (i) Study Intervention(s) Administered

[0243] This study is planned to investigate a seltorexant dose of 20 mg as an adjunctive treatment for MDDIS.

[0244] In Part 1 (6-Week DB treatment) and in Part 2, during the DB Maintenance Phase, seltorexant will be supplied as tablets of 20 mg. Placebo will be supplied as matching tablets. For Part 2, during the OL Induction and Stabilization Phases, OL 20-mg seltorexant tablets will be provided.

[0245] All participants should take their assigned study drug once daily at bedtime with or without meal.

[0246] The tablets must be swallowed whole with water and not chewed, divided, dissolved or crushed.

[0247] 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.

[0248] Study drug will be supplied in containers identified by a number. Study-site personnel will instruct participants on how to store study drug for at-home use.

[0249] (ii) SSRI / SNRI Antidepressant Administration

[0250] The baseline SSRI / SNRI antidepressant medication and dose needs to be stable for at least 6 weeks prior to the first screening visit. Participants will continue to take their baseline SSRI / SNRI antidepressant preferably at the same dose, without change, every day at approximately the same time as prior to entering the study throughout the study starting at screening and including the Follow-up Phase. Participants need to remain on one of the listed SSRI / SNRI antidepressants throughout the study. Lack of adherence to the SSRI / SNRI may be a cause for screen failure or study drug discontinuation.

[0251] However, the dose of the antidepressant may be changed during the Part 2 DB Maintenance Phase (not during screening) due to tolerability concerns.

[0252] (iii) Description of Interventions

[0253] Eligible participants in the study will continue to take the same background SSRI / SNRI used most recently. For the Part 1 DB treatment phase and the Part 2 DB Maintenance Phase, participants will be randomized in a 1 :1 ratio to receive either 20-mg seltorexant or placebo as summarized in the Table 6.

[0254] (iv) Prior and Concomitant Therapy

[0255] When possible, all sleep medication should be stopped within 21 days after signing the ICF (including sedative-hypnotics from the benzodiazepine, non-benzodiazepine and antihistamine classes). Rebound effects of stopping prestudy sleep medication and / or benzodiazepine may be remediated by tapering the medication. It should be considered if 30 days is sufficient for the discontinuation of the hypnotic / sedating medications as for chronic or high-dose benzodiazepine use a prolonged taper may be more appropriate, for which the participant should be referred to their primary care physician for clinical management and excluded from participation in this study. Screening can be extended for up to 14 days for down titration and discontinuation of prohibited medications, e.g., benzodiazapines, after discussion with the medical monitor.

[0256] Participants should continue to take their baseline SSRI / SNRI antidepressant throughout the entire study.

[0257] The dose of the baseline SSRI / SNRI antidepressant may be changed during the DB Maintenance Phase and should not be adjusted to prevent relapse.

[0258] If clinically indicated, disallowed medications may be started after the End of-Phase / Early Withdrawal visit to treat symptoms related to an AE or breakthrough MDD and / or insomnia symptoms prior to the first follow-up visit. Disallowed medication may also be used for participants who discontinue early from any phase of the study, during the extended follow-up period (after the first follow-up visit).

[0259] For safety reasons, the use of hypnotic drugs or some food supplements (see the following list of prohibited medication or food supplements) is prohibited from screening until the last study visit except for limited use as described below. Seltorexant has hypnotic properties and potential pharmacodynamics (PD) interactions with other hypnotic drugs have not been investigated.

[0260] Participants must not use the following medication or food supplements, during the study:1. Monoamine oxidase inhibitors within 4 weeks before screening until the Follow-up visit.2. Antipsychotic drugs from at least 14 days prior to Day 1 until the Follow-up visit.3. Benzodiazepines, buspirone, non-benzodiazepine hypnotics (e g., zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant and ramelteon), sedating antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin from at least 7 days prior to Day 1 until the Follow-up visit. Sleep medication should be tapered off to prevent rebound insomnia.Zolpidem (up to 10 mg / d or similar GABAergic hypnotic) may be used only during screening, and up to 2 times during between Day -7 and Day -2 as a rescue medication for insomnia. It should not be used on the day of or the day prior the second screening central ratings assessments including the patient ISI or Baseline / Day 1Limited use of benzodiazepine (up to lorazepam equivalent of 2 mg / d) and / or zolpidem (up to 10 mg / d or similar GABAergic hypnotic) is permitted for the treatment of insomnia or anxiety up to 2 doses per week in Part 1 and Part 2, with the exception of the last week (Week 6) of the DB treatment phase of Part 1 and Week 8 of the OL stabilization phase of Part 2.4. Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion,tricyclic antidepressants, agomelatine, and S-adenosyl methionine [SAMe]) from at least 7 days prior to Day 1 until the Follow-up visit.5. Opiates, and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days prior to Day 1 until the Follow-up visit (use of dextromethorphan and codeine preparations for up to 7 days per study phase, for cough or respiratory tract infection will be permitted).6. Stimulants (e g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine), and isoxsuprine from at least 7 days before Day 1 until the Follow-up visit. However, a short -term (up to 7 days) IM / IV / PO use of corticosteroids is permitted (chronic use prohibited).7. A known strong inhibitor 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 until the follow-up visit.8. Magnetic and electrical stimulation therapies, including electroconvulsive therapy, vagal nerve stimulation, deep brain stimulations, transcranial magnetic stimulation (TMS) of any type, or direct current stimulation (DCS), from screening to the end of study visit. Transcranial magnetic stimulation or direct current stimulation prior to screening is not exclusionary.9. Use of ketamine / esketamine in the current depressive episode.10. Other investigational drugs 3 months prior to and during the study.11. St. John’s wort, ephedra, 5-hydroxytryptophan, ashwagandha, Chinese herbal medications known to affect CYP3A4 or CYP2C9, ginkgo, ginseng, or kava from at least 7 days before Day 1 until the Follow-up visit.

[0261] Anticonvulsants may be permitted if they are used for any pain conditions, at a dose appropriate for the participant population and treated condition, and at a stable dose for at least 2 months before screening. Inclusion of such participants should be carefully evaluated for potential additive sedative effects.

[0262] As described in the exclusion criteria for Part 1 and Part 2 direct-entry participants, psychotherapy cannot be started during screening or during the study conduct. Ongoing psychotherapy may continue if it was started more than 6 weeks prior to the beginning of the screening period.

[0263] G. Study Assessments and Procedures

[0264] (i) Physician Withdrawal Checklist

[0265] Potential withdrawal effects will be assessed by the Physician Withdrawal Checklist (PWC). The 20 item PWC (PWC-20) is a simple and accurate method used to assess potential withdrawal symptoms following cessation of treatment. The PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms.

[0266] (ii) Columbia Suicide Severity Rating Scale (C-SSRS)

[0267] Emergence of potential suicidal ideation will be assessed using the C-SSRS at screening, and at all subsequent study visits. The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both suicidal ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS has been used frequently in clinical studies, and is a validated, standard measure for suicidal ideation assessment.

[0268] Two versions of the C-SSRS will be used in this study, the Screening / Baseline version, and the Since Last Visit version. The Baseline / Screening version of the C-SSRS will be used at the screening visit In this version, suicidal ideation will be assessed at 2 time points (“lifetime” and “in the past 6 months”) and suicidal behavior will be assessed at 2 time points (“lifetime” and “in the past year”). All subsequent C-SSRS assessments in this study will use the Since Last Visit version, which will assess suicidal ideation and behavior since the participant’s last study visit.

[0269] (iii) Arizona Sexual Experiences Scale (ASEX)

[0270] The ASEX is a patient-reported 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication / penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. The scale has shown satisfactory reliability and validity

[0271] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

[0272] 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. Itis, 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 for use in delaying relapse, or maintaining stable response or stable remission, in a patient having major depressive disorder with insomnia symptoms (MDDIS), wherein the patient is in stable response or stable remission following the administration of about 10 mg to about 20 mg of seltorexant during a treatment phase, comprising thereafter continuing to administer about 10 mg to about 20 mg of seltorexant to the patient during a maintenance phase.

2. Seltorexant for use of claim 1, wherein the patient with MDDIS is identified by clinician-reported insomnia symptoms and patient-reported sleep disturbance.

3. Seltorexant for use of claim 1 or 2, 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.

4. Seltorexant for use of any one of claims 1-3, wherein seltorexant is administered as a free base during the treatment phase and the maintenance phase.

5. Seltorexant for use of any one of claims 1-3, wherein seltorexant is administered as a hydrochloride salt during the treatment phase and the maintenance phase.

6. Seltorexant for use of any one of claims 1-3, wherein seltorexant is administered as a hydrate of the hydrochloride salt during the treatment phase and the maintenance phase.

7. Seltorexant for use of any one of claims 1-6, wherein seltorexant is administered orally during the treatment phase and the maintenance phase.

8. Seltorexant for use of any one of claims 1-7, wherein seltorexant is administered once daily during the treatment phase and the maintenance phase.

9. Seltorexant for use of any one of claims 1-8, wherein seltorexant is administered prior to sleep during the treatment phase and the maintenance phase.

10. Seltorexant for use of any one of claims 1-9, wherein seltorexant is administered at night during the treatment phase and the maintenance phase.

11. Seltorexant for use of claim 10, wherein antidepressant effect from seltorexant is maintained when the patient is awake the next day.

12. Seltorexant for use of any one of claims 1-11, wherein seltorexant treats a psychic symptom of the depression.

13. Seltorexant for use of any one of claims 1-12, wherein the patient had an inadequate response to an antidepressant other than seltorexant prior to the treatment phase.

14. Seltorexant for use of claim 13, wherein the antidepressant other than seltorexant is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or a combination thereof.

15. Seltorexant for use of any one of claims 1-14, wherein seltorexant is adjunctively administered with a second pharmaceutically active agent during the treatment phase and the maintenance phase.

16. Seltorexant for use of claim 15, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or a combination thereof.

17. Seltorexant for use of any one of claims 1-16, wherein the treatment phase is about 12 to about 16 weeks.

18. Seltorexant for use of any one of claims 1-17, wherein the maintenance phase is about 16 to about 52 weeks.

19. Seltorexant for use of any one of claims 1-18, wherein the maintenance phase is at least about six months.

20. Seltorexant for use of any one of claims 1-19, wherein about 20 mg of seltorexant is administered to the patient during the treatment phase and the maintenance phase.

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