Treatment methods for depressive disorders and patient selection for agomelatine based on EEG measurements

Abstract

The present invention relates to the use of agomelatine (or its prodrugs or salts) in the treatment of major depressive disorder or bipolar disorder, including the selection of patients who would benefit most from agomelatine.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 518,742, filed Aug. 10, 2023, which is incorporated by reference.

[0002] The present invention relates to the use of agomelatine (or its prodrug or salt) in the treatment of major depressive disorder or bipolar disorder, including the selection of patients who would most benefit from agomelatine.

Background Art

[0003] Clinical care for depression is assessed and diagnosed based on a range of symptoms assessed by the clinician and reported by the patient, including depressed mood, anhedonia, changes in appetite, and changes in sleep and psychomotor function, but not on any biological or quantitative behavioral variables. When assessments such as magnetic resonance imaging (MRI) scans or blood tests are performed, this is to rule out non-psychiatric causes of depression that may require treatment other than antidepressants, including causes such as hypothyroidism, dementia, or metabolic disorders. After a patient is diagnosed with depression, the clinician may prescribe one of several antidepressant treatments, mainly selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), or atypical antidepressants. However, it should be noted that the selection of antidepressants is purely trial and error, and there are no biological or quantitative behavioral indicators that can help in drug selection. Typically, SSRIs are chosen as first-line treatments due to their general tolerability, not because they are known to be more effective in a broader patient population or because they are more effective in specific patients. However, most patients do not respond adequately to the first medication (Trivedi et al., Am J Psychiatry, 2006, 163(1):28-4, doi:10.1176 / appi.ajp.163.1.2, PMID 16390886), and at this point, the selection of the next medication again follows a trial-and-error process. In fact, on average, failure with one SSRI does not necessarily mean that a different response with another SSRI, SNRI, or NDRI will be predicted (Rush et al., N Engl J Med. 2006, 354:1231-1242). Furthermore, there is no clear guidance on whether to increase the dosage of an underperforming antidepressant or switch to a different antidepressant, as both options yield similar outcomes. Consequently, typical clinical assessments in clinical care dialogues do not provide sufficient information for subsequent drug trial selection, and therefore, clinicians lack the external information they need to improve drug selection.

[0004] The economic, social, and personal costs of depression are enormous, and it is a leading cause of disability worldwide. This is even more pronounced in treatment-resistant depression (Amos et al., J Clin Psychiatry, 2018, 79:2, PMID 29474009), suggesting that finding the optimal medication for an individual in the early stages of treatment can bring many downstream benefits to both patients and society as a whole.

[0005] One drug that may differ from conventional SSRIs / SNRIs in its mechanism of action and clinical effects is agomelatine (N-[2-(7-methoxynaphthalene-1-yl)ethyl]acetamide), which, unlike other conventional antidepressants, stimulates melatonin receptors and serotonin 5-HT receptors. 2C It blocks receptors. Agomelatine was developed as a monotherapy antidepressant (i.e., administered to individuals not taking conventional antidepressants) and was eventually approved in Europe and Australia. However, its effectiveness is considerably debated because its effect compared to placebo has been reported to be small and variable. Norman et al., Exp. Op. Pharmacother., 20(6):647-656 (2019). In fact, this drug was developed in the United States as a monotherapy antidepressant, but its development was eventually discontinued due to insufficient evidence of effectiveness. The reasons for the variability in the observed effectiveness of agomelatine are unknown.

[0006] Furthermore, little is known about the efficacy of agomelatine when administered as an adjunct to conventional antidepressants that patients were continuing to take at the time adjunctive therapy was initiated, or as an augmentative in addition to those medications, even if the patient was unresponsive. Augmentation, adjunct, or “add-on” therapy is an important part of the paradigm for treating depression (Potmesil, Ther Adv Psychopharmacol, 2019, 9:1-11, PMID 31312426). However, while only antipsychotic drugs are approved for adjunctive use in depression, they carry a considerable burden of side effects and are poorly tolerated (Wen et al., Braz J Med Biol Res. 2014, 47(7):605-16, doi:10.1590 / 1414-431x20143672, PMID 24919175; Yan et al., Psychol Med. 2022, 52(12):2224-2231, doi:10.1017 / S0033291722001246, PMID 35993319). There have been few open-label agomelatine therapy trials employing adjuvant therapy (Laux et al., Clin Pract. 2014, 18(2):86-96), but these results do not clarify whether this response is likely to be different from placebo or alternative therapy, nor what characterizes the subpopulation of patients who respond robustly to the drug.

[0007] Melatonin agonism and 5-HT on hypothalamic regulation of circadian rhythms 2CBased on its synergistic effect with antagonistism (de Bodinat et al., Nat Rev Drug Discov, 2010, 9(8):628-42, PMID 20577266), agomelatine has been suggested to be particularly useful in treating depression accompanied by significant sleep and / or circadian rhythm disturbances (Popoli et al., CNS Drugs. 2009, 23 Suppl 2:27-34; Jakovljevic et al., Psychiatr Danub. 2011; 23:2-9). For example, agomelatine has been shown to improve sleep indices assessed using activity-based measurements, in contrast to SSRIs, which did not alter these indices (Kasper et al., J Clin Psychiatry, 2010; 71: 109-120; Quera Salva et al., Int J Neuropsychopharmacol, 2007, 10: 691-696; Quera-Salva et al., Hum Psychopharmacol, 2010, 25: 222-229). These effects included increasing the ratio of deep sleep to total sleep (Quera Salva 2007 (above); Quera Salva 2010 (above)). Deep sleep, also known as slow-wave sleep, is considered a particularly recovery-promoting aspect of sleep and is involved in processes such as memory consolidation, allowing the brain to recover from its daily activities (Rasch et al., Physiol Rev, 2013, 93: 681-766). Deep sleep is also known to be generally reduced in depression (Arfken et al., J Affect Disord, 2014, 156:36-45; Wichniak et al., Int Rev Psychiatry, 2013, 25:632-645; Riemann et al., Neuropsychopharmacology, 2020, 45:74-89).Agomelatine has also been shown to be superior to SSRIs in improving performance on trail-making tasks (Aydin et al., European Psychiatry, 2016, 33:S405), while antidepressants such as SSRIs generally have little to no effect on a wide variety of cognitive indicators, including trail-making tasks (Shilyansky et al., Lancet Psychiatry, 2016, 3(5):425-435).

[0008] Nevertheless, these effects of agomelatine on sleep or cognition do not define the characteristics of patients who respond robustly to the drug. For example, agomelatine and melatonin have been shown to phase-progress the circadian rhythm through their melatonergic agonisms (Leproult et al., Clin Endocrinol(Oxf), 2005, 63(3):298-304, PMID 16117817; Krauchi et al., Am J Physiol., 1997, 272(4 Pt 2):R1178-88, PMID 9140018), but melatonin is not an effective antidepressant (Hansen et al., Eur Neuropsychopharmacol, 2014, 24(11):1719-28, PMID 25224106; De Crescenzo et al., Acta Psychiatr Scand, 2017, 136(6):549-558, PMID 28612993). In fact, limited studies on predictors of agomelatine response suggest the opposite: an earlier circadian phase predicts a better response. Patients who were more morning types in pre-treatment circadian preference surveys were found to respond better to agomelatine (Corruble et al., Chronobiology Int'l, 2014, 31(2):283-289). In this study, or in the same or similar studies, the morning type is consistently and strongly associated with an earlier circadian phase as measured by actigraphy (Jones et al., Nat Commun, 2019, 10(1):343, PMID 30696823; Schneider et al., Chronobiol Int, 2022, 39(2):205-220, PMID 34806526; Bailey et al., Chronobiol Int, 2001, 18(2):249-61, PMID 11379665).Therefore, studies aimed at predicting the response to agomelatine show better outcomes in patients with an earlier circadian phase, while inferences based on the pharmacodynamic effects of agomelatine (which are shared with melatonin, an ineffective antidepressant) show better outcomes in patients with a later circadian phase. These conflicting findings are within the realm of circadian phase scales. Much less is known about other aspects of brain function, such as those that can be utilized through recording brain activity or behavioral tests. Thus, prior to this invention, it was unclear which patients would be most responsive to agomelatine (i.e., those for whom targeting a drug whose effectiveness is questionable in the overall unscreened depressed patient population is critical). This state of uncertainty is further amplified when considering the use of agomelatine as an adjunct to failed conventional antidepressants (for which little is clinically known).

[0009] Despite agomelatine's unique mechanism of action, SSRIs remain the most common medications prescribed in clinical practice across multiple failed drug trials, and any deviations, if any, tend towards the use of SNRIs and NDRIs alone, in combination with SSRIs, or with the addition of atypical antipsychotics (Wu et al., PLoS One, 2019, 14:e0220763). In contrast, agomelatine is the least prescribed of the conventional antidepressants in the market where it is approved (Forns et al., J Affect Disord, 2019, 249:242-252). Furthermore, since all measurements are made to patients as part of clinical care, clinicians only have access to clinical signs and symptoms reported by patients or observed by clinicians. Consequently, clinicians lack criteria for selecting any one medication compared to another, and therefore cannot identify which person will respond best to agomelatine. Therefore, there is no means to identify patients who are responsive to agomelatine before treatment. Defining these signals has a significant impact on the ability to prescribe agomelatine in a way that best matches the clinical benefit to a defined subgroup of patients with depression or comorbidities. [Overview of the project]

[0010] Surprisingly, it is now known that the effects of agomelatine, its prodrugs, or pharmaceutically acceptable salts thereof can be predicted by patterns of brain activity recorded by electroencephalography (EEG). Therefore, the present invention includes the use of one or more of these electroencephalogram (EEG) measurements as a method for identifying patients who would benefit most from agomelatine treatment.

[0011] One embodiment is a method for treating a depressive phase of major depressive disorder (MDD) or bipolar disorder in a patient, or depressive symptoms in a patient with post-traumatic stress disorder (PTSD), wherein the patient has been treated with one or more antidepressants other than agomelatine (or its prodrug or salt), but has not responded well to that antidepressant. If the patient shows high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) before initiating agomelatine treatment, the method comprises administering a therapeutically effective dose of (a) agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, and (b) one or more antidepressants. In other words, agomelatine (or its prodrug or salt thereof) is administered as adjunct therapy to one or more currently prescribed antidepressants, wherein the patient has not responded to one or more antidepressants in the past. In one embodiment, EEG measurements are taken in a resting, eyes-closed state (REC). In one embodiment, the patient suffers from major depressive disorder and PTSD.

[0012] One embodiment is a method for treating the depressive phase of bipolar disorder in a patient, wherein the patient has been treated with one or more mood stabilizers and / or one or more antidepressants other than agomelatine (or its prodrug or salt), but has not responded well to the mood stabilizers and / or antidepressants. If the patient shows high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) before initiating agomelatine treatment, the method comprises administering a therapeutically effective dose of (a) agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, and (b) one or more mood stabilizers and / or one or more antidepressants. In other words, agomelatine (or its prodrug or salt) is administered as adjunct therapy to one or more currently prescribed mood stabilizers and / or antidepressants, wherein the patient has not responded to one or more antidepressants in the past. In one embodiment, EEG measurements are taken in a resting, eyes-closed state (REC). In one embodiment, the patient suffers from major depressive disorder and PTSD.

[0013] Another embodiment is a method for treating the depressive phase of major depressive disorder or bipolar disorder in a patient, or depressive symptoms in a patient with PTSD, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) before initiating treatment with agomelatine (or its prodrug or salt) and one or more antidepressants. The method comprises administering a therapeutically effective dose of (a) agomelatine, its prodrug or a pharmaceutically acceptable salt thereof, and (b) one or more antidepressants other than agomelatine (or its prodrug or salt) (e.g., one antidepressant). In one embodiment, the EEG measurement is taken in a resting, eyes-closed state (REC). In one embodiment, the patient had not been treated with antidepressants before treatment with the combination of agomelatine (or its prodrug or salt) and one or more antidepressants. In one embodiment, the patient has major depressive disorder and PTSD.

[0014] Another embodiment is a method for treating the depressive phase of bipolar disorder in a patient, in which the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) before initiating treatment with (a) agomelatine (or its prodrug or salt) and (b) one or more antidepressants and / or mood stabilizers. This method comprises administering a therapeutically effective dose of (a) agomelatine, its prodrug or a pharmaceutically acceptable salt thereof, and (b) one or more mood stabilizers and one or more antidepressants other than agomelatine (e.g., one antidepressant). In one embodiment, the patient had not been treated with mood stabilizers and / or antidepressants before being treated with the combination of (a) agomelatine (or its prodrug or salt) and (b) one or more mood stabilizers and / or antidepressants. In one embodiment, EEG measurements are taken in a resting, eyes-closed state (REC).

[0015] In any embodiment of the methods described herein, one or more antidepressants are selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion or pharmaceutically acceptable salts thereof, or any combination thereof.

[0016] Another embodiment is a method for treating the depressive phase of major depressive disorder or bipolar disorder in a patient, or for treating depressive symptoms in a patient with PTSD, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) before initiating agomelatine treatment (or its prodrug or salt). The method comprises administering a therapeutically effective dose of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof. In one embodiment, the EEG measurement is taken in a resting, eyes-closed state (REC). In one embodiment, the patient has previously not responded to one or more antidepressants other than agomelatine (or its prodrug or salt), and treatment with one or more conventional antidepressants is discontinued upon initiation of agomelatine. In an alternative embodiment, the patient has previously not responded to one or more antidepressants other than agomelatine (or its prodrug or salt), and treatment with one or more conventional antidepressants is continued upon initiation of agomelatine. In yet another embodiment, the patient has not previously been treated with one or more antidepressants and / or mood stabilizers, and treatment with one or more antidepressants and / or mood stabilizers is initiated at the same time as initiation of agomelatine (or its prodrug or salt).

[0017] A further embodiment of the present invention is a method for maintaining a normal mood state in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II), wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) before initiating agomelatine therapy (or its prodrug or salt). The method comprises administering an effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof to maintain a normal mood state in the patient. In one embodiment, the EEG measurement is taken in a resting, eyes-closed state (REC). In one embodiment, the patient has previously not responded to one or more mood stabilizers or antidepressants other than agomelatine (or its prodrug or salt), and treatment with one or more conventional mood stabilizers and antidepressants is discontinued upon initiation of agomelatine (or its prodrug or salt). In one alternative embodiment, the patient has not previously responded to one or more mood stabilizers or antidepressants other than agomelatine (or its prodrug or salt), and treatment with one or more conventional mood stabilizers is continued at the time of initiation of agomelatine (or its prodrug or salt) (but antidepressants are not continued). In yet another embodiment, the patient has not previously been treated with one or more antidepressants and / or mood stabilizers, and treatment with one or more antidepressants and / or mood stabilizers is also initiated at the time of initiation of agomelatine (or its prodrug or salt).

[0018] In any embodiment of the methods described herein, the patient exhibits high EEG sample entropy at the Pz electrode (based on the 10-20 method of electrode placement).

[0019] In any embodiment of the methods described herein, EEG measurements are taken with the eyes closed at rest.

[0020] In any one embodiment of the methods described herein, the patient suffers from moderate to severe major depressive disorder.

[0021] In one embodiment, agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof is administered once daily at night.

[0022] In any one embodiment of the methods described herein, the method comprises orally administering about 25 to about 50 mg of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof (based on agomelatine free base) once daily (preferably every night). In one embodiment, the method comprises orally administering about 25 mg of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof (based on agomelatine free base) once daily (preferably every night). In another embodiment, the method comprises orally administering about 50 mg of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof (based on agomelatine free base) once daily. In yet another embodiment, the method comprises orally administering about 30 mg of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof (based on agomelatine free base) once daily.

[0023] In any embodiment of the methods described herein, the method comprises orally administering about 25 to about 50 mg of agomelatine per day. In a preferred embodiment, the method comprises orally administering about 25 to about 50 mg of agomelatine once per day, every evening.

[0024] In any one embodiment of the methods described herein, the method comprises orally administering about 25 mg of agomelatine per day. In a preferred embodiment, the method comprises orally administering about 25 mg of agomelatine once per day, every evening.

[0025] In any embodiment of the methods described herein, the method comprises orally administering about 50 mg of agomelatine per day. In a preferred embodiment, the method comprises orally administering about 50 mg of agomelatine once daily, every evening.

[0026] In one embodiment of any of the methods described herein, agomelatine is administered once a day before bedtime.

[0027] Yet another embodiment of the invention is a method of treating a depressive phase of major depressive disorder (MDD) or bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II) in a patient, or treating depressive symptoms in a patient having post-traumatic stress disorder (PTSD), the method comprising: (a) analyzing one or more indicators of a patient's responsiveness to agomelatine (or a prodrug or pharmaceutically acceptable salt thereof) as a treatment for a depressive phase of major depressive disorder or bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II), or depressive symptoms in a patient having PTSD; (b) administering (e.g., orally) to the patient an effective amount of agomelatine, a prodrug thereof, or a pharmaceutically acceptable salt thereof (e.g., from about 25 to about 50 mg of agomelatine per day, e.g., 25 mg of agomelatine once a day or 50 mg of agomelatine once a day (e.g., once every evening)), wherein the patient has been determined to be responsive to agomelatine (or a prodrug or salt thereof) based on one or more indicators. The one or more indicators can be selected from EEG measurements of entropy or complexity, and any combination of any of the foregoing.

[0028] Yet another embodiment of the invention is a method of maintaining a euthymic state in a patient having bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II), comprising: (a) analyzing one or more indicators of a patient's responsiveness to agomelatine (or a prodrug or pharmaceutically acceptable salt thereof) as a method for maintaining a euthymic state in a patient suffering from bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II); (b) A method comprising administering to a patient an effective dose of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof (e.g., orally) (e.g., about 25 to about 50 mg of agomelatine daily, e.g., 25 mg of agomelatine once daily, or 50 mg of agomelatine once daily (e.g., once every evening)), wherein the patient has been determined to be responsive to agomelatine (or its prodrug or salt) based on one or more indicators. One or more indicators may be selected from EEG measurements of entropy or complexity, and any combination of any of the foregoing (such as those described herein). In one embodiment, the patient has previously been unresponsive to one or more mood stabilizers or antidepressants other than agomelatine (or its prodrug or salt), and treatment with one or more conventional mood stabilizers and antidepressants is discontinued upon initiation of agomelatine (or its prodrug or salt). In one alternative embodiment, the patient has not previously responded to one or more mood stabilizers or antidepressants other than agomelatine (or its prodrug or salt), and treatment with one or more conventional mood stabilizers is continued at the time of initiation of agomelatine (or its prodrug or salt). In yet another embodiment, the patient has not previously been treated with one or more antidepressants and / or mood stabilizers, and treatment with one or more antidepressants and / or mood stabilizers is also initiated at the time of initiation of agomelatine (or its prodrug or salt).

[0029] The EEG measurement can be selected from a range of measurements that index neural complexity (see Figure 1). These include complexity measurements such as Higuchi fractal dimension, Katz fractal dimension, trend-removed variation analysis, maximum Lyapunov exponent, approximate entropy, sample entropy, multiscale entropy, modified multiscale entropy, and aperiodic exponent. In one embodiment, the EEG measurement is sample entropy.

[0030] In one embodiment, EEG measurements indicate that the patient exhibits higher sample entropy.

[0031] In one embodiment, a patient (e.g., a patient with major depressive disorder) has previously been treated with one or more antidepressants but has not achieved an adequate response, and continues treatment with one or more antidepressants even after initiation of agomelatine therapy (or its prodrug or salt). In other words, agomelatine (or its prodrug or salt) is offered as monotherapy, as adjunct therapy to one or more antidepressants, or in combination with one or more antidepressants different from those previously administered to the patient. In one embodiment, the one or more antidepressants do not include monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants. In another embodiment, the one or more antidepressants are selected from (i) serotonin reuptake inhibitors, (ii) serotonin-norepinephrine reuptake inhibitors, (iii) bupropion (or a pharmaceutically acceptable salt thereof, e.g., bupropion hydrochloride) (optionally accompanied by another agent, e.g., dextromethorphan), and (iv) any combination of any of the above. The patient may have major depressive disorder or bipolar disorder.

[0032] In another embodiment, one or more indicators in step (a) are analyzed using stored subject history data, including data from multiple subjects having major depressive disorder or bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II) treated with agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof. This data may include, for multiple subjects, one or more indicators used to analyze the efficacy of agomelatine treatment (or its prodrug or salt) and the patient.

[0033] In one embodiment, step (a) comprises determining a probability score (e.g., z-score) of agomelatine efficacy for the patient based on stored historical data of the subject, and step (b) comprises administering to the patient an effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient has been determined to be responsive to agomelatine based on the probability score. The probability score may be binary (i.e., 0 or 1 (categorical)) or continuous. In one embodiment, the probability score is bounded, for example, any value between 0 and 1.

[0034] This method can be administered to patients newly diagnosed with major depressive disorder or bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II). This method can also be administered to patients receiving treatment for major depressive disorder or bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II) (where the treatment does not include agomelatine (or its prodrug or salt).

[0035] In any embodiment of the methods described herein, EEG measurements are taken with the eyes closed at rest.

[0036] To better understand the present invention, including its features and advantages, a detailed description of the invention is provided herewith with reference to the accompanying drawings. [Brief explanation of the drawing]

[0037] [Figure 1A] This shows a thresholded topographic map (p<0.05) of the channel-level correlation between sample entropy and the rate of change in MADRS score from baseline to week 4 of agomelatine treatment. REC = resting eyes closed, REO = resting eyes open. The frequency bands are as follows: delta (2-4Hz), theta (4-7Hz), lower alpha (8-10Hz), upper alpha (10-12Hz), lower beta (13-20Hz), upper beta (20-30Hz), lower gamma (30-40Hz), upper gamma (40-50Hz). [Figure 1B]This shows a thresholded topographic map (p<0.05) of the channel-level correlation between sample entropy and the rate of change in MADRS score from baseline to week 6 of agomelatine treatment. REC = resting eyes closed, REO = resting eyes open. The frequency bands are as follows: delta (2-4Hz), theta (4-7Hz), lower alpha (8-10Hz), upper alpha (10-12Hz), lower beta (13-20Hz), upper beta (20-30Hz), lower gamma (30-40Hz), upper gamma (40-50Hz). [Figure 1C] This shows a thresholded topographic map (p<0.05) of the channel-level correlation between sample entropy and the rate of change in MADRS score from baseline to week 8 of agomelatine treatment. REC = resting eyes closed, REO = resting eyes open. The frequency bands are as follows: delta (2-4Hz), theta (4-7Hz), lower alpha (8-10Hz), upper alpha (10-12Hz), lower beta (13-20Hz), upper beta (20-30Hz), lower gamma (30-40Hz), upper gamma (40-50Hz). [Figure 2A] This report presents a mixed-model repeated measures (MMRM) analysis of patient-to-patient changes in MADRS scores in response to agomelatine, as predicted by an EEG sample entropy machine learning model in response to agomelatine. Data are plotted for patients excluded from each iteration of model training during cross-validation. One-sided p-values ​​and Cohen's d-effect size for contrast between predicted responders and predicted non-responders are also shown. [Figure 2B] This report presents a mixed-model repeated measures (MMRM) analysis of patient-to-patient changes in MADRS scores in response to agomelatine, as predicted by an EEG sample entropy machine learning model in response to agomelatine. Data are plotted against a holdout trial dataset, which includes participants not included in the training dataset and is therefore an independent replication trial. One-sided p-values ​​and Cohen's d-effect size for contrast between predicted responders and predicted non-responders are also shown. [Figure 2C]This report presents a mixed-model repeated measures (MMRM) analysis of changes in MADRS scores in response to agomelatine among patients with high sample entropy at the Pz electrode, using low-gamma frequency range EEG. Data are plotted for the entire sample, combining patients excluded from each iteration of model training during cross-validation with patients from the holdout dataset. One-sided p-values ​​and Cohen's d-effect size for contrast between predicted responders and predicted non-responders are also shown. [Figure 3A] This paper presents a mixed-model repeated measures (MMRM) analysis of the change in MADRS scores in patients in the placebo-treated group of a randomized trial, based on their predicted agomelatine response using an agomelatine EEG sample entropy machine learning model. The p-values ​​and Cohen's d-effect size for the contrast between predicted agomelatine responders and predicted non-responders regarding the observed placebo response are also shown. [Figure 3B] This report presents a mixed-model repeated measures (MMRM) analysis of the change in MADRS scores in patients receiving a new SSRI or SNRI, based on their predicted agomelatine response using an agomelatine EEG sample entropy machine learning model. The p-values ​​and Cohen's d-effect size for the contrast between predicted agomelatine responders and predicted non-responders regarding the observed response to the SSRI / SNRI are also shown. [Figure 4] The image shows a thresholded topographic map at p<0.05 of the channel-level correlation between the low gamma sample entropy of Pz and the low gamma power envelope connectivity between Pz and each other electrode (REC). The datasets shown are baseline EEG data from the agomelatine study (far left, N=117) and baseline data from three other studies on depression (from second from left to right: dataset 1 N=894, dataset 2 N=793, dataset 3 N=215). [Modes for carrying out the invention]

[0038] Agomelatine (N-[2-(7-methoxynaphthalene-1-yl)ethyl]acetamide) and its synthesis are described in European Patent Publication No. 447285A1 and U.S. Patent No. 5,225,442, both of which are incorporated herein by reference in their entirety. Agomelatine is a melatonin agonist (i.e., MT1 and MT2 receptor site agonism) and 5HT 2c He is an antagonist.

[0039] The term "prodrug" refers to a precursor of agomelatine that, after administration to a subject, produces agomelatine in vivo via chemical or physiological processes such as solvolysis or enzymatic cleavage, or under physiological conditions (for example, a prodrug adjusted to physiological pH is converted to agomelatine). Agomelatine prodrugs can be prepared by modifying functional groups present on the compound so that the modifications are cleaved in vivo when the prodrug is administered to a subject. This modification is typically achieved by synthesizing agomelatine with the prodrug substituent. Prodrugs are explicitly incorporated herein by reference, respectively: (i) Bundegaard, H. “Design of Prodrugs” pp. 1-92, Elesevier, New York-Oxford (1985); (ii) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); (iii) A Textbook of Drug Design and Development, 3 rdThe preparations may be made as described in (iv) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992), (v) N. Nielsen, et al., Journal of Pharmaceutical Sciences, 77:285-298 (1988), and (vi) N. Kakeya, et al., Chem. Pharm. Bull., 32:692-698 (1984). In one embodiment, the prodrug substituents induce the compound into the lymphatic system. Such prodrug substituents are described in International Publications WO2019 / 046491 and WO2021 / 159021, respectively, which are incorporated herein by reference. Such prodrug substituents can be conjugated to agomelatine, for example, via the methoxy or acetamide group of agomelatine.

[0040] The terms major depressive disorder, bipolar disorder, bipolar disorder type I, and bipolar disorder type II are intended to be as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which is incorporated herein by reference. The severity of depression may be measured by the Montgomery-Asberg Depression Rating Scale (MADRS), the Patient Health Questionnaire-9 (PHQ-9), the Clinical Global Impression-Severity Scale (CGI-S), the Hamilton Depression Rating Scale (HDRS), or any combination of any of the aforementioned.

[0041] In the context of administering therapy to a patient, the terms “to treat,” “to treat,” and “to treat” refer to the reduction or suppression of the progression and / or duration of a disease or condition, the reduction or improvement of the severity of a disease or condition, and / or the improvement of one or more of its symptoms, resulting from the administration of one or more therapies.

[0042] In certain embodiments, the patient had an inadequate response to other antidepressant therapies (i.e., one or more antidepressants other than agomelatine or its prodrugs or salts). In one embodiment, “inadequate response,” as used herein, refers to a patient who experiences a reduction of less than 50% in the severity of depressive symptoms since the initiation of treatment. Typically, an inadequate response occurs during a current / ongoing episode of depression. In some embodiments, “inadequate response,” refers to a patient who experiences a reduction of 0% to less than approximately 50% in the severity of depressive symptoms since the initiation of treatment. In some embodiments, an inadequate response refers to a patient who (a) experiences a reduction of less than approximately 50% in the severity of depressive symptoms since the initiation of treatment and (b) experiences at least a specific level of symptoms, e.g., at least 10 on the PHQ9. The patient’s response may be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, an inadequate response is measured by the ATRQ (Antidepressant Therapy Response Questionnaire), MADRS, PHQ-9, CGI-S, or HDRS.

[0043] The term “antidepressant” includes, unless otherwise indicated, selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, escitalopram, citalopram, and sertraline), selective serotonin and norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, and milnacipran), norepinephrine and dopamine reuptake inhibitors (e.g., bupropion), atypical antidepressants, and any combination of any of the above. In one embodiment, the antidepressant is selected from SSRIs, SNRIs, or bupropion. In another embodiment, the antidepressant is selected from SSRIs (other than fluvoxamine), SNRIs, or bupropion.

[0044] As used herein, “mood stabilizers” may be lithium carbonate, lithium orotate, lithium salts, valproic acid, divalprox sodium, propranolol, clonazepam, sodium valproate, lamotrigine, carbamazepine, gabapentin, oxycarbazepine, topiramate, their pharmaceutically acceptable salts, or any combination thereof.

[0045] As used herein, the term “high EEG sample entropy” refers to an EEG signal whose sample entropy is within a higher range of the distribution within the patient compared to, for example, the mean entropy value in a healthy population. In one embodiment, EEG sample entropy is calculated as a standardized score (e.g., z-score, T-score, standard score, scale score, percentile rank, or Stanine score) that normalizes the patient to a healthy population (e.g., with respect to age, sex, or education level). For example, a subject may have an EEG sample entropy above the mean for a similar healthy subject if the z-score is greater than zero, greater than z=0.25, greater than z=0.5, greater than z=0.75, greater than z=1, greater than z=1.5, or greater than z=2 (e.g., z-scores of approximately 0.5 or 0.75 to approximately 1 or approximately 2, or z-scores of approximately 0.75 or 1 to approximately 2). In one embodiment, a patient is considered to have higher entropy if the z-score is at least 0, 0.5, 1.0, 1.5, or 2.0 (e.g., at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0). In one embodiment, raw EEG data from the patient is first loaded and subjected to a preprocessing step including resampling, notch application, and bandpass filtering. The data then undergoes interpolation of bad channels and artifact removal, is then rereferenced, quality-checked, and stored for analysis.

[0046] As used herein, the terms “subject” and “patient” are interchangeable and refer to a human patient unless otherwise indicated. In one embodiment, the patient has moderate to severe major depressive disorder. In another embodiment, the patient has moderate to severe major depressive disorder and has been receiving treatment with an SSRI, SNRI, or bupropion (e.g., bupropion or a pharmaceutically acceptable salt thereof in combination with another drug such as dextromethorphan) for at least six weeks and has not had a dose change in the past two weeks. In yet another embodiment, the patient has moderate to severe major depressive disorder and has not responded well to an existing antidepressant, including an SSRI, SNRI, or bupropion (e.g., bupropion or a pharmaceutically acceptable salt thereof in combination with another drug such as dextromethorphan), for at least six weeks and has not had a dose change in the past two weeks.

[0047] EEG measurements for indexing neural complexity include, but are not limited to, Higuchi fractal dimension, Katz fractal dimension, trend-removed variation analysis, maximum Lyapunov exponent, approximate entropy, sample entropy, multiscale entropy, modified multiscale entropy, and aperiodic exponent. Such measurements are described in Lau et al., Eur J Neurosci, 2022, 56(7):5047-5069; doi:10.1111 / ejn.15800; PMID 35985344), which is incorporated herein by reference.

[0048] Treatment method Agomelatine (or its prodrug or salt) may be administered via any route, e.g., orally, rectally, transdermally, or by parenteral injection. The preferred route of administration is orally. Agomelatine (or its prodrug or salt) may be administered in the form of tablets, capsules, granules, or oral liquid. In one embodiment, agomelatine (or its prodrug or salt) is administered once daily (e.g., in the form of a tablet). In another embodiment, 25 mg of agomelatine (or its prodrug or salt) is administered once daily (e.g., in the form of an oral tablet). In yet another embodiment, 50 mg of agomelatine (or its prodrug or salt) is administered once daily (e.g., in the form of an oral tablet). In one preferred embodiment, this dose is administered orally once daily before bedtime.

[0049] The amount of agomelatine (or its prodrug or salt) administered may range from about 0.1 to about 150 mg / day, for example, from about 0.1 to about 100 mg / day, about 0.5 to about 50 mg / day, about 1 to about 50 mg / day, or about 1 to about 5 mg / day. In one embodiment, the daily dose of agomelatine (or its prodrug or salt) is 25 mg to 50 mg per day, preferably administered orally. In another embodiment, the daily dose of agomelatine (or its prodrug or salt) is 25 mg per day, administered orally. In yet another embodiment, the daily dose of agomelatine (or its prodrug or salt) is 50 mg per day, administered orally (for example, before bedtime).

[0050] In one embodiment, treatment with oral agomelatine at a dose of 25 mg once daily is initiated to treat the patient. If there is no improvement in symptoms, the dose may be increased to oral agomelatine at a dose of 50 mg once daily. In one embodiment, if the daily dose is increased to more than 25 mg (e.g., to 50 mg), the patient undergoes liver function testing. In another embodiment, liver function testing is performed on the patient before initiating agomelatine treatment and before increasing the daily dose to 50 mg. In a particular embodiment, if the serum transaminase level exceeds twice the upper limit of the patient's normal range, agomelatine treatment is not initiated.

[0051] Patient selection In one embodiment, EEG measurement is performed using electrodes arranged according to the 10-20 method. [Examples]

[0052] Example 1 The inventors conducted two parallel, open-label clinical trials of agomelatine 25 mg once bedtime in patients with major depressive disorder (NCT05118750 and NCT05157945; data from these studies were pooled in the analysis). These patients had moderate to severe depression and needed to be taking a stable, sufficient dose of antidepressants (particularly SSRIs, SNRIs, or bupropion) that had responded poorly to treatment (i.e., agomelatine treatment was adjunct to antidepressants). Patients were evaluated during the 8-week treatment period.

[0053] EEG data were collected pre-treatment at rest (including both open and closed eye states) using a 19-channel EEG system covering 10-20 conventional electrode positions. A total of 107 patients with moderate to severe depression (MADRS ≥ 20 and PHQ-9 ≥ 10) had EEG data (107 with open-eye (REO) EEG and 105 with closed-eye (REC) EEG). Quality control evaluations were performed to obtain 105 REO patient datasets and 103 REC patient datasets. These data were split into a training dataset for identifying predictive signals and a separate holdout dataset for further testing of the predictive signals. The training dataset consisted of 60 REO patient datasets and 60 REC patient datasets. The holdout set consisted of 49 REO patient datasets and 46 REC patient datasets.

[0054] The brain is an inherently nonlinear and complex dynamic system. Statistical features derived from information theory and chaos theory, such as sample entropy and Lyapunov exponents, can capture nonlinear aspects of the system that standard linear features cannot. This may improve our ability to characterize EEG recordings and potentially identify disease-related brain patterns (Lau et al., Eur J Neurosci, 2022, 56(7):5047-5069, doi:10.1111 / ejn.15800, PMID 35985344; Rodriguez-Bermudez and Garcia-Laencina, Appl.Math Inf.Sci.9(5):2309-2321, 2015). In particular, sample entropy measures the irregularity of the system. Low sample entropy indicates low randomness, high regularity (i.e., repeating patterns), and high dependence between data points. High sample entropy, conversely, indicates high randomness, low regularity, and low dependence between data points (Delgado-Bonal and Marshak, Entropy (Basel), 2019, 21(6):541, doi:10.3390 / e21060541, PMID:33267255).

[0055] Sample entropy is a variation of approximate entropy, which is a variation of Kolmogorov-Sinai (KS) entropy (Delgado-Bonal and Marshak, 2019, op. cit.). KS entropy is directly related to the "entropy rate" of a dynamic system, measuring how much information is needed over time (on average) to describe a process. However, KS entropy can only be practically calculated for well-defined systems when there is no measurement noise and a large amount of data is available. Approximate entropy solves this problem based on the same principle as KS entropy, but it can be used with real data (Pincus, PNAS, 1991, 88(6):2297-301, doi:10.1073 / pnas.88.6.2297, PMID:11607165). Approximate entropy measures the frequency at which fixed-length data fragments are nearly repeated and remain similar for subsequent samples. Approximate entropy is known to be a biased measurement, especially with small amounts of data. Sample entropy is a measurement very similar to approximate entropy, but it has been modified to address this issue (Delgado-Bonal and Marshak, 2019, op. cit.). Therefore, channel-level EEG sample entropy was calculated in the following analysis.

[0056] As seen in Figures 1A–1C (subsections A, B, and C), channel-level sample entropy measurements correlate with the rate of change in MADRS scores from baseline (up to weeks 4, 6, and 8) at p<0.05 across multiple frequency ranges and multiple scalp locations in the training dataset. To compile these individual signals into a single EEG composite entropy model for predicting treatment outcomes, we performed 10-fold cross-validated machine learning with elastic network regularization for high-response vs. low-response outcomes to agomelatine. Cross-validation iteratively splits the training dataset into 9 / 10 for training the machine learning model and 1 / 10 (i.e., participants who were excluded from training itself but were part of the aforementioned training dataset) for evaluating the predictive utility of the model. The training sample is then split in this manner until each participant is excluded from the training subset.

[0057] Figure 2A shows the results of these cross-validations for data excluded in the training dataset, demonstrating statistically significant predictions of agomelatine outcomes at all weeks of treatment. The Cohen d-effect size at all these weeks was >0.4, which represents a substantial effect size of prediction, especially considering that the effect size for all-comers (i.e., unselected depressed patients) calculated meta-analyzed for the difference in treatment response to agomelatine (as monotherapy) compared to placebo was d=0.26 (Cipriani et al., Lancet., 2018, 391(10128):1357-1366, PMID:29477251). A similar pattern of effect sizes was observed in the holdout dataset, with the difference between non-responders and predicted agomelatine responders regarding observed changes in MADRS scores being d≧0.4 at weeks 4, 6, and 8. Statistical significance was achieved in the holdout trial sets at weeks 6 and 8 (see Figure 2B), demonstrating the replication of the prediction of agomelatine outcomes by EEG sample entropy in independent patient groups. Thus, surprisingly, it was found that an EEG complexity measure, in this case sample entropy, could predict which patients receiving adjunctive treatment with 25 mg of agomelatine were more likely to experience a reduction in depressive symptoms. Notably, other measures, such as chronobiology, sleep, and cognition, were not found to be predictive of whether adjunctive treatment with agomelatine was effective in reducing depressive symptoms.

[0058] The inventors investigated the weights assigned to each electrode using a machine learning model and revealed a significant role for EEG sample entropy calculated with the Pz electrode in low-gamma frequency data (30-40 Hz). Figure 2C plots the MADRS changes in patients with high low-gamma sample entropy calculated with Pz (where z≧0.27 was used) compared with patients with low Pz low-gamma sample entropy across all test samples, demonstrating a strong and statistically significant prediction of treatment outcomes over all weeks.

[0059] To understand whether this machine learning model identifies patients who respond better to agomelatine compared to placebo or standard SSRI or SNRI treatment, we applied an EEG sample entropy machine learning model to EEG data from patients who progressed to 8 weeks of placebo treatment as part of a randomized trial in depression (Trivedi et al., J Psychiatr Res., 2016, 78:11-23, PMID:27038550). As shown in Figure 3A, there was no significant difference in placebo response among patients predicted by the EEG model to respond better or worse to agomelatine. In fact, these data showed a slight effect in the opposite direction, thereby indicating that predicted agomelatine responders performed numerically worse when given placebo. Similarly, patients given a new SSRI or SNRI showed no difference in outcomes over 8 weeks when split based on the agomelatine EEG model (Figure 3B). When using only the Pz signal instead of the full machine learning model, very similar results were observed, with low-entropy patients (i.e., predicted agomelatine non-responders) similarly outperforming placebo or SSRI / SNRI in terms of response. Therefore, these data demonstrate the specificity of the EEG sample entropy model for predicting agomelatine outcomes, thus providing a novel and non-trivial tool for identifying who should and should not be administered agomelatine for the treatment of depression. Surprisingly, single-electrode sample entropy in the low gamma frequency range (i.e., Pz) was able to robustly and specifically predict agomelatine outcomes.

[0060] Assuming a positive prevalence of approximately 50% on the EEG machine learning model, the agomelatine-placebo difference in EEG-predicted agomelatine responders can be estimated by adding an all-commer effect size (d=0.26) to the enrichment of EEG-predicted responders that outperform the all-commer population. This enrichment is calculated by halving the effect size between EEG-predicted responders and non-responders, since the mean of these two groups is the all-commer population. The calculation assumed no difference in placebo response depending on the EEG-predicted agomelatine response (a conservative assumption considering the results in Figure 3A). Performing the above calculation using the full sample effect size shown in Figure 2B, it is shown that the agomelatine-placebo response in EEG-predicted responders at week 8 is d=0.58, which is more than twice the effect size of the all-commer (i.e., all-commer without therapeutic predictive signal benefits) previously observed in agomelatine monotherapy for depression. Similarly, the agomelatine-placebo difference shown for EEG-predicted non-responders was d=-0.06, suggesting that there is no difference between agomelatine monotherapy and placebo in patients predicted to be unresponsive based on EEG sample entropy. Very similar results were obtained using only Pz low-gamma sample entropy (d=0.51 in high-entropy patients and d=0.0 in low-entropy patients based on the results for the entire sample). Therefore, there is a clear clinical utility in the EEG agomelatine predictive signal, with the drug benefit occurring only in patients predicted to be responsive to agomelatine, and not in patients predicted to be unresponsive based on EEG.

[0061] In addition to sample entropy, the inventors developed a similar machine learning model to test the predictive utility of a range of other EEG complexity measures and other common EEG indices. As seen in Tables 1A and 1B below (significant results are shown in bold: uncorrected p-values ​​are provided), significant predictions of agomelatine outcomes were achieved by using several other complexity measures (approximate entropy, trend-removed variability analysis, Higuchi fractal dimension, Katz fractal dimension, maximum Lyapunov exponent, modified multiscale entropy, multiscale entropy, and aperiodic exponent). Significant predictions of agomelatine outcomes were not achieved with some complexity measures used, including Lemper-Zib complexity, permutation entropy, and Tsaris entropy. Therefore, certain complexity measures appear to have a consistent and strong predictive effect on agomelatine outcomes. Aperiodic indices (Park et al., Front Comput Neurosci., 2023, 17:1169288, PMID:37122995; Deco et al., J Neurosci., 2014, 34(23):7886-98, PMID:24899711; Donoghue et al., Nat Neurosci., 2020, 23(12):1655-1665, PMID:33230329), another measure that is sensitive to the balance between excitation and inhibition and may have some relationship with complexity, are also predictive (significant at week 4). However, general EEG indices such as relative power are not predictive. [Table 1-1] [Table 1-2] [Table 1-3] [Table 2-1] [Table 2-2] [Table 2-3]

[0062] Since it was found that higher EEG sample entropy was predicted to lead to a better agomelatine response, the inventors hypothesized that more unstable, unpredictable, and irregular EEG signals (i.e., higher entropy) might degrade information transfer between brain regions with these characteristics and other brain regions. Information transfer in the EEG can be tested using connectivity measurements such as orthogonalized power envelope connectivity (Hipp et al., Nat Neurosci., 2012, 15(6):884-90, PMID:22561454). Therefore, the inventors investigated whether lower gamma frequency entropy at higher Pz could predict lower power envelope connectivity from Pz. As shown in Figure 4, higher low gamma Pz sample entropy was predicted to lead to lower Pz connectivity, particularly to the frontal midline region (e.g., at electrode Fz). The location of this electrode suggests that reduced connectivity affects the default mode network in the brain, a neural network identified as playing a central role in depression (Runia et al., Neruosci Biobehav Rev., 2022, 132:433-438, PMID:34890601; Tozzi et al., Neuroimage Clin., 2021, 30:102570; PMID:33540370). Therefore, connectivity measurements can also be used to distinguish between agomelatine responders and non-responders, insofar as they reflect the correlation of entropy.

[0063] Example 2 A randomized, double-blind, placebo-controlled clinical trial of agomelatine in adults with MDD is currently underway. This trial includes adult patients (18–<71 years) with moderate to severe MDD who meet the following inclusion and exclusion criteria. This trial is a 6-week, multicenter, double-blind (DB), placebo-controlled clinical trial of agomelatine 25 mg once nightly as an adjunctive add-on treatment for adults with MDD who are currently taking another prescribed antidepressant but have an inadequate response (<50% improvement with current treatment). Participants will continue their current antidepressant throughout the trial, without dose changes between the screening and double-blind segments, unless there are safety concerns. Prior to taking the study drug, participants will be screened for electroencephalogram-based enrichment markers (based on electroencephalography (EEG), computer-aided neurocognition tests, and / or wearable behavioral tracking data) and subdivided into biomarker subgroups for data analysis. To minimize bias, participants and site staff will be blinded to biomarker status. To treat depression based on biomarkers of interest, this study will evaluate the efficacy of adjunctive agomelatine versus placebo using enrichment strategies. The trial objective is to validate biomarkers that can be used to predict the likelihood of any patient responding to agomelatine in a personalized or individualized manner (precision psychiatry).

[0064] Following the screening period and the collection of baseline biomarkers, participants will be randomized in a 1:1 ratio to receive either agomelatine 25 mg once nightly or an equivalent placebo over the DB period, based on sex and enrichment marker status. A 6-week follow-up will be conducted, consisting of five trial visits, including day 1 when the trial intervention begins. Participants who complete the trial intervention during the DB period may enter an optional 8-week open-label (OL) period receiving agomelatine 25 mg once nightly (open-label), and may also make four additional visits. Open-labeling of the DB intervention will not occur between DB visits and OL visits. After participants complete the OL period, or at the end of the DB period for participants who do not enter the OL period, or after early discontinuation of the study drug for participants who choose not to continue the study, an End-of-Period (EOP) visit will be held, followed approximately one week later by a Safety Follow-up (FUV) visit. If a participant discontinues the study intervention before the end of the treatment period, they may choose to complete the remaining visits for that period (DB or OL), including FUV. Participants who discontinue the study intervention during the DB period are not eligible to enter the OL period.

[0065] Approximately 200 participants will be randomized, stratified by sex and biomarker status, and treated during the DB period. To achieve 200 randomized participants, approximately 1000 participants (a maximum of 1250 screenings are permitted) need to be screened.

[0066] Selection Criteria: To be eligible to participate in this study, individuals must meet all of the following criteria: Applicants must be between 18 and 71 years of age. • Having a diagnosis of MDD based on SCID-5, and: - Having moderate to severe depression as assessed by a score of ≥10 on the PHQ-9, according to the DSM-5 criteria for depression. - Having moderate to severe MDD as confirmed by a total MADRS score of ≥22 as performed by the MGH-CTNI remote evaluation device prior to agomelatine treatment, and passing the SAFER interview. • Participants should take a single antidepressant, such as an SSRI (other than fluvoxamine), SNRI, or bupropion, at a stable dose (participants should take the antidepressant at least 5 days a week during screening, but full compliance is preferred). The antidepressant has been taken for ≥6 weeks at an appropriate dose as defined by the Antidepressant Therapeutic Response Questionnaire (ATRQ), and the dose has not been changed for ≥2 weeks. • Having a <50% improvement in response to currently prescribed antidepressants as defined by the ATRQ. Based on clinical evaluation, one of the following must be true: - Regardless of the number of failed antidepressants, you must have had at least two consecutive months of remission (not meeting the DSM-5 criteria for MDD) in the past 26 months, or - No period of remission for at least two consecutive months in the past 26 months, and no more than three antidepressants (including current antidepressants) have failed at appropriate dosage and duration as defined by the ATRQ within the past 24 months. • Body Mass Index (BMI) is ≥17 and ≤41 • Males and / or females who are neither pregnant, breastfeeding, and have no plans to become pregnant or have children during the period of taking the study drug and for 60 days after the completion of the study.

[0067] Exclusion criteria Participants will be excluded from this study if they meet any of the following criteria: Medical condition 1. Any of the following medical conditions: - Liver impairment (i.e., cirrhosis or active / chronic liver disease). - Baseline serum transaminase (aspartate transaminase (AST) or alanine transaminase (ALT)) levels exceed twice the ULN level. - You are pregnant, breastfeeding, or planning to become pregnant. - Severe impairment of vision, hearing, comprehension, and / or hand movement that interferes with the examination tasks. - Any contraindications to EEG (i.e., conditions requiring high concentrations of oxygen). - Active suicidal ideation as determined by either a score of 3 (agree) or 4 (strongly agree) on item 11 or 12 of the CHRT-SR12, or by the investigator's assessment based on the results of the CHRT-C and / or clinical evaluation. - Moderate to severe alcohol use disorder (AUD), or ongoing moderate to severe substance use disorder (SUD) other than nicotine, will be excluded by clinical evaluation. SUD in remission for three months is acceptable. - A clinically significant history or evidence of acute or unstable cardiovascular, respiratory, renal, gastrointestinal, endocrine, neurological (e.g., within the past year: seizure, cerebrovascular disease, traumatic brain injury), immunological, or other major medical condition as determined by the investigator at the institution. Stable chronic medical conditions are permitted. - Gastric bypass, gastric wrap band, and / or gastric sleeve in the past year (as this may prevent the complete and safe absorption and metabolism of the investigational drug). Preceding / Combination Therapy 2. In combination with any of the following: - Monoamine oxidase inhibitors (MAOIs) - Low-dose trazodone taken no more than 3 days a week I am taking multiple current antidepressants other than (≤100mg / day). - Atomoxetine, biloxazine, or mirtazapine - Melatonin, ramelteon, or other melatonin agonists (including dietary supplements containing melatonin) - Potent CYP1A2 inhibitors (e.g., fluvoxamine and ciprofloxacin) - Mood stabilizers (Anticancers for non-psychiatric reasons may be permitted with the approval of the clinical trial sponsor) - Antipsychotic drugs - Benzodiazepines, stimulants, or opioid analgesics used more than three times a week and which cannot be reduced to three days or less per week if necessary. These medications must not be used for 24 hours prior to biomarker evaluation. - Hypnotics (including trazodone) taken more than three times a week, which cannot be reduced to three days or less per week if necessary, and which were not taken within 24 hours prior to biomarker evaluation. Note: If clinically directed, medications may be changed to meet the selection criteria. To ensure that no withdrawal symptoms are present, medications must be discontinued for a sufficient period before agomelatine treatment. 3. In the current depressive episode, the patient is receiving electroconvulsive therapy (ECT), deep brain stimulation (DBS), vagus nerve stimulation (VNS), or more than two doses of ketamine or esketamine (a new depressive episode occurs if the DSM-5 criteria for MDD are not met for two consecutive months). 4. Unstable psychotherapy, defined by changes in the frequency and / or type of individual or group therapy, if the frequency is 2 times / month or less, in the 6 weeks prior to agomelatine treatment, or if the therapy is more than 2 times / month (approximately weekly), in the past 3 months. Experience in prior / concurrent clinical trials 5. Administration of any other central nervous system (CNS) investigational drug or device within 6 months of the initial trial visit, and two or more CNS intervention trials within the past 12 months. Non-CNS intervention trials or CNS observational trials may be permitted within the past 6-12 months after review by the sponsor. 6. Past participation in trials using ALTO-300 or agomelatine. Diagnostic evaluation 7. Diagnosis of bipolar disorder or mental disorder or symptoms based on the SCID of DSM-5. 8. Diagnosis of dementia based on medical history or clinical evaluation. 9. Significant current PTSD symptoms based on an early PCL-5 level >50. Other exclusions 10. Positive uremic toxicity test (excluding marijuana or documented prescriptions). One retest during screening is permitted. Current moderate or severe substance use disorder (SUD) (excluding nicotine) as determined by clinical evaluation is excluded. Participants with a history of SUD must be in remission for at least 3 months prior to the start of the study. 11. Excessive alcohol use, defined as exceeding 21 standard drinks per week for men and 14 standard drinks per week for women (on average). 12. Known hypersensitivity to agomelatine, its components, or any of the excipients used in its formulation. 13. Employees of the clinic facility / family members of employees. 14. Any other conditions and / or circumstances that the Principal Investigator believes could interfere with participant safety, the conduct of the study, or the interpretation of study data. Considerations regarding lifestyle During the trial, the use of abusive drugs is not permitted, except for limited amounts of cannabis (any form, up to 3 times a week, and not meeting the criteria for SUD). Participants are required to follow the Centers for Disease Control and Prevention (CDC) recommendations regarding alcohol consumption: one standard beverage per day (week average) for women and two standard beverages per day (week average) for men. Restrictions on concomitant medications are described in Section 6.5. Cannabis and alcohol should not be used for 24 hours prior to any trial visit.

[0068] All publications, patents, and patent applications cited herein are incorporated herein by reference as being described herein in their entirety. While the present invention has been described with reference to exemplary embodiments, this description is not intended to be constrained. As with other embodiments of the present invention, various modifications and combinations of the exemplary embodiments will be apparent to those skilled in the art after referring to this description. Accordingly, the appended claims are intended to encompass such modifications and enhancements.

Claims

1. A method for treating a depressive phase of major depressive disorder or bipolar disorder in a patient, or for treating depressive symptoms in a patient with post-traumatic stress disorder (PTSD), wherein the patient has been treated with an antidepressant other than agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, but has not responded well to the antidepressant, and the method comprises administering a therapeutically effective dose of (a) agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, and (b) the antidepressant, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30–40 Hz) before initiating treatment with agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof.

2. A method for treating a depressive phase of bipolar disorder in a patient, wherein the patient is being treated with (i) a mood stabilizer, (ii) an antidepressant other than agomelatine, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or (iii) both, but is not responding well to the mood stabilizer, the antidepressant, or both, and the method comprises administering a therapeutically effective dose of (a) agomelatine, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and (b) the mood stabilizer, the antidepressant, or both, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30–40 Hz) prior to initiating agomelatine treatment.

3. A method for treating a depressive phase of major depressive disorder or bipolar disorder in a patient, or for treating depressive symptoms in a patient with post-traumatic stress disorder (PTSD), the method comprising administering a therapeutically effective amount of (a) agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, and (b) an antidepressant other than agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) prior to initiation of treatment with agomelatine and the antidepressant.

4. A method for treating the depressive phase of bipolar disorder in a patient, the method comprising administering a therapeutically effective amount of (a) agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, and (b) (i) one or more mood stabilizers, (ii) one or more antidepressants other than agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, or (iii) a combination thereof, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30-40 Hz) prior to initiation of treatment with agomelatine and the one or more mood stabilizers, one or more antidepressants, or a combination thereof.

5. The method according to claim 4, wherein the patient had not been treated with an antidepressant prior to treatment with agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof in combination with an antidepressant.

6. The method according to any one of the prior claims, wherein the antidepressant comprises a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, bupropion or a pharmaceutically acceptable salt thereof, or any combination thereof.

7. A method for treating a depressive phase of major depressive disorder or bipolar disorder in a patient, or for treating depressive symptoms in a patient with post-traumatic stress disorder (PTSD), the method comprising administering a therapeutically effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30–40 Hz) prior to initiating agomelatine treatment.

8. The method according to any one of the prior claims, wherein the patient suffers from major depressive disorder and post-traumatic stress disorder.

9. The method according to any one of the prior claims, wherein the patient exhibits high EEG sample entropy (based on the 10-20 method of electrode arrangement) at the Pz electrode.

10. The method according to any one of the prior claims, wherein the patient is suffering from moderate to severe major depressive disorder.

11. The method according to any one of the prior claims, comprising orally administering approximately 25 to approximately 50 mg of agomelatine per day.

12. The method according to any one of the prior claims, comprising administering approximately 25 mg of agomelatine orally per day (preferably every night).

13. The method according to any one of the prior claims, comprising orally administering approximately 30 mg of agomelatine per day.

14. The method according to any one of claims 1 to 10, comprising orally administering approximately 50 mg of agomelatine per day.

15. The method according to any one of the prior claims, comprising administering agomelatine once daily before bedtime.

16. A method for treating the depressive phase of major depressive disorder or bipolar disorder in a patient, (a) Analyzing one or more indicators of the patient's responsiveness to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof as a treatment, wherein the one or more indicators are selected from EEG measurements of entropy or complexity and any combination of the foregoing, (b) The method comprising administering to the patient an effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient has been determined to be responsive to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof based on one or more of the indicators.

17. The method according to claim 16, wherein the patient suffers from moderate to severe major depressive disorder.

18. The method according to claim 16 or 17, wherein the patient did not respond well to antidepressants.

19. The method according to claim 18, wherein the antidepressant is selected from SSRIs, SNRIs, bupropion or pharmaceutically acceptable salts thereof, or any combination thereof.

20. The method according to claim 18, wherein the antidepressant is an SSRI.

21. The method according to any one of claims 18 to 20, wherein when the patient is treated with agomelatine or a prodrug thereof or a pharmaceutically acceptable salt thereof, the patient is simultaneously treated with the antidepressant.

22. The method according to any one of claims 16 to 21, wherein the patient is simultaneously treated with a second antidepressant.

23. The method according to claim 22, wherein the second antidepressant is selected from an SSRI, bupropion or a pharmaceutically acceptable salt thereof, or any combination thereof.

24. The method according to claim 23, wherein the second antidepressant is an SSRI.

25. The method according to any one of claims 16 to 24, wherein the EEG measurement value is a measurement value that indexes neuronal complexity.

26. The method according to any one of claims 16 to 25, wherein the EEG measurement is a measurement of predictability, a measurement of regularity, or any combination thereof.

27. The method according to claim 26, wherein the EEG measurement is selected from approximate entropy, trend-removed variation analysis, Higuchi fractal dimension, Katz fractal dimension, maximum Lyapunov exponent, modified multiscale entropy, multiscale entropy, aperiodic exponent, and any combination of the above.

28. The method according to claim 26, wherein the EEG measurement value is sample entropy.

29. The method according to any one of claims 16 to 28, wherein one or more indicators in step (a) are analyzed using stored subject history data, which includes data from a plurality of subjects having a depressive phase of major depressive disorder or bipolar disorder treated with agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, the data includes, for the plurality of subjects, one or more of the indicators used to analyze the efficacy of agomelatine treatment and the patients.

30. The method according to claim 29, wherein step (a) comprises determining a potential agomelatine efficacy score for the patient based on the stored subject history data, and step (b) comprises administering to the patient an effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient is determined to be responsive to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof based on the potential score.

31. A method for maintaining a normal mood state in a patient with bipolar disorder, the method comprising administering an effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof to the patient, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30–40 Hz) prior to initiating agomelatine treatment.

32. The method according to any one of the prior claims, wherein the EEG measurement is taken with the eyes closed at rest.

33. A method for treating major depressive disorder in a patient, wherein the patient has been treated with an antidepressant other than agomelatine, its prodrug or a pharmaceutically acceptable salt thereof, but has not responded well to the antidepressant, the method comprising administering to the patient a therapeutically effective dose of (a) agomelatine, its prodrug or a pharmaceutically acceptable salt thereof, and (b) the antidepressant, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30–40 Hz) before initiating agomelatine treatment.

34. The method according to claim 33, wherein the patient had a response to the antidepressant of less than 50%, as defined by the Antidepressant Therapeutic Response Questionnaire (ATRQ), before initiating treatment with agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof.

35. The method according to claim 33 or 34, wherein the dosage of the antidepressant was not altered for at least two weeks prior to agomelatine treatment.

36. A method for treating major depressive disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of (a) agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, and (b) an antidepressant other than agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30–40 Hz) before initiating agomelatine treatment.

37. The method according to any one of claims 33 to 36, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, bupropion or a pharmaceutically acceptable salt thereof, or any combination thereof.

38. The method according to claim 37, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or bupropion or a pharmaceutically acceptable salt thereof.

39. The method according to claim 37 or 38, wherein the selective serotonin reuptake inhibitor is not fluvoxamine.

40. A method for treating major depressive disorder in a patient, the method comprising administering to the patient a therapeutically effective dose of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient exhibits high EEG sample entropy using electroencephalography in the low gamma frequency range (30–40 Hz) prior to initiating agomelatine treatment.

41. The method according to any one of claims 33 to 40, wherein the patient exhibits high EEG sample entropy (based on the 10-20 method of electrode arrangement) at the Pz electrode.

42. The method according to any one of claims 33 to 41, wherein the patient is suffering from moderate to severe major depressive disorder.

43. The method according to any one of claims 33 to 42, comprising orally administering approximately 25 to approximately 50 mg of agomelatine per day.

44. The method according to claim 43, comprising orally administering approximately 25 mg of agomelatine per day.

45. The method according to claim 43, comprising orally administering approximately 30 mg of agomelatine per day.

46. The method according to claim 43, comprising orally administering approximately 50 mg of agomelatine per day.

47. The method according to any one of claims 33 to 46, comprising administering agomelatine once daily before bedtime.

48. The method according to any one of claims 33 to 46, comprising administering agomelatine once daily, nightly.

49. A method for treating major depressive disorder in patients, (a) Analyzing one or more indicators of the patient's responsiveness to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof as a treatment, wherein the one or more indicators are selected from EEG measurements of entropy or complexity and any combination of the foregoing, (b) The method comprising administering to the patient an effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient has been determined to be responsive to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof based on one or more of the indicators.

50. The method according to claim 49, wherein the patient suffers from moderate to severe major depressive disorder.

51. The method according to claim 49 or 50, wherein the patient did not respond well to antidepressants.

52. The method according to claim 51, wherein the antidepressant is selected from SSRIs, SNRIs, bupropion or pharmaceutically acceptable salts thereof, or any combination thereof.

53. A method for treating major depressive disorder in a patient, wherein the patient has been treated with an antidepressant other than agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, but has not adequately responded to the antidepressant, and the method is (a) Analyzing one or more indicators of the patient's responsiveness to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof as a treatment, wherein the one or more indicators are selected from EEG measurements of entropy or complexity and any combination of the foregoing, (b) The method comprising administering to the patient an effective amount of (a) agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, and (b) the antidepressant, wherein the patient has been determined to be responsive to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof based on one or more of the indicators.

54. The method according to claim 53, wherein the patient had a response to the antidepressant of less than 50%, as defined by the Antidepressant Therapeutic Response Questionnaire (ATRQ), before initiating treatment with agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof.

55. The method according to claim 53 or 54, wherein no changes were made to the dosage of the antidepressant for at least two weeks prior to agomelatine treatment.

56. The method according to any one of claims 53 to 55, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, bupropion or a pharmaceutically acceptable salt thereof, or any combination thereof.

57. The method according to claim 56, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or bupropion or a pharmaceutically acceptable salt thereof.

58. The method according to claim 56 or 57, wherein the selective serotonin reuptake inhibitor is not fluvoxamine.

59. The method according to any one of claims 49 to 58, wherein the EEG measurement value is a measurement value that indexes neuronal complexity.

60. The method according to any one of claims 49 to 59, wherein the EEG measurement is a measurement of predictability, a measurement of regularity, or any combination thereof.

61. The method according to claim 60, wherein the EEG measurement is selected from approximate entropy, trend-removed variation analysis, Higuchi fractal dimension, Katz fractal dimension, maximum Lyapunov exponent, modified multiscale entropy, multiscale entropy, aperiodic exponent, and any combination of the above.

62. The method according to claim 60, wherein the EEG measurement value is the sample entropy.

63. The method according to any one of claims 49 to 62, wherein one or more indicators in step (a) are analyzed using stored subject history data, which includes data from a plurality of subjects having a depressive phase of major depressive disorder or bipolar disorder treated with agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, the data includes, for the plurality of subjects, one or more of the indicators used to analyze the efficacy of agomelatine treatment and the patients.

64. The method according to claim 63, wherein step (a) comprises determining a potential agomelatine efficacy score for the patient based on the stored subject history data, and step (b) comprises administering to the patient an effective amount of agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof, wherein the patient is determined to be responsive to agomelatine, its prodrug, or a pharmaceutically acceptable salt thereof based on the potential score.

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