Effective treatment of depression with benzylpiperazine-aminopyridine drugs in patients with learning and / or memory impairment or specific EEG features

Abstract

The present invention relates to the use of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone (NSI-189) or a pharmaceutically acceptable salt thereof in the treatment of depressively predominant psychiatric conditions, including major depressive disorder (MDD), bipolar disorder, post-traumatic stress disorder, substance use disorder, and depression-related aspects of schizophrenia (e.g., negative symptoms), in selected patients exhibiting learning and / or memory impairment. The present invention also relates to the use of NSI-189 or a pharmaceutically acceptable salt thereof in the treatment of depressively predominant psychiatric conditions, including major depressive disorder (MDD), in selected patients exhibiting learning and / or memory impairment or specific electroencephalographic characteristics.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 386,137, filed December 5, 2022, and U.S. Provisional Application No. 63 / 579,547, filed August 30, 2023, each of which is incorporated herein by reference.

[0002] Technical Field The present invention relates to the use of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone (NSI-189) or a pharmaceutically acceptable salt thereof in the treatment of depressively dominated psychiatric conditions, such as major depressive disorder (MDD) and / or post-traumatic stress disorder (PTSD), for example, in selected patients exhibiting learning and / or memory impairment. [Background technology]

[0003] Clinical treatment for depression involves evaluation and diagnosis based on a set of clinician-assessed and patient-reported symptoms, including depressed mood, lethargy, impaired thinking and concentration, appetite changes, and sleep and psychomotor changes, but not specifically on biological or quantitative behavioral variables. Evaluations, such as magnetic resonance imaging (MRI) and blood tests, are often performed to rule out nonpsychiatric causes of depression that require treatment other than antidepressants, including tumors, hypothyroidism, dementia, and metabolic disorders. After a patient is diagnosed with depression, such as major depressive disorder (MDD), clinicians may prescribe one of several antidepressant medications, primarily including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs), or atypical antidepressants.

[0004] Notably, antidepressant selection is a trial-and-error process, with no symptom profile or biological or quantitative behavioral indicators to guide drug selection. SSRIs are typically chosen as first-line medications because they are generally well tolerated, not because they are known to be more effective in general or for certain patients. However, most patients do not respond adequately to their first medication, at which point a trial-and-error process is underway to select the next medication. This next medication may be a switch (discontinuing one antidepressant and starting another) or adjunctive therapy (adding a new medication to the current antidepressant). On average, failure of one SSRI does not necessarily translate into a different response to another SSRI than to an SNRI or NDRI (29). Therefore, typical clinical evaluations do not provide useful information for subsequent medication selection, and external information unavailable to clinicians is needed to improve medication selection.

[0005] A similar situation exists for bipolar depression (including both bipolar I and bipolar II disorders). The only approved medications are atypical antipsychotics, which have limited efficacy and high rates of discontinuation due to intolerance, operate via the same mechanism, and are selected on a trial-and-error basis. (41) Traditional antidepressants are ineffective, are not approved by the U.S. FDA for the treatment of bipolar depression, and there are concerns that they may be more likely to induce mania.

[0006] The economic, social, and personal costs of depression are enormous, making it a leading cause of disability worldwide. This is even more pronounced in treatment-resistant depression (28), suggesting that identifying the optimal medication for an individual early in treatment could have many benefits for patients and society as a whole.

[0007] Similar clinical needs exist for other related conditions in which depressive symptoms are present. These symptoms include depressed mood, lack of pleasurable experiences (anhedonia), decreased motivation, and impaired attention, cognition, and decision-making. These conditions include major depressive disorder, bipolar depression (e.g., bipolar I disorder or bipolar II disorder), post-traumatic stress disorder, substance use disorder, and depression-related aspects of schizophrenia (e.g., negative symptoms). Importantly, these various depression-related symptoms or areas of dysfunction may co-occur and be functionally related. For example, patients with major depression may report depressed mood and lack of motivation. Similarly, patients diagnosed with other conditions that may co-occur with similar disorders, such as bipolar depression, post-traumatic stress disorder, and substance use disorder, may report the same symptoms. While schizophrenia is often thought of in terms of prominent hallucinations and delusions, negative symptoms, such as depression, often contribute significantly to long-term disability and impairment. Therefore, therapeutic approaches that encompass these multiple, related functional systems may be important for any one of these clinical conditions and may be equally applicable across them.

[0008] It has been proposed that depression and depressive symptoms (e.g., in PTSD) arise, at least in part, from impaired neuronal proliferation, impaired neuronal growth and differentiation, and impaired elaboration of neuronal substructures important for neurotransmission and neuroplasticity in the adult brain (1-7). Furthermore, some theories suggest that drugs that reverse one or more of these dysfunctions could be effective antidepressants (1-7). For example, drugs clinically proven to be effective antidepressants in human patients with depression have also been demonstrated to induce neuronal growth and differentiation in the brains of adult animals (1, 3, 4).

[0009] Previous studies have shown that certain benzylpiperazine-aminopyridines or their open-chain forms can induce neuronal proliferation and maturation in the adult brains of animals (8, 9). One such benzylpiperazine-aminopyridine, NSI-189, was discovered by screening a chemical library against an in vitro model of hippocampal neurogenesis. Unlike recently approved antidepressants (e.g., SSRIs) by the U.S. Food and Drug Administration (FDA), the precise mechanism of action of NSI-189 remains unclear. No other drugs in this class have been approved by the FDA. The first small-scale Phase 1b clinical trial in patients with major depression provided promising evidence of potential antidepressant efficacy with NSI-189 at total daily doses of 40 mg, 80 mg, and 120 mg (10). However, because this trial was conducted in a small number of patients and aimed to establish safety and tolerability, only 18 patients were enrolled at all effective dose levels (six patients on placebo), and definitive efficacy data were not available.

[0010] A phase 2 trial was subsequently conducted in 220 patients with major depression (11). In this trial, patients were randomly assigned to receive a total daily dose of 40 mg or 80 mg of NSI-189 or a placebo in the first phase of the clinical trial design. Patients who received placebo and did not respond to the placebo were then re-randomized to 40 mg, 80 mg, or placebo in the second phase of the study. Treatment in both phases lasted 6 weeks. This design, known as a sequential parallel clinical design (SPCD), involves combining and statistically analyzing the differences in outcomes between related groups (e.g., drug vs. placebo) in each phase in a predefined manner. The FDA has approved two outcome measures for the evaluation of depression in adults. See the June 2018 FDA draft guidance, "Major Depressive Disorder: Therapeutic Drug Development." These were the study's primary outcome, the Montgomery-Asberg Depression Rating Scale (MADRS), and its key secondary outcome, the Hamilton Depression Rating Scale (HDRS). However, despite promise from animal studies and early human trials, the results of this 220-patient study failed to demonstrate evidence of antidepressant efficacy on the primary outcome, the MADRS, or the secondary outcome, the HDRS, in either the overall SPCD analysis or the analyses of each stage alone (11). The 80 mg daily dose did not demonstrate efficacy on any of the study measures (11). The benefits of NSI-189 on depression and cognitive function were reported to be independent effects (27).

[0011] Although nominally significant effects were observed at the 40 mg dose (but not at the 80 mg dose) compared with placebo on several secondary measures, these results were not corrected for multiple comparisons (and would not have withstood correction) and do not reflect measures acceptable to the U.S. FDA to support a drug's efficacy as an antidepressant. Therefore, NSI-189 was found to be an ineffective antidepressant. Furthermore, given that uncorrected results on secondary measures are sometimes used to draw positive conclusions about a compound's efficacy, these results suggest the potential for efficacy at 40 mg, but not at 80 mg. While higher doses are typically expected to be more effective than lower doses, this is surprising, reflecting an inverse dose-response curve. Following these results, development of NSI-189 was discontinued.

[0012] There is a continuing need for improved treatments for depression, such as antidepressants with different mechanisms of action than those currently used in treatment. Summary of the Invention

[0013] The inventors have discovered that (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone (NSI-189) (e.g., 80 mg of NSI-189) is effective in treating depression (e.g., improves depressive symptoms) in patients who: (i) have an objectively determined learning and / or memory impairment (e.g., verbal memory impairment as determined, for example, by VM-REACT (a computerized test of verbal memory recall)); or (ii) exhibit an electroencephalogram (EEG) comprising: (A) a low acyclic index; (B) high power in the low gamma range (e.g., 31-50 Hz, 31-60 Hz, or 35-45 Hz); (C) low power in the alpha frequency (8-12 Hz); or (D) any combination of (A), (B), and (C); or (iii) both (i) and (ii). This is surprising because NSI-189 was previously reported to be ineffective in treating major depressive disorder, and the 80 mg dose did not demonstrate efficacy on any study endpoint for the entire study population (including all secondary endpoints).

[0014] One embodiment of the present invention is a method for treating major depressive disorder, or one or more symptoms thereof, in a human patient with an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), by orally administering to the patient about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily. In one embodiment, the patient exhibits an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range; (iii) low power in the alpha frequency; or (iv) any combination of any of (i), (ii), and (iii).

[0015] Another embodiment is a method for treating major depressive disorder, or one or more symptoms thereof, in a human patient exhibiting an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range (31-50 Hz); (iii) low power in the alpha frequency range; or (iv) any combination of the foregoing. The method comprises orally administering to the patient about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily. In one embodiment, about 60 to about 100 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily. In one embodiment, about 80 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily.

[0016] Yet another embodiment is a method of treating bipolar depression, or one or more symptoms thereof, in a human patient with an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), by orally administering about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily. In one embodiment, the patient exhibits an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range; (iii) low power in the alpha frequency; or (iv) any combination of any of (i), (ii), and (iii).

[0017] Another embodiment is a method for treating bipolar depression, or one or more symptoms thereof, in a human patient exhibiting an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range (31-50 Hz); (iii) low power in the alpha frequency range; or (iv) any combination of the foregoing. The method comprises orally administering to the patient about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily. In one embodiment, about 60 to about 100 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily. In one embodiment, about 80 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily.

[0018] Yet another embodiment is a method of selecting a therapy for treating a human patient for major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, bipolar depression, or one or more symptoms thereof, the method comprising: (a) objectively assessing whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to have a learning disability and / or memory impairment. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to not have a learning disability and / or memory impairment.

[0019] Yet another embodiment is a method of selecting a therapy for and treating a human patient for major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, bipolar depression, or one or more symptoms thereof, the method comprising: (a) diagnosing the patient as suffering from major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, an episode of major depressive disorder, or bipolar depression; (b) To objectively assess whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment as determined by the VM-REACT) for the purpose of selecting a treatment for the patient; and (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into account the patient's diagnosis and an objective assessment that the patient has a learning disability and / or memory impairment; (d) if NSI-189 or a pharmaceutically acceptable salt thereof is optionally prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0020] Yet another embodiment is a method for determining whether a patient suffering from major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, or bipolar depression can be effectively treated with NSI-189, and for treating a human patient susceptible to such treatment, the method comprising: (a) objectively determining whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment); (b) if the patient is determined to have a learning disability and / or memory impairment from step (a), initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is determined to not have a learning disability and / or memory impairment from step (a).

[0021] Yet another embodiment is a method of treating major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, bipolar depression, or one or more symptoms thereof in a human patient, comprising: (a) prescribing about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to a patient daily, the prescribing being carried out in response to (i) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, major depressive episode, bipolar depression, or one or more symptoms thereof, in a patient having an objectively determined learning disability and / or memory impairment, and (ii) an objective determination that the patient has a learning disability and / or memory impairment (e.g., verbal memory impairment); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0022] Yet another embodiment is a method of treating major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, bipolar depression, or one or more symptoms thereof in a human patient, comprising: (a) diagnosing a patient as suffering from major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, or bipolar depression, or one or more symptoms thereof; (b) prescribing about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to a patient daily, the prescribing being in response to (i) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, major depressive episode, bipolar depression, or one or more symptoms thereof, in a patient with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), and (ii) an objective determination that the patient has a learning disability and / or memory impairment; (c) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0023] Yet another embodiment is a method of treating major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, bipolar depression, or one or more symptoms thereof in a human patient, comprising: (a) analyzing one or more indicators of the patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include an objectively determined learning impairment and / or memory impairment; (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof.

[0024] Yet another embodiment is a method of selecting a therapy for and treating a human patient for major depressive disorder or one or more symptoms thereof, comprising: (a) For purposes of selecting a treatment for a patient, assess whether the patient (i) has an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), (ii) exhibits an electroencephalogram (EEG) that includes (A) a low aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (b) if the patient is assessed from step (a) as satisfying (i), (ii), or (iii), initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) as not having a learning disability and / or memory impairment.

[0025] Yet another embodiment is a method of selecting a therapy for and treating a human patient for major depressive disorder or one or more symptoms thereof, comprising: (a) diagnosing the patient as suffering from major depressive disorder; (b) for the purpose of selecting a treatment for the patient, assessing whether the patient (i) has an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), (ii) exhibits an electroencephalogram (EEG) that includes (A) a low aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into consideration the patient's diagnosis and an assessment that the patient meets (i), (ii), or (iii); (d) if NSI-189 or a pharmaceutically acceptable salt thereof is selectively prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0026] Yet another embodiment is a method for determining whether a patient suffering from major depressive disorder can be effectively treated with NSI-189 and treating a human patient susceptible to such treatment, the method comprising: (a) For purposes of selecting a treatment for a patient, assess whether the patient (i) has an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), (ii) exhibits an electroencephalogram (EEG) that includes (A) a low aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (b) if step (a) determines that the patient satisfies (i), (ii), or (iii), commencing oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises step (c), if step (a) determines that the patient does not have a learning disability and / or memory impairment, not commencing oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0027] Yet another embodiment is a method of treating major depressive disorder or one or more symptoms thereof in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, the prescribing being performed in response to: (I) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment of major depressive disorder, or symptoms thereof, in (i) a patient having an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), (ii) a patient exhibiting an electroencephalogram (EEG) comprising: (A) a low acyclic index; (B) high power in the low gamma range (31-50 Hz); (C) low power in the alpha frequency; or (D) an electroencephalogram (EEG) comprising any combination of (A), (B), and (C); or (iii) a patient exhibiting both (i) and (ii); and (II) a determination that the patient satisfies (i), (ii), or (iii); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0028] Yet another embodiment is a method of treating major depressive disorder or one or more symptoms thereof in a human patient, comprising: (a) diagnosing a patient as suffering from major depressive disorder; (b) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, the prescribing being performed in response to: (I) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment of major depressive disorder, or symptoms thereof, in (i) a patient with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), (ii) a patient exhibiting an electroencephalogram (EEG) comprising: (A) a low acyclic index; (B) high power in the low gamma range (31-50 Hz); (C) low power in the alpha frequency; or (D) any combination of (A), (B), and (C); or (iii) a patient exhibiting both (i) and (ii); and (II) a determination that the patient satisfies (i), (ii), or (iii); (c) orally administering to the patient the formulated (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

[0029] Yet another embodiment is a method of treating major depressive disorder or one or more symptoms thereof in a human patient, comprising: (a) analyzing one or more indicators of a patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include: (i) an objectively determined learning and / or memory impairment (e.g., verbal memory impairment); (ii) an electroencephalogram (EEG) comprising (A) a low acyclic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, or (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof.

[0030] Yet another embodiment is a method for treating major depressive episodes in a human patient with an objectively determined learning and / or memory impairment (e.g., verbal memory impairment) by oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily. In one embodiment, about 60 to about 100 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily. In a preferred embodiment, about 80 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily.

[0031] Yet another embodiment is a method of selecting a therapy for and treating a major depressive episode in a human patient in need thereof, the method comprising: (a) objectively assessing whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to have a learning disability and / or memory impairment. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to not have a learning disability and / or memory impairment.

[0032] Yet another embodiment is a method of selecting a therapy for a major depressive episode in a human patient and treating the patient, comprising: (a) diagnosing the patient as suffering from a major depressive episode; (b) To objectively assess whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment as determined by the VM-REACT) for the purpose of selecting a treatment for the patient; and (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into account the patient's diagnosis and an objective assessment that the patient has a learning disability and / or memory impairment; (d) if NSI-189 or a pharmaceutically acceptable salt thereof is selectively prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0033] Yet another embodiment is a method for determining whether a patient suffering from a major depressive episode can be effectively treated with NSI-189 and treating a human patient susceptible to such treatment, the method comprising: (a) objectively determining whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment); (b) if the patient is determined to have a learning disability and / or memory impairment from step (a), initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is determined to not have a learning disability and / or memory impairment from step (a).

[0034] Yet another embodiment is a method of treating a major depressive episode in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in response to (i) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for major depressive episodes in patients with an objectively determined learning disability and / or memory impairment, and (ii) an objective determination that the patient has a learning disability and / or memory impairment (e.g., verbal memory impairment); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0035] Yet another embodiment is a method of treating a major depressive episode in a human patient, comprising: (a) diagnosing a patient as suffering from a major depressive episode; (b) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to the patient, wherein the prescribing is carried out in response to (i) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for major depressive episodes in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), and (ii) an objective determination that the patient has a learning disability and / or memory impairment; (c) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0036] Yet another embodiment is a method of treating a major depressive episode in a human patient, comprising: (a) analyzing one or more indicators of the patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include an objectively determined learning impairment and / or memory impairment; (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof.

[0037] Yet another embodiment is a method of selecting and initiating therapy for and treating a major depressive episode in a human patient, comprising: (a) assessing whether a patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to have an objectively determined learning and / or memory impairment. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to not have an objectively determined learning and / or memory impairment.

[0038] Yet another embodiment is a method of selecting a therapy for a major depressive episode in a human patient and treating the patient, comprising: (a) diagnosing the patient as suffering from a major depressive episode; (b) assessing whether the patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting the patient's treatment; (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into account the patient's diagnosis and an assessment that the patient has an objectively determined learning and / or memory impairment; (d) if NSI-189 or a pharmaceutically acceptable salt thereof is optionally prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0039] Yet another embodiment is a method for determining whether a patient suffering from a major depressive episode can be effectively treated with NSI-189 and treating a human patient susceptible to such treatment, the method comprising: (a) assessing whether a patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) upon determination from step (a) that the patient has an objectively determined learning disability and / or memory impairment, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises step (c), upon determination from step (a) that the patient does not have an objectively determined learning disability and / or memory impairment, not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0040] Yet another embodiment is a method of treating a major depressive episode in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in accordance with marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for major depressive episodes in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0041] Yet another embodiment is a method of treating a major depressive episode in a human patient, comprising: (a) diagnosing a patient as suffering from a major depressive episode; (b) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in accordance with marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment of major depressive episodes in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment); (c) orally administering to the patient the formulated (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

[0042] Yet another embodiment is a method of treating a major depressive episode in a human patient, comprising: (a) analyzing one or more indicators of a patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include an objectively determined learning impairment and / or memory impairment (e.g., verbal memory impairment); (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment of any of the methods of treating a major depressive episode described herein, the patient is suffering from major depressive disorder.

[0044] In one embodiment of any of the methods of treating a major depressive episode described herein, the patient is suffering from bipolar depression.

[0045] In one embodiment of any of the methods of treating a major depressive episode described herein, the patient is suffering from bipolar I depression.

[0046] In one embodiment of any of the methods of treating a major depressive episode described herein, the patient is suffering from bipolar II depression.

[0047] Yet another embodiment is a method for treating bipolar depression in a human patient with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) by oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily. In one embodiment, about 60 to about 100 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily. In a preferred embodiment, about 80 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotics, mood stabilizers, or any combination of any of the foregoing. In one embodiment, the patient exhibits an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range; (iii) low power in the alpha frequency; or (iv) any combination of any of (i), (ii), and (iii).

[0048] Yet another embodiment is a method of selecting a therapy for and treating bipolar depression in a human patient in need thereof, the method comprising: (a) For purposes of selecting a treatment for a patient, assess whether the patient (i) has an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), (ii) exhibits an electroencephalogram (EEG) that includes (A) a low aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (b) initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) as satisfying (i), (ii), or (iii). In one embodiment, the method further comprises step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) as not satisfying (i) or (ii). In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0049] Yet another embodiment is a method of selecting a therapy for bipolar depression in a human patient and treating the patient, comprising: (a) diagnosing the patient as suffering from bipolar depression; (b) for the purpose of selecting a treatment for the patient, assessing whether the patient (i) has an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), (ii) exhibits an electroencephalogram (EEG) that includes (A) a low aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into consideration the patient's diagnosis and an objective assessment that the patient meets (i), (ii), or (iii); (d) if NSI-189 or a pharmaceutically acceptable salt thereof is optionally prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0050] Yet another embodiment is a method for determining whether a patient suffering from bipolar depression can be effectively treated with NSI-189 and treating a human patient susceptible to such treatment, the method comprising: (a) For purposes of selecting a treatment for a patient, assess whether the patient (i) has an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), (ii) exhibits an electroencephalogram (EEG) that includes (A) a low aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (b) if step (a) determines that the patient satisfies (i), (ii), or (iii), initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises step (c) if step (a) determines that the patient does not have a learning disability and / or memory impairment, not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0051] Yet another embodiment is a method of treating bipolar depression in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in response to: (I) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for bipolar depression in (i) a patient with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), (ii) a patient exhibiting an electroencephalogram (EEG) comprising: (A) a low acyclic index; (B) high power in the low gamma range (31-50 Hz); (C) low power in the alpha frequency; or (D) any combination of (A), (B), and (C); or (iii) a patient exhibiting both (i) and (ii); and (II) a determination that the patient satisfies (i), (ii), or (iii); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0052] Yet another embodiment is a method of treating bipolar depression in a human patient, comprising: (a) diagnosing a patient as suffering from bipolar depression; (b) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is performed in response to (I) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for bipolar depression in (i) a patient with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), (ii) a patient exhibiting an electroencephalogram (EEG) comprising (A) a low acyclic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, or (D) any combination of (A), (B), and (C), or (iii) a patient exhibiting both (i) and (ii); and (II) a determination that the patient satisfies (i), (ii), or (iii); and (c) orally administering the prescribed NSI-189 or a pharmaceutically acceptable salt thereof to the patient. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0053] Yet another embodiment is a method of treating bipolar depression in a human patient, comprising: (a) analyzing one or more indicators of a patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include: (i) an objectively determined learning and / or memory impairment (e.g., verbal memory impairment); (ii) an electroencephalogram (EEG) comprising (A) a low acyclic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, or (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0054] Yet another embodiment is a method of selecting a therapy for bipolar depression in a human patient and treating the patient, comprising: (a) assessing whether a patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to have an objectively determined learning and / or memory impairment. In one embodiment, the method further comprises step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to not have an objectively determined learning and / or memory impairment. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0055] Yet another embodiment is a method of selecting a therapy for bipolar depression in a human patient and treating the patient, comprising: (a) diagnosing the patient as suffering from bipolar depression; (b) assessing whether the patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting the patient's treatment; (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into account the patient's diagnosis and an assessment that the patient has an objectively determined learning and / or memory impairment; (d) if NSI-189 or a pharmaceutically acceptable salt thereof is optionally prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0056] Yet another embodiment is a method for determining whether a patient suffering from bipolar depression can be effectively treated with NSI-189 and treating a human patient susceptible to such treatment, the method comprising: (a) assessing whether a patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) upon determination from step (a) that the patient has an objectively determined learning and / or memory impairment, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if determination from step (a) that the patient does not have an objectively determined learning and / or memory impairment. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0057] Yet another embodiment is a method of treating bipolar depression in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in accordance with marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for bipolar depression in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0058] Yet another embodiment is a method of treating bipolar depression in a human patient, comprising: (a) diagnosing a patient as suffering from bipolar depression; (b) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in accordance with marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment for bipolar depression in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment); and (c) orally administering to the patient the prescribed (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0059] Yet another embodiment is a method of treating bipolar depression in a human patient, comprising: (a) analyzing one or more indicators of a patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include an objectively determined learning impairment and / or memory impairment (e.g., verbal memory impairment); (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof. In one embodiment, NSI-189 is administered as monotherapy. In another embodiment, the patient is concurrently treated with one or more antipsychotic agents, mood stabilizers, or any combination of any of the foregoing.

[0060] Yet another embodiment is a method for treating post-traumatic stress disorder (PTSD), or one or more symptoms thereof, in a human patient with an objectively determined learning and / or memory impairment (e.g., verbal memory impairment), by oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily. In one embodiment, about 60 to about 100 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily. In one embodiment, about 80 mg of NSI-189 or a pharmaceutically acceptable salt thereof is administered daily.

[0061] Yet another embodiment is a method of selecting a therapy for and treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient in need thereof, the method comprising: (a) objectively assessing whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to have a learning disability and / or memory impairment. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to not have a learning disability and / or memory impairment.

[0062] Yet another embodiment is a method of selecting a therapy for and treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) diagnosing the patient as suffering from post-traumatic stress disorder (PTSD); (b) To objectively assess whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment as determined by the VM-REACT) for the purpose of selecting a treatment for the patient; and (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into account the patient's diagnosis and an objective assessment that the patient has a learning disability and / or memory impairment; (d) if NSI-189 or a pharmaceutically acceptable salt thereof is optionally prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0063] Yet another embodiment is a method for determining whether a patient suffering from post-traumatic stress disorder (PTSD) can be effectively treated with NSI-189 and for treating a human patient susceptible to such treatment, the method comprising: (a) objectively determining whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment); (b) if the patient is determined to have a learning disability and / or memory impairment from step (a), initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is determined to not have a learning disability and / or memory impairment from step (a).

[0064] Yet another embodiment is a method of treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in response to (i) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment of PTSD or symptoms thereof in a patient having an objectively determined learning disability and / or memory impairment, and (ii) an objective determination that the patient has a learning disability and / or memory impairment (e.g., verbal memory impairment); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0065] Yet another embodiment is a method of treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) diagnosing a patient as suffering from post-traumatic stress disorder (PTSD); (b) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to the patient, wherein the prescribing is carried out in response to (i) marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment of PTSD or symptoms thereof in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), and (ii) an objective determination that the patient has a learning disability and / or memory impairment; (c) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0066] Yet another embodiment is a method of treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) analyzing one or more indicators of the patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include an objectively determined learning impairment and / or memory impairment; (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof.

[0067] Yet another embodiment is a method of selecting a therapy for and treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) assessing whether a patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to have an objectively determined learning and / or memory impairment. In one embodiment, the method further comprises the step (c) of not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily if the patient is assessed from step (a) to not have an objectively determined learning and / or memory impairment.

[0068] Yet another embodiment is a method of selecting a therapy for and treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) diagnosing the patient as suffering from post-traumatic stress disorder (PTSD); (b) assessing whether the patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting the patient's treatment; (c) selectively prescribing NSI-189 or a pharmaceutically acceptable salt thereof to the patient, taking into account the patient's diagnosis and an assessment that the patient has an objectively determined learning and / or memory impairment; (d) if NSI-189 or a pharmaceutically acceptable salt thereof is optionally prescribed, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0069] Yet another embodiment is a method for determining whether a patient suffering from PTSD can be effectively treated with NSI-189 and treating a human patient susceptible to such treatment, the method comprising: (a) assessing whether a patient has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment) for the purpose of selecting a treatment for the patient; (b) upon determination from step (a) that the patient has an objectively determined learning disability and / or memory impairment, initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily. In one embodiment, the method further comprises step (c), upon determination from step (a) that the patient does not have an objectively determined learning disability and / or memory impairment, not initiating oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof to the patient daily.

[0070] Yet another embodiment is a method of treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in accordance with marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment of PTSD or symptoms thereof in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment); (b) orally administering the formulated NSI-189 or a pharmaceutically acceptable salt thereof to the patient.

[0071] Yet another embodiment is a method of treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) diagnosing a patient as suffering from post-traumatic stress disorder (PTSD); (b) prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to a patient, wherein the prescribing is carried out in accordance with marketing NSI-189 or a pharmaceutically acceptable salt thereof as providing an effective treatment of PTSD or symptoms thereof in patients with an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment); (c) orally administering to the patient the formulated (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

[0072] Yet another embodiment is a method of treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a human patient, comprising: (a) analyzing one or more indicators of a patient's responsiveness to NSI-189 or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include an objectively determined learning impairment and / or memory impairment (e.g., verbal memory impairment); (b) if the patient is determined to be responsive to NSI-189 or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof.

[0073] Yet another embodiment is a method of prescribing NSA-189 to a human patient suffering from major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, a major depressive episode, bipolar depression, or one or more symptoms thereof, comprising: (a) objectively assessing whether a patient has a learning disability and / or memory impairment (e.g., verbal memory impairment) for purposes of selecting a treatment for the patient; (b) if the patient is assessed as having a learning and / or memory impairment from step (a), prescribing about 40 to about 240 mg per day of NSI-189 or a pharmaceutically acceptable salt thereof to the patient. In one embodiment, the method further comprises the step (c) of not prescribing NSI-189 to the patient if the patient is assessed as not meeting (i) or (ii) from step (a).

[0074] Yet another embodiment is a method of treating a human patient suffering from major depressive disorder, bipolar depression, or one or more symptoms thereof, comprising administering NSI-189 to the patient, (a) Assess whether the patient (i) has an objectively determined learning disability and / or memory impairment (e.g., verbal memory impairment), (ii) exhibits an electroencephalogram (EEG) that includes (A) a low aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii); (b) if the patient is assessed from step (a) as meeting (i), (ii), or (iii), prescribing the patient for oral administration of about 40 to about 240 mg of NSI-189 or a pharmaceutically acceptable salt thereof per day. In one embodiment, the method further comprises step (c) of not prescribing NSI-189 to the patient if the patient is assessed from step (a) as not meeting (i) or (ii).

[0075] In any of the methods described herein, in one embodiment, the patient is treated with NSI-189 or a pharmaceutically acceptable salt thereof as monotherapy.

[0076] In any of the methods described herein, in one embodiment, the patient is concurrently treated with a second antidepressant (e.g., an SSRI, SNRI, mirtazapine, or bupropion) in addition to NSI-189 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient is concurrently treated with an SSRI, SNRI, mirtazapine, or bupropion. In another embodiment, the patient is concurrently treated with an SSRI. In yet another embodiment, the patient is concurrently treated with an SNRI. In yet another embodiment, the patient is concurrently treated with mirtazapine. In yet another embodiment, the patient is concurrently treated with bupropion.

[0077] In any of the methods described herein, in one embodiment, the patient is concurrently treated with an antipsychotic drug in addition to NSI-189 or a pharmaceutically acceptable salt thereof. In one embodiment, the antipsychotic drug is quetiapine, cariprazine, aripiprazole, brexpiprazole, lumateperone, or olanzapine. In another embodiment, the antipsychotic drug is quetiapine, lurasidone, cariprazine, or a combination of olanzapine and fluoxetine. In yet another embodiment, the antipsychotic drug is a combination of brexpiprazole and sertraline. In yet another embodiment, for the treatment of major depressive disorder, the patient is concurrently treated with NSI-189 or a pharmaceutically acceptable salt thereof and an antipsychotic drug selected from quetiapine, cariprazine, aripiprazole, brexpiprazole, and olanzapine. In yet another embodiment, for the treatment of bipolar depression, a patient is concurrently treated with NSI-189 or a pharmaceutically acceptable salt thereof and an antipsychotic selected from quetiapine, lurasidone, cariprazine, lumateperone, or a combination of olanzapine and fluoxetine. In yet another embodiment, for the treatment of PTSD, a patient is concurrently treated with NSI-189 or a pharmaceutically acceptable salt thereof and an antipsychotic selected from a combination of brexpiprazole and sertraline.

[0078] In one embodiment of any of the methods described herein, prior to treatment with NSI-189 or a pharmaceutically acceptable salt thereof, the patient has had an inadequate response to an antidepressant other than NSI-189 or a pharmaceutically acceptable salt thereof (e.g., an SSRI, SNRI, mirtazapine, or bupropion). Such patients may be treated simultaneously with (i) NSI-189 or a pharmaceutically acceptable salt thereof and (ii) the antidepressant to which the patient previously did not respond adequately. Alternatively, the patient may receive NSI-189 or a pharmaceutically acceptable salt thereof as monotherapy.

[0079] In any of the methods described herein, in one embodiment, the objectively assessed learning and / or memory impairment 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.

[0080] In one embodiment of any of the methods described herein, a patient with an objectively determined learning and / or memory impairment and / or the aforementioned EEG characteristic(s) is administered about 60 to about 100 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof, e.g., about 80 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof. In one embodiment, such a patient is administered about 40 mg of NSI-189 or a pharmaceutically acceptable salt thereof twice daily.

[0081] In any of the methods described herein, in one embodiment, NSI-189 or a pharmaceutically acceptable salt thereof is administered as (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone phosphate.

[0082] In any of the methods described herein, the learning disability and / or memory impairment may be assessed by a test such as VM-REACT (RecAll Computerized Test of Verbal Memory), Rey Auditory Verbal Learning Test, California Verbal Learning Test (including CVLT-II and CVLT-3), California Verbal Learning Test-Short Form, California Verbal Learning Test-Child Version, Hopkins Verbal Learning Test, Hopkins Verbal Learning Test-Revised, Philadelphia Verbal Learning Test, International Shopping List Test, Language Section of the Repeated Battery for the Assessment of Neuropsychological Status, Cerad Neuropsychological Assessment Battery. Word List Task, Children's Auditory Verbal Learning Test, Children's Memory Scale, Bay Area Verbal Learning Test, Cogstate Battery (including the following subtests: Behavioral Pattern Separation Test, Serial Paired Associate Learning Test, Face-Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List, One-Card Learning Test), CANTAB (including the following subtests: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Association, Paired Associate Learning, Verbal Recognition Memory), Penn Computerized Neurocognitive Battery (including the following subtests: Penn Word Memory Task, Penn The NIH Toolbox and its subtests (Face-Name Associative Memory Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test), the Memory Module of the Neuropsychological Assessment Battery (which may include the following subtests and their delayed recall and recognition components: List Learning, Figure Learning, Story Learning, and Daily Life Memory), the WHO / UCLA Auditory Verbal Learning Test, the Repeatable Neuropsychological Status Assessment Battery (which may include the following subtests and their delayed recall and recognition components: List Learning, Story Memory, and Figure Recall), and the Comprehensive Assessment of Memory and Learning (which may include the following subtests and their delayed recall and recognition components: List Learning, Story Memory, and Figure Recall). Components of intelligence: Picture memory, Design learning, Narrative memory, Verbal learning), Buschke Selective Recall Test, Wechsler Memory Scale (including the following subtests and their delayed recall and recognition components: Logical memory, Verbal paired association, Design, Visual reproduction), Woodcock-Johnson Long Term Recall Factor (including the following subtests and their delayed recall and recognition components: Narrative recall, Visual-auditory learning), Test of Memory and Learning (including the following subtests and their delayed recall and recognition components: Narrative memory, Face memory, Word selective memory, Visual selective memory, Abstract visual memory, Object recall, Visual sequential memory, Paired recall,Location Memory), NEPSY (including the following subtests and their delayed recall and cognitive components: List Memory, Design Memory, Face Memory, Name Memory, Story Memory, Sentence Repetition, and Word List Interference), Brief Visuospatial Memory Test-Revised, Benton Visual Retention Test, Rey Osterreith Complex Figure Test, and any combination of any of the foregoing. In a preferred embodiment, learning and / or memory impairment is assessed by the VM-REACT. In one embodiment, a composite of two or more scores on learning and / or memory impairment is used to assess the patient's learning and / or memory impairment.

[0083] In any of the methods described herein, the learning and / or memory impairment may be indicated by poor immediate recall on a verbal memory test such as the VM-REACT. In other words, the patient has a learning and / or memory impairment as objectively determined by poor immediate recall on a verbal memory test such as the VM-REACT.

[0084] In any of the methods described herein, the learning and / or memory impairment may be indicated by poor delayed recall on a verbal memory test such as the VM-REACT. In other words, the patient has a learning and / or memory impairment as objectively determined by poor delayed recall on a verbal memory test such as the VM-REACT.

[0085] In one embodiment of any of the methods described herein, the patient is not being treated concomitantly with a second antidepressant.

[0086] In another embodiment of any of the methods described herein, the patient is concurrently treated with a second antidepressant (eg, an SSRI, SNRI, mirtazapine, or bupropion).

[0087] In yet another embodiment of any of the methods described herein, prior to treatment with NSI-189 or a pharmaceutically acceptable salt thereof, the patient had an inadequate response to an antidepressant (e.g., an SSRI, SNRI, mirtazapine, or bupropion) (e.g., a standard of care antidepressant) other than NSI-189 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient has had an inadequate response to an antidepressant (e.g., an SSRI, SNRI, mirtazapine, or bupropion) in the current depressive episode. In another embodiment, the patient continues treatment with the previous antidepressant concurrently with administration of NSI-189 or a pharmaceutically acceptable salt thereof.

[0088] In another embodiment of any of the methods described herein, the patient is concurrently treated with an antipsychotic, a mood stabilizer, or a combination thereof, in addition to NSI-189 or a pharmaceutically acceptable salt thereof.

[0089] In a preferred embodiment, about 80 mg of NSI-189 or a pharmaceutically acceptable salt thereof (eg, NSI-189 phosphate) is administered daily.

[0090] The methods described herein can also be used to treat geriatric depression (e.g., patients with late-onset depression (first episode of depression after age 60)) in patients who are at least 50 years of age (e.g., at least 60 or 65 years of age) instead of major depressive disorder.

[0091] The above-described methods may be used to treat one or more symptoms, including depressive symptoms, anhedonia, loss of interest, apathy, decreased emotional expression, sensory loss, amotivation, lethargy, impaired thinking, psychomotor retardation, fatigue, or any combination of the foregoing, in human patients suffering from post-traumatic stress disorder (PTSD), bipolar depression, substance use disorder, or schizophrenia instead of major depressive disorder. For example, in one embodiment, the methods described herein are used to treat depressive symptoms of major depressive disorder, bipolar depression (e.g., bipolar I disorder or bipolar II disorder), post-traumatic stress disorder, substance use disorder, and depression-related aspects of schizophrenia (e.g., negative symptoms) in a patient in need thereof. For example, the methods can be used to treat depressive symptoms of bipolar I depression in a patient suffering from bipolar I depression (but not major depressive disorder).

[0092] In yet another embodiment, the patient is concurrently treated with one or more antidepressants (other than NSI-189 or a pharmaceutically acceptable salt thereof) (e.g., an SSRI, an SNRI, mirtazapine, or bupropion). In yet another embodiment, the patient is concurrently treated with one or more antipsychotics, mood stabilizers, or any combination of any of the foregoing.

[0093] Yet another embodiment includes (a) assessing whether a patient (i) is objectively determined to have impaired learning and / or memory, (ii) whether the patient exhibits an electroencephalogram (EEG) comprising (A) a low cycle index, (B) high power in the low gamma range (31-50 Hz), (C) low power in alpha frequencies, or (D) any combination of (A), (B), and (C), or (iii) both (i) and (ii), for the purpose of selecting a treatment for the patient; and (b) assessing whether a patient has an objectively determined learning and / or memory impairment, or exhibits an electroencephalogram (EEG) comprising (A) a low cycle index, (B) high power in the low gamma range (31-50 Hz), (C) low power in alpha frequencies, or (D) any combination of (A), (B), and (C). and administering an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof (e.g., about 40 mg to about 120, 160, or 240 mg, e.g., about 40 to about 120 mg, about 60 mg to about 100 mg, or about 80 mg of NSI-189 or a pharmaceutically acceptable salt thereof daily orally) to a patient exhibiting an electroencephalogram (EEG) containing the above-mentioned symptoms.

[0094] The above-described methods may be used to treat the negative symptoms of schizophrenia in a human patient instead of major depressive disorder. In another embodiment, the patient is not concurrently treated with an antidepressant (other than NSI-189) (e.g., an SSRI, SNRI, mirtazapine, or bupropion). In yet another embodiment, the patient is concurrently treated with one or more antidepressants (other than NSI-189 or a pharmaceutically acceptable salt thereof), antipsychotics, or mood stabilizers, or any combination of the foregoing.

[0095] One embodiment is a method of treating major depressive disorder, bipolar disorder, geriatric depression, schizophrenia, post-traumatic stress disorder, a substance use disorder, depressive symptoms (such as depressive symptoms of any of the foregoing disorders) or negative symptoms (such as negative symptoms of schizophrenia) in a patient, comprising: (a) receiving data consisting of one or more neurophysiological measures including a patient's EEG measurements (e.g., (A) aperiodic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, or (D) any combination of (A), (B), and (C); (b) optionally, receiving data comprising one or more indicators of the patient's cognitive impairment, slow or poor cognition, or difficulty in decision-making (e.g., one or more indicators of learning disability and / or memory impairment, such as verbal memory impairment); (c) administering an effective amount of NSI-189 or a pharmaceutically acceptable salt thereof to the patient, wherein the patient is determined to be responsive to NSI-189 based on data consisting of one or more neurophysiological measures and, optionally, one or more indicators of cognitive impairment, slowed or poor cognition, or difficulty in decision-making (e.g., one or more indicators of learning impairment and / or memory impairment). In one embodiment, the patient suffers from bipolar disorder in which depressive symptoms are prominent, geriatric depression, schizophrenia, post-traumatic stress disorder, or substance use disorder. In another embodiment, the patient suffers from major depressive disorder. In one embodiment, the patient is concurrently treated with one or more antidepressants (other than NSI-189 or a pharmaceutically acceptable salt thereof), antipsychotics, mood stabilizers, or any combination of the foregoing. In another embodiment, the patient is not concurrently treated with an antidepressant (other than NSI-189).

[0096] The neurophysiological measurement can be a measurement of brain activity, such as by electroencephalography (EEG). The EEG recording can measure power at one or more frequencies, relative power between frequencies, power ratio between frequencies (e.g., theta-gamma power ratio), coordance, power envelope connectivity, coherence, virtual coherence, phase-locking value, phase lag index, weighted phase lag index, spatial covariance, spectrally normalized spatial covariance, cross-frequency coupling, aperiodic index, alpha peak frequency, alpha peak frequency proximity, or information theory index and entropy. In one embodiment, the patient's EEG recording shows low power at central parietal electrodes at theta frequencies, low power at central parietal electrodes at alpha frequencies, low power at frontal electrodes at alpha frequencies, high aperiodic index at one or more occipital electrodes, or any combination of the foregoing.

[0097] The one or more indicators of cognitive impairment, cognitive slowness or poverty, or decision-making difficulty may include learning impairment and / or memory impairment (such as verbal memory impairment). The one or more indicators of cognitive impairment, cognitive slowness or poverty, or decision-making difficulty may include, for example, one or more measures from a simple reaction time task, a choice reaction time task, a one-back working memory task, a verbal learning and / or memory task, and a visual learning task, as well as a self-report questionnaire. In a preferred embodiment, the one or more indicators include a measure of learning and / or memory, such as verbal memory (e.g., VM-REACT). The indicators may also include those related to learning and / or memory described herein, including tests of learning and / or memory described herein (e.g., VM-REACT). In a preferred embodiment, the indicator is learning impairment and / or memory impairment assessed by VM-REACT. Other measures include the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Repeatable Neuropsychological Assessment Test (RBANS), Dementia Rating Scale (DRS), Cambridge Neuropsychological Test Automated Battery (CANTAB) and its subtests (Motor Screening, Matching to Sample Visual Search, Delayed Matching to Sample, Pattern Recognition Memory Immediate / Delayed, Spatial Recognition Memory, Paired Associate Learning, Spatial Span, Spatial Working Memory, Big / Little Circle, Intra- / Extra-dimensional Shift, Rapid Visual Processing, Time to Remeasure, Cambridge Stockings), TabCAT and its subtests (Dot Counting, Flanker, Matching , Running Dots, Set Shifting, Tempo, Favorites, Animal Fluency, Rapid Naming, and Quick Tap), NIH Examiner and its subtests (Dot Counting, N-Back, Flanker, Continuous Performance Test, Non-Performance Errors, Set Shifting, Phoneme Fluency, Category Fluency, Unstructured Task, Insight), NIH Toolbox and its subtests (Dimensional Change Card Sorting Test, Face-Name Associative Memory Test, Flanker Inhibitory Control and Attention Test, List Sorting Working Memory Test, Oral Reading Recognition Test, Oral Symbol Digit Count Test, Pattern Comparison Processing Speed ​​Test, Picture Sequence Memory Test, Picture Word Test, Rey Auditory Verbal Learning Test, Speed ​​Matching Test, and Visual Reasoning Test),The Penn Computerized Neuropsychological and Neurocognitive Battery and its subtests (Penn Conditional Exclusion Test, Penn Serial Performance Test, Letter N-Back Task, Penn Word Memory Task, Penn Face Memory Task, Visual Object Learning Test, Penn Verbal Reasoning Test, Penn Matrix Reasoning Test, Penn Line Orientation Test, Penn Emotion Discrimination Test, Penn Emotion Differentiation Test, Penn Age Differentiation Test), the Cogstate Battery and its subtests (Behavioral Pattern Separation Test, Serial Paired Associative Learning Test, Detection Test, Face-Name Associative Memory Test, Finger Tapping Test, Groton Maze Learning Test, Identification Test, International Everyday Symbol Substitution Test - Drugs, International Digit Symbol Substitution Test, International Shopping List Test, One-Back Test, One-Card Learning Test, Psychomotor Vigilance Test, Social-Emotional Cognition Test, Sustained Attention Test, Sustained Response Attention Test, Two-Back Test), the Digit Symbol Substitution Task, Oddball Task, Flanker Task, Wisconsin Card Sorting Task, Modified Wisconsin Card Sorting Task, Examples of tests include the Delis-Kaplan Executive Function System (D-KEFS) Sorting Task, Category Test, Trail Making Task, D-KEFS Trail Making Test, Spatial / Corsi Block Task, Digit Span Task, Backward Digit Span Task, Verbal Fluency Task, D-KEFS Verbal Fluency Test, Figure Design Fluency Task, D-KEFS Design Fluency Test, Symbol Digit Modality Test, Continuous Performance Test (CPT), Wechsler Adult Intelligence Scale (WAIS) Coding Subtest, Digit Vigilance Test, d2 Attention Test, WAIS Symbol Search Subtest, WAIS Cancellation Subtest, Neuropsychological Assessment Battery (NAB) Digit Letter Subtest, NAB Digit Span Subtest, Ruff 2 & 7 Selective Attention Test, Stroop Color Word Test, NAB Maze and Other Mazes Test, Spatial Planning / Tower Test, Stroop Test, D-KEFS Color-Word Interference Test, or Repeatable Neuropsychological Assessment Battery (RBANS) Coding Subtest. In one embodiment, the measures include typing fluency, verbal fluency (e.g., verbal fluency task or D-KEFS verbal fluency task), simple reaction time, choice reaction time, digit symbol substitution task, trail making task (parts A and B), Wisconsin card sorting task,and one or more measures from the Flanker task. One or more measures of cognitive impairment can be calculated as a standardized score (e.g., z-score, T-score, standard score, scale score, percentile rank, Stanine score) that normalizes the patient to a healthy population. In one embodiment, one or more measures of cognitive impairment, cognitive slowness or poverty (e.g., memory impairment and / or learning disability), and / or decision-making difficulty are combined into a composite cognitive task performance score.

[0098] In one embodiment, machine learning or multivariate modeling (such as those described in International Publication No. WO2020 / 081609 and U.S. Patent Publication Nos. 2021 / 0038150, 2019 / 126055, 2020 / 054888, and 2020 / 0401938, the specifications of each of which are incorporated herein by reference) is applied to predict a patient's responsiveness to administration of NSI-189.

[0099] In one embodiment of any of the methods described herein, about 40 to about 120, 160, or 240 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof is administered to the patient. For example, about 40 to about 120 mg, about 60 to about 120 mg, about 70 to about 120 mg, or about 80 to about 100 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof is administered to the patient. In a preferred embodiment, about 80 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof is administered to the patient. In any of the methods described herein, the preferred route of administration is oral.

[0100] In one embodiment of any of the foregoing methods, the patient has previously been treated with one or more antidepressants (e.g., an SSRI, an SNRI, mirtazapine, or bupropion) but has failed to respond thereto, and continues treatment with the one or more antidepressants after treatment with NSI-189 (or a pharmaceutically acceptable salt thereof) is initiated. In other words, NSI-189 or a pharmaceutically acceptable salt thereof is provided as adjunctive therapy to the one or more antidepressants (e.g., an SSRI, an SNRI, mirtazapine, or bupropion). 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 serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, mirtazapine, bupropion, and any combination of any of the foregoing. The patient may be suffering from major depressive disorder. In one embodiment, 40 mg of NSI-189 or a pharmaceutically acceptable salt thereof, eg, NSI-189 phosphate, is administered orally twice daily.

[0101] In one embodiment of any of the aforementioned methods, the patient has bipolar depression and has previously been treated with, but failed to respond to, one or more mood stabilizers, antipsychotics, or any combination of the foregoing, and continues to receive treatment with, one or more mood stabilizers, antipsychotics, or any combination of the foregoing after treatment with NSI-189 (or a pharmaceutically acceptable salt thereof) is initiated. In other words, NSI-189 or a pharmaceutically acceptable salt thereof is provided as adjunctive therapy to one or more mood stabilizers, antipsychotics, or any combination of the foregoing. In one embodiment, 40 mg of NSI-189 or a pharmaceutically acceptable salt thereof, e.g., NSI-189 phosphate, is orally administered twice daily.

[0102] In one embodiment, the patient is suffering from anhedonia, hi another embodiment, the patient is suffering from suicidal tendencies.

[0103] In another embodiment of any of the methods described herein, the patient suffers from both major depressive disorder and post-traumatic stress disorder.

[0104] Yet another embodiment comprises: at least one data processor; and at least one memory storing instructions that, when executed by said at least one data processor, result in operations including: (a) receiving data comprising one or more neurophysiological measurements (such as those described herein) in a patient; (b) optionally, receiving data comprising one or more indicators of cognitive impairment or cognitive decline (including those described herein, learning impairment and / or memory impairment) in the patient; (c) using a multivariate model (e.g., a machine learning model) to analyze (i) data consisting of one or more neurophysiological measurements in the patient, and (ii) optionally, data consisting of one or more indicators of cognitive impairment or cognitive decline, to predict the patient's responsiveness to NSI-189; and (d) outputting a prediction of the patient's responsiveness to NSI-189 based on the analyzed data;

[0105] Prior to step (c), a multivariate model (e.g., a machine learning model) may be used to analyze data from previous patients who have been administered NSI-189 (or a pharmaceutically acceptable salt thereof), one or more neurophysiological measures from those patients, and optionally one or more indicators of cognitive impairment (e.g., learning impairment and / or memory impairment).

[0106] In one embodiment, the instructions provide for an operation further comprising outputting a recommendation for administering an effective amount of NSI-189, or a pharmaceutically acceptable salt thereof.

[0107] The neurophysiological measurement can be an electroencephalogram (EEG) recording, for example, an EEG recording. The EEG recording can measure power at one or more frequencies, relative power between frequencies, power ratio between frequencies, codance, power envelope connectivity, coherence, virtual coherence, phase-locking value, phase lag index, weighted phase lag index, spatial covariance, cross-frequency coupling, aperiodic index, alpha peak frequency, spectrally normalized spatial covariance, alpha peak frequency coherence, or information theory index and entropy. In one embodiment, the patient's EEG recording exhibits low power at central parietal electrodes at theta frequencies, low power at central parietal electrodes at alpha frequencies, low power at frontal electrodes at alpha frequencies, high aperiodic index at one or more occipital electrodes, or any combination of any of the foregoing.

[0108] The one or more indicators of cognitive impairment, slowness or poverty of cognition, learning and memory impairment (e.g., verbal memory impairment), and / or difficulty in decision-making can include one or more measures from a simple reaction time task, a choice reaction time task, a one-back working memory task, a verbal learning and / or memory task, and a visual learning task, as well as self-report questionnaires. In preferred embodiments, the one or more indicators include a measure of learning and / or memory, such as verbal memory (e.g., VM-REACT). The indicators can also include indicators of learning and / or memory described herein. Other measures include the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Repeatable Neuropsychological Assessment Test (RBANS), Dementia Rating Scale (DRS), Cambridge Neuropsychological Test Automated Battery (CANTAB) and its subtests (Motor Screening, Matching to Sample Visual Search, Delayed Matching to Sample, Pattern Recognition Memory Immediate / Delayed, Spatial Recognition Memory, Paired Associate Learning, Spatial Span, Spatial Working Memory, Big / Little Circles, Intra- / Extra-Dimensional Shifting, Rapid Visual Processing, Time to Remeasure, Cambridge Stockings), TabCAT and its subtests (Dot Counting, Flanker, Match, Running Dot, Set Shifting, Tempo, Favourite, Animal Fluency, Rapid Naming, Quick Tap), NIH Examiner and its subtests (Dot Counting, N-Ba ck, Flanker, Continuous Performance Test, Non-Performance Errors, Set Shifting, Phonemic Fluency, Category Fluency, Unstructured Task, Insight), NIH Toolbox and its subtests (Dimensional Change Card Sorting Test, Face-Name Associative Memory Test, Flanker Inhibitory Control and Attention Test, List Sorting Working Memory Test, Oral Reading Recognition Test, Oral Symbol Digit Scaling Test, Pattern Comparison Processing Speed ​​Test, Picture Sequence Memory Test, Picture Word Test, Rey Auditory Verbal Learning Test, Speeded Matching Test, and Visual Reasoning Test), Penn Computerized Neuropsychological Neurocognitive Battery and its subtests (Penn Conditional Exclusion Test, Penn Continuous Performance Test, Letter N-Back Task, Penn Word Memory Task, Penn Face Memory Task, Visual Object Learning Test, Penn Verbal Reasoning Test, Penn Matrix Reasoning Test, Penn Line Orientation Test, Penn Emotion Discrimination Test, Penn Emotion Differentiation Test, Penn Age Differentiation Test),Cogstate battery and its subtests (Behavioral Pattern Separation Test, Serial Paired Associative Learning Test, Detection Test, Face-Name Associative Memory Test, Finger Tapping Test, Groton Maze Learning Test, Discrimination Test, International Everyday Symbol Substitution Test - Drugs, International Digit Symbol Substitution Test - Symbols, International Shopping List Test, One-Back Test, One-Card Learning Test, Psychomotor Vigilance Test, Social-Emotional Cognition Test, Sustained Attention Test, Sustained Response Attention Test, Two-Back Test), Digit Symbol Substitution Task, Oddball Task, Flanker Task, Trail Making Task, Corsi Block Task, Digit Span Task, Reverse Digit Span Task, Verbal Learning and Memory Task, Verbal Fluency Task The cognitive impairment assessment may include one or more measures from the Symbol Digit Modalities Test, the Continuous Performance Test (CPT), the Wechsler Adult Intelligence Scale (WAIS) Coding Subtest, the Digit Vigilance Test, the d2 Attention Test, the WAIS Symbol Search Subtest, the WAIS Cancellation Subtest, the Neuropsychological Assessment Battery (NAB) Digit Letters Subtest, the NAB Digit Span Subtest, the Ruff 2 & 7 Selective Attention Test, the Stroop Color Word Test, the NAB Maze and Other Mazes Test, the Delis-Kaplan Executive Function System (D-KEFS) Design Fluency Subtest, or the Repeatable Neuropsychological Assessment Battery (RBANS) Coding Subtest. One or more indicators of cognitive impairment, slowness or poor cognitive performance, or difficulty making decisions may be calculated as a standardized score (e.g., z-score, T-score, standard score, scaled score, percentile rank, and Stanine score) that benchmarks the patient against a healthy population. These standardized scores may be calculated based on measurements such as reaction time, accuracy, accuracy of memory recall, items recalled, and reaction time variability. In one embodiment, one or more indicators of cognitive impairment, slowness or poor cognition, or difficulty in decision-making are combined into a composite cognitive task performance score. In one embodiment, a composite of two or more scores relating to learning and / or memory impairment is used to assess a patient's learning and / or memory impairment.

[0109] In one embodiment, machine learning or multivariate modeling is applied to predict a patient's responsiveness to administration of NSI-189.

[0110] In one embodiment, a patient is administered about 10 to about 130 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof. For example, about 20 to about 120 mg, about 80 to about 120 mg / day, or about 10 to about 40 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof. In a preferred embodiment, a patient is administered about 80 mg / day of NSI-189 or a pharmaceutically acceptable salt thereof.

[0111] In one embodiment of any of the methods described herein, measured impairment of executive and / or attentional function can be used as a surrogate for objectively impaired learning and / or memory. For example, one embodiment is a method of treating major depressive disorder, PTSD, bipolar depression, or one or more symptoms thereof, in a human patient with measured impairment of executive and / or attentional function, comprising orally administering to the patient daily about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

[0112] For a more complete understanding of the present invention, including its features and advantages, reference is made to the following detailed description of the invention taken in conjunction with the accompanying drawings, in which: [Brief explanation of the drawings]

[0113] [Figure 1]Figure 1A is a graph showing the change from baseline in MADRS depression scores of Example 1 at Phases 1 and 2 for all patients (i.e., all-persons analysis) who received placebo or 40 mg or 80 mg of NSI-189. Figure 1B is a graph showing the change from baseline in MADRS depression scores of Example 1 at Phases 1 and 2 for cognitively poor patients (defined as cognitive composite scores below the patient mean) who received placebo or 40 mg or 80 mg of NSI-189. Figure 1C is a graph showing the change from baseline in MADRS depression scores of Example 1 at Phases 1 and 2 for cognitively good patients (defined as cognitive composite scores above the patient mean) who received placebo or 40 mg or 80 mg of NSI-189. [Figure 2] Figure 2A is a graph showing the change from baseline in MADRS depression scores at Phases 1 and 2 in patients with cognitive impairment, defined as a cognitive composite score below the patient mean, administered placebo or 80 mg of NSI-189 in Example 1. Figure 2B is a graph showing the change from baseline in MADRS depression scores at Phases 1 and 2 in patients with cognitive impairment, defined as a CPFQ score greater than 25, administered placebo or 80 mg of NSI-189 in Example 1. [Figure 3]Figure 3A is a graph showing the change from baseline in MADRS scores from Example 2 in patients with poor cognition, defined as a cognitive composite score of z≦−0.75, compared to patients with good cognition (z>−0.75). The analysis adjusts for monotherapy versus adjunctive NSI-189 therapy. Cohen's d and p-values ​​are shown on the graph. Figure 3B is a graph showing the change from baseline in MADRS scores from Example 2 in patients with poor cognition, defined as poor memory recall of a learned word list (verbal memory recall index), z≦−0.75, compared to patients with good memory recall (z>−0.75). The analysis adjusts for monotherapy versus adjunctive NSI-189 therapy. Cohen's d and p-values ​​are shown on the graph. Figure 3C is a graph showing the change from baseline in MADRS scores from Example 2 in patients with subjective cognitive poorness, defined as a CPFQ score >25, compared to patients with good cognition (score≦25). Analyses are adjusted for monotherapy versus adjunctive NSI-189 therapy. Cohen's d and p values ​​are shown on the graphs. Figure 3D is a graph showing the change from baseline in MADRS scores for Example 2 on subjective memory recall poorness (poor is moderate or greater decline, good is minimal or less decline) as defined by one item on the CPFQ scale. Analyses are adjusted for monotherapy versus adjunctive NSI-189 therapy. Cohen's d and p values ​​are shown on the graphs. [Figure 4]Figure 4A is a graph showing the change from baseline in MADRS scores from Example 2 in groups receiving NSI-189 as monotherapy, comparing cognitively poor patients, defined by a learning and memory impairment (low recall index) score of z≦−0.75, with cognitively well patients (z>−0.75). Cohen's d and p values ​​are shown on the graph. Figure 4B is a graph showing the change from baseline in MADRS scores from Example 2 in groups receiving NSI-189 as adjunctive therapy, comparing cognitively poor patients, defined by a learning and memory impairment (low recall index) score of z≦−0.75, with cognitively well patients (z>−0.75). Cohen's d and p values ​​are shown on the graph. Figure 4C shows the change from baseline in MADRS scores from Example 2 in patients with an inadequate response to at least one antidepressant and receiving NSI-189 as monotherapy or adjunctive therapy, comparing cognitively poor patients, as defined by a learning and memory impairment (low recall index) score of z≦−0.75, with cognitively well-performing patients (z>−0.75). Cohen's d and p values ​​are shown on the graph. [Figure 5]Figure 5A is a graph showing the correlation between the change in MADRS score from baseline to week 6 (A) and learning and memory (recall index) in Example 2, demonstrating a continuous relationship between the degree of cognitive impairment (more negative z-scores) and the degree of treatment response (more negative change scores). Also shown are the correlation coefficients (r) and p-values ​​for the correlation between learning and memory (poor recall index) and MADRS change in the NSI-189 monotherapy group, the NSI-189 adjunctive therapy group, and the group of patients who had not responded adequately to at least one antidepressant and were receiving NSI-189 as monotherapy or adjunctive therapy. Figure 5B is a graph showing the correlation between the change in MADRS score from baseline to week 8 (A) and learning and memory (recall index) in Example 2, demonstrating a continuous relationship between the degree of cognitive impairment (more negative z-scores) and the degree of treatment response (more negative change scores). Also shown are the correlation coefficients (r) and p-values ​​for the correlation between learning and memory (poor recall index) and MADRS change in the NSI-189 monotherapy group, the NSI-189 adjunctive therapy group, and the group of patients who had an inadequate response to at least one antidepressant and were receiving NSI-189 as monotherapy or adjunctive therapy. [Figure 6]Figure 6A is a graph showing the change from baseline in MADRS scores from Example 2 in groups receiving NSI-189 as monotherapy, comparing cognitively poor patients, as defined by a learning and memory (low recall index) score of z≦−0.418, with cognitively well patients (z>−0.418). Cohen's d and p values ​​are shown on the graph. Figure 6B is a graph showing the change from baseline in MADRS scores from Example 2 in groups receiving NSI-189 as adjunctive therapy, comparing cognitively poor patients, as defined by a learning and memory (low recall index) score of z≦−0.418, with cognitively well patients (z>−0.418). Cohen's d and p values ​​are shown on the graph. Figure 6C shows the change from baseline in MADRS scores from Example 2 in patients with an inadequate response to at least one antidepressant and receiving NSI-189 as monotherapy or adjunctive therapy, comparing patients with poor cognition, as defined by a Learning and Memory (low recall index) score of z≦−0.418, with patients with good cognition (z>−0.418). Cohen's d and p values ​​are shown on the graph. [Figure 7] Figure 1 shows the mean, standard error of the mean (SEM), and p-values ​​for t-tests comparing various cognitive measures between cognitively poor patients (score z≦−0.75) and cognitively well-matched patients (score z>−0.75) in Example 2. Cognitively poor patients, even when defined by a single measure such as learning or memory, have poorer cognition (more negative z-scores) across a wide range of cognitive tests and domains. DSST = Digit Symbol Substitution Task, RT = Reaction Time, FERT = Face Emotion Recognition Test. [Figure 8]Figure 8A is a graph of the MADRS response rate (defined as a 50% or greater reduction in symptoms from baseline to week 6) in poor patients compared with good patients with learning and memory (recall measures) for various definitions of the clinical population in Example 2. Figure 8B is a graph of the MADRS remission rate (defined as a 50% or greater reduction in symptoms from baseline to week 6) in poor patients compared with good patients with learning and memory (recall measures) for various definitions of the clinical population in Example 2. Figure 8C is a graph of the drug-placebo difference (plotted as Cohen's d) in poor learning and memory patients from the second Phase 2 study and poor cognition patients from the first Phase 2 study compared with the drug-placebo difference reported in the overall depressed population receiving approved antidepressants or medications used to augment or adjunct antidepressants (e.g., antipsychotics). [Figure 9] Figure 9A shows a set of graphs of EEG resting eye-closed power spectral density plots from Example 2, comparing EEG power at different frequencies in responders (≥50% reduction in MADRS score from baseline) and non-responders to NSI-189 (both monotherapy and combination therapy). Stars indicate channels with significant differences between groups (dots or lines at the corresponding frequencies at the top of each channel panel). Figure 9B shows a set of graphs of EEG resting eye-closed power spectral density plots from Example 2, comparing EEG power at different frequencies in individuals who were given the drug in combination with an antidepressant that was not responding well to the drug. Stars indicate channels with significant differences between groups (dots or lines at the corresponding frequencies at the top of each channel panel). 9C shows a set of graphs of EEG resting eyes-closed power spectral density plots from Example 2 comparing EEG power at different frequencies in individuals who had an inadequate response to antidepressants in their current episode (and were receiving NSI-189 as monotherapy or adjunct to antidepressants). Asterisks indicate channels with significant differences between groups (shown at the top of each channel panel as dots or lines for the corresponding frequencies). [Figure 10]Figure 10A is a graph showing the change from baseline in MADRS scores from Example 2 in patients receiving NSI-189 as monotherapy or adjunctive therapy, comparing patients with high acyclic indices with patients with low acyclic indices (below the patient median). The analysis is adjusted for monotherapy versus adjunctive NSI-189 therapy. Cohen's d and p values ​​are shown on the graph. The top panel shows a channel-by-channel correlation plot of EEG resting eyes-closed acyclic indices and percent change from baseline in MADRS scores (more positive correlations indicating better outcomes for patients with lower acyclic indices). Figure 10B is a graph showing the change from baseline in MADRS scores from Example 2 in patients receiving NSI-189 adjunctively to an antidepressant who had an inadequate treatment response, comparing patients with high acyclic indices with patients with low acyclic indices (below the patient median). The analysis is adjusted for monotherapy versus adjunctive NSI-189 therapy. Cohen's d and p values ​​are plotted on the graph. The top panel shows the channel-by-channel correlation between the resting, eyes-closed EEG acyclic index and the percent change from baseline in the MADRS score, plotted on an EEG topography (with a more positive correlation indicating a better outcome in patients with a smaller acyclic index). Figure 10C shows the change from baseline in the MADRS score for Example 2 in patients who had an inadequate response to antidepressants in the current episode (regardless of whether they were receiving NSI-189 as monotherapy or adjunctive to that antidepressant), contrasting patients with a high acyclic index with those with a low acyclic index (below the patient median). The analysis adjusts for monotherapy versus adjunctive NSI-189 therapy. Cohen's d and p values ​​are plotted on the graph. The figure above shows the correlation between the resting EEG aperiodic index at eyes closed and the percentage change from baseline in the MADRS score per channel plotted on EEG topography (a more positive correlation indicating better outcomes in patients with a smaller aperiodic index). [Figure 11]This figure shows the correlation between the aperiodic index value and learning and memory ability (using the recall index score) in Example 2. The upper figure is an electroencephalogram (EEG) topography plot of the correlation between the aperiodic index and the recall index score for each channel during rest with eyes closed. The stronger the positive correlation between the aperiodic index value and learning and memory (recall index), the worse the learning and / or memory state of patients with smaller aperiodic indices. [Figure 12] 1 is a graph showing the change from baseline in CAPS-5 scores in PTSD patients of Example 3 in patients with poor cognition, defined by a score of z≦−0.5 compared to patients with good cognition (z>−0.5). DETAILED DESCRIPTION OF THE INVENTION

[0114] Unless specifically stated or clear from the context, as used herein, the term "or" is understood to be inclusive.

[0115] Unless specifically stated or clear from the context, as used herein, the terms "a," "an," and "the" are understood to be singular or plural.

[0116] It is understood that ranges provided herein are shorthand notations for all values ​​within that range.

[0117] Unless specifically stated or clear from the context, the term "about" as used herein is understood to be within normal tolerances in the art, for example, within two standard deviations of the mean. About can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein can be modified by the term about.

[0118] The transitional phrase "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrepeated elements or method steps. In contrast, the transitional phrase "consisting of" excludes elements, steps, or ingredients not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to the specified materials or steps, "and which do not materially affect the basic and novel characteristic(s) of the claimed invention."

[0119] The term "monotherapy" refers to treatment with a single active ingredient.

[0120] Unless otherwise noted, the term "NSI-189" refers to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone, the structure of which is as follows: [ka] NSI-189 can be synthesized as described in U.S. Patent Nos. 7,560,553, 7,858,628, 9,278,933, and 9,572,807, each of which is incorporated by reference in its entirety. Pharmaceutically acceptable salts of NSI-189 include, but are not limited to, halides, maleates, succinates, nitrates, and phosphates. A preferred pharmaceutically acceptable salt of NSI-189 is (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone phosphate (e.g., (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone monophosphate (also referred to as NSI-189 phosphate). NSI-189 or a pharmaceutically acceptable salt thereof can be administered in the form of a dosage form containing one or more pharmaceutically acceptable excipients, such as an oral dosage form (e.g., a tablet, capsule, granules, or oral liquid).

[0121] The terms major depressive disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder, substance use disorder, and schizophrenia are intended as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Ed. text revision (“DSM-5-TR”), American Psychiatric Association, 2022, which is incorporated herein by reference. The term “bipolar depression” generally refers to a depressive episode associated with bipolar I or II disorder.

[0122] As used herein, the terms "brain activity" or "brain activity level" refer to measurable (e.g., quantifiable) neural activity. Measurable neural activity includes, but is not limited to, activity magnitude, activity frequency, activity latency, activity duration, etc. Brain activity levels may be measured (e.g., quantified) during periods when no stimuli are presented. In embodiments, brain activity levels measured in the absence of stimuli are referred to as baseline brain activity levels. This may be done with eyes closed or eyes open. Alternatively, brain activity levels may be measured (quantified) when one or more stimuli (e.g., an emotional conflict task) are presented. In embodiments, brain activity levels measured in the presence of stimuli are referred to as response brain activity levels. Brain activity levels may be measured simultaneously or sequentially across the entire brain, or may be limited to specific brain regions (e.g., frontopolar cortex, lateral prefrontal cortex, dorsal anterior cingulate cortex, anterior insular cortex). In embodiments, brain activity levels are determined relative to a baseline brain activity level measured during a baseline period. A baseline period is typically a period during which no stimuli are presented or are not presented for a sufficient period of time (e.g., at least 0.05, 0.1, 0.15, 0.25, 0.5, 1, 2, 3, 4, 5, 10, 15, 30, 60 seconds or more).

[0123] Brain activity levels may also encompass assessment of functional brain region connectivity. For example, neural activity recorded in multiple brain regions may have a specific time course between brain regions that can be correlated to reveal functional brain connectivity patterns (e.g., a first brain region exhibits increased neural activity at a first time point, and a second brain region exhibits increased activity at a second time point). Thus, in embodiments, brain activity levels are measurements (e.g., quantification) of the time course of neural activity across multiple brain regions. In embodiments, brain activity levels are a series of brain region activity levels measured (e.g., quantification) across different brain regions over time. In embodiments, brain activity levels are functional brain region connectivity patterns.

[0124] The term "electroencephalography (EEG)" refers to a noninvasive neurophysiological technique that uses electronic monitoring devices to measure and record electrical activity in the brain. Power and acyclic indices may be measured across central or fronto-centro-parietal electrodes. References to "low power" or "high power" in a given frequency range (e.g., the low gamma range (e.g., 31-50 Hz, 31-60 Hz, 35-45 Hz)) refer to power (e.g., calculated as a standardized score, such as a z-score) below or above the 50th percentile of demographically similar healthy individuals, or a lower or higher cutoff value, respectively, based on age similarity to the patient. The term "low acyclic indices" refers to acyclic indices (e.g., calculated as a standardized score, such as a z-score) below the 50th percentile of demographically similar healthy individuals, or a lower cutoff value, based on age similarity to the patient. For example, a subject may have low alpha power or a low acyclic index value that is less than the 50th percentile of similar healthy subjects, with a z-score of less than zero, less than z=-0.25, less than z=-0.5, less than z=-0.75, less than z=-1, or less than z=-2 (e.g., a z-score of about -0.5 or -0.75 to about -1 or about -2, or a z-score of about -0.75 or -1 to about -2). In one embodiment, a patient is considered to have low alpha power or a low acyclic index value if the z-score is less than -0.2, -0.25, -0.3, -0.35, -0.4, -0.45, -0.5, -0.55, -0.6, -0.65, -0.7, -0.75, -0.8, -0.85, -0.9, -0.95, or -1.0. In another embodiment, a patient is considered to have low alpha power or low acyclic index value if the z-score is less than -1.2, -1.25, -1.3, -1.35, -1.4, -1.45, -1.5, -1.55, -1.6, -1.65, -1.7, -1.75, -1.8, -1.85, -1.9, -1.95, or -2.0.In another embodiment, a subject may have high gamma power, with a z-score greater than zero and greater than z=0.25, z=0.5, z=0.75, z=1, or z=2 (e.g., a z-score of about 0.5 or 0.75 to about 1 or about 2, or a z-score of about 0.75 or 1 to about 2). In one embodiment, a patient is considered to have high gamma power if the z-score is greater than 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.0. In another embodiment, a patient is considered to have high gamma output if the Z-score is greater than 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, or 2.0.

[0125] References herein to standardized scores may be calculated as z-scores, T-scores, standard scores, scale scores, percentile ranks, or Stanine scores.

[0126] The terms "treat," "treatment," and "treating," in the context of administering therapeutics to a patient, refer to the shortening or inhibition of the progression and / or duration of a disease or condition, the reduction or amelioration of the severity of a disease or condition, and / or the amelioration of one or more symptoms of a disease or condition that results from the administration of one or more therapeutics.

[0127] The term "administering" includes, but is not limited to, oral administration, administration as a suppository, topical contact, intravenous administration, transdermal administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, nasal administration, rectal administration, transdermal administration, or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, into a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. In embodiments, administration does not include administration of active agents other than the active agent described. One preferred route of administration is oral.

[0128] An "effective amount" is an amount of a compound sufficient to achieve a stated purpose compared to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, decrease enzyme activity, increase enzyme activity, decrease a signal transduction pathway, or alleviate one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, delay, suppression, inhibition, or alleviation of symptoms or signs of a disease or disorder, which may also be referred to as a "therapeutically effective amount." "Alleviation" of a symptom (and grammatical equivalents thereof) means a reduction in the severity or frequency of the symptom(s), or the elimination of the symptom(s). An "effective amount" of a drug can be the amount of drug that, when administered to a subject, has the intended preventative effect, e.g., preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete preventative effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. The actual amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Dosages may vary depending on the requirements of the patient and the compound being used. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose may also be determined by the existence, nature, and extent of any adverse side effects. Determination of the appropriate dosage for a particular situation is within the skill of the physician.

[0129] Questionnaires (e.g., self-report or clinician-administered questionnaires) may be used to assess the effectiveness of treatment for psychiatric disorders (e.g., depression, major depression, bipolar depression, post-traumatic stress disorder (PTSD)). Non-limiting examples of questionnaires useful for assessing the effectiveness of treatment for psychiatric disorders (e.g., depression, major depression) include the Hamilton Depression Rating Scale (HDRS); the Hamilton Depression Rating Scale 17-item (HDRS17 or HDRS-17); the 21-item HDRS (HDRS21), the 24-item HDRS (HDRS24); the Quick Inventory for Depressive Symptoms (QIDS); the Patient Health Questionnaire (PHQ-9); the Cognitive and Physical Functioning Questionnaire (CPFQ); the Mood and Symptom Questionnaire subscale scores for anxiety arousal, anhedonic depression, and general distress; the Montgomery-Asberg Depression Rating Scale (MADRS); the Beck Depression Rating Scale, the Clinical Global Impression (GCI) scale; and the Snaith-Hamilton Pleasure Scale (SHAPS). Questionnaires may be completed before, during, and after treatment, and changes in scores may be used to determine treatment efficacy. In some embodiments, HDRS17 is used to determine treatment efficacy. In some embodiments, HDRS is used to determine treatment efficacy. In some embodiments, HDRS21 is used to determine treatment efficacy. In some embodiments, HDRS24 is used to determine treatment efficacy. In some embodiments, QIDS is used to determine treatment efficacy. In some embodiments, Mood and Symptom Questionnaire subscale scores for anxious arousal, anhedonic depression, and general distress are used to determine treatment efficacy. In some embodiments, MADRS is used to determine treatment efficacy. In embodiments, the Beck Depression Rating Scale is used to determine treatment efficacy. In some embodiments, Clinical Global Impression (CGI) scale is used to determine treatment efficacy. In some embodiments, treatment efficacy is determined by measuring (e.g., quantitating) changes in scores on HDRS6, MADRS6, or HDRS17. In some embodiments, treatment efficacy is determined by measuring (e.g., quantitating) changes in scores on HDRS21.In some embodiments, therapeutic efficacy is determined by measuring (e.g., quantifying) a change in score on the HDRS. In some embodiments, therapeutic efficacy is determined by measuring (e.g., quantifying) a change in score on the HDRS24. In some embodiments, therapeutic efficacy is determined by measuring (e.g., quantifying) a change in score on the QIDS. In some embodiments, therapeutic efficacy is determined by measuring (e.g., quantifying) a change in Mood and Symptom Questionnaire subscale scores for anxious arousal, anhedonic depression, and general distress. In some embodiments, therapeutic efficacy is determined by measuring (e.g., quantitating) a change in score on the MADRS. In embodiments, therapeutic efficacy is determined by measuring (e.g., quantitating) a change in Beck Depression Rating Scale score. In some embodiments, therapeutic efficacy is determined by measuring (e.g., quantitating) a change in score on the CGI. A non-limiting example of a questionnaire useful for assessing the efficacy of a treatment for PTSD is the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). In another embodiment, the questionnaire for assessing the effectiveness of a treatment for PTSD is the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV). In yet another embodiment, the questionnaire for assessing the effectiveness of a treatment for PTSD is a self-report such as the PCL (PTSD Checklist) (e.g., the PTSD Checklist for DSM-5 (PCL-5)). In some embodiments, the effectiveness of treatment is determined by measuring (e.g., quantifying) scores on the questionnaires described herein during a baseline period before treatment and scores on the questionnaires described herein reported 1, 2, 3, 4, 6, 8, or more weeks after treatment initiation or treatment termination.

[0130] Treatment may result in a reduction in symptoms (e.g., a response) or remission. In embodiments, a reduction in symptoms is referred to as a response. In embodiments, a response is a 50% or greater reduction in symptoms. Response to treatment (e.g., a 50% or greater reduction in symptoms) may be determined by measuring (e.g., quantitating) a change in score on a questionnaire, such as described herein, including its embodiments, on a questionnaire, such as described herein, including its embodiments. In embodiments, remission is a score of 7 or less on the HDRS17 assessment item. In embodiments, remission is a score of 7 or less on the HDRS assessment item. In embodiments, remission is a score of 10 or less on the HDRS24. In embodiments, remission is a score of 5 or less on the QIDS. In embodiments, remission is a score of 7 or less on the MADRS. In embodiments, remission is a score of 4 or less on the PHQ9.

[0131] "Learning and / or memory" includes the following tests: VM-REACT (REcAll Computerized Test of Verbal Memory), Rey Auditory Verbal Learning Test, California Verbal Learning Test (including CVLT-II and CVLT-3), California Verbal Learning Test-Short Form, California Verbal Learning Test-Child Version, Hopkins Verbal Learning Test, Hopkins Verbal Learning Test-Revised, Philadelphia Verbal Learning Test, International Shopping List Test, Language Section of the Repeated Battery for the Assessment of Neuropsychological Status, Word List Task of the Serrado Neuropsychological Assessment Battery, and Pediatric Auditory Verbal Learning Test. Tests, Child Memory Scale, Bay Area Verbal Learning Test, Cogstate Battery (including the following subtests: Behavioral Pattern Separation Test, Serial Paired Associate Learning Test, Face-Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List, One-Card Learning Test), CANTAB (including the following subtests: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Association, Paired Associate Learning, Verbal Recognition Memory), Penn Computerized Neurocognitive Battery (including the following subtests: Penn Word Memory Task, Penn Face Memory Task, Visual Object Learning) Test), NIH Toolbox and its subtests (Face-Name Associative Memory Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test), Memory Module of Neuropsychological Assessment Battery (which may include the following subtests and their delayed recall and recognition components: List Learning, Figure Learning, Story Learning, and Daily Life Memory), WHO / UCLA Auditory Verbal Learning Test, Repeatable Neuropsychological Status Assessment Battery (which may include the following subtests and their delayed recall and recognition components: List Learning, Story Memory, and Figure Recall), Comprehensive Assessment of Memory and Learning (which may include the following subtests and their delayed recall and recognition components: : Picture Memory, Design Learning, Narrative Memory, Verbal Learning), Buschke Selective Recall Test, Wechsler Memory Scale (including the following subtests and their delayed recall and recognition components: Logical Memory, Verbal Paired Association, Design, Visual Reproduction), Woodcock-Johnson Long-Term Recall Factor (including the following subtests and their delayed recall and recognition components: Narrative Recall, Visual-Auditory Learning), Test of Memory and Learning (including the following subtests and their delayed recall and recognition components: Narrative Memory, Face Memory, Word Selective Memory, Visual Selective Memory, Abstract Visual Memory, Object Recall, Visual Serial Memory, Paired Recall, Location Memory),Objective assessment can be performed using one or more of the tests described herein, including the NEPSY (including the following subtests and their delayed recall and cognitive components: List Memory, Design Memory, Face Memory, Name Memory, Story Memory, Sentence Repetition, and Word List Interference), the Miniature Visuospatial Memory Test-Revised, the Benton Visual Retention Test, the Rey Osterreith Complex Figure Test, and any combination of any of the foregoing. VM-REACT (Verbal Memory Recall Computerized Test) is described in Naparstek et al., J. Psychiatr. Res., 2019, 114:170-177 (PMID 31096177), incorporated herein by reference. In one embodiment, the patient's learning and / or memory performance is objectively assessed using the VM-REACT (Verbal Memory Recall Computerized Test).

[0132] Memory is often assessed by a recall index. The term "recall index" refers to a measure of the accuracy of immediate and / or delayed recall of learned material. For example, recall can be assessed immediately after learning and again after a time interval (e.g., 20 minutes). Alternatively, recall can be assessed using only one of these conditions. Similarly, unrelated distractor learning trials can be administered to further separate the learning and memory assessments. Thus, a recall index encompasses one or more assessments of recall after learning has occurred.

[0133] The term "learning and / or memory impairment" refers to a subject having learning and / or memory, as measured by one or more tests, below the 50th percentile or lower cutoff value (i.e., z-score<0) of healthy subjects of similar demographics, such as based on age similarity to the patient. A z-score is an example of a standardized score that can be used to characterize a subject as "impaired." The z-score reflects a transformation of learning and / or memory ability to the distribution of healthy subjects, which may take into account factors such as age, education, and gender. A z-score below zero indicates that the subject's performance is below the 50th percentile of similar healthy subjects, while a z-score above zero indicates that the subject's performance is above the 50th percentile of similar healthy subjects. For example, a subject may have a learning and / or memory score below the 50th percentile of similar healthy subjects with a z-score of less than zero, less than z=-0.25, less than z=-0.5, less than z=-0.75, less than z=-1, or less than z=-2 (e.g., a z-score of about -0.5 or -0.75 to about -1 or about -2, or a z-score of about -0.75 or -1 to about -2). In one embodiment, a patient is considered to have a learning and / or memory impairment if the z-score is less than -0.2, -0.25, -0.3, -0.35, -0.4, -0.45, -0.5, -0.55, -0.6, -0.65, -0.7, -0.75, -0.8, -0.85, -0.9, -0.95, or -1.0. In another embodiment, a patient is considered to have a learning and / or memory impairment if the z-score is less than -1.2, -1.25, -1.3, -1.35, -1.4, -1.45, -1.5, -1.55, -1.6, -1.65, -1.7, -1.75, -1.8, -1.85, -1.9, -1.95, or -2.0. In one embodiment, the learning and / or memory impairment is assessed (in part or in whole) based on:

[0134] In one embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.5. In another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.3. In yet another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.35. In yet another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.40. In yet another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.45. In yet another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.55. In yet another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.60. In yet another embodiment, a patient (e.g., a patient with major depressive disorder, major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.65.In yet another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.70. In yet another embodiment, a patient (e.g., a patient with major depressive disorder, a major depressive episode, bipolar depression, or post-traumatic stress disorder) is considered to have a learning and / or memory impairment if the z-score as determined by VM-REACT is less than -0.75.

[0135] The term "cognitively poor" (or "cognitively poor"), unless otherwise defined, refers to a subject whose cognitive function, as measured by one or more cognitive tests, is below the 50th percentile of demographically similar, e.g., healthy subjects (z-score<0). The z-score reflects a transformation of performance on a cognitive task to the distribution of healthy subjects, which may take into account factors such as age, education, and gender. A z-score below zero indicates that the subject's performance is below the 50th percentile of similar healthy subjects, while a z-score above zero indicates that the subject's performance is above the 50th percentile of similar healthy subjects. For example, the subject may have a cognitive score below the 50th percentile of similar healthy subjects with a z-score of less than zero, less than z=-0.25, less than z=-0.30, less than z=-0.35, less than z=-0.40, less than z=-0.45, less than z=-0.5, less than z=-0.75, less than z=-1, or less than z=-2 (e.g., a z-score of about -0.5 or -0.75 to about -1 or about -2, or a z-score of about -0.75 or -1 to about -2).

[0136] Cognition can be assessed by methods known in the art, including those described in DSM-5 (see, e.g., pages 593-595). For example, cognition can be measured by a simple reaction time test, a choice reaction time test, a one-back working memory task, a visual learning task, learning and / or memory (e.g., verbal learning and / or memory), or any combination of the foregoing. In one embodiment, learning and / or memory is assessed. In one embodiment, the subject's cognitive ability is measured using the Cogstate Brief Battery, as described in Maruff et al., Arch. Clin. Neuropsychol. 2009, 24(2):165-78, which is incorporated herein by reference. Cognitive tests (e.g., assessing information processing speed, working memory, learning, and attention) include, but are not limited to, the digit symbol substitution task, oddball task, flanker task, Wisconsin card sorting task, trail-making task, Corsi block task, digit span task, reverse digit span task, verbal learning and memory task, and verbal fluency task. Slow information processing speed, slow decision-making, or difficulty making decisions may be diagnosed by tests that assess performance under reaction time or speed-based task instructions (e.g., a reduced number of correct symbols in a digit symbol substitution task or reduced verbal fluency in a given time period), such as those described in J. DeLuca and J.H. Kalmar, "Information Processing Speed ​​in Clinical Populations," Taylor & Francis Group (2008), incorporated herein by reference. Decision-making (including slow decision-making and difficulty making decisions) can be assessed by performance on tasks that assess the decision-making process in the face of competing options (e.g., a gambling simulation) (DSM-5, p. 593).Attentional deficits can be assessed by: (1) sustained attention: maintaining attention over time (e.g., pressing a button each time a sound is heard over a period of time), (2) selective attention: maintaining attention despite competing stimuli or distractions: listening to numbers and letters spoken and being asked to count only the letters, and (3) divided attention: attending to two tasks in the same time period: tapping rapidly while learning a story being read to you. Processing speed can be quantified by timing any task (e.g., time to assemble a block design, time to match symbols with numbers, reaction speed such as counting speed or serial three speed).

[0137] Working memory decline can be assessed by the ability to briefly hold and manipulate information (e.g., summing a list of numbers, repeating a series of numbers or words backward, or repeating a series of actions).

[0138] Memory decline can also be assessed using the following methods (in addition to the working memory assessment methods described above):

[0139] (1) Immediate memory span: The ability to repeat lists of words, numbers, or sequences of actions.

[0140] (2) Learning and Retention: Assessing the process of encoding new information (e.g., word lists (which may be repeated many times), short stories, or diagrams). Impaired acquisition or retention of new information can be diagnosed through tests that assess learning and memory (e.g., learning a list of words or symbols in a series of trials and recalling them after a 15-30 minute delay; learning a short story or complex diagram and recalling it after a 20-30 minute delay), such as those described in E. Strauss, E. M. Sherman, and O. Spreen (2006), A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. (3rd Edition). Oxford University Press, New York, NY, incorporated herein by reference). Aspects of recent memory that can be examined include 1) free recall (e.g., subjects are asked to recall as many words, pictures, or story elements as possible); 2) cued recall (e.g., subjects are given semantic cues such as "Name all the foods on the list" or "Name all the children in the story"); 3) recognition memory (e.g., "Was 'apple' on the list?" or "Did you see this diagram or picture?"); and 4) recall of the original list of items or words after presentation of a distractor list of items or words. Recent memory can also be assessed as a combination of various aspects, such as recall of the original list of items or words following a distractor list, or free recall, such as that described in RJ Ivnik, JF Marec, EG Tangalos, R.C. Petersen, E. Kokmen, and L.T. Kurland (1992), Mayo's Older Americans Normative Studies: Updated AVLT norms for ages 56 to 97, The Clinical Neuropsychologist 6, 83-104.Other aspects of memory that can be assessed include semantic memory (memory for facts), autobiographical and episodic memory (memory for personal events and people), and implicit (procedural) learning (unconscious learning of skills).

[0141] The term "cognitive slowness," unless otherwise defined, refers to a subject whose slow cognitive function, as measured by one or more tests of information processing speed (e.g., simple reaction time test or choice reaction time test), is below the 50th percentile of age-matched healthy subjects or another cutoff value (e.g., z-score < 0).

[0142] Processing speed can be quantified by timing any task (e.g., time to assemble a block design, time to match symbols to numbers, reaction speed such as counting speed or speed of three in a row).

[0143] Learning and / or memory decline can be assessed using the methods described above for immediate memory span and learning and retention.

[0144] Declines in executive function are seen, for example, in E. Strauss, E. M. Sherman, and O. Spreen (2006), G.A. Gioia, P.K. Isquith, S.C. Guy, and L. Kenworthy (2015), Behavior Rating Inventory of Executive Function®, Second Edition (BRIEF® 2), Lutz, FL: PAR Inc.; and Delis, D.C., Kaplan, E., & Kramer, J.H. (2001), Delis-Kaplan Executive Function System (D-KEFS), The Psychological Corporation, San Antonio, TX. Gioia, G.A., Isquith, P.K., Guy, S.C., Kenworthy These tests can assess flexibility of thought (e.g., alternating between digits and letters), abstract / conceptual reasoning and problem solving (e.g., completing a complex puzzle), planning (e.g., completing a maze), organization (e.g., sorting a list of words based on semantic clues), working memory (e.g., holding and manipulating information in one's mind), creativity, generativity, and initiation (e.g., spontaneously producing words beginning with a particular letter), impulse control and inhibition (e.g., deliberately inhibiting automatic responses to test stimuli), and self-monitoring (e.g., checking whether an answer is accurate), such as those described in L. (2015).

[0145] In one embodiment, the cognitive impairment, poor or slow cognition, or difficulty in decision-making is due, at least in part, to impaired attention, memory, learning, working memory, or any combination of the foregoing.

[0146] As used herein, the terms "subject" and "patient" are used interchangeably and refer to a human patient unless otherwise indicated.

[0147] Antidepressants suitable for combination therapy include, but are not limited to, (i) serotonin and norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, milnacipran, sibutramine, SEP-227162, or LY2216684), (ii) selective serotonin reuptake inhibitors (SSRIs) (e.g., escitalopram, fluoxetine, fluvoxamine, sertraline, citalopram, vilazodone, and paroxetine), (iii) atypical antidepressants (e.g., agomelatine, mianserin, mirtazapine, nefazodone, opipramol, tianeptine, and trazodone), and (iv) norepinephrine and dopamine reuptake inhibitors (NDRIs) (e.g., bupropion, amineptine, prolintane, dexmethylphenidate, and pipradrol). In one embodiment, the antidepressant is selected from an SSRI, an SNRI, mirtazapine, bupropion, or any combination of any of the foregoing. In another embodiment, the antidepressant is not a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressant (TCA) (such as amitriptyline, imipramine, clomipramine, and desipramine), or ketamine.

[0148] Suitable mood stabilizers include, but are not limited to, lithium carbonate, divalproex sodium, valproic acid, valproate semisodium, sodium valproate, tiagabine, levetiracetam, lamotrigine, gabapentin, carbamazepine, oxcarbazepine, topiramate, zonisamide, aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, lurasidone, lumateperone, cariprazine, verapamil, clonidine, propranolol, mexiletine, guanfacine, and omega-3 fatty acids.

[0149] In certain embodiments of any of the methods described herein, the learning and / or memory impairment is measured using one or more of the following learning and / or memory tests: [Table 1-1] [Table 1-2] [Table 1-3]

[0150] "Advertising" refers to announcing, informing, and / or informing one or more individuals of information (e.g., the effectiveness of a pharmaceutical product containing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof in treating major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof, in patients with learning disabilities and / or memory disorders) through mass media, including, but not limited to, newspapers, magazines, internet advertisements, television commercials, billboards, etc. As used herein, the term "advertising" also includes the inclusion in the labeling of a pharmaceutical product that contains (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof for treating major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof, in patients with learning disabilities and / or memory disorders.

[0151] The term "marketing" refers to the act or process of selling a product (e.g., a pharmaceutical product containing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof (e.g., a phosphate salt thereof)) and includes, but is not limited to, selling or offering to sell the product, as well as advertising. This marketing may be directed, for example, to physicians (e.g., psychiatrists or general practitioners) who treat subjects suffering from major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof. Marketing may include including in the labeling of a pharmaceutical product containing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof (e.g., a phosphate salt thereof) a statement that the product can effectively treat major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof in patients with learning disabilities and / or memory disorders.

[0152] In any of the methods described herein, (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof (e.g., (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone phosphate) may be incorporated into a pharmaceutical product. The pharmaceutical product may be a therapeutic package including: (a) (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof (e.g., (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone phosphate); (b) a container containing one or more dosage forms; and (c) written material, such as a label, directing use of the dosage form in treating major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof, in a patient with a learning disability and / or memory impairment.

[0153] "Pharmaceutical product" refers to a pharmaceutical product containing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof, such as (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone phosphate. The pharmaceutical product may contain one or a dosage form (e.g., a tablet) of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof (e.g., (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone phosphate). [Example]

[0154] Example 1: Phase 2 Clinical Trial of NSI-189 A retrospective analysis of 220 patients from the aforementioned Phase 2 trial of NSI-189 was conducted (11). In this trial, patients with major depressive disorder were randomly assigned to receive NSI-189 at a total daily dose of 40 mg or 80 mg or placebo during the first phase (first 6 weeks) of the clinical trial design. Patients who received placebo and did not respond to the placebo were re-randomized to 40 mg, 80 mg, or placebo during the second phase (last 6 weeks). The remaining patients continued treatment in Phase 2 of the trial. Treatment in both phases lasted 6 weeks. Patients were 18 to 60 years of age, had current major depressive disorder according to DSM-5, lasting at least 8 weeks, diagnosed by the Structured Clinical Interview for the DSM-5 Clinical Trials (SCID-5-CT) at screening and remote assessment visits, and had a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20 at screening, remote assessment, and baseline visits. In the phase 2 trial, cognitive task performance data were collected before treatment and again after both phases 1 and 2 of the treatment protocol to determine whether treatment with the compound resulted in improvements in cognitive function as measured by various behavioral indices.

[0155] Prior to our retrospective analysis, the use of behavioral measures to predict treatment outcome had not been explored, and no analyses to this effect had been conducted. Cognitive ability was not considered a predictor and was used solely as an outcome measure. The analyses described herein focused on four cognitive task measures included in the Cogstate battery, and these data were available as z-scores that normalized each individual's performance to that of a larger, healthy population. Tasks in this battery included a simple reaction time (RT) task, a choice RT task, a one-back working memory task, and a visual learning task. Furthermore, once converted to z-scores, a composite cognitive task performance score may be calculated by averaging the z-scores for each of the four tasks included in the battery. The analysis focused on the study's primary outcome, the MADRS. Statistical analysis used the SPCD analysis method reported in the original study and focused on the full study (incorporating outcomes from both Phases 1 and 2), thereby allowing comparisons with the original statistical analysis plan. To predict change from baseline in clinical scores (at weeks 2, 4, and 6), we used a mixed model for repeated measures (MMRM) and included covariates for group (i.e., cognitively poor or good as defined by a given measure of interest), time, time × group, time × baseline MADRS, and baseline MADRS. These covariates were also used in the original study, so the results here can be compared with the previously reported full-participant results. Therefore, statistical significance was assessed for the primary outcome (change from baseline in MADRS at 6 weeks across the SPCD design). Figure 1(A) shows the change in MADRS scores in the full-participant (i.e., initial sample) analysis for comparison with subgroups defined by cognitive task performance.

[0156] To examine the impact of baseline cognition on clinical outcomes, individuals were divided by the mean average z-score across all tasks (hence, the cognitive composite score). This generated two groups: cognitively poor (below the mean, negative z-score) and cognitively good (above the mean, positive z-score). The cognitively poor group can also be described as cognitively impaired. The mean composite score cutoff for good and poor cognitive performance was z = -0.32, which corresponds to the median score for this patient group (a negative z-score indicates a score below the median for the corresponding healthy population). Notably, this mean value is consistent with the expectation that cognitive performance is generally moderately impaired in depression (12, 13).

[0157] Surprisingly, although the initial all-patient analysis did not reveal a statistically significant difference in the primary outcome, the MADRS, a robust statistically significant effect was observed in the 80 mg group compared with the placebo group for change in MADRS score in the cognitively impaired group, using the cognitive composite score (SPCD analysis, p = 0.014; Figure 1B). This corresponds to a drug-placebo effect size of Cohen's d = 0.58, approximately twice the typical effect size (d = 0.3) of standard-of-care antidepressants in the overall patient population (31). Comparisons of the 80 mg group and the placebo group in the first phase of the study also revealed statistically significant differences at weeks 2 (d = 0.55, p = 0.045), 4 (d = 0.7, p = 0.01), and 6 (d = 0.59, p = 0.03), with the 80 mg group demonstrating a higher response rate than the placebo group. Although the 40 mg group demonstrated visually intermediate outcomes compared with the 80 mg and placebo groups, this effect was not significant (p = 0.39; Figure 1(B)). In contrast, no significant differences were observed between either drug group and the placebo group in the cognitively favorable group (p = 0.25; Figure 1(C)). Thus, cognitive task performance not only successfully differentially predicted outcomes between drug and placebo, but this appeared to be significantly stronger for the 80 mg treatment compared with the 40 mg treatment, contrary to expectations from the previous treatment effect analysis of the data discussed above (11). This is also surprising, as previous studies in depressed patients have reported that poor cognition was a consistent predictor of poor response to SSRIs and SNRIs (Groves et al., Front. Psychiatry, 9:382, 2018; Etkin et al., Neuropsychopharmacology, 40(6):1332-1342, 2015).

[0158] We investigated whether cognitive impairment could be defined in other ways, by having patients assess their cognition using self-report questionnaires. One such questionnaire is the Cognitive and Physical Functioning Questionnaire (CPFQ) (15). This scale is notable for its use in analyses conducted when the antidepressant vortioxetine was approved by both the FDA and the European Medicines Agency (EMA). In these analyses, subjective cognitive impairment was defined as a CPFQ score of >25. Therefore, we investigated whether CPFQ-based cognitive impairment could identify individuals who would likely benefit from treatment with NSI-189 80 mg. As shown in Figure 2, when comparing cognitive impairment defined using the composite cognitive performance score (shown previously) with cognitive impairment defined by the CPFQ, no differences were observed between the treatment groups in patients with self-reported cognitive impairment. The difference in CPFQ-defined cognitive impairment between the 80 mg and placebo groups was similar to that observed in the overall patient population. Thus, surprisingly, not only is objective cognitive impairment a predictor of improved drug response, but this impairment must be measured via performance on cognitive tasks such as those used here. Objective measures cannot be substituted by the use of patient-reported assessments of the patient's own cognitive symptoms. Furthermore, we did not rely on the cutoff value used in the CPFQ to define patients with cognitive impairment, as multiple other cutoff values ​​have been used to define subjective cognitive impairment in the CPFQ, none of which were predictive of drug response.

[0159] While data from this phase 2 study showed that cognitively poor patients responded better to NSI-189 than cognitively well-controlled patients, the clinical sample was uninformative as to whether NSI-189 would be more effective in cognitively poor patients who had an inadequate response to standard-of-care antidepressants, as only 18% of patients receiving 80 mg of NSI-189 had an inadequate response to an adequate trial of antidepressants according to the Antidepressant Treatment Response Questionnaire (ATRQ) in this phase 2 sample.

[0160] Example 2 - Phase 2 Clinical Trial with NSI-189 as Monotherapy or Adjunctive Therapy in Depression To determine whether cognitive impairment predicts a better response to NSI-189 80 mg in both patients not receiving other antidepressant treatment and those with an inadequate response to standard-of-care antidepressants, a large, open-label, phase 2 clinical trial was conducted in patients with MDD and / or PTSD receiving NSI-189 80 mg (40 mg twice daily) for up to 8 weeks. These patients also underwent more comprehensive cognitive testing than in previous phase 2 trials. As described above, MMRM analysis was applied to the change in MADRS score from baseline in patients with MDD. This analysis included 90 patients, 37 of whom were receiving NSI-189 monotherapy (i.e., without other antidepressants) and 53 of whom were receiving NSI-189 adjunctively to standard-of-care antidepressants for which they had an inadequate response. Antidepressant doses (i.e., separate from NSI-189) were not changed during the study, even if present at baseline. Of the total sample, 61 had an inadequate response to at least one appropriate trial of antidepressant medication within the current episode, including all patients receiving adjunctive NSI-189 therapy and some receiving monotherapy. In this study, the current episode was defined as the shorter of the previous 2 years or the time since the last occurrence of 2 consecutive months of euthymia within the previous 2 years. An inadequate response to antidepressant medication in the current episode was defined as less than 50% symptom reduction (e.g., based on the MADRS or HDRS total score).

[0161] To control for the influence of NSI-189 treatment context in the overall analysis, we first analyzed the entire sample using the MMRM, which included basic items for time, baseline, group (i.e., cognitively poor vs. cognitively good groups defined by a given measure of interest), time × group, and time by baseline, as well as additional covariates for monotherapy / adjunctive therapy, time × monotherapy / adjunctive therapy, and time × group × monotherapy / adjunctive therapy. In all analyses, we identified patients with poor cognition using a cutoff value of z = -0.75 to ensure that patients with poor cognition were impaired on these tasks (z scores were determined in reference to a separate healthy control population). Approximately 40% of the MDD population in this study had cognitive scores below the cutoff value of -0.75, implying that the poor cognition subpopulation constitutes an important and meaningful segment of the overall depression population. Furthermore, as further detailed below, the relationship between degree of cognitive impairment (i.e., lower z-scores) and better clinical outcomes (i.e., greater MADRS change from baseline) is continuous, thereby supporting multiple cut-points for defining cognitive poorness below z=0 (i.e., the patient's age- and sex-matched healthy mean score).

[0162] We analyzed a comprehensive cognitive performance variable consisting of measures of executive function (digit-symbol substitution task, Wisconsin card sorting task, trail making task, Corsi blocks, verbal fluency), information processing speed (flanker task, choice RT, simple RT), and verbal learning and / or memory. As seen in Figure 3(A), patients with poor cognitive function showed significantly better improvement in depressive symptoms (reduction in MADRS scores) in response to treatment with NSI-189, further supporting findings from a reanalysis of a previous phase 2 trial in which a general measure of cognitive impairment encompassing executive function, processing speed, and learning was used.

[0163] The ability of cognitive impairment to predict favorable depressive symptom outcomes was most strongly driven by verbal learning and / or verbal memory. Learning and / or memory was assessed using a word list task, in which patients were given a word list with five learning trials and were asked to recall those word lists immediately after learning and again after a delay of approximately 20 minutes (including after the inclusion of a new distractor list of words). This computer-implemented task was named VM-REACT (Computerized Verbal Memory Recall Test) and is further described in Naparstek et al., J. Psychiatr. Res., 2019, 114:170-177 (PMID 31096177). Poor recall of these word lists predicted significantly better MDD outcomes. This can be seen in Figure 3(B), where recall was quantified using a recall index, which averaged both immediate and delayed recall across the verbal learning and memory tasks into a single recall index. Furthermore, poor immediate recall significantly predicted MDD outcome at weeks 6 and 8 (Cohen's d = 0.48, p = 0.022; Cohen's d = 0.56, p = 0.010, respectively), and poor delayed recall significantly predicted MDD outcome at weeks 2 (Cohen's d = 0.43, p = 0.028), 4 (Cohen's d = 0.40, p = 0.045), 6 (Cohen's d = 0.67, p = 0.001), and 8 (Cohen's d = 0.61, p = 0.004). Furthermore, as seen in a reanalysis of a prior phase 2 trial, patient-reported cognitive impairment (assessed by the CPFQ scale) did not predict outcome. Using the same definition of poor cognition as above (i.e., CPFQ > 25), there was no significant difference between patients with self-reported poor cognition and those with good cognition (Figure 3(C)). Similarly, when considering only the memory recall item of the CPFQ, the patient-reported subjective measure most similar to the scale in Figure 3(B), moderate or greater subjective decline in memory recall did not predict outcome on the NSI-189 (Figure 3(D)). Therefore, it is important to directly assess cognition using standardized behavioral tasks.

[0164] We separately analyzed the predictive value of cognitive impairment, as defined by [ ], for NSI-189 treatment outcomes for patients receiving NSI-189 as monotherapy, as adjunctive therapy to an antidepressant with an inadequate response, or as a function of whether they had an inadequate response to an antidepressant in the current episode (regardless of whether NSI-189 was used monotherapy or adjunctively). As shown in Figures 4A and 4B, there was a similarly large and statistically significantly greater response to NSI-189 in patients with poor cognition compared with patients with good cognition, both in monotherapy and adjunctive therapy. Thus, cognitive impairment predicts favorable outcome for depressive symptoms when NSI-189 is used as an adjunctive treatment for depression, as well as in NSI-189 monotherapy; no conclusions can be drawn from a prior phase 2 study that did not include adjunctive therapy. Similarly, patients who had an inadequate response to at least one standard-of-care antidepressant in the current depressive episode were also considered, but the prior phase 2 study population was too small to allow for conclusions. As shown in Figure 4C, in these patients, cognitive impairment also significantly predicted a favorable response to 80 mg of NSI-189. Thus, this new phase 2 clinical trial builds on the previous phase 2 clinical trial by revealing novel evidence that NSI-189 may be even more effective in patients with cognitive impairment who are not responding adequately to antidepressant treatment in their current episode and who receive NSI-189 as monotherapy or adjunctive to an antidepressant. Furthermore, this new clinical trial builds on the previous phase 2 clinical trial by demonstrating that verbal memory recall, a measure of cognitive impairment not previously assessed, strongly predicts favorable response to NSI-189, whether administered as monotherapy or adjunctive to an antidepressant.

[0165] Furthermore, while the above analysis used a cutoff value of z = -0.75 to define patients with poor cognition, the relationship between the degree of cognitive impairment and the degree of improvement in response to depression treatment is continuous. This can be seen in the correlation between the change in MADRS score from baseline to week 6 (Figure 5(A)) or week 8 (Figure 5(B)) and baseline learning and / or memory (recall measures). As can be seen, there is a significant correlation between each of these time points and each subpopulation examined (monotherapy, adjunctive therapy, and one or more inadequate treatment trials). Thus, poor cognition can be defined by a z score for a cognitive measure below 0, which indicates the mean value for the corresponding healthy population. The lower the z score cutoff, the greater the expected clinical response to NSI-189 in patients with poor cognition defined in this way. To illustrate this, in Figure 6, we present results similar to those in Figure 4, in which poor verbal memory predicts favorable outcomes with NSI-189, but using a cutoff value of z = -0.418 instead of z = -0.75. A cutoff of z = -0.418 corresponds to the median score for patients in this study. Similar to Figure 4, Figure 6(A) shows patients receiving NSI-189 as monotherapy, Figure 6(B) shows patients receiving NSI-189 adjunctively to an antidepressant who have had an inadequate response, and Figure 6(C) shows patients receiving NSI-189 who have had an inadequate response to an antidepressant in the current episode (whether or not they are still taking an adjunctive antidepressant).

[0166] While the above analysis focuses on the use of poor learning and / or poor memory to define cognitively impaired individuals, doing so defines individuals with impairments across a wide range of cognitive and behavioral measures. As seen in Figure 7, cognitively impaired individuals defined by poor learning and / or poor memory (recall measures) exhibited impairments across a variety of cognitive tasks, including verbal fluency (number of words produced in response to cues), working memory in the Corsi Block Test (maximum number of correct consecutive actions after observing a series of actions), executive function and information processing speed in the Digit-Symbol Substitution Task (number of correct symbol-to-digit conversions based on a given symbol-digit mapping), executive function and information processing speed in the Flanker Task (matching reaction time), information processing speed in a choice or simple reaction time task, information processing speed (completion time) in the Trail A Task, interference resolution in the Flanker or Trail B Task (reaction time and completion time, respectively), and emotion recognition accuracy in a facial emotion recognition task (accuracy for angry, fearful, or happy facial expressions as well as overall accuracy). However, learning and memory have been found to be better predictors of success in treating depression with NSI-189 than other objective cognitive measures.

[0167] To further understand the clinical significance of cognitive prediction of antidepressant outcome, we plotted the response rate (Figure 8(A)) and remission rate (Figure 8(B)) in patients as a function of poor learning and / or memory versus good learning and / or memory. Thus, regardless of the clinical population defined (i.e., overall depression, monotherapy, adjunctive therapy, or one or more inadequate antidepressant treatment responses in the current episode), the response and remission rates in patients with poor learning and / or memory were consistently approximately twice those in patients with good learning and / or memory. As an absolute response level, the response rates of 60–82% in patients with poor learning and / or memory are significantly higher than typical placebo response rates (approximately 35% for monotherapy and approximately 20% for adjunctive therapy) (31–32), even considering the open-label nature of this study. Considered in the context of definitive clinical treatment, where the final drug is administered open-label, such high response rates contrast with current antidepressants, where only one-third to one-half of patients respond to treatment ( 33 – 34 ).

[0168] Next, we sought to understand the response of patients with poor cognition, poor learning, and poor memory to NSI-189 compared with the typical response to antidepressants or antipsychotics when used in combination with an antidepressant for which treatment efficacy was inadequate. To do so, we calculated the estimated drug-placebo difference for these patients based on two data points: 1) the known overall drug-placebo difference from the preceding phase 2 study (Cohen's d approximately 0.2) plus 2) the enrichment of the learning / memory poor subpopulation relative to the overall depressed population (represented by Cohen's d) observed in the second phase 2 study. Figure 8(C) shows the calculated drug-placebo Cohen's d for patients with poor learning and memory in the second phase 2 study (d = 0.79), as well as the Cohen's d for patients with poor cognition in the preceding phase 2 study (d = 0.58) when averaging responses from phases 1 and 2. This significant effect of the drug contrasts with the effect sizes of a wide variety of antidepressants and antipsychotics (combinations) (31-32, 35-38), which are typically roughly half the magnitude of the response to NSI-189. These results demonstrate the significant clinical significance of identifying cognitive impairment as a predictor of favorable response to NSI-189 in depression. Furthermore, cognitive impairment has been shown to be associated with poorer placebo response, and this estimated drug-placebo difference may be even greater if patients with poor cognitive impairment respond more poorly to placebo than those with favorable placebo response (39). Similarly, cognitive impairment predicts poorer response to standard-of-care antidepressants (e.g., SSRIs and SNRIs) (40), in stark contrast to the NSI-189 response, which is greater in patients with poor cognitive impairment.

[0169] Next, we investigated whether signals obtained from resting electroencephalograms (EEG) could predict NSI-189 treatment outcomes. We examined the power spectral density (PSD) distribution of EEG data. A schematic diagram showing EEG power spectral density is presented in Figures 1A and 1B in A.T. Hill et al., Dev. Cogn. Neurosci. 54:101076, 2022. As seen in Figure 9(A) herein, PSD across multiple channels indicates that depressive symptom responders to NSI-189 have significantly higher power in the high beta frequency range (20–30 Hz) and low gamma frequency range (31–50 Hz) (calculated on the central electrode). Furthermore, responders have lower power in the alpha frequency range (8–12 Hz). The same pattern is seen in patients receiving concomitant NSI-189 (Figure 9(B)) and in patients who have not responded adequately to at least one antidepressant (Figure 9(C)). This EEG pattern suggests that higher brain excitability (particularly differences in low-gamma power) predicts a better response to NSI-189.

[0170] Another way to analyze the PSD is through the observation that background trends in the data can be quantified as a measure of background neural activity and have a 1 / f relationship (where f is frequency). One way to quantify this signal is the aperiodic index, estimated as the negative slope of the line best fit in the 1-50 Hz range of the power spectral density in logarithmic space (T. Donoghue, et al., Nat. Neurosci, 23(12):1655-1665, December). We examined the channel-by-channel correlation between the aperiodic index and treatment outcome (as a percentage change in MADRS score from baseline). Figure 10(A) (top panel) shows that a lower aperiodic index (i.e., a flatter PSD) (calculated over central electrodes) positively predicted better depression treatment outcome (a more negative percentage change in MADRS score from baseline). This relationship was particularly strong at central-parietal electrode locations. The figure below shows an MMRM analysis of predicted changes from baseline in the MADRS, dividing the patient population by median, showing that patients with a low aperiodic index had significantly better depression outcomes than patients with a high aperiodic index. A similar relationship between a decrease in the aperiodic index and favorable depression treatment outcomes was observed in patients who received NSI-189 concomitantly (Figure 10(B)) and in patients who had an inadequate response to antidepressants in the current episode (Figure 10(C)).

[0171] To understand the relationship between these EEG signals and memory recall indices, we correlated either the aperiodic index or low-gamma power per channel with patients' recall scores. As seen in Figure 11, a larger aperiodic index (higher PSD frequencies, more steeply declining power) was significantly correlated with a larger recall index (better learning and memory). This is consistent with the findings above that improved NSI-189 treatment outcomes were predicted by either lower aperiodic index (flatter PSD) scores and lower recall index scores, but also correlated EEG and learning and / or memory signals.

[0172] In summary, findings from this Phase 2 study indicate that patients with poorer cognition (measured by impaired learning and memory recall) and / or higher brain excitability (measured by lower acyclic index or higher low-gamma power) had better treatment outcomes with NSI-189 for depression, whether they received NSI-189 monotherapy, as an adjunct to an inadequately responding antidepressant, or had an inadequate response to antidepressants in the current episode, regardless of whether they received NSI-189 monotherapy or as an adjunct to an antidepressant.

[0173] Example 3 - Phase 2 Clinical Trial with NSI-189 in PTSD To investigate whether cognitive impairment is a predictor of a better response to 80 mg of NSI-189 in PTSD, we next examined data from PTSD patients in the open-label Phase 2 clinical trial described above in Example 2. These patients underwent the same cognitive battery as the depressed patients. As above, MMRM analysis was applied to the change from baseline scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) in PTSD patients. Eighty-four patients were included in this analysis. All patients received 40 mg of NSI-189 twice daily, similar to the depressed patients described above.

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[0175] All publications, patents, and patent applications cited herein are incorporated by reference as if set forth in their entirety. While the present invention has been described with reference to exemplary embodiments, this description is not intended to be construed in a limiting sense. Various modifications and combinations of the exemplary embodiments, as well as other embodiments of the invention, will be apparent to those skilled in the art after reference to the description. Accordingly, it is intended that the appended claims encompass all such modifications and enhancements.

Claims

1. 1. A method for treating major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof, in a human patient having an objectively determined learning and / or memory impairment, comprising orally administering to said patient from about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

2. 10. The method of claim 1, wherein the patient has an objectively determined verbal learning disorder and / or verbal memory disorder.

3. 10. The method of any preceding claim, wherein the human patient is suffering from major depressive disorder or one or more symptoms thereof and exhibits an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range; (iii) low power in the alpha frequency; or (iv) any combination of any of (i), (ii), and (iii).

4. 10. The method of any preceding claim, wherein the human patient is suffering from major depressive disorder or one or more symptoms thereof and exhibits an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range; or (iii) both.

5. 1. A method of treating major depressive disorder, or one or more symptoms thereof, in a human patient exhibiting an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range; (iii) low power in the alpha frequency range; or (iv) any combination of any of (i), (ii), and (iii), comprising orally administering to said patient from about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

6. 6. The method of claim 5, wherein the human patient exhibits an electroencephalogram (EEG) comprising: (i) a low acyclic index, (ii) high power in the low gamma range, or (iii) both.

7. 10. The method of any one of the preceding claims, wherein about 60 to about 100 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof is administered daily.

8. 10. The method of any one of the preceding claims, wherein about 80 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof is administered daily.

9. The method of any one of claims 5 to 8, wherein the patient has an objectively determined verbal learning disorder and / or verbal memory disorder.

10. The human patient is administered the VM-REACT (Computerized Verbal Memory Recall Test), the Rey Auditory Verbal Learning Test, the California Verbal Learning Test, the California Verbal Learning Test-Short Version, the California Verbal Learning Test-Child Version, the Hopkins Verbal Learning Test, the Hopkins Verbal Learning Test-Revised, the Philadelphia Verbal Learning Test, the International Shopping List Test, the Language Section of the Repeatable Battery for the Assessment of Neuropsychological Status, the Cerad Neuropsychological Assessment Battery Word List Task, the Children's Auditory Verbal Learning Test, the Children's Memory Scale, the Bay Area Verbal Learning Test, the Cogstate Battery (which may include the following subtests: the Behavioral Pattern Separation Object Test, the Serial Paired Associative Learning Test, the Face-Name Associative Memory Test, the Groton Maze Test and its delayed recall and delayed reverse recall versions, the International Shopping List, the One-Catalog Test ... Neuropsychological Assessment Battery Memory Module, WHO / UCLA Auditory Verbal Learning Test, Repeatable Battery for the Assessment of Neuropsychological Status, Comprehensive Assessment of Memory and Learning, Buschke Selective Recall Test, Wechsler Memory Scale, Woodcock-Johnson Long-Term Recall Factor, Test of Memory and Learning, NEPSY, Brief Visuospatial Memory Test-Revised, Benton Visual Retention Test, Rey 10. A method according to any one of the preceding claims, wherein the individual suffers from a learning and / or memory impairment as indicated by the Osterreith Complex Figure Test, and any combination of any of the foregoing.

11. 10. The method of any one of the preceding claims, wherein the patient is not concurrently treated with a second antidepressant.

12. 12. The method of any one of claims 1 to 11, wherein the patient is concurrently treated with a second antidepressant.

13. 10. The method of any one of the preceding claims, wherein prior to treatment with (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof, the patient has had an inadequate response to antidepressants other than (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

14. 14. The method of claim 13, wherein the antidepressant is a standard of care antidepressant.

15. 15. The method of claim 13 or 14, wherein the patient has had an inadequate response to the antidepressant in the current depressive episode.

16. 16. The method of any one of claims 1 to 10 and 12 to 15, wherein (i) prior to treatment with (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof, the patient has had an inadequate response to an antidepressant other than (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof, and (ii) the patient is being treated concomitantly with an antidepressant and (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

17. 10. The method of any of the preceding claims, wherein said patient is concurrently treated with an antipsychotic drug in addition to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

18. 18. The method of claim 17, wherein the antipsychotic is quetiapine, aripiprazole, or brexpiprazole.

19. 1. A method of selecting a therapy for and treating a human patient for major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof, comprising: (a) objectively assessing whether said patient has a learning and / or memory impairment for the purpose of selecting a treatment for said patient; (b) if the patient is assessed as having a learning and / or memory impairment from step (a), commencing oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient daily.

20. 20. The method of claim 19, wherein step (a) comprises objectively assessing whether the patient has a verbal learning disorder and / or a verbal memory disorder, and step (b) comprises, if the patient is assessed as having a verbal learning disorder and / or a verbal memory disorder from step (a), initiating oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient daily.

21. 21. The method of claim 19 or 20, further comprising the step (c) of not initiating daily oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient if the patient is assessed from step (a) to be free of learning and / or memory impairment.

22. 1. A method of selecting a therapy for and treating a human patient for major depressive disorder, post-traumatic stress disorder, or one or more symptoms thereof, comprising: (a) diagnosing the patient as suffering from major depressive disorder, post-traumatic stress disorder, or both; (b) objectively assessing whether said patient has a learning and / or memory disorder for the purpose of selecting a treatment for said patient; (c) selectively prescribing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to said patient in light of said patient's diagnosis and an objective assessment that said patient has a learning and / or memory disorder; (d) if (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)-pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof is optionally prescribed, commencing oral administration to the patient of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)-pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

23. 23. The method of claim 22, wherein step (b) comprises objectively assessing whether the patient has a verbal learning disorder and / or verbal memory disorder, and step (c) comprises selectively prescribing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient in light of the patient's diagnosis and the objective assessment that the patient has a verbal learning disorder and / or verbal memory disorder.

24. 1. A method for determining whether a patient suffering from major depressive disorder, post-traumatic stress disorder, or both, can be effectively treated with (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone, and treating a human patient susceptible to such treatment, said method comprising: (a) objectively determining whether the patient has a learning and / or memory disorder; (b) if the patient is determined to have a learning and / or memory impairment from step (a), commencing oral administration to the patient of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

25. 25. The method of claim 24, further comprising the step (c) of not initiating daily oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to said patient if it is determined from step (a) that said patient does not have a learning and / or memory impairment.

26. 26. The method of claim 24 or 25, wherein step (a) comprises objectively assessing whether the patient has a verbal learning disorder and / or a verbal memory disorder, and step (b) comprises initiating oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient daily if step (a) determines that the patient has a verbal learning disorder and / or a verbal memory disorder.

27. 1. A method for treating major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof, in a human patient, comprising: (a) (i) marketing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone, or a pharmaceutically acceptable salt thereof, as providing effective treatment of major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof, in a patient having an objectively determined learning and / or memory impairment; and (ii) prescribing to said patient about 40 mg to 240 mg per day of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone, or a pharmaceutically acceptable salt thereof, the prescription being administered in response to an objective determination that said patient has a verbal learning and / or memory impairment; (b) orally administering to the patient the formulated (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

28. 28. The method of claim 27, wherein the prescribing is in response to (i) marketing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof as providing effective treatment of major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof, in a patient having an objectively determined verbal learning disorder and / or verbal memory disorder, and (ii) an objective determination that the patient has a verbal learning disorder and / or verbal memory disorder.

29. 1. A method for treating major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof, in a human patient, comprising: (a) diagnosing a patient as suffering from major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof; (b) (i) marketing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone, or a pharmaceutically acceptable salt thereof, as providing effective treatment of major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof, in a patient having an objectively determined learning and / or memory impairment; and (ii) prescribing to said patient about 40 mg to about 240 mg per day of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone, or a pharmaceutically acceptable salt thereof, a regimen administered in response to an objective determination that said patient has a verbal learning and / or memory impairment; (c) orally administering to the patient the formulated (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

30. 30. The method of claim 29, wherein the prescribing is in response to (i) marketing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof as providing effective treatment of major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof, in a patient having an objectively determined verbal learning and / or memory impairment, and (ii) an objective determination that the patient has a verbal learning and / or verbal memory impairment.

31. 1. A method for treating major depressive disorder, post-traumatic stress disorder, both major depressive disorder and post-traumatic stress disorder, or one or more symptoms thereof, in a human patient, comprising: (a) analyzing one or more indicators of a patient's responsiveness to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein the one or more indicators include an objectively determined learning impairment and / or memory impairment; (b) if the patient is determined to be responsive to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof based on one or more indicators, orally administering to the patient an effective amount of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

32. 32. The method of claim 31, wherein the one or more indicators include an objectively determined verbal learning impairment and / or verbal memory impairment.

33. 1. A method of selecting a therapy for and treating a human patient for major depressive disorder or one or more symptoms thereof, comprising: (a) assessing whether said patient (i) has an objectively determined learning and / or memory impairment, (ii) whether said patient exhibits an electroencephalogram (EEG) comprising: (A) a low acyclic index; (B) high power in the low gamma range (31-50 Hz); (C) low power in the alpha frequency; (D) any combination of (A), (B), and (C); or (iii) both (i) and (ii), for the purpose of selecting a treatment for said patient; (b) if the patient is assessed from step (a) as satisfying (i), (ii), or (iii), commencing oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient daily.

34. 34. The method of claim 33, further comprising the step (c) of not initiating daily oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient if step (a) assesses that the patient does not meet (i) or (ii).

35. 1. A method of selecting a therapy for and treating a human patient for major depressive disorder or one or more symptoms thereof, comprising: (a) diagnosing a patient as suffering from major depressive disorder; (b) assessing whether said patient (i) has an objectively determined learning and / or memory impairment, (ii) whether said patient exhibits an electroencephalogram (EEG) comprising: (A) a low acyclic index; (B) high power in the low gamma range (31-50 Hz); (C) low power in the alpha frequency; (D) any combination of (A), (B), and (C); or (iii) both (i) and (ii), for the purpose of selecting a treatment for said patient; (c) selectively prescribing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient, taking into account the patient's diagnosis and an assessment that the patient satisfies (i), (ii), or (iii); (d) upon selectively prescribing (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)-pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof, commencing oral administration to said patient of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)-pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

36. 1. A method for determining whether a patient suffering from major depressive disorder can be effectively treated with (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone, and treating a human patient susceptible to such treatment, said method comprising: (a) assessing whether said patient (i) has an objectively determined learning and / or memory impairment, (ii) whether said patient exhibits an electroencephalogram (EEG) comprising: (A) a low acyclic index; (B) high power in the low gamma range (31-50 Hz); (C) low power in the alpha frequency; (D) any combination of (A), (B), and (C); or (iii) both (i) and (ii), for the purpose of selecting a treatment for said patient; (b) if it is determined from step (a) that the patient satisfies (i), (ii), or (iii), initiating oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient daily.

37. 37. The method of claim 36, further comprising the step (c) of not initiating oral administration of about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to the patient daily if it is determined from step (a) that the patient does not satisfy (i), (ii), or (iii).

38. 1. A method of treating major depressive disorder or one or more symptoms thereof in a human patient, comprising: (a) prescribing about 40 to about 240 mg per day of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)-pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to a patient (i) having an objectively determined learning and / or memory impairment, (ii) exhibiting an electroencephalogram (EEG) comprising (A) a low acyclic index, (B) a high power in the low gamma range (31-50 Hz), (C) a low power in the alpha frequency, or (D) any combination of (A), (B), and (C), or (iii) exhibiting both (i) and (ii); (b) orally administering to the patient the formulated (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

39. 1. A method of treating major depressive disorder or one or more symptoms thereof in a human patient, comprising: (a) diagnosing a patient as suffering from major depressive disorder; (b) prescribing about 40 to about 240 mg per day of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)-pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof to a patient (i) having an objectively determined learning and / or memory impairment, (ii) exhibiting an electroencephalogram (EEG) comprising (A) a low acyclic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, or (D) any combination of (A), (B), and (C), or (iii) exhibiting both (i) and (ii), wherein the patient is a patient of a pharmaceutically acceptable salt thereof, and (c) orally administering to the patient the formulated (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

40. 1. A method of treating major depressive disorder or one or more symptoms thereof in a human patient, comprising: (a) analyzing one or more indicators of responsiveness of said patient to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof as a therapeutic agent, wherein said one or more indicators include (i) objectively determined learning and / or memory impairment, (ii) an electroencephalogram (EEG) comprising (A) a low acyclic index, (B) high power in the low gamma range (31-50 Hz), (C) low power in the alpha frequency, or (D) any combination of any of (A), (B), and (C), or (iii) both (i) and (ii); (b) if the patient is determined to be responsive to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof based on the one or more indicators, orally administering to the patient an effective amount of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

41. 41. The method of any one of claims 19 to 40, wherein the patient is treated with (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof as monotherapy.

42. 41. The method of any one of claims 19 to 40, wherein the patient is concurrently treated with a second antidepressant in addition to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

43. 43. The method of any one of claims 19 to 40 and 42, wherein the patient is concurrently treated with an antipsychotic drug in addition to (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

44. 44. The method of claim 43, wherein the antipsychotic is quetiapine, aripiprazole, or brexpiprazole.

45. 45. The method of any one of claims 19 to 44, wherein prior to treatment with (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof, the patient has had an inadequate response to an antidepressant other than (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof.

46. 46. ​​The method of claim 45, wherein the patient is treated concurrently with (i) (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof, and (ii) an antidepressant to which the patient has previously failed to respond adequately.

47. 10. The method of any one of the preceding claims, wherein the objectively assessed learning and / or memory impairment is calculated as a z-score normalizing the patient to a population of healthy individuals.

48. 48. The method of any one of claims 19 to 47, wherein about 60 to about 100 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof is administered to the patient.

49. 49. The method of claim 48, wherein about 80 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof is administered to the patient.

50. 49. The method of claim 48, wherein about 40 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof is orally administered twice daily.

51. 10. The method of any one of the preceding claims, wherein the (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof is administered as (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone phosphate.

52. 52. The method of any one of claims 33 to 51, wherein the objectively determined learning and / or memory disorder is an objectively determined verbal learning disorder and / or verbal memory disorder.

53. 33. The method of any one of claims 1, 2, and 19-32, wherein the patient suffers from major depressive disorder and post-traumatic stress disorder.

54. 1. A method for treating a major depressive episode in a human patient with an objectively determined learning and / or memory impairment, comprising orally administering to said patient from about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

55. 1. A method for treating bipolar depression in a human patient with an objectively determined learning and / or memory impairment, comprising orally administering to said patient from about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

56. 1. A method of treating bipolar depression, or one or more symptoms thereof, in a human patient exhibiting an electroencephalogram (EEG) comprising: (i) a low acyclic index; (ii) high power in the low gamma range; (iii) low power in the alpha frequency range; or (iv) any combination of any of (i), (ii), and (iii), comprising orally administering to said patient from about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

57. 1. A method of treating post-traumatic stress disorder in a human patient having an objectively determined learning and / or memory impairment, comprising orally administering to said patient from about 40 to about 240 mg of (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone or a pharmaceutically acceptable salt thereof daily.

58. 10. The method of any one of the preceding claims, wherein the patient has a learning and / or memory impairment as objectively determined by poor immediate recall in a verbal memory test.

59. 10. A method according to any one of the preceding claims, wherein the patient has a learning and / or memory impairment as objectively determined by poor delayed recall in a verbal memory test.

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