Methods and compositions for treating negative symptoms in non-schizophrenic patients

Abstract

To provide methods and compositions for treating at least one negative symptom in a human patient without a clinical diagnosis of schizophrenia.SOLUTION: A compositions employ a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 341,590, filed May 25, 2016, which is incorporated by reference in its entirety.

[0002] Field of Disclosure The present disclosure in some aspects relates generally to methods and compositions for treating negative symptoms, and more specifically, to methods and compositions for treating negative symptoms in non-schizophrenic patients without a clinical diagnosis of schizophrenia. [Background technology]

[0003] Negative symptoms generally refer to a decline in normal functioning and include five main subdomains: blunted affect (flattened affect, flat facial expression), aphasia (poverty of speech), amotivation (loss of willpower), anhedonia (reduced ability to expect and experience pleasure) and antisocial (social withdrawal). Negative symptoms are a well-documented and intensively studied aspect of schizophrenia, but symptoms of this kind have also been identified in patients with other psychiatric and neurological disorders, e.g., Alzheimer's disease and other dementias, especially frontotemporal dementia (FTD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (e.g., Boone et al, J. of Internat. Neuropsycol. Soc., 2003, Vol 9, pages 698-709; Bastiaansen, J. et al., J. Autsim Dev. Disord. 2011, Vol 41:1256-1266; Getz, K. et al., Am. J. Psychiatry 2002, Vol 159:644-651; Winograd-Gurvich, C. et al., Brain Res. Bulletin, 2006, Vol. 70:312-321; Galynker et al., Neuropsychiatry Neuropsychol Behav Neurol 2000, Vol 13:171-176; Galynker I, et al., J. Nerv. Ment. Dis 1997, Vol 185:616-621; Chaudhury, S., et al. al., Indian J. of Neurotrauma 2005, Vol 2:13-21; see Ameen, S et al., German J. of Psychiatry 2007).

[0004] In fact, as early as 2001, it was proposed that negative symptoms are common in psychiatric disorders (Herbener and Harrow, Schizophrenia Bulletin 2001, Vol. 27:527-537). Furthermore, several population studies have concluded that 20-22% of the general population have one or more negative symptoms, and that the majority of patients with negative symptoms do not exhibit a clinical diagnosis of psychiatric disorder (Werbeloff, N. et al., PLoS ONE 2015, Vol 10:e0119852; Barrantes-Vidal, N., et al., Schizophr. Res. 2010, Vol 122:219-225). There are currently no effective treatments for the negative symptoms of schizophrenia or other psychotic or neurological conditions. Summary of the Invention

[0005] The disclosure herein is based in part on results from a promising Phase IIb, 12-week, randomized, double-blind, placebo-controlled, parallel-group clinical trial that demonstrated a statistically significant effect of MIN-101 32 mg and 64 mg versus placebo in improving negative symptoms in a population of 244 schizophrenia patients with negative symptoms. Positive symptoms remained stable and no EPS were observed over the 12-week period, consistent with the notion that MIN-101 has a direct, specific effect on negative symptoms rather than improving other symptoms. MIN-101 is being developed by Minerva Neurosciences, Inc. (Waltham, Massachusetts) for the treatment of negative symptoms in patients with schizophrenia. The active ingredient in MIN-101 (previously CYR-101 or MT-210) has the chemical name 2-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one monohydrochloride dihydrate and the structure of the free salt is Formula I (Compound I): [ka] It is. Compound I is σ 2 , 5-hydroxytryptamine-2A (5-HT 2A ), but exhibits low affinity for α1-adrenergic receptors. MIN-101 exhibits very low or no affinity for other receptors, including dopamine, muscarinic, cholinergic, and histamine receptors. In vivo functional studies have shown that MIN-101 inhibits 5-HT 2A and σ 2 It has been established that MIN-101 is an antagonist of both the valproate and valproate receptors. Two metabolites of MIN-101 have been identified, designated BFB-520 and BFB-999. The BFB-520 metabolite has been associated with QT interval prolongation at supratherapeutic levels.

[0006] In one aspect, the disclosure provides a composition comprising a compound of formula (I) (Compound I), or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof, for use in treating at least one negative symptom in a non-schizophrenic human patient, wherein the method of treatment comprises orally administering to the patient a therapeutically effective amount of the composition. In one embodiment, the composition is formulated for oral delivery and the therapeutically effective amount is between about 1 mg and about 64 mg per day of Compound I. In one embodiment, the therapeutically effective amount is between about 10 mg and about 64 mg, between about 20 mg and about 64 mg, or between about 30 mg and about 64 mg per day of Compound I. In one embodiment, the therapeutically effective amount is about 8 mg, about 16 mg, about 32 mg, or about 64 mg of Compound I per day.

[0007] In another aspect, the disclosure provides a method for treating at least one negative symptom in a non-schizophrenic human patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) (Compound I), or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof. In one embodiment, the method comprises orally administering about 1 mg to about 64 mg of Compound I per day. In one embodiment, the dosage of Compound I is between about 10 mg and about 64 mg, between about 20 mg and about 64 mg, or between about 30 mg and about 64 mg per day. In one embodiment, the dosage of Compound I is about 8 mg, about 16 mg, about 32 mg, or about 64 mg per day.

[0008] In both aspects of this disclosure, the negative symptoms treated are primary negative symptoms rather than secondary negative symptoms. In one embodiment, the primary negative symptoms are selected from the group consisting of blunted affect, aphasia, apathy, anhedonia, and antisociality. In one embodiment, the primary negative symptoms are selected from the group consisting of blunted affect, emotional withdrawal, poor intimacy, passive / disinterested social withdrawal, difficulty with abstract thinking, lack of conversational spontaneity and fluency, and stereotyped thinking.

[0009] In some embodiments of the above aspects of this disclosure, the non-schizophrenic patient is diagnosed with a psychotic or neurological condition. In one embodiment, the psychotic or neurological condition is selected from the group consisting of dementia, frontotemporal dementia (FTD), Alzheimer's disease, autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), borderline personality disorder, Parkinson's disease, temporal lobe epilepsy, cerebrovascular accident (CVA), traumatic brain injury (TBI), posterior brain trauma syndrome, mild to moderate mental retardation, viral encephalitis, and drug addiction. In one embodiment, the disease or condition is MDD or BVD. In one embodiment, the disease or condition is Parkinson's disease.

[0010] In some embodiments of the above aspects of this disclosure, Compound I, or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered to the patient for an initial treatment period long enough to achieve improvement in at least one negative symptom, hi one embodiment, the initial treatment period is at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks.

[0011] In some embodiments of the above aspects of this disclosure, if the patient experiences improvement of at least one negative symptom in the first treatment period, administration of a therapeutically effective amount of Compound I, or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof, is continued for a second treatment period of at least 12 weeks, at least 24 weeks, at least 48 weeks, or until the patient is determined to be in remission from the negative symptoms.

[0012] In some embodiments of the above aspects of this disclosure, Compound I or a pharma- ceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once in the morning or evening.In one embodiment, Compound I or a pharma- ceutically acceptable salt, hydrate, solvate or polymorph thereof is administered at least 2 hours before a meal.

[0013] In some embodiments of the above aspects of this disclosure, the patient is administered a polymorph of Compound I. In one embodiment, the polymorph is known as crystalline form (A) of Compound (I)·HCl·2H2O (or referred to as crystalline form (A)), and is characterized in International Patent Application No. PCT / US2015 / 062985 (published as WO2016 / 089766) and U.S. Patent Application No. 14 / 954264 (published as US2016-0152597A1), the contents of which are incorporated herein by reference in their entireties.

[0014] In some embodiments of the above aspects of this disclosure, Compound I or its polymorphic crystalline form (A) is administered to a patient as part of a pharmaceutical composition, which comprises a release modifier that prevents the maximum plasma concentration (Cmax) of Compound I or its crystalline form (A) from exceeding 50 ng / mL when a dosage of about 1 mg to about 64 mg of the formulation is administered to a human. In one embodiment, the pharmaceutical composition provides a maximum plasma concentration (Cmax) of BFB-520 metabolites of less than 10.0 ng / mL, less than 5.0 ng / mL, less than 4.5 ng / mL, less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, or less than 1.0 ng / mL and an area under the curve (AUC) of BFB-520 of less than 40 hr*ng / mL, less than 35 hr*ng / mL, less than 30 hr*ng / mL, less than 25 hr*ng / mL, less than 20 hr*ng / mL, less than 15 hr*ng / mL, or less than 10 hr*ng / mL.

[0015] In some embodiments of the above aspects of this disclosure, the human patient is at least 18 years of age, and in other embodiments of the above aspects of this disclosure, the human patient is under 18 years of age. In some embodiments of the above aspects of this disclosure, the human patient has not been previously treated with an antipsychotic drug. In other embodiments of the above aspects of this disclosure, the human patient has been discontinued from previous antipsychotic treatment due to inadequate response or intolerable side effects. [Brief description of the drawings]

[0016] The foregoing summary, as well as the following description of the invention, will be better understood when read in conjunction with the appended drawings.

[0017] [Figure 1] Figure 1 shows the mean change from baseline (pentagon model, vertical axis) in negative subscale scores of the Positive and Negative Symptoms Scale (PANSS) after 12 weeks of treatment with placebo (continuous line), MIN-101·32 mg (long dashed line), and MIN-101·64 mg (short dashed line) per day.

[0018] [Diagram 2] Figure 2 shows the mean change from baseline (y-axis) in the three-factor negative symptoms subscale scores of the PANSS after 12 weeks of placebo (continuous line), MIN-101·32 mg (long dashed line), and MIN-101·64 mg (short dashed line) per day.

[0019] [Diagram 3] Figure 3 shows the mean change from baseline in total score after 12 weeks of treatment with BNSS placebo (continuous line), MIN-101·32 mg (long dashed line), and MIN-101·64 mg (short dashed line).

[0020] [Figure 4] FIG. 4 shows the powder X-ray diffraction of the crystalline form (A) of compound (I)·HCl·2H2O.

[0021] [Diagram 5] FIG. 5 is an IR spectrum of the crystalline form (A) of compound (I)·HCl·2H2O.

[0022] [Figure 6] Figure 6 shows the 1H-NMR spectrum of the crystalline form (A) of compound (I)·HCl·2H2O.

[0023] [Figure 7] Figure 7 is the 13C-NMR spectrum of the crystalline form (A) of compound (I)·HCl·2H2O. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] As described in the Examples below, a daily dose of 32 mg or 64 mg of Compound I was shown to provide a statistically significant improvement in negative symptoms in patients with schizophrenia compared to placebo. These data and the efficacy of Compound I in reducing sigma 2Based on the antagonism of activity, the present disclosure predicts that similar improvement in negative symptoms will be obtained in non-schizophrenic human patients, where non-schizophrenic patients means patients who exhibit at least one negative symptom but have not been diagnosed with schizophrenia.

[0025] It is therefore an object of the present disclosure to provide a method of treating at least one negative symptom in a non-schizophrenic patient, the method comprising administering to the patient a therapeutically effective amount of a composition comprising Compound I or a pharma- ceutically acceptable salt, hydrate, solvate or polymorph thereof.

[0026] It is also an object of the present disclosure to provide a composition comprising Compound I or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof for use in treating at least one negative symptom in a human patient, by a method comprising administering to the patient a therapeutically effective amount of the composition.

[0027] It is a further object of the present disclosure to treat at least one negative symptom in a non-schizophrenic human patient diagnosed with a psychotic or neurological condition using the disclosed compositions and methods.

[0028] In one embodiment, the negative symptoms are one of five major subdomains of negative symptoms: blunted affect, aphasia, apathy, anhedonia, and antisocial. Core features of each subdomain are described below.

[0029] Flat affect (affective flattening) is characterized by a reduction in the range and intensity of emotional expressions expressed in verbal and non-verbal communication, including intonation (prosody), facial expressions, and gestures.

[0030] Aphasia (poverty of speech) is characterized by a decrease in the amount of speech, a decline in spontaneous speech, and a loss of speech fluency.

[0031] Amotivation (loss of will) is characterized by a lack of initiation and maintenance of goal-oriented activities such as work, study, exercise, personal hygiene, and daily tasks. It is also characterized by a lack of desire to perform such activities, especially when they require effort (cognitive and physical) and significant organization. This subdomain also relates to apathy and lack of energy.

[0032] Anhedonia (diminished ability to anticipate and experience pleasure) is characterized by the enjoyment of a reward, entertainment, or other enjoyable experience (desire) being more significantly and consistently impaired than the appreciation of the experience itself (preference) (consummary anhedonia).

[0033] Antisociality (social withdrawal) is characterized by a decline in appreciation, motivation or interest in social interactions with others such as family and friends, loss of interest in intimate (sexual) relationships independent of physical problems, and for children may include loss of interest in playing with other children.

[0034] In this application, unless otherwise specified, the term "treatment" includes the care and management of a non-schizophrenic patient for the purpose of ameliorating negative symptoms, and includes the administration of Compound I for a treatment period and in an amount sufficient to suppress the onset of one or more negative symptoms, to reduce the severity or intensity and frequency of one or more negative symptoms, to prevent or delay the development of additional negative symptoms, or any combination of these therapeutic purposes. In one embodiment, the efficacy of Compound I treatment is assessed by comparing the severity of the patient's negative symptoms to baseline (e.g., before treatment with Compound I) and after at least one treatment period. In one embodiment, the treatment period is at least one week, at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, or at least twelve weeks.

[0035] In this application, unless otherwise stated, the terms "subject" and "patient" are interchangeable and refer to a human of any age. In one embodiment, the non-schizophrenic patient is 6 years of age or older. In one embodiment, the patient is at least 18, 19, 20, or 21 years of age. The non-schizophrenic patient exhibits one or more negative symptoms but does not have a diagnosis of schizophrenia. In some embodiments, the non-schizophrenic patient does not have a diagnosis of a psychotic or neurological condition. In another embodiment, the non-schizophrenic patient has a diagnosis of a psychotic or neurological condition.

[0036] In some embodiments, the disclosed methods or compositions are used to treat non-schizophrenic patients who are not undergoing antipsychotic treatment. In this application, antipsychotic refers to any drug approved by a government agency for the treatment of psychosis, excluding Compound I. Exemplary antipsychotics include, but are not limited to, fluphenazine, risperidone, olanzapine, clozapine, quetiapine, zibrasidone, aripiprazole, sertindole, zotepine, perospirone, and the like.

[0037] In another embodiment, the disclosed methods or compositions are used to treat non-schizophrenic patients who have previously been treated with antipsychotic drugs but discontinued treatment due to insufficient improvement in negative symptoms and / or intolerance of the side effects of the drug.

[0038] In some embodiments, the disclosed methods or compositions are used to treat non-schizophrenic patients who are not receiving antidepressant treatment. In this application, antidepressant refers to any agent that does not include Compound I and is approved by a government agency for the treatment of major depressive disorder. Examples of antidepressants include, but are not limited to, fluoxetine, citalopram, escitalopram, venlafaxine, duloxetine, bupropion, etc.

[0039] In another embodiment, the disclosed methods or compositions are used to treat non-schizophrenic patients who have previously been treated with antidepressants but who discontinued treatment due to insufficient improvement in negative symptoms and / or intolerance of the side effects of the medication.

[0040] For purposes of the disclosure contained herein, the term "negative symptoms" is understood to include the early negative symptoms typically associated with schizophrenia, negative symptoms as measured by the PANSS negative subscale score, and negative symptoms as measured by the BNSS.

[0041] The disclosed methods involve administering to a patient a therapeutically effective amount of Compound I or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof. As used herein, a "therapeutically effective amount" refers to an amount effective to reduce the severity of at least one negative symptom by at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% compared to baseline. The improvement in symptoms in a patient may be measured by any measurement tool commonly accepted in the art, including, but not limited to, PANSS negative subscale scores and BNSS by pentagonal model. In one embodiment, a therapeutically effective amount results in a 20% or greater reduction in PANSS negative subscale scores from baseline after a 2-week, 4-week, or 8-week treatment period.

[0042] In yet another aspect of the disclosure, the disclosed compositions are formulated and administered to a patient to provide a dosage of Compound I that is substantially equivalent to the oral administration of the specifically recited daily dosages. One of skill in the art can select a formulation and route of administration that provides such basic equivalence.

[0043] The disclosure also provides the use of Compound I, or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof, in the manufacture of a medicament for treating at least one negative symptom in a non-schizophrenic human patient. For example, the medicament is suitable for oral administration. For example, the medicament has a therapeutically effective amount of Compound I, corresponding to a daily dose of about 1 mg to about 64 mg of Compound I.

[0044] It will be understood by those skilled in the art that the treating physician may select the dosage and dosing regimen that he believes to be optimal based on the symptoms and health of the patient being treated, along with the desired therapeutic outcome, in accordance with the above guidelines. For example, the treating physician may choose to initiate treatment with a lower therapeutically effective dose of Compound I and increase the dose to the targeted therapeutically effective dose. For example, the daily dose of Compound I may be a single dose or multiple doses.

[0045] In this application, quantitative expressions described as a range from about a value X to about a value Y include values ​​10% above and below each X and Y, and also include any value between X and Y. Thus, for example, a dose of about 32 mg includes doses from 30 to 34 mg.

[0046] All references to Compound I include all pharma- ceutically acceptable salts, all solvates, and other physical forms unless otherwise specified. All doses described herein are based on the free base weight of Compound I, rather than its pharma- ceutical acceptable salts, hydrates, solvates, or excipients in the composition, unless otherwise specified. Furthermore, all doses of Compound I described herein are flat doses (e.g., not dependent on patient weight), unless otherwise specified.

[0047] For therapeutic administration in accordance with the present disclosure, Compound I may be used as its free base, but is preferably used in the form of a pharma- ceutically acceptable salt. In one embodiment, Compound I used in the disclosed methods and compositions is 2-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one monohydrochloride dihydrate, having the molecular formula C 22 H 23 FN2O2·HCl·2H2O, molecular weight is 438.92.

[0048] Compound I can be synthesized according to standard synthetic methods and procedures for the preparation of organic molecules and functional group transformation and manipulation, including the use of protective groups, obtained from relevant scientific literature or standard textbooks in the field.Reference textbooks on organic synthesis include, but are not limited to, Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 3rd; John Wiley & Sons: New York, 1999.The preparation of compound (I) is described in U.S. Patent No. 7,166,617.

[0049] The disclosed methods and compositions may use crystalline form (A) of Compound I. Pharmaceutical compositions containing crystalline form (A) of Compound I may be prepared as described in International Patent Application PCT / US2015 / 062985 (published as WO2016 / 089766).

[0050] In one embodiment, other salts of Compound I with pharma- ceutically acceptable acids may also be used in therapy, such as salts derived from functionally free salts and acids, including, but not limited to, palmitic acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, salicylic acid, citric acid, oxalic acid, lactic acid, malic acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0051] As described herein, all solvates, all alternative physical forms of Compound I or pharma- ceutically acceptable derivatives thereof are also encompassed within the scope of this disclosure, including, but not limited to, alternative crystalline forms, amorphous forms, polymorphs, etc. All references to a compound of Formula I (or Compound I) include all pharma- ceutically acceptable salts, all solvates, and all alternative physical forms thereof.

[0052] For therapeutic administration, Compound I or a pharma- ceutically acceptable salt thereof, such as the hydrochloride salt, may be administered in pure form, but may preferably be formulated into any pharma- ceutically acceptable effective composition, which provides an effective concentration of the active ingredient in the body.

[0053] The term "pharmaceutically acceptable" as used herein with respect to a compound or composition refers to a form of the compound or composition that may enhance or increase the availability or solubility of the compound in a patient to enhance or promote the bioavailability of the compound or composition. In one embodiment, the disclosure encompasses pharmaceutically acceptable hydrates, solvates, stereoisomers, or amorphous forms of the individual embodied compounds or compositions. For example, the term "pharmaceutically acceptable salt" describes one or more salt forms of the composition that are provided to enhance the solubility of the compound in the gastric fluids of the gastrointestinal tract of a patient to enhance the dissolution and bioavailability of the compound and / or composition. In one embodiment, pharmaceutically acceptable salts include pharmaceutically acceptable inorganic or organic acids and bases. Suitable salts include those derived from alkali metals such as potassium, sodium, alkaline earth metals such as calcium, magnesium, ammonium salts, and many other acids well known in the pharmaceutical field. Sodium and potassium salts are preferred as neutral salts of carboxylic acids and free phosphates and are included in the disclosure. The term "salt" is intended to mean any salt consistent with the use of the compound encompassed by this disclosure. In the pharmaceutical applications of this compound, including the treatment of depression, the term "salt" is intended to mean a pharma- ceutically acceptable salt, consistent with the use of Compound I as a pharmaceutical agent.

[0054] As used herein, the term "pharmaceutically acceptable derivative" or "derivative" describes any pharmaceutically acceptable prodrug form (such as an ester, ether or other prodrug group) which, upon administration to a patient, directly or indirectly provides the subject compound or an active metabolite thereof.

[0055] As mentioned above, the composition contains a pharma- ceutically acceptable salt of the compound in the composition.In another embodiment, the acid used to prepare the pharma-ceutically acceptable acid addition salt of the compound is an acid that forms a non-toxic acid addition salt, i.e., a salt containing a pharma-ceutically acceptable anion, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, superphosphate, acetate, lactate, citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate [i.e., 1,1'-methylenebis-(2-hydroxy-3-naphthoic acid) salt], among others.

[0056] In one embodiment, the compositions include base addition salts of the subject compounds. Chemical bases used as reagents to prepare pharma- ceutically acceptable base salts of the subject compounds that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from pharma- ceutically acceptable cations, such as alkali metal cations (e.g., potassium, sodium), alkaline earth metal cations (e.g., calcium, magnesium), ammonium, water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium and other pharma-ceutically acceptable organic amines.

[0057] The term pharma- ceutically acceptable salt or complex, as used herein, refers to a salt or complex (e.g., solvates, polymorphs) that retains the desired biological activity of the parent compound and minimizes undesired toxicological effects, if any. Non-limiting examples of such salts include: (a) Acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with N,N-dibenzylethylenediamine, ammonium, or ethylenediamine; (c) A combination of (a) and (b) above, such as zinc-tannate;

[0058] Modifications of the compounds can affect the solubility, bioavailability and rate of metabolism of the active species, thereby controlling the delivery of the active species. Furthermore, the modifications can affect the tranquilizer activity of the compounds, which in some cases can exceed the activity of the parent compound. This can be readily assessed by preparing derivatives and testing them as described herein or by other methods known to those skilled in the art.

[0059] In one embodiment, the compositions may be formulated in a conventional manner or administered as a controlled release formulation using one or more pharma- ceutically acceptable carriers.The pharma-ceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-related substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0060] The compositions included herein may be administered orally. In another embodiment, the compositions may be administered parenterally, by inhalation spray, topical administration, rectal, nasal, buccal, vaginal, or via implanted reservoir. The term "parenteral" as used herein includes subcutaneous, transdermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion. As will be appreciated by those skilled in the art, in view of the embodiments included herein, the dosage of the active ingredient or ingredients (e.g., the compound of formula I) may be adjusted upwards or downwards based on the selected route of administration. Furthermore, it will be understood that dose optimization of the active ingredient for any selected dosage form is desirable, and the effectiveness of the anxiolytic compound may be evaluated by the methods described herein or known to those skilled in the art.

[0061] The pharmaceutical compositions embodied herein can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. In one embodiment, lubricants such as magnesium stearate are added. For oral administration in capsule form, commonly used diluents include lactose and / or dried cornstarch, as two non-limiting examples. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may be added.

[0062] Pharmaceutical compositions encompassed by this disclosure may also be administered by nasal aerosol or inhalation. Such compositions may be prepared in saline solution, using benzyl alcohol or other preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and other solubilizing or dispersing agents, according to techniques well known in the art of drug formulation.

[0063] In one embodiment, a therapeutically effective amount of Compound I is administered independently of any other medication prescribed for the treatment of a psychiatric or neurological condition.

[0064] In another embodiment, a therapeutically effective amount of Compound I is administered in conjunction with one or more medications to treat a coexisting condition, including a psychiatric or neurological condition. Such other medications may be administered in a manner and in dosages known to those of skill in the art, or in conjunction with or in the same manner as the above-described administration of a compound of Formula I. The other medications may be administered before, after, or simultaneously with Compound I, for the desired duration of treatment.

[0065] The present disclosure includes, but is not limited to, the following aspects. Aspect 1: Compound of Formula I (Compound I) [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof; The composition is used in a method for treating at least one negative symptom in a non-schizophrenic human patient, the method comprising orally administering to the patient a therapeutically effective amount of the composition, the effective amount being a daily dose of about 1 mg to about 64 mg of Compound I.

[0066] Embodiment 2: The composition of embodiment 1, wherein the therapeutically effective amount is a daily dose of Compound I of about 10 mg to about 64 mg, 20 mg to about 64 mg, or about 30 mg to about 64 mg.

[0067] Embodiment 3: The composition of embodiment 2, wherein the therapeutically effective amount is a daily dose of 30 mg to 64 mg of Compound I.

[0068] Embodiment 4: The composition of embodiment 1, wherein the therapeutically effective amount is a daily dose of about 8 mg, about 16 mg, about 32 mg, or about 64 mg of Compound I.

[0069] Embodiment 5: The composition of embodiment 4, wherein the therapeutically effective amount is a daily dose of 32 mg of Compound I.

[0070] Embodiment 6: The composition of embodiment 4, wherein the therapeutically effective amount is a daily dose of 64 mg of Compound I.

[0071] Embodiment 7: A method of treating at least one negative symptom in a non-schizophrenic human patient, the method comprising orally administering to the patient a therapeutically effective amount of Compound I, or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the therapeutically effective amount is a daily dose of about 1 mg to about 64 mg of Compound I.

[0072] Embodiment 8: The method of embodiment 7, wherein the therapeutically effective amount is a daily dose of Compound I from about 10 mg to about 64 mg, from about 20 mg to about 64 mg, or from about 30 mg to about 64 mg.

[0073] Embodiment 9: The method of embodiment 8, wherein the therapeutically effective amount is a daily dose of Compound I of 30 mg to 64 mg.

[0074] Embodiment 10: The method of embodiment 7, wherein the daily dose of Compound I is about 8 mg, about 16 mg, about 32 mg, or about 64 mg.

[0075] Embodiment 11: The method of embodiment 10, wherein the therapeutically effective amount is a daily dose of Compound I of 32 mg.

[0076] Embodiment 12: The method of embodiment 10, wherein the therapeutically effective amount is a daily dose of Compound I of 64 mg.

[0077] Aspect 13: A compound of formula I (Compound I): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate or polymorph thereof in the manufacture of a medicament for treating at least one negative symptom in a non-schizophrenic human patient, the method comprising orally administering to the patient a therapeutically effective amount of the composition, the therapeutically effective amount being a daily dose of about 1 mg to about 64 mg of Compound I.

[0078] Embodiment 14: The use of embodiment 13, wherein the therapeutically effective amount is a daily dose of compound I of about 10 mg to about 64 mg, 20 mg to about 64 mg, or about 30 mg to about 64 mg.

[0079] Embodiment 15: The use of embodiment 13, wherein the therapeutically effective amount is a daily dose of compound I of 30 mg to 64 mg.

[0080] Embodiment 16: The use of embodiment 13, wherein the therapeutically effective amount is a daily dose of Compound I of about 8 mg, about 16 mg, about 32 mg, or about 64 mg.

[0081] Embodiment 17: The use of embodiment 13, wherein the therapeutically effective amount is a daily dose of 32 mg of compound I.

[0082] Embodiment 18: The use of embodiment 13, wherein the therapeutically effective amount is a daily dose of compound I of 64 mg.

[0083] Embodiment 19: The composition, method or use of any of embodiments 1 to 18, wherein the negative symptoms are selected from the group consisting of blunted affect, aphasia, apathy, anhedonia and antisociality.

[0084] Aspect 20: The composition, method or use of any of aspects 1 to 18, wherein the negative symptoms are selected from the group consisting of emotional blunting, emotional withdrawal, poor intimacy, passive / disinterested social withdrawal, difficulties with abstract thinking, lack of conversational spontaneity and fluency, and stereotyped thinking.

[0085] Embodiment 21: The composition, method or use of any of embodiments 1 to 20, wherein the non-schizophrenic patient is diagnosed with a psychotic or neurological condition.

[0086] Embodiment 22: The composition, method or use of embodiment 21, wherein the psychiatric or neurological condition is selected from the group consisting of dementia, frontotemporal dementia (FTD), Alzheimer's disease, autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, cerebrovascular accident (CVA), traumatic brain injury (TBI), posterior brain trauma syndrome, mild to moderate mental retardation, viral encephalitis and drug addiction.

[0087] Embodiment 23: The composition, method or use of embodiment 22, wherein the psychiatric or neurological condition is FTD or Alzheimer's disease.

[0088] Embodiment 24: The composition, method or use of embodiment 22, wherein the psychiatric or neurological condition is MDD or BPD.

[0089] Embodiment 25: The composition, method or use of embodiment 22, wherein the psychiatric or neurological condition is Parkinson's disease.

[0090] Embodiment 26: The composition, method or use of any of embodiments 1 to 25, wherein compound I is administered to the patient for at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks or at least 12 weeks of the initial treatment period.

[0091] Embodiment 27: The composition, method or use of embodiment 26, wherein once the patient experiences improvement of at least one negative symptom in a first treatment period, administration of a therapeutically effective amount of compound I is continued for a second treatment period of at least 12 weeks, at least 24 weeks or at least 48 weeks, or until the patient determines remission of the negative symptoms.

[0092] Embodiment 28: The composition, method or use of any of embodiments 1 to 27, wherein compound I is administered once in the morning under fasting conditions at least 2 hours before a meal.

[0093] Embodiment 29: The composition, method or use of any of embodiments 1 to 28, wherein polymorphic crystalline form (A) of Compound I is administered to the patient.

[0094] Embodiment 30: The composition, method, or use of any of Embodiments 1-29, wherein Compound I or polymorphic crystalline Form (A) of Compound I is administered as part of a pharmaceutical composition, the composition comprising a release modifier such that the maximum serum concentration (Cmax) of Compound I is less than 50 ng / mL when about 1 mg to about 64 mg of the formulation is administered to a human.

[0095] Embodiment 31: The composition, method or use of embodiment 29 or 30, wherein the pharmaceutical composition provides a maximum serum concentration (Cmax) of the BFB-520 metabolite of less than 5.0 ng / mL, less than 4.5 ng / mL, less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL or less than 1.0 ng / mL and an area under the curve (AUC) of BFB-520 of less than 40 hr*ng / mL, less than 35 hr*ng / mL, less than 30 hr*ng / mL, less than 25 hr*ng / mL, less than 20 hr*ng / mL, less than 15 hr*ng / mL or less than 10 hr*ng / mL.

[0096] Embodiment 32: The composition, method or use of any of embodiments 1 to 31, wherein the non-schizophrenic patient is not receiving treatment with an antipsychotic.

[0097] Embodiment 33: The composition, method or use of any of embodiments 1 to 31, wherein the non-schizophrenic patient has discontinued previous antipsychotic treatment due to inadequate response and / or intolerance of side effects.

[0098] Embodiment 34: The composition, method or use of any of embodiments 1 to 33, wherein the non-schizophrenic patient is not receiving treatment with an antidepressant.

[0099] Embodiment 35: The composition, method or use of any of embodiments 1 to 33, wherein the non-schizophrenic patient has discontinued previous antidepressant treatment due to inadequate response and / or intolerance of side effects.

[0100] Aspect 36: The composition, method, or use of any of Aspects 1-35, wherein the form of Compound I administered is 2-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one monohydrochloride dihydrate.

[0101] Embodiment 37: The composition, method, or use of any of embodiments 1 to 36, wherein the daily dose of compound I is administered in a single dose.

[0102] Embodiment 38: The composition, method or use of any of embodiments 1 to 36, wherein the daily dose of compound I is administered multiple times, such as two, three or four times daily.

[0103] Positive and Negative Symptoms Scale (PANSS) Below is a description of the Positive and Negative Symptom Scale (PANSS) used in the clinical trials described in the Examples. Positive and Negative Symptoms Scale (PANSS) scale

[0104] [General evaluation guidelines] The data collected during this evaluation will be used to assess the PANSS. Each of the 30 items will have a specific definition and established criteria for all seven points. These seven points represent increasing levels of psychopathology, as follows: 1. None 2. Very mild 3. Mild 4. Moderate 5. Moderately severe 6. Severe 7. Most severe When assigning a score, one must first determine whether all of the items are present as determined by their definition. If the item is absent, the score is 1, and if present, the fixation point must be referenced to a specific criterion to determine its severity. Always assign the highest score possible, even if the patient meets lower-level criteria. In determining severity, the assessor must use a holistic perspective to determine which fixation point best characterizes the patient's functioning and evaluate whether all elements of the description are observed. Scores 2 to 7 correspond to increasing levels of symptom severity: A rating of 2 (very mild) may indicate questionable, subtle, or equivocal symptoms, or may indicate the extreme end of the normal range.

[0105] A rating of 3 (mild) indicates symptoms whose presence is clearly established but which are barely noticeable and do not interfere with daily functioning. A rating of 4 (moderate) characterizes symptoms that represent a serious problem, but that are only occasional or to the extent that they interfere with daily life. A rating of 5 (Moderately Severe) indicates significant illness that clearly affects a person's functioning, but is not all-consuming and usually can be contained voluntarily. A rating of 6 (severe) represents global disease that is frequent, extremely disruptive to life, and often requires direct management. A rating of 6 (severe) refers to the most severe level of psychopathology, in which the condition dramatically interferes with many or major functions and typically requires close supervision and support across multiple disciplines. Each item is rated in consultation with the definitions and criteria provided in this manual. Ratings are made according to each characteristic by circling the appropriate number on the PANNS rating form.

[0106] [PANSS evaluation form] [Table 1-1] [Table 1-2] [Table 1-3]

[0107] Scoring Instructions Of the 30 items included in the PANSS, 7 are positive, 7 are negative, and the remaining 16 are general psychopathology. These scores are compiled by cross-assessing each item, allowing for a range of 7-49 for the positive and negative scales, and 16-112 for the general psychopathology scale. In addition, a mixed scale is used by subtracting the negative from the positive scales. This gives a bipolarity index ranging from -42 to +42, which is essentially a score reflecting the dominance of one symptom over the other.

[0108] Positive scale (P) P1. Delusions Unfounded, unrealistic and outlandish beliefs. Basis of assessment: Assess the thoughts expressed during the interview and their impact on social relationships and behavior. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - Presence of one or two vague, nonspecific, and non-persistent delusions that do not affect thinking, social interactions, or behavior. 4. Moderate: Kaleidoscope-like, fragile and unstable delusions or robust delusions that occasionally affect thinking, social interactions, and behavior. 5. Moderately severe: There are many well-established delusions that are persistent and at times affect thinking, social interactions, and behavior. 6. Severe - The stable presence of multiple, specific, structured, and persistent delusions that clearly affect thinking, social interactions, and / or behavior. 7. Severe - Highly structured or numerous delusions are present and stable, dominating major aspects of the patient's life, often resulting in inappropriate and irresponsible behavior that may endanger the safety of the patient or others.

[0109] P2. Conceptual integration disorder: Failure to integrate thought processes, characterized by goal-directedness, e.g. circuitous thinking, loss of connections, sidetracking, illogicality, or breakdowns in thought. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - Thinking is circuitous, digressive or illogical. Goal-directed thinking is difficult and can be evident when under pressure. 4. Moderate - Able to focus on ideas when communications are short and structured, but becomes inaccurate or misguided with more complex communications or minimal pressure. 5. Moderately severe: Generally has difficulty organizing thoughts, is often disoriented, and acknowledges feelings of loneliness and loss of connection even in the absence of pressure. 6. Severe - Thinking is seriously disrupted and internally incoherent, with severely disorienting and confusing thought processes occurring almost constantly. 7. Most severe: thinking is disrupted and the patient becomes incoherent. There is a total inability to communicate with significant loss of association, e.g., "word salad" or mutism.

[0110] P3. Hallucinated behavior Behavioral or verbal reports that indicate perceptions not evoked by external stimuli. Occurs in the auditory, visual, olfactory, and somatosensory domains. Assessment basis: Assessment is based on verbal reports observed during the interview, physical manifestations, and behavioral reports from family members or nursing staff. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - One or two clearly formed but infrequent hallucinations, plus many vaguely abnormal perceptions that do not result in distortion of thought or behavior. 4. Moderate Hallucinations are frequent but not continuous. The patient's thoughts and behavior are affected, but only to a small extent. 5. Moderately severe: Hallucinations occur frequently, involve more than one sensory modality, and tend to result in distortions of thought and behavior. Patients interpret these experiences in delusional ways and respond emotionally and sometimes verbally. 6. Severe - Hallucinations are almost constantly present and primarily cause confusion of thought and behavior. The patient perceives these as real perceptions and movement is often hindered by emotional and verbal responses. 7. Severe: The patient is so consumed by the hallucinations that they virtually control thinking and behavior. The hallucinations provide rigid interpretations and actually control verbal and behavioral responses, including submitting to the control of the hallucinations.

[0111] P4. Agitation Excessive behavior reflected by increased motor behavior, increased responsiveness to stimuli, hypervigilance, or excessive emotional lability. Assessment basis: Behavioral manifestations observed during the interview along with behavioral reports from family members and / or nursing staff. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Slightly excited, hypervigilant, or a little agitated throughout the interview, but no obvious episodes of agitation or significant emotional instability. Speaks in a slightly authoritarian manner. 4. Moderate - Agitation and general agitation are evident throughout the interview, affecting speech and general mobility. There are sporadic outbursts. 5. Moderately severe: Significant hyperactivity or frequent bouts of motor activity are observed, with the patient having difficulty remaining still for more than a few minutes at any one time. 6. Severe: Marked agitation dominates the encounter, limits attention, and interferes to some extent with personal functioning such as eating and sleeping. 7. Severe: Marked agitation severely affects eating and sleeping, interpersonal communication is virtually impossible, speech and accelerated motor activity become incoherent and exhausting.

[0112] P5. Grandiosity – Exaggerated self-assertion and unrealistic belief in superiority. Includes delusions of extraordinary ability, wealth, knowledge, prestige, power, or moral righteousness. Evaluation Basics Evaluate the thoughts expressed during the interview and their influence on behavior. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Grandiosity or arrogance is evident, but without grandiose delusions. 4. Moderate - A clear and unrealistic sense of superiority over others. There may be slightly formed delusions of special status or abilities, but no action is taken. 5. Moderately severe: Clear delusions of significant power, status, or power are present and affect attitudes but not behavior. 6. Severe: A distinct delusion of marked superiority involving two or more parameters (wealth, knowledge, prestige, etc.) manifests and significantly affects communication and behavior. 7. Most Severe. Thought communication and behavior may take on a bizarre nature, dominated by numerous delusions of extraordinary abilities, wealth, knowledge, prestige, power and / or moral status.

[0113] P6. Suspicion / Persecution – An unrealistic and exaggerated idea of ​​being persecuted, manifested by a wary and suspicious attitude, excessive caution, and an outright delusion that others are going to harm oneself. Evaluation criteria Evaluation is based on the thoughts expressed during the interview and their impact on behavior. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - Cautious or openly distrustful, but thought, communication, and behavior are minimally affected. 4. Moderate - Distrust is evident and intrusive in the interview and / or behavior, but there is no evidence of paranoia. Alternatively, there may be signs of a loosely formed paranoia, but it does not seem to affect the patient's attitude or relationships. 5. Moderately severe: The patient displays marked distrust, leading to widespread disruption of relationships, or there is clear paranoia that has a limited effect on relationships and behavior. 6. Severe: The paranoia is widespread, systematized, and severely interferes with interpersonal relationships. 7. Severe: An organized network of delusions dominates the patient's thinking, social interactions, and behavior.

[0114] P7. Hostility – Verbal and non-verbal expressions of anger and resentment and can include sarcasm, passive-aggressive behavior, verbal violence and aggression. Evaluation basis: Evaluation is based on interpersonal behavior observed during the interview and reports from family members or nursing staff. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Indirect or restrictive communication such as sarcasm, rudeness, hostility, and occasional irritability. 4. Moderate - Openly hostile, often showing direct expressions of irritability, anger, and resentment. 5. Moderately severe: The patient is very agitated and occasionally verbally abusive or threatening. 6. Severe: Incoherence and verbal or physical intimidation significantly affect interactions and seriously impact social relationships. The patient may be violent and disruptive but is not physically aggressive. 7. Severe: Marked anger produces extreme uncooperativeness or stories of physical aggression towards others, making communication impossible.

[0115] Negative scale (N) N1. Flat affect: Decreased emotional reactivity characterized by a decrease in facial expressions, appropriate emotional and communicative gestures. Evaluation basis: Emotional tone and physical expressions of emotional reactivity are evaluated based on observation during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Facial expressions and gestures of communication appear stiff, pretentious, and uncoordinated. 4. Moderate: The range of facial expressions and some expressive gestures is reduced, resulting in a dull, sluggish appearance. 5. Moderately severe: Although there are occasional changes in facial expression, emotions are generally flat and there are few gestures to communicate intentions. 6. Severe: Most often marked flatness and lack of emotion is present. There may be extreme, unregulated emotional outbursts such as excitement, rage, or inappropriate, unrestrained laughter. 7. Most severe: Virtually no basis for facial expression or gestures of communication. The patient always displays a bare, tree-like facial expression.

[0116] N2. Emotional withdrawal: Not showing interest or concern in what is happening around you. Evaluation basis: Evaluation is based on observation of interpersonal behavior during the interview and reports from family members or nursing staff. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Usually lacks initiative and shows no interest in what is going on around them. 4. Moderate: The patient generally distances himself emotionally from the environment or challenges but will confront them if prompted. 5. Moderately severe: The patient resists all efforts at engagement and is noticeably emotionally detached from the people and environment around them. The patient appears cold, quiet, and aimless, but is able to participate in at least brief communication and attend to personal obligations, sometimes with assistance. 6. Severe. A clear lack of interest and emotional involvement limits conversation with others and frequently neglects personal functioning. Patient requires supervision. 7. Severe: A profound lack of interest and emotional involvement results in the patient becoming almost totally withdrawn, non-communicative, and abandoning personal needs.

[0117] N3. Communication problems: Lack of empathy and openness in conversation, as well as closeness and interest in the interviewer. Manifested by reduced verbal and non-verbal communication and interpersonal distance. Evaluation basis Evaluation will be based on interpersonal behavior during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - Conversation is characterized by a stiff, strained, or pretentious tone. It lacks emotional depth and tends to remain at an impersonal intellectual level. 4. Moderate: Typically the patient is reserved and socially distant, responds mechanically to questions, and displays a bored or disinterested demeanor. 5. Moderately severe: The disconnect is obvious and clearly impedes the productivity of the interview. 6. Severe: The patient is extremely apathetic and has a marked interpersonal distance. Responses are dismissive and there are few nonverbal signs of engagement. Direct eye contact is often avoided. 7. Severe: The patient is almost universally disinterested in the interview. During the interview, the patient is disinterested and consistently avoids verbal and non-verbal communication.

[0118] N4. Social withdrawal due to passivity / indifference Passivity, apathy, lack of drive, and lack of will result in decreased interest and independence in social interactions. This leads to decreased interpersonal relationships and indifference to daily life. Evaluation basis: Social skills are evaluated based on reports from family members or nursing staff. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - Occasional interest in social activities but little initiative. Usually only engages with others when approached. 4. Moderate: Passively follows many social activities, but responds indifferently or mechanically. Tends to lose momentum. 5. Moderately severe - Passively involved in only a few activities but virtually no interest or initiative. Generally does not communicate with others. 6. Severe: Apathetic and reclusive, rarely participates in social activities, and often neglects personal needs. Almost no spontaneous social contact. 7. Severe: Indifference, isolation and personal neglect are severe.

[0119] N5. Difficulties with Abstract Thinking: Impairment in thinking in abstract / symbolic forms, as manifested by difficulties categorizing, generalizing, and moving beyond concrete or egocentric thinking in problem-solving. Assessment Basics Evaluate responses to questions about analogies and proverb interpretation, and the use of concrete versus abstract thinking during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - Tends to give literal or personal interpretations to more difficult proverbs and can have problems with fairly abstract or distantly related concepts. 4. Moderate: Occasionally uses concrete methods. Has difficulty with many sayings and certain areas. Tends to be distracted by features and functions. 5. Moderately severe: Copes primarily in concrete ways and has difficulty in many areas. 6. Severe - No metaphor or proverb can grasp the abstract meaning, only simple similarities can be formulated to define the classification. Thought is either empty or reduced to functional aspects, characteristics and idiosyncratic interpretations. 7. Most severe - Only concrete ways of thinking are possible. No understanding of proverbs, common metaphors or similes, or simple classifications is possible. Neither traits nor functional aspects can be used as a basis for classification. This rating may also be applied to individuals whose significant cognitive impairments prevent them from engaging in even minimal interaction with the examiner.

[0120] N6. Lack of spontaneity and fluency in conversation Disruption of the normal flow of conversation associated with apathy, lack of motivation, defensiveness or cognitive deficits. This manifests as a decrease in fluency and productivity in the process of verbal interaction. Assessment Basics Evaluate the cognitive and linguistic processes observed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild. Little to no conversational autonomy. Patient's responses are short and unadorned and require direct, guided questioning by the interviewer. 4. Moderate: Conversation is not free-flowing and seems uneven or incomplete. Directing questions are often needed to elicit appropriate responses and move the conversation forward. 5. Moderately severe: The patient shows a significant lack of autonomy and openness and only responds to the interviewer's questions in short sentences of one or two words. 6. Severe: In order to avoid or shorten communication, the patient's responses are limited mainly to a few words or short sentences (e.g., "I don't know" or "I can't tell you"). As a result, conversation is greatly impaired and the interview is extremely unproductive. 7. Most severe: Linguistic output is limited to occasional speech at most; conversation is not possible.

[0121] N7. Stereotyped thinking: Fluency, spontaneity and flexibility of thought are reduced, resulting in rigid, repetitive and poor thinking content. Assessment Basics Evaluate the cognitive and linguistic processes observed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - There is some rigidity in attitudes and beliefs. The patient may refuse to consider alternative situations or have difficulty moving from one idea to another. 4. Moderate: Difficulty moving conversations around recurring themes and onto new topics. 5. Moderately severe: Despite the interviewer's efforts, thinking becomes rigid and conversation is repeatedly limited to only a few dominant topics. 6. Severe: Uncontrollable repetition of requests, statements, ideas, or questions that seriously interfere with conversation. 7. Most severe: Thought, behavior and speech are dominated by fixed ideas or restricted phrases, leading to a general rigidity, inappropriateness and restriction of the patient's communication.

[0122] Global Psychopathology Rating Scale (G) G1. Hypochondriasis - physical complaints or beliefs of being sick or unwell. This can range from a vague feeling of being unwell to outright delusions of incurable physical illness. Evaluation basics: Evaluate the thoughts expressed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - There are clear worries about health or physical ailments, but no delusional beliefs and the preoccupations are mitigated by a sense of security. 4. Moderate - Complaints about poor health or physical ailments, but no delusional beliefs, and mitigated by a sense of security. 5. Moderately severe: The patient complains of many or frequent complaints about physical illness or ailments, or manifests one or two clear, non-preoccupied delusions involving these themes. 6. Severe: The patient is preoccupied with clear delusions of physical illness or tissue malfunction, but his emotions are not entirely absorbed in these subjects and thoughts can be diverted by the interviewer's efforts. 7. Most severe: Many and repeated somatic delusions are reported, or only somatic delusions of a catastrophic nature that dominate the patient's moods and thinking.

[0123] G2. Anxiety - The subjective experience of irritability, worry, anxiety, or restlessness ranging from excessive worry about the present or future to a feeling of panic. Evaluation basics: Evaluate the information expressed during the interview and the corresponding physical symptoms. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Some anxiety, excessive worry, or subjective restlessness is expressed but no physical or behavioral consequences are reported or demonstrated. 4. Moderate: The patient complains of clear neurotic symptoms, reflected in mild physical manifestations such as slight hand tremors and excessive sweating. 5. Moderately severe: Patients complain of severe anxiety problems with significant physical and behavioral consequences, such as noticeable tension, poor concentration, palpitations or sleep disturbances. 6. Severe: The subjective state is one of almost constant anxiety, involving morbid fear, marked restlessness or numerous physical manifestations. 7. Severe: The patient's life is seriously disrupted by anxiety, which is almost constant and is associated with pathological fears that sometimes reach panic proportions, or is manifested by actual panic attacks.

[0124] G3. Guilt Feelings of remorse or self-blame for past wrongdoings, real or imagined. Assessment Basics Assess the guilt expressed during the interview and its impact on behavior and thinking. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild The questioning elicits vague feelings of guilt or self-blame for a minor incident, but the patient is clearly not overly concerned. 4. Moderate: Expresses concern about one's own responsibility regarding actual minor incidents in one's life, but is not preoccupied and attitudes and behavior are essentially unaffected. 5. Moderately severe: The patient expresses strong feelings of guilt, associated with self-deprecation or the belief that he or she should be punished. The feelings of guilt may be delusional, may volunteer themselves, may be the source of concerns or depressive modes, but cannot be alleviated by the interviewer. 6. Severe: Intense thoughts of guilt are of a delusional nature and lead to feelings of hopelessness and worthlessness. The patient believes that he or she deserves severe punishment, such as a criminal offense. 7. Most severe: The patient's life is dominated by an unrelenting delusion or feeling of guilt, and they feel they deserve extreme punishments such as life imprisonment, torture, or the death penalty. This may be associated with suicidal thoughts, attributing the problems of others to their own misdeeds.

[0125] G4. Tension: Physical manifestations of fear, anxiety, or restlessness, such as stiffness, trembling, excessive sweating, or restlessness. Assessment criteria: Evaluate the severity of verbal manifestations of anxiety and physical signs of tension observed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild. Posture and movements such as slight rigidity, occasional restlessness, shifting, and small, rapid tremors indicate slight concern. 4. Moderate - A clearly nervous appearance emerges from a variety of manifestations such as fidgety behavior, obvious hand tremors, excessive sweating or nervous mannerisms. 5. Moderately Severe: Significant nervousness is indicated by numerous manifestations such as nervous trembling, profuse sweating and restlessness, but performance during the interview is not significantly affected. 6. Severe: Marked tension interferes with communication. Patients may, for example, be constantly fidgety, unable to sit still for long periods of time, or hyperventilate. 7. Severe: Extreme tension indicated by accelerated movements and signs of panic, e.g., rapid, restless pacing, inability to sit for more than a minute, and inability to hold a sustained conversation.

[0126] G5. Pedanticism and Awkward Postures Awkward postures characterized by an awkward, pretentious, confused, or odd appearance. Evaluation basis: Evaluation is based on observation of physical expressions during the interview and reports from nursing staff or family members. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Movements are clumsy and posture is slightly rigid. 4. Moderate: Movements are particularly clumsy or uncoordinated, or awkward postures are maintained for short periods. 5. Moderately severe: Strange rituals and contorted postures are observed, and abnormal postures are maintained for long periods of time. 6. Severe. Bizarre rituals, often featuring stereotyped or stereotypical movements or controlled postures maintained for long periods of time. 7. Severe - Function is seriously impaired by virtually constant involvement in ritualistic, stereotyped, or archetypal movements or by unnatural, rigid postures sustained for much of the time.

[0127] G6. Depression Feelings of sadness, discouragement, helplessness, emptiness, etc. Assessment Basics: Observe and assess the depressed mood expressed during the interview and its impact on attitudes and behavior. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Expresses sadness or dejection only in response to questioning, but general attitude and behavior do not indicate depression. 4. Moderate: There are overt feelings of sadness or despair that may be spontaneously expressed, but the depressed mood does not significantly affect behavior or social functioning, and the patient usually feels cheerful. 5. Moderately severe: Overtly depressed mood is associated with obvious sadness, pessimism, loss of social interest, psychomotor slowing, and interference with appetite and sleep. The patient does not easily get well. 6. Severe: A markedly depressed mood is associated with persistent feelings of distress, often crying, hopelessness and worthlessness. In addition, there is major interference with appetite and / or sleep, as well as with normal motor and social functioning, and there may be signs of self-neglect. 7. Severe - Depressed feelings seriously interfere with many major functions, as manifested by frequent crying, obvious physical symptoms, impaired concentration, psychomotor slowing, social disinterest, self-neglect, depressive or nihilistic delusions, and / or suicidal thoughts or behaviors.

[0128] G7. Hypokinetic Decreased motor activity as manifested by slowed or diminished movement and speech, decreased response to stimuli, and decreased physical condition. Assessment basis: Assessment is based on symptoms observed during the interview and reports from nursing staff or family members. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: There is a slight decrease in the speed of speech and movement. The patient is not productive in speech and behavior. 4. Moderate: The patient's movements are noticeably slower, with long reaction latencies, extended pauses, and slower speech characteristics. 5. Moderately severe: A marked decline in motor activity makes communication extremely unproductive and limits functioning in social and professional situations. Patients are usually found sitting or lying down. 6. Severe - Movements are extremely slow and activity and conversation are minimal. The individual essentially spends the day sitting or lying down. 7. Severe: The patient is almost completely immobile and virtually unresponsive to external stimuli.

[0129] G8. Non-cooperativeness Engaging in activities that refuse to go along with the wishes of significant others such as interviewers, hospital staff, family members, etc. May be accompanied by distrust, defensiveness, stubbornness, refusal, resistance to authority, hostility, or combativeness. Evaluation basis: Evaluation is based on interpersonal behavior observed during the interview and reports from nursing staff or family members. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild - Fits attitudes of resentment, impatience, and cynicism. May be unpleasantly resistant to sensitive scrutiny. 4. Moderate: Often completely refuses to conform to normal social expectations, such as making one's own bed or participating in scheduled activities. Patients may develop hostile, defensive, and negative attitudes, but are usually able to work together. 5. Moderately severe: The patient usually does not comply with the demands of the environment and is characterized by others as an "outcast" or as someone with "serious attitude problems." Uncooperativeness is projected into overt defensiveness or irritability toward the interviewer and unwillingness to deal with many questions. 6. Severe: The patient is very uncooperative, pessimistic, and combative. Refuses to comply with many social requirements and is unwilling to initiate or terminate full conversations. 7. Severe. Active resistance impacts virtually every major area of ​​functioning. The patient is unable to participate in social activities, attend to personal hygiene, or converse or participate in interviews with family or staff. They may reject both.

[0130] G9. Unnatural Thought Content Thought characterized by unusual, fantastical, or bizarre ideas, ranging from irrelevant and atypical to distorted, irrational, and downright absurd. Evaluation basis: Evaluate the thoughts expressed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Thoughts are odd or unusual, or familiar ideas are organized irregularly. 4. Moderate - Thoughts are often distorted and sometimes seem bizarre. 5. Moderately Severe: Patients express many strange, fantastical thoughts (such as being adopted by the King or being an escapee from death row) or some that are clearly absurd (such as having hundreds of children or having fillings in their teeth or not receiving radio messages from outer space). 6. Severe: Patients express illogical and absurd ideas, some of which are quite bizarre (e.g. having three heads, being a visitor from another world, etc.). 7. Most severe: Thoughts are filled with absurd, strange and bizarre ideas.

[0131] G10. Disorientation: Loss of awareness of one's relationship to the environment, including people, place, and time, which may be caused by dysphoria or autism. Assessment Basics Assess responses to questions related to orientation. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Good general orientation but difficulty with specifics. For example, a patient knows their location but not their street address; knows the names of hospital staff but not their functions; knows the month but cannot tell the next day of the week; gets dates wrong by more than one day, etc. Narrowed interests are demonstrated in a direct but non-extendable environment, such as the ability to identify staff but not mayors, governors, or presidents. 4. Moderate Recognition of person, place, and time is only partial. For example, the patient knows he or she is in a hospital but not its name; knows the name of the city but not the ward or neighborhood; knows the name of the primary therapist but not many of the other direct caregivers; knows the season and year but is uncertain about the month, etc. 5. Moderately severe: There are significant errors in the recognition of people, places, and time. The patient has only a vague sense of where they are and is unfamiliar with many of the people around them. The patient may know the year accurately or nearly accurately, but not the month, day of the week, or even the season. 6. Severe: There are significant errors in the recognition of person, place, and time. For example, the patient does not know where he or she is, dates are confused for more than a year, and the patient can only name one or two people in his or her current life. 7. Severe: The patient appears completely confused about people, place, and time. There is total confusion or complete ignorance about people's whereabouts, the current year, closest family members such as parents, spouse, friends, primary caregivers, etc.

[0132] G11. Attention disorder: Difficulty concentrating on one's attention. Distraction by internal and external stimuli and difficulty shifting, maintaining, or directing attention to new stimuli. Evaluation basis: Evaluation is based on findings made during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Often vulnerable to distractions and stumbling during the interview, with limited concentration. 4. Moderate: Conversation is affected by tendency to be easily distracted, difficulty maintaining attention on a given subject for long periods of time, and problems shifting attention to new topics. 5. Moderately severe: Poor concentration, moderate distractibility, and difficulty shifting focus appropriately such that conversation is severely impair 6. Severe: The patient's attention can only be suppressed for short periods of time or with difficulty due to significant distractibility by internal and external stimuli. 7. Severe - Attention is so impaired that even a short conversation is impossible.

[0133] G12. Lack of Judgment and Insight Impaired awareness or understanding of one's own mental state or life situation. This impairment is manifested by failure to understand past or present psychiatric illness or symptoms, refusal of psychiatric admission or treatment, decisions that show poor foresight, and unrealistic long-term or short-term plans. Evaluation basis: Evaluate the thoughts expressed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild – Recognizes mental illness but underestimates its severity, the implications of treatment, and the steps that can be taken to avoid relapse. 4. Moderate: The patient has a vague, shallow awareness of the illness. There may be fluctuating acknowledgment of the illness and little awareness of the major symptoms, such as delusions, disorganized thinking, distrust, and social withdrawal. The patient may rationalize the need for treatment in terms of relief of milder symptoms, such as anxiety, tension, and sleep problems. 5. Moderately severe: Recognizes past psychiatric illness but not current illness. When pointed out, the patient may concede and state the presence of certain unrelated or insignificant symptoms. This tends to be explained by sheer misunderstanding or delusional thinking. The need for treatment of the psychiatric illness is also not recognized. 6. Severe: The patient denies having ever suffered from any mental illness, denies the presence of any psychiatric symptoms in the past or present, and is compliant but denies the need for treatment or hospitalization. 7. Severe - There is intense denial of past and present mental illness. The current hospitalization and treatment are given delusional interpretations (e.g., as punishment for wrongdoing, as an act of persecution by a persecutor), and the patient refuses to cooperate with the therapist, medication, or other treatment.

[0134] G13. Disorders of Willpower Disorders of independent initiation, maintenance, and control of thoughts, movements, behavior, and speech. Evaluation basis: Evaluate the thoughts and behaviors observed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: There is some indecisiveness in speech and thinking, which may impede verbal cognitive processes to some extent. 4. Moderate: The patient is often indecisive and has obvious difficulties in reaching decisions. Speech is impaired by thought modifications, resulting in a clear impairment of verbal cognition. 5. Moderately severe: Intentional confusion interferes with thinking and behavior, and the patient exhibits marked indecisiveness and difficulty in initiating and continuing social and motor activities, which is also manifested by halting speech. 6. Severe - Intentional confusion interferes with simple involuntary motor functions such as dressing and grooming and greatly affects speech. 7. Severe: Almost complete impairment of willpower and total inhibition of movement and speech, resulting in immobility and muteness.

[0135] G14. Impulse control disorder A disorder of inhibition or regulation of behavior in response to internal demands, resulting in sudden, uncoordinated, erratic or erroneous release of tensions and emotions without consideration of the consequences. Evaluation basis: Evaluation is based on behavior during the interview and reports from nursing staff or family members. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Patients tend to become easily angry, frustrated, or deny gratification when faced with stress, but rarely act impulsively. 4. Moderate: The patient becomes angry and abusive at minimal provocation, is occasionally threatening and destructive, and has been involved in physical confrontations or minor fights. 5. Moderately severe: Patient exhibits recurrent impulsive manifestations that may include verbal abuse, destruction of property, and physical threats. May include severe assaults, necessitating isolation, physical restraints, and PRN sedation of the patient. 6. Severe: Patients frequently exhibit impulsive aggression and are obsessive, demanding, destructive, and seemingly without consideration for the consequences. Patients exhibit aggressive behavior, have sexual aggression, and act on hallucinated cues. 7. Severe: The patient is homicidal, sexually violent, repeatedly cruel, and self-destructive. He or she is unable to control dangerous impulses and requires constant direct supervision and external restraints.

[0136] G15. Preoccupation - Preoccupation with internally generated thoughts, emotions, and autistic experiences that results in loss of real-world orientation and appropriate behavior. Evaluation basis: Evaluate the interpersonal behavior observed during the interview. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Excessive inclusion of personal needs and problems in conversation, digressions back to self-centered themes, and decreased interest shown in others. 4. Moderate: Patients often seem self-absorbed, as if in a daydream or involved in inner experiences, which interferes with communication with others. 5. Moderately severe: Patients often appear to be engaging in autistic experiences, such as blank stare, mumbling, talking to themselves, or engaging in typical motor patterns, which are manifested in behaviors that interfere with social communication functions. 6. Severe - Marked preoccupation with autistic experiences that segments the ability to concentrate, speak, and adapt to the environment. Patients may often smile, laugh, mutter, or yell to themselves. 7. Most severe - Total preoccupation with the autistic experiences that significantly affects all major areas of behavior. The patient constantly responds verbally or behaviorally to the hallucinations and pays little attention to other people or the external environment.

[0137] G16. Active social avoidance: Voluntary social avoidance: reduced social interaction accompanied by unfounded fear, hostility, or distrust. Evaluation basis: Evaluation is based on reports from nursing staff or family members. 1. None The definition is not correct. 2. Very mild - questionable pathology; perhaps at the upper end of the normal range. 3. Mild: Patients participate in social functions as needed, but are easily made to feel ill in the presence of others and prefer to spend time alone. 4. Moderate: The patient participates reluctantly in all or most social activities but needs persuasion and may terminate prematurely due to anxiety, distrust, or hostility. 5. Moderately severe: Patients avoid social interactions, fearfully or angrily, despite efforts by others to involve them. Tend to spend unstructured time alone. 6. Severe: Patients rarely participate in social activities because of fear, hostility, or distrust. When challenged, patients have a strong tendency to withdraw from interactions and generally tend to isolate themselves from others. 7. Severe: Because of deep fear, hostility, or paranoia, the patient is unable to participate in social activities. To the extent possible, they avoid all interaction and remain isolated from others.

[0138] Simple Negative Symptom Scale Below is a description of the Brief Negative Symptom Scale (BNSS) used in the clinical study of the examples. [Table 2]

[0139] Brief Negative Symptom Scale (Manual) This instrument was developed to measure the original degree of severity of negative symptoms for schizophrenia and schizophrenic disorders. Negative symptoms are the reduction or absence of behavioral or thematic experiences that are normally present in people of the same culture and age. Negative symptoms include anhedonia, antisociality, amotivation, blunted affect, and aphasia, although other symptoms may also belong to this category. Negative symptoms are clearly distinguished from other schizophrenia and related disorders (including psychotic, disorganized, depressive, and anxiety symptoms) and from cognitive deficits. This manual, designed for training purposes, contains items in addition to probes and anchors. A workbook is used during the assessment, but contains only probes and anchors. A score sheet is a separate document. The scale is intended for use in treatment trials, but may also be used for other purposes, such as non-research clinical evaluation and tracking of change. No attempt is made to define negative symptom subtypes or syndromes in this scale. Five subscales are included, one for each negative symptom listed above. There is another item not included in one of these subscales, the distress item.

[0140] All assessments are based on semi-structured interviews with prompts and questions. It is important to include the content of the semi-structured interview as a minimum. However, any additional questions necessary to assess the items should be asked. Items are rated on a 7-point scale (0-6), with anchors usually ranging from no symptoms (0) to severe symptoms (6). Assessments should be anchored and should avoid adjusting to expectations of how a person with a mental illness would normally behave. The time frame for assessment is one week, and assessments based on the patient's overall survival should be avoided. It may be necessary to remind the patient of this time frame from time to time. Although many of the assessments in this chapter require self-reporting, observations of the patient during the interview should also be considered when making the assessment, as appropriate, as should observations provided by an external observer during the assessment. For individual items, a patient may perform normally in some areas but be clearly impaired in others. In this case, the patient's rating should be an integration of performance in that area, not the most or least abnormal; that is, the patient should be given the score that is most representative of his or her overall performance in that area. Note that if two scores on a scale are tied, e.g., 3 and 4, the lower score should be chosen. Across the scales, raters should strive not to carry over the rating of one item to another within a subscale, or from one subscale to another. For example, reduced vocal expressivity (in blunted affect) does not affect the rating of reduced verbal output (speech deficit). In general, ratings of anhedonia, ansociality, and amotivation should be based on what is reasonably available to the patient, and in most cases there should be some form of pleasure, socialization, and opportunity for initiative available.

[0141] I. Anhedonia Subscale This subscale measures two aspects of pleasure: pleasure during the activity (intensity and frequency are assessed separately) and anticipated or predicted pleasure in future activities. For all three items in this subscale, all possible sources of pleasure for the patient are considered, including social activities, physical sensations, recreational activities, and work / school. The intensity rating is based on the greatest pleasure the patient had (or expected) in that area and on the patient's description. For the anhedonia subscale, raters consider pleasure associated with social activities, and for the amotivation subscale, raters consider initiative and persistence in social activities. [Probe Question: Items 1 & 2] [Table 3]

[0142] Item 1: Intensity of pleasure during the activity 0: Normal - Able to fully enjoy a wide range of activities. No impairment in the intensity of pleasure. 1: Skeptical - Not as extreme as other people, but still within the normal range. 2: Mild - Intensity of enjoyment in activities is slightly decreased and outside the normal range. 3: Moderate: There is some decrease in the intensity of enjoyment in many activities, and in some cases the intensity is decreased more. 4: Very severe: The intensity of enjoyment in many activities is at least significantly reduced, and in one area it is seriously reduced. 5: Severe - The intensity of enjoyment in many activities is seriously reduced. The ability to experience enjoyment remains, but even what would otherwise be highly enjoyable experiences are experienced with little or no enjoyment. 6: Severe - Inability to experience pleasure, regardless of the environment.

[0143] Item 2: Frequency of pleasure during the activity 0: Normal - A variety of activities are frequently enjoyed. There is no impairment in frequency of enjoyment. 1: Skeptical - Doesn't enjoy things as often as other people, but is still within the normal range. 2: Mild - Frequency of enjoyment in activities is slightly decreased and outside the normal range. 3: Moderate: Enjoyment of most activities is somewhat decreased in frequency, with some activities being enjoyed more frequently. 4: Very severe: At least a considerable decrease in frequency of enjoyment in many activities and a serious decrease in one area. 5: Severe - The frequency of pleasure in many activities is seriously reduced. The ability to experience pleasure remains, but even strongly enjoyable experiences are experienced only with little pleasure. 6: Severe - Inability to experience pleasure, regardless of the environment.

[0144] Item 3: Anticipated or anticipated pleasure in a future activity [Probe Question] [Table 4]

[0145] Some patients may have difficulty understanding the concept of anticipated pleasure, which is the basis of this item. This may be due to cognitive impairment, lack of global pleasure, or some other reason. If the patient does not understand the concept, give it a score of 6 and check the box below: 0: Normal - Experiences pleasure when thinking about future activities. No impairment in predicting the pleasure of future activities. 1: Skeptical When thinking about future activities, I'm not as excited as other people, but that's within the normal range. 2: Mild - Some decrease in pleasure when thinking about future activities is outside the normal range. 3: Moderate - When thinking about future activities, pleasure is significantly less than normal, but some pleasure is still experienced. 4: Very severe: Thinking about some future activities may allow you to experience pleasure, but usually does not. 5: Severe - Rarely experiences pleasure from thinking about future activities, even when considering activities that would be enjoyable. 6: Very severe - There is no pleasure in thinking about future activities, whatever they may be.

[0146] II. Anguish This item assesses the patient's experience of any unpleasant or distressing emotion: sadness, depression, anxiety, grief, anger, etc. The source of the distress is not taken into account, e.g. unpleasant emotions associated with psychiatric symptoms are considered here. Item 4: Distress [Probe Question] [Table 5] 0: Normal - Normal ability to experience distress or unpleasant things. 1: Skeptical - When faced with something upsetting, you are not as distressed as others and are still within the normal range. 2: Mild - Slightly more distressed than normal when confronted with something upsetting. 3: Moderate - When confronted with something upsetting, you are significantly less upset than normal, but still experience some distress. 4: Very severe May be very bothered, but usually requires a severe challenge to resolve. 5: Severe - Experiences only slight distress when faced with severe challenges. 6: Very severe: No distress is experienced, no matter what challenge is encountered.

[0147] III. Antisocial Subscale Antisociality involves reduced social activity and decreased interest in forming close relationships with others. This subscale is intended to capture apathetic antisociality. Item ratings are based on reports of both internal experiences and observed behavior; the former involves the extent to which patients value and desire close social ties, and the latter the extent to which patients actually engage in interactions with others. These items are intended to avoid questionable assessments of social withdrawal. Antisocial behaviors include; a) In social situations, they engage only superficially or in brief exchanges, remain reserved or recede into the background; b) There is no one to discuss personal matters with, c) Lack of involvement in activities or incidents with others. Non-social internal experiences include; a) The belief that close intimate relationships are unimportant and worthless; b) Lack of interest in sharing and mutual care with others; c) a preference for non-social activities; d) Isolation does not make me feel lonely; e) Lack of interest in working and cooperating with others.

[0148] Scores on behavior and inner experience may be quite different, i.e. behavior may not be in keeping with inner experience. For example, a patient may be isolated because of poor social skills or paranoia - a high (impaired) score on item 5 - but may be very lonely, care deeply about others, desire relationships and score normally on item 6. Assessment should be made in the areas of family relationships, intimate relationships, and friendships; if the patient does not mention anyone, the interviewer should ask. Interactions with the assessor should also be considered in the scoring. If the patient has no contact because they cannot contact family members (dead or refuse contact) or have no other social opportunities, the lack of contact should not be considered in the asocial assessment. The unavoidable realities of a patient's life must also be accommodated. For example, a patient may be chronically institutionalized or inpatient and therefore may not have access to family or friends. In such cases, assessments should be based on what is acceptable to the patient, including other patients and staff. In such circumstances, it is possible to form relationships with others, or not, and to feel lonely, or not.

[0149] Item 5: Antisocial behavior [Probe Question] [Table 6] 0: No Disorder - Often interacts with others, openly discusses personal matters with one or more people. Within the normal range. 1: Very slight defect. Has close relationships where most personal matters can be discussed and discusses personal matters with others. 2: Mild Deficit. Social interactions are not infrequent, but are not as active as most people and only discuss some personal matters. Relationships are not close. 3: Moderately deficient. Does not have close relationships with others; is indifferent to involvement and involvement in events, but does not usually avoid others. 4: Very severe deficiencies. Contracts and involvement with other companies tend to be infrequent and superficial, and there is a tendency to avoid others. Generally does not discuss personal matters with others. 5: Severely deficient. Interactions with others are almost always superficial and the person chooses not to spend time with others. 6: Most severe impairment: Rarely interacts with others and actively avoids them much of the time.

[0150] Item 6: Non-social inner experiences [Probe Question] [Table 7]

[0151] 0: No impairment. The patient is very interested in relationships, considers relationships with others to be the most important part of life, feels lonely when isolated, and wishes to never be alone. 1: Very slight deficit. The patient values ​​relationships and is interested in other people. When isolated, they feel lonely and wish not to be alone. 2: Mild Deficit: The patient considers close relationships with family members to be somewhat important and is quite interested in relationships with others, but they are only considered occasional, rather than close or intimate. 3: Moderate Deficit The patient does not consider close relationships important and often desires closeness. 4: Severely impaired. Able to tolerate or ignore close relationships with others. Generally does not wish to discuss personal matters with others, rarely desires closer relationships or feels inconvenienced by the loss of them. 5: Severe Deficit: Patient experiences little interest in close relationships with others and attributes little importance to them, but is not lonely. 6: Most severe defect: Patients have no interest in relationships with others and do not mind the loss of close relationships.

[0152] IV. Disengagement subscale Amotivation is a decrease in initiating and sustaining activities. Both ratings of behavior and inner experience may be due to several sources that do not reflect nuclear negative symptoms, such as decreased opportunities or paranoid beliefs, as failures to initiate and sustain activities. A patient may have decreased goal-directed behavior but still receive a relatively low rating for amotivation if he or she wishes to engage in such behavior. For example, a depressed patient may have difficulty initiating and sustaining goal-directed behavior and may receive a high score (deficit) on item 7. However, the same patient may feel guilty and ashamed about his or her underachievement, often think about his or her obligations, and may receive a low score (normal) on item 8. Assessment should be based on achievement of work, school, hobbies / recreation / pastime, and self-care. Social activities are assessed on the nonsocial subscale, not on this subscale. Self-care encompasses grooming, laundry, obtaining housing, maintaining family, health-related appointments, and other activities may also be part of self-care. Patients should not be penalized for not having opportunities. For example, in the case of a hospitalized patient, it would not be appropriate to punish them for not finding housing if discharge is not forthcoming. In the following probes, work is loosely defined to include housework, caring for children, caring for a recovering family member, etc. Additionally, if the patient has little income or is physically disabled, it may be difficult to participate in recreational activities, and initiation and persistence in this area is not considered important. In the assessment of this area of ​​behavior and inner experience, very strong motivation and interest in one area may lead to a relatively normal rating if that interest occupies much of the patient's available time and effort. For example, a caregiver for small children may score normal on the demotivation subscale if he or she is absorbed in that task with little time for anything else. As with antisocial behavior, some allowance should be made for the unavoidable realities of the patient's life. For example, chronically institutionalized or hospitalized patients cannot pursue competitive employment or education. The assessment should be based on what is available to the patient, such as the activities available on the ward. Even in such an environment, it is possible to find things to do, choose not to do, become bored or not do things.

[0153] Item 7 Demotivation: Behavior [Probe Question] [Table 8]

[0154] 0: No Impairment. Patient is able to initiate and sustain work or school, recreation / hobbies / pastime, and self-care to the fullest extent possible. 1: Very slight deficit. The onset and duration of activity is somewhat less consistent than in most people, but only relative to the clinical question. 2: Mild Deficits Mild deficits in initiating and sustaining activities, e.g., adequately initiated activities over the past week but with limited sustained activity, or others take the initiative as often as the patient. 3: Moderate Deficits - There are significant defects in initiating and sustaining activities, and activities are often not initiated or are not sustained for long periods. Others often provide the impetus for activities. 4: Very severe deficits: Significant deficits in initiation; some activities are initiated but not sustained for long. Others usually provide the impetus for activities. 5: Severe Deficit - There is a clear deficit in initiating and sustaining activities. Sometimes activities are initiated but not sustained. Other people provide almost all of the impetus for the patient's activities. 6: Most severe defect. Total lack of initiation of activity.

[0155] Item 8: Loss of motivation Internal experience [Probe Question] [Table 9]

[0156] 0: No Impairment. Patient is interested in school / work, recreational activities, and self-care. Reports thinking about these things often and taking care of himself / herself. Apparently normal in this domain. 1: Very Minor Deficiencies You are somewhat less interested and motivated than most people in these matters, but only as the clinical question arises. 2: Mild Deficits - Patients are typically motivated in these areas, but often show a lack of interest or motivation. They report thinking about and managing these things, but to a lesser extent than usual extent. 3: Moderate Deficits. The patient is usually motivated in these areas, but there is a clear lack of interest or motivation. They remain in the work environment, but show no interest in making any improvements, and spend little time thinking about relationships or recreation. 4: Very severe deficit. The patient has little motivation or thought in this area. 5: Severe Deficit: Clear lack of interest or motivation in the area. Little thought or control. 6: Most severely deficient. Essentially no interest in the area; no thought or control.

[0157] V. Affective blunting subscale Affective blunting is a reduction in the outward expression of emotion, and interview prompts are designed to elicit emotion. If the patient does not respond to prompts asking about emotional experiences, this item can be rated based on responses to other questions during the interview. Facial Expressions When assessing facial expressions, consider facial movements across all parts of the face, including the eyes (e.g., raising eyebrows), mouth (smiling or frowning), and central face (e.g., frowning in disgust).

[0158] Item 9: Facial Expressions 0: No impairment. Facial expression is activated well within normal limits when describing emotional experiences, with many appropriate changes in facial expression. 1: Very slight deficit. When emotional experiences are recounted, there is a very slight decrease in the frequency and intensity of facial expressions that is of questionable clinical relevance. 2: Mild Deficits. Mild reduction in frequency and intensity of facial expressions; showing at least two changes in the face during each recount of emotional experiences. 3: Moderate Deficiency - A marked reduction in the frequency and intensity of facial expressions, with only one facial change in response to each question; 4: Very severe deficits in recounting emotional experiences. Significant deficits in facial expression, showing facial expression in response to only one or two questions; perhaps only three or four changes in the course of an entire conversation. 5: Severe Deficits. Visible absence of positive and negative facial expressions in response to all questions; may only show one or two slight changes in facial expression during an entire conversation. 6: Most severe impairment. Total or nearly total absence of facial expression throughout conversation. Verbal Expressions One component of emotional blunting is vocal modulation, which includes the rate, volume, and pitch of what is being said, without assessing the content or amount of what is being said.

[0159] Item 10: Oral expression 0: No impairment. Normal variation in all three dimensions: rate, loudness, and pitch. 1: Very slight imperfection. A slight decrease in any one of the three dimensions. 2: Minor deficiency - slight loss in two dimensions or moderate loss in one dimension. 3: Moderate defect - significant reduction in one dimension. 4: Very severe deficiency: Significant reduction in two or three dimensions or severe reduction in one aspect. 5: Marked Deficiency: Severe impairment in at least one dimension and considerable impairment in at least one other dimension. 6: Severely impaired. Severe reduction in two or three dimensions (rate, loudness, and pitch). 9: Not rated. The patient does not talk.

[0160] Expressive gestures Expressive gestures include not only gestures made with the hands, but also those of the head (e.g., nodding), shoulders (pushing), and torso (leaning forward). Dyskinetic movements are not assessed here. Item 11: Expression gestures 0: No impairment. Gestures are well within normal limits; use of arms, hands, shoulders, head and / or body when recounting emotional experiences. 1: Very slight impairment: Very slight decrease in frequency of expressive gestures. Slight decrease in use of arms, hands, head or body of clinically questionable relevance. 2: Mild Defects - Mild decrease in frequency of expressive gestures. Demonstrates at least two expressive gestures during each emotional experience recount. 3: Moderately deficient. There is a significant decrease in the frequency of expressive gestures. There may be a slight gesture in response to each question. 4: Very severe deficits. Noticeable deficits in expressive gestures displayed in response to only one or two questions; may display only three or four gestures throughout an entire conversation. 5: Marked Deficits. Obvious deficits in expressive gestures; reduced number of gestures in response to all questions. May only show one or two minor gestures throughout an entire conversation. 6: Severe Deficiency - Almost total absence of expressive gestures; virtually no movement of arms, hands, head or body during recounting of each emotional experience.

[0161] VI. Aphasia subscales There is no specific probe for the aphasia subscale; it is assessed based on responses to all questions asked throughout the conversation. Amount of conversation This item refers to the volume of words spoken. Other speech abnormalities such as disorganization, neologisms, and psychotic content are not assessed here. For example, a disorganized subject would produce a large amount of talk and would receive a low (normal) score on this item.

[0162] Item 12 Amount of conversation 0: No impairment. Normal amount of conversation or patient talks excessively. 1: Very slight impairment. Questionable reduction in conversational activity; responses are usually brief. 2: Minor flaws Answers are usually short. 3: Moderate deficiencies Many answers are only one or two words. 4: Very severe deficiencies. At least half of the answers are only one or two words. 5: Significant deficiencies. Most answers are only one or two words. 6: Severely Deficient - All or almost all answers are one or two words only. 9: Not evaluated The patient does not talk.

[0163] Spontaneous elaboration This item assesses the amount of information given beyond what is precisely necessary to respond to the interviewer's question. It does not consider whether the patient's response is appropriate or not, so elaboration in this sense can include inappropriate or unnecessary material, delusional, or disorganized responses, as well as appropriate background information given to clarify the answer.

[0164] Item 13: Spontaneous elaboration 0: No Impairment. The patient usually provides more information than is necessary in response to a question, but this information may or may not be relevant. The patient may be overly talkative or feel pressured into conversation. 1: Very slight deficiency. Patients often provide more information than is necessary in response to a question, although sometimes more information might have been appropriate. 2: Mild Deficiency: The patient gives additional information on several occasions, but responses are usually limited to the required information. 3: Moderate Deficiency Patient occasionally gives additional information; interviewer occasionally asks for more details. 4: Very severe deficits: The patient rarely provides more information than is necessary to answer the question; the interviewer asks several times for more details. 5: Significant Deficiencies Nearly all responses are limited to or below the required information; the interviewer often needs to ask for more details. 6: Severe Deficiencies - No spontaneous elaboration on any point during the interview. 9: Not evaluated. The patient does not communicate. The embodiments encompassed herein are described with reference to the following examples, which are presented for illustrative purposes only, and the disclosure herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations that become evident from the teachings herein. EXAMPLES

[0165] Example 1 MIN-101 improves negative symptoms in schizophrenic patients with negative symptoms. A promising Phase IIb clinical trial (12 weeks, randomized, double-blind, placebo-parallel) was conducted to evaluate the efficacy, safety and tolerability of MN-101 in patients with schizophrenia with negative symptoms. The study was intended to evaluate the efficacy of MN-101 monotherapy on negative symptoms, using PSM of the PANSS as the primary endpoint. A total of 244 patients were randomized into equal groups to receive daily doses of 32 mg, 64 mg, and placebo in 32 medical centers in Russia and five European countries. To participate in the study, patients were required to have stable positive and negative symptoms for the 3 months prior to enrollment; a PANSS negative subscore of 20 or greater, and the following PANSS scores less than 4: agitation, hyperactivity, hostility, suspiciousness, uncooperativeness, and impulsivity dysregulation. The inclusion and exclusion criteria as described in the protocol are as follows:

[0166] Study Inclusion Criteria Each potential patient must meet the following criteria before being enrolled in the trial and before receiving the drug: 1. The patient or the patient's legal representative must provide informed consent. 2. Male or female between the ages of 18 and 60 (inclusive). 3. Patients meet diagnostic criteria for schizophrenia as defined in the Statistical and Diagnostic Manual of Mental Disorders, Fifth Edition (DSM-5) as established by a psychiatric interview coupled with the Mini-Instrumental Interview for Mental Illnesses (MINI). 4. The patient must have stable positive symptoms of schizophrenia for the past three months under the care of a psychiatrist. 5. The patient has been experiencing negative symptoms of schizophrenia for the past three months under the treatment of a psychiatrist. 6. Patients must have a PANSS negative subscore of at least 20. 7. Patients have a PANSS score of <4 for the following items: P4: Excitement, hyperactivity P7: hostility P6: Suspicion P8: Uncooperativeness P14: Impulse control disorder 8. Patients may be psychoactive during the start of the washout period during which psychotropic medications may be discontinued as long as this does not jeopardize patient safety. 9. No changes to psychotropic medication will be made during the final month (this is acceptable if done for a reason or with the consent of the sponsor's medical officer) 10. No history of violence against self, others or property. 11. In the opinion of the Investigator, the patient is advised to switch to an alternative psychotropic medication or to start a new psychotropic medication. 12. For female patients of childbearing potential, a pregnancy test must be negative and a double barrier method of contraception must be used. 13. Patients must be normal metabolizers (P450 CYP2D6) as determined by genotyping testing prior to first drug administration. 14. Patients must be able to understand the nature of the clinical trial. 15. Patients are deemed by the investigator to be trustworthy and likely to cooperate with the evaluation procedures.

[0167] Patient Exclusion Criteria Candidate patients who meet any of the following criteria will be excluded from participating in the study prior to drug administration. 1. Currently have bipolar disorder, panic disorder, obsessive-compulsive disorder or mental retardation. 2. The patient's condition is due to the direct physiological effects of a substance (e.g., drug abuse, medication) or a general drug condition. 3. Significant risk of suicide or suicide attempt, or danger to self or others. 4. Patients with a history of substance abuse (excluding caffeine and tobacco) during the 3 months at screening. 5. Positive urine drug screen, except for prescribed benzodiazepines and opioids recently prescribed for an episode of acute pain (e.g., tooth extraction). 6. Patients who are unable to discontinue psychotropic medications other than those tolerated. 7. Patients who have received clozapine in the 6 months prior to screening. [Country-specific exception: Russian patients are allowed to receive <100 mg / day for the treatment of insomnia.] 8. Patients receiving depot antipsychotics can participate in the study 4 weeks after their last dose. 9. Other major or unstable conditions; patients with a history of neurological, neurosurgical (e.g., head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, or urological conditions. 10. Patients with a history of epileptic seizures (patients with a history of childhood febrile seizures are eligible to participate in the clinical trial). 11. Patients who have received electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), or repetitive transcranial magnetic stimulation (r-TMS) in the 3 months prior to screening, or who are scheduled to receive ECT, VNS, or r-TMS during the study. 12. Patients with abnormalities in hematology, blood chemistry, ECG or basic outpatient physical exam. 13. Patients with a body mass index (BMI) of over 35. 14. Patients with current systemic infection (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency virus [HIV], or tuberculosis [TB]). Patients with a positive hepatitis B core antibody test and a negative hepatitis B surface antigen [HBsAg] test may participate in the study if their aminotransferase levels (alanine aminotransferase / serum glutamic pyruvic transaminase [ALT / SGOT] and aspartate aminotransferase / serum glutamic oxaloacetic transaminase [AST / SGOT]) do not exceed twice the upper limit of normal (ULN). 15. Patients who require or may require concurrent use of other medications that increase the QT interval (e.g., paroxetine, fluoxetine, duloxetine, amiodarone, etc.). 16.Patients who require therapy that inhibits CYP2D6. 17. Patients with clinically significant electrocardiogram (ECG) abnormalities that may be a safety issue in a clinical trial, such as a QT interval corrected for heart rate using the Fridericia formula (QTcF) of >430 milliseconds in men and >460 milliseconds in women. 18. Patients with a history of myocardial infarction based on medical history or screening ECG examination. 19. Patients with familial or personal long QT syndrome or additional risk factors for ventricular arrhythmias (e.g., hypokalemia, hypomagnesemia). 20. Women of childbearing potential or men who are unable or unwilling to use accepted methods of contraception. 21. Women with a positive pregnancy test, who are breastfeeding, or who are planning to become pregnant during the trial. 22. Patients who participated in another clinical trial within 3 months prior to screening.

[0168] All three groups were matched for demographic and baseline disease characteristics shown in the table immediately below. [Table 10]

[0169] The mean change from baseline in PANNS negative subscale scores over 12 weeks of treatment for the placebo and treatment groups is shown in Figure 1. Statistically significant improvements were seen at both doses: 32mg P≦0.023, effect size 0.45 64 mg P≦0.003, effect size 0.57

[0170] As shown in Figure 2, this trial further demonstrated that both doses of MIN-101 had a statistically significant effect versus placebo (PANSS three-factor negative symptoms subscale): 32 mg P≦0.006, effect size 0.55 64mg P≦0.003, effect size 0.70 Furthermore, a statistically significant effect of MIN-101 versus placebo was also demonstrated in the PANSS total score: 32mg No significant difference, effect size 0.35 64 mg P≦0.003, effect size 0.59

[0171] Improvement in negative symptoms with both doses of MIN-101 was also observed as measured using the BNSS total score, as shown in FIG. MIN-101 was reported to be generally well tolerated, and the occurrence and type of side effects did not differ significantly between the MIN-101 and placebo groups. Based on previous preclinical and clinical experience, QTcF, a measure of cardiac function, was closely monitored. Criteria for discontinuation due to QTcF prolongation were built into the protocol. Two of 162 patients treated with MIN-101 discontinued the study due to this criterion, both of which were at the high dose (64 mg). Unlike many currently marketed antipsychotics, no metabolic side effects, weight loss, extrapyramidal symptoms, or prolactin elevations were observed.

[0172] Equivalents and Incorporation by Reference The invention is described herein with reference to certain preferred embodiments, however, the invention should not be construed as limited based on the disclosure made herein, as variations therein may be apparent to those of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification and claims, the singular encompasses the plural unless the context clearly dictates otherwise. It should be understood that at least some portions of the description of the present invention have been simplified to focus on elements relevant for a clear understanding of the invention, and that other elements that would be understood by one of ordinary skill in the art and may form part of the invention have been omitted for purposes of clarity, however, because such elements are well known to those of ordinary skill in the art and would not necessarily facilitate an understanding of the invention, a description of such elements is not provided herein. Moreover, to the extent the method does not depend on the particular order of steps described herein, the particular order of steps should not be considered a limitation on the claims. Claims directed to the methods of the present disclosure are not limited to steps being performed in the order described, and one of ordinary skill in the art will recognize that steps may be varied and still be within the scope and spirit of the present disclosure. All patents, patent applications, references and publications cited herein are hereby incorporated by reference in their entirety.

Claims

[Claim 1] A compound of formula (I): 【Chemistry 1】 A composition comprising a pharma- ceutically acceptable salt, hydrate, solvate or polymorph thereof, 2. A method for treating at least one negative symptom in a non-schizophrenic human patient, comprising: the negative symptoms are selected from the group consisting of blunted affect, aphasia, lethargy, anhedonia, antisociality, emotional withdrawal, poor intimacy, passive / apathetic social withdrawal, difficulty with abstract thinking, lack of spontaneity and conversational fluency, and stereotyped thinking, wherein a therapeutically effective amount of the composition is orally administered to the patient, the therapeutically effective amount being from about 1 mg to about 64 mg of total Compound I per day; The composition, wherein Compound I is administered to a patient for at least two weeks.

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