Use of lorperidone in preventing relapse in patients with schizophrenia

Abstract

The present application relates to a method of preventing relapse in a patient suffering from schizophrenia comprising administering to the patient a therapeutically effective amount of lorperidone.

Description

[Technical field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 309,874, filed February 14, 2022, which is incorporated by reference in its entirety and for all purposes.

[0002] The present disclosure relates generally to preventing relapse in patients with schizophrenia. [Background technology]

[0003] Lorperidone ("MIN-101") is a novel cyclic amide derivative with antagonist activity for serotonergic 5-HT2A, sigma 2, α1A-adrenergic, and to a lesser extent α1B-adrenergic receptors. Lorperidone has very low or no affinity for dopaminergic (DA), muscarinic, cholinergic, and histaminergic receptors. The molecule was specifically designed to allow for the improvement of primary negative symptoms without blocking the brain's DA-driven reward system, as is also the case for currently available treatments called antipsychotics, which interfere with DA neurotransmission. Also, because lorperidone does not bind to DA or histaminergic receptors, it does not produce secondary negative symptoms such as parkinsonism and sedation.

[0004] Schizophrenia is a chronic, severe and debilitating mental illness characterized by distortions of thinking, perception, emotion, language, sense of self and behavior. According to the World Health Organization, schizophrenia affects approximately 1% of the general population. Most individuals with schizophrenia suffer from psychosis or positive symptoms, negative symptoms and cognitive impairment. Positive symptoms are manifested as delusions and hallucinations, while negative symptoms are characterized by blunted affect, allopathic, anorexia, anhedonia and antisociality (Marder, et al. “The Current Conceptualization of Negative Symptoms in Schizophrenia,” World Psychiatry, 2017, 16(1), 14-24).

[0005] Negative symptoms are a major contributor to poor functional outcomes in patients with schizophrenia (Harvey et al., “Effects of Roluperidone (MIN-101) on Two Dimensions of the Negative Symptoms Factor Score: Reduced Emotional Experience and Reduced Emotional Expression,” Schizophr. Res. 2020, 215, 352-356) and are associated with transition to end-stage schizophrenia in ultra-high-risk adolescents (Gomes and Grace, “Adolescent Stress as a Driving Factor for Schizophrenia Development - a Basic Science Perspective” Schizophrenia Bulletin, 2017, 43, 10.1093 / schbul / sbx033). Currently, there are no approved treatments for the negative symptoms of schizophrenia in the United States.

[0006] Schizophrenia is a lifelong, chronic illness characterized by periods of acute exacerbation or worsening of symptoms and periods of remission or improvement of symptoms. Relapse is associated with a substantial deterioration in social and occupational functioning and an overall decrease in quality of life (Jorgensen, “Predicting time to relapse in patients with schizophrenia according to patients' relapse history: a historical cohort study using real-world data in Sweden,” BMC Psychiatry, 2021, 21(634), 1-12). Summary of the Invention

[0007] In one aspect, the present application relates to a method of preventing relapse in a patient with schizophrenia, the method comprising administering a therapeutically effective amount of lorperidone to the patient with schizophrenia.

[0008] In one aspect, the application relates to lorperidone for use in a method of preventing relapse in a patient with schizophrenia, the method comprising administering a therapeutically effective amount of lorperidone to a patient with schizophrenia.

[0009] In some embodiments, a therapeutically effective amount of lorperidone is administered to a patient with schizophrenia once or twice daily.

[0010] In some embodiments, a therapeutically effective amount of lorperidone is administered once daily to a patient with schizophrenia.

[0011] In some embodiments, a therapeutically effective amount of lorperidone is orally administered to a patient suffering from schizophrenia.

[0012] In some embodiments, the therapeutically effective amount of lorperidone is from about 1 to about 100 mg.

[0013] In some embodiments, the therapeutically effective amount of lorperidone is 1-100 mg.

[0014] In some embodiments, the therapeutically effective amount of lorperidone is about 16 mg, about 24 mg, about 32 mg, about 40 mg, about 48 mg, about 56 mg, about 64 mg, about 72 mg, about 80 mg, about 88 mg, or about 96 mg.

[0015] In some embodiments, the therapeutically effective amount of lorperidone is 16 mg, 24 mg, 32 mg, 40 mg, 48 mg, 56 mg, 64 mg, 72 mg, 80 mg, 88 mg, or 96 mg.

[0016] In some embodiments, the therapeutically effective amount of lorperidone is about 32 mg.

[0017] In some embodiments, the therapeutically effective amount of lorperidone is 32 mg.

[0018] In some embodiments, the therapeutically effective amount of lorperidone is about 64 mg.

[0019] In some embodiments, the therapeutically effective amount of lorperidone is 64 mg.

[0020] In some embodiments, the schizophrenic patient also does not exhibit behaviors that put the patient, or those around the patient, at risk of physical injury.

[0021] In some embodiments, a schizophrenic patient has low level symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness.

[0022] In some embodiments, the schizophrenic patient does not experience high levels of depression or anxiety.

[0023] In some embodiments, the schizophrenia patient has stable positive symptoms prior to initiating treatment with lorperidone.

[0024] In some embodiments, the schizophrenia patient is free of positive symptoms prior to initiating treatment with lorperidone.

[0025] In some embodiments, the schizophrenia patient has stable positive symptoms for about 1 to about 6 months prior to initiating treatment with lorperidone.

[0026] In some embodiments, the schizophrenia patient is free of positive symptoms for about 1 to about 6 months prior to initiating treatment with lorperidone.

[0027] In some embodiments, the schizophrenia patient has stable positive symptoms for about 3 to about 6 months prior to initiating treatment with lorperidone.

[0028] In some embodiments, the schizophrenia patient is free of positive symptoms for about 3 to about 6 months prior to initiating treatment with lorperidone.

[0029] In some embodiments, the schizophrenic patient has negative symptoms that are moderate to severe.

[0030] In some embodiments, the schizophrenia patient has a PANSS (Positive and Negative Symptoms Scale) negative subscore of greater than 20.

[0031] In some embodiments, the negative symptoms of a schizophrenic patient are primary negative symptoms.

[0032] In some embodiments, the schizophrenia patient's negative symptoms have stabilized for about 1 to about 6 months prior to initiating treatment with lorperidone.

[0033] In some embodiments, the schizophrenia patient's negative symptoms have been stable for about 3 to about 6 months prior to initiating treatment with lorperidone.

[0034] In some embodiments, the schizophrenia patient has previously been administered an antipsychotic drug.

[0035] In some embodiments, administration of an antipsychotic to a schizophrenia patient was discontinued at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months before the schizophrenia patient was administered lorperidone.

[0036] In some embodiments, the relapse is an increase in positive symptoms in a schizophrenia patient, optionally characterized by an increase in the patient's PANSS positive subscore over one or more consecutive visits.

[0037] In one aspect, the present application relates to a method of selecting a patient for schizophrenia and preventing relapse in a patient for schizophrenia, the method comprising: (a) selecting the schizophrenia patient as having a form of schizophrenia characterized by the schizophrenia patient having moderate to severe negative symptoms that are stable for about 3 to about 6 months; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0038] In one aspect, the present application relates to lorperidone for use in a method for preventing relapse in a patient with schizophrenia, the method comprising: (a) selecting the schizophrenia patient as having a form of schizophrenia characterized by the schizophrenia patient having moderate to severe negative symptoms that are stable for about 3 to about 6 months; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0039] In some embodiments, the schizophrenia patient has a PANSS negative subscore of greater than 20.

[0040] In some embodiments, the negative symptoms of a schizophrenic patient are primary negative symptoms.

[0041] In some embodiments, the schizophrenia patient has stable positive symptoms prior to initiating treatment with lorperidone, and optionally, the schizophrenia patient has stable positive symptoms for about 1 to about 6 months, or about 3 to about 6 months, prior to initiating treatment with lorperidone.

[0042] In some embodiments, the schizophrenia patient is free of positive symptoms prior to initiating treatment with lorperidone, and optionally, the schizophrenia patient is free of positive symptoms for about 1 to about 6 months, or about 3 to about 6 months, prior to initiating treatment with lorperidone.

[0043] In some embodiments, a patient with schizophrenia does not experience or exhibit behaviors that put the patient or those around the patient at risk of physical injury, have low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness, and / or do not experience high levels of depression or anxiety.

[0044] In some embodiments, the schizophrenia patient has previously been administered an antipsychotic drug.

[0045] In some embodiments, administration of an antipsychotic to a schizophrenia patient was discontinued at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months before the schizophrenia patient was administered lorperidone.

[0046] In some embodiments, the relapse is an increase in positive symptoms in a schizophrenia patient, optionally characterized by an increase in the patient's PANSS positive subscore over one or more consecutive visits.

[0047] In some embodiments, a therapeutically effective amount of lorperidone is administered to a patient with schizophrenia once or twice daily.

[0048] In some embodiments, a therapeutically effective amount of lorperidone is administered once daily to a patient with schizophrenia.

[0049] In some embodiments, a therapeutically effective amount of lorperidone is orally administered to a patient suffering from schizophrenia.

[0050] In some embodiments, the therapeutically effective amount of lorperidone is from about 1 to about 100 mg.

[0051] In some embodiments, the therapeutically effective amount of lorperidone is 1-100 mg.

[0052] In some embodiments, the therapeutically effective amount of lorperidone is about 16 mg, about 24 mg, about 32 mg, about 40 mg, about 48 mg, about 56 mg, about 64 mg, about 72 mg, about 80 mg, about 88 mg, or about 96 mg.

[0053] In some embodiments, the therapeutically effective amount of lorperidone is 16 mg, 24 mg, 32 mg, 40 mg, 48 mg, 56 mg, 64 mg, 72 mg, 80 mg, 88 mg, or 96 mg.

[0054] In some embodiments, the therapeutically effective amount of lorperidone is about 32 mg.

[0055] In some embodiments, the therapeutically effective amount of lorperidone is 32 mg.

[0056] In some embodiments, the therapeutically effective amount of lorperidone is about 64 mg.

[0057] In some embodiments, the therapeutically effective amount of lorperidone is 64 mg. [Brief description of the drawings]

[0058] [Figure 1]FIG. 1 shows the effect of lorperidone administered orally at 32 mg / day and 64 mg / day compared to placebo in schizophrenia patients, ITT population (Study #1). [Diagram 2] FIG. 2 shows the effect of lorperidone administered orally at 32 mg / day and 64 mg / day on Clinical Global Indicator-Severity Scale (CGI-S) scores in patients with schizophrenia compared to placebo (Study #2). [Diagram 3] FIG. 3 shows the effect of lorperidone administered orally at 32 mg / day and 64 mg / day compared to placebo on PANSS total score in patients with schizophrenia (Study #2). [Figure 4] FIG. 4 shows the effect of lorperidone administered orally at 32 mg / day and 64 mg / day compared to placebo in schizophrenia patients, ITT population (Study #2). [Diagram 5] FIG. 5 shows the effect of lorperidone administered orally at 32 mg / day and 64 mg / day compared to placebo on reduced affective experience scores in schizophrenic patients (Study #2). [Figure 6] FIG. 6 shows time to relapse in the ITT population of the double-blind period of Study #2 in schizophrenia patients receiving oral lorperidone at 32 mg / day and 64 mg / day compared to placebo. [Figure 7] FIG. 7 shows the time to relapse in the ITT population of the open-label period of Study #2 in schizophrenia patients who received placebo in the DB period and then oral lorperidone at 32 mg / day or 64 mg / day, or oral lorperidone at 32 mg / day or 64 mg / day in both the DB and OL periods. [Figure 8] FIG. 8 summarizes the overall statistical testing of Study No. 1 ("MIN-101C03"), Study No. 2 ("MIN-101C07"), and the Integrated Study of the Combined ITT Population ("ISE"). [Figure 9]Figure 9 is a Kaplan-Meier plot of time to relapse in the pooled ITT population for the double-blind period in patients with schizophrenia receiving (1) lorperidone 32 mg / day, (2) lorperidone 64 mg / day orally, or (3) placebo. [Figure 10] FIG. 10 is a plot of the change from active baseline in NSFS score for the pooled ITT population for the open-label period showing the change in NSFS score for the four treatment groups: (1) placebo in the DB period → oral lorperidone at 32 mg / day in the OL period, (2) placebo in the DB period → oral lorperidone at 64 mg / day in the OL period, (3) oral lorperidone at 32 mg / day in the DB and OL periods, and (4) oral lorperidone at 64 mg / day in the DB and OL periods. [Figure 11] FIG. 11 is a plot of the change from active baseline in PSP total score for the ITT population during the open-label period showing the change in NSFS score for the four treatment groups: (1) placebo in the DB period → oral lorperidone at 32 mg / day in the OL period, (2) placebo in the DB period → oral lorperidone at 64 mg / day in the OL period, (3) oral lorperidone at 32 mg / day in the DB and OL periods, and (4) oral lorperidone at 64 mg / day in the DB and OL periods. [Figure 12] FIG. 12 is a plot of the change from active baseline in CGI-S score for the pooled ITT population during the open-label period showing the change in CGI-S score for the four treatment groups: (1) placebo in the DB period → oral lorperidone at 32 mg / day in the OL period, (2) placebo in the DB period → oral lorperidone at 64 mg / day in the OL period, (3) oral lorperidone at 32 mg / day in the DB and OL periods, and (4) oral lorperidone at 64 mg / day in the DB and OL periods. [Figure 13]FIG. 13 is a plot of the change from active baseline in GSI-I score for the pooled ITT population for the open-label period showing the change in GSI-I score for the four treatment groups: (1) placebo in the DB period → oral lorperidone at 32 mg / day in the OL period, (2) placebo in the DB period → oral lorperidone at 64 mg / day in the OL period, (3) oral lorperidone at 32 mg / day in the DB and OL periods, and (4) oral lorperidone at 64 mg / day in the DB and OL periods. [Figure 14] FIG. 14 is a Kaplan-Meier plot of time to relapse in the pooled ITT population across studies in patients with schizophrenia who received (1) placebo in the DB period followed by oral lorperidone at 32 mg / day in the OL period, (2) placebo in the DB period followed by oral lorperidone at 64 mg / day in the OL period, (3) lorperidone at 32 mg / day (oral) throughout the study, (4) lorperidone at 64 mg / day (oral) throughout the study, and (5) placebo (only in the DB period). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] Terms used in this specification have their ordinary meanings, and the meaning of such terms is independent at each occurrence. Notwithstanding the foregoing, and unless otherwise stated, the following definitions apply throughout this specification and claims.

[0060] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, unless otherwise specified or the context clearly indicates otherwise, the term "about" is used herein to modify a stated numerical value above and below by a variance of 20%. In some embodiments, the term "about" refers to a variance of 10%, a variance of 5%, a variance of 3%, or a variance of 1%. For example, "about 64 mg" corresponds to a range of 57.6 mg to 70.4 mg (10% variance), or a range of 60.8 mg to 67.2 mg (5% variance), or a range of 63.36 mg to 64.64 mg (1% variance).

[0061] "Administering" refers to introducing an agent, such as lorperidone or a dosage form thereof, into a subject. The related terms "administering" and "administration of" (and grammatical equivalents) refer to both direct administration, which may be administration to a subject by a medical professional or the subject by self-administration, and / or indirect administration, which may be the act of prescribing a drug, such as the dosage forms described herein. For example, a physician or clinical investigator who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug, administers the drug to the patient.

[0062] As used herein, the Personal and Social Performance Scale ("PSP") is a validated clinician-rated scale intended to reflect real-life situations that measure personal and social functioning in four domains: (a) socially useful activities, (b) personal and social relationships, (c) self-care, and (d) disruptive and aggressive behaviors. Scores are based on the patient's assessment of performance in the four domains. The PSP total score is a single measure of functioning ranging from 1 to 100, with higher scores representing better functioning. A score of 91 to 100 indicates excellent functioning in all four major domains, with the patient being appreciated for their good qualities, dealing adequately with life problems, and engaging in a wide range of interests and activities. A score of 1 to 10 indicates a lack of autonomy in basic functioning, with extreme behaviors but not survival risks (scores 6 to 10), or survival risks (scores 1 to 5). An increase in the scale indicates a beneficial response. A review of the relevant scientific literature, and an analysis of the psychometric properties of the four domains resulting in the generation of a PSP total score, supported the appropriateness and cross-cultural applicability of the use of the PSP in the development of medications for the prevention of manifestations and relapse of negative symptoms of schizophrenia.

[0063] As used herein, the Clinical Global Impression-Severity Scale ("CGI-S") is a clinician-rated scale designed to assess the severity of a patient's illness at the time of evaluation, including knowledge of the patient's medical history, psychosocial situation, symptoms, behavior, and the impact of symptoms on the patient's ability to function compared with the clinician's past experience with patients with the same diagnosis and similar improvement with treatment. Taking into account the overall clinical experience, patients are rated for the severity of their mental illness at the time of evaluation, where 1=normal (not sick at all), 2=borderline psychotic, 3=mildly sick, 4=moderately sick, 5=markedly sick, 6=severely sick, or 7=extremely sick.

[0064] As used herein, the Clinical Global Impression-Improvement scale ("CGI-I") is a 7-point scale that requires clinicians to rate how much a patient's illness has improved or worsened compared to their baseline condition at the start of an intervention, rated as 1 = very improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worsened, 6 = much worse, or 7 = very worse.

[0065] As used herein, the "BNSS" is the Brief Negative Symptom Scale. The "BNSS" is a 13-item instrument designed to measure negative symptoms, specifically blunted affect, allopathic, antisocial, anhedonia, and amotivation (Kirkpatrick, et al., "The Brief Negative Symptom Scale: Psychometric Properties," Schizophr. Bull., 2011, 37(2), 300-5.).

[0066] "Time to recurrence" in the DB period is defined as the number of days from day 1 to the date of early study termination due to recurrence. If a patient did not recur during the DB period, they were censored at the end or completion of the DB period. Treatment differences in time to recurrence in the DB period were analyzed using a Cox regression model with treatment group and baseline PANSS total score as covariates. For the analysis of the OL period, this analysis was repeated to analyze treatment differences in time to recurrence in the study. For the OL period analysis, patients with no observed recurrence in the study were censored at the study termination date. Kaplan-Meier plots of DB period, OL period, and time to recurrence in the study were generated.

[0067] "Comprising" or "comprising" as applied to a particular dosage form, composition, method, or process described or claimed herein means that the dosage form, composition, or method includes all of the elements recited in the particular description or claim, but does not exclude other elements. "Consisting essentially of" and "consisting essentially of" mean that the composition, dosage form, method, or process described or claimed does not exclude other materials or steps that do not substantially affect the recited physical, pharmacological, pharmacokinetic properties, or therapeutic effect of the composition, dosage form, method, or process. "Consisting of" and "consisting of" mean the exclusion of more than trace elements and substantial method or process steps of other ingredients.

[0068] "CYP2D6 allele" refers to one of over 100 named versions of the CYP2D6 gene that are present in the general population and typically fall into one of three categories: active (functional), reduced activity (partially active or reduced function), and inactive (non-functional).

[0069] Active CYP2D6 alleles are * 1. * 2. * 2A, * 33, * 35, * 39, * 48, and * Includes 53.

[0070] Decreased activity CYP2D6 alleles are * 9. * 10. * 17, * 29, * 41, * 49, * 50, * 54, * 55, * 59, * 69, and * Includes 72.

[0071] Inactive CYP2D6 alleles are * 3.* 4. * 5 (deletion), * 6. * 7. * 8. * 11. * 12. * 13. * 14A, * 14B, * 15, * 18, * 19, * 20, * twenty one, * 38, * 40, * 42, * 44, * 56, * 56A, * 56B, and * Includes 68.

[0072] "CYP2D6 extensive metabolizer (EM) genotype" as applied to a subject means that the subject has a CYP2D6 that results in CYP2D6 metabolic activity that is considered normal. The CYP2D6 EM genotype includes combinations of (a) two active CYP2D6 alleles, (b) one active and one reduced activity CYP2D6 alleles, and (c) one active and one inactive CYP2D6 alleles.

[0073] A "CYP2D6 intermediate metabolizer (IM) genotype" as applied to a subject means that the subject has a CYP2D6 genotype that results in reduced CYP2D6 metabolic activity. CYP2D6 IM genotypes include combinations of (a) one inactive and one reduced activity CYP2D6 allele, and (c) two reduced activity CYP2D6 alleles.

[0074] "CYP2D6 PM genotype" as applied to a subject means that the subject has a positive test result for the CYP2D6 poor metabolizer genotype and therefore likely does not have CYP2D6 activity. The CYP2D6 PM genotype is two inactive alleles.

[0075] "CYP2D6 UM genotype" as applied to a subject means that the subject has a positive test result for the CYP2D6 very rapid metabolizer genotype and is therefore likely to have higher than average CYP2D6 activity. A CYP2D6 UM genotype is three or more active alleles.

[0076] As used herein, the terms "patient" or "subject" are used interchangeably and refer to humans of any age.

[0077] As used herein, a "schizophrenia patient" refers to a human who has been previously diagnosed with schizophrenia, i.e., the patient met diagnostic criteria for schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) established by a full psychiatric interview in conjunction with the Mini International Neuropsychiatric interview.

[0078] As used herein, "antipsychotic" refers to a drug administered to treat the symptoms of schizophrenia. In some embodiments, the antipsychotic is a first generation antipsychotic. In some embodiments, the antipsychotic is a second generation antipsychotic. In some embodiments, the antipsychotic is an atypical antipsychotic. In some embodiments, the antipsychotic is amisulpride, clozapine, olanzapine, quetiapine, risperidone, sartindole, ziprasidone, zotepine, haloperidol, chlorpromazine, perphenazine, brixiprazole, cariprazine, or lumateperone.

[0079] While not wishing to be limited by a definition, in some embodiments, the antipsychotic may be any of the antipsychotics listed in the clinical literature, e.g., BAGNALL, et al., “A systematic review of atypical antipsychotic drugs in schizophrenia,” Health Technology Assessment, 2003, 7(13), 1-214; BARMAN, et al., “Newer antipsychotics: Brexpiprazole, cariprazine, and lumateperone: A pledge or another unkept promise?” World J. Psychiatr., December 19, 2021, 11(12), 1228-1238; BEASLEY, Jr., et al., “A Double-Blind, Randomized, Placebo-Controlled Trial of Olanzapine in the Prevention of Psychotic Relapse,” Journal of Clinical Psychopharmacology, December 2003, 23(6), 582-594; and KRAUSE, et al. al., “Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis,” European Archives of Psychiatry and Clinical Neuroscience, 2018, 268, 625-639, the contents of which are incorporated herein in their entirety.

[0080] "PANSS" as used herein refers to the positive and negative symptoms scale used by doctors and clinicians to measure the severity of symptoms in patients with schizophrenia. The scale is divided into three parts: a positive scale providing a "PANSS positive subscore", a negative scale providing a "PANSS negative subscore", and a general psychopathology scale. The sum of these three parts provides a PANSS total score, which ranges from 30 to 210 (higher scores indicate more severe symptoms). (Kay, SR, et al. "The positive and negative syndrome scale (PANSS) for schizophrenia," Schizophr Bulletin, 13(2), 261-276 (1987)).

[0081] In some embodiments, schizophrenia patients with moderate negative symptoms have a PANSS negative subscore of greater than 20 but less than 35. In some embodiments, schizophrenia patients with moderate negative symptoms have a PANSS negative subscore of greater than 15 but less than 35. In some embodiments, schizophrenia patients with moderate negative symptoms have a PANSS negative subscore of greater than 10 but less than 35.

[0082] In some embodiments, schizophrenia patients with severe negative symptoms have a PANSS negative subscore of 35 or greater.

[0083] As used herein, the PANSS Marder negative symptoms factor score ("NSFS") refers to a selection of seven PANSS items used by doctors and clinicians to measure the severity of negative symptoms in patients with schizophrenia. (See Tables 5A and 5B.) The NSFS total score ranges from 7 to 49. (Marder, SR et al. "The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials," J Clin Psychiatry. 1997; 58: 538-46).

[0084] In some embodiments, schizophrenia patients with moderate negative symptoms have an NSFS score of greater than 20 but less than 35. In some embodiments, schizophrenia patients with moderate negative symptoms have an NSFS score of greater than 15 but less than 35. In some embodiments, schizophrenia patients with moderate negative symptoms have an NSFS score of greater than 10 but less than 35.

[0085] In some embodiments, schizophrenia patients with severe negative symptoms have an NSFS score of 35 or greater.

[0086] In some embodiments, schizophrenia patients are referred to herein as having "stable" positive or negative symptoms as judged by the treating physician or investigator.

[0087] In some embodiments, the treating physician or investigator determines that a patient with schizophrenia has a PANSS positive or negative subscore that is stable if the patient's subscore is within about ±4 points on two consecutive PANSS assessments, and the period between two consecutive assessments is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 3 months, or any period in between.

[0088] In some embodiments, the treating physician or investigator determines that a patient with schizophrenia has a PANSS positive or negative subscore that is stable if the patient's subscore is within about ±4 points on two out of three consecutive PANSS assessments, and the period between the two consecutive assessments is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or any period in between.

[0089] Positive symptoms generally involve experiences in perception or ideation that should not normally exist. For example, hallucinations and delusions represent perceptions or beliefs that should not normally be experienced. In addition to hallucinations and delusions, patients with schizophrenia often have significant disturbances in the logical process of thought. Specifically, psychotic thought processes are characteristically loose, disorganized, illogical, or bizarre. These disturbances in thought process often result in observable patterns of behavior that are both disorganized and bizarre. Severe disturbances in thought content and process, including positive symptoms, are often the most recognized and prominent feature of schizophrenia. Positive symptoms, such as hallucinations and delusions, are responsible for most of the acute distress associated with schizophrenia.

[0090] Negative symptoms are believed to be responsible for many of the chronic and long-term social and occupational disabilities associated with schizophrenia. Negative symptoms generally refer to a decline in normal functioning and include five major subdomains: blunted affect (flattened affect, blunted expression, reduced emotional response), allopathic (poverty of vocalization), amotivation (loss of will), anhedonia (reduced ability to experience or anticipate pleasure) and asociality (social withdrawal). As used herein, the term "negative symptoms" should be understood to include the primary negative symptoms typically associated with schizophrenia, negative symptoms measured by the PANSS negative symptoms subscale score, negative factor scores based on the pentagonal structural model method (White, "Empirical Assessment of the Factorial Structure of Clinical Symptoms in Schizophrenia," Psychopathology 1997, 30(5), 263-74), Marder negative symptoms subscore, and negative symptoms measured by the BNSS.

[0091] In some embodiments, the negative symptoms are one of the five major sub-domains of negative symptoms: blunted affect, allogy, apathy, anhedonia, and asociality. Blunted affect (flattened affect, blunted expression) is characterized by a decrease in the intensity and range of emotional expression manifested through vocal and non-verbal modes of communication, including intonation (prosody), facial expressions, hand gestures, and body movements. Allogy (poverty of speech) is characterized by a decrease in the volume of speech, a decrease in spontaneous speech, and a loss of fluidity of speech. Apathy (loss of will) is characterized by a deficit in initiating and maintaining goal-directed behaviors, such as work, study, sports, personal hygiene, and daily tasks, especially when they require effort (cognitive or physical) and significant organization, as well as a deficit in the motivation to perform such activities. This sub-domain is associated with emotional numbness and lack of energy. Anhedonia (diminished ability to experience or anticipate pleasure) is characterized by the anticipation of reward, recreational or other enjoyable experiences ("wanting") being more significantly and consistently impaired (anticipatory anhedonia) than the awareness ("liking") of the experience itself (complete anhedonia). Antisociality (social withdrawal) is characterized by diminished interest, motivation and recognition in social interactions with others such as family and friends, loss of interest in intimate (sexual) relationships unrelated to physical problems, which in children may include loss of interest in playing with other children.

[0092] In some embodiments, the negative symptoms are primary negative symptoms, including, for example, blunted affect, allopathic, apathy, anhedonia, and antisocial.

[0093] In some embodiments, the negative symptoms are secondary negative symptoms that may overlap with the primary negative symptoms, but in contrast to the primary negative symptoms, are associated with comorbid illnesses or treatment side effects. In some embodiments, the secondary negative symptoms are caused by, for example, comorbid depression and / or side effects of medication.

[0094] In some embodiments, secondary negative symptoms occur in association with positive symptoms (Kirkpatrick, "Recognizing Primary vs. Secondary Negative Symptoms and Apathy vs. Expression Domains," J. Clin. Psychiatry, 2014, 75(4):e09. (doi:10.4088 / JCP.13049tx3c.).

[0095] In some embodiments, the secondary negative symptom is a movement disorder.

[0096] In some embodiments, the secondary negative symptom is an extrapyramidal symptom, such as akathisia, tardive dyskinesia, dystonia, or parkinsonism.

[0097] In some embodiments, the secondary negative symptom is depression. Lorperidone

[0098] Lorperidone, 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2), refers to a compound having the following structure: [ka]

[0099] Lorperidone can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformation and manipulation, including the use of protective groups, which can be obtained from relevant scientific literature or standard reference textbooks in the field.Recognized reference textbooks of organic synthesis, without being limited to any one or several sources, include 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 method of preparing lorperidone is described in U.S. Patent No. 7,166,617, the contents of which are incorporated herein in their entirety.

[0100] Lorperidone is the dihydrate of hydrochloride.The "therapeutically effective amount" of lorperidone referred to in the method of the present disclosure is based on the corresponding amount of the free base form of lorperidone that is sufficient to prevent relapse, as defined herein.For example, a therapeutically effective amount of 32.0mg refers to 32.0mg of free base, which is equivalent to 38.4mg of lorperidone (dihydrate hydrochloride), and a therapeutically effective amount of 64.0mg refers to 64.0mg of free base, which is equivalent to 76.8mg of lorperidone (dihydrate hydrochloride).

[0101] Dosage forms containing lorperidone are disclosed in U.S. Patent Nos. 9,458,130, 9,730,920, 10,258,614, 10,799,493, and 11,464,744, each of which is incorporated herein by reference in its entirety. In some embodiments, the methods of the present disclosure are practiced using any of the dosage forms disclosed therein. recurrence

[0102] Relapse in schizophrenia patients is characterized by a recurrence of the illness and can have serious economic and personal consequences. It manifests as a recurrence of delusions and hallucinations and / or the onset or worsening of negative symptoms. Relapse can be characterized by an acute increase in positive and / or negative symptoms. In addition to putting patients at risk of harming themselves or others, relapse can jeopardize personal relationships, educational pursuits, and / or employment status. In addition, relapse results in patients being exposed to further stigma from the illness (EMSLEY, et al., “The nature of relapse in schizophrenia,” BMC Psychiatry, 2013, 13(50), 1-8).

[0103] Relapse also carries the added risk that patients will not be able to return to their previous level of functioning even if treatment is resumed. Patients who experience multiple relapses may require longer recovery times and may have a reduced chance of regaining their previous (pre-relapse) level of health and function (Jorgensen, et al., “Predicting time to relapse in patients with schizophrenia according to patients' relapse history: a historical cohort study using real-world data in Sweden,” BMC Psychiatry, 2021, 21(634), 1-12).

[0104] One factor that may lead to an increased risk of relapse in patients with schizophrenia is the discontinuation of prescribed antipsychotics that are currently available to reduce the risk of relapse. Studies comparing antipsychotic maintenance with antipsychotic discontinuation have shown that patients who discontinue medication are more likely to relapse (Leucht S.,et al.,“Antipsychotic drugs versus placebo for relapse prevention in schizophrenia:a systematic review and meta-analysis.Lancet.2012 Jun 2;379(9831):2063-71.doi:10.1016 / S0140-6736(12)60239-6.Epub 2012 May 3.PMID:22560607).

[0105] Many antipsychotics, including second-generation antipsychotics, cause weight gain, and some "atypical" antipsychotics cause more extreme weight gain, as well as glucose and lipid abnormalities, or even diabetes, thus increasing the risk of cardiovascular disorders. Antipsychotics have also been reported to cause sexual dysfunction and other undesirable effects (Moncrieff, et al., "Antipsychotic Maintenance Treatment: Time to Rethink? PLOS Medicine, August 4, 2015, 1-7). These treatment-emergent side effects of antipsychotics are often a limiting factor for their long-term use, despite the fact that antipsychotics have been shown to reduce the risk of relapse.

[0106] In some embodiments, relapse, as used herein, refers to the psychiatric hospitalization of a patient, i.e., either involuntary or voluntary admission to a psychiatric hospital for the resolution of the patient's schizophrenic symptoms.

[0107] In some embodiments, relapse, as used herein, refers to an increase in the level of care (e.g., from outpatient to inpatient care).

[0108] In some embodiments, relapse, as used herein, refers to a patient having suicidal thoughts.

[0109] In some embodiments, relapse, as used herein, refers to a patient having homicidal ideation.

[0110] In some embodiments, relapse, as used herein, refers to a patient who suffers from their own deliberate self-harm.

[0111] In some embodiments, a recurrence, as used herein, is a patient exhibiting aggressive disease.

[0112] In some embodiments, relapse is when the patient displays aggressive behavior towards others.

[0113] In some embodiments, relapse, as used herein, refers to a patient not taking proper care of themselves, for example, by not eating or not washing or cleaning themselves.

[0114] In some embodiments, a relapse, as used herein, is a patient exhibiting agitation.

[0115] In some embodiments, relapse, as used herein, is indicated by an increase in the PANSS total score.

[0116] In some embodiments, relapse, as used herein, is indicated by about a 20% increase in the PANSS total score in a patient on two consecutive assessments.

[0117] In some embodiments, relapse, as used herein, is indicated by an increase of about 20% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 40.

[0118] In some embodiments, relapse, as used herein, is indicated by an increase of about 20% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 50.

[0119] In some embodiments, relapse, as used herein, is indicated by about a 25% increase in the PANSS total score in a patient on two consecutive assessments.

[0120] In some embodiments, relapse, as used herein, is indicated by an increase of about 25% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 40.

[0121] In some embodiments, relapse, as used herein, is indicated by an increase of about 25% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 50.

[0122] In some embodiments, relapse, as used herein, is indicated by about a 30% increase in the PANSS total score in a patient on two consecutive assessments.

[0123] In some embodiments, relapse, as used herein, is indicated by an increase of about 30% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 40.

[0124] In some embodiments, relapse, as used herein, is indicated by an increase of about 30% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 50.

[0125] In some embodiments, relapse, as used herein, is indicated by an increase of about 35% in the PANSS total score in a patient on two consecutive assessments.

[0126] In some embodiments, relapse, as used herein, is indicated by an increase of about 35% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 40.

[0127] In some embodiments, relapse, as used herein, is indicated by an increase of about 35% in the PANSS total score in two consecutive assessments in a patient who originally scored higher than 50.

[0128] In some embodiments, relapse, as used herein, is indicated by an increase of about 5 or more points in the PANSS total score in a patient on two consecutive assessments.

[0129] In some embodiments, relapse, as used herein, is indicated by an increase of about 5 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0130] In some embodiments, relapse, as used herein, is indicated by a 5 or more point increase in the patient's PANSS total score on two consecutive assessments.

[0131] In some embodiments, relapse, as used herein, is indicated by a 5 or more point increase in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0132] In some embodiments, relapse, as used herein, is indicated by an increase of about 10 or more points in the PANSS total score in a patient on two consecutive assessments.

[0133] In some embodiments, relapse, as used herein, is indicated by an increase of about 10 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0134] In some embodiments, relapse, as used herein, is indicated by a 10 or more point increase in the PANSS total score in a patient on two consecutive assessments.

[0135] In some embodiments, relapse, as used herein, is indicated by an increase of 10 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0136] In some embodiments, relapse, as used herein, is indicated by an increase in the patient's PANSS total score of about 12 or more points on two consecutive assessments.

[0137] In some embodiments, relapse, as used herein, is indicated by an increase of about 12 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0138] In some embodiments, relapse, as used herein, is indicated by a 12 or more point increase in the PANSS total score in a patient on two consecutive assessments.

[0139] In some embodiments, relapse, as used herein, is indicated by an increase of 12 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0140] In some embodiments, relapse, as used herein, is indicated by an increase in the patient's PANSS total score of about 15 or more points on two consecutive assessments.

[0141] In some embodiments, relapse, as used herein, is indicated by an increase of about 15 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0142] In some embodiments, relapse, as used herein, is indicated by a 15 or more point increase in the PANSS total score in a patient on two consecutive assessments.

[0143] In some embodiments, relapse, as used herein, is indicated by an increase of 15 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0144] In some embodiments, relapse, as used herein, is indicated by an increase in the patient's PANSS total score of about 20 or more points on two consecutive assessments.

[0145] In some embodiments, relapse, as used herein, is indicated by an increase of about 20 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0146] In some embodiments, relapse, as used herein, is indicated by a 20 or more point increase in the PANSS total score in a patient on two consecutive assessments.

[0147] In some embodiments, relapse, as used herein, is indicated by a 20 or more point increase in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0148] In some embodiments, relapse, as used herein, is indicated by an increase in the patient's PANSS total score of about 25 or more points on two consecutive assessments.

[0149] In some embodiments, relapse, as used herein, is indicated by an increase of about 25 or more points in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0150] In some embodiments, relapse, as used herein, is indicated by a 25 or more point increase in the PANSS total score in a patient on two consecutive assessments.

[0151] In some embodiments, relapse, as used herein, is indicated by a 25 or more point increase in the patient's PANSS total score on two consecutive assessments, and the patient's baseline PANSS total score was 40 or less.

[0152] In some embodiments, relapse, as used herein, is indicated by an increase in a PANSS positive subscore in a schizophrenia patient over two consecutive visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0153] In some embodiments, for any of the methods disclosed herein, a schizophrenia patient has not relapsed if their PANSS positive subscore is within 4 points (absolute difference) for 2 out of 3 visits, the visits being 1 day apart, 1 week apart, 1 month apart, or any time period in between.

[0154] In some embodiments, for any of the methods disclosed herein, relapse refers to an increase in positive symptoms in a schizophrenia patient, as determined by any of the methods of assessing those known to one of skill in the art.

[0155] In some embodiments, for any of the methods disclosed herein, relapse refers to an increase in positive symptoms in a schizophrenia patient as determined by the schizophrenia patient's PANSS positive subscore.

[0156] In some embodiments, for any of the methods disclosed herein, relapse refers to a 4 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0157] In some embodiments, for any of the methods disclosed herein, relapse refers to a 5 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0158] In some embodiments, for any of the methods disclosed herein, relapse refers to a 6 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0159] In some embodiments, for any of the methods disclosed herein, relapse refers to a 7 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0160] In some embodiments, for any of the methods disclosed herein, relapse refers to an 8 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0161] In some embodiments, for any of the methods disclosed herein, relapse refers to a 9 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0162] In some embodiments, for any of the methods disclosed herein, relapse refers to a 10 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0163] In some embodiments, for any of the methods disclosed herein, relapse refers to an increase of 11 or more points in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0164] In some embodiments, for any of the methods disclosed herein, relapse refers to a 12 point or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0165] In some embodiments, for any of the methods disclosed herein, relapse refers to a 13 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0166] In some embodiments, for any of the methods disclosed herein, relapse refers to a 14 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0167] In some embodiments, for any of the methods disclosed herein, relapse refers to a 15 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0168] In some embodiments, for any of the methods disclosed herein, relapse refers to a 16 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0169] In some embodiments, for any of the methods disclosed herein, relapse refers to a 17 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0170] In some embodiments, for any of the methods disclosed herein, relapse refers to an increase of 18 or more points in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0171] In some embodiments, for any of the methods disclosed herein, relapse refers to a 19 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0172] In some embodiments, for any of the methods disclosed herein, relapse refers to a 20 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0173] In some embodiments, for any of the methods disclosed herein, relapse refers to a 21 point or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0174] In some embodiments, for any of the methods disclosed herein, relapse refers to a 22 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0175] In some embodiments, for any of the methods disclosed herein, relapse refers to a 23 point or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0176] In some embodiments, for any of the methods disclosed herein, relapse refers to a 24 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0177] In some embodiments, for any of the methods disclosed herein, relapse refers to a 25 or more point increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0178] In some embodiments, for any of the methods disclosed herein, relapse refers to a 26 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0179] In some embodiments, for any of the methods disclosed herein, relapse refers to a 27 or greater increase in a PANSS positive subscore in a patient with schizophrenia over two consecutive visits, where the visits are one day apart, one week apart, one month apart, or any time period in between.

[0180] In some embodiments, relapse, as used herein, is indicated by patients scoring 6 (severely ill) or 7 (among the most severely ill patients) on the CGI-S.

[0181] In some embodiments, relapse, as used herein, is indicated by a patient receiving a CGI-I rating of 6 (much worse clinically compared to the baseline visit) or 7 (very worse clinically compared to the baseline visit).

[0182] In some embodiments, for any of the methods disclosed herein, relapse refers to a patient who terminates early during treatment (or a clinical trial) due to worsening psychosis or adverse events or general symptoms in Table 1. [Table 1]

[0183] Methods for preventing relapse in patients with schizophrenia In one aspect, the disclosure relates to a method of preventing relapse in a patient with schizophrenia comprising administering a therapeutically effective amount of lorperidone to the patient with schizophrenia.

[0184] In some embodiments, a therapeutically effective amount of lorperidone is administered to a patient with schizophrenia once or twice daily.

[0185] In some embodiments, a therapeutically effective amount of lorperidone is administered once daily to a patient with schizophrenia.

[0186] In some embodiments, a therapeutically effective amount of lorperidone is administered twice daily to a patient suffering from schizophrenia.

[0187] In some embodiments, a therapeutically effective amount of lorperidone is orally administered to a patient suffering from schizophrenia.

[0188] In some embodiments, the therapeutically effective amount of lorperidone is from about 1 mg to about 100 mg, from about 4 mg to about 96 mg, from about 5 mg to about 90 mg, from about 6 mg to about 85 mg, from about 16 mg to about 80 mg, from about 25 mg to about 75 mg, or from about 30 mg to about 70 mg.

[0189] In some embodiments, the therapeutically effective amount of lorperidone is between 1 mg and 100 mg, between 4 mg and 96 mg, between 5 mg and 90 mg, between 6 mg and 85 mg, between 16 mg and 80 mg, between 25 mg and 75 mg, or between 30 mg and 70 mg.

[0190] In some embodiments, the therapeutically effective amount of lorperidone is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30 mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg , about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg.

[0191] In some embodiments, the therapeutically effective amount of lorperidone is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, g, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, or 100 mg.

[0192] In some embodiments, the therapeutically effective amount of lorperidone is about 16 mg, about 24 mg, about 32 mg, about 40 mg, about 48 mg, about 56 mg, about 64 mg, about 72 mg, about 80 mg, about 88 mg, or about 96 mg.

[0193] In some embodiments, the therapeutically effective amount of lorperidone is 16 mg, 24 mg, 32 mg, 40 mg, 48 mg, 56 mg, 64 mg, 72 mg, 80 mg, 88 mg, or 96 mg.

[0194] In some embodiments, the therapeutically effective amount of lorperidone is 16 mg.

[0195] In some embodiments, the therapeutically effective amount of lorperidone is about 16 mg.

[0196] In some embodiments, the therapeutically effective amount of lorperidone is 24 mg.

[0197] In some embodiments, the therapeutically effective amount of lorperidone is about 24 mg.

[0198] In some embodiments, the therapeutically effective amount of lorperidone is 32 mg.

[0199] In some embodiments, the therapeutically effective amount of lorperidone is about 32 mg.

[0200] In some embodiments, the therapeutically effective amount of lorperidone is 40 mg.

[0201] In some embodiments, the therapeutically effective amount of lorperidone is about 40 mg.

[0202] In some embodiments, the therapeutically effective amount of lorperidone is 48 mg.

[0203] In some embodiments, the therapeutically effective amount of lorperidone is about 48 mg.

[0204] In some embodiments, the therapeutically effective amount of lorperidone is 56 mg.

[0205] In some embodiments, the therapeutically effective amount of lorperidone is about 56 mg.

[0206] In some embodiments, the therapeutically effective amount of lorperidone is 64 mg.

[0207] In some embodiments, the therapeutically effective amount of lorperidone is about 64 mg.

[0208] In some embodiments, the schizophrenic patient also does not exhibit behaviors that put the patient, or those around the patient, at risk of physical injury.

[0209] In some embodiments, a schizophrenic patient has low level symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness.

[0210] In some embodiments, the schizophrenic patient has a low level of symptoms associated with agitation.

[0211] In some embodiments, the schizophrenic patient has low levels of symptoms related to impulse control.

[0212] In some embodiments, the schizophrenic patient has low levels of symptoms related to hostility.

[0213] In some embodiments, the schizophrenic patient has low levels of symptoms related to suspiciousness.

[0214] In some embodiments, the schizophrenic patient has a low level of symptoms related to incoordination.

[0215] In some embodiments, the schizophrenic patient does not experience high levels of depression or anxiety.

[0216] In some embodiments, the schizophrenia patient has stable positive symptoms prior to initiating treatment with lorperidone.

[0217] In some embodiments, the schizophrenia patient has stable positive symptoms for 1 to 6 months prior to initiating treatment with lorperidone.

[0218] In some embodiments, the schizophrenia patient has stable positive symptoms for 3 to 6 months prior to initiating treatment with lorperidone.

[0219] In some embodiments, the schizophrenia patient has positive symptoms that are stable for at least one day prior to initiating treatment with lorperidone.

[0220] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least one week prior to initiating treatment with lorperidone.

[0221] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least two weeks prior to initiating treatment with lorperidone.

[0222] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 3 weeks prior to initiating treatment with lorperidone.

[0223] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least one month prior to initiating treatment with lorperidone.

[0224] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least two months prior to initiating treatment with lorperidone.

[0225] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 3 months prior to initiating treatment with lorperidone.

[0226] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least four months prior to initiating treatment with lorperidone.

[0227] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 5 months prior to initiating treatment with lorperidone.

[0228] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 6 months prior to initiating treatment with lorperidone.

[0229] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 7 months prior to initiating treatment with lorperidone.

[0230] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 8 months prior to initiating treatment with lorperidone.

[0231] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 9 months prior to initiating treatment with lorperidone.

[0232] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 10 months prior to initiating treatment with lorperidone.

[0233] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 11 months prior to initiating treatment with lorperidone.

[0234] In some embodiments, the schizophrenia patient has positive symptoms that have been stable for at least 12 months prior to initiating treatment with lorperidone.

[0235] In some embodiments, the schizophrenia patient is free of positive symptoms prior to initiating treatment with lorperidone.

[0236] In some embodiments, the schizophrenia patient is free of positive symptoms for 1 to 6 months prior to initiating treatment with lorperidone.

[0237] In some embodiments, the schizophrenia patient is free of positive symptoms for 3 to 6 months prior to initiating treatment with lorperidone.

[0238] In some embodiments, the schizophrenia patient is free of positive symptoms for at least one day prior to initiating treatment with lorperidone.

[0239] In some embodiments, the schizophrenia patient is free of positive symptoms for at least one week prior to initiating treatment with lorperidone.

[0240] In some embodiments, the schizophrenia patient is free of positive symptoms for at least two weeks prior to initiating treatment with lorperidone.

[0241] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 3 weeks prior to initiating treatment with lorperidone.

[0242] In some embodiments, the schizophrenia patient is free of positive symptoms for at least one month prior to initiating treatment with lorperidone.

[0243] In some embodiments, the schizophrenia patient is free of positive symptoms for at least two months prior to initiating treatment with lorperidone.

[0244] In some embodiments, the schizophrenia patient is free of positive symptoms for at least three months prior to initiating treatment with lorperidone.

[0245] In some embodiments, the schizophrenia patient is free of positive symptoms for at least four months prior to initiating treatment with lorperidone.

[0246] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 5 months prior to initiating treatment with lorperidone.

[0247] In some embodiments, the schizophrenia patient is free of positive symptoms for at least six months prior to initiating treatment with lorperidone.

[0248] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 7 months prior to initiating treatment with lorperidone.

[0249] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 8 months prior to initiating treatment with lorperidone.

[0250] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 9 months prior to initiating treatment with lorperidone.

[0251] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 10 months prior to initiating treatment with lorperidone.

[0252] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 11 months prior to initiating treatment with lorperidone.

[0253] In some embodiments, the schizophrenia patient is free of positive symptoms for at least 12 months prior to initiating treatment with lorperidone.

[0254] In some embodiments, the schizophrenia patient has no positive symptoms when the schizophrenia patient has a PANSS positive subscore of 15 or less.

[0255] In some embodiments, the schizophrenia patient has no positive symptoms when the schizophrenia patient has a PANSS positive subscore of 14 or less.

[0256] In some embodiments, the schizophrenia patient has no positive symptoms when the schizophrenia patient has a PANSS positive subscore of 13 or less.

[0257] In some embodiments, the schizophrenia patient has no positive symptoms when the schizophrenia patient has a PANSS positive subscore of 12 or less.

[0258] In some embodiments, the schizophrenia patient has no positive symptoms when the schizophrenia patient has a PANSS positive subscore of 11 or less.

[0259] In some embodiments, the schizophrenia patient has no positive symptoms when the schizophrenia patient has a PANSS positive subscore of 10 or less.

[0260] In some embodiments, the schizophrenia patient does not have positive symptoms if the schizophrenia patient has a PANSS positive subscore of 9 or less.

[0261] In some embodiments, the schizophrenia patient does not have positive symptoms if the schizophrenia patient has a PANSS positive subscore of 8 or less.

[0262] In some embodiments, the schizophrenia patient has no positive symptoms if the schizophrenia patient has a PANSS positive subscore of 7.

[0263] In some embodiments, the schizophrenia patient has negative symptoms that are moderate to severe. In some embodiments, the schizophrenia patient has negative symptoms that are moderate. In some embodiments, the schizophrenia patient has negative symptoms that are severe.

[0264] In some embodiments, a patient with schizophrenia has a PANSS negative subscore of 20-25, 25-30, 30-35, 35-40, 40-45, or 45-49.

[0265] In some embodiments, a patient with schizophrenia has a PANSS negative subscore of 20-29, 30-39, or 40-49.

[0266] In some embodiments, a patient with schizophrenia has a PANSS negative subscore of 20-35 or 35-49.

[0267] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 20.

[0268] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 21.

[0269] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 22.

[0270] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 23.

[0271] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 24.

[0272] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 25.

[0273] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 26.

[0274] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 27.

[0275] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 28.

[0276] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 29.

[0277] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 30.

[0278] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 31.

[0279] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 32.

[0280] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 33.

[0281] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 34.

[0282] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 35.

[0283] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 36.

[0284] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 37.

[0285] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 38.

[0286] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 39.

[0287] In some embodiments, the patient with schizophrenia has a PANSS negative subscore of greater than 40.

[0288] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 41.

[0289] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 42.

[0290] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 43.

[0291] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 44.

[0292] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 45.

[0293] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 46.

[0294] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 47.

[0295] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of greater than 48.

[0296] In some embodiments, the patient with schizophrenia has a PANSS Negative subscore of 49.

[0297] In some embodiments, the negative symptoms of a schizophrenic patient are primary negative symptoms.

[0298] In some embodiments, the negative symptom of the schizophrenic patient is not a secondary negative symptom.

[0299] In some embodiments, the negative symptoms of the schizophrenia patient are stable prior to initiating treatment with lorperidone.

[0300] In some embodiments, the schizophrenia patient's negative symptoms have been stable for 1-6 months prior to initiating treatment with lorperidone.

[0301] In some embodiments, the schizophrenia patient's negative symptoms have been stable for 3-6 months prior to initiating treatment with lorperidone.

[0302] In some embodiments, the negative symptoms of the schizophrenia patient are stable for at least one day prior to initiating treatment with lorperidone.

[0303] In some embodiments, the negative symptoms of the schizophrenia patient are stable for at least one week prior to initiating treatment with lorperidone.

[0304] In some embodiments, the negative symptoms of the schizophrenia patient are stable for at least two weeks prior to initiating treatment with lorperidone.

[0305] In some embodiments, the negative symptoms of the schizophrenia patient are stable for at least 3 weeks prior to initiating treatment with lorperidone.

[0306] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least one month prior to initiating treatment with lorperidone.

[0307] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least two months prior to initiating treatment with lorperidone.

[0308] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least 3 months prior to initiating treatment with lorperidone.

[0309] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least four months prior to initiating treatment with lorperidone.

[0310] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least 5 months prior to initiating treatment with lorperidone.

[0311] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least 6 months prior to initiating treatment with lorperidone.

[0312] In some embodiments, the schizophrenia patient's negative symptoms have been stable for at least 7 months prior to initiating treatment with lorperidone.

[0313] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least 8 months prior to initiating treatment with lorperidone.

[0314] In some embodiments, the schizophrenia patient's negative symptoms have been stable for at least 9 months prior to initiating treatment with lorperidone.

[0315] In some embodiments, the negative symptoms of the schizophrenia patient have been stable for at least 10 months prior to initiating treatment with lorperidone.

[0316] In some embodiments, the schizophrenia patient's negative symptoms have been stable for at least 11 months prior to initiating treatment with lorperidone.

[0317] In some embodiments, the schizophrenia patient's negative symptoms have been stable for at least 12 months prior to initiating treatment with lorperidone.

[0318] In some embodiments, the schizophrenia patient has previously been administered an antipsychotic drug.

[0319] In some embodiments, administration of the antipsychotic to the schizophrenic patient is discontinued at the same time that the schizophrenic patient is administered lorperidone.

[0320] In some embodiments, administration of the antipsychotic to the schizophrenic patient was discontinued before the schizophrenic patient was administered lorperidone.

[0321] In some embodiments, administration of an antipsychotic to a schizophrenia patient was discontinued at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months before the schizophrenia patient was administered lorperidone.

[0322] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least one day before the schizophrenic patient was administered lorperidone.

[0323] In some embodiments, administration of an antipsychotic to a schizophrenic patient was discontinued at least 2 days before the schizophrenic patient was administered lorperidone.

[0324] In some embodiments, administration of an antipsychotic to a schizophrenic patient was discontinued at least 3 days before the schizophrenic patient was administered lorperidone.

[0325] In some embodiments, administration of an antipsychotic to a schizophrenic patient was discontinued at least 4 days before the schizophrenic patient was administered lorperidone.

[0326] In some embodiments, administration of an antipsychotic to a schizophrenic patient was discontinued at least 5 days before the schizophrenic patient was administered lorperidone.

[0327] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least 6 days before the schizophrenic patient was administered lorperidone.

[0328] In some embodiments, administration of an antipsychotic to a schizophrenic patient was discontinued at least one week before the schizophrenic patient was administered lorperidone.

[0329] In some embodiments, administration of an antipsychotic to a schizophrenic patient was discontinued at least 2 weeks before the schizophrenic patient was administered lorperidone.

[0330] In some embodiments, administration of an antipsychotic to a schizophrenic patient was discontinued at least 3 weeks before the schizophrenic patient was administered lorperidone.

[0331] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least one month before the schizophrenic patient was administered lorperidone.

[0332] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least 2 months before the schizophrenic patient was administered lorperidone.

[0333] In some embodiments, administration of an antipsychotic to the schizophrenia patient was discontinued at least 3 months before the schizophrenia patient was administered lorperidone.

[0334] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least 4 months before the schizophrenic patient was administered lorperidone.

[0335] In some embodiments, administration of an antipsychotic to the schizophrenia patient was discontinued at least 5 months before the schizophrenia patient was administered lorperidone.

[0336] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least 6 months before the schizophrenic patient was administered lorperidone.

[0337] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least 7 months before the schizophrenic patient was administered lorperidone.

[0338] In some embodiments, administration of an antipsychotic to the schizophrenic patient was discontinued at least 8 months before the schizophrenic patient was administered lorperidone.

[0339] In some embodiments, administration of an antipsychotic to the schizophrenia patient was discontinued at least 9 months before the schizophrenia patient was administered lorperidone.

[0340] In some embodiments, administration of an antipsychotic to the schizophrenia patient was discontinued at least 10 months before the schizophrenia patient was administered lorperidone.

[0341] In some embodiments, administration of an antipsychotic to the schizophrenia patient was discontinued at least 11 months before the schizophrenia patient was administered lorperidone.

[0342] In some embodiments, administration of an antipsychotic to the schizophrenia patient was discontinued at least 12 months before the schizophrenia patient was administered lorperidone.

[0343] In some embodiments, the schizophrenic patient is also currently receiving an antipsychotic when initiating treatment with lorperidone to prevent relapse.

[0344] In some embodiments, a schizophrenia patient currently receiving an antipsychotic when initiating treatment with lorperidone to prevent relapse is tapered off the antipsychotic over a period of time, for example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more, until the schizophrenia patient is treated with lorperidone alone.

[0345] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms, and selecting a patient as having a form of schizophrenia characterized by having stable moderate to severe negative symptoms; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0346] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms; have stable moderate to severe negative symptoms, and (c) selecting the patient as having a form of schizophrenia characterized by the absence of behaviors that place the patient or those around the patient at risk of physical injury; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0347] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms; have stable moderate to severe negative symptoms, and having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0348] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms; have stable moderate to severe negative symptoms, and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0349] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms; Stable moderate to severe negative symptoms having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0350] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms; Stable moderate to severe negative symptoms There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0351] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms; Stable moderate to severe negative symptoms There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0352] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have stable positive symptoms; Stable moderate to severe negative symptoms There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; Having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0353] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months, and Selecting as having a form of schizophrenia characterized by moderate to severe negative symptoms that have been stable for 3 to 6 months; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0354] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months Have moderate to severe negative symptoms that have been stable for 3-6 months, and (c) selecting the patient as having a form of schizophrenia characterized by the absence of behaviors that place the patient or those around the patient at risk of physical injury; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0355] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months Have moderate to severe negative symptoms that have been stable for 3-6 months, and having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0356] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months Have moderate to severe negative symptoms that have been stable for 3-6 months, and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0357] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months Have moderate to severe negative symptoms that have been stable for 3-6 months having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0358] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months Have moderate to severe negative symptoms that have been stable for 3 to 6 months There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0359] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months Have moderate to severe negative symptoms that have been stable for 3 to 6 months There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0360] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Have stable positive symptoms for 3-6 months Have moderate to severe negative symptoms that have been stable for 3-6 months There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; Having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0361] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, have no positive symptoms, and selecting a patient as having a form of schizophrenia characterized by having stable moderate to severe negative symptoms; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0362] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Absence of positive symptoms have stable moderate to severe negative symptoms, and (c) selecting the patient as having a form of schizophrenia characterized by the absence of behaviors that place the patient or those around the patient at risk of physical injury; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0363] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Absence of positive symptoms have stable moderate to severe negative symptoms, and having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0364] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Absence of positive symptoms have stable moderate to severe negative symptoms, and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0365] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Absence of positive symptoms Stable moderate to severe negative symptoms having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0366] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Absence of positive symptoms Stable moderate to severe negative symptoms There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0367] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Absence of positive symptoms Stable moderate to severe negative symptoms There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0368] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, Absence of positive symptoms Stable moderate to severe negative symptoms There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; Having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0369] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3-6 months, and Selecting as having a form of schizophrenia characterized by moderate to severe negative symptoms that have been stable for 3 to 6 months; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0370] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3 to 6 months Have moderate to severe negative symptoms that have been stable for 3-6 months, and (c) selecting the patient as having a form of schizophrenia characterized by the absence of behaviors that place the patient or those around the patient at risk of physical injury; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0371] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3 to 6 months Have moderate to severe negative symptoms that have been stable for 3-6 months, and having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0372] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3 to 6 months Have moderate to severe negative symptoms that have been stable for 3-6 months, and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0373] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3 to 6 months Have moderate to severe negative symptoms that have been stable for 3 to 6 months having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0374] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3 to 6 months Have moderate to severe negative symptoms that have been stable for 3-6 months There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0375] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3 to 6 months Have moderate to severe negative symptoms that have been stable for 3-6 months There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; and selecting as having a form of schizophrenia characterized by having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0376] In another aspect, the disclosure relates to a method for selecting a patient with schizophrenia and preventing relapse in a patient with schizophrenia, the method comprising: (a) A patient with schizophrenia, Schizophrenia patients, No positive symptoms for 3 to 6 months Have moderate to severe negative symptoms that have been stable for 3-6 months There is no evidence of behaviour that places the patient or those around the patient at risk of physical injury; Having low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness; and selecting as having a form of schizophrenia characterized by not experiencing high levels of depression or anxiety; and (b) administering a therapeutically effective amount of lorperidone to a patient suffering from schizophrenia.

[0377] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient has stable positive symptoms over the past 1, 2, 3, 4, 5, or 6 months according to the treating psychiatrist and based on documentation in the clinical chart.

[0378] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient has had no positive symptoms over the past 1, 2, 3, 4, 5, or 6 months according to the treating psychiatrist and based on documentation in the clinical chart.

[0379] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient has stable negative symptoms over the past 1, 2, 3, 4, 5, or 6 months according to the treating psychiatrist and based on documentation in the clinical chart.

[0380] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient has stable positive and negative symptoms over the past 1, 2, 3, 4, 5, or 6 months according to the treating psychiatrist and based on documentation in the clinical chart.

[0381] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient has a PANSS negative subscore, i.e., the original PANSS scale [sum of N1+N2+N3+N4+N5+N6+N7]) of greater than 20 at the first visit (i.e., screening).

[0382] In some embodiments, for any of the methods disclosed herein, the PANSS Negative subscore of a patient with schizophrenia is within 4 points (absolute difference) for two consecutive visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0383] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient's PANSS Negative subscore is within 4 points (absolute difference) for two out of three visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0384] In some embodiments, for any of the methods disclosed herein, the PANSS Negative subscore of a patient with schizophrenia is within 4 points (absolute difference) for 2 out of 4 consecutive visits, the visits being 1 day apart, 1 week apart, 1 month apart, or any time period in between.

[0385] In some embodiments, for any of the methods disclosed herein, the PANSS positive subscore of a patient with schizophrenia is within 4 points (absolute difference) for two consecutive visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0386] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient's PANSS positive subscore is within 4 points (absolute difference) for two out of three visits, the visits being one day apart, one week apart, one month apart, or any time period in between.

[0387] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient's PANSS positive subscore is within 4 points (absolute difference) for 2 out of 4 consecutive visits, where the visits are 1 day apart, 1 week apart, 1 month apart, or any time period in between.

[0388] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient is administered at least one functional allele (e.g., * 1 or * 2) are extensive metabolizers of cytochrome P450 (CYP2D6).

[0389] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient has not been diagnosed with or does not suffer from major depressive disorder, bipolar disorder, panic disorder, obsessive-compulsive disorder, or intellectual disability (e.g., intellectual developmental disorder diagnosed by age 14).

[0390] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient does not have PANSS item scores greater than 4 in P4 (agitation / hyperactivity), P6 (suspiciousness / paranoia), P7 (hostility), G8 (uncooperativeness), G14 (poor impulse control).

[0391] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient does not have a Calgary Depression Scale for Schizophrenia (CDSS) total score greater than 6.

[0392] In some embodiments, for any of the methods disclosed herein, the schizophrenia patient does not have a score of ≧2 on any of items 1, 2, or 3, or a score of ≧3 on item 4 of the Barnes Akathisia Rating Scale (BARS). Example 1 - Overview of Studies Nos. 1 and 2 - Overview, Endpoints, and Efficacy Evaluations

[0393] The results of studies no. 1 ("MIN-101C03") and 2 ("MIN-101C07") provide substantial clinical evidence of the efficacy of a 64 mg dose of lorperidone administered once daily as monotherapy for the treatment of patients with moderate to severe negative symptoms and stable positive symptoms of schizophrenia. A summary of these studies is provided in Table 2 below. They also provide for the first time evidence that lorperidone is effective in preventing relapse in patients with schizophrenia (see below).

[0394] The primary pooled analysis of efficacy of lorperidone compared with placebo for the treatment of negative symptoms of schizophrenia is based on the change from baseline to week 12 in the PANSS Marder Negative Symptoms factor score (referred to in this document as NSFS). Efficacy is also supported by analyses of the change from baseline to week 12 in the PSP total score and CGI-S. Overall, MIN-101C03 and MIN-101C07 used comparable endpoints to evaluate the efficacy of lorperidone in patients with schizophrenia (Table 3). [Table 2] [Table 3]

[0395] Efficacy evaluation The efficacy evaluations described below were conducted in both the MIN-101C03 and MIN-101C07 studies. Results of other efficacy evaluations conducted only in the individual studies are summarized in Tables 8 and 9, respectively.

[0396] PANSS-based assessment items PANSS was designed to be used in patients with schizophrenia to measure the overall severity of schizophrenia symptoms. The scale has been validated in different cultures and languages, and is reliable and acceptable to regulatory authorities as the primary measure for determining the effectiveness of interventions in schizophrenia. The name refers to two types of symptoms in schizophrenia, as defined by the American Psychiatric Association: positive symptoms, which refer to an excess or distortion of normal function (e.g., hallucinations and delusions), and negative symptoms, which represent a decrease or loss of normal function.

[0397] Patients are rated 1 to 7 for 30 different symptoms based on interviews and reports from family members or primary care hospital workers. The original PANSS included three groups of symptoms and subscale scores positive, negative, and general psychopathology. Since the inception of the PANSS, investigators have proposed additional groupings of the PANSS, such as the Marder structure (Marder, SR et al. “Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia: consensus statements,” Schizophrenia Bulletin Open. 2020; 1(1). doi:10.1093 / schizbullopen / sgz001) and the White structure (White, L. et al. “Empirical assessment of the factorial structure of clinical symptoms in schizophrenia”. Psychopathology. 1997; 30263-274). In addition, additional constructs of negative symptoms assessed with the help of PANSS items have been proposed, such as the emotional expression and emotional experience subgroupings (Harvey, PD, et al., “Effects of Roluperidone (MIN-101) on two dimensions of the negative symptoms factor score: reduced emotional experience and reduced emotional expression” Schizophrenia Res. 2020; 215: 352-356).

[0398] The PANSS was assessed at the time points listed in Table 4. Because the PANSS Marder Negative Symptoms factor score (referred to in this document as the NSFS) was deemed the most appropriate measure of negative symptoms of schizophrenia, the MIN-101C03 data were reanalyzed using the NSFS to ensure that the results of this study and MIN-101C07 were comparable and could be combined. [Table 4]

[0399] The PANSS-derived endpoints used in these studies and pooled analyses are listed in Table 5A, and a summary of the individual PANSS items used by physicians and clinicians to measure symptom severity in patients with schizophrenia is provided in Table 5B. The scale is divided into three parts: a positive scale providing a "PANSS positive subscore," a negative scale providing a "PANSS negative subscore," and a general psychopathology scale. The sum of these three parts provides the PANSS total score, which ranges from 30 to 210 (higher scores indicate more severe symptoms). (See Kay, SR, et al. “The positive and negative syndrome scale (PANSS) for schizophrenia,” Schizophr Bulletin, 13(2), 261-276 (1987) and Gopal, S., et al. “Improvement of Negative Symptoms in Schizophrenia with Paliperidone Palmitate 1-Month and 3-Month Long-Acting Injectables: Results from a Phase 3 Non-Inferiority Study” Neuropsychiatric Disease and Treatment,, 681-690, DOI:10.2147 / NDT.S226296, both of which are incorporated by reference). [Table 5A] [Table 5B]

[0400] PSP The PSP is a validated clinician-rated scale intended to reflect real-life situations that measure personal and social functioning in four domains: (a) socially useful activities, (b) personal and social relationships, (c) self-care, and (d) disruptive and aggressive behaviors. Scores are based on the patient's assessment of their performance in the four domains. The PSP total score is a single measure of functioning ranging from 1 to 100, with higher scores representing better functioning. A score of 91 to 100 indicates excellent functioning in all four major domains, with the patient being appreciated for their good qualities, dealing adequately with life problems, and engaging in a wide range of interests and activities. A score of 1 to 10 indicates a lack of autonomy in basic functioning, with extreme behaviors but not survival risks (scores 6 to 10), or survival risks (scores 1 to 5). An increase in the scale indicates a beneficial response. A review of the relevant scientific literature, and an analysis of the psychometric properties of the four domains resulting in the generation of a PSP total score, supported the appropriateness and cross-cultural applicability of the use of PSP in the development of medications for the prevention of negative symptom manifestations and relapse in schizophrenia. PSP was assessed at the time points listed in Table 6. Changes from baseline in PSP total score and individual domain scores after 12 weeks of treatment were exploratory efficacy endpoints in the MIN-101C03 study, the total score was the key secondary efficacy endpoint, and PSP domain scores were exploratory endpoints in the MIN-101C07 study. [Table 6]

[0401] CGI-S and CGI-I The CGI-S is a clinician-rated scale designed to assess the severity of a patient's illness at the time of evaluation, including knowledge of the patient's medical history, psychosocial situation, symptoms, behavior, and the impact of symptoms on the patient's ability to function compared to the clinician's past experience with patients with the same diagnosis and similar improvement in treatment. Taking into account the overall clinical experience, patients are rated for the severity of their mental illness at the time of evaluation, where 1 = normal (not ill at all), 2 = borderline psychotic, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, or 7 = extremely ill.

[0402] The CGI-I is a 7-point scale that requires clinicians to rate the extent to which a patient's illness has improved or worsened compared to their baseline condition at the start of the intervention, rated as 1 = very improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worsened, 6 = much worse, or 7 = very worse.

[0403] The CGI-S and CGI-I were assessed at the time points listed in Table 7. The CGI-S and CGI-I were exploratory endpoints in the MIN-101C03 and MIN-101C07 studies. [Table 7]

[0404] Example 2 - Overview of Phase 2B Study #1 Phase 2b Study #1 (also referred to herein as "MIN-101C03") is a Phase 2b, double-blind ("DB"), placebo-controlled, randomized, multicenter, 12-week study followed by a 24-week open-label ("OL") extension to evaluate the efficacy, safety, and tolerability of lorperidone in patients ≧18 to ≦60 years of age with negative symptoms of schizophrenia. The primary objective of the study was to evaluate the efficacy of lorperidone compared to placebo in improving negative symptoms of schizophrenia as measured by change from baseline in PANSS Negative Factor Score for PSM ("PANSSPSM") over 12 weeks of treatment.

[0405] The study consisted of a pretreatment screening period of up to 28 days (including washout), a 12-week DB, placebo-controlled period, and a 24-week OL period. Eligible patients (those who had been symptomatically stable for at least 3 months and had a PANSS negative subscale score of at least 20) were randomized in a 1:1:1 ratio to receive oral lorperidone (controlled release, "MR", formulation) 32 mg QD, lorperidone 64 mg QD, or placebo for 12 weeks. If patients were receiving antipsychotic treatments, they were discontinued and allowed a 2-day washout period before starting their assigned study treatment. During the 24-week OL treatment extension period, patients initially randomized to lorperidone 32 mg or 64 mg continued on the same dose, while patients initially randomized to placebo were crossed over to lorperidone 32 mg or 64 mg in a 1:1 ratio.

[0406] Selection Criteria Overview

[0407] Diagnosis / Disease Criteria / Medical Conditions: Patients must meet diagnostic criteria for schizophrenia as defined in DSM-5, established by a full psychiatric interview in conjunction with the Mini International Neuropsychiatric Interview. The patient had been stable with respect to both positive and negative symptoms of schizophrenia over the past three months according to his treating psychiatrist. Patients with a PANSS negative subscale score of at least 20. Patients with PANSS item scores <4: P4 agitation, hyperactivity. P7 hostility, P6 suspiciousness, G8 uncooperativeness, and G14 poor impulse control.

[0408] Drug therapy: Patients could have been receiving any psychotropic medication prior to the study, provided that the psychotropic medication was discontinued at the beginning of the washout phase without endangering patient safety. · No changes in psychotropic medication during the previous month (changes were permitted for administrative reasons or with the permission of the sponsor's responsible medical director). Patients who, in the opinion of the investigator, indicated switching to an alternative antipsychotic or initiating an antipsychotic.

[0409] Trust / Compliance / Consent: The patient or the patient's legal representative had to give informed consent and the patient had to be able to understand the nature of the study. Patients were deemed by the investigator to be trustworthy and likely to cooperate with evaluation procedures.

[0410] sex: Male or female. · Female patients, if of childbearing potential, must have tested negative for pregnancy and must be using a double barrier method of contraception.

[0411] age: 18~60 years old, inclusive.

[0412] CYP2D6 P450 Status: Patients must be extensive metabolizers of CYP2D6 P450 as determined by genotypic testing prior to receiving the first drug dose.

[0413] Violence History: ·No history of violence towards self, others, or property.

[0414] Summary of exclusion criteria

[0415] Diagnosis / Disease Criteria / Medical Conditions: Current evidence of bipolar disorder, panic disorder, obsessive-compulsive disorder, or mental retardation.

[0416] Drug therapy: Patients who have been unable to discontinue non-authorized psychotropic medications. Patients who received clozapine within 6 months of the screening visit (country-specific exception for Russian patients: doses ≤ 100 mg / day were allowed for the treatment of insomnia). Patients receiving treatment with a depot antipsychotic had to be enrolled in the study 4 weeks after their last injection.

[0417] Other medical conditions: The patient's condition was due to the direct physiological effects of a substance (e.g., a drug of abuse or a medication) or a general medical condition. Patients who had received electroconvulsive therapy, vagus nerve stimulation, or repetitive transcranial magnetic stimulation within 3 months prior to the screening visit, or who were scheduled to receive electroconvulsive therapy, vagus nerve stimulation, or repetitive transcranial magnetic stimulation at any time during the study. Patients with a history of significant other major or unstable neurological, neurosurgical (e.g., head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, metabolic, gastrointestinal, or urinary disorders. Patients with a history of epileptic seizure disorder (patients with a history of one childhood febrile seizure can be enrolled in this study). Patients with clinically significant abnormalities in hematology, blood chemistry, electrocardiogram, or physical exam did not recover by the baseline visit. · Current systemic infection (e.g., Hepatitis B, Hepatitis C, HIV, tuberculosis). Patients were included in the study if their aminotransferase levels (alanine aminotransferase / serum glutamic pyruvic transaminase and aspartate aminotransferase / serum glutamic oxaloacetic transaminase) did not exceed twice the upper limit of normal (ULN), they had a positive Hepatitis B core antibody test, and they had a negative HBsAg test. Patients who require or may require concomitant treatment with any other medication likely to increase the QT interval (e.g., paroxetine, fluoxetine, duloxetine, amiodarone). -Patients who require drugs that inhibit CYP2D6. Patients with clinically significant ECG abnormalities that may have been a safety issue in this study, including QT interval values ​​corrected for heart rate using a QT interval value of >430 milliseconds for men and >450 milliseconds for women. -Patients with a history of myocardial infarction based on medical history or ECG findings at the time of screening. ·Having a family or personal history of long QT syndrome or additional risk factors for polymorphic ventricular tachycardia.

[0418] sex: Women or men of childbearing potential who are unwilling or unable to use an accepted method of contraception. Women who have a positive pregnancy test, are breastfeeding, or plan to become pregnant during the study.

[0419] BMI: >35kg / m 2 .

[0420] Substance use: Patients had a history of substance abuse (country-specific exception for Romanian patients: "DSM-based dependence") within 3 months prior to the screening visit (excluding caffeine and cigarette smoking). · A positive urine drug screen, except in cases related to prescribed benzodiazepines and sedatives recently prescribed for an episode of acute pain (e.g., tooth extraction).

[0421] History of suicidal behavior: · Suicide or suicide attempt, or significant risk of danger to self or others.

[0422] others: -Patients who participated in another clinical trial within 3 months prior to screening. Double-blind (DB) period

[0423] Disposition and baseline characteristics of patients during the DB period.

[0424] A total of 244 patients were randomized and all received treatment (safety population) (83 patients in the placebo group, 78 patients in the 32 mg lorperidone group, and 83 patients in the 64 mg lorperidone group). The intention-to-treat ("ITT") population (234 patients, 95.9%) consisted of all patients in the safety population who had a post-baseline PANSS total score of at least 1. Demographic characteristics were comparable between the three treatment groups for age, sex, race, and BMI. The overall mean age of the patients was 40 years (range: 18-60 years), 56% were male, all patients were white, and the mean BMI was 26 kg / m 2 All patients enrolled in this study were to be extensive metabolizers of CYP2D6 (as a strategy to minimize the risk of QT prolongation in patients randomized to lorperidone).

[0425] All baseline disease characteristics, including NSFS, PSP total score, CGI-S, and PANSS total and subscale scores, were comparable between the three treatment groups.At baseline, the overall mean NSFS score was 25, the mean PSP total score was 52, the mean CGI-S score was 4, the mean PANSS total score was 80, the mean PANSS negative subscale score was 27, and the mean PANSS positive subscale score was 14. DB Period Results

[0426] Of the 169 patients (69%) who completed the DB period of the study through week 12 of treatment, a greater proportion completed in the lorperidone treatment groups: 56 patients (68%) in the placebo group completed, 55 patients (71%) in the 32 mg group completed, and 58 patients (70%) in the 64 mg group completed. The most frequent reasons for patient discontinuation across all treatment groups were inadequate treatment response (14%) and withdrawal of consent (7%), both with the highest rates in the placebo group.

[0427] Lorperidone was generally well tolerated, with mostly limited mild or moderate treatment-emergent adverse events (TEAEs) and few serious adverse events (SAEs), and the study did not detect any new safety signals during up to 36 weeks of treatment. Lorperidone- and placebo-treated patients had similar rates of TEAEs leading to discontinuation, which were primarily psychiatric disorders. QTcF prolongation of ≥450 ms and increases in QTcF compared to baseline of ≥30 ms were observed in a dose-related manner in the lorperidone group. Clinically significant QTcF prolongation of >500 ms and changes from baseline of QTcF of >60 ms were reported in two patients in the 64 mg lorperidone group and in none in the 32 mg lorperidone group or placebo group during the DB period of the study. Mean changes across all vital sign parameters were small from baseline to each study visit during the DB period of the study.

[0428] A summary of the efficacy results from the MIN-101C03 trial is shown in Table 8 below. [Table 8-1] [Table 8-2]

[0429] The primary efficacy analysis of change from baseline to week 12 in the PANSSPSM showed a statistically significant improvement for the 64 mg lorperidone group compared to the placebo group (p ≤ 0.003). A post-hoc analysis of change from baseline to week 12 in the NSFS showed a statistically significant improvement for the 64 mg lorperidone group compared to placebo (p ≤ 0.001). Other secondary / exploratory efficacy analyses showed statistically significant improvements for the 64 mg lorperidone group compared to placebo after the 12-week DB period for the PANSS total score, PANSS unpleasant mood factor, PANSS activity factor, PANSS general psychopathology scale, PANSS negative scale, CGI-S score, CGI-I score, BNSS total score, CDSS total score, PSP total score, and PSP personal and social relationships, PSP self-care, and PSP disruptive and aggressive behavior domain scores.

[0430] The effect of 64 mg lorperidone was already evident after 2 weeks for NSFS (p ≤ 0.002) and 4 weeks for PSP total score (p ≤ 0.1007) and CGI-S (p ≤ 0.0032), and continued to increase during the 12-week DB period. For PANSS negative factor scores, further increases were observed during the 36-week OL period. Responder analysis showed that 33% of the 64 mg lorperidone group reported a 20% reduction in NSFS compared to 17% of the placebo group (p ≤ 0.049, Table 8), and 13% of the 64 mg lorperidone group reported a 30% reduction compared to 4% of the placebo group (not significant). Similarly, 48% of the 64 mg lorperidone group reported a 7-point increase and a 10-point increase compared to 30% of the placebo group (not significant).

[0431] Relapse rates (during the DB period) were lowest for the 64 mg lorperidone group (7 [9%]) and the 32 mg lorperidone group (5 [7%]) and were similar to the placebo group (8 [10%]). This was consistent with the changes seen in PANSS positive symptom scores with 64 mg lorperidone, which remained similar to placebo (Figure 1).

[0432] These findings support the conclusion that lorperidone at both doses is superior to placebo and that the observed treatment effect is a true effect of lorperidone.

[0433] Open label (OL) period Of 169 patients who completed the 12-week DB period, 142 (84%) enrolled in the 24-week OL period. Ninety-eight patients who received lorperidone during the DB period continued their previously administered lorperidone dose (45 patients at 32 mg and 53 patients at 64 mg), and patients who previously received placebo were randomized 1:1 to receive either 32 mg or 64 mg lorperidone. Of the 44 patients in the placebo group who entered the 24-week OL period, 25 patients received 32 mg lorperidone and 19 patients received 64 mg lorperidone.

[0434] Results of OL period A total of 88 patients completed the OL period (28 overall in the 32 mg lorperidone groups, 32 overall in the 64 mg lorperidone groups, 15 in the placebo to 32 mg lorperidone groups, and 13 in the placebo to 64 mg lorperidone groups). For PANSSPSM, the trend of improvement continued during the OL period for placebo-treated patients who crossed over to lorperidone treatment, as well as throughout the entire study ("WS") period for patients treated from the start of the study with lorperidone.

[0435] During the OL period (when a placebo control was not available), continued improvement was seen with lorperidone for efficacy parameters that had previously shown improvement during the DB period.

[0436] Example 3 - Overview of Phase 3 Study #2 Study #2 (also referred to herein as "MIN101C07") was a Phase 3, randomized, DB, placebo-controlled, parallel-group 12-week study followed by a 40-week OL extension to evaluate the efficacy and safety of lorperidone in patients ≥18 to ≤55 years of age with negative symptoms of schizophrenia. The study consisted of a pre-treatment screening period of up to 28 days (including an antipsychotic washout period), a 12-week DB, placebo-controlled period, and a 40-week OL period. Eligible patients (with moderate to severe negative symptoms and stable positive symptoms of schizophrenia, but without severe symptoms of suspiciousness, agitation, hostility, uncooperativeness, or poor impulse control) were randomized 1:1:1 to receive oral lorperidone 32 mg QD, lorperidone 64 mg QD (GR01 / B formulation, see U.S. Patent No. 11,464,744), or placebo for 12 weeks. If patients were receiving antipsychotic treatment, they were discontinued and allowed a 2-day washout period before starting their assigned study treatment. During the 40-week OL treatment extension period, patients initially randomized to lorperidone 32 mg or 64 mg continued treatment with the same dose, while patients initially randomized to placebo were crossed over to lorperidone 32 mg or 64 mg in a 1:1 ratio.

[0437] Selection Criteria Overview

[0438] Diagnosis / Disease Criteria / Medical Conditions: Patients must meet diagnostic criteria for schizophrenia as defined in DSM-5, established by a full psychiatric interview in conjunction with the Mini International Neuropsychiatric Interview. Have a documented diagnosis of schizophrenia for at least one year prior to screening for this study. Patients were stable with respect to both positive and negative symptoms of schizophrenia over the past 6 months according to the treating clinician and / or as documented in the clinical chart or medical record. Patients with or without positive symptoms were admitted if their symptoms had been stable over the past 6 months. Patients with a PANSS negative subscale score (sum of the original PANSS scale [N1+N2+N3+N4+N5+N6+N7]) >20 at screening (Visit N1) and baseline (Visit 3) and an absolute difference of <4 points between the two visits.

[0439] Drug therapy: Patients may have been receiving any psychotropic medication prior to the study, provided that the psychotropic medication was discontinued at the beginning of the washout phase without endangering the patient's clinical status or safety.

[0440] Trust / Compliance / Consent: · The patient and the patient's legal representative, if applicable, must provide informed consent before the start of any study-related procedures, and the patient must be determined by the investigator to be able to understand the study requirements. Caregivers or family members or health care professionals were available to provide information about the evaluation and to advocate for the patient regarding compliance with the protocol. Caregivers needed frequent contact with the patient and were not expected to change during the study. Patients and caregivers were deemed by the investigator to be trustworthy and likely to cooperate with assessment procedures.

[0441] sex Male or female. Female patients of non-childbearing potential, defined as those who are postmenopausal (defined as at least 1 year of spontaneous amenorrhea or at least 6 months of spontaneous amenorrhea confirmed by a follicle-stimulating hormone result of ≥ 40 IU / mL) or who have been permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy). · Female patients, if of childbearing potential, must have tested negative for pregnancy and must be using a double barrier method of contraception.

[0442] age: 18~55 years old, inclusive.

[0443] BMI: <35 kg / m at screening 2 .

[0444] CYP2D6 P450 Status: The patient is a patient who has at least one functional allele (e.g., * 1, or * 2) Patients must be extensive metabolizers (normal) of CYP2D6 P450.

[0445] History of violence · No history of violence against self or others in the past year.

[0446] others: Patients are currently outpatients and have not been hospitalized in the past 6 months due to acute exacerbation or worsening of symptoms. Patients who have been hospitalized for social reasons in the past 6 months or who are currently hospitalized for social reasons can only be included if approved by the sponsor's responsible medical director (and for Ukraine only, the following criteria must be met: patients have a permanent place of residence, have legal capacity, and have a caregiver). Social reasons must be documented in the electronic case report form.

[0447] Summary of exclusion criteria

[0448] Diagnosis / Disease Criteria / Medical Conditions: · Current major depressive disorder, bipolar disorder, panic disorder, obsessive-compulsive disorder, or intellectual disability (intellectual developmental disorder diagnosed before age 14). Patients with PANSS item scores >4: P4 agitation / hyperactivity, P6 suspiciousness / paranoia, P7 hostility, G8 uncooperativeness, G14 poor impulse control. · Calgary Depression Scale for Schizophrenia total score of >6. #4) A score of ≥2 on any two of items 1, 2, or 3, or a score of ≥3 on item 4 of the Barnes Akathisia Rating Scale (BARS).

[0449] Drug therapy: Patients who have been unable to discontinue non-authorized psychotropic medications. Patients who had taken clozapine within 6 months prior to the screening visit, except for use for insomnia at doses ≤100 mg per day. Patients receiving treatment with a long-acting or depot antipsychotic, except that the next scheduled dose occurs during the protocol screening period and may be omitted to allow sufficient washout before administering study drug.

[0450] Other medical conditions: The patient's condition was due to the direct physiological effects of a substance (e.g., a drug of abuse or a medication) or a general medical condition. Patients who had received electroconvulsive therapy, vagus nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to the screening visit, or who were scheduled to receive electroconvulsive therapy, vagus nerve stimulation, or repetitive transcranial magnetic stimulation at any time during the study. Patients with a history of significant other major or unstable neurological, neurosurgical (e.g., head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, metabolic, gastrointestinal, or urinary disorders. Patients with a history of seizures (patients with a history of one childhood febrile seizure can be enrolled in this study). Patients with clinically significant abnormalities in hematology, blood chemistry, electrocardiogram, or physical exam that had not resolved by the baseline visit and were judged by the investigator to be precluding study participation. Current systemic infection (e.g., hepatitis B, hepatitis C, HIV, tuberculosis). Patients were included in the study if their aminotransferase levels (alanine aminotransferase / serum glutamic pyruvic transaminase and aspartate aminotransferase / serum glutamic oxaloacetic transaminase) were not more than twice the upper limit of normal (ULN), they had a positive hepatitis B core antibody test, and they had a negative hepatitis B surface antigen test. Patients who require or may require concomitant treatment with any other medication likely to increase the QT interval (e.g., paroxetine, fluoxetine, duloxetine, amiodarone). Patients who require drugs that inhibit CYP2D6 or CYP3A4. Patients with clinically significant ECG abnormalities that may have been a safety issue in this study, including QT interval values ​​corrected for HR with a QTcF of >430 milliseconds for men and >450 milliseconds for women. -Patients with a history of myocardial infarction based on medical history or ECG findings at the time of screening. ·Having a family or personal history of long QT syndrome or additional risk factors for polymorphic ventricular tachycardia. Patients with safety laboratory test results showing one or more of the following: potassium <3.40 mmol / L, or calcium <2.07 mmol / L, or magnesium <0.70 mmol / L. Patients with unexplained syncope.

[0451] sex: Women or men of childbearing potential who are unwilling or unable to use an accepted method of contraception. Women who have a positive pregnancy test, are breastfeeding, or plan to become pregnant during the study.

[0452] Substance use: Patients had a history of a substance use disorder within 3 months of the screening visit (excluding caffeine and cigarette smoking). ·Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines, cannabinoids, sedatives, benzodiazepines, and barbiturates), tricyclic antidepressants, and alcohol (excluding prescription benzodiazepines).

[0453] History of suicidal behavior: · Had a current or recent history of serious suicidal behavior within the past year.

[0454] others: Patients who had participated in another clinical study within 3 months prior to screening, or had previously received lorperidone, or had previously participated in >2 clinical studies with experimental medications within the past 2 years (prior participation in 3 clinical studies with experimental medications was to require sponsor approval before determining eligibility).

[0455] Patient characteristics

[0456] A total of 515 patients were randomized during the DB period, and 513 received treatment (172 patients received placebo, 170 patients received 32 mg lorperidone, and 171 patients received 64 mg lorperidone). These 513 patients were included in the ITT population. Demographic characteristics were comparable between the three treatment groups for age, sex, race, and BMI. The overall mean age of patients was 41 years (range: 18-55 years), 61% were male, 88% were white, and the mean BMI was 26 kg / m 2 All patients enrolled in the study were to be extensive metabolizers of CYP2D6 (as a strategy to minimize the risk of QT prolongation in patients receiving lorperidone). All baseline disease characteristics were comparable between the three treatment groups, including NSFS, PSP total score, CGI-S, and PANSS total and subscale scores. The overall mean NSFS score was 25, the mean PSP score was 53, the mean CGI-S score was 4, the mean PANSS total score was 79, the mean PANSS negative subscale score was 27, and the mean PANSS positive subscale score was 14.

[0457] DB Period Results In total, 379 (74%) of 515 patients completed the DB period of the study through week 12 of treatment, with similar proportions across treatment groups: 130 (76%) of 172 patients in the placebo group, 123 (72%) of 170 patients in the 32 mg lorperidone group, and 126 (74%) of 171 patients in the 64 mg lorperidone group. The most frequent reason for patient discontinuation across all treatment groups was withdrawal of consent (17% of patients in the placebo group, 19% of patients in the 32 mg group, and 23% of patients in the 64 mg group). A blinded review of data from one study site reported concerns about data integrity, leading to the exclusion of all patient data from this site into a modified intention-to-treat population. The mITT population included 496 patients: 167 patients each received placebo and 32 mg lorperidone, and 162 patients received 64 mg lorperidone.

[0458] Lorperidone was generally well tolerated, and no new safety signals were detected. The incidence of TEAEs was slightly higher in the lorperidone group than in the placebo group during the DB period (42% in the 32 mg lorperidone group, 37% in the 64 mg lorperidone group, and 33% in the placebo group). The majority of reported TEAEs were systemic organ class (SOC) psychiatric disorders. The most commonly reported TEAEs were insomnia, schizophrenia, anxiety, agitation, and headache. Lorperidone did not induce significant changes in safety laboratory parameters, including prolactin. It did not induce significant changes in vital signs, including weight and waist circumference. Dose-related QT prolongation was observed, with the majority of clinically significant QT prolongation observed at the 64 mg dose. In total, six patients met the discontinuation criteria due to QT prolongation, and four of the six patients discontinued the study due to such prolongation. The remaining two patients discontinued for other reasons before confirmation of QT prolongation.

[0459] The efficacy results of this study are summarized in Table 9 below. [Table 9-1] [Table 9-2]

[0460] A statistically significant change in NSFS from baseline to week 12 was observed in the mITT population for the 64 mg dose of lorperidone compared with placebo. Despite the greater than expected placebo response for NSFS, unadjusted statistical superiority was also observed at weeks 4 and 8 for NSFS and PSP total score.

[0461] Additionally, statistically significant improvements (unadjusted) in NSFS from baseline were observed at weeks 4 and 8 for the 64 mg lorperidone group and at week 4 for the 32 mg lorperidone group compared with placebo for both the ITT and mITT populations.

[0462] The key secondary efficacy endpoint, change from baseline to week 12 in PSP total score, showed a nominally statistically significant improvement for the ITT population for the 64 mg lorperidone group (least squares (LS) mean difference vs. placebo: 2.2 [95% CI: 0.3, 4.1], p ≤ 0.021).

[0463] Analyses of other secondary and exploratory endpoints also demonstrated statistically significant improvements at week 12 for the 64 mg lorperidone group compared with the placebo group in the change from baseline in PANSS negative subscale scores, NSFS emotional experience scores, Marder's PANSS positive symptom factor scores, and "socially useful activities" PSP domain scores in all ITT populations. Responder analyses demonstrated a 20% reduction in NSFS in 39% of the 64 mg lorperidone group compared with 23% of the placebo group (p ≤ 0.006) and a 30% reduction in NSFS in 20% of the 64 mg lorperidone group compared with 13% of the placebo group (Table 9).

[0464] Similarly, a 7-point increase in PSP total score was reported by 20% of the 64 mg lorperidone group compared with 13% of the placebo group (p ≤ 0.032), and a 10-point increase was reported by 30% of the 64 mg lorperidone group compared with 22% of the placebo group (not significant).

[0465] The proportion of patients who experienced a relapse in the ITT population was similar in the placebo (8 [5%]) and 64 mg lorperidone groups (9 [5%]) and was higher in the 32 mg lorperidone group (18 [11%]) (see Table 10). [Table 10]

[0466] This was consistent with the changes observed in PANSS positive symptom scores with 64 mg lorperidone, which remained similar to placebo (Figure 4).Among patients who relapsed, the mean number of days to relapse was 79.8 days in the placebo group and 82.1 and 124.9 days in the 64 mg and 32 mg lorperidone groups, respectively (Table 10 (above) and Figure 6).

[0467] In the MIN-101C07 study, the above data support the conclusion that 64 mg of lorperidone was superior to placebo and that the observed treatment effect was a true effect of lorperidone. Open-label period

[0468] Patient Disposition: Of the 379 patients who completed the 12-week DB period, 333 patients participated in the 40-week OL period, including 107 patients who received 32 mg lorperidone throughout the study, 104 patients who received 64 mg lorperidone throughout the study, 59 patients who received placebo during the DB period and switched to 32 mg lorperidone during the OL period, and 63 patients who received placebo during the DB period and switched to 64 mg during the OL period.

[0469] A total of 202 patients (72 in the overall 32 mg lorperidone group, 59 in the overall 64 mg lorperidone group, 35 in the placebo to 32 mg lorperidone group, and 36 in the placebo to 64 mg lorperidone group) completed the OL period. Results of OL period

[0470] NSFS scores continued to improve for all treatment groups during the OL period, with treatment effects sustained through week 52 of continued study drug. Similarly, continued improvement was observed in PSP total scores during the OL period. Results of additional secondary and exploratory endpoints during the OL period showed either continued improvement or maintenance of stability from the DB period.

[0471] The number (proportion) of patients experiencing relapse in the ITT population was low for all three treatment groups (6 [5%] for placebo plus lorperidone combined, 9 [8%] for 32 mg lorperidone, and 10 [10%] for 64 mg lorperidone) (Table 11). Among patients who relapsed, the mean number of days to relapse was 260.4 in the placebo to lorperidone groups, 232.4 in the 32 mg lorperidone group, and 186.7 in the 64 mg lorperidone group. The time to relapse during the OL period is shown in Table 11 and Figure 7. [Table 11]

[0472] Example 4 - Comparison and analysis of results across studies #1 and #2

[0473] Efficacy data from studies no. 1 and 2 were pooled. The majority of patients in the pooled ITT population completed the DB period (502 patients overall, 66.3%), with similar percentages in each treatment group (placebo: 69.8%, 32 mg lorperidone: 65.3%, and 64 mg lorperidone: 63.8%) (Table 12). The majority of patients (62.7%) who completed the DB period entered the OL period. The most common reason for discontinuation during the DB period across patients was withdrawal of consent (15.6%), followed by adverse events (7.3%) and lack of efficacy (5.4%) (Table 12). The proportion of patients who withdrew consent was comparable between treatment groups. Approximately twice as many patients in the lorperidone group (32 mg: 8.5%, 64 mg: 9.1%) discontinued due to adverse events compared with patients in the placebo group (4.3%). More patients in the placebo group discontinued due to lack of efficacy (6.7%) than in the lorperidone group (32 mg: 4.4%, 64 mg: 5.1%). The low number of patients who discontinued due to lack of efficacy or withdrawal of consent probably reflects the low level of worsening of positive symptoms. [Table 12]

[0474] Similar percentages of patients in each OL treatment group entered the OL period from the DB period (range: 61.3%-65.6%) (Table 13). The most common reason for patient discontinuation in the OL period was withdrawal of consent (93 patients, 12.3%), followed by adverse events (45 patients, 5.9%) and lack of efficacy (16 patients, 2.1%). The proportions of patients who withdrew consent, discontinued due to adverse events, or discontinued due to lack of efficacy were comparable between treatment groups. [Table 13]

[0475] Demographic and baseline characteristics were well balanced between treatment groups during the DB period (Table 14). The majority of patients (85.7% overall) had moderate severity of negative symptoms of schizophrenia (NSFS score <20-30). [Table 14-1] [Table 14-2]

[0476] Previous drug therapy

[0477] Nearly all patients had received prior pharmacotherapy (98.4%), with findings across treatment groups (>97% of patients in each group). As expected, the majority of patients had received antipsychotic medications. Antipsychotic medications taken by >10% of patients overall were risperidone (40.3%), olanzapine (19.8%), aripiprazole (14.0%), haloperidol (13.6%), and amisulpride (10.8%), distributed evenly across treatment groups. Comparison of efficacy results across studies

[0478] The pooled analyses supporting the efficacy of lorperidone as a treatment for negative symptoms of schizophrenia in adults are presented below. A summary of the results of the pooled efficacy analyses is presented in Table 15. The clinical efficacy of lorperidone 64 mg administered once daily is demonstrated by the results of the primary efficacy endpoint of the NSFS and supported by the results of the PSP total score, and the CGI-S and CGI-I. [Table 15]

[0479] NSFS The primary efficacy outcome measure was the change from baseline to week 12 in NSFS in the pooled ITT population. At baseline, mean (SD) NSFS scores were similar between treatment groups: 24.6 (3.37) for placebo, 25.3 (3.67) for 32 mg lorperidone, and 25.3 (3.51) for 64 mg lorperidone. At week 12, there was a statistically significant improvement, expressed as LS mean reduction from baseline, compared with placebo in both the 32 mg lorperidone group (-3.5, 95% CI: -4.0, -2.9, p ≤ 0.023) and the 64 mg lorperidone group (-3.9, 95% CI: -4.4, -3.4, p < 0.001) (Table 16).

[0480] Unadjusted p values ​​for the 64 mg lorperidone group at weeks 2, 4, and 8 demonstrated an early and consistent significantly different reduction from baseline in NSFS scores compared to placebo (Table 16). Starting at week 4, a similar trend was observed for the unadjusted p value for the 32 mg lorperidone group. Similar results were observed for the change in NSFS scores for the pooled mITT population. [Table 16]

[0481] At week 12, there was a greater change in NSFS in the 64 mg lorperidone group (19% and 13% showing moderate (magnitude of change 6-8) and severe (magnitude of change >8) improvement, respectively, 32% total) compared with the 32 mg lorperidone (18% and 5% showing moderate and severe improvement, respectively, 23% total) and placebo groups (9% and 8% showing moderate and severe improvement, respectively, 17% total). Consistent with this observation, responder analysis showed that there were statistically significantly more patients in the 64 mg lorperidone group compared with the placebo group who had a 20% (p ≤ 0.002) and 30% (p ≤ 0.037) reduction in NSFS score from baseline.

[0482] Consistent with the healthy NSFS results observed at week 12, the 64 mg lorperidone group demonstrated a statistically significant improvement in change from baseline to week 12 compared to placebo for PANSS Murder positive symptoms (p ≤ 0.004). We did not find statistically significant differences from placebo for change from baseline in disorganized thoughts, uncontrolled hostility / agitation, or anxiety / depression scores for either lorperidone group.

[0483] PANSS total score At baseline, mean (SD) PANSS total scores were comparable across treatment groups (78.1 [(10.52], 80.3 [11.25], and 79.3 [10.67] for placebo, 32 mg lorperidone, and 64 mg lorperidone groups, respectively). At week 12, LS mean changes from baseline were greater for both the 32 mg lorperidone group (-1.9, 95% CI: -3.9, 0.0, p ≤ 0.051) and the 64 mg lorperidone group (-2.8, 95% CI: -4.7, -0.9, p ≤ 0.004) compared with placebo (Table 17).

[0484] Unadjusted p values ​​for the 64 mg lorperidone group at weeks 4 and 8 demonstrated earlier, more consistent and significantly different reductions from baseline in PANSS total scores compared to placebo (Table 17). The unadjusted p value for the 32 mg lorperidone group was statistically significant only at week 4.

[0485] Responder analysis showed that there were statistically significantly more patients in the 64 mg lorperidone group who achieved a 20% (p≦0.005) reduction in PANSS total score from baseline compared to the placebo group. [Table 17]

[0486] PANSS positive subscale score At baseline, mean (SD) PANSS positive subscale scores were similar across treatment groups (14.2 [3.48], 14.7 [3.83], and 14.1 [3.72] for the placebo, 32 mg lorperidone, and 64 mg lorperidone groups, respectively).

[0487] At week 12, LS mean change from baseline showed stable PANSS positive subscale scores and a trend towards improvement compared to placebo for both the 32 mg lorperidone group (-0.3, 95% CI: -0.8, 0.3, p ≤ 0.394) and the 64 mg lorperidone group (-0.4, 95% CI: -1.0, 0.2, p ≤ 0.190) (Table 18). PANSS positive subscale scores at baseline and after 12 weeks of treatment were mild and stable and, more importantly, remained so at week 12, consistent with patient inclusion criteria. [Table 18]

[0488] PANSS negative subscale score At baseline, mean (SD) PANSS negative subscale scores were comparable across treatment groups (26.5 [3.51], 27.0 [3.61], and 27.1 [3.51] for placebo, 32 mg lorperidone, and 64 mg lorperidone, respectively). At week 12, there was a greater LS mean change from baseline compared to placebo for both the 32 mg lorperidone group (-0.7, 95% CI: -1.5, 0.0, p ≤ 0.05) and the 64 mg lorperidone group (-1.3, 95% CI: -2.0, -0.6, p ≤ 0.050), with differences statistically significant in favor of the 64 mg lorperidone group and trending toward statistical significance for the 32 mg lorperidone group (Table 19).

[0489] Unadjusted p values ​​for the 64 mg lorperidone group at weeks 4 and 8 demonstrated early and consistent significantly different changes from baseline in PANSS negative subscale scores compared to placebo (Table 19). Unadjusted p values ​​for the 32 mg lorperidone group were statistically significant at weeks 4 and 8. [Table 19]

[0490] PSP Total Score Results of the analysis of the change from baseline in PSP total score followed the same trends as results of the change from baseline in the PANSS Marder NSFS for the 64 mg lorperidone group, showing a statistically significant improvement compared with placebo at week 12. At baseline, mean (SD) PSP total scores were comparable across treatment groups (52.3 [12.06], 52.7 [12.23], and 51.9 [11.92] for the placebo, 32 mg lorperidone, and 64 mg lorperidone groups, respectively). At week 12, there was a greater LS mean change from baseline compared to placebo for both the 32 mg lorperidone group (0.5, 95% CI: -1.4, 2.4, p ≤ 0.614) and the 64 mg lorperidone group (3.6, 95% CI: 1.7, 5.5, p ≤ 0.001), with the difference being statistically significantly better for the 64 mg lorperidone group and not reaching statistical significance for the 32 mg lorperidone group (Table 20). Unadjusted p values ​​for the 64 mg lorperidone group at weeks 4 and 8 showed an earlier, more consistent, and more statistically significantly different increase from baseline in PSP total score compared to placebo (Table 20). Similar results were observed for the pooled mITT population for change in PSP total score. [Table 20]

[0491] There was a greater response in the 64 mg lorperidone group with 7% and 36% showing moderate improvement (magnitude of change 7-9) to strong improvement (magnitude of change ≥ 10) (43% total) compared with the 32 mg lorperidone (7% and 26% showing moderate and strong improvement, respectively, 33% total) and the placebo group (5% and 25% showing moderate and strong improvement, respectively, 30% total). In line with this observation, responder analysis showed that there were statistically significantly more patients in the 64 mg lorperidone group (p ≤ 0.005) who had a 7-point increase in PSP total score from baseline compared with the placebo group.

[0492] CGI-S At baseline, mean (SD) CGI-S scores were comparable across treatment groups (4.1 [0.63], 4.1 [0.62], and 4.1 [0.64] for placebo, 32 mg lorperidone, and 64 mg lorperidone, respectively). At week 12, there was a greater LS mean change from baseline compared to placebo for both the 32 mg lorperidone group (-0.1, 95% CI: -0.2, 0.0, p ≤ 0.084) and the 64 mg lorperidone group (-0.2, 95% CI: -0.3, -0.0, p ≤ 0.007), with the difference being statistically significantly superior to the 64 mg lorperidone group (Table 21).

[0493] Unadjusted p values ​​for the 64 mg lorperidone group at weeks 4 and 8 demonstrated early and consistent significantly different changes from baseline in CGI-S scores compared to placebo (Table 21). [Table 21]

[0494] CGI-I For CGI-I scores at week 12, there was no LS mean difference for the 32 mg lorperidone group compared to placebo (-0.0, 95% CI: -0.2, 0.2, p ≤ 0.760) and a statistically significantly better LS mean for the 64 mg lorperidone group compared to placebo (-0.2, 95% CI: -0.4, -0.0, p ≤ 0.037) (Table 22). Unadjusted p values ​​for the 64 mg lorperidone group at weeks 4 and 8 showed earlier and more consistent significantly different changes in CGI-S scores compared to placebo (Table 22). Unadjusted p values ​​for the 32 mg lorperidone group were statistically significant only at week 4. [Table 22]

[0495] General statistical tests (GST) of pooled efficacy data For the pooled data, using the mITT population from the MIN-101C07 study, a combined GST of the primary and secondary efficacy endpoints from the MIN-101C03 study and the primary and key secondary efficacy endpoints from the MIN-101C07 study for both lorperidone dose groups achieved overall significant efficacy with p-values ​​of 0.0249 (32 mg) and 0.0001 (64 mg, Figure 8). Additional GST after adding several secondary endpoints from the MIN-101C03 and MIN-101C07 studies described for the individual studies showed that both the lorperidone 32 mg and 64 mg dose groups achieved overall significant efficacy with p-values ​​of 0.0149 and 0.0001, respectively (Figure 8). These findings support the conclusion that for the pooled data, lorperidone at both doses is superior to placebo and that the observed treatment effects are true effects of lorperidone. recurrence

[0496] The number (proportion) of patients who experienced a relapse in the pooled ITT population was similar in the placebo (14 [5%]) and 64 mg lorperidone groups (16 [6%]) and was higher in the 32 mg lorperidone group (19 [8%]) (Table 23). Among patients who relapsed, the mean number of days to relapse was 79.4 days in the placebo group and 128.3 and 81.4 days in the 32 mg and 64 mg lorperidone groups, respectively (Table 23 and Figure 9). [Table 23]

[0497] Antipsychotic efficacy after lorperidone use An analysis of the potential impact of lorperidone administration on antipsychotic efficacy was specifically conducted to assess whether patients taking lorperidone who exhibited worsening of positive symptoms experienced diminished benefit after discontinuation of lorperidone and initiation of antipsychotic treatment. Across MIN-101C03 and MIN-101C07, 57 patients reported AEs / SAEs during the DB period that required discontinuation of lorperidone and treatment with an antipsychotic. Median time to symptom improvement was similar regardless of treatment received (19 days for placebo, 12 days for 32 mg lorperidone, and 17 days for 64 mg lorperidone). Median time to symptom improvement after initiating an antipsychotic was numerically greater in patients receiving placebo compared to patients receiving lorperidone, but values ​​were too small to infer differences. These durations of symptom improvement with antipsychotics are consistent with the ranges reported in the literature (Agid, O., et al. “The” delayed onset” of antipsychotic action - an idea whose time has come and gone.” J Psychiatry Neurosci. 2006;31(2):93-100). These data indicate that the efficacy of antipsychotics was not diminished or affected by exposure to lorperidone.

[0498] Comparison of subgroup results

[0499] Subgroup analyses were performed for DB duration in the pooled ITT population for NSFS, PSP total score, CGI-S, and CGI-I. Subgroup analyses included age (≤40 years, >40 years), BMI (<25 kg / m 2 , 25~<30kg / m 2 , ≧30kg / m 2 ), sex (male, female), race (white, other), previous antipsychotic use (group of patients receiving antipsychotics only before the study), baseline PANSS Marder NSFS score (<20, ≥20 to <30, ≥30), baseline CGI-S (<4, ≥4), and CYP2D6 (normal / extensive group only). Furthermore, for the MIN-101C07 study, which is the only study including patients in the United States, we present a subpopulation analysis by region of patients in the United States compared with patients in the rest of the world.

[0500] Age (≦40 years vs. >40 years) - Overall, treatment differences observed in various efficacy endpoints for age subgroups (≦40 years and >40 years) for the 32 mg and 64 mg lorperidone groups vs. placebo groups were similar.

[0501] Body Mass Index - Overall, efficacy of the 64 mg and 32 mg lorperidone groups compared with placebo was generally similar in normal (<25 kg / m2) and overweight (25 to <30 kg / m2) BMI subgroups. Lower improvements in efficacy were observed in the obese (≥30 kg / m2) BMI subgroup in the 64 mg lorperidone group compared with other BMI categories. The lower efficacy observed in the 64 mg lorperidone group in the obese subgroup should be interpreted with caution due to small sample size and may be due to reduced exposure to lorperidone. For the change from baseline in NSFS score at week 12, the 64 mg lorperidone group had a greater improvement compared with placebo for both the normal and overweight BMI subgroups (LS mean change from baseline compared with placebo was -1.7 and -1.4, respectively), but the improvement was smaller in the obese patient subgroup (LS mean change from baseline compared with placebo was -0.1).

[0502] Gender. Overall, no gender differences were observed for the 64 mg lorperidone group compared with placebo.

[0503] Race. Patients in this study were primarily white (694 / 757 [91.7%] patients were white and 63 / 757 [8.3%] patients were of other races), so meaningful comparisons could not be made between white and other race subgroups for any of the outcomes.

[0504] Prior antipsychotic use - Subgroup analyses show superiority of 64 mg lorperidone over placebo for most outcome measures in these patients.

[0505] Severity of disease (moderate vs. severe vs. very severe) Baseline NSFS score: Overall, the effect of 64 mg lorperidone compared to placebo observed in patients with NSFS <20 at baseline (less severe disease, n=8) was similar to that observed in patients with NSFS scores ≥20 to <30 at baseline (moderately severe disease, n=221), but we observed no effect compared to placebo in patients with NSFS ≥30 at baseline (severe disease, n=25). However, findings in the severe group should be interpreted with caution based on the small sample size in this group and the large variability in the placebo group. We observed similar results for PSP total score in the 64 mg lorperidone group compared to placebo by NSFS baseline score. We observed similar patterns of PSP total score by baseline score group as well as 32 mg lorperidone compared to placebo by NSFS baseline score. Baseline CGI-S score: Overall, the effect of 64 mg lorperidone compared with placebo observed in patients with moderate to severe disease at baseline (CGI-S score of ≥4, n=218) was similar to that observed in patients with mild disease at baseline (CGI-S score of <4, n=36). The small number of patients with mild disease at baseline does not allow conclusions to be drawn. We observed a similar trend for PSP total score in the 64 mg lorperidone group compared with placebo by CGI-S baseline score. We observed a similar pattern for PSP total score by baseline score group as well as for 32 mg lorperidone compared with placebo by NSFS baseline score.

[0506] Efficacy in US and Non-US Patients - In the ITT population at baseline in the MIN-101C07 study, there were 81 patients in the US region (27 patients in the placebo and lorperidone groups, respectively) compared with 432 in the rest of the world (145 patients in the placebo group, 143 patients in the 32 mg lorperidone group, and 144 patients in the 64 mg lorperidone group). Subgroup analysis of these two subgroups for change from baseline to week 12 in NSFS showed generally similar results across all treatment arms in both regions. The 64 mg dose showed a healthy effect in both the US and non-US sites, with a larger effect size in the US site (0.32) compared with the non-US site (0.20), despite a larger than placebo response in the US. These findings should be interpreted with caution due to the small sample size in the US region.

[0507] Efficacy and / or tolerability Durability of effect

[0508] The improvements in efficacy parameters observed during the DB period were sustained and continued during the OL period. Overall, the changes from baseline in NSFS and PSP total scores were sustained throughout the OL period for patients on 32 mg and 64 mg lorperidone across groups, and the changes in efficacy parameters observed for patients who switched from placebo to 32 mg and 64 mg lorperidone were consistent with the lorperidone group during the DB period (Figures 10 and 11). Furthermore, based on the MIN-101C07 study, at follow-up visits, when patients were no longer receiving lorperidone, improvements in NSFS scores for both doses were sustained for at least 2 weeks after the last dose (Table 24). Changes from baseline in CGI-S and CGI-I scores continued to show improvement during the OL period (Figures 12 and 13). In summary, the results of the OL period indicate a sustained and robust response in patients treated with 32 mg or 64 mg lorperidone based on the primary efficacy endpoint of the NSFS score, and supported by the results observed in the PSP total score (the primary secondary endpoint of the MIN-101C07 study), as well as the CGI-S and CGI-I.

[0509] Open-label pooled efficacy results NSFS-The improvement in mean NSFS scores observed during the DB period for the 32 mg and 64 mg lorperidone groups was maintained and continued during the OL period, including 2 weeks after the end of study treatment (based on the assessment at week 54 in the MIN-101C07 study). Improvements from baseline in mean NSFS scores were also observed in patients who switched from placebo to 32 mg and 64 mg lorperidone, which was consistent with the lorperidone treatment group during the DB period (Table 24 and Figure 10). Week 24 was the only common week shared between the MIN-101C03 and MIN-101C07 studies in the OL period, but from Figure 10 it can be observed that the improvement in NSFS scores was maintained throughout the OL period for the 32 and 64 mg lorperidone groups. [Table 24-1] [Table 24-2]

[0510] PSP Total Score The improvements in PSP total scores observed during the DB period for the 32 mg and 64 mg lorperidone arms were sustained and continued during the OL period of the MIN-101C07 study (Figure 11). (PSP total scores were not obtained in the OL period of the MIN-101C03 study.) Similar mean changes in PSP total scores from active baseline at Week 52 were observed in the placebo plus 32 mg treatment group (11.7) compared with the placebo plus 64 mg treatment group (11.8).

[0511] CGI-S The improvements in CGI-S scores observed during the DB period for the 32 mg and 64 mg lorperidone groups were sustained and continued during the OL period, and the changes from baseline in CGI-S observed for patients switched from placebo to 32 mg and 64 mg lorperidone were consistent with the lorperidone treatment groups during the DB period (Figure 12).

[0512] CGI-I The improvements in CGI-I scores observed during the DB period for the 32 mg and 64 mg lorperidone groups were sustained and continued during the OL period, and the improvements in CGI-I scores observed for patients switched from placebo to 32 mg and 64 mg lorperidone were consistent with the lorperidone treatment groups during the DB period (Figure 13).

[0513] recurrence

[0514] The number (proportion) of patients who experienced relapse (worsening of symptoms) in the ITT population during the OL period was low compared with literature reports for all four treatment groups (9 [11%] for placebo to 32 mg lorperidone, 1 [1%] for placebo to 64 mg lorperidone, 10 [7%] for 32 mg lorperidone throughout, and 12 [8%] for 64 mg lorperidone throughout). Among patients who relapsed, the mean number of days to relapse was 256.3 in the total placebo to lorperidone groups, 234.8 in the 32 mg lorperidone group, and 188.1 in the 64 mg lorperidone group. A Kaplan-Meier plot of the time to relapse over the entire period is shown in Figure 14.

[0515] Although discontinuation rates vary widely between different trials and antipsychotics evaluated, discontinuation rates reported in the literature over similar trial periods are approximately 40% for placebo patients and 20% or more for antipsychotic patients. See, for example, Leucht et al., “Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis,” www.thelancet.com, June 2, 2012, 379, 2063-2071, (27% drug relapse rate after 1 year - data from 116 reports of 65 trials with 6,493 patients), Arato et al., “A 1-year, double-blind, placebo-controlled trial of ziprasidone 40,80 and 160 mg / day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study,” International Clinical See Psychopharmacology, 2002, 17, 207-215, (ziprasidone 40, 80, and 160 mg / day groups, 43%, 35%, and 36% relapse rates after one year, respectively), and Durgam et al., “Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial,” Schizophrenia Research, 2016, 176, 264-271, (cariprazine, 24.8% relapse rate). Example 5 – Summary of two late-stage clinical trials

[0516] At 36 weeks in Study #1 and 52 weeks in Study #2, re-emergence or increase in positive symptoms occurred in only a limited number of patients. This is reflected by the stability of both the positive symptoms PANSS subscale scores and the PANSS total score, as well as the low incidence of relapse. Only 15.2% of subjects in Study #1 and 11.7% of subjects in Study #2 discontinued study participation due to worsening positive symptoms. (Table 25.) [Table 25]

[0517] In contrast, relapse rates reported in the literature for other antipsychotics are higher (see above). The low discontinuation rate observed in Applicant's study, compared with rates reported in the literature, further highlights the unique characteristics of lorperidone in preventing relapse in schizophrenia patients in general, and in the schizophrenia patient population selected by the enrollment criteria of these two studies. Example 6: Lorperidone Monotherapy Prevents Relapse for Over 2 Years

[0518] Patient X showed uniform efficacy, limited emotional expression, poor motivation to do much more than watch television, and occasionally participated in occupational therapy for a few hours per week. The patient was unable to concentrate well enough to read. During the course of monotherapy with lorperidone (64 mg / day), the patient experienced gradual improvement in negative and cognitive symptoms. This enabled the patient to find employment. Her affect is no longer limited, she reads novels regularly without loss of concentration, and enjoys and looks forward to various daily activities. She has not relapsed in the two years that she has taken lorperidone (64 mg / day) as monotherapy.

Claims

1. 1. A pharmaceutical composition for use in preventing relapse in a patient with schizophrenia, said pharmaceutical composition comprising a therapeutically effective amount of lorperidone.

2. The pharmaceutical composition described in claim 1, wherein the therapeutically effective amount of lorperidone is administered to the schizophrenic patient once or twice daily.

3. The pharmaceutical composition described in claim 1, wherein the therapeutically effective amount of lorperidone is administered to the schizophrenic patient once a day.

4. The pharmaceutical composition described in claim 1, wherein the therapeutically effective amount of lorperidone is orally administered to the patient with schizophrenia.

5. The pharmaceutical composition described in claim 1, wherein the pharmaceutical composition is used so that the therapeutically effective amount of lorperidone is administered in an amount of about 1 to about 100 mg.

6. The pharmaceutical composition of claim 5, wherein the therapeutically effective amount of lorperidone is administered at about 16 mg, about 24 mg, about 32 mg, about 40 mg, about 48 mg, about 56 mg, about 64 mg, about 72 mg, about 80 mg, about 88 mg, or about 96 mg.

7. The pharmaceutical composition described in claim 5, wherein the pharmaceutical composition is used so that the therapeutically effective amount of lorperidone is administered at approximately 32 mg.

8. The pharmaceutical composition described in claim 5, wherein the pharmaceutical composition is used so that the therapeutically effective amount of lorperidone is administered at approximately 64 mg.

9. 10. The pharmaceutical composition of claim 1, wherein the schizophrenic patient does not exhibit any behavior that puts the patient or those around the patient at risk of physical injury.

10. 10. The pharmaceutical composition of claim 1, wherein the schizophrenic patient has low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness.

11. 10. The pharmaceutical composition of claim 1, wherein the schizophrenic patient does not experience high levels of depression or anxiety.

12. 2. The pharmaceutical composition of claim 1, wherein the schizophrenia patient (i) has stable positive symptoms before initiating treatment with lorperidone, or (ii) is free of positive symptoms before initiating treatment with lorperidone.

13. 2. The pharmaceutical composition of claim 1, wherein the schizophrenic patient (i) has positive symptoms that are stable for about 1 to about 6 months, or about 3 to about 6 months, before initiating treatment with lorperidone, or (ii) is free of positive symptoms for about 1 to about 6 months, or about 3 to about 6 months, before initiating treatment with lorperidone.

14. The schizophrenic patient, (i) have moderate to severe negative symptoms, or 2. The pharmaceutical composition of claim 1, wherein (ii) the patient has a PANSS negative subscore of greater than 20.

15. The pharmaceutical composition according to claim 14, wherein the negative symptoms of the schizophrenic patient are primary negative symptoms.

16. 15. The pharmaceutical composition of claim 14, wherein the negative symptoms of the schizophrenic patient have been stable for about 1 to about 6 months prior to initiating treatment with lorperidone.

17. 15. The pharmaceutical composition of claim 14, wherein the negative symptoms of the schizophrenic patient have been stable for about 3 to about 6 months prior to initiating treatment with lorperidone.

18. 10. The pharmaceutical composition of claim 1, wherein the schizophrenic patient has previously been administered an antipsychotic drug.

19. 19. The pharmaceutical composition of claim 18, wherein the administration of the antipsychotic to the schizophrenic patient was discontinued at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months before the schizophrenic patient was administered the pharmaceutical composition.

20. The pharmaceutical composition of claim 1, wherein the relapse is an increase in positive symptoms in the schizophrenia patient, and optionally, the increase in positive symptoms in the schizophrenia patient is characterized by an increase in the patient's PANSS positive subscore over one or more consecutive visits.

21. The pharmaceutical composition described in claim 1, wherein the schizophrenic patient has a form of schizophrenia characterized by moderate to severe negative symptoms that are stable for about 3 to about 6 months.

22. 22. The pharmaceutical composition of claim 21, wherein the schizophrenia patient has a PANSS negative subscore of greater than 20.

23. The pharmaceutical composition according to claim 21, wherein the negative symptoms of the schizophrenic patient are primary negative symptoms.

24. 22. The pharmaceutical composition of claim 21, wherein the schizophrenia patient has stable positive symptoms before initiating treatment with lorperidone, and optionally, the schizophrenia patient has stable positive symptoms for about 1 to about 6 months, or about 3 to about 6 months, before initiating treatment with lorperidone.

25. 22. The pharmaceutical composition of claim 21, wherein the schizophrenia patient is free of positive symptoms prior to initiating treatment with lorperidone, and optionally, the schizophrenia patient is free of positive symptoms for about 1 to about 6 months, or about 3 to about 6 months, prior to initiating treatment with lorperidone.

26. 22. The pharmaceutical composition of claim 21, wherein the schizophrenic patient does not exhibit any behaviors that put the patient or those around the patient at risk of physical injury, has low levels of symptoms related to agitation, impulse control, hostility, suspiciousness, or uncooperativeness, and / or does not experience high levels of depression or anxiety.

27. 22. The pharmaceutical composition of claim 21, wherein the schizophrenic patient has previously been administered an antipsychotic drug.

28. 28. The pharmaceutical composition of claim 27, wherein the administration of the antipsychotic to the schizophrenic patient was discontinued at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months before the schizophrenic patient was administered the pharmaceutical composition.

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