Dosing regimen of iloperidone for treatment of bipolar type I disorders and schizophrenia

Abstract

Embodiments of the present invention generally relate to the treatment of schizophrenia or bipolar type I disorders, and more particularly, to the administration of iloperidone in such treatments, including the titration administration of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite. A first aspect of the invention provides a method of treating a patient suffering from a bipolar type I disorder, the method comprising administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to ameliorate at least one symptom of mania in the patient.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of priority to co - pending U.S. Provisional Patent Application Serial No. 63 / 476,161, filed on December 19, 2022, and co - pending U.S. Provisional Patent Application Serial No. 63 / 470,574, filed on June 2, 2023, which are hereby incorporated by reference in their entireties. Background of the Invention

[0003] Iloperidone

[0004] Iloperidone (1 - [4 - [3 - [4 - (6 - fluoro - 1,2 - benzisoxazol - 3 - yl) - 1 - piperidinyl]propoxy] - 3 - methoxyphenyl]ethanone) is a D2, 5 - HT 2A and α1 - adrenergic mixed antagonist and is an atypical antipsychotic drug approved by the FDA for the treatment of schizophrenia in adults.

[0005] The cytochrome P450 2D6 gene (CYP2D6) is located on chromosome 22 and encodes the phase I drug - metabolizing enzyme debrisoquine hydroxylase. Many drugs are known to be metabolized by debrisoquine hydroxylase, including iloperidone. Mutations in the CYP2D6 gene are associated with several drug - metabolism - related phenotypes. These include ultrarapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) phenotypes.

[0006] When a particular drug can produce undesirable physiological effects in its metabolized or non - metabolized form, it is desirable to determine whether a patient is a poor metabolizer of the drug prior to its administration. Undesirable physiological effects associated with increased concentrations of iloperidone or its metabolites are prolongation of the electrocardiogram QT interval and induction of orthostatic hypotension (OH).

[0007] Methods of administering iloperidone to a patient based on the patient's CYP2D6 genotype are described, for example, in U.S. Patent No. 10,272,076, which is hereby incorporated by reference in its entirety. Generally, patients known to be CYP2D6 poor metabolizers are administered a reduced dose (usually half) of iloperidone compared to patients known not to be CYP2D6 poor metabolizers.

[0008] Known poor metabolizer genotypes described in the ’076 patent include, for example, the AA and AG genotypes at CYP2D6 G1846A and the TT and CT genotypes at CYP2D6 C100T. Although the CYP2D6 G1846A (AA or AG) genotype and the CYP2D6 C100T (CT or TT) genotype are specifically described therein, the methods of the present invention can employ other genotypes that result in reduced activity of CYP2D6 protein towards iloperidone and / or its metabolites. Identifying other CYP2D6 genotypes that result in reduced enzymatic activity towards iloperidone and / or its metabolites is within the skill of the art.

[0009] Similarly, patients treated with a strong CYP2D6 inhibitor or a CYP3A4 inhibitor are administered a reduced dose (usually half) of iloperidone compared to patients not treated with a strong CYP2D6 inhibitor or a CYP3A4 inhibitor.

[0010] To minimize OH and / or QT prolongation, iloperidone is typically administered twice daily (b.i.d.) and titrated upward from a lower initial dose over several days to reach a therapeutic or effective dose. The FDA-approved titration is 1 mg twice daily (2 mg / day b.i.d.) on Day 1, 2 mg twice daily (4 mg / day b.i.d.) on Day 2, 4 mg twice daily (8 mg / day b.i.d.) on Day 3, 6 mg twice daily (12 mg / day b.i.d.) on Day 4, 8 mg twice daily (16 mg / day b.i.d.) on Day 5, 10 mg twice daily (20 mg / day b.i.d.) on Day 6, and 12 mg twice daily (24 mg / day b.i.d.) on Day 7 and thereafter.

[0011] Post hoc analyses have shown that when patients receiving iloperidone continue treatment after the titration period, the efficacy of iloperidone in treating schizophrenia is comparable to that of haloperidol and risperidone. This highlights the need to titrate iloperidone to the therapeutic level as conveniently as possible.

[0012] Bipolar I disorder

[0013] Bipolar I disorder (bipolar mania) is a manic-depressive illness characterized by the occurrence of at least one manic episode, and may or may not have mixed or psychotic features. Most patients also exhibit one or more depressive episodes, and often have one or more major depressive episodes. Bipolar I disorder may coexist with other disorders such as posttraumatic stress disorder (PTSD), substance use disorder, and mood disorders. Bipolar disorder is estimated to affect 2.8% of the US population.

[0014] The core symptom of bipolar I disorder is sleep disorder. During manic episodes, this typically presents as a reduced need for sleep, with 69% to 99% of patients with bipolar I disorder reporting a reduced need for sleep or difficulty falling asleep and / or staying asleep. Summary of the Invention

[0015] A first aspect of the present invention provides a method for treating a patient suffering from bipolar I disorder, the method comprising: administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to improve at least one symptom of mania in the patient.

[0016] A second aspect of the present invention provides a method for treating a patient suffering from schizophrenia, the method comprising: administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to improve at least one symptom of schizophrenia in the patient, and administering according to the following regimen: 1 mg twice daily on day 1, 3 mg twice daily on day 2, 6 mg twice daily on day 3, 9 mg twice daily on day 4, and 12 mg twice daily on day 5 and every day thereafter; or, 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

[0017] A third aspect of the present invention provides an improvement in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient, comprising: administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, 6 mg twice daily on day 3, 9 mg twice daily on day 4, and 12 mg twice daily on day 5 and every day thereafter.

[0018] A fourth aspect of the present invention provides an improvement in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient, comprising: administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

[0019] A fifth aspect of the present invention provides an improvement in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient known to be a poor CYP2D6 metabolizer, the improvement comprising: administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

[0020] The sixth aspect of the present invention provides an improvement in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient being treated with a strong CYP2D6 inhibitor, comprising: administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

[0021] The seventh aspect of the present invention provides an improvement in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient being treated with a CYP3A4 inhibitor, comprising: administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

[0022] The eighth aspect of the present invention provides a method of administering a therapeutically effective dose of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient, the method comprising: administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

[0023] The ninth aspect of the present invention provides a method of administering a therapeutically effective dose of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient, the method comprising: administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, 6 mg twice daily on day 3, 9 mg twice daily on day 4, and 12 mg twice daily on day 5 and every day thereafter.

[0024] The tenth aspect of the present invention provides a method of treating a patient suffering from bipolar type I disorder, the method comprising: administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to improve one or more symptoms selected from the group consisting of reduced sleep, reduced sleep requirement, and refusal of sleep requirement in bipolar type I disorder.

[0025] A eleventh aspect of the present invention provides a method for treating a patient suffering from bipolar type I disorder, the method comprising: determining or having determined from a biological sample of the patient that the patient's genotype comprises at least one copy of the rs55837573 single nucleotide polymorphism (SNP); and administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to improve at least one symptom of the patient's mania.

[0026] From the following detailed description, these and other aspects, advantages and salient features of the present invention will become apparent. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] These and other features of the present disclosure will be more readily understood from the following detailed description of various aspects of the present disclosure in conjunction with the accompanying drawings, which depict various embodiments of the present disclosure, wherein:

[0028] Figure 1 is a graph of the change in the least squares mean difference (LSMD) of the Young Mania Rating Scale (YMRS) for patients treated with iloperidone and placebo.

[0029] Note that the drawings of the present disclosure are not necessarily drawn to scale. The drawings are intended to depict only typical aspects of the present disclosure and should not be considered as limiting the scope of the present disclosure. In the drawings, the same reference numerals denote the same elements between the drawings. DETAILED DESCRIPTION

[0030] Data from recent studies have demonstrated the efficacy of iloperidone in the treatment of adult bipolar type I disorder and the tolerability of a more rapid iloperidone titration regimen.

[0031] Treatment of Bipolar Type I Disorder

[0032] In a phase III clinical study of iloperidone treatment for acute mania and mixed episodes associated with bipolar type I disorder, approximately 400 volunteers with a history of bipolar disorder and currently suffering from manic episodes were randomly assigned to receive iloperidone or placebo in a 1:1 ratio. The Young Mania Rating Scale (YMRS), as well as the Clinician's Global Impression of Severity (CGI-S) and the Clinician's Global Impression of Change (CGI-C), were used to evaluate treatment efficacy. The Young Mania Rating Scale is a known clinical severity rating scale for the core symptoms of mania.

[0033] YMRS assessments were made at baseline and during days 7, 10, 14, 21, and 28 using the following key:

[0034] 0 = reported no reduction in sleep;

[0035] 1 = Sleep is less than normal by up to one hour;

[0036] 2 = Sleep is more than one hour less than normal;

[0037] 3 = Reported reduced sleep need; and

[0038] 4 = Rejected sleep need.

[0039] Patients received four weeks of double-blind treatment, including administration of iloperidone at 24 mg / d b.i.d (12 mg twice daily), 12 mg / d b.i.d (6 mg twice daily) for poor metabolizers, or placebo. For CYP2D6 non-poor metabolizers, they were titrated to a clinical dose of 24 mg / day (12 mg twice daily) by administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, 6 mg twice daily on day 3, 9 mg twice daily on day 4, and 12 mg twice daily on day 5 and thereafter. For CYP2D6 poor metabolizers, they were titrated to 12 mg / day (6 mg twice daily) by administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and thereafter.

[0040] Table 1 below provides the demographics and baseline characteristics of the study participants.

[0041]

[0042] Patients treated with iloperidone showed greater improvement than those treated with placebo. The YMRS assessment showed that patients treated with iloperidone had a statistically significant benefit as early as the end of week 2. At the end of week 4, the difference was highly statistically significant (p = 0.000008).

[0043] The least-squares mean difference (LSMD) in change from baseline to day 28 was statistically significant for the YMRS sleep component, and iloperidone was favorable relative to placebo (iloperidone = -1.26, placebo = -0.95, p = 0.008). The results are shown in Figure 1 in.

[0044] The assessments of CGI-S and CGI-C also showed statistically significant improvement in patients treated with iloperidone compared to those treated with placebo (p = 0.0005 and 0.0002, respectively).

[0045] Table 2 below shows the changes in the YMRS, CGI-S, and CGI-C scales at endpoint (Day 28) and the total MADRS score relative to baseline. Table 2 below shows the changes in the YMRS, CGI-S, and CGI-C scales at endpoint (Day 28) and the total MADRS score relative to baseline.

[0046]

[0047] Table 3 below shows the frequencies of somnolence and sedation as treatment-emergent adverse events.

[0048]

[0049] The incidence of somnolence and sedation was low in the treatment groups and may not account for the improvement in the YMRS sleep item scores.

[0050] These results suggest that iloperidone at 24 mg / d (or 12 mg / d for CYP2D6 poor metabolizers) is more effective than placebo in improving reduced sleep and reduced need for sleep or refusal of sleep demand, as measured by the sleep component of the YMRS in patients with bipolar I disorder.

[0051] Iloperidone also showed statistically significant improvement in the acute treatment of manic or mixed episodes associated with adult bipolar I disorder, as measured by multiple efficacy-related measures including the total YMRS score, CGI-S, and CGI-C, suggesting that iloperidone treatment of manic symptoms may contribute to improved sleep duration and improved perception of sleep need.

[0052] Genetic variants associated with iloperidone response in BD1 treatment were also observed. In the iloperidone treatment group (n = 167), the variants shown in Table 4 below were associated with statistically significant changes in the YMRS.

[0053] Table 4

[0054]

[0055] The RELN gene encodes an extracellular protein that is crucial for cell localization and neuronal migration. NAV2 is a neuronal navigation gene that may play a role in cell growth and migration. The FAT3 gene encodes an atypical cadherin that is thought to be involved in cell-cell adhesion and act upstream in dendrite development and neuronal migration. The SHROOM3 gene may play a role in regulating cell shape. None of these genes were associated with the YMRS at baseline, indicating that the YMRS changes can be attributed to iloperidone treatment.

[0056] Drug responders were defined as subjects with a greater than 50% reduction in YMRS at the end of the study compared to baseline. RELNSNP rs55837573 was identified as the most significantly associated genetic variant among drug responders.

[0057] Tolerance of rapid iloperidone titration

[0058] A clinical study of adults (n = 12, aged 18 to 65 years, including the endpoints) with schizophrenia or bipolar I disorder was conducted to evaluate the tolerance of a faster iloperidone titration regimen. Patients were assigned to one of two groups based on CYP2D6 phenotype.

[0059] CYP2D6 non-poor metabolizers were titrated to a clinical dose of 24 mg / day (12 mg twice daily) by administering 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, 6 mg twice daily on Day 3, 9 mg twice daily on Day 4, and 12 mg twice daily on Day 5. CYP2D6 poor metabolizers were titrated to 12 mg / day (6 mg twice daily) by administering 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3. In each case, the target dose of 24 mg / day or 12 mg / day was continued until Day 7.

[0060] OH in patients was monitored by measuring blood pressure after 3 minutes of supine and 2 minutes of standing. OH was defined as a systolic blood pressure drop of more than 20 mmHg or a diastolic blood pressure drop of more than 10 mmHg.

[0061] The results were compared with historical placebo data from a prior study of an FDA-approved titration regimen.

[0062] Only one patient receiving iloperidone met the OH criteria. This case had no clinical manifestations. This was in contrast to 26 of 147 patients (17.7%) assigned placebo in the historical study.

[0063] The study results showed no other adverse events. There were no deaths, serious treatment-emergent events, or clinically significant changes in laboratory parameters, ECG findings, or vital signs. And no events of dizziness, syncope, or accidental trauma were reported. Among patients assigned placebo in the historical study, 1.4% (n = 2) exhibited OH and 6.8% (n = 10) reported dizziness.

[0064] These results suggest that faster titration of iloperidone is well tolerated and that the observed rate of OH is similar to historical placebo data. This suggests that it may be possible to reach the therapeutic range of iloperidone (12 - 24 mg / day, administered b.i.d.) one to two days earlier than the FDA-approved dosing regimen while continuously reducing the risk of OH. As mentioned above, in the treatment of schizophrenia, it has been determined that it is necessary to titrate iloperidone to the therapeutic level as conveniently as possible.

[0065] Similarly, the invention described herein allows for the treatment of acute episodes of bipolar disorder with accelerated efficacy while still balancing tolerability, particularly with respect to OH and QT prolongation.

[0066] Although the paragraphs herein relate to the administration of "iloperidone", it should be understood that, according to embodiments of the present invention, iloperidone, an iloperidone metabolite, or a pharmaceutically acceptable salt thereof may be administered to a patient in need of treatment. Iloperidone metabolites include metabolite P88, including its enantiomeric forms, S-P88 and R-P88. The S-P88 and / or R-P88 metabolites of iloperidone are described in International Patent Application Publication Nos. WO2003 / 020707 and WO2013 / 138602 and U.S. Patent Nos. 7,977,356 and 8,314,129, each of which is incorporated herein by reference in its entirety.

[0067] The present invention encompasses the treatment of patients with any disease or disorder improved by the administration of iloperidone. As mentioned above, such diseases or disorders include, for example, schizoaffective disorder including schizophrenia, depression including bipolar depression, and other conditions such as arrhythmia, Tourette syndrome, psychotic disorder, and delusional disorder.

[0068] Those skilled in the art will recognize that iloperidone, an iloperidone metabolite, or a pharmaceutically acceptable salt thereof may be administered in any number of ways. Oral administration is likely to be typical, but other routes include, for example, parenteral, nasal, buccal, transdermal, sublingual, intramuscular, intravenous, rectal, vaginal, etc.

[0069] According to some embodiments of the present invention, iloperidone, an iloperidone metabolite, or a pharmaceutically acceptable salt thereof may be administered in a depot form. Such depot forms are described, for example, in U.S. Patent Nos. 7,767,230, 8,815,293, 8,293,765, 8,227,488, and 8,614,232, each of which is incorporated herein by reference in its entirety. Those skilled in the art will understand that when administered in a depot form, the phrase "daily dose" as used herein refers to the desired or expected dose to which an individual is effectively exposed over the course of a day.

[0070] Although the present invention has been described in connection with the specific embodiments outlined above, it will be apparent that many alternatives, modifications, and variations are obvious to those skilled in the art. Accordingly, the embodiments of the present invention as described above are intended to be illustrative and not restrictive. Various changes may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A method for treating a patient suffering from bipolar I disorder, the method comprising: administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to improve at least one symptom of mania in the patient.

2. The method according to claim 1, wherein, Improvement of at least one symptom of mania is measured using one or more of the Young Mania Rating Scale (YMRS), Clinician's Global Impression - Severity (CGI - S), or Clinician's Global Impression - Change (CGI - C).

3. The method according to claim 1, wherein, The effective amount is from about 8 mg / day to about 24 mg / day.

4. The method according to claim 1, wherein, The effective amount is from about 8 mg / day to about 16 mg / day.

5. The method according to claim 1, wherein, The effective amount is from about 12 mg / day to about 24 mg / day.

6. The method according to claim 1, wherein, The effective amount is administered in divided doses twice daily.

7. The method according to claim 1, wherein The administration includes titrating the daily dose of iloperidone upward until the effective amount.

8. The method according to claim 7, wherein, Titration includes administering 1 mg twice daily on day 1, 2 mg twice daily on day 2, 4 mg twice daily on day 3, 6 mg twice daily on day 4, 8 mg twice daily on day 5, 10 mg twice daily on day 6, and 12 mg twice daily on day 7 and thereafter.

9. The method according to claim 7, wherein Titration includes administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, 6 mg twice daily on day 3, 9 mg twice daily on day 4, and 12 mg twice daily on day 5 and thereafter.

10. The method according to claim 7, wherein Titration includes administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and thereafter.

11. The method according to claim 1, wherein, The method further comprises: determining whether the patient has a CYP2D6 genotype associated with being a CYP2D6 poor metabolizer.

12. The method according to claim 11, wherein, In the case where the patient is determined to have a CYP2D6 genotype associated with being a CYP2D6 poor metabolizer, the effective dose is 12 mg / day, and the administration includes titrating the daily dose of iloperidone upward until the effective amount according to the following regimen: 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and thereafter.

13. The method according to claim 12, wherein The CYP2D6 poor metabolizer genotypes are selected from the group consisting of: AA at CYP2D6 G1846A, AG at CYP2D6 G1846A, TT at CYP2D6 C100T, and CT at CYP2D6 C100T.

14. A method for treating a patient suffering from schizophrenia, the method comprising: administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to improve at least one symptom of schizophrenia in the patient, and the administration is according to the following regimen: 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, 6 mg twice daily on Day 3, 9 mg twice daily on Day 4, and 12 mg twice daily on Day 5 and thereafter; or 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and thereafter.

15. The method according to claim 14, wherein, The method further comprises: determining whether the patient has a CYP2D6 genotype associated with being a CYP2D6 poor metabolizer.

16. The method according to claim 15, wherein, In the case where the patient is determined to have a CYP2D6 genotype associated with being a CYP2D6 poor metabolizer, the regimen is 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and thereafter.

17. The method according to claim 16, wherein The CYP2D6 poor metabolizer genotypes are selected from the group consisting of: AA at CYP2D6 G1846A, AG at CYP2D6 G1846A, TT at CYP2D6 C100T, and CT at CYP2D6 C100T.

18. An improvement, the improvement comprising, in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient: administering 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, 6 mg twice daily on Day 3, 9 mg twice daily on Day 4, and 12 mg twice daily on Day 5 and thereafter.

19. The improvement according to claim 18, wherein, The patient has schizophrenia.

20. The improvement according to claim 18, wherein The patient has bipolar I disorder.

21. An improvement, the improvement comprising, in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient: administering 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and thereafter.

22. The improvement according to claim 21, wherein The patient has schizophrenia.

23. The improvement according to claim 21, wherein, The patient has bipolar I disorder.

24. An improvement, the improvement comprising, in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient known to be a CYP2D6 poor metabolizer: administering 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and thereafter.

25. The improvement according to claim 24, wherein, The patient has schizophrenia.

26. The improvement according to claim 24, wherein, The patient has bipolar I disorder.

27. The improvement according to claim 24, wherein, The patient has a genotype selected from the group consisting of: AA at CYP2D6 G1846A, AG at CYP2D6 G1846A, TT at CYP2D6 C100T, and CT at CYP2D6 C100T.

28. An improvement, the improvement comprising, in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient being treated with a strong CYP2D6 inhibitor: Administer 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and every day thereafter.

29. The improvement according to claim 28, wherein, The patient has schizophrenia.

30. The improvement according to claim 28, wherein, The patient has bipolar type I disorder.

31. An improvement, the improvement comprising, in a method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient being treated with a CYP3A4 inhibitor: Administer 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and every day thereafter.

32. The improvement according to claim 31, wherein, The patient has schizophrenia.

33. The improvement according to claim 31, wherein The patient has bipolar type I disorder.

34. A method of administering a therapeutically effective dose of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient, the method comprising: Administer 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and every day thereafter.

35. The method according to claim 34, wherein, The patient has schizophrenia.

36. The method according to claim 34, wherein, The patient has bipolar type I disorder.

37. The method according to claim 34, wherein, The patient is a poor CYP2D6 metabolizer.

38. The method according to claim 34, wherein The patient has a CYP2D6 genotype selected from the group consisting of AA at CYP2D6 G1846A, AG at CYP2D6 G1846A, TT at CYP2D6 C100T, and CT at CYP2D6 C100T.

39. The method according to claim 34, wherein, The patient is being treated with a strong CYP2D6 inhibitor.

40. The method according to claim 34, wherein, The patient is being treated with a CYP3A4 inhibitor.

41. A method of administering a therapeutically effective dose of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite to a patient, the method comprising: Administer 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, 6 mg twice daily on Day 3, 9 mg twice daily on Day 4, and 12 mg twice daily on Day 5 and every day thereafter.

42. The method according to claim 41, wherein, The patient has schizophrenia.

43. The method according to claim 41, wherein, The patient has bipolar type I disorder.

44. A method of treating a patient with bipolar type I disorder, the method comprising: Administering to the patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of an iloperidone metabolite, wherein the effective amount is an amount effective to improve one or more symptoms of bipolar type I disorder, the symptoms selected from the group consisting of reduced sleep, reduced sleep need, and refusal of sleep need.

45. The method according to claim 44, wherein, Measuring the improvement of the at least one using one or more of the Young Mania Rating Scale (YMRS), Clinician's Global Impression of Severity (CGI-S), or Clinician's Global Impression of Change (CGI-C).

46. The method according to claim 44, wherein, The effective amount is from about 8 mg / day to about 24 mg / day.

47. The method according to claim 44, wherein, The effective amount is from about 8 mg / day to about 16 mg / day.

48. The method according to claim 44, wherein The effective amount is from about 12 mg / day to about 24 mg / day.

49. The method according to claim 44, wherein, The effective amount is administered twice daily in divided doses.

50. The method according to claim 44, wherein, Administration includes titrating the daily dose of risperidone upward to the effective amount.

51. The method according to claim 50, wherein, Titration includes administering 1 mg twice daily on day 1, 2 mg twice daily on day 2, 4 mg twice daily on day 3, 6 mg twice daily on day 4, 8 mg twice daily on day 5, 10 mg twice daily on day 6, and 12 mg twice daily on day 7 and every day thereafter.

52. The method according to claim 50, wherein titration includes administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, 6 mg twice daily on day 3, 9 mg twice daily on day 4, and 12 mg twice daily on day 5 and every day thereafter.

53. The method according to claim 50, wherein titration includes administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

54. The method according to claim 44, wherein, The method further comprises: determining whether the patient has a CYP2D6 genotype associated with being a CYP2D6 poor metabolizer.

55. The method according to claim 54, wherein In the case where the patient is determined to have a CYP2D6 genotype associated with being a CYP2D6 poor metabolizer, the effective dose is 12 mg / day, and administration includes titrating the daily dose of risperidone upward to the effective amount according to the following regimen: 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and every day thereafter.

56. The method according to claim 55, wherein, The CYP2D6 poor metabolizer genotypes are selected from the group consisting of: AA at CYP2D6 G1846A, AG at CYP2D6 G1846A, TT at CYP2D6 C100T, and CT at CYP2D6 C100T.

57. A method of treating a patient having bipolar type I disorder, the method comprising: determining or having determined from a biological sample of the patient that the patient's genotype comprises at least one copy of the rs55837573 single nucleotide polymorphism (SNP); and administering to the patient an effective amount of risperidone, a pharmaceutically acceptable salt of risperidone, an active metabolite of risperidone, or a pharmaceutically acceptable salt of a risperidone metabolite, wherein the effective amount is an amount effective to improve at least one symptom of mania in the patient.

58. The method according to claim 57, wherein, Improvement of at least one symptom of mania is measured using one or more of the Young Mania Rating Scale (YMRS), Clinician's Global Impression - Severity (CGI - S), or Clinician's Global Impression - Change (CGI - C).

59. The method according to claim 57, wherein, The effective amount is from about 8 mg / day to about 24 mg / day.

60. The method according to claim 57, wherein, The effective amount is from about 8 mg / day to about 16 mg / day.

61. The method according to claim 57, wherein, The effective amount is from about 12 mg / day to about 24 mg / day.

62. The method according to claim 57, wherein, The effective amount is administered twice daily in divided doses.

63. The method according to claim 57, wherein Administration includes titrating the daily dose of risperidone upward to the effective amount.

64. The method according to claim 63, wherein, Titration includes administering 1 mg twice daily on Day 1, 2 mg twice daily on Day 2, 4 mg twice daily on Day 3, 6 mg twice daily on Day 4, 8 mg twice daily on Day 5, 10 mg twice daily on Day 6, and 12 mg twice daily on Day 7 and every day thereafter.

65. The method according to claim 63, wherein, Titration includes administering 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, 6 mg twice daily on Day 3, 9 mg twice daily on Day 4, and 12 mg twice daily on Day 5 and every day thereafter.

66. The method according to claim 63, wherein, Titration includes administering 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and every day thereafter.

67. The method according to claim 57, wherein The method further includes: determining whether the patient has a CYP2D6 genotype associated with being a poor metabolizer of CYP2D6.

68. The method according to claim 67, wherein, In the case where the patient is determined to have a CYP2D6 genotype associated with being a poor metabolizer of CYP2D6, the effective dose is 12 mg / day, and administration includes titrating the daily dose of increasing iloperidone to the effective amount according to the following regimen: 1 mg twice daily on Day 1, 3 mg twice daily on Day 2, and 6 mg twice daily on Day 3 and every day thereafter.

69. The method according to claim 68, wherein, The CYP2D6 poor metabolizer genotypes are selected from the group consisting of: AA at CYP2D6 G1846A, AG at CYP2D6 G1846A, TT at CYP2D6 C100T, and CT at CYP2D6 C100T.

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