Dosage regimens of iloperidone for the treatment of bipolar I disorder and schizophrenia

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to pending U.S. Provisional Patent Application No. 63 / 476,161, filed December 19, 2022, and pending U.S. Provisional Patent Application No. 63 / 470,574, filed June 2, 2023, which are incorporated herein by reference as if fully set forth herein. [Background technology]

[0002] Iloperidone Iloperidone (FANAPT®) (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone) is a mixed D2 antagonist, 5-HT 2A antagonist and alpha1-adrenergic antagonist, and is an atypical antipsychotic approved by the FDA for the treatment of schizophrenia in adults.

[0003] The cytochrome P450 2D6 gene (CYP2D6), located on chromosome 22, encodes debrisoquine hydroxylase, a phase I drug-metabolizing enzyme. Many drugs, including iloperidone, are known to be metabolized by debrisoquine hydroxylase. Mutations in the CYP2D6 gene have been associated with several drug metabolism-related phenotypes. These include ultra-rapid metabolizers (UMs), normal metabolizers (EMs), and urinary tract infections. These include extensive metabolizers, intermediate metabolizers (IM), and poor metabolizers (PM).

[0004] If a particular drug may cause undesirable physiological effects in either the metabolized or non-metabolized form, it is advisable to determine whether the patient is receiving the inactive form of the drug prior to administration. Undesirable physiological effects associated with elevated concentrations of iloperidone or its metabolites include prolongation of the electrocardiogram QT interval and induction of orthostatic hypotension (OH).

[0005] Methods of administering iloperidone based on a patient's CYP2D6 genotype are described, for example, in U.S. Patent No. 10,272,076, which is incorporated herein by reference in its entirety. Generally, patients known to be CYP2D6 inactive are administered a lower dose (typically half the dose) of iloperidone compared to patients known not to be CYP2D6 inactive.

[0006] Known inactive genotypes described in the '076 patent include, for example, the CYP2D6G1846A AA and AG genotypes and the CYP2D6C100T TT and CT genotypes. While the CYP2D6G1846A (AA or AG) genotype and the CYP2D6C100T (CT or TT) genotype are specifically described in the patent, the methods of the present invention can also utilize other genotypes that result in reduced activity of the CYP2D6 protein toward iloperidone and / or its metabolites. Identifying additional CYP2D6 genotypes that result in reduced enzyme activity toward iloperidone and / or its metabolites is within the ability of one of ordinary skill in the art.

[0007] Similarly, patients receiving strong CYP2D6 or CYP3A4 inhibitors are given a lower dose (typically half the dose) of iloperidone compared to patients not receiving strong CYP2D6 or CYP3A4 inhibitors.

[0008] To minimize OH and / or QT prolongation, iloperidone is typically administered twice daily (bid) and titrated from a low initial dose over several days to reach a therapeutic or effective dose. The FDA-approved titration regimen is 1 mg twice daily on day 1 (2 mg bid), 2 mg twice daily on day 2 (4 mg bid), 4 mg twice daily on day 3 (8 mg bid), 6 mg twice daily on day 4 (12 mg bid), 8 mg twice daily on day 5 (16 mg bid), 10 mg twice daily on day 6 (20 mg total daily), and 12 mg twice daily on day 7 and each day thereafter (24 mg total daily).

[0009] Post-hoc analyses showed that when iloperidone was continued after the titration period, its efficacy in treating schizophrenia was comparable to that of haloperidol and risperidone, emphasizing the need to titrate iloperidone to therapeutic levels as rapidly as possible.

[0010] Bipolar I disorder Bipolar I disorder (bipolar mania) is a manic-depressive illness characterized by the occurrence of at least one manic episode, with or without mixed or psychotic features. Most patients also experience one or more depressive episodes and often have a history of one or more major depressive episodes. Bipolar I disorder may also be comorbid with other disorders, such as post-traumatic stress disorder (PTSD), substance use disorders, and mood disorders. Bipolar disorder is estimated to affect approximately 2.8% of the U.S. population.

[0011] A major symptom of bipolar I disorder is sleep disturbance. During manic episodes, this often manifests as a decreased need for sleep, with 69-99% of individuals with bipolar I disorder reporting decreased sleep desire or difficulty falling asleep and / or staying asleep. Summary of the Invention

[0012] A first aspect of the present invention provides a method of treating a patient suffering from bipolar I disorder, 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 a metabolite of iloperidone, wherein the effective amount is effective to ameliorate at least one manic symptom in the patient.

[0013] A second aspect of the present invention provides a method of treating a patient suffering from schizophrenia, 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 a metabolite of iloperidone, wherein the effective amount is effective to ameliorate at least one symptom of schizophrenia in the patient, and is administered according to a regimen of 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 each 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 each day thereafter.

[0014] A third aspect of the invention provides an improvement in a method of administering to a patient iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone, 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 each day thereafter.

[0015] A fourth aspect of the 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 a metabolite of iloperidone 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 each day thereafter.

[0016] 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 a metabolite of iloperidone to a patient known to have an inactive CYP2D6 form, 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 each day thereafter.

[0017] A 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 a metabolite of iloperidone to a patient receiving treatment 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 each day thereafter.

[0018] A seventh aspect of the 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 a metabolite of iloperidone to a patient receiving treatment 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 each day thereafter.

[0019] An eighth aspect of the present invention provides a method of administering to a patient a therapeutically effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone, 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 each day thereafter.

[0020] A ninth aspect of the invention provides a method of administering to a patient a therapeutically effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone, 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 each day thereafter.

[0021] A tenth aspect of the present invention provides a method of treating a patient suffering from bipolar I disorder, 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 a metabolite of iloperidone, wherein the effective amount is effective to ameliorate one or more symptoms of bipolar I disorder selected from the group consisting of decreased sleep, decreased need for sleep, and denial of a need for sleep.

[0022] An eleventh aspect of the present invention provides a method of treating a patient suffering from bipolar I disorder, comprising determining or having determined from a biological sample from 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 a metabolite of iloperidone, wherein the effective amount is effective to ameliorate at least one manic symptom in the patient.

[0023] These and other aspects, advantages and distinguishing features of the present invention will become apparent from the following detailed description. [Brief explanation of the drawings]

[0024] These and other features of the present disclosure will be more readily understood from the following detailed description of the various aspects of the disclosure, taken in conjunction with the accompanying drawings which illustrate various embodiments of the disclosure. [Figure 1] Figure 1 is a plot showing the least squares mean difference (LSMD) of change in the Young Mania Rating Scale (YMRS) in patients receiving iloperidone and patients receiving placebo. It should be noted that the drawings in this disclosure are not necessarily to scale. The drawings are intended to depict only exemplary embodiments of the disclosure and should not be construed as limiting the scope of the disclosure. In the drawings, like numbers represent like elements between drawings. DETAILED DESCRIPTION OF THE INVENTION

[0025] Recent data indicate that iloperidone is effective in treating bipolar I disorder in adults and that more rapid iloperidone titration regimens are well tolerated.

[0026] Treatment of bipolar I disorder In a Phase 3 clinical trial of iloperidone for the treatment of acute manic and acute mixed episodes associated with bipolar I disorder, approximately 400 volunteers with a history of bipolar disorder and a current manic episode will be randomly assigned in a 1:1 ratio to receive either iloperidone or placebo. Treatment efficacy will be assessed using the Young Mania Rating Scale (YMRS), a well-known rating scale of the clinical severity of the core symptoms of mania, as well as the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Change (CGI-C).

[0027] YMRS assessments will be performed at baseline and on days 7, 10, 14, 21, and 28 using the following criteria: 0 = no reported sleep loss; 1 = Sleeping up to 1 hour less than usual. 2 = Sleeping more than 1 hour less than usual. 3 = Reports decreased need for sleep. 4 = Denies need for sleep.

[0028] Patients will receive 4 weeks of double-blind treatment with iloperidone 24 mg / day (12 mg twice daily), 12 mg / day (6 mg twice daily) for CYP2D6-inactive patients, or placebo. Patients with non-CYP2D6-inactive patients will be titrated up to the 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 each day thereafter. Patients with CYP2D6-inactive patients will be titrated up to the clinical dose of 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 each day thereafter.

[0029] Table 1 below presents the demographic and baseline characteristics of the study participants.

[0030] [Table 1]

[0031] Patients receiving iloperidone showed greater improvement than those receiving placebo. YMRS assessment showed a statistically significant effect in iloperidone-treated patients already at the end of week 2. At the end of week 4, the difference was highly statistically significant (p=0.000008).

[0032] The least squares mean difference (LSMD) of the change from baseline to day 28 was statistically significant for iloperidone versus placebo in the YMRS sleep component (iloperidone = -1.26, placebo = -0.95, p = 0.008). The results are shown in Figure 1.

[0033] Patients receiving iloperidone also demonstrated statistically significant improvements compared to placebo-treated patients as assessed by the CGI-S and CGI-C (p=0.0005 and 0.0002, respectively).

[0034] Table 2 below shows the change from baseline in the YMRS, CGI-S, and CGI-C scales, and the MADRS total score at endpoint (day 28).

[0035] [Table 2]

[0036] Table 3 below shows the frequency of somnolence and sedation as treatment-emergent adverse events.

[0037] [Table 3]

[0038] The incidence of drowsiness and sedation was low in both treatment groups and is unlikely to explain the improvement in YMRS sleep item scores.

[0039] These results indicate that 24 mg / day (12 mg / day for CYP2D6 inactive individuals) of iloperidone is more effective than placebo in improving sleep reduction and sleep need reduction or sleep need denial as measured by the YMRS sleep component in patients with bipolar I disorder.

[0040] Iloperidone also demonstrated statistically significant improvements in the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults as measured by multiple efficacy-related measures, including the YMRS total score, CGI-S, and CGI-C, suggesting that iloperidone treatment for manic symptoms may contribute to improvements in sleep duration and perception of sleep need.

[0041] Genetic variants associated with iloperidone response in the treatment of bipolar I disorder (BD1) were also observed. Within the iloperidone-treated group (n=167), the variants shown in Table 4 below were associated with statistically significant changes in the YMRS.

[0042] [Table 4]

[0043] The RELN gene encodes an extracellular protein important for cell positioning and neuronal migration. NAV2 is a neuronal navigator gene that may play a role in cell growth and migration. The FAT3 gene encodes an atypical cadherin that is involved in cell-cell adhesion and is thought to act upstream of dendritic development and neuronal migration. The SHROOM3 gene may play a role in regulating cell shape. These genes were not associated with baseline YMRS, suggesting that changes in YMRS may be attributable to iloperidone treatment.

[0044] Drug responders were defined as subjects who achieved a 50% or greater reduction in YMRS from baseline at the end of the study. The RELN SNP rs55837573 was identified as the most significantly associated genetic variant among drug responders.

[0045] Tolerability of more rapid iloperidone titration A clinical trial will be conducted in adults with schizophrenia or bipolar I disorder (n=12, ages 18-65 years, inclusive) to evaluate the tolerability of a more rapid iloperidone titration schedule. Patients will be assigned to one of two cohorts based on their CYP2D6 phenotype.

[0046] In patients with non-active CYP2D6, the clinical dose will be titrated up to 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. In patients with inactive CYP2D6, the clinical dose will be titrated up 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 both cases, the target dose of 24 mg / day or 12 mg / day will be continued until day 7.

[0047] Patients will be monitored for OH by measuring blood pressure after 3 minutes of supine rest and 2 minutes of standing. OH is defined as a decrease in systolic blood pressure of ≥ 20 mmHg or a decrease in diastolic blood pressure of ≥ 10 mmHg.

[0048] Results will be compared with historical placebo data from a previous trial of the FDA-approved titration regimen.

[0049] Only one patient receiving iloperidone met the criteria for OH, and this single event was without clinical symptoms. This compares with 26 of 147 (17.7%) placebo-assigned patients in previous trials.

[0050] No other adverse events were observed during the study. There were no deaths, serious treatment-related events, or clinically significant changes in laboratory values, electrocardiograms, or vital signs. There were also no reports of dizziness, syncope, or accidental trauma. Among patients assigned to placebo in previous studies, 1.4% (n=2) experienced OH and 6.8% (n=10) reported dizziness.

[0051] These results suggest that more rapid iloperidone titration is well tolerated, with observed rates of OH comparable to historical placebo data. This suggests that it may be possible to reach the therapeutic range of iloperidone (12-24 mg / day twice daily) one to two days earlier than the FDA-approved dosing regimen while still reducing the risk of OH. As discussed above, the need to titrate iloperidone to therapeutic levels as rapidly as possible has been identified in the treatment of schizophrenia.

[0052] Similarly, the invention described herein allows for the treatment of acute episodes of bipolar I disorder with accelerated efficacy while maintaining a balance of tolerability, particularly with regard to OH and QT prolongation.

[0053] Although the description herein refers to the administration of "iloperidone," it is understood that, according to embodiments of the present invention, a patient in need of treatment may be administered iloperidone, an iloperidone metabolite, or a pharmaceutically acceptable salt thereof. Metabolites of iloperidone include the metabolite P88, which includes the enantiomeric forms S-P88 and R-P88. The S-P88 and / or R-P88 metabolites of iloperidone are described in WO 2003 / 020707 and WO 2013 / 138602, as well as U.S. Pat. Nos. 7,977,356 and 8,314,129, which are incorporated by reference as if fully set forth herein.

[0054] The present invention encompasses the treatment of patients for any disease or condition that is ameliorated by the administration of iloperidone, including, as noted above, schizoaffective disorders, including schizophrenia, depression, including bipolar depression, and other conditions such as cardiac arrhythmias, Tourette's syndrome, psychotic disorders, and delusional disorders.

[0055] Iloperidone, a metabolite of iloperidone, or a pharmaceutically acceptable salt thereof can be administered in any of a variety of ways, as will be appreciated by those skilled in the art. Oral administration may be typical, but other routes of administration include, for example, parenteral, nasal, buccal, transdermal, sublingual, intramuscular, intravenous, rectal, vaginal, etc.

[0056] In some embodiments of the present invention, iloperidone, iloperidone metabolites, or pharmaceutically acceptable salts thereof may be administered in the form of a depot. Such depots 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, which are incorporated by reference as if fully set forth herein. Those skilled in the art will understand that when administered in depot form, the term "daily dose" as used herein refers to the expected or intended dose that an individual will be exposed to in a single day.

[0057] While the present invention has been described in conjunction with the specific embodiments outlined above, it will be apparent that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the above-described embodiments of the invention are intended to be illustrative, and not limiting. Various changes may be made without departing from the spirit and scope of the invention, as defined in the following claims.

Claims

1. administering to a patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone; The effective amount is an amount effective to improve at least one manic symptom in a patient. A method of treating a patient suffering from bipolar I disorder.

2. 10. The method of claim 1, wherein the improvement in at least one manic symptom is measured using one or more of the Young Mania Rating Scale (YMRS), Clinical Global Impression - Severity (CGI-S), and Clinical Global Impression - Change (CGI-C).

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

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

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

6. 10. The method of claim 1, wherein the effective amount is administered twice daily.

7. 10. The method of claim 1, wherein said administering comprises titrating the daily dose of iloperidone to said effective amount.

8. 8. The method of claim 7, wherein the titrating comprises 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 each day thereafter.

9. 8. The method of claim 7, wherein the titrating comprises 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 each day thereafter.

10. 8. The method of claim 7, wherein the titrating comprises administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and each day thereafter.

11. 10. The method of claim 1, further comprising determining whether the patient has a CYP2D6 genotype associated with being a CYP2D6 poor metabolizer.

12. 12. The method of claim 11, wherein if the patient is determined to have a CYP2D6 genotype associated with an inactive CYP2D6 form, the effective amount is 12 mg / day, and the administration comprises titrating the daily dose of iloperidone to the effective amount according to a regimen of 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and each day thereafter.

13. 13. The method of claim 12, wherein the CYP2D6 inactive genotype is selected from the group consisting of AA in CYP2D6G1846A, AG in CYP2D6G1846A, TT in CYP2D6C100T, and CT in CYP2D6C100T.

14. administering to a patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone; the effective amount is an amount effective to ameliorate at least one symptom of schizophrenia in the patient; 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 each day thereafter; or Administered 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 each day thereafter; A method of treating a patient suffering from schizophrenia.

15. 15. The method of claim 14, further comprising determining whether the patient has a CYP2D6 genotype associated with an inactive CYP2D6 form.

16. 16. The method of claim 15, wherein if the patient is determined to have a CYP2D6 genotype associated with being CYP2D6 inactive, 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 each day thereafter.

17. 17. The method of claim 16, wherein the CYP2D6 inactive genotype is selected from the group consisting of AA in CYP2D6G1846A, AG in CYP2D6G1846A, TT in CYP2D6C100T, and CT in CYP2D6C100T.

18. 1. A method of administering to a patient iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone, comprising: said improvement 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 each day thereafter.

19. 19. The improvement of claim 18, wherein the patient is suffering from schizophrenia.

20. 19. The improvement of claim 18, wherein the patient is suffering from bipolar I disorder.

21. 1. A method of administering to a patient iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone, comprising: said 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 each day thereafter.

22. 22. The improvement of claim 21, wherein the patient is suffering from schizophrenia.

23. 22. The improvement of claim 21, wherein the patient is suffering from bipolar I disorder.

24. A method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone to a patient known to have an inactive CYP2D6 form, comprising: said 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 each day thereafter.

25. 25. The improvement of claim 24, wherein the patient is suffering from schizophrenia.

26. 25. The improvement of claim 24, wherein the patient is suffering from bipolar I disorder.

27. 25. The improvement of claim 24, wherein the patient's genotype is selected from the group consisting of AA for CYP2D6G1846A, AG for CYP2D6G1846A, TT for CYP2D6C100T, and CT for CYP2D6C100T.

28. A method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone to a patient receiving treatment with a strong CYP2D6 inhibitor, comprising: said 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 each day thereafter.

29. 29. The improvement of claim 28, wherein the patient is suffering from schizophrenia.

30. 29. The improvement of claim 28, wherein the patient is suffering from bipolar I disorder.

31. A method of administering iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone to a patient receiving treatment with a CYP3A4 inhibitor, comprising: said 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 each day thereafter.

32. 32. The improvement of claim 31 , wherein the patient is suffering from schizophrenia.

33. 32. The improvement of claim 31 , wherein the patient is suffering from bipolar I disorder.

34. 1. A method of administering to a patient a therapeutically effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone, comprising: A 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 each day thereafter.

35. 35. The method of claim 34, wherein the patient is suffering from schizophrenia.

36. 35. The method of claim 34, wherein the patient is suffering from bipolar I disorder.

37. 35. The method of claim 34, wherein the patient is CYP2D6 inactive.

38. 35. The method of claim 34, wherein the patient has a CYP2D6 genotype selected from the group consisting of AA at CYP2D6G1846A, AG at CYP2D6G1846A, TT at CYP2D6C100T, and CT at CYP2D6C100T.

39. 35. The method of claim 34, wherein the patient is undergoing treatment with a potent CYP2D6 inhibitor.

40. 35. The method of claim 34, wherein the patient is undergoing treatment with a CYP3A4 inhibitor.

41. 1. A method of administering to a patient a therapeutically effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone, comprising: 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 each day thereafter.

42. 42. The method of claim 41, wherein the patient is suffering from schizophrenia.

43. 42. The method of claim 41, wherein the patient is suffering from bipolar I disorder.

44. administering to a patient an effective amount of iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, or a pharmaceutically acceptable salt of a metabolite of iloperidone; The effective amount is an amount effective to improve one or more symptoms of bipolar I disorder selected from the group consisting of decreased sleep, decreased need for sleep, and denial of the need for sleep. A method of treating a patient suffering from bipolar I disorder.

45. 45. The method of claim 44, wherein the at least one improvement is measured using one or more of the Young Mania Rating Scale (YMRS), Clinical Global Impression - Severity (CGI-S), and Clinical Global Impression - Change (CGI-C).

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

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

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

49. 45. The method of claim 44, wherein the effective amount is administered twice daily.

50. 45. The method of claim 44, wherein said administering comprises titrating the daily dose of iloperidone to said effective amount.

51. 51. The method of claim 50, wherein the titrating comprises 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 each day thereafter.

52. 51. The method of claim 50, wherein the titrating comprises 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 each day thereafter.

53. 51. The method of claim 50, wherein the titrating comprises administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and each day thereafter.

54. 45. The method of claim 44, further comprising determining whether the patient has a CYP2D6 genotype associated with an inactive CYP2D6 form.

55. 55. The method of claim 54, wherein if the patient is determined to have a CYP2D6 genotype associated with being CYP2D6 inactive, the effective amount is 12 mg / day and the administration comprises titrating the daily dose of iloperidone to the effective amount according to a regimen of 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and each day thereafter.

56. 56. The method of claim 55, wherein the CYP2D6 inactive genotype is selected from the group consisting of AA in CYP2D6G1846A, AG in CYP2D6G1846A, TT in CYP2D6C100T, and CT in CYP2D6C100T.

57. 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); 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 a metabolite of iloperidone; The effective amount is an amount effective to improve at least one manic symptom in a patient. A method of treating a patient suffering from bipolar I disorder.

58. 58. The method of claim 57, wherein the improvement in at least one manic symptom is measured using one or more of the Young Mania Rating Scale (YMRS), Clinical Global Impression - Severity (CGI-S), and Clinical Global Impression - Change (CGI-C).

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

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

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

62. 58. The method of claim 57, wherein the effective amount is administered twice daily.

63. 58. The method of claim 57, wherein said administering comprises titrating the daily dose of iloperidone to said effective amount.

64. 64. The method of claim 63, wherein the titrating comprises 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 each day thereafter.

65. 64. The method of claim 63, wherein the titrating comprises 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 each day thereafter.

66. 64. The method of claim 63, wherein the titrating comprises administering 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and each day thereafter.

67. 58. The method of claim 57, further comprising determining whether the patient has a CYP2D6 genotype associated with an inactive CYP2D6 form.

68. 68. The method of claim 67, wherein if the patient is determined to have a CYP2D6 genotype associated with an inactive CYP2D6 form, the effective amount is 12 mg / day and the administration comprises gradually increasing the daily dose of iloperidone to the effective amount according to a regimen of 1 mg twice daily on day 1, 3 mg twice daily on day 2, and 6 mg twice daily on day 3 and each day thereafter.

69. 69. The method of claim 68, wherein the CYP2D6 inactive genotype is selected from the group consisting of AA in CYP2D6G1846A, AG in CYP2D6G1846A, TT in CYP2D6C100T, and CT in CYP2D6C100T.

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