Iloperidone in Mixed States of Bipolar Disorder

Open Label Study of Iloperidone (IL) as Adjunctive Treatment in Mixed States (MS) of Bipolar Disorder (BD)

1. To assess the acute and long-term bimodal efficacy of iloperidone (IL), as an adjunct to ongoing treatment with lithium (Li) or divalproex (DIV) or lamotrigine (LAM) or any combination of the three thereof, in a group of patients with an index episode of a mixed state in BD.
2. To assess background, baseline features, and behavioral components which characterize treatment response/non-response in the acute and long term management of MS

This is a prospective 20-week, open-label study of iloperidone added to ongoing treatment regimen with mood stabilizers (Li or DIV or LAM or any combination of these) in the acute and maintenance treatment of MS- Total number of subjects: 40.

Severity of the illness and psychopathological features will be measured by the following rating scales: YMRS, MADRS, CGI-S and GAS, and the BISS .

The study will monitor the safety and tolerability of the combination iloperidone plus mood stabilizers.

Efficacy Measures: Primary efficacy measures include 1) Mixed effects repeat measure of change from baseline in BISS total score and, secondarily, manic and depression subscale scores.

Secondary Efficacy Measures: 1) response defined as 50% reduction in YMRS and MADRS and 2) Time to intervention or discontinuation for any mood episode.

Iloperidone will be initiated at 2 mg at hs on day 1 with increase to 4mg at hs on day 2, 8 mg at hs on day 3. All patients will have iloperidone titrated to receive a dosage of at least 12 mg a day. Dosages can be titrated up to 24 mg a day based on tolerability and clinical indication. Dosage of iloperidone can be reduced to 6 mg a day if patients develop side effects necessitating a reduction in the dosage

Inclusion Criteria:

1. Male or female;

2. Age 18 years and older

3. Patients on:

   • Li at a stable dose for 2 weeks or longer, and a serum level at screening of greater than or equal to 0.5 mEq/l OR
   • DIV dose for 2 weeks or longer, and a serum level at screening of greater than or equal to 45 ug/ml OR
   • LAM (dosage/day ≥100mg) at a stable dose for 2 weeks or longer OR
   • Any combination 3a, 3b, or 3c

4. Patients meeting DSM-IV TR diagnosis of bipolar disorder, I or II, as assessed using the MINI, (Sheehan et al., 1998) PLUS any ONE of criteria 5 or 6 or 7

5. Patients meeting DSM-IV TR diagnostic criteria for a mixed manic episode with Young Mania Rating Scale (YMRS) score>/=14 and Montgomery Asberg Depression Rating Scale (MADRS) score>/=14

6. Patients meeting the criteria for a manic/hypomanic episode for at least 2 days with the simultaneous presence of Young Mania Rating Scale (YMRS) score>/=14 PLUS Montgomery Asberg Depression Rating Scale (MADRS) score>/=14 ;

7. Patients meeting DSM-IV TR diagnostic criteria for a major depressive episode with the simultaneous presence of MADRS score>/=14 PLUS meeting the criteria for a manic/hypomanic episode for at least 2 days with the simultaneous presence of Young Mania Rating Scale (YMRS) score>/=14

Exclusion Criteria:

1. Patients with a current Axis I diagnosis of schizophrenia, schizophreniform disorder, schizotypal disorder, bipolar disorder with psychotic sub-type that requires hospitalization, drug induced mania or AIDS induced mania
2. Women with a positive pregnancy test or who are lactating
3. Women of child-bearing potential who are not practicing a clinically accepted method of contraception
4. Patients with general medical conditions that contraindicate psychoactive medications or uncontrolled medical disorder or central nervous system diseases.
5. Patients whose clinical status requires inpatient or day hospital treatment
6. History of severe side effects associated with therapeutic doses of Li, DIV, LAM
7. Alcohol or drug dependent at time of enrollment
8. Suicidal at time of enrollment.
9. Current or previous exposure to iloperidone
10. Patients taking medication that cause QTC prolongation
11. Patients with serious cardiac disease