Treatment Study of Bipolar Depression

Phase 4

Terminated

Brief Summary: The purpose of this study is to determine whether a single intravenous administration of an N-methyl-D-aspartate antagonist is safe and effective for the acute treatment of bipolar depression.

Detailed Description: Bipolar disorder (BPD) is a common, recurrent, and disabling medical condition. Although mania is the defining feature of BPD, depression represents the majority of illness burden in patients with this devastating condition. Despite the high degree of morbidity and mortality associated with bipolar depression, currently available treatments are few and often inadequate. Recently, a single intravenous (IV) dose of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in severe unipolar depression. Therefore, the objective of the current study is to investigate the safety and efficacy of a single IV dose of ketamine in treatment-resistant bipolar depression (TRBD).

Recruitment & Eligibility

Inclusion Criteria

Male or female patients, 21-70 years;
Primary diagnosis of bipolar I or II disorder as assessed by the SCID-P and confirmed by a study psychiatrist;
Current depressive episode ≥ 8 weeks duration;
History of a failure to respond to at least three (3) adequate pharmacotherapy trials in the current depressive episode (see above for definition for adequate trials);
Subjects must be on a stable dose of divalproex ER with serum levels greater than 55 mcg/ml prior to enrollment;
Subjects must be free of psychotropic medication for at least 2 weeks (4 weeks for fluoxetine) prior to enrollment (with the exception of divalproex ER as above);
Subjects must have scored ≥ 32 on the IDS-C30 at both Screening and Infusion Day #1 and #2;

Exclusion Criteria

Women who plan to become pregnant, are pregnant or are breast-feeding;
Any unstable medical illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease;
Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG;
Lifetime history of schizophrenia, schizoaffective disorder, OCD, mental retardation, pervasive developmental disorders, or Tourette's syndrome;
Current presence of psychotic, mixed or manic symptoms;
Lifetime history of antidepressant-induced switch to a manic episode;
History of rapid cycling bipolar subtype;
Drug or alcohol abuse within the preceding 3 months or dependence within the preceding 5 years;
Lifetime exposure to ketamine or phencyclidine;
Patients judged by study investigator to be at high risk for suicide.

Arm && Interventions

Group	Intervention	Description
Ketamine/Midazolam	ketamine	Patients receive both treatment conditions (ketamine and midazolam) in a single arm, crossover design. Patients are randomized to ketamine-midazolam. Each treatment occurs as a single intravenous infusion on one treatment day. The two treatment conditions occur 2 weeks apart.
Ketamine/Midazolam	midazolam	Patients receive both treatment conditions (ketamine and midazolam) in a single arm, crossover design. Patients are randomized to ketamine-midazolam. Each treatment occurs as a single intravenous infusion on one treatment day. The two treatment conditions occur 2 weeks apart.
Midazolam/Ketamine	ketamine	Patients receive both treatment conditions (ketamine and midazolam) in a single arm, crossover design. Patients are randomized to midazolam-ketamine. Each treatment occurs as a single intravenous infusion on one treatment day. The two treatment conditions occur 2 weeks apart.
Midazolam/Ketamine	midazolam	Patients receive both treatment conditions (ketamine and midazolam) in a single arm, crossover design. Patients are randomized to midazolam-ketamine. Each treatment occurs as a single intravenous infusion on one treatment day. The two treatment conditions occur 2 weeks apart.

Primary Outcome Measures

Name	Time	Method
Montgomery-Asberg Depression Rating Scale (MADRS)	24 hrs post-infusion compared to baseline

Secondary Outcome Measures

Name	Time	Method
Quick Inventory of Depressive Symptomatology, Self Report (QIDS-SR)	24 hrs post-infusion compared to baseline
Young Mania Rating Scale (YMRS)	24 hrs post-infusion compared to baseline
Brief Psychiatric Rating Scale (BPRS)	4 hrs post-infusion compared to baseline
Clinician-Administered Dissociative States Scale (CADSS)	4 hrs post-infusion compared to baseline
Systematic Assessment for Treatment Emergent Effects (SAFTEE)	4 hrs post-infusion compared to baseline