Treatment Study of Bipolar Depression

Study Overview
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Brief Summary
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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
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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).

Official Title
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Intravenous Ketamine in Treatment-Resistant Bipolar Depression

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: ketamine
* Drug: midazolam


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine/Midazolam<br>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. | Drug: ketamine<br>* a single IV infusion of ketamine, IV 0.5 mg/kg<br>Drug: midazolam<br>* a single IV infusion of midazolam, 0.045 mg/kg<br>|
| Experimental: Midazolam/Ketamine<br>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. | Drug: ketamine<br>* a single IV infusion of ketamine, IV 0.5 mg/kg<br>Drug: midazolam<br>* a single IV infusion of midazolam, 0.045 mg/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale (MADRS) |  | 24 hrs post-infusion compared to baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar Disorder, Depression, Treatment-Resistant, ketamine, antidepressant, glutamate