Intravenous Ketamine in the Treatment of Obsessive-Compulsive Disorder

Phase 1

Terminated

Brief Summary: Obsessive-Compulsive Disorder (OCD) is a chronic and disabling anxiety disorder and a leading cause of worldwide disability that presents a significant public health problem. Treatment options are limited and many OCD patients fail to respond completely or quickly to standard treatments, including pharmacotherapy and psychotherapy. At this time, patients who fail to respond to treatment with serotonergic drugs, augmenting antipsychotic agents, and behavioral therapy, have few additional treatment options aside from deep brain stimulation. Therefore, despite advances in current pharmacological and behavioral treatments, and the utility of serotonergic drugs, it is likely that other neurotransmitter systems are involved and that targeting these systems may increase treatment efficacy. Despite little evidence for serotonergic dysfunction in OCD, there is significant evidence that glutamatergic dysregulation may contribute to the development and progression of the disorder. Also, preliminary studies suggest that glutamatergic modulators (i.e. riluzole and d-cycloserine), particularly agents acting at the NMDA receptor (i.e. memantine), may be useful in OCD. The NMDA antagonist, ketamine, has demonstrated rapid effects when delivered as a single intravenous (IV) dose in depressed patients. Therefore, the objective of the current study is to investigate the safety and efficacy of a single dose of IV ketamine in treatment-resistant OCD.

Detailed Description: This study will test the safety and efficacy of a single intravenous (IV) dose of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, in treatment-resistant OCD.

Recruitment & Eligibility

Inclusion Criteria

Male or female patients, 21-65 years
Women of childbearing potential must agree to use a medically accepted means of contraception for the duration of the study
Primary diagnosis of Obsessive-Compulsive Disorder as assessed by the SCID-P, with symptoms for at least 1 year (Patients who meet criteria for OCD will be required to be medication free or have all psychotropics aside from SSRIs and as needed benzodiazepines tapered. Prior to study entry, proscribed psychotropics are tapered, and subjects must be on the same SSRI for at least 8 weeks with no change in dose for at least 4 weeks and throughout the study. However, subjects will be allowed to use benzodiazepines as needed throughout the study.)
History of a failure to respond to at least two (2) adequate pharmacotherapy trials and CBT for OCD
Subjects must have scored ≥ 21 on the Y-BOCS at Screening, and to not be in remission on Treatment Day #1, and Treatment Day #2
Each subject must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document
Subjects must be able to identify a family member, physician, or friend who will participate in the Treatment Contract and serve as an emergency contact.

Exclusion Criteria

Women who plan to become pregnant within the next six months, are pregnant or are breast-feeding
Non-English speakers
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, bipolar disorder, mental retardation, or pervasive developmental disorders
Current evidence of psychotic or manic symptoms
Drug or alcohol abuse or dependence within the preceding 6 months
Lifetime abuse or dependence on ketamine or phencyclidine
Patients judged by study investigator to be at high risk for suicide
Current use of psychotropics other than SSRIs

Arm && Interventions

Group	Intervention	Description
Ketamine	Ketamine	Study participants will receive a one-time intravenous infusion of 0.5 mg/kg racemic ketamine hydrochloride
Midazolam	Midazolam	Study participants will receive a one-time intravenous infusion of 0.045 mg/kg midazolam

Primary Outcome Measures

Name	Time	Method
Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCCS) Rating OCD Symptom Severity From Baseline to 24-hours After Ketamine Administration	Baseline and 24 Hours	The primary efficacy outcome is change in the Y-BOCCS rating score on a scale from baseline to 24 hrs post-administration of ketamine. The 10 Y-BOCCS items are each scored on a four-point scale from 0 = "no symptoms" to 4 = "extreme symptoms." The sum of the first five items is a severity index for obsessions. The sum of the last five an index for compulsions. A translation of total score into an approximate index of overall severity is: 0-7 - subclinical; 8-15 - mild; 16-23 - moderate; 24-31 - severe; 32-40 - extreme.

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients Who Meet Response and Remission	up to 14 days	Percentage of patients who meet response (defined as 25% reduction in Y-BOCCS score) and remission (defined as Y-BOCS score ≤10) criteria at 24 hrs post-infusion and durability of efficacy up to two weeks after administration. Assessments will be performed 24, 48 and 72 hrs post-infusion and after 7, 10, and 14 days.