Ketamine Infusion for Obsessive-Compulsive Disorder

• ClinicalTrials.gov Identifier: NCT01349231
• Recruitment Status: Completed
• First Posted: May 6, 2011
• Results First Posted: June 9, 2014
• Last Update Posted: June 9, 2014
• Sponsor: Yale University
• Collaborator: National Alliance for Research on Schizophrenia and Depression
• Information provided by (Responsible Party): Yale University

Study Description

Brief Summary:

Roughly one-third of patients with obsessive-compulsive disorder (OCD) do not experience significant clinical benefit from first-line interventions such as pharmacotherapy with selective serotonin reuptake inhibitors (SSRI) or cognitive behavioral therapy (CBT). Furthermore, OCD patients typically experience the full treatment benefits of first-line interventions only after a time-lag of two to three months. Inadequate symptom relief and delay of symptom relief from first-line treatments are sources of substantial morbidity and decreased quality of life in OCD patients. Converging lines of evidence from neuroimaging, genetic and pharmacological studies support the importance of glutamate abnormalities in the pathogenesis of OCD.

The investigators are conducting an open, uncontrolled study of ketamine in treatment-refractory OCD. Ketamine is a potent antagonist of the N-methyl-D-aspartate (NMDA) receptor and has been demonstrated to have rapid anti-depressant effects in patients with Major Depressive Disorder. The investigators have additionally provided evidence for rapid improvement of comorbid OCD and trichotillomania after ketamine infusion in a depressed woman.

Failure of symptom relief and delay of symptom relief from first-line treatments are a source of substantial morbidity and decreased quality of life in OCD patients. Ketamine represents the possibility to provide rapid symptom relief to OCD patients and may provide the mechanism for future drug development to treat OCD more rapidly and effectively.

Condition or disease	Intervention/treatment	Phase
Obsessive-compulsive Disorder	Drug: ketamine	Phase 2

Detailed Description:

Roughly one-third of patients with obsessive-compulsive disorder (OCD) fail to experience significant clinical benefit from first-line interventions such as pharmacotherapy with selective serotonin reuptake inhibitors (SSRI) or cognitive behavioral therapy (CBT). Antipsychotic augmentation is the only pharmacological strategy for treatment-refractory OCD with demonstrated efficacy in multiple double-blind trials (2). Antipsychotic augmentation only benefits around 1 in 3 treatment-refractory OCD. Furthermore, OCD patients typically experience the full treatment benefits of first-line interventions only after a time-lag of two to three months. Failure of symptom relief and delay of symptom relief from first-line treatments are sources of substantial morbidity and decreased quality of life in OCD patients.

Converging lines of evidence from neuroimaging, genetic and pharmacological studies support the importance of glutamate abnormalities in the pathogenesis of OCD. In Magnetic Resonance Spectroscopy studies elevated concentrations of glutamate and related compounds have been demonstrated in the caudate nucleus and orbitofrontal cortex of OCD patients compared to normal controls. In genetic studies, single nucleotide polymorphisms within the glutamate transporter gene SLC1A1 have been associated with the diagnosis of OCD. Open-label, pharmacological treatment studies have suggested that glutamate modulating agents such as riluzole, n-acetylcysteine and memantine may be effective in the treatment of OCD.

Ketamine is a potent antagonist of the N-methyl-D-aspartate (NMDA) receptor, a major type of glutamate receptor in the brain. In a placebo-controlled study completed at Yale a single dose of ketamine (0.5 mg/kg, intravenously) had rapid antidepressant effects in depressed patients. In these subjects ketamine infusion produced mild psychotomimetic symptoms and euphoria that dissipated within 120 minutes, while the antidepressant effects of ketamine infusion emerged over the first 180 minutes and persisted over 72 hours. Fifty percent of depressed patients receiving ketamine were treatment responders at Day 3 compared to 12.5% in the placebo infusion group. These results have been replicated in a recent double-blind study performed at NIMH and a third unpublished study conducted by members of our group at Yale.

Our goal is to conduct an open-label study in treatment-refractory OCD to determine if ketamine may be an effective acute anti-obsessional agent.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Ketamine Infusion for Obsessive-Compulsive Disorder
• Study Start Date: February 2009
• Actual Primary Completion Date: December 2011
• Actual Study Completion Date: December 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ketamine; Ketamine will be given at a dose of 0.5mg/kg over 40 minutes. This dose is identical to that used in previous anti-depressant studies of ketamine.	Drug: ketamine; Ketamine (a single 0.5mg intravenously over 40 minutes).

Outcome Measures

Primary Outcome Measures :

1. OCD Severity [ Time Frame: Baseline and 1 day after ketamine infusion ]
   We will examine change from baseline in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) ratings of OCD severity at 1 day following infusion. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) assesses obsessive and compulsive symptom severity. Obsessions are rated on a scale from 0-20 and compulsions are rated on a scale of 0-20, for a total scale of 0-40. Scores on the obsessions scale and scores on the compulsions scale are summed to obtain the total score. The higher the score, the more severe the OCD.
2. OCD Severity [ Time Frame: Baseline and 2 days following infusion ]
   We will examine change from baseline in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) ratings of OCD severity at 2 days following infusion. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) assesses obsessive and compulsive symptom severity. Obsessions are rated on a scale from 0-20 and compulsions are rated on a scale of 0-20, for a total scale of 0-40. Scores on the obsessions scale and scores on the compulsions scale are summed to obtain the total score. The higher the score, the more severe the OCD.
3. OCD Severity [ Time Frame: Baseline and 3 days following infusion ]
   We will examine change from baseline in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) ratings of OCD severity at 3 days following infusion. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) assesses obsessive and compulsive symptom severity. Obsessions are rated on a scale from 0-20 and compulsions are rated on a scale of 0-20, for a total scale of 0-40. Scores on the obsessions scale and scores on the compulsions scale are summed to obtain the total score. The higher the score, the more severe the OCD.

Secondary Outcome Measures :

1. Depression Symptoms [ Time Frame: Baseline, Day 1, Day 2, and Day 3 ]
   We will examine change from baseline in Hamilton Rating Scale for Depression (HRDS) ratings of depression severity at day 1-3 following a single ketamine infusion. The HRDS assesses severity of, and change in, depressive symptoms. The HRDS is a 21 item scale with scores ranging from 0-66. The higher the score, the more severe the depression.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult between the ages of 18 and 65 years.
2. Meet DSM IV criteria for obsessive-compulsive disorder by structured clinical interview (SCID) and have a Y-BOCS score >24.
3. Have treatment-refractory OCD. Have Y-BOCS>24 despite two SSRI trials of adequate dose and duration and been offered prior CBT treatment.
4. Stable psychiatric medications. Subjects must have had stable doses of all psychiatric medications for the month prior to treatment and have been on stable doses of SSRI and clomipramine for at least 2 months prior to study enrollment.
5. Medically and neurologically healthy.
6. Able to provide written informed consent according to the Yale HIC guidelines.

Exclusion Criteria:

1. Lifetime history of substance dependence (other than nicotine and caffeine)
2. Suicide attempt or suicidal ideation requiring psychiatric hospitalization in the previous 6 months
3. Being Pregnant
4. Known hypersensitivity to ketamine

Contacts and Locations

Locations

United States, Connecticut

Connecticut Mental Health Center/ YNHH

New Haven, Connecticut, United States, 06520

Sponsors and Collaborators

Yale University

National Alliance for Research on Schizophrenia and Depression

Investigators

• Principal Investigator: Michael H Bloch, MD, MS; Yale University

More Information

Additional Information:

Yale OCD Research Clinic 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Niciu MJ, Grunschel BD, Corlett PR, Pittenger C, Bloch MH. Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after ketamine infusion in patients with obsessive-compulsive disorder and a history of major depressive disorder. J Psychopharmacol. 2013 Jul;27(7):651-4. doi: 10.1177/0269881113486718. Epub 2013 May 15.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT01349231
• Other Study ID Numbers: 0901004660
• First Posted: May 6, 2011
• Results First Posted: June 9, 2014
• Last Update Posted: June 9, 2014
• Last Verified: May 2014

Keywords provided by Yale University:

obsessive-compulsive disorder; ketamine; glutamate

Additional relevant MeSH terms:

Disease; Compulsive Personality Disorder; Obsessive-Compulsive Disorder; Pathologic Processes; Personality Disorders; Mental Disorders; Anxiety Disorders; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action