Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, Pittenger C. Biol Psychiatry. 2012 Dec 1;72(11):964-70.
About 30% of individuals diagnosed with obsessive-compulsive disorder (OCD) do not respond significantly to either cognitive behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs). Although antipsychotic augmentation of SSRIs can be beneficial for treatment-refractory individuals, only about one in three refractory individuals achieve a satisfactory response and the benefits are usually substantially delayed. The need for additional and improved treatments for OCD is pressing. Theoretical considerations and a recent promising case report prompted the ketamine treatment study by Dr. Bloch and colleagues in the Child Study Center and the Department of Psychiatry.
Evidence from neuroimaging, genetic, and pharmacological studies are suggestive of a role for glutamate-related abnormalities in the pathogenesis of OCD. Open-label treatment studies of glutamate modulating agents including riluzole, N-acetylcysteine, and memantine have been promising and have further increased in interest in glutamate. Ketamine is an antagonist of the N-methyl-D-aspartate (NMDA) receptor, a major glutamate receptor in the brain. Prior studies initiated by Yale investigators found ketamine (0.5 mg/kg IV) to cause a short-term, but substantial, reduction in depressive symptoms in individuals with major depression. In those studies, ketamine infusion produced initial mild psychotomimetic symptoms and euphoria that dissipated within two hours, while antidepressant effects emerged over the first three hours and persisted for about three days.
Although OCD symptoms in the 10 individuals studied Bloch and colleagues did improve in the first few hours, most of this acute improvement was attributed to early dissociative aspects and euphoria (see Figure). Later OCD symptom reduction was minimal and not considered clinically meaningful. As expected, depressive symptoms did improve in the 7 individuals with co-morbid depression. In contrast to the prior case report, the results indicate that ketamine will not be useful for OCD. Thus, unlike the SSRIs that are useful for both OCD and depressive symptoms, ketamine appears to have quite different effects on the two symptoms clusters. However, the potential benefit in OCD of other glutamate-modulating agents needs further careful evaluation.