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Obsessive-compulsive disorder (OCD) is a leading cause of illness-related disability.1 Identifying more effective treatments with faster onset of action would be a major advance. Medications thought to modulate the glutamate system are promising new agents: for example, open trials of riluzole, memantine, and minocyline as augmentation to serotonin reuptake inhibitors (SRI) suggest that up to half of OCD patients may experience reductions in symptoms.2–7 We chose to test intravenous ketamine (a non-competitive N-methyl-D-aspartate [NMDA] receptor antagonist) in an OCD patient for three reasons: 1) it is known to modulate the glutamate system, sharing some mechanistic similarity to memantine;8 2) mice with a genetic deletion in a postsynaptic scaffolding protein (SAPAP3) have OCD-like compulsive behavior thought to be caused by increased NMDA activity and ketamine decreases NMDA activity;9 3) it has been safely used in patients with depression and can relieve depressive symptoms in hours.10, 11
The following case report describes the rapid resolution of obsessions in an OCD patient when she received ketamine in a double-blind cross-over design of intravenous ketamine versus saline. To our knowledge, this is the first report to describe the use of ketamine in an OCD patient.
A 24-year-old woman with DSM-IV OCD (and no other Axis-I disorder) presented in May 2010 for treatment of her obsessions about symmetry/exactness (needing to have objects in the right place or else it doesn’t “feel right”) and associated repeating/checking compulsions. She spent nearly 8 hours a day managing her OCD symptoms, which interfered with her work and social relationships. She was medically healthy and not on medication due to failing 3 prior SRI trials: fluoxetine 60mg, escitalopram 30mg, clomipramine 200mg (each for over 3 months). Augmentation strategies were unsuccessfully attempted (e.g. she refused a trial of an anti-psychotic due to the possible side effect of weight gain and did not adhere to a trial of cognitive behavioral therapy with exposure and ritual prevention). At baseline, she had severe OCD (Yale-Brown Obsessive Compulsive Scale [YBOCS] = 30)12 and minimal depressive symptoms (Hamilton Depression Rating Scale = 7).13 Her sister has OCD, and her mother has depression. She provided written informed consent after a full explanation of the research procedures and their risks. The institutional review board approved the study.
Following the protocol used in a prior depression study,11 she received two double-blind intravenous infusions over 40 minutes given 1 week apart of saline or 0.5 mg/kg ketamine hydrochloride. An anesthesiologist provided continuous monitoring during the infusion. The patient’s symptoms were assessed at baseline, every 10 minutes during the 40 minute infusion (to detect rapid changes in symptoms if they occurred), and at several post-infusion time-points (both on the day of the infusion and up to 1 week later) using the OCD Visual Analogue Scale (OCD-VAS, a modified self-rating scale used previously to detect rapid changes in OCD symptoms;14–16 we focused on obsessions, which are more readily assessed rapidly than compulsions). She reported minimal reduction in obsessions during the first infusion (placebo/saline) (Figure 1A), but complete cessation of obsessions during the second infusion (ketamine) (Figure 1B). Obsessions partially re-emerged 40 to 230 minutes post-infusion (Figure 1B), plateauing until post-infusion Day 2; the obsessions did not return to baseline levels until post-infusion Day 7.
During both the saline and ketamine infusion, vital signs remained within normal limits. At all time points, she denied symptoms of mania (Young Mania Rating Scale=0), psychosis (Brief Psychiatric Rating Scale=0) or intoxication (Visual Analogue Scale for Intoxication=0) using standard scales.10, 17, 18 During the saline infusion, she reported lightheadedness. During the ketamine infusion, she reported lightheadedness, dry mouth, and feelings of unreality (Clinician-Administered Dissociative States Scale=1)19 that resolved 5 minutes after the infusion stopped.
This case report suggests that ketamine might have rapid anti-obsessional effects that persist from 1 to 7 days post-infusion, long after the drug has cleared. Limitations include small sample size and the difficulties of blinding due to the psychoactive effects of ketamine. A larger trial is underway to further evaluate ketamine’s efficacy, safety, duration, and mechanism of effect. In sum, ketamine may provide a useful tool to study the glutamatergic mechanism implicated in OCD and, if proven effective, may help identify novel drug targets for this disabling illness.
Funding support: This investigation was supported a grant from National Institutes of Mental Health (5T32 MH015144-31), the Pisetsky Young Investigator Award, and the Molberger Scholar Award (to Dr. Rodriguez).
James Bender for independent evaluations. Dr. Bender reports no additional financial or other relationships relevant to the subject of this letter.
Previous Presentation: None
Financial disclosures: Drs. Rodriguez, Kegeles, Flood, and Simpson report no additional financial or other relationships relevant to the subject of this letter.
Clinical Trials Registration: clinicaltrials.gov Identifier: NCT01100255