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Tetrabenazine Augmentation in Treatment-Resistant Schizophrenia: A 12-Week, Double-Blind, Placebo-Controlled Trial

Remington, Gary MD, PhD, FRCPC*†; Kapur, Shitij MBBS, PhD, FRCPC; Foussias, George MD, MSc, FRCPC*†; Agid, Ofer MD*†; Mann, Steve MSc; Borlido, Carol BA; Richards, Sandy BScN; Javaid, Naima BSc

Journal of Clinical Psychopharmacology: February 2012 - Volume 32 - Issue 1 - p 95–99
doi: 10.1097/JCP.0b013e31823f913e
Brief Reports

Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5–75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA’s role and evidence that “endogenous sensitization” may occur over the course of the illness.

From the *Department of Psychiatry, University of Toronto; †Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Canada; and ‡Institute of Psychiatry, King’s College, London, England.

Received January 23, 2011; accepted after revision July 21, 2011.

Reprints: Gary Remington, MD, PhD, FRCPC, Schizophrenia Program, Centre for Addiction and Mental Health (CAMH), 250 College St, Toronto, Ontario, Canada M5T 1R8 (e-mail:

This work was supported through a grant from the Stanley Medical Research Institute (01T-073) awarded to Drs Remington and Kapur.

© 2012 Lippincott Williams & Wilkins, Inc.