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Original Research

Exposure Therapy, d-Cycloserine, and Functional Magnetic Resonance Imaging in Patients With Snake Phobia: A Randomized Pilot Study

Andrea M. Nave, BS; David F. Tolin, PhD; and Michael C. Stevens, PhD

Published: September 15, 2012

Article Abstract

Objective:d-Cycloserine may enhance fear extinction. The effects of d-cycloserine on human brain function are not well understood, with findings suggesting that d-cycloserine could augment exposure therapy via its effects on the neural substrates of emotional learning and extinction or by acting upon different neural pathways. The aim of this exploratory study was to investigate differences in neural response in patients receiving d-cycloserine or placebo in addition to exposure therapy.

Method: Twenty adults with snake phobia (DSM-IV specific phobia) received 50 mg of d-cycloserine or placebo (double-blind, randomized) 1 hour prior to a single session of graded exposure therapy in an outpatient specialty clinic. One week before and after treatment, patients completed a clinical examination and snake-stimuli symptom provocation functional magnetic resonance imaging (fMRI) task (primary outcome measure).

Results: The d-cycloserine and placebo groups responded equally well to treatment, although the d-cycloserine patients reached the top of the exposure hierarchy more quickly (t=2.61, P<.05). Only right dorsolateral prefrontal cortex showed an equivalent decrease in hyperactivation to snake stimuli in both groups. Compared to placebo, d-cycloserine augmentation resulted in different ventromedial prefrontal brain activation during processing of phobic stimuli, including enhanced medial orbitofrontal (F=11.52, P=.001) and subgenual anterior cingulate activation (F=7.41, P=.008) and normalized perigenual cingulate “deactivation” (F=3.85, P=.05) to snakes.

Conclusions: A single administration of d-cycloserine combined with exposure therapy can lead to lasting changes in ventromedial and other prefrontal cortex response to phobic stimuli. These changes are qualitatively different from those seen in patients receiving exposure therapy without d-cycloserine.

Trial Registration: identifier: NCT01450306

J Clin Psychiatry 2012;73(9):1179-1186

Submitted: November 29, 2011; accepted April 30, 2012(doi:10.4088/JCP.11m07564).

Corresponding author: David F. Tolin, PhD, Institute of Living, 200 Retreat Ave, Hartford, CT 06106 (

Volume: 73

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