Review of: Hofmeijer-Sevink MK et al, J Clin Psychopharmacol 2017;37(5):531–539

The mainstay of current treatment for panic disorder involves SSRIs and psychotherapy, specifically either cognitive behavioral therapy (CBT) or exposure with response prevention (ERP) therapy. D-cycloserine (DCS) is a partial N-methyl-D-aspartate (NMDA) receptor agonist that may enhance extinction learning—the gradual decrease in the panic response during ERP. Several studies have evaluated whether adding DCS to ERP therapy might enhance the effectiveness of the therapy, but there have been mixed results.

Conducted at outpatient clinics at 3 mental health care institutions in the Netherlands, this study was a randomized, double-blinded, placebo-controlled study of the effectiveness of adding DCS to panic disorder treatment. Fifty-seven patients with panic disorder and agoraphobia were randomized to 1 of 3 treatment arms: DCS before the ERP session, DCS after the ERP session, or placebo.

DCS or placebo was administered orally in a single 125 mg fixed dose, either at the beginning or the end of treatment, depending on the condition. All study participants underwent 12 weekly, 90-minute individual ERP sessions. The primary outcome was the mean score on the “alone” subscale of the Mobility Inventory (MI), which is a self-report tool used to measure agoraphobic avoidance behavior in various situations. Measurements were taken at baseline and during sessions 4, 8, and 12, and then at 3- and 6-month follow-up.

There was no difference in the primary outcome between those who received DCS (either pre- or post-ERP session) and placebo. However, within the two DCS treatment groups, the DCS post-ERP group showed a significant improvement in the primary outcome (p = 0.009; effect size = 0.6) measured at 3-month follow-up compared to the DCS pre-ERP group.

TCPR’s Take
DCS augmentation of psychotherapy for anxiety disorders sounds plausible in theory, but many studies, including this one, don’t show a significant difference when comparing DCS to placebo. However, the authors mention that this study had many limitations. First, the study may have been too small to show an effect—the researchers’ power calculations called for 20 subjects per treatment arm, but only 19 were randomized to each arm. Second, the dosing of 125 mg of DCS may have been too high. This may sound illogical, but the way DCS is thought to work is by activating the NMDA receptor. At higher doses, though, DCS has partial NMDA receptor antagonist effects, which reduces its effect on extinction learning. Also, with higher doses and more administrations, patients are more likely to develop tolerance to DCS.

It’s interesting that this study showed a small signal that DCS might be effective after treatment, but we’ll need larger studies with more robust results before recommending that you start using DCS in your practice.