A controlled trial of the adjunct use of d-cycloserine to facilitate cognitive behavioral therapy outcomes in a cocaine-dependent population

Abstract

Cocaine dependence is a chronically relapsing disorder for which its predominant behavioral therapies are associated with only partial efficacy. The goal of this study was to determine if the N-methyl-d-aspartate (NMDA) glutamate receptor partial agonist and cognitive enhancer, d-cycloserine (DCS), could boost the cocaine abstinence and treatment retention goals of cognitive behavioral therapy (CBT). This study employed a placebo-controlled, randomized double-blind trial design of 44 cocaine-dependent men enrolled in a 4-week outpatient Substance Abuse Treatment Program (SATP) at the Atlanta Veteran's Administration Medical Center. Subjects received 50 mg of DCS or placebo prior to four weekly sessions of a condensed version of a manual-based CBT for cocaine dependence. Cocaine abstinence and treatment retention measures represented primary outcome variables. Relative to a 12-step based treatment-as-usual, an under-dosed CBT was associated with significant improvements in drug abstinence and treatment retention at 4-weeks and for maintenance of drug abstinence after four more weeks of follow-up. The robust response to the under-dosed CBT was not enhanced by the adjunct administration of DCS at either the 4- or 8-week endpoints. This controlled clinical trial failed to demonstrate an ability of DCS to boost the relapse prevention or treatment retention goals of CBT.

Introduction

Cocaine addiction is a chronically relapsing disorder associated with high rates of recidivism in treatment-seeking individuals. To date, treatment for cocaine addiction remains solely reliant on behavioral therapies; there are currently no FDA approved pharmacotherapies for cocaine addiction. The major behavioral therapies including cognitive behavioral therapy (CBT), 12-Step, and contingency management approaches have proven to be effective in promoting recovery and relapse prevention for drug-dependent individuals (Garcia-Rodriguez et al., 2009, Maude-Griffin et al., 1998, Weiss et al., 2005). However, the available addiction behavioral treatments have limited or partial efficacy in reducing the susceptibility to relapse. While drug antibody (Haney et al., 2010, Martell et al., 2009) and targeted enzyme (Brimijoin et al., 2008, Collins et al., 2009) approaches may eventually provide therapeutic advantages, a more proximal approach might be represented by the adjunct use of a cognitive enhancer to boost the therapeutic cognitions and thus efficacy associated with a behavioral therapy based strongly on learning and memory processes.

Recent theories related to the drug addiction process emphasize the roles of learning and memory processes (Kelley, 2004, Robbins et al., 2008). The formation of addiction memories are dynamic processes reflecting associative learning mechanisms by which conditioned drug cues can elicit intense drug seeking and wanting (Robinson & Berridge, 2001). Neural processing networks exhibiting drug use experience-dependent plasticity represent addiction learning and its associated memories (Everitt et al., 2008). Similarly, in modifying cognitions and behaviors associated with drug addiction, CBT relies for its effectiveness on engaging competing learning and memory processes represented by differing networks modified by treatment experience-dependent neuroplasticity. One of the goals of addiction therapy is relapse prevention due to the drug conditioned stimulus (CS) no longer predicting the conditioned response (CR) represented by drug seeking and use behaviors. This goal can be accomplished by either extinction of the CR to a CS or by changing contingencies such that the drug CS now predicts a different CR. Both processes involve new learning and memory. Extinction-based psychotherapies such as prolonged imaginal exposure are effective in extinguishing pathological learned associations in anxiety disorders such as posttraumatic stress disorder (PTSD) (Foa et al., 2005). However, the use of analogous cue exposure therapy (CET) approaches to extinguish the learned associative values of drug use cues in drug-addicted individuals have met with largely negative results (Conklin and Tiffany, 2002, Price et al., 2009) and, in at least one instance, in increases in relapse rates (Marissen, Franken, Blanken, van den Brink, & Hendriks, 2007). Cognitive behavioral therapy for cocaine addiction involves the identification of the thoughts, feelings, and events that precede and follow episodes of cocaine use and the learning and deployment of coping skills to counter drug use urges (Carroll, 1998). Unlike CET, controlled clinical trials have demonstrated the efficacy of CBT in producing significant, enduring drug abstinence in cocaine-addicted populations (Carroll et al., 2004). The maximal beneficial effects of CBT appear to be delayed, suggesting that the coping skills take time to be learned and consolidated (Carroll et al., 2000, Epstein et al., 2003).

The N-methyl-d-aspartate (NMDA) glutamate receptor is critical for the activity-dependent control of synaptic efficacy, exemplified by long-term potentiation (LTP) or depression (LTD) of synaptic signals, a molecular mechanism of experience-dependent neuroplasticity that underlies learning and memory formation (Malenka and Bear, 2004, Rebola et al., 2010). d-Cycloserine (DCS), a partial agonist at the NMDA glutamate receptor, binds to the glycine binding regulatory site to facilitate glutamatergic neurotransmission (Kaye, Sansom, & Biggin, 2006). DCS also enhances NMDA receptor-dependent synaptic potentials and facilitates the long-term synaptic plasticity of glutamate neurotransmission (Billard and Rouaud, 2007, Nitsche et al., 2004, Rouaud and Billard, 2003). Several preclinical studies have established that DCS can enhance learning and memory processes related to extinction (Walker, Ressler, Lu, & Davis, 2002) and operant behavior (Hood et al., 1989, Lelong et al., 2001, Monahan et al., 1989). Recent controlled clinical trials have explored the use of adjunct DCS to enhance learning and memory processes related to behavioral therapies for patients with anxiety disorders. The major effect of the adjunct use of DCS with extinction-based psychotherapies for anxiety disorders seems to be an acceleration of extinction learning and memory (Hofmann et al., 2006, Kushner et al., 2007, Ressler et al., 2004, Wilhelm et al., 2008). This effect is mirrored in a facilitation of the rate of extinction of learned associations to cocaine cues in animal models (Botreau et al., 2006, Nic Dhonnchadha et al., 2009, Paolone et al., 2009, Thanos et al., 2009, Torregrossa et al., 2010), suggesting that DCS facilitates the extinction of both aversively and appetitively-conditioned associations. A recent report (Otto et al., 2010) indicated that DCS also facilitates the learning and memory processes associated with CBT in individuals with panic disorder. Based on these observations we hypothesized that DCS might facilitate the rate and extent of therapeutic learning and memory processes associated with CBT for cocaine addiction, and thus lead to enhanced relapse prevention and treatment retention outcomes. This hypothesis was tested using a placebo-controlled, double-blind clinical trial design that assessed the interaction between DCS and a condensed version of a manualized CBT for cocaine addiction (Carroll, 1998).