The primary goals of this controlled clinical trial were to ascertain the acute treatment efficacy (0–4 weeks) and post-treatment durability of DCS administration as a means of boosting the relapse prevention and treatment retention goals of CBT, an empirically supported therapy with partial efficacy for the treatment of cocaine addiction. A major barrier to drug abstinence in this population is the uncountered drug use motivation triggered by conditioned external and internal drug-related cues that predict drug seeking and use behaviors. These learned associations are associated with strongly consolidated drug use memories that are highly resistant to extinction (F. Weiss, et al., 2001
), a property that perhaps underlies the general ineffectiveness of extinction-based CET approaches to prevent relapse (Conklin & Tiffany, 2002
). Alternative treatment approaches such as CBT seek to counter addiction by modifying cognitive and behavioral representations of drug use that oppose the prior learned associations such that conditioned drug cues no longer predict drug abuse. A premise of this study was that CBT, like extinction, involves therapeutic learning and memory processes that are mediated by glutamatergic neurotransmission and are thus amenable to enhancement with DCS administration. This premise was tested by pairing weekly DCS pretreatments with four weekly sessions of CBT representing a condensed version of a 12-session CBT (Carroll, 1998
). This abbreviated CBT protocol was used to allow the assessment of possible response-enhancing effects of DCS. A similar strategy was recently used to demonstrate DCS augmentation of exposure-based CBT outcomes for individuals with panic disorder (Otto, et al., 2010
The results of this clinical trial indicate that a condensed and abbreviated version of a manual-based 12-session CBT for cocaine addiction (Carroll, 1998
) resulted in significant improvements in relapse prevention and treatment retention, the primary study outcome variables. The gains relative to the TAU group also endured over a one-month follow-up period. The effect sizes for CBT versus TAU, irrespective of receiving placebo or DCS, reflected small to moderate enhancements (d = 0.13–0.55) of the relapse prevention outcomes for TAU. This clinical trial also revealed that DCS as an adjunct treatment to CBT offered no advantage relative to placebo in promoting drug abstinence and treatment retention in a cocainedependent population; both CBT arms were comparably more effective than a relatively intensive 12-Step-based TAU. Therefore, the intent of the study design to assess the ability of DCS to boost the partial clinical response to an “under-dosed” version of CBT was not realized.
A robust response to brief CBT precluded the opportunity to assess the ability of co-administered DCS to facilitate the clinical response to CBT. Attrition in addiction treatment programs and loss to follow-up for clinical trials in drug-dependent populations are well-recognized problems. The goal of combination therapies to facilitate a more rapid and efficient treatment response (i.e., fewer CBT sessions) would be of significant clinical value. The pairing of DCS with a more standardized, dose-adjusting form of CBT such as computerized CBT (Carroll, et al., 2008
) would perhaps represent an improved experimental design of heightened translational significance.
A major premise of this study is that DCS would facilitate the retention of therapeutic learning and memory consolidation. Recent fMRI studies have demonstrated that DCS facilitates hippocampal mechanisms of learning and memory consolidation in humans (Kalisch, et al., 2009
; Onur, et al., 2010
). Future studies of the value of DCS as a treatment adjunct in cocaine-addicted individuals could be enhanced by a similar use of in vivo functional neuroimaging technology to define its effect on putative neural mechanisms of therapeutic learning and memory processes.
4.1 Strengths and Limitations
Strengths of the study include that all of the study participants were involved in active treatment (i.e. all subjects received the standard of care at the Atlanta VAMC study site). It should be mentioned, however, that interaction between the 12-Step-based TAU and the study CBT might have limited the ability to assess the efficacy of adjunctive DCS. The comparison of CBT outcomes with and without DCS in the absence of the 12-Step TAU would have been a less ambiguous design. Adherence to the regimen of DCS study medication was 100% as noted by observation and no spontaneous reports of adverse events occurred throughout the clinical trial. An added strength of the study was that it was an outpatient study, which allowed the assessment of treatment response by subjects exposed to cocaine cues in their everyday environment. An inpatient study could have possibly caused inflated treatment effects while in the controlled setting of the hospital and dramatic decreases in treatment efficacy once the patient was re-exposed to his drug use environment. Spot urinalysis was conducted in halfway house settings when subject’s behavior required further surveillance and was indicated in the EMR, and thus complemented the random UDS measures of relapse in the SATP.
Limitations of the study include that the majority of the participants were homeless and with varying shelter environments making this a difficult clinical population for longitudinal study. Another limitation of the study is that the SATP is an abstinence-based treatment program in which a lapse to cocaine use could trigger termination of treatment. Therefore, a common measure of treatment response – the cumulative incidence of drug positive urines as a function of time - could not be ascertained. The fixed study dose of 50 mg of DCS was selected based on the effectiveness of this dose in boosting the response to extinction-based behavioral therapies and CBT in individuals with anxiety disorders, and the dose-dependent properties of DCS as a partial NMDA receptor agonist. However, it is unknown as to whether acknowledged differences in the cognitive mechanisms of drug addiction and anxiety disorders would justify a differing dose-relatedness of the cognitive enhancing effects of DCS to the differing therapies for the two groups of disorders. It is also unknown as to whether clinical response to a longer trial of CBT, or a longer follow-up period of assessment, would represent a more effective trial of the clinical value of adjunctive DCS. Finally, the robust response to the CBT also precluded the ability to estimate the variance of the effect size.