Clinical efficacy of sertraline alone and augmented with gabapentin in recently abstinent cocaine-dependent patients with depressive symptoms.

BACKGROUND: Cocaine dependence is a major public health problem with no available robustly effective pharmacotherapy. This study's aim was to determine if treatment with sertraline (SERT) or SERT plus gabapentin (GBP) improved treatment retention, depressive symptoms, and/or cocaine use. METHODS: Depressed cocaine-dependent patients (N = 99) were enrolled in a 12-week, double-blind, randomized, placebo (PLA)-controlled, clinical trial and placed in research beds at a residential treatment facility (Recovery Centers of Arkansas). They were randomized by depressive symptom severity and inducted onto 1 of the following while residing at the Recovery Centers of Arkansas: SERT (200 mg/d), SERT (200 mg/d) plus GBP (1200 mg/d), or PLA. Participants transferred to outpatient treatment at the start of their third week, continued receiving study medications or PLA (weeks 3-12), and participated in weekly individual cognitive behavioral therapy. Compliance was facilitated through the use of contingency management procedures. Supervised urine samples were obtained thrice weekly and self-reported mood weekly. At the end of 12 weeks, participants were tapered off the study medication over 5 days and referred to a local treatment program. RESULTS: Sertraline, but not SERT plus GBP, showed a significantly lower overall percentage of cocaine-positive urine samples compared with that of PLA. A significantly greater percentage of participants experienced relapse in the PLA group (88.9%) compared with that of the SERT group (65.2%). Hamilton depression ratings decreased significantly over time regardless of the treatment group. Retention in treatment did not differ significantly between the treatment groups. CONCLUSIONS: Sertraline plus GBP may not be superior to SERT alone in delaying relapse among abstinent cocaine-dependent individuals undergoing cognitive behavioral therapy.

Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, buprenorphine-assisted detoxification procedure.

This pilot study examined the efficacy of the N-type calcium channel blocker gabapentin to improve outcomes during a brief detoxification protocol with buprenorphine. Treatment-seeking opioid-dependent individuals were enrolled in a 5-week, double-blind, placebo-controlled trial examining the effects of gabapentin during a 10-day outpatient detoxification from buprenorphine. Participants were inducted onto buprenorphine sublingual tablets during Week 1, were randomized and inducted onto gabapentin or placebo during Week 2, underwent a 10-day buprenorphine taper during Weeks 3 and 4, and then were tapered off gabapentin/placebo during Week 5. Assessments included thrice-weekly opioid withdrawal scales, vitals, and urine drug screens. Twenty-four individuals (13 male; 17 Caucasian, 3 African American, 4 Latino; mean age 29.7 years) participated in the detoxification portion of the study (gabapentin, n = 11; placebo, n = 13). Baseline characteristics did not differ significantly between groups. Self-reported and observer-rated opioid withdrawal ratings were relatively low and did not differ between groups during the buprenorphine taper. Urine results showed a Drug × Time interaction, such that the probability of opioid-positive urines significantly decreased over time in the gabapentin versus placebo groups during Weeks 3 and 4 (OR = 0.73, p = .004). These results suggest that gabapentin reduces opioid use during a 10-day buprenorphine detoxification procedure.

Effects of disulfiram on QTc interval in non-opioid-dependent and methadone-treated cocaine-dependent patients.

OBJECTIVES: Methadone and cocaine are each known to prolong the QTc interval, a risk factor for developing potentially fatal cardiac arrhythmias. Disulfiram, often administered in the context of methadone maintenance to facilitate alcohol abstinence, has been shown to have some efficacy for cocaine dependence. Disulfiram has differential effects on cocaine and methadone metabolism, but its impact on methadone- or cocaine-induced changes in QTc interval is unclear. Thus, the effects of disulfiram on QTc interval in a subset of cocaine-dependent patients participating in a 14-week, randomized, double-blind, placebo-controlled clinical trial of disulfiram were prospectively determined. METHODS: Opioid-dependent participants were inducted onto methadone (weeks 1-2; MT) and both MT and non-opioid-dependent (UT) participants were randomized to receive disulfiram (weeks 3-14) at one of the following doses: 0, 250, 375, or 500 mg/d. Electrocardio-grams were obtained before study entry and during weeks 2 and 4. RESULTS: Complete QTc-interval data in 23 MT and 18 UT participants were analyzed. QTc interval tended to be higher in MT participants relative to UT participants, regardless of disulfiram dose and time point, but disulfiram did not differentially alter QTc interval. QTc interval was, however, significantly greater in participants with recent cocaine use than in those with no recent use. CONCLUSIONS: These results suggest that cocaine use and possibly MT status, but not disulfiram, are risk factors for QTc prolongation.

Effects of prototypic calcium channel blockers in methadone-maintained humans responding under a naloxone discrimination procedure.

Accumulating evidence suggests that L-type calcium channel blockers (CCBs) attenuate the expression of opioid withdrawal and the dihydropyridine L-type CCB isradipine has been shown to block the behavioral effects of naloxone in opioid-maintained humans. This study determined whether two prototypic L-type CCBs with differing chemical structures, the benzothiazepine diltiazem and the phenylalkamine verapamil, attenuate the behavioral effects of naloxone in methadone-maintained humans trained to distinguish between low-dose naloxone (0.15 mg/70 kg, i.m.) and placebo under an instructed novel-response drug discrimination procedure. Once discrimination was acquired, diltiazem (0, 30, 60, 120 mg) and verapamil (0, 30, 60, 120 mg), alone and combined with the training dose of naloxone, were tested. Diltiazem alone produced 33-50% naloxone- and novel-appropriate responding at 30 and 60 mg and essentially placebo-appropriate responding at 120 mg. Verapamil alone produced 20-40% naloxone- and 0% novel-appropriate responding. Diltiazem at 60 mg decreased several ratings associated with positive mood and increased VAS ratings of "Bad Drug Effects" relative to placebo, whereas verapamil increased ratings associated with euphoria. When administered with naloxone, diltiazem produced 94-100% naloxone-appropriate-responding with 6% novel-appropriate responding at 60 mg (n=3). When administered with naloxone, verapamil produced 60-80% naloxone- and 0% novel-appropriate responding (n=5). Diltiazem decreased diastolic blood pressure and heart rate whereas verapamil decreased ratings of arousal relative to placebo. These results suggest that CCBs with different chemical structures can be differentiated behaviorally, and that diltiazem and verapamil do not attenuate the discriminative stimulus effects of naloxone in humans at the doses tested.

Does the learning deficit observed under an incremental repeated acquisition schedule of reinforcement in Ts65Dn mice, a model for Down syndrome, change as they age?

The Ts65Dn mouse is partly trisomic at chromosome 16 and is considered to be a valid mouse model of human Down syndrome. Prior research using an incremental repeated acquisition (IRA) schedule of reinforcement has revealed that there is a significant learning deficit in young, adult Ts65Dn mice compared to littermate controls. The purpose of this study was to examine whether this deficit changes during the life-span of these mice. In order to determine if changes in the deficit were caused by motoric or motivational deficiencies, a second group of mice was trained to respond under a performance version of the task (IRA-P). The IRA-P task required the same motor responses to produce the reinforcer, but no learning or acquisition was required. Data collected under the IRA task demonstrated that there was a significant learning impairment that persisted up to 24 months of age in the Ts65Dn mice compared to littermate controls. There was a significant decrease in the rate of responding and the number of milk presentations earned by the Ts65Dn mice after 19 months of age. However, during this time, response accuracy, which is independent of mobility and possibly motivation, did not decrease. Under the IRA-P schedule, there was no decrease observed in the number of milk presentations of either line as they aged, but the trend in the rate of responding of the Ts65Dn mice was similarly declining as the rate of responding observed in the Ts65Dn mice under the IRA task. These data indicate that the ability to learn in Ts65Dn mice does not decline with age as measured by the IRA task and suggests that perhaps Ts65Dn mice do not exhibit the same early onset Alzheimer's disease phenotype that is typically seen in human patients.

Working memory in the Ts65Dn mouse, a model for Down syndrome.

This study used a matching-to-position schedule of reinforcement to examine working memory in Ts65Dn and littermate control mice. Initially there appeared to be a memory deficit in the Ts65Dn mice, which disappeared with extended practice. Thus, what appeared as a memory deficit may actually be the result of a delay in learning the concept of matching. These results suggest that delayed learning may be an important factor in other procedures examining working memory in Ts65Dn mice and have important implications for clinical treatment of Down syndrome patients.