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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 11, February 2013 — Guest Commentator: Ashwin A. Patkar, MD, MRCPsych, Duke University Medical Center, Durham, NC

Randomized Trial of Long-Acting Sustained-Release Naltrexone Implant vs Oral Naltrexone or Placebo for Preventing Relapse to Opioid Dependence

Krupitsky E, Zvartau E, Blokhina E, et al.

Arch Gen Psychiatry. 2012;69(9):973-981.

Objective: Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. This study compared outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment.

Methods: Six-month double-blind, double-dummy, randomized trial conducted in addiction treatment programs in St Petersburg, Russia. Participants included 306 opioid-addicted patients recently undergoing detoxification. Biweekly counseling and 1 of the following 3 treatments were given for 24 weeks: 1,000 mg naltrexone implant and oral placebo (NI+OP group; 102 patients); placebo implant and 50 mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or placebo implant and oral placebo (PI+OP group; 102 patients). Percentage of patients retained in treatment without relapse was utilized as the main outcome measure.

Results: By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P<.001) and 11 of 102 patients in the PI+OP group (10.8%) (P<.001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P=.07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P<.001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P=.02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P=.12), and all resolved with anti-allergy medication treatment. Other non local-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found.

Conclusions: The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment.

Clinical Commentary
Naltrexone is a mu-opioid antagonist that reduces the positive reinforcing effects of opioids and is approved to treat opioid dependence in the U.S. and several countries. Unfortunately, adherence to oral naltrexone is poor and clinical use has been limited except in selected groups of motivated patients. This study was done in Russia, where use of prescription opioid agonists (eg, methadone) to treat opioid addiction is highly restricted. The results showed that a 1,000 mg subcutaneous biodegradable 2-month naltrexone implant was superior to placebo implant and oral naltrexone on the primary outcome measure of retention without relapse. The outcome differences were striking. Over the 6-month study period, approximately 53% of patients in the naltrexone implant group remained in treatment without relapse compared to 16% in the oral naltrexone and 11% in the placebo group. All participants received biweekly drug counseling. Those with an active implant had a higher rate of wound infections (~5%) compared to the placebo implant group (~1%), but the infections were minor and successfully treated with oral antibiotics. The clinical considerations worth noting are: (1) Delivery systems that ensure sustained administration of naltrexone are effective to treat opioid dependence when combined with counseling; (2) Compliance with oral naltrexone limits its clinical utility; (3) Given the potential for diversion, misuse, and overdose of opioid agonists, naltrexone, a non-abusable and effective drug, deserves attention. Although naltrexone implant is not available in the U.S., an extended release, once monthly formulation of naltrexone is FDA approved. Commercial considerations are likely to influence future availability of the implant in the US.


Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive 'Bath Salts' Products

Baumann MH, Partilla JS, Lehner Kr, et al

Neuropsychopharmacology. 2012;Oct 17. doi: 10.1038/npp.2012.204. [Epub ahead of print]

Objective: The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods.

Methods: In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats.

Results: We found that MDPV blocks uptake of [(3)H]dopamine (IC(50)=4.1 nM) and [(3)H]norepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of [(3)H]serotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats.

Conclusions: Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.

Clinical Commentary

MDPV is the primary ingredient in "bath salts," synthetic designer drugs that are labeled as such to avoid criminal prosecution. Bath salts have seen a tremendous increase in popularity in recent years as drugs of abuse and have only been classified recently as controlled substances in the United States and some other countries. Intoxications with bath salts can have serious adverse effects, including acute psychosis with delusions, hallucinations, and bizarre behavior such as self-mutilation and violence. Physical effects can include hypertension, arrhythmias, and seizures. There has been limited information on mechanism of action of MDPV and its addictive potential. This preclinical study clearly demonstrates that MDPV is more selective and potent than cocaine in inhibiting the monoamine uptake leading to acute increase in dopaminergic transmission. This mechanism can explain the reinforcing nature of bath salt use, and the potentially dangerous physical and psychiatric manifestations of toxicity. It is worth noting that MDPV was 10 times more potent than cocaine in producing adverse cardiovascular effects in this study. Intoxication with bath salts should be a differential diagnosis in acute psychotic episodes, especially in young adults or adolescents who have a history of substance abuse. MDPV is not detected by routine drug screens but overdose can be life-threatening. Hence, clinicians must be especially vigilant about assessment of bath salt use.


A Double-Blind Randomized Controlled Trial of N-acetylcysteine in Cannabis-Dependent Adolescents

Gray KM, Carpenter MJ, Baker NL, et al

Am J Psychiatry. 2012;169(8):805-812.

Objective: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy.

Methods: In an 8-week, double-blind, randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1,200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group.

Results: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4; 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events.

Conclusions: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

Clinical Commentary

Cannabis is the most commonly used illicit drug among adolescents. Heavy use of cannabis has been associated with a variety of adverse effects. Existing behavioral treatments are associated with modest abstinence rates in adolescents. Furthermore, there is no medication that has demonstrated consistent efficacy in cannabis dependence. N-acetylcysteine (NAC) is an inexpensive, over-the-counter supplement that has been shown to upregulate the cysteine-glutamate exchanger and modulate glutaminergic neurotransmission. NAC also has anti-inflammatory properties that are linked to oxidative pathways. This is the first randomized controlled pharmacotherapy trial for cannabis dependence that showed a positive primary abstinence outcome as opposed to decreased use of cannabis in adolescents. About 41% of the NAC group were abstinent during the study compared to 27% of placebo-treated subjects.
At the dose employed (2.4 g per day), NAC did not have any significant side effects. While it is tempting to think of NAC as a daily supplement for cannabis dependence, more information is required. In this single-site study, NAC was effective when added to contingency management and brief cessation counseling. Will it be as effective in the absence of adjunctive psychosocial treatments? Are the effects of NAC sustained beyond the post-treatment period? Will it work for patients with dependence on other substances or high levels of psychopathology? It is hoped that we may have these answers in the near future. A large, federally funded, multi-site controlled trial of NAC for marijuana dependence in adolescents is underway.

Integrated Exposure-Based Therapy for Co-occurring Posttraumatic Stress Disorder and Substance Dependence: A Randomized Controlled Trial

Mills KL, Teesson M, Back SE, et al

JAMA. 2012;308(7):690-699.

Objective: There is concern that exposure therapy, an evidence-based cognitive-behavioral treatment for posttraumatic stress disorder (PTSD), may be inappropriate because of risk of relapse for patients with co-occurring substance dependence. This study aimed to determine whether an integrated treatment for PTSD and substance dependence, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), can achieve greater reductions in PTSD and substance dependence symptom severity compared with usual treatment for substance dependence.

Methods: Randomized controlled trial enrolling 103 participants who met DSM-IV-TR criteria for both PTSD and substance dependence. Participants were recruited from 2007-2009 in Sydney, Australia; outcomes were assessed at 9 months post baseline, with interim measures collected at 6 weeks and 3 months post baseline. Participants were randomized to receive COPE plus usual treatment (n=55) or usual treatment alone (control) (n=48). COPE consists of 13 individual 90-minute sessions (ie, 19.5 hours) with a clinical psychologist. The main outcome measures were change in PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS; scale range, 0-240) and change in severity of substance dependence as measured by the number of dependence criteria met according to the Composite International Diagnostic Interview version 3.0 (CIDI; range, 0-7), from baseline to 9-month follow-up. A change of 15 points on the CAPS scale and 1 dependence criterion on the CIDI were considered clinically significant.

Results: From baseline to 9-month follow-up, significant reductions in PTSD symptom severity were found for both the treatment group (mean difference, -38.24 [95% CI, -47.93 to -28.54]) and the control group (mean difference, -22.14 [95% CI, -30.33 to -13.95]); however, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity (mean difference, -16.09 [95% CI, -29.00 to -3.19]). No significant between-group difference was found in relation to improvement in severity of substance dependence (0.43 vs 0.52; incidence rate ratio, 0.85 [95% CI, 0.60 to 1.21), nor were there any significant between-group differences in relation to changes in substance use, depression, or anxiety.

Conclusion: Among patients with PTSD and substance dependence, the combined use of COPE plus usual treatment, compared with usual treatment alone, resulted in improvement in PTSD symptom severity without an increase in severity of substance dependence.

Clinical Commentary

Exposure therapy, a cognitive-behavioral therapy involving exposure to memories and reminders of past trauma, has long been regarded as a gold standard treatment for PTSD. However, there has been a concern that exposure therapy may be inappropriate for patients with co-occurring substance dependence because it may activate unpleasant memories and trigger relapse. To date, there was an absence of evidence to support or refute this belief because most trials of PTSD treatment have excluded individuals with substance dependence. Mills and colleagues from Australia have published the first large, randomized controlled trial of an integrated treatment for PTSD and substance dependence that incorporated prolonged exposure therapy. The researchers found that from the beginning of the study to 9-month follow-up, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity compared with the control group. By 9 months, rates of substance dependence had decreased to 45.4% in the treatment group and 56.2% in the control group; however, the difference between groups was not statistically significant. There are two important take-home messages from the study. First, most patients continued to use substances throughout the study. This indicates that abstinence from substances is not required for exposure therapy to be effective for PTSD in patients with comorbid substance abuse. Second, it is important to integrate exposure therapy with evidence-based treatments for substance dependence because no significant benefits were observed for substance-related outcomes with exposure therapy. We await replication of these results in a US sample, especially in those with combat trauma.


Randomized Controlled Trial of Contingency Management for Stimulant Use in Community Mental Health Patients With Serious Mental Illness

McDonell MG, Srebnik D, Angelo F, et al

Am J Psychiatry. 2012 Nov 9. doi: 10.1176/appi.ajp.2012.11121831. [Epub ahead of print]

Objective: The primary objective of this study was to determine whether contingency management was associated with increased abstinence from stimulant drug use in stimulant-dependent patients with serious mental illness treated in a community mental health center. Secondary objectives were to determine whether contingency management was associated with reductions in use of other substances, psychiatric symptoms, HIV risk behavior, and inpatient service utilization.

Methods: A randomized controlled design was used to compare outcomes of 176 outpatients with serious mental illness and stimulant dependence. Participants were randomly assigned to receive 3 months of contingency management for stimulant abstinence plus treatment as usual or treatment as usual with reinforcement for study participation only. Urine drug tests and self-report, clinician-report, and service utilization outcomes were assessed during the 3-month treatment period and the 3-month follow-up period.

Results: Although participants in the contingency management condition were significantly less likely to complete the treatment period than those assigned to the control condition (42% compared with 65%), they were 2.4 times (95% CI=1.9-3.0) more likely to submit a stimulant-negative urine test during treatment. Compared with participants in the control condition, they had significantly lower levels of alcohol use, injection drug use, and psychiatric symptoms and were one-fifth as likely as those assigned to the control condition to be admitted for psychiatric hospitalization during treatment. They also reported significantly fewer days of stimulant drug use during the 3-month follow-up.

Conclusions: When added to treatment as usual, contingency management is associated with large reductions in stimulant, injection drug, and alcohol use. Reductions in psychiatric symptoms and hospitalizations are important secondary benefits.

Clinical Commentary

About 50% of patients with serious mental illness suffer from a substance use disorder at some point in their lives. Contingency management is an evidence-based intervention for substance dependence in which individuals are provided with reinforcers (eg, vouchers, prizes) based on abstinence from drugs. The present study is the first adequately powered randomized controlled trial conducted to evaluate the efficacy of 12-week, contingency management alone or as an adjunct to treatment as usual for cocaine and/or methamphetamine dependence in 176 patients with schizophrenia, bipolar disorder, or recurrent major depressive disorder. The results were impressive. Participants who received the contingency management intervention showed favorable effects on stimulant-negative urine samples during treatment (primary outcome) as well as several secondary outcomes such as alcohol use, HIV risk behavior, psychiatric symptoms, and inpatient care (138 fewer days of hospitalization in treatment group versus control group). Of note, the positive effects of contingency management on stimulant abstinence persisted after treatment was discontinued. The intervention was delivered at low cost. For example, the cost of urine testing and reinforcers was $256 per participant for the treatment group. The principal limitation was that 42% of subjects completed contingency management compared to 65% in the control group, suggesting that acceptability of the intervention among patients with serious mental illness is not universal. Unfortunately, despite empirical support and potential cost savings, it appears that contingency management will continue to be underutilized in clinical settings until payers provide funding for the costs of delivering this treatment.

The Role of the Asn40Asp Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review

Ray LA, Barr CS, Blendy JA, et al

Alcohol Clin Exp Res. 2012;36(3):385-394.

The endogenous opioid system has been implicated in the pathophysiology of alcoholism, as it modulates the neurobehavioral effects of alcohol. A variant in the mu-opioid receptor gene (OPRM1), the Asn40Asp polymorphism has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: genetic association studies; behavioral studies of alcoholism; neuroimaging studies; pharmacogenetic studies and clinical trials; and preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response.

Clinical Commentary

The research enthusiasm for advancing our understanding of the genetic underpinnings of alcohol dependence has yet to be translated into clinical benefit. There is convergence of evidence that the mu-opioid receptor gene (OPRM1) may be a promising candidate gene in alcohol dependence. This review focuses on effects of the allelic variations in the OPRM1 gene, the Asn40Asp polymorphism in particular, on the etiopathology and treatment of alcohol dependence. Clinicians and researchers should take note of the rapidly accumulating evidence for the effect of the ORM1 Asn40Asp polymorphism on alcohol-related endophenotypes and response to opioid antagonist medications. Post hoc analyses of the COMBINE study, one of the largest controlled trial in alcohol dependence, showed that this polymorphism predicted response to naltrexone, an FDA-approved medication for alcohol dependence. If these findings are confirmed by a prospective randomized controlled pharmacogenetic clinical trial, it opens up the possibility for the OPRM1 receptor to be examined as a genetic biomarker for alcohol dependence and moreover for the FDA to consider pharmacogenetic indications in alcohol dependence. Although much work remains to be done, it appears that this line of research holds promise for increased understanding of pathways to risk and recovery from alcohol dependence and improving treatment outcomes.

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