A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence.

BACKGROUND: Modafinil is a medication approved for narcolepsy and shift work sleep disorder. It has both dopaminergic and glutamatergic activity that could be useful for the treatment of cocaine dependence. Modafinil has reduced cocaine subjective effects and cocaine self-administration in human laboratory trials and has reduced cocaine use in cocaine dependent patients in some clinical trials. METHODS: This was an 8-week, double blind, placebo controlled clinical trial involving 94 cocaine dependent subjects. Subjects received 300mg of modafinil or identical placebo daily along with weekly individual therapy. The primary outcome measure was cocaine use measured by self-report, and confirmed by twice weekly urine benzoylecgonine tests (UBT). Additional outcome measures included cocaine craving measured by the Brief Substance Craving Scale and global improvement measured by the Clinical Global Impression Scale (CGI). RESULTS: The odds ratio (OR) in favor of abstinence for modafinil vs. placebo was 2.54 (p=. 03) and modafinil-treated subjects were significantly more likely than placebo-treated subjects to be abstinent from cocaine during the last 3 weeks of the trial, 23% vs. 9%, χ(2)=3.9, p<.05. Modafinil treated subjects were more likely to report very low levels of cocaine craving intensity and duration on the Brief Substance Craving Scale (OR=2.04, p=.03 and OR 1.06, p=.03 respectively). Modafinil-treated subjects were also more likely than placebo-treated subjects to rate themselves as "very much improved" on the CGI (OR=2.69, p=.03). CONCLUSION: Modafinil may be an efficacious treatment for cocaine dependence.

A pilot trial of injectable, extended-release naltrexone for the treatment of co-occurring cocaine and alcohol dependence.

BACKGROUND: There is a high co-occurrence of cocaine and alcohol use disorders, and patients with both of these problems are difficult to treat. There is a reasonable rationale and some empirical data to justify a pilot trial of an injectable, extended-release formulation of naltrexone for treating co-occurring cocaine and alcohol addiction. METHODS: Eighty cocaine (n = 80) and alcohol dependent, treatment-seeking subjects were randomly assigned to receive either two monthly extended-release injections of naltrexone or two matching placebo injections in an 8-week clinical trial, with weekly medical management plus cognitive behavioral therapy visits. RESULTS: No differences in reduction in cocaine or alcohol use were observed between the injectable naltrexone and placebo groups during the 8-week trial. CONCLUSIONS: Injectable extended-release naltrexone, while an ideal method for ensuring medication adherence in these traditionally hard-to-treat patients, did not result in any measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment.

The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction.

The risk for drug addiction is partially heritable. Genes of the dopamine system are likely candidates to harbour risk variants, as dopamine neurotransmission is involved in mediating the rewarding effects of drugs of abuse. One functional single nucleotide polymorphism in dopamine receptor D2 (DRD2), rs1076560, is involved in regulating splicing of the gene and alters the ratio of DRD2 isoforms located pre- and postsynaptically. rs1076560 has been previously associated with cocaine abuse and we set out to confirm this association in a sample of European American (EA) (n = 336) and African American (AA) (n = 1034) cocaine addicts and EA (n = 656) and AA (n = 668) controls. We also analysed the role of rs1076560 in opioid dependence by genotyping EA (n = 1041) and AA (n = 284) opioid addicts. rs1076560 was found to be nominally associated with opioid dependence in EAs (p = 0.02, OR = 1.27) and AAs (p = 0.03, OR = 1.43). When both opioid-addicted ancestral samples were combined, rs1076560 was significantly associated with increased risk for drug dependence (p = 0.0038, OR = 1.29). This association remained significant after correction for multiple testing. No association was found with cocaine dependence. These data demonstrate the importance of dopamine gene variants in the risk for opioid dependence and highlight a functional polymorphism that warrants further study.

Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence.

BACKGROUND: Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence. METHODS: Alcohol dependent subjects (n=40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM). RESULTS: There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6-13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial. CONCLUSIONS: Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.

A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence.

BACKGROUND: Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs. METHODS: The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings. RESULTS: Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate. DISCUSSION: Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.

A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence.

OBJECTIVES: To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial α4ß2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence. METHODS: Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13. RESULTS: The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild. CONCLUSIONS: Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence.

Case-control association study of WLS variants in opioid and cocaine addicted populations.

The opioid receptor family is involved in the development and maintenance of drug addiction. The mu-opioid receptor (MOR) mediates the rewarding effects of multiple drugs, including opiates and cocaine. A number of proteins interact with MOR, potentially modulating MOR function and altering the physiological consequences of drug use. These mu-opioid receptor interacting proteins (MORIPs) are potential therapeutic targets for the treatment of addiction. The Wntless (WLS) protein was recently identified as a MORIP in a yeast two-hybrid screen. In this study, we conducted a case-control association analysis of 16 WLS genetic variants in opioid and cocaine addicted individuals of both African-American (opioid n=336, cocaine n=908) and European-American (opioid n=335, cocaine n=336) ancestry. Of the analyzed SNPs, three were nominally associated with opioid addiction and four were nominally associated with cocaine addiction. None of these associations were significant following multiple testing correction. These data suggest that the common variants of WLS analyzed in this study are not associated with opioid or cocaine addiction. However, this study does not exclude the possibilities that rare variants in WLS may affect susceptibility to drug addiction, or that common variants with small effect size may fall below the detection level of our analysis.

Low frequency genetic variants in the µ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine.

The µ-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute - Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24-0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study.

Current status of co-occurring mood and substance use disorders: a new therapeutic target.

Mood and substance use disorders commonly co-occur, yet there is little evidence-based research to guide the pharmacologic management of these comorbid disorders. The authors review the existing empirical findings, some of which may call into question current clinical pharmacotherapy practices for treating co-occurring mood and substance use disorders. The authors also highlight knowledge gaps that can serve as a basis for future research. The specific mood disorders reviewed are bipolar and major depressive disorders (either one co-occurring with a substance use disorder). Overall, findings from the relatively small amount of available data indicate that pharmacotherapy for managing mood symptoms can be effective in patients with substance dependence, although results have not been consistent across all studies. Also, in most studies, medications for managing mood symptoms did not appear to have an impact on the substance use disorder. In a recent trial for comorbid major depression and alcohol dependence, combination treatment with a medication for depression and another for alcohol dependence was found to reduce depressive symptoms and excessive drinking simultaneously. However, research has only begun to address optimal pharmacologic management of co-occurring disorders. In addition, current clinical treatment for alcohol and drug dependence often excludes new pharmacotherapies approved by the U.S. Food and Drug Administration for treating certain types of addiction. With new data becoming available, it appears that we need to revisit current practice in the pharmacological management of co-occurring mood and substance use disorders.

Further evidence for association of polymorphisms in the CNR1 gene with cocaine addiction: confirmation in an independent sample and meta-analysis.

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide insights for effective treatment. As endocannabinoid signaling and dopamine neurotransmission have been shown to be involved in drug reward, genes related to these systems are plausible candidates for susceptibility to CD. The cannabinoid receptor 1 protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the cannabinoid receptor gene, CNR1, have been associated previously with substance dependence. In this study, we attempt to replicate findings associating CNR1 with CD in African Americans. Cocaine-addicted individuals (n=860) and unaffected controls (n=334) of African descent were genotyped for two single nucleotide polymorphisms (SNPs) in CNR1 (rs6454674, rs806368). We observed a significant difference in genotype frequencies between cases and controls for both SNPs (P≤0.042). A meta-analysis was also performed combining our data with that of Zuo et al. who also studied these polymorphisms in African American cocaine addicts (total n=1253 cases versus 543 controls). When our data were combined, rs6454674 increased in significance to P=0.027; however, rs806368 was no longer significant. This study confirms the association between rs6454674 and CD. However, because there is considerable co-morbidity of CD with other drugs of abuse, additional studies are necessary to determine whether polymorphisms in CNR1 induce a general susceptibility to substance dependence or are specific to cocaine addiction. Furthermore, as this population consists of American individuals of African descent, the possibility of population stratification should not be excluded.

Neuronal calcium sensor-1 and cocaine addiction: a genetic association study in African-Americans and European Americans.

Genes involved in drug reward pathways are plausible candidates for susceptibility to substance use disorders. Given the prominent role of dopamine in drug reward, dopamine receptor-interacting proteins (DRIPs) such as the neuronal calcium sensor-1 (NCS-1) protein have been hypothesized to play a role in the pathophysiology of cocaine addiction (CA). In this study, we investigated whether genetic variants in the NCS-1 gene confer risk to CA. We genotyped 8 SNPs (rs4837479, rs7849345, rs3824544, rs10819611, rs947513, rs2277200, rs7873936 and rs1342043) in our discovery sample (cases n = 796, controls n = 416) of African descent. Confirmation of associated or trending SNPs (rs7849345, rs10819611, rs1342043) was attempted using a replication sample of African American (AA) ethnicity (cases n = 335, controls n = 336) and European-American (EA) ancestry (cases n = 336, controls n = 656). Secondary sex specific analysis was also carried out for each SNP in both AA and EA individuals. Genotyping of the discovery cohort showed significant genotypic (p = 0.0005, corrected q-value) as well as allelic (p = 0.005, corrected q-value) associations of rs1342043 with CA in AAs; however, this marker could not be confirmed in either the AA or EA replication sample. Combined analysis of all AA samples (n = 1883) for rs1342043 showed a significant association with CA (genotypic p = 0.0001, allelic p = 0.002) with a gender specific effect for males (allelic p = 0.005, genotypic p = 0.0003). Our data suggest that genetic variants in the NCS-1 gene contribute to susceptibility of CA in individuals of African descent.

A double-blind, placebo-controlled trial of modafinil for cocaine dependence.

This is a randomized, double-blind, placebo-controlled study of modafinil treatment for cocaine dependence. Patients (N = 210) who were actively using cocaine at baseline were randomized to 8 weeks of modafinil (0 mg/day, 200 mg/day, or 400 mg/day) combined with once-weekly cognitive-behavioral therapy. Our primary efficacy measure was cocaine abstinence, based on urine benzoylecgonine (BE) levels, with secondary measures of craving, cocaine withdrawal, retention, and tolerability. We found no significant differences between modafinil and placebo patients on any of these measures. However, there was a significant gender difference in that male patients treated with 400 mg/day tended to be more abstinent than their placebo-treated counterparts (p = .06). Our negative findings might be explained by gender differences and/or inadequate psychosocial treatment intensity in patients with severe cocaine dependence.

Results of an initial clinical trial of varenicline for the treatment of cocaine dependence.

BACKGROUND: Cocaine use, abuse and dependence remains a pressing public health problem. Based on its mechanism of action, varenicline, an alpha4beta2 partial agonist seemed to be a likely candidate for treating cocaine dependence. METHODS: Cocaine dependent participants (n=37) were enrolled in a 9-week double-blind placebo controlled clinical trial. Varenicline was titrated up to a target dose of 1mg BID during the first week of medication. RESULTS: Varenicline was associated with lower odds of cocaine use than placebo (OR=2.02, p=0.08), as measured by thrice-weekly urinalysis results. Compared to placebo-treated participants, varenicline treated participants had significantly decreased rates of cocaine reward, as measured by the Multiple Choice Procedure (MCP) (p=0.02). CONCLUSIONS: Varenicline appears to decrease cocaine use and reward, suggesting that further investigation of varenicline may be warranted.

Efficacy of extended-release naltrexone in patients with relatively higher severity of alcohol dependence.

BACKGROUND: Because some literature reviews have suggested that naltrexone's benefit may be limited to less-severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended-release naltrexone (XR-NTX 380 mg) in patients with relatively higher severity alcohol dependence. METHODS: Post hoc analyses examined data from a multicenter, placebo-controlled, 24-week randomized trial of XR-NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol-dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead-in abstinence prior to treatment-a major predictor of good outcome in the original study. RESULTS: Higher severity alcohol-dependent patients, defined by the ADS, when receiving XR-NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy-drinking days in-trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy-drinking days compared with 27.4% for placebo-treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR-NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead-in abstinence experienced significantly better maintenance of initial and 6-month abstinence. CONCLUSIONS: These secondary analyses support the efficacy of XR-NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy.

Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone.

The emergence of extended-release naltrexone (XR-NTX) raises the opportunity to explore the role of endorphin blockade on hedonic response during long-term alcohol dependence treatment. A hedonic survey was administered to 74 alcohol dependent patients treated for an average of 3.5 years with nearly continuous month-long intramuscular XR-NTX. The paper-and-pencil, one-time survey asked patients about the degree of pleasure they experienced in the past 90 days with drinking alcohol, sex, exercise and other daily activities. The data revealed lower pleasure ratings for alcohol than for sex, exercise and 10 other common activities. Mean responses to drinking alcohol and gambling were significantly lower than to listening to music, sex, reading, being with friends, eating good food, eating spicy food, and playing video/card games. This effect was independent of XR-NTX dose or duration. Although this exploratory study lacked baseline data, a comparison group or control for the impact of patient discontinuation, the data indicate the feasibility of examining long-term hedonic response in recovery. The differential hedonic ratings suggest that, in patients who persist with long-term continuous therapy, XR-NTX may selectively inhibit the pleasure associated with drinking alcohol, compared to a variety of other activities.

A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence.

BACKGROUND: Acamprosate is a medication shown to be effective for the treatment of alcohol dependence. Although the exact mechanism of action of acamprosate is unknown, evidence suggests that it decreases excitatory amino acid activity by post-synaptic inhibition of the NMDA subtype of glutamate receptors. It is possible that the activity of acamprosate via modulating glutamatergic activity could also reduce craving for cocaine and impact abstinence in cocaine dependence. Therefore, we conducted a double-blind placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. METHODS: Sixty male and female cocaine dependent patients were included in a nine week double-blind, placebo-controlled trial. After a one-week baseline, patients were randomized to receive acamprosate 666 mg three times daily or identical placebo tablets for eight weeks. The primary outcome measure was cocaine use as determined by twice weekly urine drug screens. RESULTS: Thirty-six patients (60%) completed the trial, with no significant between-group difference in treatment retention. Percent cocaine positive urine drug screens did not differ between the two groups. Acamprosate was no better than placebo in reducing cocaine craving, reducing cocaine withdrawal symptoms, or improving measures of drug use severity from the Addiction Severity Index. Adverse events in this trial were generally mild and were evenly distributed between the two groups. DISCUSSION: Acamprosate was well tolerated but was no more efficacious than placebo in promoting abstinence from cocaine in cocaine dependent patients. Acamprosate does not appear to be a promising medication for the treatment of cocaine dependence.

Gender differences in alcohol treatment: an analysis of outcome from the COMBINE study.

BACKGROUND: Relatively few studies have examined gender differences in the effectiveness of specific behavioral or pharmacologic treatment of alcohol dependence. The aim of this study is to assess whether there were gender differences in treatment outcomes for specific behavioral and medication treatments singly or in combination by conducting a secondary analysis of public access data from the national, multisite NIAAA-sponsored COMBINE study. METHODS: The COMBINE study investigated alcohol treatment among 8 groups of patients (378 women, 848 men) who received medical management (MM) with 16 weeks of placebo, naltrexone (100 mg/day), acamprosate (3 g/day), or their combination with or without a specialist-delivered combined behavioral intervention. We examined efficacy measures separately for men and women, followed by an overall analysis that included gender and its interaction with treatment condition in the analyses. These analyses were performed to confirm whether the findings reported in the parent trial were also relevant to women, and to more closely examine secondary outcome variables that were not analyzed previously for gender effects. RESULTS: Compared to men, women reported a later age of onset of alcohol dependence by approximately 3 years, were significantly less likely to have had previous alcohol treatment, and drank fewer drinks per drinking day. Otherwise, there were no baseline gender differences in drinking measures. Outcome analyses of 2 primary (percent days abstinent and time to first heavy drinking day) and 2 secondary (good clinical response and percent heavy drinking days) drinking measures yielded the same overall pattern in each gender as that observed in the parent COMBINE study report. That is, only the naltrexone by behavioral intervention interaction reached or approached significance in women as well as in men. There was a naltrexone main effect that was significant in both men and women in reduction in alcohol craving scores with naltrexone-treated subjects reporting lower craving than placebo-treated subjects. CONCLUSIONS: This gender-focused analysis found that alcohol-dependent women responded to naltrexone with COMBINE's Medical Management, similar to the alcohol-dependent men, on a wide range of outcome measures. These results suggest that clinicians can feel comfortable prescribing naltrexone for alcohol dependence in both men and women. In this study, it is also notable that fewer women than men reported receiving any alcohol treatment prior to entry into the COMBINE study. Of note, women tend to go to primary health care more frequently than to specialty substance abuse programs for treatment, and so the benefit we confirm for women of the naltrexone and MM combination has practical implications for treating alcohol-dependent women.

A double-blind, placebo-controlled study with quetiapine as adjunct therapy with lithium or divalproex in bipolar I patients with coexisting alcohol dependence.

BACKGROUND: This study evaluated the efficacy of quetiapine versus placebo as an adjunct to lithium or divalproex in reducing alcohol consumption in patients with bipolar I disorder and coexisting alcohol dependence. METHODS: Male and female outpatients (21 to 60 years) with a history of bipolar I disorder and alcohol dependence were included in this 12-week, placebo-controlled study. Patients treated with lithium or divalproex (ongoing or assigned at screening) were randomized to receive quetiapine (dosed up to 400 mg/d over 7 days, followed by 300 to 800 mg/d flexible dosing until study end) or placebo. The primary outcome measure was the change in the proportion of heavy drinking days from baseline to Week 12 (as derived from the Timeline Followback method). Secondary outcome measures included time to the first consecutive 2 weeks of abstinence, changes from baseline to Week 12 in the proportion of nondrinking days, mean number of standardized drinks per day, and Clinical Global Impressions-Severity of Illness score. RESULTS: Of 362 enrolled patients (mean 38.6 years), 176 were randomized to receive quetiapine and 186 to placebo. The mean proportion of heavy drinking days at baseline was 0.66 in the quetiapine group and 0.67 in the placebo group. At Week 12, the mean change in the proportion of heavy drinking days was -0.36 with quetiapine and -0.36 with placebo (p = 0.93). No statistically significant differences in any of the secondary outcome measures were noted between the quetiapine and placebo groups. The incidence of adverse events was consistent with the previously known tolerability profile of quetiapine. CONCLUSIONS: The efficacy of quetiapine in the treatment of bipolar disorder is already well established. In this study, however, quetiapine added to lithium or divalproex did not result in significantly greater improvement compared with placebo in measures of alcohol use and dependence in patients with bipolar I disorder and alcohol dependence.

A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence.

OBJECTIVE: Empirical evidence has only weakly supported antidepressant treatment for patients with co-occurring depression and alcohol dependence. While some studies have demonstrated that antidepressants reduce depressive symptoms in individuals with depression and alcohol dependence, most studies have not found antidepressant treatment helpful in reducing excessive drinking in these patients. The authors provide results from a double-blind, placebo-controlled trial that evaluated the efficacy of combining approved medications for depression (sertraline) and alcohol dependence (naltrexone) in treating patients with both disorders. METHOD: A total of 170 depressed alcohol-dependent patients were randomly assigned to receive 14 weeks of treatment with sertraline (200 mg/day [N=40]), naltrexone (100 mg/day [N=49]), the combination of sertraline plus naltrexone (N=42), or double placebo (N=39) while receiving weekly cognitive-behavioral therapy. RESULTS: The sertraline plus naltrexone combination produced a higher alcohol abstinence rate (53.7%) and demonstrated a longer delay before relapse to heavy drinking (median delay=98 days) than the naltrexone (abstinence rate: 21.3%; delay=29 days), sertraline (abstinence rate: 27.5%; delay=23 days), and placebo (abstinence rate: 23.1%; delay=26 days) groups. The number of patients in the medication combination group not depressed by the end of treatment (83.3%) approached significance when compared with patients in the other treatment groups. The serious adverse event rate was 25.9%, with fewer reported with the medication combination (11.9%) than the other treatments. CONCLUSIONS: More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol, had delayed relapse to heavy drinking, reported fewer serious adverse events, and tended to not be depressed by the end of treatment.

Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence.

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide novel insights for effective treatment. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to CD. The dopamine receptor D(2) (DRD2) protein and dopamine transporter (DAT1) protein play regulatory roles in dopamine neurotransmission. The TaqI A single-nucleotide polymorphism (SNP) in the DRD2 gene and the 3' variable number tandem repeat (VNTR) polymorphism in the DAT1 gene have been implicated in psychiatric disorders and drug addictions. In this study, we hypothesize that these polymorphisms contribute to increased risk for CD. Cocaine-dependent individuals (n=347) and unaffected controls (n=257) of African descent were genotyped for the polymorphisms in the DRD2 and DAT1 genes. We observed no statistically significant differences or trends in allele or genotype frequencies between cases and controls for either of the tested polymorphisms. Our study suggests that there is no association between the DRD2 and DAT1 polymorphisms and CD. However, additional studies using larger sample sizes and clinically homogenous populations are necessary before confidently excluding these variants as contributing genetic risk factors for CD.