Do routinely measured risk factors for obesity explain the sex gap in its prevalence? Observations from Saudi Arabia.

BACKGROUND: The prevalence of adult obesity is higher in women than men in most countries. However, the pathways that link female sex with excess obesity are still not fully understood. We examine whether socioeconomic and behavioural factors may mediate the association between sex and obesity in the Saudi Arabian setting where there is female excess in obesity. METHODS: We performed a mediation analysis using a cross-sectional, national household survey from Saudi Arabia with 4758 participants (51% female). A series of multivariable regression models were fitted to test if socioeconomic position, physical activity, sedentary behaviour, diet, and smoking mediate the association between sex and obesity (BMI >=30). The findings were confirmed using causal mediation analysis. RESULTS: Women in this sample were roughly twice as likely as men to be obese (crude OR 1.9; 95% CI 1.6-2.3). The odds ratio remained significantly higher for women compared to men in models testing for mediation (OR range 1.95-2.06). Our data suggest that indicators of socio-economic position, physical activity, sedentary behaviour, diet, and smoking do not mediate the sex differences in obesity. CONCLUSIONS: Our analysis shows that most commonly measured risk factors for obesity do not explain the sex differences in its prevalence in the Saudi context. Further research is needed to understand what might explain the female excess in obesity prevalence. We discuss how data related to the lived experience of Saudi men and women may tap into underlying mechanisms by which the sex difference in obesity prevalence are produced.

A randomized, double-blind, placebo-controlled trial of venlafaxine for the treatment of depressed cocaine-dependent patients.

OBJECTIVE: This study tested the hypothesis that the antidepressant venlafaxine would be an effective treatment for cocaine abusers with concurrent depressive disorders. METHODS: This was a randomized, 12-week, double-blind, placebo-controlled trial of outpatients (N = 130) meeting DSM-IIIR criteria for cocaine dependence and major depression or dysthymia (by SCID interview). Participants were treated with venlafaxine, up to 300 mg/day versus placebo. All patients received weekly individual manual-guided relapse prevention therapy. Weekly outcome measures included Clinical Global Impression Scale (CGI), self-reported cocaine use, urine toxicology and the Hamilton Depression Scale (Ham-D). RESULTS: Mood response, defined as a 50% reduction in the Ham-D between randomization and end of study, was 41% (26/64) on venlafaxine, and 33% (22/66) on placebo (p = .39). Measures of depression (Ham-D and CGI) improved more rapidly on venlafaxine than placebo, but these differences disappeared by weeks 6-8. Cocaine outcomes did not differ between treatment groups, and the proportion of patients achieving three or more consecutive weeks of urine-confirmed abstinence was low (venlafaxine: 16%; placebo: 15%). Reduction in cocaine use was associated with mood response. CONCLUSIONS: Overall, venlafaxine was not superior to placebo on either mood or cocaine use outcomes. Mood improvement was associated with improvement in cocaine use. However, placebo mood response was only moderate, and the proportion of patients achieving sustained abstinence was low. This suggests that the subgroup of cocaine-dependent patients with depressive disorders is relatively treatment resistant, and that further research is needed to improve outcomes for these patients.

Dextromethorphan and quinidine combination for heroin detoxification.

Dextromethorphan (DM) is a low-affinity, non-competitive NMDA receptor antagonist that has shown promise in preclinical and preliminary clinical studies for the reduction of opioid withdrawal symptoms, but when used at higher doses, it is associated with deleterious side effects attributed to its metabolite, dextrorphan. A clinical trial was therefore conducted to test the withdrawal-suppressant effect of a combination of dextromethorphan with quinidine (DM/Q). Quinidine inhibits the metabolism of dextromethorphan, reducing dextrorphan levels. Opioid-dependent patients were admitted to an inpatient unit, stabilized for three days on morphine (25 mg, sc, every six hours), and randomly assigned on day 2 to DM/Q (30 mg/30 mg, twice a day) (n = 22) or matching placebo (n = 9) prior to the discontinuation of morphine on day 4. Withdrawal symptoms, measured with the Modified Himmelsbach Opioid Withdrawal Scale (MHOWS), increased significantly on days 4 and 5 (Z = 3.70, p = .0002), and by day 6, 90% of the sample (28/31) had dropped out of the study. There were no differences between treatment groups on either outcome measure. The combination of dextromethorphan and quinidine appears ineffective as a primary treatment for opioid withdrawal. Future studies should examine dextromethorphan as an adjunct to other anti-withdrawal medications and focus more on the relationship between dextrorphan levels and withdrawal suppression.

Effects of major depressive disorder and attention-deficit/hyperactivity disorder on the outcome of treatment for cocaine dependence.

Co-occurring psychiatric disorders have been associated with poor prognosis among substance-dependent patients, but few studies have examined this association among patients with cocaine dependence (CD). We compared baseline characteristics and treatment outcome between cocaine-dependent patients with major depressive disorder (MDD; n = 66), those with attention-deficit/hyperactivity disorder (ADHD; n = 53), and those with CD without comorbid disorders (CD alone; n = 48) who had been randomized to the placebo arms of clinical trials with venlafaxine, methylphenidate, and gabapentin, respectively. The three groups differed significantly in racial makeup, with more Caucasians and Hispanics among patients with MDD and those with ADHD but more African Americans among those with CD alone. The groups did not differ significantly in treatment retention, with retention rates ranging from 42% to 47%; neither did they differ in the rates of achieving 2 consecutive weeks of urinalysis-confirmed abstinence, with rates ranging from 40% to 50%. Using logistic regression for repeated measures with general estimating equations, modeling the likelihood of a cocaine-positive week over time in treatment, we found the diagnostic group to interact with the baseline level of cocaine use and time. Among cocaine-dependent patients who achieved abstinence at baseline, those with MDD and those with ADHD had better outcome over time as compared with patients with CD alone. However, among patients with cocaine-positive urine specimens at baseline, those with MDD and those with ADHD were associated with poor outcome as compared with patients with CD alone. The findings suggest that diagnosis and treatment of co-occurring disorders such as depression and ADHD may be important components of treatment planning for CD and that the baseline level of cocaine use should be included as a covariate in studies evaluating the impact of such treatment.

Management of relapse in naltrexone maintenance for heroin dependence.

UNLABELLED: Opioid dependence is a growing public health problem. Maintenance on the antagonist naltrexone for clinic- or office-based treatment of opioid dependence is plagued by high rates of relapse. This paper identifies critical determinants of lapses to opioid use during naltrexone maintenance. Time retained in treatment was examined as a function of whether lapses to opioid use occurred while adherent to naltrexone (blocked use), or after having missed naltrexone doses (unblocked). METHOD: Participants (N=83) met DSM-IV criteria for opioid dependence and identified a significant other willing to participate in their treatment. Following inpatient detoxification, participants were enrolled in a 26-week outpatient course of therapy and naltrexone maintenance. RESULTS: Patients with unblocked use had a very high rate of dropout (10% retained at 6 months), dropout usually occurring within 2 weeks after unblocked use. Patients with only blocked use had less dropout (33% retained at 6 months). However, episodes of blocked use were often followed by unblocked use and dropout. CONCLUSIONS: During naltrexone maintenance for opioid dependence unblocked opioid use calls for immediate intervention, such as detoxification or switching to the partial agonist buprenorphine. Episodes of blocked use warrant increased clinical attention, such as direct observation of naltrexone ingestion, increased dose, or increased intensity of treatment contact. Maintenance on oral naltrexone is a fragile treatment because it is so easily undermined by episodes of opioid use while non-compliant. New long-acting injectable or implantable formulations of naltrexone may address this limitation and should be investigated for treatment of opioid dependence.

A pilot double-blind treatment trial of memantine for alcohol dependence.

BACKGROUND: There is growing evidence that N-methyl-d-aspartate (NMDA) receptor antagonists may have potential for the treatment of alcohol disorders. Memantine is a selective noncompetitive NMDA receptor antagonist that has been shown to decrease alcohol craving in moderate drinkers. This 16-week double-blind outpatient pilot clinical trial determined if memantine was more effective than placebo at reducing alcohol use in actively drinking alcohol-dependent patients. METHODS: Forty-four treatment-seeking alcohol-dependent individuals were enrolled, with 34 patients stratified to either the memantine group (n=19; maximum dose of 40 mg/d) or the placebo (PBO; n=15) group. The primary outcome measures were related to alcohol use (average drinks per day, average drinks per drinking day, percentage of heavy drinking days, and percentage of days abstinent) based on the timeline follow-back (TLFB). Secondary outcome measures included the Obsessive Compulsive Drinking Scale, Clinical Global Impression ratings, and gamma-glutamyltransferase (GGT), a biomarker of recent alcohol use. To enhance retention, patients received voucher incentives for clinic attendance. RESULTS: Of those randomized, approximately 80% (27) completed the entire 16-week trial. Longitudinal analysis of drinks per day and drinks per drinking day showed a significant reduction in alcohol use, but no difference between the 2 groups. Further, the percentage of heavy drinking days indicated that both groups showed a significant decrease in drinking behavior, but there was significant treatment effect in favor of the PBO group. Similarly, for the percentage of days abstinent, the PBO group achieved a significantly greater percentage of days abstinent at a faster rate than the memantine group. Lastly, the memantine group reported a greater number of side effects compared with the PBO group, such that 26% of patients had their drug dose decreased or discontinued due to memantine-related side effects. CONCLUSIONS: The results of this double-blind placebo-controlled pilot trial do not support the use of memantine for the treatment of actively drinking alcohol-dependent patients. However, voucher incentives did facilitate retention.

Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo.

The purpose of this double-blind 14-week trial was to compare the efficacy of sustained-release methylphenidate (MPH) to placebo (PBO) in treating adult attention deficit hyperactivity disorder (ADHD) symptoms in current cocaine dependent (CD) treatment seekers. The randomized sample consisted of 106 participants who were predominately male (83%) and 60% Caucasian, 14% Hispanic, 20% African-American and 6% other. All participants met DSM-IV criteria for ADHD and CD. There were no significant demographic differences between the two treatment groups. All participants received weekly individual cognitive behavioral therapy. There was no difference in retention rate based on treatment group (p=.91). The majority of the PBO group and the MPH group reported >30% improvement in their ADHD symptoms (55% versus 47%), with no significant difference between the two groups (p=.44). Using a combined outcome measure (>30% reduction in ADHD symptoms and CGI <3), the response rates were similar for both groups (28% PBO versus 30% MPH; p=.83). Longitudinal analyses of the urine toxicology data using generalized estimating equations, revealed a decrease in the probability of cocaine positive urine samples during the trial for the MPH group compared to the PBO group (p=.001). Further analysis suggested that for the MPH group, ADHD treatment responders, based on a semi structured clinical interview, were more likely to have a reduction in cocaine use compared to the non-ADHD responders. Although sustained-release MPH did not show superiority over PBO in treating ADHD symptoms, this trial provides some evidence that improvement in ADHD symptoms (clinician rated) among those patients receiving MPH, but not placebo, was associated with a reduction in cocaine use.

Effects of alternative reinforcer and craving on the choice to smoke cigarettes in the laboratory.

We examined to what extent craving for cigarettes and the magnitude of an alternative monetary reinforcer were predictors of the choice to smoke in the human laboratory. Twelve non-treatment-seeking nicotine-dependent volunteers participated in a series of outpatient sessions during which they had repeated opportunities to select between three puffs of a cigarette and a variety of monetary alternatives ($0.50-3), responding under a progressive-ratio schedule. Level of cigarette craving was measured at baseline and between each choice opportunity. The probability of choosing a cigarette decreased significantly with the increase in the magnitude of the alternative reinforcer. Baseline level of craving did not significantly alter the probability of choosing a cigarette, but a craving component related to the anticipation of positive effects from smoking, assessed repeatedly between choice opportunities, was predictive of the choice to smoke. These results demonstrate that the cigarette puff self-administration procedure is sensitive to environmental manipulations and cigarette puff choice can be modified by the availability of an alternative reinforcer. This paradigm models the motivational component associated with choice to smoke and could be used to evaluate the effects of pharmacological and behavioral interventions to decrease cigarette smoking.

Concurrent cannabis use during treatment for comorbid ADHD and cocaine dependence: effects on outcome.

Cannabis is the most widely used illicit substance in the United States with especially high prevalence of use among those with psychiatric disorders. Few studies have examined the relationship between concurrent cannabis use and treatment outcome among patients receiving treatment for comorbid substance abuse and psychiatric disorders. This study investigated the effects of cannabis use on treatment retention and abstinence from cocaine among cocaine dependent patients with Attention Deficit Hyperactivity Disorder (ADHD). Cocaine dependent patients diagnosed with current ADHD (DSM-IV, N = 92) aged 25 to 51 participated in a randomized clinical trial of methylphenidate for treatment of ADHD and cocaine dependence in an outpatient setting. The majority of patients (69%) used cannabis during treatment. Results suggest that moderate/intermittent cannabis users had greater retention rates compared to abstainers and consistent users (p = .02). This study is the first to examine concurrent cannabis use in cocaine dependent patients diagnosed with ADHD.

Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo.

The purpose of this double-blind, three-arm, 12-week trial was to compare the efficacy of sustained-release methylphenidate or sustained-release bupropion to placebo in treating adult attention deficit hyperactivity disorder (ADHD) symptoms. The randomized sample consisted of 98 methadone-maintained patients who were pre-dominantly male (57%) and 40% Caucasian, 40% Hispanic and 20% African American. All participants met DSM-IV criteria for adult ADHD, with 53% meeting DSM-IV criteria for cocaine dependence/abuse. In addition to medication and treatment as usual at a methadone program, individuals received weekly individual cognitive behavioral treatment. Other than current employment status, there were no significant demographic differences across the three treatment groups. Seventy percent completed the 12-week trial. There were no differences in retention rate based on treatment group. A reduction in ADHD symptoms using the adult ADHD rating scale was observed in all three groups, but there were no significant differences in outcome between treatments. The placebo response rate was high, with 46% of the placebo group self-reporting substantial improvement in their ADHD symptoms (>30% reduction in adult ADHD rating scale). Using other ADHD outcome measures, the placebo response and medication response rates were substantially lower. There was no evidence of misuse of medication or worsening of cocaine use among those randomized to methylphenidate. Taken together, sustained-release methylphenidate or sustained-release bupropion did not provide a clear advantage over placebo in reducing ADHD symptoms or additional cocaine use in methadone-maintained patients.

A randomized placebo-controlled trial of gabapentin for cocaine dependence.

BACKGROUND: In laboratory animals, augmentation of GABA neurotransmission results in inhibition of cocaine self-administration and inhibition of reinstatement to cocaine-seeking behaviors. If parallel effects were observed in humans, GABA-ergic medication should be effective both in the abstinence-induction as well as in the relapse-prevention phase of cocaine dependence treatment. Gabapentin is an anticonvulsant medication that increases human brain GABA levels. We evaluated the safety and efficacy of gabapentin combined with relapse-prevention therapy in the treatment of cocaine-dependent individuals. DESIGN: The study involved 129 individuals with cocaine dependence. Of the 99 participants, who were randomized into a double-blind trial 88% were males, 66% were minorities and with an average age of 39 years (range 22-58 years). After 2 weeks of placebo lead-in, participants were randomized to receive either gabapentin 3200 mg (1600 mg bid) or placebo for 12 weeks, followed by 2 weeks of placebo lead-out. Prior to randomization, participants were stratified into four groups based on the principal route of cocaine use (smokers versus intranasal users) and the level of cocaine use during the 2 weeks of lead-in (high level versus low level). Throughout the 16 weeks study, participants received weekly individual relapse-prevention therapy. The outcome measures included: days of cocaine use and a binary indicator of abstinence based on urine toxicology test, self-reported cocaine craving and retention in treatment. RESULTS: Forty-nine percent of randomized patients completed 12 weeks of the trial. Retention did not differ by treatment group but cocaine-smokers dropped out of treatment at a significantly faster rate than intranasal users. For the entire sample, odds of cocaine use over the course of the study did not differ between gabapentin- and placebo-treated individuals. There was a significant difference in the odds of cocaine use between high and low-use groups, with the odds in high-use groups decreasing over time and odds in the low-use groups gradually increasing over the course of the study, such that by the end of the study low and high users were similarly likely to use cocaine. In the low-use group, there was a non-significant trend suggesting that gabapentin-treated subjects had more favorable outcome compared to placebo-treated individuals. There was no treatment effect on abstinence rates, craving or other substance use. Gabapentin at 3200 mg/day was very well tolerated in this group of cocaine-dependent participants. CONCLUSIONS: When combined with weekly individual relapse-prevention therapy, gabapentin 1600 mg bid was no more effective than placebo in the treatment of cocaine dependence. When reviewed in conjunction with other published studies, gabapentin and other GABA enhancing anticonvulsant medications may deserve further study as relapse-preventive agents in cocaine-dependent individuals who achieve abstinence early in treatment.

Utility of lead-in period in cocaine dependence pharmacotherapy trials.

We examined whether drug use behaviors during a 2-week lead-in for a pharmacotherapy trial were predictive of retention in treatment and of the level of cocaine use during the subsequent 12 weeks of treatment. Fifty cocaine dependent patients were grouped based on: (1) principal route of cocaine administration: intranasal versus smoking, and (2) level of cocaine use during the 2-week lead-in: high versus low. Results indicate that level of cocaine use during the 2-week lead-in was a significant predictor of cocaine use during the subsequent 12 weeks of treatment. Patients with reported higher level of use during the lead-in period were more likely to continue using cocaine during the treatment. Patients who used smoking as their primary route of cocaine use were more likely to drop out early in the treatment. Findings of this study suggest that route and level of cocaine use during lead-in be used as a covariate in models testing treatment effect.