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Objectives: Yoga and exercise have beneficial effects on mood and anxiety. γ-Aminobutyric acid (GABA)-ergic activity is reduced in mood and anxiety disorders. The practice of yoga postures is associated with increased brain GABA levels. This study addresses the question of whether changes in mood, anxiety, and GABA levels are specific to yoga or related to physical activity. Methods: Healthy subjects with no significant medical/psychiatric disorders were randomized to yoga or a metabolically matched walking intervention for 60 minutes 3 times a week for 12 weeks. Mood and anxiety scales were taken at weeks 0, 4, 8, 12, and before each magnetic resonance spectroscopy scan. Scan 1 was at baseline. Scan 2, obtained after the 12-week intervention, was followed by a 60-minute yoga or walking intervention, which was immediately followed by Scan 3. Results: The yoga subjects ( n = 19) reported greater improvement in mood and greater decreases in anxiety than the walking group ( n = 15). There were positive correlations between improved mood and decreased anxiety and thalamic GABA levels. The yoga group had positive correlations between changes in mood scales and changes in GABA levels. Conclusions: The 12-week yoga intervention was associated with greater improvements in mood and anxiety than a metabolically matched walking exercise. This is the first study to demonstrate that increased thalamic GABA levels are associated with improved mood and decreased anxiety. It is also the first time that a behavioral intervention (i.e., yoga postures) has been associated with a positive correlation between acute increases in thalamic GABA levels and improvements in mood and anxiety scales. Given that pharmacologic agents that increase the activity of the GABA system are prescribed to improve mood and decrease anxiety, the reported correlations are in the expected direction. The possible role of GABA in mediating the beneficial effects of yoga on mood and anxiety warrants further study. [ABSTRACT FROM AUTHOR]

Context: Hypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system.Objective: To determine if topiramate is a safe and efficacious treatment for alcohol dependence.Design, Setting, and Participants: Double-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites.Interventions: Up to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention.Main Outcome Measures: Primary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma gamma-glutamyltransferase).Results: Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%).Conclusion: Topiramate is a promising treatment for alcohol dependence.Trial Registration: clinicaltrials.gov Identifier: NCT00210925. [ABSTRACT FROM AUTHOR]

Context: Alcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.Objectives: To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.Design, Setting, and Participants: Randomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.Interventions: Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.Main Outcome Measures: Percent days abstinent from alcohol and time to first heavy drinking day.Results: All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone x behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.Conclusions: Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.Trial Registration: clinicaltrials.gov Identifier: NCT00006206. [ABSTRACT FROM AUTHOR]

This article highlights the proceedings of a symposium presented at the 27th Annual Scientific Meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, June 29, 2004. The organizers and co-chairs were Bankole A. Johnson, MD, PhD, and Robert M. Swift, MD, PhD. The presentations included (1) Introduction, by Bankole A. Johnson; (2) Safety, Tolerability, and Efficacy of gamma-Hydroxybutyric Acid and Baclofen in the Treatment of Alcohol Addiction, by Giovanni Addolorato; (3) Safety of Gabapentin in Treating Alcoholism, by Hugh Myrick; (4) New Data on the Safety and Effectiveness of Topiramate in the Treatment of Alcohol Dependence, by Bankole A. Johnson; (5) Evaluating the Risk of Benzodiazepine Prescription to Alcohol-Dependent Individuals, by Domenic A. Ciraulo; and (6) Safety and Efficacy of GABAergic Agents in Treating Alcoholics: Discussion, by Robert M. Swift. [ABSTRACT FROM AUTHOR]

A multi-site, open-label study of methylphenidate for treating patients with comorbid diagnoses of attention deficit/hyperactivity disorder and cocaine dependence was performed. Forty-one participants, who met DSM-IV criteria for adult attention deficit/hyperactivity disorder and cocaine dependence, were enrolled into this ten week outpatient study. The targeted total daily dose of methylphenidate was 60 mg (20 mg TID). Participants received individual substance abuse therapy throughout the trial. Safety measures included adverse events, vital signs, and electrocardiograms. Methylphenidate's efficacy was assessed by both objective and subjective measures. Seventy percent of the participants completed final study measures. Safety measures indicated that methylphenidate was well tolerated by the participants. Subjective efficacy measures suggested that participants evidenced improvement in both cocaine dependence and adult attention deficit/hyperactivity disorder symptoms. Quantitative benzoylecgonine indicated that only those participants categorized as being compliant showed improvement. A double-blind, placebo-controlled study of methylphenidate for this population may be warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND: The urge to drink alcohol can be robustly and reliably induced via actual exposure to a person's preferred alcoholic beverage. Unfortunately, these exposure paradigms are unwieldy for functional magnetic resonance imaging studies. The goal of this study was to examine whether viewing a personalized videotaped cue could induce alcohol craving. The following hypotheses were tested: (1) individualized cue videotapes can reliably elicit the urge to drink alcohol in alcohol-dependent participants and (2) alcohol drinking histories can predict reactivity to cue. METHODS: DSM-IV criteria were used to identify an alcohol-dependent group (ADG). Controls included a light-drinking group and a moderate-drinking group. Urge to drink alcohol was assessed at baseline and after each of five in vivo exposure conditions: water (W), alcohol 1 (A1), mood induction (M), alcohol 2 (A2), and relaxation (R). The entire exposure session was videotaped. Each participant's video footage was digitally edited to produce a 17.5-min cue that was presented to the participant 24 to 72 hr later. Ratings of urge to drink alcohol across the five exposure conditions were compared for both the in vivo and the video exposure sessions. RESULTS: Fourteen participants (five in the light-drinking group, four in the moderate-drinking group, and five in the ADG) completed both sessions. Participants in each group showed differences between neutral cue exposure (W and R) and alcohol-related cue exposure (A1, M, and A2) in both the in vivo cue session (p < 0.002) and the videotape session (p < 0.02). Post hoc comparisons among the groups to alcohol-related cues established that, in both sessions (p(in vivo) = 0.04; p(videotape) = 0.04), the ADG demonstrated the greatest urge to drink. CONCLUSIONS: Alcohol cue reactivity can be reliably induced and assessed in alcohol-dependent participants via personalized videotapes. History of alcohol consumption is positively correlated with the degree of cue reactivity. This study advances our ability to assess alcohol cue reactivity in the absence of alcohol. [ABSTRACT FROM AUTHOR]

Alcohol use disorder has been linked to dysregulation of the brain stress systems, producing a negative emotional state leading to chronic relapsing behavior. Vasopressin receptors appear to have a regulatory role in stress, anxiety, and alcohol. This study evaluated the novel compound, ABT-436, a V1b receptor antagonist, in alcohol-dependent participants in a 12-week clinical trial. Men and women (n=150) who met criteria for DSM-IV alcohol dependence were recruited across four sites. Participants received double-blind ABT-436 or placebo, and a computerized behavioral intervention. ABT-436 was titrated to 800 mg/day during weeks 2-12. Although the primary outcome, percentage of heavy drinking days, was lower in participants receiving ABT-436 compared with placebo, this difference was not statistically significant (31.3 vs 37.6, respectively; p=0.172; d=0.20). However, participants receiving ABT-436 had significantly greater percentage of days abstinent than those receiving placebo (51.2 vs 41.6, respectively; p=0.037; d=0.31). No significant differences were found between treatment groups on any other measures of drinking, alcohol craving, or alcohol-related consequences. Smokers receiving ABT-436 smoked significantly fewer cigarettes per week than those receiving placebo (p=0.046). ABT-436 was well tolerated, with diarrhea (mild-to-moderate severity) being the most common side effect. In subgroup analyses, participants with relatively higher baseline levels of stress responded better to ABT-436 than placebo on select drinking outcomes, suggesting there may be value in testing medications targeting the vasopressin receptor in high stress, alcohol-dependent patients.

Substance use disorders (SUDs) can be viewed as a pathology of neuroadaptation. The pharmacological overstimulation of neural mechanisms of reward, motivated learning and memory leads to drug-seeking behavior. A critical characteristic of SUDs is the appearance of craving, the motivated desire and urge to use, which is a main focus of current pharmacological and behavioral therapies. Recent proof-of-concept studies have tested the effects of noninvasive brain stimulation on craving. Although its mechanisms of action are not fully understood, this approach shows interesting potential in tuning down craving and possibly consumption of diverse substances. This article reviews available results on the use of repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES) in SUDs, specifically tobacco, alcohol and psychostimulant use disorders. We discuss several important factors that need to be addressed in future works to improve clinical assessment and effects of noninvasive brain stimulation in SUDs. Factors discussed include brain stimulation devices and parameters, study designs, brain states and subjects' characteristics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Both maladaptive and adaptive emotion regulation strategies have been linked with psychopathology. However, previous studies have largely examined them separately, and little research has examined the interplay of these strategies cross-sectionally or longitudinally in patients undergoing psychological treatment. This study examined the use and interplay of adaptive and maladaptive emotion regulation strategies in 81 patients receiving cognitive-behavioral interventions for comorbid alcohol use and anxiety disorders. Patients completed measures of emotion regulation strategy use and symptoms of psychopathology pre- and post-treatment. Cross-sectionally, higher use of maladaptive strategies (e.g., denial) was significantly related to higher psychopathology pre- and post-treatment, whereas higher use of adaptive strategies (e.g., acceptance) only significantly related to lower psychopathology post-treatment. Prospectively, changes in maladaptive strategies, but not changes in adaptive strategies, were significantly associated with post-treatment psychopathology. However, for patients with higher pre-treatment maladaptive strategy use, gains in adaptive strategies were significantly associated with lower post-treatment psychopathology. These findings suggest that psychological treatments may maximize efficacy by considering patient skill use at treatment outset. By better understanding a patient's initial emotion regulation skills, clinicians may be better able to optimize treatment outcomes by emphasizing maladaptive strategy use reduction predominately, or in conjunction with increasing adaptive skill use., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Multiple models guide researchers' payment practices but few studies have assessed subjects' expectations for payment. Payments in excess of subjects' expectations may result in undue inducement, while payments below these expectations may be associated with exploitation. Data on subjects' payment expectations will help inform practices to avoid undue inducement and exploitation. This study examined subjects' expectations for payment for common research procedures and explored the relationship between subjects' honesty and payment expectations. One-hundred subjects who participated in two or more studies in the last year reported the minimum payment they expect for completing study procedures. They were also asked about their use of deception while screening for studies. Subjects expected $20 on average to complete the least risky and least burdensome procedure. Subjects' expectations for payment consistently increased with greater procedure risks. Subjects who denied using deception to enroll in studies refused more procedures than subjects who reported using deception. Among subjects who used deception, the rate of procedure refusal increased with procedure risks, suggesting that these subjects have some risk aversion and may act to protect themselves from undue inducement. Although subjects expect greater payments for more risky procedures, ethical considerations for limiting undue inducement may prevent researchers from meeting subjects' expectations. Subjects who use deceptive practices appear to be more risk-tolerant than subjects who deny using deception; nonetheless, these deceptive subjects also exercise some risk aversion when they refuse higher-risk procedures. These subjects may be able to protect themselves from undue inducement by refusing procedures that exceed their risk tolerance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The anticonvulsant topiramate not only decreases ethanol consumption in alcohol dependence (AD) but also may produce several adverse events including cognitive impairment. Zonisamide is a structurally related anticonvulsant that is a promising agent for the treatment of AD and may have greater tolerability than topiramate. This study evaluated the effects of zonisamide (400 mg/d) on alcohol consumption and its neurotoxic effects in subjects with AD. A double-blind placebo-controlled clinical trial was conducted using 2 comparator anticonvulsant drugs, topiramate (300 mg/d) and levetiracetam (2000 mg/d), which does not impair cognition. Study medications were administered for 14 weeks, including a 2-week taper period. Medication adherence was facilitated using Brief Behavioral Compliance Enhancement Treatment. The neurotoxicity of the study drugs was assessed using neuropsychological tests and the AB-Neurotoxicity Scale. Compared with placebo, both zonisamide and topiramate produced significant reductions in the drinks consumed per day, percent days drinking, and percent days heavy drinking. Only the percent days heavy drinking was significantly decreased in the levetiracetam group. The topiramate cell was the only group that had a significant increase on the mental slowing subscale of the Neurotoxicity Scale compared with placebo at study weeks 11 and 12. Topiramate and zonisamide both produced modest reductions in verbal fluency and working memory. These findings indicate that zonisamide may have efficacy in the treatment of AD, with effect sizes similar to topiramate. Both of these drugs produced similar patterns of cognitive impairment, although only the topiramate group reported significant increases in mental slowing.

Sleep-wake (S-W) disturbances are frequently associated with alcohol use disorders (AUD), occurring during periods of active drinking, withdrawal, and abstinence. These S-W disturbances can persist after months or even years of abstinence, suggesting that chronic alcohol consumption may have enduring negative effects on both homeostatic and circadian sleep processes. It is now generally accepted that S-W disturbances in alcohol-dependent individuals are a significant cause of relapse in drinking. Although significant progress has been made in identifying the socio-economic burden and health risks of alcohol addiction, the underlying neurobiological mechanisms that lead to S-W disorders in AUD are poorly understood. Marked progress has been made in understanding the basic neurobiological mechanisms of how different sleep stages are normally regulated. This review article in seeking to explain the neurobiological mechanisms underlying S-W disturbances associated with AUD, describes an evidence-based, easily testable, novel hypothesis that chronic alcohol consumption induces neuroadaptive changes in the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT). These changes include increases in N-methyl-d-aspartate (NMDA) and kainate receptor sensitivity and a decrease in gamma-aminobutyric acid (GABAB)-receptor sensitivity in the CCC-PPT. Together these changes are the primary pathophysiological mechanisms that underlie S-W disturbances in AUD. This review is targeted for both basic neuroscientists in alcohol addiction research and clinicians who are in search of new and more effective therapeutic interventions to treat and/or eliminate sleep disorders associated with AUD., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Activation of Kv7 potassium channels may decrease the reactivity of mesolimbic dopaminergic neurons that are implicated in mediating the reinforcing effects of ethanol., Objectives: The objective of this study was to determine whether the administration of the Kv7 potassium channel opener retigabine would decrease ethanol intake in Long Evans rats., Methods: A limited access two-bottle choice model of alcohol (10% solution) consumption was used in this study. A separate group of animals was tested to evaluate the actions of retigabine on sucrose (5% solution) consumption to determine whether this drug might produce non-selective impairment of the ability of rats to drink liquids. Animals were treated with either vehicle or increasing doses (2.5-7.5 mg/kg SC) of retigabine administered over a 3-day period., Results: Compared to vehicle, retigabine at a dose of 7.5 mg/kg produced a reduction in the amount of ethanol consumed. These effects did not occur in association with significant changes in water consumption. A significant time effect was found for the actions of retigabine in sucrose-drinking rats with a trend for an increase in sucrose intake with the highest dose of retigabine administered., Conclusions: These results indicate that the administration of retigabine may produce a decrease in ethanol consumption by rats at doses that do not significantly reduce the drinking of either water or a sucrose solution. These findings are consistent with the hypothesis that activation of Kv7 channels facilitates the reduction of alcohol consumption in the rat.

Bright light therapy (BLT) is considered among the first-line treatments for seasonal affective disorder (SAD), yet a growing body of literature supports its use in other neuropsychiatric conditions including non-seasonal depression. Despite evidence of its antidepressant efficacy, clinical use of BLT remains highly variable internationally. In this article, we explore the autonomic effects of BLT and suggest that such effects may play a role in its antidepressant and chronotherapeutic properties. After providing a brief introduction on the clinical application of BLT, we review the chronobiological effects of BLT on depression and on the autonomic nervous system in depressed and non-depressed individuals with an emphasis on non-seasonal depression. Such a theory of autonomic modulation via BLT could serve to integrate aspects of recent work centered on alleviating allostatic load, the polyvagal theory, the neurovisceral integration model and emerging evidence on the roles of glutamate and gamma-hydroxybutyric acid (GABA).

Background: Evidence on the use of bright light therapy for conditions beyond seasonal affective disorder continues to accrue; however, data on the prevalent use of bright light therapy in the community or in hospitals remain limited, particularly in the United States., Method: We conducted a 5-minute e-mail survey of practicing psychiatrists in Massachusetts using the membership roster through the Massachusetts Psychiatric Society to evaluate prevalent use of bright light therapy as well as to solicit attitudes toward the treatment. Three e-mails were sent out over a 2-week period, and responses were obtained from March 2-24, 2013. An iPad raffle was used to incentivize survey completion., Results: Of the 1,366 delivered e-mails, 197 responses were obtained. Of respondents, 72% indicated that they used bright light therapy in their practice, and, among these, all but 1 used bright light therapy for seasonal affective disorder. Only 55% of responding psychiatrists who use bright light therapy consider it to treat nonseasonal depression, and 11% of respondents who recommend bright light therapy would consider its use in inpatient settings. Lack of insurance coverage for light-delivery devices was identified as the largest barrier to using bright light therapy, being cited by 55% of respondents. Survey results suggest that limitations in practitioner knowledge of bright light therapy and the absence of bright light therapy in treatment algorithms are the 2 leading modifiable factors to encourage broader implementation., Limitations: The principal limitation of our survey was the low response rate. As such, we consider these data preliminary., Conclusions: Response bias very likely led to an overestimation in prevalent use of bright light therapy; however, this bias notwithstanding, it appears that bright light therapy is used significantly less often for nonseasonal depression than for seasonal affective disorder. Further, its use in inpatient settings is significantly less than in outpatient settings. We expect that efforts to educate practitioners on the use and efficacy of bright light therapy for various psychiatric disorders combined with its inclusion on treatment algorithms may foster greater prevalent use.

The effects of the antidepressant venlafaxine (VEN-225 mg daily) and transdiagnostic cognitive behavioral treatment (CBT) alone and in combination on alcohol intake in subjects with co-morbid alcohol use disorders (AUDs) and anxiety disorders were compared. Drinking outcomes and anxiety were assessed for 81 subjects treated for 11 weeks with one of 4 conditions: 1) VEN-CBT, 2) VEN-Progressive Muscle Relaxation therapy (PMR), 3) Placebo (PLC)-CBT and 4) a comparison group of PLC-PMR. For subjects who reported taking at least one dose of study medication, the Time×Group interaction was significant for percent days of heavy drinking and drinks consumed per day. For the measure of percent days heavy drinking, the paired comparison of PLC-CBT versus PLC-PMR group indicated that the PLC-CBT group had greater drinking reductions, whereas other groups were not superior to the comparison group. In Week 11, the proportion of subjects in the PLC-CBT group that had a 50% reduction from baseline in percent days heavy drinking was significantly greater than those in the comparison group. Of the 3 "active treatment" groups only the PLC-CBT group had significantly decreased heavy drinking when contrasted to the comparison group. This finding suggests that the transdiagnostic CBT approach of Barlow and colleagues may have value in the management of heavy drinking in individuals with co-morbid alcoholism and anxiety., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial α4β2 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.

Importance: Cocaine dependence is a significant public health problem, yet no validated pharmacological treatment exists. The potent γ-aminobutyric acid (GABA)ergic medication vigabatrin has previously been shown to be effective in a double-blind single-site study conducted in Mexico., Objective: To evaluate the safety and efficacy of vigabatrin for the treatment of cocaine dependence in a U.S. sample., Design and Setting: Multisite, randomized, double-blind, placebo-controlled, 12-week clinical trial with follow-up visits at weeks 13, 16, 20, and 24 in 11 U.S. sites., Participants: In total, 186 treatment-seeking participants with cocaine dependence (mean age, 45 years). Approximately 67% were male, and about 60% were of African American race/ethnicity., Interventions: Participants received twice-daily doses of vigabatrin (total dosage, 3.0 g/d) or matched placebo, plus weekly computerized cognitive behavioral therapy and biweekly individual counseling for 13 weeks. Contingency management encouraged the provision of urine samples., Main Outcomes and Measures: The primary outcome measure was the proportion of participants with cocaine abstinence during the last 2 weeks of the 12-week treatment phase as assessed by self-reports and quantitative urine drug screens. The weekly fraction of cocaine use days and the number of drug-free urine samples during weeks 1 through 13 were key secondary measures., Results: No significant differences were observed between the vigabatrin group and the placebo group on the primary outcome measure (P = .67), key secondary measures (P > .99), or other outcome measures. However, while pill counts and self-reports indicated that more than 66% of all participants (and >63% of the vigabatrin group) took more than 70% of their medication, post hoc vigabatrin urine concentration levels suggested that approximately 40% to 60% of patients taking vigabatrin may not have been adherent. This lack of adherence may have obscured any evidence of vigabatrin efficacy. No visual acuity or visual field deterioration occurred in any of the participants., Conclusions and Relevance: No protocol-defined differences in efficacy between vigabatrin treatment and placebo were detected for any outcome variable. This may have been due to medication nonadherence or, alternatively, due to the weak efficacy of vigabatrin., Trial Registration: clinicaltrials.gov Identifier: NCT00611130.

Repeated exposure to an anxiogenic stressor (AS) is a known environmental factor for the development of depression, yet the progression of sleep-wake (S-W) changes associated with the onset of AS-induced depression (ASID) is not completely understood. Thus, the aim of this study was to identify these progressive S-W changes by developing ASID in rats, via repeated exposure to an AS, and compare this ASID-associated sleep phenotype with the sleep phenotype of human depression. To achieve this aim, rats were first recorded for a 6 h period of baseline S-W activity without AS. Then, rats were subjected to 5 days of AS [Day 1: inescapable foot-shock; 5 trials of 3 s foot-shocks (1.0 mA) at 3 min intervals; Days 3-5: 15 trials of 5 s foot-shocks at 45 s intervals]. S-W activity was recorded for 6 h immediately after each AS treatment session. Two days later rats were again recorded for 6 h of S-W activity, but with no exposure to the AS (NASD). Compared to the baseline day: Day 1 of AS (ASD-1) increased wakefulness, slow-wave sleep (SWS) latency, and rapid-eye movement (REM) sleep latency, but decreased the total amount of REM sleep; ASD-2 animals remained awake throughout the 6 h S-W recording period; ASD-3, ASD-4, and ASD-5 (ASDs-3-5) decreased wakefulness, SWS latency, and REM sleep latency, but increased the total amount of REM sleep. Interestingly, these results reveal that initial exposure to the AS versus later, repeated exposure to the AS produced opposing S-W changes. On NASD, animals exhibited baseline-like S-W activity, except slightly less REM sleep. These results suggest that repeated AS produces a sleep phenotype that resembles the sleep phenotype of depression in humans, but consistent re-exposure to the AS is required. These results are promising because the methodological simplicity and reversibility of the ASID-associated S-W phenotype could be more advantageous than other animal models for studying the pathophysiological mechanisms that underlie the expression of ASID.

Background: Subjects who enroll in multiple studies have been found to use deception at times to overcome restrictive screening criteria. Deception undermines subject safety as well as study integrity. Little is known about the extent to which experienced research subjects use deception and what type of information is concealed, withheld, or distorted., Purpose: This study examined the prevalence of deception and types of deception used by subjects enrolling in multiple studies., Methods: Self-report of deceptive behavior used to gain entry into clinical trials was measured among a sample of 100 subjects who had participated in at least two studies in the past year., Results: Three quarters of subjects reported concealing some health information from researchers in their lifetime to avoid exclusion from enrollment in a study. Health problems were concealed by 32% of the sample, use of prescribed medications by 28%, and recreational drug use by 20% of the sample. One quarter of subjects reported exaggerating symptoms in order to qualify for a study and 14% reported pretending to have a health condition in order to qualify., Limitations: Although this study finds high rates of lifetime deceptive behavior, the frequency and context of this behavior is unknown. Understanding the context and frequency of deception will inform the extent to which it jeopardizes study integrity and safety., Conclusion: The use of deception threatens both participant safety and the integrity of research findings. Deception may be fueled in part by undue inducements, overly restrictive criteria for entry, and increased demand for healthy controls. Screening measures designed to detect deception among study subjects would aid in both protecting subjects and ensuring the quality of research findings.

A theory is proposed to explain the benefits of yoga practices in diverse, frequently comorbid medical conditions based on the concept that yoga practices reduce allostatic load in stress response systems such that optimal homeostasis is restored. It is hypothesized that stress induces (1) imbalance of the autonomic nervous system (ANS) with decreased parasympathetic nervous system (PNS) and increased sympathetic nervous system (SNS) activity, (2) underactivity of the gamma amino-butyric acid (GABA) system, the primary inhibitory neurotransmitter system, and (3) increased allostatic load. It is further hypothesized that yoga-based practices (4) correct underactivity of the PNS and GABA systems in part through stimulation of the vagus nerves, the main peripheral pathway of the PNS, and (5) reduce allostatic load. Depression, epilepsy, post traumatic stress disorder (PTSD), and chronic pain exemplify medical conditions that are exacerbated by stress, have low heart rate variability (HRV) and low GABAergic activity, respond to pharmacologic agents that increase activity of the GABA system, and show symptom improvement in response to yoga-based interventions. The observation that treatment resistant cases of epilepsy and depression respond to vagal nerve stimulation corroborates the need to correct PNS underactivity as part of a successful treatment plan in some cases. According to the proposed theory, the decreased PNS and GABAergic activity that underlies stress-related disorders can be corrected by yoga practices resulting in amelioration of disease symptoms. This has far-reaching implications for the integration of yoga-based practices in the treatment of a broad array of disorders exacerbated by stress., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Prior findings concerning the use of mirtazapine in the treatment of a variety of substance use disorders and its antagonistic actions at the serotonin 5-HT(2A) receptor suggest that this drug may have efficacy in the treatment of cocaine dependence in the presence of a depressive disorder., Methods: Depressed cocaine-dependent subjects received either mirtazapine (target dose 45 mg daily) or placebo for 12 weeks. Urine concentrations of benzoylecgonine and self-report were used to assess cocaine consumption. Depression and sleep quality were evaluated using the Hamilton Depression Rating Scale (HAM-D) and the Pittsburgh Sleep Quality Index, respectively., Results: Cocaine consumption during the treatment period did not differ significantly between the mirtazapine (n = 11) and placebo (n = 13) groups in this study. In week 4 sleep latency was significantly lower in the active medication than in the placebo group. Positive effects of mirtazapine treatment on early insomnia were suggested by an item analysis of the HAM-D., Conclusions and Scientific Significance: The results of this study suggest that mirtazapine is superior to placebo in improving sleep in patients with comorbid depression and cocaine dependence, but is not more effective than placebo in reducing cocaine use.

Objectives: The objectives of this study are to assess the tolerability and efficacy of the anticonvulsant zonisamide in an open label trial of the treatment of alcohol dependence., Methods: In this trial, zonisamide (400-mg daily) was administered to alcohol-dependent subjects (ADS) (n = 16) over 13 weeks. The mean daily consumption of standard alcoholic drinks and performance on a verbal fluency task, the COWAT, and on a measure of attention and visuomotor speed, the DSMT were assessed, and the occurrence of adverse events was monitored weekly., Results: The mean number of drinks consumed daily was significantly reduced from baseline levels during the treatment period. Performances on the COWAT and on the DSMT were not significantly reduced by zonisamide treatment. Overall, zonisamide was well tolerated by the study subjects., Conclusion: These results indicate that zonisamide administration may not impair verbal fluency in ADS, and are consistent with other studies that found zonisamide administration may reduce alcohol intake.

Recent studies have shown that deep brain stimulation (DBS) of the nucleus accumbens (NAcc) has an inhibitory effect on drug-seeking behaviors including reinstatement responding for cocaine. The objective of the present study was to expand on these findings by assessing the effects of DBS on behaviors related to alcohol consumption. The specific aim of this study was to determine whether DBS delivered to either the shell or core of the NAcc would reduce ETOH intake in rats using a two-bottle choice limited access procedure. Long Evans rats were induced to drink a 10% ethanol solution using a saccharin fading procedure. Bipolar electrodes were implanted bilaterally into either the core or shell of the NAcc. During testing animals received DBS 5 min prior to and during a 30-minute test session in which both ETOH and water bottles were accessible. Current was delivered at amplitudes ranging from 0 to 150 microA. ETOH consumption was significantly reduced from baseline levels at the 150 microA current for both shell and core electrode placements. A significant current effect was not found for water consumption for either site. These results provide evidence that DBS delivered either to the nucleus accumbens core or shell subregions can significantly reduce ethanol intake in the rat.

Objective: The purpose of this study is to examine the effects of zonisamide on ethanol self-administration and subjective effects in risky drinkers using a human laboratory paradigm., Method: We conducted a double-blind, placebo-controlled study of the effects of zonisamide 100 mg on ethanol self-administration and urge to drink in risky drinkers (N = 10) ( [1] )., Result: During the second hour of a 2-hour self-administration session ethanol consumption was 50% lower in the zonisamide group as compared to the placebo group. Urge to drink was also significantly lower under the zonisamide condition., Conclusion: These results indicate that a single dose of zonisamide reduces urge to drink and the quantity of ethanol self-administered by risky drinkers during their second hour of access to alcohol., Scientific Significance: Zonisamide may help individuals drinking at risky levels reduce their intake of alcohol.

Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 muA. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.

Treatment dropout is a problem of great prevalence and stands as an obstacle to recovery in cocaine-dependent (CD) individuals. Treatment attrition in CD individuals may result from impairments in cognitive control, which can be reliably measured by the Stroop color-word interference task. The present analyses contrasted baseline performance on the color-naming, word-reading, and interference subtests of the Stroop task in CD subjects who completed a cocaine treatment trial (completers: N=50) and those who dropped out of the trial before completion (non-completers: N=24). A logistic regression analysis was used to predict trial completion using three models with the following variables: the Stroop task subscale scores (Stroop model); the Hamilton depression rating scale (HDRS) scores (HDRS model); and both the Stroop task subscale scores and HDRS scores (Stroop and HDRS model). Each model was able to significantly predict group membership (completers vs non-completers) better than a model based on a simple constant (HDRS model p=0.02, Stroop model p=0.006, and Stroop and HDRS model p=0.003). Models using the Stroop preformed better than the HDRS model. These findings suggest that the Stroop task can be used to identify cocaine-dependent subjects at risk for treatment dropout. The Stroop task is a widely available, reliable, and valid instrument that can be easily employed to identify and tailor interventions of at risk individuals in the hope of improving treatment compliance.

Objective: We sought to determine the time course for onset of effect of intramuscular injectable extended-release naltrexone (XR-NTX), which has demonstrated efficacy for alcohol dependence., Method: A post hoc analysis of a randomized, double-blind, placebo-controlled, multicenter study was conducted. In the study, actively drinking men and women who met DSM-IV-TR criteria for alcohol dependence were randomly assigned to receive injections of XR-NTX 380 mg (N = 205) or 190 mg (N = 210) or placebo (N = 209) every 4 weeks for 24 weeks. Patients also received 12 sessions of standardized, low-intensity psychosocial intervention. Drinking data were analyzed by month and, during the first month, by day to explore the time course for onset of effect on heavy drinking days in patients receiving XR-NTX versus placebo. The study data were collected between February 2002 and September 2003., Results: During the first month following injection, patients receiving XR-NTX 380 mg had 37% fewer heavy drinking days versus placebo (p < .01). By day 2, a significant reduction in the median number of drinks consumed per day was observed in patients given XR-NTX 380 mg compared with placebo (p < .05). By day 3, XR-NTX 380 mg resulted in a significant reduction in the percentage of patients reporting heavy drinking compared with placebo (p < .05); this reduction was maintained throughout the study. A dose-response effect was observed, with intermediate results for XR-NTX 190 mg., Conclusion: XR-NTX 380 mg provided a rapid onset of therapeutic effect in the first 2 days after the first injection that was sustained throughout the 24-week trial. Potential clinical implications of the rapid, early onset of effect of this medication's delivery system for patients who are dependent on alcohol include facilitation of early engagement in treatment, motivation to continue treatment, and focus on the goals established in counseling.

Background: Cocaine's increase of dopamine is strongly associated with its reinforcing properties and, thus, agents that reduce dopamine have received much attention as candidate cocaine-dependence treatments. The potential efficacy of reserpine, a dopamine depletor, for treating cocaine dependence is suggested by both pre-clinical research and a small clinical trial., Method: One hundred and nineteen participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double-blind, placebo-controlled outpatient trial. Participants received either reserpine (0.5 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine results, cocaine craving, addiction severity index scores, and clinical global impression scores. Safety measures included adverse events, EKGs, vital signs, laboratory tests, and the Hamilton Depression Inventory., Results: Seventy-nine participants (i.e., 66%) completed the 12-week trial. The safety results suggest that reserpine was safe and well tolerated by the participants. The efficacy measures indicated no significant differences between reserpine and placebo., Conclusion: These results do not support the efficacy of reserpine as a cocaine-dependence treatment.

Background: The potential efficacy of tiagabine for treating cocaine dependence is suggested by both pre-clinical research and two small clinical trials., Method: One hundred and forty one participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double blind, placebo controlled outpatient trial. Participants received either tiagabine (20 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine (BE) results, and qualitative and quantitative urine toxicology measures. Safety measures included adverse events, EKGs, vital signs, and laboratory tests., Results: Seventy-nine participants (i.e., 56%) completed the 12-week trial. The safety results suggest that tiagabine was safe and generally well tolerated by the participants. Participants in both groups improved significantly on cocaine craving and global functioning, with no significant differences between the groups. There were no significant changes in cocaine use as measured by self-report confirmed by urine BE or by quantitative urine toxicology results. Qualitative urine toxicology results suggest a possible weak effect for tiagabine in reducing cocaine use., Conclusion: These results suggest that tiagabine, at a dose of 20 mg/day, did not have a robust effect in decreasing cocaine use.

This study was conducted to explore differences in gray and white matter volume between cocaine-dependent and healthy comparison subjects using optimized voxel-based morphometry (VBM). Brain magnetic resonance imaging (MRI) and neuropsychological function tests were performed for 40 cocaine-dependent subjects (41.4+/-6.9 years, 27 men) and 41 healthy age- and sex-matched comparison subjects (38.7+/-8.8 years, 26 men). Optimally normalized whole brain MR images were segmented, modulated, smoothed, and compared between groups with statistical parametric mapping. The cocaine-dependent group had lower gray matter volumes in bilateral premotor cortex (Brodmann area (BA) 6, 8; 16.6%), right orbitofrontal cortex (BA 10, 15.1%), bilateral temporal cortex (BA 20, 38; 15.9%), left thalamus (12.6%), and bilateral cerebellum (13.4%) as well as lower right cerebellar white matter volume (10.0%) relative to the comparison group at a corrected p<0.05 for multiple comparisons. Duration of cocaine use negatively correlated with right and left cerebellar gray matter volumes (r=-0.37, r=-0.39, respectively). In cocaine-dependent subjects, lower cerebellar hemispheric gray and white matter volumes were correlated with deficits in executive function and decreased motor performance. This study reports that cocaine-dependent subjects have lower gray matter volumes in cerebellar hemispheres as well as in frontal, temporal cortex, and thalamus. These findings are the first to suggest that the cerebellum may be vulnerable to cocaine-associated brain volume changes, and that cerebellar deficits may contribute to neuropsychological deficits and motor dysfunction frequently observed in cocaine-dependent subjects.

Chronic cocaine abusers experience brain and peripheral vascular dysfunction, the severity of which tends to be greater in men than women. The mechanisms underlying these effects of cocaine are unknown. Because nitric oxide (NO) abnormalities play key roles in development of vascular dysfunction in several disorders, we determined whether vascular nitric oxide end product (NOx) levels, which can serve as markers of systemic vascular NO production, are reduced in cocaine-dependent (CD) subjects. Plasma samples from 24 CD men, 12 CD women, and matched comparison subjects (19 men, 14 women) were analyzed with a Sievers 280i nitric oxide chemiluminescence detection analysis system. NOx levels in comparison in women and men were 24.9 ± 6.6 and 23.3 ± 5.7 μmol/L, and in CD women and men were 22.5 ± 8.4 and 13.0 ± 9.6 μmol/L, respectively. ANCOVA analysis, adjusted for lifetime smoking, indicated group (P < 0.0005) and sex (P = 0.04) effects, both of which survived posthoc Scheffe tests. Reduced NOx levels in CD men drove the group difference. These data suggest that chronic cocaine abuse is associated with reduced NOx levels in men, although the finding also may be attributable to factors indirectly related to cocaine abuse, including cohort differences in other drug use or lifestyle factors. These findings warrant additional studies to more directly characterize vascular NO turnover in cocaine abusers and to establish whether NO abnormalities contribute to cocaine-associated vascular dysfunction and to sex differences in cocaine's effects.

Several anticonvulsant agents, including topiramate and valproate, have been found to reduce alcohol consumption in rodent models of drinking. The question of whether the novel anticonvulsant agent, zonisamide, shares similar actions in either mice or rats was investigated in the present experiments. In an initial experiment, the consumption of a 10% ethanol-5% sucrose solution, available for one hour, by Wistar rats treated with lactose, topiramate, or zonisamide was determined. In a second experiment, the intake of a 10% ethanol/water solution, accessible for two hours, by C57BL/B6N mice treated with either zonisamide or vehicle was assessed. In the rat, 50 mg/kg (PO) doses of either topiramate or zonisamide produced significant, but moderate decreases in ethanol/sucrose intake. The administration of a 50 mg/kg (IP) dose of zonisamide to mice resulted in a marked lowering in ethanol consumption. These results provide evidence that zonisamide administration will decrease ethanol consumption by both mice and rats in limited access models of drinking, and might, like topiramate, be useful as a medication for alcoholism.

Objectives: The aim of this study was to compare changes in brain gamma-aminobutyric (GABA) levels associated with an acute yoga session versus a reading session. It was hypothesized that an individual yoga session would be associated with an increase in brain GABA levels., Design: This is a parallel-groups design., Settings/location: Screenings, scan acquisitions, and interventions took place at medical school-affiliated centers., Subjects: The sample comprised 8 yoga practitioners and 11 comparison subjects., Interventions: Yoga practitioners completed a 60-minute yoga session and comparison subjects completed a 60-minute reading session., Outcome Measures: GABA-to-creatine ratios were measured in a 2-cm axial slab using magnetic resonance spectroscopic imaging immediately prior to and immediately after interventions., Results: There was a 27% increase in GABA levels in the yoga practitioner group after the yoga session (0.20 mmol/kg) but no change in the comparison subject group after the reading session ( -0.001 mmol/kg) (t = -2.99, df = 7.87, p = 0.018)., Conclusions: These findings demonstrate that in experienced yoga practitioners, brain GABA levels increase after a session of yoga. This suggests that the practice of yoga should be explored as a treatment for disorders with low GABA levels such as depression and anxiety disorders. Future studies should compare yoga to other forms of exercise to help determine whether yoga or exercise alone can alter GABA levels.

Cocaine administration can be disruptive to sleep. In compulsive cocaine users, sleep disruption may be a factor contributing to relapse. The effects of cocaine on sleep, particularly those produced by low doses, have not been extensively studied. Low dose cocaine may stimulate brain reward systems that are linked to the liability of abusing of this drug. This study was designed to assess the effects of the acute administration of low to moderate cocaine doses on sleep in the rat. Polygraphic recordings were obtained from freely moving, chronically instrumented rats over a 6-h period after the administration of either cocaine (as a 2.5-10 mg/kg intraperitoneal dose) or saline. Following cocaine administration, time spent by the rats in wakefulness increased and slow wave sleep decreased in a dose-dependent manner, compared to controls. These changes lasted between 1 to 3 h following the cocaine administration. Rapid eye movement (REM) sleep was decreased during a 2- to 3-h period following the injection of 5 and 10 mg/kg doses of cocaine. In contrast, REM sleep increased during the periods 2-4 h after the administration of 2.5 and 5 mg/kg doses of cocaine. These results indicate that sleep can be significantly altered by low doses of cocaine when administered subacutely.

Primary-care practitioners confront myriad issue in managing their patients with depression and/or anxiety. Understanding the scope and epidemiology of these disorders is essential to understanding their shared characteristics. Do we always recognize these patients in practice? What are the barriers to diagnosis and treatment, and how can they overcome? What are the treatment options of these sometimes life-altering conditions, and how do we choose from among the many that exist?

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Rationale: There is evidence that prefrontal lobe GABA levels are low in cocaine-dependent (CD) individuals, and treatment with GABA agonists decreases cocaine self-administration., Objectives: The aim of the study is to measure changes in GABA levels in CD subjects at baseline and after 8 weeks of treatment with pramipexole, venlafaxine, or placebo., Methods: CD subjects enrolled in a treatment trial for cocaine dependence were recruited for this proton (1H) magnetic resonance spectroscopy (MRS) study. GABA levels in the prefrontal lobe were measured before and after treatment., Results: Mean percentage changes in GABA levels were as follows: pramipexole +17.0+/-28.0%, venlafaxine +13.0+/-11.0%, and placebo -2.1+/-19.5%. Pramipexole-treated subjects had significantly increased brain GABA levels compared to placebo (p=0.031). Venlafaxine treatment was nonsignificantly associated with increased GABA levels compared to placebo (p=0.16). The overall statistical model for the effect of drug treatment vs placebo on brain GABA levels, including adjustment for baseline levels, was highly significant (p=0.002). Despite significant changes in GABA levels, there were no significant differences in the number of urine samples positive for cocaine metabolites., Conclusions: This study demonstrates that 1H MRS can measure changes in GABA levels following pharmacologic treatment. The increase in GABA levels, although significant, is modest compared to other MRS studies of depression or epilepsy associated with clinical improvements. The failure to see larger increases in GABA levels and an associated reduction in cocaine consumption may reflect the relatively low doses of medication used.

Aims: In the current study, nefazodone, an antidepressant with dual action on serotonin and norepinephrine reuptake as well as 5-HT(2A) receptor antagonist effects, was studied in subjects with cocaine dependence and depressive symptoms, to determine its efficacy in reducing cocaine use., Design: An 8-week, double blind, placebo-controlled design was used., Setting: The study was conducted at the Medication Development Research Unit (MDRU) at the VA Boston Healthcare System and the Manhattan Department of Veterans Affairs (DVA) Medical Center., Participants: Subjects (n = 69) met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and had Hamilton Depression Scores of 12 or higher., Intervention: Subjects were assigned randomly to receive nefazodone 200 mg twice daily (n = 34) or matching placebo (n = 35). All subjects received individual counseling., Measurements: Urinary measurements of benzoylecgonine (BE, three times per week) and self-reports of cocaine use were the primary outcome measures. Secondary outcome measures included assessments of psychiatric functioning, cocaine craving and social functioning., Findings: Median weekly BE declined more rapidly in the nefazodone than in the placebo group. Median urine BE at baseline was, however, significantly greater in nefazodone than in the placebo group. Scores for strength of cocaine craving also decreased more rapidly in the nefazodone group compared to the placebo group. Both groups had equivalent improvement in mood, psychosocial functioning and self-reported cocaine use., Conclusions: These results suggest that nefazodone administration can reduce cocaine craving after it has been administered for several weeks. Although the nefazodone group had a greater rate of decrease in BE levels than the placebo group, the interpretation of this finding is obscured by significant group differences in baseline BE levels.

Aims: The Cocaine Rapid Efficacy Screening Trials (CREST) were designed by the National Institute on Drug Abuse Division of Treatment Research and Development (NIDA, DT R&D) to rapidly screen a number of medications potentially useful for the treatment of cocaine dependence., Design: Each CREST trial was designed to compare several medications in a single trial against an unmatched placebo. The placebo group was included in each trial to avoid the nearly universal positive response to medications seen in open-label trials. In addition, a common set of procedures and outcome measures were employed throughout to increase comparability of results obtained from different trials and from different times., Participants: In all, 18 medications were screened in seven different trials, conducted in four different sites throughout the United States involving 398 cocaine-dependent patients., Findings: Three medications were found to be promising enough to include in subsequent larger trials. Common statistical procedures for evaluating medications were developed to facilitate comparisons across sites and across time. A portion of the data were pooled and analyzed, which yielded some useful insights into cocaine dependence and its treatment. Finally, a review of individual trials together with the pooled analysis revealed several potential improvements for future screening trials., Conclusions: Overall, the CREST trials proved to be useful for rapidly screening medications for treatment of cocaine dependence, but several modifications in design should be made before this framework is applied further.

Aims: The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence., Design: A multi-arm, modified blinded, placebo-controlled design was used., Setting: The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU)., Participants: Participants met criteria for cocaine dependence during a 2-week screening period., Intervention: Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study., Measurements: Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period., Findings: None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated., Conclusions: This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups.

Quetiapine is an atypical antipsychotic that has sedative effects. In this retrospective study, indices of alcohol use were compared for alcohol-dependent subjects who either were (n = 30) or were not (n = 20) treated with quetiapine (25 to 200 mg nightly) for disturbed sleep. Indices examined included total days of abstinence, number of hospitalizations for detoxification, and days to first relapse over 1 year of clinic treatment. Subjects were male veterans. All subjects had a diagnosis of alcohol dependence, and 90% of subjects in each group were also diagnosed with posttraumatic stress disorder. Both treatment groups contained a large number of subjects treated with psychiatric medications other than quetiapine. Significant differences were not found between the groups with respect to mean age, detoxifications undergone during the previous year, frequency of comorbid posttraumatic stress disorder or depression, or antidepressant use. The mean number of days abstinent was significantly greater, and the number of hospitalizations was significantly lower for the quetiapine than for the control group during the period studied. The mean number of days to relapse approached significance for the quetiapine as compared to the control group. This study has the usual limitations of a retrospective review, including the lack of standardized assessments of alcohol use. The results of this study are consistent with the hypothesis that the use of quetiapine to improve disturbed sleep may help alcohol-dependent patients maintain abstinence, although decreased drinking may also be a result of improving posttraumatic stress disorder symptoms or of a direct action of quetiapine to reduce alcohol use.

The prevalence, severity, and location of white matter signal hyperintensities (WMH) on brain magnetic resonance images were compared in patients with cocaine or opiate dependence and healthy subjects. Patients with cocaine (n=32) and opiate dependence (n=32), whose diagnoses were confirmed with the Structured Clinical Interview for DSM-IV, and age- and sex-matched healthy subjects (n=32) were scanned using a 1.5 T whole body GE magnetic resonance scanner. Axial proton-density and T2-weighted images were obtained as well as fluid-attenuated inversion recovery axial images. The severity of WMH was assessed separately for deep (and insular) and periventricular WMH, using a modified composite version of the rating scales of Fazekas and Coffey. The cocaine-dependent group had greater severity of WMH than the opiate-dependent group, which in turn had greater severity of WMH than the healthy comparison group (odds ratios=2.54 and 2.90, respectively). The cocaine-dependent group had greater lesion severity of deep and insular WMH than the opiate-dependent group and the healthy comparison group (odds ratio>3.25 for deep WMH; odds ratio>4.38 for insular WMH). For periventricular WMH, there were no significant differences between the three groups. The frontal lobes were the predominant locations of WMH in both substance-dependent groups. The greater prevalence and severity of WMH in cocaine-dependent subjects than in opiate-dependent subjects may reflect the fact that cocaine induces more ischemia via vasoconstriction than opiates. Also, there was a trend for lower WMH severity in substance-dependent women relative to the healthy comparison group, possibly due to estrogen's protective effect against cerebrovascular accidents.

Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects (N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group (N=20). At treatment baseline, mean GABA concentrations were 0.93+/-0.27 mM/kg in cocaine-dependent subjects and 1.32+/-0.44 mM/kg in the comparison sample (t [d.f.=53]=3.65, P<0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder (N=23) had significantly lower baseline GABA levels (0.87 mM/kg) (t [d.f.=41]=4.31, P<0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder (N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects (t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.

Given the heterogeneous nature of substance abuse, it is notable that several predictors of response are independent of the primary drug of abuse or the treatment setting [208]. Although the strength of the relationship of predictor to outcome varies, the following factors have been identified consistently: severity of dependence or withdrawal; psychiatric comorbidity; substance-related problems; motivation (abstinence commitment); length of treatment; negative affective states; cognitive factors; personality traits and disorders; coping skills; multiple substance abuse; contingency contracting or coercion; genetic factors; sleep architecture; urges and craving; self-efficacy; and economic and social factors. Although it is well known that severity of dependence (including polysubstance abuse), serious psychiatric comorbidity, and social problems are associated with poor treatment response, only recently has research examined the efficacy of intervention strategies that specifically address these problems. Adequate treatment of psychiatric comorbidity and improvement in social, economic, and family functioning lead to better treatment outcomes. The development of specific techniques to enhance self-efficacy, motivation, coping skills, and functioning in the community are concrete examples of how the identification of factors associated with positive outcomes has led to the development of new treatments. Despite significant accomplishments, the field is left with many unanswered questions. Although several biologic markers, such as neuroendocrine response and sleep architecture, show promise as outcome predictors, it is not known whether these are critical factors in the initiation of substance use or its progression to dependence. Determining whether biologic markers are epiphenomena reflecting the amount and duration of substance abuse or are fundamental to the pathophysiology of dependence is a matter of urgent concern. With some exceptions, identification of biologic predictors has not led to innovative therapies. One of these exceptions is the development of naltrexone for the treatment of alcoholism, which was based in a solid theoretical rationale and followed by hypothesis-driven experiments. Similar opportunities should emerge from current basic science and clinical research. The application of pharmacogenetic techniques to the field of addiction also holds great promise. As future studies are undertaken, researchers and clinicians must be mindful that differences in outcome predictors across drugs of abuse and treatments may emerge as subgroups of individuals with addictive disorders and new therapies are identified. There is already evidence that early onset alcoholism is associated with poor response under some circumstances, yet may be a predictor of response to targeted pharmacotherapy with ondansetron [64, 112]. As the ability to subtype disorders based on meaningful biologic differences grows, it is anticipated that several relevant outcome predictors that are specific for pharmacotherapy will emerge.

We examined kinetic and dynamic factors to determine the pharmacological and behavioral safety and tolerability of low versus high doses of an opiate antagonist, naltrexone (50 mg/day vs. 100 mg/day), and acamprosate (2 g/day vs. 3 g/day), a functional N-methyl-D-aspartate receptor antagonist, both independently and combined, among non-treatment-seeking, alcohol-dependent individuals. This double-blind, double-dummy, placebo-controlled, randomized, 23-day, four-way crossover study involved 23 subjects assigned to one of four groups. Placebo washout (phase I) preceded phase II, where subjects received low-dose or high-dose naltrexone or acamprosate. In phases III and IV, the alternative medication type at its lower and higher doses, respectively, was administered with continuation of the phase II medication. Predetermined behavioral, performance, and pharmacological criteria determined significant pathological change from baseline (phase I). Case records were reviewed. Criterion-significant increases in symptoms from baseline with monotherapy included nervousness and fatigue with 3 g acamprosate and somnolence and headache with 50 mg and 100 mg naltrexone, respectively. Combined treatment at various doses evinced anger, depression, somnolence, nervousness, diarrhea, and headache. Notably, for all but one subject who dropped out, increased symptoms did not produce any remarkable clinical deterioration. Naltrexone administration significantly increased plasma acetylhomotaurine (i.e., acamprosate) levels, presumably by prolonging gastric emptying. The level of neither plasma acetylhomotaurine nor plasma 6-beta naltrexol (i.e., naltrexone's metabolite) predicted adverse-event frequency. Naltrexone and acamprosate, both alone and in combination at the tested doses, were behaviorally and pharmacologically safe. Adverse events were infrequent, were of moderate intensity, and resolved with reassurance and symptomatic treatment. More side effects were noted with the combination of medications than with either medication alone. Naltrexone administration significantly increased plasma acamprosate levels.

Increased aggressive behavior can occur in association with posttraumatic stress disorder (PTSD). This study tested the hypothesis that low-dose risperidone reduces aggression and other PTSD-related symptoms in combat veterans. Subjects were male combat veterans with PTSD who scored 20 or higher on cluster D (hyperarousal) of the Patient Checklist for PTSD-Military Version (PCL-M). Subjects were randomly assigned to either risperidone or placebo treatment groups. Drugs were administered over a 6-week treatment period in a double-blind manner. Subjects received either risperidone (0.5 mg/day; n = 7) or matched placebo (n = 8) tablets during the first 2 weeks of the treatment period. The dose of risperidone could then be increased up to 2.0 mg/day on the basis of response. Prerandomization psychotropic regimens were continued. Subjects were evaluated with the PCL-M and the Overt Aggression Scale-Modified for Outpatients (OAS-M). In comparison with placebo treatment, reductions in scores between baseline and the last week of treatment were significantly greater for OAS-M irritability and PCL-M cluster B (intrusive thoughts) subscales and on the PCL-M total scale. These results suggest that low-dose risperidone administration reduces irritability and intrusive thoughts in combat-related PTSD.

Evidence from cocaine self-administration studies suggests that increasing the activity of cyclic AMP (cAMP) pathways within the nucleus accumbens may produce a reduction in cocaine's reinforcing effects. Rolipram may increase intra-cellular levels of cAMP by selectively inhibiting Type IV phosphodiesterases, enzymes that catalyze cAMP breakdown. The present study was undertaken to test the hypothesis that infusion of rolipram into the nucleus accumbens would decrease cocaine-induced enhancement of the sensitivity of brain stimulation reward (BSR) pathways. BSR thresholds were determined in rats after the systemic administration of cocaine (4 mg/kg IP) and the infusion of rolipram (0.2 microg/side) into the nucleus accumbens both alone and in combination. Thresholds also were determined after the systemic administration of rolipram alone and, as a positive control, for amphetamine (10 microg/side) infused into the nucleus accumbens. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration suggesting that cannulae were in place to allow perfusion of reward pathways. Compared to values for saline alone, thresholds were lower after the injection of cocaine (4 mg/kg IP) or the infusion of rolipram (0.2 microg/side) into the nucleus accumbens. Treatment with the combination of cocaine and intra-nucleus accumbens rolipram produced a greater lowering of the BSR threshold than did administration of either rolipram or cocaine alone. Systemic administration of rolipram (0.5 mg/kg IP) either blocked the effects of BSR or raised BSR thresholds and produced stimulation-induced head jerking in most of the test animals. These results suggest that infusion into the nucleus accumbens of rolipram, an agent that putatively elevates cAMP levels in this structure, can enhance the sensitivity of reward pathways to BSR and can augment cocaine's actions on these pathways.