Mecamylamine treatment for alcohol dependence: a randomized controlled trial.

BACKGROUND AND AIMS: The nicotinic acetylcholine receptor antagonist, mecamylamine, is a potential novel pharmacotherapy for alcohol use disorder. The aims were to compare alcohol consumption between mecamylamine and placebo and test if smoking status modified treatment effects. DESIGN: Out-patient, randomized, double-blind clinical trial for 12 weeks of treatment with mecamylamine (10 mg) (n = 65) versus placebo (n = 63). SETTING: Connecticut, USA. PARTICIPANTS: Individuals had current alcohol dependence (n = 128), had an average age of 48.5 [standard deviation (SD) = 9.4], 110 (85.9%) were men, and included 74 smokers (57.8%) and 54 non-smokers (42.2%). Participants were randomized to mecamylamine 10 mg per day or placebo. All subjects also received medical management therapy administered by trained research personnel. MEASUREMENTS: Primary outcome was percentage of heavy drinking days during the last month of treatment; other outcomes included drinking days, drinks per drinking days, alcohol craving, smoking, symptoms of nicotine withdrawal and side effects. FINDINGS: There were no significant differences in the percentage of heavy drinking days at 3 months between the mecamylamine (mean = 18.4, SD = 29.0) and placebo treatment groups (mean = 20.4, SD = 29.2) [F1, 100  = 1.3, P = 0.25; effect size d = 0.07; mean difference = 2.06, 95% confidence interval (CI) = -8.96 to 13.08]. There were no significant differences in percentage of drinking days or in drinks per drinking day at month 3 between the mecamylamine and placebo groups; there were no significant interactions. CONCLUSIONS: Mecamylamine 10 mg per day did not reduce alcohol consumption significantly in treatment-seeking smokers and non-smokers with alcohol use disorder.

A Randomized Trial of Contingency Management for Smoking Cessation During Intensive Outpatient Alcohol Treatment.

INTRODUCTION: This randomized clinical trial was designed to evaluate the efficacy of contingency management (CM) for smoking cessation for smokers with alcohol abuse or dependence delivered concurrently with intensive outpatient alcohol treatment. The study also explored the indirect effects of CM smoking treatment and smoking cessation on alcohol and drug use outcomes. METHODS: Alcohol abuse/dependent smokers were randomized to cognitive behavioral therapy plus nicotine replacement therapy plus contingency management (CBT+NRT+CM) or to cognitive behavior therapy plus nicotine replacement therapy (CBT+NRT) delivered concurrent with a three-week intensive outpatient alcohol treatment program. RESULTS: Participants in the CBT+NRT+CM condition were significantly more likely to be cigarette abstinent at the end of treatment (χ2(1)=8.48, p=.004) with approximately double the carbon monoxide confirmed quit rate (60%) compared with the CBT+NRT condition (29%). At the one-month and six-month time-points there were nonsignificant differences in smoking abstinence outcomes by condition. Smoking treatment condition did not directly affect alcohol abstinence outcomes, but we observed an indirect effect of smoking treatment on alcohol and drug abstinence at one-month follow-up that was mediated by smoking cessation at the end of treatment. CONCLUSIONS: Adding CM to an evidence-based smoking cessation treatment that included medication and behavioral counseling doubled the quit rate at the end of treatment. This finding provides strong evidence for the efficacy of CM for helping alcohol dependent smokers reach the milestone of initial smoking abstinence.

Prazosin for Veterans with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence: A Clinical Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is an important and timely clinical issue particularly for combat veterans. Few pharmacologic options are available to treat PTSD, particularly among military personnel, and they are not based on rational neurobiology. The evidence for noradrenergic dysregulation in PTSD is strong, and the alpha-adrenergic agonist prazosin is one of the most promising medications to treat sleep disturbances associated with PTSD as well as PTSD symptoms among both veterans and civilians. Evidence also implicates noradrenergic dysregulation in the pathophysiology of alcohol dependence (AD); prazosin also may have efficacy in treating this disorder. The use of prazosin represents a rational and compelling approach for the treatment of PTSD and comorbid AD. Given the high rates of comorbid AD in trauma survivors with PTSD, and the enormous impact that these comorbid disorders have on psychosocial function and well-being, finding effective treatments for this population is of high clinical importance. METHODS: Ninety-six veterans with PTSD and comorbid AD were randomized to receive prazosin (16 mg) or placebo in an outpatient, randomized, double-blind, clinical trial for 13 weeks. Main outcomes included symptoms of PTSD, sleep disturbances, and alcohol use. RESULTS: Symptoms of PTSD improved over time, but contrary to the hypothesis, there was no medication effect on PTSD symptoms, or on sleep. Alcohol consumption also decreased over time, but there were no significant differences in outcomes between medication groups. CONCLUSIONS: Prazosin was not effective in treating PTSD symptoms, improving sleep, or reducing alcohol consumption overall in this dually diagnosed group. This does not support the use of prazosin in an actively drinking population and suggests that the presence of a comorbid condition affects the efficacy of this medication. This study highlights the importance of conducting clinical trials in "real-world" patients, as results may vary based on comorbid conditions.

Concurrent alcohol and tobacco treatment: Effect on daily process measures of alcohol relapse risk.

OBJECTIVE: The aim of this study was to compare the effects of alcohol treatment along with concurrent smoking treatment or delayed smoking treatment on process measures related to alcohol relapse risk. METHOD: Alcohol dependent smokers (N = 151) who were enrolled in an intensive outpatient alcohol treatment program and were interested in smoking cessation were randomized to a concurrent smoking cessation (CSC) intervention or to a waiting list for delayed smoking cessation (DSC) intervention scheduled to begin 3 months later. Daily assessments of relapse process measures were obtained using an Interactive Voice Response (IVR) system for 12 weeks after the onset of smoking treatment in the CSC condition, and before beginning smoking treatment in the DSC condition. Smoking outcomes were assessed at 2 and 13 weeks after starting treatment. RESULTS: Seven-day carbon monoxide (CO) verified smoking abstinence in the CSC condition was 50.5% at 2 weeks and 19.0% at 13 weeks compared with 2.2% abstinence at 2 weeks and 0% abstinence at 13 weeks for those in the DSC condition. Drinking outcomes were not significantly different for CSC versus DSC treatment conditions. On daily IVR assessments, CSC participants had significantly lower positive alcohol outcome expectancies relative to DSC participants. Multilevel modeling (MLM) analyses of within-person effects across the 12 weeks of daily monitoring showed that daily smoking abstinence was significantly associated with same day reports of lower alcohol consumption, lower urge to drink, lower negative affect, lower positive alcohol outcome expectancies, greater alcohol abstinence self-efficacy, greater alcohol abstinence readiness to change, and greater perceived self-control demands. CONCLUSIONS: Analyses of process measures provide support for recommending smoking intervention concurrent with intensive outpatient alcohol treatment. (PsycINFO Database Record

Smoking cessation during alcohol treatment: a randomized trial of combination nicotine patch plus nicotine gum.

AIMS: The primary aim was to compare the efficacy of smoking cessation treatment using a combination of active nicotine patch plus active nicotine gum versus therapy consisting of active nicotine patch plus placebo gum in a sample of alcohol-dependent tobacco smokers in an early phase of out-patient alcohol treatment. A secondary aim was to determine whether or not there were any carry-over effects of combination nicotine replacement on drinking outcomes. DESIGN: Small-scale randomized double-blind placebo-controlled clinical trial with 1-year smoking and drinking outcome assessment. SETTING: Two out-patient substance abuse clinics provided a treatment platform of behavioral alcohol and smoking treatment delivered in 3 months of weekly sessions followed by three monthly booster sessions. PARTICIPANTS: Participants were 96 men and women with a diagnosis of alcohol abuse or dependence and smoking 15 or more cigarettes per day. INTERVENTION: All participants received open-label transdermal nicotine patches and were randomized to receive either 2 mg nicotine gum or placebo gum under double-blind conditions. FINDINGS: Analysis of 1-year follow-up data revealed that patients receiving nicotine patch plus active gum had better smoking outcomes than those receiving patch plus placebo gum on measures of time to smoking relapse and prolonged abstinence at 12 months. Alcohol outcomes were not significantly different across medication conditions. CONCLUSIONS: Results of this study were consistent with results of larger trials of smokers without alcohol problems, showing that combination therapy (nicotine patch plus gum) is more effective than monotherapy (nicotine patch) for smoking cessation.

Efficacy of dose and contingency management procedures in LAAM-maintained cocaine-dependent patients.

Opioid- and cocaine-dependent participants (N=140) were randomly assigned to one of the following in a 12-week clinical trial: LAAM (30, 30, 39 mg/MWF) with contingency management (CM) procedures (LC); LAAM (30, 30, 39 mg/MWF) without CM (LY); LAAM (100, 100, 130 mg/MWF) with CM (HC); LAAM (100, 100, 130 mg/MWF) without CM (HY). Urine samples were collected thrice-weekly. In CM, each urine negative for both opioids and cocaine resulted in a voucher worth a certain monetary value that increased for consecutively drug-free urines. Subjects not assigned to CM received vouchers according to a yoked schedule. Vouchers were exchanged for mutually agreed upon goods and services. Groups generally did not differ on retention and baseline characteristics. Overall opioid use was least in the HC and HY groups; opioid use decreased most rapidly over time in the HC group relative to the HY, LC and LY groups. Overall cocaine use was least in the HC group relative to the HY, LC, and LY groups; cocaine use decreased over time most rapidly in the HC and LY groups. Abstinence from both was greatest in the HC group. Opioid withdrawal symptoms decreased most rapidly in the high-dose groups relative to the low-dose groups. These results suggest that an efficacious maintenance dose is necessary for contingencies to be effective in facilitating both opioid and cocaine abstinence.

Management of psychiatric issues in patients with intellectual disability.

The psychiatric treatment of people with intellectual disability and mental illness has progressed substantially. Not only have our interventions improved, the willingness and ability of psychiatrists to provide such care has grown enormously. Inclusion of psychiatric residents in this endeavor enhances the likelihood of future treatment interest by them as professionals in their own careers. Meaningful improvement in functional capacity and in reduction of symptom burden is achievable in most patients. Multiple levels of service delivery are adapted readily to care provision for this population when attention is paid to the environment of care and the education and training of staff is addressed. With greater attention now being paid to this population, continued improvement in the quality and capacity of service delivery is on the horizon.

Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results of a randomized pilot study.

AIMS: We sought to evaluate the safety and efficacy of the GABAergic agent tiagabine in reducing cocaine use among methadone-treated patients. DESIGN: Ten-week randomized double-blind placebo-controlled trial. SETTING: Opiate Treatment Research Program, Veteran's Affairs Connecticut Healthcare System in West Haven, Connecticut, USA. PARTICIPANTS: The participants were 45 cocaine-dependent methadone-treated patients who were predominately Caucasian (75.6%), male (77.8%) and never married (53%) with an average age of 38 years (SD = 6.5). INTERVENTIONS: Comparison groups received tiagabine 12 mg/day (n = 15), tiagabine 24 mg/day (n = 15) or placebo (n = 15). MEASURES: Baseline assessments included the Structured Clinical Interview for DSM-IV, the Addiction Severity Index, a urine drug test, self-reported use and opiate withdrawal scales. Urine drug tests were performed thrice weekly. FINDINGS: Treatment retention was over 80% for all treatment groups. The sample mean (+/- SE) of cocaine-free urines for the first week after study entry and before tiagabine was started was 1.16 (0.19) urines/week. During weeks 9 and 10 cocaine-free urines increased significantly from baseline by 33% with high-dose tiagabine (24 mg/day), by 14% with low-dose tiagabine (12 mg/day) and decreased by 10% with placebo (hierarchical linear model, Z= 2.03; P < 0.05). Self-reported cocaine use also decreased significantly more with active medications than with placebo. CONCLUSIONS: Tiagabine at 24 mg/day was well tolerated among these methadone-treated patients with only one reporting headache. Tiagabine appears to be a promising GABAergic medication that moderately improves cocaine-free urines.

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients.

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25-29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.

The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics.

The functions of thyrotropin-releasing hormone (TRH) in the central nervous system (CNS) can be conceptualized as performed by four anatomically distinct components that together comprise a general TRH homeostatic system. These components are 1) the hypothalamic-hypophysiotropic neuroendocrine system, 2) the brainstem/midbrain/spinal cord system, 3) the limbic/cortical system, and 4) the chronobiological system. We propose that the main neurobiological function of TRH is to promote homeostasis, accomplished through neuronal mechanisms resident in these four integrated systems. This hypothesis offers a unifying basis for understanding the myriad actions of TRH and TRH-related drugs already demonstrated in animals and humans. It is consistent with the traditional role of TRH as a regulator of metabolic homeostasis. An appreciation of the global function of TRH to modulate and normalize CNS activity, along with an appreciation of the inherent limitations of TRH itself as a therapeutic agent, leads to rational expectations of therapeutic benefit from metabolically stable TRH-mimetic drugs in a remarkably broad spectrum of clinical situations, both as monotherapy and as an adjunct to other therapeutic agents. The actions of TRH are numerous and varied. This has been viewed in the past as a conceptual and practical impediment to the development of TRH analogs. Herein, we alternatively propose that these manifold actions should be considered as a rational and positive impetus to the development of TRH-based drugs with the potential for unique and widespread applicability in human illness.

Ketoconazole increases cocaine and opioid use in methadone maintained patients.

Stress plays an important role in substance abuse problems. For example, in studies with rodents stress induces reinstatement of opioid and cocaine self-administration. In addition, attenuation of the stress response by pharmacological adrenalectomy using ketoconazole, a cortisol synthesis inhibitor, reduces cocaine self-administration in rodents. In contrast, studies in primates and humans have produced conflicting results using cortisol synthesis inhibitors for attenuating cocaine-related behaviors and subjective effects. To explore the treatment implications of these findings, ketoconazole's (600-900 mg daily) ability to reduce heroin and cocaine use was compared with placebo in 39 methadone maintained patients with a history of cocaine abuse or dependence during a 12-week double blind trial. Contrary to the predicted effects, both heroin and cocaine use increased after patients were stabilized on methadone and ketoconazole. Depressive and withdrawal symptoms improved no more with ketoconazole than with placebo treatment, and side effects were greater on ketoconazole than placebo. As reported before with methadone treatment, morning cortisol levels were significantly lower than normal values throughout the clinical trial, but were not lower with ketoconazole than placebo treatment. Thus, in agreement with the negative results from acute dosing studies in primates and humans, chronic ketoconazole treatment does not appear to reduce cocaine or opioid use in humans maintained on methadone.

Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.

The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration. Conventional heteromeric NMDARs composed of NR1 and NR2A-D subunits require dual agonists, glutamate and glycine, for activation. They are also highly permeable to Ca2+, and exhibit voltage-dependent inhibition by Mg2+. Coexpression of NR3A with NR1 and NR2 subunits modulates NMDAR activity. Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A. From in situ and immunocytochemical analyses, NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. Remarkably, when co-expressed in Xenopus oocytes, NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a co-activator of conventional NMDARs. Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or -3B 'NMDARs' constitute a type of excitatory glycine receptor.

Butorphanol and nalbuphine in opioid-dependent humans under a naloxone discrimination procedure.

Opioid-maintained volunteers were trained to distinguish between a low dose of the opioid antagonist naloxone (0.15 mg/70 kg, i.m.; i.e., Drug A) and placebo (i.e., Drug B) under an instructed novel-response drug-discrimination procedure in which subjects identify the drug condition as "A," "B," or "N" (neither A nor B--'novel'). Once the discrimination was acquired, doses of naloxone (000.15 mg/70 kg, i.m.) and the mixed-action opioid agonist/antagonists butorphanol (0-1.5 mg/70 kg, i.m.) and nalbuphine (0-3.0 mg/70 kg, i.m.) were tested. Naloxone produced dose-related increases in naloxone-appropriate responding with little or no 'novel'-appropriate responding. Butorphanol produced a dose-related increase in naloxone- and 'novel'-appropriate responding, occasioning approximately 70% and 29%, respectively, at the highest dose tested. Nalbuphine produced 40-65% naloxone-appropriate responding at all doses tested and 33% 'novel'-appropriate responding at the highest doses. Self-reported effects produced by each agent differed only slightly. These results suggest that mixed-action opioid agonist/antagonists may be distinguished from the opioid antagonist naloxone based on their discriminative-stimulus effects under a novel-response naloxone discrimination procedure.