Effects of cabergoline and dimethylcabergoline on the sexual behavior of male rats.

RATIONALE: Cabergoline (CAB) is an ergot derivative typically prescribed for the treatment of hyperprolactinemia. It suppresses the release of prolactin through agonist actions on dopamine (DA) D2 receptors; however, it possesses binding affinity for other DA and 5-HT receptors. Side effects that exacerbate valvular heart disease can occur with high doses. OBJECTIVE: The present study examined the acute, subchronic, and chronic dose-response effects of CAB and a derivative dimethylcabergoline (DMC) which acts as an antagonist instead of agonist at 5-HT 2B receptors, on appetitive and consummatory sexual behaviors of male rats. METHODS: CAB (0, 0.03, 0.15, or 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 68 days. Sexual behavior was tested every 4 days during this period for a total of 16 trials. On the 17th trial, rats were administered their dose of CAB, and 4 h after were overdosed with sodium pentobarbital, perfused intracardially, and their brains processed for Fos immunohistochemistry. DMC (0, 0.03, 0.15, 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 36 days. Sexual behavior was tested every 4 days for a total of 9 trials. RESULTS: CAB increased anticipatory level changes, intromissions, and ejaculations significantly across all timepoints, with the medium and high doses being most potent. The medium and high doses also increased Fos protein significantly within the medial preoptic area, whereas in the nucleus accumbens shell, the low and medium doses decreased Fos protein but the high dose increased it significantly from control. Similar to CAB, the medium and high doses of DMC increased the number of ejaculations significantly. Rats in all drug dose groups appeared healthy for the duration of the experiments. CONCLUSIONS: Both CAB and DMC facilitate ejaculations, and CAB further facilitates measures of anticipatory sexual motivation and intromissions. These data suggest that both could be used as treatments for sexual arousal disorders and ejaculation/orgasm disorders with little or no untoward side effects at low doses.

Alcohol Craving and Psychiatric Disorders Among Current Drinkers.

BACKGROUND AND OBJECTIVES: Previous research has shown that alcohol craving is associated with psychiatric comorbidities. However, no population studies have examined the odds of psychiatric disorders in cravers and noncravers. The purpose of this study was to investigate current prevalence rates and odds ratios of psychiatric disorders among alcohol drinkers with and without alcohol craving in a population-based sample. We also compared four craving groups (cravers with and without alcohol use disorder [AUD], noncravers with and without AUD) for psychiatric comorbidities. METHODS: The study data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). A subset of the NESARC sample (N = 22 000) who reported alcohol use during the past 12 months was included. Prevalence rates of psychiatric disorders were compared among current drinkers with alcohol craving (N = 900) and without alcohol craving (N = 21 500). RESULTS: Cravers had higher prevalence rates of current psychiatric disorders than noncravers. Even after adjustment for other psychiatric disorders including AUD, cravers had significantly higher odds of any substance use disorder (adjusted odds ratio [AOR], 9.01), any mood disorder (AOR, 1.78), any anxiety disorder (AOR, 1.86), and any personality disorder (AOR, 1.92) than noncravers. Interestingly, cravers without AUD had even higher rates of any anxiety disorder and any personality disorder than noncravers with AUD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Alcohol craving is associated with a higher prevalence of various psychiatric disorders. These findings suggest that alcohol craving may be related to transdiagnostic features that are present across various psychiatric disorders. (Am J Addict 2021;30:34-42).

A Comparative Study of Obsessionality in Medical Students, Law Students, and Controls.

Understanding obsessive-compulsive behavior in medical students and law students is necessary for administrators and educators to properly work with students struggling with obsessionality. We aim to compare the differences in obsessive symptoms between medical students, law students and a control population. A total of 100 third-year medical students, 102 third-year law students and 103 control subjects drawn from the general population completed the Leyton Obsessional Inventory (LOI). Subjects were examined on all three sections (symptoms/traits, resistance and interference) of the LOI. Obsessional symptom scores for medical students (14.29 ± 7.33) and law students (13.65 ± 6.61) were significantly greater than for the control group (11.58 ± 7.45). Medical and law students were both more likely to report checking, order, routine and attention to detail as obsessive symptoms. Medical students were more likely than law students to possess the obsessive symptoms of cleanliness and conscientiousness, while law students were more likely than medical students to possess obsessive symptoms related to difficulty in making up their mind and doubting themselves. While medical students and law students are more obsessional than the control population, each group is more likely to report different obsessive symptoms.

High-Dose Naltrexone Treatment and Gender in Alcohol Dependence.

OBJECTIVES: Little is known about whether safety and effectiveness of high-dose naltrexone (150 mg/d) are different in alcohol-dependent women and men. This study investigated sex differences in safety and treatment outcomes in alcohol-dependent women and men on high-dose naltrexone (150 mg/d). METHODS: In this exploratory study, safety and effectiveness of high-dose naltrexone (150 mg/d) were examined in men and women with alcohol dependence (n = 24; 11 men and 13 women) treated in an 8-week outpatient setting. RESULTS: Women and men had similar dropout rates, adverse effects, tolerability, and hepatic function during high-dose naltrexone treatment (150 mg/d). Drinking outcomes were significantly improved in both women and men, but no sex differences were found. CONCLUSIONS: High-dose naltrexone seems to be well tolerated, safe, and effective in both men and women with alcohol dependence in this small study. Given the small sample size of the current study, our results cannot be considered definitive, and larger trials with longer durations are needed to confirm these findings.

N-Acetylcysteine in the Treatment of Excoriation Disorder: A Randomized Clinical Trial.

IMPORTANCE: Excoriation (skin-picking) disorder (SPD) is a disabling, underrecognized condition in which individuals repeatedly pick at their skin, leading to noticeable tissue damage. To date, there has been no clearly effective pharmacologic or psychological treatment for SPD. OBJECTIVE: To determine whether N-acetylcysteine, an amino acid that appears to restore extracellular glutamate concentration in the nucleus accumbens, will be more effective than placebo in reducing compulsive picking behavior. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind trial was conducted at ambulatory care centers at the University of Minnesota (September 12, 2011, to June 15, 2012) and the University of Chicago (December 17, 2012, to June 26, 2015) and included 66 adults with SPD. Data analysis was performed from July 16 to September 9, 2015. INTERVENTIONS: N-acetylcysteine (dosing range, 1200-3000 mg/d) or placebo was administered for 12 weeks. MAIN OUTCOMES AND MEASURES: Participants were assessed using measures of skin-picking severity, including the modified Yale-Brown Obsessive Compulsive Scale (NE-YBOCS); total scores range from 0 to 40, with higher scores reflective of greater symptom severity. Another measure of skin-picking severity was the Clinical Global Impression-Severity Scale; total scores range from 1 (normal) to 7 (among the most extremely ill patients), and improvement ratings range from 7 (very much worse) to 1 (very much improved). Selected cognitive tasks included the Intra-dimensional/Extra-dimensional Shift Task to examine cognitive flexibility, with the key outcome measures being the number of errors, and Stop-Signal Reaction Time task, which evaluates motor inhibition. Outcomes were examined using a linear mixed-effects model. RESULTS: Of the 66 participants (31 randomized to placebo and 35 to N-acetylcysteine) included in the analysis, 59 (89%) were women; mean (SD) age was 34.8 (11.0) years. Compared with placebo, N-acetylcysteine treatment was associated with significant improvements in the NE-YBOCS. At baseline, NE-YBOCS scores were 18.9 and 17.9 for the treatment and placebo groups, respectively, and at 12 weeks, the scores were 11.5 and 14.1 for the treatment and placebo groups, respectively (P = .048). For the Clinical Global Impression-Severity scale, baseline scores were 3.5 and 4.0 and 12-week scores were 3.0 and 4.2, respectively (P = .003). These effects were significant both in terms of treatment by time interactions and post hoc tests at 1 or more individual time points. At the study's end point, of the 53 participants who completed the study, 15 of the 32 participants (47%) receiving N-acetylcysteine were much or very much improved compared with 4 of the 21 participants (19%) receiving placebo (P = .03). There were no significant differences between the active and placebo arms in terms of psychosocial functioning. CONCLUSIONS AND RELEVANCE: N-acetylcysteine treatment resulted in significant reductions in skin-picking symptoms and was well tolerated. The glutamate system may prove a beneficial target in treating SPD and other compulsive behaviors. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01063348.

Suicidal ideation and suicide attempts in five groups with different severities of gambling: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions.

BACKGROUND AND OBJECTIVES: Problem and pathological gamblers show high rates of suicidal behavior. However, previous research of suicide among this population has been inconsistent. Discrepancies may stem from methodological issues, including variable use of suicide nomenclature and selection bias in study samples. Furthermore, earlier research has rarely examined gambling severity aside from problem or pathological categories. This study utilized subgroups derived from a nationally representative data set, examining different characteristics of suicidal behavior and several gambling levels, including subclinical groups. METHODS: Participants included 13,578 individuals who participated in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and provided information on gambling behavior, lifetime suicidal ideation, and/or lifetime suicide attempts. Five gambling groups were derived using DSM-IV criteria for pathological gambling; non-gambling, low-risk gambling, at-risk gambling, problem gambling, and pathological gambling. RESULTS: Problem gambling was associated with suicidal ideation [adjusted odds ratio (AOR) = 1.64, 95% confidence interval (CI) = 1.19-2.26] and suicide attempts [(AOR) = 2.42, 95% (CI) = 1.60-3.67] after adjustment for sociodemographic variables. Pathological gambling was associated with suicidal ideation [(AOR) = 2.86, 95% (CI) = 1.98-4.11] and suicide attempts [(AOR) = 2.77, 95% (CI) = 1.72-4.47) after adjustment for sociodemographic variables. DISCUSSION, CONCLUSIONS, AND SCIENTIFIC SIGNIFICANCE: Our results from this population sample reinforce increased rates of suicidal behavior amongst smaller, clinical samples of problem and pathological gamblers. Education for providers about gambling is recommended, including screening for gambling-related symptoms such as suicidal behavior.

A single-blind study of 'as-needed' ecopipam for gambling disorder.

BACKGROUND: Gambling disorder is a disabling illness experienced by 1% to 3% of adults. Pharmacologic management of gambling disorder has produced mixed results, with some but not all studies showing medication to be more effective than placebo. Ecopipam may offer promise for treating gambling disorder because of its antagonism of dopamine-1 receptors. METHODS: Twenty-eight individuals with gambling disorder were enrolled and received ≥1 dose of oral ecopipam in an 8-week trial (1 week placebo lead-in, 6 weeks of medication (50 to 100 mg/d as needed), and 1 week follow-up. Participants were enrolled between September 2010 and June 2011 at 3 sites in the United States. Change from baseline to study endpoint on the Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) was the primary outcome measure. RESULTS: Treatment was associated with statistically significant reductions in the PG-YBOCS total score (baseline score of 25.6 reduced to 14.0 at study endpoint; P>.001) and PG-YBOCS subscales (Thought-Urge and Behavior, P>.001). CONCLUSIONS: These findings suggest that pharmacologic targeting of the dopamine-1 receptor may be beneficial in gambling behavior. Placebo-controlled, double-blind studies are warranted to confirm these preliminary findings.

Brain circuitry of compulsivity and impulsivity.

Impulsivity and compulsivity have been considered opposite poles of a continuous spectrum, but their relationship appears to be more complex. Disorders characterized by impulsivity often have features of compulsivity and vice versa. The overlaps of the constructs of compulsivity and impulsivity warrant additional investigation, not only to identify the similarities and differences, but also to examine the implications for prevention and treatment strategies of both compulsive and impulsive behaviors.

The opiate antagonist, naltrexone, in the treatment of trichotillomania: results of a double-blind, placebo-controlled study.

Trichotillomania (TTM) is characterized by repetitive hair pulling resulting in hair loss. Data on the pharmacological treatment of TTM are limited. This study examined the opioid antagonist, naltrexone, in adults with TTM who had urges to pull their hair. Fifty-one individuals with TTM were randomized to naltrexone or placebo in an 8-week, double-blind trial. Subjects were assessed with measures of TTM severity and selected cognitive tasks. Naltrexone failed to demonstrate significantly greater reductions in hair pulling compared to placebo. Cognitive flexibility, however, significantly improved with naltrexone (P = 0.026). Subjects taking naltrexone with a family history of addiction showed a greater numerical reduction in the urges to pull, although it was not statistically significant. Future studies will have to examine whether pharmacological modulation of the opiate system may provide promise in controlling pulling behavior in a subgroup of individuals with TTM.

A randomized, placebo-controlled trial of N-acetylcysteine plus imaginal desensitization for nicotine-dependent pathological gamblers.

OBJECTIVE: Pathological gambling is associated with elevated proportions of nicotine dependence, and tobacco smoking in pathological gamblers has been associated with increased problem-gambling severity. This study examined the addition of N-acetylcysteine to imaginal desensitization in adults with co-occurring nicotine dependence and pathological gambling. METHOD: Twenty-eight individuals with co-occurring DSM-IV nicotine dependence and pathological gambling who were receiving behavioral therapy were recruited from December 2009 to February 2012 and randomized to augmentation with N-acetylcysteine or placebo in an 12-week, double-blind trial. Subjects were assessed with measures of nicotine and gambling severity and followed for 3 months after treatment. The primary outcomes were the Fagerström Test for Nicotine Dependence and the pathological gambling adaptation of the Yale-Brown Obsessive-Compulsive Scale. RESULTS: During the first 6 weeks, there was a significant benefit of N-acetylcysteine treatment versus placebo on Fagerström Test for Nicotine Dependence total scores (t = -2.224; P = .031). After the initial 6 weeks, all subjects significantly (P < .001) benefited from imaginal desensitization. During the 3-month follow-up, there was a significant additional benefit for N-acetylcysteine versus placebo on measures of problem-gambling severity (t = 2.069; P = .043). CONCLUSIONS: N-acetylcysteine treatment during therapy facilitates long-term application of behavioral therapy techniques once patients are in the community after therapy has been completed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00967005.

A proof of concept study of tolcapone for pathological gambling: relationships with COMT genotype and brain activation.

Pathological gambling (PG) is a disabling disorder experienced by 1-3% of adults, and empirically validated treatments are lacking. Perturbations of prefrontal-dependent cognitive functions are implicated in the pathophysiology of PG. The enzyme catechol-O-methyl-transferase (COMT) is responsible for degradation of dopamine in the cortices and thereby is known to regulate such cognitive functions and their neural substrates. The objective of this study was to determine whether tolcapone, a COMT inhibitor, improves symptoms of PG and to explore whether such effects are dependent on COMT val-158-met polymorphism status and relate to concomitant changes in fronto-parietal activation. Twenty-four individuals with PG were enrolled in an 8-week trial of oral tolcapone (100mg/day titrated to 100mg thrice/day) and 12 undertook pre- and post-treatment fMRI to examine brain activation during an executive planning task in a pre-defined fronto-parietal network. At baseline, patients with PG showed fronto-parietal under-activation versus controls during executive planning. Treatment was associated with statistically significant reductions on PG-Yale Brown Obsessive Compulsive Scale (PG-YBOCS), the extent of which correlated significantly with augmentation of planning-related fronto-parietal activation. Symptom improvement was also significantly more pronounced in subjects with the val/val COMT polymorphism. Tolcapone improved PG symptoms, and the extent of symptomatic improvement was significantly related to augmentation of fronto-parietal activation (fMRI probe) and COMT status. Objective genetic and fMRI markers hold promise in the search for targeting treatment and elucidating brain mechanisms associated with optimal clinical outcomes.

Synthesis of novel analogs of cabergoline: improving cardiovascular safety by removing 5-HT2B receptor agonism.

The dopamine agonist cabergoline has been used to treat prolactinomas, Parkinson's disease, Cushing's disease and sexual dysfunction. However, its clinical use was severely curtailed when it was found that patients taking cabergoline had an increased risk of developing cardiac-valve regurgitation. This potentially life-threatening condition has been associated with drugs, such as cabergoline, that are 5-HT2B receptor agonists. We prepared analogs of cabergoline and have identified several that have limited or no agonism at the 5-HT2B receptor.

Suicide attempts in 107 adolescents and adults with kleptomania.

Suicide attempts in kleptomania have received little investigation. This study examined rates, correlates, and predictors of suicide attempts in kleptomania. A total of 107 adolescent and adult subjects (n = 32 [29.9%] males) with DSM-IV kleptomania were assessed with standard measures of symptom severity, psychiatric comorbidity, and functional impairment. Subjects had high rates of suicide attempts (24.3%). The suicide attempt in 92.3% of those who attempted suicide was attributed specifically to kleptomania. Suicide attempts were associated with current and life-time bipolar disorder (p = .047) and lifetime personality disorder (p = .049). Individuals with kleptomania have high rates of suicide attempts. Bipolar disorder is associated with suicide attempts in individuals with kleptomania and underscores the importance of carefully assessing and monitoring suicidality in patients with kleptomania.

Genome-wide linkage analysis of obsessive-compulsive disorder implicates chromosome 1p36.

BACKGROUND: Obsessive-compulsive disorder (OCD) has a complex etiology involving both genetic and environmental factors. However, the genetic causes of OCD are largely unknown, despite the identification of several promising candidate genes and linkage regions. METHODS: Our objective was to conduct genetic linkage studies of the type of OCD thought to have the strongest genetic etiology (i.e., childhood-onset OCD), in 33 Caucasian families with ≥2 childhood-onset OCD-affected individuals from the United States (n = 245 individuals with genotype data). Parametric and nonparametric genome-wide linkage analyses were conducted with Morgan and Merlin in these families using a selected panel of single nucleotide repeat polymorphisms from the Illumina 610-Quad Bead Chip. The initial analyses were followed by fine-mapping analyses in genomic regions with initial heterogeneity logarithm of odds (HLOD) scores of ≥2.0. RESULTS: We identified five areas of interest (HLOD score ≥2) on chromosomes 1p36, 2p14, 5q13, 6p25, and 10p13. The strongest result was on chromosome 1p36.33-p36.32 (HLOD = 3.77, suggestive evidence for linkage after fine mapping). At this location, several of the families showed haplotypes co-segregating with OCD. CONCLUSIONS: The results of this study represent the strongest linkage finding for OCD in a primary analysis to date and suggest that chromosome 1p36, and possibly several other genomic regions, may harbor susceptibility loci for OCD. Multiple brain-expressed genes lie under the primary linkage peak (approximately 4 megabases in size). Follow-up studies, including replication in additional samples and targeted sequencing of the areas of interest, are needed to confirm these findings and to identify specific OCD risk variants.

Open-label pilot study of memantine in the treatment of compulsive buying.

BACKGROUND: Although compulsive buying (CB) is relatively common, pharmacotherapy research for CB is limited. Memantine, an N-methyl-D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive behaviors, suggesting it may help individuals with CB. METHODS: Nine patients (8 females) with CB were enrolled in a 10-week open-label treatment study of memantine (dose ranging from 10 to 30 mg/d). Participants were enrolled from December 2008 until May 2010. The primary outcome measure was change from baseline to study endpoint on the Yale-Brown Obsessive Compulsive Scale-Shopping Version (Y-BOCS-SV). RESULTS: Of the 9 participants, 8 (88.9%) completed the 10-week study. Y-BOCS-SV scores decreased from a mean of 22.0 ± 1.3 at baseline to 11.0 ± 5.3 at endpoint (P < .001). Hours spent shopping per week and money spent shopping both decreased significantly (P < .001). The mean effective dose of memantine was 23.4 ± 8.1 mg/d. Memantine treatment was associated with diminished impulsive buying and improvements on cognitive tasks of impulsivity. In addition, the medication was well-tolerated. CONCLUSIONS: These findings suggest that pharmacologic manipulation of the glutamate system may target the impulsive behavior underlying CB. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design.

Selective decision-making deficits in at-risk gamblers.

Despite reasonable knowledge of pathological gambling (PG), little is known of its cognitive antecedents. We evaluated decision-making and impulsivity characteristics in people at risk of developing PG using neuropsychological tests. Non-treatment seeking volunteers (18-29 years) who gamble ≥ 5 times/year were recruited from the general community, and split into two groups: those "at risk" of developing PG (n=74) and those social, non-problem gamblers (n=112). Participants undertook the Cambridge Gamble and Stop-signal tasks and were assessed with the Mini-International Neuropsychiatric Interview and the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling. On the Cambridge Gamble task, the at-risk subjects gambled more points overall, were more likely to go bankrupt, and made more irrational decisions under situations of relative risk ambiguity. On the Stop-signal task, at-risk gamblers did not differ from the social, non-problem gamblers in terms of motor impulse control (stop-signal reaction times). Findings suggest that selective cognitive dysfunction may already be present in terms of decision-making in at-risk gamblers, even before psychopathology arises. These findings implicate selective decision-making deficits and dysfunction of orbitofronto-limbic circuitry in the chain of pathogenesis between social, non-problematic and pathological gambling.

Strategic vs nonstrategic gambling: characteristics of pathological gamblers based on gambling preference.

BACKGROUND: Although prior studies have examined various clinical characteristics of pathological gambling (PG), limited data exist regarding the clinical correlates of PG based on preferred forms of gambling. METHODS: We grouped patients meeting DSM-IV criteria for pathological gambling into 3 categories of preferred forms of gambling: strategic (eg, cards, dice, sports betting, stock market), nonstrategic (eg, slots, video poker, pull tabs), or both. We then compared the groups' clinical characteristics, gambling severity (using the Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling, the Clinical Global Impression-Severity scale, and time and money spent gambling) and psychiatric comorbidity. RESULTS: The 440 patients included in this sample (54.1% females; mean age 47.69±11.36 years) comprised the following groups: strategic (n = 56; 12.7%), nonstrategic (n = 200; 45.5%), or both (n = 184; 41.8%). Nonstrategic gamblers were significantly more likely to be older and female. Money spent gambling, frequency of gambling, gambling severity, and comorbid disorders did not differ significantly among groups. CONCLUSIONS: These preliminary results suggest that preferred form of gambling may be associated with certain age groups and sexes but is not associated with any specific clinical differences.

Dronabinol, a cannabinoid agonist, reduces hair pulling in trichotillomania: a pilot study.

RATIONALE: Trichotillomania is characterized by repetitive pulling causing noticeable hair loss. Pharmacological treatment data for trichotillomania are limited. OBJECTIVE: Dronabinol appears to reduce the exocitotoxic damage caused by glutamate release in the striatum and offers promise in reducing compulsive behavior. METHODS: Fourteen female subjects (mean age = 33.3 ± 8.9) with DSM-IV trichotillomania were enrolled in a 12-week open-label treatment study of dronabinol (dose ranging from 2.5-15 mg/day). The primary outcome measure was change from baseline to study endpoint on the Massachusetts General Hospital Hair Pulling Scale (MGH-HPS). In order to evaluate effects on cognition, subjects underwent pre- and post-treatment assessments using objective computerized neurocognitive tests. Data were collected from November 2009 to December 2010. RESULTS: Twelve of the 14 subjects (85.7%) completed the 12-week study. MGH-HPS scores decreased from a mean of 16.5 ± 4.4 at baseline to 8.7 ± 5.5 at study endpoint (p = 0.001). Nine (64.3%) subjects were "responders" (i.e., ≥ 35% reduction on the MGH-HPS and "much or very much improved" Clinical Global Impression scale). The mean effective dose was 11.6 ± 4.1 mg/day. The medication was well-tolerated, with no significant deleterious effects on cognition. CONCLUSIONS: This study, the first to examine a cannabinoid agonist in the treatment of trichotillomania, found that dronabinol demonstrated statistically significant reductions in trichotillomania symptoms, in the absence of negative cognitive effects. Pharmacological modulation of the cannabinoid system may prove useful in controlling a range of compulsive behaviors. Given the small sample and open-label design, however larger placebo-controlled studies incorporating cognitive measures are warranted.