Effects of atomoxetine on subjective and neurocognitive symptoms of nicotine abstinence.

Nicotine dependence has been linked to attention-deficit hyperactivity disorder (ADHD) symptoms in both clinical and general populations. This behavioural pharmacology study used a within-subject, double-blind, crossover design to test the effects of atomoxetine, a medication for ADHD, on nicotine abstinence symptoms. Fifty non treatment-seeking smokers (>/=15 cigarettes/day) completed a baseline session when they were smoking as usual and then two laboratory testing sessions after overnight abstinence and treatment with 7 days of either atomoxetine (1.2 mg/kg) or placebo. During each laboratory session, participants completed subjective measures of abstinence symptoms and performed neurocognitive tasks. In mixed effects models, atomoxetine, compared with placebo, was found to be associated with a reduction in abstinence-induced subjective withdrawal symptoms. Atomoxetine was also associated with significant reductions in self-reported smoking urges amongst smokers who scored high on a baseline measure of smoking for stimulation. However, atomoxetine had no effect on any of the cognitive tasks employed in the study. Thus, atomoxetine may reduce cravings to smoke among smokers who use nicotine to increase arousal.

Association of OPRM1 A118G variant with the relative reinforcing value of nicotine.

RATIONALE: The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement. METHODS: In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence. RESULTS: The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups. CONCLUSIONS: This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women.

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial.

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

Predicting treatment response to naltrexone: the influence of craving and family history.

Naltrexone has repeatedly been shown to reduce drinking in alcohol-dependent patients. Previous clinical research suggests that naltrexone may be more effective at reducing drinking among patients with high levels of alcohol craving at the beginning of treatment. In addition, laboratory studies suggest that naltrexone may be more efficacious among patients with a high familial loading of alcohol problems. We explored both of these possibilities in the context of the first 12-week phase of a double blind, placebo-controlled naltrexone trial. A total of 121 patients were randomized to receive 100 mg/day naltrexone and 62 patients were randomized to receive placebo. Both naltrexone and placebo were given in conjunction with a psychosocial intervention designed to be integrated with the use of pharmacotherapy. This intervention was administered by nurse practitioners. Overall, patients randomized to naltrexone reported drinking five or more drinks on fewer days than did placebo controls (p = .04). Interactions were observed between medication group assignment and both craving level prior to randomization (p = .02) and family loading of alcohol problems (p = .05). In both cases, the interaction was in the predicted direction. These data suggest that patients with high levels of alcohol craving or a strong family history of alcoholism are more likely to benefit from naltrexone treatment.

Double-blind clinical trial of sertraline treatment for alcohol dependence.

Clinical studies that have evaluated serotonergic medications to reduce alcohol consumption have yielded conflicting results. These studies primarily treated patients with alcohol dependence, excluding those with a current depressive disorder, in an effort to differentiate any medication effects directly on drinking from those on mood. Yet despite the exclusion of current depression, a group of alcohol-dependent patients who are not depressed can be highly heterogeneous. For example, this subgroup can include those with a lifetime depressive disorder. If these patients were more sensitive to serotonergic medications than patients without a lifetime depressive disorder, medication effects in a subgroup of patients who were not depressed could be obscured. Thus, the purpose of this study was to examine the efficacy of sertraline for treating alcohol dependence in patient groups that were differentiated by the presence or absence of lifetime depression. This study examined the effectiveness of sertraline (200 mg/day) or placebo for 14 weeks in 100 alcohol-dependent subjects with (N = 53) or without (N = 47) a lifetime diagnosis of comorbid depression. Sertraline treatment seemed to provide an advantage in reducing drinking in alcohol-dependent patients without lifetime depression, illustrated best with a measure of drinking frequency during treatment. However, sertraline was no better than placebo in patients with a diagnosis of lifetime comorbid depression, and current depression did not change the results. Treatment with selective serotonin reuptake inhibitors may be useful in alcohol-dependent patients who are not depressed. Subtyping those with alcohol dependence on the basis of the absence versus the presence of a lifetime depressive disorder may help to resolve conflicting findings in the literature on the treatment of alcohol dependence with serotonergic medications.

6-beta-naltrexol reduces alcohol consumption in rats.

BACKGROUND: In humans, 6-beta-naltrexol is the major metabolite of naltrexone, and its effectiveness at suppressing alcohol consumption in any species has not been previously investigated. Naltrexone is an opiate antagonist that reduces excessive drinking in many species, including humans with alcohol dependence. Whether 6-beta-naltrexol is an active metabolite that contributes to the efficacy of naltrexone remains unknown. METHODS: Placebo and four doses of 6-beta-naltrexol were given by intraperitoneal injection to outbred Wistar rats and alcohol consumption was measured using a limited access model. RESULTS: 6-beta-Naltrexol reduced alcohol consumption in a dose-dependent manner. At doses 7.5, 12.5, and 25 mg/kg, 6-beta-naltrexol significantly decreased consumption of a 6% ethanol solution compared with saline control groups. CONCLUSIONS: These data suggest that there may be a potential clinical use for 6-beta-naltrexol in recovering alcoholics.

Gender and psychiatric comorbidity: impact on clinical presentation of alcohol dependence.

We examined differences in clinical presentation for outpatient alcohol treatment in: 1) males and females, considering comorbidity; and 2) three comorbid groups, considering gender. Drinking indices and emotional, physical, and sexual abuse reports were compared in 127 male and 69 female alcohol-dependent patients who have a current (36.2%) or lifetime (20.4%) psychiatric disorder or who never had a psychiatric disorder (43.4%). Females reported more emotional and physical abuse than males. Females reported drinking smaller volumes of alcohol but on more days than males. All with current comorbidity, irrespective of gender, reported more days of heavy drinking than other groups. When evaluating drinking status, gender and comorbidity should be considered.

Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype.

BACKGROUND: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline. METHODS: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk/severity (Type A: n = 55) and higher-risk/severity (Type B: n = 45) subgroups. RESULTS: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo. CONCLUSIONS: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.

Effects of triazolam at three phases of the menstrual cycle.

This study investigated the subjective and behavioral effects of a commonly used benzodiazepine, triazolam, in healthy women at three phases of the menstrual cycle: follicular, periovulatory, and luteal. Ovarian hormones or their metabolites have direct and indirect actions on neuronal receptors, which may affect responses to psychoactive drugs acting on the same central nervous system receptors. This study explored the effect of menstrual cycle phase on the mood-altering and performance effects of a single oral dose of the benzodiazepine triazolam. Twenty women received triazolam (0.25 mg orally) or placebo at the follicular, periovulatory, and luteal phases of their menstrual cycles in a within-subject design. Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of triazolam, estradiol, progesterone, and allopregnanolone. After administration of triazolam, most subjects reported the expected increases in fatigue and decreases in arousal and psychomotor performance. Neither plasma levels nor mood and performance effects of triazolam differed across the three phases. This study illustrates a useful methodology for assessing responses to psychoactive drugs in normally cycling women and shows that the effects of this drug were highly stable across the cycle.

Open trials as a method of prioritizing medications for inclusion in controlled trials for cocaine dependence.

This paper describes a rapid and systematic method of using open trials to identify medications that may be useful for the treatment of cocaine dependence. Results of these open trials can be used to prioritize medications for inclusion in subsequent double-blind, placebo-controlled trials. Preliminary results are presented from the evaluation of propranolol, nefazodone, and the combination of phentermine and fenfluramine (phen/fen). Each medication was evaluated in an open trial, and results were compared to results obtained from a group that received a multivitamin. Outcome measures included treatment retention, urine toxicology screens, self-reported cocaine use, and changes on the Addiction Severity Index (ASI). Treatment retention was significantly better in the propranolol group than in the multivitamin group. Concurrent alcohol abuse was associated with increased rates of attrition in the multivitamin group, and the phen/fen group, but not in the propranolol group. Neither the nefazodone nor the phen/fen groups showed any outcome advantages over the multivitamin group. We conclude that propranolol may enhance retention among cocaine-dependent patients, especially among those who also abuse alcohol. These results encourage a double-blind, placebo-controlled trial of propranolol.

Acute effects of triazolam in women: relationships with progesterone, estradiol and allopregnanolone.

This study investigated hormone levels and mood in normal women to explore relationships between levels of circulating hormones and i) baseline mood states and ii) effects of triazolam on mood. Certain ovarian hormones or their metabolites have direct actions on neuronal receptors. These actions may result in changes in mood state, or changes in responses to psychoactive drugs which act on the same receptors. The present study explored relationships between estrogen, progesterone and a metabolite of progesterone, allopregnanolone, and the mood-altering and performance effects of an acute dose of triazolam. Triazolam is a short-acting benzodiazepine which acts via the GABAA receptor complex. Twenty women received triazolam (0.25 mg) or placebo at the follicular, ovulatory and luteal phases of their menstrual cycle. Each subject participated in six conditions (i.e., drug and placebo at each of the three phases), across two menstrual cycles. Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of estradiol, progesterone, allopregnanolone, and triazolam. Mood and performance measures were not clearly related to hormone levels when data from all three phases were examined. However, within the luteal phase, higher levels of allopregnanolone were associated with lower self-reported arousal before any drug administration (i.e., at baseline). After administration of triazolam, most subjects reported the expected decreases in rating of arousal. However, the subjects with the highest levels of allopregnanolone reported increases in ratings of arousal. Thus, hormone levels were related to mood and responses to triazolam, particularly during the luteal phase of the cycle. However, the drug-hormone interactions on mood and behavior were complex.

Gender differences in comorbidly depressed alcohol-dependent outpatients.

UNLABELLED: Clinical profiles of alcohol-dependent male and female outpatients were evaluated at treatment entry to compare the level of clinical severity in alcoholics with a coexistent comorbid depressive disorder to alcoholics who have never been depressed. Due to a higher proportion of females than males in the depressed alcoholic population, selected patient groups were oversampled to create a study group with equivalent number of males and females with and without comorbid depression. Clinical severity was assessed by examining both the extent of alcohol problems, and depressive symptomatology at treatment entry with respect to gender differences (unrelated to depression), effects of comorbid depression (unrelated to gender), and effects from the interaction of gender and depression. There were 93 DSM-III-R alcohol-dependent outpatients (50 males, 43 females), half of whom had a current or lifetime DSM-III-R depressive disorder. The amount of drinking in the 90 days before treatment entry, the degree of alcohol severity, and the number of lifetime drinking-related consequences were collected in the first week after detoxification. Diagnoses of lifetime and current depression were determined via the Structured Clinical Interview for DSM-III-R, and depressive symptoms were evaluated with rating scales 1 week after detoxification. In most cases, a depressive disorder was diagnosed only if sometime in the patient's history depressive symptoms had either predated problem drinking or been present during a 6-month abstinent period. RESULTS: depressed males had a more severe clinical profile with respect to their alcoholism (i.e., more drinking, drinking-related problems, and alcohol severity than depressed females and never-depressed males). Surprisingly, females who had never been depressed (also no family history of depression) reported drinking the same quantities of alcohol in the 90 days before treatment and had comparable alcohol severity and number of consequences as males who had never been depressed. Depressed females, however, were more severely depressed (i.e., reported more intensive depressive symptoms than depressed male alcoholics). Thus, determining the type and extent of clinical severity at treatment entry in comorbidly depressed alcoholics depends on the gender of the patient The significant interaction between gender and the presence of comorbid depression that was found in this study may have important implications for predicting success in treatment.

Acute subjective responses to paroxetine in normal volunteers.

The purpose of this study was to compare the subjective effects of the selective serotonin reuptake inhibitor, paroxetine, to those of the prototypic stimulant, d-amphetamine. Ten healthy volunteers attended 5 sessions and received paroxetine (10, 20, 50 mg), d-amphetamine (20 mg), and placebo. Subjective effects were measured at regular intervals for 26-30 h. Paroxetine and d-amphetamine produced highly dissimilar effects on mood. For example, whereas d-amphetamine increased ratings of euphoria, drug high, and desire for drug, paroxetine produced no effects on these measures. Conversely, whereas paroxetine increased ratings of Confusion and Fatigue, d-amphetamine did not. These findings suggest that serotonin does not play a significant role in mediating the positive subjective effects of stimulant drugs.

Candida epididymitis: newly recognized opportunistic epididymal infection.

Epididymitis is common, yet it is rarely associated with fungal pathogens. We report a case of Candida albicans epididymitis in a diabetic which was ultimately treated by orchiectomy. Opportunistic infections of the genitourinary tract in immunosuppressed patients are becoming more prevalent; examples include fungal infections in patients with acquired immune deficiency syndrome or after organ transplant. The fact that opportunistic organisms can invade the epididymis and produce infection suggests that in cases of persistent epididymitis, which have failed to respond to conventional therapy, more aggressive diagnostic procedures should be considered. Needle aspiration with cultures for fungus and viral organisms should be performed. This is especially true in patients with preexisting chronic illness or an immune compromised state.