A Preliminary, Open-Label Study of Naltrexone and Bupropion Combination Therapy for Treating Binge Drinking in Human Subjects.

AIMS: The combination of bupropion and naltrexone has shown efficacy in reducing binge drinking in animal models. This study assessed the tolerability and potential utility of combined naltrexone and bupropion in reducing binge drinking in human subjects. METHODS: This preliminary study employed an open-label, single-arm, 12-week, prospective design. Twelve men and women who exhibited a minimum of five (men) or three (women) binge drinking episodes per month over the past 3 months were recruited. All subjects received both bupropion-extended release 300 mg/day and naltrexone 50 mg/day and were monitored throughout the 3-month treatment period. Binge drinking was assessed using the timeline follow-back method. RESULTS: Treatment with combined naltrexone and bupropion reduced the average number of drinks per binge drinking day from 7.8 drinks to 6.4 drinks and reduced the average percentage of binge drinking days per month from 19% (5.7 days/month) to 5% (1.5 days/month). Naltrexone and bupropion were generally well tolerated, with insomnia, headache and nausea/diarrhea being the most common side effects. Six subjects elected to stay on medication after the trial. CONCLUSIONS: This study suggests that combined naltrexone and bupropion therapy should be further investigated for tolerability and efficacy in reducing binge drinking in humans.

Centrally-mediated sensory information processing is impacted with increased alcohol consumption in college-aged individuals.

Alcohol consumption can have an impact on a variety of centrally-mediated functions of the nervous system, and some aspects of sensory perception can be altered as a result of long-term alcohol use. In order to assess the potential impact of alcohol intake on sensory information processing, metrics of sensory perception (simple and choice reaction time; static and dynamic threshold detection; amplitude discrimination with and without pre-exposure to conditioning stimulation) were tested in college-aged subjects (18 to 26 years of age) across a broad range of levels of alcohol consumption. The analysis indicated no detectable associations between reaction time and threshold measures with alcohol consumption. However, measures of adaptation to short duration (0.5s) conditioning stimuli were significantly associated with alcohol consumption: the impact of a confounding conditioning stimulus on amplitude discriminative capacity was comparable to values reported in previous studies on healthy controls (28.9±8.6) for light drinkers while the same adaptation metric for heavy drinkers (consuming greater than 60 drinks per month) was significantly reduced (8.9±7.1). The results suggest that while some of the sensory perceptual metrics which are normally impacted in chronic alcoholism (e.g., reaction time and threshold detection) were relatively insensitive to change with increased alcohol consumption in young non-alcoholic individuals, other metrics, which are influenced predominantly by centrally-mediated mechanisms, demonstrate a deviation from normative values with increased consumption. Results of this study suggest that higher levels of alcohol consumption may be associated with alterations in centrally-mediated neural mechanisms in this age group.

Effects of paroxetine on cardiovascular response to mental stress in subjects with a history of coronary artery disease and no psychiatric diagnoses.

RATIONALE: Paroxetine may decrease mental stress-induced cardiovascular responses and so benefit individuals with heart disease, even those with no psychiatric illness. OBJECTIVES: The effects of paroxetine on cardiovascular measures during a speech task were evaluated in psychiatrically healthy subjects with a history of coronary artery disease (CAD). METHODS: Eight subjects completed this double-blind, placebo-controlled, cross-over study in which each subject took 1 month of paroxetine and 4 weeks of placebo in random order. While on each study, medication, blood pressure, heart rate, and plasma norepinephrine concentrations were measured during a period of relaxation and during a mental stressor. The mental stressor consisted of thinking about a stressful topic, speaking about the topic, and listening to a tape-recorded replay of the speech. RESULTS: While on paroxetine, systolic blood pressure and diastolic blood pressure were 10-15% lower (p < 0.005) during the stressor, relative to measures obtained while on placebo. Pulse and plasma norepinephrine concentrations during stress trended lower during paroxetine treatment but did not reach statistical significance. CONCLUSION: Paroxetine has antihypertensive properties during periods of psychological stress in psychiatrically healthy subjects with a history of CAD, and so should be evaluated for potential cardio-protective qualities.

Association between preference for sweets and excessive alcohol intake: a review of animal and human studies.

This report reviews a series of studies demonstrating a relationship between the consumption of sweets and alcohol consumption. There is consistent evidence linking the consumption of sweets to alcohol intake in both animals and humans, and there are indications that this relationship may be at least partially genetic in nature. Alcohol-preferring rats have a tendency to consume sucrose and saccharin solutions far beyond the limits of their normal fluid intake and this has been proposed to be a model of the clinical phenomenon known as loss of control. Furthermore, rats and mice, genetically bred to prefer alcohol, tend to choose more concentrated sweet solutions, compared to animals which do not prefer alcohol. Similar tendencies to prefer ultra-sweet solutions have been noted in studies of alcoholic subjects, with most alcoholics preferring sweeter sucrose solutions than do controls. Evidence also exists that those alcoholics who prefer sweeter solutions may represent a familial form of alcoholism. Finally, consumption of sweets and/or sweet solutions may significantly suppress alcohol intake in both animals and in alcoholics. Carbohydrate structure and sweet taste may contribute to this effect through different physiological mechanisms involving serotonergic, opioid, and dopaminergic functions. The possibility that there is concordance between sweet liking and alcohol consumption and/or alcoholism has theoretical, biological, and diagnostic/practical implications.

Pharmacological treatment of alcohol dependence: a review of the evidence.

CONTEXT: Alcoholism affects approximately 10% of Americans at some time in their lives. Treatment consists of psychosocial interventions, pharmacological interventions, or both, but which drugs are most effective at enhancing abstinence and preventing relapse has not been systematically reviewed. OBJECTIVE: To evaluate the efficacy of 5 categories of drugs used to treat alcohol dependence--disulfiram, the opioid antagonists naltrexone and nalmefene, acamprosate, various serotonergic agents (including selective serotonergic reuptake inhibitors), and lithium. DATA SOURCES: Reports of randomized controlled trials, nonrandomized trials, and other study designs in English, French, and German identified from multiple searches of MEDLINE, EMBASE, and specialized databases; hand searching bibliographies of review articles; searches for unpublished literature; and discussions with investigators in the field. STUDY SELECTION: We included all studies on alcohol-dependent human subjects aged 18 years or older from all inpatient and outpatient settings between 1966 and December 1997 that met our inclusion criteria. DATA EXTRACTION: We abstracted the following information: study design and blinding, diagnostic instrument and severity assessment, drug interventions and cointerventions, demographic and comorbidity details about patients, compliance, and numerous outcome measures (eg, relapse, return to drinking, drinking or nondrinking days, time to first drink, alcohol consumed per unit of time, craving). We graded quality of the individual articles (scale, 0-100) independently from the strength of evidence for each drug class (A, strong and consistent evidence of efficacy in studies of large size and/or high quality; B, mixed evidence of efficacy; C, evidence of lack of efficacy; and I, insufficient evidence). DATA SYNTHESIS: Of 375 articles evaluated, we abstracted and analyzed data from 41 studies and 11 follow-up or subgroup studies. Naltrexone (grade A) reduces the risk of relapse to heavy drinking and the frequency of drinking compared with placebo but does not substantially enhance abstinence, ie, avoidance of any alcohol consumption. Acamprosate (grade A, from large-scale studies in Europe) reduces drinking frequency, although its effects on enhancing abstinence or reducing time to first drink are less clear. Controlled studies of disulfiram (grade B) reveal a mixed outcome pattern--some evidence that drinking frequency is reduced but minimal evidence to support improved continuous abstinence rates. The limited data on serotonergic agents were not very promising (grade I), although most studies were confounded by high rates of comorbid mood disorders. Lithium lacks efficacy (grade C) in the treatment of primary alcohol dependence. CONCLUSIONS: Recent reports documenting that naltrexone and acamprosate are more effective than placebo in the treatment of alcoholism justify clinical interest in use of these medications for alcohol-dependent patients. Use of disulfiram is widespread but less clearly supported by the clinical trial evidence; however, targeted studies on supervised administration of disulfiram may be warranted. Use of existing serotonergic agents or lithium for patients with primary alcohol dependence does not appear to be supported by the efficacy data available at this time; these medications may still have a positive effect in patients with coexisting psychiatric disorders.

Preference for higher sugar concentrations and Tridimensional Personality Questionnaire scores in alcoholic and nonalcoholic men.

Animal studies have shown a positive association between the consumption of high concentrations of sweet solutions and subsequent alcohol intake. In a previous clinical study, it was shown that a preference for a high (0.83 M) concentration of sucrose (sweet liking) is characteristic of alcoholics, compared with controls. The present study was designed to determine whether personality variables, reported to be associated with subtypes of alcoholism, differentiate sweet liking alcoholics from sweet liking controls. Fifty-two male controls and 26 alcoholic patients were tested for sweet preference and administered the Tridimensional Personality Questionnaire. Sweet liking alcoholics scored significantly higher on the Tridimensional Personality Questionnaire Novelty Seeking and Harm Avoidance scales and related subscales when compared with sweet liking controls. Further analysis showed that preferred sucrose concentration, Harm Avoidance score, and Novelty Seeking predicted alcoholic versus nonalcoholic group status at 65% sensitivity and 94% specificity, with a correct classification in 85% subjects. We hypothesize that sweet liking may identify a specific alcoholism subtype also characterized by high novelty seeking and high harm avoidance. These findings may have theoretical biological significance and practical clinical implications.

Thyrotropin releasing hormone analog TA-0910 suppresses alcohol intake in alcohol drinking African green monkeys.

In previous studies, we found that single injections of the thyrotropin-releasing hormone analog TA-0910 dose-dependently reduced alcohol intake and preference in alcohol-preferring (P) and Fawn-Hooded (FH) rats over a 24-hr period of continuous access to alcohol and water. However, several consecutive daily injections of TA-0910 resulted in the development of tolerance to these effects. In the present study, we found that in a 5-hr limited-access schedule in which monkeys could select an aqueous alcohol solution (7.5% v/v) or tap water, single doses of TA-0910 (0.0625, 0.125, 0.25, 0.5, and 0.75 mg/kg), similar to those found effective in P and FH rats, reduced consumption of alcohol. In this protocol, tolerance to the attenuating effects of TA-0910 on alcohol intake was not evident after five consecutive once-daily doses of 0.5 mg/kg. Furthermore, it was shown that a single dose of 0.75 mg/kg TA-0910 did not significantly influence 24-hr water intake when water was the only available fluid, but did reduce the intake of a preferred solution of saccharin. These findings suggest that activation of brain thyrotropin-releasing hormone systems reduces alcohol intake in primates and that tolerance to this effect is not evident within 5 days under a limited access schedule.

Evidence of preference for a high-concentration sucrose solution in alcoholic men.

OBJECTIVE: The purpose of this study was to test in humans the finding from animal studies indicating an association between preference for more concentrated sweet solutions and excessive alcohol drinking. METHOD: The hedonic response to five different concentrations of sucrose solution was evaluated in 20 detoxified alcoholic and 37 nonalcoholic Caucasian men. All subjects repetitively tasted solutions with 0.05, 0.10, 0.21, 0.42, and 0.83 M sucrose concentrations and rated themselves on two scales measuring the intensity of sweetness and the likability of the solutions. RESULTS: A bimodal distribution of responses to the sweet solutions occurred in the nonalcoholic comparison group, with peaks at 0.05 M and 0.42 M. In the alcoholic group, 65% of the subjects preferred the highest sucrose concentration (0.83 M), compared with only 16% of the nonalcoholic group. CONCLUSIONS: The results of this exploratory study support the hypothesis suggesting a positive association between the preference for stronger sweet solutions and alcohol dependence.

Involvement of dopamine D2 receptors in the suppressive effect of the thyrotropin-releasing hormone analog TA-0910 on alcohol intake in alcohol-preferring rats.

Pharmacological experiments were conducted to determine the neuronal mechanisms involved in the suppressive effects of the thyrotropin-releasing hormone analog TA-0910 on alcohol intake in alcohol-preferring (P) rats. We previously reported that single intraperitoneal injections of TA-0910 dose-dependently reduced alcohol intake in P rats without altering fluid or total calorie intake; however, after several consecutive, once-daily injections, P rats developed tolerance to the suppressive effects of TA-0910 on alcohol intake and cross-tolerance to like effects of the dopamine D2 agonist bromocriptine, but not to like effects of the serotonin uptake inhibitor fluoxetine. In the present study, rats were injected with vehicle or different doses of the D2 antagonist s(-)-eticlopride (0.01 to 0.05 mg/kg) or the D1 antagonist R(+)-SCH23390 (0.1 to 0.5 mg/kg) and 20 min later with TA-0910 (0.75 mg/kg). Alcohol and water intakes were measured at 2, 4, 6, and 24 hr, and food was measured every 24 hr. Both s(-)-eticlopride and R(+)-SCH23390 produced modest reductions in alcohol intake alone; however, only s(-)-eticlopride antagonized the suppressive effect of TA-0910 on alcohol intake. In related experiments, it was confirmed that the dopamine D3 agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin reduced alcohol intake in P rats, and it was found that tolerance to this effect did not develop during or after seven consecutive once-daily injections. Furthermore, this effect of 7-hydroxy-N,N-di-n-propyl-2-aminotetralin was not diminished in rats made tolerant to the effect of TA-0910 on alcohol intake. These data, those of previous studies, and recent preliminary findings support involvement of dopamine D2, but not D1 or D3 receptors in mediating the suppressive effect of TA-0910 on alcohol intake of P rats.

Thyrotropin-releasing hormone analog TA-0910 reduces voluntary alcohol intake of P rats subchronically in a limited scheduled access paradigm.

We previously reported that single intraperitoneal injections of the thyrotropin-releasing hormone analog TA-0910 dose-dependently reduce alcohol intake in alcohol-preferring (P) rats in a free-choice continuous access protocol. We later showed, using the same protocol, that a transient tolerance develops to this effect after several consecutive, once-daily injections. In the present study, P rats that had been accustomed to continuous access to alcohol were acclimated to a limited scheduled access protocol in which alcohol was available only between 10 and 11 AM. This resulted in an elevated rate of alcohol intake. Rats were then injected once daily with TA-0910 (0.75 mg/kg) or an equal volume of a saline vehicle at 9:45 AM for 12 consecutive days. After 11 days of scheduled access, rats were allowed continuous access to alcohol. Intake of alcohol and water was measured each day at 11:00 AM. Compared with vehicle, TA-0910 reduced alcohol intake on the 11 days of scheduled access and during the first hour of day 12 when continuous access was restored, but did not reduce total (24 hr) alcohol intake on day 12. Data from this experiment show that TA-0910 reduces alcohol intake over a long period of time in a limited scheduled access protocol.

Dose-response studies with thyrotropin-releasing hormone: evidence for differential pituitary responses in men with major depression, alcoholism, or no psychopathology.

A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) has been reported in both alcoholic and depressed men. To discern whether the pathophysiological basis of a reduced TSH response is similar in these two disorders, the present study compares the dose-response patterns of TSH and prolactin (PRL) to TRH in depressed, alcoholic, and control men. Four doses of TRH (25, 100, 500, and 800 micrograms) were given at several day intervals to 6 men with major depression, 8 men with alcohol dependence, and 7 control men. Examination of the pattern of TRH-induced TSH and PRL response revealed differences for each paired group comparison: depressed versus control, depressed versus alcoholic, and alcoholic versus control. Compared with controls, depressed men had low TSH and low PRL responses to TRH, whereas alcoholic men had low TSH responses and normal PRL responses. Levels of neither thyroid hormones, cortisol, or sex steroids, nor age or body size, explained these differences. These findings suggest that the pathophysiological basis of a reduced TSH response to TRH is different in alcoholism, compared with depression.

Thyrotropin and prolactin responses to thyrotropin-releasing hormone in young men at high or low risk for alcoholism.

A reduced thyrotropin (TSH) response to TSH-releasing hormone (TRH) has been reported in a portion of abstinent alcoholic men without evidence of cirrhosis of the liver. It is not known whether this neuroendocrine change is a precursor of alcoholism or a sequelae of heavy alcohol consumption. Three of four published studies have found evidence for differences in TRH-induced TSH response in subjects at high risk for alcoholism, based on family history, compared with subjects at low risk for alcoholism. To test further the hypothesis that the TRH-induced TSH response is a vulnerability marker for alcoholism, we tested 25 young men with an alcoholic father [family history-positive (FHP)] and matched them, on alcohol consumption, to 25 young men with no identified first- or second-degree relatives with alcoholism [family history-negative (FHN)]. FHP subjects were further categorized based on whether their father had shown signs of alcohol problems before age 25 years (FHP-Early, n = 10) or after age 24 years (FHP-Late, n = 12). FHP subjects did not differ from FHN subjects in their baseline levels of thyroid hormones, glucose, cortisol, or TSH. However, the distribution of TSH responses in the FHP subjects was skewed toward lower values, compared with FHN subjects (p = 0.12). Furthermore, FHP-Late subjects had lower TSH responses than FHN subjects (p = 0.02), whereas the TSH response of FHP-Early subjects was not different from FHN subjects. Prolactin responses to TRH were similar across all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-response studies with protirelin.

BACKGROUND: A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (protirelin [TRH]) has been found consistently in a portion of patients with major depression. One hypothesis to explain this observation is that pituitary TRH receptors are down-regulated in major depression. One prediction stemming from this hypothesis is that prolactin (PRL) as well as TSH responses to TRH should be attenuated. To adequately test the pattern of protirelin-induced TSH and PRL responses with a protirelin dose-response design is necessary. METHODS: Four doses of protirelin (25, 100, 500, and 800 micrograms) were infused in an ascending schedule at intervals of 3 to 7 days in patients with major depression and in control subjects. Seven women and six men with major depression were compared with age- and gender-matched controls (five women and seven men). The TSH and PRL responses were measured at regular intervals following each dose of protirelin. RESULTS: No significant group differences in baseline levels of thyroid hormones or cortisol were present. Depressed men exhibited significant reductions in both TSH and PRL responses to protirelin across all doses compared with control men. Depressed women exhibited significant reductions in TSH responses but not in PRL responses compared with control women. CONCLUSIONS: The findings that men with major depression exhibit reductions in both protirelin-induced TSH and PRL responses support the hypothesis that TRH receptors are downregulated in depression. The findings in women are less clear and may represent the greater variance in the protirelin-induced PRL responses found in women.

The subchronic effects of the TRH analog TA-0910 and bromocriptine on alcohol preference in alcohol-preferring rats: development of tolerance and cross-tolerance.

In a previous study, we showed that a single injection of the thyrotropin-releasing hormone analog TA-0910 dose-dependently reduced alcohol intake in alcohol-preferring (P) rats and increased their water intake over a 24-hr period. In the present study, the effects of seven consecutive, once-daily injections of TA-0910 (0.75 mg/kg, ip) on alcohol preference were determined. P rats developed tolerance to the attenuating effects of TA-0910 on alcohol intake within 3-5 days. Following the development of tolerance to TA-0910, rats were injected with the dopamine agonist bromocriptine (0.5 mg/kg, sc). In the presence of tolerance to TA-0910, the attenuating effect of bromocriptine on alcohol intake was reduced. When rats were made tolerant to the attenuating effects of bromocriptine, they exhibited tolerance to the attenuating effects of TA-0910. These findings indicate that tolerance to the effects of TA-0910 on alcohol intake occurs and suggest dopamine involvement in the mechanism of action of TA-0910 in reducing alcohol intake in P rats.

Effects of thyroid state on preference for and sensitivity to ethanol in Fischer-344 rats.

1. It has been reported by several groups that thyroid status can alter ethanol preference in rats. However, results using different methods and different strains of rats have not been consistent. 2. In this study, thyroidectomy or T4 augmentation was used to produce hypothyroidism or hyperthyroidism, respectively, in adult male Fischer-344 rats. 3. Preference for weak solutions (4 or 5%) of ethanol or tap water and ethanol-induced sedation and hypothermia were compared in hypothyroid, hyperthyroid and euthyroid rats. 4. No significant differences in preference indices (the ratios of ethanol to total liquid consumed) among the three groups were observed; however, for ethanol to contribute a greater portion of total calories ingested by hypothyroid rats than by euthyroid or hyperthyroid rats. 5. The duration of sleep resulting from a single i.p. injection of 2.5 mg/kg ethanol was increased (by 34%) in hyperthyroid rats and decreased (by 16%) in hypothyroid rats compared to euthyroid controls. Only the effect of hyperthyroidism was significant at the 0.05 level. 6. Colonic temperatures differed with thyroid state (hyperthyroid > euthyroid > hypothyroid) but the decrease produced by ethanol did not differ by thyroid state. 7. Observed differences in ethanol-induced sedation are consistent with differences in brain TRH levels and effects on neurotransmitter systems associated with different thyroid states.

Effects of ethanol and control liquid diets on the hypothalamic-pituitary-thyroid axis of male Fischer-344 rats.

The effects of a high dextrose liquid diet containing ethanol and two different control liquid diets on serum and brain thyroid axis hormones and liver and brain deiodinase activities were studied in groups of adult male Fischer-344 (F-344) rats. Rats received either lab chow, ad libitum; a nutritionally complete 10% (w/v) ethanol liquid diet, ad libitum; a volume of either a high carbohydrate (HC) or a high fat (HF) isocaloric control liquid diet equal to the volume of diet consumed by rats given the ethanol diet; or the HC control diet, ad libitum. Consumption of liquid diets was measured daily and body weights recorded every other day throughout the study. Hormones were measured after 2, 4, or 8 weeks and deiodinase activities after 4 or 8 weeks. Also, groups of rats were given the 10% ethanol diet, ad libitum, or pair-fed the HC control diet intermittently for 8 weeks, and thyroid hormones and thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) were determined. Within 2 weeks rats became accustomed to all diets and thereafter weight gain was comparable in all groups. Small differences between serum thyroid hormones of rats fed the ethanol diet and pair-fed HC or HF controls may have been caused by lower T4 secretion in ethanol-fed rats. Marked differences in free and total T4 and T3 between F-344 rats fed liquid diets for 4 or 8 weeks and rats fed lab chow probably resulted from higher liver 5'-deiodinase activity in rats fed liquid diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for normal feedback inhibition of triiodothyronine on the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in abstinent male alcoholics.

Disturbances in the hypothalamic-pituitary-thyroid (HPT) axis have been reported in abstinent, noncirrhotic alcoholics, including a reduction in thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) and reductions in triiodothyronine (T3). Some evidence has suggested that a portion of alcoholics may also exhibit a disturbance in the feedback inhibition of thyroid hormone on TSH release. To evaluate the function of the HPT axis negative feedback system in abstinent, noncirrhotic alcoholic men we compared the TSH response with TRH before and after a standard suppressive dose of T3. Ten alcoholic subjects were studied and compared with four control subjects from a previous study and to literature values. The mean percent reduction in TSH response in the alcoholic subjects of 74 +/- 7% was almost identical to the 71 +/- 9% reduction observed in normal subjects. The present findings indicate that noncirrhotic, abstinent alcoholic men exhibit normal suppression of the TSH response to TRH following T3.