The role of selective serotonin reuptake inhibitors in reducing alcohol consumption.

Preclinical and clinical studies demonstrated an inverse relationship between serotonergic activity and alcohol consumption. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and fluvoxamine have subsequently been examined for their ability to reduce alcohol consumption in alcoholic subjects. Interindividual variability in response to SSRIs is large, with reductions in alcohol consumption ranging from 10% to more than 70%. Several factors, including gender, alcoholic subtype, and extent of drinking, appear to affect the treatment efficacy of the SSRIs. A significant challenge for researchers is to identify the subject variables that predict treatment response, providing a basis for guiding alcohol-dependent individuals to the treatment that is most likely to be effective for them. This article reviews the available clinical studies, discusses possible mechanisms of action for the SSRIs, and describes a model for predicting treatment responses in alcoholic subjects.

Variations in response to citalopram in men and women with alcohol dependence.

OBJECTIVE: To examine the differential effects of citalopram on alcohol consumption in nondepressed women and men with mild to moderate alcohol dependence. DESIGN: Prospective, placebo-controlled study. PARTICIPANTS: Sixty-one subjects (34 men and 27 women). INTERVENTIONS: After a 2-week baseline, subjects were randomly assigned to 12 weeks of citalopram (40 mg per day) (n = 15 women, 16 men) or placebo (n = 12 women, 18 men). All received brief standard psychosocial interventions. OUTCOME MEASURES: Alcohol Dependence Scale, Montgomery-Asberg Depression Scale, Michigan Alcohol Screening Test, State-Trait Anxiety Inventory and daily alcohol intake. RESULTS: Pretreatment sex differences were evident in alcohol consumption, alcohol dependence, alcohol-related problems and on anxiety and depression measures. After treatment, analyses of covariance with depression and anxiety scores as covariates revealed a differential benefit of citalopram for men. Men receiving citalopram reduced average drinks per day by 44%, whereas women exhibited a 27% decrease (p < 0.05). CONCLUSIONS: Men may benefit more than women from citalopram in the treatment of alcohol dependence. These findings highlight the importance of examining sex as a significant variable in evaluating response to pharmacotherapy.

Metabolic interactions of central nervous system medications and selective serotonin reuptake inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed alone and in combination with other psychotropic medications in the treatment of a variety of psychiatric disorders. Such combinations create the potential for pharmacokinetic interactions by affecting the activity of the cytochromes P450 (CYP450), drug metabolizing oxidative enzymes. SSRIs are not equivalent in their potential for interactions when combined with other central nervous system (CNS) medication. Generally citalopram and sertraline are characterized by weaker inhibition of CYP450 enzymes and, therefore, hold less potential for interaction than the other SSRIs. Paroxetine potently inhibits CYP2D6, which can result in increased neuroleptic serum concentrations, accompanied by increased CNS side-effects. Similarly, as a potent inhibitor of CYP2D6, fluoxetine can increase serum concentrations of neuroleptics and antidepressants and numerous case reports have documented concomitant adverse events. Fluoxetine also inhibits CYP3A and CYP2C19, increasing serum concentrations of some benzodiazepines. Fluvoxamine is a potent inhibitor of CYP1A2, a moderate inhibitor of CYP3A and a mild inhibitor of CYP2D6. Therefore, interactions with clozapine and benzodiazepines are evident.

Naloxone-induced analgesia and morphine supersensitivity effects are contingent upon prior exposure to analgesic testing.

Repeated administrations of naloxone have been found to result in the development of analgesia. Pretreatment with naloxone can also produce supersensitivity to morphine. This study examined whether the development of these phenomena is affected by exposure to pain (hot-plate testing) during opiate blockade. During acquisition, two experimental groups of rats received identical treatment with respect to repeated naloxone injections (5 mg/kg) and the environment in which the injections were administered. A "contingent" group (NAL-C) received hot-plate testing under the influence of naloxone, while a "noncontingent" group (NAL-NC) experienced hot-plate testing and naloxone separated by an interval of 24 h. At test, NAL-C rats manifested naloxone-induced analgesia (NIA) whereas the NAL-NC animals did not. The NAL-C rats also showed supersensitivity to the analgesic effects of morphine (3 mg/kg) and to the cataleptic effects of morphine (17.5 mg/kg) while the NAL-NC rats did not differ from saline controls. Thus, both NIA and morphine supersensitivity were completely dependent on testing in the drug state during acquisition; mere exposure to an identical regime of naloxone injections was insufficient to produce these phenomena.

Naloxone-induced analgesia: effects of the benzodiazepine antagonist Ro 15-1788.

Repeated exposure to pain under the influence of the opiate antagonists naloxone and naltrexone leads to the recruitment of substantial analgesia as measured by paw-lick latency on the hot-plate test (4,11). One hypothesis to explain this naloxone-induced analgesia (NIA) is that nociceptive stimulation in the face of opiate blockade becomes stressful enough to activate an analgesic adaptation that otherwise would not occur. This hypothesis was examined in two experiments by the administration of a benzodiazepine antagonist with anxiogenic properties (Ro 15-1788, in a dose of 10 mg/kg) in conjunction with repeated administrations of naloxone (5 mg/kg). One experiment incorporated defecation as a relatively direct measure of stress. Ro 15-1788 reliably augmented NIA. Defecation was increased by naloxone alone and in combination with Ro 15-1788. Overall, the results were most consistent with the hypothesis that NIA is a form of stress-induced analgesia that is at least partly nonopiate in nature.