Serotonin-Uptake Inhibitors in Treatment of Substance Abuse
SEROTONIN-UPTAKE INHIBITORS IN TREATMENT OF SUBSTANCE ABUSE
The development of effective pharmacological treatments for alcohol and drug abuse depends on our understanding of the biological mechanisms that start and maintain these behaviors. Studies in animals and humans have confirmed that Serotonin is one of several Neurotransmitters that influence drug-reinforcing behaviors. Pharmacological agents that enhance central serotonergic neurotransmission—in particular, serotonin-uptake inhibitors (several of which have been marketed as antidepressants)—show considerable promise, as of the early 1990s, as effective treatments for the abuse of alcohol and some other drugs. These work by blocking the re-uptake of serotonin and thereby increase its concentration in the nerve Synapse.
In the late 1980s, serotonin-uptake inhibitors were tested in various animal models of alcoholism—including selectively bred alcohol-preferring rats given a choice between water and an alcohol solution—and showed consistent decreases in the self-administration of alcohol in a dose-dependent manner. The results of these preclinical studies led to research in human alcohol abusers. In four placebo-controlled, double-blind, randomized clinical trials, serotonin-uptake inhibitors decreased short-term (1 to 4 weeks) alcohol intake by averages of 14 to 20 percent, as compared with pretreatment. No other treatment or advice was given. The effect developed rapidly after a serotonin-uptake inhibitor was administered and disappeared rapidly after discontinuation. All subjects had had mild or moderate (not severe) alcohol dependence but no current or past depression, anxiety, other psychiatric disorder, or other substance-abuse disorder. No aversive interactions with alcohol or changes in depression or anxiety levels were observed; therefore they could not account for the effects on alcohol intake. Adverse side effects were few and mild. However, concomitant decreases in desire/urge to drink were reported by subjects during treatment with serotonin-uptake inhibitors. Therefore, experimental drinking sessions, following one or two weeks of treatment with serotonin-uptake inhibitor and placebo, were incorporated into two research studies—fluoxetine (Prozac) and citalopram, each with a placebo control—to specifically measure variations in self-reported desire to drink alcohol. Desire for alcohol was lower during the experimental drinking sessions after taking serotonin-uptake inhibitors than after taking placebos. In both of these studies, the effects of serotonin-uptake inhibitors on alcohol intake were also confirmed in the outpatient weeks preceding the experimental drinking sessions.
The observation that serotonin-uptake inhibitors decrease desire to drink indicates a possible mechanism of their effects on alcohol intake. In the outpatient trials, an increase in abstinent days was often the means by which alcohol intake was reduced, and similarly, in trials with animals, serotonin-uptake inhibitors decreased their number of drinking "bouts." Therefore, serotonin uptake inhibitors may, by decreasing the desire to drink, reduce the likelihood of initiating drinking. The consistency of the pharmacological effects is quite remarkable, considering the many other factors influencing drinking behavior. In an effort to enhance the pharmacological effects of serotonin-uptake inhibitors and determine their therapeutic value, a brief psychosocial intervention was combined with citalopram in a long-term (12 week) treatment research study with sixty-two mildly/moderately dependent alcoholics. Average decreases in daily alcoholic drinks from baseline were 47.9 percent during the first week of citalopram (n = 31) and only 26.1 percent during the first week of placebo (n = 31), indicating a significant improvement with citalopram. From the second to twelfth weeks of treatment, the average decreases were similar: 33.4 percent and 40.5 percent during citalopram and placebo, respectively. Craving for alcohol also decreased similarly with both citalopram and placebo. Thus, the short-term effects of citalopram are synergistic with a brief psychosocial intervention, and serotonin-uptake inhibitors seem to facilitate the initiation of reduced drinking. The true therapeutic value of serotonin-uptake inhibitors is yet to be determined, but they may be appropriate for specific applications. For example, relapse is a frequent problem among recovering alcoholics; serotonin-uptake inhibitors, by decreasing desire or urge to drink, may be particularly suitable adjuncts for relapse-prevention strategies.
Abuse of Cocaine increased in the 1980s; it is also common among Heroin addicts—some who use it alone and some together with heroin. Fluoxetine decreased cocaine craving and abuse in some heroin addicts who were in a Methadone Maintenance program. These interesting results merit further study in a controlled trial.
Cigarette smoking has not been affected by serotonin-uptake inhibitors in heavy drinkers who were not trying to reduce their smoking. Fluoxetine was found to prevent the weight gain that accompanies smoking cessation and, therefore, may be helpful in preventing relapse among exsmokers. The results of studies on the use of serotonin-uptake inhibitors in patients participating in smoking-cessation programs have not been reported yet.
Individuals who abuse alcohol and/or drugs often have psychological or psychiatric disorders. The establishment of cause-and-effect relationships can be difficult. There is evidence that comorbidity (two disease processes) adversely influences outcome in treatments of substance abuse. Some patients may self-medicate symptoms of Anxiety or Depression with a drug of abuse, such as alcohol. Therefore, successful pharmacological treatment of the anxiety or depression may reduce the need for other drugs (the alcohol).
As antidepressants, serotonin-uptake inhibitors would be particularly suitable for treating depressed substance abusers. No research studies have been conducted, but a comparison between treatment outcomes of depressed substance abusers receiving a serotonin-uptake inhibitor and those receiving other antidepressants would be of interest.
Severe cognitive deficits (memory loss) are a frequent complication of chronic Alcoholism. Low brain levels of serotonin may be a factor in this type of memory loss. Fluvoxamine, a serotonin-uptake inhibitor, improved episodic memory in patients with alcohol amnestic disorder. This might greatly facilitate success in cognitively oriented treatments for alcoholism.
Serotonin-uptake inhibitors decrease short-term alcohol intake and desire to drink. Their effects are synergistic with a brief psychosocial intervention for alcoholism; however, their long-term efficacy and clinical importance have not been determined. One small study indicated that a serotonin-uptake inhibitor may reduce cocaine abuse. There is currently no evidence that serotonin uptake inhibitors reduce cigarette smoking or opiate abuse.
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Claudio A. Naranjo
Karen E. Bremner