Editors: Spanagel, Rainer; Mann, Karl F.
Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition
Copyright ©2005 Springer
> Table of Contents > Serotonergic compounds: clinical data
Serotonergic compounds: clinical data
Bankole A. Johnson
South Texas Addiction Research & Technology Center, Departments of Psychiatry and Pharmacology, The University of Texas Health Science Center at San Antonio, 3939 Medical Drive, Suite 100, San Antonio, Texas 78229-3900, USA, and Departments of Psychiatric Medicine and Neuroscience, University of Virginia, P.O. Box 800623, Charlottesville, VA 22908-0623, USA
In the last two decades, serotonergic agents have been studied intensely as potential treatments for alcoholism. Basic science studies have implicated the serotonin (5-HT) system, and especially its interaction with midbrain and cortico-mesolimbic dopamine pathways, as being central to the expression and appreciation of alcohol's reinforcing effects associated with its abuse liability. Such studies have increased our understanding of the bio-behavioral basis of alcoholism and provided the foundation for testing medications that interact with specific 5-HT receptor subtypes as treatment for particular types of alcoholic both with and without co-morbid psychiatric disorder.
The sections of this chapter are organized, first, to briefly provide an overview of the scientific rationale for testing a particular class of serotonergic medications for treating alcoholism and, subsequently, to evaluate the reported efficacy of these agents in clinical studies.
Selective serotonin reuptake inhibitors
Ethanol preference can be altered by lesions or pharmacological manipulations that result in 5-HT depletion and reduced 5-HT turnover [1, 2]. Augmentation of serotonergic function by administration of selective serotonin reuptake inhibitors (SSRIs) decreases voluntary ethanol consumption in preference paradigms [3, 4, 5, 6 and 7]. SSRI-associated suppression of ethanol consumption may be due to a decrease in the reinforcing effects of alcohol as well as an effect of SSRIs to reduce consummatory behavior [8, 9 and 10]. Operant studies show that the SSRI, fluoxetine, dose-dependently decreases ethanol responding [11, 12]. Hence, the results of basic science studies suggest that SSRIs would be efficacious in treating alcohol dependence.
Clinical data on the utility of SSRIs as a single agent for the treatment of alcoholics without major depressive disorder have been inconsistent. Early clinical trials of small sample size reported that SSRIs could produce short-term
(1-4 weeks) reductions in alcohol consumption among problem drinkers [13, 14, 15, 16 and 17]. Nevertheless, these studies had three additional limitations. First, the cohort was predominantly male [13, 14 and 15], thereby reducing the generalizability of the results to women. Second, standardized psychosocial treatments, which have a tendency to diminish the effect size of the response to pharmacotherapy, were used infrequently; hence, non-specific factors might be responsible for at least some of the clinical improvement that was observed. Third, the short treatment period did not allow for determination of whether SSRI-related clinical improvement in problem drinkers was sustained. Studies that have employed longer SSRI treatment periods have not demonstrated efficacy. For example, Gorelick and Paredes  showed that an initial dramatic decrease in alcohol consumption (approx. 15%) during the first of four weeks in a clinical trial did not result in an overall therapeutic treatment response for fluoxetine compared with placebo over the entire trial period. Naranjo and co-workers  also were unable to show differences in alcohol consumption between the SSRI, citalopram (40 mg/day), and placebo after 12 weeks of treatment. Kabel and Petty  also did not find 12 weeks of fluoxetine (60 mg/day) treatment to be superior to placebo at reducing drinking among 28 alcohol-dependent men. Furthermore, Kranzler and colleagues , in a well-executed 12-week study, did not find fluoxetine 60 mg/day to be superior to placebo in treating alcoholism. Interestingly, predicated on the findings of human laboratory studies that alcoholics with an early onset of disease may have reduced 5-HT levels [22, 23, 24 and 25], Kranzler and colleagues  re-analyzed their data. Presumably, their premise was that if type B alcoholics, or those who develop the disease early in life, were deficient in 5-HT, then SSRIs would be expected to be particularly beneficial for this alcoholic subtype. Paradoxically, fluoxetine appeared to actually worsen rather than improve the clinical benefit of the adjunctive cognitive behavioral therapy, and it was certainly no better than placebo. Interestingly, Pettinati and colleagues  have shown that sertraline (another SSRI) appears to improve the drinking outcomes of type A alcoholics, or those who develop the disease later in life. Early-onset (i.e., type B-like) alcoholics differ from late-onset (i.e., type A-like) alcoholics by having greater family history and greater propensity toward impulse dyscontrol, serotonergic dysfunction, and antisocial behaviors [28, 29]. It is, therefore, tempting to speculate that the relationship between 5-HT dysfunction and the onset of alcoholism might not be a simple deficiency state but may be due to more fundamental biological differences within the 5-HT system [30, 31].
Although outside the scope of this chapter, SSRIs may be useful in treating alcoholics with severe co-morbid major depression ; however, further studies are needed to fully characterize these results, given that tricyclic antidepressants provided to similar populations in other studies have been shown to reduce the dysphoric symptoms with little effect on drinking behavior [33, 34].
In conclusion, SSRIs are not efficacious at improving the drinking outcomes of a heterogeneous alcoholic group. SSRIs may, however, be useful as
treatment for alcoholics who develop the disease later in life, or alcoholics with co-morbid major depression.
5-HT1 partial agonists
The 5-HT1A partial agonist, buspirone, reduces ethanol consumption in a variety of animal paradigms. For instance, buspirone decreases volitional ethanol consumption by up to 60% in macaque monkeys . Also, buspirone suppresses ethanol intake in Sprague-Dawley rats induced to drink by repeated brain-stem injection of tetrahydropapaveroline . Dose-specific effects of buspirone to suppress ethanol intake also have been reported among medium alcohol-preferring rats . Further, buspirone decreases stimulus-conditioned responding for ethanol . Results of studies conducted with relatively 5-HT-deficient Fawn-Hooded rats show that they have a high propensity toward ethanol consumption ; correspondingly, alcohol-preferring rats, compared with their non-alcohol-preferring counterparts, have reduced cortical and subcortical gray matter reductions in 5-HT [40, 41 c.f. 42]. Hence, enhancing 5-HT neurotransmission should decrease ethanol consumption. 5-HT1A receptors manifest differential sensitivity, the greater effect being seen at the postsynaptic receptor compared with the autoreceptor. Chronic buspirone administration, therefore, raises 5-HT function and down-regulates autoreceptor function . Despite the paucity of operant dose-response studies examining buspirone's effects on ethanol consumption, there appears to be ample foundation for testing its efficacy as a treatment agent for alcoholism.
Generally, the results of clinical trials do not support a finding of efficacy for buspirone in treating alcoholics without concurrent co-morbid anxiety disorder. Indeed, Malcolm and colleagues  did not find that buspirone was superior to placebo at decreasing either the symptoms of anxiety or drinking among anxious alcoholics. In a similarly well-executed trial (N = 61), Kranzler and co-workers  did not find buspirone to be an efficacious treatment for alcoholism. An authoritative review of five published studies and a more recent re-evaluation of the data  also did not support the utility of buspirone in treating alcoholics; however, in contrast to the study of Kranzler and colleagues , alcoholics with co-morbid anxiety disorder appeared to derive therapeutic benefit [47, 48]. Finally, George and colleagues  showed that the younger the age of onset, the lower was the cerebrospinal fluid level of 5-HT's major metabolite, 5-hydroxyindole-acetic acid (5-HIAA). Despite the likelihood of 5-HT facilitation by chronic buspirone treatment, buspirone was not superior to placebo at improving the drinking outcomes of early-onset alcoholics. Again, this demonstrates that the apparent 5-HT dysfunction among alcoholics early in life may have complex bio-genetic underpinnings.
In sum, buspirone does not appear to be an effective treatment for alcoholics without co-morbid disease. Buspirone may, however, be useful in treating alcoholics with co-morbid anxiety disorder.
Animal studies show that the 5-HT2 receptor antagonist, ritanserin, can reduce ethanol consumption in a variety of paradigms [50, 51 c.f. 52]. Other 5-HT2 antagonists such as amperozide [53, 54 and 55] and FG 5974 [56, 57] also appear to be effective at attenuating ethanol intake . Mechanistically, 5-HT2 receptor antagonist-mediated acute anti-ethanol-drinking behavior may be attributable to substitution for alcohol's pharmaco-behavioral effects through increased levels of burst firing in cortico-mesolimbic dopamine neurons  and, later, reciprocal feedback inhibition of dopaminergic activity .
In a large (N = 423) multi-center, randomized, double-blind clinical trial by Johnson and colleagues , ritanserin (2.5 mg/day or 5 mg/day) was not significantly superior to placebo at improving drinking outcomes. Furthermore, in a later study using a similar methodology, even the higher ritanserin dose of 10 mg/day, compared with placebo, showed no efficacy in treating alcoholism . While it is tempting to speculate that even higher ritanserin doses may show efficacy in treating alcoholism, the potential to test this possibility is limited by ritanserin's ability to produce dose-dependent prolongation of the QTc interval on the electrocardiogram, thereby increasing the potential for serious cardiac arrhythmias and, consequently, sudden death.
In conclusion, ritanserin (2.5 mg/day to 10 mg/day) is not an efficacious treatment for alcoholism. At present, there are no double-blind data from controlled clinical trials on the use of other 5-HT2 antagonists as a treatment for alcoholism.
The 5-HT3 antagonist, ondansetron, is a promising medication for treating alcoholism . Basic science studies show that ethanol potentiates 5-HT3 receptor-mediated ion currents in NCB-20 neuroblastoma cells [63, 64] and human embryonic kidney 293 cells transfected with 5-HT3RA cDNA . 5-HT3 receptor antagonists block these effects . Hence, the 5-HT3 receptor is an important site of action for ethanol's effects in the brain [67, 68]. Pharmaco-behavioral studies show that 5-HT3 receptor antagonists attenuate dopamine or ethanol-induced hyperlocomotion in the rat , suppress DiMe-C7 (a neurokinin)-induced hyperlocomotion, an effect also diminished by the dopamine antagonist, fluphenazine [70, 71], and reduce alcohol consumption in a variety of animal models and across different species [37, 72, 73, 74, 75, 76, 77 and 78 c.f. 79]. Hence, preclinical studies show that 5-HT3 receptor antagonists are promising medications for treating alcoholism. In humans, ondansetron reduces alcohol's positive subjective effects [80, 81 c.f. 82] and preference for alcohol . Based upon the promising basic science, animal, and human laboratory data, rigorous double-blind clinical studies were needed to test ondansetron's efficacy in treating alcoholism.
In a preliminary 6-week double-blind clinical trial of non-severely alcohol-dependent males (N = 71), Sellers and colleagues  showed that ondansetron 0.5 mg/day, but not 4 mg/day, was associated with a non-significant trend (p = 0.06) toward a reduction in alcohol consumption. When those who consumed more than 10 standard drinks/drinking day (N = 11) were excluded from consideration during secondary data analysis, there was a significant treatment effect in favor of ondansetron 0.5 mg/day compared with placebo (p = 0.001). Justification for excluding this group was that such severe drinkers would typically not be enrolled in contemporary clinical trials (and are more likely to have received inpatient treatment), as their persistent level of intoxication may have reduced the validity of their self-reported drinking. Notably, as with other preliminary studies, there are some limitations that should be taken into consideration when evaluating the results, such as the relatively short treatment period (i.e., six weeks), low subject numbers and, therefore, decreased statistical power, and the enrollment of mostly white males, which reduces the generalizability of the findings to the general population. Notwithstanding these limitations, these findings suggested the possibility of efficacy for ondansetron in treating alcoholism in a large-scale clinical trial. Also, the study of Sellers and colleagues  suggested the possibility that in humans, as reported in animals, ondansetron might have a non-linear dose-response curve.
In a recent large-scale (N = 321), double-blind, randomized, controlled, 12-week clinical trial, Johnson and colleagues  showed that early- but not late-onset alcohol-dependent men and women who received ondansetron (1, 4, and 16 mcg/kg b.i.d.) compared with placebo had fewer drinks/day (1.89, 1.56, and 1.87 versus 3.30; p = 0.03, p = 0.01, and p = 0.02, respectively) and drinks/drinking day (4.75, 4.28, and 5.18 versus 6.90; p = 0.03, p = 0.004, and p = 0.03, respectively). Ondansetron (4 mcg/kg b.i.d.) was more efficacious than placebo at increasing percentage of days abstinent (70.10 versus 50.20; p = 0.02) and total days abstinent per study week (6.74 versus 5.92; p = 0.03). Among early-onset alcoholics, there also was a significant difference in the mean log carbohydrate-deficient transferrin ratio—a biochemical marker of heavy alcohol consumption—between those who received ondansetron (1 and 4 mcg/kg b.i.d.) and those who got placebo (-0.17 and -0.19 versus 0.12; p = 0.03 and p = 0.01, respectively) . Data from a cohort (N = 253) of this study also showed that ondansetron (4 mcg/kg b.i.d.), compared with placebo, was associated with a significant decrease in craving among early-onset alcoholics . More recently, Kranzler and colleagues  showed that ondansetron (4 mcg/kg b.i.d.)-treated early-onset alcoholics had significantly better drinking outcomes and fewer alcohol-related problems compared with their late-onset alcoholic counterparts.
Taken together, these results show that ondansetron is efficacious in treating early- but not late-onset alcoholics, as exemplified by improved drinking outcomes and decreased alcohol craving.
Other 5-HT receptor subtypes
5-HT4 receptor antagonists might play a role in alcohol-induced brain reward mechanisms . Interestingly, Panocka and colleagues  have shown that subcutaneous injection of the 5-HT4 antagonist GR113808 (1, 3, or 10 mg/kg) significantly reduces volitional ethanol intake. Supplemental animal studies are, however, needed to establish this result. To date, no human studies have been conducted on the effects of 5-HT4 antagonists on alcohol consumption.
Basic science studies have contributed greatly to our knowledge about the neurochemical pathways associated with the acquisition and maintenance of the drive to drink. Of particular importance have been serotonergic pathways, due to their modulatory effects on dopamine function, the critical substrate by which alcohol mediates its reinforcing effects associated with its abuse liability. Naturally, this has resulted in the study of serotonergic agents as treatments for alcoholism.
Serotonergic agents remain a promising area for the development of efficacious pharmacotherapies to treat alcohol dependence. Various types of serotonergic medication do, however, appear to have differential effects on drinking behavior. SSRIs are not efficacious treatment for a heterogeneous alcoholic group. SSRIs may, however, be efficacious in treating alcoholics who develop the disease later in life, or among alcoholics with co-morbid depression. The 5-HT1A partial agonist, buspirone, is not efficacious for treating alcoholics without co-morbid disease. Buspirone may, however, be useful in treating alcoholics with co-morbid anxiety disorder. Ritanserin, a 5-HT2 antagonist, at pharmacologically relevant clinical doses, does not appear to be an effective treatment for alcoholism. Ondansetron, a 5-HT3 antagonist, is an efficacious and promising medication for the treatment of alcoholics who develop the disease early in life.
The differential response to SSRIs and ondansetron among various subtypes of alcoholic is intriguing. New knowledge on the relationship between molecular genetic and environmental predisposition might aid in better characterizing alcoholics by subtype. Such knowledge would improve our chances of predicting what subtype of alcoholic would respond best to a particular serotonergic agent.
This work was supported by grants # AA10522-05 and AA10522-0551 from the National Institute on Alcohol Abuse and Alcoholism. I would also like to thank the following colleagues affiliated with my group (in alphabetical order)—Drs. N. Ait-Daoud, M. Devous, J. Hensler, M. Javors, R. Lamb, and J. Roache—for their comments in developing this hypothesis for the differential effectiveness of specific serotonergic agents in treating alcoholic subtypes. I also am grateful to Mr. Robert Cormier, B.A., for his skilled assistance with preparing the manuscript.
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