Compelling reasons exist to study the efficacy and safety of quetiapine as a treatment for alcohol-dependent patients. Quetiapine binds to multiple targets, including serotonin 5-HT1A, 5-HT2A, dopamine D1 and D2, histamine H1, and adrenergic α1 and α2 receptors (AstraZeneca, 2010
), which have been shown to alter alcohol-seeking and drinking behavior, primarily in animal models (Litten et al., 2005
; Johnson, 2007
). Moreover, recent preliminary clinical results have suggested that quetiapine reduces heavy drinking in alcohol-dependent patients (Ray et al., 2010
). Nonetheless, in this multisite study, there was no effect on the primary outcome measure percent days heavy drinking. Similarly, there was no difference between quetiapine and placebo groups in other drinking outcome measures, including percent days abstinent, drinks per drinking day, and drinks per day, as well as the dichotomous measures–percent of subjects with no heavy drinking days and percent of subjects who are abstinent. Moreover, the negative result with the primary outcome measure was not moderated by quantity of medication taken, the presence of side effects, nor the presence of sleep disturbances. The negative findings in this study, in contrast with promising earlier studies, demonstrate the complexity of biological mechanisms associated with alcohol addiction in humans, as well as the need for adequately powered studies.
Quetiapine has been approved to treat depression in bipolar patients and also has been shown to improve sleep disturbances (Endicott et al., 2008
; Robert et al., 2005
). In the current study, quetiapine also significantly reduced depressive symptoms and improved sleep compared to placebo, although both depression and sleep scores were near normal in patients at baseline ( and ). This was similar to the results reported by Kampman et al. (2007)
in a study of quetiapine for alcohol dependent patients. In their study, depression and anxiety scores were also in the normal range at baseline and during treatment, yet a significant decrease in depression and anxiety was observed during treatment. In other nondrinking outcomes, quetiapine failed to improve anxiety, alcohol craving, quality of life, and alcohol-related consequences ().
So far, the alcohol medications that have shown effectiveness do not work in all individuals, only in subgroups. A previous study by Kampman and colleagues (2007)
suggested that the immediate-release formulation of quetiapine may be beneficial for Type B alcoholics. In that study, Type B participants exhibited very heavy drinking at baseline (average 20 drinks/drinking day), and at least one of the following: early onset of alcohol dependence, depression, or antisocial personality disorder. Approximating this definition of Type B alcoholism, we conducted a subgroup analysis, but found no significant differential treatment effect for quetiapine above placebo as a function of Type B status on the primary outcome drinking measure. One reason for this lack of concordance between the Kampman et al. study and our study may be that our Type B definition did not include antisocial personality disorder since these data were available in our study. Another more likely reason may have to do with study population differences between the two studies. For example, in the Kampman et al. study, 49 percent of study participants had a comorbid psychiatric illness, including major depression, posttraumatic stress disorder (PTSD), or other anxiety disorders. While quetiapine has been shown to improve many symptoms of these disorders (Endicott et al., 2008
; Martinotti et al., 2008
; Croissant et al., 2006
; Robert et al., 2005
), our study recruited very heavy drinking alcohol-dependent patients without serious psychiatric comorbidity, a design factor that may account for the treatment effect differences between our study and that of Kampman and colleagues (2007)
. Even though we excluded people with major psychiatric disorders in our study, we expected patients with chronic very heavy levels of drinking at baseline would also concurrently report elevated levels of anxiety, depressive symptoms, and poor sleep. This hypothesis is supported by recent theories of allostasis and addiction—that long-term drinking results in a homeostatic dysregulation, resulting in negative emotion (e.g., dysphoria, depression, irritability, and anxiety) and an elevation of the reward set point (Koob, 2008
; Koob and Le Moal, 2006
). However, counter to our assumptions, despite consuming very large amounts of alcohol for an extended period of time, these study participants on average reported normal levels of levels of anxiety and depression, and only modest sleep disturbances at baseline. It is likely that quetiapine's efficacy in reducing drinking observed in previous studies was due to the amelioration of psychiatric symptoms experienced by those patients. Our failure to find an effect for quetiapine in this study may be in part due to the high functionality and lack of psychiatric symptoms of the study population. An argument can be made that if depression, anxiety, and sleep disturbance mediate or moderate the effects of quetiapine on drinking outcome, larger treatment effects might potentially be found in a population with higher pathology of these factors. We cannot discount this possibility and recommend that future studies of quetiapine test its efficacy in comorbid alcohol dependent populations.
During the past 20 years, the majority of patients recruited for alcohol clinical trials have been required to be abstinent for at least 3 to 4 days before randomization. However, in several recent alcohol trials, patients were allowed or even required to drink right up to randomization (Garbutt et al., 2005
; Johnson et al., 2007
). Considerable discussion has ensued among alcohol researchers as to whether a relapse prevention study model, where pre-randomization abstinence is required, versus a more naturalistic cessation-initiation model is more appropriate and optimally sensitive for proof of concept testing of new medications. Each of these models has different practical and theoretical merits. Abstinence or significant reduction in drinking before randomization appears to influence treatment outcome. For example, Epstein and colleagues (2005)
showed that patients who cut back on drinking before treatment had better drinking outcomes. However, as treatment outcome improves in the placebo group, it may become more difficult to demonstrate a significant medication treatment effect, as observed in depression and schizophrenia studies (Kemp et al., 2010
; Kirsch et al., 2008
, Mallinckrodt et al., 2010
; Walsh et al., 2002
). Epstein et al (2005)
provided several explanations for this self initiated reduction in drinking prior to treatment. The reduction in drinking may be prompted by merely (1) viewing an advertisement, (2) discussing the decision to seek help with individuals within in the same social network, or (3) the realization of the extent and severity of the drinking problem by acknowledging and discussing one's drinking with another individual (Epstein et al., 2005
; Sobell et al., 2003
). In this study, we elected to allow patients to regulate their own drinking before randomization. We then evaluated analytically whether those patients who reduced their drinking before randomization had better treatment outcomes, and whether prerandomization “reducer status” would increase the sensitivity to detect a treatment effect. Approximately 30% of the patients reduced their drinks per drinking day by at least 50% before starting study medication. These “reducers,” of whom 44% were abstinent one week before randomization, had better treatment outcomes on all drinking measures, including drinks per drinking day, percent days abstinence, drinks per day, and percent heavy drinking days than the “nonreducers” (). Similar results were also obtained when drinks per day and number of heavy drinking days were the endpoints used to define reducers and nonreducers (data not shown). Interestingly, however, there was no reducer by treatment interaction, suggesting that neither of the prerandomization drinking models had a clear advantage in detecting a treatment effect.
At present, there is no single medication that decreases alcohol use in all alcohol-dependent individuals. Although disulfiram—a medication that causes aversive symptoms when taken with alcohol—should have high efficacy among patients who take the therapeutic dosage, disulfiram has had limited success in treatment due to poor compliance (Allen & Litten, 1992
; Jorgensen et al., 2011
). Development of more effective medications may, in part, require a better understanding of brain circuits and mechanisms underpinning alcohol addiction, as well as a more accurate delineation of its subtypes. In essence, a more targeted approach may be required to foster the creation of medications that will be truly efficacious. For now, alcohol pharmacotherapy trials need to focus on subpopulations that appear most likely to respond to medication. In this study, we hypothesized and recruited an alcohol-dependent population of very heavy drinkers as the cohort who would most likely respond to quetiapine. Even though the primary analyses were negative, further secondary analyses will be continued, exploring various subgroups that might benefit from quetiapine. For the present, however, we cannot recommend the use of quetiapine as a medication to treat alcohol-dependent individuals.