Efficacy of antidepressants in substance use disorders with and without comorbid depression

Abstract

Antidepressants are commonly used in substance abusers due to the potential effect on some underlying mechanisms involved in drug use disorders and to treat comorbid depression. A systematic review of the literature of the efficacy of antidepressant drugs in subjects with drug abuse disorders, including alcohol, cocaine, nicotine and opioid, with and without comorbid depression was performed. Only randomised, double-blind, controlled trials have been evaluated. A meta-analysis was done with the included studies that used common evaluation procedures in alcohol, cocaine and opioid dependence. Based on the present review some recommendations may be proposed.

The prescription of antidepressants for drug abuse seems only clear for nicotine dependence with or without previous comorbid depression (bupropion and nortryptiline). In alcohol dependence without comorbid depression, the use of any antidepressant seems not justified, while in cocaine dependence has to be clarified. The use of antidepressants in alcohol, cocaine or opioid dependence with comorbid depression needs more studies in well-defined samples, adequate doses and duration of treatment to be really conclusive. Interestingly, SSRIs do not seem to offer significant advantages compared with tricyclic drugs in substance abuse disorders. Differences both related to individual characteristics and specific antidepressant drugs need to be clarified in future studies.

Introduction

Antidepressants are commonly used in substance abusers to treat comorbid depression (Nunes et al., 1994, Thase et al., 2001) and for the potential action of these drugs on some of the underlying mechanisms of addiction (Lima et al., 2002, Hughes et al., 2003, Pettinati et al., 2003), particularly in alcohol, cocaine and nicotine dependence.

In alcohol dependence, antidepressants are administered according to evidence that serotonin (5-HT) neurotransmitter system is involved in the consumption of alcohol. Preclinical studies of acute alcohol administration in animals and humans, neuropathological examination of alcohol-preferring animals and application of pharmacological probes that affect the 5-HT system have all suggested that there is a link between serotonergic neurotransmission and alcohol intake. Dysfunction of the 5-HT system has also been implicated in alcohol disorders. Consequently, pharmacological agents that are selective for 5-HT receptors have been used to treat alcohol dependence, although the efficacy of the selective serotonergic reuptake inhibitors (SSRI) is unclear (Garbutt et al., 1999, Pettinati, 2001).

Antidepressants and dopaminergic agonists have been widely investigated in cocaine dependence (Gawin and Ellinwood, 1988). Acute administration of cocaine produces an increase in the intracellular content of dopamine, serotonin, and norepinephrine levels by blocking the presynaptic reuptake of these substances, whereas chronic cocaine abuse leads to down-regulation of monoamine systems. Depression and craving after cocaine use may be related to this down-regulation mechanism. Preclinical studies have suggested that increased monoamine concentrations due to the action of antidepressants could alleviate cocaine abstinence symptoms, as well as to relieve dysphoria and craving. Therefore, many antidepressants have been studied as potential therapeutic drugs for cocaine dependence disorder. However, in a meta-analysis of randomised clinical trials (RCT) in which any antidepressant drug for the treatment of cocaine dependence was considered, it was concluded that there was no evidence supporting the clinical use of antidepressants in the treatment of cocaine dependence (Lima et al., 2003).

Treatment for tobacco dependence involves the combination of behavioral therapies and pharmacological treatment. The most common pharmacological approach includes nicotine replacement therapy and non-nicotine medications, such as antidepressants. Hughes et al. (2003), have reported a systematic review with further meta-analysis of all the RCT published and unpublished about the efficacy of any antidepressant drug in any smoker sample, measuring abstinence from smoking assessed at follow-up at least 6 months from start of treatment. It was concluded that bupropion and nortriptyline, but not SSRI, could help patients to quit smoking.

Previous reviews of the efficacy of antidepressants in the treatment of substance abuse have been focused on the potential effect on these drugs on some underlying mechanisms involved in drug dependence disorders, without considering the influence of depressive comorbidity (Naranjo and Knoke, 2001, Pettinati, 2001, Lima et al., 2002, Hughes et al., 2003). It is well recognised that major depression is one of the most prevalent comorbid psychiatric disorders in substance abusers. Population-based studies have shown that lifetime major depression is strongly associated with substance-use disorders, with an odds ratio between 2.4 and 5.2. (Regier et al., 1990, Kessler et al., 1994, Grant and Harford, 1995). In studies of patients seeking treatment for substance use disorders, the lifetime prevalence of major depression is high: 12–67% in chronic alcoholics, 32–52% in cocaine abusers, 44–54% in opioid-dependent subjects (Kranzler and Rounsaville, 1998), and about 60% in individuals with nicotine dependence (Glassman et al., 1988). Longitudinal studies of opioid-, cocaine-, alcohol-, and nicotine-dependent patients with major depression have demonstrated that the prognosis of these subjects is poor (Rounsaville et al., 1982, Rounsaville et al., 1987, Hasin and Nunes, 1998, Hasin et al., 2002, Sullivan and Covey, 2002), and have emphasized the need of treatment to improve both depression and substance abuse disorders.

Because previous reviews were not focused on comorbid depression, we here present a systematic review of the literature of the efficacy of antidepressant drugs in subjects with drug abuse disorders with and without a definite diagnosis of comorbid depression. Alcohol, cocaine, nicotine, and opioid are the drug dependence disorders considered. The efficacy of antidepressant medications was quantified through the use of meta-analysis.