Pharmacotherapy for comorbid depression and alcohol dependence

In a study of adolescents, Cornelius et al¹⁸ failed to find any differences between fluoxetine and placebo in any depression or drinking-related outcomes. This study compared the efficacy of fluoxetine, 20 mg/d, with placebo in 50 adolescents with MDD and AUDs who also received intensive, manual-based cognitive-behavioral therapy and motivational enhancement therapy. All patients improved during the trial, but there were no significant differences between fluoxetine- and placebo-treated adolescents.

Other serotonergic medications. Two studies have evaluated nefazodone, a serotonin (5-HT2) antagonist, in dually diagnosed patients. In a 12-week trial, Roy-Byrne et al¹⁹ evaluated the efficacy of nefazodone (mean daily dose: 460 mg) vs placebo in 64 actively drinking alcohol-dependent patients who had ≥1 prior episode of depression; all participated in a weekly psychoeducation group on alcoholism. Nefazodone was associated with significantly greater reduction in depressive symptoms but no reductions in drinking compared with placebo. However, a 10-week study of nefazodone²⁰ (mean daily dose: 413 mg) vs placebo in 41 alcohol-dependent patients with current major depression found that those who received nefazodone significantly reduced heavy drinking days compared with the placebo group. There were no significant differences in depressive symptoms between groups.

Older studies of SSRIs conducted in patients with AUDs but not depression suggested that these medications may exacerbate AUDs in certain populations, specifically women and individuals with early onset AUD.^21-23 Use caution if you prescribe SSRIs to alcohol-dependent patients without comorbid depression. When prescribing SSRIs for those with comorbid AUDs, carefully monitor patients’ drinking.

Conflicting evidence on TCAs

Although several studies suggest TCAs may help reduce depressive symptoms in patients with AUDs, results on their ability to reduce drinking are conflicting (Table 2).^24-26 In 1 study, 6 months of desipramine (mean daily dose: 200 mg) reduced drinking in 28 alcohol-dependent individuals with secondary depression²⁴; in another, 12 weeks of imipramine plus weekly relapse prevention psychotherapy did not affect drinking-related outcomes in 69 actively drinking alcoholic outpatients with current depressive disorders.²⁵

Table 2

Limited evidence supports TCAs for comorbid depression and AUDs

Study	Sample	Results
Mason et al, 199624	Outpatients with AD and secondary depression. Part of larger study including non-depressed patients with AD (N = 71) 1. Desipramine (mean daily dose 200 mg; n = 15) 2. Placebo (n = 13)	Greater reduction in depressive symptoms and drinking in desipramine-treated patients compared with placebo-treated patients
McGrath et al, 199625	Outpatients with AD or AA and major depression, dysthymia, or depressive disorder NOS 1. Imipramine (mean daily dose 260 mg; n = 36) 2. Placebo (n = 33)	Greater reduction in depressive symptoms for imipramine-treated patients compared with placebo-treated patients. Drinking-related outcomes were not directly affected by medication except improvements in mood led to reduced alcohol use
Altintoprak et al, 200826	Inpatients with AD and MDD 1. Mirtazapine (30 mg/d; n = 24) 2. Amitriptyline (100 mg/d; n = 20)	Drinking-related outcomes were not emphasized because all patients were required to abstain from drinking during the study. Both treatments reduced depressive symptoms; there were no significant differences between groups
AA: alcohol abuse; AD: alcohol dependence; AUDs: alcohol use disorders; MDD: major depressive disorder; NOS: not otherwise specified; TCAs: tricyclic antidepressants

Studies of TCAs largely were abandoned when SSRIs were introduced because SSRIs have a better safety profile. However, disappointing results with SSRIs have rekindled an interest in TCAs and other types of antidepressants.

Altintoprak et al²⁶ compared the efficacy of the antidepressant mirtazapine, 30 mg/d, with the TCA amitriptyline, 100 mg/d, in 44 patients with comorbid alcohol dependence and MDD. All patients were required to abstain from drinking alcohol during the study. Both medications resulted in steady reductions in depressive symptoms and alcohol cravings; however, researchers found no significant differences between the 2 treatment groups.

Analyses of combined studies

Pettinati²⁷ conducted a qualitative review of antidepressants for patients with depression and alcohol dependence that included 8 controlled clinical trials (2 on TCAs and 6 on serotonergic medications) conducted between 1994 and 2004. In this review, both TCAs and serotonergic medications were similarly effective in reducing depressive symptoms but not consistently effective in reducing drinking.

Nunes and Levin²⁸ conducted a systematic, meta-analysis of the efficacy of antidepressants for patients with depression and alcohol and/or other substance use disorders that reviewed 8 placebo-controlled trials that included patients with depression and AUDs. Of these 8 trials, 2 used TCAs, 5 used serotonergic agents, and 1 used viloxazine, a bicyclic antidepressant morpholine derivative not available in the United States that acts as a selective norepinephrine reuptake inhibitor. Similar to Pettinati,