Abstract: We included 33 studies in the review (2242 participants). Antidepressants were compared to placebo (22 studies), psychotherapy (two studies), other medications (four studies), or other antidepressants (five studies). The mean duration of the trials was 9.9 weeks (range 3 to 26 weeks). Eighteen studies took place in the USA, 12 in Europe, two in Turkey, and one in Australia. The antidepressant included in most of the trials was sertraline; other medications were amitriptyline, citalopram, desipramine, doxepin, escitalopram, fluoxetine, fluvoxamine, imipramine, mianserin, mirtazepine, nefazodone, paroxetine, tianeptine, venlafaxine, and viloxazine. Eighteen studies were conducted in an outpatient setting, nine in an inpatient setting, and six in both settings. Psychosocial treatment was provided in 18 studies. There was high heterogeneity in the selection of outcomes and the rating systems used for diagnosis and outcome assessment. Comparing antidepressants to placebo, low-quality evidence suggested that antidepressants reduced the severity of depression evaluated with interviewer-rated scales at the end of trial (14 studies, 1074 participants, standardized mean difference (SMD) -0.27, 95% confidence interval (CI) -0.49 to -0.04). However, the difference became non-significant after the exclusion of studies with a high risk of bias (SMD -0.17, 95% CI -0.39 to 0.04). In addition, very low-quality evidence supported the efficacy of antidepressants in increasing the response to the treatment (10 studies, 805 participants, risk ratio (RR) 1.40, 95% Cl 1.08 to 1.82). This result became non-significant after the exclusion of studies at high risk of bias (RR 1.27, 95% CI 0.96 to 1.68). There was no difference for other relevant outcomes such as the difference between baseline and final score, evaluated using interviewer-rated scales (5 studies, 447 participants, SMD 0.15, 95% CI -0.12 to 0.42). Moderate-quality evidence found that antidepressants increased the number of participants abstinent from alcohol during the trial (7 studies, 424 participants, RR 1.71, 95% Cl 1.22 to 2.39) and reduced the number of drinks per drinking days (7 studies, 451 participants, mean difference (MD) -1.13 drinks per drinking days, 95% Cl -1.79 to -0.46). After the exclusion of studies with high risk of bias, the number of abstinent remained higher (RR 1.69, 95% CI 1.18 to 2.43) and the number of drinks per drinking days lower (MD -1.21 number of drinks per drinking days, 95% CI -1.91 to -0.51) among participants who received antidepressants compared to those who received placebo. However, other outcomes such as the rate of abstinent days did not differ between antidepressants and placebo (9 studies, 821 participants, MD 1.34, 95% Cl -1.66 to 4.34; low-quality evidence). Low-quality evidence suggested no differences between antidepressants and placebo in the number of dropouts (17 studies, 1159 participants, RR 0.98, 95% Cl 0.79 to 1.22) and adverse events as withdrawal for medical reasons (10 studies, 947 participants, RR 1.15, 95% Cl 0.65 to 2.04). There were few studies comparing one antidepressant versus another antidepressant or antidepressants versus other interventions, and these had a small sample size and were heterogeneous in terms of the types of interventions that were compared, yielding results that were not informative. We found low-quality evidence supporting the clinical use of antidepressants in the treatment of people with co-occurring depression and alcohol dependence. Antidepressants had positive effects on certain relevant outcomes related to depression and alcohol use but not on other relevant outcomes. Moreover, most of these positive effects were no longer significant when studies with high risk of bias were excluded. Results were limited by the large number of studies showing high or unclear risk of bias and the low number of studies comparing one antidepressant to another or antidepressants to other medication. In people with co-occurring depression and alcohol dependence, the risk of developing adverse effects appeared to be minimal, especially for the newer classes of antidepressants (such as selective serotonin reuptake inhibitors). According to these results, in people with co-occurring depression and alcohol dependence, antidepressants may be useful for the treatment of depression, alcohol dependence, or both, although the clinical relevance may be modest.

Plain-language summary: We identified 33 medical trials involving 2242 participants: 68% were male, and the mean age was 42 years. Most studies compared antidepressants to placebo (22 studies), but some compared one antidepressant to antidepressant (five studies), to another type of medicine (four studies), or to psychotherapy (a talking treatment; two studies). The average duration of the trials was 10 weeks (range 3 to 26 weeks). A total of 18 trials took place in the USA, and the others were in Europe, Turkey, and Australia. The antidepressant used in most of the trials was sertraline; the others were: amitriptyline, citalopram, desipramine, doxepin, escitalopram, fluoxetine, fluvoxamine, imipramine, mianserin, mirtazepine, nefazodone, paroxetine, tianeptine, venlafaxine, and viloxazine. The studies used 49 different rating scales and varied in terms of design, quality, participant characteristics, tested medicines, services provided, and treatments administered. A total of 19 studies reported the source of funding (public funds: six studies; pharmaceutical industry: two studies; both funds: 10 studies). Only four trials reported a declaration of the authors reporting possible conflicts of interest. In the 22 studies comparing antidepressants to placebo, antidepressants may have reduced the severity of depression but we are uncertain whether it increased the number of people with clinical beneficial effects from the reduction of depression severity (response to treatment, i.e. people who halved the severity of depression). However, we found no difference between antidepressants and placebo in other relevant outcomes related to the severity of depression, such as the number of people without depression at the end of the trial (remission). In addition, we found that the administration of antidepressants probably reduced alcohol consumption evaluated as the number of participants abstinent during the treatment (higher among participants who received antidepressants compared to placebo) and the number of drinks consumed per drinking days (lower among participants who received antidepressants compared to placebo). However, similarly to what we found for the severity of depression, we also observed that the administration of antidepressants did not affect other relevant outcomes related to alcohol dependence, such as the rate of abstinent days, number of heavy drinkers, and time before first relapse. In terms of safety issues, the rate of people withdrawing from treatment due to side effects (undesirable effects such as dry mouth) may not differ between antidepressants and placebo. There were few studies comparing one antidepressant to another antidepressant or to other interventions, and these had a small number of participants and the same comparison was not made by more than one study, and were therefore not informative. The quality of the included studies was low or moderate for depression severity, abstinence from alcohol, rate of people withdrawal for medical reasons, and dropouts. In subgroup analyses, in the case of single types of medicines, and comparisons with other medicines, the findings of the review were limited by the small number of available studies. There is low-quality evidence supporting the use of antidepressants in the treatment of people with co-occurring depression and alcohol dependence. Antidepressants have positive effects on certain relevant outcomes related to depression and alcohol use but not on equally relevant other outcomes. However, the risk of developing side effects appears to be minimal, especially for the newer classes of antidepressants.