Pharmacotherapy for comorbid depression and alcohol dependence

²⁷ this review suggested that antidepressants can reduce depressive symptoms but not drinking. The authors also found evidence that the more the antidepressant reduced depressive symptoms, the more it reduced alcohol use. Studies published after these reviews have not substantially altered these findings.

Alcohol abuse medications

Four medications are FDA-approved for treating alcohol dependence:

• disulfiram
  
• naltrexone (in 2 formulations: oral and long-acting injectable)
  
• acamprosate.
  

After a few smaller studies suggested that naltrexone might reduce alcohol use among dually diagnosed individuals, several larger studies were initiated (Table 3).^29-31 In a 12-week study, 254 outpatients with alcohol dependence plus an additional axis I disorder (including depression) were randomized to naltrexone, disulfiram, naltrexone plus disulfiram, or no medication.³¹ Overall, medication was more effective than no medication in consecutive abstinence, but researchers found no advantage for 1 medication over the other, and no advantage to the combination. In a secondary analysis that compared 139 patients with depression to those with other axis I diagnoses, medication offered no advantage over placebo in alcohol use outcomes.²⁹ There was a significant interaction among depression, medication group, and craving—depressed patients assigned to disulfiram reported lower cravings over time than depressed patients receiving naltrexone. In this study, most patients also received medication for their comorbid condition, but no standard medication was used.

Table 3

Can medications that target alcohol use also improve depression?

Study	Sample	Results
Petrakis et al, 200729	Outpatients with AD and an axis I disorder, including depression (secondary analysis of Petrakis et al, 200531) 1. Naltrexone (50 mg/d; n = 34) 2. Disulfiram (250 mg/d; n = 43) 3. Naltrexone + disulfiram (n = 28) 4. Placebo (n = 34)	Generally, medication was more effective than no medication. No advantage of 1 medication over the other. There was no relationship between depression diagnosis and medication condition, which suggests that for patients with depression, there was no advantage to medication
Pettinati et al, 201030	Outpatients with AD and MDD 1. Sertraline (200 mg/d; n = 40) 2. Naltrexone (100 mg/d; n = 49) 3. Sertraline + naltrexone (n = 42) 4. Placebo (n = 39)	Greater proportion of patients in combined medication group abstained from alcohol and refrained from heavy alcohol use during the trial compared with those in sertraline-only or naltrexone-only groups. No significant differences among groups on depression-related outcomes
AD: alcohol dependence; MDD: major depressive disorder

In a double-blind, placebo-controlled study that compared sertraline, naltrexone, and sertraline plus naltrexone in 170 patients with comorbid alcohol dependence and MDD, a greater proportion of patients in the combined medication group abstained from alcohol or refrained from heavy alcohol use during the 14-week trial compared with those receiving sertraline or naltrexone alone.³⁰ Patients in the combined medication group also reported a longer time before relapse to any drinking. There were no significant differences between the 3 groups on depression-related outcomes, although the combined medication group reported fewer depressive symptoms in the last 3 weeks of treatment. This study suggests that when used together, combining medications to treat the underlying psychiatric disorder with medications to treat AUDs may be more effective than either medication alone.

Nevertheless, these studies suggest that medications for treating depression or AUDs have, at best, only a modest effect in patients with both disorders.

Novel agents

Several novel medications have been evaluated as possible treatments for comorbid depression and AUDs because they target the underlying neurobiology of both disorders:

• agents that target the neurotransmitter glutamate, including the N-methyl-d-aspartate glutamate receptor antagonists memantine and ketamine
  
• dopaminergic agents such as quetiapine
  
• corticotropin-releasing factor (CRF) receptor 1 (CRF₁) antagonists.
  

Research has implicated glutamate system dysfunction in both AUDs and depression and suggested that memantine and ketamine may reduce depressive symptoms and alcohol craving. Muhonen et al³² compared memantine, 20 mg/d, to the SSRI escitalopram, 20 mg/d, in 80 outpatients with MDD and alcohol dependence. Although both medications reduced symptoms of depression and anxiety, there were no significant differences between treatments; the study did not evaluate alcohol-related outcomes.
In a case study, a 55-year-old man with treatment-resistant major depression and co-occurring alcohol and benzodiazepine dependence who received a single dose of IV ketamine, 0.5 mg/kg over 50 minutes, experienced “significant improvements” in depressive symptoms that lasted throughout the 7-day follow-up.³³ This study did not report on ketamine’s effects on his alcohol use.