For patients suffering from depression and alcohol dependence, combination treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline plus naltrexone, an opiate antagonist, may offer greater benefits than with either treatment alone.

In a 14-week randomized controlled trial, a greater number of depressed alcohol-dependent patients who received both sertraline and naltrexone were able to abstain from alcohol completely for longer periods, had a longer time to a heavy-drinking relapse, and reported fewer side effects compared with either monotherapy or placebo.

Lead study author Helen M. Pettinati, Ph.D., Professor, Department of Psychiatry, University of Pennsylvania School of Medicine, told The Update that the new finding “signals an important advance in the treatment of depressed patients with alcohol dependence because the occurrence of these disorders is common in clinical practice, yet antidepressants alone are frequently not sufficient for reducing excessive drinking in these patients.”

Pettinati, who is also Director of the Addiction Treatment & Medication Development Division, Treatment Research Center, Philadelphia, said that for patients with co-occurring alcohol disorders and depression, “each of the individual disorders often worsens the other, and patients lose hope for recovery. Combining sertraline and naltrexone could be a practical approach for these patients because both have FDA approval.”

Study details

The study randomized 170 patients (mean age, 43 years; male 62%; Caucasian 65%) to treatment with sertraline 200 mg/day plus naltrexone 100 mg/day (N=42), naltrexone 100 mg/day plus placebo (N=49), sertraline 200 mg/day plus placebo (N=40), or double placebo (N=49) under double-blind conditions for 14 weeks. Throughout the trial, all participants also received weekly cognitive behavioral therapy (CBT). Inclusion criteria were drinking an average of ≥12 alcoholic beverages weekly, drinking alcohol on ≥40% of the 90 days before treatment, alcohol abstinence for 3 consecutive days before starting treatment, and a Hamilton Depression Rating Scale (HAM-D) score of ≥10 at randomization.

The two primary outcome measures for drinking were total abstinence, defined as the percentage of participants who were totally abstinent everyday of the trial, and time to relapse, defined as the median number of days prior to a heavy-drinking day (i.e., ≥5 drinks in 1 day for men; ≥4 drinks in 1 day for women).

The two primary outcome measures for depression were scores on the 24-item HAM-D at the end of the trial and no depression during the last 3 weeks of the trial, with no depression defined as a HAM-D score ≤9.

Results

Seventy-five percent of the patients reported having a family history of alcoholism or of drug problems, with approximately half of the sample also reporting a family history of depression. The average duration of alcoholism was 21 years, with an average of two prior treatments before study enrollment.

Medication adherence was relatively high — 87% for the entire sample — with no significant between-group differences. Nearly three-quarters of the patients completed at least 80% of their treatment.

The modal daily dosages were naltrexone 91 mg and sertraline 169.5 mg. The FDA recommends 50 mg/day for naltrexone and 50 mg/day as a starting dose for sertraline. However, higher target study doses were chosen based on efficacy outcomes in earlier studies that used higher-than-recommended FDA doses. The sertraline target dose of 200 mg/day was chosen based on published studies showing reduced alcohol consumption with higher SSRI doses. In the largest pharmacotherapy study on alcohol dependence — COMBINE (Combining Medications and Behavioral Interventions for Alcoholism) — the naltrexone target dose was 100 mg/day. Preclinical investigations also suggest that naltrexone >50 mg/day may achieve better outcomes than lower doses.

Patients who received only naltrexone were less successful in abstaining from alcohol during the trial, and had a shorter time before relapsing to heavy drinking compared with patients who received both study drugs. Total abstinence during treatment was greatest in the sertraline plus naltrexone group (54%) compared with the monotherapy and placebo groups (naltrexone, 21%; sertraline, 28%; placebo, 23%). The longest time to relapse to heavy drinking was in the sertraline plus naltrexone group (98 days) compared with monotherapy and placebo: naltrexone (29 days), sertraline (23 days), and placebo (26 days).

All groups experienced clinically significant reductions in depressive symptoms, which the authors suggest might be attributed to the weekly CBT sessions. More patients in the combination group tended not to be depressed in the last 3 weeks of treatment compared with the other groups. In the last week of treatment, the mean HAM-D score was 6.9 in the combination group compared with a combined HAM-D score of 9.9 for the monotherapy and placebo groups. The between-group difference in mean HAM-D scores was not significant.

The depression outcomes were surprising in view of earlier findings reporting a more robust reduction in depressive symptoms with antidepressants compared with placebo in depressed, alcohol-dependent patients, the authors write. “However, our study found no advantage in treatment with sertraline alone in depressive symptom reduction and, potentially, portrayed a tendency for a slower mood improvement rate with sertraline over the 14 weeks of treatment compared with the other treatment groups.”

The Update asked Pettinati about the use of combination treatment with long-acting injectable naltrexone (Vivitrol) in this population. “Patients suffering from co-morbidity often have difficulty taking multiple medications on a regular basis,” said Pettinati. The use of the long-acting form of naltrexone, which lasts for 30 days per injection, “would likely increase response rates in this population, when combined with sertraline, since this regimen would increase medication adherence in one of the medications [to] 100%. However, studies testing the benefit of injectable versus oral naltrexone directly have not yet been conducted with taking a second oral medication, or in the comorbid population.”

Serious adverse events (AEs) occurred at a rate of 26%, most of which required in-patient detoxification and/or rehabilitation, and were significantly lower in the combination group compared with the monotherapy and placebo groups. The most frequently reported severe or very severe AEs were anxiety/irritability (29%), fatigue (25%), decreased libido (18%), headache (14%), nausea (8%), and orgasm difficulties. Seven discontinuations due to AEs occurred in the sertraline plus naltrexone group, 2 in the naltrexone group, 2 in the sertraline group, and 1 in the placebo group.

Editorial weighs in

In an accompanying editorial,1 Ash-win A. Patkar, M.D., and Ting-Kai Li, M.D., write that clinicians have not had empirical data to support specific pharmacotherapy for treating depression in alcohol dependence, i.e., whether to use monotherapy with antidepressants or anti-alcohol medications, or their combination, to reduce the symptoms of either or both disorders. “The study by Pettinati et al. provides some answers. This is an excellent study with a real-world outpatient sample, 87% medication adherence, and higher target doses to minimize suboptimal dosing.”

Based on the Pettinati et al. findings, Paktar and Li conclude that “it is difficult to justify use of an SSRI alone in the absence of concurrent behavioral interventions and pharmacotherapy for the alcoholic patient with major depression.”

Patkar and Li also suggest that “for appropriate patients,” it may not be necessary to wait for patients to abstain from alcohol for long periods before starting pharmacotherapy. Depending upon tolerability, “it may be worth titrating naltrexone to a dose of 100 mg/day and the SSRI to the maximum therapeutic dose and then treating for at least 12 weeks to evaluate adequate response.”

Authors’ conclusions

Co-occurring depression with alcoholism is highly prevalent and difficult to treat. The current findings suggest that this syndrome is best treated with medications that target each clinical component. A “tentative observation” regarding the depression outcomes “is that there may be relatively little advantage in prescribing an antidepressant alone for depressed patients who are also alcohol dependent.”

It is not known whether the current findings may generalize to other clinical settings, or to the use of other antidepressants and anti-alcohol medications in this population. “Finally, we do not know whether the ameliorative short-term effects of our treatments are sustainable, since both depression and alcohol dependence can be lifelong illnesses.”

Before new recommendations can be made for clinical practice, the current findings will need to be replicated.

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Supported by a grant to Dr. Pettinati from the National Institute on Alcohol Abuse and Alcoholism. Pfizer, Inc., U.S. Pharmaceuticals Group donated sertraline and placebo.
Pettinati HM, Oslin DW, Kampman KM, et al.: A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry 2010; 167(6):688–675. E-mail: pettinati_h@mail.trc.upenn.edu.

REFERENCE

1. Patkar AA, Li TK: Treatment for alcohol dependence: Rethinking the role of comorbidity and clinical subtypes. Am J Psychiatry 2010; 167(6):620–655.