Results from this trial indicate there was no evidence that naltrexone enhanced treatment responses either for depression or for alcohol consumption when combined with sertraline and individualized psychosocial support. There was evidence supporting the role of elimination of heavy drinking during treatment in order to improve depression-treatment responses. Because this is one of the first clinical trials examining the efficacy of combination treatments for those with alcohol dependence and depression, it is difficult to compare the outcomes of this trial with other trials, including those using monotherapy. However, we note that overall drinking outcomes improved substantially for all subjects, with 66% having a favorable change in drinking behavior. This rate of remission for drinking is similar to the positive results from naltrexone in previous placebo-controlled trials for alcohol dependence and may relate to the effects of the psychosocial intervention and sertraline.33,49–52
However, this trial was not designed to establish the efficacy of sertraline or the psychosocial intervention, and thus statements regarding the efficacy of these treatments cannot be made. Moreover, previous trials of antidepressants in depressed, alcohol-dependent subjects have shown mixed results in reducing alcohol use.24–27
The association between heavy drinking during treatment and reduced effectiveness of depression treatment substantiates the idea of toxic effects of alcohol in this clinical context. Although complete abstinence was not associated with poor depression response, patients who had more than 2 days of any drinking also demonstrated the poorest depression response. Together, these analyses suggest that both frequency and quantity are important in treating comorbidity. Although there was a strong relationship between drinking and depression outcomes, these data do not distinguish between patients who may have returned to drinking because the depression had not improved versus those whose drinking led to a worsening of depression. Other possible explanations of our findings include reduced efficacy of sertraline due to changes in pharmacokinetics/dynamics in the presence of alcohol use, or direct CNS-toxic effects of alcohol that limit improvement in depression symptoms.
The lack of an additive effect of naltrexone should not diminish the estimation of the value of naltrexone for treating alcohol dependence in other settings. The lack of efficacy of naltrexone in the present setting may relate to differing effects of naltrexone on neurotransmission in different populations. The efficacy of naltrexone is understood by the opioid-compensation hypothesis, which posits a dysfunction in opioid neurotransmission after alcohol ingestion, leading to increased drinking. In support of this are several studies demonstrating that response to naltrexone is related to family history of alcoholism and to the presence of a specific polymorphism of the μ-opioid receptor gene (OPRM1
) that is known to change the functioning of this receptor.39,53,54
One-third of the participants in this trial were of African descent and unlikely to have the polymorphism associated with naltrexone response. Unfortunately, subjects in this trial were not genotyped, and family-history data are lacking. Thus, the lack of efficacy of naltrexone suggests that depressed alcohol-dependent patients may have normally functioning μ-opioid receptors and that the mechanism for excessive drinking may relate to dysfunction in another part of the pathway for loss of control of drinking (possibly the serotonergic, GABAergic, or another signaling pathway). It is also noted that although naltrexone has been shown to have a small-to-moderate efficacy in older adults with alcohol dependence, it is also possible that there is an age-related loss of efficacy of the medication, perhaps related to differential drive for alcohol consumption or motivation for quitting.34,55
The interaction effect between gender and treatment assignment raises the possibility of differential efficacy by gender. Currently, there are no published results suggesting differential response in women, although this difference is being examined in several ongoing trials. It is possible that the potential “toxic” effect seen in women relates to greater adverse effects of the combination of medications or a direct adverse effect of naltrexone on depression for women, given that the effect for women seemed mostly driven by a lack of improvement in depressive symptoms. However, there was no evidence of greater reporting of adverse events among women. Despite this finding and the lack of evidence from other clinical trials, heuristic clinical opinion suggests that women may not tolerate as high a dose of naltrexone as men.
One limitation of the trial was the adoption of a relatively conservative measure of response in this study, by examining the percentages of patients who improved to the point of remission of depression and lack of relapse to heavy drinking for alcohol use. This was based on the need to have a common standard of improvement across the two types of behavioral health problems we examined. The strength of this approach was the reference to meaningful standards of severity namely the use of relapse-to-heavy-drinking and a Ham-D score of ≤10. Other limitations of the study include the modest sample size, inclusion of a limited number of women, and the restricted age-range of the participants. To better understand the differential effects of combination treatments across the lifespan, a more inclusive trial should be attempted that targets young, middle-aged, and older adults with representation across gender and ethnicity.
The results of this trial also raise questions about the methods used for determining the efficacy of combination treatments. In all likelihood, a substantial proportion of subjects may be best treated with monotherapy in combination with psychosocial support. This is clearly supported by the results of this trial, in which half the patients responded favorably to the monotherapy; and even though recruitment for the trial met the estimated sample size requirements, with 80% power to detect differences of 30% or more in response, these estimates were based on the expectation of the full treatment package having moderate-to-large effects and monotherapy having modest effects. Future trials should consider alternative design strategies that may maximize differences in effect from combination treatments. Namely, future trials should consider the merits of using adaptive treatment designs or stepped-care approaches. In these approaches, standard treatment, such as monotherapy plus psychosocial support, is begun, and combination treatment is added to a random subset of those who do not respond to the initial treatment efforts. A comparison group of patients continuing on monotherapy plus psychosocial support is also maintained. This type of design would not only match clinical practice, but may also reduce exposure and the expense of combination treatments that may be unnecessary or carry additional patient burden.
In conclusion, this trial has raised many questions for future trials, including the design used for establishing combination treatments, consideration of the rationale for selecting combination treatments, and the caution that simply considering two treatments as better than one is a naive approach to clinical care. Moreover, despite the relatively positive improvement in drinking behavior seen among most participants in this trial, 47% of the sample remained significantly depressed at the end of the trial. Although the modest depression response may relate to the inclusion of patients who remained depressed after detoxification and 1 week of treatment with naltrexone, this again raises important issues with regard to the focus of treatment and sequencing of treatments. Although it was true that reduction in alcohol use was necessary for improvement in depression, this was not sufficient in all participants. The low remittance of depressive symptoms also raises questions about the diagnostic usefulness of “substance-induced depression” in this particular cohort, as we might have expected a greater response to treatment when two-thirds of subjects were judged to have depression related to alcohol use. Further work will be necessary to establish the next line of treatment in patients who decrease or eliminate alcohol use, but continue to have significant depression. It is likely that a continued integration of depression and alcoholism care will be necessary to keep these patients from returning to heavy drinking as we continue to adapt and modify the depression treatment.