A summary of the analysis of the moderators, and the clinical implications that we infer from them, is shown in (see page 735). From the association of high placebo response, absence of diagnosis during abstinence, and presence of a manual-guided psychosocial intervention for substance dependence, with lack of medication effect we infer that entry into treatment for a substance use problem, particularly if an evidence-based psychosocial intervention is offered, often results in substantial improvement in depression, such that specific antidepressant treatment is not needed. This could result from reducing substance use, which in turn reduces depression symptoms caused by substances (ie, dysphoria related to intoxication, withdrawal, chronic use, or the stress of the lifestyle of an addicted patient). It could also result from direct beneficial effects of treatment for substance dependence on depression. Manual-guided interventions such as relapse prevention feature modules on how to handle bad moods, which resemble approaches to treatment of depression used in effective psychotherapeutic methods for depression such as cognitive behavioral therapy. This is also not surprising, given well-known observational studies showing that entry into treatment is associated with improved depression.9–13
TABLE A Summary of the Meta-analysis of Placebo-controlled Trials of Antidepressant Medication among Substance Dependent Patients with Depressive Disorders18
Thus, the obvious clinical recommendation is to always initiate treatment for the substance use disorder, and allow at least a week or two to observe whether mood will improve with this alone. Treatment options for the substance use disorder would include hospitalization, outpatient behavioral or psychosocial treatments, or medications. Among behavioral treatments, consideration should be given to those that are manual guided and evidence-based, as suggested by the moderator analysis19
as well as outcome of depression symptoms in other trials of approaches such as the community reinforcement approach for treatment of substance abuse.38
Medications would include methadone12
or buprenorphine for opioid dependence and naltrexone or disulfiram for alcohol dependence.39,40
How long to wait for after abstinence, or substantial reduction in substance use, to be achieved (1 week, 2 weeks, 1 month) depends upon clinical judgment and how long the dysphoric effects of the substances that a given patient has been taking might be expected to last.
The exception to this guidance would be if the depression is severe and/or obviously independent (eg, a patient who is currently drinking, but has a past history of major depressive episodes while abstinent and currently has substantial suicidal ideation). Reliable semi-structured clinical interviews have been developed for diagnosing independent depressive disorders (in the DSM-IV sense), even in the presence of current substance use, the best developed being the Psychiatric Research Interview for Substance and Mental Disorders (PRISM).8,41
Work with the PRISM to date has focused on alcohol, opioids, or cocaine and may need to be updated to address the relationship between depression and cannabis dependence, a common comorbidity particularly among adolescents and young adults.42,43
It is important to note that a recent large study, which used the PRISM to select outpatient alcoholics with major depression, and also required depression to persist during at least a week of abstinence, yielded a high placebo response rate and no clear beneficial effect of medication. 44
Perhaps one week is too short of a wait among alcohol-dependent patients. In any case, more research is needed on diagnostic criteria that would select good candidates for antidepressant medication. In the meantime, there remains an important role for clinical judgment. Factors that might also be taken into account could include past history of independent major depression, family history of depression, or past history of good response to antidepressant medication. Another approach that has been suggested is that a depression that develops during a stable period of substance use may be more likely an independent depression, compared with a depression that emerges during a period of either escalating use or cessation of use.45,46
That the findings were inconsistent for SSRI antidepressants35,37
is intriguing, given that SSRIs have been associated with no benefit, or even worse drinking outcome, in several studies among alcoholics not selected for depression, but with the early onset alcohol dependence47,48
and a similar pattern among patients with PTSD and depression treated with sertraline.49
On the other hand, several of the largest beneficial effects of medication were demonstrated among alcoholics with major depression, diagnosed on inpatient units after at least a week of abstinence.21,25
A recently published study among adolescent patients with substance use disorders, conduct disorder, and major depression found fluoxetine beneficial for depression outcome, but not substance use outcome.50
We continue to favor SSRIs as the first line of treatment because of their good safety and tolerability, and low levels of sedation, suggesting less risk of adverse interactions with substances of abuse. However, if an SSRI trial fails, or there is a history of failed SSRI trials, a non-SSRI, with dopaminergic, noradrenergic, or mixed mechanisms of action should be tried (eg, bupropion, venlafaxine, duloxetine, mirtazapine, or even a tricyclic antidepressant). There is little direct evidence on the efficacy of any of these among depressed substance abusers, other than for tricyclics where the evidence is substantial. Tricyclics, however, are associated with more side effects and toxicity than the other new generation medications.
That the beneficial effects of antidepressant medication are clearer among alcohol-dependent patients, than among drug-dependent patients19,35
suggests to us that more research is needed in the latter group. There were fewer studies among opioid- or cocaine-dependent patients, and no published controlled trials to date among cannabis-dependent patients. In the meantime, more caution is needed in approaching those patients, and more clinical judgment in regard to which depression disorders should be treated. Again, a history of past independent episodes of depression, family history of depression, or past successful trials of antidepressant medication would all weigh in favor of initiating medication treatment.
It is perhaps counterintuitive, although noteworthy, that studies including dysthymia, and studies with more or less severely depressed samples, showed equivalent effect sizes.19
This finding suggests that chronic depression, even if more mild, should be taken seriously among substance-dependent patients. A chronic course of depression offers more opportunities to examine whether the depression persisted during ups and downs of substance use, and has been associated with greater effect sizes, compared with placebo, in studies of treatment of routine outpatient depression.