The most important finding of this study is that despite greater lifetime suicidality and a greater number of concurrent Axis I psychiatric disorders at baseline, the presence of comorbid SUD in patients with chronic and/or recurrent MDD did not appear to significantly affect treatment outcomes with either a single SSRI or combination antidepressant medications in short- or long-term treatment periods. Our results extend and compliment the findings from the larger STAR*D study of first level citalopram monotheray in persons with MDD.
Curiously only 13% of the COMED participants had a concurrent SUD, which is much lower than the 30% prevalence rate found in the STAR*D MDD sample (which also used the PDSQ screening tool to assess for the presence of SUD).3,4
Possible reasons for this difference likely reflect differences in study design and subject selection. Although a formal analysis between these study samples was not conducted, the lower prevalence of concurrent SUD in the COMED study may be related to a greater representation of women in the COMED study (1:2.1 male:female) compared to STAR*D (1:1.7 male:female). Female participants in both studies were less likely to have SUD than their male counterparts; thus, effectively decreasing the population of SUD+ participants in the COMED study. Additionally, the COMED study enrolled subjects with chronic and/or recurrent depression, many of whom may have been counseled earlier in the course of their illness to decrease or abstain from substances. Entering a study involving taking two medications may have generated an unintended recruitment bias such that subjects with SUD were less likely to consent and researchers were more cautious to recruit these subjects.
Baseline characteristics of the COMED participants were similar to those of the STAR*D study in terms of ethnicity, employment, and levels of depressive symptom severity; however, a greater percentage of COMED participants endorsed chronic depression, reflecting the differences in inclusion criteria. Sociodemographically, this study supports previous observations that participants with MDD+SUD are more likely to be male49,50,51,52
and have a greater number of concurrent Axis I psychiatric disorders.6
While depressive symptom severity and side effect burden were comparable with antidepressant monotherapy and combination antidepressant therapy, the number of participants having one or more psychiatric SAEs was higher in the SUD+ group at 28 weeks, although absolute numbers were low. While the difference in number of post-baseline visits reached statistical difference, the numerical difference of less than one visit between groups is not likely to be clinically meaningful. Although the presence of comorbid SUD was not broadly associated with significant degrees of intolerability to three different antidepressant treatments, the SUD+ SUD+ participants on antidepressant combination therapy had greater rates of exit due to treatment intolerance (early termination) at 28 weeks than did SUD+ participants on monotherapy. Similarly, higher rates of early exit were observed in a study comparing combination treatment (sertraline + naltrexone) versus those on monotherapy.53
While this could reflect pharmacodynamic or pharmacokinetic differences in medication metabolism that result from substance abuse, in this study, maximum doses for all study drugs were similar between the SUD- and SUD+ groups, though there was a slight trend toward lower doses in the SUD+ group. Also of clinical importance is the finding that the SUD+ group appears to be at a higher risk of planning or making suicide attempts. The constellation of MDD, SUD and suicidality is complex with contributions from genetic, familial and sociocultural elements.54,55,56,57,58,59
These findings remind us that reinforcement of adherence to treatment, concern for medication tolerability, and need for close medical follow-up in the dual diagnosed patient are a clinically important. Clinicians need to be cognizant of the inherent risk of suicide in patients with MDD and SUD, and must offer adequate and timely treatment to reduce the risk of suicide. Fortunately, our findings demonstrate that no particular antidepressant or combination was consistently more effective regarding response, remission or side effect profile at 12 or 28 weeks and that the presence of comorbid SUD does not lessen the efficacy or tolerability of antidepressant mono- or combination medication treatments.
The strengths of the present study include 1) a large sample size with substantial minority and ethnic representation, 2) recruitment from both primary care and psychiatric care treatment settings, 3) enrollment of MDD participants from naturalistic treatment-seeking “real-world” patient populations, including those with SUD, 4) a single-blind, randomized design, and 5) a longer-term extended treatment phase.
Limitations of the present study include the use of a self-report screening tool to define concurrent SUD and other Axis I disorders while MDD was diagnoses more rigorously. We also did not gather information regarding the amounts or types of alcohol or drugs used, the types of treatment received for SUD, and the change in substance use following treatment of the depression. A more detailed diagnostic assessment and more detailed accounting of concurrent treatments and outcomes for the comorbid disorders was not obtained in view of the primary focus of the COMED study and need to limit participant burden. As such, we cannot address whether treatment of depression affected the concurrent SUD. The lack of a minimum period of abstinence prior to study entry did not systematically ensure that depressive symptoms would not spontaneously remit after sufficient abstinence. Also, we identified and examined comorbid SUD as a baseline correlate of treatment outcome to three different therapies. Ideally, prospectively randomizing groups of MDD patients with and without comorbid SUD to each of the three treatment groups would provide more definitive data on efficacy and tolerability. Lastly, since the participants were recruited from a psychiatric or primary care clinic, the results may not be generalizable to an addictions treatment clinic.
In conclusion, our findings of equivalent response and remission rates with single agent or combination antidepressant medication treatment in individuals who have chronic and/or recurrent MDD with or without SUD supports an emerging and important paradigm shift in clinical care. Namely, antidepressant medications may be equally beneficial for MDD patients who are struggling with alcohol and/or drug addictions and for MDD patients who are not. A study that prospectively addresses the clinical question of delaying or initiating antidepressant medication treatment in depressed patients while awaiting abstinence is warranted. The striking burden of suicidality imposed by the comorbidity of SUD is clear in this and other studies, and should heighten the urgency to assertively treat depression in patients who are also using drugs and/or alcohol. These findings may be useful for guiding the treatment of persons with chronic and/or recurrent MDD and concurrent SUD in primary care and psychiatric care clinics.