Time to recovery from a new-onset major depressive episode did not differ significantly for subjects with current or past alcohol or drug use disorders in this prospective, observational multisite study. This surprising finding is in contrast to the prevailing view that substance use disorders impair the ability to recover from depression. The lack of a difference is consistent, however, with findings from the NIMH Collaborative Depression Study, which reported similar outcomes for subjects with bipolar disorder and comorbid alcohol use disorders (Ostacher et al., unpublished). Lower use of antidepressants and lamotrigine in subjects with drug use disorders (and to a lesser extent alcohol use disorders) would be expected to bias those groups toward longer time to recovery, but this did not appear to be the case in this cohort.
Current and past alcohol use disorder and drug use disorder, however, were associated with an increased likelihood of switch to mania, hypomania, or mixed states prior to recovery from a major depressive episode. It is reasonable to expect that those with current alcohol use disorder or drug use disorder would be more likely to switch relative to those with a past history, but we found that current or past history conveyed a similar risk of switch. This raises the question of whether patients with any substance use disorder history may be more prone to mood instability, or, conversely, whether patients with more mood instability may be more likely to develop a substance use disorder. A post hoc analysis examining time to recovery including (rather than censoring) those who switched to a manic, hypomanic, or mixed state (and perhaps back to depression) prior to recovery, however, did not show a significant difference between groups with and without substance use disorder; overall episode length in spite of increased rates of switch was not longer in subjects with substance use disorder histories compared to those without.
The finding that the presence of substance use disorders in patients with bipolar disorder does not directly affect the length of depressive episodes in bipolar disorder are consistent with the findings of Strakowski et al. (5
) that some patients with bipolar disorder and co-occurring substance use disorders have a course of illness that is less severe than that of some patients with bipolar disorder and no substance use disorder comorbidity. Our results further suggest that patients with bipolar disorder and lifetime substance use disorder comorbidity—whether current or in the past—have inherent characteristics that may differentiate them from those without substance use disorder, including the propensity to switch from depression to manic, hypomanic, or mixed states. Similar switch rates prior to recovery from the index episode of depression in subjects with past and current substance use disorders suggests that the factors inherent in patients with bipolar disorder at risk for substance use disorders may also confer greater likelihood of switching; our data suggest that switching is not likely to occur as the direct result of current drug or alcohol use. Adding variables typically associated with both substance use disorder and worse outcome, including DSM-IV anxiety disorder, age at onset, age at study entry, sex, education, marital status, and rapid cycling in the past 12 months did not alter the results.
This study did not examine the relationship between the amount of substance use and outcome, and this is an important limitation of the study. Substance use disorders in DSM-IV are 12-month diagnoses; that is, they do not directly reflect the level of use at the time of diagnosis, and they do not account for the severity of use. Our study did not include measures of substance use severity, such as the Addiction Severity Index. It may be the case that level of alcohol and drug use present in this cohort may have been within a limited range and severity, with insufficient magnitude to interfere with recovery. It is also possible that subjects with current substance use disorder decreased their use during treatment, and this may in part explain their similarity to those with past substance use disorder. In addition, it is difficult to know whether the increased anxiety found in subjects with current substance use disorder is a result of drug or alcohol use or is a consequence of it.
The MINI is well validated and was chosen as the diagnostic tool in the study instead of the SCID to improve the feasibility of the study. It does not have a field for specific drug of abuse, however, and this is a limitation. Because of this, these data cannot be extrapolated to determine whether specific types of drug abuse are associated with the outcome we found.
Another aspect of the study worth noting is that this is a population of patients willing and able to comply with follow-up in a research study, and this may be a marker for treatment adherence and persistence. Substance use disorders in bipolar disorder are associated with lower adherence, but this may be mitigated overall in this group of treatment-seeking subjects who are able to comply with study protocol (23
). These subjects were followed primarily in academic medical centers and may not be representative of the general population of patients with bipolar disorder. It is possible that patients with bipolar disorder and severe drug use disorder and alcohol use disorder were either not enrolled in the study after evaluation or were never referred.
It remains important to try to explain the lack of difference for depression outcomes. Patients with bipolar disorder are frequently complex in their presentation, with high rates of anxiety disorder, ADHD, substance abuse, and medical comorbidity. Multiple factors have been found to be associated with poor outcome in patients with bipolar disorder—most notably anxiety disorders—so it is quite important that clinicians be aware of prognostic indicators to best approach their patients (24). Drug and alcohol use is perceived to be a modifiable risk factor for poor outcome (unlike anxiety disorder comorbidity or family history, for example), so it is understandable that clinicians might focus on changing drug and alcohol use in an effort to improve treatment outcome. What these data suggest, however, is that alcohol and drug history, past or present, may not be a reliable indicator of outcome for recovery from major depressive episodes in bipolar disorder, and that a singular focus on substance use might be less useful, perhaps, than aggressive treatment of anxiety, a specific intervention to improve treatment adherence, or the implementation of an evidence-based psychosocial treatment for bipolar depression.
Most importantly, these findings suggest that treatment for bipolar depression should not be withheld from patients with co-occurring alcohol or drug use disorders, especially given that the prognosis for an episode of bipolar depression is no worse than for those with bipolar depression and no alcohol or drug use disorder, and that engaging them in treatment is important because of their overall severity. Further understanding of subgroup characteristics associated with outcomes in bipolar disorder is needed to direct patient care. In summary, a comorbid substance use disorder was not related to recovery from depression but was associated with increased risk of switch from depression into manic/hypomanic/mixed states. Current or lifetime substance use disorder conveyed similar risks. Even in the presence of a substance use disorder, it may be possible to help these bipolar patients with appropriate treatment of their acute bipolar state.