This study adds to a growing literature examining the epidemiology and clinical features of substance-induced mood disorders. Use of the SSADDA, an instrument with demonstrated reliability in the diagnosis of DSM-IV substance use and psychiatric disorders [20
] made it possible to stratify subjects into four groups based on the presence of independent and substance-induced MDE. In contrast to the more loosely defined and less stringent approach used in DSM-IV, which does not require that full MDE criteria be met in the diagnosis of substance-induced depression, this study required subjects to met full DSM-IV criteria for a major depressive episode. This enabled us to compare more directly the MDE subtypes and has underscored the group with both types of MDE. Given its greater specificity, a diagnosis of substance-induced MDE may have greater clinical utility and predictive validity than a substance-induced mood disorder diagnosis. Hence, this study, and other studies that have used rigorous criteria to diagnose substance-induced depression [15
], is of potential utility in redefining the diagnosis of substance-induced mood disorders in DSM-V.
The comparatively large number of subjects endorsing both types of MDE (N=168) in this sample made it possible to examine their features in detail, which is the first phenomenological analysis of this group in the psychiatric literature. These subjects fared much worse on a variety of psychopathological measures, suggesting that the dichotomous distinction between independent and substance-induced depression is inadequate to characterize depressive episodes among substance-dependent individuals, and that subjects with both types of MDE may require more sustained and intensive psychiatric interventions.
Psychiatric parameters were the most robust predictors of MDE subtype, with the two best clinical predictors (i.e., the number of depressive symptoms and the number of co-morbid anxiety disorders) being elevated in the group with both types of MDE compared with those with independent MDE only or substance-induced MDE only. Age of onset of MDE, which was evaluated using survival analysis, was not a significant predictor of MDE subtype. However, among the psychiatric predictors, only the number of lifetime depressive symptoms differentiated the independent MDE group from the substance-induced MDE group. This contrasts with a recent report from the multi-site Sequential Treatment Alternatives to Relieve Depression (STAR*D) study of 4,010 non-psychotic depressed outpatients with or without concurrent substance use disorder (SUD) [28
]. In that study, subjects with co-occurring MDD and SUD reported an earlier age of onset of depression, more depressive symptoms and a greater number of comorbid anxiety disorders than those without SUD [28
]. The comparison between studies is limited by both sociodemographic differences, e.g.
, the sample from STAR*D was predominantly Caucasian (~75%) and female (~61%), while the present sample is predominantly African-American (~53%) and male (~54%), and the fact that subjects with co-occurring MDD and SUD in STAR*D included those with substance-induced MDE and both types of MDE.
There was a greater likelihood that subjects with both types of MDE had attempted suicide than subjects with independent depression. This greater risk of suicide raises the question of whether screening patients with alcohol, cocaine or opioid dependence for the presence of combined independent and substance-induced MDE could set the stage for interventions aimed at preventing additional suicide attempts in this high-risk group.
Although it did not distinguish among the MDE subtypes, ASPD was more common among individuals with either independent MDE or both types of MDE compared with substance-dependent subjects with no history of depression. In contrast, Schuckit et al
] found that ASPD was a significant predictor of independent, but not substance-induced, depression. Similarly, in the VA-based Vietnam Twin Era Registry study, shared genetic risk estimates of lifetime ASPD and major depression were 69% and 40%, and the genetic risk between major depression and alcohol and marijuana dependence was largely explained by genetic effects of ASPD [29
]. Also, in a study of 132 substance-dependent Turkish inpatients, ASPD was significantly associated with lifetime major depressive disorder, attempted suicide, and other self-injurious behaviors [30
]. Together, these findings demonstrate that the relations among SD, ASPD, and MDE are complex, but of considerable clinical importance.
In the present study, the nature of the SD diagnosis also differentiated among the subtypes of MDE. Interestingly, subjects with alcohol dependence were more likely to endorse independent depression or both types of MDE than substance-induced MDE only. These results are consistent with the hypothesis that subjects with primary depression often “self-medicate” their symptoms with alcohol. Our results are also similar to those reported from the National Epidemiologic Survey on Alcohol and Related Disorders, where high rates of depression were identified in alcohol-dependent subjects but few depressive episodes were substance-induced [7
]. Similar results were observed in the first COGA study, in which alcoholics were more likely to endorse traits associated with an independent MDE, i.e.
, female sex, white race, and a family history of an independent mood episode [15
]. However, the present findings differ from those of the first COGA study, where drug-dependent subjects were also more likely to endorse substance-induced MDE.
Race/ethnicity is also an important feature distinguishing MDE subtype in substance-dependent subjects. In the present study, African-Americans were significantly less likely to experience both types of MDE than either European-Americans or Hispanics. These findings are consistent with a prior study of a national probability sample of pre-retirement adults in which there was a significantly lower risk of MDE in African-Americans compared to whites, who had a rate of MDE that was similar to that of Hispanics [31
]. A greater prevalence of MDD was also observed in a nationally representative sample of whites aged 15–40, compared with African-Americans and Mexican-Americans [32
]. However, these findings contrast with those of Smith et al
], who found similar rates of co-morbid SUD and MDD across white, black, and Hispanic groups in a U.S. population study. The association of depression with racial/ethnic groups in these studies could be confounded by reluctance on the part of minority groups to report depressive symptoms [34
] or by inadequate differentiation of independent and substance-induced depressive symptoms.
As might be predicted given a greater period at risk, older subjects were more likely to have both types of MDE than substance-induced depression, though age did not differentiate both types of MDE from independent MDE only. Independent depression was also more likely later in life than substance-induced depression only, consistent with a decline in substance use with age. The effect of sex (i.e., both independent MDE and both types of MDE were more common among women than men) was consistent with the greater risk in the general population of independent depression among women [35
As in the COGA sample, we found that subjects endorsing independent MDE only were more likely to be female and to have ASPD [16
]. However, that study also showed the group with substance-induced MDE to have a greater number of drug dependence diagnoses, which we did not observe [16
]. Schuckit et al
] also found an increased likelihood of a family history of independent depression in the independent MDE group. Comparable data on family history obtained via direct interview with family members were not available for our sample, so we did not evaluate this measure as a predictor of MDE subtype.
Our study differed from COGA both in the ascertainment and composition of the study sample and in the assessments that were used. We excluded subjects who had no lifetime substance dependence diagnosis. In contrast, nearly half of the subjects with a lifetime independent MDE in the COGA sample failed to meet criteria for an alcohol use disorder (which was the focus of that study). We recruited subjects from family-based studies of cocaine or opioid dependence and case-control studies of alcohol, cocaine or opioid dependence. Schuckit et al
] recruited alcohol-dependent probands entering treatment for an alcohol use disorder and their family members, as well as a group of comparison families. In the COGA sample, there was an equal proportion of individuals with independent and substance-induced MDE, while in our sample the number of subjects with substance-induced MDE was more than three times the number with an independent MDE only. This difference in the relative proportions of independent and substance-induced MDE is likely due to multiple factors. First, although the SSADDA was adapted from the SSAGA (which was developed by COGA), we were able to diagnosis subjects with both independent and substance-induced MDEs. In contrast, the independent MDE group in Schuckit et al
] likely included both subjects with independent MDE only and both types of MDE. Finally, greater than 40% of the subjects in our sample had a lifetime diagnosis of MDE compared to only 23% of the subjects in the COGA sample, a difference that probably stemmed from the fact that 70% of subjects in the COGA study were family members of ascertained probands, among whom the diagnosis of SD (and the risk for substance-induced MDE) was substantially lower than it was among probands.
The importance of this diagnostic approach is supported by our findings of greater psychiatric and substance-related pathology among the group with both types of MDE. These findings are also consistent with those obtained by Nunes et al
], who divided 110 psychiatric inpatients with current MDD and alcohol, cocaine, or opiate dependence into those with independent (N=54) or substance-induced (N=56) major depression. During a 12-month follow-up period, 57% of these patients experienced recurrent major depression, with recurrence being equally likely among patients with independent or substance-induced depression. However, among the substance-induced group, a past diagnosis of independent MDD increased the likelihood of major depression during the follow-up. This is consistent with the increased psychiatric burden observed in our study in the group with both types of MDE. It should be noted that, because greater depressive symptom severity in the group with both types of MDE could have resulted from their having more lifetime episodes of depression, we controlled for the number of lifetime depressive episodes. In this analysis, subjects with both types of MDE had an earlier age of onset of a first depressive episode, more lifetime depressive symptoms and a greater likelihood of suicide attempts.
There are a number of limitations to the present study. First, we focused on lifetime co-morbidity, and, as such, the validity of the findings may be limited by recall bias. Recall bias may be more pronounced in subjects with a history of SD due to the direct toxic effects of drugs or traumatic head injury associated with increased risk-taking behavior leading to persistent cognitive impairment. Second, “pseudocomorbidity” bias, or the incorrect designation of disorders as co-occurring when they are, in fact, randomly associated, is a potential limitation in all studies of co-occurring disorders such as MDD and SD, which are highly prevalent in the general population [38
]. Third, because of the high rate of co-occurring SD diagnoses, it was not possible to analyze the data separately by SD subgroup, which may have obscured different susceptibilities for the MDE subtypes in relation to specific substances. Finally, because the present study recruited subjects from case-control and family-based genetic studies, the study sample is not representative of all alcohol- and drug-dependent subjects. Rather, based on the high proportion of cocaine- and opioid-dependent subjects in our sample, our findings are most applicable to a severely affected SD population.
The findings reported here are consistent with the findings from a number of other studies that sought to differentiate independent from substance-induced depression. Our study also underscores the clinical relevance of subtyping depression among individuals with SD and the potential importance of identifying individuals who have experienced both types of depression, since we would anticipate that this group would be less treatment responsive and would, therefore, require more intensive services [27
]. Further characterization of this patient group will require prospective, longitudinal studies that examine these individuals’ response to specific treatments for depression and how that impacts the course of their substance use disorder.