To the best of our knowledge, this is the first study to integrate prospectively both neurobiological and psychosocial factors as vulnerability markers for substance use disorder in depressed and nondepressed adolescents. Consistent with our previous finding, adolescents who developed substance use disorder had higher HPA activity at intake than those who did not develop substance use disorder (17
). However, the relationship between elevated HPA activity and substance use disorder was influenced by stressful experiences such that only those adolescents who experienced high levels of stress during prospective follow-up were more likely to develop substance use disorder (16
). As demonstrated in several nonreferred adolescent samples, the frequency of substance use disorder was higher in depressed youth compared to their counterparts without depression (3
), and the co-occurrence of depression and substance use disorder was demonstrated prospectively as well (16
). However, the relationship between depression and substance use disorder was attenuated when HPA dysregulation and stressful experiences were accounted for, suggesting that their association may be explained, at least in part, by these factors (4
These results should be considered in the context of study limitations. First, the small number of adolescents with substance use disorder precludes in-depth analysis of the substance use disorder subtypes. Due to the lack of a substance use disorder group at baseline, it was not possible to systematically assess the reciprocal relationship between depression and substance use disorder. Despite the statistical significance, the combined effect of nocturnal urinary-free cortisol and stress on substance use disorder was only modest, and the follow-up interval was relatively short. Although elevated HPA activity was associated with vulnerability to substance use disorder (17
), another study reported lower cortisol response to an anticipated stressor in preadolescent boys whose biological fathers had substance use disorder (29
). In this cohort, the lower cortisol response during preadolescence was associated with “regular” substance use during adolescence. Antisocial disorders mediated the risk for substance-related problems in the “high risk” group (30
). In contrast, the elevated HPA activity in depressed adolescents in our studies was confounded by comorbid anxiety disorder (17; also see online data supplement
). The association between HPA dysregulation (lower versus higher activity) and vulnerability to substance use disorder may be influenced by the nature of psychopathology. Therefore, including a comparison group at high-risk for substance use disorder based on externalizing problems or familial risk would have been beneficial in clarifying these relationships. Also, it is important to note that HPA assessment was performed only at intake. Hence, a direct association between HPA activity and development of substance use disorder could not be assessed. Previous investigations showed that cortisol levels decline during remission from a depressive episode (31
). Although clinical state influences HPA activity, evidence suggests that variation in HPA activity is heritable (32
). High nocturnal urinary-free cortisol levels in a subgroup of high-risk controls before the development of any psychopathology also suggest the influence of heritability or the effects of being exposed previously to stressful situations.
Experimental studies in animals showed that corticosteroids increase self-administration of addictive substances (7
). Reciprocally, psychoactive substances reduce stress-induced alterations in corticosterone and adrenocorticotropin and attenuate the anxiogenic effect of corticotropin-releasing factor (11
). In humans, alcohol or cocaine consumption has been shown to reduce plasma adrenocorticotropin and cortisol responses to corticotropin-releasing hormone (CRH) or to induction of stress by various means (10
). Other studies indicated that acute withdrawal from addictive drugs is associated with activation of the HPA system (10
). It is postulated that these actions of psychoactive substances on the HPA system predispose individuals to initiate alcohol/drug use during stressful situations, finally leading to dependence. Consistent with this hypothesis, in an ongoing study of a group of adolescents with depression and/or nicotine addiction, depressed youth with nicotine addiction had significantly lower HPA response to a standard psychosocial stressor in the laboratory than their counterparts without smoking history, and also compared to smokers without depression history (Rao et al., unpublished data). Longitudinal assessment of HPA function in depressed adolescents before and after the development of substance use disorder will be helpful in clarifying whether chronic substance use downregulates the HPA system in this population.
The clinical implications of these findings are twofold. First, individual differences in HPA activity and their relation to substance use disorder vulnerability indicate a potential for the development of more specific interventions for the different subgroups and, ultimately, for an individual. For example, metyrapone, an inhibitor of corticosteroid synthesis, and CRH antagonists reduce self-administration of alcohol and cocaine in rodents (35
). Anti-glucocorticoid agents and CRH antagonists appear to have antidepressant properties and have been tested in humans for the treatment of depression (13
). Antidepressant agents also are helpful in reducing substance use, particularly in those with comorbid depression (38
). However, some individuals with comorbid depression and substance use disorder show a poor response to antidepressant drugs (38
). The differential response to antidepressant compounds in patients with substance use disorder might be related to HPA activity. It is postulated that persons with elevated HPA activity might benefit most from antidepressant agents. Data from clinical and preclinical studies suggest that treatment with antidepressant agents reduces responsivity to stress (13
). Second, the additional contribution of stressful life experiences in increasing the vulnerability to substance use disorder suggests that such persons might benefit from adjunctive psychosocial interventions (40
). Future studies should evaluate the efficacy of pharmacotherapy and psychosocial interventions, singly and in combination, in patients with depressive and/or addictive disorders stratified on HPA activity and stress levels.