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Adolescents are at heightened risk for the development of both depressive and addictive disorders. These two disorders frequently co-occur in adolescents and are associated with significant morbidity and mortality. Given the substantial economic and psychosocial burden associated with the comorbid condition, the identification of causal mechanisms associated with their co-occurrence is of great public health importance. Evidence indicates that psychosocial stress contributes to the initiation and maintenance of both depressive and addictive disorders. Research suggests that the limbic-hypothalamic-pituitary-adrenal (LHPA) axis also may be important in the development of depression as well as addictive disorders. Using a diathesis-stress model, this review will examine the interactions between stressful experiences and LHPA axis in increasing the risk for depressive and addictive disorders in adolescents. Emerging evidence suggests that the high rates of comorbidity between these two disorders may be explained, in part, by high levels of stress and altered LHPA activity. Clinical implications of these associations will be discussed.
Depression is a leading cause of morbidity and mortality in adolescents. Elevated risk for the disorder begins in the early teens and continues to rise in a linear fashion throughout adolescence, with lifetime rates estimated to range from 15% to 25% by late adolescence [1–3]. Numerous studies also have documented that adolescent depressive episodes persist or recur into adult life along with ongoing psychosocial difficulties [4–5]. These difficulties include, but are not limited to, disruption in interpersonal relationships, early pregnancy, low educational attainment, poor occupational functioning and unemployment, as well as increased risk for suicidal behavior, resulting in substantial socioeconomic burden [4–5].
Substance abuse also typically emerges during adolescence [6–7], and early-onset of substance abuse is associated with a stable and escalating course into adulthood [8–10]. Depressive and addictive disorders frequently co-occur among adolescents and adults, and when they occur together, adaptive function is compromised further [7, 11–13]. The co-occurrence of substance use disorder with depression in adolescents is associated with earlier onset and more severe substance-related problems, increased frequency of behavioral problems, more prolonged and recurrent depressive episodes, and more severe impairment in family, school and legal domains. Youth with the comorbid disorder also are at higher risk for suicidal behavior than those without comorbidity [11, 13–14]. As a result, the comorbid illness is associated with increased utilization of health services and substantially higher treatment costs compared with those who have only depression or substance use disorder . Given the economic and psychosocial burden associated with comorbid depressive and addictive disorders, understanding the underlying mechanisms associated with these comorbid conditions is of great public health importance.
Although significant advances have been made with regard to knowledge of the environmental and neurobiological factors involved in depression and substance-related disorders individually, especially in adults, the mechanisms underlying the comorbid illness are not understood well [13, 16]. It is likely that the high prevalence of these disorders occurring together reflects, in part, overlapping genetic, environmental and neurobiological factors. It is also possible that there will be differences in neurobiology based on the temporal course of development of these two disorders; whether depression precedes substance abuse or the reverse. For instance, in the former case, substance use may occur in attempts to improve mood, whereas in the latter it is possible that chronic substance use leads to neurobiological changes that increase vulnerability for depression. The purpose of this paper is to summarize information on overlapping environmental and neurobiological factors, with particular emphasis on psychosocial stress and limbic-hypothalamic-pituitary-adrenal (LHPA) axis. There is a wealth of information on the role of these two factors in association with depression and addictive disorders separately in adult animals and humans, and there is also emerging evidence in adolescent animals and humans.
Stress plays a prominent role in most theories of depression, and there is a clear link between stress and depression in children and adolescents [17–19]. The relationship between stress and depression appears to be stronger in adolescents than in children, particularly in girls [20–22]. The reasons for this are not entirely clear; hormonal effects, consolidation of cognitive styles, cumulative stress burden, and stress reactivity might have a potential role [22–23]. One theory proposes that childhood adversity, stemming from abuse, neglect, witnessing domestic violence or house-hold dysfunction, alters neurobiological and psychosocial processes whereby individuals may be sensitized to the effects of recent stressful events, leading to depression at lower levels of stress , or with greater physiological reactivity to the effects of stress [25–26]; see below for more details on the relationship between environmental stress and LHPA system. Another model suggests that childhood stressors contribute to lifetime stress burden and independently predict depression along with recent stress [27–28].
Developmental models of psychopathology also suggest a transactional perspective in which stress-exposure contributes to depressive symptoms and, in turn, depressed individuals contribute to negative events through their own behavior . Longitudinal studies have shown support for the stress-generation model, particularly with regard to interpersonal relationships [29–31]. Factors that might contribute to the generation of stress include temperament and personality characteristics [32–33], lack of interpersonal competence [30, 34], and comorbid psychopathology [31, 35]. The reciprocal model highlights the “vicious cycle” that can occur between stress and depression, and support for this reciprocal model has been found in a few studies of youngsters [29, 35–37].
Although stress clearly plays a role in depression, individuals vary in their response to stress, and how they respond to stress can affect emotional well-being and their future adjustment [17, 38]. Several studies documented interactions between cognitive styles, such as negative attributional style or low perceived self-efficacy, and life stress in the prediction of depression in youngsters [39–42]. In addition to the cognitive adaptive styles, other types of coping mechanisms, such as behavioral styles and problem-solving skills, have been examined in relation to depression in youngsters [43–44].
Stress is also a well-known risk factor in the development of addiction and vulnerability to relapse [45–47]. Various hypotheses describe stressors as cues that elicit anticipatory alcohol/drug use responses, as stimuli that evoke negative affective states and prompt substance use to alleviate this emotional distress, or as events that place adaptational demands on an individual [48–51].
Preclinical research has indicated that acute exposure to stress enhances self-administration of addictive substances or reinstates drug-seeking behavior in animals with prior exposure [51–53]. A series of cross-sectional and longitudinal studies have identified specific stressors as predictors of substance use and abuse among adolescents [54–62].
There is substantial evidence for the association between childhood adversity and vulnerability to addictive disorders [56, 63]. Recent trauma and adverse events also increase the risk for substance abuse [54–55, 59]. Both distal and proximal events appear to have independent effects on substance abuse, with the impact of cumulative adversity on escalating substance use and addiction occurring in a dose-dependent manner, even after accounting for other variables [58, 61]. Several other factors seem to influence the effect of stress on substance use. For example, the individual’s beliefs about psychoactive substance as a stress-reducing agent, and the available coping resources and social support exert an influence on the consumption of substances during stressful situations [57, 64–70]. Also, there are individual differences in stress-reducing effects of drugs which may provide reinforcement for continued use . Inherited characteristics, including temperament/personality traits and variations in the stress-response system, have been attributed to higher reinforcement for drug use and elevated risk for SUD [51, 71–73].
Acute as well as chronic stress has been linked with both depressive and addictive disorders [19, 45–47]. Chronic stress is a common element of the environmental factors associated with both depression and substance abuse (e.g., low socioeconomic status, family disruption, and dysfunctional interpersonal relationships), and therefore could account for some variance in their co-occurrence [13, 16, 74]. In a recent study of adolescents, higher magnitude of acute stress during prospective follow-up was associated with increased vulnerability to cigarette smoking  and substance use disorders . In these reports, acute stress partly accounted for the relationship between depression and addictive disorders. Alternatively, the self-medication model suggests that some individuals use addictive substances to regulate negative affect [67, 77], particularly in the context of stressful situations . The increased prevalence of addictive disorders in individuals with depressive illness [7, 12], and the effect of depression on self-generation of stress , raises the question whether psychiatric disorders conceptualized as chronic distress states partly account for the relationship between stress and substance abuse . Additionally, as described below, disruption of the stress–mediated pathways (e.g., the LHPA system) has been documented in relation to both depression and substance abuse, which might serve as a mediator in increasing vulnerability for the comorbid disorder [13, 16, 79].
The increased vulnerability to depressive episodes and substance abuse under stressful situations may be mediated or moderated by the LHPA system . The LHPA axis is one of the physiological systems that evolved in mammals to help focus and sustain emotional, cognitive, behavioral and metabolic activity in response to conditions of threat [81–82]. Upon exposure to stress, neurons in the hypothalamic paraventricular nucleus (PVN) secrete corticotropin-releasing hormone (CRH) which then stimulates the production of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH, in turn, induces the release of glucocorticoids from the adrenal cortex. Several brain circuits modulate the release of these hormones. The amygdala and monoaminergic input from the brainstem stimulate CRH neurons in the PVN, whereas the hippocampus and the prefrontal cortex (PFC; especially the left PFC) send inhibitory signals . Glucocorticoids exert negative feedback on the LHPA axis by regulating hippocampal and PVN neurons. Prolonged glucocorticoid exposure has adverse effects on the hippocampus and PFC, resulting in impaired inhibitory control of the stress pathways [81–82].
There are individual differences in the basal activity of the LHPA system and its response to stress, and these differences are regulated by the interaction of genetic and environmental determinants . Studies on the heritability of basal LHPA activity reported that genetic factors accounted for up to 62% of the variance in cortisol levels . Moderate-to-high heritability also has been demonstrated for stress-induced activation of the LHPA axis . Specifically, a twin study observed modest heritability in cortisol responses following the first exposure to a standard psychosocial stressor (h2 < 0.33), and the heritability estimates increased following two additional repetitions of the stressor (h2 > 0.97). These data on the heritability of the LHPA axis has motivated a search for genetic variants in regulating LHPA axis dynamics and vulnerability to psychiatric disorders .
Altered LHPA activity is associated with depression, and recent evidence suggests that normalization of the LHPA system might be the final step necessary for stable remission of depressive episodes . There is, however, considerable variability in the degree and direction of LHPA dysfunction in depression [88–89]. Recent research has highlighted the importance of experiential factors in explaining the heterogeneity in LHPA dysregulation in depression [90–91]. The developing central nervous system is highly sensitive to adverse experiences, and early-life stress leads to increased stress reactivity and alterations in the aforementioned neuronal circuits that persist into adult life. The behavioral effects of sustained CRH at the extra-hypothalamic regions may lead to negative mood, contributing to the development and maintenance of depression . Research indicates, however, that the long-term mood and neurobiological changes associated with early-life stress can be modified by familial/genetic factors and the quality of subsequent environment [25, 92–94].
Evidence from preclinical and clinical research suggests that LHPA axis mediates the effects of stress exposure on drug-seeking behavior [45–47]. For instance, drug administration stimulates the release of corticotropin-releasing factor (CRF) in the amygdala which, in turn, activates mesocorticolimbic dopamine pathways that are important in the rewarding properties of addictive drugs [95–96]. With chronic drug administration, however, mesocorticolimbic dopamine pathways induce a compensatory decrease in CRF receptors ; see below for further elaboration of this theme. Other studies indicated that acute withdrawal from addictive substances following chronic administration is associated with elevated LHPA activity . These findings indicate that the LHPA system plays a role in acute as well as withdrawal effects of addictive substances.
As described, the LHPA system is involved in both depression and substance abuse. Dysregulation in this system could lead to the comorbid condition in some individuals [13, 99]. In two separate investigations, depressed adolescents who had increased nocturnal cortisol secretion, a period when the LHPA system is normally quiescent, were at increased risk for developing an addictive disorder subsequently compared with their counterparts who had a relatively normal secretory pattern [76, 79]. Also, among adolescents who experimented with alcohol and/or drugs, the progression to addictive disorder was more rapid in the depressed youth compared with non-depressed youngsters [76, 79]. It is possible that the rapid progression to substance abuse in depressed adolescents might result from the addictive drug’s effect in reducing LHPA activity.
Corticosteroids increase self-administration of addictive substances in animals [45, 100]. Reciprocally, addictive substances reduce stress-induced alterations in corticosterone and ACTH and attenuate the anxiogenic effect of CRF in animals [101–102]. In humans, alcohol or cocaine consumption has been shown to reduce plasma ACTH and cortisol responses to CRH or to other forms of stress-induction [103–104]. An alternative route to the comorbidity in which substance abuse precedes depression also can be explained through the mediating effect of LHPA system. As described previously, chronic drug administration leads to altered CRH neurotransmission [97–98]. The deleterious effects of CRH hypersecretion on mood and cognition have been described extensively [80, 87, 105].
It is postulated that the above-described actions of addictive substances on the LHPA system predispose individuals (especially depressed patients with elevated LHPA activity) 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 LHPA response to a standard psychosocial stressor in the laboratory than their counterparts without smoking history, and also compared to smokers without depression history. Longitudinal assessment of LHPA function in depressed adolescents before and after the development of addictive disorder will be helpful in clarifying whether chronic substance use down-regulates the HPA system in this population.
In the adolescent studies described above, a substantial proportion of the depressed youth with higher nocturnal cortisol secretion also had comorbid anxiety disorder [76, 79]. In contrast to this finding of an association between elevated cortisol and vulnerability to addictive disorders, Moss et al. observed lower cortisol response to an anticipated stressor in pre-adolescent boys whose biological fathers had substance abuse compared with boys whose fathers did not have an addictive disorder . The lower cortisol response during pre-adolescence was associated with “regular” substance use during adolescence . Antisocial disorders mediated the risk for substance-related problems in the “high-risk” group . Other investigators also found that antisocial behaviors/disorders contributed significant variance to the association between depressive and addictive disorders, possibly through common genetic and/or environmental factors shared by all three conditions . These findings suggest that there might be two subgroups of depressed youth at risk for developing addictive disorders, one subgroup with anxiety symptoms and high LHPA function and a second subgroup with conduct symptoms, low LHPA function and high density of substance abuse in family members. It is likely that the two groups would benefit from different treatment strategies.
If LHPA activity is involved in the pathophysiology of depressive and addictive disorders, this system can be considered as a potential target of intervention for these disorders. Research in animals suggests that the administration of CRF antagonists or anti-glucocorticoid compounds ameliorates anxiety-related symptoms associated with alcohol/drug withdrawal, and also reduces the self-administration of addictive drugs [109–112]. Anti-glucocorticoid agents and CRH antagonists appear to have anti-depressant properties, and have been tested in humans for the treatment of depression [113–114]. Antidepressant agents also are helpful in reducing substance use, particularly in those with comorbid depression [115–116]. However, some individuals with comorbid depressive and addictive disorders show a poor response to antidepressant drugs . The differential response to antidepressant compounds in patients with comorbid depressive and addictive disorder might be related to the LHPA activity.
It is postulated that specifically persons with elevated LHPA activity benefit most from antidepressant agents. Data from clinical and preclinical studies suggest that treatment with antidepressant agents reduces the responsivity to stress [114, 117]. 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 . 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 LHPA activity and stress levels.
This work was supported, in part, by grants DA14037, DA15131, DA17804, DA17805, MH01419, MH62464 and MH68391 from the National Institutes of Health, and by the Sarah M. and Charles E. Seay Endowed Chair in Child Psychiatry at UT Southwestern Medical Center. The author also would like to express gratitude to Li-Ann Chen, MA, for technical support.
Financial Disclosures: The author does not have any financial conflicts of interest.