American Journal of Respiratory and Critical Care Medicine

Risk behaviors, including tobacco, alcohol, and drug use, are common in adolescents and young adults. Those who engage in one risk behavior are likely to engage in additional health risk behaviors, and as the number of risk behaviors increase, depression comorbidity emerges. For young people with chronic illness, risk behavior and depression are also common. There is some evidence that both depression and risk behavior are associated with nonadherence to medications, poor treatment outcomes, and death. The relationship between depression and asthma may involve more than one causal pathway and includes the possibility that depression can lead to a sense of hopelessness that erodes adherence and other health-promoting behavior, or that depression impacts asthma directly by altering the immune system. An assessment of the interplay between risk behavior, depression, adherence, and asthma can add important new information to our understanding about how to identify and treat those at greatest risk for poorly controlled disease and asthma-related death. New behavioral studies must overcome the shortcomings frequently seen in previous research and include well-designed and controlled investigations using valid behavioral measures of risk behavior, mood disorder, and adherence; recruitment that includes sufficient numbers of subjects and gives careful consideration of selection bias; and employment of multivariate data modeling to allow for simultaneous statistical examination of multiple relationships.

An association between risk behavior, mood disorder, and asthma morbidity in adolescents and young adults has been identified but is not clearly understood. Both depression and nonadherence complicate asthma treatment, and together they create a particularly dangerous combination. Risk behaviors, including smoking and substance abuse, are also present in young people with asthma; they may increase in the presence of depression and are associated with poor treatment adherence. Competing causal models have been hypothesized. Asthma may cause depression, or depression may cause nonadherence and consequently worsening symptoms. Other pathways may be involved, including depression-induced changes in inflammatory processes resulting in worsening asthma, or the presence of a third, possibly genetic, factor explaining the comorbidity of psychologic and physical illness. This article reviews the literature describing these associations, examines competing causal models, and offers recommendations for ongoing research strategies.

Among adolescents and young adults in the United States, both depression and risk-taking behavior are common. The Centers for Disease Control and Prevention have for over a decade conducted large national telephone surveys of risk behaviors among adolescents and young adults. Responses to the Youth Risk Behavior Surveillance System and the College Health Risk Behavior Survey reveal that risk behaviors involving sex, cigarette smoking, alcohol and substance use, driving, or poor diet are remarkably common (1, 2). For example, 18- to 22-yr-old respondents indicated that 42% had engaged in binge drinking, 52% had unprotected sex, 31% smoked cigarettes, 27% had driven a vehicle after drinking alcohol, and 10% “seriously considered attempting suicide” in the prior year (1). As suggested by these reports, risk-taking behaviors are often accompanied by depression. Psychologically distressed adolescents are more likely to smoke (3). A telephone survey of 4,023 families found that substance abuse and dependence were associated with post-traumatic stress disorder and major depressive episode among adolescent girls and boys (4). A national survey of 2,624 adolescents conducted by the Office for National Statistics in the United Kingdom found that smoking, drinking, and marijuana use were strongly associated with psychiatric diagnosis. One-third of those adolescents demonstrated depression, although the association with risk-taking behavior was not limited to those with depression (5). Risky behaviors generally do not occur in isolation; alcohol and other substance abuse, smoking, peer conflict, and school failure all tend to co-occur along with troubled parent–adolescent relationships and mood disorder (6).

Young people with chronic illness also engage in risk-taking behavior. Adolescents and young adults with chronic disease, including life-threatening conditions, manage surprisingly often to join their healthy peers who engage in risk-taking behavior. Surveys of risk behavior in chronically ill young people, however, generally report that the frequency of such behaviors is less than that typically occurring among healthy peers. In a survey of 116 adolescents with cystic fibrosis and 205 with sickle cell disease, investigators found that sexual intercourse, substance use, and delinquent behaviors occurred in both disease groups, although less commonly than in the healthy control groups matched for age, race, and sex (7). In a study of 19- to 26-yr-old patients with diabetes (n = 57), daily smoking was frequent (37%) but less than in the group of matched healthy control subjects (50%) (8). Twenty-eight percent of adolescents with myelomeningocele reported themselves to be sexually active, less than among healthy control subjects but still more than reported in two other studies (9). Studies of adolescents and young adults with asthma have examined few risk behaviors with the exception of smoking. Despite the widespread understanding that smoking is particularly detrimental for people with asthma, smoking rates among adolescents and young adults with asthma are frequently equal to rates in the general population of youth, and in one report were higher among youth with asthma than without (10). In a group of patients with asthma exacerbations requiring a trip to 1 of 64 emergency departments, 33% of patients with asthma aged 18 to 29 were daily smokers (11).

Mood disorders are more common in patients with asthma and negatively correlated with treatment adherence. Numerous studies have examined the association between depression and treatment nonadherence in adults (12), although much less is known about young people with asthma. In one study of 23 pediatric renal dialysis patients, psychologic distress was associated with decreased adherence and illness control as reflected by serum phosphorus and calcium levels (13). Depression in patients' mothers has also been linked to decreased adherence and medical outcomes in their children (14, 15).

Depression, family conflict, and nonadherence can be a particularly lethal combination for children and adolescents with asthma. Strunk and colleagues, evaluating the circumstances surrounding asthma death in children and adolescents, examined the cases of 21 patients who later died of their asthma with a stepwise discriminant analysis to evaluate the predictive role of 57 physiologic and psychologic variables (16). The emerging asthma-death risk profile included families with histories of conflict between parents and their adolescent and with medical staff; depressive symptoms in the adolescent; family dysfunction, including parental psychopathology, intense marital conflict, or alcoholism; disregard of asthma symptoms; and deficient self-care and adherence. Results from other studies, generally based on smaller samples, have similarly concluded that deaths from pediatric asthma are often associated with denial of symptoms, poor asthma management, including medication nonadherence, and increased psychologic dysfunction (17, 18).

That young people with chronic illness who are taking risks with their health by smoking or abusing alcohol would also fail to follow their treatment regimen should not be surprising. Treatment nonadherence is yet another risk behavior reflecting a general disregard for personal health, particularly where young people adopt a “nothing to lose” attitude about their future (19). A study of 286 Latino adolescents, aged 13 to 18, found that poor adherence to treatment of latent tuberculosis was associated with risk behaviors including fighting, school expulsion, and use of alcohol, cigarettes, and marijuana (20). Adolescents with asthma in Denmark who smoked cigarettes were twice as likely to fail to take daily asthma medication as those who did not smoke (21).

A number of depression studies, most of which have not included an assessment of adherence, have established an association between asthma and mood disorders (2225). The relationship may be simple: the suffering caused by inadequately controlled illness can bring distress and may, for some, induce psychologic disorders. This is the first causal pathway depicted in Figure 1. However, a careful examination of the data supporting an association between mood disorders and asthma suggests a more complex relationship. If asthma symptoms create psychologic distress, then logically a clear dose–response relationship would be expected between asthma severity and psychologic symptoms. In fact, some studies have reported that children with severe asthma demonstrate more psychologic difficulty than those with milder illness (26, 24). Still, others have found no linear relationship among asthma symptoms, pulmonary functions, and psychologic measures (27, 28). In a meta-analysis that included 26 studies of behavioral problems in children and adolescents with asthma, behavioral problems were found to increase with disease severity, but the relationship was weak and much overlap occurred between the general categories of mild, moderate, and severe asthma (24). Just as asthma may cause depression or anxiety, depression may provoke asthma symptoms through poor illness self-management, including nonadherence (29), seen in the second causal pathways in Figure 1. However, when behaviors and psychologic symptoms are carefully assessed, a convincing relationship between adherence and symptoms does not emerge. Controlling for confounding factors in a fixed-effects regression model, Goodwin and colleagues (29) showed that depression and anxiety were not directly, causally linked to asthma but rather that both the disease and emotional distress were likely linked to other life factors in adolescents and young adults with asthma. Specifically, the associations between mood disorder and asthma appeared to be related to family risk factors including socioeconomic advantage, family conflict, and parental adjustment.

In the third causal pathway, depression may introduce physiologic changes that increase inflammation and symptoms (Figure 1). This possibility has been examined in young children but not in adolescents with asthma. For example, early caregiver stress and quality of caregiving are associated with alterations in immune system, resulting in an increased likelihood that young children will develop asthma (3033). Distressed parent–child relationships in early childhood predict onset of wheezing by age 5 (34). In one component of an investigation of the impact of psychologic stress on airway inflammation, animals exposed to stressors demonstrated increased inflammatory cell mediators, including interleukin 6 (IL-6), IL-9, and IL-13 (35). The interaction of various mechanisms (e.g., oxidative stress pathways, glucocorticoid resistance, nerve–mast cell interactions, intestinal dysbiosis, cytokines, and neuropeptides) produced by cells both within and outside the immune system may interactively link stress to allergic sensitization and asthma (36).

In the fourth causal pathway (Figure 1), a shared, genetic link may exist between asthma, atopy, and mood disorder (36). This genetic vulnerability hypothesis finds some support in a report of increased prevalence of affective disorders in first-degree relatives of children with severe asthma (37), absence of a causal association between mood and asthma (29), and confirmation of a shared genetic etiology in the statistical modeling of atopic and depressive symptoms in a sample of 1,337 monozygotic and 1,506 dizygotic Finnish twins (25). Such findings remain very preliminary and await further confirmation but nonetheless raise awareness that investigators must consider alternative possibilities before assuming that depression in a patient with asthma is caused by the burden of their illness or that behavioral changes account for the impact of depression on symptom control.

The collective evidence available to date does not fully support any of the causal pathways in Figure 1. Data are insufficient to clearly establish whether depression or other forms of psychopathology in young people with asthma cause nonadherence or other behaviors reflecting disregard for health and safety. In a study of 2,039 adolescents with asthma and 2,039 matched control subjects from the National Longitudinal Study of Adolescent Health, 44% of both groups reported having ever smoked and more than half of each currently smoked. Although the incidence of smoking among the adolescents with asthma is alarming, depression did not increase the odds of smoking, whereas it did increase the odds that the adolescents would attempt to quit, usually unsuccessfully (38). The incidence of other risk behaviors, such as drug use, driving without a seatbelt, and dangerous sexual practices among adolescents with asthma, and the relationship among these behaviors, depression, and nonadherence warrant examination. Although it is generally assumed that psychologic distress, and more specifically depression, undermines disease control by causing the patient to be less adherent, the causal sequence involving depression, adherence, and health outcomes requires further investigation. Some evidence contradicts the model in which adherence behavior is the link between depression and poor outcomes. Maternal depression scores but not the measure of medication adherence were significantly predictive of asthma morbidity and emergency department visits, suggesting that depression may act on asthma independently of medication adherence (14). Another study of 367 young adults with diabetes assessed adherence by self-report and through an automated data collection system for refills of hypoglycemic medication (39). Higher levels of depressive symptoms were associated with poorer adherence to the diet and with more days of interruption of hypoglycemic medication therapy. No association emerged between symptom severity and adherence, indicating that the impact of depression on adherence was not large enough to undermine disease control. Strunk and colleagues' (16) study indicates that depression may be one part of a complex set of variables working against good asthma management, including discouragement, conflict, substance abuse, failure to reliably use controller medication, and disregard of worsening symptoms. The demonstration that adherence to placebo is also predictive of better outcomes suggests that other factors, including the beneficial effects of positive outlook and the impact of optimism on immune functioning, may also be mediating the relationship between mood and outcome (39). Therefore, the analysis of datasets that include psychologic and outcome data must determine whether the association between depression and disease control is weakened or becomes nonsignificant after adjusting for level of adherence. If so, then the argument is strengthened that adherence behavior, and not other factors, is the likely link between depression and outcome.

In young people with asthma, it is likewise probable that depression and risk taking, separately or in combination, account for some of the variance associated with treatment outcome in addition to medication adherence. The model that includes depression, risk taking, and adherence therefore is expected to explain more of disease outcome—including asthma symptoms, prednisone bursts, albuterol use, urgent care visits, physician contacts, hospitalizations, and emergency room visits—than any of the three variables alone. This interactive model including the three variables has not been adequately tested in any cohort of adolescents and young adults with asthma.

Four causal pathways that may explain the relationships among depression, risk behavior, nonadherence, and symptom control in young people with asthma have been proposed. None fully accounts for the current body of evidence. It is likely that the correct causal model will encompass several pathways. For example, severe illness likely does cause depression. At the same time, individuals with preexisting depression who develop a chronic illness may have more difficulty following a daily treatment plan. Several recommendations for further research are offered (Table 1). Multivariate analyses used in large studies afford the opportunity to critically examine the relationships between risk behavior, depression, adherence, and asthma. For example, examination of the three-way relationships including depression, adherence, and symptom control can determine whether depression contributes to declining control because of, or independently from, treatment nonadherence. Such studies require sufficient sample size and careful consideration of selection biases that particularly impact psychologic measures. Caution must be exercised with studies conducted in convenience samples of patients available in specialty clinics. Although such cohorts may provide a suitable base for clinical trials, frequent visitors to asthma centers may include a higher percentage of patients with a psychologic disorder, regardless of the severity of their disease, and may not provide an accurate representation of the psychologic and behavioral traits of the general population of patients with asthma (40). Comparison of results across studies is aided by inclusion of a detailed description of recruitment procedures and the demographic and psychologic characteristics of the study cohort. Studies consisting exclusively of nonvalidated questionnaires mailed en mass to large groups of asthma registry patients, typically achieving a partial response rate and providing no objective validation of asthma, are similarly of limited value. Behavioral studies of young people with asthma have often focused on mood disorder, adherence, or risk behavior, but seldom all three. Disentangling the complex interplay between these factors requires the use of the best available instruments for assessment of each behavioral factor, including objective measures of adherence or risk behavior and well-standardized psychologic instruments. Objective measures of adherence, including microchip-equipped inhalers or pharmacy refill surveys, generally produce greater accuracy than patient reports (41). Risk behaviors will be disclosed by young patients only when they are assured of the confidentiality of the information they provide. In particular, without assurance that such information will not be passed on to the patient's parent or physician, underreporting of risk behavior is almost certain.

TABLE 1. RECOMMENDED FEATURES IN FUTURE BEHAVIORAL RESEARCH


1. Recruit a participant cohort of sufficient size to allow multivariate modeling
2. Include measures of mood, adherence, and risk behavior within the same study
3. Consider problems of sampling bias and carefully describe the study cohort
4. Avoid data collection relying exclusively on mailed questionnaires
5. Utilize standardized and validated psychologic measures
6. Evaluate adherence with objective measures
7. Assure confidentiality to participants reporting risk behaviors

Implications of this research for clinical practice are apparent even without greater clarification of the causal relationships. Successful treatment of asthma in young people is likely to be impeded when depression and other risk behaviors are present, particularly in the face of severe asthma. Regardless of the cause-and-effect sequence, an observation of risk-taking behaviors, such as smoking or recreational drug use, in a young person with asthma should prompt further assessment for mood disorder and poor treatment adherence and be followed by appropriate action. Patients presenting with a mood disorder require referral for psychologic intervention without which improvement in mood, behavior, or asthma control are unlikely.

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Correspondence and requests for reprints should be addressed to Bruce G. Bender, Ph.D., Professor and Head, Pediatric Behavioral Health, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail:

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