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Epidemiologic Reviews Advance Access published online on July 10, 2008
Epidemiologic Reviews, doi:10.1093/epirev/mxn003
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Epidemiologic Reviews © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Article

Comorbid Forms of Psychopathology: Key Patterns and Future Research Directions

Magdalena Cerdá1,2,3, Aditi Sagdeo2 and Sandro Galea2,3,4

1 Robert Wood Johnson Foundation Health and Society Scholars Program, Department of Epidemiology, University of Michigan, Ann Arbor, MI
2 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
3 Center for Urban Epidemiologic Studies, New York Academy of Medicine, New York, NY
4 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY

Correspondence to Dr. Magdalena Cerdá, Department of Epidemiology, School of Public Health, University of Michigan, 109 South Observatory, 3639 SPH Tower, Ann Arbor, MI 48109-2029 (e-mail: mcerda{at}umich.edu or mcerda{at}nyam.org).

accepted for publication April 29, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 REVIEW OF THE LITERATURE
 FINDINGS
 CONCLUSIONS
 REFERENCES
 
The purpose of this review is to systematically appraise the peer-reviewed literature about clustered forms of psychopathology and to present a framework that can be useful for studying comorbid psychiatric disorders. The review focuses on four of the most prevalent types of mental health problems: anxiety, depression, conduct disorder, and substance abuse. The authors summarize existing empirical research on the distribution of concurrent and sequential comorbidity in children and adolescents and in adults, and they review existing knowledge about exogenous risk factors that influence comorbidity. The authors include articles that used a longitudinal study design and used psychiatric definitions of the disorders. A total of 58 articles met the inclusion criteria and were assessed. Current evidence demonstrates a reciprocal, sequential relation between most comorbid pairs, although the mechanisms that mediate such links remain to be explained. Methodological concerns include the inconsistency of measurement of the disorders across studies, small sample sizes, and restricted follow-up times. Given the significant mental health burden placed by comorbid disorders, and their high prevalence across populations, research on the key risk factors for clustering of psychopathology is needed.

anxiety • comorbidity • conduct disorder • depression • social conditions • substance-related disorders


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
REVIEW OF THE LITERATURE
 FINDINGS
 CONCLUSIONS
 REFERENCES
 
Psychiatric comorbidity is the presence, simultaneously or in sequence, of two or more disorders in an individual within a certain time period (1, 2). Psychiatric comorbidity is a prevalent phenomenon across age groups and types of populations (3–5). The Epidemiologic Catchment Area (ECA) Survey found that 35 percent of respondents with at least one lifetime disorder had one or more additional disorders during their lifetime (6); the National Comorbidity Survey Replication found that 27.7 percent of the respondents had two or more disorders during their lifetime (7).

Understanding psychiatric comorbidity has important research, clinical, and nosologic implications. From a research perspective, epidemiologic research conducted on isolated disorders may underestimate the burden imposed by mental health problems because this group may represent a select portion of the population that suffers from psychiatric disorders (8). Documenting the relation between key psychiatric disorders over the life course can provide a more accurate assessment of the psychiatric burden experienced by different population groups.

With respect to clinical concerns, comorbidity is associated with more severe psychiatric symptoms, more functional disability, longer illness duration, less social competence, and higher service utilization (9–11). Given the high prevalence of comorbidity and its clinical consequences, research efforts that aim to better understand the patterns of comorbidity over time are clearly essential to help guide its prevention.

Investigation into the distribution of comorbidity across key psychiatric disorders can also help us elucidate the structure of phenotypic psychopathology. The cooccurrence of disorders has called into question the validity of current categorical classifications of mental disorders, with critics suggesting that a dimensional approach to classifying comorbid disorders is more appropriate (12). Studying comorbid patterns can thus help us discern commonalities and distinctions in the developmental pathways of comorbid disorders and in the etiologic profiles of each comorbid disorder—elements that will provide the basis to understand whether the disorders are different expressions of the same underlying disturbance or are distinct disorders in their own right (13).

This review aims to examine current knowledge on the epidemiology of clustered forms of psychopathology over the life course, focusing on four of the most common mental disorders: anxiety, depression, conduct disorder, and substance abuse. According to the National Comorbidity Survey Replication, 28.8 percent of the US population suffered from an anxiety disorder sometime in their life, whereas 20.8 percent suffered from a mood disorder, 14.6 percent had a substance use disorder, and 9.5 percent presented symptoms of conduct disorder (7). The cooccurrence of these conditions has been consistently documented in clinical and population samples (5).

This paper systematically reviews comorbidity studies within a life course framework, focusing exclusively on prospective population-based studies. This presents a novel approach to address comorbidity and enables us to study similarities and differences in comorbidity patterns at key life stages as well as to understand how the normative developmental trajectories of disorders may influence the magnitude of comorbidity from childhood to adulthood. Focusing on population-based studies overcomes one of the key limitations of clinical studies: selection bias that may determine the patterns of comorbidity observed in the sample.


   REVIEW OF THE LITERATURE
TOP
 ABSTRACT
 INTRODUCTION
 REVIEW OF THE LITERATURE
FINDINGS
 CONCLUSIONS
 REFERENCES
 
This review encompasses the peer-reviewed literature published between 1970 and 2007. We limited our review to these years to reflect current thinking about psychiatric comorbidity and to include studies that use methods considered standard today. The literature reviewed was identified through the Social Science Citation Index and Science Citation Index, and it covered studies about concurrent and sequential comorbidity between anxiety, depression, substance use/abuse, and conduct disorder. We restricted our review to longitudinal, population-based studies that provided information about the temporal associations between disorders. As stated by Kraemer et al. (14), cross-sectional studies, particularly those that use lifetime prevalence with mixed-age samples to estimate comorbidity, run the risk of identifying instances of "pseudocomorbidity" when no real comorbidity exists.

The literature on comorbidity is vast and encompasses many different fields, from medicine to public health to psychology. We restricted our review to psychiatric definitions of the disorders because a wider review would have been beyond the scope of this project. For example, for conduct disorder, we considered measurement of symptoms or diagnoses of conduct disorder, oppositional defiant disorder, and antisocial personality disorder but not aggression or delinquency. The search was limited to English-language studies in biomedical research. Keywords and terms used for the search included primarily the following: 1) for substance abuse: substance abuse, alcohol abuse, drug abuse, cannabis, cocaine, heroin, street drugs, smoking, injection drug use; 2) for depression: depression, depression symptomatology, depression symptoms, mood disorders; 3) for conduct disorder: conduct disorder, antisocial personality disorder, antisocial, opposition defiant disorder, externalizing behavior/disorder; 4) for anxiety disorder: anxiety, anxiety symptomatology, anxiety symptoms, internalizing disorder; and 5) for comorbidity: comorbidity, joint trajectories, discordant trajectories, concurrent, cooccurrence, risk pathways, chain of risk, launch factors, transitions, risk pathways.


   FINDINGS
TOP
 ABSTRACT
 INTRODUCTION
 REVIEW OF THE LITERATURE
 FINDINGS
CONCLUSIONS
 REFERENCES
 
In this paper, we review concurrent and sequential comorbidity between the four disorders, and we present available data on concurrent comorbidity, sequential comorbidity, and contributions of each disorder to the deflection of developmental trajectories of the other three disorders. This review covers 58 studies, including those using child and adolescent samples, and then adult samples, to present available knowledge on comorbidity at key life stages. The original search provided 103 articles, of which 45 were removed because of the absence of a prospective study design. Although studies such as Kessler et al.'s (15) on the National Comorbidity Survey Replication or the cross-national comparison of comorbidity conducted by Merikangas et al. (16) offer groundbreaking data on the distribution of comorbid disorders in population-based samples, they were not included because they used retrospective measures of disorder onset in cross-sectional study designs.

The studies reviewed here (summarized in tables 1 and 2) approach the issue of causality between comorbid disorders by investigating the relative timing of the onset of each disorder and the impact that the prevalence of one disorder has on the course of the other. The strength of the causal link depends on whether the cooccurrence of the disorders persists after accounting for common risk factors (3, 17).


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  		TABLE 1. Population studies on comorbid patterns between substance abuse, anxiety, depression and conduct disorder among children and adolescents

 

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  		TABLE 2. Population studies on comorbid patterns between substance abuse, anxiety, depression and conduct disorder among adults

 
Anxiety and substance use

The evidence on the link between anxiety and substance use is mixed: most studies have been cross-sectional or retrospective in design and used dimensional rather than diagnostic measures of anxiety. The few existing prospective, diagnostic studies (18–22) propose several alternative causal associations between anxiety and substance abuse: 1) individuals with an anxiety disorder may be more likely to develop or sustain a substance use disorder, in part as a way to manage the symptoms of anxiety (21, 23, 24); 2) having an anxiety disorder may reduce or delay the onset of behavioral problems such as substance abuse either because of the high level of anxious social cognitions that serve as a reminder of the negative consequences of the behavior or because of behavioral inhibition that results from anxiety disorders (25); 3) substance use may exert physiologic effects that increase vulnerabilities to anxiety disorders; or 4) a third variable may promote the development or maintenance of both (20).

Children and adolescents.. Childhood and adolescence is a critical time to investigate the timing of onset of the comorbid disorders since anxiety has a relatively early age at onset (26). Few studies have looked prospectively at the link between anxiety and substance abuse among the younger age groups. Several studies have found support for the "self-medication" thesis: that persons with anxiety use alcohol and drugs to suppress their anxiety symptoms (18, 22, 27–29). Costello et al. (18) found that anxiety predicted later substance use disorders among a representative population sample of adolescent girls, but not among boys. However, several studies have also found support for the reverse association, in which substance dependence promotes the development of anxiety (20, 21). A particularly compelling study that followed children over 21 years and obtained prospective reports of anxiety and substance dependence found that the association between anxiety and substance dependence was largely or entirely noncausal, while substance dependence predicted anxiety disorder at follow-up. Finally, some evidence also exists for a negative relation between anxiety and substance use: Pardini et al. (25) followed the Pittsburgh Youth Study sample of boys from early adolescence to young adulthood, and they found that higher levels of anxiety/withdrawal were inversely related to symptoms and diagnoses of alcohol use disorder; a cohort study of a representative population sample aged 9–13 years at baseline found that anxiety predicted a later onset of smoking (30).

Lack of conclusive evidence is due to the heterogeneity of substance use and anxiety subtypes examined in the few available population-based studies: associations may differ between subtypes. Kaplow et al. (28) proposed that, in studies that consider anxiety as a general syndrome and fail to differentiate within its dimensions, the opposing functions of different types of anxiety may offset each other, resulting in null findings. In fact, Kaplow et al. found opposing effects for generalized anxiety disorder and separation anxiety disorder: whereas generalized anxiety disorder was positively associated with alcohol use initiation, separation anxiety disorder resulted in a lower risk of onset of alcohol use. A study of 2,548 adolescents in Germany also found that the association depended on the type of anxiety disorder examined; although the seven lifetime anxiety disorders taken as a set predicted subsequent onset of hazardous use, abuse, and persistence, only panic and social phobia were independent predictors of hazardous use and abuse and the persistence of an alcohol use disorder (22).

Adults.. Studies conducted among adults provide support for a potential reciprocal relation between anxiety and substance abuse. A study of 454 college students followed over 7 years, for example, found that having an anxiety disorder was associated with 3.5–5 times higher odds of developing a new alcohol dependence, while the odds of developing a new anxiety disorder were about four times higher for those diagnosed with alcohol dependence in previous years (24). The direction of the relation between anxiety and substances may depend on the type of substance. The Kushner et al. study (24) was limited by use of a select population that may have a more similar mental health status than the general population. In a study of a random sample of the adult population, however, Newcomb et al. (31) also found a bidirectional relation between anxiety and substance use: polydrug problems in young adulthood increased anxiety in adulthood, but anxiety was actually associated with fewer cocaine problems later in life—possibly because individuals who experience high levels of arousal would be less likely to use a drug that exacerbated that arousal.

Depression and substance abuse

Depressive symptoms are associated with substance use disorders throughout adolescence and adulthood (25). As with anxiety, the directionality and causal nature of the association remains in question: depression and substance use disorders may be linked through common confounding factors, or the association may be causal—either that alcohol and illegal substances are used as a form of self-medication to manage symptoms of depression or that substance use may increase vulnerability to depression through behavioral changes or neurophysiologic alterations (32).

Children and adolescents.. Several studies have reported that depression and substance abuse tend to cooccur in adolescence (18, 19, 21, 33–35). In a study of high school students in western New York, Windle and Davies (35) found that 24–27 percent of adolescents identified as depressed also met the criteria for heavy drinking, whereas Rao et al. (34) found that 21.1 percent of adolescent women with depression also had a substance use disorder. The nature of the association between depression and substance abuse among adolescents remains in question. Several studies found that depressed adolescents were more vulnerable to substance use; this association has been found for marijuana (27), smoking (33), alcohol abuse (25), and substance abuse problems (36). Fergusson et al. (33) and Pardini et al. (25), authors of two of the most promising studies on issues of depression–substance abuse comorbidity among adolescents, highlight the lack of conclusive evidence on this issue. Fergusson et al. followed a birth cohort of 1,265 children from birth to age 21 years and found that major depression was associated with increased rates of daily smoking and nicotine dependence, although the association could be due to confounders that affected the development of both outcomes. Pardini et al. also followed up 506 boys until young adulthood and found that increased depression in early adolescence was associated with more alcohol use disorder symptoms and alcohol abuse and dependence diagnoses by young adulthood, but only for boys with high levels of conduct problems.

Evidence also exists to support the hypothesis that substance use may increase vulnerability to depression. Hayatbakhsh et al. (21) followed a comparable cohort of 3,239 children up to age 21 years and found that symptoms of depression in childhood did not predict use of marijuana, but use of marijuana was associated with depression. A small study of 155 women aged 17–19 years also found that substance use disorders predicted worse depression symptoms at follow-up, but depression did not predict substance use disorders at follow-up (34).

Adults.. Comorbidity between depression and substance use persists until adulthood: there is a two- to fourfold higher risk of developing one disorder if the other has occurred (37, 38). As has been detected in adolescence and young adulthood, support also exists for the use of alcohol and illegal substances as a way to manage depressive symptoms in adulthood (37, 39–41). Several studies also document a reciprocal association between the two, as was the case with anxiety (42, 43). Gilman and Abraham (42) followed up participants from the Epidemiologic Catchment Area Survey and found that, although the odds of alcohol dependence increased in relation to baseline depressive symptoms, the odds of major depression also increased in response to the number of alcohol symptoms and a diagnosis of alcohol dependence.

Anxiety and depression

High rates of comorbidity have been found between anxiety and depression. An important fraction of depression cases also present symptoms of anxiety, to the point that Krueger et al. (8) proposed that "pure" cases of depression or anxiety would be unrepresentative of the entire spectrum of these disorders. In a 40-year follow-up of levels of anxiety and depression, the probability of having anxiety for those who already suffered from depression ranged from 0.54 to 0.98, while, for those who did not suffer from depression, the probability ranged from 0.03 to 0.10 (44). Anxiety and depression function in a cohesive manner and have been classified as internalizing disorders, which are stable over time (8, 45). The comorbidity of these disorders has raised some controversy. While some argue that anxiety and depression are distinct disorders with different etiologic profiles and high levels of cooccurrence, others interpret the overlap as indicative of similar psychopathologic processes and shared risks or as different manifestations of the same disease (26, 46).

Children and adolescents.. Strong heterotypic continuity exists between depression and anxiety from childhood to adulthood (2, 18, 26, 47–51). In the Great Smoky Mountains study that followed a cohort of children aged 9–13 years for 5 years, anxiety predicted depression and vice versa, even when controlling for current comorbidity (18). A gender-specific analysis indicated, however, that the associations independent of current comorbidity persisted among girls only. Another study that followed those aged 9–18 years over 9 years found that overanxious disorder in adolescence was associated with adult major depression, while major depression in adolescence predicted generalized anxiety in adulthood (50). These associations were independent of gender.

The degree of comorbidity between depression and anxiety may vary as a function of age. Wittchen et al. (26) followed 3,021 respondents aged 14–24 years at baseline over 4 years and found that, although only 9 percent of those with an anxiety disorder at ages 14–17 years also had major depressive episodes, the proportion was considerably higher among those aged 18–24 years. Moreover, depression increased considerably among those with anxiety disorder at final follow-up: almost two thirds of cases were comorbid with major depression. The variation in comorbidity by age might be a function of age at onset of the two disorders; whereas anxiety disorders tend to start in childhood and early adolescence, depressive disorders increase in late adolescence and continue to rise in those aged 20 years or older (2, 26, 52).

The frequency and type of comorbidity differ by disorder. Wittchen et al. (26) found that the odds ratio for presenting major depression at follow-up ranged from 1.7 for specific phobia to 3.4 for panic disorder and 3.9 for generalized anxiety disorder. Pine et al. (50) also found that major depression predicted generalized anxiety disorder but not simple or social phobia.

Comorbidity is related to symptom severity, degree of impairment, course, and outcome. Wittchen et al. (26) found, in a study of 3,021 respondents aged 14–24 years at first interview followed over 4–5 years, that the number of anxiety disorders present, persistence of anxious avoidance behavior, and degree of psychosocial impairment were the characteristics most strongly associated with development of secondary depression. Repetto et al. (51) confirmed, in a more restricted study of African-American adolescents at risk of school dropout, that adolescents who presented consistently high levels of depressive symptoms were more likely to present a higher number of anxiety symptoms.

Adults.. Most studies have identified anxiety as a primary disorder that precedes secondary depression, perhaps related to the difference in ages at onset as well as to the higher degree of stability of anxiety. A critical review of longitudinal studies of representative samples, however, indicates that this question remains unsettled and may depend on life stage examined, length of study follow-up, and type of anxiety disorder studied. A follow-up of a representative population sample over 10 years from early adolescence to young adulthood found that social anxiety disorder was temporally primary relative to depression in most of the cases and that the risk of subsequent depression was twofold for individuals with social anxiety disorder in comparison to those without social anxiety disorder (53). However, a study that followed up a birth cohort until age 32 years (54) found that major depression preceded generalized anxiety disorder almost as often as generalized anxiety disorder preceded major depression. Two studies in older adulthood found that anxiety preceded depression within short time intervals. A study of older Swedish twins found that over two 3-year intervals, anxiety symptoms led to depressive symptoms, while the opposite did not occur (46). The same phenomenon was reported among the elderly for depression and generalized anxiety disorder: a follow-up of a sample of community-living elderly over 3 years found that generalized anxiety disorder either remitted or progressed into depression or mixed anxiety/depression, whereas subjects with depression or depression/generalized anxiety disorder were unlikely to develop noncomorbid generalized anxiety disorder at follow-up (12).

Comorbid disorders may be more stable than "pure" cases of disease. A study that followed adults aged 19–20 years at baseline over 15 years found that substantial transitions occurred from anxiety and depression alone to comorbidity; an average of 21 percent of those with depression alone and 24 percent of those with anxiety alone developed comorbid anxiety and depression at baseline, and, once comorbidity developed, the recurrence of either disorder alone was much lower (55).

Specificity also exists in the degree of comorbidity between different types of anxiety disorders and depression. Generalized anxiety disorder has been identified as the type of anxiety disorder most closely connected with major depression (54). Wilhelm et al. (56) followed a cohort of subjects involved in teacher training in 1978–1993 and found a stronger association between number of depressive episodes and panic disorder, generalized anxiety disorder, and agoraphobia than between number of depressive episodes and either simple or social phobia. Gregory et al. (49) followed a representative birth cohort from ages 11 to 32 years and found that adult anxiety cases were more likely to have experienced juvenile depression than those without adult anxiety, except for specific phobia and panic disorder cases.

The specific nature of the associations between depression and anxiety may depend on certain interpersonal features of anxiety disorders. Two studies have found, for example, that behavioral inhibition (53) and avoidance of expressing emotions (57), rather than lack of assertion or interpersonal dependency, explained part of the transition from social anxiety disorder to depression. Grant et al. (57) hypothesized that inhibition of strong emotions to significant others as a strategy to maintain associations may lead to a loss of self, which may increase depressive symptoms.

Conduct disorder and substance use

Conduct disorder has been defined in the Diagnostic and Statistical Manual of Mental Disorders: DSM-IV as a pervasive pattern of aggressive and deceptive behavior that begins in adolescence (58). Conduct disorder and substance use have been classified under the same latent construct of externalizing disorders (8). Measelle et al. (36) found, for example, that an externalizing factor accounted for 79 percent and 95 percent of the baseline levels of antisocial behavior and substance abuse, respectively. Both disorders tend to increase through late adolescence and peak in young adulthood, and they are more prevalent among males (59). Several studies have proposed that a major fraction of the association can be attributed to common genetic factors (45).

Children and adolescents.. Most studies on conduct disorder and substance use concern adolescence and young adulthood. Similar to anxiety and depression, the directionality of the link between these conditions and conduct seems to vary across studies (18, 30, 49, 60–62). Cohen et al. (60) followed up 749 adolescents from ages 13 to 24 years and found that participants with conduct disorder in early adolescence experienced significantly elevated rates of alcohol abuse/dependency and marijuana use disorder between early adolescence and young adulthood. Kratzer and Hodgins (63) found a similar phenomenon when they followed an unselected birth cohort from pregnancy to 30 years of age: childhood conduct problems were associated with a higher risk of severe substance abuse. White et al. (64) moved beyond examining the influence of conduct disorder on levels of substance abuse and investigated its influence on both mean levels of use and change in use over time. Although conduct disorder was associated with higher overall levels of alcohol and marijuana use throughout the study period, it predicted change in levels of alcohol use only. Participants with higher levels of conduct disorder began adolescence with higher levels of alcohol use, but their level of alcohol use grew slower than that among participants who had lower initial levels of conduct disorder—possibly because of regression to the mean.

Some of the most promising studies on comorbidity have investigated the impact that conduct disorder and substance abuse have on the developmental patterns of the comorbid disorder. Conduct disorder, for example, has been found to play an important role in the shift from substance use to substance use disorders (30, 65). The Great Smoky Mountains study found that conduct disorder, particularly at earlier ages (14 and 15 years), was the strongest psychiatric predictor of the transition from substance use to a disorder (62). Substance abuse can play a role in crime desistance in young adulthood (45, 66). Hussong et al. (66) found that substance abuse may exert both proximal and distal effects on antisocial desistance over young adulthood: 1) substance abuse early in young adulthood can slow an individual's pattern of criminal desistance relative to the lifetime pattern of criminality; and 2) substance abuse can result in "time-specific" elevations in antisocial behavior relative to an individual's own antisocial trajectory. A community sample of female adolescents aged 13–15 years found that, although initial levels of antisocial behavior predicted increases in substance abuse, substance abuse also predicted slower deceleration in antisocial behavior (36); a study of female and male twin pairs reported that youths with late-onset and persisting antisocial behavior had higher rates of substance use than youths in groups without a history of antisocial behavior or a pattern of antisocial desistance (67).

Adults. We found one study that examined the influence of conduct disorder on substance abuse but used retrospective reports of age at onset for comorbid disorders. The National Comorbidity Survey Replication indicated that lifetime conduct disorder was associated with 5.9 times higher odds for substance use disorders (58). Conduct disorder was more likely to occur before substance use disorders 88.5 percent of the time. Although both active and remitted conduct disorder were significant predictors of substance use disorders, the risk of substance use disorders was significantly higher for those with active conduct disorder. The persistent effect of remitted conduct disorder may indicate that conduct disorder is a risk marker for unmeasured common causes of substance use disorders or that active conduct disorder has long-lasting consequences that persist even after the disorder has remitted. The higher risk associated with active conduct disorder may also, however, point to a causal role that conduct disorder plays in related disorders.

Conduct disorder and anxiety and depressive disorders

The limited number of studies identified that addressed the connections between conduct disorder and either depression or anxiety led us to group the review of these disorders into one section. Factor analyses of internalizing disorders, notably anxiety and depression, and externalizing disorders, of which conduct disorder constitutes an important fraction, have identified distinct developmental patterns for these two groups of disorders but have also detected a correlation across time between the two types of disorders (8, 45). Little is understood about the mechanisms that may connect conduct disorder with mood disorders. Conduct disorder may disrupt interpersonal functioning, contributing to greater conflict with parents and peers and greater social rejection and academic failure, which may generate a sense of repeated failure and feelings of anxiety or depression (68). At the same time, depression and anxiety may impede social development and generate interpersonal conflict, which may contribute to the onset of conduct problems. Common etiologic factors may also underlie both types of disorders (69).

The developmental course of conduct disorder tends to be intertwined with internalizing problems, particularly depression (36). For example, a study involving a community sample of female adolescents followed from early to late adolescence found that initial depressive and antisocial behavior symptoms predicted future increases in the other: while initial levels of antisocial symptoms predicted increases in depressive symptoms, initial levels of depression predicted a slower deceleration in antisocial problems (36). Early antisocial problems have also been found to predict depressive symptoms in adulthood (69–71). Kim et al. (70) found that, among young men followed from early adolescence to young adulthood, early antisocial behavior was associated with depressive symptoms in adulthood; Silberg et al. (71) detected a correlation between early conduct problems and later depression among adolescent female twin pairs. The link may be explained by a failure model, whereby early developmental failures associated with antisocial behavior increase vulnerability to depressive symptoms (36).

Some evidence also exists of a link between conduct disorder and specific types of anxiety (49, 58, 61, 72). A birth cohort of a representative sample followed from ages 11 to 32 years showed an association between a juvenile history of conduct disorder and posttraumatic stress disorder at age 32 years (49). A longitudinal study of a population sample assessed from ages 14 to 33 years also found that the presence of antisocial personality disorder traits at ages 14–22 years was associated with a higher risk of anxiety disorders by age 33 years, most particularly for agoraphobia (72). The National Comorbidity Survey Replication found mixed evidence about the temporal order between conduct disorder and anxiety: conduct disorder occurred after specific and social phobia but prior to all other types of anxiety disorders (58). The findings from the National Comorbidity Survey Replication require replication within a longitudinal study because they are based on retrospective reports of age at onset.

Putting it all together: internalizing and externalizing disorders as predictors of substance abuse

Most studies on comorbidity assess the interaction between pairs of disorders concurrently and over time, but they fail to determine how clusters of disorders may promote onset of psychopathology. One exception has been the area of youth risk behaviors; selected studies have investigated the relative influence of externalizing and internalizing disorders on the prevalence of substance abuse or conduct disorder. Adolescence has long been considered the stage at which risk behaviors such as delinquency and substance use are initiated and when disorders such as substance abuse become consolidated (36, 73). It is a time when multiproblem youth emerge, characterized by persistent substance use, persistent delinquency, and/or persistent internalizing problems (74). This peak in comorbidity has motivated studies of the intersections between multiple forms of psychopathology in adolescence and young adulthood.

Loeber et al. (74), for example, used longitudinal data from three samples of the Pittsburgh Youth Study to examine the cooccurrence of persistent substance use with delinquent and persistent internalizing problems in boys aged 7–18 years. The joint occurrence of mood dysregulation, in the form of internalizing problems, and behavioral dysregulation, in the form of delinquency, emerged in preadolescence and played a significant role in the persistence of substance use. During adolescence, however, only persistent delinquency predicted persistent substance use. Another publication using the Pittsburgh Youth Study expanded this investigation by examining how the cooccurrence of conduct disorder and depressive symptoms identified high-risk youth (25). The authors found that higher levels of depression led to the development of alcohol use disorder symptoms but among only those subjects who had high levels of early conduct disorder symptoms. The interaction between depression and conduct disorder may indicate a need to manage negative affective states without a high regard for social norms, or it may indicate a subgroup of individuals at particularly high risk of developing a severe form of substance use.

Summary

Prospective population studies that investigate the sequential links between comorbid disorders remain scarce. The bulk of prospective studies assess the influence of the prevalence of one disorder on the future prevalence of the comorbid disorder. Few studies actually move beyond this topic to investigate the influence that comorbidity may have on changes in the state of psychopathology, that is, in shifts from persistence to desistance, or from substance use to abuse, or from disorder-free status to onset. Such information would provide initial evidence of the specific mechanisms by which disorders influence each other. Moreover, differences in the duration of study follow-up, choice of age groups, and selections of measurement instruments and diagnostic criteria make comparability across studies more difficult.

Despite these limitations, several points emerge from our review of population-based studies of comorbid disorders. The concurrent and sequential links among conduct disorder, substance use/abuse, anxiety, and depression are neither random nor a result of bias from help-seeking clinical samples. The nature of comorbidity is specific to the type of disorder under study: evidence exists for a reciprocal relation between substance use and depression, anxiety, and conduct disorder, while the bulk of studies on depression and anxiety indicate that anxiety may precede onset of depression. The studies that address comorbidity of conduct disorder with anxiety and depression indicate that conduct disorder may precede these mood disorders, but the paucity of studies that test a reciprocal association impede us from making conclusive statements.

The mechanisms that connect disorders remain in question. Three hypotheses link comorbid disorders: 1) the association may be indirectly causal, so that a primary disorder may exert neurophysiologic, individual, or social changes that increase vulnerability to the secondary disorder; 2) disorders may be directly linked, so a primary disorder may, for example, exert neurophysiologic changes that contribute to onset of the secondary disorder; or 3) a set of common risk factors, such as common genes or the experience of childhood trauma, may explain the connection between two disorders. However, these hypotheses are difficult to distinguish from one another. For example, a social factor such as affiliation with deviant peers could predispose adolescents to both substance use disorder and conduct disorder (hypothesis 3), but conduct disorder could also lead to association with deviant peers, which would contribute to substance use disorder (hypothesis 1). A review of the risk factors associated with the initiation and maintenance of comorbid conditions can help illuminate the mechanisms that underlie comorbidity in psychopathology.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 REVIEW OF THE LITERATURE
 FINDINGS
 CONCLUSIONS
REFERENCES
 
Understanding patterns of comorbidity is essential in order to evaluate psychiatric nosology and fully understand the developmental trajectories of key forms of psychopathology. To date, a number of studies have shown that anxiety, depression, substance abuse, and conduct disorder cluster in individuals across the life course. This critical review is one of the first focused on population-based, longitudinal studies of comorbidity between these four key disorders.

The four psychiatric disorders we reviewed have been classified under two latent constructs: externalizing and internalizing disorders. Although factor analyses indicate a higher correlation between disorders within each construct, clustering also exists between externalizing and internalizing disorders. Approaching first the issue of internalizing disorders, anxiety and depression function jointly from childhood to adulthood. Comorbidity seems to be a function of age; it increases from late adolescence onward, possibly because of the later age at onset of depression relative to anxiety. Comorbidity also depends on the type of anxiety disorder concerned: several studies found a higher clustering between major depressive disorder and generalized anxiety disorder, for example, than with other anxiety disorders. In terms of externalizing disorders, conduct disorder and substance abuse show a strong reciprocal link, particularly in adolescence and young adulthood. Conduct disorder and substance abuse not only influence the onset and prevalence of the other but also influence the shift between developmental stages of the other disorder, that is, in shifts from substance use to a substance use disorder, or in the likelihood of moving from conduct disorder to desistance.

Studies have documented a link between disorders across the internalizing/externalizing divide. Studies indicate that the relation between substance abuse and anxiety or depression is reciprocal: substance abuse alone or depression/anxiety alone predicts onset of the other disorder. The impact of anxiety on substance abuse remains in question: anxiety disorders have been associated with both a higher and a lower likelihood of substance use disorders. The direction of the association may depend on the type of anxiety disorder and substance in question. Research has also addressed the question of clustering between conduct disorder and anxiety/depression, although research is less developed in this area. Depression and conduct disorder play a role in shaping the developmental trajectory of the other. Initial levels of depression have been associated with a slower rate of desistance from conduct disorder, while conduct disorder predicted increases in depressive symptoms from adolescence to adulthood. The links between anxiety and conduct disorder are less understood. The few existing studies focus on adolescence and young adulthood and have indicated that initial levels of conduct disorder were associated with higher levels of anxiety.

Existing research on comorbidity has a number of strengths. Prospective studies linking the presence of one disorder to onset of the other, as well as examining the influence that a disorder may have on developmental shifts in comorbids, are growing, and they offer promise in enabling us to understand the specific ways in which comorbid disorders are linked over the life course. Moreover, research is shifting from a focus on a pair of disorders to a more holistic approach that analyzes how clusters of disorders interact with each other. We think this line of investigation will be key in understanding the complexity of comorbid relations and in estimating the health burden that results from multiple comorbidities.

At the same time, the epidemiologic literature falls short in its consideration of key issues within comorbidity research. First, although early research in this area is promising, a need exists for study designs that make it possible to test the timing and specific nature of comorbid relations—that is, shifting from merely investigating whether disorders are "associated" with each other to understanding the ways that disorders deflect a comorbid pair from specific stages in its normative trajectory. This process involves studying the influence of disorders in promoting qualitative shifts in the comorbid disorder, from alcohol use initiation to abuse to dependence, for example. It also implies accounting for the spectrum of relevant comorbid disorders within the same study to control for spurious associations and understand how the presence of a third disorder may influence the causal link between comorbid pairs.

Second, our understanding is limited in terms of the specific comorbid patterns between subtypes of disorders. Although we recognize that specific types of anxiety disorders, for example, may show different comorbidity patterns with depression, or that alcohol abuse may have different levels of comorbidity with anxiety than illicit drug abuse does, the scarcity of available, population-based, longitudinal studies on each specific subtype combination prevented us from making critical distinctions between comorbid patterns. Studies that compare comorbid patterns between disorder subtypes across key developmental stages, from childhood to adulthood, offer a promising way to address this gap.

Third, one of the key questions that remains relates to the causes of comorbidity: the direction and mechanisms underlying causal links, as well as the potential spurious nature of such links. Investigating factors at multiple levels of influence as potential confounders, mediators, triggers, or modifiers of comorbid associations would enable us to identify groups at highest risk of the presentation of multiple disorders and distinguish features of the individual and his or her environment that are most malleable to preventive intervention. Moreover, it would enable us to establish whether associations between comorbid disorders are truly causal or are spurious phenomena resulting from common risk factors. Little effort has been invested in systematically documenting the associations between these disorders across different age groups or in reviewing the factors associated with the cooccurrence of such comorbid forms of psychopathology. Multilevel multivariate models that consider the joint influence of factors at the individual, family, and community levels on a set of comorbid disorders provide a promising avenue to attack the question of common versus distinct etiologies of comorbid disorders.


   ACKNOWLEDGMENTS
 
This project was funded by the Robert Wood Johnson Foundation Health and Society Scholars Program (M. C.) and the National Institutes of Health (grants DA 017642, DA 022720, MH 08259, and MH 078152 (S. G.)).

Conflict of interest: none declared.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 REVIEW OF THE LITERATURE
 FINDINGS
 CONCLUSIONS
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