Background The purpose of this review is to systematically appraise the peer-reviewed literature about the genetic and environmental determinants of psychiatric comorbidity, focusing on four of the most prevalent types of psychopathology: anxiety disorders, depression, conduct disorder and substance abuse. Methods We summarize existing empirical research on the relative contribution that genetic, nonshared and shared environmental factors make to the covariance between disorders, and evidence about specific genes and environmental characteristics that are associated with comorbidity. Results 94 articles met the inclusion criteria and were assessed. Genetic factors play a particularly strong role in comorbidity between major depression and generalized anxiety disorder or posttraumatic stress disorder, while the non-shared environments makes an important contribution to comorbidity in affective disorders. Genetic and non-shared environmental factors also make a moderate-to-strong contribution to the relationship between CD and SA. A range of candidate genes, such as 5HTTLPR, MAOA, and DRD1-DRD4, as well as others implicated in the central nervous system, has been implicated in psychiatric comorbidity. Pivotal social factors include childhood adversity/ life events, family and peer social connections, and socioeconomic and academic difficulties. Limitations Methodological concerns include the use of clinical case-control samples, the focus on a restricted set of individual-level environmental risk factors, and restricted follow-up times. Conclusions Given the significant mental health burden associated with comorbid disorders, population-based research on modifiable risk factors for psychiatric comorbidity is vital for the design of effective preventive and clinical interventions.

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.