Adults with chronic depression report experiencing higher levels of maltreatment and adversity in childhood than do persons with nonchronic depression.5657 For example, in a sample of 395 outpatients with chronic depression and 809 patients with nonchronic depression, Wiersma and colleagues58 reported that the chronically depressed group reported significantly higher rates of childhood emotional neglect and psychological, physical, and sexual abuse, with odds ratios ranging from 1.6 to 2.0. Differences between chronic and nonchronic depression in early adversity persist even after controlling for comorbid psychiatric disorders36 and parental depression.59
Most studies rely on retrospective assessments of childhood events conducted many years later, thus raising concerns about recall biases. However, studies using official records of childhood maltreatment have reported similar findings.60
Familial Aggregation and Genetics
First-degree relatives of probands with chronic depression exhibit higher rates of both chronic and nonchronic depressive disorders than do relatives of healthy controls.35,61 More importantly, there is also evidence of specificity of familial transmission. In both clinical and community samples, first-degree relatives of probands with chronic depressions have higher rates of chronic depression than do relatives of probands with nonchronic MDD.35,61 For example, in the Genetics of Recurrent Depression Study, Mondimore and colleagues62 found that 38% of relatives of patients with chronic depression had a history of chronic depression compared to 20% of relatives of patients with recurrent episodic MDD.
There are no twin and adoption studies of chronic depression with reasonable sample sizes, and few genetic linkage and association studies have specifically examined chronic depression phenotypes. However, several recent studies have suggested that there may be an interaction between childhood maltreatment and a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) that is specific to chronic, but not episodic, depression. In two independent samples, Uher et al.63 found that individuals with two short 5-HTTLPR alleles who also had a history of childhood maltreatment had a particularly heightened risk for “persistent depression.” In contrast, there was no effect for single-episode depression. “Persistent depression” was defined as meeting criteria for MDD during the past year in at least two of four assessments conducted over 7-14 years; hence, this category could also include some recurrent depressions. However, two other studies suggest that the effect may be specific to chronic depression. Brown and colleagues64 found a significant interaction between 5-HTTLPR genotype and childhood maltreatment for chronic depression but not new depressive onsets. Moreover, Fisher et al.65 failed to find a 5-HTTLPR by childhood maltreatment interaction in a large sample of individuals with recurrent MDD or no history of psychopathology. Taken together, these findings suggest that chronic depression may be characterized by a specific set of interacting genetic and environmental processes that are distinct from single-episode and recurrent depressions.
In conclusion, there appears to be a number of clinical and etiologically relevant differences between chronic and nonchronic depressions that are consistent with the possibility that chronicity may provide a useful means to reduce the heterogeneity of nonpsychotic depressive disorders. However, one striking gap in this literature is the lack of studies examining neurobiological correlates of the persistent/nonpersistent distinction.42 Because heterogeneity is a problem that plagues neurobiological research in depression,5 this may be a particularly fruitful area to pursue.