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Other Sources of Heterogeneity

Persistent depression is itself undoubtedly heterogeneous.22 Two potential sources of heterogeneity are childhood maltreatment and familial loading for chronic depression because these variables have been associated with differences in stress reactivity,66 course,67 and treatment response.56,68

One particularly well-established source of heterogeneity within chronic depression is another course-related feature: age of onset. Indeed, early-late onset is a modifier for persistent depression in DSM-5. A number of studies have reported that in patients with chronic depression, an early onset (< 21 years) is associated with higher rates of anxiety, substance use, and personality disorders; a history of childhood adversity; and a greater family history of mood disorder compared to a later onset.69,70

However, the early-late onset distinction is not specific to chronic depression. Age at onset appears to have similar correlates in MDD in general,71 bipolar disorder,72 and many non-mood disorders.73 Thus, age at onset is another course-based characteristic that is useful in reducing heterogeneity across the mood disorders—and perhaps for mental disorders in general.

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