Causes and Consequences of Diagnostic Heterogeneity in Depression: Paths to Discovering Novel Biological Depression Subtypes.

Depression is a highly heterogeneous syndrome that bears only modest correlations with its biological substrates, motivating a renewed interest in rethinking our approach to diagnosing depression for research purposes and new efforts to discover subtypes of depression anchored in biology. Here, we review the major causes of diagnostic heterogeneity in depression, with consideration of both clinical symptoms and behaviors (symptomatology and trajectory of depressive episodes) and biology (genetics and sexually dimorphic factors). Next, we discuss the promise of using data-driven strategies to discover novel subtypes of depression based on functional neuroimaging measures, including dimensional, categorical, and hybrid approaches to parsing diagnostic heterogeneity and understanding its biological basis.

Functional and Optogenetic Approaches to Discovering Stable Subtype-Specific Circuit Mechanisms in Depression.

Background: Previously, we identified four depression subtypes defined by distinct functional connectivity alterations in depression-related brain networks, which in turn predicted clinical symptoms and treatment response. Optogenetic functional magnetic resonance imaging offers a promising approach for testing how dysfunction in specific circuits gives rise to subtype-specific, depression-related behaviors. However, this approach assumes that there are robust, reproducible correlations between functional connectivity and depressive symptoms-an assumption that was not extensively tested in previous work.

Default mode network mechanisms of transcranial magnetic stimulation in depression.

Background: Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks-the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)-are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response.