Neural Circuitry and Therapeutic Targeting of Depressive Symptoms in Schizophrenia Spectrum Disorders.

Objective: Conceptual similarities between depressive and negative symptoms complicate biomarker and intervention development. This study employed a data-driven approach to delineate the neural circuitry underlying depressive and negative symptoms in schizophrenia spectrum disorders (SSDs).

Methods: Data from three studies were analyzed (157 participants with SSDs) to assess brain-behavior relationships: two neuroimaging studies and a randomized trial of repetitive transcranial magnetic stimulation (rTMS). Partial least squares correlation (PLSC) was used to investigate associations between resting-state functional connectivity and depressive and negative symptoms. Secondary analyses of rTMS trial data (active, N=37; sham, N=33) were used to assess relationships between PLSC-derived symptom profiles and treatment outcomes.

Results: PLSC identified three latent variables (LVs) relating functional brain circuitry with symptom profiles. LV1 related a general depressive symptom factor with positive associations between and within the default mode network (DMN), the frontoparietal network (FPN), and the cingulo-opercular network (CON). LV2 related negative symptoms (no depressive symptoms) via negative associations, especially between the FPN and the CON, but also between the DMN and the FPN and the CON. LV3 related a guilt and early wakening depression factor via negative rather than positive associations with the DMN, FPN, and CON. The secondary visual network had a positive association with general depressive symptoms and negative associations with guilt and negative symptoms. Active (but not sham) rTMS applied bilaterally to the dorsolateral prefrontal cortex (DLPFC) reduced general depressive but not guilt-related or negative symptoms.

Conclusions: The results clearly differentiate the neural circuitry underlying depressive and negative symptoms, and segregated across the two-factor structure of depression in SSDs. These findings support divergent neurobiological pathways of depressive symptoms and negative symptoms in people with SSDs. As treatment options are currently limited, bilateral rTMS to the DLPFC is worth exploring further for general depressive symptoms in people with SSDs.