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 SSDs.

Methods: Data from three studies: two neuroimaging studies and a randomized repetitive transcranial magnetic stimulation (rTMS) trial were analyzed (n=157 SSDs) to assess brain-behavior relationships. Partial Least Squares Correlation (PLSC) investigated associations between resting-state functional connectivity and depressive and negative symptoms. Secondary analysis 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 Default Mode Network (DMN), Frontoparietal Network (FPN), and Cingulo-Opercular Network (CON). LV2 related negative symptoms (no depressive symptoms) via negative associations, especially between FPN and CON, but also between DMN with FPN and CON. LV3 related a guilt and early wakening depression factor via negative rather than positive associations to 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 to the bilateral dorsolateral prefrontal cortex (DLPFC) reduced general depressive but not guilt-related or negative symptoms.

Conclusions: Our findings clearly differentiate the neural circuitry underlying depressive and negative symptoms, and even 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, rTMS to the bilateral DLPFC is worth exploring further for general depressive symptoms in people with SSDs.

Citation: Gallucci, J., Yu, J.-C., Oliver, L.D., Nakua, H., Zhukovsky, P., Dickie, E.W., Daskalakis, Z.J., Foussias, G., Blumberger, D.M., Hawco, C., Voineskos, A.N., 2024. Neural circuitry and therapeutic targeting of depressive symptoms in schizophrenia spectrum disorders. Am. J. Psychiatry 181, 910–919.