We propose that the complexity of regulatory interactions modulating brain neurochemistry and behavior is such that multiple stable responses may be supported, and that some of these alternate regulatory programs may play a role in perpetuating persistent psychological dysfunction. To explore this, we constructed a model network representing major neurotransmission and behavioral mechanisms reported in literature as discrete logic circuits. Connectivity and information flow through this biobehavioral circuitry supported two distinct and stable regulatory programs. One such program perpetuated a depressive state with a characteristic neurochemical signature including low serotonin. Further analysis suggested that small irregularities in glutamate levels may render this pathology more directly accessible. Computer simulations mimicking selective serotonin reuptake inhibitor (SSRI) therapy in the presence of everyday stressors predicted recidivism rates similar to those reported clinically and highlighted the potentially significant benefit of concurrent behavioral stress management therapy.

Toole, J & Rice, Mark & Craddock, Travis & Nierenberg, Barry & Klimas, Nancy & Fletcher, Mary & Zysman, Joel & Morris, Mariana & Broderick, Gordon. (2018). Breaking Away: The Role of Homeostatic Drive in Perpetuating Depression. Methods in Molecular Biology (Clifton, N.J.) April 29, 2018. 1781. 121-144. 10.1007/978-1-4939-7828-1_8.