Evolving Refractory Major Depressive Disorder Diagnostic and Treatment Paradigms: Toward Closed-Loop Therapeutics

Current antidepressant therapies do not effectively control or cure depressive symptoms. Pharmaceutical therapies altogether fail to address an estimated 4 million Americans who suffer from a recurrent and severe treatment-resistant form of depression known as refractory major depressive disorder. Subjective diagnostic schemes, differing manifestations of the disorder, and antidepressant treatments with limited theoretical bases each contribute to the general lack of therapeutic efficacy and differing levels of treatment resistance in the refractory population. Stimulation-based therapies, such as vagus nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation, are promising treatment alternatives for this treatment-resistant subset of patients, but are plagued with inconsistent reports of efficacy and variable side effects. Many of these problems stem from the unknown mechanisms of depressive disorder pathogenesis, which prevents the development of treatments that target the specific underlying causes of the disorder. Other problems likely arise due to the non-specific stimulation of various limbic and paralimbic structures in an open-loop configuration. This review critically assesses current literature on depressive disorder diagnostic methodologies, treatment schemes, and pathogenesis in order to emphasize the need for more stringent depressive disorder classifications, quantifiable biological markers that are suitable for objective diagnoses, and alternative closed-loop treatment options tailored to well-defined forms of the disorder. A closed-loop neurostimulation device design framework is proposed, utilizing symptom-linked biomarker abnormalities as control points for initiating and terminating a corrective electrical stimulus which is autonomously optimized for correcting the magnitude and direction of observed biomarker abnormality.