Neurosurgical treatment of bipolar depression: defining treatment resistance and identifying surgical targets

Objectives: Bipolar disorder (BD) is a complex psychiatric disorder that is often underrecognized, misdiagnosed, and challenging to detect. During the past decade, substantial progress has been made in the development of pharmacotherapeutic and psychosocial interventions for various phases of BD. Notwithstanding these developments, the majority of BD individuals, and particularly patients with bipolar depression, receiving guideline concordant care do not experience syndromal or functional recovery, underscoring the need for novel treatments. Early success with deep brain stimulation (DBS) in the treatment of major depressive episodes as part of major depressive disorder (MDD) has provided the impetus to explore its application in other treatment-resistant psychiatric disorders, notably BD. Herein, we provide the rationale for employing DBS as an alternative treatment avenue in individuals with bipolar depression. Methods: We conducted a PubMed literature search, focusing on English language articles beginning in 1950 to the present day, and employed the following search terms: bipolar disorder, neurosurgery, deep brain stimulation, neuroimaging, and circuitry. Search results were then manually reviewed and relevant articles selected for analysis. Relevance was determined by author consensus and overall manuscript quality. We also reviewed articles on currently available treatment options for BD in order to develop a coherent and practical definition of treatment resistance with a focus on surgical intervention. Results: Several lines of evidence indicate that although mania is the defining feature of bipolar I disorder, depressive symptoms and episodes dominate the longitudinal course, account for most of the illness burden including premature mortality, and are least responsive to contemporary treatments. Disease models in bipolar depression implicate abnormalities in the structure and function of discrete neural circuits that subserve affective processing and cognitive function with the subgenual cingulate cortex occupying a central role. Modulation of the cingulate cortex with DBS in treatment-resistant MDD populations has proven to offer acute and sustained antidepressant effects, suggesting possible benefits for other mood disorder populations. Conclusions: A surgical intervention for bipolar depression would not only be a proof of concept regarding disease modeling but also an important and novel treatment avenue for individuals affected by bipolar depression.