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


  • RSM has received research grants from Eli Lilly & Co., Janssen-Ortho, Shire, and AstraZeneca; and is on the advisory board for AstraZeneca, Bristol-Myers Squibb, the France Foundation, GlaxoSmithKline, Janssen-Ortho, Solvay/Wyeth, Eli Lilly & Co., Organon, Lundbeck, Biovail, Pfizer, Shire, and Schering-Plough. PG has received research funds from Eli Lilly & Co; and is on speaker/advisory boards for AstraZeneca and St. Jude Medical. SHK has received grant funding from AstraZeneca, Brain Cells, Inc., Eli Lilly & Co., GlaxoSmithKline, Janssen Ortho, Lundbeck, and St. Jude Medical; and is an advisor or consultant for Lundbeck, Pfizer, Servier, AstraZeneca, Biovail, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Janssen, St. Jude Medical; and Wyeth Pharmaceuticals. AML is a Tier I Canada Research Chair in Neuroscience; and is a consultant for Medtronic, St. Jude Medical, Eli Lilly & Co., and Boston Scientific. NL and CT have no conflicts of interest to disclose.

Corresponding author:
Nir Lipsman, M.D.
Division of Neurosurgery
Toronto Western Hospital
University Health Network
399 Bathurst Street, 4W-447
Toronto, Ontario
M2R 5S8, Canada
Fax: 416-603-5298


Lipsman N, McIntyre RS, Giacobbe P, Torres C, Kennedy SH, Lozano AM. Neurosurgical treatment of bipolar depression: defining treatment resistance and identifying surgical targets.
Bipolar Disord 2010: 12: 691–701. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S.

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.