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Mechanisms of Drug Action

Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications

Abstract

Although deep brain stimulation (DBS) is an established treatment choice for Parkinson’s disease (PD), essential tremor and movement disorders, its effectiveness for the management of treatment-resistant depression (TRD) remains unclear. Herein, we conducted an integrative review on major neuroanatomical targets of DBS pursued for the treatment of intractable TRD. The aim of this review article is to provide a critical discussion of possible underlying mechanisms for DBS-generated antidepressant effects identified in preclinical studies and clinical trials, and to determine which brain target(s) elicited the most promising outcomes considering acute and maintenance treatment of TRD. Major electronic databases were searched to identify preclinical and clinical studies that have investigated the effects of DBS on depression-related outcomes. Overall, 92 references met inclusion criteria, and have evaluated six unique DBS targets namely the subcallosal cingulate gyrus (SCG), nucleus accumbens (NAc), ventral capsule/ventral striatum or anterior limb of internal capsule (ALIC), medial forebrain bundle (MFB), lateral habenula (LHb) and inferior thalamic peduncle for the treatment of unrelenting TRD. Electrical stimulation of these pertinent brain regions displayed differential effects on mood transition in patients with TRD. In addition, 47 unique references provided preclinical evidence for putative neurobiological mechanisms underlying antidepressant effects of DBS applied to the ventromedial prefrontal cortex, NAc, MFB, LHb and subthalamic nucleus. Preclinical studies suggest that stimulation parameters and neuroanatomical locations could influence DBS-related antidepressant effects, and also pointed that modulatory effects on monoamine neurotransmitters in target regions or interconnected brain networks following DBS could have a role in the antidepressant effects of DBS. Among several neuromodulatory targets that have been investigated, DBS in the neuroanatomical framework of the SCG, ALIC and MFB yielded more consistent antidepressant response rates in samples with TRD. Nevertheless, more well-designed randomized double-blind, controlled trials are warranted to further assess the efficacy, safety and tolerability of these more promising DBS targets for the management of TRD as therapeutic effects have been inconsistent across some controlled studies.

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Acknowledgements

The Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). Its research is supported by grants from CNPq (JQ), FAPESC (JQ); Instituto Cérebro e Mente (JQ) and UNESC (JQ). JQ is a 1A CNPq Research Fellow. Dr Jair C Soares has received grants/research supports from the Pat Rutherford, Jr Endowed Chair in Psychiatry (JCS), John S Dunn Foundation from United States (JCS) and NIMH (R01MH085667-01A1; JCS), Stanley Medical Research Institute, and NIH.

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JCS received research/grant support from Bristol-Meyers Squibb, Forest Laboratories, Merck, Elan Pharmaceuticals, J&J, Stanley Medical Research Institute and has served as a consultant for Pfizer, Abbot and Astellas Pharma. The remaining authors declare no conflict of interest.

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Dandekar, M., Fenoy, A., Carvalho, A. et al. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry 23, 1094–1112 (2018). https://doi.org/10.1038/mp.2018.2

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