The Application of Vagus Nerve Stimulation and Deep Brain Stimulation in Depression

Despite the progress in the pharmacotherapy of depression, there is a substantial proportion of treatment-resistant patients. Recently, reversible invasive stimulation methods, i.e. vagus nerve stimulation (VNS) and deep brain stimulation (DBS), have been introduced into the management of treatment-resistant depression (TRD). VNS has already received regulatory approval for TRD. This paper reviews the available clinical evidence and neurobiology of VNS and DBS in TRD. The principle of VNS is a stimulation of the left cervical vagus nerve with a programmable neurostimulator. VNS was examined in 4 clinical trials with 355 patients. VNS demonstrated steadily increasing improvement with full benefit after 6–12 months, sustained up to 2 years. Patients who responded best had a low-to-moderate antidepressant resistance. However, the primary results of the only controlled trial were negative. DBS involves stereotactical implantation of electrodes powered by a pulse generator into the specific brain regions. For depression, the targeted areas are the subthalamic nucleus, internal globus pallidus, ventral internal capsule/ventral striatum, the subgenual cingulated region, and Received: November 9, 2010 Accepted after revision: January 23, 2011 Published online: July 29, 2011 Pavel Mohr, MD, PhD Prague Psychiatric Center Ustavni 91 CZ–181 03 Praha 8 (Czech Republic) Tel. +420 266 003 360, E-Mail mohr @ pcp.lf3.cuni.cz © 2011 S. Karger AG, Basel 0302–282X/11/0643–0170$38.00/0 Accessible online at: www.karger.com/nps VNS and DBS in Depression Neuropsychobiology 2011;64:170–181 171 ‘years lost due to disability’ across the world, in both lowand middle-income countries [3] . The WHO projects that, according to the measure ‘disability-adjusted life year’, depression will rise from number 3 among the 10 leading causes of burden of diseases in 2004 to the global top position in 2030. The financial costs of depression in 2000 were USD 83.1 billion per year in the US [4] and over GBP 9 billion in the UK [5] . Despite the progress in the pharmacotherapy of depression, there is still a substantial and growing proportion of patients who are not responding to available antidepressants, do not tolerate drug therapy, are partial responders, display residual symptoms, or are labeled as treatment resistant. Treatment-resistant depression (TRD) affects from 15% up to one third of depressive patients [6, 7] . TRD is defined as an episode of depression that does not respond to 1 or typically 2 or more adequate treatment trials. TRD is not a nosological entity, and most likely does not share a common etiology and pathophysiological mechanisms [8] . Treatment-refractory patients are quite a heterogeneous group not responding or not tolerating treatment due to different reasons. In addition to the recommended pharmacological strategies how to overcome treatment resistance (e.g. switch to a different class of antidepressant, augmentation, or combination) [6] , other therapeutic options, nonpharmacological interventions, are tested [8] . Modern stimulatory methods were introduced into psychiatry in the 20th century: ‘shock therapy’, insulininduced coma, Metrazol-induced convulsion, electroconvulsive therapy (ECT), and nonspecific and targeted psychosurgery [9, 10] . The renewed interest in stimulatory methods came along with the safer interventions allowing for precise targeting of key structures and with a better understanding of underlying neurobiological mechanisms of psychiatric disorders. In addition to the traditional ECT, repetitive transcranial magnetic therapy, magnetic seizure therapy, vagus nerve stimulation (VNS), and deep brain stimulation (DBS) have become alternative nonpharmacological treatment options for many psychiatric patients. Other experimental procedures, such as epidural prefrontal cortical stimulation, are under investigation [11] . VNS and DBS were adopted from neurology. The rationale behind the first use of VNS and DBS in affective disorders was originally based on anecdotal observations and case reports of neurological patients who improved independently of seizure reduction. Additional lines of reasoning stem from the administration of anticonvulsants and induced seizures (ECT) in the therapy of mood disorders. In this paper, we review the current state of the clinical evidence, the neurobiological basis, and evaluate the potential for clinical application of VNS and DBS in depression. Vagus Nerve Stimulation VNS has been available for treatment-resistant epilepsy since the 1990s; for depression, it was first registered in Europe and in Canada in 2001, and in the US in 2005. VNS is approved for patients with chronic or recurrent depression who failed to respond to at least 4 antidepressant interventions, but patients are not required to have failed to respond to ECT [12] .