Elsevier

Brain Stimulation

Volume 9, Issue 6, November–December 2016, Pages 897-904
Brain Stimulation

Five-Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression

https://doi.org/10.1016/j.brs.2016.06.054Get rights and content

Highlights

  • Five year follow-up on epidural prefrontal cortical stimulation treatment for depression.

  • Long-term safety and efficacy outcomes were assessed.

  • All 5 patients tolerated therapy at 5 years, 3/5 continued to be in remission.

  • Five adverse events resulting in suicidal ideation and/or hospitalization occurred.

Abstract

Background

Epidural prefrontal cortical stimulation (EpCS) represents a novel therapeutic approach with many unique benefits that can be used for treatment-resistant depression (TRD).

Objective

To examine the long-term safety and efficacy of EpCS of the frontopolar cortex (FPC) and dorsolateral prefrontal cortex (DLPFC) for treatment of TRD.

Methods

Adults (N = 5) who were 21–80 years old with severe TRD [failure to respond to adequate courses of at least 4 antidepressant medications, psychotherapy and ≥20 on the Hamilton Rating Scale for Depression (HRSD24)] were recruited. Participants were implanted with bilateral EpCS over the FPC and DLPFC and received constant, chronic stimulation throughout the five years with Medtronic IPGs. They were followed for 5 years (2/1/2008–10/14/2013). Efficacy of EpCS was assessed with the HRSD24 in an open-label design as the primary outcome measure at five years.

Results

All 5 patients continued to tolerate the therapy. The mean improvements from pre-implant baseline on the HRSD24 were [7 months] 54.9% (±37.7), [1 year] 41.2% (±36.6), [2 years] 53.8% (±21.7), and [5 years] 45% (±47). Three of 5 (60%) subjects continued to be in remission at 5 years. There were 5 serious adverse events: 1 electrode ‘paddle’ infection and 4 device malfunctions, all resulting in suicidal ideation and/or hospitalization.

Conclusion

These results suggest that chronic bilateral EpCS over the FPC and DLPFC is a promising and potentially durable new technology for treating TRD, both acutely and over 5 years.

Introduction

Depression is a severely disabling disorder of extreme sadness or melancholia that affects a person's activities of daily life as well as social functioning [1]. Depression is a major public health problem and is the second leading cause of disability worldwide [2]. Although pharmacotherapeutic approaches to depression treatment are effective for some, they have demonstrated limited success in large clinical studies [3]. When depression fails to remit after adequate treatment, it is labeled treatment-resistant depression (TRD) [4]. TRD represents a spectrum that is often quantified by the number and type of failed adequate trials of treatments. This typically ranges from a minimum of a single failed trial of pharmacological monotherapy to more treatment-resistant forms of TRD that fail numerous trials of pharmacological monotherapies as well as pharmacological augmentation strategies, and to the most resistant forms of TRD that fail treatment with electroconvulsive therapy (ECT) [5].

Approximately 72% of patients will fail to remit after treatment with a single pharmacological monotherapy and thus meet criteria for some degree of TRD [6]. For these patients, an interventional psychiatric approach may be considered [7], [8], with several options being available, depending in part on how many and what types of adequate trials of treatments that the patient has received. For example, transcranial magnetic stimulation (TMS) [9] is FDA-approved to treat patients who have failed treatment with a single antidepressant medication, and although no FDA recommendations currently exists for ECT, typical guidelines limit use to patients who have failed one or more antidepressant trials and/or require a rapid antidepressant response [10], [11]. In contrast, the FDA recommends treatment with vagal nerve stimulation (VNS) only for patients who have failed treatment with at least 4 antidepressants or ECT [12]. Unfortunately, many patients experience a particularly resistant form of TRD with no current FDA-approved treatment options once all treatments have failed [8]. For these patients with the most treatment-resistant form of TRD, a more invasive approach using devices implanted into the encephalon is warranted. For example, deep brain stimulation (DBS) of several structures, including the ventral striatum [13] and subgenual cingulate, is currently being developed for TRD [14]. Although DBS was initially a promising treatment option for these patients [14], large, controlled clinical trials have failed thus far to demonstrate efficacy [15], [16].

One promising target for the treatment of patients with highly treatment-resistant TRD using implanted devices is the prefrontal cortex [17], [18]. Studies have suggested that in depression, the left dorsolateral prefrontal cortex (DLPFC) is hypoactive and the right DLPFC may be hyperactive [19]. The relationship between left DLPFC activity and depression is likely causal, as repetitive TMS (rTMS) over left DLPFC has been shown to be effective and is a US Food and Drug Administration (FDA)-approved intervention for TRD [9], [20]. Furthermore, there is emerging data of utilizing transcranial direct current stimulation over DLPFC for treatment of depression [21]. Another region of the prefrontal cortex, the frontopolar cortex (FPC), specifically BA 10, is also a promising depression target. The FPC has gained attention as an important node in the mood regulatory circuitry [22], and is consistently found to have increased resting-state activity in patients with depression [23]. Thus, the FPC and DLPFC represent promising targets for neuromodulation as treatment for TRD [8].

Epidural cortical stimulation (EpCS) represents a novel therapeutic approach that can be used to stimulate the DLPFC and FPC to treat TRD [24], [25]. EpCS involves placing stimulating electrodes directly on the dura mater dorsal to the cortical areas to be stimulated [26]. Chronic EpCS of sensory or motor areas has demonstrated efficacy in managing intractable pain syndromes [27], [28], [29], [30], improving recovery from stroke [31], and addressing Parkinson's disease and other motor disorders [26].

We have previously reported outcomes up to 7 months in 5 patients with TRD that were implanted with bilateral EpCS over the DLPFC and FPC in an open-label design [24]. We continued to assess the long-term safety and efficacy of chronic intermittent EpCS for treatment of TRD and report outcomes for all 5 of these patients 5 years following initial implantation. During this time an expanded array of stimulation parameters was investigated and additional treatments were combined with EpCS during this unrestricted phase of the investigation. The efficacy and safety of EpCS endured during this follow-up period and several trends in stimulation parameters were observed and are discussed herein.

Section snippets

Methods and materials

This long-term follow-up study was conducted at the Medical University of South Carolina (MUSC) in compliance with the original Investigational Device Exemption issued to Z.N. and later transferred to E.B.S. under the guidance of the FDA. For the original study, the inclusion criteria limited enrollment to individuals with definite histories of depression with substantial treatment-resistance in order to address the ethical concerns of providing an experimental and untested intervention that

Sample characteristics

Six participants were initially enrolled, and 5 received EpCS and participated in this study. One participant withdrew consent before implantation. Table 1 summarizes the sample characteristics. The mean age (±SD) was 44.4 (±9.7) years at the time of implantation. Four were women, and 3 were diagnosed with recurrent MDD; 2 others had bipolar affective disorder I, depressed type. All were unemployed, and 3 continued to receive disability. At the time of implantation, the average length of

Discussion

Here we report on the long-term safety, tolerability, and durability of the therapeutic benefits of bilateral anterior (FPC) and lateral (DLPFC) EpCS in patients diagnosed with TRD. At the initial 7-month acute end-point, adjunctive intermittent open-label EpCS was well tolerated and associated with marked and sustained improvement in 3 of the 5 severe TRD patients [24]. Subsequently after 5 years of ongoing clinical assessment, 3 out of the 5 (60%) continued to be in remission while 2 subjects

Conclusion

Bilateral anterior pole (FPC) and midlateral (DLPFC) EpCS for TRD appear relatively safe and durable. EpCS has demonstrated an open-label improvement that continues to be efficacious after 5 years and is similar in effect side to other functional neurosurgical approaches in a TRD cohort. The relative ease of this approach compared to DBS, the apparent long-term safety, and the potential of marked efficacy in the treatment of TRD all warrant expanded, controlled, and blinded studies of EpCS for

Funding/support

Medtronic, Inc. (Minneapolis, MN) donated the devices but was otherwise not involved in the study, particularly data acquisition, analysis, or drafting the article. Ziad Nahas, MD, declares no conflict of interest in relation to the work described and was funded by a National Alliance of Research for Depression and Schizophrenia (NARSAD) Independent Investigator Award. Brandon Bentzley, MD, PhD, declares no conflict of interest in relation to the work described and was supported by NIH grants

Previous presentations

Brain stimulation. 2015;8(2):435–6.

Biological Psychiatry 2014;75(9):124S.

References (72)

  • H.S. Mayberg et al.

    Deep brain stimulation for treatment-resistant depression

    Neuron

    (2005)
  • Z. Nahas et al.

    Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI

    Biol Psychiatry

    (2001)
  • G. Hajcak et al.

    Dorsolateral prefrontal cortex stimulation modulates electrocortical measures of visual attention: evidence from direct bilateral epidural cortical stimulation in treatment-resistant mood disorder

    Neuroscience

    (2010)
  • H.B.L. Kober et al.

    Functional grouping and cortical-subcortical interactions in emotion: a meta-analysis of neuroimaging studies

    Neuroimage

    (2008)
  • J. Levesque et al.

    Neural circuitry underlying voluntary suppression of sadness

    Biol Psychiatry

    (2003)
  • J. Downar et al.

    New targets for rTMS in depression: a review of convergent evidence

    Brain Stimul

    (2013)
  • A.M. Lozano et al.

    Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression

    Biol Psychiatry

    (2008)
  • P. Riva-Posse et al.

    Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression

    Biol Psychiatry

    (2014)
  • C. Liston et al.

    Default mode network mechanisms of transcranial magnetic stimulation in depression

    Biol Psychiatry

    (2014)
  • M.D. Fox et al.

    Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate

    Biol Psychiatry

    (2012)
  • N. Williams et al.

    Relapse rates with long-term antidepressant drug therapy: a meta-analysis

    Hum Psychopharmacol

    (2009)
  • A.J. Ferrari et al.

    Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010

    PLoS Med

    (2013)
  • A.J. Rush et al.

    Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report

    Am J Psychiatry

    (2006)
  • M.T. Berlim et al.

    Current trends in the assessment and somatic treatment of resistant/refractory major depression: an overview

    Ann Med

    (2008)
  • H.A. Sackeim

    The definition and meaning of treatment-resistant depression

    J Clin Psychiatry

    (2001)
  • R.H. Howland

    Sequenced treatment alternatives to relieve depression (STAR*D) part 2: study outcomes

    J Psychosoc Nurs Ment Health Serv

    (2008)
  • N.R. Williams et al.

    Interventional psychiatry: why now?

    J Clin Psychiatry

    (2014)
  • N.R. Williams et al.

    Role of functional imaging in the development and refinement of invasive neuromodulation for psychiatric disorders

    World J Radiol

    (2014)
  • M.S. George et al.

    Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial

    Arch Gen Psychiatry

    (2010)
  • N.R. Williams et al.

    Interventional psychiatry: how should psychiatric educators incorporate neuromodulation into training?

    Acad Psychiatry

    (2014)
  • Therapy APATFoE

    The practice of ECT: recommendations for treatment, training and privileging

    Convuls Ther

    (1990)
  • N.R. Williams et al.

    Reward circuit DBS improves Parkinson's gait along with severe depression and OCD

    Neurocase

    (2016)
  • N.R. Williams et al.

    Deep brain stimulation (DBS) at the interface of neurology and psychiatry

    J Clin Invest

    (2013)
  • M.K.T.P.R. George

    Prefrontal cortex dysfunction in clinical depression

    Depression

    (1994)
  • M.S. George et al.

    SPECT and PET imaging in mood disorders

    J Clin Psychiatry

    (1993)
  • M.S. George et al.

    The expanding evidence base for rTMS treatment of depression

    Curr Opin Psychiatry

    (2013)
  • Cited by (0)

    Clinical Trials Registration: Epidural Cortical Stimulation for Depression, NCT00565617.

    1

    Co-first authors.

    2

    Co-second authors.

    View full text