Subcallosal cingulate deep brain stimulation for treatment-resistant depression:  a multi-site, randomized, sham-controlled trial

Paul  Holtzheimer; Mustafa M  Husain; Sarah H  Lisanby; Stephan F  Taylor; Louis A  Whitworth; Shawn  McClintock; Konstantin V  Slavin; Joshua  Berman; Guy M  McKhann; Parag G  Patil; Barry R  Rittberg; Aviva  Abosch; Ananda K  Pandurangi; Kathryn L  Holloway; Raymond W  Lam; Christopher Connolly; Joseph S  Neimat; Jaimie M  Henderson; Charles  DeBattista; Anthony J  Rothschild; Julie G  Pilitsis; Randall T  Espinoza; Georgios  Petrides; Alon Y  Mogilner; Keith Matthews; DeLea  Peichel; Robert  Grosse; Clement  Hamani; Andres M. Lozano; Helen S  Mayberg

doi:10.1016/S2215-0366(17)30371-1

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multi-site, randomized, sham-controlled trial

Paul Holtzheimer (Lead / Corresponding author), Mustafa M Husain, Sarah H Lisanby, Stephan F Taylor, Louis A Whitworth, Shawn McClintock, Konstantin V Slavin, Joshua Berman, Guy M McKhann, Parag G Patil, Barry R Rittberg, Aviva Abosch, Ananda K Pandurangi, Kathryn L Holloway, Raymond W Lam, Christopher Connolly, Joseph S Neimat, Jaimie M Henderson, Charles DeBattista, Anthony J RothschildJulie G Pilitsis, Randall T Espinoza, Georgios Petrides, Alon Y Mogilner, Keith Matthews, DeLea Peichel, Robert Grosse, Clement Hamani, Andres M. Lozano, Helen S Mayberg

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Abstract

Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCC) has shown promise as an intervention for patients with chronic, unremitting depression (TRD). To test the safety and efficacy of DBS for TRD, a prospective, randomized, sham-controlled trial was conducted.

Methods: Participants with TRD were implanted with a DBS system targeting bilateral SCC white matter and randomized to six months of active versus sham DBS followed by six months open-label SCC DBS. The primary outcome was response rate at the end of the six-month double-blind phase. Response was defined as a 40% or greater reduction in depression severity from baseline. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients continued to be followed for up to 24 months.

Findings: Prior to the futility analysis, 90 participants were randomized to active (N=60) versus sham (N=30) stimulation. Both groups showed improvement, but there was no statistically significant difference in response rate during the double-blind, sham-controlled phase. Participants continued to improve during the six months open-label phase. Long-term response and remission rates for all participants receiving active DBS open-label were, respectively, 40% and 19% at 12 months, 51% and 17% at 18 months, and 48% and 25% at 24 months. Twenty-eight patients experienced 39 adverse events; eight of these (in seven patients) were deemed to be related to the study device and/or surgery.

Interpretation: This study confirmed the safety and feasibility of SCC DBS as a treatment for TRD but failed to show statistically significant antidepressant efficacy in a six months double-blind, sham-controlled trial. Long-term (up to 24 months) open-label SCC DBS was associated with a response rate of nearly 50%, with 25% of participants remitted. These rates are clinically meaningful and higher than those expected in this patient population with treatment-as-usual.

Original language	English
Pages (from-to)	839-849
Number of pages	11
Journal	Lancet Psychiatry
Volume	4
Issue number	11
Early online date	4 Oct 2017
DOIs	https://doi.org/10.1016/S2215-0366(17)30371-1
Publication status	Published - Nov 2017

Keywords

depression
treatment-resistant depression
deep brain stimulation
subcallosal cingulate
subgenual cingulate
Brodmann Area 25

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10.1016/S2215-0366(17)30371-1

Author Accepted ManuscriptAccepted author manuscript, 10.1 MBLicence: CC BY-NC-ND

Matthews, Keith
- Neuroscience - Emeritus Professor
Person: Honorary

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Holtzheimer, P., Husain, M. M., Lisanby, S. H., Taylor, S. F., Whitworth, L. A., McClintock, S., Slavin, K. V., Berman, J., McKhann, G. M., Patil, P. G., Rittberg, B. R., Abosch, A., Pandurangi, A. K., Holloway, K. L., Lam, R. W., Connolly, C., Neimat, J. S., Henderson, J. M., DeBattista, C., ... Mayberg, H. S. (2017). Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multi-site, randomized, sham-controlled trial. Lancet Psychiatry, 4(11), 839-849. https://doi.org/10.1016/S2215-0366(17)30371-1

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title = "Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multi-site, randomized, sham-controlled trial",

abstract = "Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCC) has shown promise as an intervention for patients with chronic, unremitting depression (TRD). To test the safety and efficacy of DBS for TRD, a prospective, randomized, sham-controlled trial was conducted. Methods: Participants with TRD were implanted with a DBS system targeting bilateral SCC white matter and randomized to six months of active versus sham DBS followed by six months open-label SCC DBS. The primary outcome was response rate at the end of the six-month double-blind phase. Response was defined as a 40% or greater reduction in depression severity from baseline. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients continued to be followed for up to 24 months. Findings: Prior to the futility analysis, 90 participants were randomized to active (N=60) versus sham (N=30) stimulation. Both groups showed improvement, but there was no statistically significant difference in response rate during the double-blind, sham-controlled phase. Participants continued to improve during the six months open-label phase. Long-term response and remission rates for all participants receiving active DBS open-label were, respectively, 40% and 19% at 12 months, 51% and 17% at 18 months, and 48% and 25% at 24 months. Twenty-eight patients experienced 39 adverse events; eight of these (in seven patients) were deemed to be related to the study device and/or surgery. Interpretation: This study confirmed the safety and feasibility of SCC DBS as a treatment for TRD but failed to show statistically significant antidepressant efficacy in a six months double-blind, sham-controlled trial. Long-term (up to 24 months) open-label SCC DBS was associated with a response rate of nearly 50%, with 25% of participants remitted. These rates are clinically meaningful and higher than those expected in this patient population with treatment-as-usual.",

keywords = "depression, treatment-resistant depression, deep brain stimulation, subcallosal cingulate, subgenual cingulate, Brodmann Area 25",

author = "Paul Holtzheimer and Husain, {Mustafa M} and Lisanby, {Sarah H} and Taylor, {Stephan F} and Whitworth, {Louis A} and Shawn McClintock and Slavin, {Konstantin V} and Joshua Berman and McKhann, {Guy M} and Patil, {Parag G} and Rittberg, {Barry R} and Aviva Abosch and Pandurangi, {Ananda K} and Holloway, {Kathryn L} and Lam, {Raymond W} and Christopher Connolly and Neimat, {Joseph S} and Henderson, {Jaimie M} and Charles DeBattista and Rothschild, {Anthony J} and Pilitsis, {Julie G} and Espinoza, {Randall T} and Georgios Petrides and Mogilner, {Alon Y} and Keith Matthews and DeLea Peichel and Robert Grosse and Clement Hamani and Lozano, {Andres M.} and Mayberg, {Helen S}",

note = "Abbott previously known as St. Jude Medical was the study sponsor and provided all funding for this study. This role included protocol design with assistance of the consultants, FDA negotiations and communication, study execution including monitoring, data analysis, and statistical analyses.",

year = "2017",

month = nov,

doi = "10.1016/S2215-0366(17)30371-1",

language = "English",

volume = "4",

pages = "839--849",

journal = "Lancet Psychiatry",

issn = "2215-0366",

publisher = "Elsevier",

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Holtzheimer, P, Husain, MM, Lisanby, SH, Taylor, SF, Whitworth, LA, McClintock, S, Slavin, KV, Berman, J, McKhann, GM, Patil, PG, Rittberg, BR, Abosch, A, Pandurangi, AK, Holloway, KL, Lam, RW, Connolly, C, Neimat, JS, Henderson, JM, DeBattista, C, Rothschild, AJ, Pilitsis, JG, Espinoza, RT, Petrides, G, Mogilner, AY, Matthews, K, Peichel, D, Grosse, R, Hamani, C, Lozano, AM & Mayberg, HS 2017, 'Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multi-site, randomized, sham-controlled trial', Lancet Psychiatry, vol. 4, no. 11, pp. 839-849. https://doi.org/10.1016/S2215-0366(17)30371-1

TY - JOUR

T1 - Subcallosal cingulate deep brain stimulation for treatment-resistant depression

T2 - a multi-site, randomized, sham-controlled trial

AU - Holtzheimer, Paul

AU - Husain, Mustafa M

AU - Lisanby, Sarah H

AU - Taylor, Stephan F

AU - Whitworth, Louis A

AU - McClintock, Shawn

AU - Slavin, Konstantin V

AU - Berman, Joshua

AU - McKhann, Guy M

AU - Patil, Parag G

AU - Rittberg, Barry R

AU - Abosch, Aviva

AU - Pandurangi, Ananda K

AU - Holloway, Kathryn L

AU - Lam, Raymond W

AU - Connolly, Christopher

AU - Neimat, Joseph S

AU - Henderson, Jaimie M

AU - DeBattista, Charles

AU - Rothschild, Anthony J

AU - Pilitsis, Julie G

AU - Espinoza, Randall T

AU - Petrides, Georgios

AU - Mogilner, Alon Y

AU - Matthews, Keith

AU - Peichel, DeLea

AU - Grosse, Robert

AU - Hamani, Clement

AU - Lozano, Andres M.

AU - Mayberg, Helen S

N1 - Abbott previously known as St. Jude Medical was the study sponsor and provided all funding for this study. This role included protocol design with assistance of the consultants, FDA negotiations and communication, study execution including monitoring, data analysis, and statistical analyses.

PY - 2017/11

Y1 - 2017/11

N2 - Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCC) has shown promise as an intervention for patients with chronic, unremitting depression (TRD). To test the safety and efficacy of DBS for TRD, a prospective, randomized, sham-controlled trial was conducted. Methods: Participants with TRD were implanted with a DBS system targeting bilateral SCC white matter and randomized to six months of active versus sham DBS followed by six months open-label SCC DBS. The primary outcome was response rate at the end of the six-month double-blind phase. Response was defined as a 40% or greater reduction in depression severity from baseline. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients continued to be followed for up to 24 months. Findings: Prior to the futility analysis, 90 participants were randomized to active (N=60) versus sham (N=30) stimulation. Both groups showed improvement, but there was no statistically significant difference in response rate during the double-blind, sham-controlled phase. Participants continued to improve during the six months open-label phase. Long-term response and remission rates for all participants receiving active DBS open-label were, respectively, 40% and 19% at 12 months, 51% and 17% at 18 months, and 48% and 25% at 24 months. Twenty-eight patients experienced 39 adverse events; eight of these (in seven patients) were deemed to be related to the study device and/or surgery. Interpretation: This study confirmed the safety and feasibility of SCC DBS as a treatment for TRD but failed to show statistically significant antidepressant efficacy in a six months double-blind, sham-controlled trial. Long-term (up to 24 months) open-label SCC DBS was associated with a response rate of nearly 50%, with 25% of participants remitted. These rates are clinically meaningful and higher than those expected in this patient population with treatment-as-usual.

AB - Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCC) has shown promise as an intervention for patients with chronic, unremitting depression (TRD). To test the safety and efficacy of DBS for TRD, a prospective, randomized, sham-controlled trial was conducted. Methods: Participants with TRD were implanted with a DBS system targeting bilateral SCC white matter and randomized to six months of active versus sham DBS followed by six months open-label SCC DBS. The primary outcome was response rate at the end of the six-month double-blind phase. Response was defined as a 40% or greater reduction in depression severity from baseline. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients continued to be followed for up to 24 months. Findings: Prior to the futility analysis, 90 participants were randomized to active (N=60) versus sham (N=30) stimulation. Both groups showed improvement, but there was no statistically significant difference in response rate during the double-blind, sham-controlled phase. Participants continued to improve during the six months open-label phase. Long-term response and remission rates for all participants receiving active DBS open-label were, respectively, 40% and 19% at 12 months, 51% and 17% at 18 months, and 48% and 25% at 24 months. Twenty-eight patients experienced 39 adverse events; eight of these (in seven patients) were deemed to be related to the study device and/or surgery. Interpretation: This study confirmed the safety and feasibility of SCC DBS as a treatment for TRD but failed to show statistically significant antidepressant efficacy in a six months double-blind, sham-controlled trial. Long-term (up to 24 months) open-label SCC DBS was associated with a response rate of nearly 50%, with 25% of participants remitted. These rates are clinically meaningful and higher than those expected in this patient population with treatment-as-usual.

KW - depression

KW - treatment-resistant depression

KW - deep brain stimulation

KW - subcallosal cingulate

KW - subgenual cingulate

KW - Brodmann Area 25

U2 - 10.1016/S2215-0366(17)30371-1

DO - 10.1016/S2215-0366(17)30371-1

M3 - Article

SN - 2215-0366

VL - 4

SP - 839

EP - 849

JO - Lancet Psychiatry

JF - Lancet Psychiatry

IS - 11

ER -

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multi-site, randomized, sham-controlled trial

Abstract

Keywords

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