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 Rothschild & 10 others 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

    Research output: Contribution to journalArticle

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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 languageEnglish
    Pages (from-to)839-849
    Number of pages11
    JournalLancet Psychiatry
    Volume4
    Issue number11
    Early online date4 Oct 2017
    DOIs
    Publication statusPublished - Nov 2017

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    Treatment-Resistant Depressive Disorder
    Deep Brain Stimulation
    Randomized Controlled Trials
    Medical Futility
    Depression
    Safety
    Antidepressive Agents
    Equipment and Supplies

    Keywords

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

    Cite this

    Holtzheimer, P., Husain, M. M., Lisanby, S. H., Taylor, S. F., Whitworth, L. A., McClintock, S., ... 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
    Holtzheimer, Paul ; Husain, Mustafa M ; Lisanby, Sarah H ; Taylor, Stephan F ; Whitworth, Louis A ; McClintock, Shawn ; Slavin, Konstantin V ; Berman, Joshua ; McKhann, Guy M ; Patil, Parag G ; Rittberg, Barry R ; Abosch, Aviva ; Pandurangi, Ananda K ; Holloway, Kathryn L ; Lam, Raymond W ; Connolly, Christopher ; Neimat, Joseph S ; Henderson, Jaimie M ; DeBattista, Charles ; Rothschild, Anthony J ; Pilitsis, Julie G ; Espinoza, Randall T ; Petrides, Georgios ; Mogilner, Alon Y ; Matthews, Keith ; Peichel, DeLea ; Grosse, Robert ; Hamani, Clement ; Lozano, Andres M. ; Mayberg, Helen S . / Subcallosal cingulate deep brain stimulation for treatment-resistant depression : a multi-site, randomized, sham-controlled trial. In: Lancet Psychiatry. 2017 ; Vol. 4, No. 11. pp. 839-849.
    @article{bc314c75a9864f5899a6958938e32b6b,
    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 = "11",
    doi = "10.1016/S2215-0366(17)30371-1",
    language = "English",
    volume = "4",
    pages = "839--849",
    journal = "Lancet Psychiatry",
    issn = "2215-0366",
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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

    Subcallosal cingulate deep brain stimulation for treatment-resistant depression : a multi-site, randomized, sham-controlled trial. / Holtzheimer, Paul (Lead / Corresponding author); Husain, Mustafa M ; Lisanby, Sarah H ; Taylor, Stephan F ; Whitworth, Louis A ; McClintock, Shawn ; Slavin, Konstantin V ; Berman, Joshua ; McKhann, Guy M ; Patil, Parag G ; Rittberg, Barry R ; Abosch, Aviva ; Pandurangi, Ananda K ; Holloway, Kathryn L ; Lam, Raymond W ; Connolly, Christopher; Neimat, Joseph S ; Henderson, Jaimie M ; DeBattista, Charles ; Rothschild, Anthony J ; Pilitsis, Julie G ; Espinoza, Randall T ; Petrides, Georgios ; Mogilner, Alon Y ; Matthews, Keith; Peichel, DeLea ; Grosse, Robert ; Hamani, Clement ; Lozano, Andres M.; Mayberg, Helen S .

    In: Lancet Psychiatry, Vol. 4, No. 11, 11.2017, p. 839-849.

    Research output: Contribution to journalArticle

    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

    VL - 4

    SP - 839

    EP - 849

    JO - Lancet Psychiatry

    JF - Lancet Psychiatry

    SN - 2215-0366

    IS - 11

    ER -