Pilot study of stanford neuromodulation therapy (SNT) for bipolar depression

Bipolar disorder is a highly disabling illness [[1]Miller S. Dell'Osso B. Ketter T.A. The prevalence and burden of bipolar depression.J Affect Disord. 2014; 169 (S3–11)https://doi.org/10.1016/S0165-0327(14)70003-5Crossref Scopus (159) Google Scholar]. While mania and hypomania define bipolar I and II, respectively, depression accounts for the majority of disease burden in bipolar disorder. Further, 15–20% of patients with bipolar disorder die due to suicide [[2]Gonda X. Pompili M. Serafini G. Montebovi F. Campi S. Dome P. et al.Suicidal behavior in bipolar disorder: epidemiology, characteristics and major risk factors.J Affect Disord. 2012; 143: 16-26https://doi.org/10.1016/j.jad.2012.04.041Crossref PubMed Scopus (156) Google Scholar], and depressive episodes are a consistent risk factor for a suicide attempt [[2]Gonda X. Pompili M. Serafini G. Montebovi F. Campi S. Dome P. et al.Suicidal behavior in bipolar disorder: epidemiology, characteristics and major risk factors.J Affect Disord. 2012; 143: 16-26https://doi.org/10.1016/j.jad.2012.04.041Crossref PubMed Scopus (156) Google Scholar]. Unfortunately, there are relatively few evidence-based treatment options available for bipolar depression (BD). Although repetitive transcranial magnetic stimulation (rTMS) has demonstrated antidepressant efficacy in unipolar depression, there is limited evidence of [3McGirr A. Vila-Rodriguez F. Cole J. Torres I.J. Arumugham S.S. Keramatian K. et al.Efficacy of active vs sham intermittent theta burst transcranial magnetic stimulation for patients with bipolar depression: a randomized clinical trial.JAMA Netw Open. 2021; 4e210963https://doi.org/10.1001/jamanetworkopen.2021.0963Crossref Scopus (26) Google Scholar, 4Bulteau S. Beynel L. Marendaz C. Dall'Igna G. Peré M. Harquel S. et al.Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: a Randomized Sham-Controlled Pilot Study.Neurophysiol Clin. 2019; 49: 371-375https://doi.org/10.1016/j.neucli.2019.10.002Crossref PubMed Scopus (23) Google Scholar, 5Tavares D.F. Myczkowski M.L. Alberto R.L. Valiengo L. Rios R.M. Gordon P. et al.Treatment of bipolar depression with deep TMS: results from a double-blind, randomized, parallel group, sham-controlled clinical trial.Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2017; 42: 2593-2601https://doi.org/10.1038/npp.2017.26Crossref PubMed Scopus (66) Google Scholar], and ongoing debate about [[6]Kishi T. Ikuta T. Sakuma K. Hatano M. Matsuda Y. Kito S. et al.Repetitive transcranial magnetic stimulation for bipolar depression: a systematic review and pairwise and network meta-analysis.Mol Psychiatr. 2023; : 1-4https://doi.org/10.1038/s41380-023-02045-8Crossref Scopus (1) Google Scholar], its efficacy for BD. Our group previously has reported an accelerated, high-dose, functionally-targeted intermittent theta burst stimulation (iTBS, a form of rTMS) treatment approach entitled Stanford Neuromodulation Therapy (SNT, previously referred to as SAINT). SNT demonstrated significant antidepressant efficacy in unipolar depression both in open label [[7]Williams N.R. Sudheimer K.D. Bentzley B.S. Pannu J. Stimpson K.H. Duvio D. et al.High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression.Brain. 2018; 141: e18https://doi.org/10.1093/brain/awx379Crossref PubMed Scopus (115) Google Scholar,[8]Cole E.J. Stimpson K.H. Bentzley B.S. Gulser M. Cherian K. Tischler C. et al.Stanford accelerated intelligent neuromodulation Therapy for treatment-resistant depression.Am J Psychiatr. 2020; 177: 716-726https://doi.org/10.1176/appi.ajp.2019.19070720Crossref PubMed Scopus (262) Google Scholar] and double-blind, sham-controlled settings [[9]Cole E.J. Phillips A.L. Bentzley B.S. Stimpson K.H. Nejad R. Barmak F. et al.Stanford neuromodulation Therapy (SNT): a double-blind randomized controlled trial.Am J Psychiatr. 2022; 179: 132-141https://doi.org/10.1176/appi.ajp.2021.20101429Crossref PubMed Scopus (185) Google Scholar]. 3 of 27 participants from the combined open label studies were diagnosed with bipolar disorder, and the antidepressant efficacy of SNT appeared indistinguishable in these participants [[7]Williams N.R. Sudheimer K.D. Bentzley B.S. Pannu J. Stimpson K.H. Duvio D. et al.High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression.Brain. 2018; 141: e18https://doi.org/10.1093/brain/awx379Crossref PubMed Scopus (115) Google Scholar,[8]Cole E.J. Stimpson K.H. Bentzley B.S. Gulser M. Cherian K. Tischler C. et al.Stanford accelerated intelligent neuromodulation Therapy for treatment-resistant depression.Am J Psychiatr. 2020; 177: 716-726https://doi.org/10.1176/appi.ajp.2019.19070720Crossref PubMed Scopus (262) Google Scholar]. Accordingly, we performed an open label pilot study to better assess the efficacy and safety of SNT in this population. Informed consent was obtained for all participants, the study was approved by the Stanford Institutional Review Board, and the trial was prospectively registered in the U.S. Clinical Trials registry (NCT03953417). Except for the requirement of a primary diagnosis of bipolar I or bipolar II disorder without psychosis or rapid cycling, study entry criteria and the overall treatment paradigm were similar to our previous work [[8]Cole E.J. Stimpson K.H. Bentzley B.S. Gulser M. Cherian K. Tischler C. et al.Stanford accelerated intelligent neuromodulation Therapy for treatment-resistant depression.Am J Psychiatr. 2020; 177: 716-726https://doi.org/10.1176/appi.ajp.2019.19070720Crossref PubMed Scopus (262) Google Scholar,[9]Cole E.J. Phillips A.L. Bentzley B.S. Stimpson K.H. Nejad R. Barmak F. et al.Stanford neuromodulation Therapy (SNT): a double-blind randomized controlled trial.Am J Psychiatr. 2022; 179: 132-141https://doi.org/10.1176/appi.ajp.2021.20101429Crossref PubMed Scopus (185) Google Scholar]. Change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to immediate-post was the pre-specified primary outcome. As past rTMS trials of BD have reported treatment-emergent (hypo)mania [[3]McGirr A. Vila-Rodriguez F. Cole J. Torres I.J. Arumugham S.S. Keramatian K. et al.Efficacy of active vs sham intermittent theta burst transcranial magnetic stimulation for patients with bipolar depression: a randomized clinical trial.JAMA Netw Open. 2021; 4e210963https://doi.org/10.1001/jamanetworkopen.2021.0963Crossref Scopus (26) Google Scholar,[10]Kaster T.S. Knyahnytska Y. Noda Y. Downar J. Daskalakis Z.J. Blumberger D.M. Treatment-emergent mania with psychosis in bipolar depression with left intermittent theta-burst rTMS.Brain Stimul. 2020; 13: 705-706https://doi.org/10.1016/j.brs.2020.02.018Abstract Full Text Full Text PDF Scopus (7) Google Scholar], a Young Mania Rating Scale (YMRS) was performed daily for safety, and change from baseline to immediate post was our secondary outcome. Exploratory outcomes included changes in the 17-item Hamilton Rating Scale for Depression (HAM-D-17), the 6-item version of the Hamilton Rating Scale for Depression (HAM-D-6), and the Scale for Suicide Ideation (SSI). Response was defined as a ≥50% change in MADRS, and remission was defined as a MADRS<11. As a safety measure, treatment of participants with bipolar I was concluded early if end-of-day total HAM-D-6 score was consistent with remission (<5) so as to reduce the risk of a (hypo)manic switch. We used longitudinal LME models (fixed effect of time and random intercept) to assess the statistical significance of the outcomes while tolerating missing data points (analyses performed in JASP version 0.17.1). Further statistical details are provided in the online supplement. In total, 7 participants (F = 5, M = 2) ranging from 20-72 years old experiencing a major depressive episode (MDE) in the context of bipolar I (N = 2) or II (N = 5) disorder were included in this study (Supplementary Table 1). Additional participant details are available in the online supplement. Clinical outcomes are summarized in Supplementary Table 2 and Fig. 1. Mean MADRS decreased from 40.0 ± 9.8 to 5.7 ± 10.7 between baseline and immediate-post. Mean MADRS remained reduced throughout follow-up with large effect sizes (Cohen's d) throughout (immediate-post, d=3.0; week-2 post, d=2.6; week-4 post, d=2.3). The number of participants meeting remission|response criteria was 5|5 at immediate-post, 5|5 at 2-weeks post, and 3|5 at 4-weeks post, respectively. LME models demonstrated statistically significant effects with large effect sizes over time with the MADRS (F(3,16.8) = 14.5, p < 0.0001, η2p = 0.721), HAM-D-17 (F(3,16.6) = 14.1, p < 0.0001, η2p = 0.718), and HAM-D-6 (F(3,16.8) = 12.9, p = 0.00012, η2p = 0.697). (η2p > 0.14 is considered a large effect size). Pairwise estimates similarly demonstrated highly significant differences over time after correcting for multiple comparisons. In the case of the SSI, an LME model was not reliable due to a boundary singular fit (see supplement for details), but a Greenhouse-Geisser-corrected ANOVA revealed a trending effect and a large effect size of time on SSI score (F(1.2,4.8) = 5.5, p = 0.066, η2p = 0.578) (Supplementary Table 3). In terms of safety, tolerability of SNT was consistent with our prior reports [[8]Cole E.J. Stimpson K.H. Bentzley B.S. Gulser M. Cherian K. Tischler C. et al.Stanford accelerated intelligent neuromodulation Therapy for treatment-resistant depression.Am J Psychiatr. 2020; 177: 716-726https://doi.org/10.1176/appi.ajp.2019.19070720Crossref PubMed Scopus (262) Google Scholar,[9]Cole E.J. Phillips A.L. Bentzley B.S. Stimpson K.H. Nejad R. Barmak F. et al.Stanford neuromodulation Therapy (SNT): a double-blind randomized controlled trial.Am J Psychiatr. 2022; 179: 132-141https://doi.org/10.1176/appi.ajp.2021.20101429Crossref PubMed Scopus (185) Google Scholar] without any serious adverse events. No treatment-emergent (hypo)mania was observed (YMRS ranging from 0 to 7 daily throughout treatment course and ≤1 at all follow-up visits), although 2 SNT courses were shortened (1- and 2-day courses, respectively) due to HAM-D-6 = 1. In summary, this pilot study provides the first evidence of antidepressant efficacy of SNT in participants with BD, demonstrating therapeutic benefits akin to those that have been reported in the unipolar depression population. In our limited sample there was no evidence of treatment-emergent (hypo)mania despite the high treatment dose delivered with SNT (90,000 pulses over 5 days with a full course as compared to 18,000 pulses over 6 weeks with conventional iTBS), although a majority of participants were taking a mood stabilizing medication, including both participants with bipolar I. Further, both bipolar I participants received shortened courses of treatment (18,000 and 36,000 pulses, respectively) as a cautionary measure to mitigate the risk of (hypo)manic switch following early remission. While this early signal of safety and efficacy is promising, limitations such as the small sample size, open-label design, and incomplete clinical data for some participants preclude generalizability to larger populations. Further, with only 2 participants with bipolar I included, the risk of (hypo)manic switch in this population remains particularly uncertain. Altogether, these data suggest the need for controlled trials of SNT for BD to further assess efficacy and safety. Upon reasonable request that comports with Stanford University guidelines, anonymized behavioral data may be shared. Please contact Nolan Williams at [email protected] with data sharing requests. Kristin S. Raj: Writing – original draft, Writing – review & editing. Andrew D. Geoly: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Clive Veerapal: Data curation. Mia Gholmieh: Data curation. Pouya Toosi: Data curation. Flint M. Espil: Writing – original draft, Writing – review & editing. Jean-Marie Batail: Writing – original draft, Writing – review & editing. Ian H. Kratter: Writing – original draft, Writing – review & editing. Nolan R. Williams: Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; he has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and he has equity/stock options in Magnus Medical, NeuraWell, and Nooma.Dr. Raj has equity/stock options in Magnus Medical, NeuraWell, and Nooma.Clive Veerapal had no conflict of interest at the time of his study involvement but currently has equity/stock options in Magnus Medical.All other investigators declare no conflicts of interest. Supported by a Brain and Behavior Research Foundation Young Investigator Award (to Dr. Williams), Charles R. Schwab, the David and Amanda Chao Fund II, the Amy Roth PhD Fund, the Neuromodulation Research Fund, the Lehman Family, the Still Charitable Trust, the Marshall and Dee Ann Payne Fund, the Gordie Brookstone Fund, the Mellam Family Foundation, and the Baszucki Brain Research Fund. The following is the supplementary data to this article: Download .docx (.01 MB) Help with docx files Multimedia component 1