Theta burst stimulation in adolescent depression: An open-label evaluation of safety, tolerability, and efficacy

Depression is a significant cause for disability-adjusted life years [[1]Gore F.M. Bloem P.J. Patton G.C. Ferguson J. Joseph V. Coffey C. et al.Global burden of disease in young people aged 10–24 years: a systematic analysis.Lancet. 2011; 377: 2093-2102https://doi.org/10.1016/S0140-6736(11)60512-6Abstract Full Text Full Text PDF PubMed Scopus (1288) Google Scholar] and suicide [[2]Hawton K. van Heeringen K. Suicide.Lancet. 2009; 373: 1372-1381https://doi.org/10.1016/S0140-6736(09)60372-XAbstract Full Text Full Text PDF PubMed Scopus (1407) Google Scholar] among adolescents. However, existing treatments have suboptimal benefits and uncertain safety profiles [[3]Walkup J.T. Antidepressant efficacy for depression in children and adolescents: industry- and NIMH-funded studies.Aust J Pharm. 2017; 174: 430-437https://doi.org/10.1176/appi.ajp.2017.16091059Crossref Scopus (59) Google Scholar]. For example, psychotherapy and antidepressants are only moderately effective in the short term [[4]Thapar A. Collishaw S. Pine D.S. Thapar A.K. Depression in adolescence.Lancet. 2012; 379: 1056-1067https://doi.org/10.1016/S0140-6736(11)60871-4Abstract Full Text Full Text PDF PubMed Scopus (1221) Google Scholar]. Hence there is an urgent need to evaluate the safety, tolerability, and effectiveness of newer treatment modalities. Repetitive transcranial magnetic stimulation (rTMS) is a proven treatment for depression in adults [[5]Health Quality OntarioRepetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials.Ont Health Technol Assess Ser. 2016; 16: 1-66Google Scholar]. Theta burst stimulation (TBS) is a novel rTMS-paradigm where bursts of electromagnetic discharges are repeated at theta-frequency intervals [[6]Huang Y.-Z. Edwards M.J. Rounis E. Bhatia K.P. Rothwell J.C. Theta burst stimulation of the human motor cortex.Neuron. 2005; 45: 201-206https://doi.org/10.1016/j.neuron.2004.12.033Abstract Full Text Full Text PDF PubMed Scopus (2544) Google Scholar]. It is as effective and tolerable as rTMS in treating depression among adults, with the advantage of having much shorter treatment sessions [[7]Blumberger D.M. Vila-Rodriguez F. Thorpe K.E. Feffer K. Noda Y. Giacobbe P. et al.Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.Lancet. 2018; 391: 1683-1692https://doi.org/10.1016/S0140-6736(18)30295-2Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar]. This has also triggered an increase in TMS applications for depression in adults [[8]Mehta U.M. Thanki M.V. Mitra S. Arumugham S.S. Thirthalli J. Will theta burst the TMS depression clinical bubble?.Asian J Psychiatr. 2019; 40: 24-25https://doi.org/10.1016/j.ajp.2019.01.012Crossref PubMed Scopus (3) Google Scholar], and the same can be leveraged for adolescent depression. One study that examined the utility of TBS in youth depression did include adolescents; however, the mean age of their sample was ∼21 years [[9]Dhami P. Knyahnytska Y. Atluri S. Lee J. Courtney D.B. Croarkin P.E. et al.Feasibility and clinical effects of theta burst stimulation in youth with major depressive disorders: an open-label trial.J Affect Disord. 2019; 258: 66-73https://doi.org/10.1016/j.jad.2019.07.084Crossref PubMed Scopus (20) Google Scholar]. Since neurodevelopment is a critical moderator of TMS-related adverse events [[10]Gabbay V. Anterior cingulate cortexγ-aminobutyric acid in depressed adolescents: relationship to anhedonia.Arch Gen Psychiatr. 2012; 69: 139https://doi.org/10.1001/archgenpsychiatry.2011.131Crossref PubMed Scopus (145) Google Scholar], it is vital to examine these in an exclusive adolescent depression sample. Therefore, we attempted to measure the safety, tolerability, and efficacy of add-on TBS in adolescents with depression. We conducted an open-label trial of TBS as an add-on to treatment as usual in adolescents (12–18 years) admitted for treatment of depression (Trial registration: (CTRI/2018/10/016219 at www.ctri.nic.in). The Institutional Ethics Committee approved the protocol, and all participants provided assent, while their parents provided written informed consent. Participants were included if they received a diagnosis of depression (unipolar or bipolar) based on ICD 10 guidelines, ascertained by two independent psychiatrists, and confirmed using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version – K-SADS-PL [[11]Kaufman J. Birmaher B. Brent D. Rao U. Flynn C. Moreci P. et al.Schedule for affective disorders and Schizophrenia for school-age children-present and Lifetime version (K-SADS-PL): initial reliability and validity data.J Am Acad Child Adolesc Psychiatry. 1997; 36: 980-988https://doi.org/10.1097/00004583-199707000-00021Abstract Full Text PDF PubMed Scopus (7174) Google Scholar], had a Childhood Depression Rating Scale-Revised (CDRS-R) score ≥40, and Clinical Global Impression-Severity (CGI-S) score ≥4. The presence of intracranial metallic implants, clinically determined current, past, or family history of epilepsy, suicidal or catatonic patients, and those with comorbid intellectual disability or autism were excluded. We monitored safety and tolerability using a treatment-emergent side-effect checklist and a visual analog scale for scalp pain. Cognitive assessments (Montreal cognitive assessment [[12]Nasreddine Z.S. Phillips N.A. Bédirian V. Charbonneau S. Whitehead V. Collin I. et al.The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment.J Am Geriatr Soc. 2005; 53: 695-699https://doi.org/10.1111/j.1532-5415.2005.53221.xCrossref PubMed Scopus (12406) Google Scholar], digit span, spatial span [[13]Wechsler III, D. WMS-III administration and scoring manual. The Psychological Corporation, San Antonio, TX1997Google Scholar], and modified Ray's Auditory Verbal Learning Test [[14]Viswanath B. Harihara S.N. Nahar A. Phutane V.H. Taksal A. Thirthalli J. et al.Battery for ECT related cognitive deficits (B4ECT-ReCoDe): development and validation.Asian J Psychiatr. 2013; 6: 243-248https://doi.org/10.1016/j.ajp.2012.12.010Crossref PubMed Scopus (13) Google Scholar]) were performed at baseline and after 10 TBS-sessions. Clinical monitoring was performed using CDRS-R [[15]Poznanski E.O. Grossman J.A. Buchsbaum Y. Banegas M. Freeman L. Gibbons R. Preliminary studies of the reliability and validity of the children's depression rating scale.J Am Acad Child Psychiatr. 1984; 23: 191-197https://doi.org/10.1097/00004583-198403000-00011Abstract Full Text PDF PubMed Scopus (444) Google Scholar] CGI-S [[16]Guy W. ECDEU assessment manual for psychopharmacology. US Department of Health, and Welfare, 1976: 534-537Google Scholar], Brief Psychiatric Rating Scale for Children (BPRS-C) [[17]Hughes C.W. Rintelmann J. Emslie G.J. Lopez M. MacCabe N. A revised anchored version of the BPRS-C for childhood psychiatric disorders.J Child Adolesc Psychopharmacol. 2001; 11: 77-93https://doi.org/10.1089/104454601750143500Crossref PubMed Scopus (48) Google Scholar], and Children's Global Assessment Scale – CGAS [[18]Shaffer D. A children's global assessment scale (CGAS).Arch Gen Psychiatr. 1983; 40: 1228https://doi.org/10.1001/archpsyc.1983.01790100074010Crossref PubMed Scopus (2806) Google Scholar] (Table-S1 in supplement for timeline). TBS was administered targeting the dorsolateral prefrontal cortex (DLPFC) bilaterally. After locating the scalp region corresponding to the motor cortex, the resting motor threshold (RMT) was determined using standard protocols [[19]Wasserman E. Inter- and intra-individual variation in the responses to TMS.Oxford handbook of transcranial magnetic stimulation. Oxford University Press, Oxford2008Crossref Google Scholar]. The corresponding scalp location for DLPFC was estimated to be 7cm anterior to the motor hotspot along a parasagittal line [[20]Ahdab R. Ayache S.S. Brugières P. Goujon C. Lefaucheur J.-P. Comparison of “standard” and “navigated” procedures of TMS coil positioning over motor, premotor and prefrontal targets in patients with chronic pain and depression.Neurophysiologie Clinique/Clinical Neurophysiology. 2010; 40: 27-36https://doi.org/10.1016/j.neucli.2010.01.001Crossref PubMed Scopus (142) Google Scholar]. Treatment was administered at 80% RMT. Subjects received one session per day for ten days, of intermittent TBS to the left DLPFC (1800 pulses), and continuous TBS to right DLPFC (1800 pulses) in that sequence, based on Li et al. [[21]Li C.-T. Chen M.-H. Juan C.-H. Huang H.-H. Chen L.-F. Hsieh J.-C. et al.Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study.Brain. 2014; 137: 2088-2098https://doi.org/10.1093/brain/awu109Crossref PubMed Scopus (155) Google Scholar]. Of 33 eligible participants 26 consented for participation over a 1y period (acceptance rate 79%). 24/26 subjects completed all 10 TBS-sessions (one participant withdrew due to affective-switch after the third session, another dropped midway due to logistic reasons), and 23/26 were available for the 12w follow-up. The mean ± SD age of the study population was 15.8 ± 1.2 years; duration of the current episode was 14.81 ± 9.41 months. The most common diagnosis was unipolar depression (84%), followed by recurrent depressive disorder and bipolar depression (8% each). Sixty-one percent had at least one psychiatric comorbidity as evaluated on the K-SADS-PL. Twenty-five adolescents were on treatment with antidepressants, 14 on mood-stabilizers, and 16 on antipsychotics, at the time of recruitment; 17 (65%) were on more than two medications owing to clinically-determined partial response. Only two participants had not responded to at least two antidepressants in the past. TMS sessions were started after at least 7–10 days of pharmacotherapy changes. Fourteen subjects (53.8%) reported at least one adverse effect with TBS, with headache (35%) being the most common, followed by neck pain (15%) and scalp irritation (12%). Novel adverse effects noted were affective switch (n = 2, one after three days and the other after ten days of TBS) and transient lachrymation (n = 1). Details of the two individuals with affective switches have been detailed earlier [[22]Shere S.S. Baliga S.P. Mehta U.M. Girimaji S.C. Thirthalli J. Treatment emergent affective switch in depression: a possible role of theta burst stimulation.Brain Stimulation. 2020; 13: 492-493https://doi.org/10.1016/j.brs.2019.12.023Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Seventy-two percent found these adverse effects mild. None required reduction in stimulus or discontinuation of sessions, except the one participant with effective switch. None experienced seizures or subjectively reported cognitive symptoms (Table-S2). All cognitive tests showed significant improvements with effect-sizes ranging from 0.37 to 0.97 (Table-S3). There was a significant reduction of CDRS-R (F = 70.02, p < 0.01, partial η 2 = 0.46), from baseline (61.60 ± 12.8) to 10 sessions (34.3 ± 10.15); and at 12 weeks (31.4 ± 14.99). Remission (CDRS R < 28 [[23]Cheung A.H. Emslie G.J. Mayes T.L. Review of the efficacy and safety of antidepressants in youth depression.JCPP (J Child Psychol Psychiatry). 2005; 46: 735-754https://doi.org/10.1111/j.1469-7610.2005.01467.xCrossref PubMed Scopus (150) Google Scholar]) was seen in 41.6% of subjects after ten-sessions (10 out of 24) and 69.5% after 12-weeks (16 out of 23). BPRS-C (F = 142.17, p < 0.01, partial η 2 = 0.47) and CGAS (F = 72.91, p < 0.01, partial η 2 = 0.46) also improved significantly on serial evaluations (Table-S4). After 10 TBS-sessions, 26.9%, 53.8%, and 3.8% had minimal, much, and very much improvement, respectively. Partial response status did not significantly moderate clinical improvement as measured by CDRS-R on two-way repeated measures ANOVA [F = 0.412; P = 0.74]. We observed satisfactory acceptability (79%) and tolerability (72% mild side-effects) of bilateral TBS as an add-on treatment in adolescent depression. This is first study of TBS for depression in an exclusive adolescent population. A broader spectrum of the depression diagnosis and comorbidity profile enabled inferences that reflect real-world clinical practice [[24]Rohde P. Comorbidities with adolescent depression.Handbook of depression in adolescents. Routledge/Taylor & Francis Group, New York, NY, US2009: 139-177Google Scholar]. Side-effects were largely self-limiting; in line with observations from previous studies [[9]Dhami P. Knyahnytska Y. Atluri S. Lee J. Courtney D.B. Croarkin P.E. et al.Feasibility and clinical effects of theta burst stimulation in youth with major depressive disorders: an open-label trial.J Affect Disord. 2019; 258: 66-73https://doi.org/10.1016/j.jad.2019.07.084Crossref PubMed Scopus (20) Google Scholar,[25]Elmaghraby R. Sun Q. Ozger C. Shekunov J. Romanowicz M. Croarkin P.E. A systematic review of the safety and tolerability of theta burst stimulation in children and adolescents.Neuromodulation. 2021; (In press)https://doi.org/10.1111/ner.13455Abstract Full Text Full Text PDF Scopus (3) Google Scholar]. Improvement in cognition could reflect the specific effects of TBS, improvement in depression, or even practice effects [[26]Wall C.A. Croarkin P.E. McClintock S.M. Murphy L.L. Bandel L.A. Sim L.A. et al.Neurocognitive effects of repetitive transcranial magnetic stimulation in adolescents with major depressive disorder.Front Psychiatr. 2013; 4https://doi.org/10.3389/fpsyt.2013.00165Crossref PubMed Scopus (32) Google Scholar]. The emergence of affective-switch in two of our patients [[22]Shere S.S. Baliga S.P. Mehta U.M. Girimaji S.C. Thirthalli J. Treatment emergent affective switch in depression: a possible role of theta burst stimulation.Brain Stimulation. 2020; 13: 492-493https://doi.org/10.1016/j.brs.2019.12.023Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar] underscores the importance of careful symptom monitoring and considering a mood-stabilizer cover, especially in adolescents with bipolar depression [[27]Rachid F. Repetitive transcranial magnetic stimulation and treatment-emergent mania and hypomania: a review of the literature.J Psychiatr Pract. 2017; 23: 150-159https://doi.org/10.1097/PRA.0000000000000219Crossref PubMed Scopus (25) Google Scholar]. Efficacy assessments revealed a significant improvement in depression severity and overall functioning. However, these observations should be cautiously interpreted in the light of no control intervention, and the confounding effects of co-prescribed antidepressant medications and psychotherapy. Nevertheless, it was encouraging to note that clinical remission sustained and improved from day-10 of TBS (∼40%) to week-12 follow-up (∼70%). These findings provide a platform to evaluate the clinical utility of TBS for adolescent depression in more extensive multi-centre randomized controlled experiments. UMM is one of the Associate Editors at Schizophrenia Research and receives a honorarium from Elsevier for this service. None of the other authors have any conflict of interest to report. The following is the supplementary data to this article: Download .docx (.04 MB) Help with docx files Multimedia component 1

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