Trial of Enhanced Neurostimulation for Anorexia

NCT05788042 | Recruiting

• 1 other identifier: 2021-016
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Preliminary open-label studies have suggested that non-invasive brain stimulation methods of both transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) have clinical benefits for improving psychological and eating disorder related symptoms, which can persist at long-term follow ups after acute treatment (i.e., at 6 and 12 months). Here the investigators propose to conduct the first double-blinded, randomised sham-controlled study to directly compare the therapeutic effectiveness and acceptability of both treatment modalities. Participants will be recruited and treated at one inpatient setting (Northside Clinic, St Leonards, Sydney). This facility is one of the largest specialist eating disorder settings in Australia with approximately 130 new admissions every year (2019 data). All participants who give consent and who fulfill the eligibility criteria will be randomised to receive active tDCS, sham (placebo) tDCS, active rTMS or sham rTMS over 8 weeks. Trial participants, their treating psychiatrist, ward staff, and a study staff member (who will conduct blinded assessments of mood secondary outcome measures) will be blinded after assignment to intervention until the database is locked and the primary analysis completed. All participants will complete assessments of eating disorder symptoms, mood, psychological symptoms, neurocognition and functioning at baseline, end of week 4, 8 and 20. Expected outcomes include data on the relative effectiveness and acceptability for both treatment modalities in the inpatient and at-home setting (i.e., for at-home tDCS). The investigators expect that both active treatment arms will produce clinical benefits and have high acceptability, and that clinical benefits will be maintained with long-term at-home tDCS continuation treatment. These outcomes have potential to assist in reducing hospital stay and emergency re-admissions and improving day to day functioning in participants. Health economic data for both treatment modalities will additionally have utility from a service perspective, given the disparity in resource requirements between the two treatments (TMS, tDCS) in terms of costs for patients and access to treatment for people living in remote and rural areas (i.e., for at-home tDCS).

Conditions

Anorexia Nervosa

Keywords

Anorexia Nervosa; Repetitive Transcranial Magnetic Stimulation; Transcranial Direct Current Stimulation; Non-invasive brain stimulation

Outcome Measures

Primary Outcomes (2)

• Effectiveness - Eating Disorder Examination Questionnaire (EDE Q)

  Self-report instrument that measures eating disorder behaviors and attitudes. Eating Disorder Examination Questionnaire; 28-items; rating scale 0 - 6; Higher scores on the global scale and subscales indicate more problematic eating behaviours and attitudes.

  Change from baseline at 8 weeks

• Acceptability

  Number of completed sessions for active tDCS and active rTMS in the acute 8 week RCT period.

  8 weeks

Secondary Outcomes (25)

• Weight

  Change from baseline at 4 weeks

• Weight

  Change from baseline at 8 weeks

• Weight

  Change from baseline at 20 weeks

• Mood - Montgomery Asberg Depression Rating Score (MADRS)

  Change from baseline at 4 weeks

• Mood - Montgomery Asberg Depression Rating Score (MADRS)

  Change from baseline at 8 weeks

Study Arms (4)

Active transcranial Direct Current Stimulation (tDCS)

ACTIVE COMPARATOR

It will be given continuously for 30 minutes at 2 mA, twice daily (separated by \>=2 hours) over the first 4 weeks, and daily over the second 4 weeks of the 8 week acute treatment period (84 sessions total).

Device: tDCS mini-CT Stimulator (Soterix, USA: ARTG: 284637)

Sham transcranial Direct Current Stimulation (tDCS)

SHAM COMPARATOR

It will involve an initial ramping up to 0.5 mA and then a ramp down to 0 mA for the remainder of each treatment. The same number of sessions as active tDCS will be administered.

Device: tDCS mini-CT Stimulator (Soterix, USA: ARTG: 284637)

Active Repetitive Transcranial Magnetic Stimulation (rTMS)

ACTIVE COMPARATOR

Active rTMS twice per day (separated by ≥ 2 hours) over the first 4 weeks. Two sessions per day (separated by ≥ 2 hours), given on 2 days each week for the following 4 weeks. The total number of rTMS sessions over the 8 week acute treatment period will be 56.

Device: MagPro TMS device (ARTG: 204659)

Sham Repetitive Transcranial Magnetic Stimulation (rTMS)

SHAM COMPARATOR

Sham rTMS twice per day (separated by ≥ 2 hours) over the first 4 weeks. Two sessions per day (separated by ≥ 2 hours), given on 2 days each week for the following 4 weeks. The same number of sessions as active rTMS will be administered.

Device: MagPro TMS device (ARTG: 204659)

Interventions

MagPro TMS device (ARTG: 204659) DEVICE

rTMS will be administered using a MagPro TMS device (ARTG: 204659) which is approved for its intended use in this trial. rTMS involves the application of transient magnetic pulses which induce small currents in the underlying cortex via the principal of electromagnetic induction. rTMS will be administered using a patterned frequency stimulus called intermittent theta-burst stimulation (iTBS).This form of rTMS was chosen because a recent large multicentre trial showed 3 minutes of iTBS attained the same therapeutic effect as 30 minutes of standard rTMS, leading to FDA approval for depression. Each treatment session will comprise an extended iTBS session, i.e., 6.6 mins, delivered at 100% resting motor threshold (RMT). It will be targeted to the left DLPFC (F3 using the 10-20 International EEG system), consistent with the prior RCT of rTMS for AN.

Active Repetitive Transcranial Magnetic Stimulation (rTMS); Sham Repetitive Transcranial Magnetic Stimulation (rTMS)

tDCS mini-CT Stimulator (Soterix, USA: ARTG: 284637) DEVICE

tDCS will be self-administered using the 1x1 tDCS mini-CT Stimulator (Soterix, USA: ARTG: 284637) with two saline-soaked sponge electrodes held in place on the scalp using the Soterix Ole-2 headband. The device is intended to treat different neurological and psychiatric disorders. tDCS involves the passing of weak electrical current through the brain via electrodes placed upon the scalp. The current modulates the resting membrane potential of stimulated neurons which causes changes in neuronal excitability. The anode will be placed over the left F3 (10-20 System) and the cathode over F4 (electrode sizes 5 x 5cm, 25cm2). This montage was chosen to target the left DLPFC, consistent with prior pilot studies of tDCS in AN.

Active transcranial Direct Current Stimulation (tDCS); Sham transcranial Direct Current Stimulation (tDCS)

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged ≥16 years,
• A current Diagnostic and Statistical Manual of Mental Disorders (5th edition DSM-5) diagnosis of anorexia nervosa
• Willing and able to participate and comply with study requirements
• Worked or studied in a context requiring some proficiency in spoken English (to ensure validity of neuropsychological testing)
• Under ongoing care by his/her own treating psychiatrist (to ensure patient safety during the study)

You may not qualify if:

• Inability to provide informed consent
• Contraindications to tDCS/rTMS
• Failed to respond to an adequate course or rTMS (4 weeks) within the current illness course
• Had ECT in the last 3 months
• MoCA score of \<26
• Significant risk of significant self harm or suicide as assessed by study psychiatrist(s)
• Currently enrolled in another interventional clinical trial or using an investigational device/product

Sponsors & Collaborators

• The George Institute: lead
• The University of New South Wales: collaborator

Study Sites (1)

Northside Clinic

Sydney, New South Wales, 2031, Australia

RECRUITING

Related Publications (40)

• Aardoom JJ, Dingemans AE, Slof Op't Landt MC, Van Furth EF. Norms and discriminative validity of the Eating Disorder Examination Questionnaire (EDE-Q). Eat Behav. 2012 Dec;13(4):305-9. doi: 10.1016/j.eatbeh.2012.09.002. Epub 2012 Sep 19.

  PMID: 23121779 BACKGROUND

• First MB. Diagnostic and statistical manual of mental disorders, 5th edition, and clinical utility. J Nerv Ment Dis. 2013 Sep;201(9):727-9. doi: 10.1097/NMD.0b013e3182a2168a. No abstract available.

  PMID: 23995026 BACKGROUND

• Alonzo A, Fong J, Ball N, Martin D, Chand N, Loo C. Pilot trial of home-administered transcranial direct current stimulation for the treatment of depression. J Affect Disord. 2019 Jun 1;252:475-483. doi: 10.1016/j.jad.2019.04.041. Epub 2019 Apr 10.

  PMID: 31005790 BACKGROUND

• Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Arch Gen Psychiatry. 2011 Jul;68(7):724-31. doi: 10.1001/archgenpsychiatry.2011.74.

  PMID: 21727255 BACKGROUND

• Berryhill ME, Martin D. Cognitive Effects of Transcranial Direct Current Stimulation in Healthy and Clinical Populations: An Overview. J ECT. 2018 Sep;34(3):e25-e35. doi: 10.1097/YCT.0000000000000534.

  PMID: 30095685 BACKGROUND

• Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26.

  PMID: 29726344 BACKGROUND

• Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, Nejad R, Pankow H, Choi E, Aaron H, Espil FM, Pannu J, Xiao X, Duvio D, Solvason HB, Hawkins J, Guerra A, Jo B, Raj KS, Phillips AL, Barmak F, Bishop JH, Coetzee JP, DeBattista C, Keller J, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am J Psychiatry. 2020 Aug 1;177(8):716-726. doi: 10.1176/appi.ajp.2019.19070720. Epub 2020 Apr 7.

  PMID: 32252538 BACKGROUND

• Couturier J, Lock J. What is remission in adolescent anorexia nervosa? A review of various conceptualizations and quantitative analysis. Int J Eat Disord. 2006 Apr;39(3):175-83. doi: 10.1002/eat.20224.

  PMID: 16485268 BACKGROUND

• Dalton B, Bartholdy S, McClelland J, Kekic M, Rennalls SJ, Werthmann J, Carter B, O'Daly OG, Campbell IC, David AS, Glennon D, Kern N, Schmidt U. Randomised controlled feasibility trial of real versus sham repetitive transcranial magnetic stimulation treatment in adults with severe and enduring anorexia nervosa: the TIARA study. BMJ Open. 2018 Jul 16;8(7):e021531. doi: 10.1136/bmjopen-2018-021531.

  PMID: 30012789 BACKGROUND

• Dedoncker J, Brunoni AR, Baeken C, Vanderhasselt MA. A Systematic Review and Meta-Analysis of the Effects of Transcranial Direct Current Stimulation (tDCS) Over the Dorsolateral Prefrontal Cortex in Healthy and Neuropsychiatric Samples: Influence of Stimulation Parameters. Brain Stimul. 2016 Jul-Aug;9(4):501-17. doi: 10.1016/j.brs.2016.04.006. Epub 2016 Apr 12.

  PMID: 27160468 BACKGROUND

• Fairburn, G.G. Cognitive Behavior Therapy and Eating Disorders. Guilford Press, New York, 2008.

  BACKGROUND

• Garber AK, Sawyer SM, Golden NH, Guarda AS, Katzman DK, Kohn MR, Le Grange D, Madden S, Whitelaw M, Redgrave GW. A systematic review of approaches to refeeding in patients with anorexia nervosa. Int J Eat Disord. 2016 Mar;49(3):293-310. doi: 10.1002/eat.22482. Epub 2015 Dec 12.

  PMID: 26661289 BACKGROUND

• Hatch A, Madden S, Kohn M, Clarke S, Touyz S, Williams LM. Anorexia nervosa: towards an integrative neuroscience model. Eur Eat Disord Rev. 2010 May;18(3):165-79. doi: 10.1002/erv.974.

  PMID: 20443202 BACKGROUND

• Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033.

  PMID: 15664172 BACKGROUND

• Katzman DK. Medical complications in adolescents with anorexia nervosa: a review of the literature. Int J Eat Disord. 2005;37 Suppl:S52-9; discussion S87-9. doi: 10.1002/eat.20118.

  PMID: 15852321 BACKGROUND

• Khedr EM, Elfetoh NA, Ali AM, Noamany M. Anodal transcranial direct current stimulation over the dorsolateral prefrontal cortex improves anorexia nervosa: A pilot study. Restor Neurol Neurosci. 2014;32(6):789-97. doi: 10.3233/RNN-140392.

  PMID: 25189181 BACKGROUND

• Knyahnytska YO, Blumberger DM, Daskalakis ZJ, Zomorrodi R, Kaplan AS. Insula H-coil deep transcranial magnetic stimulation in severe and enduring anorexia nervosa (SE-AN): a pilot study. Neuropsychiatr Dis Treat. 2019 Aug 6;15:2247-2256. doi: 10.2147/NDT.S207630. eCollection 2019.

  PMID: 31496707 BACKGROUND

• Lewinsohn PM, Striegel-Moore RH, Seeley JR. Epidemiology and natural course of eating disorders in young women from adolescence to young adulthood. J Am Acad Child Adolesc Psychiatry. 2000 Oct;39(10):1284-92. doi: 10.1097/00004583-200010000-00016.

  PMID: 11026183 BACKGROUND

• Liu A, Voroslakos M, Kronberg G, Henin S, Krause MR, Huang Y, Opitz A, Mehta A, Pack CC, Krekelberg B, Berenyi A, Parra LC, Melloni L, Devinsky O, Buzsaki G. Immediate neurophysiological effects of transcranial electrical stimulation. Nat Commun. 2018 Nov 30;9(1):5092. doi: 10.1038/s41467-018-07233-7.

  PMID: 30504921 BACKGROUND

• Loo CK, Martin DM, Alonzo A, Gandevia S, Mitchell PB, Sachdev P. Avoiding skin burns with transcranial direct current stimulation: preliminary considerations. Int J Neuropsychopharmacol. 2011 Apr;14(3):425-6. doi: 10.1017/S1461145710001197. Epub 2010 Oct 6. No abstract available.

  PMID: 20923600 BACKGROUND

• Lovibond, S.H. & Lovibond, P.F. (1995). Manual for the Depression Anxiety Stress Scales. (2nd. Ed.) Sydney: Psychology Foundation.

  BACKGROUND

• Madden, S. (2015). Biopsychiatric theories of eating disorders. In The Wiley Handbook of Eating Disorders. Assessment, Prevention, Treatment, Policy, and Future Directions, Eds. Smolak, L., and Levine, M.P.

  BACKGROUND

• Martin DM, McClintock SM, Forster JJ, Lo TY, Loo CK. Cognitive enhancing effects of rTMS administered to the prefrontal cortex in patients with depression: A systematic review and meta-analysis of individual task effects. Depress Anxiety. 2017 Nov;34(11):1029-1039. doi: 10.1002/da.22658. Epub 2017 May 24.

  PMID: 28543994 BACKGROUND

• McClelland J, Kekic M, Campbell IC, Schmidt U. Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment in Enduring Anorexia Nervosa: A Case Series. Eur Eat Disord Rev. 2016 Mar;24(2):157-63. doi: 10.1002/erv.2414. Epub 2015 Nov 4.

  PMID: 26537308 BACKGROUND

• McClintock SM, Reti IM, Carpenter LL, McDonald WM, Dubin M, Taylor SF, Cook IA, O'Reardon J, Husain MM, Wall C, Krystal AD, Sampson SM, Morales O, Nelson BG, Latoussakis V, George MS, Lisanby SH; National Network of Depression Centers rTMS Task Group; American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments. Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. J Clin Psychiatry. 2018 Jan/Feb;79(1):16cs10905. doi: 10.4088/JCP.16cs10905.

  PMID: 28541649 BACKGROUND

• Moffa AH, Martin D, Alonzo A, Bennabi D, Blumberger DM, Bensenor IM, Daskalakis Z, Fregni F, Haffen E, Lisanby SH, Padberg F, Palm U, Razza LB, Sampaio-Jr B, Loo C, Brunoni AR. Efficacy and acceptability of transcranial direct current stimulation (tDCS) for major depressive disorder: An individual patient data meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109836. doi: 10.1016/j.pnpbp.2019.109836. Epub 2019 Dec 16.

  PMID: 31837388 BACKGROUND

• Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.

  PMID: 444788 BACKGROUND

• Murray SB, Loeb KL, Le Grange D. Treatment outcome reporting in anorexia nervosa: time for a paradigm shift? J Eat Disord. 2018 May 7;6:10. doi: 10.1186/s40337-018-0195-1. eCollection 2018. No abstract available.

  PMID: 29760916 BACKGROUND

• Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019 Mar 27;364:l1079. doi: 10.1136/bmj.l1079.

  PMID: 30917990 BACKGROUND

• Patel R, Silla F, Pierce S, Theule J, Girard TA. Cognitive functioning before and after repetitive transcranial magnetic stimulation (rTMS): A quantitative meta-analysis in healthy adults. Neuropsychologia. 2020 Apr;141:107395. doi: 10.1016/j.neuropsychologia.2020.107395. Epub 2020 Mar 4.

  PMID: 32142730 BACKGROUND

• Reitan, R. (1979). Trail Making Test. Reitan Neuropsychological Laboratory.

  BACKGROUND

• Rose JS, Vaewsorn A, Rosselli-Navarra F, Wilson GT, Weissman RS. Test-retest reliability of the eating disorder examination-questionnaire (EDE-Q) in a college sample. J Eat Disord. 2013 Nov 20;1:42. doi: 10.1186/2050-2974-1-42. eCollection 2013.

  PMID: 24999420 BACKGROUND

• Smith KE, Mason TB, Johnson JS, Lavender JM, Wonderlich SA. A systematic review of reviews of neurocognitive functioning in eating disorders: The state-of-the-literature and future directions. Int J Eat Disord. 2018 Aug;51(8):798-821. doi: 10.1002/eat.22929. Epub 2018 Aug 13.

  PMID: 30102781 BACKGROUND

• Steinhausen HC. The outcome of anorexia nervosa in the 20th century. Am J Psychiatry. 2002 Aug;159(8):1284-93. doi: 10.1176/appi.ajp.159.8.1284.

  PMID: 12153817 BACKGROUND

• Strumila R, Thiebaut S, Jaussent I, Seneque M, Attal J, Courtet P, Guillaume S. Safety and efficacy of transcranial direct current stimulation (tDCS) in the treatment of Anorexia Nervosa. The open-label STAR study. Brain Stimul. 2019 Sep-Oct;12(5):1325-1327. doi: 10.1016/j.brs.2019.06.017. Epub 2019 Jun 19. No abstract available.

  PMID: 31239105 BACKGROUND

• Wade TD, Bergin JL, Tiggemann M, Bulik CM, Fairburn CG. Prevalence and long-term course of lifetime eating disorders in an adult Australian twin cohort. Aust N Z J Psychiatry. 2006 Feb;40(2):121-8. doi: 10.1080/j.1440-1614.2006.01758.x.

  PMID: 16476129 BACKGROUND

• Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.

  PMID: 9474057 BACKGROUND

• Westwood H, Stahl D, Mandy W, Tchanturia K. The set-shifting profiles of anorexia nervosa and autism spectrum disorder using the Wisconsin Card Sorting Test: a systematic review and meta-analysis. Psychol Med. 2016 Jul;46(9):1809-27. doi: 10.1017/S0033291716000581. Epub 2016 Apr 25.

  PMID: 27109830 BACKGROUND

• Wu M, Giel KE, Skunde M, Schag K, Rudofsky G, de Zwaan M, Zipfel S, Herzog W, Friederich HC. Inhibitory control and decision making under risk in bulimia nervosa and binge-eating disorder. Int J Eat Disord. 2013 Nov;46(7):721-8. doi: 10.1002/eat.22143. Epub 2013 Jun 3.

  PMID: 23729277 BACKGROUND

• Harvey AJ, Madden S, Rodgers A, Bull M, Chatterton ML, Hadzi-Pavlovic D, Loo CK, Martin DM. Randomised controlled trial of neurostimulation for symptoms of anorexia nervosa (TRENA study): study protocol. J Eat Disord. 2023 Dec 8;11(1):218. doi: 10.1186/s40337-023-00940-7.

  PMID: 38066658 DERIVED

MeSH Terms

Conditions

Anorexia Nervosa

Condition Hierarchy (Ancestors)

Feeding and Eating Disorders; Mental Disorders

Study Officials

• Sloane Madden, Assoc. Prof.

  University of Sydney, Ramsay Health Care

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Donel Martin, Dr

CONTACT

02 9382 8353; donel.martin@unsw.edu.au

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Trial participants, their treating psychiatrist, ward staff, and a study staff member (who will conduct blinded assessments of mood secondary outcome measures) will be blinded after assignment to intervention until the database is locked and the primary analysis completed. The following measures will be taken to ensure preservation of blinding to treatment allocation: * Unblinded personnel (i.e., Neurostimulation Nurse(s) and/or tDCS research assistant), will be present during rTMS treatment delivery. tDCS will be self administered in the presence of ward staff. Team members involved in conducting blinded assessments for mood (i.e., MADRS) must not be present in the room during research treatment delivery. * Knowledge of the code (i.e., which of 'A', 'B', 'C' or 'D' refers to which randomised treatment) will only be known to study staff responsible for treatment delivery, the study CI and study statistician involved in the study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Double-blind, randomised, sham-controlled trial, parallel group design. Participants will be randomised to one of four groups (2:1:2:1 ratio): Active or sham tDCS, or Active or sham rTMS. The brain stimulation protocols involve 84 sessions of tDCS (active or sham) or 56 sessions of rTMS (active or sham) over the 8 week acute treatment period.

Study Record Dates

• First Submitted: February 21, 2023
• First Posted: March 28, 2023
• Study Start: August 2, 2023
• Primary Completion: April 1, 2026
• Study Completion: April 30, 2026
• Last Updated: September 12, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share

Locations

AU (1)