Neurostimulation – Beyond ECT to TMS and VNS

R. Hamish McAllister-Williams, MD, PhD, FRCPsych

Professor of Affective Disorders Newcastle University Hon. Consultant Psychiatrist Regional Affective Disorders Service, RVI Disclosure / conflict of interest I am employed by Newcastle University. I also work clinically in a tertiary level specialist affective disorders service in Northumberland Tyne and Wear NHS Foundation Trust I have had an interest in relation to one or more organisations that could be perceived as a possible conflict of interest in the context of the subject of this presentation. The relationships are summarised below: Interest Name of organisation Speaker fees AstraZeneca, Bristol Myers-Squibb, Eli Lilly, Ferrer, GlaxoSmithKline, Janssen-Cilag, LivaNova, Lundbeck, Merck Sharp & Dohme, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO, Sunovian, Wyeth Consultancy fees AstraZeneca, Bristol Myers-Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, LivaNova, Lundbeck, Merck Sharp & Dohme, MyTomorrows, Otsuka, Roche, Servier, Sunovian, Wyeth Independent investigator- led research support AstraZeneca, Eli Lilly, Lundbeck, Wyeth

I do not hold any shares in, nor have any ongoing financial relationship with, any company

I am a PI on a recently NIHR EME funded study of rTMS vs TBS Neurostimulatory techniques • ECT

• tDCS • CES • TMS/TBS • MST • VNS • DBS Transcranial magnetic stimulation (TMS) Types of TMS • Repetitive TMS (rTMS) – Low frequency (e.g. 1 Hz) inhibitory • Right DLPFC low frequency rTMS may be effective for MDD – High frequency (e.g. 10 Hz) excitatory • Left DLPFC high frequency the most studied TMS treatment of MDD • Intermittent theta burst stimulation (iTBS) • Less data in depression but appears to be at least as effective as rTMS rTMS – tolerability vs medication

NB seizures – risk very low if follow FDA guidance on stimulus parameters Meta-analysis of rTMS (left high frequency) vs sham in MDD

Ont Health Technol Assess Ser. 2016; 16(5): 1–66 rTMS vs ECT

Ont Health Technol Assess Ser. 2016; 16(5): 1–66 Relapse following course of rTMS therapy • Follow-up studies of rTMS vs sham rTMS – High rate of relapse – little difference cf sham at 3 months • Follow up of rTMS vs ECT – Possibly faster relapse than ECT (e.g. 1 study remission at 6 months 27% vs 18% - ECT vs rTMS

Ont Health Technol Assess Ser. 2016; 16(5): 1–66 iTBS vs sham

Berlim et al. 2017 Journal of Psychiatric Research 90:102-109 • 80% of responders still responders at 14 weeks (Li CT et al. Brain 137:2088-2098) NICE – rTMS for MDD: guidance Repetitive transcranial magnetic stimulation for depression (IPG542, Published December 2015) Recommendations: 1.1 The evidence on repetitive transcranial magnetic stimulation for depression shows no major safety concerns. The evidence on its efficacy in the short-term is adequate, although the clinical response is variable. Repetitive transcranial magnetic stimulation for depression may be used with normal arrangements for clinical governance and audit.

1.2 During the consent process, clinicians should, in particular, inform patients about the other treatment options available, and make sure that patients understand the possibility the procedure may not give them benefit.

1.3 NICE encourages publication of further evidence on patient selection, details of the precise type and regime of stimulation used, the use of maintenance treatment and long-term outcomes. rTMS – pros and cons

• Pros • Cons – No anaesthetic needed – Still uncertainty about the – Well tolerated with few side most effective way to effects administer TMS – Good evidence of efficacy in – Usually requires 5 day a week MDD treatment for 4 weeks – Probably not as effective as ECT – Relapse may be even quicker than ECT (? iTBS better??) Conclusions: • Possible option earlier in treatment algorithm than ECT. • Particularly for patients intolerant of medication The BRIGhTMIND Study

Aim To compare the efficacy and cost effectiveness of rTMS vs connectivity guided iTBS (cgiTBS) for with people with treatment resistance depression. Sites 4 Sites in Nottingham, Northampton , London and Newcastle Led by Prof Richard Morriss Sample 368 until September 2020 Study design • Random allocation to rTMS or cgiTBS • Baseline MRI scan – used to personalise location of stimulation • 20 treatments over 4-6 weeks • Follow up assessments at 8, 16 and 26 weeks • MRI at 16 weeks to explore mechanism of action Key eligibility Main inclusion criteria Main exclusion criteria criteria • 18+ years old • Bipolar • MDD • Contraindications to MRI • Moderate to severe • Major unstable medical illness depression • Change medication in last 2 weeks • Treatment resistance (2+ • Prescription of GABAergic medications antidepressants • Significant current substance misuse • Capacity The BRIGhTMIND Study

• How to get patients involved – Clinician identifies patient that could be eligible and suitable to take part. – Clinical team sends out Invite letter, reply slip and Short patient Information leaflet – Patient returns reply slip to research team • Contact: – Claire Turner • [email protected] • Tel: 0191 2081361 Neurostimulatory techniques • ECT

• tDCS • CES • TMS/TBS • MST • VNS • DBS Vagal nerve stimulation (VNS) VNS acute RCT in MDD: outcome at 12 weeks

Rush et al. 2005 Biol Psychiatry. 58(5):347-54 VNS vs treatment as usual (TAU) - NB not randomised

VNS + TAU n = 205; TAU n = 124

George et al. 2005 Biol Psychiatry. 58(5):364-73 Status of VNS: Approved Indications • United States (FDA) – Epilepsy: Medically refractory partial-onset seizures, ages 12 and up (1997) – TRD (2005) • Europe (CEA) – Epilepsy (1994) – Treatment-resistant or treatment-intolerant depression and bipolar disorder (2001) Cumulative Percent Response EndpointPrimary CumulativeFirst TAU VNS 10 20 30 40 50 60 70 0 Group: MADRSGroup: 22.3 3 8 34.4 6 16 VNS: 5 VNS: year 20.7 42.8 9 - Time Responders Visit byMonthTreatmentby Follow – 50.4 12 – 25 Response Rate VNS D VNS 27.2 53.3 18 - up Visit Month - 56.8 24 21 + D + 21 29 31.9 59.5 30 - 23, TAU23, Population) (ITT 33.3 63.6 36 Aaronsson based on based on MADRS 35.1 64.4 42 LivaNova data 37.3 66.2 48 etof PsychiatryAmerican al. 2017 Journal 38.7 67.2 54 40.9 67.8 60 VNS TAU registry at 5 years Response Rate Cumulative (NNT=4) for TAU (P<0.001) vs. 40.9% Therapy 67.8% for VNS Exploratory Analysis TAU CDE gt 5YgtTAU CDE VNS CDE gt 5Ygt CDE VNS TAU CDE le 5Y le TAU CDE VNS CDE le 5Y le CDE VNS Cumulative Percent Responders 10 20 30 40 50 60 70 0 Group: MADRSGroup: CumulativeFirst 3 23.5 20.5 9.7 6.2 6 35.1 33.2 18 14 on Length of Current Episode (<5 or >5 years)>5 or Current(<5Length Episode of on Impact of duration of depression 45.5 39.1 22.1 19.4 9 Follow VNS: – 12 46.8 26.2 24.1 - 53 VNS D21+D23 vs. TAU D21+D23VNS Population) (ITT based Time Time ResponseVisit bybyTreatmentMonth – 18 57.5 47.7 27.6 27.2 Response - up Visit Month 24 60.9 51.3 30.4 28 LivaNova 30 63.9 53.6 31.8 32.7 based on based on MADRS 36 69.1 56.3 33.2 34.3 Aaronsson 42 69.8 57.2 34.3 36 48 71.7 38.8 35.9 59 etof PsychiatryAmerican al. 2017 Journal Registry data 54 72.1 60.8 40.2 37.5 60 72.5 61.7 39.1 43 TAUyrs <5 TAUyrs >5 >5yrsVNS <5yrsVNS (5 yearat Threshold)(5 Years 5 Current MDE of Length onBased CumulativeResponse Rate TAU 5yrs)(≥ 5yrs)(≥ VNS TAU (<5 yrs) yrs)(<5 VNS (n=194) (n=50) (n=50) (n=62) (n=136) (n=136) 43.0% 72.5% 39.1% 61.7% VNS: LivaNova Registry data Bipolar vs unipolar patients

Aaronsson et al. 2017 American Journal of Psychiatry VNS: LivaNova Registry data Impact of previous response to ECT

Aaronsson et al. 2017 American Journal of Psychiatry VNS: Case series of patients receiving maintenance ECT

Aaronsson et al. 2017 Poster presented at ECNP, Paris, Sept 2017 VNS: LivaNova Registry data: Mortality

Aaronsson et al. 2017 American Journal of Psychiatry NICE – VNS for MDD: guidance Vagus nerve stimulation for treatment-resistant depression (IPG330, Published December 2009) Recommendations: 1.1 Current evidence on the safety and efficacy of vagus nerve stimulation (VNS) for treatment-resistant depression is inadequate in quantity and quality. Therefore this procedure should be used only with special arrangements for clinical governance, consent and audit or research. It should be used only in patients with treatment-resistant depression. VNS – pros and cons

• Pros • Cons – Long term follow up data – ‘Negative RCT’ (further one available currently being planned in – Appears superior to TAU USA) – Responders tend to remain – Not an acute treatment responders over long term – Requires surgical – ECT responders more likely to implantation respond than ECT non- – Requires specialist follow up responders to monitor device

Conclusions: • Potentially an alternative to maintenance ECT? • Useful for other patients with recurrent or chronic depression (though don’t wait too long!) • European registry study running over 5 years • Meets NICE requirement of close audit of VNS treatment • Any patient where there has been a clinical decision made to use VNS can be included • Access to the study is via patients being referred to RADS for an assessment • When to consider VNS? • Primary diagnosis of MDD or BD DRAFT RECOMMENDATIONS • One or more of the following: 1. ECT failure, relapse post ECT, maintenance ECT 2. Meeting MTR-MDD criteria a) ≥2 trials of a structured psychological therapy b) ≥4 antidepressants c) ≥2 augmentation strategies d) ECT 3. High service utilisation • Multiple admissions and/or an admission > 6 months SEE FLYER IN HANDOUTS – feedback welcome Conclusions

• There are increasing neurostimulation treatments available to treat depression • TMS (in one form or another) is a reasonable alternative to medication (esp. for patients who are intolerant) – NB BRIGhTMIND Study • VNS may be a useful option for the more chronic or recurrent patients – NB Restore-Life