repetitive transcranial magnetic stimulation (rtms) and intravenous ketamine … · 2017-12-07 ·...
TRANSCRIPT
![Page 1: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/1.jpg)
Repetitive Transcranial MagneticStimulation (rTMS) and intravenous
ketamine for treatment-resistantdepression (TRD)
Docent, Senior PychiatristTero TaiminenUnit of General Hospital PsychiatryTurku University HospitalFinland
![Page 2: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/2.jpg)
Disclosuresu No possessions in medical companiesu Honoraria for lectures 2007 – 2017: Astra-
Zeneca, Bayer, Bristol-Myers Squibb,Duodecim, Efeko, Eisai, GlaxoSmithKline, Cityof Helsinki, University of Helsinki, FinnishResearch Council for Medical Industry, Lilly,Lundbeck, Nexstim, Orion Pharma, Pfizer,Professio Finland, Scandinavian Association ofthe Study of Pain, Schering-Plough, FinnishDental Association, Finnish Medical Association,Finnish Psychiatric Association, City of Turku,University of Turku, UCB, Vesa Laukkanen Ltd,Jarkko Männistö Ltd, L Legal Ltd, MegaElectronics Ltd
![Page 3: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/3.jpg)
Treatment-resistant depression (TRD)uMany definitionsuMost common definition: failure to
achieve response (50 % reduction insymptom severity) in trials with twoantidepressants of different classes withadequate doses and sufficient period(Keitner and Mansfield 2012)
uTRD can be classified by differentmethods (Ruhé et al. 2012)
uMost used classification is MaudsleyStaging Model (MSM, Fekadu et al. 2009
![Page 4: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/4.jpg)
![Page 5: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/5.jpg)
Prevalence and outcome of TRDuFailure to achieve response in 20 – 30 %
of patients with major depression(Keitner and Mansfield 2012)
uOnly 40 % of patients achieve remissionu12-month prevalence in Finland about 1
% (Taiminen 2013)u In a tertiary centre (N = 118, mean MSM
10) 60 % achieved remission during the8 – 84 months follow-up (Fekadu et al.2012)
![Page 6: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/6.jpg)
Kuva 9
DepressionF32, F33
SchizphreniaF20, F23, F25
Anxiety DisordersF34, F40-42,F44, F45 , F48AlcoholdependenceF10PersonalityDisordersF21, F60–62
Sickness pensions in Finnish Private Companies in 1983–2009
![Page 7: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/7.jpg)
Costs of depression in Sweden (Sobocki et al.2007)
![Page 8: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/8.jpg)
Effect size: examples of Cohen’s d
u0.2 = height difference (hd) between 15-and 16-year-old girls in population
u0.5 = hd between 14- and 18-year-oldgirls
u0.8 = hd between 13- and 18-year-oldgirls
u1 = effect size of placebo response indepression studies
u1.7 = hd between women and men
![Page 9: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/9.jpg)
Cohen’s d of depression treatmentsu< 0.3 Second generation antipsychotic as
an adjuvantu0.3 – 0.4 Antidepressant or tDCSu0.4 – 0.6 Lithium or thyroxin as
adjuvantsu0.6 – 0.7 rTMSu0.3 – 0.4 Cognitive psychotherapyu0.7 Antidepressant and psychotherapy
combinedu0.9 bilateral or high-energy unilat. ECTu1.2 – 1.4 ketamine i.v.
![Page 10: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/10.jpg)
Responder curve of rTMS in depression is biphasic(Downar et al. 2014)
![Page 11: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/11.jpg)
rTMS in depression – early (andprimitive) theory
u In depression right DLPFC is hyperactiveand left hypoactive
uRight hyperactivity is associated withdepression severity and anxiety
uLeft hypoactivity is associated withnegative emotions
u rTMS aims at restoring balance
![Page 12: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/12.jpg)
Some observations on rTMS in depressionu rTMS releases endogenic opioids
(Lamusuo et al. 2017) and dopamine(Cho and Strafella 2009)
u rTMS increases white matter integrity infrontal middle gyrus (Peng et al. 2012) →enhancement of neuroplasticity
u rTMS normalizes brain energyconsumption (Li et al. 2010)
u rTMS normalized hyperacticity oftemporal areas associated with defaultmode network (”network ofintrospection”, Richieri et al. 2017, Ge etal. 2017)
![Page 13: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/13.jpg)
rTMS activates the endogenous opioidsystem in a wide network (Lamusuo et al.
2017)
![Page 14: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/14.jpg)
![Page 15: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/15.jpg)
Navigation with MRI
![Page 16: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/16.jpg)
![Page 17: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/17.jpg)
u Target indepression:borderbetween BA9and BA 46(Mylius et al.2013)
![Page 18: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/18.jpg)
TechniquesuActivate left DLPFC with high frequency,
e.g. 10 Hz –side effects with high energyu Inhibit right DLPFC with low frequency,
e.g. 1 Hz – efficacy also against anxiety(Diefenbach et al. 2016)
uDo bothuTheta burst stimulation with a robot –
shorter sessions < 10 minutesuMany sessions per day (Tor et al. 2016)uOption to treat more than one indication
per session, e.g. depression, chronicpain and tinnitus
![Page 19: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/19.jpg)
![Page 20: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/20.jpg)
![Page 21: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/21.jpg)
![Page 22: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/22.jpg)
Efficacy of rTMS in depression
uGood evidence → level A in FinlanduMore than 20 meta-analyses: d has
varied between 0.4 and 0.7u In general, results are better in newer
studies and with MRI-based navigation(Gross et al. 2007, Fitzgerald et al. 2009,Schönfeldt-Lecuona et al. 2010, Johnsonet al. 2013)
![Page 23: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/23.jpg)
ECT is more effective than rTMS indepression (Slotema et al. 2010)
![Page 24: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/24.jpg)
Prediction of responseuYoung patients (Aguirre et al. 2010) ¬
neuroplasticityuEffective also for psychotic depression
(Ray et al. 2011)uEffective also for ECT-refractory patients
(Connolly et al. 2012)uEkstraversion predicts good response
(Berlim et al. 2013)
![Page 25: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/25.jpg)
rTMS in psychotic depression (N = 45, 67 % ofpatients were psychotic, Ray et al. 2011)
![Page 26: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/26.jpg)
Maintenance treatment of depression
uSteady maintenance: one session perweek, fortnightly sessions probablyinsufficient (Benadhira et al. 2017)
uTapering down session frequency, c.f.ECT (Connolly et al. 2012)
uClustered maintenance: 5 sessions duringa weekend (Fitzgerald et al. 2012)
![Page 27: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/27.jpg)
rTMS is more cost-effective than antidepressants inTRD (Nguyen and Gordon 2015)
![Page 28: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/28.jpg)
Ketamine in the treatment of depression 1u Non-competative NMDA-antagonist: developed as an
anaestheticu Fastest and most effective short-term treatment for
major depressionu Activity of AMPA-receptors increases → mTOR-
pathway activates → synaptic activity and number ofdendritic spines increases → enhancement of brainplasticity (Maeng et al. 2008, Li et al. 2010, Tizabi et al.2012, Cornwell et al. 2012, Zunszain et al. 2013)
u Used as a club-drugu Most common method: racemic ketamine 0.5
mg/kg/45 min i.v. once a weeku Short-term treatment (< 2 weeks) is evidence-based,
long-term treatment is still experimentalu Reliefs painu APA consensus statement (Sanacora et al. 2017)
![Page 29: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/29.jpg)
Ketamine once vs. twice a week
![Page 30: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/30.jpg)
![Page 31: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/31.jpg)
Ketamine in the treatment of depression 2
u Effective also for ECT-refractory patients(Ibrahim ym. 2011)
u Long-term safety in unknown - our hospital haslimited length of treatments to 3 months
u In apes, ketamine is neurotoxic in doses > 10mg/kg (Slikker et al. 2007)
u Ketamine abusers have impaired memory(Morgan et al. 2009) and decline of grey-matter volume in DLPFC (Liao et al. 2011)
u Main contraindications: previousschizophreniform psychosis, abuse history,blood in urine, risk of pregnancy, psychologicalincapacity to stand cessation of treatment
![Page 32: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/32.jpg)
Ketamine-dependence and grey-matterdecline: particularly right middle frontal
gyrus (Liao et al. 2011)
![Page 33: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/33.jpg)
Combinations
uMany possibilities, e.g. venlafaxine +mirtazapine + bupropion +psychotherapy + 1 Hz rTMS + ketamine(rTMS and ketamine on different days)
uVarious combinations may have long-term additive effects (Castren 2013)
uKetamine anaesthesia does not increasethe efficacy of ECT (McGirr et al. 2017),but may boost the response (Li et al.2017) – how about ECT and ketamine onseparate days?
![Page 34: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/34.jpg)
Single Ketamine infusion andescitalopram (Hu et al. 2015)
![Page 35: Repetitive Transcranial Magnetic Stimulation (rTMS) and intravenous ketamine … · 2017-12-07 · Ketamine in the treatment of depression 2 uEffective also for ECT-refractory patients](https://reader034.vdocuments.mx/reader034/viewer/2022042620/5f3f854aefa1904ad64b7639/html5/thumbnails/35.jpg)
Ketamine anaesthesia does notboost ECT (McGirr et al. 2017)