Maintenance repetitive transcranial magnetic stimulation (rTMS) for relapse prevention in with depression: A review

Psychiatry Research xxx (xxxx) xxx–xxx

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Maintenance repetitive transcranial magnetic stimulation (rTMS) for relapse prevention in with depression: A review Fady Rachid Private practice, 7, place de la Fusterie, 1204 Geneva, Switzeland

A R T I C L E I N F O

A B S T R A C T

Keywords: Resistance Depression Relapse prevention Maintenance rTMS

Major depressive disorder is a highly prevalent condition with significant morbidity and mortality. Recurrent episodes occur in greater than 50% of patients within a one year period despite treatment with antidepressant medications, electroconvulsive therapy and psychotherapy. Longer antidepressant treatment may prevent relapses and recurrences. Urgent therapeutic alternatives are needed such as maintenance repetitive transcranial magnetic stimulation. The purpose of this review is to describe and discuss studies that have evaluated the safety and efficacy of this technique in the long-term treatment and relapse prevention of depression. The electronic literature on maintenance repetitive transcranial magnetic stimulation for depression was reviewed. A limited number of controlled, open-label studies as well as case series have been published on maintenance rTMS after successful response to acute rTMS. In the majority of these studies, most patients with treatment-resistant unipolar or bipolar depression with or without medications experienced either moderate or marked benefit with maintenance rTMS, sometimes remission for three months and up to eight years. Many of the reviewed studies have shown promising results, however, future well-designed sham-controlled studies are needed to confirm the long-term safety and efficacy of maintenance rTMS in the relapse prevention of depression.

1. Introduction Major depressive disorder (MDD) is a chronic and recurring psychiatric disorder that results in a substantial burden for individuals, their family and the community. It has a lifetime prevalence of 14.6% in higher income countries and is ranked first among global causes of disease burden with significant morbidity and mortality (Moussavi et al., 2007; WHO, 2009; McMahon et al., 2012; Zivin et al., 2012). Although antidepressant medications, electroconvulsive therapy (ECT) and effective psychotherapies lead to a reduction in the mean length of depressive episodes (Folkerts et al., 1997; Prudic et al., 2004; Mulder and Frampton, 2014), only one-third of patients respond to their first antidepressant medication prescribed at adequate dose and duration (Sackeim, 2001; Rush et al., 2003, 2009; McLoughlin et al., 2007). After multiple trials of antidepressants and multi-drug regimens, only two-thirds of patients achieve remission (Gaynes et al., 2009). In patients who achieve remission, continuation and maintenance therapy are essential to prevent relapses and recurrences (Paykel, 2001)and the maintenance therapy phase should even last indefinitely (Hirschfeld, 2001; Nemeroff, 2007; Bauer et al., 2013). Transcranial magnetic stimulation (TMS) is a non-invasive neurostimulation technique that modulates cortical excitability (Wassermann and Lisanby, 2001; Hallett, 2007; Wagner et al., 2007). It uses

electromagnetic pulses of high intensity administered through a coil. The fast passage of electric current in the coil induces a transient, high intensity magnetic field that penetrates unimpeded through the scalp and reaches the underlying cortex. In the targeted cortex, this field can generate an electric current which can induce depolarization of superficial cortical neurons and interconnected areas beneath the coil (Hallett, 2007). In repetitive TMS (rTMS), trains of several pulses are delivered through repeated stimulation over the same area with frequencies ranging from 1 to 20 Hz. The safety of rTMS has been reported in a number of studies and the most recent guidelines for their use have been published in 2009 (Rossi et al., 2009). Recent meta-analyses have demonstrated a superior efficacy of high frequency rTMS to the left dorsolateral prefrontal cortex (LDLPFC), of low frequency rTMS to the right dorsolateral prefrontal cortex (RDLPFC) (Lam et al., 2008; Schutter, 2009; Slotema et al., 2010; Berlim et al., 2013, 2014; Chen et al., 2013; Gaynes et al., 2014) and to a lesser extent of bilateral rTMS (Zhang et al., 2015) compared to sham, mostly for the acute treatment of moderately resistant depression (TRD, failure to respond to at least two antidepressants) either as monotherapy and to a lesser extent as adjunctive treatment to antidepressants (Slotema et al., 2010). These meta-analyses have only focused on acute rTMS treatment and have not included maintenance rTMS outcomes.

E-mail address: [email protected]. http://dx.doi.org/10.1016/j.psychres.2017.09.009 Received 16 March 2017; Received in revised form 24 August 2017; Accepted 7 September 2017 0165-1781/ © 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Rachid, F., Psychiatry Research (2017), http://dx.doi.org/10.1016/j.psychres.2017.09.009

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F. Rachid

An open study (Benadhira et al., 2005) investigated the maintenance of efficacy of three months of 10 Hz rTMS over the LDLPFC after an acute phase of 10 Hz rTMS over the LDLPFC (one daily session over two weeks then three weekly sessions for two weeks) in eleven patients with TRD. At the end of the first month, the patients received one weekly session of rTMS over one month then one session each fortnight. At the end of the trial, rating scale scores were maintained and no statistical difference was found between the fourth week scores and the final scores. Eight patients responded and all patients had improved after four weeks of treatment. The clinical effect was maintained during the next three months and rTMS was well tolerated without any adverse effects. In a case report (Langguth et al., 2006), the authors reported on a 60-year old woman with TRD who had failed to respond to several antidepressants as well as to augmentation strategies. She underwent 15 sessions of 20 Hz rTMS over the LDLPFC during three weeks while her medication doses were kept unchanged. Her depressive symptoms decreased after one week of rTMS and almost completely disappeared toward the end of the treatment. She relapsed twice during the following seven months. After both relapses, rTMS treatment resulted in remission of her depressive episodes. After her second relapse, she underwent five sessions of daily rTMS every fifth week and one week of daily rTMS per month as maintenance rTMS. Consequently, the patient remained free of any further depressive episodes during a follow-up period of 12 months. Dell'Osso and Altamura (2009) reported on a 60-year old woman on medications with drug-resistant bipolar I depression who showed a significant improvement to three weeks of neuro-navigated 1 Hz rTMS of the RDLPFC. She had a history of poor response to several antidepressants sometimes combined to lithium or to valproate. After the completion acute rTMS, she underwent maintenance rTMS every other week for an additional six months at the end of which she maintained her therapeutic gains. There were no side effects reported except for slight headaches. Brunelin et al. (2010) reported on a 63-year old woman with type I bipolar disorder who had a history of manic and depressive episodes despite receiving many treatment combinations (antipsychotics, mood stabilizers) along with bilateral ECT followed by maintenance ECT (one session per week for one month followed by one session every two weeks) without relapse. The patient underwent new courses of ECT after she relapsed until she remitted before developing paroxysmal atrial fibrillation. ECT was thus prohibited but the patient relapsed into depression with melancholic features. The patient was then treated with a combination of lithium and 20 sessions of 5 Hz rTMS over the LDLPFC for four weeks. After the 15th session, recovery was obtained and maintenance rTMS with two sessions once per week during four weeks was started after the 20th session after which she received two sessions the same day every two weeks for one year. During this time, the patient received only rTMS and lithium without relapse or other side effects. In a naturalistic follow-up study (Dell'Osso et al., 2011) investigated the long-term efficacy and discontinuation effects of augmentative neuro-navigated 1 Hz rTMS to the RDLPFC in 11 drug-resistant bipolar depressed patients who entered a naturalistic follow-up with maintenance rTMS. Six patients (55%) responded of whom four remitted (36%). Partial response was achieved by three patients (27%). All patients, including six full responders (including four remitters), three partial responders and two non-responders to rTMS were prospectively followed up for one year. At 1-year follow-up, four patients (36% of the sample, 66% of the responders) maintained the same level of improvement achieved after the acute phase (three patients remained remitters). In a retrospective cohort study (Connolly et al., 2012), the authors examined the effectiveness and safety of up to 30 sessions of flexibly dosed 10 Hz rTMS (six weeks) over the LDLPFC (some patients underwent 1 Hz rTMS over the RDLPFC or bilateral rTMS) adjunctive to

The scientific literature on maintenance rTMS in the treatment of depression is scarce. In this review, I describe and discuss the studies that assessed the safety and efficacy of maintenance rTMS after a successful acute course of rTMS or ECT. I also compare the results of these studies with those that focused on observation with maintenance rTMS or without treatment after acute rTMS. 2. Materials and methods Using the search terms “depression”, “maintenance", ”continuation”, “relapse prevention”, “transcranial magnetic stimulation,” “repetitive transcranial magnetic stimulation,” and “rTMS”, 20 controlled and open-label studies as well as case series on humans published in English until January 2017 were retrieved through NCBI Pubmed search. Overall, these were studies on relapse prevention of depression with maintenance rTMS, sometimes compared with observation only after response to an acute course of rTMS or ECT (Abraham and O'Brien, 2002; Li et al., 2004; Conca et al., 2004; O'Reardon et al., 2005; Benadhira et al., 2005; Langguth et al., 2006; Dell'Osso and Altamura, 2009; Brunelin et al., 2010; Dell'Osso et al., 2011; Connolly et al., 2012; Freitas et al., 2012; Chatterjee et al., 2012; Fitzgerald et al., 2013; Özten et al., 2013; Richieri et al., 2013; Dunner et al., 2014; Burton et al., 2014; Haesebaert et al., 2016; Philip et al., 2016) (Table 1). 3. Results Abraham and O'Brien (2002) reported on a 45-year old woman with recurrent MDD who for at least two years had been on different antidepressants that were minimally effective in relieving her depressive symptoms. The patient responded to 10 sessions of rTMS but relapsed during the two week post-rTMS follow-up. She was therefore offered maintenance rTMS given weekly or bi-weekly and maintained response to such treatment for four months without any adverse effects. Li et al. (2004) reported on seven patients with bipolar depression who had responded acutely to 5 Hz rTMS to the LDLPFC and were then treated for one year with weekly sessions of maintenance rTMS. Three patients maintained partial remission. Conca et al. (2004) reported on a 48-year old woman suffering from recurrent moderate resistant MDE, six months after discontinuation of maintenance unilateral d’Elia ECT. She responded to five sessions of 1 Hz rTMS to the RDLPFC and St. John's wort. One week later, she underwent continuation rTMS, three times a week for three weeks, followed by once weekly maintenance rTMS for further three weeks then rTMS bi-weekly. Her clinical condition remained stable for another eight weeks and no side effects were observed. After switching from weekly to one session bi-weekly rTMS treatment, the patient relapsed to a severe MDE. Therefore, she was switched to three sessions weekly of unilateral d’Elia ECT for one week and subsequently once per week for six weeks and went into remission. A retrospective chart review (O'Reardon et al., 2005) described longterm maintenance therapy for MDD with one to two sessions per week of 10 Hz rTMS over the LDLPFC (one patient after three weeks at 10 Hz received 1 Hz rTMS LDLPFC for the next 59 weeks, another patient subsequently at 20 Hz LDLPFC) for periods ranging from six months to six years in ten patients with TRD immediately after responding to an acute course of rTMS in an open label or randomized controlled study (Szuba et al., 2005). Fifty percent of the patients experienced marked benefit (mean number of sessions 2.1/week) for nine months to five years and 20% experienced moderate benefit (both had recurrence of MDE over a 12- to 18-month time period; mean number of sessions 1.7/week) which was sustained without the addition of concomitant antidepressant medication in three cases. Three patients had minimal benefit from maintenance rTMS (mean number of sessions 1.7/week). There were no serious adverse events and no seizures reported by any patient except for occasional headaches, one subject had dizziness and jaw tremor, another subject had ear and sinus pains and one subject had a nose bleed. 2

3

Case report

Open-label naturalistic f/u study assessed efficacy over 1 yr and d/c effects augmentative neuro-navigated 1 Hz rTMS RDLPFC in ttresistant depressed BD I or II pts

Dell’Osso et al. (2011)

Open study assessed efficacy 3 mos 10 Hz mTMS LDLPFC in TRD pts after acute rTMS LDLPFC

Benadhira et al. (2005)

Brunelin et al. (2010)

Study described long-term mTMS for TRD with 1–2 sess./ wk 10 Hz rTMS LDLPFC for 6 mos-6 yrs in pts TRD after responding to acute rTMS

O'Reardon et al. (2005)

Case report

Case report

Conca et al. (2004)

Dell'Osso and Altamura (2009)

Case series

Li et al. (2004)

Case report

Case report

Abraham and O’Brien (2002)

Langguth et al. (2006)

Study Design

Authors

Table 1 List of maintenance rTMS studies.

Meds unchanged N = 1 63 yr f BD I rapid cycling, several hospitalizations 2° mania, MDE despite tt with antipsychotics, mood stabilizers, and/or anticonvulsants), bilat. ECT then mECT (1 sess./wk for 1 mo then 1 sess. every 2 wks) without relapse N = 11 pts TRD in BD, type I (N=5) or II (N = 6), 3 m, 8 f, meds (valproate, SSRIs, SNRIs, bupropion) unchanged during f/u except for non-responders 6 responders (4 remitters), 3 partial responders, 2 non-responders to rTMS f/ u for 1 yr

N = 1 60 yr f tt-resistant BD I depression rapid cycling, poor response to paroxetine, sertraline, venlafaxine, duloxetine combined to lithium, bupropion plus valproate HDRS-21, MADRS scores 19 and 22, resp.

N = 1 60 yr f recurrent resistant MDD failed several AD and augmentation Meds unchanged (venlafaxine, escitalopram, valproate, lithium, lamotrigine)

N = 11 TRD pts failed ≥ 2 AD, 6 f, 5 m, mean age 47.2 ± 12.8 yrs, duration illness 9.0 ± 7.5 yrs, mean score HDRS baseline 24.1 ± 3.7

N = 10 pts TRD (6 f, 4 m), mean age 50 ± 16 yrs failed ≥ 1 AD, 2 pts prior responders to ECT

N = 1 48 yr f recurrent mod. resistant MDE, 6 mos after d/c mECT, resistant to various AD, score 18 HDRS-24, 5 CGI, vitamin E, St. John's wort

N = 1 45 yr f chronic recurrent MDD For 2 yrs, nefazodone, moclobemide, venlafaxine, citalopram, nortriptyline, mirtazapine min. benefits Responded partially to phenelzine N = 7 pts BD depression

Clinical and Demographic Data

15 sess., 3 wks, neuro-navigated 1 Hz rTMS RDLPFC, 110% MT, 300 pulses/sess. augmented to pts’ pharmacological tt

20 sess., 1 sess/d, 4 wks, 5 Hz rTMS LDLPFC, 110% MT, 8 s on, 22 s off, 2000 pulses/sess with lithium then mTMS, 2 sess. 1 d/wk for 4 wks then 2 sess./d every 2 wks for 1 yr

15 sess., 1/d, 3 wks, neuro-navigated 1 Hz rTMS RDLPFC, 110% MT, 5 trains, 60 s on, 60 s off, 300 pulses/sess. then mTMS every other wk (2 sess. every 15 d) for 6 mos

After 2nd relapse, 5 sess. daily mTMS every 5th wk and 1 wk daily rTMS/mo

15 sess., 5 sess./wk, 3 wks, 20 Hz LDLPFC, 90% MT, 40 trains, 2.5 s on, 25 s off, 2000 pulses/sess.

5 sess., 1 wk, 1 Hz rTMS RDLPFC, 110% MT, 1 Hz, 1 train, 600 s on, 600 pulses/sess. then cTMS3 times/wk for 3 wks then once/wk rTMS for 3 wks then rTMS biweekly (1 sess.) thenunilat. d’Elia ECT, 3 sess./wk, 15 sess., 6 wks then cECT Multiple sess. 10 Hz rTMS LDLPFC, 100% MT, 40 trains, 5 s on, 25 s off, 2000 pulses/sess. then 1–2 sess./wk, 10 Hz rTMS LDLPFC, 100% MT, 40 trains, 5 s on, 25 s off, 2000 pulses/sess., 1 pt after 3 wks 10 Hz, 1 Hz rTMS LDLPFC for next 59 wks, 1 pt subsequently at 20 Hz LDLPFC 10 Hz rTMS LDLPFC, 10 Hz, 80% MT, 26 trains, 1600 pulses/sess., 1 sess./d, 2 wks then 3 weekly sess. for 2 wks then 3 mos 10 Hz mTMS LDLPFC, 1 weekly sess. over 1 mo then 1 sess. each fortnight

5 Hz rTMS LDLPFC then weekly mTMS for 1 yr, 110% MT, 40 trains, 8 s on

10 sess. rTMS then mTMS weekly or bi-weekly, parameters not described

Stimulus Parameters

At 1-yr f/u 4 pts (36% sample, 66% responders) maintained same level improvement vs. acute phase

Depressive recurrences HDRS total score > 18 Response end point HDRS-21 score ↓ ≥ 50% vs. baseline

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6 pts (55%) responded, 4 of whom remitters (36%), 3 pts (27%) partially responded, 2 pts (18%) no response

At end mTMS, pt maintained therapeutic gains with HDRS-21, MADRS scores 7, 11 resp., CGI-I ‘very much improved’ No AEs, slight h/a After 15th rTMS sess., recovery obtained, MADRS score ↓ from 31 to 8 With mTMS MADRS scores between 7 and 9 No AEs

Despite tt with escitalopram, lithium, lamotrigine, pt relapsed twice within 7 mos Pt remitted to repeated rTMS tt then maintained remission with mTMS for 12 mos No AEs Signif. improvement to rTMS, HDRS-21, MADRS, scores 8, 11 resp., CGI-I very much improved

70% pts mod./marked benefit (7/10), 3 without AD for 9 mos-5 yrs, 2 pts with recurrence MDE over 12–18-mo, 3 pts min. benefit from mTMS (mean n sess. 1.7/wk) No serious AEs, occasional h/a, 1 pt dizziness and jaw tremor, 1 pt ear and sinus pains, 1 pt nose bleed 8 pts responded, mean HDRS scores ↓ signif. by end 1st mo (mean 10.3 ± 3.9) No statistical diff. between wk 4 and final scores Effect maintained during next 3 mos, mean HDRS score 10.4 ± 5.1 No AEs Depressive sx ↓ after 1 wktt, disappeared end rTMS tt, score HDRS-21 ↓ from 30 to 3

No AEs 7 pts with BD depression responded acutely to rTMS 3 pts completed 1 yr weekly rTMS with mean HDRS 13 ± 5.9 Pt responded to rTMS and St. John's wort Within 2 moscTMS bi-weekly, relapsed to severe MDE, HDRS score 23, CGI score 6, switched to ECT with remission within 4 wks No AEs

Pt responded to rTMS, HDRS score ↓ from 21 to 10 2 wk post-rTMS f/u, pts relapsed, HDRS score ↑ to 16 Pt responded to mTMS, well for 4 mos

Results

Monthly evaluations with HDRS-21, YMRS from beginning study, 3, 6, 12 mos

assessed at end each wk with CGI-I, HDRS-21, MADRS (Montgomery and Asberg, 1979), YMRS (Young et al., 1978) Safety, tolerability assessed at each sess. MADRS

Clinical conditions

HDRS-21

Response > 50% ↓ HDRS scores

HDRS at baseline, after 1mo, after 4 mos

Response > 50% ↓ HDRS scores

HDRS, CGI-I

HDRS-24, CGI (Guy, 1976)

HDRS

HDRS (Hamilton, 1967)

Rating Scales and Outcome Measures

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Open label study clustered mTMS pts TRD who responded to 2 courses rTMS

Case report

Prospective naturalistic study determined whether 20

Fitzgerald et al. (2013)

Özten et al. (2013)

Richieri et al. (2013)

Case report

Freitas et al. (2012)

Case report

Retrospective study assessed effectiveness, safety acute rTMS in pts treated for unipolar or bipolar MDE with flexibly dosed rTMS up to 30 sess. adjunctive to meds then mTMS for 6 mos

Connolly et al. (2012)

Chatterjee et al. (2012)

Study Design

Authors

Table 1 (continued)

N = 59 pts TRD (most pts) or refractory BD no response to ≥ 2 AD in current

N = 1 24 yr f 17-wk pregnant TRD

reboxetine, mirtazapine, neuroleptics, mood stabilizers (anti-epileptic meds), TCA, MAOIs, lithium All but 1 pt on AD Meds mostly continued until pts relapsed and subsequently during 2nd period acute tt and mTMS

20 sess., 6 d/wk, 25 Hz rTMS LDLPFC, 2 s on, 30 s off, 1000 pulses/sess. with CBT twice/wk then 10 sess. 25 Hz rTMS then 46 sess. mTMS, once/wk 6 wks acute 10 Hz rTMS LDLPFC, 120% MT, 5 s on, 25 s off, 2000 pulses/sess. or 1 Hz rTMS RDLPFC,

12 pts 1 Hz rTMS RDLPFC, 110% MT, 1 train, 900 s (5 with preceding priming 6 Hz stimulation), 9 pts sequential bilat. rTMS (6 pts bilat. 1 Hz, 3 pts 10 Hz LDLPFC and 1 Hz RDLPFC) 15 d, Then 5 sess. mTMS over 2,5 d every 4 wks

14 pts 10 Hz rTMS LDLPFC, 110% MT, 30 trains, 5 s on, 25 s off, 5 Hz rTMS LDLPFC, 110% MT, 30 trains, 10 s on, 20 s off

Further rTMS sess., 20 sess./episode, 20 Hz rTMS DLPFC, 100% MT, 20 trains, 10 s on, 60 s off, total 2000 pulses/sess. 3 wks

Thase-Rush Staging Method stage 3

N = 35 pts TRD or refractory BD, 26 (74%) MDD, 9 (26%) BD depression, mean age 44.8 ± 13.3 yrs, 8 m, 27 f, mean n failed AD 6.2 ± 4.0 Pts had all responded to 2 courses rTMS Onbenzodiazepines, SSRIs, venlafaxine, bupropion,

3 wks, 15 sess. 15 Hz rTMS LDLPFC, 100% MT, 20 trains, 10 s on, 60 s off, 3000 pulses/sess.

N = 30 yr f TRD, 3 trials AD and augmentation strategy maintained partial remission

2 mos later, 10 sess., 2 wks, 1 Hz rTMS TP3, 90% MT, 1200 pulses/sess. no mTMS for AH

15 sess., 3 wks, 20 Hz rTMS LDLPFC, 110% MT, 2 s on, 28 s off, 1600 pulses/sess. then weekly mTMS sess. for 6 mos and once every 2 wks thereafter

6 wks, initially 10 Hz rTMS LDLPFC, 110–120% MT, 5 s on, 15 s off, 4000 pulses/sess., some pts 1 Hz, 1 train, 300–1200 pulses/ sess. or bilat. rTMS rTMS RDLPDC followed by 6 mos mTMS 6 sess. over 3 wks (3 sess. wk 1, 2 in wk 2, 1 in wk 3) then sess./wk for 4 wks, 2/mo for 2 mos and 1/mo for 3 mos

N = 42 pts (49%) tt-resistant, mean 3.4 failed AD index MDE, entered 6 mos mTMS Meds unchanged 31 pts received prior ECT

N = 1 48 yr m PMD + AH, failed ECT, score 30 HDRS-24, 55 GAF, trials several AD, mood stabilizers, antipsychotics mod. relief Meds kept constant (citalopram, bupropion, quetiapine, clonazepam) Score 30 HDRS-24 and 55 GAF

Stimulus Parameters

Clinical and Demographic Data

HDRS-17, BDI, BAI, BPRS (Overall and Gorham, 1962) applied during admission and f/u

Remission HDRS score < 8

Response > 50% ↓ HDRS score

Severity AVH assessed with 11-item AH subscale PSYRATS (Haddock et al., 1999) at baseline, at end wk 2 rTMS TP3 N voices daily recorded with 7-item AHRS (Hoffman et al., 2003) Tt effects assessed daily with VAS and at 12, 36, 52 wks post-AVH tt f/u for 3 yrs

HDRS-24, BDI-II, GAF (Endicott et al., 1976) administered before, after rTMS

Enduring benefit assessed over 6 mos in pts on mTMS 1° outcome measure

2° outcomes change in HDRS, QIDS-SR (Rush et al., 2003), BDI (Beck and Beamesderfer, 1974), BAI (Beck et al., 1988)

Partial response end point HDRS-21 score ↓ between 25% and 50% Euthymia HDRS-21 score ≤8 1° outcomes response, remission rates at tt end point measured by CGI-I at 6 wks

Rating Scales and Outcome Measures

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At 20 wks,relapse rate signif. diff. between 2 gps 32 pts (54.2%) relapsed, 27 pts no relapse (45.8%)

10 additional pts continued mTMS until withdrawal from study without relapse (4 at mean 6.2 ± 4.3 mos) or until study end (6 pts mean duration 12.0 ± 9.7 mos) Pt's anxiety, depression ↓ with acute rTMS After 46 sess. mTMS, pt in remission

Only 1 pt psychotic sx During active acute rTMS, pts had ↓ HDRS-17 scores from 22.9 ± 7.6 to 6.8 ± 3.9, BDI scores from 36.2 ± 12.5 to 12.8 ± 9.5 Of 35 pts who entered study, 25 relapsed after mean 10.2 ± 9.6 mos (range 2–48 mos)

On entry to mTMS, 20 pts remission, 10 mild depressive sx, 5 mod., depressive sx

Pt's sx improved by 15 sess. After further 5 sess. sx remitted 3rd MDE 1 mo mod. resolved with 5 sess. rTMS Next 2 yrs, 2 mod. MDE 3 mos required 20 rTMS sess. Pt adequately f/u for 3 yrs for 4 MDE after starting rTMS with mean duration remission period 7 mos No AEs

No AEs

Amelioration AVH severity with rTMS TP3 (PSYRATS-AH 53% change), maintained at 3 mo, 9 mo, 1 yr, BDI-II scores at 3, 9, 12 mos 8, 11, 5, resp.

rTMSsignif. improved depression with BDI-II score from 44 to 5 lasting 14 mos, AVH unchanged

At 6 wks, CGI-I response rate 50.6%, remission rate 24.7%, HDRS response, remission rates 41.2% and 35.3%, resp. Mean change −7.8 points HDRS score, −5.4 QIDSSR, −11.4 BDI, −5.8 BAI 62% pts (26/42) maintained responder status at last assess. during mTMS d/c rate 3% acute tt phase No serious AEs during acute or maintenance tt

Results

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Case report

3-arm open-label study assessed safety, efficacy 1 Hz rTMS RDLPFC, venlafaxine or combination both as maintenance tt in pts with TRD including remitters to rTMS, venlafaxine or combination both tts continued to receive tt that led to response as maintenance tt over 12 mos.

Haesebaert et al. (2016)

Naturalistic study assessed 12 mos effectiveness rTMS following acute tt in pts with unipolar, nonpsychotic MDD who did not benefit from AD and who received acute rTMS with f/u over 52 wks

MDE, 54.2% m, mean age 53.4 ± 12.2 yrs, mean disease duration 15.6 ± 12.6 mos Pre-tt with AD and/or mood stabilizer stable for at least 2 wks prior to entry in study Pts with AD

wksmTMS or no additional rTMS associated with ↓ relapse rate depression after successful acute rTMS pts with TRD

Pt continued lamotrigine, thyroxine, olanzapine, mirtazapine, pregabalin, lithium N = 66 pts TRD including 45 remitters who responded to rTMS (N = 25), venlafaxine (N = 22) or combination both tts (N = 19) continued to receive tt that led to response as maintenance tt over 12-mo treatment

N = 1 34 yr old f MDD pregnant

After 1st mo, when majority acute rTMS tapering completed, 93 pts (36.2%) received reintroduction rTMS

Proportion pts in remission who experienced sx relapse (defined as a QIDS-SR total score ≥11 at any observation time point during long-term follow-up as noted above) examined. A QIDS-SR total score < 6 at entry into long-term follow-up defined remission. In this analysis, we used the QIDS-SR to permit a direct comparison of clinical significance with other published benchmarks, which used the same outcome measures to define remission and relapse

depression scale (Zung, 1965) Response 50% ↓ HDRS score Severity depression assessed at 1, 3, 6, 12 mos after end acute tt phase with HDRS-17

To assess efficacy maintenance strategies, compared n pts who maintained remission (HDRS-17 < 8) and n pts who did not relapse (HDRS17 < 15) at end point (mo 12) between 3 gps

1 Hz rTMS, 120% MT, 6 trains, 60 s on, 30 s off, 360 pulses/sess.

mTMS administered twice/wk for 1 mo, once/wk for 2 mos and once every 2 wks for 9 mos Venlafaxine maintained at dose that induced clinical response (150 or 225 mg/d)

Partial responders based on PHQ-9, IDS-SR decrease > 25% but < 50% at endpoint vs. baseline rating HDRS, Zung self-rated

Assessments obtained at 3, 6, 9, and 12 mos Efficacy measures CGI-S, IDS-SR, PHQ-9 (Kroenke et al., 2001) CGI-S response endpoint rating 3 or less (ie, “mildly ill” or better), remission endpoint rating 2 (“borderline mentally ill”) or 1 (“normal/not at all ill”) PHQ-9 response defined as endpoint score < 10, remission defined as endpoint score < 5 IDS-SR response defined as ≥ 50% reduction at endpoint from baseline rating, remission defined as endpoint score < 15 IDS-SR remission defined as endpoint score < 6, score ≥ 11 used to define relapse Non response PHQ-9 and IDS-SR decrease < 25% at endpoint vs. baseline rating; CGI-S end acute tt score ≥ 4 and ≤ 1 point decrement from baseline or endpoint score < 4 and no change or worsening vs.

Remission BDI score < 12 Relapse 50% ↑ sx severity between t1 (end acute rTMS) and t2 (end mTMS) 1° outcome CGI-S

anxiety after acute tt (t1), monthly during maintenance tt, and at 20 wks (t2) Response > 50% ↓ sx severity

1° measure time to 1st relapse during 20-wk period (end rTMS maintenance tt) following acute TMS tt Depression severity assessed with BDI-21 STAIState (Spielberger et al., 1983) addressed state

Rating Scales and Outcome Measures

2 wks with meds

3 d/wk, 6 wks, 18 sess. sequential bilat. 10 Hz rTMS LDLPFC, 110% MT followedby 1 Hz rTMS RDLPFC then mTMS once every

Mean n rTMS tt d 16.2 ± 21.1

10 Hz rTMS LDLPFC, 120% MT, 75 trains, 4 s on, 26 s off (no stimulation), 3000 pulses/sess. over 12 mos

120% MT, 180 s on, 30 s off, 720 pulses/sess. followed by taper phase 7 sess. over 3 wks (3 sess. wk 1, 2 sess. wks 2, 3) then pts received either 20 wks maintenance rTMS, 1 sess./wk for 2 wks, 1 sess./2 wks for 2 mos, then 1 sess./month for 2 mons (N=37) or no additional tt (N=22) If response orremission criteria achieved pt proposed to enter maintenance tt

Stimulus Parameters

N = 257 pats with unipolar, nonpsychotic MDD

or mood stabilizer monotherapy, combination AD, combination AD and mood stabilizer, anticonvulsantsNo benzodiazepine administered

Clinical and Demographic Data

Study Design

Burton et al. (2014)

Dunner et al. (2014)

Authors

Table 1 (continued)

(continued on next page)

Pt remitted after 2 acute courses rTMS then mTMS for 4 yrs, became pregnant, gave birth healthy infant Remission maintained during and after pregnancy No AEs to pt or infant during pregnancy or postnatal period At 12-mo f/u remitter rate not different between 3 gps Rates pts without relapse not different between gps: 40.0% rTMS gp, 45.1% venlafaxine gp, 36.9% combination grp At 12-mo, remission rate 18.7% (N = 3) in rTMS gp, 35.3% (N = 6) in venlafaxine gp, 33.3% (N = 4) in combination gp not statistically diff. Comparable relapse rate 4.0% in rTMS gp, 4.5% in venlafaxine gp, 5.3% in combination gp

205 pts completed evaluations through 12 mosvs. pre-rTMS baseline statistically signif. reduction mean scores CGI-S, PHQ-9, IDS-SR at end acute tt sustained throughout f/u Among 120 pts who responded or remitted at end acute rTMS, 75 (62.5%) still responders throughout long-term f/u, among 44 pts who responded, 25 (56.8%) still responders throughout at every time point of whom 5 pts (11.4%) still remitters at every time point, among 76 pts who remitted at entry into long-term f/u, 50 (65.8%) sustained response or remission (50.0%) at every time point, among 45 responders or remitters who did not maintain sustained response, sx reemergence occurred during 1st 6 mos f/u (mos 0–3: N = 17, mos 4–6: N = 14, mos 7–9: N = 9, mos 10–12: N = 5) After 1st mo, when majority acute rTMS tapering completed, 93 pts (36.2%) received reintroduction rTMS Among these, 12/15 (80.0%), 15/19 (78.9%), 15/27 (55.6%), 11/32 (34.4%) non-responders, partial responders, responders, remitters, resp., experienced later relapse illness

Among responders relapse rate signif. different between 2 gps, 14 pts in mTMSgp (37.8%) vs. 18 in non-mTMSgp (81.8%) relapsed mTMS with signif. lower relapse rate in pts tt statistically associated with ↓ relapse Among pts with relapse, mean time relapse similar both gps resp. 2.36 mos in maintenance gp, 2.22 mos (71.51) in gp without mTMS No AEs, mild h/a 5 pts (8.5%)

Results

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Randomized, open-label, multisite study assessed 12-mo outcomes comparing 2 maintenance approaches: scheduled, single monthly rTMS sess. (gp 1) vs. observation only (gp 2) in ADfree pts TRD meeting criteria for improvement after 6 wks acute rTMS.

Philip et al. (2016) 30 sess. 5 d/wk, 6 wks, 10 Hz rTMS LDLPFC, 120% MT, 75 trains, 4 s on, 26 s off, 3000 pulses/sess. followed by randomization into

mTMS for pts with response criteria acute phase single rTMS sess. once every 4 wks; or gp 2: observation only at each f/u visit

All randomized pts underwent 3 wk rTMS taper

49 pts (73%) met randomization criteria

Min. sx severity moderate CGI-S (total score ≥ 4), score HDRS-17 at least 20

Stimulus Parameters

N = 67AD-free pts unipolar, nonpsychotic TRD, m or f, aged 18–70, failed to benefit from at least 1 but no more than 4 AD, current MDE at least 4 wks but no longer than 3 yrs

Clinical and Demographic Data

Sustained response not requiring rTMS reintroduction at any observation point during maintenance for remission (HDRS-17 < 8, HDRS24 < 11) or recovery (MADRS < 10) and response (≥ 50% ↓ from baseline score MADRS, HDRS-24, HDRS-17) Sx assessed at each monthly f/u visit in both gp 1 and 2 Sx recurrence mandating rTMS reintroduction total score HDRS-17 ≥ 16 and ≥ 25% worsening from HDRS-17 score at entry into maintenance phase

HAMD-24, MADRS, CGI-S, IDS-SR, PHQ-9 Response (acute phase to endpoint) HDRS-17 score < 15 and > 25% 1° objective evaluate efficacy mTMS every 4 wks by examining % pts with sustained response throughout 12 mo maintenance phase

Rating Scales and Outcome Measures

Gp 1 pts had non-signif. longer time to 1st rTMS reintroduction, 91 ± 66 d vs. gp 2, 77 ± 52 d Gp 2 pts non-signif. more likely to need reintroduction rTMS Reintroduction lasted 14.3 ± 17.8 d (gp 1) and 16.9 ± 18.9 d (gp 2), 14/18 (78%) gp 1, 17/27 (63%) gp 2 responded to reintroduction

3 maintenance approaches similar efficacies in relapse prevention and maintenance remission in pts with TRD After 12-mo f/u, rates remitters not different between 3 gps Rates pts not relapsed not different between gps (40.0% in rTMS gp, 45.1% in venlafaxine gp, 36.9% in combination gp 16 pts (32.7%) completed 53 wks study

Results

Legend and abbreviations: AD: antidepressant; AE: adverse effect; AH: auditory hallucinations; AHRS: Auditory Hallucinations Rating Scale; AVH: auditory verbal hallucinations; BAI: Beck's Anxiety Inventory; BD: bipolar disorder; BDI: Beck's Depression Inventory bilat.: bilateral; BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression Scale; cTMS: continuation rTMS; d: day; diff.: different; f/u: follow-up; GAF: global assessment of functioning; gp(s): group(s); h/a: headache; HDRS: Hamilton Depression Rating Scale; IDS-SR: Inventory of Depressive Symptomatology; MADRS: Montgomery-Asberg Depression Rating Scale; MDE: major depressive episode; min.: minimal; mo(s): month(s); mod.: moderate; MT: motor threshold; mTMS: maintenance rTMS; n: number; pt(s): patient(s); PHQ-9: Patient Health Questionnaire; PSYRATS: psychotic symptom rating scalesresp.: respectively; s: second; signif.: significant; SNRIs: selective norepinephrine reuptake inhibitors SSRIs; selective serotonin reuptake inhibitors; STAI-State: State-Trait Anxiety Inventory; sx: symptoms; TP3: left temporoparietal; TRD: treatment-resistant depression; tt: treatment; unilat.: unilateral; VAS: visual analog scale; vs.: versus; wk(s): week(s); YMRS: Young Mania Rating Scale; yr: year; ↑: increase; ↓: decrease.

Study Design

Authors

Table 1 (continued)

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of 12.0 ± 9.7 months). Of the 25 patients who relapsed, ten (40%) were provided a course of acute intensive rTMS treatment with one treatment session five days per week for a total of 20 treatment sessions. No adverse effects were reported. Özten et al. (2013) reported on a 24-year-old, 17-week pregnant patient with TRD who underwent two courses of 25 Hz rTMS over the LDLPFC along with cognitive behavioral psychotherapy, twice a week and responded, relapsing between the two courses. After she responded to the second course of rTMS, she maintained remission at 38 weeks with weekly sessions of maintenance rTMS and delivered a healthy baby. In a prospective naturalistic study (Richieri et al., 2013), 59 patients with TRD or refractory bipolar depression who responded to up to six weeks of acute 10 Hz rTMS to the LDLPFC or 1 Hz rTMS to the RDLPFC received either 20 weeks of maintenance rTMS (N = 37) after a taper phase over three weeks or no additional rTMS treatment (n = 22). Maintenance rTMS was applied one session per week for two weeks, one session per two weeks for two months and then one session per month for two months. At 20 weeks, among the 59 patients, 32 patients (54.2%) had a relapse, 27 patients had no relapse (45.8%) and the relapse rate was significantly different between the two groups, 14 patients in the maintenance rTMS group (37.8%) compared with 18 in the non-maintenance rTMS group (81.8%). Among patients with relapse, the mean time to relapse was similar in both groups respectively 2.4 months in the maintenance group and 2.2 months in the group without maintenance rTMS. There were no major side effects except for mild headache. A naturalistic study (Dunner et al., 2014) assessed the long-term effectiveness of rTMS in 205 patients with MDD who participated in an acute efficacy rTMS treatment outcome study (Carpenter et al., 2012), did not benefit from antidepressant medication and, regardless of outcome, consented to follow-up over 12 months with 10 Hz rTMS over the LDLPFC. There was a statistically significant reduction in depressive symptoms according at the end of acute treatment which was sustained throughout follow-up. Among 120 patients who responded or remitted at the end of acute rTMS, 75 (62.5%) maintained response criteria throughout long-term follow-up and among the 44 patients who responded, 25 (56.8%) sustained response status at every time point five of whom (11.4%) sustained remission at every time point. Among the 76 patients who were remitters at entry into long-term follow-up, 50 (65.8%) sustained their response or remission status (50.0%) at every time point. Among the 45 responders or remitters who did not maintain a pattern of sustained response, symptom reemergence tended to occur during the first six months of follow-up. After the first month, when the majority of acute rTMS tapering was completed, 93 patients (36.2%) received reintroduction of rTMS. Burton et al. (2014) reported on a pregnant patient with recurrent MDD on maintenance rTMS with pharmacotherapy who achieved remission following two acute courses of three days per week for six weeks of sequential bilateral rTMS 10 Hz rTMS to the LDLPFC followed by 1 Hz rTMS to the RDLPFC and continued with maintenance rTMS (one session per week) over the course of four years during which she became pregnant while on lamotrigine and pregabalin. Then, her treatments were reduced to one every two weeks and then further to one every three weeks then increase to one every two weeks along with medications with continued remission for four years including during and after her pregnancy. A three-arm open-label study (Haesebaert et al., 2016) investigated the safety and clinical efficacy of 1 Hz rTMS applied over the RDLPFC, venlafaxine or a combination of both treatments as a maintenance treatment in 66 patients with TRD who responded or remitted to rTMS (N = 25), venlafaxine (N = 22) or a combination of both treatments (N = 19) (45 remitters; 16 remitters from the rTMS group, 17 remitters from the venlafaxine group and 12 remitters from the ‘combination’ group) in a multi-centric randomized controlled study (Brunelin et al., 2014). Patients continued to receive the treatment that led to a

medications followed by six months of maintenance rTMS in 85 patients treated for a treatment resistant MDE in either MDD (N = 65) or bipolar disorder (N = 20). The response and remission rates were 41.2% and 35.3% at six weeks, respectively. After a three-week rTMS taper phase, forty-two patients (49%) entered six months of maintenance rTMS (one session per week for one month then two sessions per month for two months then once per month for three months), 62% of patients (26/42) maintained their responder status at the last assessment during the maintenance treatment over six months. rTMS was well tolerated. No serious adverse events related to rTMS except for headache, scalp discomfort, nausea and dizziness during acute or maintenance treatments. Freitas et al. (2012) reported on a 48-year old man with chronic severe depression and auditory verbal hallucinations (AVH) with previous failure of 12 sessions of ECT and several years of psychotherapy. To treat his depressive symptoms, the patient underwent 15 daily sessions of 20 Hz rTMS over the LDLPFC for three weeks which significantly improved and stabilized his clinical condition for 14 months along with weekly/biweekly maintenance rTMS but AVH were still present. The patient thus underwent two months later a further course of ten daily sessions (over two weeks) of 1 Hz rTMS to the left temporoparietal cortex (TP3) resulting in a significant reduction of AVH severity with continued improvements noticed at three months’ follow-up and maintained at nine-month follow-up and 12 months after AVH treatment. Starting one week after rTMS for AVH, the patient continued weekly maintenance sessions of 20 Hz rTMS to the LDLPFC for depression lasting approximately six months and once every two weeks thereafter while no rTMS treatment was administered to prevent the relapse of AVH. No complications or adverse effects of TMS were experienced at any time. Chatterjee et al. (2012) reported on a 30-year old woman with TRD who had been followed up for about three years with a first MDE that lasted nine months. She had two trials of SSRIs with which she maintained partial remission until she presented with a 2nd MDE of two months duration. She was prescribed imipramine to which modafinil was added but the patient had no improvement after eight weeks of treatment. Since her symptoms worsened progressively along with treatment resistance to three adequate trials of antidepressants and augmentation strategies (Thase-Rush Staging Method stage 3) (Thase and Rush, 1997), she underwent 15 sessions of 15 Hz rTMS over the LDLPFC for three weeks. The patient's symptoms started improving by the 15th session. After five further sessions, she remitted. The 3rd MDE of one month duration was moderate in intensity and resolved with five sessions of 20 Hz rTMS. Over the next two years, there were two moderate MDE of three months duration each. During each episode, she required 20 sessions of 20 Hz rTMS. Maintenance rTMS was efficacious as a treatment for her depressive illness without any significant adverse effects. The patient was adequately followed-up for three years covering four depressive episodes after starting rTMS with an average duration of remission period of seven months without any side-effects. An open label prospective trial (Fitzgerald et al., 2013) of clustered maintenance rTMS involved 35 patients with TRD (N = 26) and bipolar depression (N = 9) who had all responded to two courses of rTMS. Fourteen patients underwent 10 Hz rTMS to the LDLPFC, 12 received 1 Hz rTMS to the RDLPFC (five with preceding ‘priming’ 6 Hz stimulation) and nine underwent sequential bilateral rTMS (six with bilateral 1 Hz and three with 10 Hz on the LDLPFC and 1 Hz on the RDLPFC). Before maintenance rTMS, 20 patients were in remission, ten had mild depressive symptoms and five had moderate, persistent depressive symptoms. Following their second course of rTMS, they received clustered maintenance rTMS consisting of five sessions over a two and a half day period every month. Twenty-five patients relapsed within the study period with a mean treatment duration of 10.2 ± 9.6 months. Ten additional patients continued maintenance rTMS until withdrawal from the study without having experienced a relapse (four at a mean of 6.2 ± 4.3 months) or until study end (six patients with mean duration 7

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might have been related to the rather low frequency of maintenance rTMS sessions i.e. once a month whereas in another study (Richieri et al., 2013), the provision of a higher number of rTMS sessions (one session per week for two weeks, one session per two weeks for two months and then one session per month for two months) may have contributed to the lower relapse rate in patients who underwent maintenance rTMS. The only study (Haesebaert et al., 2016) that investigated the safety and efficacy of maintenance rTMS compared with maintenance venlafaxine or a combination of both treatments showed that in patients with TRD who were responders or remitters to an acute course of rTMS, venlafaxine or a combination of both treatments, at 12-month followup, the rates of remitters and of patients who did not relapse were not different between groups. There was also a comparable relapse rate in the three groups of patients with a trend toward increased relapse in the venlafaxine group. Although open-label and involving a limited number of patients, several case reports (Abraham and O'Brien, 2002; Li et al., 2004; Langguth et al., 2006; Dell'Osso and Altamura, 2009; Brunelin et al., 2010; Freitas et al., 2012; Chatterjee et al., 2012; Özten et al., 2013; Burton et al., 2014) have shown that in patients with TRD or with drugresistant bipolar depression (including pregnant women) with or without medications who responded or remitted to an acute course of rTMS (neuro-navigated (Dell'Osso and Altamura, 2009)) or ECT (Brunelin et al., 2010) and underwent maintenance rTMS, most of them maintained response or remission status from four months to eight years. However, in two case reports (Abraham and O'Brien, 2002; Conca et al., 2004), a short course of acute rTMS over one to two weeks may not have been sufficient to prevent relapse after a successful response illustrating the importance of administering a longer course of acute rTMS followed by rather frequent maintenance rTMS sessions not less than once weekly or bi-weekly. In one case (Freitas et al., 2012), initially only the depressive symptoms improved markedly with acute rTMS over the LDLPFC and continued improvements were observed for 14 months with maintenance rTMS, while the AVH almost disappeared with rTMS to the TP3 and although no maintenance rTMS treatment was administered to prevent the relapse of AVH, these were mild in intensity at 12 months. A study have demonstrated that the achievement of remission after acute rTMS was predictive of maintenance of response at one year and a higher likelihood of its usefulness when required for symptom recurrence and that the absence of acute rTMS response predicted the absence of subsequent response in the long-term (Dell'Osso et al., 2011). Studies have not reported major adverse effects with rTMS except for mild headaches nightmares, anxiety, somnolence and dizziness among others. There were no cases of seizures or of mania. The majority of these studies were mostly non-randomized and heterogeneous in terms of design (duration of maintenance rTMS, diversity of stimulation parameters, adjunction of medications and dose control as well as a diversity of observation periods), rather small sample sizes, presence or absence of placebo controls, sometimes the use of subjective outcome measures such as CGI-I or the BDI rather than standard measurements, blinding of response-raters and results often confounded by other factors. This being said, it is very difficult to design randomized, placebo-controlled clinical trials of maintenance rTMS since patients often can guess whether they have received active or sham acute rTMS after un-blinding of the study except if an excellent sham control is applied.

response as a maintenance treatment over 12 months. Maintenance rTMS was administered twice per week for one month, once per week for two months, and once every two weeks for nine months. Venlafaxine was maintained at the dose that induced a clinical response. Twelve months after the end of the acute phase treatment, the rates of remitters were not statistically different between the three groups (18.7% (N = 3) in the rTMS group, 35.3% (N = 6) in the venlafaxine group and 33.3% (N = 4) in the combination group) with a trend toward increased relapse in the venlafaxine group compared with the two other groups. There was a comparable relapse rate of 4.0% in the rTMS group, 4.5% in the venlafaxine group and 5.3% in the combination group. Mean duration of follow-up in patients who did not complete the trial was 6.3 ± 3.5 months in the rTMS group, 6.7 ± 4.5 months in the venlafaxine group and 7.7 ± 4.2 months in the combination group. rTMS was safe and well tolerated. A randomized, open-label, multisite trial randomized study (Philip et al., 2016) investigated 12-month outcomes comparing two maintenance approaches, a single rTMS session delivered monthly (group 1) vs. observation only (group 2) in 49 antidepressant-free patients with non-psychotic TRD meeting criteria for improvement after six weeks of 30 sessions of rTMS administered five days per week. Of the 49 randomized patients, 23 were assigned to group 1 and 26 to group 2; 19/23 (82.6%) patients in group 1 and 23/26 (88.5%) in group 2 remitted at the time of randomization after a three-week rTMS taper. Sixteen patients (32.7%) completed all 53 weeks of the study. Group 1 patients had non-significantly longer time to first rTMS reintroduction, 91 ± 66 days compared with group 2, 77 ± 52 days who were non-significantly more likely to need reintroduction. There were no serious adverse events reported during the study except for a transient increase in suicidality in one patient. 4. Discussion A limited number of controlled and open-label studies as well as case series have been published on maintenance rTMS after successful response to an acute course of rTMS or ECT. These were described in the previous section and are next discussed. Overall in the different studies, maintenance rTMS was administered at a frequency of one to two sessions per week or every two weeks, once per month for two to three months, one week of daily rTMS per month or five sessions over a two and a half day period every month or every fifth week over a duration of one, two, three, nine, 12 months to six years. In open studies that have assessed the maintenance of response or remission in patients with TRD or resistant bipolar depression with or without medications with maintenance rTMS or no treatment (Richieri et al., 2013) after a successful acute course of rTMS (O'Reardon et al., 2005; Benadhira et al., 2005; Dell'Osso et al., 2011; Connolly et al., 2012; Fitzgerald et al., 2013; Richieri et al., 2013; Dunner et al., 2014), most patients experienced either moderate or marked benefit, sometimes remission for three months to five years although in one study (Fitzgerald et al., 2013), 71.4% of the patients relapsed with a mean treatment duration of 10.2 ± 9.6 months despite the use of high number of sessions within a short period of time but only once a month and in another (Richieri et al., 2013), 54.2% relapsed, the relapse rate being significantly different between the maintenance rTMS (37.8%) and the non-maintenance group (81.8%) despite the fact that the mean time to relapse was similar in both groups. Based on the limited number of studies, it is difficult to ascertain whether rTMS is more efficacious for the prevention of unipolar or bipolar depression. A study (Philip et al., 2016) that assessed the rate of relapse in antidepressant-free patients with TRD who remitted to an acute course of rTMS and consequently received maintenance rTMS or no treatment over 12 months, patients who underwent maintenance rTMS had a nonsignificantly longer time to first rTMS reintroduction compared with patients on no treatment. The similar rate of relapse in both groups

5. Conclusions Nowadays, there are different approaches that can be implemented to prevent the relapse of depression after patients have responded to a treatment. Patients can either benefit from continuous or maintenance rTMS or from a repeated course of rTMS (during relapses) or from longterm antidepressant medications and/or psychotherapy after they have 8

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