Repetitive transcranial magnetic stimulation for depression

# Recommendations
This document replaces previous guidance on transcranial magnetic stimulation for severe depression (interventional procedure guidance 242).
The evidence on repetitive transcranial magnetic stimulation for depression shows no major safety concerns. The evidence on its efficacy in the shortterm 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.
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.
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 longterm outcomes.# Indications and current treatments
Depression is a common disorder that can have a debilitating effect on a person's life. It is characterised by persistent sadness, loss of interest or pleasure, feelings of guilt or low selfworth, disturbed sleep, appetite and libido, tiredness and poor concentration. It is also often accompanied by feelings of hopelessness and suicidal thoughts, and can lead to suicide. Depression can last from weeks to years, and can be recurrent. It can substantially impair an individual's ability to function at work or cope with daily life. Treatments for depression include a range of psychological therapies and antidepressant medications. In severe depression that has not responded to other treatments, electroconvulsive therapy is sometimes used.# The procedure
Repetitive transcranial magnetic stimulation (rTMS) does not need anaesthesia and can be done on an outpatient basis. A purposemade electromagnetic coil is held against the scalp with the intention of inducing electric currents in the cerebral cortex. Imaging may be used to help target specific areas of the brain. Treatment is usually considered for patients with depression that has not responded to antidepressant medication or patients for whom antidepressants are not suitable.
In rTMS, repetitive pulses of electromagnetic energy are delivered at various frequencies or stimulus intensities. Conventional rTMS is a repetition of individual pulses at a preset interval (train of pulses), whereas thetaburst rTMS is a repetition of short bursts of pulses at a preset interval (train of bursts). Stimulation can either be delivered unilaterally, over the left or right dorsolateral prefrontal cortex, or bilaterally over both cortices. Bilateral stimulation may be done sequentially or simultaneously. Treatment with rTMS usually comprises daily sessions lasting about 30 minutes, typically for 2 to 6 weeks.# Efficacy
This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a systematic review of 40 randomised controlled trials including 1592 patients with depression (type unspecified) treated by repetitive transcranial magnetic stimulation (rTMS, n=751) or sham stimulation (n=632), metaanalysis of mean changes in unspecified depression rating scales showed a significant effect in favour of rTMS (Hedges' g value of 0.55, p<0.001).
In a nonrandomised comparative study of 185 patients with treatmentresistant depression treated by conventional rTMS (n=98) or thetaburst rTMS (n=87), Hamilton Depression Rating Scale (HDRS) scores (lower scores indicate less depression) decreased from 22.16.9 to 12.38.9 and from 21.15.1 to 12.77.9 respectively at 1month followup (p value within groups <0.001, p value between groups not significant). In the same study, Beck Depressive Inventory scores (scores range from 0 to 63, with lower scores indicating less depression) decreased from 35.410.8 to 22.415.5 in the conventional rTMS group and from 35.99.9 to 20.213.3 in the thetaburst rTMS group at 1month followup (p value within groups <0.001, p value between groups not significant).
In a systematic review of 63 studies including 3236 patients treated by rTMS (n=2330), sham stimulation (n=806) or electroconvulsive therapy (ECT; n=100), percentage changes in HDRS scores (lower scores indicate less depression) were pooled and converted to Clinical Global Impression  Improvement scale (CGII) scores. CGII scores range from 1 to 7: a score of 4 means no change, scores of less than 4 indicate improvements in depression and scores of more than 4 indicate worsening depression. For patients with any type of depression, the mean percentage reduction in HDRS scores was 37% (CGII equivalent 2.8) in the rTMS group and 22% (CGII equivalent 3.4) in the sham stimulation group (p<0.05). For patients with treatmentresistant depression, the mean percentage reduction in HDRS scores was 48% (CGII equivalent 2.4) in the rTMS group and 23% (CGII equivalent 3.4) in the sham stimulation group (p<0.05). When rTMS was compared against ECT in patients with any type of depression, the mean percentage reduction in HDRS scores was 34% (CGII equivalent not reported) in the rTMS group and 46% (CGII equivalent 2.45) in the ECT group (p<0.05).
In a systematic review of 10 randomised controlled trials including 634 patients with treatmentresistant depression treated by bilateral rTMS, unilateral rTMS or sham simulation, clinical response data (defined as more than a 50% improvement in HDRS or MontgomeryAsberg Depression Rating Scale scores) were compared between groups. Metaanalysis of clinical response rates in patients treated by bilateral rTMS or sham stimulation revealed a risk ratio of 3.29 in favour of bilateral rTMS (95% confidence interval  1.69 to 6.38, p=0.0004). In the same study, metaanalysis of remission data (classified according to predefined criteria in each included study) revealed no significant difference between patients treated by bilateral rTMS or sham stimulation (risk ratio 0.5; 95% CI 0.19 to 1.31, p=0.16).
In a systematic review of 10 randomised controlled trials including 429 patients with a primary major depressive episode treated by rTMS (n=217) or ECT (n=212), metaanalysis of clinical response data (defined as more than a 50% improvement in HDRS scores) revealed a risk ratio of 1.52, in favour of ECT (95% CI 1.18 to 1.95, p=0.001). Metaanalysis of remission data (classified according to predefined criteria in each included study) revealed a risk ratio of 1.42 in favour of ECT (95% CI 1.16 to 1.75, p=0.0007).
A case series evaluated 120 patients who had at least a partial response (that is, at least a 25% improvement in HDRS scores); 99 patients were recruited from the active rTMS arm of a randomised shamcontrolled trial, while 21 patients initially had sham stimulation and subsequently received active rTMS. For patients originally in the active rTMS arm of the trial, the mean HDRS score was 9.16.2 at the end of rTMS therapy and 9.07.1 at 6month followup (p=0.537), indicating a maintained treatment effect. No pretreatment scores were reported. No mean HDRS scores were reported for patients who initially had sham stimulation and subsequently received active rTMS. In the same study, the relapse rate (KaplanMeier estimate) at 6month followup was 13% in patients who were originally in the active rTMS arm of the trial and 16% in patients who initially had sham stimulation and subsequently received active rTMS (no p value reported).
Specialist advisers listed improvements in depressive symptoms and healthrelated quality of life as efficacy outcomes.# Safety
This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
A selflimiting complex partial seizure was reported in 1 patient who had unilateral repetitive transcranial magnetic stimulation (rTMS), at a frequency of 20 Hz and at 110% of the motor threshold. The patient was awake after 8 seconds; she was alert with no postictal confusion and had no memory of what happened. No subsequent physical sequelae were reported.
A hypomanic episode was reported in 1 patient, soon after completion of therapy, in a randomised controlled trial of 130 patients treated by 1 Hz or 2 Hz rTMS. The exact timing of occurrence was not reported.
Headache was reported in 10% (46/472) of patients treated by highfrequency rTMS, 4% (4/109) treated by lowfrequency rTMS and 3% (12/461) given sham stimulation in a systematic review of 40 randomised controlled trials that included 1592 patients with depression (type unspecified).
Scalp discomfort was reported in 9% (45/472) of patients treated by highfrequency rTMS, 2% (2/109) treated by lowfrequency rTMS and 2% (9/461) given sham stimulation in the systematic review of 40 randomised controlled trials that included 1592 patients with depression (type unspecified).
Pain at the rTMS application site was reported in 6% (6/99) of patients in a case series of 120 patients with major depressive disorder treated by rTMS.
Facial twitching was reported in 2% (9/472) of patients treated by highfrequency rTMS, none treated by lowfrequency rTMS (n=109) and none given sham stimulation (n=461) in the systematic review of 40 randomised controlled trials that included 1592 patients with depression (type unspecified).
Local erythema was reported in 1% (6/472) of patients treated by highfrequency rTMS, none treated by lowfrequency rTMS (n=109) and none given sham stimulation (n=461) in the systematic review of 40 randomised controlled trials that included 1592 patients with depression (type unspecified).
Drowsiness was reported in 3% (12/472) of patients treated by highfrequency rTMS, none treated by lowfrequency rTMS (n=109) and none given sham stimulation (n=461) in the systematic review of 40 randomised controlled trials that included 1592 patients with depression (type unspecified).
Vertigo was reported in no patients in the conventional rTMS (n=98) group and 1 patient in the thetaburst TMS group (n=87) in a nonrandomised comparative study of 185 patients with treatment resistant depression.
Increasingly hostile thoughts were reported in no patients in the conventional rTMS group (n=98) and 1 patient in the thetaburst rTMS group (n=85) in the nonrandomised comparative study of 185 patients with treatmentresistant depression. The timing of occurrence was not reported.
Devicerelated insomnia was reported in 1 patient in the case series of 120 patients with major depressive disorder treated by rTMS.
Devicerelated arthralgia was reported in 1 patient in the case series of 120 patients with major depressive disorder treated by rTMS.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: discomfort, unpleasant twitching, worsening psychomotor agitation in patients with mixed affective disorder, transient confusion, transient problems with concentration and/or working memory, and transient hearing loss. They did not suggest any theoretical adverse events.