We examined the efficacy and acceptability of non-invasive brain stimulation in adult unipolar and bipolar depression. Randomised sham-controlled trials of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS) and theta-burst stimulation (TBS), without co-initiation of another treatment, were included. We analysed effects on response, remission, all-cause discontinuation rates and continuous depression severity measures. Fifty-six studies met our criteria for inclusion (N = 3058, mean age = 44.96 years, 61.73% female). Response rates demonstrated efficacy of high-frequency rTMS over the left DLPFC (OR = 3.75, 95% CI [2.44; 5.75]), right-sided low-frequency rTMS (OR = 7.44, 95%CI [2.06; 26.83]) bilateral rTMS (OR = 3.68,95%CI [1.66; 8.13]), deep TMS (OR = 1.69, 95%CI [1.003; 2.85]), intermittent TBS (OR = 4.70, 95%CI [1.14; 19.38]) and tDCS (OR = 4.17, 95% CI [2.25; 7.74]); but not for continuous TBS, bilateral TBS or synchronised TMS. There were no differences in all-cause discontinuation rates. The strongest evidence was for high-frequency rTMS over the left DLPFC. Intermittent TBS provides an advance in terms of reduced treatment duration. tDCS is a potential treatment for non-treatment resistant depression. To date, there is not sufficient published data available to draw firm conclusions about the efficacy and acceptability of TBS and sTMS.

26We examined the efficacy and acceptability of non-invasive brain stimulation in adult 27 unipolar and bipolar depression. Randomised sham-controlled trials of transcranial direct 28 current stimulation (tDCS), transcranial magnetic stimulation (TMS) and theta-burst 29 stimulation (TBS), without co-initiation of another treatment, were included. We analysed 30 response, remission and all-cause discontinuation rates, and depression severity scores. Fifty-31 four studies were included (N = 2,959, mean age = 44.94 years, 61.98% female). Response 32 rates demonstrated efficacy of high-frequency rTMS over the left DLPFC (OR = 3.94, 95% 33 CI [2.52; 6.15]), right-sided low-frequency rTMS (OR = 7.44, 95% CI [2.06; 26.83]) bilateral 34 rTMS (OR = 3.68, 95% CI [1.66; 8.13]), deep TMS (OR = 1.69, 95% CI [1.003; 2.85]), 35 intermittent TBS (OR = 4.70, 95% CI [1.14; 19.38]) and tDCS (OR = 4.32, 95% CI [2.02; 36 9.29]); but not for continuous TBS, bilateral TBS or synchronised TMS. There were no 37 differences in all-cause discontinuation rates. The strongest evidence was for high-frequency 38 rTMS over the left DLPFC. Intermittent TBS provides an advance in terms of reduced 39 treatment duration. tDCS is a potential treatment for non-resistant depression. 40 41 Keywords: transcranial magnetic stimulation, theta burst stimulation, transcranial direct 42 current stimulation, major depression, meta-analysis 43 BRAIN STIMULATION DEPRESSION META-ANALYSIS (≤ 1 Hz) stimulation inhibits neural firingRosa and Lisanby 7 . 62 63The rationale for using rTMS to treat depressive illness comes from clinical symptomatology 64 and neuroanatomy as well as neuroimaging studies indicating functional impairments in 65 prefrontal cortical and limbic regions 8 . In 2008, the US Food and Drug Administration (FDA) 66 approved the first rTMS device for the treatment major depressive disorder (MDD) in which 67 there was poor response to at least one pharmacological agent in the current episode 9 , and its 68 clinical utilisation has increased since 10 . 69 BRAIN STIMULATION DEPRESSION META-ANALYSIS 70As stimulation at high frequencies can be uncomfortable during the initial stimulation period, 71 low-frequency rTMS may minimise the occurrence of undesired side effects, namely 72 headaches and scalp discomfort, and may be associated with fewer adverse events, for 73 instance by lowering the risk for seizures 11 . 74 75 Bilateral applications of rTMS have also been developed: simultaneous stimulation over the 76 left and right DLPFC (rDLPFC) or stimulation over one side followed by stimulation of the 77 other side. These applications were hypothesised to be potentially additive or synergistic to 78 reinstate any imbalance in prefrontal neural activity 12 . Moreover, there may be a selective 79 unilateral response and the likelihood for a clinical response may increase by providing both 80 types of stimulation 13 . 81 82 Technical and methodological efforts to improve the antidepressant efficacy of TMS have led 83 to several alternative treatment pro...

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