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Novel therapies are necessary for depressed bipolar patients since more than 35% of these patients are medication resistant (1)(2)(3).

As a consequence, there is a high burden of illness for depressed bipolar patients (3)—leading to increased suicide rates, inability to maintain proper work role function, and reduced quality of life.

A possible novel therapy is repetitive transcranial magnetic stimulation (rTMS), which is effective in patients with unipolar depression. However, it remains unknown whether it is also effective in those with bipolar depression.


Research question

Is rTMS effective in patients with bipolar depression who did not respond to two or more adequately dosed medication trials (1)?



rTMS combined with a mood stabilizer for the treatment of bipolar depression will result in a higher response (50% reduction of depressive symptoms) compared with sham rTMS and a mood stabilizer.



We will conduct a pragmatic multicenter, randomized, sham-controlled rTMS trial with 3 months of follow-up, post treatment. Patients in the sham rTMS group will be offered active rTMS after 3 months of follow up, post-treatment. We choose a relatively short follow up, enabling us to offer active rTMS to those who were randomized to sham rTMS.



Patients with bipolar depression who did not respond to two or more adequately dosed medication trials.



Five weeks of treatment (25 sessions) with rTMS combined with a mood stabilizer.



Five weeks of sham rTMS (25 sessions) combined with a mood stabilizer



Our primary aim is to determine the clinical efficacy of low-frequency rTMS targeting the right dorsolateral prefrontal cortex, which is determined by measuring patients’ response (50% reduction of depressive symptoms) after treatment.

Our secondary aims are as follows:

a) Perform an economic evaluation based on the general principles of a cost-effectiveness (utility) analysis, which will be performed alongside the intervention by comparing patients treated with active rTMS with those receiving sham rTMS. Patient-reported outcome measures (i.e., quality adjusted life years) will be determined (4). Additionally, societal costs and health consumption will be assessed for the economic evaluation at baseline and 3 months post-treatment.

b) Determine tolerability of rTMS, and compare the side effects between active vs. sham rTMS.

c) Determine the sustained recovery rate at 1 and 3 months post-treatment.

d) Describe opportunities and difficulties with regard to implementation.

e) Determine changes in negative and positive affect, from a patient perspective (5).


Sample size

We found a response rate of 40% in those treated with active rTMS and 21% in those with sham rTMS, when we did the requested systematic review for this proposal. However, this systematic review is hampered since it includes only 277 subjects. Moreover all studies in this review were underpowered (6). Sample size calculations show that a total sample of 206 is needed to obtain a power of 0.80 at alpha=0.05. Expecting a drop out of 10%, we need 230 patients (206/0.9), earlier rTMS studies showed dropout rates ranging between 5 and 7% (7).


Cost-effectiveness analysis/budget impact analysis

An economic evaluation from a societal perspective and a budget impact analysis according to state of the art guidelines will be embedded in the trial.


Time schedule

In the first 3 months, we will finalize the ethical approval and prepare for the study, including trial registration and training of staff and attunement of the standard operating procedures within and across centers. We will only include centers that are experienced in the recruitment of patients with bipolar depression for scientific studies.

Within 36 months, we will recruit and treat (sham or active rTMS) 230 patients with bipolar depression: each of the five centers has to recruit and treat 1.3 patient per month. After the last follow-up assessments, we will finalize the study within 6 months and report the results. The study will be completed within 48 months.

We will use two approaches to recruit patients with bipolar depression.

First, 4,000 eligible bipolar patients from the five participating centers are available. Of them, 35% (n=1,400) of the bipolar patients have a medication-resistant depression (1)(2)(3). Based on the findings of previous studies, we assume that 25% (n=350) of the 1,400 depressed bipolar patients are willing to participate in the here described RCT. Of the 350 depressed bipolar patients who are willing to participate, we will only include 230 patients in the trial.

Second, we will ask patients to participate by self-referral via the patient organization for bipolar disorders (plus/minus) and the Dutch Foundation for Bipolar Disorders.

A combination of traditional recruitment at specialized services for bipolar patients and self-referral will allow us to recruit the 230 patients.


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