Bipolar depression is associated with mania-hypomania, and natural switch rates are considered to be approximately 4.6% to 6.7% [8]. The review by Xia et al. of controlled clinical studies showed that the risk of hypomania-mania shift in bipolar depression was nine times higher than in unipolar depression [8]. They argued that this might be because patients with bipolar depression had been mistakenly evaluated as unipolar. In order to avoid such mistakes, we investigated both the manic and hypomanic histories of patients and their families in detail, and no such history was found.

The same study found that emergent hypomania-mania rates in rTMS treatments were 0.84% in the rTMS group and 0.73% in the sham group and that following the application of rTMS treatment for unipolar depression, the hypomania-mania shift rate was 0.34%, while in bipolar disorder depressive phase, the rate was 3.1%. Mood switching was considered to be related to the nature of the disease and aggressive doses of rTMS [8]. Similarly, in the case studies reported by Sakkas et al. and Hausmann et al., hypomania-mania symptoms were observed during 20 Hz rTMS applications [9, 12]. In the present report, cases of 419 patients treated between January 2007 and December 2011 were evaluated.

In the Hausmann et al. study, manic symptoms occurred during 20 Hz, 2,000 pulses rTMS treatment of a patient with bipolar depression [12]. When the protocol was changed to 1 Hz, 1,200 pulses, RDLPFC, and antidepressants were replaced by clozapine, manic symptoms disappeared. The rTMS protocol in our four cases was 25 Hz, LDLPFC, 1,000 pulses/day, and 100% MT. Hypomanic symptoms were observed during the initial treatment period in all four of our cases. In each case, antidepressants were replaced by valproic acid, and the protocol was changed to 1 Hz, 250 pulses RDLPFC. In all cases, hypomanic symptoms disappeared following the protocol changes. This could be related to either the impact of the change in medication or changes in the rTMS application. However, it should be noted that Ella et al. observed manic symptoms in a patient with recurrent major depressive disorder taking tranylcypromine, haloperidol, and lorazepam and treated with 1 Hz, 1,200 pulses, RDLPFC rTMS [10]. This result is in contrast to our findings and demonstrates that there is still a lack of data regarding manic and hypomanic symptoms triggered by rTMS applications.

It is known that any remedial effects of treatment can potentially arise from two sources: one related to the specific properties of the treatment and the other associated with the patient's expectations for the treatment (placebo effect). The magnitude of the placebo effect varies according to its supposed effectiveness and emotional impact on the treated subject [13]. Many studies reported response rates for patients who received placebo treatment. Klein et al. reported a control group response rate as high as 25% [14]. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression.

There are many variations in the way rTMS can be given as a clinical treatment, involving choices over treatment site, stimulation parameters, and treatment course. Studies to date have differed with respect to these, with almost no two studies using identical rTMS parameters, except in deliberate attempts at replication. High-frequency rTMS to the left prefrontal cortex has been used in most trials, a choice influenced by positive early results from this approach. Imaging studies have shown evidence of reduced blood flow in the left prefrontal cortex in patients with depression [15]. Some investigators have tried low-frequency rTMS to the right prefrontal cortex. Motor cortex studies suggest that high- and low-frequency rTMS have opposite effects on the excitability of neurons in the brain cortex [16]. There is considerable evidence from neuropsychological, lesion, and imaging studies that the left and right hemispheres have contrasting roles in mood regulation [17]. Therefore, it might be expected that low-frequency rTMS to the right prefrontal cortex may be as likely to have antidepressant effects as high-frequency rTMS to the left prefrontal cortex. However, there is no strong evidence for either side in the peer-reviewed literature. Stimulus frequency of rTMS was within the range of 5 to 25 Hz in several studies as changes in cortical excitability have been demonstrated with this range of frequency [16]. Results suggest that higher stimulus frequencies may have greater antidepressant potency. The majority of rTMS trials have reported stimulus intensity relative to the subject's resting motor threshold, that is, the lowest stimulus intensity necessary to produce a motor response in a relaxed contralateral muscle when TMS is given over the primary motor cortex. Researchers have reported that stimulus intensity is an important factor in inducing lasting changes in cortical excitability that may be responsible for antidepressant effects. In depressed subjects, studies comparing different intensities of stimulation (100% and 90% of motor threshold) showed that higher stimulation intensity was significantly associated with greater improvement [18]. However, an overview of studies in the literature does not support an association between higher intensities (110% or 120% of motor threshold) and greater response rates. rTMS trials have moved in the direction of administering longer-duration protocols with greater doses of magnetic pulses [19–21]. These clinical studies suggest that treating depressed patients with higher doses improves response and remission rates with rTMS.

The main limitation of our report is that, in each of the four cases, the rTMS was initiated together with initiation or increase of high-dose antidepressant medication. Therefore, the ‘switch’ may also be due to the antidepressant medication and cannot be necessarily contributed to rTMS. However, further research is needed on this topic.