Dr. Gregory Marsella Uses Bilateral rTMS as an alternative treatment for Patients suffering from Treatment Resistant Depression in South Florida

Paul B. Fitzgerald, M.B.B.S., M.P.M., Ph.D., F.R.A.N.Z.C.P. Jessica Benitez, B.Sci., Grad. Cert. Clin. Nurse (Psych.) Anthony de Castella, B.A., Dip. App. Sci. Z. Jeff Daskalakis, M.D., F.R.C.P.(C.) Timothy L. Brown, Grad. Dip. Clin. Nurse (Psych.) Jayashri Kulkarni, M.B.B.S., M.P.M., Ph.D., F.R.A.N.Z.C.P.

Major depressive disorder is a severe illness, and a significant percentage of patients fail to respond to standard therapies. Over the last 10 years, a number of clinical trials of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depressive illness have been conducted. Most of these trials used high-frequency rTMS, usually between 5 and 20 Hz, applied to the left dorsolateral prefrontal cortex. More recently, an alterative paradigm, involving the provision of low-frequency stimulation to the right dorsolateral prefrontal cortex, has also been shown to have antidepressant activity. Low- and high-frequency TMS stimulation are proposed to have opposite effects on cortical activity, possibly underlying these clinical findings. However, although most of these studies have shown that the antidepressant effects of active rTMS are greater than those of placebo stimulation, these differences have been of limited magnitude, and considerable questions remain as to whether rTMS has clinically relevant effects.

Despite the evidence for the efficacy of both left- and right-side TMS stimulation, the effectiveness of sequentially combining these two forms of stimulation has not been rigorously evaluated in studies with substantial group sizes. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the efficacy of sequential "bilateral" rTMS, sequentially combining both high-frequency left-side stimulation with low-frequency right-side rTMS. We hypothesized that bilateral active rTMS would produce a greater therapeutic effect than placebo stimulation with no significant cognitive side effects. In addition to combining the two forms of rTMS, we also provided treatment for up to 6 weeks.

This double-blind, placebo-controlled, parallel-group trial found a significant therapeutic benefit of sequentially applied bilateral rTMS in patients with treatment-resistant depressive illness. We found that rTMS produced a therapeutic response that was evident by 2 weeks into the trial and progressively increased for a total of 6 weeks. Most critically, a significant therapeutic response was achieved by about half of the patients in the active treatment group, and a significant proportion of patients achieved clinical remission.

The response rate for patients in this study was greater than the vast majority of published reports of rTMS treatment in depression and of a degree that we consider clinically relevant and applicable. This is in spite of the selection of a relatively heterogeneous group of patients with a marked degree of treatment resistance. Of importance, this is the first rTMS study to show a clinically significant percentage of patients achieving remission criteria. Cohen et al. published a case series showing significant benefit for four of seven patients treated with similar treatment parameters. Hausmann et al. compared a group of patients also receiving high-frequency left-side and low-frequency right-side TMS stimulation to unilateral-side rTMS and a placebo group and showed no differences among all three groups. However, the size per group was considerably smaller than in our study, the patients were treated for a total of only 2 weeks, and new antidepressant medication was commenced concurrently with the rTMS—all confounding interpretation. The same group had also previously compared high-frequency left to bilateral (high-frequency left and low-frequency right) TMS stimulation, but the capacity of this study to show differences between active stimulation groups was also limited by its size.

It is not clear why the response rate in this trial was significantly greater than in previous studies of rTMS, but combining the two treatment types could potentially enhance response in several ways. First, it is possible that some patients have left-side treatment-responsive depression and some have right-side treatment-responsive depression. Therefore, by giving everyone both treatments, we maximized the likelihood of a treatment response in any individual patient. This should ensure the maximal number of treatment responders. Second, it is notable that despite providing more pulses on the left, we actually gave more right-side pulses (420 versus 300) at a higher intensity (110% versus 100% of the resting motor threshold) than in previous studies. Therefore, it is possible that our improved results compared to our previous study came about because of the greater degree of right-side TMS stimulation alone. However, given the well-established antidepressant properties of high-frequency left-side rTMS, this seems somewhat doubtful. Alternatively, the two treatments may have a synergistic effect in likely treatment responders. Theoretically, this also seems quite plausible given that unilateral stimulation can produce effects bilaterally. However, it is possible that the greater benefits seen with rTMS in this study did not relate to the combination of the two types of treatment but arose purely from the increased duration of treatment provided as stimulation for 6 weeks although it has not previously been investigated. In support of this, we saw progressive decreases in depression severity across the full 6 weeks of the study in the active group. However, because the rates of response at 4 weeks were already quite good compared to the response rates in previous studies, such as our own, we cannot definitely conclude that the response rate was purely an effect of longer treatment duration. These issues will only be resolved with a large randomized trial comparing unilateral and bilateral approaches.

In conclusion, sequential bilateral rTMS combining high-frequency left-side and low-frequency right-side treatment appears to be a promising antidepressant strategy for treatment-resistant depressive illness. Bilateral rTMS applied over 6 weeks induces clinically meaningful responses, including clinical remission in a clinically relevant subgroup of patients, and is superior to placebo stimulation.