Theta-burst transcranial magnetic stimulation in depression: when less may be more

Major depressive disorder is associated with increased mortality, significant morbidity, and substantial impairments in functioning. It is estimated that by the year 2020, depression will be second only to heart disease in terms of disease burden as measured by disability-adjusted life years (Murray and Lopez, 1996). Treatment-resistant depression is conventionally defined as a failure to respond to at least two adequate medication trials or as a relapse during treatment; it represents a common dimension of this illness that translates into significant public healthcare costs. Only one-third of patients with major depressive disorder achieve full remission of their symptoms after a single trial of antidepressant medication and even with multiple medication trials, 30–40% of patients fail to respond fully (Keller et al., 1992). Treatmentresistant depression is associated with significantly greater medical costs and productivity loss than treatment-responsive forms, highlighting the need for more effective non-pharmacological strategies. In this issue of Brain, Li et al. (2014). report data from a randomized sham-controlled study to show that a modified form of repetitive transcranial magnetic stimulation (TMS) produces therapeutic benefits in patients with treatment-resistant depression. High frequency (e.g. 10 Hz) repetitive TMS applied to the left dorsolateral prefrontal cortex is an FDA approved treatment for adults with resistant depression. A number of large multicentre studies and recent meta-analyses have indicated that high frequency repetitive TMS has reasonable therapeutic efficacy compared to sham stimulation. For example, O’Reardon et al. (2007) reported response rates of 24.5% with high frequency repetitive TMS compared to 13.7% with sham repetitive TMS following 6 weeks of treatment. In a recent meta-analysis, Berlim et al. (2014) reported response rates of 29.3% with high frequency repetitive TMS compared to 10.4% with sham repetitive TMS. Collectively, these results indicate that high frequency repetitive TMS can be effective in treatment-resistant depression, but there is clearly scope for improvement. Modification of repetitive TMS parameters such as stimulus frequency and duration may be one means of enhancing repetitive TMS efficacy. Conventional high frequency repetitive TMS paradigms, such as those used in the abovementioned trial (O’Reardon et al., 2007), deliver 3000 pulses of 10 Hz stimulation over the course of 37.5 min. An alternative approach is theta-burst stimulation (TBS), in which a three-pulse 50-Hz burst is applied at 5 Hz. In intermittent TBS, a 2-s train of TBS is delivered every 10 s for 190 s (600 pulses in total). Intermittent TBS induces a form of plasticity that resembles long-term potentiation (Huang et al., 2005), changes to which are increasingly implicated in the pathophysiology of major depressive disorder (Player et al., 2013). Huang et al. (2005) demonstrated that application of intermittent TBS to motor cortex produced a consistent increase in the TMSinduced motor evoked potential (MEP) compared to baseline: an increase that could be considered a marker of cortical plasticity. By contrast, continuous TBS, which involves a continuous 40 s train of TBS to give a total of 600 pulses, produced a decrease in the TMS-induced MEP compared to baseline; a change that may be a marker of long-term depression (Huang et al., 2005). In this issue of Brain, Li et al. (2014) provide the first direct evidence that intermittent TBS applied to the left dorsolateral prefrontal cortex or a combination of intermittent plus continuous TBS applied to the left and right dorsolateral prefrontal cortex, respectively, are significantly more effective than continuous TBS or sham TBS in treatment-resistant depression. Response rates after 10 treatment sessions were 40% for intermittent TBS and 66.7% for the combination of intermittent plus continuous TBS— considerably higher than those reported in the high frequency repetitive TMS studies. This greater efficacy is reason enough to be encouraged by these findings. However, there are several other reasons. First, this study demonstrates that intermittent TBS can be applied safely and effectively over a much shorter time period (10 min versus 40 min using traditional high frequency approaches) (O’Reardon et al., 2007) and may permit about four times more treatments per day than standard approaches. Given that large numbers of individuals are affected by treatment-resistant depression and that repetitive TMS is one of very few clinically proven treatments for this disorder, such modifications may lead to more widespread use of repetitive TMS through reduced costs and the ability to manage greater patient volumes. Equally important, however, is the glimpse this study provides vis à vis the neural mechanisms involved in resistant depression. As mentioned above, intermittent TBS was initially shown to consistently induce plasticity in motor cortex (Huang et al., 2005). Other plasticity-inducing neurostimulation methods include transcranial direct current stimulation (DCS) and paired associative stimulation (PAS). Unlike intermittent TBS, transcranial DCS and PAS take upwards of 30 min to produce plasticity enhancing effects and only transcranial DCS has shown evidence of treatment efficacy in depression. There are many reasons why future intermittent TBS treatment studies in resistant depression should evaluate plasticity as a biomarker of treatment response. First, it is conceivable that intermittent TBS-induced changes in neural plasticity may predict treatment response and/or help to optimize the treatment course. That is, greater plasticity in response to intermittent TBS at baseline may predict greater intermittent TBS 1860 | Brain 2014: 137; 1854–1862 Scientific Commentaries