Valutazione dell’efficacia di due protocolli di stimolazione Theta Burst intermittente accelerata in un campione di pazienti affetti da depressione maggiore unipolare: risultati preliminari.

Background: Major depressive disorder (MDD) is a widespread disease, the most frequent psychiatric disorder in the general population and the leading cause of disability and premature death in Western countries by 2030 in according to the World Health Organization. Antidepressants are the first-line treatment for MDD but the response rate to medications is low. Thus, the search for innovative therapeutic approaches is underway. Transcranial Magnetic Stimulation (TMS) is one of the newer options to treat MDD. TMS is a non-invasive, safe, and well tolerated method of brain stimulation in which magnetic fields created by a coil placed close to the scalp are used to generate electric currents that induce stimulation of the cerebral cortex. Over the years, researchers came up with modalities to deliver multiple pulses in a short interval which came to be known as repetitive TMS (rTMS). Robust evidence confirms that rTMS is safe and effective in treatment-resistant depression (TRD), with response rates reaching 67,7%. Therefore, in 2008 rTMS has been approved by the US Food and Drug Administration for use in TRD. Since previous research on the application of rTMS in MDD has shown a dose-response effect, continuing progress of TMS technology have made it possible to develop a new repetitive TMS protocol, known as Theta Burst Stimulation (TBS), which delivers an even greater number of stimuli, at higher frequencies and in a shorter time. Although TBS protocols are not inferior in terms of efficacy and safety to rTMS protocols, standard TBS protocols apply daily sessions spread over four weeks, with a significant impact in terms of duration of treatment and, consequently, costs for the healthcare system and treatment discontinuation. In order to reduce the number of days required to complete a treatment course, obtain greater therapeutic adherence, optimize healthcare resources, anticipate the onset of the effect and increase clinical responses, intensified or accelerated iTBS protocols have been evaluated with encouraging results but still limited evidence. Objectives: We aimed to examine the effects and safety of two accelerated protocols of iTBS as an adjunctive treatment in a group of unipolar depressed patients, using an extensive depression assessment scale and electroencephalographic (EEG) recordings to extrapolate quantitative data from EEG traces. Methods: In this randomized double-blind sham-controlled crossover study, 60 depressed patients were randomized to two treatment arms that received two different intensive protocol of accelerated iTBS applied over the left dorsolateral prefrontal cortex (lDLPFC). The first treatment protocol (Active protocol iTBS 600x4x5) consisted of 20 sessions spread over 5 days at 4 sessions per day; in each session, patients received 600 pulses. The second treatment protocol (Active protocol iTBS 1200x2x5) consisted of 10 sessions spread over 5 days at 2 sessions per day; in each session, patients received 1200 pulses. In the crossover design, each of the two active treatments were compared with inactive stimulation, during which real cortical stimulation was not provided. Results: Both accelerated iTBS treatment procedures were found to be safe and resulted in a statistically significant decreases in depressive symptoms after 4 weeks. However, only the 1200x2x5 protocol resulted in a statistically significant reduction in hopelessness. On the contrary, sham stimulation did not cause statistically significant changes for any of the administered psychometric scales. Furthermore, after active stimulation, we documented a significant modification of the distribution of the neural network with an increase in the characteristics of small-worldness in the theta band, an increase in global theta activity and in theta activity on the lDLPFC and a correlation between antidepressant response and theta activity, with a more marked effect after the 1200x2x5 protocol. In accordance with clinical data, sham stimulation did not cause changes in poststimulation theta activity. Conclusions: Our findings indicate that only five days of the accelerated iTBS treatment that we applied to the lDLPFC in MDD may lead to meaningful clinical responses with in four weeks poststimulation. The correlation between clinical and neurophysiological data supports the hypothesis that our accelerated iTBS protocols induce an increase in theta activity in terms of global power, topography and connectivity, a phenomenon which is associated with neuroplastic changes potentially implicated in the clinical efficacy of the treatment.