Introduction
Major depressive disorder (MDD) is a principal cause of disability worldwide and is often associated with high morbidity and mortality rates. Although there are several therapies available for the treatment of depression, about one-third of patients with MMD will not respond to two or more antidepressant drugs with different mechanisms; the patients are then referred to as having treatment-resistant depression (TRD).1 Patients with TRD have a poorer quality of life, greater economic burden and increased suicidal behaviours.1 Therefore, new antidepressant treatments that are effective, safe, long-lasting and tolerable are needed. Ketamine infusion, intranasal esketamine and transcranial magnetic stimulation (TMS) have been used to treat early stage TRD.2 A recent review suggests that electroconvulsive therapy (ECT) may be superior to ketamine for reducing depression severity in the acute treatment of TRD.3 Another review found that ECT was more effective in treating TRD than repetitive TMS (rTMS).1
As neurostimulation treatments, ECT and rTMS are recommended for individuals insufficiently responsive to pharmacotherapy and psychosocial interventions.4 Despite being the most effective strategy for patients with TRD--and in some situations, a first-line choice in the acute setting--ECT treatment is limited by its side effects, high costs and administrative impediments.5 rTMS is a non-invasive, focal and cortical stimulation technique that has demonstrated moderate efficacy with few safety concerns for patients with MDD who have either failed or not tolerated antidepressant treatments during the acute episode and maintenance phase of the illness.6 But, like ECT, rTMS requires specialised equipment, a particular setting, and well-trained operators to carry out the procedure. The risks of headache and potential seizure also reduce the acceptability of rTMS.7
Similar to the electrical current used in ECT, alternating current is also utilised in transcranial alternating current stimulation (tACS),8 a unique form of non-invasive brain stimulation. tACS has shown efficacy and safety in chronic insomnia,9 MDD7 and other treatment-resistant psychiatric conditions such as clozapine-resistant schizophrenia and treatment-resistant obsessive-compulsive disorder.10 Currently, however, there is no consensus on tACS procedures and parameters for different brain disorders in clinical practice and research.7 11 The electrical current frequency and amplitude, treatment sessions and electrode locations have varied widely.7 11 One of our recent studies revealed that a single session of 77.5 Hz tACS with a current amplitude of 15 mA via the forehead and both mastoids given 5 days a week for 4 weeks, totalling 20 sessions, (referred to as a once-daily protocol) is effective in reducing depressive symptoms in first episode and drug-naïve MDD.7 However, whether15 mA, 77.5 Hz tACS is effective for treating TRD remains unclear.
Due to the refractory nature of TRD, we hypothesised that more sessions of tACS may effectively treat TRD. Therefore, in this initial study, we used the same amplitude and frequency of tACS as our previous studies7 but changed the treatment course from once a day to twice a day. In doing so, the patients received 40 sessions (twice-daily tACS), instead of 20 sessions, during the 4-week treatment phase. Accordingly, this study aimed to examine the acute therapeutic potential of twice-daily tACS in TRD.