Serum levels of D-cycloserine predict antidepressant effects in pharmacologically enhanced intermittent theta-burst stimulation

Background: Transcranial magnetic stimulation is an important treatment option for treatment resistant major depressive disorder. Pairing stimulation with adjuncts such as the partial N-Methyl-D-Aspartate (NMDA) receptor agonist, D-Cycloserine, has emerged as a strategy to enhance treatment outcomes. However, the effects of DCycloserine are concentration dependent, and higher concentrations may blunt TMS-induced plasticity. This is clinically important due to the potential for accumulation with repeated dosing and individual differences in volume of distribution. Methods: We recruited n = 12 individuals with a moderate-severe depressive episode for a pharmacokinetic characterization of repeated D-Cycloserine dosing in the context of a 4 week (20 treatments) open-label trial pairing intermittent theta-burst stimulation (iTBS) using a weight based dose of D-Cycloserine (25 mg/17.5 kg). Prior to treatment, we serially sampled peripheral blood with a 100 mg dose for comparison. Then, serum samples were characterized in conjunction with 25 mg/17.5 kg dosing for the first, the 5th (accumulation), and the 6th (elimination) doses. Results: iTBS+D-Cycloserine was associated with a potent antidepressant effect, achieving 83.3 % response and 75.0 % remission at treatment end with no serious adverse events. Improvements in depressive symptoms were predicted by serum D-Cycloserine concentration. Although we found evidence for accumulation after five doses, the weekend hiatus was sufficient for elimination and the concentration remained within the NMDA receptor agonist range. Serum concentrations did not significantly differ between 100 mg and 25 mg/17.5 kg doses. Conclusions: Our data confirm the antidepressant effects and safety of extended iTBS+D-Cycloserine, while highlighting the importance of adequate serum concentrations within the agonist range. Weight-based dosing may not be required by default.