title: Clinical trial design in non-invasive brain stimulation psychiatric research.
abstract: Major depressive disorder (MDD) trials - investigating either non-pharmacological or pharmacological interventions - have shown mixed results. Many reasons explain this heterogeneity, but one that stands out is the trial design due to specific challenges in the field. We aimed therefore to review the methodology of non-invasive brain stimulation (NIBS) trials and provide a framework to improve clinical trial design. We performed a systematic review for randomized, controlled MDD trials whose intervention was transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in MEDLINE and other databases from April 2002 to April 2008. We created an unstructured checklist based on CONSORT guidelines to extract items such as power analysis, sham method, blinding assessment, allocation concealment, operational criteria used for MDD, definition of refractory depression and primary study hypotheses. Thirty-one studies were included. We found that the main methodological issues can be divided in to three groups: (1) issues related to phase II/small trials, (2) issues related to MDD trials and, (3) specific issues of NIBS studies. Taken together, they can threaten study validity and lead to inconclusive results. Feasible solutions include: estimating the sample size a priori; measuring the degree of refractoriness of the subjects; specifying the primary hypothesis and statistical tests; controlling predictor variables through stratification randomization methods or using strict eligibility criteria; adjusting the study design to the target population; using adaptive designs and exploring NIBS efficacy employing biological markers. In conclusion, our study summarizes the main methodological issues of NIBS trials and proposes a number of alternatives to manage them.
authors.affiliation: Hospital Universitário, University of São Paulo, São Paulo, Brazil.
authors.forename: André Russowsky
authors.initials: AR
authors.lastname: Brunoni
authors.forename: Felipe
authors.initials: F
authors.lastname: Fregni
mesh_terms: D002986:Clinical Trials as Topic; D003865:Major Depressive Disorder / Q000628:therapy*; D004599:Electric Stimulation Therapy / Q000379:methods*; D005260:Female; D005793:Generalization, Psychological; D006801:Humans; D016239:MEDLINE / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012107:Research Design