Ethics of medication-free research in schizophrenia.

Bola’s study highlights two important points about the ethics of medication-free research in early episode schizophrenia. First, the question of whether ‘‘biological toxicity’’ results from short periods of medication-free research in early episode schizophrenia is an important, though very narrow, question in the debate over ethics of medication-free research in schizophrenia. Second, even on this narrow question, the paucity of good data is striking. Based on a meta-analysis of 623 participants in 4 randomizedcontrolled trials and3quasi-experimental studies otherwise meeting his selection criteria for study inclusion, Bola concludes that ‘‘in the absence of substantive evidence of long-term harm from short periods of medication-free research in schizophrenia, a categorical prohibition of medication-free research in early episode schizophrenia on ethical grounds of harm to human subjects should probably be reconsidered.’’ Instead, he suggests applying Emanuel and Miller’s ‘‘middle ground’’ approach. Following Bola’s suggestion, we illustrate the important, though limited, role of the biological toxicity question in thedebate over the ethical acceptability of medication-free research in schizophrenia and comment on the implications of his findings for the ethical debate. Emanuel and Miller’s ‘‘middle ground’’ approach involves assessing individual research protocols for the ethical acceptability of brief medication-free periods, using three criteria: (1) a compelling scientific rationale justifies the study and its design; (2) research participants experiencing deliberate study-related medicationfree periods ‘‘should not be substantially more likely than those in the active-treatment group to die; to have irreversible morbidity or disability or to suffer other harm; to suffer reversible but serious harm; or to experience severe discomfort’’; and (3) trials that meet these methodological and ethical criteria must nevertheless institute safeguards to minimize risks of harm.