Time to Stop Using the Term Relapse in Schizophrenia Clinical Trials
Year: 2022
Type: editorial
Abstract: In clinical trials designed to evaluate the efficacy of new antipsychotic medications for maintenance treatment, relapse prevention in stable persons with a diagnosis of schizophrenia is the usual primary endpoint. Success with this methodology depends on more frequent relapse in participants assigned to placebo rather than to the drug being tested. (Although definitions of relapse in schizophrenia trials differ, for this editorial, relapse is considered a worsening of illness symptoms that will usually require hospitalization or more intense care.)1 If full relapse is the study endpoint, there is a potential for substantial harm to study participants. The consequences of relapse are often long lasting and serious in persons with schizophrenia and often include self-injury, violent behavior, and a deterioration in social and work function that may last for months.2 We believe that it is essential that the ethical understanding of the nature of relapse, including pattern of recovery, is reflected in the inclusion/exclusion criteria and protections provided to potential participants, but such details are often not adequately detailed in published reports. In order to ensure an ethical basis for a maintenance treatment clinical trial, we suggest that the following 3 issues be integrated in protocol methodology and study findings. Study findings should include the degree of clinical exacerbation and the outcome for participants. Specifically, have a previous history of a serious adverse event associated with medication withdrawal should be discontinued from the study. Potential research participants should be excluded if there is historical evidence that a relapse is associated with substantial risk. The risk may include an unacceptable delay in recovery; loss of housing or job; or increased suicidality or other serious consequences. The criteria for identifying and excluding high-risk subjects should be included in study reports. In order to minimize the adverse effects of a beginning exacerbation, the research design must include a method for early detection and therapeutic response. Clinical intervention early in the relapse process reduces the risk of severe consequences.3 Study participants who have an exacerbation during the study should be followed over time to assure proper treatment and record the consequences of relapse. The follow-up data on participants who reach a study relapse endpoint should be provided in the public presentation of study data. This is critical information for any broad appreciation of the ethical basis for justification of risks. Ethical guidelines require that the risk to participants is justified by a study’s potential to advance knowledge. The first step is to exclude participants where risk is unacceptably high and the second critical element is to define early detection and intervention as exacerbation unfolds.4 This is an issue to highlight in justifying placebo substitution studies where harm to some participants is assured. The testing of “me-too” drugs is difficult to justify where efficacy for the therapeutic mechanism is well established. Comparing the new compound with an approved compound can test a superiority hypothesis, but the superiority to placebo is not in doubt. The article by Berkhout5 in this series provides a framework for evaluating whether a particular study meets the criteria for clinical equipoise. This principle states that for a study to meet these criteria, there is a genuine doubt as to whether the 2 conditions in a randomized clinical trial are different in their effectiveness. Since antipsychotic medications that are effective for acute treatment have been consistently found to reduce the risk of psychotic exacerbations or relapses, studies comparing an active antipsychotic to a placebo do not meet these criteria. A study that exposed placebo-treated patients to a serious risk of a psychotic episode for a purely commercial interest without advancing knowledge would not be considered to be in clinical equipoise. Placing persons with schizophrenia at risk for relapse is not justified by the intent to place another “me too” drug on the market. There are important questions in the long-term treatment of schizophrenia that can be addressed with placebos and which will still meet the criteria for clinical equipoise. As noted in the accompanying article by Rubio and Perez-Rodriguez,6 there are important questions regarding the long-term use of antipsychotics beyond 2 or 3 years after a relapse. Also, there may be populations of patients where it is unclear whether the adverse effects of antipsychotics are balanced by their effects in preventing the recurrence of symptoms. As noted by Lawrence7 in this section, new information about the nature of psychotic relapse and biomarkers may lead to long-term placebo-controlled trials. These studies, in our opinion, should include safeguards that we have noted and should include outcomes other than relapse. A final issue. We believe that the term “relapse” should be dropped and replaced by a term such as “exacerbation” accompanied by clarity on the degree of exacerbation in each study design. The risk to study participants will vary with degree of exacerbation used to define an outcome. The risk and how it is evaluated will be more informative and IRBs may better evaluate risk when degree of exacerbation is explicit. The authors have declared that there are no conflicts of interest in relation to the subject of this study.
Source: Schizophrenia Bulletin Open
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,322
OpenAlex ID: W4312942629