Methodological Issues in Current Antipsychotic Drug Trials

Abstract

Every year numerous reports on antipsychotic drug trials are being published in neuropsychiatric journals, adding new information to our knowledge in the field. The information however is often hard for the reader to interpret, sometimes contradictory to comparable available studies and leaves more questions open than it actually answers. Although the overall quality of the studies is rather good, there are manifold options for further improvement in the conception, conduct, and reporting of antipsychotic drug trials. In this survey, we address methodological challenges such as the limited generalizability of outcomes due to patient selection and sample size; the vague or even lacking definition of key outcome parameters such as response, remission or relapse, insufficient blinding techniques, the pitfalls of surrogate outcomes and their assessment tools; the varying complex statistical approaches; and the challenge of balancing various ways of reporting outcomes. The authors present practical examples to highlight the current problems and propose a concrete series of suggestions on how to further optimize antipsychotic drug trials in the future.

Time to discontinuation of antipsychotic drugs in a schizophrenia cohort: influence of current treatment strategies

“…However, data from randomized studies may not suffice in informing the clinicians about optimal antipsychotic drug treatment in everyday clinical practice. The low and selective recruitment (10-30% of eligible patients) and high attrition rates (30-50%) [Leucht et al 2008] invariably found in RCTs including also the pragmatic studies limit the generalizability of currently available evidence [Duggan et al 2005;Asenjo Lobos et al 2010]. Moreover, in RCTs of LAI antipsychotics the most severely ill patients do not consent to participate, which has the important consequence that the drugs are not tested in the most relevant patient groups [Adams et al 2001].…”

Trajectories of change in depression severity during treatment with antidepressants

“…First, the arbitrary nature of the definition of remission becomes apparent when we compare the definitions of response and remission across disorders. In depression, ' response ' is commonly defined as a 50 % reduction in the initial symptom score (Montgomery, 1994), but in schizophrenia, 40 % or even 20 % improvement is accepted as a response (Leucht et al 2008). When an empirical test of a cut-off for response in depression was attempted, the results suggested that a 60 % improvement may be a more valid definition (Mulder et al 2003).…”

Assessing and Reporting the Adverse Effects of Antipsychotic Medication

“…[60][61][62][63] Similarly, a probability sample of 243 patients found higher rates of emotional (18.8%) and cutaneous (17.3%) effects than EPS such as body rigidity (11.4%) and tardive dyskinesia (7.6%; although not akathisia: 27.1%). 64 Further limitations in reporting and interpretation of AE data reflected those previously observed in existing reviews of antipsychotic trials 22,[65][66][67] as well as other medical disciplines. [20][21] These included timeframes that were insufficient to detect AEs with long induction periods, inadequate detail about AE frequency/duration, reporting aggregated subscale scores from different measures rather than specifying individual effects, not reporting numericised results of Likert-scale severity measures and/or using ambiguous severity summaries (e.g., 'the majority of patients were not Specific limitations in the design of clinical studies included the use of firstgeneration agents as comparators (which is likely to inflate EPS incidence data), only reporting AEs noted in at least 10% of patients or those that significantly differed between test and comparator drugs, not providing follow-up on withdrawn participants, and not clearly specifying whether cognitive/affective changes were the results of medication or underlying psychiatric states.…”

“…While separate reporting of tolerability and efficacy as reasons for premature discontinuation is encouraging, this failure to specify the AEs impairs the consistency and expediency of the measure, particularly if efficacy-related events (e.g., worsening of psychosis) are included in the AE category. 67 Furthermore, most studies prioritised quantifying AEs over establishing their subjective impact. Even with our lenient criteria (e.g.…”