Later is not necessarily better: limitations of survival analysis in studies of long-term drug treatment of psychiatric conditions

Survival analysis is routinely used to assess differences between groups in relapse prevention and treatment discontinuation studies involving people with long-term psychiatric conditions. The actual outcome in survival analysis is 'time to event', yet, in the mental health field, there has been little consideration of whether a temporary delay to relapse is clinically relevant in a condition that can last for decades. Moreover, in psychiatric drug trials, a pattern of elevated early relapses following randomisation to placebo or no treatment is common. This may be the result of the withdrawal of previous treatment leading to physiological withdrawal effects, which may be mistaken for relapse, or genuine relapse precipitated by the process of withdrawal. Such withdrawal effects typically produce converging survival curves eventually. They inevitably lead to differences in time to relapse, even when there is little or no difference in the cumulative risk of relapse at final follow-up. Therefore, statistical tests based on survival analyses can be misleading because they obscure these withdrawal effects. We illustrate these difficulties in a trial of antipsychotic reduction versus maintenance, and a trial of prophylactic esketamine in people with treatment-resistant depression. Both illustrate withdrawal-related effects that underline the importance of long-term follow-up and question the use of tests based on time to event. Further discussion of the most relevant outcome and appropriate approach to analysis, and research on patient and carer preferences is important to inform the design of future trials and interpretation of existing ones.