Risk of relapse during tapering of antipsychotic medication after a first psychotic episode: association with D2 receptor affinity but not with tapering speed
Authors: Shiral S. Gangadin, Franciska de Beer, Ben Wijnen, Marieke Begemann, Nico van Beveren, Nynke Boonstra, Lieuwe de Haan, Martijn Kikkert, Sanne Koops, Jim van Os, Wim Veling, Sybren Wiersma, Iris E.C. Sommer
Journal: World Psychiatry (2025)

While antipsychotic maintenance treatment effectively prevents relapse after a first psychotic episode, many remitted antipsychotic users wish to reduce or discontinue their medication, due to side effects, long‐term health concerns, stigma, or the desire to regain autonomy. Current guidelines suggest gradual tapering, but what the optimal speed of this tapering should be, especially in patients who remitted from a first psychotic episode, remains unclear. Furthermore, D2 receptor affinity of the antipsychotic drug may also affect relapse risk. This study examined relapse risk and time to relapse, within the first 18 months after remission from a first psychotic episode, in 227 individuals who tapered antipsychotic medication. Relapse was defined dichotomously using consensus criteria based on the Positive and Negative Syndrome Scale, hospitalization for psychosis, or explicit clinical judgement of the treating psychiatrist. Tapering speed (in olanzapine equivalents mg/day) was calculated as the difference of antipsychotic dose between the start and the end of tapering, divided by the number of days in between. Antipsychotics were classified into partial D2 agonists, or antagonists with low or high D2 affinity. Logistic and Cox proportional hazards regression analyses were controlled for age, sex, cannabis use, and duration of first psychotic episode, as well as for differences in clinical and sociodemographic characteristics between the three drug D2 affinity groups using inverse probability of treatment weighting. During the follow‐up period, 45.8% (N=104) of participants experienced a relapse after tapering. The average tapering speed was 10 mg olanzapine equivalents over 75 days, with an average tapering duration of 124 days (range: 6‐334 days). Logistic regression analysis showed that the tapering speed did not predict the risk of relapse (z=0.989, p=0.323). Compared with users of high D2 affinity antagonists (N=57), patients using low D2 affinity antagonists (N=116) and partial D2 agonists (N=54) had a lower risk of relapse (respectively, z=−2.104; odds ratio, OR=0.48, p=0.035; and z=−2.278, OR=0.44, p=0.023). Users of high D2 affinity antagonists had a shorter time between the end of tapering and relapse (mean: 280 days) than low D2 affinity antagonist users (mean: 351 days, p=0.027) and partial D2 agonist users (mean: 357 days, p=0.040). Thus, D2 receptor affinity of the antipsychotic was more important than tapering speed in predicting psychotic relapse risk in individuals remitted from a first psychotic episode. Users of high D2 affinity antipsychotics had an about twice higher risk of relapse than users of other types of antipsychotics. This higher risk of relapse after tapering should be regarded as a relevant factor when selecting an antipsychotic drug for people with a first psychotic episode. For patients using strong D2 antagonists after remission from a first psychotic episode, extra monitoring during tapering is required.