Are depot antipsychotics ever self-tapering? Exploring the discontinuation of long-acting injectable psychosis drugs and those with delayed onset through in silico modelling

Background and Hypothesis Reducing and stopping antipsychotic medications can have longer-term positive outcomes for some patients. Despite common wisdom, abrupt discontinuation of several long-acting injectable (LAI) antipsychotic drugs results in rapid D2 occupancy reductions. We explored if abrupt discontinuation of LAI antipsychotics with slow clearance remained within specified constraints on rate of D2 occupancy change (RODOC), which might reduce risk of emerging symptoms of psychosis related to withdrawal or relapse. Study Design Pharmacokinetic data were collated for six LAI antipsychotic forms (aripiprazole lauroxil, olanzapine pamoate, paliperidone palmitate 1-, 3-, and 6-monthly, and risperidone microspheres). 52 studies comprising 6146 patients were included. In silico modelling was completed to predict RODOC from abrupt discontinuation. We used RODOC thresholds of five percentage point (pp) difference per month as a proxy measure to theoretically estimate the likelihood of withdrawal effects emerging, with sensitivity analyses for 2.5 and 10 pp/month. Study Results Abrupt cessation of LAIs is likely to exceed 5pp/month RODOC for all examined LAIs except paliperidone palmitate 6-monthly. Peak rates of D2 occupancy change per month for an average person ranged from 5pp/month (paliperidone palmitate 6-monthly) to 66.1pp/month (risperidone microspheres). Significant interpersonal variation in pharmacokinetic factors was observed. Conclusions Almost all LAI antipsychotic medications could theoretically cause withdrawal effects in most patients if abruptly discontinued without oral supplementation. However, abrupt discontinuation of longer-acting paliperidone palmitate could theoretically be successful for some patients. Prescribers must collaborate with patients when devising tapering regimens to ensure schedules are personalised and responsive to individual experience.