Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis

Abstract

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D₂ receptor (D₂R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D₂R occupancy curves showed that the risk increased substantially when D₂R occupancy exceeded 75-85%, except for D₂R partial agonists that had smaller ORs albeit high D₂R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D₂R therapeutic window for EPS.

Fig. 1. PRISMA flow diagram.

The flow diagram shows the study selection process.

Fig. 2. Dose-response curves of 16 antipsychotics for extrapyramidal side-effects.

This figure shows the dose-response curves of 16 individual antipsychotics for extrapyramidal side-effects (EPS) in different subgroups of patients with schizophrenia. The X-axis displays the daily antipsychotic dose (mg/d), while the Y-axis displays the odds ratios (ORs) for the risk of EPS associated with a specific antipsychotic dose compared to non-exposure (i.e., placebo or 0 mg/d). The colored areas display the 95% confidence intervals (95%CI). The color key displays the confidence in the evidence according to the GRADE approach (green=high, blue=moderate, yellow=low, red=very low). a: different formulations were pooled; b: knot locations at the 10th, 50th, and 90th percentiles were used; n. studies=number of studies; n. arms=number of arms; N=number of participants; OR odds ratio; EPS extrapyramidal side-effects.

Fig. 3. Dopamine 2 receptor (D₂R) occupancy and risk of extrapyramidal side-effects of seven individual antipsychotics.

This figure shows the relationships between dopamine 2 receptor (D₂R) occupancies and risk of extrapyramidal side-effects (EPS) of seven individual antipsychotics (amisulpride, aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). The X-axis displays the median D₂R occupancies (%) calculated from prescribed daily doses using formulas from Lako et al 2013 [11]. There were no available data and/or formulas for the other antipsychotics considered in this review. The Y-axis displays the corresponding ORs for the risk of EPS associated with a specific level of D2R occupancy compared with non-exposure (i.e., placebo or 0%). The colored areas display the 95% confidence intervals (95%CI). The color key displays the confidence in the evidence according to the GRADE approach (green=high, blue=moderate, yellow=low, red=very low). D₂R dopamine 2 receptor; EPS extrapyramidal side-effects; OR odds ratio.

Fig. 4. Dopamine 2 receptor (D₂R) occupancy and risk of extrapyramidal side-effects of D₂R antagonists combined.

This figure shows the relationships between dopamine 2 receptor (D₂R) occupancies and risk of extrapyramidal side-effects (EPS) of D₂R antagonists combined (amisulpride, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). The X-axis displays the median D₂R occupancies (%) calculated from prescribed daily doses using formulas from Lako et al 2013 [11]. There were no available data and/or formulas for the other antipsychotics considered in this review. The Y-axis displays the corresponding ORs for the risk of EPS associated with a specific level of D2R occupancy compared with non-exposure (i.e. placebo or 0%). The colored areas display the 95% confidence intervals (95%CI). The color key displays the confidence in the evidence according to the GRADE approach (green=high, blue=moderate, yellow=low, red=very low). D₂R dopamine 2 receptor; EPS extrapyramidal side-effects; OR odds ratio.