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.

Brexpiprazole‐related tardive dystonia in a young patient with schizophrenia: A case report

“…Accordingly, our study examined the association between plasma cytokine concentrations during pregnancy and one month postpartum and depressive status one month postpartum. However, as pointed out in the paper by Kikuchi et al, 3 postpartum depression is observed with similar frequency even after 12 months. Therefore, it will be necessary to investigate long-term postpartum mood states and plasma cytokine concentrations, as pointed out by Veltre et al In previous reports, Corwin et al 4 measured cytokine levels (IL-6, IFN-γ, TNF-α, IL-1b, IL-10, IL-8) over time from 7 days through to 6 months (day 7, day 14, 1-, 2-, 3-and 6-month) postpartum, and compared these cytokine levels between postpartum women subgroups with EPDS greater than and less than 10.…”

“…2 Around 10% of patients taking brexpiprazole experienced EPS in clinical trials and research indicates that its risk for doses up to 3.4 mg is comparable to placebo. 2,3 This report presents a case of brexpiprazole-related tardive dystonia. Written informed consent was obtained from the patient for the publication of the details of her case.…”

Comparison of brexpiprazole, aripiprazole, and placebo for Japanese major depressive disorder: A systematic review and network meta‐analysis

“…Correlations have been found between the dose of antipsychotic drugs and the incidence of adverse events. For example, the risk of extrapyramidal side effects increases dose‐dependently 11 . Second, empirical clinical studies suggest that East Asian patients may require lower dosages of psychotropic drugs, such as antipsychotics, lithium, and antidepressants, than non‐Asians 12 .…”

“…For example, the risk of extrapyramidal side effects increases dose‐dependently. 11 Second, empirical clinical studies suggest that East Asian patients may require lower dosages of psychotropic drugs, such as antipsychotics, lithium, and antidepressants, than non‐Asians. 12 Racial and ethnic groups differ genetically in the activity of cytochrome P450, which participates in the metabolism of many drugs.…”

Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays

“…Clozapine and olanzapine are associated with a higher risk of metabolic side effects [24], followed by the medium-risk drugs quetiapine and risperidone and the low-risk drugs ziprasidone and aripiprazole [25][26][27]. Furthermore, although less frequently than first-generation APs, atypical APs can also induce extrapyramidal side effects [28][29][30]. Although the exact underlying mechanisms of various adverse effects are not well understood, an increasing body of evidence has linked both typical and atypical APs to disturbed mitochondrial function [31,32].…”