Is the risk higher if patient experienced akathesia and or other eps on other 2nd generation antipsychotics?

The short version: a history of akathisia or EPS from other second-generation antipsychotics is a strong clinical signal that the same class of drugs is likely to produce the same reaction again, and the evidence here supports that concern.

The 2015 phase-3 trial of the 3-month paliperidone palmitate formulation reported akathisia in 4.4% of the drug group versus 0.7% on placebo [1]. That is a real rate, but it comes from a manufacturer-funded trial designed to show efficacy, not to study patients with prior EPS. The trial excluded anyone with a history of neuroleptic malignant syndrome or severe EPS, which means the people most at risk were already screened out [1]. The reported rate is therefore a floor, not a ceiling.

A 2025 genome-wide association study identified specific genetic loci linked to antipsychotic-induced movement disorders, including akathisia, and showed that polygenic risk scores could predict these outcomes with AUCs up to 0.80 [2]. That means susceptibility is partly heritable and measurable. If a patient has already reacted to one drug in this class, they are more likely to carry the genetic variants that make them vulnerable to the whole class.

A 2020 cross-sectional study in Ethiopia found drug-induced akathisia in 12.4% of patients on psychotropic medications overall, with female sex and higher chlorpromazine-equivalent doses as significant predictors [3]. A 2016 study in adults with intellectual disability found akathisia in 9% of those on antipsychotics, and the risk rose sharply with polypharmacy and higher dosing [4]. These are not paliperidone-specific, but they show that akathisia is a class-wide problem and that prior vulnerability compounds it.

The evidence here does not contain a single study that directly answers your question: no trial that took patients with prior EPS from other second-generation drugs, gave them paliperidone palmitate, and measured how many got akathisia again. That study has not been published, or at least was not captured by this search. What the evidence does show is that akathisia is a known, dose-related side effect of paliperidone [1], that genetic susceptibility to these movement disorders exists and can be predicted [2], and that prior antipsychotic exposure is a risk factor for movement disorders in general [4].

My call: a patient with prior akathisia or EPS from other second-generation antipsychotics is at elevated risk for the same reaction with paliperidone palmitate. The mechanism is class-wide, the genetic evidence supports shared vulnerability, and the trials that exist were not designed to test this question. Confidence: moderate – the logic is strong, but the direct evidence is absent.