Influence of antipsychotic medications on hyperlipidemia risk in patients with schizophrenia: evidence from a population-based cohort study and in vitro hepatic lipid homeostasis gene expression

Abstract

Introduction: Schizophrenia increases the risk of mortality and cardiovascular disease (CVD) risk. However, the correlation between antipsychotics (APs) and CVD remains controversial. Hyperlipidemia is a significant risk factor for CVD.

Methods: We conducted a nationwide population-based retrospective cohort study to investigate the effects of APs on the risk of hyperlipidemia and lipid homeostasis gene expression. We used data from the Longitudinal Health Insurance Database of Taiwan on new-onset schizophrenia patients and a comparison cohort without schizophrenia. We used a Cox proportional hazards regression model to analyze the differences in hyperlipidemia development between the two cohorts. Furthermore, we examined the effects of APs on the hepatic expression of lipid homeostasis-related genes.

Results: After adjusting for potential interrelated confounding factors, the case group (N = 4,533) was found to have a higher hyperlipidemia risk than the control cohort (N = 4,533) [adjusted hazard ratio (aHR), 1.30, p < 0.001]. Patients with schizophrenia without APs had a significantly higher risk of hyperlipidemia (aHR, 2.16; p < 0.001). However, patients receiving APs had a significantly lower risk of hyperlipidemia than patients not receiving APs (all aHR ≤ 0.42, p < 0.001). First-generation antipsychotics (FGAs) induce the expression of hepatic lipid catabolism genes in an in vitro model.

Discussion: Patients with schizophrenia had a higher risk of hyperlipidemia than controls; however, compared with non-treated patients, AP users had a lower risk of hyperlipidemia. Early diagnosis and management of hyperlipidemia may help prevent CVD.

Keywords: antipsychotic medications; cohort study; hyperlipidemia; lipid homeostasis; schizophrenia.

Figure 1

Cumulative incidence of hyperlipidemia compared between patients with and without schizophrenia using the Kaplan–Meier method. Case group mean follow-up years 9.93 (SD = 4.87). Control group mean follow-up years 9.12 (SD = 4.98).

Figure 2

Viability of HepaRG cells following exposure to antipsychotic medications (APs). HepaRG cells were exposed to FGAs [Chlorpromazine (0.844 μM), Chlorprothixene (1.450 μM), Clothiapine (0.465 μM), Droperidol (0.226 μM), Flupentixol (0.010 μM), Fluphenazine (0.020 μM), Haloperidol (0.027 μM), Levomepromazine (2.435 μM), Loxapine (0.029 μM), Pimozide (0.041 μM), Prochlorperazine (0.013 μM), Sulpiride (1.180 μM), Thioridazine (0.540 μM), and Trifluoperazine (0.006 μM)] and SGAs [Amisulpride (1.611 μM), Aripiprazole (0.468 μM), Brexpiprazole (0.323 μM), Clozapine (2.359 μM), Lurasidone (0.076 μM), Olanzapine (0.256 μM), Paliperidone (0.141 μM), Quetiapine (0.985 μM), Risperidone (0.027 μM), Ziprasidone (0.310 μM), and Zotepine (0.059 μM)] for 72 h. Cell viability was monitored by measuring cellular acid phosphatase activity using p-nitrophenylphosphate as a substrate. The data shown are the mean ± standard error (SE) (n = 3).

Figure 3

Expression of hepatic lipid homeostasis-related genes following treatment with antipsychotic medications (APs). Differentiated HepaRG cells were treated for 72 h with FGAs [Chlorpromazine (0.844 μM), Chlorprothixene (1.450 μM), Clothiapine (0.465 μM), Droperidol (0.226 μM), Flupentixol (0.010 μM), Fluphenazine (0.020 μM), Haloperidol (0.027 μM), Levomepromazine (2.435 μM), Loxapine (0.029 μM), Pimozide (0.041 μM), Prochlorperazine (0.013 μM), Sulpiride (1.180 μM), Thioridazine (0.540 μM), and Trifluoperazine (0.006 μM)] and SGAs [Amisulpride (1.611 μM), Aripiprazole (0.468 μM), Brexpiprazole (0.323 μM), Clozapine (2.359 μM), Lurasidone (0.076 μM), Olanzapine (0.256 μM), Paliperidone (0.141 μM), Quetiapine (0.985 μM), Risperidone (0.027 μM), Ziprasidone (0.310 μM), and Zotepine (0.059 μM)]. Following treatment, RNA was extracted, and the expression levels of (A) LRP1; (B) HL; and (C) LPL were analyzed by quantitative reverse transcription-polymerase chain reaction. Values were normalized to the expression of β-actin, with the β-actin levels of dimethyl sulfoxide (DMSO)-treated cells set at 1. Results are expressed as means ± standard error (SE) (n = 3), *, p < 0.05; **, p < 0.01; ***, p < 0.001 compared with cells treated with DMSO. LRP1, low-density lipoprotein receptor-related protein 1; HL, hepatic lipase; LPL, lipoprotein lipase.