Antipsychotic Polypharmacy and Risk of Metabolic Disorders in Schizophrenia


What is the risk of diabetes, hypertension, or hyperlipidemia with antipsychotic polypharmacy in patients with schizophrenia? Researchers investigated these associations in a population-based prospective cohort study.




“Mr Ren” is a 32-year-old male with a history of chronic schizophrenia. The onset of his psychotic disorder was at age 21 years. He failed previous trials of aripiprazole and olanzapine. He has been taking paliperidone palmitate 234 mg IM monthly for the past 6 months but has significant residual positive symptoms. He has a history of comorbid obesity and type 2 diabetes, but he does not have hypertension or hyperlipidemia.

At an outpatient visit, the psychiatrist discusses a trial of clozapine, which Mr Ren declines due to concerns about adverse effects of weight and his diabetes. Mr Ren reports significant initial insomnia and inquires about quetiapine, which he says helped him sleep during a previous psychiatric hospitalization. He asks about the cardiometabolic risks of polypharmacy with paliperidone LAI and quetiapine. As his psychiatrist, how would you respond?

Patients with schizophrenia die on average 20 years prematurely compared to the general population,1 in part due to cardiometabolic disorders, including diabetes, obesity, hypertension, and hyperlipidemia.2 Cardiometabolic adverse effects are common with antipsychotic medications.3

Although lacking a strong evidence base, antipsychotic polypharmacy (APP) is frequently used.4,5 Data on cardiometabolic effects of APP, which have the potential for increased adverse effects, are inconsistent and low quality.6

The Current Study

Eyles and colleagues7 used the UK Clinical Practice Research Datalink (CPRD) to investigate associations between APP exposure and risk of developing cardiometabolic disorders. Primary care data were obtained from more than 700 general practices in the United Kingdom. Data were linked to hospital episode statistics records and the Mental Health Services Dataset.

The authors conducted a cohort study using CPRD records for patients with ICD-10 or READ codes for schizophrenia between July 1994 and Augusta 2018. Cohort entry was date of first antipsychotic prescription within 6 months of an incident diagnosis of schizophrenia. Patients were followed for up to 5 years, with a median follow-up of 14 months. Patients were followed up to 5 years or until they had a prescription and/or a diagnostic code for diabetes, hypertension, hyperlipidemia, death, or lack of contact with the general practice.

Patients aged <18 years and those with a history of myocardial infarction or stroke were excluded. The authors formed 3 cohorts from the study population, based on patients who did not have diabetes (cohort 1), hypertension (cohort 2), or hyperlipidemia (cohort 3).

The exposure of interest was time (days) exposed to antipsychotic polypharmacy versus monotherapy, as well as whether APP was with first-generation and/or second-generation antipsychotics. The exposure periods were based on the duration of each prescription and included a 90-day washout period. Outcomes were time to incidence of diagnosis or prescription for diabetes, hypertension, or hyperlipidemia.

Covariates included age, sex, ethnicity, BMI, IMD score, smoking, alcohol and illicit drug use, practice region, year of diagnosis, number of comorbidities, number of consultations, hospitalizations, and mental health service encounters, and the ratio of the prescribed daily dose (PDD) to defined daily dose (DDD). Data were analyzed using an even-time stratified multivariable Cox proportional hazards model with time-varying exposures on daily data and prescribed antipsychotic generation.

The study cohorts included 1633 (diabetes), 1268 (hypertension), and 1668 (hyperlipidemia) patients with schizophrenia. During follow-up, 4.4% developed diabetes, 6.6% developed hypertension, and 3.8% developed hyperlipidemia. Patients diagnosed with cardiometabolic comorbidities were significantly older and had more medical comorbidities. In the adjusted Cox models, compared to antipsychotic monotherapy, there was no evidence that APP was associated with an increased risk of diabetes or hyperlipidemia.

However, APP was associated with an increased risk of hypertension (HR=3.2, 95% CI 1.2-8.4). The risk was higher in patients with APP exclusively with first-generation compared to combined first- and second-generation agents. There was no evidence that exclusive second-generation APP was associated with an increased risk of cardiometabolic disorders compared to APP with first-generation agents.

Study Conclusions

The authors concluded that compared to monotherapy, APP had an increased risk of hypertension. Findings suggest that associated risks should be considered when making clinical decisions about APP. Study strengths include use of a prospective, representative, population-based database of primary care in the United Kingdom, which reduced selection bias. Another strength is that the CPRD includes detailed medical information, and the authors considered multiple potential confounding factors.

A limitation of the present study is that patients with unstable schizophrenia are managed in secondary/tertiary care, and prescription data for these patients were not available. Furthermore, there were small numbers of subjects with APP with only second-generation agents, which may have influenced findings for diabetes and hyperlipidemia. The observational nature of the study also delimits making causal inferences regarding these associations.

The Bottom Line

Antipsychotic polypharmacy (versus monotherapy) is associated with an increased risk of hypertension, but not diabetes or hyperlipidemia. For these patients, regular blood pressure monitoring, and antihypertensive treatment when indicated, appear warranted.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophreniaAnnu Rev Clin Psychol. 2014;10:425-448.

2. Bushe C, Holt R. Prevalence of diabetes and impaired glucose tolerance in patients with schizophreniaBr J Psychiatry Suppl. 2004;47:S67-S71.

3. Rojo LE, Gaspar PA, Silva H, et al. Metabolic syndrome and obesity among users of second generation antipsychotics: a global challenge for modern psychopharmacologyPharmacol Res. 2015;101:74-85.

4. Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trialsSchizophr Bull. 2009;35(2):443-

5. Harrington M, Lelliott P, Paton C, et al. The results of a multi-centre audit of the prescribing of antipsychotic drugs for in-patients in the UK. Psychiatric Bull. 2002;26:414-418.

6. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1)Arch Gen Psychiatry. 2006;63(10):1079-1087.

7. Eyles E, Margelyte R, Edwards HB, et al. Antipsychotic medication and risk of metabolic disorders in people with schizophrenia: a longitudinal study using the UK clinical practice research datalink [published online ahead of print, 2023 Aug 25]. Schizophr Bull. 2023;sbad126.

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