Antipsychotic Polypharmacy vs Monotherapy

Psychiatric TimesVol 41, Issue 6

What is their comparative safety?




“Mr Conley” is a 62-year-old man with chronic schizophrenia. Onset was in his 20s, but he has not required inpatient psychiatric treatment in more than 20 years. He lives with his mother, but functions independently.

He currently takes paliperidone palmitate 234 mg intramuscularly every 4 weeks, oral paliperidone 6 mg once daily, and quetiapine 800 mg at bedtime, which he has taken for years. He has comorbid obesity, hypertension, hyperlipidemia, and type 2 diabetes.

Mr Conley has chronic auditory hallucinations and delusions of reference, particularly when watching television. His mother reports that he talks to himself and argues with family members. He also has chronic mild thought disorder. He has never attempted suicide and has no history of substance use disorder. On examination, his demeanor is pleasant and cooperative, his affect is smiling, and he does not appear to be attending to internal stimuli.

Mr Conley and his mother have declined a trial of clozapine, primarily due to the need for routine blood monitoring and metabolic adverse effects. Given the potential cardiometabolic risks of polypharmacy with 2 second-generation antipsychotics, what is next?

Little is known about the benefits and safety of further increasing doses vs adding another antipsychotic following nonresponse.1 Yet, antipsychotic polypharmacy is common, with a prevalence of up to 50%.1 According to the most recent American Psychiatric Association Practice Guidelines, there is no evidence that antipsychotic polypharmacy is more harmful than monotherapy.2

A recent meta-analysis found evidence for reduction of negative symptoms with add-on aripiprazole.3 There is also evidence from observational studies that antipsychotic polypharmacy may be associated with lower risk of relapse and mortality1 as well as treatment discontinuation.4

The Current Study

Taipale et al5 aimed to investigate the safety of antipsychotic polypharmacy vs monotherapy, indexed by hospitalization due to physical illness or for cardiovascular reasons. They also aimed to examine the risk of relapse, indexed by psychiatric rehospitalization. The investigators used a within-individual analysis to eliminate selection bias.

The investigators studied patients with schizophrenia (N = 61,889) in Finland with a diagnosis of schizophrenia while in inpatient care between 1972 and 2014 and who were alive on January 1, 1996. Follow-up started on January 1, 1996, or the date of first diagnosis, and ended either on December 31, 2017, or at the time of death (whichever occurred first).

Study outcomes were nonpsychiatric hospitalization, hospitalization due to circulatory system disease, and psychiatric hospitalization. Antipsychotic dispensing data were modeled by defined daily dose (DDD) using the PRE2DUP method and were divided into periods of polypharmacy and monotherapy.6 (The Table presents DDDs.7)

Table. Defined Daily Doses as Determined by the World Health Organization

Table. Defined Daily Doses as Determined by the World Health Organization7

Mean age was 47 years, and 50% of participants were men. The mean interval since first inpatient diagnosis of schizophrenia was 9 years, and the median follow-up duration was 15 years. During follow-up in outpatient care, monotherapy was used 46%, polypharmacy 34%, and antipsychotic nonuse 20% of person-time.

The risk of nonpsychiatric hospitalization was significantly lower during polypharmacy use at all total dosage categories above 1.1 DDDs/day, with differences up to 13% than during monotherapy use of the same dosage category for patients who used both monotherapy and polypharmacy. The risk of cardiovascular hospitalization was significantly lower for polypharmacy at the highest total dosage category.

The pattern of findings between monotherapy and no use and polypharmacy and no use within the same individual were similar. Comparison of any polypharmacy use with any monotherapy use showed no significant difference for nonpsychiatric or cardiovascular hospitalization. Any antipsychotic polypharmacy was associated with a 6% lower risk of psychiatric hospitalization compared with monotherapy.

Study Conclusions

In this first study comparing antipsychotic polypharmacy vs monotherapy safety in schizophrenia, the authors found more than 40% of patients had used high-dose monotherapy and more than 50% of patients had used high-dose polypharmacy. The first nonpsychiatric hospitalization was lower for polypharmacy at total dose categories above 1.1 DDDs/day and the risk of cardiovascular hospitalization was 18% lower for polypharmacy at the highest total dosage category.

Study strengths include the use of a large nationwide cohort and within-participants design. Study limitations include the absence of information on the frequency of monitoring visits, as more intensive monitoring might have contributed to the risk of hospitalization, and the assumption that time-varying covariates are multiplicatively related to the hazard.

The Bottom Line

Antipsychotic monotherapy is not associated with a lower risk of hospitalization for severe physical health problems compared with polypharmacy when high total dosage is assessed. Treatment guidelines should not explicitly encourage monotherapy instead of polypharmacy; the investigators argue for a more agnostic approach to this issue.

Regarding Mr Conley, this study suggests that continuing both paliperidone and quetiapine is a reasonable option, although regular cardiometabolic monitoring is warranted.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Psychiatric Times editorial board. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Tiihonen J, Taipale H, Mehtälä J, et al. Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophreniaJAMA Psychiatry. 2019;76(5):499-507.

2. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With SchizophreniaAm J Psychiatry. 2020;177(9):868-872.

3. Galling B, Roldán A, Hagi K, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysisWorld Psychiatry. 2017;16(1):77-89.

4. Weiser M, Davis JM, Brown CH, et al. Differences in antipsychotic treatment discontinuation among veterans with schizophrenia in the U.S. Department of Veterans AffairsAm J Psychiatry. 2021;178(10):932-940.

5. Taipale H, Tanskanen A, Tiihonen J. Safety of antipsychotic polypharmacy versus monotherapy in a nationwide cohort of 61,889 patients with schizophreniaAm J Psychiatry. 2023;180(5):377-385.

6. Tanskanen A, Taipale H, Koponen M, et al. From prescription drug purchases to drug use periods – a second generation method (PRE2DUP)BMC Med Inform Decis Mak. 2015;15:21.

7. Definition and general considerations. Norwegian Institute of Public Health. Last updated February 7, 2018. Accessed April 25, 2024.

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