Case Vignette
“Mr. Conley” is a 62-year-old man with chronic schizophrenia. Although his condition first began in his 20s, he has not received inpatient psychiatric treatment for over 20 years. He lives with his mother but is independent.
He is currently taking paliperidone palmitate 234 mg intramuscularly every 4 weeks, paliperidone 6 mg orally once daily, and quetiapine 800 mg at bedtime, which he has been taking for years.He has comorbid obesity, hypertension, hyperlipidemia, and type 2 diabetes.
Mr. Conley suffers from chronic auditory hallucinations and delusions, especially while watching television. According to his mother, he talks to himself and argues with family members. He also has a 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 paying attention to internal stimuli.
Conley and his mother declined a trial of clozapine, primarily due to the need for regular blood monitoring and metabolic side effects. Given the potential cardiometabolic risks of polypharmacy with two second-generation antipsychotics, what happens next?
Little is known about the benefit and safety of further increasing the dose versus adding another antipsychotic after failure to respond.1 However, antipsychotic polypharmacy is common, with prevalence rates reaching up to 50%.1 According to the most recent American Psychiatric Association clinical practice guidelines, there is no evidence that combination antipsychotic therapy is more harmful than monotherapy.2
A recent meta-analysis found evidence that add-on aripiprazole reduced negative symptoms.3 There is also evidence from observational studies that antipsychotic polypharmacy may reduce the risk of relapse and death.1 The same applies to discontinuing treatment.Four
Current Research
Taipare et al.Five The aim was to investigate the safety of antipsychotic combination therapy versus monotherapy, as measured by hospitalization for physical or cardiovascular disease, and to examine the risk of relapse, as measured by psychiatric readmission. The researchers used within-person analyses to eliminate selection bias.
Researchers studied Finnish patients with schizophrenia (N = 61,889) who were diagnosed with schizophrenia during hospitalization between 1972 and 2014 and were alive on January 1, 1996. Follow-up began on January 1, 1996 or the date of first diagnosis and ended on December 31, 2017 or at time of death, whichever occurred first.
Study outcomes were non-psychiatric hospitalizations, cardiovascular hospitalizations, and psychiatric hospitalizations.Antipsychotic dispensing data were modelled with daily doses (DDDs) defined using the PRE2DUP methodology and separated into polypharmacy and monotherapy periods.6 ( table Introducing DDD.7)
table. World Health Organization Daily Intake7
The mean age was 47 years and 50% of participants were male. The mean time from first inpatient diagnosis of schizophrenia was 9 years and the median follow-up was 15 years. During follow-up in outpatient care, monotherapy was used in 46% of person-times, polypharmacy in 34% and no antipsychotic use in 20% of person-times.
The risk of non-psychiatric hospitalization was significantly reduced during polypharmacy in all total dose categories above 1.1 DDD/day, with differences of up to 13% for patients who used both monotherapy and polypharmacy compared with monotherapy in the same dose category. The risk of cardiovascular hospitalization was significantly reduced during polypharmacy in the highest total dose category.
The patterns of findings between monotherapy vs. no use and polytherapy vs. no use within the same individuals were similar. No significant differences in nonpsychiatric or cardiovascular hospitalizations were observed when comparing polytherapy use with monotherapy use. Antipsychotic polytherapy was associated with a 6% lower risk of psychiatric hospitalization compared with monotherapy.
Study conclusions
In the first study comparing the safety of antipsychotic polypharmacy versus monotherapy in schizophrenia, the authors found that more than 40% of patients used high-dose monotherapy and more than 50% of patients used high-dose polypharmacy. In total dose categories of more than 1.1 DDD/day, there were fewer first nonpsychiatric hospitalizations due to polypharmacy, and in the highest total dose category, there was an 18% lower risk of cardiovascular hospitalization due to polypharmacy.
Strengths of this study include the use of a large, nationwide cohort study and a within-participant design. Limitations include the lack of information on the frequency of monitoring visits (more intensive monitoring may contribute to hospitalization risk) and the assumption that time-varying covariates are multiplicatively associated with hazards.
Conclusion
When total doses were assessed as high, antipsychotic monotherapy was not associated with a lower risk of hospitalization for serious physical health problems compared with polypharmacy. Treatment guidelines should not explicitly recommend monotherapy instead of polypharmacy; researchers argue for a more agnostic approach to the issue.
For Conley, the study suggests that continuing both paliperidone and quetiapine would be a reasonable option, although regular cardiometabolic monitoring would be necessary.
Dr. Miller Professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. Psychiatry Times Editorial Board. The authors report receiving research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
References
1. Tiihonen J, Taipale H, Mehtälä J, et al. Association of antipsychotic polypharmacy and monotherapy with psychiatric rehospitalization in adults with schizophrenia. JAMA Psychiatry. 2019;76(5):499-507.
2. Keepers GA, Fochtmann LJ, Anzia JM, et al. American Psychiatric Association Guidelines for the Treatment of Schizophrenia. American Journal of Psychiatry. 2020;177(9):868-872.
3. Galling B, Roldán A, Hagi K, et al. Antipsychotic augmentation versus monotherapy in schizophrenia: systematic review, meta-analysis, and meta-regression.. World Psychiatry. 2017;16(1):77-89.
4. Weiser M, Davis JM, Brown CH, et al. Differences in antipsychotic treatment discontinuation among US Department of Veterans Affairs veterans with schizophrenia. American Journal of Psychiatry. 2021;178(10):932-940.
5. Taipale H, Tanskanen A, Tiihonen J. Safety of antipsychotic combination therapy and monotherapy in a nationwide cohort of 61,889 patients with schizophrenia. American Journal of Psychiatry. 2023;180(5):377-385.
6. Tanskanen A, Taipale H, Koponen M, et al. From prescription drug purchase to duration of drug use – a second generation method (PRE2DUP). BMC Medical Inform Decismac. 2015;15:21.
7. Definitions and general considerations. Norwegian Institute of Public Health. Last updated February 7, 2018. Accessed April 25, 2024. https://atcddd.fhi.no/ddd/definition_and_general_considera/ Original translation
