Which Pharmacotherapies Are Most Effective for Schizoaffective Disorder?

Brian Miller, MD, PhD, MPH

Psychiatric Times, Vol 38, Issue 5, Volume 05,

There is debate whether schizoaffective disorder is a separate illness or is part of the continuum of schizophrenia and mood disorder spectrum.


Schizoaffective disorder includes both psychotic and affective symptoms (Table 1), with separate bipolar and depressive subtypes.1-3 ICD-11 aims to improve the diagnostic accuracy and differential diagnosis of schizoaffective disorder.4 There is debate whether schizoaffective disorder is a separate illness or is part of the continuum of schizophrenia and mood disorder spectrum.5

Pharmacotherapy recommendations for schizoaffective disorder are generally derived from studies on schizophrenia and bipolar disorder; thus, symptoms are most commonly treated with antipsychotics, mood stabilizers, and/or antidepressants. Only paliperidone has an approved treatment indication specifically for schizoaffective disorder.

Cohorts Studied

To explore the efficacy of pharmacotherapies for schizoaffective disorder, Lintunen and colleagues6 looked at 2 nationwide cohorts. Treatments included oral and long-acting injectable (LAI) antipsychotics, mood stabilizers, antidepressants, and benzodiazepines and nonbenzodiazepines together (zopiclone, zolpidem, and zaleplon, also known as Z-drugs).

Lintunen et al analyzed 2 cohorts from nationwide Finnish and Swedish registers. The Finnish cohort included 7655 patients treated for schizoaffective disorder, based on inpatient care as recorded in the Finnish Hospital Discharge Register. The Swedish cohort included 7525 individuals aged 16 to 64 years with schizoaffective disorder who were identified based on inpatient registers, specialized outpatient registers, disability pensions, and a social insurance agency register.6 Cohort members were followed from July 2006 until death, change in diagnosis to schizophrenia, or study end (December 2016 for the Swedish cohort and December 2017 for the Finnish cohort). Sensitivity analyses were performed excluding anyone who received a schizophrenia diagnosis during follow-up.

The main exposure was antipsychotics, based on Anatomical Therapeutic Chemical classification code N05A (except lithium); adjunctive medicine included mood stabilizers, antidepressants, and benzodiazepines and/or Z-drugs. Psychotropic medication use periods were based on the PRE2DUP methodThe primary outcome measure was hospitalization due to psychosis. The authors also analyzed a composite measure of treatment failure, which included psychiatric hospitalization, change in medication, and death.

Analyses were conducted in each cohort separately using within-individual design and Cox regression models (hazard ratios [HRs] and 95% CIs), with P values adjusted for multiple comparisons. For antipsychotic effectiveness, the reference was antipsychotic nonuse. Nonantipsychotic medications were considered as adjunctive therapies, with antipsychotic use without adjunctive use as the reference (eg, olanzapine monotherapy was the reference for comparisons with olanzapine–mood stabilizer analyses). Data on 16 most commonly used antipsychotics were reported. Five oral antipsychotics (clozapine, olanzapine, quetiapine, risperidone, and aripiprazole) and LAIs (as a single category) were analyzed in combinations with adjunctive pharmacotherapies.

The Outcomes

In both cohorts, 60% of the study subjects were female. Mean age was 45 to 47 years. During follow-up, 13% of the Finnish cohort and 22% of the Swedish cohort were censored because of a change in diagnosis to schizophrenia. The median follow-up was 8 years in the Swedish cohort and 11 years in the Finnish cohort. During the follow-up, about half of the participants had a hospitalization for psychosis. Approximately 90% of individuals used antipsychotics during the follow-up; first-generation agents were more common in Sweden, and clozapine and antipsychotic polypharmacy were more common in Finland. About half of the patients had concurrent antipsychotic and antidepressant use, whereas mood stabilizers were used in 41% of the Swedish and 47% of the Finnish cohort. Benzodiazepines/Z-drugs were used in 72% of the Swedish and 61% of the Finnish cohort.

In both groups, use of clozapine (HR, 0.49-0.50), LAIs, and polypharmacy (HR, 0.51-0.57) were consistently associated with a decreased risk of inpatient hospitalization versus antipsychotic nonuse (Table 2). Notably, quetiapine use was not associated with a decreased risk of psychosis hospitalization in either country. In sensitivity analyses, the pattern of findings was similar.

Antipsychotics plus mood stabilizers were associated with a 16% to 24% decreased risk of a psychosis hospitalization (HR, 0.76-0.84). Antidepressant use was associated with a 10% decreased risk of inpatient hospitalization in the Swedish cohort (HR, 0.90), but not in the Finnish cohort (HR, 1.00). By contrast, Z-drug use was associated with a 7% to 21% increased risk of hospitalization, even after censoring the first 30 days of use. The overall pattern of findings remained similar with the broader outcome of any psychiatric hospitalization (instead of hospitalization for psychosis).

The authors found that exposure to antipsychotics was associated with a decreased risk for inpatient hospitalization in patients with schizoaffective disorder. Furthermore, the combination of antipsychotics and adjunctive mood stabilizers (versus antipsychotic monotherapy) was also associated with lower risk of psychosis hospitalization. The evidence was much less robust for adjunctive antidepressants. Adjunctive use of benzodiazepines/Z-drugs was associated with an increased risk of hospitalization.

Study strengths include the use of 2 large nationwide cohorts with multiple years of follow-up and use of the within-individual model, which inherently controls for time-invariant covariates. Study limitations include the lack of availability of some clinically relevant factors and the potential diagnostic uncertainty of register-based data.

Concluding Thoughts

The use of antipsychotics, particularly clozapine and LAIs, and adjunctive mood stabilizers was associated with a decreased risk of hospitalization for psychosis among individuals with schizoaffective disorder in 2 nationwide cohorts. In contrast, benzodiazepines/Z-drugs were associated with an increased risk of psychosis-related hospitalization. Future studies of adjunctive treatments should consider the bipolar and depressive subtypes of schizoaffective disorder separately.

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


1. Murru A, Pacchiarotti I, Nivoli AM, et al. What we know and what we don’t know about the treatment of schizoaffective disorder. Eur Neuropsychopharmacol. 2011;21(9):680-690.

2. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th revision. World Health Organization; 1992.

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013.

4. Peterson DL, Webb CA, Keeley JW, et al. The reliability and clinical utility of ICD-11 schizoaffective disorder: a field trial. Schizophr Res. 2019;208:235-241.

5. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al. Does schizoaffective disorder really exist? A systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders. J Affect Disord. 2008;106(3):209-217.

6. Lintunen J, Taipale H, Tanskanen A, et al. Long-term real-world effectiveness of pharmacotherapies for schizoaffective disorder. Schizophr Bull. 2021;sbab004. ❒

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