The Battle of the Sexes in First-Episode Psychosis

Brian Miller, MD, PhD, MPH

How do men versus women with schizophrenia fare clinically, functionally, and neuropsychologically over the long term?

RESEARCH UPDATE

A common belief is that women with schizophrenia have a more favorable disease course and overall outcomes than men.1 However, previous studies of sex-outcome differences in patients with first-episode psychosis (FEP) have produced mixed results. Furthermore, there is an indication that, in general, short- and long-term outcomes in schizophrenia may differ.2,3 No previous studies have specifically explored long-term sex differences in patients with FEP after being discharged from a psychosis early intervention service (EIS).

Ayesa-Arriola and colleagues4 aimed to explore long-term sex differences in patients with FEP through several outcomes (clinical, functional, cognition, and treatment), as well as sex differences in the maintenance of benefits of EIS treatment after patients are transferred to regular care. They hypothesized similar outcomes in men and women 10 years after FEP.

Data were obtained from the First Episode Psychosis Clinical Program (Program of Attention and Intervention First-Episode Psychosis [PAFIP] and [PAFIP-10]) studies,5 which are incidence and 10-year follow-up studies of all subjects with FEP presenting to a local catchment area with an EIS service in Cantabria, Spain, after February 2001. Patients received 3 years of evidence-based phase-specific EIS for psychosis: low-dose antipsychotic medication, patient and family psychoeducation, and support for functional recovery. Participants were between the ages of 15 to 60 years, lived in the catchment area, experienced their first episode of DSM-IV non-affective psychosis, and had a total lifetime antipsychotic treatment for < 6 weeks. Individuals with drug or alcohol dependence, intellectual disability, or a history of neurological disease or head injury were excluded.

The same senior consultant psychiatrist interviewed patients at baseline, and at 1-, 3-, and 10-years’ follow-up. Clinical symptoms were assessed using the Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS), the Brief Psychiatric Rating Scale, and the Calgary Depression Scale for Schizophrenia. Global functioning was measured using the Disability Assessment Scale. An assessment of global cognitive function (GCF) was also performed. Recovery, defined as symptomatic remission and adequate psychosocial function at 1, 3, and 10 years following FEP, was determined based on SANS and SAPS scale scores. Data on relapses, mean antipsychotic daily doses, and extrapyramidal symptoms were also obtained. General linear models with repeated measures analysis of covariance were conducted to test longitudinal outcomes among males and females. Kaplan-Meier survival analysis was used to examine the relationship between relapse and time.

Three-hundred and seven patients (N = 179 male and N = 128 female) had baseline PAFIP measures. Of these, 297 were re-tested at 1 year; 259 at 3 years; and 209 tested about 8 to 16 years (of whom 183 were assessed by in-person interview). Non-completers had significantly lower education, lived in urban areas, were unemployed, and used cannabis. There was a trend toward higher participation in the 10-year reassessment in women.

When comparing individuals who completed the 10-year reassessment, at baseline females were significantly older at illness onset (aged 31 years in females versus 27 years in males); had higher premorbid functioning, IQ, and education; and were more likely to be living independently of parents, be employed, and have a partner and children. Schizophrenia diagnosis, alcohol and cannabis use were more frequent among men. Ten years later, women continued living independently of parents (70% versus 45%) and more frequently had a partner (38% versus 26%). Schizophrenia diagnosis (63% versus 84%) tobacco (45% versus 61%), and cannabis use (4% versus 12%) remained more frequent among men.

Clinical, functional, neuropsychological, and antipsychotic treatment information over the 10-year follow-up period were available for 151 patients (N = 66 male and N = 85 female). Women showed greater improvements in negative symptoms than males. No sex differences were found in Disability Assessment Scale or Global Cognitive Functioning scores. Survival curves showed that most of the relapses occurred during the first 3 years of follow-up, with no significant differences between females and males.Symptomatic and functional recovery was significantly more likely in females at 1 year (37% versus 22%) and 3 years (50% versus 31%) years, but not 10-year (47% versus 34%) follow-up. Women used significantly lower therapeutic antipsychotic dosages, but antipsychotic doses increased over time following discharge from EIS. Males and females did not significantly differ in the occurrence of extrapyramidal symptoms.

The authors concluded that better outcomes for women were found after 3 years of treatment at an EIS were underpinned by more favorable premorbid and baseline characteristics. They noted that after an average of 10 years of treatment, outcomes for women and men converged, except for the course of negative symptoms. Antipsychotic doses increased in both sexes once patients were discharged from the EIS program toward community-based services.

The strength of the present investigation is that no other published longitudinal studies have explored sex differences in long-term outcomes. The authors note that a limitation of the study is that relative contributions of biological (eg, estrogen), psychosocial, and environmental factors on sex differences and their interplay were not explored.

The Bottom Line

Better outcomes seen among women during the first 3 years after FEP occurred in the context of more favorable premorbid and baseline characteristics. After an average of 10 years of follow-up, with the exception of negative symptoms, outcomes for women approximated those for men.

CASE VIGNETTE

Ms H is a 42-year-old Black female with a history of schizophrenia and catatonia. The onset of her psychotic illness was at aged 26 years. She had several inpatient psychiatric hospitalizations during the first 3 years of her illness, but none in the past 14 years. She experienced prolonged remission of catatonia and positive symptoms of psychosis, and minimal residual negative symptoms following treatment with long-acting injectable antipsychotic medication. She has hypertension and diabetes but no substance use disorder comorbidity. For the past 5 years, Ms H has worked full time, bought a vehicle, has been in a romantic relationship, and lives independently. She is planning to pursue online coursework toward completion of a bachelor’s degree.

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 and Behavior Research Foundation, and the Stanley Medical Research Institute.

References

1. Wils RS, Gotfredsen DR, Hjorthøj C, et al. Antipsychotic medication and remission of psychotic symptoms 10 years after a first-episode psychosis. Schizophr Res. 2017;182:42-48.

2. Morgan C, Lappin J, Heslin M, et al. Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study. Psychol Med. 2014;44:2713-2726.

3. Gotfredsen DR, Wils RS, Hjorthøj C, et al. Stability and development of psychotic symptoms and the use of antipsychotic medication - long-term follow-up. Psychol Med. 2017;47:2118-2129.

4. Ayesa-Arriola R, de la Foz VO, Setien-Suero E, et al. Understanding sex differences in long-term outcomes after a first episode of psychosis. NPJ Schizophrenia. 2020;6:33.

5. Longitudinal Long-term Study (10 Years) of the Sample of First Episode of Non-affective Psychosis: PAFIP (10PAFIP). Updated December 26, 2020. Accessed February 4, 2021. https://clinicaltrials.gov/ct2/show/NCT02200588