Sex differences in schizophrenia have been observed since the beginning of the 20th century, when the pioneering German psychiatrist Emil Kraepelin noted that “dementia praecox” (the diagnostic precursor of schizophrenia) was more prevalent and severe in men.1,2 The most consistently noted sex difference in schizophrenia pertains to age of onset: In men, age of onset peaks between ages 15 and 25 years, whereas in women, peak onset is between 20 and 35 years of age, with a subsequent smaller peak between the ages of 45 to 49 years, a period that coincides with a significant drop in estrogen levels.1 Differences in clinical presentations have also been noted between the sexes. Men display more negative symptoms such as poor social functioning, flat affect, amotivation, and poverty of speech, whereas women are prone to more positive symptoms, such as auditory hallucinations and persecutory delusions. Some studies also suggest that men have more cognitive impairment and a more severe course of illness.3,4 The reasons for the sex differences in schizophrenia have not been fully elucidated, but a widely held hypothesis is that endogenous estrogen may function as a protective agent, thus modifying symptom severity.5

Julie Walsh-Messinger, PhD, a psychology professor at the University of Dayton in Ohio, told Psychiatry Advisor that there remain many unknowns about sex differences in schizophrenia, which is currently a topic of intense clinical interest: “In medicine, research studies were often conducted on predominantly male samples, and those findings were generalized to females with the assumption that they could be. During the last decade, scientists have begun to recognize that male and female biology is different, and therefore findings in men cannot generalize to females. But because this was overlooked for so long, there are just so many questions. To begin with, we believe these differences [in schizophrenia] are biological and likely related to hormone exposure, but we still need to figure out the critical time points and the specific mechanism by which this happens.” She noted that although social gender norms also affect behavior, they are not as likely to be the primary contributing factor to the sex differences observed in schizophrenia.

The majority of studies that have demonstrated sex differences in schizophrenia have involved cohorts of young and middle-aged patients.6 There is a paucity of research conducted among patients in later life, when declining estrogens levels may affect the course of disease in women.6 University of Maryland School of Medicine professor Anjana Muralidharan, PhD, and colleagues undertook a study to examine sex differences in neurocognition and social skills among community-dwelling middle-aged older adults with schizophrenia, and enrolled 242 patients aged 40 to 85 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder with current active illness. Global cognition, social skill levels, and symptoms were assessed with a comprehensive neuropsychological battery, including assessment of attention and concentration, executive functioning, verbal learning, memory, and fluency; the Social Skills Performance Assessment; and the Positive and Negative Syndrome Scale, respectively.

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Results showed that cognitive impairment was higher in men than women; however, the effect of sex on cognitive impairment did not differ by age. No differences between men and women were found for social skills performance, a finding consonant with prior schizophrenia studies in older and middle-aged patients and contrary to those performed in younger patients, which generally show that women demonstrate better social skills than men. The most significant results were found in the domain of expressive deficits, such as flat affect and poverty of speech. In men, the severity of expressive deficits increased with age, whereas in women, older age was associated with better expressive negative symptoms. Commenting on the study in an accompanying editorial, Tarek K. Rajji, MD, FRCPC, from Toronto’s Centre for Addiction and Mental Health, Ontario, Canada, wrote “This double dissociation is very exciting and could have direct clinical implications for the development of interventions that target negative symptoms in older adults with schizophrenia.”7

Dr Walsh-Messinger told Psychiatry Advisor that Dr Muralidharan’s study is important because it is 1 of the few to examine sex differences in an older population of patients with schizophrenia. “The findings don’t directly support the long-held hypothesis that symptoms worsen in females as estrogen levels drop with age, but they did find more intact cognition in females, which as suggested by the authors, may point to the importance of the cognitive reserve believed to be facilitated by later onset in women,” she stated.

“This is certainly possible, and if so, points to the importance of cognitive remediation as a treatment in schizophrenia,” she continued. “However, I’d caution the field to not yet abandon the hypothesis that declining estrogen is not a factor, as my collaborators and I have published several studies where we report converse findings in males and females with schizophrenia. It may very well be that the disease expression in males and females is just different, and that declining estrogen is playing a role, but the symptom expression looks different in females than males. It’s also possible that age of onset could be confounding these findings, as onset in women is typically delayed by 7 to 20 years. You can’t compare same-age males and females with schizophrenia without the confound of illness progression.”

References

1. Mendrek A, Mancini-Marïe A. Sex/gender differences in the brain and cognition in schizophrenia. Neurosci Biobehav Rev. 2016;67:57-78.

2. Salem JE, Kring AM. The role of gender differences in the reduction of etiologic heterogeneity in schizophrenia. Clin Psychol Rev. 1998;18(7):795-819.

3. Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl. 2000;401:3-38.

4. Ochoa S, Usall J, Cobo J, Labad X, Kulkarni J. Gender differences in schizophrenia and first-episode psychosis: a comprehensive literature review. Schizophr Res Treatment. 2012;2012:916198.

5. Gogos A, Sbisa AM, Sun J, Gibbons A, Udawela M, Dean B. A role for estrogen in schizophrenia: clinical and preclinical findings. Int J Endocrinol. 2015;2015:615356.

6. Muralidharan A, Harvey PD, Bowie CR. Associations of age and gender with negative symptom factors and functioning among middle-aged and older adults with schizophrenia. American J Geriatr Psychiatry. 2018;26:1215-1219.

7. Rajji TK. Late-life schizophrenia and gender matters. Am J Geriatr Psychiatry. 2018;26(12):1220-1221.