To the best of our knowledge, this is the first study of sex differences in cognitive impairment with first-episode drug-naïve schizophrenia in China. The main finding of our current study is that patients with schizophrenia have demonstrable cognitive dysfunction. The study showed that FEDN schizophrenia patients had lower scores in MCCB total score, speed of processing, attention, working memory, verbal learning, visual learning, reasoning and problem solving than the normal controls, but there was no significant difference in category fluency and social cognition. This pattern is consistent with previous studies. Additionally, there were clear sex differences in cognitive impairment with FEDN schizophrenia in this sample. Male patients performed worse than female patients in symbol coding, digital sequence and verbal learning. Interestingly, we also found that there were six indexes and MCCB total score that showed diagnosis-by-sex interactions, belonging to the speed of processing, attention, working memory, and verbal learning. Lastly, sex differences in cognitive impairment were significantly related to multiple clinical symptoms and general characteristics (Table 4).
A great deal of research and analysis has been devoted to evaluating the neuropsychologic disorders suffered by schizophrenia patients in several cognitive fields. Language ability, executive function, attention, and the ability to filter irrelevant stimuli are all impaired. Working memory and executive function of patients with schizophrenia are also impaired [27–29]. Consistent with this finding, several cognitive deficits have been reported in adolescent schizophrenia. For example, Victoria et al. used MCCB to examine samples of cognitive impairment in Mexican adolescents with schizophrenia. After 3 and 6 months of treatment, all domains were improved except for social cognition . In recent years, Oxytocin (OXT) has emerged as a novel strategy for treating social cognitive and social behavioral deficits in schizophrenia-spectrum disorders, an intriguing prospect from both the evolutionary perspective and the neurodevelopmental-cognitive model. Therefore more research is needed to determine the utility of OXT as a treatment option or adjuvant therapy for schizophrenia [31, 32]. Other preliminary studies have shown that male patients with chronic schizophrenia have more severe cognitive impairment than female patients in domains such as immediate memory and delayed memory, though these differences were not found in language, visuospatial or attention indices . The difference between schizophrenia and the normal control is the result of a combination of factors. In-depth study of these differences can help to guide the treatment in the future.
Stress has been shown to damage memory and lead to cognitive impairment in multiple clinical contexts, and Corticotropin releasing factor (CRF) likely plays a primary role in mediating stress mnemonic dysfunction. Wiersielis KR assessed whether the projection of CRF into the medial septum (MS) of the hippocampus would affect memory formation in male and female rats . Interestingly, the results indicated that men are more vulnerable than women to be affected by the memory impairment caused by CRF in the MS. This may help explain why schizophrenia is more common in men and also why men usually show greater cognitive impairment. In men and women, CRF1 antagonists can prevent MS-mediated memory impairment caused by high levels of CRF, which may be related to stressful events. Collectively, CRF1 antagonists may be a viable option for the treatment of cognitive impairment in stressed individuals with mental disorders.
Another possible reason for demonstrated sex differences in the clinical presentation of schizophrenia may be the biological differences in sex hormones. Women often display more mild symptoms, and one hypothesis is that estrogen may have a protective effect on schizophrenia. The relationship between estrogen and BDNF, NMDA receptors, GABA receptors and luteinizing hormone may be an important way to understand sex differences . Estrogen has therapeutic effects and exerts neuroprotective effects, including anti-excitotoxicity and oxidation. Another major female gonadal hormone is progesterone, and available data indicate that it is a key modulator in the regulation of the central system through the dopaminergic system .
Women and men with schizophrenia show similar pervasive neuropsychological damage , though available evidence strongly supports sex differences in neuropsychological performance. Female patients have a later age of onset, better functional outcomes, less negative symptomatology and cognitive impairment, and more severe positive symptoms . Nevertheless, consistent with the studies mentioned above, our study showed that male schizophrenia patients performed worse in symbol coding, digital sequence and verbal learning in the first-episode schizophrenia group. However, there were no gender differences in other cognitive functions. We also found that men are significantly worse than women on PANSS total score, Negative symptom scale, General psychopathology scale and HAMD total score. Consistent with this finding, Li found sex differences in first-episode psychosis from 360 patients in Hong Kong participants were diagnosed with mental illness for the first time between the ages of 26 and 55 and had received antipsychotic treatment for less than 12 months. In women, memory was significantly associated with onset age, negative symptoms and side effects. Selective attention was correlated with the age of onset and education in men, as well as positive symptoms and short-term symptoms .
For sex differences in cognitive deficits, Zhang enrolled 248 patients with chronic schizophrenia and 188 healthy controls, using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), then found that the brain-derived neurotrophic factor (BDNF) levels were lower patients with chronic schizophrenia. Furthermore, male schizophrenic patients had significantly lower BDNF and poorer memory performance than their female counterparts, and in female patients BDNF correlated significantly with immediate and delayed memory. There was no gender difference in the normal control group . In addition, the impairment of visual perceptual organization ability is a cognitive defect repeatedly observed in patients with schizophrenia, but we did not find differences in visual learning between genders. There are inconsistencies in the literature on sex differences in these cognitive deficits. A Spanish study enrolled 74 female and 86 male participants who suffered from the first episode of psychosis. Although women scored higher than men on verbal memory, men scored higher than women on reaction time, visual memory, and planned tasks. In that study, there were no gender-group interactions in any the neuropsychological tests .
There are some limitations in this study. First, this is a cross-sectional design that cannot clearly demonstrate the longitudinal course of illness that a long-term study might. Second, the age of the patients in the first-episode drug-naïve schizophrenia group were younger than that of the control group. The inclusion criteria of symptoms less than 60 months and antipsychotic naivete likely skewed the age younger in this group. Nevertheless, the effect of these data on cognitive function is more useful and less confounded than in patients who have received long-term treatment for schizophrenia. Third, although we initially enrolled more patients, the sample size diminished admittedly due to exclusion criteria, incorrect questionnaires, and incomplete cognitive assessment. Finally, we chose MCCB as the cognitive testing, which may have data bias. More measurements and laboratory data need to be collected to better evaluate the cognitive impairment and sex differences in patients with schizophrenia. In the future, sample size should ideally be expanded, characteristics such as education controlled for, and longitudinal studies should be conducted to track cognitive changes.