Abstract

Bipolar disorder (BD) is worldwide a prevalent mental illness and a leading risk factor for suicide. Over the past three decades, it has been discovered that sex differences exist throughout the entire panorama of BD, but the etiologic regions and mechanisms that generate such differences remain poorly characterized. Available evidence indicates that the dorsolateral prefrontal cortex (DLPFC), a critical region that controls higher-order cognitive processing and mood, exhibits biological disparities between male and female patients with psychiatric disorders, which are highly correlated with the co-occurrence of psychotic symptoms. This review addresses the sex differences in BD concerning epidemiology, cognitive impairments, clinical manifestations, neuroimaging, and laboratory abnormalities. It also provides strong evidence linking DLPFC to the etiopathogenesis of these sex differences. We emphasize the importance of identifying gene signatures using human brain transcriptomics, which can depict sexually different variations, explain sex-biased symptomatic features, and provide novel targets for sex-specific therapeutics.

Introduction

Bipolar disorder (BD) is a severe mood disorder that is categorized by extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). According to the intensity of mood elevation, two major forms of BD are distinguished: bipolar I disorder (with mania) and bipolar II disorder (with hypomania). In 2019, more than 40 million people experienced BD worldwide (Kakhramonovich, 2022). Approximately half to 70% of BD patients develop psychotic features during their lifetime (Van Bergen et al., 2019). A history of psychotic features has been associated with earlier onset of BD, more frequent hospitalizations, severer cognitive impairments, lower response to lithium, and worse psychosocial prognosis, particularly for manic episodes (Van Bergen et al., 2019, Maj, 2003, Glahn et al., 2007, Maj et al., 2002). As a major hazard of psychiatric illnesses, life expectancy in patients with BD has been reported to be decreased by 10–۲۰ years, with suicide serving as the primary culprit (Kessing et al., 2015). Suicidal behaviors are prevalent among patients with BD, as 20–۶۰% of them attempt suicide at least once in their lifetime (Dome et al., 2019). The incidence of suicide death among patients with BD can be more than 20 times higher than in the general population, particularly when untreated (Grande et al., 2016). In addition, the lethal index, a parameter defined as the ratio of suicidal attempts to suicide completion, is more than 10 times lower for BD patients (3:1) than for the general population (35:1) (Dome et al., 2019).

A distinct feature that underpins the high suicidality in BD is its sex difference. Among bipolar patients, suicide attempters were 35% more frequent in females than in males, regardless of the diagnostic subtypes (Tondo et al., 2016). When patients had manic episodes, females were 2.4 times more likely to die by suicide than males (Bhattacharya et al., 2011). This sex-related suicide rate was up to 3 times higher in female patients with a first-episode psychosis than in male counterparts, but suicidality can be better remitted by therapeutic interventions in female than in males (Chang et al., 2011, Tseliou et al., 2017). These data suggest that the manic episodes and psychotic features are major risk factors for suicide. The higher prevalence of suicide rate in females with BD, and the observation that suicidality increased with the development of psychotic symptoms and was reduced after medical care, have led to the idea that unraveling the neurobiological basis of sex differences in BD, particularly in patients with comorbid psychosis (bipolar psychosis), may provide novel therapeutic targets for extending the lifespan of BD populations.

Conclusions

Due to the asymmetry in research intensity between the clinical and biological literature that has controlled for sex, at present, we could merely provide our speculative explanation for the origin of sex disparities in clinical symptoms and cognitive impairments in BD. While there are highly promising preliminary findings, research on the pathophysiology of BD has yet to fully analyze the confounding factors, particularly psychotic features, and suicide in relation to sex. Transcriptomic approaches to study the neurobiology of BD in both sexes have been discussed. These techniques place a strong emphasis on discovering the key cells and molecules across psychiatric diagnoses as well as comorbidities based on diverse clusters of symptoms.

Despite the fact that the effect of female sex hormones and neurosteroids on BD is beginning to be understood, studies should evaluate treatments in terms of female hormonal fluctuations, such as entering puberty, menstrual cycle stage, menopausal stage, or use of hormonal contraception. There should be clinical and laboratorial consensus that, in BD research at multi-dimensional levels, data are analyzed including sex as a confounder.