As shown in the results, 100% (ten out of ten) of our selected large samples studies (n > 1,000) published in the last ten years (2011-2020), showed a predominance of female gender in their samples of bipolar patients. These results could support our hypothesis of a relatively recent increase in BD prevalence among individuals with female gender. However, our results seem to be in contradiction with previously published literature about BD prevalence in the two genders.1-4,14 Causes for this difference could lay in the size of the samples analysed, being that the majority of the studies presented in literature analyse much smaller samples. Moreover, one could argue that the higher percentage of females diagnosed with BD-II could interfere with the gender distribution of the samples analysed, and therefore be the cause of our findings. However, of note, Bobo et al.,32 Buoli et al.,33 Karanti et al.,27 and Vieta et al.,34 had a higher proportion of BDI patients in their samples, and Kalman et al.36 only had BDI patients in their sample. Findings of a higher prevalence of female patients in these four studies could further support our hypothesis, being BDI the type of BD traditionally more commonly associated with equal prevalence in the two genders.2,3
Even though not all of the studies discussed here are epidemiological, all of them represent the gender distribution of wide national or international coverage studies, with high numbers of patients, and therefore report a fairly realistic picture of the distribution of the disease in the population to which they refer. Buoli et al.33 analysed the sample of a nationwide epidemiological study, Hayes et al.28 and Yoon et al.30 recruited patients from samples representative of the national population, while Crump et al.26 recruited patients from the Swedish National Registry, which included every person at least 20 years of age that lived in Sweden for at least two years as of January 1, 2003.
Overall, the gender distribution of BD reported in these studies, along with the increase of BD diagnosis in the last decade,20 could be signals of more efficient BD diagnosis, especially in the female gender. Since female gender in BD has already been associated with higher rates of rapid cycling,37 dysphoria, and lifetime prevalence of depressive episodes,38 and suicide attempts,10 indicating that BD in women can exhibit characteristics of non-inferior severity of illness and reduced quality of life, compared to their male counterparts, prompt recognition of BD in female patients is crucial in order to provide more adequate treatment. In particular, the frequent observation of a prevalent depressive polarity in female patients,10 with more frequent first manifestation of BD through a major depressive episode (MDE) and the higher lifetime number of MDEs, represent significant challenges for clinicians who may misdiagnose them as affected by unipolar MDD and consequently treat them with antidepressants rather than with mood stabilizers and atypical antipsychotics, a treatment that, particularly if administered in monotherapy, could concur in the onset of rapid cycling.39
Moreover, BD in women poses a significant burden on pregnancy, with a higher risk of adverse pregnancy outcomes and a higher frequency of relapses during the postpartum period,40-42 making prophylactic medication during pregnancy fundamental in order to maintain mood stability postpartum.41 Of note, the correlation between the physiology of pregnancy and BD relapses could underlay hormonal and endocrinological influence on BD symptoms and presentation, as it has already been demonstrated for unipolar MDD.43-45 The extensively reported correlations between sex hormones and mood dysregulation in women, could be significant also for BD, not only in terms of prevalence, but also for providing better care for female BD patients, which could benefit from personalized and hormonal treatments, as it already happens for unipolar MDD.45 It has already been suggested, in this regard, that women treated for BD show greater degrees of menstrual-entrained mood fluctuations, which could be mitigated by mood stabilizing treatments (i.e. Lamotrigine).46
In conclusion, as BDs represent highly comorbid, disabling, difficult-to-treat and life-threatening conditions, clinicians should be aware of the recently reported increase in the prevalence of such conditions in the female gender and pay additional attention in the differential diagnosis with unipolar MDD, particularly when the first manifestation of BD is represented by a MDE. Prompter diagnosis and appropriate treatment for females with BD, in fact, could reduce acute inefficacy, longer-term relapses, suicide attempts, treatment-emergent affective switching, and onset of rapid-cycling.
Although in the ten large samples studies analysed here it is possible to identify a higher prevalence of female BD patients, the majority of these studies are not epidemiological, and their samples are collected over many years, many in BD Specialty Clinics, which commonly report having more female than male patients. In this regard, the often reported comorbid substance use disorders in male patients might concur in the fewer men seeking treatment in Bipolar Disorder Specialty Clinics. To avoid these confounding factors, nationwide or international epidemiological studies are needed in order to confirm our preliminary observation.
Moreover, the studies analysed here recruited samples from specific areas or nations. It could be, from this point of view, that our conclusions cannot be extended to the international population but are only true for the specific regions of interest. It is well known, in fact, that the gender distribution of the general population varies across the world, with some countries (especially eastern countries) with a predominant male population. It is therefore possible that, for these countries, further and more specific studies on the subject should be carried out.