Monica Macellaro, MD

 (BD) affects 1% to 3% of the world’s population and is characterized by alterations in mood, levels of energy, and functioning. Despite these common features, BD includes a group of polymorphic and heterogeneous conditions in terms of clinical presentation, course, response to treatment, and functional outcome.

 Several sociodemographic and clinical variables have been investigated as potential factors influencing the development and course of illness, such as age at onset, employment status, marital status, number of manic/depressive episodes, predominant polarity, and—above all—gender and sex.

There has been a rising interest in gender-related specificities in BD (

However, the presence of clinical and epidemiological distinctions between male and female patients and their role in the diagnostic and therapeutic process is still controversial.

 Sex specificity may affect many variables, including incidence, prevalence, subtypes (BD I and BD II), rapid cycling, suicidal behavior, comorbidities, treatment response, and adverse effects. Moreover, among females, hormonal oscillations related to the menstrual and reproductive cycle may influence the disease and its treatment.

Compelling evidence has documented an almost equal male-female sex ratio in incidence and lifetime BD prevalence rates (

 Estimated Prevalence Among Males and Females

Nonetheless, recent studies suggest an increased frequency of BD diagnosis among women, for both BD I and BD II. Furthermore, hypomania, and consequently BD II subtype, are more frequently associated with female sex.

Although age at first mood episode does not apparently differ between women and men, men more commonly experience a first manic episode during childhood.

 Men more often have a first manic episode, whereas women seem more likely to face a depressive one.

 In addition, being female is more frequently related to depressive recurrences, depressive predominant polarity, and higher lifetime prevalence of psychotic depression.

Women more often report depression and large fluctuations in mood as well as more frequent mood oscillations across the menstrual cycle.

 On this basis, the identification of BD in women may be more challenging, leading to a higher rate of misdiagnosis of major depressive disorder. Indeed, some other characteristics may help clinicians in the successful recognition of BD in women, including lifetime rapid cycling

 The probability of mixed symptoms in females increases consistently with the severity of hypomania but decreases at the most severe levels of hypomania.

Suicide attempt rates have been significantly more frequent among females, even though death by suicide has occurred more commonly in men.

 As a result, physicians should consider the possibility of an unrecognized bipolar diathesis if they see frequent depressive recurrences despite antidepressant therapy, the presence of psychotic features during a depressive episode, and a high number of suicide attempts in women.

Psychiatric and medical comorbidities often negatively affect BD course, regardless of sex. Comorbidity with alcohol and other substance use disorders (eg, cannabis abuse/dependence and pathological gambling) has been more frequently documented among males.

 However, Goodwin and Jamison have suggested a higher prevalence of alcohol abuse among women with BD II.

 Co-occurrence of personality disorders (particularly of cluster B), eating disorders such as bulimia, and posttraumatic stress disorder was generally observed with a higher frequency among females.

 A sex-specific effect has also been illustrated for comorbid obsessive-compulsive disorder (OCD) and anxiety spectrum disorders, with increased OCD rates in males and panic disorder in females. Organic conditions such as migraine, thyroid disorders (especially hypothyroidism), and autoimmune disorders seem to be more commonly associated with female gender in BD.

Previous investigation of sex differences in the most affected domains in BD—including executive function, verbal and visual memory, verbal learning, attention and processing speed—did not identify differing results. However, recent findings showed a better performance in working memory tasks among males, whereas a better performance was found in verbal learning and memory recognition tasks among females.

 Finally, a sex differential emerged in psychosocial functioning, with females with BD tending to report better social and occupational status than their male counterparts.

The correlation between sex/gender and response to pharmacological treatment has been extensively investigated, with a particular focus on mood stabilizers and antipsychotics. Beyond an increased use of antidepressants, women with BD seem to more frequently receive a combination treatment, whereas men have more often reported receiving lithium.

 Considering sex differences in clinical response to lithium, a pooled data analysis outlined response rates of 65.6% in women and 61.0% in men. Another longitudinal study found that, in comparison with men treated with lithium, women treated with lithium had a significantly longer median time to first recurrence.

The use of antipsychotics in BD has increased in past decades, apparently with no differences in their prescription.

 Regarding efficacy, in an 8-week trial of treatment with placebo, olanzapine, or olanzapine/fluoxetine in combination, male patients with depression and manic-predominant polarity experienced higher rates of improvement compared with those with depressive polarity. Among females, no differences in terms of response were observed by means of predominant polarity.

Some authors have hypothesized a correlation between sex and occurrence, intensity, and type of medication adverse effects, thus influencing their prescribing patterns. Regarding lithium, female sex emerged as the main risk factor for the development of hypothyroidism during treatment, especially for women aged 40 to 59 years. Valproate use in females may lead to polycystic ovaries, polycystic ovary syndrome, hyperandrogenism, and obesity. Valproate needs to have an extremely low priority in women of childbearing potential due to the important risks of neurodevelopmental delays and polycystic ovary. However, it can be effective and well tolerated in females not of reproductive potential. Moreover, many typical and some atypical antipsychotics may be associated with hyperprolactinemia, which can result in galactorrhea, amenorrhea, and other menstrual cycle irregularities.

 Although females with BD were generally more adherent to therapeutic indications, they nonetheless seemed to be more concerned about adverse effects like weight gain.

In terms of nonpharmacological strategies, female patients with depression underwent significantly fewer antidepressant drug trials than their male counterparts before being prescribed electroconvulsive therapy. When used in patients with schizophrenia, its effectiveness was greater in females, but this difference was not replicated in individuals with BD, possibly because of the small sample size.

 No evidence supported the notion of a different response to psychotherapy between genders.

Women physiologically experience endogenous fluctuations in ovarian hormone levels, including recurring oscillation of estradiol and progesterone. These fluctuations may affect BD pathophysiology and clinical presentation. It is worth noting that symptoms may worsen when gonadal hormone levels are low, either during the premenstrual phase of the cycle—thus hindering the distinction from premenstrual dysphoric disorder4—and postpartum.

 This period may be burdened by a relevant risk of BD onset and relapse. For instance, a recent meta-analysis found an overall postpartum relapse risk of 37%, with almost a quarter of those suffering from affective psychosis, mania, mixed episodes, or relapses requiring hospitalization, and the remaining patients suffering from nonpsychotic affective episodes, mostly depressive.

 Accordingly, clinical trials suggested that exogenous estrogenic treatments may improve specific symptoms of BD.

During pregnancy, women with BD should undergo close monitoring because of the correlation between BD and pregnancy complications, as well as potential congenital anomalies in infants. The discontinuation of medications may trigger a mood recurrence and thus lead to disruption of daily living functioning, including a patient’s ability to take care of the child.

 By contrast, the teratogenic potential of various mood stabilizers must be kept in mind; lithium may enhance the risk of cardiovascular malformations (such as Ebstein anomaly), and valproate and carbamazepine are both associated with the risk of neural tube defects, including spina bifida. Hence, when treating women with BD who wish to become pregnant, the risk-benefit ratio should be assessed by evaluating the teratogenic risk of pharmacotherapy and the negative impact of untreated BD symptoms on the pregnant woman and the fetus.

The same shrewdness should be promoted in treating women with BD during breastfeeding. Some mood stabilizers, including carbamazepine and valproate, are not contraindicated, whereas lithium is not compatible with lactation. In addition, there is no consensus regarding the use of antipsychotics during pregnancy and breastfeeding.

Finally, during the menopause transition, many women face unspecific mood symptoms. In females with BD, the perimenopausal phase may enhance mood instability, with increased depressive symptoms and reduced manic symptoms.

Some epidemiological and clinical characteristics of BD may differ between the sexes. Although further investigation is encouraged, the preceding preliminary findings may guide practitioners in clinical practice by facilitating BD identification, especially in case of depressive onset, and by orienting treatment interventions, with a special focus on life events related to the female reproductive cycle. The effort should go towards avoiding valproate and carbamazepine in women of child-bearing potential, unless associated with hormonal contraceptives.

is an associate professor of psychiatry at the University of Milan, and director of the psychiatric clinic of the Ospedale Luigi Sacco-Polo Universitario of Milan. He is also a scientific advisor in the Department of Psychiatry and Behavioral Sciences of Stanford University and cochair of the International College of Obsessive Compulsive Spectrum Disorders. 

is a psychiatrist in the Department of Psychiatry, University of Milan. 

 is a resident in psychiatry in the Department of Biomedical and Clinical Sciences of the University of Milan. 

In the last 3 years, Dr Dell’Osso has received lecture honoraria and research grants from Angelini, Lundbeck, Janssen, Pfizer, Otzuka, Neuraxpharm, and Livanova. The other authors have no conflicts to declare.

Is sex important? gender differences in bipolar disorder.

Sex differences in schizophrenia, bipolar disorder, and post-traumatic stress disorder: are gonadal hormones the link?

Has bipolar disorder become a predominantly female gender related condition? analysis of recently published large sample studies.

6. Kennedy N, Boydell J, Kalidindi S, et al. 

Gender differences in incidence and age at onset of mania and bipolar disorder over a 35-year period in Camberwell, England.

7. Altshuler LL, Kupka RW, Hellemann G, et al. 

Gender and depressive symptoms in 711 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Outcome Network.

8. Nivoli AMA, Pacchiarotti I, Rosa AR, et al. 

Gender differences in a cohort study of 604 bipolar patients: the role of predominant polarity.

9. Buoli M, Cesana BM, Dell’osso B, et al. 

Gender-related differences in patients with bipolar disorder: a nationwide study.

Sex-specific self-reported mood changes by patients with bipolar disorder.

11. Schneck CD, Miklowitz DJ, Miyahara S, et al. 

The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD.

12. Buoli M, Cesana BM, Maina G, et al; ISBD Italian Chapter Epidemiologic Group. 

Correlates of current rapid-cycling bipolar disorder: results from the Italian multicentric RENDiBi study.

Gender differences in the phenomenology of bipolar disorder.

15. Suppes T, Mintz J, McElroy SL, et al. 

Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon.

Gender differences in bipolar disorder: age of onset, course, comorbidity, and symptom presentation.

Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, Second Edition

18. Baldassano CF, Marangell LB, Gyulai L, et al. 

Gender differences in bipolar disorder: retrospective data from the first 500 STEP-BD participants.

19. Suominen K, Mantere O, Valtonen H, et al. 

Gender differences in bipolar disorder type I and II.

20. Saunders EFH, Fitzgerald KD, Zhang P, McInnis MG. 

Clinical features of bipolar disorder comorbid with anxiety disorders differ between men and women.

Sex differences in neurocognitive and psychosocial functioning in bipolar disorder.

22. Sanchez-Autet M, Arranz B, Safont G, et al. 

Gender differences in C-reactive protein and homocysteine modulation of cognitive performance and real-world functioning in bipolar disorder.

23. Karanti A, Bobeck C, Osterman M, et al. 

Gender differences in the treatment of patients with bipolar disorder: a study of 7354 patients.

24. Viguera AC, Tondo L, Baldessarini RJ. 

Sex differences in response to lithium treatment.

25. Viguera AC, Baldessarini RJ, Tondo L. 

Response to lithium maintenance treatment in bipolar disorders: comparison of women and men.

Predominant previous polarity as an outcome predictor in a controlled treatment trial for depression in bipolar I disorder patients.

Gender differences in electroconvulsive therapy: a retrospective chart review.

28. Vega P, Barbeito S, Ruiz de Azúa S, et al. 

Bipolar disorder differences between genders: special considerations for women.

29. Wesseloo R, Kamperman AM, Munk-Olsen T, et al. 

Risk of postpartum relapse in bipolar disorder and postpartum psychosis: a systematic review and meta-analysis.

Bipolar II postpartum depression: detection, diagnosis, and treatment.

Articles

What are the differences in epidemiological and clinical characteristics of bipolar disorder between the sexes?

Gender and Sex Issues in Bipolar Disorder

Valproic Acid: Overused in Bipolar Disorder?

article by David N. Osser, MD, “Valproic Acid: Overused in Bipolar Disorder?”

. Other authors have taken exception to the National Institute for Health Care and Excellence (NICE) Bipolar Guideline’s similar approach to valproic acid (VPA), namely to avoid this medication in women of child-bearing potential.

 Indeed, we think that to give VPA such a low priority for all patients with bipolar seems like an over-response to VPA’s limitations, as this medicine can be effective and well-tolerated in males, as well as in females not of child-bearing potential (especially in very young or older females). Admittedly, VPA needs to have an extremely low priority in women of child-bearing potential due to the important risks of neurodevelopmental delays and polycystic ovary. The article correctly points out this fact; however, it fails to note mitigating information such as treatments for the latter include hormonal contraceptives.

The article stated that the last 2 VPA studies were negative, and VPA has a small effect size in acute mania.

 However, even though the last 2 controlled trials were negative, perhaps due to methodological limitations, divalproex sodium and divalproex sodium extended release are currently FDA-approved for the treatment of acute mania in monotherapy, in consideration of the efficacy showed by previous results on adults.

 In addition, 1 negative study from the point of view of efficacy was positive from the point of view of safety (rather than efficacy) in children and adolescents.

The article correctly pointed out that VPA was not FDA-approved for bipolar maintenance treatment. However, this may have been due to the “non-enriched” (for acute valproate response) design of the VPA bipolar maintenance study.

 Indeed, VPA can be an effective bipolar maintenance treatment if using an “enriched” (for acute valproate response) design.

 It can be challenging to link logic to FDA-approval status of medications, as several second-generation antipsychotics (SGA) have already been FDA-approved to add to VPA (or lithium) in drug-resistant bipolar maintenance treatment. Additionally, lurasidone was FDA-approved to add to VPA (or lithium) in treatment-resistant acute bipolar depression.

The piece noted that a few small studies (4 studies with 142 participants) have been consistent with VPA efficacy in acute bipolar depression.

 However, in the absence of economic incentive, it may be unlikely that a larger acute bipolar depression VPA study will be undertaken.

VPA may be more effective than lithium in bipolar mania with dysphoria.

 This is an important consideration, given the importance of bipolar mixed states in DSM-IV-TR

 and the emerging importance of mixed depression in DSM-5.0.

Head-to-head studies suggest more weight gain with valproate versus olanzapine, as noted in the article. However, olanzapine (even with fluoxetine) has been even more widely avoided than valproate due to risks of weight gain and metabolic abnormalities.

The article stated that suicidality (suicide or suicide attempt) was twice as likely with VPA versus controls. However, this statement is problematic if lithium (which has anti-suicide effects) is the control agent. Even compared with placebo, the number of suicide events was too small to allow any conclusion about VPA effect on suicidality. Nevertheless, the FDA has included an anticonvulsant suicidality warning for valproate and other anticonvulsants (including carbamazepine).Carbamazepine appears to be a poor option for women of child-bearing potential as it also entails teratogenicity (including spina bifida) and has multiple drug interactions (including interfering with hormonal contraceptive efficacy).

Liver dysfunction and, less commonly, pancreatitis, thrombocytopenia, and polycystic ovaries are other significant adverse effect issues with VPA, as explained in the article. Although this is true, it also makes it clear in whom VPA needs to be carefully avoided—women of child-bearing potential, patients with low platelets, and hepatic transaminases over twice the upper limit of normal.

The article correctly stated that VPA was widely used in the treatment of bipolar disorder and, in fact, in a recently published multicenter report, including American (Stanford) and Italian (Milan) patients with bipolar disorder, it was the most common individual mood stabilizer (33% of the overall sample). In particular, individual VPA usage was higher in Milan than Stanford for both patients with BDI (44.4% versus 35.9%) and BDII (26.9% versus 11.3%); patients with BDI had significantly higher rates of taking VPA compared to those with BDII (40.1% versus 17.5%).

Although VPA has utility in bipolar disorder, we agree that clinicians should think of lithium, second-generation antipsychotics, lamotrigine, and carbamazepine prominently in selecting medication for bipolar disorder patients.

is an associate professor of psychiatry at the University of Milan and Director of the Psychiatric Clinic of the Ospedale Luigi Sacco-Polo Universitario of Milan, Italy. He is also Scientific Advisor at the Department of Psychiatry and Behavioral Sciences of Stanford University and Co-Chair of the International College of Obsessive Compulsive Spectrum Disorders (ICOCS). 

is resident in psychiatry at the University of Milan. 

of psychiatry and behavioral sciences, and founder and chief of the Bipolar Disorder Clinic at Stanford University.

1. Curtis D, Kerr M. NICE recommendations for valproate treatment are unhelpful. 

2. Vasudev K, Mead A. Use of valproate in women of childbearing potential: pre- and post-NICE bipolar guidelines. 

3. Kowatch RA, Scheffer RE, Monroe E, Delgado S, Altaye M, Lagory D. Placebo-controlled trial of valproic Acid versus risperidone in children 3-7 years of age with bipolar I disorder. 

4. Hirschfeld RM, Bowden CL, Vigna NV, Wozniak P, Collins M. A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania. 

5. Bowden CL, Davis J, Morris D, Swann A, Calabrese J, Lambert M, et al. Effect size of efficacy measures comparing divalproex, lithium and placebo in acute mania. 

6. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM, Rush AJ, Small JG, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. 

7. Bowden CL, Swann AC, Calabrese JR, et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. 

8. Wagner KD, Redden L, Kowatch RA, Wilens TE, Segal S, Chang K, et al. A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. 

9. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. 

10. Bowden CL, Swann AC, Calabrese JR, McElroy SL, Morris D, Petty F, et al. Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. 

11. Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. 

12. Wang PW, Nowakowska C, Chandler RA, Hill SJ, Nam JY, Culver JL, et al. Divalproex extended-release in acute bipolar II depression. 

13. Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, et al. Depression during mania. Treatment response to lithium or divalproex. 

14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). American Psychiatric Association; 2000.

15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). American Psychiatric Association; 2013.

16. Ketter TA, Post RM, Worthington K. Principles of clinically important drug interactions with carbamazepine. Part I. 

17. Ketter TA, Post RM, Worthington K. Principles of clinically important drug interactions with carbamazepine. Part II. 

18. Davis AR, Westhoff CL, Stanczyk FZ. Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding. 

19. Dell’Osso B, Cremaschi L, Arici C, et al. Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode. 

Is valproic acid dismissed out of hand? Three doctors discuss its potential as a treatment. 

Monica Macellaro, MD

Articles

Gender and Sex Issues in Bipolar Disorder

Giving Valproic Acid a Higher Priority in Bipolar Patients