Risks associated with gender differences in bipolar I disorder

Journal of Affective Disorders 151 (2013) 1033–1040

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Research report

Risks associated with gender differences in bipolar I disorder Jean-Michel Azorin a,n, Raoul Belzeaux a, Arthur Kaladjian a, Marc Adida a, Elie Hantouche b, Sylvie Lancrenon c, Eric Fakra a a

Department of Psychiatry, Sainte Marguerite Hospital, Marseille, France Anxiety and Mood Center, CTAH, Paris, France c Sylia-Stat, Bourg-la-Reine, Paris, France b

art ic l e i nf o

a b s t r a c t

Article history: Received 27 June 2013 Received in revised form 21 August 2013 Accepted 23 August 2013 Available online 6 September 2013

Background: Previous studies have demonstrated that bipolar patients may differ in several features according to gender, but a number of the differences found remain controversial. Methods: The demographic, illness course, clinical, comorbidity and temperament characteristics of a total of 1090 consecutive DSM-IV bipolar I manic inpatients were compared according to gender. Results: Bipolar illness in women was characterised by the predominance of depression, as indicated by a depressive polarity at onset, higher rates of mixed mania, more suicidal behaviour, and a greater number of temperaments with depressive propensities. In contrast, the manic component was found to predominate in men. Men also had an earlier onset of their illness. Women displayed more comorbidities with eating, anxiety, and endocrine/metabolic disorders, whereas men were more comorbid with alcoholism and other forms of substance abuse, neurological, and cancer disorders. The following independent variables were associated with male gender: being single (þ), depressive temperament ( ), excessive alcohol use (þ ), cyclothymic temperament ( ), excessive other substance use (þ ), mood congruent psychotic features (þ ), and manic polarity at onset (þ ). Limitations: The retrospective design and the sample being potentially not representative of the bipolar disorder population are limitations. Conclusions: Findings from this study tend to confirm most of the differences previously observed among bipolar men and women. Furthermore, these results draw attention to the risks that may be specifically linked to gender differences in bipolar I patients. & 2013 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder Gender Men Women Sex

1. Introduction Studies of gender differences in major depressive disorder indicate that women are more prone to depression, experience different symptoms, and have a more refractory course of illness (Goodwin and Jamison, 1990). Less attention has been paid to the study of gender differences in bipolar disorder, despite an increasing number of publications in recent years (McElroy et al., 2011). Although mania appears to be equally prevalent in women and men, bipolar disorder may differ between the two genders in clinically important ways. The main differences are likely to concern the phenomenology, course, and comorbidity of the bipolar spectrum (McElroy et al., 2011). However, a number of these differences remain controversial (Nivoli et al., 2011). Therefore, there is a need for further studies in this domain. The Epidemiology of Mania (EPIMAN) II-Mille study represents one of the largest observational studies conducted in patients suffering

n Correspondence to: SHU Psychiatrie Adultes, Hôpital Ste Marguerite. 13274 Marseille Cedex 9-France. Tel.: þ3349 1744 082; fax: þ 3349 1745 578. E-mail addresses: [email protected], [email protected] (J.-M. Azorin).

0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.08.031

from bipolar disorder. This large-scale study offers a unique opportunity to examine specific aspects of this pathology. The aims of the current investigation were (1) to examine this large sample of bipolar I patients with respect to the sex ratio, (2) to determine the main characteristics of bipolar I patients according to gender, and (3) to assess the clinical correlates and features of bipolar disorder in males compared to females.

2. Methods 2.1. Study population Patients included in the study were hospitalised for a manic episode of bipolar I disorder. The diagnosis was made using the French version of the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1997; Bordeleau, 1997). 2.2. Study design EPIMAN II Mille, implemented in France, was a multicentre naturalistic study conducted at 19 medical centres between

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December 2000 and April 2002. The primary aim of the study was to further characterise the validity of the different subtypes of bipolar I disorder and estimate their prevalence in this national clinical sample. Our objective was to enrol 1000 patients. To reach this goal, each of the 317 psychiatrists had to recruit at least two consecutive manic patients (with a maximum of 6). All psychiatrists working in public, university, or private hospitals had considerable clinical experience in studies involving bipolar disorder patients. This large sample size gave us the opportunity to compare the characteristics of bipolar I manic patients according to gender. 2.3. Clinical assessments During the screening phase, demographic characteristics and illness history were collected, as well as information about psychotropic treatment administered during the previous year. The age at onset was obtained from structured interviews with the patients and their relatives and from their medical records. It was defined as the age at which the patient first met the Research Diagnostic Criteria for an affective episode (Roy-Byrne et al., 1985; Daban et al., 2006); this definition does not necessarily include the presence of psychotic symptoms or a hospitalisation. Patients reporting any clinical history of substance use disorder could be included in the study. The search for associated substanceinduced disorders was based on a clinician-friendly approach to lighten the burden of the protocol and facilitate the feasibility of this multi-site investigation. Alcohol and other substance use was defined as “excessive” when it was continued for 41 month in the year preceding mania onset despite social, occupational or psychological problems associated with the substance. It was judged as “moderate” in the other cases and judged as “no use” when absent. The intensity of mania was assessed using the Mania State Rating Scale (MSRS) (Beigel et al., 1971; Akiskal et al., 2003). Depression was evaluated using the Montgomery Ǻsberg depression rating scale (MADRS) (Montgomery and Ǻsberg, 1979; Pellet et al., 1981). The presence of mixed symptoms was assessed with a depression checklist that included eight symptoms: depressed mood, psychomotor retardation, anhedonia, hypersomnia, hopelessness/helplessness, suicidal ideation and/or attempts, guilt and fatigue. This checklist was derived from those initially proposed by McElroy et al. (1992) and Akiskal et al. (2000) but after the removal of items that were found to be unable to discriminate “pure mania” from “mixed mania” (Hantouche et al., 2006). Based on the findings from the latter study, the threshold to define mixed mania was set at Z2 depressive symptoms. Anxiety was measured with the anxiety scale extracted from the French version of the association for methodology and documentation in psychiatry (AMDP AT) (Bobon et al., 1985). From days 1 to 7 following inclusion, patients were requested to keep a daily mood record, with “best I ever felt ( þ5)” to “worst I ever felt (  5)” used as anchor points and with the midpoint anchored as “normal” based on a validated methodology by Gottschalk et al. (1995). Patients were instructed to complete the scale three times a day (approximately 8 a.m., 12 p.m. and 6 p.m.) by placing an X on the line that best reflected their present mood state in relation to the anchor points. Maximal variation on mood rating was taken as a proxy for mood instability. After marked improvement of the manic episode, on average 21 days from admission, affective temperaments were assessed with the use of 4 questionnaires corresponding to the hyperthymic, depressive, cyclothymic and irritable temperamental components; these tools are self-report, yes-or-no type questionnaires that represent the French version of TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris and San Diego—auto-questionnaire version) and allow assessment of temperamental components according to a predefined threshold for the number of yes-type answers on each component (Hantouche et al., 2001). In addition,

lifetime anxious and eating disorder comorbidity was assessed, again using the SCID probes. Stressful life events during the 3 months before the original onset of illness were reconstructed as far as possible on the basis of interviews with patients and their families and hospital records, following the guidelines for assessment of the DSM-IV Axis—IV (American Psychiatric Association, 1994). Finally, using a medical history form, patients were asked for lifetime comorbid organic disorders, and only histories of illnesses diagnosed by physicians were scored as positive. Most scales were used in their respective French versions, as validated in our prior EPIMAN study (Akiskal et al., 1998; Azorin et al., 2000). The MADRS and AMDP-AT scales have been validated by others as noted above. The study was reviewed and approved by the appropriate ethics committee, and patients participated with informed, voluntary, written consent. 2.4. Statistical analyses To compare the likelihood of having been exposed to a risk factor among male bipolar patients to the likelihood of exposure among female bipolar patients, raw odds ratios were computed in univariate analyses. A stepwise logistic regression model was then used to identify the factors associated with male gender. Based on the results of univariate analyses and variables selected from a literature search, the following were entered into the model as independent variables: age, marital status, MSRS total scores, MADRS total scores, AMDP-AT total scores, mood instability, psychotic features, hyperthymic temperament, depressive temperament, cyclothymic temperament, age at onset, manic vs depressive/mixed polarity at onset, number of previous episodes, rapid cycling, number of suicide attempts in lifetime, marital/ family conflict at onset, professional changes at onset, death of a relative at onset, alcohol use at onset, other substance use at onset, excessive alcohol use, excessive use of other substances than alcohol, anorexia, bulimia, specific phobia, comorbid endocrine/ metabolic disorders, comorbid neurologic disorders, comorbid cardiovascular disorders, and comorbid cancer. Odds ratios with 95% confidence intervals were used for the observed associations.

3. Results 3.1. Patients A total of 1090 manic patients were included in the study. All were bipolar I patients who had experienced manic plus depressive episodes (bipolar I disorder, most recent episode manic or mixed, according to DSM-IV), except for 82 patients who experienced their first episode of illness (bipolar I disorder, single manic or mixed episode) at inclusion. The mean current age was 437 14 years. The mean number of prior episodes was 7.278. Multiple hospitalisations were recorded in 66.1% of patients. 3.2. Prevalence Four hundred sixty-one (42.3%) patients were of the male gender, and 629 (57.7%) were female. 3.3. Demographic and clinical characteristics The demographic and clinical characteristics of male and female bipolar patients are summarised in Table 1. Compared with females, males were younger and more often single. Males scored higher on the MSRS, and females had higher scores on the MADRS and the AMDP-AT, with more associated depressive symptoms during

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Table 1 Demographic and clinical characteristics of 1090 bipolar manic patients according to gender. Male n ¼461 Age (y), mean, (SD) Marital status, (%) Single MSRS total score, mean (SD) MADRS total score, mean (SD) AMDP-AT total score, mean (SD) Z 2 Depressive symptoms, (%) Suicidal ideation, (%) Mood instability, mean (SD) Psychotic features, (%) Congruent Incongruent Affective temperaments, categorical measures, (%) Hyperthymic Depressive Cyclothymic Irritable

Female n¼ 629

Odds ratio (95% confidence interval)

41.29 (13.63)

44.12 (13.71)

0.92 (0.90–0.94)

48.6 223.51(75.38) 14.30 (7.09) 19.52 (11.67) 25.0 6.7 1.4 (1.1)

30.0 210.97(33.0) 16.08 (7.36) 20.75 (10.88) 34.3 11.2 1.9 (1.6)

2.12 (1.41–2.99) 1.02 (1.00–1.03) 0.94 (0.92–0.97) 0.93 (0.92–0.94) 0.89 (0.87–0.92) 0.88 (0.84–0.91) 0.90 (0.88–0.92)

38.6 12.8

29.6 19.2

1.28 (1.00–1.49) 0.94 (0.92–0.96)

78.5 22.0 49.2 25.0

70.1 31.9 60.2 22.9

1.18 (1.09–1.25) 0.95 (0.93–0.98) 0.97 (0.95–0.98) 1.02 (0.51–3.89)

Table 2 Illness course characteristics of 1090 bipolar manic patients according to gender.

Age (y) at onset, mean, (SD) Duration (y) of illness, mean (SD) Delay (y) before correct diagnosis Z5, (%) First episode polarity, (%) Manic Depressive Mixed No. of previous episodes in lifetime, mean (SD) Multiple hospitalizations, (%) Rapid cycling, (%) No. of suicide attempts in lifetime, mean (SD) Stressors before illness onset, (%) At least one Marital/family conflits Professional changes Death of a relative Alcohol use Other substance use Prior treatment (previous year), (%) Lithium Anticonvulsants (at least one) Antipsychotics (at least one) Antidepressants (at least one) Benzodiazepines (at least one)

Male n¼ 461

Female n¼ 629

Odds ratio (95% confidence interval)

27.69 (10.32) 15.50 (11.33) 32.7

28.96 (10.95) 13.11 (11.70) 38.9

0.96(0.95–0.97) 1.15(1.05–1.42) 0.92(0.90–0.95)

58.9 28.3 12.8 6.98 (8.30) 62.9 8.9 0.72 (1.82)

47.7 39.3 13.0 8.31(8.14) 68.5 9.1 1.31 (6.86)

1.29 (1.01–1.67) 0.90 (0.85–0.94) 0.99 (0.95–3.18) 0.89 (0.85–0.91) 0.93 (0.90–0.96) 0.98 (0.97–2.04) 0.87 (0.78–0.92)

42.5 15.4 38.2 16.3 11.3 10.2

40.6 25.3 24.3 17.2 5.1 4.8

1.21 (0.88–2.01) 0.88 (0.75–0.90) 1.78 (1.37–2.54) 0.98 (0.73–2.04) 2.01 (1.58–3.11) 1.89 (1.52–2.83)

22.3 48.6 47.9 25.4 31.5

21.5 45.9 45.3 33.5 37.2

1.08 (0.64–2.07) 1.10 (0.73–2.28) 1.21 (0.81–2.42) 0.87 (0.79–0.92) 0.91 (0.89–0.94)

the index manic episode. Women displayed more suicidal ideation during the index manic episode. Mood instability was greater in women. Men had more mood congruent psychotic features and women more incongruent psychotic features. Men displayed more hyperthymic temperaments, and women displayed more depressive and cyclothymic temperaments. The two groups did not differ in regard to irritable temperament.

illness, men had more professional changes, alcohol use and other substance use; women displayed more marital/family conflicts. The two groups did not differ regarding death of a relative. During the previous year, females received more antidepressants and benzodiazepines, and the two groups received the same amounts of lithium, anticonvulsants and antipsychotics. 3.5. Comorbid conditions

3.4. Course of illness Table 2 summarises the characteristics of illness course in the two groups. Men had an earlier age at onset with a longer duration of illness. Women displayed longer delays before correct diagnosis. The first episode polarity was more often manic in males. Women had a greater number of previous episodes with more hospitalisations. The two groups did not differ for rapid cycling. The number of prior suicide attempts was higher in women. Before the onset of

Excessive alcohol and other substance use was more frequent among males (Table 3). Females displayed more comorbid anorexia and bulimia. The two groups did not differ for comorbid anxiety disorders, except for specific phobia, which was more frequent in women. Women had more comorbid endocrine/ metabolic disorders, and men had more neurologic and cancer disorders. The rates of cardiovascular disorders were comparable in the two groups.

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3.6. Correlates of male gender The factors significantly associated with male gender are displayed in Table 4. Being single, excessive alcohol use, excessive use of other substances than alcohol, presence of mood congruent psychotic features and manic polarity at onset increased the odds of male gender, whereas depressive and cyclothymic temperament decreased the odds.

4. Discussion

obtain treatment (Mechanic, 1986). In addition, family members may be more likely to bring ill female relatives rather than ill male relatives to mental health facilities. This difference may be due to the different expectations of normative behaviours according to gender and/or, as it was the case in the current study, to the higher likelihood for women to live with their families. The second reason is that the high comorbidity rate of alcohol and drug use in men may have led to a psychiatric admission diagnosis of substance abuse rather than mania (Hendrick et al., 2000). Finally, as the prevalence of mixed mania is higher in women than in men, women are more likely to be hospitalised to prevent the risk of suicide associated with mixed pictures (Hantouche et al., 2006).

4.1. Prevalence According to the vast majority of epidemiological studies, bipolar I disorder is considered to be approximately equally common in men and women, whereas bipolar II disorder may be more common in women than in men (American Psychiatric Association, 1994). We observed a higher prevalence of women in our study. Three main explanations may account for this discrepancy. The first explanation is related to the fact that we included only patients who were hospitalised. It has been previously reported that women may experience a significantly greater number of hospitalisations for mania compared with men (Hendrick et al., 2000). This finding was deemed to reflect a greater tendency for women to seek and

Table 3 Comorbid conditions of 1090 bipolar manic patients according to gender. Male n¼ 461

Alcohol use, (%) Excessive Other substance use, (%) Excessive Eating disorders, (%) Anorexia Bulimia Anxiety disorders, (%) Panic Agoraphobia Specific phobia Social Phobia Obsessive compulsive disorder Posttraumatic stress disorder Generalized anxiety disorder Organic disorders, (%) Cardiovascular Endocrine/metabolic Neurologic Cancer

Female n¼ 629

Odds ratio (95% confidence interval)

11.1

4.3

2.09 (1.10–4.13)

4.6

2.4

1.64 (1.14–3.17)

1.2 2.8

7.4 21.7

0.89 (0.85–0.94) 0.76 (0.70–0.81)

5.2 3.3 2.8 2.0 1.7

5.1 4.6 15.2 2.9 1.3

1.04 (0.51–2.26) 0.94 (0.43–3.12) 0.92 (0.85–0.96) 0.98 (0.96–2.78) 1.21 (0.87–3.10)

2.2

1.9

1.13 (0.91–2.98)

19.5

20.2

1.01 (0.93–3.16)

7.4 5.4 11.9 4.3

5.9 11.0 7.1 2.1

1.28 0.91 1.32 1.05

(0.94–4.32) (0.83–0.95) (1.18–2.25) (1.01–1.13)

4.2. Demographic and clinical characteristics In comparison with women, men were found to be younger at inclusion and less often married. The mean age difference between the sexes (2.8 years) may be explained by their difference in age at onset (1.3 years). However, the latter is unlikely to explain the 19% higher rate of being single found for men. The difference in marital status could be more plausibly related to the difference in polarity at onset, with an 11.2% higher rate of manic onset for men. The earlier age at onset of mania with the impact of recurrent manic episodes on social life at young age may have contributed to the lower rates of marital life observed in men (Janowsky et al., 1970). The clinical picture of mania in female patients was characterised by higher levels of mixed symptoms, as reflected by their higher scores on the MADRS, and the higher number of associated depressive symptoms as well as greater suicidal ideation, which is in accordance with existing literature (McElroy et al., 2011). This picture is also in agreement with the higher proportion of depressive and cyclothymic temperaments, as it was previously observed that mixed states are likely to occur when mood episodes arise from baseline temperaments of opposite polarity (Akiskal et al., 1998). In addition, higher levels of anxiety, as assessed with the AMDP-AT scale, are in line with reports that anxiety may load with depressed mood in mania (Cassidy et al., 1998; Dilsaver et al., 1999). In contrast, more male patients presented with pure mania, as reflected by their higher scoring on the MSRS and their greater proportion of baseline “hypomanic” temperamental dysregulations (Akiskal et al., 1998). A greater number of pure manic symptoms in men, compared with women, has been already observed in several studies (Kawa et al., 2005). We previously demonstrated that incongruent psychotic features were likely to be driven by an instability of mood in manic patients and particularly in mixed manic patients (Azorin et al., 2006), which is in accordance with current findings. In support of this, it was found that compared with psychotic manic men, psychotic manic women had more hallucinations, more delusions of reference and paranoid delusions, as well as more mixed states (Bräunig et al., 2009). The higher proportion of congruent psychotic features in men is in accordance with the higher severity of their pure manic picture (American Psychiatric Association, 1994).

Table 4 Significant correlates for male gender according to stepwise logistic regression.

Single Depressive temperament Excessive alcohol use Cyclothymic temperament Excessive other substance use Congruent (vs incongruent) psychotic features Manic (vs depressive/mixed) polarity at onset

Wald

P

Odds ratio (95% confidence interval)

26.34 6.66 7.26 7.25 7.21 3.92 3.51

o .0001 .009 .007 .007 .007 .04 .05

2.22 (1.63–3.01) 0.94 (0.91–0.98) 2.38 (1.27–4.49) 0.96 (0.93–0.98) 1.72 (1.21–3.34) 1.36 (1.01–1.86) 1.33 (1.00–1.79)

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4.3. Course of illness Our finding of an earlier age at onset in men compared with women is in agreement with several previous reports, despite some controversial results (McElroy et al., 2011). This difference in age at onset (1.3 years) may also explain the difference in illness duration (1.4 years). Nevertheless, the difference in age of onset is very small and may not be clinically relevant. First of all, it is worth noting that the mean age at illness onset for our total population (28.42710.70 years) was relatively high compared with several other large samples of bipolar patients. For example, in the STEP-BD (Perlis et al., 2004), the mean age at onset was 17.3778.67 years, and in the NIMH Bipolar Genetics Initiative (Potash et al., 2007; Saunders et al., 2012), it was 20.078.8 years. These differences cannot be explained by the method the age at onset was obtained, as the methods used were roughly comparable and because the age at onset was referring to the first episode of illness in all studies. We believe that these differences are likely to reflect differences found in clinical samples drawn from Europe and the USA. In a previous study (Bellivier et al., 2011), we used an admixture analysis to identify the model best fitting the observed distributions of age at onset of two large samples of bipolar I patients from Europe and USA. It was observed that the proportion of patients belonging to the early onset subgroup was higher in the USA sample (63 vs 25%) and that the mean age at onset (7SD) in the early onset subgroup was lower for the USA sample (14.574.9 vs 1972.7 years), whereas the intermediate and late-onset subgroups had similar characteristics in the two samples. An admixture analysis conducted in the EPIMAN II-Mille sample indicated distributions of age at onset that were close to those found for the European sample in the previous study (Azorin et al., 2013). In accordance with the vast majority of previous studies (McElroy et al., 2011), we found that the first episode of illness was more often manic in men but depressive in women. This difference in initial presentation was deemed to be responsible for the longer delay before correct diagnosis in female patients, as confirmed by our study. In fact, bipolar disorder has been found to be more frequently misdiagnosed as unipolar depression among women compared with men (Kupfer et al., 2002; Baldessarini et al., 1999). Our findings of a higher number of prior episodes and hospitalisations in women are consistent with the results of previous studies (Robb et al., 1998; Hendrick et al., 2000; Kennedy et al., 2005; Suominen et al., 2009; Nivoli et al., 2011). Contrary to some previous studies (Robb et al., 1998; Burt and Rasgon, 2004; Altshuler et al., 2010), rapid cycling did not differ across gender in our sample, confirming results from previous large studies (Baldassano et al., 2005; Lee et al., 2010; Nivoli et al., 2011) and a meta-analysis (Tondo and Baldessarini, 1998). As previously discussed, the higher number of suicide attempts experienced by female patients may reflect their higher levels of depressive symptomatology (McElroy et al., 2011). We did not find any difference between male and female patients regarding the number of stressors before illness onset. The literature is divided on this topic as some studies have found that a greater proportion of men than women reported life events before onset of bipolar illness (Mathew et al., 1994; Dunner et al., 1979a), whereas other studies have found no gender differences (Ambelas, 1987; Hlastala et al., 2000; Kessing et al., 2004). Nevertheless, our findings may be consistent with the results of previous studies that reported higher rates of family conflicts before depressive episodes in women (Christensen et al., 2003) but higher rates of work difficulties before manic compared with depressive episodes (Dunner et al., 1979b). The only difference found across gender regarding previous treatment was related to higher rates of antidepressants and benzodiazepines in women. These higher rates are likely to reflect the

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higher prevalence of mixed mania in women, as antidepressants and benzodiazepines have been found to be more commonly used in mixed manic patients, compared to pure manics (Azorin et al., 2009). The higher rates could also reflect the higher comorbidity with specific phobia, as both types of medication have been reported to be more prescribed in comorbid anxious bipolar patients than in patients without this comorbidity (Simon et al., 2004; Saunders et al., 2012), whereas no specific pattern of psychotropic drugs has been found with bipolar patients to be associated with either eating or substance use disorder comorbidities (Simon et al., 2004). 4.4. Comorbid conditions The comorbidities reported in the current study differ markedly from other samples with much lower rates of alcohol and substance use and anxiety disorders (Perlis et al., 2004; Simon et al., 2004; Otto et al., 2006; Potash et al., 2007; Saunders et al., 2012). The criteria used to diagnose alcohol and substance use could partly explain such discrepancies, but this cannot apply to anxiety comorbidities. The differences found for the comorbidity rates are more likely to be due to the differences in age at onset that were previously discussed. Comorbidities in bipolar disorder have usually been associated with an earlier age at onset of the illness (McElroy et al., 2001; Krishnan, 2005). Comorbidity with alcohol and other substance use both in lifetime and at illness onset was significantly more frequent in men than in women. These findings are in agreement with epidemiological data of the general population (Regier et al., 1990, Kessler et al., 1993; Angst et al., 2010) and among bipolar patients (Hendrick et al., 2000; Kessing, 2004; Kawa et al., 2005; Baldassano et al., 2005; Benedetti et al., 2007; Suominen et al., 2009; Nivoli et al., 2011), despite a few controversial reports in literature (Strakowski et al., 1992; Frye et al., 2003). Eating and/or anxiety disorders have been found to be more common in women in general and have also been reported to be more common in women with bipolar disorder than in men with bipolar disorder (Lewinsohn et al., 2000; MacKinnon et al., 2000; Baldassano et al., 2005; Calabrese et al., 2003; Frank et al., 2002; Kawa et al., 2005; McElroy et al., 2006). Our findings on eating disorders are particularly in agreement with those from another European study, with comparable rates of anorexia and bulimia for both samples, along with lower rates of anorexia and bulimia in women compared with men (Suominen et al., 2009). It is noteworthy that, as in the latter, the only anxiety disorder found to be more common in women was specific phobia. Interestingly, comorbidity with substance use was the only comorbidity to survive multivariate analysis. This was also found in the study by Suominen et al. (2009) but, in their study, eating disorder comorbidity also survived. As the presence of eating disorders in females has been reported to be associated with cyclothymic temperament (Signoretta et al., 2005), the fact that cyclothymic temperament was significantly and negatively associated with male gender in the logistic regression model could explain the absence of eating disorders in this model. As in the study by Suominen et al. (2009), specific phobia did not survive multivariate analysis. This was interpreted by these authors as a confirmation of previous findings from Kawa et al. (2005) indicating a lack of significant gender differences in the rates of lifetime comorbid anxiety disorders. However, as already mentioned, this may be in contradiction with the results of other studies reporting higher rates of anxious comorbidity, including specific phobia in bipolar women (Perlis et al., 2004; Altshuler et al., 2010; Saunders et al., 2012). The relationship between anxiety and bipolar disorder is particularly complex. Anxiety disorders may be comorbid, but anxiety is also a common manifestation of the bipolar state, particularly mixed episodes, as previously discussed. In addition,

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the index phase of bipolar disorder has been reported to affect the comorbidity, with anxiety disorder prevalence being highest in patients with a current mixed episode (Mantere et al., 2006). It was also suggested that some temperamental features might explain differences in anxious comorbidity (Mantere et al., 2006), which is agreement with the finding that mixed mania may occur on the basis of other temperamental propensities than those found for pure mania (Akiskal et al., 1998). Specific associations between affective temperaments and psychopathology clusters were recently identified in a population of bipolar disorder patients (Iasevoli et al., 2013), indicating, among other things, significant correlations between phobic anxiety and depressive as well cyclothymic temperament. Therefore, we cannot exclude that the presence of depressive as well cyclothymic temperament in the logistic regression model may partly account for the existence of a true comorbidity with specific phobia among the bipolar women of our sample. Regarding comorbidity with organic disorders, our findings on endocrine/metabolic disorders are in accordance with those from previous studies that demonstrated that thyroid disease (Blehar et al., 1998; Calabrese et al., 2003; Baldassano et al., 2005) and obesity (McElroy et al., 2001) or being overweight (Elmslie et al., 2000) were more common in bipolar women than in bipolar men. It could be easily hypothesised that, among the latter, at least some of them are the consequences of the higher prevalence of eating disorders in bipolar women. The finding that men displayed more neurologic comorbid conditions than women may be surprising, as the most well-known neurologic comorbidity of bipolar patients, migraine, has been found to be more common among bipolar women (McIntyre et al., 2006). However, neurologic complications of substance abuse are numerous, including trauma, infection, seizures, stroke, as well as persistent altered mentation (Brust, 2002). Therefore, the higher neurologic comorbidity of bipolar men may be due to their higher comorbidity with substance abuse. This hypothesis could be supported by the fact that if neurologic comorbidity did not survive multivariate analysis, excessive alcohol or other substance use did. The same may be true for the higher comorbidity with cancer found in men. Not only excessive alcohol use could be involved but higher use of tobacco also could be involved, as the latter has been reported to be more common among bipolar men compared with bipolar women (Waxmonsky et al., 2005). These risk factors may also be responsible for the trend observed for bipolar men to present more comorbid cardiovascular disorders. A higher comorbidity with cardiovascular disease has been previously reported in bipolar men compared with bipolar women (Oreški et al., 2012).

4.5. Clinical implications The study findings are likely to have several clinical implications, particularly with respect to the risks that may be differentially shared by bipolar women and bipolar men. These risks are related to misdiagnosis, psychiatric complications and comorbidity issues. The risk of misdiagnosis may differ across gender. As previously mentioned, in women, the first episode as well as predominant polarity are more often depressive (Robb et al., 1998; Nivoli et al., 2011). Thus, bipolar women are more likely to receive a diagnosis of unipolar depression, leading to the prescription of antidepressants with the additional risk of illness destabilisation. In the most severe cases, when female patients are presenting with mood incongruent psychotic features, they are likely to receive diagnoses of schizophrenia and related disorders. As far as bipolar men, their disorder may be confounded with substance use disorders and with delusional disorders, more commonly of the grandiose type (Perugi et al., 1998), when they present mood congruent psychotic features.

Bipolar women and bipolar men may also differ in regard to the psychiatric complications of their illness. As previously shown, women are at a higher risk of suicidal behaviour, whereas bipolar men, most likely due to their higher rates of substance abuse, may be more likely to become involved with the legal system (Baldassano et al., 2005). Finally, gender may also influence the organic pictures associated with bipolar disorder. Women are more likely to suffer from metabolic disorders, but men are more likely to suffer from neurologic conditions. It is also possible that psychotropic drugs reveal this different liability. For example, women in one study (Henry, 2002) treated with lithium exhibited more weight gain and hypothyroidism, whereas men developed more tremor. The risks of developing cancer or cardiovascular diseases may also differ according to gender among bipolar patients. 4.6. Study limitations The results of the current study must be considered in the context of several limitations. First, most of our data were retrospectively collected and therefore subject to recall bias. Second, our population consisted of bipolar I inpatients only, which may have led to an overinclusion of women and limit the application of our findings to different subgroups. Third, the details about the nature of comorbid organic disorders could not be collected with sufficient accuracy. Finally, 317 psychiatrists working at 19 medical centres in France participated as investigators, which may have reduced the reliability of the evaluations.

5. Conclusions Despite these limitations, the current study was able to confirm several of the differences associated with gender in bipolar patients. Depressive features may predominate in women, whereas manic features are at the fore in men. This phenomenon is likely to influence the diagnosis process and illness course, as well as treatment. Bipolar women and bipolar men appear to differ in regards to psychiatric comorbidity. We also found differences in medical comorbidities with more endocrine/metabolic disorders in women and more neurological and cancer disorders in men. We hypothesise that the differences in psychiatric comorbidity may to a certain extent account for the differences found in medical comorbidity. However, further research is warranted to confirm this hypothesis. In any event, the differences in medical comorbidities may suggest gender-specific preventive measures.

Role of funding source This study was supported by an unrestricted grant from Sanofi-aventis, CNS Department, Paris, France. Sanofi-aventis had no further role in study design, in the collection and analysis of data, in the writing of the report, and in the decision to submit the article for publication.

Conflict of interest No conflict declared.

Acknowledgement The authors of this report would like to thank the support of Sanofi-aventis, CNS Department, Paris, France.

References Akiskal, H.S., Hantouche, E.G., Bourgeois, M.L., Azorin, J.M., Sechter, D., Allilaire, J.-F., Lancrenon, S., Fraud, J.P., Châtenet-Duchêne, L., 1998. Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN). Journal of Affective Disorders 73, 7–18.

J.-M. Azorin et al. / Journal of Affective Disorders 151 (2013) 1033–1040

Akiskal, H.S., Bourgeois, M.L., Angst, J., Post, R., Moller, H., Hirschfeld, R., 2000. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. Journal of Affective Disorders 59 (1), 55–530. Akiskal, H.S., Azorin, J.M., Hantouche, E.G., 2003. Proposed multidimensional structure of mania: beyond the euphoric–dysphoric dichotomy. Journal of Affective Disorders 85, 45–52. Altshuler, L.L., Kupka, R.W., Hellemann, G., Frye, M.A., Sugar, C.A., McElroy, S.L., Nolen, W.A., Grunze, H., Leverich, G.S., Keck Jr, P.E., Zermeno, M., Post, R.M., Suppes, T., 2010. Gender and depressive symptoms in 711 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Outcome Network. American Journal of Psychiatry 167, 708–715. Ambelas, A., 1987. Life events and mania. A special relationship? British Journal of Psychiatry 150, 235–240. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatic Association, Washington, DC. Angst, J., Cui, L., Swendsen, J., Rothen, S., Cravchik, A., Kessler, R.C., Merikangas, K.R., 2010. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. American Journal of Psychiatry 167, 1194–1201. Azorin, J.M., Hantouche, E., Akiskal, H., Bourgeois, M., Allilaire, J., Sechter, D., Lancrenon, S., Châtenet-Duchêne, L., 2000. Structure factorielle du syndrome maniaque: revue de la littérature et résultats de l′étude Française EPIMAN. Annales Medico-Psychologiques 158, 279–289. Azorin, J.M., Akiskal, H., Hantouche, E., 2006. The mood instability hypothesis in the origin of mood-congruent versus mood incongruent psychotic distinction in mania: validation in a French National Study of 1090 patients. Journal of Affective Disorders 96, 215–223. Azorin, J.M., Aubrun, E., Bertsch, J., Reed, C., Gerard, S., Lukasiewicz, M., 2009. Mixed states vs pure mania in the French sample of the EMBLEM study: results at baseline and 24 months-European mania in bipolar longitudinal evaluation of medication. BMC Psychiatry 9, 33. Azorin, J.M., Bellivier, F., Kaladjian, A., Adida, M., Belzeaux, R., Fakra, E., Hantouche, E., Lancrenon, S., Golmard, J.L., 2013. Characteristics and profiles of bipolar I patients according to age-at-onset: findings from an admixture analysis. Journal of Affective Disorders. (Jun 11 [Epub ahead of print]). Baldassano, C.F., Marangell, L.B., Gyulai, L., Ghaemi, S.N., Joffe, H., Kim, D.R., Sagduyu, K., Truman, C.J., Wisniewski, S.R., Sachs, G.S., Cohen, L.S., 2005. Gender differences in bipolar disorder: retrospective data from the first 500 STEP-BD participants. Bipolar Disorders 7, 465–470. Baldessarini, R.J., Tondo, L., Hennen, J., 1999. Treatment delays in bipolar disorders. American Journal of Psychiatry 156, 811–812. Beigel, A., Murphy, D., Bunney, W., 1971. The Manic State Rating Scale construction, reliability and validity. Archives of General Psychiatry 25, 256–262. Bellivier, F., Etain, B., Malafosse, A., Henry, C., Kahn, J.P., Elgabli-Wajsbrot, O., Jamain, S., Azorin, J.M., Frank, E., Scott, J., Grochocinski, V., Kupfer, D.J., Golmard, J.L., Leboyer, M., 2011. Age at onset in bipolar I aflective disorder in the USA and Europe. World Journal of Biological Psychiatry, December, 21. ([Epub ahead of print]). Benedetti, A., Fagiolini, A., Casamassina, F., Mian, M.S., Adamovit, A., Musetti, L., Lattanzi, L., Cassano, G.B., 2007. Gender differences in bipolar disorder type 1: a 48-week prospective follow-up of 72 patients treated in an Italian tertiary care center. Journal of Nervous and Mental Disease 195, 93–96. Blehar, M.C., DePaulo Jr, J.R., Gershon, E.S., Reich, T., Simpson, G.S., Nurnberger, J.I., 1998. Women with bipolar disorder: findings from the NIMH Genetics Initiative sample. Psychopharmacology Bulletin 34, 239–243. Bobon D., von Frenckell R., Troisfontaines B., Mormont C., Pellet J., 1985. Construction et validation préliminaire d′une échelle d′anxiété extraite de l′AMDP francophone, l′AMDP-AT. Encephale 52, 947–959. Bordeleau L., 1997. Centre Hospitalier Universitaire du Québec. Quebec Canada: Ste Foy. PG2V4G2. Bräunig, P., Sarkar, R., Effenberger, S., Schoofs, N., Krüger, S., 2009. Gender differences in psychotic bipolar mania. Gender Medicine 6, 356–361. Brust, J.C.M., 2002. Neurologic complications of substance abuse. Journal of Acquired Immune Deficiency Syndromes 31, 529–534. Burt, V.K., Rasgon, N., 2004. Special considerations in treating bipolar disorder in women. Bipolar Disorders 6, 2–13. Calabrese, J.R., Hirschfeld, R.M., Reed, M., Davies, M.A., Frye, M.A., Keck, P.E., Lewis, L., McElroy, S.L., McNulty, J.P., Wagner, K.D., 2003. Impact of bipolar disorder on a U.S community sample. Journal of Clinical Psychiatry 64, 425–432. Cassidy, F., Forest, K., Murry, E., Carroll, B.J., 1998. A factor analysis of signs and symptoms of mania. Archives of General Psychiatry 55, 27. (21). Christensen, E.M., Gjerris, A., Larsen, J.K., Bendtsen, B.B., Larsen, B.M., Rolff, H., Ring, G., Schaumburg, E., 2003. Life events and onset of a new phase in bipolar affective disorder. Bipolar Disorders 5, 536. (361). Daban, C., Colom, F., Sanchez-Moreno, J., Garcia-Amador, M., Vieta, E., 2006. Clinical correlates of first-episode polarity in bipolar disorder. Comprehensive Psychiatry 47, 433–437. Dilsaver, S.C., Chen, R., Shoaib, A.M., Swann, A.C., 1999. Phenomenology of mania: evidence for distinct depressed, dysphoric, and euphoric presentations. American Journal of Psychiatry 156, 426–430. Dunner, D.L., Patrick, V., Fieve, R.R., 1979a. Life events at the onset of bipolar affective illness. American Journal of Psychiatry 136, 508–511. Dunner, D.L., Murphy, D., Stallone, F., Fieve, R.R., 1979b. Episode frequency prior to lithium treatment in bipolar manic-depressive patients. Comprehensive Psychiatry 20, 511–515.

1039

Elmslie, J.L., Silverstone, J.T., Mann, J.I., Williams, S.M., Romans, S.E., 2000. Prevalence of overweight and obesity in bipolar patients. Journal of Clinical Psychiatry 61, 179–184. First, M., Spitzer, R., Williams, J., 1997. Structured Clinical Interview for the Diagnostic and Statistical Manual, fourth ed. American Psychiatric Association, Washington, DC. (Patient Version). Frank, E., Cyranowski, J.M., Rucci, P., Shear, M.K., Fagiolini, A., Thase, M.E., Cassano, G.B., Grochocinski, V., Kostelnik, B., Kupfer, D.J., 2002. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Archives of General Psychiatry, 905–911. Frye, M.A., Altshuler, L.L., McElroy, S.L., Suppes, T., Keck, F.r.P.E., Denicoff, K., Nolen, W.A., Kupka, R., Leverich, G.S., Pollio, C., Grunze, H., Walden, J., Post, R.M., 2003. Gender differences in prevalence, risk, and clinical comelates of alcoholism comorbidity in bipolar disorder. American Journal of Psychiatry 160, 883–889. Goodwin, F.K., Jamison, K.R., 1990. Manic Depressive Illness, Oxford University Press. Gottschalk, A., Bauer, M.S., Whybrow, P.C., 1995. Evidence of chaotic mood variation in bipolar patients. Archives of General Psychiatry 52, 947–959. Hantouche, E., Kochman, F., Akiskal, H., 2001. Evaluation des tempéraments affectifs: version complète des outils d′auto-évaluation. Encephale 27, 24–30. Hantouche, E.G., Akiskal, H.S., Azorin, J.M., Châtenet-Duchêne, L., Lancrenon, S., 2006. Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients. Journal of Affective Disorders 96, 225–232. Hendrick, V., Altshuler, L.L., Gitlin, M.J., Delrahim, S., Hammen, C., 2000. Gender and bipolar illness. Journal of Clinical Psychiatry 61, 393–396. Henry, C., 2002. Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder: sex differences. Journal of Psychiatry & Neuroscience 27, 104–107. Hlastala, S.A., Frank, E., Kowalski, J., Sherrill, J.T., Tu, X.M., Anderson, B., Kupfer, D.J., 2000. Stressful life events, bipolar disorder, and the ‘kindling model′. Journal of Abnormal Psychology 109, 777–786. Iasevoli, F., Valchera, A., Di Giovambattista, E., Marconi, M., Rapagnani, M.P., De Berardis, D., Martinotti, G., Fornaro, M., Mazza, M., Tomasetti, C., Buonaguro, E.F., Di Giannantonio, M.D., Perugi, G., de Bartolomeis, A., 2013. Affective temperament are associated with specific clusters of symptoms and psychopathology: a cross-sectional study an bipolar disorder inpatients in acute manic, mixed, or depressive relapse. Journal of Affective Disorders. (Jul 12 [Epub ahead of print]). Janowsky, D.S., Leff, M., Epstein, R.S., 1970. Playing the manic game. Interpersonal maneuvers of the acutely manic patient. Archives of General Psychiatry 22, 252–261. Kawa, I., Carter, J.D., Joyce, P.R., Doughty, C.J., Frampton, C.M., Wells, J.E., Walsh, A.E. S., Olds, R.J., 2005. Gender differences in bipolar disorder: age of onset, course, comorbidity, and symptom presentation. Bipolar Disorders 7, 119–125. Kennedy, N., Boydell, J., Kalidindi, S., Fearon, P., Jones, P.B., van Os, J., Murray, R.M., 2005. Gender differences in incidence and age at onset of mania and bipolar disorder over a 35-year period in Camberwell, England. American Journal of Psychiatry 162, 257–262. Kessing, L.V., 2004. Gender differences in the phenomenology of bipolar disorder. Bipolar Disorders 6, 421–425. Kessing, L.V., Agerbo, E., Mortensen, P.B., 2004. Major stressful life events and other risk factors for first admission with mania. Bipolar Disorders 6, 122–129. Kessler, R.C., McGonagle, K.A., Swartz, M., Liu, J., Swartz, M., Blazer, D.G., 1993. Sex and depression in the National Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. Journal of Affective Disorders 29, 85–96. Krishnan, K.R.R., 2005. Psychiatric and medical comorbidities of bipolar disorder. Psychosomatic Medicine 67, 1–8. Kupfer, D.J., Frank, E., Grochocinski, V.J., Cluss, P.A., Houck, P.R., Stapf, D.A., 2002. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. Journal of Clinical Psychiatry 63, 120. (15). Lee, S., Tsang, A., Kessler, R.C., Jin, R., Sampson, N., Andrade, L., Karam, E.G., Mora, M.E., Merikangas, K., Nakane, Y., Popovici, D.G., Posada-Villa, J., Sagar, R., Wells, J.E., Zarkov, Z., Petukhova, M., 2010. Rapid-cycling bipolar disorder: cross-national community study. British Journal of Psychiatry 196, 217–225. Lewinsohn, P.M., Striegel-Moore, R.H., Seeley, J.R., 2000. Epidemiology and natural course of eating disorders in young women from adolescence to young adulthood. Journal of the American Academy of Child and Adolescent Psychiatry 39, 1284–1292. MacKinnon, D.F., Zandi, P.P., Cooper, J., Potash, J.B., Simpson, S.G., Gershon, E., Nurnberger, J., Reich, T., Depaulo, J.R., 2000. Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. American Journal of Psychiatry 159, 30–35. Mantere, O., Melartin, T.K., Suominen, K., Rytsälä, H.J., Valtonen, H.M., Arvilommi, P., Leppämäki, S., Isometsä, E.T., 2006. Differences in Axis I and II comorbidity between bipolar I and II disorders and major depressive disorder. Journal of Clinical Psychiatry 67, 584–593. Mathew, M.R., Chandrasekaran, R., Sivakumar, V., 1994. A study of life events in mania. Journal of Affective Disorders 32, 157–161. McElroy, S.L., Keck, P.E., Pope, H.G., Hudson, J.I., Faedda, G.L., Swann, A.C., 1992. Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. American Journal of Psychiatry 149, 1633–1644. McElroy, S.L., Altshuler, C.L., Suppes, T., Keck Jr, P.E., Frye, M.A., Denicoff, K.D., Nolen, W.A., Kupka, R.W., Leverich, G.S., Rochussen, J.R., Rush, A.J., Post, R.M., 2001. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. American Journal of Psychiatry 158, 420–426.

1040

J.-M. Azorin et al. / Journal of Affective Disorders 151 (2013) 1033–1040

McElroy, S.L., Kotwal, R., Keck Jr, P.E., 2006. Comorbidity of eating disorders with bipolar disorder and treatment implications. Bipolar Disorders 8, 686–695. McElroy, S.L., Arnold, L.M., Altshuler, L.L., 2011. Bipolarity in women: therapeutic issues. In: Akiskal, H.S., Tohen, M. (Eds.), Bipolar Psychopharmacotherapy: Caring for the Patient, second ed. John Wiley & Sons, Chichester, Ltd, pp. 317–350. McIntyre, R.S., Konarski, J.Z., Wilkins, K., Bouffard, B., Soczynska, J.K., Kennedy, S.M., 2006. The prevalence and impact of migraine headache in bipolar disorder: results from the Canadian Community Health Survey. Headache 46, 973–982. Mechanic, D., 1986. Illness behavior: an overview. In: McHugh, S., Vallis, T.M. (Eds.), Illness Behavior: A Multidisciplinary Model. Plenum, New York, NY, pp. 101–109. Montgomery, S.A., Ǻsberg, M., 1979. A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382–389. Nivoli, A.M.A., Pacchiarotti, I., Rosa, A.R., Popovic, D., Murru, A., Valenti, M., Mar Bonnin, C., Grande, I., Sanchez-Moreno, J., Vieta, E., Colom, F., 2011. Gender differences in a cohort study of 604 bipolar patients: the role of predominant polarity. Journal of Affective Disorders 133, 443–449. Oreški, I., Jakovljević, M., Aukst-Margetić, B., Crnčević/Orlić, Ž., Vuksan-Cusa, B., 2012. Comorbidity in patients with schizophrenia and bipolar disorder: similarities and differences. Psychiatria Danubina 24, 80–85. Otto, M.W., Simon, N.M., Wisniewski, S.R., Miklowitz, D.J., Kagan, J.N., ReillyHarrington, A., Frank, E., Nierenberg, A.A., Marangell, C.B., Sagduyu, K., Weiss, R.D., Miyahara, S., Thase, M.E., Sachs, G.S., Pollack, M.H., 2006. for the STEP-BD Investigators, 2006. Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders. British Journal of Psychiatry 189, 20–25. Pellet, J., Bobon, D., Mormont, I., Lang, F., Massardier, A., 1981. Etude princeps de validation Française de la MADRS, sous échelle de dépression de la CPRS; compte rendu du Congrès de Psychiatrie et de Neurologie de Langue Française. Masson, Paris. Perlis, R.H., Miyahara, S., Marangell, L.B., Wisniewski, S.R., Ostacher, M., DelBello, M.P., Bowden, C.L., Sachs, G.S., Nierenberg, A.A., 2004. for the STEP-BD Investigators, 2004. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the Systematic Treatment enhancement program for bipolar disorder (STEP-BD). Biological Psychiatry 55, 875–881. Perugi, G., Akiskal, H.S., Rossi, L., Paiano, A., Quilici, C., Madaro, D., Musetti, L., Cassano, G.B., 1998. Chronic mania. Family history, prior course, clinical picture and social consequences. British Journal of Psychiatry 173, 514–518. Potash, J.B., Toolan, J., Steele, J., Miller, E.B., Pearl, J., Zandi, P.P., Schulze, T.G., Kassem, L., Simpson, S.G., Lopez, V., MacKinnon, D.F., McMahon, F.J., 2007. NIMH Genetics

Initiative Bipolar Disorder Consortium, 2007. The bipolar disorder phenome database: a resource for genetic studies. American Journal of Psychiatry 264, 1229–1237. Regier, D.A., Farmer, M.E., Rae, D.S., Locke, B.Z., Keith, S.J., Judd, L.L., Goodwin, F.K., 1990. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. Journal of the American Medical Association 264, 2511–2518. Robb, J.C., Young, L.T., Cooke, R.G., Joffe, R.T., 1998. Gender differences in patients with bipolar disorder influence outcome in the medical outcomes survey (SF20) subscale scores. Journal of Affective Disorders 49, 189–193. Roy-Byrne, P., Port, R.M., Uhde, T.W., Porcu, T., Davis, D., 1985. The longitudinal course of recurrent affective illness: life chart data from research patients at the NIMH. Acta Psychiatrica Scandinavica. Supplementum 317, S1–S34. Saunders, E.F.H., Fitzgerald, K.D., Zhang, P., McInnis, M.G., 2012. Clinical features of bipolar disorder comorbid with anxiety disorders differ between men and women. Depression and Anxiety 29, 739–746. Signoretta, S., Maremmani, I., Liguori, A., Perugi, G., Akiskal, H.S., 2005. Affective temperament traits measured by TEMPS-I and emotional–behavioral problems in clinically-well children, adolescents, and young adults. Journal of Affective Disorders 85, 169–180. Simon, N.M., Otto, M.W., Weiss, R.D., Bauer, M.S., Miyahara, S., Wisniewski, S.R., Thase, M.E., Kogan, J., Frank, E., Nierenberg, A.A., Calabrese, J.R., Sachs, G.S., 2004. Pollack MH for STEP-BD Investigators, 2004. Pharmacotherapy for bipolar disorder and comorbid conditions. Baseline data from STEP-BD. Journal of Clinical Psychopharmacology 24, 512–520. Strakowski, S.M., Tohen, M., Stoll, A.L., Faedda, G.L., Goodwin, D.C., 1992. Comorbidity in mania at first hospitalization. American Journal of Psychiatry 149, 554–556. Suominen, K., Mantere, O., Valtonen, H., Arvilommi, P., Leppämäki, S., Isometsä, E., 2009. Gender differences in bipolar disorder types I and II. Acta Psychiatrica Scandinavica 120, 464–473. Tondo, L., Baldessarini, R.J., 1998. Rapid cycling in women and men with bipolar manic-depressive disorders. American Journal of Psychiatry 155, 1434–1436. Waxmonsky, J.A., Thomas, M.R., Miklowitz, D.J., Allen, D.M., Wisniewski, S.R., Zhang, H., Ostacher, M.J., Fossey, M.D., 2005. Prevalence and correlates of tobacco use in bipolar disorder: data from the first 2000 participants in the Systematic Treatment Enhancement Program. General Hospital Psychiatry 27, 321–328.