Endometriosis is a gynaecological condition that is

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1 Revisiting the Association Between Endometriosis and Bipolar Disorder Vikaash Kumar, MD, 1 Mustaq Khan, PhD, 2 George A. Vilos, MD, 3 Verinder Sharma, MBBS 4,5,6 1 Department of Medicine, University of Toronto, Toronto ON 2 Mood Disorders Program, Regional Mental Health Care, London ON 3 St. Joseph s Health Care, Department of Obstetrics and Gynecology, University of Western Ontario, London ON 4 Department of Psychiatry, University of Western Ontario, London ON 5 Department of Obstetrics and Gynecology, University of Western Ontario, London ON 6 Perinatal Clinic, St. Joseph s Health Care, London ON This paper was presented in part at the 4th World Congress on Women s Mental Health, Madrid, Spain, March 18, Abstract Objective: We sought to study the association between endometriosis and bipolar disorder. Methods: Using the Structured Clinical Interview for Axis I Disorders, the prevalence of bipolar disorder was compared in 27 patients with endometriosis and 12 women with pelvic pain not related to endometriosis who were seen at a specialty gynaecology clinic for women with chronic pelvic pain. Results: A significantly greater proportion of women in the endometriosis group were found to have bipolar disorder and a poorer quality of life than women with pelvic pain not related to endometriosis. Conclusion: There may be an association between endometriosis and bipolar disorder. An optimal approach to managing endometriosis should include evaluation and treatment of psychiatric comorbidity, particularly bipolar disorder. Résumé Objectif : Nous cherchions à étudier l association entre l endométriose et le trouble bipolaire. Méthodes : Au moyen de la Structured Clinical Interview visant les Axis I Disorders, la prévalence du trouble bipolaire a été comparée chez 39 femmes qui ont consulté une clinique gynécologique spécialisée desservant les femmes qui connaissent des douleurs pelviennes chroniques : 27 femmes présentant une endométriose et 12 femmes qui connaissaient des douleurs pelviennes n étant pas associées à une endométriose. Key Words: Bipolar disorder, depression, endometriosis, women s health Competing Interests: None declared. Received on April 7, 2011 Accepted on June 8, 2011 Résultats : Nous avons constaté qu une proportion considérablement supérieure de femmes du groupe «endométriose» présentaient un trouble bipolaire et une qualité de vie moindre, par comparaison avec les femmes qui connaissaient des douleurs pelviennes n étant pas associées à une endométriose. Conclusion : Il pourrait y avoir une association entre l endométriose et le trouble bipolaire. Une approche optimale envers la prise en charge de l endométriose devrait comprendre l évaluation et la prise en charge des comorbidités psychiatriques, particulièrement celles du trouble bipolaire. INTRODUCTION Endometriosis is a gynaecological condition that is characterized by the presence of endometrial-like tissue outside the uterus, most commonly on the ovaries. It affects 6% to 10% of women of reproductive age and is one of the common causes of pelvic pain and infertility. 1 3 Pelvic pain due to endometriosis is usually chronic and is commonly associated with dysmenorrhea, dyspareunia, deep pelvic pain, and lower abdominal pain with or without back pain. Endometriosis is a major cause of disability and impaired quality of life in women of reproductive age. 4 High rates of psychopathology including depressive symptoms, anxiety, and poor quality of life have been reported in women with endometriosis. In a prospective study of 104 women with pelvic endometriosis, 86.5% had symptoms of depression, and 87.5% had symptoms J Obstet Gynaecol Can 2011;33(11): NOVEMBER JOGC NOVEMBRE

2 of anxiety. 5 Depression is more prevalent in women with endometriosis who have chronic pelvic pain than in women without pain symptoms. 6 There are conflicting data on the association between endometriosis and bipolar disorder. In one study, 12 of 16 women with endometriosis met DSM-III criteria for a mood disorder. 7 More strikingly, 10 of these women had a diagnosis of bipolar disorder, and nine of these had firstdegree relatives with a history of severe mood disorder. By contrast, another study that compared 14 women with endometriosis and 55 without endometriosis did not find a significant difference in the prevalence of mood disorders. 8 The women in the latter study were a heterogeneous group recruited from both a private clinic and a university clinic. Almost one half of the participants were asymptomatic and had been referred because of infertility or for tubal ligation. The objective of this study was to determine whether women with endometriosis have a higher prevalence of bipolar disorder than women with pelvic pain not related to endometriosis. MATERIALS AND METHODS This cross-sectional study was conducted from June 2002 to August 2003 at the Women s Clinic, St. Joseph s Health Care, London, Ontario. The sample consisted of women who were referred to a specialty gynaecology clinic for treatment of pelvic pain. Eligibility criteria for participation were age 18 years or over, history of pelvic pain of at least six months in duration, and endometriosis confirmed or ruled out by diagnostic laparoscopy. The two groups for comparison in the study were women with a diagnosis of endometriosis and women with pelvic pain due to other gynaecological causes. Of the 89 patients eligible to participate, 39 consented. The sample yielded 27 patients with endometriosis and 12 with pelvic pain not due to endometriosis (Figure). All interviews were conducted by a medical student who was blind to participants group membership. ABBREVIATIONS DSM-III Diagnostic and Statistical Manual of Mental Disorders, third edition Diagnostic and Statistical Manual of Mental Disorders, fourth edition FH-RDC Family History-Research Diagnostic Criteria FPS LSQ SCID-I Functional Pain Scale Life Satisfaction Questionnaire Structured Clinical Interview for Axis I Disorders SF-MPQ Short-Form McGill Pain Questionnaire Demographic information (age, marital status, number of children, education level, and gynaecological history) was obtained. In addition, pelvic pain, life satisfaction, personal psychiatric history, and family history of mental disorders were assessed. For assessing pelvic pain, the Pelvic Pain Questionnaire, which consists of the Short-Form McGill Pain Questionnaire and the Functional Pain Scale, was administered. The SF-MPQ consists of 15 pain descriptors (11 sensory, 4 affective) each rated on a Likert scale from no pain to severe pain. Three pain scores were derived: sensory, affective, and total. 9 The FPS assesses the effect of pelvic pain on specific functions of daily living (e.g., bladder and bowel functions, intercourse, walking, running, lifting, working, and sleeping). 10 Patient ratings of these functions range from no pain to incapable of function. Life satisfaction was measured using the empirically validated Life Satisfaction Questionnaire. 11 In addition to being validated for use among women, the LSQ has been used in chronic pain populations. 12 For diagnosing mental disorders, the intervieweradministered SCID-I was used in face-to-face interviews. 13 All diagnoses of mental disorders made by the interviewer were checked by one of the authors (V.S.), who was a psychiatrist blind to each participant s gynaecological diagnosis. For co-rated SCID-I interviews, there was complete agreement between interviewers for diagnosing manic, hypomanic, and major depressive episodes. For test-retest interviews, Cohen s kappa coefficients were 0.99 for bipolar disorder type I, 0.99 for bipolar disorder type II, and 0.98 for major depressive disorder. The existence of Axis I disorders in first-degree relatives was investigated using the FH-RDC, 14 which addresses the presence of depression, mania, schizophrenia, alcoholism, drug use disorder, antisocial personality, and any other mental problem. The FH-RDC was administered over the telephone or in person to a first-degree relative whose contact information was provided by the patient. Ethics approval for the study was obtained from the University of Western Ontario Research Ethics Board for the Review of Health Sciences Research Involving Human Subjects. RESULTS The mean age of participants was 30.3 years (range 19 to 44) in the endometriosis group and 35.6 years (range 23 to 47) in the non-endometriosis pelvic pain group, a non-significant difference (independent groups t = 1.97, df = 37, P = 0.06). In the endometriosis group, 63% (17/27) were married and in the pelvic pain group 1142 NOVEMBER JOGC NOVEMBRE 2011

3 Revisiting the Association Between Endometriosis and Bipolar Disorder Schema showing the study groups 89 eligible patients 39 patients consented 27 with endometriosis* 12 without endometriosis* 12 with bipolar disorder 5 with other disorder 10 no diagnosis 0 with bipolar disorder 3 with other disorder 9 no diagnosis *Laparoscopically confirmed criteria for bipolar disorder I, bipolar disorder II, and bipolar disorder not otherwise specified Including major depressive disorder and other Axis I disorders 75% (9/12) were married. Of women in the endometriosis group, over 29% (8/27) had previously given birth, compared with 58% (7/12) in the pelvic pain group. The level of education attained was similar in both groups, with approximately two thirds of women having post-secondary education. According to respondents, there was a family history of mood disorder in 37% of women in the endometriosis group (10/27) and 50% of women in the pelvic pain group (6/12). Four women in the endometriosis group had a family history of mania. None of the participants was undergoing treatment with a GnRH agonist. The obtained and expected frequency counts for psychiatric diagnoses are shown in the Table. Of the 27 women in the endometriosis group, 10 did not receive a diagnosis. Among the remaining 17, one had bipolar I disorder, three had bipolar II disorder, eight had bipolar disorder not otherwise specified, four had major depressive disorder, and one had panic disorder. In the pelvic pain group, nine women did not receive a diagnosis, and three had a diagnosis of major depressive disorder. A 2 3 chi-square analysis was carried out on group membership (endometriosis, pelvic pain not due to endometriosis) against the three psychiatric diagnostic groups (no mental disorder, bipolar disorder, major depressive disorder and other mental disorders). There was a statistically significant association between the two variables (χ 2 = 7.96, df = 2, P < 0.019). The major association was between group membership and two of the diagnostic categories no mental disorder versus bipolar disorder. More women in the endometriosis group had a bipolar disorder than would be expected, and more women in the pelvic pain group had no psychiatric diagnosis than would be expected. Bonferroni post hoc tests of individual cells proposed by Agresti 15 and recommended by MacDonald and Gardner, 16 making use of the adjusted residuals, indicated significantly more individuals with bipolar disorder in the endometriosis group and significantly fewer in the pelvic pain group (z = ± 2.78) than would be expected by chance. There was a tendency towards fewer women with no mental disorder in the endometriosis group and more in the pelvic pain group; however, this tendency was not statistically significant with the Bonferroni adjustment. A major reason for this trend is that there were no participants in the pelvic pain group who had a diagnosis of bipolar disorder. When the analysis was reduced to a 2 2 chi-square by eliminating those participants with a diagnosis of major depressive disorder, the result was still significant (χ 2 = 8.010, df = 1, P < 0.005). In the endometriosis and pelvic pain groups, the respective mean SF-MPQ ratings were 24.1 (SD 10.1) and 22.1 (SD 9.7). Mean FPS ratings were 16.9 (SD 6.0) and 14.2 (SD 7.4), NOVEMBER JOGC NOVEMBRE

4 Obtained and expected frequency counts corresponding to gynaecological and psychiatric diagnostic groups among 39 participants Gynaecological diagnosis Psychiatric diagnosis Endometriosis n = 27 n* Pelvic pain n = 12 n* No mental disorder 10 (13.1) 9 (5.9) Bipolar disorder 12 (8.3) 0 (3.7) Major depressive and other disorders 5 (5.5) 3 (2.5) *Expected frequencies in parentheses respectively. The mean LSQ ratings in the endometriosis and pelvic pain groups were 52.2 (SD 10.0) and 54.0 (SD 8.8), respectively. The higher the LSQ score, the better the patient s perceived quality of life. A 2 3 analysis of variance on the three dependent measures (SF-MPQ, FPS, and LSQ) could not be done because the pelvic pain bipolar cell contained no individuals. Consequently, a single factor analysis of variance was carried out on each of the dependent measures, contrasting the remaining five groups. Statistically significant effects were obtained only for the LSQ measure (F = 2.88, df = 4,33, P < 0.038). Post hoc tests of means using the least significant difference procedure indicated that the endometriosis bipolar cell had a significantly lower mean LSQ of 45.8 (SD 10.0) than did the endometriosis no mental disorder cell (mean 55.6, SD 7.6) (t = 2.63, df = 33; P < 0.025), the pelvic pain no mental disorder cell (mean 54.7, SD 9.1) (t = 2.31, df = 33; P < 0.05), and the endometriosis major depressive disorder cell (mean 60.6, SD 3.2) (t = 2.73, df = 33; P < 0.01). The pelvic pain major depressive disorder mean (52.0, SD = 9.6) did not differ significantly from any of the other means. DISCUSSION Unlike the results of the study by Walker et al., 8 our results showed an association between endometriosis and bipolar disorder. There are several possible explanations for the discrepant results. While the sample of Walker et al. was a heterogeneous group drawn from two clinics, our cohort was a homogeneous group of women assessed at a university-based specialty clinic for chronic pelvic pain. The patients were recruited from the practice of a gynaecologist who specializes in the treatment of endometriosis. Thus, the overall higher rates of psychopathology in our study could have been related to various gynaecologic symptoms, particularly chronic pelvic pain. The prevalence of bipolar disorder was not as high as in the study of Lewis et al., 7 which did not have a control group and whose study participants did not have laparoscopically confirmed endometriosis. Reasons for the association between bipolar disorder and endometriosis are unknown because of the paucity of research on the subject. The association should not be interpreted as cause and effect. Both are common conditions among women of reproductive age and are influenced by ovarian hormones. The GnRH agonists that are used to treat endometriosis can also cause emotional lability and depression. 17 The strengths of this study include having a homogeneous group of women with chronic pelvic pain and a laparoscopically confirmed diagnosis of endometriosis, all of whom were seen by the same gynaecologist. An additional strength is that the pain levels were equivalent in the two patient groups, a finding that would argue against the differential rates of comorbid mood disorders being due to different levels of chronic pain. The major limitation of the study is the relatively small number of women in the non-endometriosis pelvic pain group. A second limitation is that the study was conducted in a specialized clinic for women with endometriosis. It is possible that the women in this setting have a chronic or more debilitating form of the disorder, thus reducing the generalizability of the results. It is also possible that many of the women who agreed to participate in the study may have been experiencing mood difficulties before their diagnosis of endometriosis. Our findings have important clinical and research implications. The majority of the psychiatric disorders found in the study were un and therefore untreated. None of the cases of bipolar disorder had been previously. Until there is validation, the data justify consideration of careful psychiatric screening of all women with pelvic pain, especially women with endometriosis. Because comorbid bipolar disorder could influence the effects of endometriosis through several factors such as psychological well-being and quality of life, it is important that a comprehensive approach to endometriosis should include evaluation and treatment of psychiatric comorbidity. Antidepressants have been recommended as adjuncts in the management of chronic pelvic pain. 18 As the use of these medications in patients with a bipolar diathesis could lead to induction of mania, accelerated cycle frequency, and suicidality, it is important to rule out bipolar disorder before the initiation of antidepressants. 19 A better understanding of the association between endometriosis and bipolar disorder may also contribute to our etiological understanding as well as to effective treatment of these disorders. A real understanding of any association will await better studies of a true epidemiologic nature; the cost of such studies 1144 NOVEMBER JOGC NOVEMBRE 2011

5 Revisiting the Association Between Endometriosis and Bipolar Disorder may preclude them from being conducted, but they may be performed as part of a study of much broader scope. ACKNOWLEDGEMENTS Vikaash Kumar was supported by the Summer Research Program Training Grant from the Schulich School of Medicine and Dentistry. The authors wish to thank Dr Robert Gardner for performing the statistical analysis and Carley Pope for her help in the preparation of this manuscript. REFERENCES 1. Giudice LC, Sweirsz LM, Burney RO. Endometriosis. In: Jameson JL, De Groot LJ, eds. Endocrinology, 6th ed. New York: Elsevier; Goldstein DP, decholnoky C, Emans SJ, Leventhal JM. Laparoscopy in the diagnosis and management of pelvic pain in adolescents. J Reprod Med 1980;24: Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clinics North Am 1997;24: Tripoli TM, Sato H, Sartori MG, Fernando de Araujo F, Girão MJ, Schor E. Evaluation of quality of life and sexual satisfaction in women suffering from chronic pelvic pain with or without endometriosis. J Sex Med 2011;8: Sepulcri R de P, do Amaral VF. Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 2009;142: Lorençatto CA, Petta C, Navarro MJ, Bahamondes L, Matos A. Depression in women with endometriosis with and without pelvic pain. Acta Obstet Gynecol Scand 2006;85: Lewis DO, Comite F, Mallouh C, Zadunaisky L, Hutchinson-Williams K, Cherksey BD, et al. Bipolar mood disorder and endometriosis: preliminary findings. Am J Psychiatry 1987;144: Walker E, Katon W, Jones LM, Russo J. Relationship between endometriosis and affective disorder. Am J Psychiatry 1989;146: Melzack R. The Short-Form McGill Pain Questionnaire. Pain 1987;30: Ménard CM, Jarrell JF, Seidel J, Taenzer P. Reliability and validity of the Functional Pelvic Pain Scale: a new measure of pelvic pain severity. J Soc Obstet Gynaecol Can 1996;18: Carlsson M, Hamrin E. Evaluation of the life satisfaction questionnaire (LSQ) using structural equation modelling (SEM). Qual Life Research 2002;11: Boonstra AM, Reneman MF, Posthumus JB, Stewart RE, Schiphorst Preuper HR. Reliability of the Life Satisfaction Questionnaire to assess patients with chronic musculoskeletal pain. Intern J Rehab Research 2008;31: First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for clinical version (SCID-CV) (User s guide and interview). Washington, DC: American Psychiatric Press; Andreasen NC, Endicott J, Spitzer RL, Winokur G. The family history method using diagnostic criteria. Reliability and validity. Arch Gen Psychiatry 1977;34: Agresti A. An introduction to categorical data analysis. New York: Wiley; MacDonald PL, Gardner RC. Type I error rate comparisons of post hoc procedures for I J chi-square tables. Educ Psychol Meas 2000;60: Patten SB, Barbui C. Drug-induced depression: a systematic review to inform clinical practice. Psychother Psychosom 2004;73: Jarrell JF, Vilos GA, Allaire C, Burgess S, Fortin C, Gerwin R, et al., Chronic Pelvic Pain Working Group; Society of Obstetricians and Gynaecologists of Canada. Consensus guidelines for the management of chronic pelvic pain. SOGC Clinical Practice Guideline, No. 164, Pt 2, September J Obstet Gynaecol Can 2005;27: Ghaemi SN, Ko JY, Goodwin FK. The bipolar spectrum and the antidepressant view of the world. J Psychiatr Pract 2001;7: NOVEMBER JOGC NOVEMBRE