Increased risk of depressive disorders in women with polycystic ovary syndrome

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1 Increased risk of depressive disorders in women with polycystic ovary syndrome Elizabeth Hollinrake, B.S., a Alison Abreu, M.D., b Michelle Maifeld, R.N.C., a Bradley J Van Voorhis, M.D., a and Anuja Dokras, M.D. a a Department of Obstetrics and Gynecology and b Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa Objective: Polycystic ovary syndrome (PCOS) is associated with several metabolic complications. A few small studies have also suggested an increased risk of depression in women with PCOS. The goals of this study were to estimate the prevalence of depressive disorders in women with PCOS compared with controls and to evaluate the correlation between depression, hyperandrogenism, and other metabolic markers. Design: Cohort study. Setting: University Hospital. Patient(s): Women with PCOS (Rotterdam criteria; n 103). Women without PCOS seen during the same time period for an annual exam were used as control subjects (n 103). Intervention(s): Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ) and the Beck Depression Inventory. Main Outcome Measure(s): Depressive disorders. Result(s): Women with PCOS were at an increased risk for depressive disorders (new cases) compared with controls (21% vs. 3%; odds ratio 5.11 [95% confidence interval (CI) ]; P.03). The overall risk of depressive disorders in women with PCOS was 4.23 (95% CI ; P.01) independent of obesity and infertility. Compared with the nondepressed PCOS subjects, the depressed PCOS subjects had a higher body mass index (BMI) and evidence of insulin resistance (P.02). Conclusion(s): We report a significantly increased risk of depressive disorders (as defined by the Diagnostic and Statistical Manual IV) in women with PCOS and recommend routine screening in this population. (Fertil Steril 2007;87: by American Society for Reproductive Medicine.) Key Words: Polycystic ovary syndrome, depression, mood disorders, obesity Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women in the United States, affecting 5% 10% of this population (1, 2). Women with PCOS are at an increased risk for hypertension (3), dyslipidemia (4), insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus (5). Many aspects of the syndrome, such as physical appearance, menstrual abnormalities, and difficulty conceiving, are associated with a lower degree of satisfaction with health, self, and sex (6). Health-related quality of life scores have been consistently lower in subjects with PCOS (6, 7). Although PCOS is associated with a number of medical comorbidities, the risk of depression in women with PCOS is unknown. Depressive disorders include Major Depressive Disorder (MDD), Dysthymic Disorder, and Depression Not Otherwise Specified (DNOS), based on the Diagnostic and Statistical Manual IV (DSM-IV) (8). Major Depressive Disorder affects nearly 14.8 million American adults each year and is more prevalent in women (9). In a recent U.S. survey, the Received March 8, 2006; revised and accepted November 7, Presented at the 61st Annual Meeting of the American Society of Reproductive Medicine, October Reprint requests: Anuja Dokras, M.D., Ph.D., Department of Obstetrics and Gynecology, University of Iowa, 200 Hawkins Drive, Iowa City, IA (FAX: ; anuja-dokras@uiowa.edu). prevalence of MDD in women aged years ranged from 12% to 14%, with a mean age of onset of 30.4 years (10). Compared with men, women with major depression tend to have an earlier age of onset, a greater family history of affective disorders, and poorer social adjustment and quality of life (11). Up to 25% of women will satisfy the criteria for MDD during their lifetime. The overall prevalence of depressive disorders in a large multicenter study of obstetric-gynecologic patients was reported to be approximately 12% (6% rate for MDD and 6% for Other Depression) (12). These data underscore the importance of timely identification of depression in reproductive-age women. A few small studies have analyzed depressive symptoms in women with PCOS but are limited by small sample size, lack of control subjects, and use of continuous scales for the definition of depression. Higher scores for depression using the German version of the Symptom Checklist Revised were reported in PCOS women (n 50) compared with controls (n 50) (6). A U.S. study reported a 50% rate of depression in women with PCOS (n 32) (13); however, there were no control subjects included in the study. Using the Center for Epidemiological Studies Depression Rating Scale, the investigators found higher scores among women with insulin resistance and in women with elevated body mass index (BMI). Another study compared mood states in PCOS sub /07/$32.00 Fertility and Sterility Vol. 87, No. 6, June 2007 doi: /j.fertnstert Copyright 2007 American Society for Reproductive Medicine, Published by Elsevier Inc. 1369

2 jects with those of weight-matched healthy women (n 27), using a number of questionnaires, including a depression adjective checklist, and found that acute and long-standing depressive symptoms were significantly higher in the PCOS group (14). The authors also reported that free testosterone levels were related to depression but not in a linear fashion. Collectively, these studies have concluded that PCOS confers an increased risk for depressive symptoms. None of these studies, however, specifically estimated the risk of MDD or other depressive syndromes as defined by the DSM-IV in women with PCOS. The aims of the present study were to estimate the prevalence of depressive disorders in women with PCOS and to determine the role of androgens and other metabolic markers associated with PCOS in the development of depression. MATERIALS AND METHODS Subjects This was a cohort study approved by the University of Iowa Institutional Review Board. All subjects were women years old and were seen at the University of Iowa Hospitals and Clinics (UIHC) between May 2004 and August The PCOS subjects were recruited from women visiting the UIHC Reproductive Endocrinology and Infertility Clinic. The diagnosis of PCOS was based on the Rotterdam criteria (2). Control subjects were randomly selected from women who had regular menses and absence of hirsutism and were seen for an annual exam in the gynecology clinic over the same time period as the PCOS patients. In both groups, 90% 94% of subjects approached agreed to participate in the study. Study Protocol The study protocol involved completing three questionnaires: the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ) (15), the Beck Depression Inventory (BDI) (16), and a demographic questionnaire designed specifically for this study. The demographic questionnaire included information regarding the subject s race, education, employment, marital status, cigarette and alcohol use, medications, obstetric history, personal history of psychiatric illness and previous counseling or treatments, and family history of psychiatric illness. The questionnaires were completed during the subject s clinic visit. The questionnaires were scored as directed by each form s standard instructions. Subjects with Major Depressive Episode had depressed mood and loss of interest or pleasure in daily activities for a period of at least 2 weeks. In addition they experienced at least four of the following symptoms nearly every day for at least 2 consecutive weeks: changes in appetite, psychomotor retardation or agitation, feelings of worthlessness or guilt, thoughts of death or suicidal ideation, changes in sleep, decreased energy, and difficulty thinking or concentrating. Minor Depression, classified under DNOS, is similar to MDD in that depressive symptoms must be present for at least 2 consecutive weeks and interfere with daily activities. However, fewer than 5 symptoms are required to meet criteria for Minor Depression. Subjects who screened positive for depressive disorders (either MDD or Other Depression) on the PRIME-MD PHQ or who indicated suicidal ideation on the BDI were contacted by phone by a psychiatrist. If subjects could not be reached by telephone, they were sent a letter indicating the positive screen and were offered referral for further evaluation and treatment of depression. Subjects who indicated that they were currently undergoing treatment for depression were not contacted. Laboratory Data Laboratory and clinical data were collected from the subjects medical records. Clinical data included height, weight, blood pressure, menstrual interval, presence of hirsutism, and transvaginal ultrasound results. In women with PCOS, fasting laboratory data included glucose, total insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol, and triglycerides. Other laboratory data included TSH, free T4, PRL, DHEAS, 17 alpha hydroxy P, SHBG, and free and total T. Quantitative insulin sensitivity check index (QUICKI), defined as 1/(log (glucose) log (insulin)), was used as a surrogate marker for insulin resistance. All laboratory assays were performed in the clinical chemistry laboratory of the UIHC. Thyroid-stimulating hormone, PRL, total T, and insulin were measured by electrochemiluminescence immunoassay. Sex hormone binding globulin was performed by chemiluminescent immunoassay. The DHEAS level was determined using immunometric chemiluminescence hydroxyprogesterone, total cholesterol, triglycerides, HDL cholesterol, and glucose were measured using enzymatic methods. The LDL cholesterol and free T levels were mathematically derived. Statistical Analysis The sample size was calculated to give the study 80% power to detect at least a 25% risk of depression in PCOS women (assuming a 10% depression rate in control subjects) at a P value of.05. Continuous variables were analyzed using a two-tailed t test or Wilcoxon rank sum test. A chi-squared or Fisher exact test was used to evaluate categoric variables. Logistic regression analysis was used to adjust for differences in dependent variables (new cases and prevalence of depression) between subjects with PCOS and control subjects. Pearson correlation was used to examine the relationship between BDI scores (square root transformation to normalize the distribution of the data) and other hormonal and metabolic variables. Multiple linear regression analysis for BDI score was performed with BMI and fasting glucose as independent variables in the model. Results are reported as mean SD. Statistical significance was defined as P Hollinrake et al. PCOS and depression Vol. 87, No. 6, June 2007

3 TABLE 1 Demographic data for women with polycystic ovary syndrome (PCOS) and control subjects. PCOS (n 103) Control (n 103) Age (mean SD) Body mass index (kg/m 2 ) (mean SD) * Education High school diploma/ged 10.6% (11) 9.7% (10) College 86% (89) 79% (81) Race/ethnicity White, non-hispanic 93% (96) 86% (88) Black 1.9% (2) 1.9% (2) Hispanic 1.9% (2) 1.9% (2) Other 2.9% (3) 11% (11) Marital status Married 67% (69) 60% (62) Single 18% (19) 16% (16) In steady relationship 11% (11) 19% (20) Separated/divorced/widowed 3.9% (4) 1.9% (2) Unknown 0% (0) 2.9% (3) Employment status Full time 66% (68) 57% (59) Part time 16% (17) 24% (25) Not working/disabled 17% (18) 18% (19) Smokers 15% (15) 12% (12) Marijuana use 0.9% (1) 0.9% (1) Alcohol use ( 4 drinks/wk) 2.9% (3) 9.7% (10) Family history of depression 51% (48)* 29% (30) Currently attempting pregnancy 47% (48)* 6% (6) Delivery within last 6 months 0.9% (1) 3.9% (4) * P.05. RESULTS A total of 103 subjects with PCOS and 103 control subjects were enrolled in this study and completed the required questionnaires. The demographic characteristics and potential moderators for depression in the two groups are shown in Table 1. There was no significant difference in the mean ages for the two groups. The PCOS subjects had a significantly higher BMI ( ) than the control group ( ; P.05). There were no differences in race, education, marital status, drug use, or employment. More women with PCOS had an immediate family member with a history of depression compared with control subjects (51% vs. 29%; P.05). Because the PCOS women were recruited from the Reproductive Endocrinology and Infertility clinic, a significantly higher proportion were attempting pregnancy compared with the control subjects who were visiting the hospital for an annual exam (47% vs. 6%; P.05). Of the PCOS women attempting pregnancy, 44% (21 of 48) had achieved a successful pregnancy in the past. Therefore the primary infertility rate was 26.2% in the PCOS group. Only 5 of the 206 subjects in the study had delivered within the past 6 months. Most women with PCOS had irregular menses and hyperandrogenism (95.2%). Figure 1 depicts the proportion of subjects in each group that were classified as having depression. New cases included subjects that screened positive for either MDD or Other Depression based on the PRIME-MD PHQ completed at UIHC. The number of new cases of depressive disorders in women with PCOS was significantly higher (22 out of 103, 21%) than in control subjects (3 out of 103, 3%) (P.005). The risk of MDD was significantly higher in PCOS women (14 out of 103) than in control subjects (2 out of 103) (P.002). Also, the risk of DNOS was significantly higher in PCOS women (8 out of 103) than in control subjects (1 out of 103) (P.03). After adjusting for BMI and family history of depression, the odds ratio for a positive screen among PCOS subjects compared with controls was 5.11 (95% CI ; P.03). In addition to the new cases, total cases included subjects that had been diagnosed with depression before the study and were currently being treated with antidepressant medications. The number of total Fertility and Sterility 1371

4 FIGURE 1 Risk of depression diagnosed by the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ) (positive screens) and prevalence of depression (total cases) in women with polycystic ovary syndrome (PCOS) (n 103) and control subjects (n 103) (P.01). cases of depressive disorders in the PCOS group was significantly higher (36 out of 103, 35%) than in the control group (11 out of 103, 10.7%) (P.0001). The adjusted odds ratio for overall depressive disorders in women with PCOS (controlling for BMI, family history of depression, and history of infertility) was 4.23 (95% CI ; P.01). The average BDI score, which reflects depression symptom severity, was significantly higher in the entire PCOS group ( ) than in the control group ( ) (P.001). We found fatigue and sleep disturbances to be the two commonest symptoms reported for the diagnosis of depressive disorders, followed by appetite changes and diminished interest in doing things (Table 2). Binge eating disorder (BED) was more common in PCOS subjects (12.6%) than in control subjects (1.9%) (P.01). Among the PCOS subjects, a higher proportion of depressed women had BED (30.5%) compared with nondepressed women (3%). Other comorbidities included a high risk for anxiety disorders (panic disorder and other anxiety disorder) in women with PCOS (14.5%) compared with control subjects (0.9%) (P.001). To further examine the role of obesity, we examined the risk of depressive disorders only in obese women (BMI 30; n 87). Obese PCOS women had a higher risk of depressive disorders (n 73; 44%) than obese control subjects (n 14; 7%) (P.02). Using BMI as a continuous measure, we did not find a positive correlation between BMI and BDI scores for all PCOS subjects (r 0.17; P.094). To determine the association between androgens and metabolic markers with depression, the PCOS group was further analyzed based on presence or absence of depression. Table 3 summarizes the comparison of the two groups with respect to demographic variables and potential modifiers for depressive disorders and depressed mood, such as a family history of MDD (8), obesity (17, 18), and infertility (19 21). Compared with the nondepressed PCOS subjects, the depressed PCOS subjects had a significantly higher BMI (P.01). Other demographic variables, such as race, marital status, and education were similar in both groups; however, depressed PCOS women reported less full-time employment. Interestingly, there were no significant differences between the two groups with respect to family history of depression or history of infertility. To investigate potential causes for the increased risk of depressive disorders in PCOS, biochemical variables were also analyzed and compared between the two groups (Table 4). Although some studies in the literature suggest that androgens have an influence on mood (22 24), we did not find a significant difference in ovarian and adrenal androgen levels between the depressed and nondepressed PCOS subjects. A similar proportion of subjects in both groups were using oral contraceptives. The depressed PCOS group had significantly higher (P.02) fasting insulin levels and lower values for QUICKI than the nondepressed PCOS group. These findings suggest a higher risk of insulin resistance in the PCOS subjects with depressive disorders. A higher proportion (22%) of the depressed PCOS subjects were also classified as having impaired fasting glucose (fasting glucose 100 mg/dl and 125 mg/dl), and 4 out of 36 (11%) of the depressed PCOS subjects had frank diabetes mellitus (fasting glucose 126 mg/dl). By comparison, among the nondepressed PCOS subjects, 12% had impaired fasting glucose and none had diabetes mellitus. A similar proportion of women in both groups were treated with metformin for ovulation induction. Lipid profiles, including total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, were also compared, and no differences were found between depressed and nondepressed PCOS subjects. Using Pearson correlation, fasting glucose levels were found to have a weak but positive correlation with the BDI TABLE 2 Depression symptom frequency for women newly diagnosed with depression (n 25). Fatigue 96% Sleep disturbance 88% Diminished interest 84% Appetite changes 84% Feeling down 72% Feels like failure 72% Difficulty concentrating 48% Psychomotor disturbance 16% Suicidal thoughts 12% 1372 Hollinrake et al. PCOS and depression Vol. 87, No. 6, June 2007

5 TABLE 3 Comparison of demographic variables and depression risk factors within the polycystic ovary syndrome (PCOS) group. PCOS women with depression (n 36) PCOS women without depression (n 67) Age (mean SD) Body mass index (kg/m 2 ) (mean SD) * Education High school diploma/ged 13.8% (5) 8.9% (6) College 86.1% (31) 91% (61) Race/ethnicity White, non-hispanic 91.7% (33) 94.0% (63) Black 2.8% (1) 1.5% (1) Hispanic 2.8% (1) 1.5% (1) Other 2.8% (1) 3.0% (2) Marital status Married 55.5% (20) 73.1% (49) Single 22.2% (8) 16.4% (11) In steady relationship 13.9% (5) 9.0% (6) Separated/divorced/widowed 8.3% (3) 1.5% (1) Family history of depression 58.3% (21) 40.3% (27) Employment status Full time 47.2% (17)* 76.1% (51)* Part time 16.7% (6) 16.4% (11) Not working/disabled 36.1% (13)* 7.5% (5)* Currently attempting pregnancy 36.1% (13) 52.2% (35) Smokers 19.4% (7) 11.9% (8) Marijuana use 2.8% (1) 0% (0) Alcohol use ( 4 drinks/wk) 5.5% (2) 1.5% (1) Current oral contraceptive use 16.7% (6) 22.4% (15) Current metformin use 33.3% (12) 34.3% (23) * P.01. scores (r 0.23; P.023). Multiple linear regression analysis using BMI and fasting glucose in the model demonstrated a low contribution of these two variables to the overall BDI score (6.8%). DISCUSSION This is the first study examining the risk of depressive disorders in women with PCOS and geographically matched controls based on DSM-IV diagnostic criteria. We report a significantly higher prevalence of depressive disorders in the reproductive-age PCOS population (35%) than in control subjects (10.7%). Potential moderators for depression, such as age, race, education level, employment, and martial status, were similar in both groups. The increased risk of depressive disorders in women with PCOS was found to be independent of obesity. After adjusting for other variables, such as family history of depression, the adjusted odds ratio for overall depression in the PCOS group was 4.23 (95% CI ; P.01). Our screening tool, the PRIME-MD PHQ, has been validated for use in gynecology outpatients (12). The PRIME-MD PHQ is a four-page self-administered version of the PRIME-MD, a clinician-administered diagnostic tool used in a primary care setting to screen, evaluate, and diagnose mental disorders based on DSM-IV criteria. In addition to assessing mood, anxiety, eating, alcohol, and somatoform disorders, the PHQ version also asks women specific questions regarding premenstrual syndrome, postpartum and menopausal mood disorders, menstruation, pregnancy, and fertility. The sensitivity and specificity of the PHQ for MDD are 73% and 98%, respectively, so it is unlikely that our results are overestimated (25). A physician requires 1 5 minutes to evaluate the answers and rule out physical causes of depression or anxiety, normal bereavement, and a history of a manic episode (12). One of the strengths of the present study was the inclusion of a control group similar to the PCOS group in terms of age distribution, race, education, and marital status. The preva- Fertility and Sterility 1373

6 TABLE 4 Comparison of biochemical variables in the polycystic ovary syndrome (PCOS) group with and without depression. PCOS women with depression (n 36) PCOS women without depression (n 67) T (ng/dl) Free T (pg/ml) DHEAS (ng/ml) P (ng/dl) Fasting insulin ( U/mL) * Fasting glucose (mg/dl) * QUICKI * Cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Note: Values are mean SD. HDL high-density lipoprotein; LDL low-density lipoprotein. * P.02. lence of depressive disorders in this control group was similar to a large study (n 3,000) conducted in an outpatient gynecologic population from seven different sites in the U.S. (12). The investigators also used the PRIME-MD PHQ and reported a 12% rate for depressive disorders despite a different ethnic population (39% non-hispanic white). However, one of the limitations of the present study was the inability to evaluate the effects of PCOS on future risk of depression, because the study was cross-sectional in design. Most women with PCOS have clinical or biochemical hyperandrogenism. We did not observe any significant differences in total or free T levels or in the adrenal androgen DHEAS between depressed women with PCOS and nondepressed women with PCOS. A similar proportion of women in both groups were treated with oral contraceptives for menstrual regulation. The relationship between androgens and mood in women is controversial. Although a few small studies suggest a correlation between depressive symptoms and serum androgens (14, 22, 23), other studies have failed to demonstrate this association (13). It has been suggested that women with PCOS suffer from lower self-esteem, more negative self-image (14, 26), and have higher levels of depression owing to the physical features of hyperandrogenism. Other studies, however, have shown no association between depressive symptoms and variables such as hirsutism, alopecia, or acne (13). We did not quantify the extent of clinical hyperandrogenism in our study and therefore were unable to determine the association with depression. The data regarding risk of depressive disorders in women with infertility are controversial and limited (19 21). The influence of variables such as cause of infertility, duration of infertility, and type of treatment (oral agents vs. IVF) has not been fully examined. There is some evidence that during the time that couples attempt to conceive, women with fertility problems experience more negative emotional feelings than women who successfully conceive spontaneously (19). In the present study a larger number of women with PCOS were attempting pregnancy, but a significant proportion of these had been pregnant previously. Although infertility is a feature of PCOS, the majority of women with PCOS will respond to ovulation induction agents and achieve a pregnancy. There are no studies specifically examining the effects of PCOS-related infertility on MDD. In the present study, women with PCOS had a higher risk of depressive disorders even after adjusting for infertility. Interestingly on analysis of the PCOS group alone, similar numbers of depressed and nondepressed PCOS women reported a history of infertility. There is limited and conflicting information on the effects of insulin resistance and metabolic syndrome on depressive disorders, especially in women (13). We found depressed women with PCOS to have a higher evidence of insulin resistance and impaired fasting glucose than PCOS women without depression. Similar findings have been described earlier (13). In a small study, impaired insulin sensitivity associated with depression improved after treatment of depression with tricyclic antidepressants (27). There are plausible physiologic connections between depression and insulin resistance. Depression is associated with increased cortisol, increased sympathetic activity, and decreased CNS serotonin, features also associated with insulin resistance. If depression modulates insulin sensitivity, then women with PCOS and depression may be at a higher risk for progression to diabetes. Also, patients with diabetes are at a significantly 1374 Hollinrake et al. PCOS and depression Vol. 87, No. 6, June 2007

7 increased risk for depression, and conversely depression is associated with a higher risk of subsequent diabetes (28). In the present study, four subjects with PCOS had untreated diabetes compared with no patients in the control group. Further studies are needed to evaluate this link and study the effects of treatment of depression on insulin resistance and glucose metabolism. Although our study detected a high rate of depressive disorder independent of BMI in women with PCOS, our data also suggest an association between depression scores as measured by BDI and BMI. However, this association was not strong enough to fully account for the increased risk of depressive disorders. There is varying information on the effects of obesity on the risk of MDD. Depressive symptoms and mood disorders are common in persons of all ages seeking treatment for obesity (26). Given the increasing prevalence of obesity in the U.S., there is a strong probability that obesity and depression will occur together. It is unclear how much of the clinical overlap between mood disorders and obesity is due to iatrogenic factors, co-occurrence of two common disorders, or inherited pathogenic factors. Based on the current literature, MDD with atypical features (namely, BED), MDD with juvenile onset, and bipolar disorder are associated with overweight and obesity (29). In the present study a high proportion of depressed PCOS women had BED, which may mediate the relationship between obesity and depression. Conversely, community-based studies have shown obesity to have a positive association with MDD (18, 29, 30). Obesity was associated with increased odds of past-year MDD among women (OR 1.37, 95% CI ) (30). Some studies also suggest that morbid obesity is primarily associated with depression (31). Although the present study demonstrated a higher risk of depression in women with PCOS independent of BMI, given that 60% 70% of women with PCOS are obese, treatment of both of these disorders will need to be addressed in most women. Treatment of obesity leads to a decrease in depression. In a study of patients who underwent gastric-restrictive weightloss surgery (females, n 412), weight loss was associated with a significant and sustained decrease in BDI score (26). There are few studies describing the effects of weight loss in infertile obese women (32). Sixty-four women completed a 24-week program, which included exercise, information about healthy eating and group discussion sessions with significant improvement on ratings of self-esteem and depression. Obese patients seeking treatment for mood disorders may need different management strategies such as improving depressive symptoms with pharmacotherapy prior to initiating weight loss programs. Current treatment guidelines for mood disorders do not address the management of comorbid obesity and vice versa. In conclusion, the present study shows that women with PCOS are at a significant risk for depressive disorders including MDD. Larger studies may be needed to further validate our results, and specifically, studies evaluating the effects of pharmacotherapy, weight loss, and glucose control on depression in women with PCOS are needed. Major depression is associated with patient suffering, disability, lost productivity, and a higher mortality rate (33). Depressed patients can spend 20% of their lives in depressive episodes, and these episodes recur in 75% 80% of these cases. Depression costs U.S. employers $44 billion per year in absenteeism and lost productivity compared with $13 billion in lost productivity among workers without depression. Because the peak incidence of depression is during the reproductive years, gynecologists are front-line professionals in the effort to identify and treat women with PCOS who have depression. As seen in the present study, women with depression may describe their presenting problems are sleep disturbances or fatigue and therefore the diagnosis may be missed. Compared with obstetrician-gynecologists, family medicine physicians and general internists are more likely to use formal diagnostic criteria, assess for psychiatric comorbidity, and make direct assessments for suicide (34). Increased vigilance and routine use of brief questionnaires is imperative, despite time constraints, to allow identification of women with depression. Data from the National Comorbidity Survey application found that only 41.1% of individuals diagnosed with mood disorders received some form of treatment (35). It is known that with adequate treatment, 50% 70% of patients with depression recover completely. 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