Evidence-Based Reviews

When not to treat depression in PCOS with antidepressants

Current Psychiatry. 2005 February;4(2):47-60

Other medications may help women with hormone dysregulation and insulin resistance

References

1. Rasgon NL, Carter MS, Elman S, et al. Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review. Curr Drug Targets Immune Endocr Metabol Disord 2002;2(1):97-102.

2. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333(13):853-61.

3. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR (eds). Polycystic ovary syndrome. Oxford, UK: Blackwell Scientific, 1992;377-84.

4. Rasgon NL, Rao R, Elman S, et al. Depression in women with polycystic ovary syndrome: clinical and biochemical correlates. J Affect Disord 2003;74(3):299-304.

5. Weiner CL, Primeau M, Ehrmann DA. Androgens and mood dysfunction in women: Comparison of women with polycystic ovarian syndrome to healthy controls. Psychosom Med 2004;66:356-62.

6. Fava GA, Grandi S, Savron G, et al. Psychosomatic assessment of hirsute women. Psychother Psychosom 1989;51:96-100.

7. Rasgon NL, Altshuler LL, Gudeman D, et al. Medication status and PCO syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry 2000;61:173-8.

8. Okamura F, Tashiro A, Utsumi A, et al. Insulin resistance in patients with depression and its changes in the clinical course of depression: a report on three cases using the minimal model analysis. Internal Med 1999;38(3):257-60.

9. Okamura F, Tashiro A, Utsumi A, et al. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism 2000;49(10):1255-60.

10. Rasgon NL, Altshuler LL, Birtan JA, et al. Menstrual abnormalities in women with bipolar disorder (presentation). San Francisco: American Psychiatric Association annual meeting, May 2003.

11. Figlewicz DP. Endocrine regulation of neurotransmitter transporters. Epilepsy Res 1999;37(3):203-10.

12. Nathan RS, Sachar EJ, Asnis GM, et al. Relative insulin insensitivity and cortisol secretion in depressed patients. Psychiatry Res 1981;4:291.-

13. Elmslie JL, Silverstone TJ, Mann JI, Williams SM. Determinants of overweight and obesity in patients with bipolar disorder. J Clin Psychiatry 2000;61:179.-

14. Istvan J, Zavela K, Weidner G. Body weight and psychological distress in NHANES I. Int J Obes Relat Metab Disord 1992;16(12):999-1003.

15. Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci 1999;96(5):513.-

16. Pasquali R, Biscotti D, Spinucci G, et al. Pulsatile secretion of ACTH and cortisol in premenopausal women: effect of obesity and body fat distribution. Clin Endocrinol 1998;48(5):603.-

17. Moghetti P, Castello R, Negri C, et al. Insulin infusion amplifies 17 alpha-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metabol 1996;81(3):881.-

18. Bailey CJ, Day C, Bray GA, et al. Role of adrenal glands in the development of abnormal glucose and insulin homeostasis in genetically obese (ob/ob) mice. Horm Metab Res 1986;18(6):357.-

19. Sills SE, Perloe M, Palermo GD. Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes. Eur J Obstet Gynecol Reprod Biol 2000;91(2):135.-

20. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338(26):1876.-

21. Velasquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43(5):647.-

22. Chaouloff F. Effects of acute physical exercise on central serotonergic systems. Med Sci Sports Exerc 1997;29(1):58.-

23. Salazar M. Alpha lipoic acid: a novel treatment for depression. Medical Hypoth 2000;55:510.-

24. Spritzer PM, Lisboa KO, Mattiello S, Lhullier F. Spironolactone as a single agent for long-term therapy of hirsute patients. Clin Endocrinol 2000;52:587.-

25. Moghetti P, Tosi F, Castello R, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metabol 1996;81(3):952.-

26. Zobel AW, Nickel T, Kunzel HE. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatric Res 2000;34:171.-

27. Healy DG, Harkin A, Cryan JF, et al. Metyrapone displays antidepressant-like properties in preclinical paradigms. Psychopharmacol 1999;145(3):303.-

28. Bech P, Raabaek Olsen L, Jarløv N, et al. A case of sequential anti-stress medication in a patient with major depression resistant to amine-reuptake inhibitors. Acta Psychiatr Scand 1999;100:76.-

29. Wolkowitz OM, Reus VI, Chan T, et al. Antiglucocorticoid treatment of depression: double-blind ketoconazole. J Biol Psychiatry 1999;45(8):1070.-

30. Murphy BE, Filipini D, Ghadirian AM. Possible use of glucocorticoid receptor antagonists in the treatment of major depression: preliminary results using RU 486. J Psychiatry Neurosci 1993;18(5):209.-

31. Schatzberg AF, Rothschild AJ, Langlais PJ, et al. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res 1985;19(1):57.-

Women with depression and polycystic ovary syndrome (PCOS) can be trapped in a vicious cycle of hormonal dysregulation. Treating these patients appropriately—with or without antidepressants—requires an understanding of their underlying metabolic disorder.

This article presents a case¹ that exemplifies the association between depression and PCOS (Box 1).^2-4 Based on our research and clinical experience, we offer recommendations to help you manage depression in patients with PCOS.

CHRONIC DEPRESSION WITH AMENORRHEA

Ms. K, age 30, presented for psychiatric evaluation of treatment-resistant recurrent major depression. Her symptoms included sad mood, sleep disturbance, decreased energy, anhedonia, poor concentration, and feelings of guilt and worthlessness. Her score of 28 on the Hamilton Rating Scale for Depression (HAM-D-21) indicated severe depression.

Box 1

Depression often accompanies PCOS

Polycystic ovary syndrome (PCOS) is the most common cause of menstrual disturbance in women of reproductive age, affecting approximately 5% of U.S. women.¹ Clinically, it is the association of hyperandrogenism with chronic anovulation, without specific underlying adrenal or pituitary gland disease.²

PCOS has been shown to be associated with depression, though little research has been done in this area. We conducted a pilot study (the first, to our knowledge) to examine the rate of depression among women with documented PCOS and to correlate Center for Epidemiological Studies Depression Scale (CES-D) scores indicative of depression with clinical and biochemical markers of PCOS. We found an increased prevalence of depression in women with PCOS and an association between depression, insulin resistance, and body mass index. Specifically, among 32 women with documented PCOS,³ 16 (50%) had CES-D scores indicating depression.

This was Ms. K’s third episode of major depression, with the first two occurring at ages 24 and 26. She reported similar symptoms each time. Previous psychiatrists had tried a variety of antidepressants with no therapeutic benefit before she responded to citalopram, 40 mg/d, at age 27. With this selective serotonin reuptake inhibitor, her depressive symptoms resolved for >1 year, except for mild irritability and low mood the week before menses.

Her depressive symptoms returned, however, and her previous psychiatrist treated her for approximately 13 months with extended-release venlafaxine, 225 mg/d. When she remained depressed, she was referred to our clinic for evaluation. Based on her history, we could not determine whether she had become euthymic at age 27 or her symptoms had improved but still met criteria for a major depressive episode.

Ms. K reported having PCOS symptoms from age 19. These included amenorrhea since menarche, hirsutism, hair loss, alopecia, central fat distribution characteristic of PCOS, and male-pattern hair growth on her abdomen and thighs. She was not obese—with a body mass index (BMI) of approximately 25—but had gained 10 to 15 lbs while taking venlafaxine.

Ms. K had never been treated for PCOS but reported that her desire to become pregnant made her more concerned about her symptoms and possible infertility.

Diagnosis. PCOS is usually diagnosed using endocrinologic, clinical, and ultrasonographic criteria (Table 1). Obesity is not a presenting symptom in all women with PCOS. As with Ms. K, about 50% of patients have normal BMI.

Causes of depression in PCOS. Depressed mood in PCOS may be both physiologic and psychological:

Hypothalamic, pituitary, and other end-organ system dysregulation occurs in both PCOS and affective disorders, which share clinical and biochemical markers including insulin resistance, obesity, and hyperandrogenism.
PCOS’ clinical sequelae—hirsutism, acne, obesity, hormonal disturbances, fear of infertility, and psychological distress—may damage their self-esteem and female identity.

PCOS’ physical symptoms alone apparently do not account for patients’ worsened mood states. Weiner et al⁵ found that women with PCOS and free testosterone (FT) of 10 to 26 pg/mL (just above normal range) were more depressed than women without PCOS (FT <10 pg/mL) and women with PCOS and FT >26 pg/mL. Women with PCOS with the lower and higher FT levels had similar demographic profiles, but those with the highest FT levels were not the most depressed.

Similarly, in a study of 32 women with PCOS, we found no association between depression and other possibly distressing PCOS symptoms, including hirsutism, irregular menses, acne, or alopecia.⁴

Testosterone and mood disorders. Women such as Ms. K with hyperandrogenic syndromes are at increased risk for mood disorders.⁶ Many metabolic changes associated with PCOS—insulin resistance, obesity, and hyperandrogenism—are also described in patients with affective disorders. Our investigation of reproductive status in women with bipolar disorder found no clinical or biochemical evidence of PCOS with mood-stabilizer treatment. We did find that menstrual disturbances were common, however, and sometimes preceded bipolar disorder onset.⁷

Insulin resistance and depression. Others have linked insulin resistance and depression;⁸ depression has been shown to be associated with impaired insulin sensitivity and hyperinsulinemia.⁹ Depressed persons also tend to eat more sweets, drink more alcohol, exercise less, and sleep fewer hours than the nondepressed—all of which contribute to insulin sensitivity and insulin resistance.¹⁰