When not to treat depression in PCOS with antidepressants
Other medications may help women with hormone dysregulation and insulin resistance
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.
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
WHAT LINKS ENDOCRINE, MOOD DISORDERS?
Insulin and serotonin. Insulin affects central serotonin (5-HT) levels.11 Thus, central 5-HT system dysregulation that causes depression might also affect peripheral insulin sensitivity—or vice versa.9
Tryptophan, a serotonin precursor, competes with other large neutral amino acids for access to the transport system that moves them across the blood-brain barrier. Insulin stimulates uptake of the competing amino acids—but not tryptophan—into muscle tissue. The resulting increased tryptophan ratio in plasma affords it greater access to the transport system to contribute toward serotonin synthesis. Insulin also promotes central catecholaminergic activity, perhaps by suppressing norepinephrine reuptake and prolonging its residence in the synaptic cleft.10
Diagnostic signs of PCOS
Chronically elevated plasma free and total testosterone levels
Increased luteinizing hormone (LH) secretion because of enhanced pituitary sensitivity to GnRH stimulation
Low or normal plasma follicle-stimulating hormone (FSH) levels
Hyperinsulinemia and peripheral insulin resistance
Metabolic abnormalities of hyperinsulinemia and peripheral insulin resistance, including obesity and increased susceptibility to type 2 diabetes and cardiovascular disease
Anovulation or menstrual abnormalities
Ovaries may appear to have multiple cysts 8 to 10 mm in diameter
Several studies have found that insulin resistance and hyperinsulinemia can resolve after depression recovery.9,12 Because insulin resistance is a cardinal feature in PCOS pathophysiology,2 insulin resistance may be a common link between depression and PCOS.
Weight gain and obesity also have been described in patients with affective disorders.13 Not known is whether the weight gain precedes the psychopathology or is caused by long-term exposure to drugs used to treat affective disorders.
Hormonal treatments with possible antidepressant effects in PCOS
CRH antagonists. Corticotropin-releasing hormone (CRH) receptor antagonists have been suggested as possible antidepressants.26 Depression and anxiety scores have declined during treatment with the cortisol synthesis inhibitors metyrapone27 and ketoconazole.28,29 These trials do not reveal whether these agents treat depression symptoms—rather than the underlying pathophysiology—or if the affective disorder will recur after long-term administration.26
GR antagonists. Glucocorticoid receptor (GR) antagonists such as mifepristone (RU-486) have been suggested as antidepressants in depressed patients with elevated basal cortisol levels.30 Mifepristone may be useful for treating psychotic depression, in which the HPA axis is particularly hyperactive.31 Mifepristone is contraindicated in most women with PCOS, however, as its progesterone antagonism would lead to infertility—already a common problem for women with PCOS.
MR antagonists. Spironolactone, a mineralocorticoid receptor (MR) antagonist, decreases insulin resistance and fasting insulin levels in PCOS patients.25 We propose that insulin resistance may provide a common link in the pathophysiology of PCOS and depression. Therefore, treatment with insulin resistance-lowering medications such as spironolactone may induce antidepressant effects in women with depression and PCOS.
We reported a correlation between depression and BMI in women with PCOS.4 Depression might be independently associated with BMI, as weight gain and obesity are distressing symptoms associated with depression.14 However, we found no association between depression and other possibly distressing PCOS symptoms. Thus, the correlation between BMI and depression might more likely reflect the relationship between depression and insulin resistance, as degree of insulin resistance is known to correlate with BMI.
Elevated cortisol. Clearly, other factors—such as hypothalamus-pituitary-adrenal (HPA) axis dysfunction—are known to link affective and endocrine disorders. Hypercortisolemia can lead to both insulin resistance and obesity. Cortisol is one of the glucocorticoids the body secretes in response to stress to mobilize energy by increasing blood glucose levels. Early life stress and chronic emotional stress:
- can impair the negative feedback system that limits cortisol production during stress
- are associated with depression.
Approximately one-half of individuals with depression have elevated serum cortisol.10 Epidemiologic data show a positive correlation between cortisol levels and insulin resistance,15 and an association between HPA dysfunction and obesity has been described.16 Insulin can trigger androgen production by enhancing adrenal sensitivity to adrenocorticotrophic hormone (ACTH).17
CASE: IMPROVING INSULIN RESISTANCE
We referred Ms. K to an endocrinologist for PCOS evaluation and treatment. Her serum glucose and insulin levels were 83 mg/dL (normal range 70 to 125 mg/dL) and 19.0 uIU/mL (normal range <10 uIU/mL), respectively. These values indicated insulin resistance as determined by the homeostasis model assessment (HOMA) ratio (fasting insulin x fasting glucose/22.5). Values >3.2 indicate insulin resistance, and Ms. K had a HOMA ratio of 3.9. The endocrinologist recommended:
- metformin, starting at 850 mg/d and gradually increased to 2,550 mg/d
- spironolactone, 100 mg/d.
Metformin, a biguanide approved for treating for type 2 diabetes, inhibits hepatic glucose production and increases peripheral insulin sensitivity, but it does not modify pancreatic insulin secretion. It may decrease insulin resistance by reducing gut absorption of glucose, improving glucose uptake by tissues, and/or increasing the number of insulin receptors.18 In treating PCOS, metformin can:
- restore ovulation19
- decrease insulin resistance, acne, hirsutism, total and bioavailable testosterone, BMI, and waist-hip ratio.20,21
Although the link between insulin resistance and depression is unclear, insulin is known to contribute to 5-HT synthesis by promoting tryptophan influx into the brain.22 Therefore, drugs used to treat insulin resistance—such as metformin and alpha lipoic acid23—might be useful in treating depression.
Spironolactone, a mineralocorticoid receptor (MR) antagonist, reduces hirsutism in women with PCOS.24 It also can decrease insulin resistance and fasting insulin levels in PCOS patients and reduce serum testosterone.25
Evidence on treating mood disorders with hormonal agents such as spironolactone is scarce, although treatment-resistant depression has been reported to resolve with antiglucocorticoid use (Box 2).25-31 Modulating HPA axis activity to treat affective disorders has been investigated.
CASE: GOING ANTIDEPRESSANT-FREE
At first, Ms. K said she wanted to continue taking venlafaxine with the PCOS treatment. After 2 weeks of combined therapy, however, she chose to stop the antidepressant after her depressive symptoms persisted, and her HAM-D-21 score remained at 28.
During the next 4 weeks, as we tapered off the venlafaxine, Ms. K’s HAM-D-21 score dropped to 7, indicating depressive symptom resolution. Despite slow venlafaxine titration, withdrawal symptoms of excessive crying, not feeling “present,” and tingling sensations occurred. Three days of fluoxetine, 20 mg/d, alleviated these symptoms.
Insulin-sensitizing medications used to treat PCOS
Common side effects
500 mg tid
Headache, GI effects (nausea, diarrhea, flatulence) at start of therapy, weight loss, taste disturbances
15 to 45 mg once daily
Swelling, headache, respiratory infection, abdominal discomfort, muscle soreness
4 to 8 mg once daily
Headache, mild weight gain
We continued Ms. K’s treatment without antidepressants, and her mood continued to improve with metformin, 2,550 mg/d, and spironolactone, 100 mg/d.
PCOS therapy may take up to 6 months to resolve symptoms such as anovulation or hirsutism, but affective symptoms may improve during the first 6 weeks, as this case shows. Choosing medications to treat depression in patients such as Ms. K depends on whether their PCOS is being treated when they present for psychiatric evaluation.
Patient not being treated for PCOS. Refer her to an endocrinologist for PCOS treatment with an insulin-sensitizing medication, such as metformin (Table 2). Treating the insulin resistance associated with PCOS may also resolve the depression. PCOS drug therapy may also include antiandrogens such as spironolactone to treat hirsutism, male-pattern baldness, and acne. We suggest that spironolactone’s antiandrogen effects may help reduce depressive symptoms.