Evidence-Based Reviews

When not to treat depression in PCOS with antidepressants

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

References

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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

Table 1

Diagnostic signs of PCOS

Endocrine
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
Clinical
Hirsutism
Acne
Infertility
Anovulation or menstrual abnormalities amenorrhea oligomenorrhea dysfunctional uterine bleeding
Morphologic
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.

Box 2

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: