When not to treat depression in PCOS with antidepressants
Other medications may help women with hormone dysregulation and insulin resistance
- 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.
Table 2
Insulin-sensitizing medications used to treat PCOS
| Medication | Normal dosage | Common side effects |
| Metformin | 500 mg tid | Headache, GI effects (nausea, diarrhea, flatulence) at start of therapy, weight loss, taste disturbances |
| Pioglitazone | 15 to 45 mg once daily | Swelling, headache, respiratory infection, abdominal discomfort, muscle soreness |
| Rosiglitazone | 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.
TREATMENT RECOMMENDATIONS
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.
If your patient is not taking an antidepressant at presentation, try PCOS treatment first. If depressive symptoms persist after 3 months, consider adding an antidepressant. If your patient is taking an antidepressant at presentation but continues to be depressed, offer two options:
- taper off the antidepressant while starting PCOS treatment
- continue the antidepressant while starting PCOS treatment.
The first option allows you to try PCOS treatment alone. If the depression is caused by a common underlying pathophysiology—such as insulin resistance—treating PCOS alone may alleviate her depressive symptoms. Monitor for withdrawal symptoms, which may be minimized with a short-term SSRI, such as fluoxetine.
The second option may help patients who have responded to antidepressants in the past. Adjunctive PCOS treatment may “jump-start” the antidepressant response without withdrawal symptoms, but you will not be sure whether the antidepressant response was caused by PCOS therapy alone or the combination therapy.
Patient being treated for PCOS. Treat her with antidepressants, and consult with her endocrinologist to consider more-aggressive insulin-sensitizing medications, especially if she exhibits high levels of insulin resistance.
Other interventions that increase insulin sensitivity and improve glycemic control—such as improving dietary management and sleep habits, reducing alcohol consumption, and increasing physical activity—might have an antidepressant effect. Therefore, recommend these health practices to patients as adjuncts to drug therapies.
CASE: DEPRESSION IN REMISSION
At the 3-month follow-up visit, Ms. K scored zero on the HAM-D-21 scale. With metformin treatment, she had lost approximately 10 lbs and resumed menstruating approximately every 33 days. She reported experiencing low mood, decreased energy, and irritability during the week before her periods, but these symptoms resolved with menses onset.
Serum glucose was within normal range at 89 mg/dL, and serum insulin was 15.0 uIU/Ml. Her HOMA ratio had dropped to 2.8 (below the 3.2 cut-off for insulin resistance).
Ms. K’s endocrinologist monitored her spironolactone and metformin therapy for approximately 1 year, when she became pregnant.
Discussion. PCOS treatment duration depends on the patient’s response and her goals for therapy. Whether or not she continues PCOS treatment, her primary care physician or endocrinologist should continue to monitor her for insulin resistance’s metabolic consequences, including increased risk of type 2 diabetes and cardiovascular disease.
