To determine if augmentation with the oral-contraceptive pill containing drospirenone and ethinyl estradiol is more effective than placebo in the treatment of premenstrual breakthrough of depression.

Inclusion criteria

1. Women who are non-smokers between the ages of 18-45 years (smokers 18-34 years);
2. Regular menstrual cycles (26-34 days in length, predictable within 7 days) for the past 6 months;
3. Determination that the antidepressant medication was initiated for the treatment of unipolar major depression, minor depression (depression, not otherwise specified), or dysthymia. Major depression and dysthymia will be evaluated through administration of the Mini-International Neuropsychiatric Interview (MINI). Minor depression will be evaluated by administration of the Structured Clinical Interview for Diagnosis-IV(SCID)10 section J.3.
4. Use of an antidepressant for at least 3 months for treatment of a depressive disorder, with stable dose for at least 2 months. It is acceptable to be on more than one psychiatric medication as long as one of them is an antidepressant.
5. Expected continued use of the same antidepressant at the same dose for the duration of the study;
6. 30% increase of the mid-follicular phase Montgomery-Åsberg Depression Rating Scale (MADRS) score to the late-luteal phase MADRS will be required for eligibility during the tracking phase of the study and will be assessed prospectively over 1 menstrual cycle.
7. Normal pelvic exam and PAP smear in the past 12 months;
8. Normal TSH at screen - if on thyroid medication, must be on a stable dose for 2 months or greater, and have a normal TSH at screen;
9. Negative serum HCG at baseline, and negative urine HCG at visits 3 and 5;
10. Normal potassium (K) levels at screen;
11. Willingness to use barrier contraceptive methods during the study, if sexually active;
12. Good general health.

Exclusion Criteria:

1. Amenorrhea or irregular menstrual periods (defined as unable to predict within 7 days) during past 6 months

2. Pregnancy or breastfeeding (serum HCG test administered at baseline study visit, and urine HCG at visits 3 and 5)

3. Current cigarette smoking in women who are older than 34 years

4. Presence of any of the following psychiatric and substance use disorders, based on administration of the MINI at the baseline study visit:

   Any history of mania or hypomania suggesting bipolar disorder Any lifetime history of a psychotic disorder

5. Depression deemed by the physician investigator to be too severe to be treated in the study

6. Use of benzodiazepines or antipsychotic to target premenstrual symptoms

7. Luteal-phase dose adjustment of the antidepressant. Use of a hormone releasing IUD (intrauterine device)

8. Use of an OCP or other systemic hormonal therapies (oral, transdermal or injection preparations of androgens, estrogens, or progestins) in the past 2 months;

9. Any contraindication or previous adverse event to any OCP therapy;

10. Current use of ketoconazole, rifampin, carbamazepine, topiramate, oxcarbazepine, modafinil, phenytoin, or phenobarbital (because of interaction with hormonal therapy).

11. Current use of potassium-sparing agents, such as potassium-sparing diuretics (e.g., spironolactone), ACE inhibitors, angiotensin-II receptor antagonists, heparin, aldosterone antagonists, NSAIDS, potassium sparing diuretics or potassium-supplements (because of risk of developing arrhythmia with two potassium-elevating agents).

12. Hepatic dysfunction, renal insufficiency, pulmonary, adrenal, or metabolic diseases (including elevated serum potassium levels, if known) that may put subject at risk when treated with study medication.