The purpose of this study is to determine whether an oxytocin ad-on, or oxytocin and tibolone ad-on can induce a response to antidepressants in patients with treatment resistant depression.

We are examining the efficacy and safety of oxytocin or oxytocin and tibolone with an antidepressant (SSRIs) in treatment resistant depression in a double-blind randomized clinical trial.

A secondary objective is the evaluation of neurobiological factors contributing to drug efficacy in treatment resistant depression.

Inclusion Criteria:

• Women
• 18-45 years
• Current DSM-IV diagnosis of Major Depression
• Comorbid anxiety disorders secondary to depression will be included
• Past history of at least 2 failed treatment responses (including SSRIs) at the highest tolerated dose for at least 4-6 weeks
• A MADRS score >20 at randomization
• Women on a stable dose of an SSRI (sertraline, citalopram, escitalopram, paroxetine, fluoxetine or fluvoxamine) for at least 4-6 weeks.
• A negative pregnancy test at screening
• A clinically acceptable Pap smear within the past 2 years
• Must be able to use intranasal spray and swallow tablets

Patients may take up to 2 sleep medications permitted at a dose considered reasonable by the investigating team. Limited adjustments in sleep medication are acceptable. Patients will be asked to notify the researchers of any changes to their sleep medication.

Exclusion Criteria:

• Any previous history of adverse side-effects to escitalopram (or other SSRI)
• Use of oral contraceptives (or any hormonal method of contraception) for the duration of the study
• DSM-IV defined substance dependence, history of bipolar disorder, schizoaffective disorder or schizophrenia
• Significant unstable medical illness including epilepsy, diabetes or cardiac related, renal or liver disease, hormone dependent cancer or pregnancy
• A BMI<18 or > 34kg/m2
• Planning for pregnancy
• Renal disease, history of cerebrovascular disease, thrombo-embolic disorders, myocardial infarction or angina at any time before study entry or thrombo-phlebitis within the last 5 years, or any other major illness that has occurred within the last 6 months.
• An undiagnosed genital bleeding
• Moderate to severe acne or hirsutism, have used antiandrogen therapy for acne or hirsutism in the preceding 5 years, have androgenic alopecia ( will exclude women with clinically meaningful androgen excess)
• Active malignancy, or treatment for malignancy in the preceding 6 months (excluding non-melanotic skin cancer)
• Alcohol consumption in excess of 3 standard drinks per day
• Lactose intolerance
• An abnormal thyroid stimulating hormone (TSH) value at screening confirmed by a Free T4 outside the normal laboratory range (patients with an abnormal TSH, normal Free T4 and no clinical signs or symptoms of thyroid disease, with or without replacement treatment, may be admitted to the study).
• A history of allergic reactions to androgens (oral or patch)
• Chronic medications: aspirin and warfarin