The purpose of the study is to determine whether adding a low dose of testosterone to current antidepressant therapy improves depression and fatigue in women who remain depressed despite necessary adequate doses of anti-depressants. Testosterone will be given over an 8-week period.

Testosterone is a hormone that occurs naturally in the body. In women it comes from the ovaries and adrenal glands and is found in amounts that are ten to twenty times lower than in men.

In early research studies, testosterone has been shown to have some antidepressant effects in the following groups of subjects:

• Women with anorexia nervosa
• Women who have low testosterone levels because their pituitary glands do not work
• Men with Selective Serotonin Reuptake Inhibitor (SSRI)-resistant depression.

However, testosterone administration in women with SSRI or Serotonin-norepinephrine reuptake inhibitor (SNRI) -resistant depression has not been studied.

Inclusion Criteria:

• Female, age 18-75
• Written informed consent
• Meet Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria (by Structured Clinical Interview for DSM-IV (SCID)) for Major Depressive Disorder
• Meet DSM-IV criteria for a current major depressive episode, as assessed by SCID
• Montgomery-Asberg Depression Rating Scale (MADRS) greater than or equal to 16 at baseline visit
• Currently treated with SSRI or SNRI, with or without adjunctive therapy, at an adequate dose (see adequate dose table below) for at least six weeks

Exclusion Criteria:

• Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (to include oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy)
• Serious suicide or homicide risk, as assessed by evaluating clinician
• Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic (including uncontrolled seizure disorder)
• Substance use disorder active within last six months
• Psychotic features (current episode or lifetime), as assessed by SCID
• Laboratory evidence of untreated hypothyroidism
• If treated hypothyroidism, significant change in levo-thyroxine dose within the prior three months
• If receiving oral estrogen therapy, including oral contraceptives or transdermal estrogen therapy, significant change in dose in the prior three months
• Use of androgens or androgen precursors, including testosterone, Dehydroepiandrosterone (DHEA) and methyltestosterone, within the prior three months
• Any investigational psychotropic drug within the last two weeks
• In the judgment of the study clinician, unlikely to be able to participate safely throughout the study period (three or more episodes of self-harm in the past year, documented history of poor treatment adherence, or frequent missed appointments (greater than 50%) in the past year)
• Alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal.
• Creatinine greater than 1.5 times upper limit of normal
• History of a hormone-responsive cancer
• History of congestive heart failure
• MADRS greater than 31

8-weeks