This study aims to openly test the long-term safety, tolerability and effectiveness of repeated administration of IM/SC ketamine for treatment resistant MDD.

Major depression disorder (MDD) is a common psychiatric disorders with considerable impact on patients' quality of life, social and occupational function. MDD also significantly increase suicide rate. About a third of the patients with MDD suffer from moderate to severe symptoms that are fully or partially unresponsive to accepted pharmaco and / or psycho therapy. Ketamine is a widely used anesthetic. Multiple studies done over the recent years had shown its therapeutic effects in resistant depressive patients. Unlike regular antidepressants, ketamine exerts its effect within hours to few days which implies an alternative mechanism of action not fully studied. So far, there are only few reports on using repeated ketamine administration to maintain the antidepressant effect or on intra-muscular or sub-cutaneous application that can be safer and more tolerable than the intravenous route.

In the present study, the investigators aim to openly assess the safety, tolerability and effectiveness of repeated, individually tailored IM or SC ketamine for treatment resistant major depression. The investigators intend to explore questions regarding optimal dose, treatment frequency and duration. The investigators will also assess potential cognitive effects of long-term ketamine treatment and look for possible treatment outcome predictors using the Neurotrax computerized cognitive battery.

Inclusion Criteria:

• Diagnosed with unipolar/bipolar depression with MADRS Score>= 20
• Inadequate response to >= 3 adequate treatment trials [>=2 trials in the present episode]
• If on psychopharmacological Tx, it should be stable since 4 weeks prior to enrollment
• QTc WNL

Exclusion Criteria:

• Hypersensitivity to ketamine
• Other major psychiatric diagnosis
• High suicidality
• Unstable physical illness
• S/P CVA / brain SOL
• Pregnant or breast feeding women
• Illicit drug/alcohol abuse during last year
• History of ketamine abuse