The relationship between depression and trauma is well established. Co-occuring depression and post-traumatic stress disorder (PTSD) are associated with more severe symptoms and lower levels of functioning. Veterans with both depression and PTSD have been shown to be at much higher risk of suicide than individuals with only one of these disorders. Ketamine has been shown to have rapid antidepressant effects and also therapeutic action over PTSD symptoms. The purpose of this study is to see whether ketamine, when given as repeated infusions, can produce quick and sustained improvement in depression and PTSD symptoms for individuals who have not had their symptoms effectively treated by current treatments.

The proposed study is a pilot study designed to determine the efficacy and safety of serial ketamine infusions among veterans with treatment-resistant depression (TRD) as well as chronic post-traumatic stress disorder (PTSD). The investigators hypothesize that six infusions of ketamine will be effective in decreasing severity of depressive symptoms and maintaining response.

Participants will be male/female veterans (18 to 75 years old) of any era or military background who suffer from TRD and chronic PTSD. Potential participants will be recruited from Mental Health clinics and screened for eligibility using a two stage process (phone/chart review, followed by interview). Participants will receive six ketamine infusions on a Monday-Wednesday-Friday schedule over 2 weeks. On the day of infusion, participants will be required to stay at the clinical site for 3 hours after the medication has been given. Follow-up visits will occur at different time points over the course of 2 months after the two week infusion period has been completed.

Inclusion Criteria:

• Male or female veterans aged 18 to 75 years.
• Participants must have a telephone in their home and ability to hear telephone conversations.
• Participants must meet current DSM-IV criteria for major depressive disorder (MDD), single or recurrent, without psychotic features
• Participants must meet DSM-5 criteria for current post-traumatic stress disorder (PTSD) and have received a diagnosis of PTSD greater than or equal to 3 months prior to assessment.
• Current major depressive episode resistant to treatment.
• If applicable, current antidepressant dosages including augmenting agents and/or frequency and duration of psychotherapy sessions must remain stable for at least 6 weeks prior to beginning of the study.

Exclusion Criteria:

• Inability to speak English
• Inability or unwillingness to provide written informed consent
• Moderate/severe cognitive impairment .
• Current or lifetime diagnosis of psychosis-related disorder, bipolar I or II disorder, substance-induced mood disorder, or any mood disorder due to a general medical condition.
• Current or lifetime diagnosis of a Cluster B disorder.
• History of moderate or severe traumatic brain injury, Parkinson's disease, dementia of any type, multiple sclerosis, seizures or other CNS related disorders.
• History of comorbid substance disorder within 6 months of screening as assessed using the Mini International Neuropsychiatric Interview (MINI), plus positive urine toxicology screen test during baseline assessments.
• Prior use of ketamine as an antidepressant.
• Clinically unstable medical illness that could compromise the patient's ability to tolerate or likely interfere with the study procedures (e.g., history of or current myocardial ischemia or arrhythmias, congestive heart failure, severe pulmonary, renal, or hepatic disease, uncontrolled hypertension)
• Current or within less than 14 days use of barbiturates or monoamine oxidase inhibitors (MAOI).
• History of antidepressant- or substance-induced hypomania.
• History of first degree relative(s) with an Axis I psychotic disorder.
• For women: pregnancy (confirmed by baseline lab test), the initiation of female hormonal treatments within 3 months of screening, or inability or unwillingness to use a medically accepted contraceptive method for the duration of the study.
• Imminent risk of suicidal/homicidal ideation and/or behavior with intent and/or plan.