The goal of this observational study is to learn about the role of mitochondria in response to S-ketamine. in individuals with Treatment-Resistant Depression.

the Research Questions are

1. Does S-ketamine treatment modulate mitochondrial function in peripheral blood cells, as reflected by mitochondrial content and circulating mitochondrial biomarkers such as GDF15?
2. Can changes in mitochondrial function serve as biomarkers for predicting or monitoring clinical response to S-ketamine treatment?

Samples will be collected at baseline, 3 hours after the first treatment, and 6 weeks post-exposure, and compared between responders and non-responders

Inclusion Criteria:

Male or female, 18-65 years of age Diagnosis of Major Depressive Disorder according to the DSM-V Patient has a HAM-D≥23 Treatment resistant -Did not respond to two antidepressants trial Medically stable: No active physical disease: malignancy, cardiac condition, hypertension , stable medications for the past month etc.

Exclusion Criteria:

Known sensitivity to ketamine drug or alcohol abuse Patient taking lithium or corticosteroids Pregnant or breast-feeding has another axis I diagnosis attention deficits disorder a history or current serious neurological, metabolic autoimmune bone marrow, oncologic or additional psychiatric disorders

We will recruit ten normal controls, 30 Patients with the diagnosis of treatment-resistant depression (TRD), failed to at least two antidepressants