The primary purpose of this study is to determine whether empagliflozin, a medication in a class known as sodium-glucose cotransporter-2 inhibitors (SGLT2) inhibitors, may reduce symptoms of depression. Since this medication helps the body make metabolites known as ketone bodies which can serve as an alternate energy source for the brain, the investigators can also test whether ketone bodies help with depressed mood.

Inclusion Criteria:

• Provide written informed consent, as approved by the NYU Institutional Research Ethic Board (IRB).
• Patients ages 18-65;
• Current/acute Major Depressive Disorder (MDD) diagnosis, per MINI psychiatric interview;
• At least moderate severity of depression (Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 20 at initial screen);

Exclusion Criteria:

• DSM-5 diagnosis of Bipolar disorders, Cyclothymia, Schizoaffective disorder, Schizophrenia; any psychotic disorder or affective psychosis;
• Subjects that have had more than two failures of adequate anti-depressant trials in the current MDD episode;
• Subjects on psychotropic medications other than SSRIs, NDRIs, SNRIs, or mirtazapine (occasional use of sleep agents, equivalent to lorazepam 1 mg or zolpidem 10 mg, will be allowed);
• Those that have previously been on SGLT2 inhibitors;
• A significant history of non-adherence to treatments;
• History of neurologic / seizure disorder;
• A significant history of non-adherence to treatments;
• History of dementia/cognitive dysfunction (MOCA < 22);
• A primary diagnosis of a personality disorder, in the opinion of the screening clinician;
• DSM-5 substance use disorder (drug/alcohol) active within the past 12 months, or positive urine toxicology at screening;
• History of diabetic ketoacidosis;
• History of recurrent genital mycotic infection;
• GFR <45;
• HgA1c.>8.0%
• History of an allergic reaction to an SGLT2 inhibitor.
• Pregnancy or lactation (women of reproductive age, ie <50 years old, should be on licensed hormonal or barrier method contraception).
• Any known pancreatic disease resulting in insulin deficiency (T1D, history of pancreatitis, pancreatic surgery);
• History of liver or kidney disease;
• Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE.

The de-identified participant data from the final research dataset used in the published manuscript will be shared upon reasonable request beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research provided the investigator who proposes to use the data executes a data use agreement with NYU Langone Health. Requests may be directed to David.Liebers@nyulangone.org. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

The investigator who proposed to use the data will be granted access upon reasonable request. Requests should be directed to David.Liebers@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.