The glutamate system is emerging as target for the development of novel antidepressant medication, in particular compounds modulating the NMDA receptor. While the NMDA receptor antagonist ketamine is an effective option for many treatment-restistant patients, it is also accompanied by dissociative and cognitive effects and also bears the risk to develop addiction, side effects that are significantly restricting its clinical utility. There is now compelling evidence of the antidepressant potential of D-serine, a NMDAR co-agonist. Compared to ketamine, D-serine goes along without any psychotomimetic effects or other side effects and thus might be a prom-ising novel antidepressant.

This study represents the first randomized control trial to test the efficacy of D-serine as an adjuvant therapy in patients with depression and thereby adds to re-cent efforts to establish novel glutamatergic antidepressants. Besides clinical measures, this study also explores the biological mechanisms underlying D-serine's clinical effect.

Inclusion Criteria:

• Age 18-60
• Inpatients with a diagnosis of MDD with a current moderate-to-severe episode (HAM-D score > 16) (7)
• Treatment as usual (TAU) for depression. TAU for depression may include no treatment at all or standard pharmacotherapy (antidepressants and antipsychotics such as aripiprazole, risperidone or quetiapine) and / or psychotherapy.
• Able to read and understand study procedures and participant's information

Exclusion Criteria:

• Other primary psychiatric diagnoses than MDD such as substance use and psychotic disorders
• Serious suicide attempts
• Contradiction for MRI (no pacemaker, MRI incompatible metal implants or splinters in the body, past heart/head surgery, past stroke/brain injury, claustrophobia)
• Pregnant or lactating women (pregnancy test)