Questions regarding the exact molecular mechanisms of ketamine and its effects on the brain circuitry and networks for the treatment of clinical depression remain largely unanswered. Thus, in the present study the investigators aim to elucidate the effect of ketamine on 1) reconsolidation of autobiographical memories, 2) connectivity of brain circuits involved in autobiographical memories, 3) measures of emotional processing, reward processing and emotional memory in patients suffering from treatment resistant depression. The ultimate goal of this project is to elucidate the antidepressant mechanisms of action of ketamine to facilitate the development of rapid acting antidepressants targeting the glutamatergic system.
Clinical depression often includes a pessimistic view of things which have happened in the past and an impairment in the ability to experience pleasure or looking forward to things. A licensed drug called ketamine affects the levels of glutamate, a chemical messenger in the brain, and has been used as a treatment particularly for depression which hasn't got better with other types of medication. Glutamate plays a role in learning and memory so the investigators are interested in understanding how ketamine can affect how people with depression remember past negative and positive memories and how they experience reward.~The investigators are conducting a study in depressed participants who did not improve with the standard antidepressant treatment to expand our understanding on how ketamine can influence memory, the way people understand emotions and learn from rewards and punishments. Study participants will undergo medical and psychiatric health screening, drug administration (ketamine or saline), questionnaires and computer tasks before and after the administration of the study drug, and an MRI scan after administration of the drug. MRI is a type of brain scan that allows us to see how the brain responds during for example memories of things which have happened in the past. This project will help us understand how NMDA antagonists may work in depression.