Depression is common and disabling. There are effective treatments for depression but around 30% of patients are not helped by existing treatments. Recent evidence suggests that these patients respond well to a new class of medication acting on the brain's glutamate system. For example, a low dose of the anaesthetic agent ketamine, which acts on the glutamate system, led to improvements in depression very quickly which lasted for up to a week. Ketamine itself is not an ideal treatment for depression since it is also a drug of abuse and has many side effects. There is therefore a huge need to develop similar drugs to ketamine, which work well in this subgroup of patients but without these unwanted effects. Potential new drugs exist but it is very time consuming and expensive to test all these drugs, at different doses, in full clinical trials. Experimental medicine models can help as they allow these drugs to be tested in smaller groups in the lab, exploring effects on key mechanisms of illness rather than less sensitive clinical ratings of mood. This is thought to provide more accurate information and help select the most promising treatments to take forward to full clinical trial testing. Data from rodent models suggests that drugs like ketamine may have distinct effects on the brain and behaviour. These involve effects on how rewarding information is handled and how emotional memories are retrieved and experienced. However, these mechanisms have not been tested in humans. We therefore plan to test the effects of ketamine on reward learning and emotional memory retrieval in humans. We will first characterise these effects in healthy people as this will allow us to identify core processes affected by ketamine and ascertain whether these actions are dose specific. We will then validate these mechanisms in depressed patients who have not responded to conventional treatments. We will assess learning about reward and punishment and the recall of established memories as well as the brain networks which underpin these effects. We think that ketamine will have effects on a network in the brain involving the lateral habenula, medial prefrontal cortex and hippocampus, which have been implicated in the ketamine studies using animals and which play a key role in learning, memory and emotion. These two studies will help develop a set of measures which can be used in future studies to select the most promising drug treatments for treatment resistant depression.