MICA: An experimental medicine model for fast acting antidepressant drug treatment in treatment resistant depression

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.

30% of depressed patients do not respond to conventional antidepressant treatments. However, recent evidence suggests that the NMDA antagonist ketamine can be effective in treatment resistant depression (TRD) with a fast onset of action. Preclinical animal models suggest distinct mechanisms underpinning these clinical effects. First, ketamine has been found to rapidly reduce burst firing of neurones in the lateral habenula (LHb) in rodents, a core site for learning about reward and punishment. Second, behavioural models of emotional memory suggest that while conventional antidepressants affect how new information is processed, ketamine reduces the retrieval of established negative memories. However, these distinct neuropsychological mechanisms have not been tested in humans. A new wave of drug candidates targeting the glutamate system is in development yet there is no current way of screening and selecting the best of these treatments. The current project will use a translational approach to develop an experimental medicine model for fast acting antidepressant drug activity: In study one, healthy volunteers will be randomised to receive one of two doses of ketamine (0.5mg/kg, 0.1 mg/kg) or placebo in a double blind design. The day after dosing, reward and punishment learning (with optimised 7T fMRI scanning) will be assessed using a task robustly associated with LHb function in human participants. Emotional (vs neutral) memory retrieval and consolidation will be assessed using an autobiographical memory task and a prior self-referent encoding task. In study 2, we will test the translation of these effects to patients with TRD, randomised to ketamine compared to placebo. This approach will identify core neurocognitive mechanisms involved in response to fast acting antidepressants in humans, which can be used for target development and screening of novel compounds, achieved via our collaboration with Janssen.

Depression is a leading cause of disability worldwide, and a major contributor to the overall global burden of disease. Current treatments are limited in terms of efficacy, particularly in patients who fail to respond to first line approaches, so called 'treatment resistant depression' (TRD). Acute administration of the NMDA antagonist ketamine has been found to have remarkable effects in this subgroup of patients, yet remains a difficult to use treatment. New agents targeting the NMDA receptor, or other components of the glutamate system, are in development for the treatment of depression but past experience suggests that around 90% of these new compounds will fail during clinical development, largely because of problems with efficacy. We need a way of selecting the most promising subset of candidate treatments to take forward to time and cost intensive phases of clinical testing as it is impossible to test all possible compounds. Dose selection is also often based on maximal tolerated dose but functional measures may be preferable given the inverted U shaped dose response curve of many medicines in this field. An experimental medicine model focused on fast acting agents can help with this process; by providing information about likely success, best dose and target patient groups.

The present study aims to characterise the mechanisms underpinning the effects of the fast acting antidepressant agents in healthy volunteers and in patients with TRD.

Therefore the beneficiaries of this research are those developing novel treatments for depression, including the pharmaceutical Industry and academic groups. This group will benefit from the ability to make mechanistic predictions about the value of different treatment approaches as well as selecting the most promising compounds to take forward into randomised clinical trials. The difficult in predicting the likely efficacy of drugs for mental health has contributed to the reduction in interest in developing compounds for this important area. As such promising results may invigorate the field and stimulate more companies to develop portfolios in this area.

The ultimate beneficiaries are the patients with depression and their families. In addition, because people with TRD are often unable to work, treatments which facilitate recovery will produce a substantial economic benefit to the UK as a whole.

Because of the lack of effective treatments, clinicians often find the management of TRD difficult; accordingly the availability of new treatments will be of great value to professionals striving to help their TRD patients.