HCR.20.021 – Pharmacotherapy responsivity in psychiatry. A cross-species approach towards prediction PREP-CAP

Route: Health care research, sickness prevention and treatment

Cluster question: 083 How do neurological, psychiatric, and mental disorders arise, and how can we prevent, mitigate, or cure them?

A core issue unresolved in psychiatry is prediction who will respond to what medication. This problem and resulting treatment-algorithms, high burden for patients and huge healthcare costs is exemplified by Unipolar (Major) Depressive Disorder (MDD). The efficacy of the slow-acting first-line monoaminergic treatment in MDD is at most moderate, with ~55% responders and <35% remitters after 2 antidepressant trials. This suggests that in a subset of MDD-patients monoaminergic treatment does not affect primary disease mechanisms, requiring alternative approaches. Recently, the rapid-acting glutamate (NMDA) receptor antagonist esketamine has been licensed in Europe for treatment resistant depression (TRD; i.e. non-responders to >=2 antidepressants). However, as this treatment will be extremely expensive, it is highly needed to predict who will respond to esketamine treatment and who will subsequently maintain this response/remission. We aim to translationally investigate mechanisms of esketamine response and (persistent) remission in TRD. An important target of esketamine is the lateral habenula, which is hyperactive in depression, negatively connected to reward-related brain-areas, and inhibited by esketamine treatment in animal models. We hypothesize that TRD-patients with a hyperactive habenula are most responsive to esketamine, and that remission relates to persistent disinhibition of reward areas and increased ability to make efforts to obtain reward. With advanced, standardized neuroimaging techniques, an effort-based behavioural learning task and computational modelling, we will predict response and the risk of depressive relapse/recurrence. With our translational approach, facilitating human-animal comparisons we aim to deepen understanding of changes in brain-networks and behavioural parameters at a neurochemical and molecular level. Our results provide new fundamental knowledge about mechanisms underlying TRD, substratification of MDD/TRD heterogeneity, working mechanisms and personalization of pharmacotherapy

Keywords

Esketamine, GABA, Habenula, Humans, Major Depressive Disorder, Neuroimaging, neuropsychology, Pharmacotherapy, prediction, Rats, Reward

Other organisations

Depressie Vereniging, Janssen-Cilag BV, Radboud Universiteit Nijmegen (RU), Trimbos Institute

Submitter

Organisation Radboudumc (RUMC)
Name Dr. H.G. (Eric) Ruhe
E-mail Eric.Ruhe@Radboudumc.nl
Website https://www.ru.nl/donders/research/theme-3-plasticity-memory/research-groups-theme-3/recurrence-treatment-resistance-unipolar/