Immunopsychiatry: Golam Khandaker
Mental illnesses affect one in four people in the lifetime, but current treatments for depression and schizophrenia are ineffective for up to one in three people, highlighting the need for new and more targeted effective interventions. Accumulating evidence suggests that inflammation/immunity is a promising avenue for new mechanistic explanation and therapeutics development for depression and schizophrenia. However, the success of immunological treatment development requires optimal selection of treatment targets in future clinical trials based on evidence of causality and acceptable safety profile, and appropriate patient stratification informed by biology-based illness subtyping.
The Immunopsychiatry Programme investigates the role of inflammation (e.g., immune proteins, cells, genes) in depression, other psychiatric/neurodevelopmental disorders, and cognition using Mendelian randomization (MR) and other cutting-edge epidemiological and genetic methods applied to large-scale psychiatric, genomic, and immunological data. We are also interested in the role of inflammation in physical and psychiatric multimorbidity. The aim of this work is to identify immunological causal mechanisms for psychiatric disorders and to inform the development of future immunotherapy trials.
Aims and Objectives
1. Examining the causal role of inflammation: We use MR and population-based cohort studies to interrogate whether inflammatory cytokines and other immunological proteins/pathways play a causal role in depression, schizophrenia, and other psychiatric/neurodevelopmental disorders to identify immune-related mechanisms and optimal treatment targets for future trials.
2. Exploring the safety of immune modulation: We use MR to assess likely causal effects of immune proteins/pathways on various clinical and biomarker outcomes to understand potential safety of targeting immune pathways for therapeutic purpose and to identify biomarkers associated with immune modulation.
3. Understanding specificity vs commonality of effect of inflammation: We use genomic and other approaches to examine whether inflammation represents a shared mechanism for psychiatric/neurodevelopmental disorders, and to identify potential underlying causes of any shared effect.
4. Dissecting the role of inflammation in illness heterogeneity: We use data-driven approaches to identify and validate inflammation-related subgroups of depression, and to demonstrate clinical utility of these subgroups, to inform patient selection in future clinical trials.
1. Evidence of causality using population data: We have conducted some of the first population-based longitudinal studies (e.g., Khandaker et al. JAMA Psychiatry 2014) and genetic Mendelian randomization studies (e.g., Milaneschi et al. Molecular Psychiatry 2021; Perry et al. Brain Behav Immunity 2021) providing evidence indicative of a causal role for the inflammatory cytokine interleukin 6 (IL-6) in depression and schizophrenia.
2. Translation using proof-of-concept RCTs: In collaboration with the NIHR and NHS, we are conducting RCTs of tocilizumab (anti-inflammatory drug that inhibits IL-6 classical and trans-signalling by binding with the IL-6 receptor) in patients with depression (Insight study) and first episode psychosis (PIMS Trial) to further examine the causal role and therapeutic potential of IL-6 in depression and schizophrenia.