Immune mechanisms in psychosis and antipsychotic treatment resistance

A PhD project for the 2022 doctoral clinical fellows programme with Katharina Schmack (primary supervisor, Crick) and James MacCabe (King’s College London).

Project description

James MacCabe

Professor of Epidemiology and Therapeutics, King’s College London

Psychotic disorders are devastating conditions that affect approximately 1% of the population in their lifetime. The biological mechanisms underlying psychosis are currently not well understood.

A variety of genetic and environmental factors point to an overactive immune system: psychotic disorders are associated with variants in immune-related genes, early-life infections, autoimmune disorders and increased pro-inflammatory cytokines. An overactive immune system might also underlie resistance to antipsychotic treatment, as indicated by increased low-level inflammation in patients with treatment-resistant schizophrenia (1). In line with this, immunomodulatory effects have been demonstrated for clozapine, the antipsychotic drug with unique efficacy in treatment-resistant schizophrenia. Clozapine treatment is associated with increased susceptibility to infections such as pneumonia (2) and COVID-19 (3). Clozapine treatment is also associated with an initial immune activation response followed by a reduction in immunoglobulins (4), and this effect may be predictive of treatment response. This suggests that treatment resistant psychosis might be mediated by an immune process directed at the brain, and this immune process might be modulated by clozapine.

This project will be concerned with the mechanisms by which the immune system and the brain interact in treatment resistant psychosis. Using transcriptomic-proteomic profiling and auto-antibody screening, we will test which immune signals are altered in the blood and cerebrospinal fluid of treatment-resistant schizophrenia patients. We will compare patients before and after clozapine initiation to identify immune alterations that relate to clinical response. We will then probe in mice how the identified alterations can lead to psychosis-like behaviour, and how clozapine treatment can reverse such immune-mediated psychosis-like behaviour. To measure psychosis-like behaviour, we will use established behavioural assays as well as our recently developed approach for measuring hallucination-like perception in mice (5). Our cross-species approach allows us to move back and forth between our mouse model and patients to elucidate the role of brain-directed immunity in psychosis. Ultimately, this will enable the development of novel immune-related treatment targets for psychotic disorders. 

The candidate will join the recently established Schmack lab operating at the intersection of neuroscience, immunology and psychiatry. There will be ample opportunities for hands-on-supervision, as required. Clinical context and access to patient samples will be provided through co-supervision through Prof MacCabe at King’s College London. The MacCabe lab is situated at the largest psychosis research centre in the world, and leads the UK in clinical research on treatment-resistant psychosis. The project proposed here will be further developed in discussions with the supervisors. Candidates are also welcome to discuss ideas for projects related to the project proposed here, dependent upon the candidate’s interests and background.

The partner institution for this project is King’s College London.

References

  1. Fond G, Godin O, Boyer L, Berna F, Andrianarisoa M, Coulon N, Brunel L, Bulzacka E, Aouizerate B, Capdevielle D, Chereau I, D’Amato T, Dubertret C, Dubreucq J, Faget C, Leignier S, Lançon C, Mallet J, Misdrahi D, Passerieux C, Rey R, Schandrin A, Urbach M, Vidailhet P, Llorca PM, Schürhoff F, Leboyer M, FACE-SZ FACOEFSG. Chronic low-grade peripheral inflammation is associated with ultra resistant schizophrenia. Results from the FACE-SZ cohort. Eur Arch Psychiatry Clin Neurosci. 2019;269:985-992.)
  2. De Leon J, Sanz EJ, De Las Cuevas C. Data from the World Health Organization’s Pharmacovigilance Database Supports the Prominent Role of Pneumonia in Mortality Associated with Clozapine Adverse Drug Reactions. Schizophr Bull. 2020;46(1):1–3.
  3. Govind R, Fonseca de Freitas D, Pritchard M, Hayes RD, MacCabe JH. Clozapine treatment and risk of COVID-19 infection: retrospective cohort study. Br J Psychiatry. Published online July 27, 2020:1-7. doi:10.1192/bjp.2020.151
  4. Ponsford M, Castle D, Tahir T, et al. Clozapine is associated with secondary antibody deficiency. Br J Psychiatry. Published online September 27, 2018:1-7. doi:10.1192/bjp.2018.152
  5. Schmack K, Bosc M, Ott T, Sturgill JF, Kepecs A (2021). Striatal dopamine mediates hallucination-like perception in mice. Science, 372(6537), eabf4740