Emerging Research in Psychosis: Can Antibodies Be Used as Biomarkers?

Effective biomarkers can allow for the early identification and prevention of disease, as well as measurement of treatment response.¹ Neuroimaging and blood-based biomarkers have received considerable attention within the field of psychiatry; however, neither has been able to differentiate psychotic disorders from other psychiatric diagnoses.²

Evidence supporting the role of immune dysfunction in the pathophysiology of psychiatric diseases, including psychotic disorders such as schizophrenia, has been mounting over the past several years.³ Even more specifically, antibodies have been gaining momentum as a possible biomarker.²

Antibodies as Diagnostic Biomarkers

To date, the diagnostic value of antibodies is limited to identification of secondary, or organic, psychotic disorders (eg, autoimmune encephalitis).² Measurement of neuronal autoantibodies seen in this disease may be incorporated into the initial assessment of a patient presenting with first-episode psychosis or acute relapse.² 

Drs Thomas Pollak and Jonathan Rogers, researchers from King’s College London and co-lead authors of a review recently published in Schizophrenia Bulletin,² further elaborated in an interview with Psychiatry Advisor on the value of studying antibodies in autoimmune encephalitis. 

“There is ongoing research aiming to determine whether these same antineuronal antibodies that cause encephalitis may have prognostic potential in a wider group of patients with psychosis but without the characteristic hallmarks of autoimmune encephalitis,” they said.  

The most significant impact of antibodies on psychiatric diagnostic testing has been in pediatric medicine, namely for pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).²  Both disease types may be characterized by the presence of antibodies against the basal ganglia, dopamine receptors, enolase, β-tubulin, and lysogangliosides.²

A positive antibody test may also have utility in diagnosing systemic diseases that present with psychosis, such as systemic lupus erythematosus, antiphospholipid syndrome, or neurosyphilis.² The antibodies may be used as biomarkers of diseases included in the differential for cause of psychosis; however, the antibodies generally are not specific to psychosis.   

Antibodies as Prognostic Biomarkers

The goal of prognostic biomarkers is to predict a disease’s trajectory.¹ Prognostication is difficult but valuable for patients with psychotic disorders.

“A fundamental challenge in the management of patients with psychosis is that the course of the disorder is remarkably heterogeneous,” Drs Pollak and Rogers wrote.  “These different types of patients require very different types and levels of clinical care.”

One approach has been to study biomarkers of domains that are known to be impaired in psychotic disease and whose dysfunction may be predictive of outcome, such as cognition. Cognition is an especially salient target of investigation given that these deficits are oftentimes refractory to pharmacologic intervention. Antibodies to herpes simplex virus type 1, cytomegalovirus, and toxoplasma may be associated with cognitive deficits in psychosis.²

Infective antibodies may also serve as prognostic indicators even when unrelated to cognition. For example, mortality in schizophrenia may be marked by antibodies to herpes simplex virus type 1, toxoplasma, and Epstein-Barr virus, and suicidality may be marked by antibodies to cytomegalovirus and toxoplasma. The caveat to using positive infective antibody tests to inform management is the high seroprevalence of these antibodies; however, confounding is likely.²  

“Thomas Pollak and other members of our group are involved in examining the role of neuronal antibodies and antibodies to infectious pathogens in predicting outcomes in individuals who are at high clinical risk of developing psychosis,” Dr Rogers told Psychiatry Advisor. “If these antibodies can help us identify, before the disease has developed, who is likely to have the poorest prognosis, we can focus our efforts on these individuals in terms of early interventions.”

Antibodies as Theranostic Biomarkers

Theranostic biomarkers may be used to predict treatment response.  Recent research has pointed to neuronal autoantibodies as possible predictive biomarkers.  Michael Zandi, PhD, from the University College London, and colleagues published a case series report in Schizophrenia Research suggesting that N-methyl-D-aspartate receptors (NMDAR) could predict response to varying combinations of corticosteroids, plasmapheresis, intravenous immunoglobulin, mycophenolate mofetil, and rituximab.⁴

“One of the most important studies being undertaken in this area is the SINAPPS2 trial [ClinicalTrials.gov Identifier: NCT0319485]…a phase 2 clinical trial investigating immunotherapy against placebo for individuals with psychosis and antineuronal antibodies,” Drs Pollak and Rogers explained to Psychiatry Advisor. SINAPPS, or Study of Immunology in Antibody Positive Psychosis, is being led by Belinda Lennox, MD, from Oxford University.⁵

Note that NMDAR antibodies disrupt glutamatergic signaling.  Patients with psychosis driven by glutamatergic pathology (vs dopaminergic pathology) may be nonresponsive to antipsychotic medications, which target dopaminergic signaling, and an alternative option may be warranted (eg, immunotherapy).   Further research is therefore needed.²

Future Directions

Drs Pollak and Rogers shared multiple insights with Psychiatry Advisor regarding future avenues of research. “In recent years, psychiatric genetics has undergone a revolution in changing from a ‘top-down’ hypothesis-driven model to a ‘bottom-up’ atheoretical approach, using high-throughput approaches that are agnostic  as to the relevance of any one gene,” they explained. “It may be that the same approach is required in searching for relevant antibodies in the prediction and prognostication of psychosis.”

“Future work examining the longitudinal relevance of antibodies would be helpful, as most studies to date have been merely cross-sectional,” they added. “Knowing how antibody levels go up and down with symptoms may offer us insights into mechanisms of disease but may also provide a useful way to track disease activity.”

References

1. Biomarkers Definition Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Therapeutics.  2001;69:89-95.
2. Pollak TA, Rogers JP, Nagele RG, et al. Antibodies in the diagnosis, prognosis, and prediction of psychotic disorders [published online February 21, 2018]. Schizophr Bull.  doi.org/10.1093/schbul/sby021
3. Altmann DM. Neuroimmunology and neuroinflammation in autoimmune, neurodegenerative and psychiatric disease. Immunology. 2018;154(2):167-168. 
4. Zandi MS, Deakin JB, Morris K, et al. Immunotherapy for patients with acute psychosis and serum N-methyl D-aspartate receptor (NMDAR) antibodies: a description of a treated case series. Schizophr Res.  2014;160(1-3):193-5. 
5. Study of Immunotherapy in Autoantibody Positive Psychosis. http://sinapps.org.uk.  Accessed June 2, 2018.