Novel blood markers in psychosis

Psychotic disorders such as schizophrenia maintain a 1% point prevalence in society at large. They cause much suffering to the patients and exact grave costs on society. There is an urgent need for better diagnosis and treatment of psychotic disorders. Patients with psychotic disorders are primarily treated for deteriorating psychiatric symptoms and often somatic comorbidities are overlooked. Accelerated ageing and metabolic comorbidities such as adiposity, diabetes and cardiovascular disease are common in psychosis patients, with often 15-20 years shortened life expectancy. The main pathophysiological elements of psychotic disorders and schizophrenia remain elusive. There is increasing evidence to suggest that psychotic disorders such as schizophrenia are in fact a group of related disorders advocating a more individualized evidence-based treatment than that currently available. Biomarkers are by definition useful tools for describing individual patient centered disease states or selecting treatment approaches.

The main aim of this thesis was to investigate putative blood biomarkers which describe the previously reported ongoing pathological processes inflammation, mitochondrial dysfunction and metabolic disturbances. In paper I we assessed, mitochondrial DNA (mtDNA), a proxy for mitochondrial dysfunction in patients of psychotic disorder. We additionally investigated the effect of anti-psychotic drug treatment on the mtDNA copy number of neuro-epithelial stem cell derived human neurons. In paper II and III, we explored plasma levels of GDF-15, an anti-inflammation marker gaining traction in the field of cardiovascular disease, in the context of psychotic disorders. In paper IV we report the initial findings of a larger study of inflammation in first episode psychosis (FEP) patients recruited for exercise intervention. We investigated a pre-selected group of cytokines, ligands and receptors in patients with FEP.

The major findings from this thesis work includes 1) We were the first to report elevated plasma GDF-15 levels in patients with psychotic disorders compared to healthy age and gender matched controls. 2) We detected that GDF-15 robustly associated with aging and levels of established analyte biomarkers for cardiovascular disease, while not with the acute inflammation marker C-reactive protein. 3) Treatment with clozapine and risperidone was associated with a depletion of whole blood and neuronal mtDNA. 4) In those not treated with clozapine or risperidone, the mtDNA copy number was reduced with age and with more severe psychosis. 5) Most FEP patients, 70%, had markedly elevated plasma fractalkine levels, while the rest had low healthy control levels, reflecting an on/off pattern. FEP patients could be divided into four immunologically distinct groups categorized by how fractalkine levels changed over 12 weeks physical exercise. One group likely represents patients with milder psychosis. The present thesis provides findings from pre-clinical and basic research with a potential to support the development of better clinical therapy for patients of psychotic disorders.

List of scientific papers

I. Kumar P, Efstathopoulos P, Millischer V, Olsson E, Bin Wei Y, Brüstle O, Schalling M, Villaescusa JC, Ösby U, Lavebratt C. Mitochondrial DNA copy number is associated with psychosis severity and anti-psychotic treatment. Scientific Reports. 2018 August Vol. 8, Article no. 12743.
https://doi.org/10.1038/s41598-018-31122-0

II. Kumar P, Millischer V, Villaescusa JC, Nilsson IAK, Östenson CG, Schalling M, Ösby U, Lavebratt C. Plasma GDF15 level is elevated in psychosis and inversely correlated with severity. Scientific Reports. 2017 August Vol. 7, Article no. 7906.
https://doi.org/10.1038/s41598-017-07503-2

III. Kumar P, Olsson E, Forsberg S, Hukic DS, Westman J, Schalling M, Edman G, Eriksson SV, Ösby U, Lavebratt C. Cardiac biomarkers for patients with psychotic disorder in Sweden. [Manuscript]

IV. Kumar P, Lambden B, Yacaman-Mendez D, Ekblom Ö, Skott M, Fogdell Hahn A, Forsell Y, and Lavebratt C. Elevated plasma Fractalkine levels in first episode psychosis patients is normalized by exercise intervention. [Manuscript]