Biomarkers of a five-domain translational substrate for schizophrenia and schizoaffective psychosis

Abstract

Background: The Mental Health Biomarker Project (2010-2014) selected commercial biochemistry markers related to monoamine synthesis and metabolism and measures of visual and auditory processing performance. Within a case-control discovery design with exclusion criteria designed to produce a highly characterised sample, results from 67 independently DSM IV-R-diagnosed cases of schizophrenia and schizoaffective disorder were compared with those from 67 control participants selected from a local hospital, clinic and community catchment area. Participants underwent protocol-based diagnostic-checking, functional-rating, biological sample-collection for thirty candidate markers and sensory-processing assessment.

Results: Fifteen biomarkers were identified on ROC analysis. Using these biomarkers, odds ratios, adjusted for a case-control design, indicated that schizophrenia and schizoaffective disorder were highly associated with dichotic listening disorder, delayed visual processing, low visual span, delayed auditory speed of processing, low reverse digit span as a measure of auditory working memory and elevated levels of catecholamines. Other nutritional and biochemical biomarkers were identified as elevated hydroxyl pyrroline-2-one as a marker of oxidative stress, vitamin D, B6 and folate deficits with elevation of serum B12 and free serum copper to zinc ratio. When individual biomarkers were ranked by odds ratio and correlated with clinical severity, five functional domains of visual processing, auditory processing, oxidative stress, catecholamines and nutritional-biochemical variables were formed. When the strengths of their inter-domain relationships were predicted by Lowess (non-parametric) regression, predominant bidirectional relationships were found between visual processing and catecholamine domains. At a cellular level, the nutritional-biochemical domain exerted a pervasive influence on the auditory domain as well as on all other domains.

Conclusions: The findings of this biomarker research point towards a much-required advance in Psychiatry: quantification of some theoretically-understandable, translationally-informative, treatment-relevant underpinnings of serious mental illness. This evidence reveals schizophrenia and schizoaffective disorder in a somewhat different manner, as a conglomerate of several disorders many of which are not currently being assessed-for or treated in clinical settings. Currently available remediation techniques for these underlying conditions have potential to reduce treatment-resistance, relapse-prevention, cost burden and social stigma in these conditions. If replicated and validated in prospective trials, such findings will improve progress-monitoring and treatment-response for schizophrenia and schizoaffective disorder.

Keywords: Biomarkers; Mental illness; Noradrenaline; Psychosis; Schizophrenia; Sensory processing; Translational.

Figure 1

Cofactor vitamins and minerals in relationship to catecholamine biochemistry. DOPA – dihydroxyphenylalanine, BH4 - tetrahydrobiopterin BH2 – dihydrobiopterin, MTHFR- Methylenetetrahydrofolate reductase, MAT - Methionine adenosyltransferase, SAMe - S-Adenosylmethionine, MT - Methyltransferase, SAH- S-Adenosylhomocysteine, SAHH - S-Adenosylhomocysteine-hydrolase, CBS - Cystathione Beta Synthetase, BHMT - Betainehomocysteine methyltrasferase, DMG - Dimethylglycine, TMG - Trimethylglycine, MSR - Methionine sulphoxide reductase, MS - Methionine synthase, 5HIAA – 5-hydroxyondolacetic acid, HVA – homovanillic acid, MAO- monoamineoxidase., MHMA - 3-methoxy-4-hydroxymandelic acid = VMA-Vanillylmandelic acid, FAD - flavin adenine dinucleotide, MHPG -4-hydroxy-3-methoxyphenylglycol, DOPAL – dihydroxyphenylacetaldehyde, DOPAC - dihydroxyphenylacetic acid, DOPEGAL – dihydroxyphenylglycolaldehyde, DOMA – dihydroxymandelic acid DHPG – dihydroxyphenylglycal, COMT- catechol-o-methyl-transferase.

Figure 2

Percentage translational relationships of strength-ranked biomarkers for schizophrenia and schizoaffective disorder, where R ₂ = goodness of fit.

Figure 3

Translational cross-talk between biomarker domains.

Figure 4

Office assessment equipment.

Figure 5

Sensory speed of processing equipment.