Gene Variant Related Neurological and Molecular Biomarkers Predict Psychosis Progression, with Potential for Monitoring and Prevention

Abstract

The (MTHFR) C677T gene polymorphism is associated with neurological disorders and schizophrenia. Patients diagnosed with schizophrenia and schizoaffective disorder and controls (n 134) had data collected for risk factors, molecular and neuro-sensory variables, symptoms, and functional outcomes. Promising gene variant-related predictive biomarkers were identified for diagnosis by Receiver Operating Characteristics and for illness duration by linear regression. These were then analyzed using Spearman's correlation in relation to the duration of illness. Significant correlations were ranked by strength and plotted on graphs for each MTHFR C677T variant. Homozygous MTHFR 677 TT carriers displayed a mid-illness switch to depression, with suicidality and a late-phase shift from lower to higher methylation, with activated psychosis symptoms. MTHFR 677 CC variant carriers displayed significant premorbid correlates for family history, developmental disorder, learning disorder, and head injury. These findings align with those of low methylation, oxidative stress, multiple neuro-sensory processing deficits, and disability outcomes. Heterozygous MTHFR 677 CT carriers displayed multiple shifts in mood and methylation with multiple adverse outcomes. The graphically presented ranked biomarker correlates for illness duration allow a perspective of psychosis development across gene variants, with the potential for phase of illness monitoring and new therapeutic insights to prevent or delay psychosis and its adverse outcomes.

Keywords: MTHFR C677T; bipolar; disease progression; hostility; methylation; prognosis; risk prediction; schizophrenia; sensory processing; suicide; treatment resistance.

Figure 1

Methylation-related biochemical pathways. INTERMEDIATE SUBSTANCES: SAMe—S-adenosylmethionine, SAH—S-adenosylhomocysteine, MHMA—3-methoxy-4-hydroxymandelic acid, HVA—homo vanillic acid, MHPG—4-hydroxy-3-methoxyphenylglycol, VMA—Vanillylmandelic acid, GSH—Glutathione (reduced, active antioxidant form), GSSH—Glutathione (oxidized form). ENZYMES: MTHFR—Methylenetetrahydrofolate reductase, BHMT—Betaine homocysteine methyltransferase, CBS—Cystathionine Beta Synthetase, MAO—monoamine oxidase, COMT—catechol-o-methyltransferase, HMT—histamine methyl transferase, DAO—diamine oxidase. RIBOFLAVIN DERIVED COFACTORS: FMN—flavin mononucleotide and FAD—flavin adenine dinucleotide, OTHER COFACTORS: 5-MTHF—5-methylenetetrahydrofolate, B6 (PLP)—pyridoxal phosphate (the activated form of vitamin B6), B12—vitamin B12 (cobalamin). Cu⁺⁺—Free (unbound) copper (Cu), Zn—zinc.

Figure 2

Mapping MTHFR 677 CC variant-related predictive biomarkers correlates with the duration of illness, where Spearman’s correlation rho (RHO) score range on the x- and y-axes = 0–1 and the diagonal black arrow is a virtual timeline trajectory. (Vitamin B2 metabolites ROC = Significant Receiver Operating Characteristic (Area under curve—AUC p < 0.05), for urine HPLC Peak 1 riboflavin co-analyte (presumed metabolite)).

Figure 3

Mapping MTHFR 677 TT variant-related predictive biomarkers correlates with the duration of illness, where Spearman’s correlation rho (RHO) score range on the x- and y-axes = 0–1 and the diagonal black arrow is a virtual timeline trajectory.

Figure 4

Mapping MTHFR 677 CT variant-related predictive biomarkers correlates with the duration of illness, where Spearman’s correlation rho (RHO) score range on the x- and y-axes = 0–1 and the diagonal black arrow is a virtual timeline trajectory.

Figure 5

A stepped care approach to rehabilitation for psychosis.

Figure 6

Method sequences for mapping the progression of psychosis.