Background: Neuroscience can assist clinical understanding and therapy by finding neurobiological markers for mental illness symptoms. Objectives: To quantify biomarkers for schizophrenia and schizoaffective disorder and relate these to discrete symptoms of psychosis. Methods: Within a case-control design with multiple exclusion criteria to exclude organic causes and confounding variables, 67 DSM IV-R diagnosed and 67 control participants from a defined hospital, clinic and community catchment area were investigated for candidate markers. Participants underwent protocol-based diagnostic-checking and symptom rating via Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale, functional-rating scales, biological sample-collection and sensory-processing assessment. Blood and urine samples were analysed for monoamine neurotransmitters, their metabolites, vitamin cofactors and intermediate-substances related to oxidative stress and metabolism of monoamines. Neurocognitive assessment of visual and auditory processing was conducted at both peripheral and central levels. Biomarkers were defined by Receiver Operating Curve (ROC) analysis. Spearman’s analysis explored correlations between discrete symptoms and the biomarkers. Results: Receiver Operating Curve (ROC) analysis identified twenty-one biomarkers: elevated urinary dopamine, noradrenaline, adrenaline and hydroxy pyrroline-2-one as a marker of oxidative stress. Other biomarkers were deficits in vitamins D, B6 and folate, elevation of serum B12 and free serum copper to zinc ratio, along with deficits in dichotic listening, distance vision, visual and auditory speed of processing, visual and auditory working memory and six middle ear acoustic reflex parameters. Discrete symptoms such as delusions, hostility, suicidality and auditory hallucinations were biomarker-defined and symptom biomarker correlations assumed an understandable pattern in terms of the catecholamines and their relationship to biochemistry, brain function and disconnectivity. Conclusions: In the absence of a full diagnosis, biomarker-symptom-signatures inform psychiatry about the structure of psychosis and provide an understandable pattern that points in the direction of a new neurobiological system of symptom-formation and treatment.
“The study indicates that finely-tuned relative-strengths between noradrenaline, adrenaline and dopamine (NA, AD and DA) levels are critical in differentiating symptom-formation in schizophrenia and schizoaffective disorder. The graduated difference between the elevated NA biomarker and the level of DA appears to turn symptom correlates from manic (with high DA) to disorganized and distracted (high NA and somewhat lower AD and DA), to depressive and negative (low DA ± high NA, or low DA alone), to dissociative symptoms such as experiencing “blank periods” that are characterised by generally low or absent catecholamine correlates. DA gives high frequency conditioning to glutaminergic synapses in order to potentiate goal-directed sensory information flow around the cortex, whilst high NA raises arousal and vigilance and AD promotes flight . In moderate amounts NA also promotes sensory attention, however disproportionately excessive amounts of NA are reported to suppresses and disrupt DA-facilitated information flow around the cortex -. In this project the elevated NA biomarker correlated strongly with symptom severity as measured by the Symptom Intensity Rating (SIR) index. Elevated NA also correlated significantly with symptoms representing sensory flow disruption and symptoms indicative of sensory-disconnectivity within the cortex, such as impaired attention and cognitive disorganisation.
We believe that noradrenergic disrupted internal sensory processing strain then activates the hypothalamic pituitary adrenal axis (HPA) -, stimulating further catecholamine synthesis and setting in motion a vicious cycle of raised catecholamine output related to symptom formation in antipsychotic-free and antipsychotic treated persons, alike . In this setting of increased catecholamine requirement, any deficiency of vitamin B6 due to poor nutrition  will be exacerbated by its increased requirement as a cofactor by the DAsynthesis- enzyme tyrosine hydroxylase and also for NA-synthesis by the enzyme dopa-decarboxylase  , (Figure 1). Vitamin B6 is also necessary to combat oxidative stress by the brain anti-oxidant glutathione, which utilises B6 in its synthesis via cystathione beta synthase (CBS) and cystathionase , (Figure 1). Low folate precursor can theoretically reduce synthesis of upstream S-adenosylmethionine (SAMe)  and if SAMe is depleted, then the catechol-o-methyl transferase (COMT) enzyme is inhibited, since SAMe acts as a necessary cofactor for this enzyme which resides at the end-stage of catecholamine metabolism . Therefore, in the absence of its cofactor, catecholamines will be elevated. The predominance of noradrenaline over dopamine and adrenaline in this study may then be further explained by the role of free copper in promoting the synthesis of noradrenaline from dopamine (Figure 1). In this setting, low folate (which serves as a remote precursor of SAMe), may also contribute to SAMe unavailability and by lessening conversion of adrenaline from noradrenaline, further contribute to noradrenaline excess (Figure 1, Table 12). Taken together, these two dynamics explain why SAMe unavailability allows prominence of noradrenaline (NA) in this project’s findings, with relatively lesser levels of dopamine (DA) and adrenaline (AD) in the presence of low folate and high free copper. These are interesting integrated findings which may provide an alternative explanation for the role of the COMT enzyme which has been already implicated in schizophrenia  .
Elevated noradrenaline’s ability to disrupt DA’s promotion of the sensory signal around the cortex from frontal to temporal-hippocampal areas, fits well with the findings of this study where high NA correlates with symptoms of poor attention, disorganisation, self-neglect and delusions, provide residual evidence of fronto-hippocampal disconnectivity. At the same time noradrenergic fronto-parietal sensory signal disruption - isolates the frontal cortex and also the default network  , resulting in poor frontal surveillance symptoms such judgement impairment, mixed with hostility, symptomatic of frontally unrestrained amygdala function. Our findings have also demonstrated that such disconnectivity may also be induced by oxidative stress (with elevated HPL), with vitamin deficits and elevated free copper also known to cause neuronal damage in sensory processing circuits  .
Urinary HPL is thought to arise under conditions of extreme oxidative stress where it is excreted as a byproduct of haeme-related porphyrin synthesis -. In this study, HPL established its value as a biomarker that is notably linked with clinical severity, with elevated neurotransmitter levels, with impaired auditory working memory, with dichotic deficit, with delayed auditory processing systems and also with significant negative symptoms and anxiety. Taken together, this gives the impression that oxidative stress aligns with and potentiates the action of elevated catecholamines in disrupting sensory processing circuits in the cortex, leading to anxiety and rebound HPA activation, with potential for a vicious cycle of elevated catecholamine synthesis. In literature, elevated HPL is reported to relate to vitamin B6 and zinc deficiency, since HPL is a breakdown product from porphyrin synthesis and such synthesis is impaired in a setting of vitamin B6 and zinc unavailability . Despite such reports, our study only found marginal correlates for elevated HPL with high free copper: zinc ratio (Figure 2).
In keeping with their various influences on catecholamine biochemistry (Figure 1), biomarkers for nutritional deficits such as vitamin deficiency (D, B6, folate) and low zinc, correlated significantly with elevated catecholamine levels and appear to impact a diffuse range of predominantly positive symptoms. Folate has been reported to be low in schizophrenia  and low zinc has been found related to noradrenaline excess . Low vitamin D is an established finding in schizophrenia  and in this study, its biomarker correlated highly with auditory processing biomarkers and moderately with middle ear and elevated catecholamine biomarkers. A proposed mechanism linking elevated catecholamines and low vitamin D levels occurs via parathyroid hormone, the secretion of which is primed by catecholamines, which function to encourage parathyroid hormone action with release of calcium (Ca2+) ions from neuronal cells-an effect that relates to neuronal excitotoxicity, but which is directly opposed by the action of vitamin D -. Thus catecholamine-induced draw-down on body reserves of this over-utilised vitamin together with the indoor lifestyle and lack of sun exposure that may accompany the schizophrenia condition, may work together to potentiate these effects.
Evidence of significant correlative relationships between elevated catecholamines and auditory and visual processing speed and working memory deficits are postulated to occur via a vicious cycle of catecholamine excess, whereby NA is progressively elevated until fronto-temporal disconnectivity occurs . Auditory and visual working memory deficits (low reverse digit span and visual span), dichotic listening deficits and pre-aged visual and auditory processing speed deficits not attributable to anti-psychotic medication may occur in this manner and have been reported in schizophrenia -. In this study, we have established that these deficits qualify as biomarkers, which inter-correlate with each other, with elevated catecholamines, with delay in both auditory and visual speed of processing and also with clinical symptom severity within the research patient population.
In keeping with this noradrenergic fronto-temporal disconnection hypothesis, low visual span may represent ramped-up noradrenaline-induced disconnectivity, reducing the action of the higher visual cortical magnocellular pathway and forcing reliance on the lower parvocellular visual pathway within the default brain network . In this study, the range of symptoms correlating with reduced visual span, appear to reflect absence of the magnocellular pathway since this symptom repeatedly combines with symptoms of parietal inattention, disorganization and delayed visual speed of processing. At the same time, hippocampal isolation arising from hippocampal disconnection from frontal rationalization processes, allows internal semantic confabulation, resulting in delusional thought-formation. At the sub-cortical level the amygdala is similarly isolated from frontal cortical inhibition, with resultant hostility.
Middle ear ROC reflex findings of elevated tympanic contraction gradient and increased volume of the external auditory canal—yet collateral attainment of low middle ear peak pressure—indicate that middle ear patency problems associated with tympanic membrane pathology or Eustachian tube dysfunction are an integral part of schizophrenia and schizoaffective disorder . Significant correlations for some of these variables with elevated catecholamine biomarkers may further explain catecholamine-related acoustic-hypersensitivity findings reported by Adler et al. in 1990 . Our findings imply that in the setting of elevated catecholamines, tympanic muscle contraction facilitates hearing by undergoing compensatory over-contraction, which is then transmitted across the middle ear to influence stronger, delayed stapes muscle contraction at the other end of the ossicle chain. Such stronger stapes contraction then over-dampens and delays the passage of sound as it enters the cochlear. This may be the peripheral cause of the postulated pre-attentive auditory processing deficit in schizophrenia  . Our findings also demonstrated significant ROC correlations between high external ear canal volume, low attainment of middle ear pressure and delayed offset of stapes contraction in relationship to delayed auditory speed of processing, confirming our understanding that the overall outcome of exacerbated tympanic muscle contraction transmission to the stapes muscle is increased delay of the auditory signal as it enters the cochlear and that this significantly relates to delayed auditory speed of processing. It is therefore of further interest that our study found prominent correlation of these middle ear auditory dampening and delay biomarkers with elevated NA and AD and negative symptoms of emotional withdrawal and lack of verbal spontaneity. In contrast, other peripheral biomarkers, such as long-distance vision abnormality correlate with clinical symptom severity and activated symptoms of motor-hyperactivity, grandiosity, excitement, bizzare-behaviour and hallucinations. If the brain does not get signals from its senses it constructs them internally. These peripheral findings represent unmet needs within the patient participants in our study and, imply that broader clinical assessment and targeted remediation of these conditions may assist symptom reduction in schizophrenia and schizoaffective disorder.”
“Examining symptoms in relationship to biomarkers reveals that schizophrenic and schizoaffective disorder symptoms consist of a conglomerate of biochemical and neurophysiological dysfunctions related to dysregulation of visual and auditory sensory processing and neurochemistry relating to the biosynthesis and metabolism of catecholamines. Through the remote and direct action of cofactors associated with catecholamine synthesis and metabolism, noradrenaline levels are generally elevated which delays and disrupts cortical visual and auditory sensory processing pathways. This in turn activates the hypothalamic pituitary adrenal axis to produce further catecholamines. In this process, elevated free copper facilitates noradrenaline synthesis at the expense of dopamine and also promotes oxidative stress, whilst vitamin B6 over-utilisation reflects HPA pressure for dopamine synthesis and such lack also accentuates oxidative stress. Low folate remotely influences the ability of catecholamines to be metabolized by COMT via its cofactor, SAMe. Under the variable influence of these cofactors, altering ratios between noradrenaline, adrenaline and dopamine correlate meaningfully with mood, attention and behavioural effects of these catecholamines. In this setting, a predominance of very high-noradrenaline causes fronto-temporal disconnectivity resulting in symptoms of delayed, disrupted and disorganised visual and auditory attention, mixed with frontal disconnection and disinhibition symptoms of poor judgement, poor executive function, poor working memory and poor impulse control. Isolated temporal regions are then left to function alone with impaired insight and delusions, whilst the isolated amygdala within the unmasked default network manifests as symptoms of agitation, aggression and hostility.
This research provides a new understanding of the substructure of many symptoms within the context of psychosis. In particular, biomarkers correlate and combine to underlie symptoms and behaviours of key relevance within the clinical setting, such as suicidality, hostility and auditory hallucinations.
In this context, suicidality is seen to relate to high adrenaline levels representing the flight impulse, together with low-dopamine-related symptom of emotional withdrawal. In addition high noradrenaline levels convey the capacity to act-out on the basis of these impulses and symptoms, in the setting of a psychotic break in sensory processing with dichotic listening deficit, visual and auditory processing deficits, middle ear pathology and deficiency of all three nutrients—D, B6 and folate.
In the context of predicting and preventing aggression in psychosis, the biomarker profile of hostile, aggressive behaviour is of particular interest. Hostility is seen to relate to high noradrenaline levels and has a strong correlate with the symptom of blunted affect. Hostility also relates to impaired visual span and auditory processing difficulty and has underlying pathology relating to vitamin D deficiency and middle ear pathology.
Auditory hallucinations are seen to relate to high levels of both noradrenaline and adrenaline with delays in both auditory and visual processing speed, together with reduced visual span. In addition, dichotic listening deficit, middle ear pathology, low folate, low vitamin D and B6 contribute to the constellation of disorders and dysfunctions that subtly accumulate to produce this distressing symptom.
Anxiety is also seen to relate to elevated noradrenaline and adrenaline levels, with impairment of visual span and visual processing speeds to a greater extent than delayed auditory processing. In addition, auditory working memory and dichotic listening deficits impair sensory processing. Underlying this dysfunction resides peripheral abnormalities of long distance vision and the middle ear function, in addition to oxidative stress and low vitamin D and folate.
Biomarkers of acoustic reflexes relating to middle ear pathology, distance vision deficits, dichotic listening disorder and biochemical-nutritional deficits generally represent unmet needs within the clinical population assessed.This implies that there is scope for broader clinical assessment and remediation of persons with schizophrenia and schizoaffective disorder.”
“Biomarkers that correlate with discrete symptoms or sets of symptoms have therapeutic potential for targeted correction towards cure. They inform about the structure of psychosis, symptom-formation and the patterns in which symptoms present, allowing clinicians greater confidence in diagnosis and management of discrete, resistant, difficult or dangerous symptoms. Such multi-domain understandings provide a template for new biological system of symptom-interpretation in serious mental illness states. In the wider social context, the demonstration of clear biological underpinnings for schizophrenia and schizoaffective psychosis will reduce social stigma associated with these conditions and improve outcome expectations for patients and their families.”