In Schizophrenia, Depression, Anxiety, and Physiosomatic Symptoms Are Strongly Related to Psychotic Symptoms and Excitation, Impairments in Episodic Memory, and Increased Production of Neurotoxic Tryptophan Catabolites: a Multivariate and Machine Learning Study

Abstract

The depression, anxiety and physiosomatic symptoms (DAPS) of schizophrenia are associated with negative symptoms and changes in tryptophan catabolite (TRYCAT) patterning. The aim of this study is to delineate the associations between DAPS and psychosis, hostility, excitation, and mannerism (PHEM) symptoms, cognitive tests as measured using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and IgA/IgM responses to TRYCATs. We included 40 healthy controls and 80 participants with schizophrenia. Depression and anxiety symptoms were measured with The Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales, respectively. Physiosomatic symptoms were assessed with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF). Negative symptoms as well as CERAD tests, including Verbal Fluency Test (VFT), Mini-Mental State Examination (MMSE), Word List Memory (WLM), and WL Delayed Recall were measured, while ratios of IgA responses to noxious/protective TRYCATs (IgA NOX_PRO) were computed. Schizophrenia symptoms consisted of two dimensions, a first comprising PHEM and negative symptoms, and a second DAPS symptoms. A large part of the variance in DAPS was explained by psychotic symptoms and WLM. Of the variance in HAM-D, 58.9% was explained by the regression on excitement, IgA NOX_PRO ratio, WLM, and VFT; 29.9% of the variance in HAM-A by psychotic symptoms and IgA NOX/PRO; and 45.5% of the variance in FF score by psychotic symptoms, IgA NOX/PRO, and WLM. Neural network modeling shows that PHEM, IgA NOX_PRO, WLM, and MMSE are the dominant variables predicting DAPS. DAPS appear to be driven by PHEM and negative symptoms coupled with impairments in episodic memory, especially false memory creation, while all symptom dimension and cognitive impairments may be driven by an increased production of noxious TRYCATs, including picolinic, quinolinic, and xanthurenic acid.

Towards a new classification of stable phase schizophrenia into major and simple neuro‐cognitive psychosis: Results of unsupervised machine learning analysis

“…Although our clustering analysis provided a class, which broadly agreed with the characteristics of deficit schizophrenia, it would be inadequate to use a label stressing negative symptoms, including “deficit schizophrenia.” Indeed, external validation shows that cluster 2 is characterized by many more features, which adequately discriminate this cluster from controls and cluster 1. Firstly, cluster 2 is accompanied by increased IgA responses to noxious TRYCATs (indicating increased production) and by lowered levels of IgM responses to the same noxious TRYCATs (indicating lowered regulation) pointing to increased activities of these noxious TRYCAT species . Secondly, cluster 2 is characterized by important deficits in episodic and sematic memory and a decline in neuropsychological functioning as indicated by a lower MMSE, which are all strongly associated with negative symptoms .…”

“…The same day as the interviews, we measured body height (in meter) and weight (in kg) and computed the BMI as weight (kg)/height (meter 2 ). In addition, we computed z unit‐weighted composite scores reflecting severity of different symptomatic dimensions (see Data S1). Health‐related quality of life was measured using the World Health Organization Quality of Life Instrument‐abbreviated version .…”

“…Secondly, many individuals with schizophrenia experience clinically meaningful depression and anxiety symptoms . Recent research suggests that these mood symptoms are highly significantly associated with neurocognitive impairments, including executive functions, visual memory, attention and social cognition, and especially with the negative symptoms of schizophrenia .…”

“…Chronic schizophrenia is also characterized by signs of immune activation and neuro‐oxidative stress as indicated by elevated levels of macrophage inflammatory protein, eotaxin, soluble tumour necrosis factor (TNF) receptor p60/p80 (TNFR1 and TNFR2), and protein carbonyls . Th‐1 and M1 cytokines and oxidative stress may activate indoleamine 2,3‐dioxygenase driving tryptophan to increased synthesis of tryptophan catabolites (TRYCATs) some of which have neurotoxic, excitotoxic, neuroimmune, neuro‐oxidative, and neuro‐nitrosative effects . We detected that deficit schizophrenia is accompanied by very specific changes in IgA and IgM‐mediated responses directed to TRYCATs .…”

“…Thus, deficit schizophrenia is accompanied by increased IgA‐mediated immune responses directed to noxious TRYCATs, including picolinic acid (PA), xanthurenic acid (XA), quinolinic acid (QA), and 3‐hydroxykynurenin (3HK), and decreased IgM responses to the same TRYCATs, indicating increased production and lowered regulation of those TRYCATs . Importantly, negative, mood, and physiosomatic symptoms, including SCCs, as well as objective cognitive deficits as measured with CERAD and CANTAB, were significantly associated with changes in IgA/IgM responses to TRYCATs, suggesting that elevations in noxious TRYCATs or the antecedents of TRYCAT pathway stimulation could specifically contribute to the development of these specific psychopathological manifestations …”