Relationship between agmatine pathway metabolites and neurocognition, sleep and sensory profiles in schizophrenia spectrum patients with and without auditory hallucinations and healthy adults

Introduction and Objective: Schizophrenia is a chronic mental disorder diagnosed in approximately 1% of the world population. Today, the diagnosis of schizophrenia is made for clinical conditions in which psychotic symptoms are decisive but also non-psychotic symptoms such as cognitive deficiencies, autistic patterns, sleep disorders and neurotic features are frequently accompanied, and is used to describe a heterogeneous clinical syndrome rather than a single disease. It is possible that psychotic components such as delusions, hallucinations, thought disorganization, and non-psychotic symptoms and findings such as sensory processing disorders, sleep problems and cognitive deficiencies are the common result of a series of etiopathogenetic mechanisms in the schizophrenia spectrum. One of the structures that is likely responsible for the common neurobiological pathogenesis is the thalamic reticular nucleus (TRN), which provides GABAergic inhibition on the thalamus under physiological conditions. Considering the afferent inputs that TRN receives from the thalamocortical and corticothalamic pathways, the brainstem reticular formation and the basal forebrain; auditory hallucinations, sensory processing/gating disorders, sleep problems and cognitive deficits in schizophrenia spectrum cases are likely to be related to each other. There are reports in the literature that TRN has an important role in the development of these pathologies. Another etiopathogenetic mechanism held responsible for the schizophrenia clinic is the oxidative stress load in patients. In many studies, the plasma level of nitric oxide (NO), a prooxidant, has been found to be increased in schizophrenia cases. The nitric oxide synthase (NOS) enzyme, which is responsible for NO production, also leads to citrulline production. NO synthesis is associated with long-term potentiation and synaptic plasticity, and it is known that NO has an improving effect on inadequate neurocognition and sleep profiles observed in schizophrenia patients since the prodromal period onwards. However, excessive synthesis of NO leads to an increase in oxidative stress, glutamate production and a tendency towards psychosis. Compounds that provide inhibitory control over the NOS enzyme are agmatine and its main metabolite, putrescine. Putrescine, spermine and spermidine, which are metabolites of agmatine, have xxi antioxidant properties, unlike NO of which they inhibit, and reduce the risk of neurotoxicity. However, agmatine and putrescine also have N-methyl-D-aspartate (NMDA) receptor blocking properties; so, while providing neuroprotection on one hand, on the other hand they may be related to symptoms in the schizophrenia spectrum and neurocognition. However, no study has been found in the literature that has examined plasma agmatine metabolites (putrescine, spermidine and spermine) and NOS products (NO and citrulline) together in the schizophrenia spectrum and healthy control (HC) groups and examined the relationship between these metabolites and neurocognitive functions, auditory hallucinations, sleep and sensory profiles. In this study, we aimed to investigate the relationship between plasma agmatinase, putrescine, spermidine, spermine, NO and citrulline levels and auditory hallucinations, sensory profile abnormalities, neurocognitive deficits and sleep disorders and evaluated the following hypotheses: 1. Plasma levels of NO in the schizophrenia spectrum patients will be higher than healthy controls. 2. Plasma levels of the agmatinase enzyme and its products (putrescine, spermine, spermidine) and the NOS enzyme products (NO and citrulline) will be different in schizophrenia spectrum patients with auditory hallucinations (AH+) and without auditory hallucinations (AH-) and healthy controls. 3. Plasma levels of agmatinase, putrescine, spermidine, spermine, NO and citrulline will be associated with neurocognition, sleep and sensory profile impairments. Materials and Methods: Sociodemographic data, neurocognition (executive functions via Wisconsin Card Sorting Test (WCST), attention functions via Stroop Test, working memory via Digit Span Learning Test), sleep profile (via Pittsburgh Sleep Quality Index (PSQI)) and sensory profile (via Adolescent/Adult Sensory Profile Questionnaire-AASP) were evaluated in 29 IV(+) cases, 27 IV(-) cases and 25 HC matched for age, gender and education status. Chlorpromazine equivalent doses were matched in the patient groups and symptom severity was assessed with Positive and Negative Syndrome Scale (PANSS). Samples obtained from blood were examined for plasma levels of agmatinase, putrescine, spermine, spermidine, nitric oxide and citrulline via ELISA kits. Comparisons between three groups were made with one way ANOVA when data were normally distributed, and with Kruskal Wallis ANOVA when xxii not distributed normally. Comparisons between two groups were made with student t test when data were normally distributed, and with Mann Whitney U test when not distributed normally. Receiver operating characteristic (ROC) analysis was performed to distinguish continuous variables between two groups, and cut-off values were determined with Youden Index. Correlations for clinical variables were examined with Pearson or Spearman correlation analyses according to normal distribution criteria, and logistic and linear regression analyses were applied. Results: Sensory profile abnormalities and plasma NO levels were found to be significantly higher in schizophrenia spectrum patients than in HC; however, there was no difference between AH(+) and AH(-) groups. Plasma antioxidant polyamine levels, WCST performance deficiencies, past and current sleep disorders, positive symptom severity and delusion-hallucination count were found to be significantly higher in AH(+) patients compared to AH(-) patients, while plasma citrulline level and suicide attempt count were found to be significantly lower. The strongest predictors of being in the schizophrenia spectrum were plasma NO level, plasma spermine level, AASP-low recording score and WCST total correct score. The strongest predictors in distinguishing patients with and without auditory hallucinations were WCST total correct number and PSQI total score. Neurocognitive deficits in the schizophrenia spectrum showed a positive correlation with AASP-sensory sensitivity score and a highly negative correlation with suicide attempts. Low WCST performance and high PSQI scores; showed a positive correlation with plasma levels of antioxidant polyamines and a negative correlation with plasma citrulline levels. Discussion: The higher NO was levels in schizophrenia spectrum patients compared to the HC group could be explained by the neuroprotective and healing effects of NO on neurocognition and sleep problems which were higher in the patient group ; however, a continuous high level of NO in the central nervous system could increase oxidative stress, cause downstream glutamatergic increase and psychosis tendency as well. Therefore, the high NO that we found in the schizophrenia spectrum patients can also be related to the neurodegenerative process in schizophrenia. Indeed, in our study, plasma NO level showed a positive correlation with the PANSS negative symptom score. The fact that executive functions, past and current sleep xxiii profiles, positive symptom severity and number of delusions-hallucinations were ranked as worst in the AH(+) group, intermediate in the AH(-) group and best in the HC group indicates that executive function deficiency and sleep disorders, as well as positive symptom severity and number of delusions-hallucinations in the schizophrenia spectrum, are also associated with auditory hallucinations. Antioxidant polyamines, which we found to be decreased in the overall schizophrenia spectrum group, were ranked as AH(-)