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Nitric oxide (NO) signalling has been implicated in the pathogenesis of several mental illnesses; however, its specific contribution remains unclear. We investigated whether peripheral NO concentration is associated with specific diagnoses, and whether there is a correlation with genetic variation in NO synthase (NOS) genes. We included 185 participants in the study; 52 healthy controls, 43 major depressive disorder (MDD) patients, 41 bipolar disorder (BPD) patients, and 49 schizophrenia (SCZ) patients. Clinical, genetic, and biochemical data were collected at admission to a psychiatric hospital and at discharge. Serum was used to quantify concentration of the stable NO metabolites nitrite and nitrate. Individuals were genotyped for the NOS1 exon 1f variable number of tandem repeats 1 (VNTR1) polymorphism, and single nucleotide polymorphisms (SNPs) in the NOS1, NOS1AP and NOS3 genes. At admission, SCZ patients were found to have significantly higher peripheral NO metabolite (NOx-) concentrations compared to healthy controls, MDD and BPD patients. NOS1 exon 1f VNTR1 short allele carriers were found to have significantly increased NOx- concentration. Moreover, this result was still significant in patients even at discharge. The data also revealed that patients who did not remit in their depressive symptoms had significantly increased NOx- concentration compared to remitters at discharge, supported by the finding of a significant positive correlation between depression symptom severity and NOx- concentration. Taken together, it is possible that elevated peripheral NOx- concentration is associated with increased severity of psychopathology, potentially due to NOS1 exon1f VNTR1 genotype. Our results further implicate NO signalling in mental illness pathogenesis, supporting its possible use as a peripheral biomarker, and imply that NOS genotype may play a significant role in regulating peripheral NOx- concentration.

Objective:Sensorimotor gating is experimentally operationalized by the prepulse inhibition (PPI) of the startle response (SR). Previous studies suggest high test-retest reliability of PPI and potential correlation with working memory (WM). Here, we aimed to validate and extend the test-retest reliability of PPI in healthy humans and its correlation with WM performance.Methods:We applied an acoustic startle PPI paradigm with four different prepulse intensities (64, 68, 72 and 76 dB) and two different WM tasks [n-back, change detection task (CDT)] in a group of 26 healthy adults (final sample size n = 23). To assess test-retest reliability, we performed all tests on two separate days ~27 days (range: 21–32 days) apart.Results:We were able to confirm high test-retest reliability of the PPI with a mean intraclass correlation (ICC) of > 0.80 and significant positive correlation of PPI with n-back but not with CDT performance. Detailed analysis showed that PPI across all prepulse intensities significantly correlated with both the 2-back and 0-back conditions, suggesting regulation by cross-conditional processes (e.g. attention). However, when removing the 0-back component from the 2-back data, we found a specific and significant correlation with WM for the 76-dB PPI condition.Conclusion:With the present study, we were able to confirm the high test-retest reliability of the PPI in humans and could validate and expand on its correlation with WM performance.

Background Previous studies have linked disturbances in the kynurenine pathway, responsible for the main catabolism of tryptophan and a key regulator of the immune system, to mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). However, the relationship between tryptophan catabolism and the presentation of psychiatric disorders seems to be rather complex, as up to now results have mostly been inconsistent or even contradictory. In this study, we measured plasma levels of tryptophan catabolites (TRYCATs: tryptophan, kynurenine, kynurenic acid and quinolinic acid) in a sample of in total 175 participants consisting of individuals suffering from an acute disease episode seeking inpatient treatment as well as healthy controls (HC) to investigate whether individual metabolites could serve as a biomarker for differential diagnosis. Results Significantly decreased levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid were found in the patient group as a whole. This was mainly driven by the difference between BD patients and HC. Specifically, the manic symptom domain in manic and mixed phase BD patients displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between the psychiatric disorders disqualifying TRYCATs as biomarkers for differential diagnosis. None of the assessed potential demographic or pharmaceutical confounding factors revealed a significant correlation to TRYCAT concentrations. Upon reaching (partial) remission, the changes in TRYCAT levels partially normalized in the patient group. Conclusions Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD. Although we cannot prove a causal relationship, underlying mechanisms might include pro-inflammatory states in the central nervous system and/or increased neurotoxicity contributing to the immune assault. Also considering the manifold, but inconsistent previous analyses regarding TRYCAT concentrations in psychiatric disease, larger, cross-sectional and longitudinal studies will be needed for detangling the mystery about the role the tryptophan catabolism plays in the pathophysiology of mental disorders and for answering the burning question if it might constitute a possible therapeutic target in the future.

Introduction Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits. Method Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33 224 healthy subjects (UK Biobank). Finding We observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r = 0.35; P = .0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG. Conclusion Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and nonsocial visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept, and schizophrenia resilience models.