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Background: Meta-analyses show increased copper (Cu) levels in major depression disorder. However, the association of Cu biomarkers with clinical classification in other mental health disorders has not been fully explored., Methods: To this aim, we compared an extensive panel of Cu biomarkers, composed of Cu, ceruloplasmin (Cp) Cp activity, Cp specific activity, Cu not bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in 171 consecutive patients affected by psychiatric disorders and in 61 healthy controls (HC) using MANOVA adjusting for the effect of sex and age, and studied their association with the clinical scale outcomes at psychiatric examination, namely Global Assessment of Functioning, Clinical Global Impression, and Brief Psychiatric Rating Scale., Results: individuals with psychiatric disorders were classified as 109 patients affected by mood spectrum disorders (MSD), 20 patients with schizophrenia spectrum disorders (SSD), and 42 with personality disorders (PD). Cu and non-Cp Cu were increased in psychiatric individuals than in HC, which also differed among the patients stratified per the clinical classification, being higher in the MSD individuals. The analysis stratified for sex revealed that women from the patient group, and specifically from the MSD group, had increased levels of Cu and non-Cp Cu than healthy women, while no difference was revealed in men. A logistic regression model considering the effect of sex and age revealed that non-Cp Cu could explain 26 % increased odds of having MSD per µmol/L unit increase (OR = 1.26; p = 0.0008; 95 % CI 1.099-1.436), that reached 40 % when considering only women. This result was driven by non-Cp Cu that correctly classified 64.1 % MSD (70 % in women) individuals vs. HC in a decision tree model, with values higher than 2.1 µmol/L which could distinguish the majority of MSD patients (86.3 % MSD vs. 13.7 % HC in women). None of the biological variables under study correlated with outcomes of the clinical scales, substances, or alcohol abuse., Conclusion: Current results suggest mild Cu toxicity in women with MSD, as revealed by a value of non-Cp Cu higher than 2.1 µmol/L, which can be further investigated to assess its potential diagnostic accuracy in bigger and longitudinal cohorts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Current treatments for mental disorders, like pharmacotherapy or psychological approaches, do not lead to full remission in all individuals. Physical activity (PA) is effective at improving psycho-physical health in major depressive and anxiety disorders. However, the efficacy of PA as an adjunctive treatment for borderline personality disorder (BPD) has not been studied. To date, there are no approved pharmacological treatments for this severe condition and limited accessibility to effective psychotherapeutic interventions. This study tests the efficacy of a structured PA programme as an additional treatment for BPD outpatients., Methods: The PABORD is a randomised controlled trial for female outpatients (18-40 years) with a BPD diagnosis. The intervention group (n = 32) will participate in a 12-week structured PA programme supervised by a sport medicine physician and preceded by three psychoeducation sessions on healthy eating habits. The control group (n = 32) will receive a 12-week psychoeducation programme on PA, diet, and health risks of a sedentary lifestyle for a total of 8 sessions. The study aims to determine if the PA intervention is superior to the control in reducing BPD symptoms. Secondary aims include improving PA levels and physical and psychological health. Assessments will be conducted at baseline, post-intervention, and 3 months post-intervention., Discussion: The structured PA programme is expected to outperform the control group in terms of health and PA outcomes at the end of the intervention. Repeated assessments will also help to identify psychosocial factors that influence PA maintenance. Findings will support the potential widespread implementation of PA programmes for BPD treatment., Trial Registration: ClinicalTrials.gov NCT06461104. Registered on 6 June 2024 {2a}., (© 2024. The Author(s).)

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Major depressive disorder (MDD) is a common, chronic, debilitating mood disorder that causes serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment option; however, only approximately one third of patients respond to the first treatment because of the ineffectiveness or side effects of antidepressants. Precision medicine in psychiatry might offer clinicians the possibility to tailor treatment according to the best possible evidence of efficacy and tolerability for each subject. In this context, our study aims to carry out a clinical validation of a combinatorial pharmacogenomics (PGx) test in an Italian MDD patient cohort with advocacy license independence., Methods: Our study is a prospective participant- and rater-blinded, randomized, controlled clinical observational trial enrolling 300 MDD patients who are referred to psychiatric services to receive a new antidepressant due to the failure of their current treatment and/or the onset of adverse effects. Eligible participants are randomized to the TGTG group (Treated with Genetic Test Guide) or TAU group (Treated as Usual). For all subjects, DNA is collected with a buccal brush. The primary outcome is the reduction in depressive symptomatology. The secondary outcomes involve a range of scales that assess MDD symptoms and social functioning outcomes. The assessment is performed at four timepoints: baseline and 4, 8, and 12 weeks., Discussion: This project represents the first randomized controlled clinical trial to investigate whether a non-commercial PGx test improves outcomes in an MDD naturalistic cohort. Moreover, the identification of new genetic variants associated with non-response or side effects will improve the efficacy of the test, leading to further cost-saving., Trial Registration Number: ClinicalTrials.gov NCT04615234. Registered on November 4, 2020., (© 2021. The Author(s).)

Background: Improving the quality of medical laboratory services is a high priority in many countries. However, quality management systems for laboratories in resource-limited settings are often inadequate., Objectives: This article shares the experiences, benefits and challenges of the laboratory journey towards accreditation in a primary healthcare laboratory in Addis Ababa, Ethiopia., Methods: A retrospective review of laboratory records in Addis Ketema Health Center was conducted from 2012 to 2015. The study was supplemented by observations from some of the authors of this article who worked in the laboratory., Results: The laboratory journey towards accreditation began with a baseline assessment in 2012 using the World Health Organization African Region Stepwise Laboratory Quality Improvement Process Towards Accreditation; the baseline score was 78 points (0 stars). After mentorship support, the laboratory improved to 198 points (3 stars) in 2013 and 249 points (5 stars) in 2014. The laboratory scaled up to International Organization for Standardization 15189 requirements and received limited-scope accreditation for tuberculosis sputum microscopy and hematology tests in 2015. After adopting and implementing the standards, steady improvement was observed in the reliability of the laboratory services. Lack of resources was the major challenge the laboratory encountered., Conclusion: Even though a remarkable quality performance improvement was observed over the entire process, inadequate skilled personnel was the major challenge identified in the road towards accreditation. Therefore, an appropriate, workload-based staffing structure should be developed to improve and sustain medical laboratory quality standards in resource-limited settings., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2019. The Authors.)

The Health of the Nation Outcome Scale (HoNOS) (Lora et al. Epidemiol Psichiatr Soc 10(3):198-212, 2001) is widely used. However, clinicians have expressed concerns about its ability to describe severe mentally ill patients, as it does not consider some relevant clinical aspects. This study aims to develop and validate the HoNOS-Residential Facility (HoNOS-RF) in order to pursue a thorough assessment of patients admitted to psychiatric residential facilities (RFs). The final version of the HoNOS-RF was administered to 409 patients admitted to four RFs. Exploratory factor analysis, Cronbach' alpha (α), Intraclass Correlation Coefficients (ICC) were used to assess construct validity, internal consistency and reliability, respectively. Concurrent criterion validity was assessed through correlations with the Brief Psychiatric Rating Scale-Expanded Version (BPRS-E) (Roncone et al. Acta Psychiatric Scand 100(3):229-36, 1999), Personal and Social Performance Scale (PSP) (Morosini et al. Acta Psychiatric Scand 101(4): 323-29, 2000), and comparisons across diagnostic groups. The final version of the HoNOS-RF consisted of 31 items, grouped into the following eight factors (overall explaining 55% of the total variability): personal and interpersonal functioning; environment; behavior and burden of care; cognitive function; somatic problems; anxiety-depression symptoms; psychotic symptoms; and other psychiatric symptoms. The scale showed high internal consistency (α = .807), and the correlations with PSP and BPRS-E ranged from adequate to moderate. The ICCs were in the excellent range for almost all items. These findings support the validity and the reliability of the HoNOS-RF, thus it may be a useful tool for the assessment of patients admitted to RFs, as it addresses clinical aspects that were mostly not included in the original version.

Impairment of glutamatergic neurotransmission is one of the major hypotheses proposed to explain the neurobiology of schizophrenia. Therefore, the genes involved in the glutamate neurotransmitter system could be considered potential candidate genes for schizophrenia susceptibility. A systematic study on alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor genes has been carried out and the results obtained from the analysis on GRIA2, GRIA3 and GRIA4 are reported. No evidence of association with schizophrenia was found for the GRIA2 and GRIA4 genes; strong evidence of association with schizophrenia was found for GRIA3. This X-linked gene showed a different behavior in the two genders; a positive association with schizophrenia was observed among females but not in males. Female carriers of rs1034428 A allele were found to have a 2.19-fold higher risk of developing schizophrenia compared to non-carriers and 3.28-fold higher risk for developing a non-paranoid phenotype. The analysis at the haplotype level showed that susceptibility to schizophrenia was associated with the specific haplotype rs989638-rs1034428-rs2227098 CAC (P = 0.0008). We conclude that, of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females., (2007 Wiley-Liss, Inc.)

Reactive oxygen species (ROS) have been suggested to play an important role in physiopathology of schizophrenia. The polymorphisms in the genes encoding antioxidant enzymes, such as manganese superoxide dismutase (MnSOD) should, thus, result in predisposition to this psychiatric disorder. A functional amino acid polymorphism (Ala9Val) has been described in the signal sequence of enzyme associated with a decreased defense capacity against oxidative stress. Preliminary evidence in a Turkey population indicated that this polymorphism contributes to physiopathogenesis of schizophrenia. The object of this study was to verify the association between Ala9Val and schizophrenia in a representative Italian sample. The polymorphism was genotyped by PCR amplification and Single-Stranded Conformational Polymorphism (SSCP) analysis in 212 DSMIV schizophrenic patients and 257 healthy volunteers. No association was observed between cases and controls (genotype and allele frequencies: p = 0.72, p = 0.55, respectively) even when a sample stratification for gender, age at onset and diagnostic subtypes was performed. This suggests that the gene variant could not be a risk factor for schizophrenia susceptibility in an Italian sample.

Objective: Repetitive transcranial magnetic stimulation (rTMS) is proposed for the treatment of drug-resistant depression. Studies performed in accordance with evidence-based medicine (EBM) are scarce, particularly in seeking optimal treatment and evaluation parameters. We aimed to test various types of rTMS in a large sample of depressed patients following EBM rules and to investigate treatment-related changes in plasma levels of neurotransmitters involved in depression., Methods: Seventy-one drug-resistant depressed patients were randomly assigned to low (1 Hz) or high (17 Hz) rate TMS, applied for 5 days over the left dorsolateral prefrontal cortex (L-DLPFC). Patients were separated into two study designs. One group (20 patients) received only active treatment, while the other entered a double-blind, placebo-controlled, crossover design. Pre- and post-treatment blood samples were taken for evaluation of plasma levels of dopamine and serotonin., Results: After a week of treatment patients had a measurable benefit. However, overall the placebo stimulation did not differ significantly from real stimulation, nor were differences observed between the two rates of rTMS. The only difference emerged when the real stimulation was applied at 17 Hz following placebo treatment. Plasma levels of neurotransmitters between active and placebo rTMS were similar., Conclusions: Using the treatment schedule of 1 week, although a clinical improvement after active treatment was indeed observed, this was both clinically and biochemically indistinguishable from that seen in the placebo arm., Significance: This suggests that most of the previous emphasis, for short period of treatment, should be tempered down and that further work is required in order to verify whether optimal stimulation and evaluation parameters for TMS-treatment of depression beyond the placebo effect may be found following EBM rules.

Glycogen synthase kinase-3 (GSK-3) is a downstream component of the Wnt pathway and recent studies have reported abnormal levels of GSK-3beta in schizophrenia. In a sample of 147 schizophrenic patients and 212 healthy individuals, we analyzed two common SNPs at position -1727 A/T and -50 C/T and a (CAA)(n) repeat polymorphism localized in intron 1 of the gene. The results showed that the allele, genotype and haplotype distributions for the three polymorphisms investigated do not differ between schizophrenic patients in general and control subjects. However, in the subtype of paranoid schizophrenic patients, we found that the (CAA)(3)/(CAA)(5) heterozygotes were more often represented. Although taken from a small sample, our results support the reports that GSK-3beta appears to be involved in a subtype of schizophrenic patients, but not in schizophrenia in general. In conclusion, we would speculate that this gene may be linked to some features of psychotic disorders rather than to schizophrenia itself., (Copyright 2004 S. Karger AG, Basel)

It has been established that cytokines play a critical role in the regulation of the CNS and recent studies have suggested that dysfunctions of both pro-inflammatory (IL-1beta, IL-6, and TNF-alpha) and anti-inflammatory (IL-1RA and IL-10) cytokines could be involved in the pathophysiology of schizophrenia. Previous studies have reported that functional polymorphisms in some cytokines genes may have important regulatory effects on such system. Therefore, the aim of the present study was to explore the possible role of the IL-1beta -511C/T and IL-1RA (86bp)(n) repeats polymorphisms in schizophrenia. A case control association study comparing genotype and allele frequencies in 346 northen Italian subjects (169 schizophrenic patients and 177 unrelated healthy volunteers) was performed. The frequencies of IL-1beta -511C and IL-1RA allele 1 (86bp)(4) are significantly higher in schizophrenic patients compared to controls (IL-1beta -511 P=0.047; IL-1RA (86bp)(n) P=0.002). Moreover our data show a protective effect of the IL-1RA allele 2 (86bp)(2) against schizophrenia (OR=0.59 95%CI:0.388-0.910; P=0.016) and this effect is enhanced by the concomitant presence of IL-1beta -511T (OR=0.48 95%CI:0.30-0.76; P=0.002). Our findings support the hypothesis that genetically determined changes in IL-1 metabolism regulation may contribute to the pathogenesis of schizophrenia confirming a role of IL-1 gene cluster in disease susceptibility.

Background: Schizophrenia is one of the most severe psychiatric disorders, with a worldwide incidence of 1%. Several reports show abnormal cytokine levels in psychotic patients and indicate a possible role of the immune response system in the pathogenesis of schizophrenia. Increased concentrations of interleukin 10 (IL-10) have been found in plasma of schizophrenic patients, suggesting its potential role as a candidate gene for susceptibility to schizophrenia. IL-10 gene maps on chromosome 1 (q31-q32), a locus associated with genetic susceptibility to schizophrenia. Three functional haplotypes of the gene (GCC, ACC, ATA) have been described, derived from different combinations of three "single nucleotide polymorphisms" and directly related to the expression levels of the protein., Methods: We analyzed allele, genotype, and haplotype distributions in an association case-control study involving 106 schizophrenic patients and 143 unrelated healthy volunteers using polymerase chain reaction (PCR)-Single Strand Conformation Polymorphism and PCR Restriction Fragment Length Polymorphism methods., Results: Our results show a significant increase of GCC homozygotes (the high IL-10-producing haplotype) in schizophrenic patients compared to control subjects (chi(2) = 13, p =.023; odds ratio = 3.03; 95% confidence interval, 1.274-7.355)., Conclusions: These data could partly explain the abnormal secretion of IL-10 occurring in schizophrenic patients in response to infections or different stressors and suggest a potential role of IL-10 as a candidate gene for susceptibility to schizophrenia.

Schizophrenia is a severe psychiatric illness characterised by disturbance of thought, hallucination and delusions.(1) Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and in particular an excessive activation of glutamate receptors seems to be related to the disruption of neuronal ionic gradients leading to excitotoxicity.(2-7) Numerous findings suggested that the kainate ionotropic glutamate receptors are primarily involved in this mechanism. Recently it has been demonstrated that the GRIK3 gene encoding for the ionotropic glutamate receptor kainate 3 contains a functional polymorphism (T928G) leading to the substitution of a serine with an alanine in position 310 of the protein sequence.(8-11) We performed an association study between the ser310ala GRIK3polymorphism and schizophrenia in a sample of 99 schizophrenic patients and 116 controls. We found a significant difference in the genotype distribution and in particular considering the ala allele as dominant (P = 0.0105, odds ratio (OR) 2.031, 95% confidence interval (CI) 1.177-3.504). This finding suggests a potential role for GRIK3 for susceptibility to schizophrenia.

Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in schizophrenia. In particular, the prodynorphin (PDYN), the precursor of the dynorphin opioid peptides, has been shown to play an important role in several aspects of human mental diseases. Recently, a functional polymorphism in the promoter of PDYN gene has been described. We studied the possible relationship between this polymorphism and schizophrenia and we found no significant difference in allelic and genotype distributions between schizophrenic patients and control subjects. However, we observed a significant interactive effect with the receptor 3 of dopamine gene (DRD3); in particular, the frequency of subjects carrying PDYN allele 3 being also homozygotes for DRD3 Gly allele (of Ser9Gly polymorphism) was significantly greater in patients than controls. We conclude that PDYN gene polymorphism alone does not alter the risk for schizophrenia but, by an epistatic interaction with the Gly allele of DRD3 gene, may contribute to the susceptibility to this disorder., (Copyright 2002 S. Karger AG, Basel)

Recently, it was shown that schizophrenia is accompanied by an activation of the inflammatory response system with signs of an acute phase response, such as increased plasma haptoglobin (Hp) concentrations. Hp is characterized by a molecular variation with three known phenotypes, i.e. Hp 1-1, Hp 2-1 and Hp 2-2. The aim of the present study was to examine Hp phenotypic and genotypic frequencies in schizophrenic patients. Hp phenotyping was carried out in 98 Northwestern Italian schizophrenic patients and the phenotypic and genotypic distributions were compared with the distributions established in the Northwestern Italian population. Plasma Hp concentrations were determined by means of a laser nephelometric method. The allele frequency of the Hp phenotypes in schizophrenia, i.e. Hp 1-1 (9.2%), Hp 2-1 (38.8%) and Hp 2-2 (52.0%), was significantly different from that in the Northwestern Italian population, i.e. Hp 1-1 (17.0%), Hp 2-1 (51.3%) and Hp 2-2 (38.5%). The frequency of the Hp-2 gene was significantly higher in schizophrenic patients (71.7%) as compared with the observed frequency in the Northwestern Italian population (62.5%). The alterations in Hp phenotypic and genotypic distribution were more pronounced in the schizo-affective, disorganized, undifferentiated and residual schizophrenic patients than in paranoid schizophrenic patients. More than a third (35.7%) of the schizophrenic patients showed plasma Hp concentrations which were higher than the upper limits of normality. Schizophrenia is accompanied by an altered distribution of the Hp phenotypes and genotypes, suggesting that genetic variation on chromosome 16 may be associated with schizophrenia.

Previous studies have reported that the cAMP-dependent protein kinase and one of its substrates, namely Rap1, are altered in patients with affective disorders. Abnormalities in the cAMP-dependent protein kinase have also been reported in platelets of patients with obsessive compulsive disorder and schizophrenia. However, it remains to be determined whether abnormalities in Rap1 are specifically related to affective disorders or may also be present in schizophrenia and obsessive compulsive disorder. Thus, we investigated Rap1 in platelets from 12 drug-free patients with obsessive compulsive disorder, ten drug-free patients with schizophrenia, and 20 healthy subjects. While no difference was observed in the levels of Rap1 between groups, the phosphorylation state of Rap1 was significantly lower in patients with obsessive compulsive disorder than in schizophrenic patients and controls. These data further support the idea that abnormalities of cAMP signalling pathway could be associated, albeit in a somewhat different way, with several psychiatric disorders.

Abnormalities in the cAMP-dependent protein kinase (PKA), a central component of cAMP signaling, have been reported in several psychiatric disorders. Previous studies showed cAMP signaling alterations in schizophrenic patients but less is known about the involvement of PKA in such disorder. Therefore, we investigated the PKA subunits by Western blot analysis in platelets from 12 patients with schizophrenia and 13 controls. The results showed that the immunolabeling of the PKA regulatory subunits type I (RI) and type II (RII) was significantly reduced in patients compared with controls whereas no differences were observed in the catalytic (C) subunit of the enzyme. These preliminary data suggest that schizophrenic patients have altered PKA levels, thus supporting that dysfunctions in the components of cAMP signaling may contribute to the pathophysiology of schizophrenia.