The contribution of cannabis use to the increased psychosis risk among minority ethnic groups in Europe.

BACKGROUND: We examined whether cannabis use contributes to the increased risk of psychotic disorder for non-western minorities in Europe. METHODS: We used data from the EU-GEI study (collected at sites in Spain, Italy, France, the United Kingdom, and the Netherlands) on 825 first-episode patients and 1026 controls. We estimated the odds ratio (OR) of psychotic disorder for several groups of migrants compared with the local reference population, without and with adjustment for measures of cannabis use. RESULTS: The OR of psychotic disorder for non-western minorities, adjusted for age, sex, and recruitment area, was 1.80 (95% CI 1.39-2.33). Further adjustment of this OR for frequency of cannabis use had a minimal effect: OR = 1.81 (95% CI 1.38-2.37). The same applied to adjustment for frequency of use of high-potency cannabis. Likewise, adjustments of ORs for most sub-groups of non-western countries had a minimal effect. There were two exceptions. For the Black Caribbean group in London, after adjustment for frequency of use of high-potency cannabis the OR decreased from 2.45 (95% CI 1.25-4.79) to 1.61 (95% CI 0.74-3.51). Similarly, the OR for Surinamese and Dutch Antillean individuals in Amsterdam decreased after adjustment for daily use: from 2.57 (95% CI 1.07-6.15) to 1.67 (95% CI 0.62-4.53). CONCLUSIONS: The contribution of cannabis use to the excess risk of psychotic disorder for non-western minorities was small. However, some evidence of an effect was found for people of Black Caribbean heritage in London and for those of Surinamese and Dutch Antillean heritage in Amsterdam.

Longitudinal trajectories of psychosocial functioning in patients with pre-existing mental disorders after one year of COVID-19 pandemic.

Aims of the present study were to prospectively assess psychosocial functioning trajectories during the COVID pandemic and the possible impact of sociodemographic variables, as well as of COVID-19 pandemic-related factors, on these trajectories, in a sample of patients with pre-existing severe mental disorders. Moreover, we aimed at identifying predictors of impairment in psychosocial functioning over a period of 9 months of COVID-19 pandemic. Patients were recruited during the 3rd wave of the COVID-19 pandemic (T0, March-April 2021) while strict containment measures were applied in Italy, and reassessed after 3 months (T1, June-July 2021), and after 6 months from T1 (T2- November-December 2021), during the 4th wave of COVID pandemic. A sample of 300 subject (out of the 527 subjects recruited at baseline) completed the T2 evaluation. Patients were assessed by: Work and Social Adjustment Scale (WSAS) for psychosocial functioning, Generalized Anxiety Disorder 7-Item (GAD-7) for anxiety symptoms, Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms and the Impact of Events Scale-Revised, for post-traumatic symptoms. Cluster analyses identified 4 trajectories of functioning: the High, Stable Functioning group (N = 77), the Improvement Functioning group (N = 62), the Progressive Impairment group (N = 83) and the Persistent Severe Impairment group (N = 78) respectively. We found that predictors of higher WSAS score at T2 were higher WSAS score at T0 (B = 0.43, p < .001), PHQ scores at baseline >10 (B = 2.89, p < .05), while not living alone was found to be a protective factor (B = -2.5, p < .05). Results of the present study provides insights into the vulnerability of individuals with psychiatric disorders during times of crisis. Study findings can contribute to a better understanding of the specific needs of this population and inform interventions and support strategies.

Genetic and psychosocial stressors have independent effects on the level of subclinical psychosis: findings from the multinational EU-GEI study.

AIMS: Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample. METHODS: Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of 'Genetic' models (solely fitted with PRS-SZ), 'Environmental' models (solely fitted with each environmental stressor), 'Independent' models (with PRS-SZ and each environmental factor), and 'Interaction' models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models. RESULTS: There were no genes-environment associations. PRS-SZ was associated with positive dimensions (ß = 0.092, R2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension. CONCLUSIONS: This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum.

AIMS: Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum. METHODS: The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components). RESULTS: Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions. CONCLUSIONS: The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Gender and 5-years course of psychosis patients: focus on clinical and social variables.

Most studies on gender and psychosis have focused on gender differences at illness onset or on the long-term outcome, whereas little is known about the impact of gender on the first years after psychosis onset. A total of 185 first episode psychosis (FEP) patients were followed for 5 years after psychosis onset, and gender differences were explored in psychopathology (PANSS), needs for care (CAN), and insight (SAI-E). Male patients showed more negative symptoms than females over time, whereas female patients showed higher levels of depressive symptoms than males throughout the study period. In addition, female patients presented more functioning unmet needs for care, but higher levels of insight into illness than males. Therapy and rehabilitative programs for FEP patients should be gender-targeted, as gender has proved to impact on psychopathology, needs for care, and insight in the very first years following psychosis onset.

Influence of childhood trauma on diagnosis and substance use in first-episode psychosis.

BackgroundChildhood trauma has been significantly associated with first-episode psychosis, affective dysfunction and substance use.AimsTo test whether people with first-episode psychosis who had experienced childhood trauma, when compared with those who had not, showed a higher rate of affective psychosis and an increased lifetime rate of substance use.MethodThe sample comprised 345 participants with first-episode psychosis (58% male, mean age 29.8 years, s.d. = 9.7).ResultsSevere sexual abuse was significantly associated with a diagnosis of affective psychosis (χ2 = 4.9, P = 0.04) and with higher rates of lifetime use of cannabis (68% v 41%; P = 0.02) and heroin (20% v 5%; P = 0.02). Severe physical abuse was associated with increased lifetime use of heroin (15% v 5%; P = 0.03) and cocaine (32% v 17%; P = 0.05).ConclusionsPatients with first-episode psychosis exposed to childhood trauma appear to constitute a distinctive subgroup in terms of diagnosis and lifetime substance use.

Transcriptomic analyses and leukocyte telomere length measurement in subjects exposed to severe recent stressful life events.

Stressful life events occurring in adulthood have been found able to affect mood and behavior, thus increasing the vulnerability for several stress-related psychiatric disorders. However, although there is plenty of clinical data supporting an association between stressful life events in adulthood and an enhanced vulnerability for psychopathology, the underlying molecular mechanisms are still poorly investigated. Thus, in this study we performed peripheral/whole-genome transcriptomic analyses in blood samples obtained from 53 adult subjects characterized for recent stressful life events occurred within the previous 6 months. Transcriptomic data were analyzed using Partek Genomics Suite; pathway and network analyses were performed using Ingenuity Pathway Analysis and GeneMANIA Software. We found 207 genes significantly differentially expressed in adult subjects who reported recent stressful life experiences (n=21) compared with those without such experiences (n=32). Moreover, the same subjects exposed to such stressful experiences showed a reduction in leukocyte telomere length. A correlation analyses between telomere length and transcriptomic data indicated an association between the exposures to recent stressful life events and the modulation of several pathways, mainly involved in immune-inflammatory-related processes and oxidative stress, such as natural killer cell signaling, interleukin-1 (IL-1) signaling, MIF regulation of innate immunity and IL-6 signaling. Our data suggest an association between exposures to recent stressful life events in adulthood and alterations in the immune, inflammatory and oxidative stress pathways, which could be also involved in the negative effect of stressful life events on leukocyte telomere length. The modulation of these mechanisms may underlie the clinical association between the exposure to recent Stressful life events in adulthood and an enhanced vulnerability to develop psychiatric diseases in adulthood.

Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene.

Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.

Psychosis Incident Cohort Outcome Study (PICOS). A multisite study of clinical, social and biological characteristics, patterns of care and predictors of outcome in first-episode psychosis. Background, methodology and overview of the patient sample.

AIMS: This paper aims at providing an overview of the background, design and initial findings of Psychosis Incident Cohort Outcome Study (PICOS). METHODS: PICOS is a large multi-site population-based study on first-episode psychosis (FEP) patients attending public mental health services in the Veneto region (Italy) over a 3-year period. PICOS has a naturalistic longitudinal design and it includes three different modules addressing, respectively, clinical and social variables, genetics and brain imaging. Its primary aims are to characterize FEP patients in terms of clinical, psychological and social presentation, and to investigate the relative weight of clinical, environmental and biological factors (i.e. genetics and brain structure/functioning) in predicting the outcome of FEP. RESULTS: An in-depth description of the research methodology is given first. Details on recruitment phase and baseline and follow-up evaluations are then provided. Initial findings relating to patients' baseline assessments are also presented. Future planned analyses are outlined. CONCLUSIONS: Both strengths and limitations of PICOS are discussed in the light of issues not addressed in the current literature on FEP. This study aims at making a substantial contribution to research on FEP patients. It is hoped that the research strategies adopted in PICOS will enhance the convergence of methodologies in ongoing and future studies on FEP.

The influence of gender on clinical and social characteristics of patients at psychosis onset: A report from the Psychosis Incident Cohort Outcome Study (PICOS).

BACKGROUND. This paper examined the hypothesis that males with first-episode psychosis (FEP) experience lower pre-morbid adjustment, greater social disability and more self-perceived needs at illness onset than females(by controlling for duration of untreated psychosis, diagnosis, age and symptoms at onset). Results disconfirming this hypothesis were thought to suggest the potentially mediating role of social context in determining the impact of symptoms and disability on the everyday lives of male patients in the early phase of psychosis. METHOD. A large epidemiologically representative cohort of FEP patients (n=517) was assessed within the Psychosis Incident Cohort Outcome Study (PICOS) framework ­ a multi-site research project examining incident cases of psychosis in Italy's Veneto region. RESULTS. Despite poorer pre-morbid functioning and higher social disability at illness onset, males reported fewer unmet needs in the functioning domain than females did. An analysis of help provided by informal care givers showed that males received more help from their families than females did. This finding led us to disconfirm the second part of the hypothesis and suggest that the impact of poorer social performance and unmet needs on everyday life observed in male patients might be hampered by higher tolerance and more support within the family context.CONCLUSIONS. These findings shed new light on rarely investigated sociocultural and contextual factors that may account for the observed discrepancy between social disability and needs for care in FEP patients. They also point to a need for further research on gender differences, with the ultimate aim of delivering gender-sensitive effective mental health care.

Expanding the range of ZNF804A variants conferring risk of psychosis.

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Copy number variations of chromosome 16p13.1 region associated with schizophrenia.

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Yttrium-aluminum-garnet laser therapy of esophageal granular cell tumor.

BACKGROUND: Granular cell tumor (GCT) is a rare lesion. Approximately 4% to 6% of these tumors occur in the gastrointestinal tract, one-third of them affecting the esophagus. Almost all GCTs are benign lesions. Approximately 1% to 3% are malignant. Endoscopic ultrasonography (EUS) is a diagnostic support. The best treatment for esophageal GCT is not yet clear, whether surgical excision, periodic observation, endoscopic excision, or yttrium-aluminum-garnet (YAG) laser therapy. METHODS: From November 1992 to December 2000, four patients with GCTs of the esophagus were observed. All the patients underwent EUS evaluation and endoscopic YAG laser therapy of the esophageal neoplasm. At each session, a biopsy at the tumor site was obtained. The treatment was continued until endoscopic and histologic evidence of the tumor disappeared. RESULTS: After the YAG laser therapy, no evidence of the tumor was found in any of the four patients with esophageal GCT. At this writing, the patients remain disease free after a mean follow-up period of 66 months. No complication has been observed. Only four sessions for each patient were necessary to eliminate the tumor. CONCLUSIONS: Therapy with YAG laser was effective in all four patients with esophageal GCT, and complete necrosis of the submucosal neoplastic cells was achieved. Endoscopic YAG laser therapy appears to be a good compromise between esophageal dissection and long-term observation without tumor excision. Esophageal laser therapy is safe if correctly used, and previous EUS evaluation increases treatment safety.

Targeting of calsequestrin to sarcoplasmic reticulum after deletions of its acidic carboxy terminus.

Calsequestrin (CS) is the Ca(2+) binding protein of the junctional sarcoplasmic reticulum (jSR) lumen. Recently, a chimeric CS-HA1, obtained by adding the nine-amino-acid viral epitope hemagglutinin (HA1) to the COOH terminus of CS, was shown to be correctly segregated to the sarcoplasmic reticulum [A. Nori, K. A. Nadalini, A. Martini, R. Rizzuto, A. Villa, and P. Volpe. Am. J. Physiol. 272 (Cell Physiol. 41): C1420-C1428, 1997]. A putative targeting mechanism of CS to jSR implies electrostatic interactions between negative charges on CS and positive charges on intraluminal domains of jSR integral proteins, such as triadin and junctin. To test this hypothesis, 2 deletion mutants of chimeric CS were engineered: CS-HA1DeltaGlu-Asp, in which the 14 acidic residues [-Glu-(Asp)(5)-Glu-(Asp)(7)-] of the COOH-terminal tail were removed, and CS-HA1Delta49(COOH), in which the last, mostly acidic, 49 residues of the COOH terminus were removed. Both mutant cDNAs were transiently transfected in HeLa cells, myoblasts of rat skeletal muscle primary cultures, or regenerating soleus muscle fibers of adult rats. The expression and intracellular localization of CS-HA1 mutants were studied by epifluorescence microscopy with use of antibodies against CS or HA1. CS-HA1 mutants were shown to be expressed, sorted, and correctly segregated to jSR. Thus short or long deletions of the COOH-terminal acidic tail do not influence the targeting mechanism of CS.