Empirical validity of Leonhard's psychoses: A long-term follow-up study of first-episode psychosis patients.

The validation of nosological diagnoses in psychiatry remains a conundrum. Leonhard's (1979) nosology seems to be one of the few acceptable alternative categorical models to current DSM/ICD systems. We aimed to empirically validate Leonhard's four classes of psychoses: systematic schizophrenia (SSch), unsystematic (USch), cycloid psychosis (Cyclo), and manic-depressive illness (MDI) using a comprehensive set of explanatory validators. 243 patients with first-episode psychosis were followed between 10 and 31 years. A wide-ranging assessment was carried out by collecting data on antecedent, illness-related, concurrent, response to treatment, neuromotor abnormalities, and cognitive impairment variables. Compared with USch, Cyclo, and MDI, SSch displayed a pattern of impairments significantly larger across the seven blocks of explanatory variables. There were no significant differences between Cyclo and MDI in explanatory variables. Except for the majority of illness-onset features, USch displayed more substantial abnormalities in the explanatory variables than Cyclo and MDI. SSch and MDI showed higher percentages of correctly classified patients than USch and Cyclo in linear discriminant analyses. Partial validation of Leonhard's classification was found. SSch showed differences in explanatory variables with respect to Cyclo and MDI. USch showed also significant differences in explanatory variables regarding Cyclo and MDI, although with a lower strength than SSch. There was strong empirical evidence of the separation between both Leonhard's schizophrenia subtypes; however, the distinction between the Cyclo and MDI groups was not empirically supported. A mild to moderate discriminative ability between Leonhard's subtypes on the basis of explanatory blocks of variables was observed.

Effect of polygenic risk score, family load of schizophrenia and exposome risk score, and their interactions, on the long-term outcome of first-episode psychosis.

BACKGROUND: Consistent evidence supports the involvement of genetic and environmental factors, and their interactions, in the etiology of psychosis. First-episode psychosis (FEP) comprises a group of disorders that show great clinical and long-term outcome heterogeneity, and the extent to which genetic, familial and environmental factors account for predicting the long-term outcome in FEP patients remains scarcely known. METHODS: The SEGPEPs is an inception cohort study of 243 first-admission patients with FEP who were followed-up for a mean of 20.9 years. FEP patients were thoroughly evaluated by standardized instruments, with 164 patients providing DNA. Aggregate scores estimated in large populations for polygenic risk score (PRS-Sz), exposome risk score (ERS-Sz) and familial load score for schizophrenia (FLS-Sz) were ascertained. Long-term functioning was assessed by means of the Social and Occupational Functioning Assessment Scale (SOFAS). The relative excess risk due to interaction (RERI) was used as a standard method to estimate the effect of interaction of risk factors. RESULTS: Our results showed that a high FLS-Sz gave greater explanatory capacity for long-term outcome, followed by the ERS-Sz and then the PRS-Sz. The PRS-Sz did not discriminate significantly between recovered and non-recovered FEP patients in the long term. No significant interaction between the PRS-Sz, ERS-Sz or FLS-Sz regarding the long-term functioning of FEP patients was found. CONCLUSIONS: Our results support an additive model of familial antecedents of schizophrenia, environmental risk factors and polygenic risk factors as contributors to a poor long-term functional outcome for FEP patients.

Neurocognitive correlates of the varied domains of outcomes at 20 year follow-up of first-episode psychosis.

Little is known about long-term outcomes of the first episode of psychosis (FEP) other than in the symptomatic domain. We hypothesised that cognitive impairment is associated with poorer multi-domain outcomes at a long-term follow-up of FEP patients. We followed-up 172 FEP patients for a mean of 20.3 years. Ten outcome dimensions were assessed (symptomatic, functional and personal recovery, social disadvantage, physical health, suicide attempts, number of episodes, current drug use, chlorpromazine equivalent doses (CPZ), and schizophrenia/schizoaffective disorder final diagnosis). Cognition was assessed at follow-up. Processing speed and verbal memory deficits showed significant associations with poor outcomes on symptomatic, social functioning, social disadvantage, higher number of episodes, and higher CPZ. Significant associations were found between visual memory impairments were significantly associated with low symptomatic and functional recovery, between attentional deficits and a final diagnosis of schizophrenia/schizoaffective disorder, and between social cognition deficits and poor personal recovery.Lower cognitive global scores were significantly associated with all outcome dimensions except for drug abuse and physical status. Using multiple outcome dimensions allowed for the inclusion of the patients' perspective and other commonly neglected outcome measures. Taken together, cognitive impairment in FEP patients is strongly related to poor performance on several outcome dimensions beyond symptomatic remission.

Association and epistatic analysis of white matter related genes across the continuum schizophrenia and autism spectrum disorders: The joint effect of NRG1-ErbB genes.

BACKGROUND: Schizophrenia-spectrum disorders (SSD) and Autism spectrum disorders (ASD) are neurodevelopmental disorders that share clinical, cognitive, and genetic characteristics, as well as particular white matter (WM) abnormalities. In this study, we aimed to investigate the role of a set of oligodendrocyte/myelin-related (OMR) genes and their epistatic effect on the risk for SSD and ASD. METHODS: We examined 108 SNPs in a set of 22 OMR genes in 1749 subjects divided into three independent samples (187 SSD trios, 915 SSD cases/control, and 91 ASD trios). Genetic association and gene-gene interaction analyses were conducted with PLINK and MB-MDR, and permutation procedures were implemented in both. RESULTS: Some OMR genes showed an association trend with SSD, while after correction, the ones that remained significantly associated were MBP, ERBB3, and AKT1. Significant gene-gene interactions were found between (i) NRG1*MBP (perm p-value = 0.002) in the SSD trios sample, (ii) ERBB3*AKT1 (perm p-value = 0.001) in the SSD case-control sample, and (iii) ERBB3*QKI (perm p-value = 0.0006) in the ASD trios sample. DISCUSSION: Our results suggest the implication of OMR genes in the risk for both SSD and ASD and highlight the role of NRG1 and ERBB genes. These findings are in line with the previous evidence and may suggest pathophysiological mechanisms related to NRG1/ERBBs signalling in these disorders.

Monoamine oxidase A (MAOA) interaction with parenting practices on callous-unemotional traits in preschoolers

Background and Objectives: From a gene-by-environment perspective, parenting in interaction with the polymorphism in the Monoamine oxidase A (MAOA) gene (MAOA-uVNTR) might also be associated with increased callous-unemotional traits (CU) in preschoolers. MAOA-uVNTR results in differential enzyme activity, so that high-activity alleles (MAOA-H) are linked to reduced dopamine, serotonin, and norepinephrine availability in comparison to low-activity allele (MAOA-L). As MAOA-uVNTR has been previously described to moderate the relationship between childhood parental maltreatment and aggressive and antisocial behavior, it may also play a role in CU traits etiology.MethodsData was collected through questionnaires answered by parents and teachers. MAOA-uVNTR was genotyped in 368 Caucasian children from a community sample (51.9% male). Multiple linear regression analyses were conducted to analyze the interaction effect of MAOA genotypes and both positive parenting and punitive parenting practices on CU traits at two different periods (3 and 5 years old) and separately by sex.ResultsNo significant interactions were found for boys. Among girls, a significant interaction effect was found for MAOA-LL carriers, who showed higher CU traits at age 5 when exposed to higher punitive or positive parenting at age 3.ConclusionsOur study provides the first evidence for significant MAOA × early parenting effects on CU traits in preschoolers, specifically among female MAOA-LL carriers. This suggests that the MAOA-LL genotype for girls is associated with higher sensitivity to both positive and punitive parenting in girls, so that MAOA-LL emerges as a genotype that confers higher vulnerability to parental influences. (AU)

The effect of the AKT1 gene and cannabis use on cognitive performance in healthy subjects.

BACKGROUND: Evidence suggests that the AKT1 gene may modulate the degree to which cannabis use induces cognitive alterations in patients with a psychotic disorder. AIM: To examine the interplay between AKT1 and cannabis use in terms of the cognitive performance of the general population. METHODS: Our sample consisted of 389 Spanish university students. Sustained attention was measured via the Continuous Performance Test-Identical Pairs, immediate and delayed verbal memory with the Logical Memory subtest of the Wechsler Memory Scale, and working memory with the Wisconsin Card Sorting Test. Lifetime cannabis use frequency was assessed and individuals were classified as cannabis users or non-users. Two single nucleotide polymorphisms of the AKT1 gene were genotyped and, according to previous studies, each subject was defined as a carrier of two, one or no copies of the haplotype (rs2494732(C)-rs1130233(A)). Multiple linear regressions were conducted to test the effect of the genetic variability and cannabis use (and their interaction) on cognitive performance. RESULTS: An effect of the AKT1 haplotype was found on attention scores: individuals with two copies of the haplotype performed better (ß=0.18, p<0.001 (adjusted for false discovery rate)), while neither cannabis nor the AKT1-cannabis interaction was associated with attention. No effect of AKT1, cannabis or the AKT1-cannabis interaction was found on verbal memory or working memory. CONCLUSIONS: Our study provides additional evidence that AKT1 modulates cognitive performance. However, in our non-clinical sample, the previously reported interaction between cannabis use and the AKT1 gene was not replicated.

The role of schizotypal traits and the OXTR gene in theory of mind in schizophrenia: A family-based study.

BACKGROUND: There is consistent evidence that theory of mind (ToM) is impaired in schizophrenia (SZ); however, it remains unclear whether such deficits are trait- or state-dependent. We evaluated ToM in patients with schizophrenia spectrum disorders (SSDs), their healthy first-degree relatives, and controls to test its suitability as an endophenotypic marker. We also studied the modifying effect of markers of clinical and genetic liability to SZ (schizotypy and genetic variability in the oxytocin receptor gene: OXTR) on ToM in healthy individuals. METHODS: The sample included 38 stable SSD patients, 80 unaffected first-degree relatives, and 81 controls. ToM was assessed using the Hinting Task (HT) and schizotypy via the Schizotypal Personality Questionnaire-Brief (SPQ-B), which generates interpersonal (SPQ-IP), cognitive-perceptual (SPQ-CP), and disorganization (SPQ-D) scores. The polymorphism rs53576 of OXTR was genotyped. RESULTS: Patients presented poorer HT performance than relatives and controls (p = 0.003 and p < 0.001). High SPQ-IP and SPQ-CP scores correlated with poorer ToM performance in relatives (p = 0.010 and p = 0.030), but not in controls. OXTR was not associated with HT scores, but it showed a modifying effect within controls; high SPQ-CP was related to HT poorer performance conditional to GG genotype (p = 0.007). CONCLUSIONS: ToM deficits were present in patients but not in unaffected relatives or controls. However, our data indicate the usefulness of clinical and genetic liability markers to characterize differences in ToM abilities within healthy individuals. Then, the observed link between ToM and SZ liability suggests the putative role of ToM as an endophenotypic marker. Nevertheless, new analyses in larger samples are needed.

The synergetic effect of childhood trauma and recent stressful events in psychosis: associated neurocognitive dysfunction.

BACKGROUND: A higher incidence of childhood trauma (CT) has been reported in first episode of psychosis (FEP). There is, however, a lack of knowledge about the synergetic effect between CT and recent stressful events (RSE). METHODS: Information on specific types of CT (under 17 years) and RSE (within the past 3 years) was available for 290 FEP patients and 52 healthy controls (HC). Cognitive function at baseline was assessed through a comprehensive neuropsychological test battery. RESULTS: While 45.2% of FEP patients and 25% of HC reported at least one CT event, 62.7% of FEP and 21.2% of HC reported an RSE. Meanwhile, 36.2% of FEP patients and 9.6% of HC encountered both childhood and recent stressful events. The patients that just reported CT showed normality in all but the verbal memory cognitive domain; those with additive CT and RSE presented worse general cognitive function, specifically on working memory, processing speed, and executive function. RSE and general cognitive dysfunction were significant determinants of psychosis onset. CONCLUSIONS: These results support a synergetic influence of trauma and stressful events on brain function and allow a better understanding of mediators for psychotic disorders useful in the design of specific strategies based on stress-targeted therapies.

Epigenetics-by-sex interaction for somatization conferred by methylation at the promoter region of SLC6A4 gene.

BACKGROUND: Depression, anxiety and somatoform disorders are all more prevalent in women than in men. However, specific biological mechanisms contributing to such sex differences remain unknown. Serotonergic pathways are involved in mood and behavior regulation and thus have been suggested to be altered in several psychiatric disorders. The serotonin transporter (SERT), encoded by SLC6A4 gene, has received major attention due to its crucial role in serotonergic transmission. METHODS: 148 monozygotic twin subjects were assessed for (i) lifetime categorical diagnosis of anxious-depressive disorders, following SCID-I-based DSM-IV criteria, and (ii) current psychiatric symptomatology, from a dimensional approach, by means of the Brief Symptom Inventory (BSI). SLC6A4 gene methylation was analyzed by means of Infinium HumanMethylation450 in a subset of the sample. CpG-specific methylation at the promoter region of SLC6A4 gene was further analyzed by means of pyrosequencing technology in the total sample. RESULTS: SLC6A4 methylation was found to be significantly higher in women when compared to men independent of DSM-IV diagnosis. SLC6A4 methylation was further associated with the BSI-derived somatization dimension. CONCLUSIONS: Female hypermethylation of a discrete region located within SLC6A4 promoter region could underlie differential SERT expression in women when compared to men and could be one of the causative mechanisms by which women exhibit increased prevalence of somatic symptoms.

Neurotrophins role in depressive symptoms and executive function performance: Association analysis of NRN1 gene and its interaction with BDNF gene in a non-clinical sample.

BACKGROUND: Neuritin-1 is a neurotrophic factor involved in synaptic plasticity that has been associated with depressive disorders, schizophrenia and cognitive performance. The study of genotype-phenotype relationships in healthy individuals is a useful framework to investigate the etiology of brain dysfunctions. We therefore aimed to investigate in a non-clinical sample whether NRN1 gene contributes to the psychopathological profile, with a particular focus on the clinical dimensions previously related to the NRN1 gene (i.e. depressive and psychotic). Furthermore, we aimed to analyze: i) the role of NRN1 on executive functions, ii) whether the association between either NRN1-psychopathological profile or NRN1-cognitive performance is moderated by the BDNF gene. METHODS: The sample comprised 410 non-clinical subjects who filled in the self-reported Brief Symptom Inventory (BSI) and were assessed for executive performance (Verbal Fluency, Wisconsin Card Sorting Test (WCST) and Letter-Number subscale (WAIS-III)). Genotyping included nine SNPs in NRN1 and one in BDNF. RESULTS: i) GG homozygotes (rs1475157-NRN1) showed higher scores on BSI depressive dimension and on total scores compared to A carriers (corrected p-values: 0.0004 and 0.0003, respectively). ii) a linear trend was detected between GG genotype of rs1475157 and a worse cognitive performance in WCST total correct responses (uncorrected p-value: 0.029). iii) Interaction between rs1475157-NRN1 and Val66Met-BDNF was found to modulate depressive symptoms (p=0.001, significant after correction). LIMITATIONS: Moderate sample size; replication in a larger sample is needed. CONCLUSIONS: NRN1 is associated with depressive symptoms and executive function in a non-clinical sample. Our results also suggest that the role of NRN1 seems to be modulated by BDNF.

Familial aggregation of schizotypy in schizophrenia-spectrum disorders and its relation to clinical and neurodevelopmental characteristics.

INTRODUCTION: This study explored schizotypy as a familial liability marker for schizophrenia-spectrum disorders (SSD) by examining: 1) the aggregation of schizotypy in families with a SSD patient, 2) whether familial resemblance of schizotypy is associated with ridge dissociations (RD), another SSD liability marker, 3) whether schizotypy aggregation patterns influence patients' psychopathology. METHODS: The sample comprised 30 SSD patients and 82 healthy first-degree relatives. Schizotypy was assessed using the Structured Interview for Schizotypy-Revised (SIS-R). Patients' psychopathology was evaluated using the Comprehensive Assessment of Symptoms and History (CASH). RD were identified as anomalies of the dermal ridge junction. Familiality of SIS-R was investigated using a linear mixed model (LMM) and its strength was assessed using an intraclass correlation coefficient (ICC). Another LMM using the absolute differences in SIS-R scores between all possible pairs of relatives as the dependent variable was fitted to obtain an intra-family resemblance score, a family-specific indicator of resemblance of SIS-R scores within each family. RESULTS: 1) Schizotypy was familial (ICC = 0.30); families with high resemblance displayed low schizotypy, whereas families with low resemblance included at least one healthy relative with high schizotypy (p < 0.001). 2) Relatives with RD had higher SIS-R scores (p = 0.018) and belonged to families with discordant schizotypy scores among members (p < 0.001). 3) Patients from high schizotypy families showed more severe disorganized symptoms at the psychotic episode (p = 0.035) and 1 year later (p = 0.011). CONCLUSIONS: Schizotypy is a marker of vulnerability for SSD that runs within a subgroup of families. The schizotypy familial aggregation pattern correlates with RD in relatives and with patients' psychopathology.

An integrative review of methylation at the serotonin transporter gene and its dialogue with environmental risk factors, psychopathology and 5-HTTLPR.

Gene-environment (G×E) interactions have largely been regarded as the root of many complex disorders, including several psychiatric disorders. In this regard, it has been hypothesized that epigenetic mechanisms may be the main mediators of such interactions. Of particular interest is the previously described interaction between psychosocial stress and genetic variability of the serotonin transporter gene (SLC6A4) in its polymorphic region 5-HTTLPR. Here we review the literature concerning SLC6A4 methylation in association with environmental, clinical or genetic variables. While SLC6A4 hypermethylation has typically been described to be independently associated with both early life stress and depressive disorders, only a few papers address whether methylation could mediate the interaction between stress and 5-HTTLPR in predicting psychopathological risk. Nevertheless, research preliminarily indicates a methylation-driven increased vulnerability of carriers of the short allele of 5-HTTLPR to psychiatric disorders when exposed to early stress or soon after exposure to stress.

Evidence of an epistatic effect between Dysbindin-1 and Neuritin-1 genes on the risk for schizophrenia spectrum disorders.

BACKGROUND: The interest in studying gene-gene interactions is increasing for psychiatric diseases such as schizophrenia-spectrum disorders (SSD), where multiple genes are involved. Dysbindin-1 (DTNBP1) and Neuritin-1 (NRN1) genes have been previously associated with SSD and both are involved in synaptic plasticity. We aimed to study whether these genes show an epistatic effect on the risk for SSD. METHODS: The sample comprised 388 SSD patients and 397 healthy subjects. Interaction was tested between: (i) three DTNBP1 SNPs (rs2619537, rs2743864, rs1047631) related to changes in gene expression; and (ii) an haplotype in NRN1 previously associated with the risk for SSD (rs645649-rs582262: HAP-risk C-C). RESULTS: An interaction between DTNBP1 rs2743864 and NRN1 HAP-risk was detected by using the model based multifactor dimensionality reduction (MB-MDR) approach (P=0.0049, after permutation procedure), meaning that the risk for SSD is significantly higher in those subjects carrying both the A allele of rs2743864 and the HAP-risk C-C. This interaction was confirmed by using a logistic regression model (P=0.033, OR (95%CI)=2.699 (1.08-6.71), R2=0.162). DISCUSSION: Our results suggest that DTNBP1 and NRN1 genes show a joint effect on the risk for SSD. Although the precise mechanism underlying this effect is unclear, the fact that these genes have been involved in synaptic maturation, connectivity and glutamate signalling suggests that our findings could be of value as a link to the schizophrenia aetiology.

Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study.

BACKGROUND: Glutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients' cognitive performance. METHODS: The sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses. RESULTS: The haplotype GAGACT at DAOA was under-transmitted to patients (P=0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P=0.018) in SZ patients only. RGS4 analyses did not report significant results. CONCLUSIONS: Our findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling.

Effect of DISC1 polymorphisms on the long-term course of neurocognitive deficits in non-affective psychosis.

Neurocognitive deficits are core symptoms of schizophrenia that determine a poorer outcome. High variability in the progression of neuropsychological deficits in schizophrenia has been described. It is still unknown whether genetic variations can affect the course of cognitive deficits. Variations in the Disrupted in Schizophrenia 1 (DISC1) gene have previously been associated with neurocognitive deficits. This study investigated the association between 3 DISC1 polymorphisms (rs6675281 (Leu607Phe), rs1000731, and rs821616 (Ser704Cys)) and long-term (3 years) cognitive performance. One-hundred-thirty-three Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped. Cognitive function was assessed at baseline and after 3 years of initiating treatment. Other clinical and socio-demographic variables were recorded to eliminate potential confounding effects. Patients carrying the A allele of rs1000731 exhibited a significant improvement in Working Memory and Attention domains, and the homozygosity of the A allele of rs821616 showed a significant improvement in Motor Dexterity performance over 3 years of follow-up. In conclusion, DISC1 gene variations may affect the course of cognitive deficits found in patients suffering from the first episode of non-affective psychosis.

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis.

Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across 5 consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05-0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.

Further evidence of DEPDC7 DNA hypomethylation in depression: A study in adult twins.

Late and early stressful factors have widely been recognized to play a role in the aetiology of depression. Recent research indicates that such adverse environmental stimuli may alter gene expression in humans via epigenetic modifications. While epigenetic changes such as DNA methylation are likely involved in these processes, it is still unknown what specific genomic loci may be hyper- or hypo-methylated in depression. The association between depressive symptoms during the last 30 days (Brief Symptom Inventory [BSI]) and peripheral-blood DNA methylation levels at genomic loci previously reported as epigenetically altered in saliva and brain of depressive patients was evaluated in a community sample of 34 adult Caucasian MZ twins (17 pairs). Intrapair DNA methylation differences in an intron of DEPDC7 (chr11:33040743) were associated with intrapair differences in current depressive symptoms. Accordingly, a site-specific 10% DNA hypomethylation in a co-twin would correlate with a current depressive symptom score around 3.1 BSI points above the score of his/her less-depressed co-twin. These findings indicate that DEPDC7 hypomethylation in peripheral blood DNA may be associated with recent depressive symptomatology, in line with previous results.