Cognitive Inflexibility Predicts Negative Symptoms Severity in Patients with First-Episode Psychosis: A 1-Year Follow-Up Study.

Negative symptoms and cognitive deficits play a major role in psychosis and significantly influence the functional outcomes of patients, particularly those with a first episode of psychosis (FEP). However, limited research has explored the predictive capacity of cognitive deficits during FEP for subsequent negative symptomatology. Drawing from the Athens FEP research study, we conducted a retrospective longitudinal study in 80 individuals with FEP. All patients were drug naive at admission. Cognitive tests were administered at 1-month and 1-year post-admission, while negative symptomatology was assessed at the same time points using PANSS by trained raters. We considered confounding factors such as age, gender, duration of untreated psychosis (DUP), treatment received, premorbid social adjustment, and premorbid IQ. Univariate regression analysis identified cognitive domains that correlated with negative symptomatology. These, along with the confounders, were incorporated into a multiple regression, with the 1-year PANSS negative scale serving as the dependent variable. Employing the backward elimination technique, we found a statistically significant inverse relationship between the categories completed in the Wisconsin card sorting test (WCST) and the 1-year PANNS negative scale (p = 0.01), beyond the associations with DUP and the 1-month PANSS negative scale. Our results suggest that cognitive flexibility, a key component of executive functions, predicts negative symptom severity one year after FEP.

Diminished social motivation in early psychosis is associated with polygenic liability for low vitamin D.

Insufficiency of vitamin D levels often occur in individuals with schizophrenia and first-episode psychosis (FEP). However, it is unknown whether this represents a biological predisposition, or it is essentially driven by illness-related alterations in lifestyle habits. Lower vitamin D has also been associated with adverse neurodevelopmental outcomes and predominant negative psychotic symptoms. This study aimed to investigate the contribution of polygenic risk score for circulating 25-hydroxyvitamin D concentration (PRS-vitD) to symptom presentation among individuals with FEP enrolled in the Athens First-Episode Psychosis Research Study (AthensFEP n = 205) and the Psychosis Incident Cohort Outcome Study (PICOS n = 123). The severity of psychopathology was evaluated using the Positive and Negative Syndrome Scale at baseline and follow-up assessments (AthensFEP: 4-weeks follow-up, PICOS: 1-year follow-up). Premorbid intelligence and adjustment domains were also examined as proxy measures of neurodevelopmental deviations. An inverse association between PRS-vitD and severity of negative symptoms, in particular lack of social motivation, was detected in the AthensFEP at baseline (adjusted R2 = 0.04, p < 0.001) and follow-up (adjusted R2 = 0.03, p < 0.01). The above observation was independently validated in PICOS at follow-up (adjusted R2 = 0.06, p < 0.01). No evidence emerged for a relationship between PRS-vitD and premorbid measures of intelligence and adjustment, likely not supporting an impact of lower PRS-vitD on developmental trajectories related to psychotic illness. These findings suggest that polygenic vulnerability to reduced vitamin D impairs motivation and social interaction in individuals with FEP, thereby interventions that encourage outdoor activities and social engagement in this patient group might attenuate enduring negative symptoms.

Role of Clinical Insight at First Month in Predicting Relapse at the Year in First Episode of Psychosis (FEP) Patients.

INTRODUCTION: Clinical insight constitutes a useful marker of the progress and outcome of the First Episode of Psychosis (FEP), and lack of insight has been associated with more severe psychopathology, treatment non-adherence, and rehospitalization/relapse. In this study, we aimed to further investigate the possible role of insight as a predictor of relapse, its relation to diagnosis, and other parameters of positive psychotic symptomatology (delusions, hallucinations, and suspiciousness). METHODS: The Athens FEP study employed a prospective, longitudinal cohort design in which consecutive newly diagnosed patients with psychosis were interviewed and asked to voluntarily participate after completing informed consent. A total of 88/225 patients were examined at three different time points (baseline, month, and year). Their scores in the relevant items of the Positive and Negative Syndrome Scale (PANSS) were compared (G12 for insight, P1 for delusions, P3 for hallucinations, and P6 for suspiciousness), and they were further associated to diagnosis and the outcome at the end of the year (remission/relapse). RESULTS: In total, 22/88 patients with relapse at the year had greater scores in G12 for both the month and the year, and this finding was corroborated after adjusting the statistical analysis for demographics, diagnosis, social environment, and depression via multiple logistic regression analysis. Moreover, delusions and suspiciousness were significantly higher in patients diagnosed with non-affective psychosis compared to those diagnosed with affective psychosis (p < 0.001) at the first month. CONCLUSIONS: Lack of insight at the first month may serve as a predictor of relapse at the year.

A Missense Variant in CASKIN1's Proline-Rich Region Segregates with Psychosis in a Three-Generation Family.

The polygenic nature of schizophrenia (SCZ) implicates many variants in disease development. Rare variants of high penetrance have been shown to contribute to the disease prevalence. Whole-exome sequencing of a large three-generation family with SCZ and bipolar disorder identified a single segregating novel, rare, non-synonymous variant in the gene CASKIN1. The variant D1204N is absent from all databases, and CASKIN1 has a gnomAD missense score Z = 1.79 and pLI = 1, indicating its strong intolerance to variation. We find that introducing variants in the proline-rich region where the D1204N resides results in significant cellular changes in iPSC-derived neurons, consistent with CASKIN1's known functions. We observe significant transcriptomic changes in 368 genes (padj < 0.05) involved in neuronal differentiation and nervous system development. We also observed nominally significant changes in the frequency of action potentials during differentiation, where the speed at which the edited and unedited cells reach the same level of activity differs. Our results suggest that CASKIN1 is an excellent gene candidate for psychosis development with high penetrance in this family.

Association of Alcohol Use Disorder Risk With ADH1B, DRD2, FAAH, SLC39A8, GCKR, and PDYN Genetic Polymorphisms.

BACKGROUND/AIM: Alcohol use disorder (AUD) is a chronic, multifactorial psychiatric condition with an enormous impact on public health and social cost. Genetic studies suggest a heritability, and genome-wide association studies (GWAS) have revealed genetic polymorphisms influencing AUD development. Our study aimed to investigate known variants located in ADH1B, DRD2, FAAH, SLC39A8, GCKR, and PDYN genes (rs1229984, rs7121986, rs324420, rs13107325, rs1260326, rs2281285 respectively) in an AUD Greek cohort in order to shed more light on the genetic predisposition to AUD. MATERIALS AND METHODS: Alcohol-dependent individuals (n=251) meeting both the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the ICD-10 guidelines for alcohol abuse and dependence, and control individuals (n=280) were recruited. DNA was extracted from whole blood and PCR-restriction fragment length polymorphism (RFLP-PCR) or allele-specific PCR method was used for genotyping. RESULTS: Individuals carrying the FAAH rs324420 A allele were significantly associated with increased risk of AUD (p<0.0001). SLC39A8 rs13107325 T allele and ADH1B rs1229984 T allele are overrepresented in control subjects (p<0.0001 and p<0.0001, respectively). The associations are maintained following an adjustment for age and sex and Bonferroni correction. GCKR rs13107325, DRD2 rs7121986, and PDYN rs2281285 polymorphisms did not show a significant association with AUD in the studied population after Bonferroni correction. CONCLUSION: Susceptibility to AUD is related to variations in FAAH, ADH1B, and SLC39A8 genes. These polymorphisms could serve as potential biomarkers for AUD risk.

Don't blame psychosis, blame the lack of services: a message for early intervention from the Greek standard care model.

BACKGROUND: Early Intervention Services (EIS) aim to reduce relapse rates and achieve better treatment and functional outcomes for first episode psychosis (FEP) patients. Existing models of services in Greece are still treatment as usual (TAU), however a reform of mental health services is underway and initial steps have been taken to shift standard care towards EIS. The purpose of the study is to address therapeutic gaps by exploring service engagement and relapse rates in the current standard care model for psychosis. METHODS: We examined follow-up and relapse rates one year after initial treatment contact in the first longitudinal FEP study conducted in Greece. 225 patients were enrolled between 2015-2020. Sociodemographic, clinical and functional characteristics were assessed in association with follow-up and relapse rates. RESULTS: Within a TAU follow-up setting, one year attrition rates were high. Only 87 patients (38,7%) retained contact with services after one year and within this time frame, 19 of them (21,8%) experienced a severe relapse requiring rehospitalization. Demographic, clinical and functional contributors failed to predict service engagement and relapse rates, with the exception of treatment adherence. CONCLUSION: Both follow-up and one-year rehospitalization rates in our FEP sample, highlight the need for the implementation of early intervention services, that will aim at engagement maximization and relapse prevention. These indexes also provide a benchmark against which future early intervention services for psychosis in Greece will have to demonstrate superior efficacy.

Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability.

Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility. Over-expression of C4A has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity, CUB and Sushi multiple domains 1 (CSMD1) gene, has been implicated in SZ risk and cognitive ability. Herein, we examined C4A and CSMD1 mRNA expression in peripheral blood from antipsychotic-naive individuals with first-episode psychosis (FEP; n = 73) and mentally healthy volunteers (n = 48). Imputed C4 locus structural alleles and C4A serum protein levels were investigated. Associations with symptom severity and cognitive domains performance were explored. A significant decrease in CSMD1 expression levels was noted among FEP patients compared to healthy volunteers, further indicating a positive correlation between C4A and CSMD1 mRNA levels in healthy volunteers but not in FEP cases. In addition, C4 copy number variants previously associated with SZ risk correlated with higher C4A mRNA levels in FEP cases, which confirms the regulatory effect of C4 structural variants on gene expression. Evidence also emerged for markedly elevated C4A serum concentrations in FEP cases. Within the FEP patient group, higher C4A mRNA levels correlated with more severe general psychopathology symptoms and lower CSMD1 mRNA levels predicted worse working memory performance. Overall, these findings suggest C4A complement pathway perturbations in individuals with FEP and corroborate the involvement of CSMD1 in prefrontal-mediated cognitive functioning.

The relationship between early symptom severity, improvement and remission in first episode psychosis with jumping to conclusions.

It is suggested that Jumping To Conclusions (JTC) reasoning bias might contribute to the distortion of external reality. However, the association between psychotic manifestations and JTC is obscure, especially if general intelligence is considered as a mediator. The aim of this study is to investigate the relation between severity, early clinical improvement and remission of symptoms in First Episode Psychosis (FEP) with JTC as an explanatory factor. One hundred seventy-one FEP individuals were evaluated with the Positive and Negative Syndrome Scale (PANSS) at baseline and one month after treatment initiation. Clinical improvement was ascribed as symptom change one-month post-baseline measurements. Symptomatic remission was assessed with the Andreasen severity criteria and JTC with the Beads Task, operationalized through Draws To Decision (DTD) (the lower the number of DTD, the higher the JTC bias). Regarding symptoms severity, total psychotic, total positive psychotic, and hallucinations-item PANSS scores showed a negative association with JTC after controlling for IQ. Regarding early clinical improvement, the association with JTC was non-significant. No significant association was detected between one month remission status of FEP and JTC. Our findings indicate that severity of positive symptoms is not associated with hastiness in decision-making, but rather with a heightened conservatism in terms of increased data gathering. Further research is required to replicate the results and clarify the cognitive processes involved.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Organization framework and preliminary findings from the Athens First-Episode Psychosis Research Study.

AIMS: Athens First-Episode Psychosis (FEP) Research study, aims to explore the potential associations between multiple genetic, environmental and neurometabolic risk factors of psychotic disorders, through the clinical management of FEP patients with minimal exposure (<2 weeks) to antipsychotic treatment at entry. The goal of this paper is to introduce the background, rationale and design of the study and present its preliminary findings. METHODS: We developed a longitudinal cohort study of FEP patients 16-45 years old, presenting at the emergency units of five psychiatric hospitals across Athens, Greece. Research timeline includes baseline, 1-month and 1-year follow-up. Clinical, genetic, environmental, cognitive and biochemical parameters are measured, using psychometric tools, clinical interviews and laboratory tests. A descriptive analysis of baseline and 1-month assessments was performed including demographic characteristics, family history, medication, clinical picture, traumatic experiences, drug use and cognitive functioning. RESULTS: During the last 3 years, 130 subjects have been enrolled in the study. Data so far reveal that, despite the severity of baseline presentation, at 1-month the majority (57.4%) met the Andreasen symptom severity criteria for remission, without the time criterion and showed mild functional improvement. Several environmental adversities and poor cognitive performance were identified, which need to be further elaborated. CONCLUSIONS: Athens FEP Research study is the first gene-environment interaction study in Greece. In this article we introduce the organization and methodological framework of the project, along with its basic initial findings. Future analysis will allow the validation of tractable predictors and risk factors implicated in the development and outcome of psychosis.

Screening Human Embryos for Polygenic Traits Has Limited Utility.

The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

No additive effect of cannabis on cognition in schizophrenia.

BACKGROUND: We aimed to examine the association between lifetime cannabis use and estimates of both premorbid and current cognitive function in psychotic disorders in an Australian cohort. METHODS: In an Australian multicenter cohort, 1237 participants with an established ICD-10 diagnosis of psychotic disorder were categorised according to history of lifetime cannabis use (non-users, n=354; cannabis users, n=221; cannabis dependency, n=662). Groups were analyzed according to available indices of cognitive ability: the National Adult Reading Test - Revised (NART-R) for ability prior to illness onset; and the Digit Symbol Coding Test (DSCT) for current ability. Two-way analysis of variance was conducted without any covariate, followed by a two-way analysis of covariance (using age, age at onset of psychiatric illness, premorbid IQ and the Socio-Economic Index for Areas (SEIFA) rankings). RESULTS: Whilst there appeared to be a significant association between cannabis use and mean DSCT (higher DSCT scores in cannabis using groups) F(2,1080)=9.478, p<0.001, η2=0.017), once covariates were used in the analysis there were no significant differences between groups in mean DSCT scores (F(2,1011)=0.929, p=0.395, η2=0.002). Similarly there were no differences between groups in mean NART scores once, age, age at illness onset and SEIFA rankings were used as covariates (F(2,1032)=1.617, p=0.199, η2=0.003). CONCLUSIONS: Confounding variables underpin the association between cannabis use and cognitive function in psychotic disorders. Taken together, it would appear that cannabis use or dependence has no additive effect on cognitive dysfunction in these disorders.

The effect of drug use on the age at onset of psychotic disorders in an Australian cohort.

BACKGROUND: We aimed to examine the association between illicit substance use and age at onset in psychotic disorders in an Australian cohort. METHODS: Retrospectively acquired information on substance use during the year prior to illness onset was collected from 1642 participants enrolled in the Australian National 2010 Survey of High Impact Psychosis study (SHIP), with an ICD-10 diagnosis of schizophrenia spectrum or affective psychosis. Latent class analysis was performed according to illicit substance use, using age as an active covariate; identified classes were subsequently validated. Cox regression was used to examine the independent contribution of the identified substance use classes and several confounding variables to the prediction of age at onset of psychosis. RESULTS: Three classes according to substance use were identified: non-users (n=803), cannabis predominant users (n=582), and polysubstance users (n=257). For participants with schizophrenia spectrum disorders, cannabis predominant users had a higher hazard of earlier age at onset than for non-users (adjusted HR=1.38, 95% CI=1.2-1.6); polysubstance users had an even higher hazard (adjusted HR=1.95, 95% CI=1.5-2.4). In contrast, for participants with affective psychosis, cannabis predominant users (adjusted HR=1.10, 95% CI=0.8-1.4) and polysubstance users (adjusted HR=0.87, 95% CI=0.6-1.3) did not have a higher hazard of earlier age at onset compared with non-users. CONCLUSIONS: Illicit substance use in the 12 months prior to psychosis onset has a differential effect on age at onset in schizophrenia spectrum and affective psychotic disorders. Our findings are compatible with the notion that illicit drugs bring forward age at onset in schizophrenia spectrum disorders but not affective psychotic disorders.

Age at initiation of amphetamine use and age at onset of psychosis: the Australian Survey of High Impact Psychosis.

Individuals with a psychotic disorder who had a premorbid history of amphetamine use (n=382) were analyzed in groups according to age of initiation to amphetamine (AIA) and mean number of years of duration of premorbid exposure to amphetamine (DPEA) was calculated. Univariate General Linear Models were used to test for group differences in age at onset of psychotic illness (AOI) and DPEA. Although a temporal direct relationship between AIA and AOI was detected (mean duration 5.3 years), our findings suggested this association was spurious and better explained by a later initiation to amphetamine than to cannabis (by 2-3 years).

Age at initiation of cannabis use predicts age at onset of psychosis: the 7- to 8-year trend.

We investigated the existence of a temporal association between age at initiation of cannabis use and age at onset of psychotic illness in 997 participants from the 2010 Survey of High Impact Psychosis (SHIP) in Australia. We tested for group differences in age at onset of psychotic illness and in the duration of premorbid exposure to cannabis (DPEC). Analyses were repeated in subgroups of participants with a schizophrenia-spectrum disorder (SSD), a diagnosis of lifetime cannabis dependence (LCD), and a comorbid SSD/LCD diagnosis. The association between age at initiation of cannabis use and age at onset of psychotic illness was linear and significant, F(11, 984) = 13.77, P < .001, even after adjusting for confounders. The effect of age at initiation of cannabis use on DPEC was not significant (mean duration of 7.8 years), and this effect was similar in participants with a SSD, LCD, and comorbid SSD/ LCD diagnosis although a shift toward shorter premorbid exposure to cannabis was noted in the SSD/LCD subgroup (mean duration of 7.19 years for SSD/LCD). A temporal direct relationship between age at initiation of cannabis use and age at onset of psychotic illness was detected with a premorbid exposure to cannabis trend of 7-8 years, modifiable by higher severity of premorbid cannabis use and a diagnosis of SSD. Cannabis may exert a cumulative toxic effect on individuals on the pathway to developing psychosis, the manifestation of which is delayed for approximately 7-8 years, regardless of age at which cannabis use was initiated.

Does accumulating exposure to illicit drugs bring forward the age at onset in schizophrenia?

OBJECTIVE: Whilst cannabis has been associated with an earlier age at onset in schizophrenia, the impact of amphetamine and/or cocaine plus cannabis consumption on age at onset remains unclear. The present study was designed to test the hypothesis that consumption of amphetamine and/or cocaine in addition to cannabis would lead to an earlier age at onset of schizophrenia than that seen for cannabis consumption alone. A secondary objective was to determine what kind of effect additional substance use exerted (e.g. additive, multiplicative). METHOD: Patients with a diagnosis of schizophrenia were recruited from consecutive admissions to the inpatient and outpatient services of a large psychiatric hospital in Perth, Australia and 167 participants were assessed using the Diagnostic Interview for Psychosis, which included detailed inquiry into illicit drug use in the 12 months prior to the onset of psychiatric symptoms. Participants were categorized into four groups: no illicit substance use (n = 65), cannabis use (n = 68), cannabis plus amphetamine use (n = 25), and cocaine plus cannabis/cocaine plus cannabis plus amphetamine use (n = 9). Analysis of variance was performed to detect trends, and linear regression used to analyze the consumption of each additional substance as a predictor of age at onset. RESULTS: We observed a linear trend for mean age at onset: 23.34 (SD = 6.91) years for no illicit substance use, 22.51 (SD = 5.27) years for cannabis use, 20.84 (SD = 3.48) years for cannabis plus amphetamine use, and 19.56 (SD = 3.54) years for cocaine plus cannabis/cocaine plus cannabis plus amphetamine use; the variation in the means between groups was statistically significant: F(1,163) = 5.66, p = 0.008, Cohen's d = 0.38. For the consumption of each additional substance, age at onset was earlier by 1.2 years: R (2) = 0.034, F(1,165) = 5.72, p = 0.018. CONCLUSIONS: Whilst preliminary, these findings suggest that additional consumption of each substance predicted an earlier age at onset by approximately 1 additional year.

The role of serotonergic genes and environmental stress on the development of depressive symptoms and neuroticism.

BACKGROUND: Depression is considered to be the result of a complicated synergy between genetic and environmental factors. Several genes of the serotonergic neurotransmission have been related to depression phenotypes, however results are inconsistent, possibly due to the oversight of the role of environmental stress. METHODS: We examined gene-environment (GxE) interactions with serotonergic genes on depressive symptoms and neuroticism in a homogeneous population-based sample of 415 females. We chose several genetic variants within candidate genes (SLC6A4, TPH2, HTR1A) that have been previously found to provide some evidence of association with depression outcomes. RESULTS: Single marker analyses showed a significant GxE interaction with several TPH2 variants, including rs4570625, on depressive symptoms. Significant GxE interactions were also observed with TPH2 haplotypes. No reliable associations were observed with SLC6A4 and HTR1A genes. We did not find any robust evidence of a direct impact of serotonergic genes on depressive symptoms or neuroticism. LIMITATIONS: Due to the high number of analyses conducted, results must be interpreted with caution. CONCLUSIONS: The present study indicates an association between TPH2 and depressive symptoms that is conditional on prior experience of stressful life events. Further evidence is provided about the role of the environment in genetic vulnerability to depression.