Psychiatry - Research Publications
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ItemCortico-cognition coupling in treatment resistant schizophrenia(ELSEVIER SCI LTD, 2022-06-08)BACKGROUND: Brain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC). METHOD: Forty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted. RESULTS: Univariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients. CONCLUSIONS: MB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature.
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ItemGenome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders(SPRINGERNATURE, 2022-04-07)Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.
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ItemFRONTOSTRIATAL CONNECTIVITY IN TREATMENT-RESISTANT SCHIZOPHRENIA: RELATIONSHIP TO POSITIVE SYMPTOMS AND COGNITIVE FLEXIBILITY(OXFORD UNIV PRESS, 2018-04-01)
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ItemS187. EXPLORING NEURODEVELOPMENTAL AND FAMILIAL ORIGINS OF NEUROLOGICAL SOFT SIGNS IN SCHIZOPHRENIA(Oxford University Press (OUP), 2020-05-18)
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ItemPeripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia(FRONTIERS MEDIA SA, 2017-11-06)Investigation of peripheral gene expression patterns of transcripts within the NRG-ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG-ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini-Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG-ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG-ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.
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ItemBiomarker investigations related to pathophysiological pathways in schizophrenia and psychosis(FRONTIERS MEDIA SA, 2013-06-26)Post-mortem brain investigations of schizophrenia have generated swathes of data in the last few decades implicating candidate genes and protein. However, the relation of these findings to peripheral biomarker indicators and symptomatology remain to be elucidated. While biomarkers for disease do not have to be involved with underlying pathophysiology and may be largely indicative of diagnosis or prognosis, the ideal may be a biomarker that is involved in underlying disease processes and which is therefore more likely to change with progression of the illness as well as potentially being more responsive to treatment. One of the main difficulties in conducting biomarker investigations for major psychiatric disorders is the relative inconsistency in clinical diagnoses between disorders such as bipolar and schizophrenia. This has led some researchers to investigate biomarkers associated with core symptoms of these disorders, such as psychosis. The aim of this review is to evaluate the contribution of post-mortem brain investigations to elucidating the pathophysiology pathways involved in schizophrenia and psychosis, with an emphasis on major neurotransmitter systems that have been implicated. This data will then be compared to functional neuroimaging findings as well as findings from blood based gene expression investigations in schizophrenia in order to highlight the relative overlap in pathological processes between these different modalities used to elucidate pathogenesis of schizophrenia. In addition we will cover some recent and exciting findings demonstrating microRNA (miRNA) dysregulation in both the blood and the brain in patients with schizophrenia. These changes are pertinent to the topic due to their known role in post-transcriptional modification of gene expression with the potential to contribute or underlie gene expression changes observed in schizophrenia. Finally, we will discuss how post-mortem studies may aid future biomarker investigations.
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ItemEffects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis(NATURE PUBLISHING GROUP, 2013-04-01)Prospective studies have suggested genetic variation in the neuregulin 1 (NRG1) and D-amino-acid oxidase activator (DAOA) genes may assist in differentiating high-risk individuals who will or will not transition to psychosis. In a prospective cohort (follow-up=2.4-14.9 years) of 225 individuals at ultra-high risk (UHR) for psychosis, we assessed haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning NRG1 and DAOA for their association with transition to psychosis, using Cox regression analysis. Two NRG1 htSNPs (rs12155594 and rs4281084) predicted transition to psychosis. Carriers of the rs12155594 T/T or T/C genotype had a 2.34 (95% confidence interval (CI)=1.37-4.00) times greater risk of transition compared with C/C carriers. For every rs4281084 A-allele the risk of transition increased by 1.55 (95% CI=1.05-2.27). For every additional rs4281084-A and/or rs12155594-T allele carried the risk increased ∼1.5-fold, with 71.4% of those carrying a combination of 3 of these alleles transitioning to psychosis. None of the assessed DAOA htSNPs were associated with transition. Our findings suggest NRG1 genetic variation may improve our ability to identify UHR individuals at risk for transition to psychosis.
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ItemThe Brain-Derived neurotrophic Factor Val66Met Polymorphism Moderates the effects of childhood abuse on severity of Depressive symptoms in a Time-Dependent Manner(FRONTIERS MEDIA SA, 2016-08-29)Cross-sectional studies have demonstrated that the brain-derived neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism moderates the association between exposure to negative life events and depression outcomes. Yet, it is currently unclear whether this moderating effect is applicable to positive life events and if the moderating effect is stable over time. To address these gaps in the literature, we examined clinical and BDNF genotypic data from a 5-year prospective cohort of 310 primary care attendees. Primary care attendees were selected based on existence of depressive symptoms at screening. Depressive symptoms were assessed at baseline and annually for 5 years post-baseline using the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9). Linear mixed models assessed differences in depressive symptom severity over the 5-year follow-up period by BDNF Val66Met and history of life events, both negative and positive. Analysis identified a novel three-way interaction between the BDNF Val66Met polymorphism, history of severe childhood abuse, and time. Post hoc analysis stratified by time showed a two-way interaction between Val66Met and severe childhood abuse at baseline that was not detectable at any other time point. An interaction between Val66Met and positive life events was not detected. Our longitudinal results suggest that the BDNF Val66Met polymorphism moderates the depressive symptom severity experienced by those with a history of severe childhood abuse but does so in a time-dependent manner. Our results further support the notion that gene-environment-depression interactions are dynamic and highlight the importance of longitudinal assessment of these interactions. Given these novel longitudinal findings; replication is required.
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ItemPathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations(SPRINGERNATURE, 2017-02-21)Genome-wide association studies have confirmed the polygenic nature of schizophrenia and suggest that there are hundreds or thousands of alleles associated with increased liability for the disorder. However, the generalizability of any one allelic marker of liability is remarkably low and has bred the notion that schizophrenia may be better conceptualized as a pathway(s) disorder. Here, we empirically tested this notion by conducting a pathway-wide association study (PWAS) encompassing 255 experimentally validated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways among 5033 individuals diagnosed with schizophrenia and 5332 unrelated healthy controls across three distinct ethnic populations; European-American (EA), African-American (AA) and Han Chinese (CH). We identified 103, 74 and 87 pathways associated with schizophrenia liability in the EA, CH and AA populations, respectively. About half of these pathways were uniquely associated with schizophrenia liability in each of the three populations. Five pathways (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across all three populations and the single-nucleotide polymorphism sets representing these five pathways were enriched for single-nucleotide polymorphisms with regulatory function. Our findings provide empirical support for schizophrenia as a pathway disorder and suggest schizophrenia is not only a polygenic but likely also a poly-pathway disorder characterized by both genetic and pathway heterogeneity.
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ItemSerotonin transporter polymorphism (5HTTLPR), severe childhood abuse and depressive symptom trajectories in adulthood(ROYAL COLL PSYCHIATRISTS, 2015-06-01)