Changes in BDNF methylation patterns after cognitive remediation therapy in schizophrenia: A randomized and controlled trial.

Although cognitive remediation therapy (CRT) produces cognitive benefits in schizophrenia, we do not yet understand whether molecular changes are associated with this cognitive improvement. A gene central to synaptic plasticity, the BDNF, has been proposed as one potential route. This study assesses whether BDNF methylation changes following CRT-produced cognitive improvement are detected. A randomized and controlled trial was performed with two groups (CRT, n = 40; TAU: Treatment as Usual, n = 20) on a sample of participants with schizophrenia. CRT was delivered by trained therapists using a web-based computerized program. Mixed Models, where the interaction of treatment (CRT, TAU) by time (T0: 0 weeks, T1: 16 weeks) was the main effect were used. Then, we tested the association between the treatment and methylation changes in three CpG islands of the BDNF gene. CRT group showed significant improvements in some cognitive domains. Between-groups differential changes in 5 CpG units over time were found, 4 in island 1 (CpG1.2, CpG1.7, CpG1.10, CpG1.17) and 1 in island 3 (CpG3.2). CRT group showed increases in methylation in CpG1.2, CpG1.7 and decreases in pG1.10, CpG1.17, and CpG3.2. Differences in the degree of methylation were associated with changes in Speed of Processing, Working Memory, and Verbal Learning within the CRT group. Those findings provide new data on the relationship between cognitive improvement and changes in peripheral methylation levels of BDNF gene, a key factor involved in neuroplasticity regulation. Trial Registration: NCT04278027.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Diurnal cortisol throughout pregnancy and its association with maternal depressive symptoms and birth outcomes.

BACKGROUND: Depression during pregnancy is a common complication that can negatively affect fetal health and birth outcomes. Cortisol is believed to be a key mediator of this association. Although pregnancy entails a natural increase in cortisol levels, preclinical depression could alter its circadian rhythm, producing excessively high overall diurnal cortisol levels that might be harmful for the fetus and future offspring development. OBJECTIVES: Using a prospective longitudinal design, we aimed to study (i) trimestral cortisol circadian rhythm and its overall levels throughout pregnancy in healthy women, (ii) the extent to which maternal depressive symptoms influence both cortisol rhythmicity and overall levels, and (iii) the possible adverse consequences of elevated maternal cortisol on the offspring's weight and gestational age at birth. STUDY DESIGN: 112 healthy pregnant women from the general Spanish population were recruited before their first pregnancy. To assess cortisol circadian rhythm, participants provided four saliva samples at each trimester of pregnancy (at awakening, 30 min after awakening, before lunch and before going to bed). Overall cortisol levels were calculated with AUCg approximation. Depressive symptoms were evaluated in each trimester and defined according to EPDS cut-off values (1st trimester, EPDS ≥ 11; 2nd and 3rd trimesters, EPDS ≥ 10). At birth, the risk for low weight, prematurity and weight birth percentile was retrieved for 100 infants. Mixed models and simple effects were employed to study changes of maternal cortisol circadian rhythm and overall levels throughout pregnancy and the possible influence of maternal depressive symptoms. Finally, logistic regressions were performed to assess the associations between maternal overall cortisol levels in each trimester of pregnancy and birth anthropometrics. RESULTS: Although overall diurnal cortisol levels increase throughout pregnancy, cortisol circadian rhythm is preserved in all trimesters [1st (F(3110)= 92.565, p < .001), 2nd (F(3,85)= 46.828, p < .001) and 3rd (F(3,90)= 65.555, p < .001)]. However, women with depressive symptoms showed a flattened cortisol circadian pattern only during the second trimester, characterized by a blunted awakening peak and reduced evening decline (F(3,85)= 4.136, p = .009), but not during the first (F(3,11)= 1.676, p = .176) or the third (F(3,90)= 1.089, p = .358) trimesters. Additionally, they did not show a cortisol increase from second to third trimester (p = .636). Finally, higher maternal cortisol levels in second and third trimesters seemed to be associated with increased risk of prematurity (adjusted OR -0.371, 95% CI 0.490-0.972, p = .034) and low birth weight percentile (adjusted OR -0.612, 95% CI 0.348-0.846, p = .007) respectively. CONCLUSION: Maternal cortisol levels increased throughout pregnancy, although cortisol circadian rhythm was preserved in all trimesters of pregnancy. However, prenatal depressive symptoms were associated with flattened maternal cortisol circadian rhythm in mid-pregnancy. Therefore, it seems that women with depressive symptoms tended to increase less gradually their cortisol levels from mid to late pregnancy. Finally, higher maternal cortisol levels in mid and late-pregnancy seem to be associated with poorer birth anthropometrics Early detection of depressive symptoms in general population could help to prevent putative obstetrical and birth adverse outcomes.

Exploring the genetics of lithium response in bipolar disorders.

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3ß. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Evaluation of the CHROMagar Candida Plus medium for presumptive identification of yeasts and MALDI-TOF MS identification.

Rapid and accurate yeasts species identification in clinical laboratories is important for appropriate and timely antifungal treatment. We evaluate the performance of the new medium CHROMagar™ Candida Plus for presumptive identification of yeasts species and MALDI-TOF identification. We identify 303 strains belonging to 60 clinically relevant yeasts species by using the new medium. Presumptive identification was correct at the Candida albicans complex, Candida tropicalis and Pichia kudriavzevii (Candida krusei) species. However, although this medium was able to identify all Candida auris and Candida glabrata strains, other species were misidentified as C. auris or C. glabrata. A total of 215 strains were identified by using MALDI-TOF and evaluated two incubation temperatures (30°C and 37°C) and two incubation times (24 h and 72 h). Most strains (94%; 202/215) were correctly identified at the species (n:190) or complex level (n:12) at both temperatures and incubation times. However, we observed that the time of incubation (24 h vs. 72 h) affects the score values when yeasts are incubated at 37°C, but does not affect score values when yeasts are incubated at 30°C. In conclusion, the new medium has a good performance in the presumptive identification of the C. albicans complex, C. tropicalis and P. kudriavzevii (C. krusei). In addition, this medium is useful for the screening of C. auris and C. glabrata isolates, but identification should be confirmed by other more specific techniques, like MALDI-TOF.

Common genetic variants contribute to heritability of age at onset of schizophrenia.

Schizophrenia (SCZ) is a complex disorder that typically arises in late adolescence or early adulthood. Age at onset (AAO) of SCZ is associated with long-term outcomes of the disease. We explored the genetic architecture of AAO with a genome-wide association study (GWAS), heritability, polygenic risk score (PRS), and copy number variant (CNV) analyses in 4 740 subjects of European ancestry. Although no genome-wide significant locus was identified, SNP-based heritability of AAO was estimated to be between 17 and 21%, indicating a moderate contribution of common variants. We also performed cross-trait PRS analyses with a set of mental disorders and identified a negative association between AAO and common variants for SCZ, childhood maltreatment and attention-deficit/hyperactivity disorder. We also investigated the role of copy number variants (CNVs) in AAO and found an association with the length and number of deletions (P-value = 0.03), whereas the presence of CNVs previously reported in SCZ was not associated with earlier onset. To our knowledge, this is the largest GWAS of AAO of SCZ to date in individuals from European ancestry, and the first study to determine the involvement of common variants in the heritability of AAO. Finally, we evidenced the role played by higher SCZ load in determining AAO but discarded the role of pathogenic CNVs. Altogether, these results shed light on the genetic architecture of AAO, which needs to be confirmed with larger studies.

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.

Genotypic Diversity and Antifungal Susceptibility of Clinical Isolates of Cryptococcus Gattii Species Complex from Argentina.

The aim of this study was to determine the genotypic diversity of 22 Cryptococcus gattii species complex clinical isolates from Argentina and to place these genotypes within the diversity of clinical, veterinary and environmental isolates from Latin America. Mating type and antifungal susceptibility of the isolates were also determined. By URA5-RFLP, nine isolates were identified as molecular type VGI, 10 as VGII, one as VGIII and two as VGIV. Multilocus sequence typing (MSLT), following the International Society for Human and Animal Mycology (ISHAM) consensus MLST scheme, was used to determine the genotypic diversity. Our results suggest that, in Argentina, VGI isolates have low genetic diversity, while VGII isolates have high genetic diversity. Both isolates identified as VGIV by URA5-RFLP were genotyped by MLST as belonging to the currently named VGVI clade. From all isolates, eight sequence types (STs) were unique for Argentina, while five STs have been reported already in other countries, being of high interest the genotypes ST20 and ST7 since they belong to the subtypes VGIIa and VGIIb, respectively, which are associated with hypervirulent strains responsible for outbreaks in North America. To note, geographical analysis showed that some genotypes may be associated with some regions in Argentina. Most isolates were MATα, but we are reporting one isolate MATa for the first time in the country. Antifungal susceptibility tests showed that itraconazole, voriconazole and posaconazole had high activity against all isolates, while amphotericin B, fluconazole and 5-fluorocytosine were the least active drugs against all studied isolates.

Prefrontal abnormalities, executive dysfunction and symptoms severity are modulated by COMT Val158Met polymorphism in first episode psychosis.

INTRODUCTION: Core dysfunctions proposed for psychotic disorders include prefrontal cortex (PFC) dopaminergic hypoactivity, executive function (EF) deficits and reduced gray matter in the PFC. The Val variant of COMT Val158Met polymorphism is associated with reduced dopaminergic signaling in the PFC. However, it is unclear how COMT Val158Met modulates PFC gray matter reduction, EF deficits and symptom severity at the time of the first psychotic episode. METHODS: The effect of COMT on both EF performance and prefrontal volume (PFC-VOL) was tested in 158 first episode psychosis (FEP) patients and 141 healthy controls (HC) matched for age (range 9-35 years), sex, ethnicity, handedness and COMT Val158Met distribution. EF and PFC-VOL were compared between FEP and HC groups within each polymorphism status (Met/Met versus Val carriers) to assess whether COMT influenced diagnostic differences. Next, correlations between PFC-VOL and EF performance were computed, as well as between both variables and other clinical characteristics of interest (PANSS scores, PAS infancy and premorbid IQ) in the FEP sample. RESULTS: COMT influenced the diagnostic differences mainly in PFC-VOL, but also in EF performance. FEP-Val carriers showed lower EF scores and reduced PFC-VOL compared to the HC group but also poorer EF performance than FEP Met/Met. Poorer EF performance was associated with smaller PFC-VOL, and both were related to increased severity of negative symptoms, poorer premorbid adjustment, and lower estimated premorbid IQ in FEP patients. CONCLUSIONS: Our findings suggest that COMT Val158Met polymorphism might contribute to PFC-VOL reductions, executive dysfunctions and symptom severity in FEP patients.

NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches.

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset ≤ 18 years) and 71 adult-onset (AO) trios) and an independent case-control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180-rs10484320-rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ.

Combining fMRI and DISC1 gene haplotypes to understand working memory-related brain activity in schizophrenia.

The DISC1 gene is one of the most relevant susceptibility genes for psychosis. However, the complex genetic landscape of this locus, which includes protective and risk variants in interaction, may have hindered consistent conclusions on how DISC1 contributes to schizophrenia (SZ) liability. Analysis from haplotype approaches and brain-based phenotypes can contribute to understanding DISC1 role in the neurobiology of this disorder. We assessed the brain correlates of DISC1 haplotypes associated with SZ through a functional neuroimaging genetics approach. First, we tested the association of two DISC1 haplotypes, the HEP1 (rs6675281-1000731-rs999710) and the HEP3 (rs151229-rs3738401), with the risk for SZ in a sample of 138 healthy subjects (HS) and 238 patients. This approach allowed the identification of three haplotypes associated with SZ (HEP1-CTG, HEP3-GA and HEP3-AA). Second, we explored whether these haplotypes exerted differential effects on n-back associated brain activity in a subsample of 70 HS compared to 70 patients (diagnosis × haplotype interaction effect). These analyses evidenced that HEP3-GA and HEP3-AA modulated working memory functional response conditional to the health/disease status in the cuneus, precuneus, middle cingulate cortex and the ventrolateral and dorsolateral prefrontal cortices. Our results are the first to show a diagnosis-based effect of DISC1 haplotypes on working memory-related brain activity, emphasising its role in SZ.

Prefrontal abnormalities, executive dysfunction and symptoms severity are modulated by COMT Val158Met polymorphism in first episode psychosis / Modulación de alteraciones prefrontales por el polimorfismo COMT Val158Met en los primeros episodios psicóticos

Introduction: Core dysfunctions proposed for psychotic disorders include prefrontal cortex (PFC) dopaminergic hypoactivity, executive function (EF) deficits and reduced gray matter in the PFC. The Val variant of COMT Val158Met polymorphism is associated with reduced dopaminergic signaling in the PFC. However, it is unclear how COMT Val158Met modulates PFC gray matter reduction, EF deficits and symptom severity at the time of the first psychotic episode.Methods: The effect of COMT on both EF performance and prefrontal volume (PFC-VOL) was tested in 158 first episode psychosis (FEP) patients and 141 healthy controls (HC) matched for age (range 9–35 years), sex, ethnicity, handedness and COMT Val158Met distribution. EF and PFC-VOL were compared between FEP and HC groups within each polymorphism status (Met/Met versus Val carriers) to assess whether COMT influenced diagnostic differences. Next, correlations between PFC-VOL and EF performance were computed, as well as between both variables and other clinical characteristics of interest (PANSS scores, PAS infancy and premorbid IQ) in the FEP sample.Results: COMT influenced the diagnostic differences mainly in PFC-VOL, but also in EF performance. FEP-Val carriers showed lower EF scores and reduced PFC-VOL compared to the HC group but also poorer EF performance than FEP Met/Met. Poorer EF performance was associated with smaller PFC-VOL, and both were related to increased severity of negative symptoms, poorer premorbid adjustment, and lower estimated premorbid IQ in FEP patients.Conclusions: Our findings suggest that COMT Val158Met polymorphism might contribute to PFC-VOL reductions, executive dysfunctions and symptom severity in FEP patients. (AU)

Introducción: Algunas de las alteraciones descritas en los trastornos psicóticos incluyen una hipoactividad dopaminérgica en la corteza prefrontal (CPF), déficits en la función ejecutiva (FE) y reducción de la materia gris en la CPF. La variante Val del polimorfismo COMT Val158Met se asocia con una menor disponibilidad dopaminérgica en la CPF. Sin embargo, está aún pendiente de determinar la forma en la que COMT modula la materia gris de la CPF, la FE y la gravedad de los síntomas en el momento del primer episodio psicótico (PEP).Métodos: El efecto de COMT en el rendimiento de la FE y el volumen prefrontal (VOL-CPF) se evaluó en 158 pacientes con PEP y 141 controles sanos (CS) emparejados por edad (9-35 años), sexo, etnia y distribución de COMT. La FE y el VOL-CPF se compararon entre los grupos de PEP y CS, y en función de la variante alélica del polimorfismo (Met/Met versus portadores Val) para evaluar si COMT modula las diferencias diagnósticas. Además, se llevaron a cabo correlaciones entre FE y VOL-CPF, así como entre ambas variables y las puntuaciones en la PANSS, el ajuste premórbido y el CI premórbido.Resultados: COMT moduló las diferencias diagnósticas en VOL-CPF y el rendimiento de FE. Los PEP portadores de la variante Val presentaron menores puntuaciones en FE y reducción del VOL-CPF en comparación con el grupo CS, y menor rendimiento de FE que los PEP Met/Met. Un menor rendimiento en FE se asoció con un menor VOL-CPF, y ambas variables estaban relacionadas con un incremento en la gravedad de síntomas negativos, un peor ajuste premórbido y un menor CI premórbido en pacientes con PEP.Conclusiones: Nuestros hallazgos evidencian que el polimorfismo COMT Val158Met podría contribuir a la reducción del VOL-CPF, la disfunción ejecutiva y la gravedad de los síntomas en los pacientes con PEP. (AU)

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach.

BACKGROUND: Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. AIMS: To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. METHOD: This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. RESULTS: The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. CONCLUSIONS: Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.