Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.

A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup.

Psychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. The integration of multimodal biological data could reveal different subtypes of psychosis onset to target for the personalization of care. In this study, we tested the existence of subgroups of patients affected by first-episode psychosis (FEP) with a possible immunopathogenic basis. To do this, we designed a data-driven unsupervised machine learning model to cluster a sample of 127 FEP patients and 117 healthy controls (HC), based on the peripheral blood expression levels of 12 psychosis-related immune gene transcripts. To validate the model, we applied a resampling strategy based on the half-splitting of the total sample with random allocation of the cases. Further, we performed a post-hoc univariate analysis to verify the clinical, cognitive, and structural brain correlates of the subgroups identified. The model identified and validated two distinct clusters: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A and CXCR3); 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). None of the subgroups was related to specific symptoms dimensions or longitudinal diagnosis of affective vs non-affective psychosis. FEP patients included in the balanced immune subgroup showed a thinning of the left supramarginal and superiorfrontal cortex (FDR-adjusted p-values < 0.05). Our results demonstrated the existence of a FEP patients' subgroup identified by a multivariate pattern of immunomarkers involved in inflammatory activation. This evidence may pave the way to sample stratification in clinical studies aiming to develop diagnostic tools and therapies targeting specific immunopathogenic pathways of psychosis.

Clinical validation of a combinatorial PharmAcogeNomic approach in major Depressive disorder: an Observational prospective RAndomized, participant and rater-blinded, controlled trial (PANDORA trial).

BACKGROUND: Major depressive disorder (MDD) is a common, chronic, debilitating mood disorder that causes serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment option; however, only approximately one third of patients respond to the first treatment because of the ineffectiveness or side effects of antidepressants. Precision medicine in psychiatry might offer clinicians the possibility to tailor treatment according to the best possible evidence of efficacy and tolerability for each subject. In this context, our study aims to carry out a clinical validation of a combinatorial pharmacogenomics (PGx) test in an Italian MDD patient cohort with advocacy license independence. METHODS: Our study is a prospective participant- and rater-blinded, randomized, controlled clinical observational trial enrolling 300 MDD patients who are referred to psychiatric services to receive a new antidepressant due to the failure of their current treatment and/or the onset of adverse effects. Eligible participants are randomized to the TGTG group (Treated with Genetic Test Guide) or TAU group (Treated as Usual). For all subjects, DNA is collected with a buccal brush. The primary outcome is the reduction in depressive symptomatology. The secondary outcomes involve a range of scales that assess MDD symptoms and social functioning outcomes. The assessment is performed at four timepoints: baseline and 4, 8, and 12 weeks. DISCUSSION: This project represents the first randomized controlled clinical trial to investigate whether a non-commercial PGx test improves outcomes in an MDD naturalistic cohort. Moreover, the identification of new genetic variants associated with non-response or side effects will improve the efficacy of the test, leading to further cost-saving. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04615234. Registered on November 4, 2020.

Classification of Psychoses Based on Immunological Features: A Machine Learning Study in a Large Cohort of First-Episode and Chronic Patients.

For several years, the role of immune system in the pathophysiology of psychosis has been well-recognized, showing differences from the onset to chronic phases. Our study aims to implement a biomarker-based classification model suitable for the clinical management of psychotic patients. A machine learning algorithm was used to classify a cohort of 362 subjects, including 160 first-episode psychosis patients (FEP), 70 patients affected by chronic psychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder) with psychosis (CRO) and 132 health controls (HC), based on mRNA transcript levels of 56 immune genes. Models distinguished between FEP, CRO, and HC and between the subgroup of drug-free FEP and HC with a mean accuracy of 80.8% and 90.4%, respectively. Interestingly, by using the feature importance method, we identified some immune gene transcripts that contribute most to the classification accuracy, possibly giving new insights on the immunopathogenesis of psychosis. Therefore, our results suggest that our classification model has a high translational potential, which may pave the way for a personalized management of psychosis.

Alterations observed in the interferon α and ß signaling pathway in MDD patients are marginally influenced by cis-acting alleles.

Major depressive disorder (MDD) is a common psychiatric disorder with a multifactorial aetiology determined by the interaction between genetic and environmental risk factors. Pieces of evidence indicate that inflammation and immune activation may contribute to the onset of MDD playing a role in the pathogenetic mechanism. To date, it is not known to which extent the association between MDD and inflammation is shaped by the genetic background or by the presence of environmental factors. To clarify this issue, we analyzed genotype and blood RNA profiles of 463 MDD cases and 459 controls (NIMH-Study 88/Site621) estimating the Genetic and Environmental Regulated eXpression component of gene expression (GReX and EReX respectively). Both components were tested for association with MDD. Many genes belonging to the α/ß interferon signaling pathway showed an association between MDD and EReX, only two between MDD and GReX. Also other MDD differentially expressed genes were more influenced by the EReX than by GReX. These results suggest that impact of the genetic background on MDD blood gene expression alterations is much lower than the contribution of environmental factors and almost absent for the genes of the interferon pathway.

Inflammation-related microRNAs are involved in stressful life events exposure and in trauma-focused psychotherapy in treatment-resistant depressed patients.

Background: About 30% of major depressive disorder (MDD) patients are classified as resistant to treatment (treatment-resistant depression, TRD). Among the factors associated with unfavourable treatment outcomes, stressful life events play a relevant role, and trauma-focused psychotherapy has been successfully proposed for the treatment of patients with a history of such events. Stressful experiences are related to enhanced inflammation and, recently, microRNAs (miRNAs) have emerged as potential mediators of the association between these experiences and psychiatric disorders. To date, no study has explored the effects of stressful life events on miRNAs in MDD patients. Objective: The objective of the present study was to assess possible miRNA blood expression alterations in TRD patients induced by the exposure to stressful life events and to investigate the effects of trauma-focused psychotherapy on the expression profiles of the same miRNAs, as well as their possible predictivity in relation to therapy outcome. Method: The basal levels (T0) of seven candidate miRNAs (miR-15a/miR-29a/miR-125b/miR-126/miR-146a/miR-195/let-7f) were measured in the whole blood of 41 TRD patients. A subgroup of patients (n = 21) underwent trauma-focused psychotherapy; for all of them, miRNA levels were also longitudinally assessed (T4: after 4 weeks of treatment; T8: end of treatment; T12: follow-up visit), contextually to clinical evaluations. Results: miR-146a levels negatively correlated with recent stressful life event scores (p = .001), whereas the levels of miR-15a, miR-29a, miR-126, miR-195, and let-7f changed during the psychotherapy (best p = 1.98*10-9). miR-29a was also identified as a response predictor, with lower baseline levels predicting non-response (p = .019) or worse improvement in mood symptoms (p = .032). Conclusions: The study results could contribute to clarify the underlying molecular mechanisms and to identify novel biomarkers of stressful experiences and response to targeted treatments.

Antecedentes: Alrededor del 30% de los pacientes con un Trastorno Depresivo Mayor (TDM) son clasificados como resistentes a tratamiento (Depresión Resistente a Tratamiento, TRD por su sigla en inglés). Entre los factores asociados a resultados de tratamiento desfavorables, los eventos vitales estresantes juegan un rol relevante, y la psicoterapia con foco en el trauma ha sido propuesta con éxito para el tratamiento de los pacientes con historia de tales eventos. Las experiencias estresantes están relacionadas a un aumento de la inflamación y, recientemente, microARNs (miARNs), han surgido como potenciales mediadores de la asociación entre estas experiencias y trastornos psiquiátricos. A la fecha, ningún estudio ha explorado los efectos de los eventos vitales estresantes sobre los miARNs en pacientes con TDM.Objetivo: El objetivo del presente estudio fue evaluar posibles alteraciones en la expresión de miARN en sangre en pacientes con TRD inducidas por la exposición a eventos vitales estresantes e investigar los efectos de la psicoterapia con foco en el trauma sobre los perfiles de expresión de los mismos miARNs, así como su posible predictividad en relación al resultado de la terapia.Método: Los niveles basales (T0) de 7 miARN candidatos (miR-15a/miR-29a/miR-125b/miR-126/miR-146a/miR-195/let-7f) fueron medidos en la sangre completa de 41 pacientes con TRD. Un subgrupo de pacientes (n = 21) se sometió a psicoterapia con foco en el trauma; para todos ellos, los niveles de miARN fueron también evaluados longitudinalmente (T4: después de 4 semanas de tratamiento; T8: fin del tratamiento; T12: visita de seguimiento), contextualmente a evaluaciones clínicas.Resultados: Los niveles de miR-146a se correlacionaron negativamente con los puntajes de eventos vitales estresantes recientes (p = .001), mientras que los niveles de miR-15a, miR-29a, miR-126, miR-195, y let-7f cambiaron durante la psicoterapia (mejor p = p = 1.98*10−9). miR-29a también fue identificado como un predictor de respuesta, con menores niveles basales prediciendo falta de respuesta (p = .019) o menor mejoría en los síntomas anímicos (p = .032).Conclusiones: Los resultados del estudio contribuyen a clarificar los mecanismos moleculares subyacentes y a identificar nuevos biomarcadores de experiencias estresantes y respuesta a tratamientos dirigidos.

Genetic determinants of circulating VEGF levels in major depressive disorder and electroconvulsive therapy response.

Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome-wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome-wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy-one patients with treatment-resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR-corrected p = 2.4 × 10-5 ) and in patients with major depressive disorder (best SNP: FDR-corrected p = 2.6 × 10-3 ). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p = .01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy.

Childhood trauma and glucose metabolism in patients with first-episode psychosis.

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.

Correlations between immune and metabolic serum markers and schizophrenia/bipolar disorder polygenic risk score in first-episode psychosis.

AIMS: There is a strong interest in identifying the biological mechanisms involved in the genetic risk for psychotic disorders. In this study, we evaluated the correlation between serum concentrations of specific molecular markers and the genetic component for schizophrenia and bipolar disorder. METHODS: We analysed the association between the polygenic risk score (PRS) and the serum levels of different inflammatory/metabolic markers in a sample of 81 first-episode psychosis patients (FEP) with a diagnosis of schizophrenia or bipolar disorder and 33 controls. RESULTS: A positive correlation of schizophrenia and bipolar disorder PRS with the inflammatory marker C-C Motif Chemokine Ligand 4 serum concentration (ρ = 0.42, P = 1.56 × 10-04 and ρ = 0.40, P = 1.65 × 10-03 , respectively) and a negative correlation with the serum ghrelin content (ρ = - 0.35, P = 4.27 × 10-03 and ρ = - 0.45, P = 6.05 × 10-04 , respectively) were observed. CONCLUSION: These findings provide new insight into the biological underpinnings of the PRS component, thus supporting a role of the genetic liability on the inflammatory and metabolic alterations that characterize psychosis onset.

miR-146a and miR-181a are involved in the progression of mild cognitive impairment to Alzheimer's disease.

The identification of mechanisms associated with Alzheimer's disease (AD) development in mild cognitive impairment (MCI) would be of great usefulness to clarify AD pathogenesis and to develop preventive and therapeutic strategies. In this study, blood levels of the candidate microRNAs (small noncoding RNAs that play a pivotal role in gene expression) miR-146a, miR-181a, miR-181b, miR-24-3p, miR-186a, miR-101, miR-339, miR-590, and miR-22 have been investigated for association to AD conversion within 2 years in a group of 45 patients with MCI. Baseline miR-146a (p = 0.036) and miR-181a (p = 0.026) showed a significant upregulation in patients with MCI who later converted to AD. These alterations were related to AD hallmarks: a significant negative correlation was found with amyloid beta cerebrospinal fluid concentration for miR-146a (p = 0.006) and miR-181a (p = 0.001). Moreover, higher levels of miR-146a were associated to apolipoprotein E ε4 allele presence, smaller volume of the hippocampus (p = 0.045) and of the CA1 (p = 0.013) and the subiculum (p = 0.027) subfields. Increased levels of miR-146a (p = 0.031) and miR-181a (p = 0.002) were also linked with diffusivity alterations in the cingulum. These data support a role for miR-146a and miR-181a in the mechanisms of AD progression.

BDNF Genotype and Baseline Serum Levels in Relation to Electroconvulsive Therapy Effectiveness in Treatment-Resistant Depressed Patients.

OBJECTIVES: Electroconvulsive therapy (ECT) represents one of the most effective therapies for treatment-resistant depression (TRD). The brain-derived neurotrophic factor (BDNF) is a neurotrophin implicated in major depressive disorder and in the effects of different therapeutic approaches, including ECT. Both BDNF peripheral levels and Val66Met polymorphism have been suggested as biomarkers of treatment effectiveness. The objective of this study was to test the potential of serum BDNF levels and Val66Met polymorphism in predicting ECT outcome in TRD patients. METHODS: Seventy-four TRD patients scheduled to undergo ECT were included in the study. Illness severity was assessed through the Montgomery and Asberg Depression Rating Scale before beginning ECT (T0), the day after the end of ECT (T1), and 1 month after the end of ECT (T2). At T1, patients were classified as responders/nonresponders and remitters/nonremitters, whereas at T2, they were classified as sustained responders/nonresponders and sustained remitters/nonremitters. Serum concentrations of BDNF were measured at T0, and the BDNF Val66Met polymorphism was genotyped. RESULTS: No difference in BDNF concentrations was observed in responders versus nonresponders, in remitters versus nonremitters, in sustained responders versus sustained nonresponders, and in sustained remitters versus sustained nonremitters. No association of Val66Met polymorphism was detected with both the response and the remission status. CONCLUSIONS: Baseline serum BDNF levels and the BDNF Val66Met polymorphism showed no clinical utility in predicting ECT outcome in TRD patients.

miR-146a Plasma Levels Are Not Altered in Alzheimer's Disease but Correlate With Age and Illness Severity.

miR-146a is a microRNA (miRNA) involved in neuroinflammation and aging; alterations in its expression were described in Alzheimer's disease (AD). However, most of the studies conducted so far on this miRNA included a limited number of participants and produced contradictory results. We compared miR-146a levels in plasma from 33 AD patients vs. 28 age-matched non-affected controls (CTRL) through quantitative real-time polymerase chain reaction (qRT-PCR). No difference between the case and the control group was evidenced, but a correlation was detected between miR-146a levels and subjects' age (p < 0.001) as well as between miR-146a levels and patients' Mini-Mental State Examination (MMSE) scores (p = 0.011), in an enlarged group of 51 AD patients and 45 CTRL supporting a role for this miRNA in aging processes and disease progression.

Immune and metabolic alterations in first episode psychosis (FEP) patients.

The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets.

Insulin-like growth factor binding protein 2 in bipolar disorder: An expression study in peripheral tissues.

OBJECTIVES: Insulin-like growth factor binding protein 2 (IGFBP2) is a member of the family of high-affinity binding proteins (IGFBP1-6) and appears to play a governing role in insulin-like growth factor (IGF) regulation in the central nervous system. This study aimed to investigate the putative involvement of IGFBP2 in mood disorder pathogenesis by measuring its expression levels in patient peripheral tissues. METHODS: IGFBP2 protein and mRNA levels were measured in the serum of 93 controls, 41 bipolar disorder (BD) and 43 major depressive disorder (MDD) patients and in the skin fibroblasts from 15 controls, 12 BD and 23 MDD patients. RESULTS: The results indicated reduced expression of IGFBP2 in both tissues of BD patients, whereas no difference was found in MDD patients compared with controls. CONCLUSIONS: Our findings in peripheral tissues are consistent with previous results in the brain and support a downregulation of IGFBP2 expression that is specific for BD, suggesting a role for this protein in the alterations in neurodevelopment and neuroprotection observed in the disorder. Further studies in independent and larger cohorts are warranted to confirm the involvement of IGFBP2 in BD.

Study of the in vitro modulation exerted by the antidepressant drug escitalopram on the expression of candidate microRNAs and their target genes.

Recent studies indicated a role of microRNAs (miRNAs, small non-coding RNAs which regulate the expression of target genes by acting on mRNAs) in several neural processes, in the pathogenetic mechanisms of neuropsychiatric diseases and in the action of psychotropic drugs. A modulation induced by the antidepressant drug escitalopram on the expression levels of 30 miRNAs was highlighted in the blood of patients suffering from major depressive disorder. With the aim to investigate the effects of escitalopram in an in vitro model, we performed an analysis of the effects produced by escitalopram on the profiles of the 6 miRNAs found to be more significantly modulated in the above-mentioned study (miR-130b, miR-26a and -26b, let-7f, miR-770-5p, miR-34c-5p) in human U87 glioblastoma cells. Cells were treated with the drug for 24, 48 and 72h. The obtained results confirmed a significant increase of let-7f, both after 48 (p=0.031) and 72h (p=0.022), and of miR-26a after 48h (p=0.032). On the same experimental model, a transcriptome analysis was conducted after 72h, highlighting a drug-induced modulation of 1184 protein-coding genes, 207 of which represent let-7f targets. Particularly interesting was the downregulation of BCOR, CCND1 and ATR, validated let-7f targets, which play a key role in the mechanisms of neurogenesis, neuroplasticity and protection from oxidative stress in the brain, indicating that escitalopram could exert downstream effects on gene expression through the regulation of specific miRNAs.

Effects of Intranasal Oxytocin on Long-Term Memory in Healthy Humans: A Systematic Review.

Preclinical Research The neuropeptide oxytocin (Oxt) is implicated in complex emotional and social behaviors and appears to play an important role in learning and memory. Animal studies have shown that the effects of exogenous Oxt on memory vary according to the timing of administration, context, gender, and dose and may improve the memory of social, but not nonsocial stimuli. Oxt is intimately involved in a broad array of neuropsychiatric functions and may therefore be a pharmacological target for several psychiatric disorders. This review summarizes the potential effects of Oxt on long-term memory processes in healthy humans based on a PubMed search over the period 1980-2016. The effects of intranasal Oxt on human memory are controversial and the studies included in this review have applied a variety of learning paradigms, in turn producing variable outcomes. Specifically, data on the long-term memory of nonemotional stimuli found no effect or even worsening in memory, while studies using emotional stimuli showed an improvement of long-term memory performance. In conclusion, this review identified a link between long-term memory performance and exogenous intranasal Oxt in humans, although these results still warrant further confirmation in large, multicenter randomized controlled trials. Drug Dev Res 77 : 479-488, 2016. © 2016 Wiley Periodicals, Inc.

Nanomedicine in Psychiatry: New Therapeutic Opportunities from Research on Small RNAs.

Preclinical Research Alterations in small non-coding RNAs have been observed in many human disease states including cancer, cardiovascular, developmental, neurological, and psychiatric disorders. These molecules have recently raised the interest of the scientific community for novel therapeutic approaches. Nanotechnologies, including the development of sophisticated nanoparticles, offer new ways for the delivery of small RNA-based therapies. The nanoparticle delivery method appears attractive, but so far most of the work in this area has been conducted in the context of cancer. New therapeutic strategies are needed for psychiatric disorders, where treatment is often ineffective, leading to frequent patient hospitalizations and a growing economic burden. In this article, we discuss the role of small RNAs in psychiatric diseases and how this new knowledge, combined with innovations in nanotechnologies, could lead to the development of novel therapeutic approaches. Drug Dev Res 77 : 453-457, 2016. © 2016 Wiley Periodicals, Inc.

Serum Levels of Insulin-Like Growth Factor-1 and Obsessive-Compulsive Disorder: A Case-Control Study.

BACKGROUND/AIMS: Recent findings suggest an involvement of insulin-like growth factor-1 (IGF-1) in the pathogenesis of many psychiatric disorders; however, there is a lack of data regarding IGF-1 in patients with obsessive-compulsive disorder (OCD). The aims of the present study were (1) to analyze putative alterations of IGF-1 serum content in patients with OCD compared to patients with major depressive disorder (MDD) and healthy controls, and (2) to analyze putative changes of IGF-1 levels during drug treatment in subjects with OCD compared to patients with MDD. METHODS: We recruited 40 OCD patients, 37 MDD patients, and 43 healthy controls. All participants were adults. Serum IGF-1 levels were measured by the ELISA method on venous blood samples collected at baseline and after 10 ± 1 weeks of drug treatment. RESULTS: IGF-1 levels were increased in OCD patients compared to controls (149.9 ± 60.2 vs. 121.2 ± 51.6 ng/ml; p = 0.040). No correlations were observed between baseline IGF-1 levels, clinical features, and response to treatment at follow-up in OCD or MDD patients. No changes in serum IGF-1 were observed after drug treatment. CONCLUSION: Our results show for the first time that serum IGF-1 levels are altered in patients with OCD. Further research on the role of IGF-1 in OCD is warranted.

Absolute Measurements of Macrophage Migration Inhibitory Factor and Interleukin-1-ß mRNA Levels Accurately Predict Treatment Response in Depressed Patients.

BACKGROUND: Increased levels of inflammation have been associated with a poorer response to antidepressants in several clinical samples, but these findings have had been limited by low reproducibility of biomarker assays across laboratories, difficulty in predicting response probability on an individual basis, and unclear molecular mechanisms. METHODS: Here we measured absolute mRNA values (a reliable quantitation of number of molecules) of Macrophage Migration Inhibitory Factor and interleukin-1ß in a previously published sample from a randomized controlled trial comparing escitalopram vs nortriptyline (GENDEP) as well as in an independent, naturalistic replication sample. We then used linear discriminant analysis to calculate mRNA values cutoffs that best discriminated between responders and nonresponders after 12 weeks of antidepressants. As Macrophage Migration Inhibitory Factor and interleukin-1ß might be involved in different pathways, we constructed a protein-protein interaction network by the Search Tool for the Retrieval of Interacting Genes/Proteins. RESULTS: We identified cutoff values for the absolute mRNA measures that accurately predicted response probability on an individual basis, with positive predictive values and specificity for nonresponders of 100% in both samples (negative predictive value=82% to 85%, sensitivity=52% to 61%). Using network analysis, we identified different clusters of targets for these 2 cytokines, with Macrophage Migration Inhibitory Factor interacting predominantly with pathways involved in neurogenesis, neuroplasticity, and cell proliferation, and interleukin-1ß interacting predominantly with pathways involved in the inflammasome complex, oxidative stress, and neurodegeneration. CONCLUSION: We believe that these data provide a clinically suitable approach to the personalization of antidepressant therapy: patients who have absolute mRNA values above the suggested cutoffs could be directed toward earlier access to more assertive antidepressant strategies, including the addition of other antidepressants or antiinflammatory drugs.

Peripheral whole blood microRNA alterations in major depression and bipolar disorder.

Major depression (MD) and bipolar disorder (BD) are severe and potentially life-threating mood disorders whose etiology is to date not completely understood. MicroRNAs (miRNAs) are small non-coding RNAs that regulate protein synthesis post-transcriptionally by base-pairing to target gene mRNAs. Growing evidence indicated that miRNAs might play a key role in the pathogenesis of neuropsychiatric disorders and in the action of psychotropic drugs. On these bases, in this study we evaluated the expression levels of 1733 mature miRNAs annotated in miRBase v.17, through a microarray technique, in the blood of 20 MD and 20 BD patients and 20 healthy controls, in order to identify putative miRNA signatures associated with mood disorders. We found that 5 miRNAs (hsa-let-7a-5p, hsa-let-7d-5p, hsa-let-7f-5p, hsa-miR-24-3p and hsa-miR-425-3p) were specifically altered in MD patients and 5 (hsa-miR-140-3p, hsa-miR-30d-5p, hsa-miR-330-5p, hsa-miR-378a-5p and hsa-miR-21-3p) in BD patients, whereas 2 miRNAs (hsa-miR-330-3p and hsa-miR-345-5p) were dysregulated in both the diseases. The bioinformatic prediction of the genes targeted by the altered miRNAs revealed the possible involvement of neural pathways relevant for psychiatric disorders. In conclusion, the observed results indicate a dysregulation of miRNA blood expression in mood disorders and could indicate new avenues for a better understanding of their pathogenetic mechanisms. The identified alterations may represent potential peripheral biomarkers to be complemented with other clinical and biological features for the improvement of diagnostic accuracy.