The D-amino acid oxidase inhibitor luvadaxistat improves mismatch negativity in patients with schizophrenia in a randomized trial.

Several attempts have been made to enhance N-methyl-D-aspartate (NMDA) receptor function in schizophrenia, but they have yielded mixed results. Luvadaxistat, a D-amino acid oxidase (DAAO) inhibitor that increases the glutamate co-agonist D-serine levels, is being developed for the treatment of cognitive impairment associated with schizophrenia. We conducted a biomarker study in patients, assessing several endpoints related to physiological outcomes of NMDA receptor modulation to determine whether luvadaxistat affects neural circuitry biomarkers relevant to NMDA receptor function and schizophrenia. This was a randomized, placebo-controlled, double-blind, two-period crossover phase 2a study assessing luvadaxistat 50 mg and 500 mg for 8 days in 31 patients with schizophrenia. There were no treatment effects of luvadaxistat at either dose in eyeblink conditioning, a cerebellar-dependent learning measure, compared with placebo. We observed a nominally significant improvement in mismatch negativity (MMN) and a statistical trend to improvement for auditory steady-state response at 40 Hz, in both cases with 50 mg, but not with 500 mg, compared with placebo. Although the data should be interpreted cautiously owing to the small sample size, they suggest that luvadaxistat can improve an illness-related circuitry biomarker at doses associated with partial DAAO inhibition. These results are consistent with 50 mg, but not higher doses, showing a signal of efficacy in cognitive endpoints in a larger phase 2, 12-week study conducted in parallel. Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction.

Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A.

AIMS: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069). METHODS: Two randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD]). RESULTS: TAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide. CONCLUSION: The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.

The Neuronal Glutamate Transporter EAAT3 in Obsessive-Compulsive Disorder.

Obsessive compulsive disorder (OCD) is a heterogeneous psychiatric disorder affecting 1%-3% of the population worldwide. About half of OCD afflicted individuals do not respond to currently available pharmacotherapy, which is mainly based on serotonin reuptake inhibition. Therefore, there is a critical need to search novel and improved therapeutic targets to treat this devastating disorder. In recent years, accumulating evidence has supported the glutamatergic hypothesis of OCD, and particularly pointing a potential role for the neuronal glutamate transporter EAAT3. This mini-review summarizes recent findings regarding the neurobiological basis of OCD, with an emphasis on the glutamatergic neurotransmission and EAAT3 as a key player in OCD etiology.

Correction: Behavioral and synaptic alterations relevant to obsessivecompulsive disorder in mice with increased EAAT3 expression.

The original version of this Article contained an error in the spelling of the author Anna K Radke, which was incorrectly given as Anna R Radke. This has now been corrected in both the PDF and HTML versions of the Article.

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression.

Obsessive-compulsive disorder (OCD) is a severe, chronic neuropsychiatric disorder with a strong genetic component. The SLC1A1 gene encoding the neuronal glutamate transporter EAAT3 has been proposed as a candidate gene for this disorder. Gene variants affecting SLC1A1 expression in human brain tissue have been associated with OCD. Several mouse models fully or partially lacking EAAT3 have shown no alterations in baseline anxiety-like or repetitive behaviors. We generated a transgenic mouse model (EAAT3glo) to achieve conditional, Cre-dependent EAAT3 overexpression and evaluated the overall impact of increased EAAT3 expression at behavioral and synaptic levels. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3glo/CMKII mice revealed changes in NMDA receptor subunit composition and altered NMDA-dependent synaptic plasticity. By recapitulating relevant behavioral, neurophysiological, and psychopharmacological aspects, our results provide support for the glutamatergic hypothesis of OCD, particularly for the increased EAAT3 function, and provide a valuable animal model that may open novel therapeutic approaches to treat this devastating disorder.

Pharmacogenetics of antidepressant response: A polygenic approach.

BACKGROUND: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait. METHODS: Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756). RESULTS: No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results. DISCUSSION: We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.

Identification of 15 genetic loci associated with risk of major depression in individuals of European descent.

Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 × 10(-5) in the meta-analysis were further analyzed in a replication data set (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint analysis over all three data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics.

An Integrative Genomic Study Implicates the Postsynaptic Density in the Pathogenesis of Bipolar Disorder.

Genome-wide association studies (GWAS) have identified several common variants associated with bipolar disorder (BD), but the biological meaning of these findings remains unclear. Integrative genomics-the integration of GWAS signals with gene expression data-may illuminate genes and gene networks that have key roles in the pathogenesis of BD. We applied weighted gene co-expression network analysis (WGCNA), which exploits patterns of co-expression among genes, to brain transcriptome data obtained by sequencing of poly-A RNA derived from postmortem dorsolateral prefrontal cortex from people with BD, along with age- and sex-matched controls. WGCNA identified 33 gene modules. Many of the modules corresponded closely to those previously reported in human cortex. Three modules were associated with BD, enriched for genes differentially expressed in BD, and also enriched for signals in prior GWAS of BD. Functional analysis of genes within these modules revealed significant enrichment of several functionally related sets of genes, especially those involved in the postsynaptic density (PSD). These results provide convergent support for the hypothesis that dysregulation of genes involved in the PSD is a key factor in the pathogenesis of BD. If replicated in larger samples, these findings could point toward new therapeutic targets for BD.

Translating Neurogenomics Into New Medicines.

Brain disorders remain one of the defining challenges of modern medicine and among the most poorly served with new therapeutics. Advances in human neurogenetics have begun to shed light on the genomic architecture of complex diseases of mood, cognition, brain development, and neurodegeneration. From genome-wide association studies to rare variants, these findings hold promise for defining the pathogenesis of brain disorders that have resisted simple molecular description. However, the path from genetics to new medicines is far from clear and can take decades, even for the most well-understood genetic disorders. In this review, we define three challenges for the field of neurogenetics that we believe must be addressed to translate human genetics efficiently into new therapeutics for brain disorders.

Translating human genetics into novel treatment targets for schizophrenia.

Human genetics is a rational starting point for target identification in drug discovery, yet this approach has found little application in neuroscience. Recent large-scale analyses have begun to identify robust genetic loci for schizophrenia, providing an opportunity to derive novel drug targets. Here, we summarize a strategy for applying human genetics to neuroscience drug discovery.

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes.

Toll-like receptors (TLRs) play a key role in innate immunity. Apart from their function in host defense, dysregulation in TLR signalling can confer risk to autoimmune diseases, septic shock or cancer. Here we report genetic variants and transcripts that are active only during TLR signalling and contribute to interindividual differences in immune response. Comparing unstimulated versus TLR4-stimulated monocytes reveals 1,471 expression quantitative trait loci (eQTLs) that are unique to TLR4 stimulation. Among these we find functional SNPs for the expression of NEU4, CCL14, CBX3 and IRF5 on TLR4 activation. Furthermore, we show that SNPs conferring risk to primary biliary cirrhosis (PBC), inflammatory bowel disease (IBD) and celiac disease are immune response eQTLs for PDGFB and IL18R1. Thus, PDGFB and IL18R1 represent plausible candidates for studying the pathophysiology of these disorders in the context of TLR4 activation. In summary, this study presents novel insights into the genetic basis of the innate immune response and exemplifies the value of eQTL studies in the context of exogenous cell stimulation.

Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive-compulsive disorder.

Despite compelling evidence for major genetic contributions to the etiology of obsessive-compulsive disorder (OCD), few genetic variants have been consistently associated with this debilitating illness. Molecular genetic studies in children and adolescents with OCD are of particular interest, since early onset of the disease has been observed to be associated with increased familiality. We replicate here for the first time in early-onset OCD patients, a previously reported association of OCD with the common gain-of-function LA allele at the serotonin transporter linked polymorphic region known as 5-HTTLPR in a collection of parent-offspring trios. The present meta-analysis of this recently refined serotonin transporter gene variant revealed further support for the LA allele conferring increased genetic susceptibility to OCD. We conclude that the 5-HTTLPR is currently the single best supported risk variant for OCD, in regards of early-onset OCD, albeit of modest effect size and the possibility that the conferred risk might not be specific to OCD.

Genetic susceptibility for bipolar disorder and response to antidepressants in major depressive disorder.

The high heterogeneity of response to antidepressant treatment in major depressive disorder (MDD) makes individual treatment outcomes currently unpredictable. It has been suggested that resistance to antidepressant treatment might be due to undiagnosed bipolar disorder or bipolar spectrum features. Here, we investigate the relationship between genetic susceptibility for bipolar disorder and response to treatment with antidepressants in MDD. Polygenic scores indexing risk for bipolar disorder were derived from the Psychiatric Genomics Consortium Bipolar Disorder whole genome association study. Linear regressions tested the effect of polygenic risk scores for bipolar disorder on proportional reduction in depression severity in two large samples of individuals with MDD, treated with antidepressants, NEWMEDS (n=1,791) and STAR*D (n=1,107). There was no significant association between polygenic scores for bipolar disorder and response to treatment with antidepressants. Our data indicate that molecular measure of genetic susceptibility to bipolar disorder does not aid in understanding non-response to antidepressants.

Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder.

To evaluate the hypothesis that functionally over-expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT-linked polymorphic region 5-HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine-to-valine at position 425 (I425V). The higher expressing 5-HTTLPR/rs25531 LA allele was more prevalent in TD probands than in controls (χ(2) = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing LAC haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 0.0013; OR, 2.14). Furthermore, the rare gain-of-function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family-adjusted significance of χ(2) = 15.03 (P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 Movement Disorder Society.

Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity.

Individuals with obsessive-compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders.

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes.

The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.

miR-15a and miR-16 regulate serotonin transporter expression in human placental and rat brain raphe cells.

The serotonin transporter (SERT) is a key regulatory molecule in serotonergic transmission implicated in numerous biological processes relevant to human disorders. Recently, it was shown that SERT expression is controlled by miR-16 in mouse brain. Here, we show that SERT expression is regulated additionally by miR-15a as well as miR-16 in human and rat tissues. This post-transcriptional regulation was observed and characterized in reporter assays and likewise when endogenous SERT expression was evaluated in human placental choriocarcinoma JAR cells and rat brain raphe RN46A cells - two cell lines that endogenously express SERT. Similar effects for miR-16 to those of miR-15a were found in both human and rat cell lines. The effects of miR-15a and miR-16 were comparable in extent to those originally reported for miR-16 in mice. These findings represent a novel layer of complexity for SERT expression regulation exerted by the mir-15a/16 cluster, whose genes are adjacently located at human chromosome 13q14.3.

Contribution of common genetic variants to antidepressant response.

BACKGROUND: Pharmacogenetic studies aiming to personalize the treatment of depression are based on the assumption that response to antidepressants is a heritable trait, but there is no compelling evidence to support this. METHODS: We estimate the contribution of common genetic variation to antidepressant response with Genome-Wide Complex Trait Analysis in a combined sample of 2799 antidepressant-treated subjects with major depressive disorder and genome-wide genotype data. RESULTS: We find that common genetic variants explain 42% (SE = .180, p = .009) of individual differences in antidepressant response. CONCLUSIONS: These results suggest that response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect.

Age-modulated association between prefrontal NAA and the BDNF gene.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p = 0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 × age interaction on NAA level (p = 0.031). Specifically, the effect of rs1519480 on NAA level became significant at age ⩾34.17 yr. NAA level decreased with advancing age for genotype TT (p = 0.001) but not for genotype CT (p = 0.82) or CC (p = 0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions.

Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis.

BACKGROUND: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. METHODS AND FINDINGS: The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. CONCLUSIONS: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.