Showing papers in "Molecular Psychiatry in 2007"
TL;DR: Behavioral, theoretical and neurobiological work, including the regions in which extinction-related plasticity occurs and the cellular and molecular processes that are engaged are covered, along with a discussion of clinical implications.
Abstract: Excessive fear and anxiety are hallmarks of a variety of disabling anxiety disorders that affect millions of people throughout the world. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear and anxiety is attracting increasing interest in the research community. In the laboratory, fear inhibition most often is studied through a procedure in which a previously fear conditioned organism is exposed to a fear-eliciting cue in the absence of any aversive event. This procedure results in a decline in conditioned fear responses that is attributed to a process called fear extinction. Extensive empirical work by behavioral psychologists has revealed basic behavioral characteristics of extinction, and theoretical accounts have emphasized extinction as a form of inhibitory learning as opposed to an erasure of acquired fear. Guided by this work, neuroscientists have begun to dissect the neural mechanisms involved, including the regions in which extinction-related plasticity occurs and the cellular and molecular processes that are engaged. The present paper will cover behavioral, theoretical and neurobiological work, and will conclude with a discussion of clinical implications.
1,174 citations
TL;DR: Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation, and presumably clarify a vulnerability trait to become depressed.
Abstract: Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). Monoamine depletion studies investigate the direct effects of monoamines on mood. Acute tryptophan depletion (ATD) or para-chlorophenylalanine (PCPA) deplete 5-HT, acute phenylalanine/tyrosine depletion (APTD) or alpha-methyl-para-tyrosine (AMPT) deplete NE/DA. Available depletion studies found conflicting results in heterogeneous populations: healthy controls, patients with previous MDD in remission and patients suffering from MDD. The decrease in mood after 5-HT and NE/DA depletion in humans is reviewed and quantified. Systematic search of MEDLINE and EMBASE (1966-October 2006) and cross-references was carried out. Randomized studies applying ATD, PCPA, APTD or AMPT vs control depletion were included. Pooling of results by meta-analyses was stratified for studied population and design of the study (within or between subjects). Seventy-three ATD, 2 PCPA, 10 APTD and 8 AMPT studies were identified of which 45 ATD and 8 APTD studies could be meta-analyzed. 5-HT or NE/DA depletion did not decrease mood in healthy controls. 5-HT or NE/DA depletion slightly lowered mood in healthy controls with a family history of MDD. In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants. In conclusion, monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed.
758 citations
TL;DR: The data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.
Abstract: Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the synaptic plasticity underlying the acquisition and/or consolidation of certain forms of memory. Additionally, a role has been suggested for neurotrophin function within the hippocampus in protection from anxiety and depressive disorders. Understanding the function of this important gene in adult animals has been limited however, because standard knockouts are confounded by gene effects during development. There are no BDNF receptor-specific pharmacological agents, and infusions of neuropeptides or antibodies have other significant limitations. In these studies, we injected a lentivirus expressing Cre recombinase bilaterally into the dorsal hippocampus in adult mice floxed at the BDNF locus to facilitate the site-specific deletion of the BDNF gene in adult animals. Significant decreases in BDNF mRNA expression are demonstrated in the hippocampi of lenti-Cre-infected animals compared with control lenti-GFP-infected animals. Behaviorally, there were no significant effects of BDNF deletion on locomotion or baseline anxiety measured with startle. In contrast, hippocampal-specific BDNF deletions impair novel object recognition and spatial learning as demonstrated with the Morris water maze. Although there were no effects on the acquisition or expression fear, animals with BDNF deletions show significantly reduced extinction of conditioned fear as measured both with fear-potentiated startle and freezing. These data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.
625 citations
TL;DR: This review on the Genetics of AD will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism.
Abstract: Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.
612 citations
TL;DR: A hypothesis integrating current concepts of neurotransmission and hypothalamus–pituitary–adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD is presented.
Abstract: Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-gamma, or tumor necrosis factor-alpha activate the tryptophan- and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes - counteracting this metabolism due to the lack of an enzyme of this metabolism - have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid.
594 citations
TL;DR: Although research efforts should concentrate on elucidating the genetic underpinnings of behavior rather than the environment itself, the identification of rGE may suggest targets for environmental intervention even in highly heritable disease.
Abstract: Family studies have demonstrated genetic influences on environmental exposure: the phenomenon of gene-environment correlation (rGE). A few molecular genetic studies have confirmed the results, but the identification of rGE in studies that measure genes and environments faces several challenges. Using examples from studies in psychology and psychiatry, we integrate the behavioral and molecular genetic literatures on rGE, describe challenges in identifying rGE and discuss the implications of molecular genetic findings of rGE for future research on gene-environment interplay and for attempts to prevent disease by reducing environmental risk exposure. Genes affect environments indirectly, via behavior and personality characteristics. Associations between individual genetic variants and behaviors are typically small in magnitude, and downstream effects on environmental risk are further attenuated by behavioral mediation. Genotype-environment associations are most likely to be detected when the environment is behaviorally modifiable and highly specified and a plausible mechanism links gene and behavior. rGEs play an important causal role in psychiatric illness. Although research efforts should concentrate on elucidating the genetic underpinnings of behavior rather than the environment itself, the identification of rGE may suggest targets for environmental intervention even in highly heritable disease. Prevention efforts must address the possibility of confounding between rGE and gene-environment interaction (G x E).
533 citations
TL;DR: A significant association of the s/s variant of 5-HTTLPR with remission rate and both s/ s and s/l variants with response rate is observed and this effect is quite robust to ethnic differences although a significant heterogeneity is present in Asian samples.
Abstract: Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients
502 citations
TL;DR: It is shown that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.
Abstract: Disrupted in Schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein–protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called ‘DISC1 interactome’ contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cell-cycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.
419 citations
TL;DR: A critical review of the clinical and preclinical studies which have been responsible for the controversy over the BDNF hypothesis of depression, outlining pharmacological, behavioural and genetic evidence which demonstrates the contrasting role of BDNF in regulating mood and antidepressant effects throughout the brain.
Abstract: The brain-derived neurotrophic factor (BDNF) hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and that its restoration may underlie the therapeutic efficacy of antidepressant treatment. While this theory has received considerable experimental support, an increasing number of studies have generated evidence which is not only inconsistent, but also directly contradicts the hypothesis. This article provides a critical review of the clinical and preclinical studies which have been responsible for this controversy, outlining pharmacological, behavioural and genetic evidence which demonstrates the contrasting role of BDNF in regulating mood and antidepressant effects throughout the brain. I will also review key studies, both human and animal, which have investigated the association of a BDNF single-nucleotide polymorphism (Val66Met) with depression pathogenesis, and detail the number of inconsistencies which also afflict this novel area of BDNF research. The article will conclude by discussing why now is a critical time to reassess the original BDNF hypothesis of depression, and look towards the formation of new models that can provide a more valid account of the complex relationships between growth factors, mood disorders and their treatment.
405 citations
TL;DR: A model is proposed in which a combination of various factors that may compromise5-HT functioning in one person can result in depression or other 5-HT-related pathology, and it is proposed that vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action.
Abstract: In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs.
356 citations
Wellcome Trust Centre for Human Genetics1, Tottori University2, Yale University3, University of California, Los Angeles4, QIMR Berghofer Medical Research Institute5, Virginia Commonwealth University6, Tallinn University of Technology7, Université de Montréal8, McGill University9, Max Planck Society10, University of Oxford11, Ludwig Maximilian University of Munich12, University of Aberdeen13, GlaxoSmithKline14, University of Pretoria15, Rockefeller University16, University of Helsinki17, New York University18
TL;DR: It is shown that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity, and the first putative genetic effect on variability in human brain asymmetry is found.
Abstract: Left–right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P = 0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P = 0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution. Molecular Psychiatry (2007) 12, 1129–1139; doi:10.1038/sj.mp.4002053; published online 31 July 2007
TL;DR: Key findings are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects, and the influence of a 5-HT2C polymorphism in antipsychotic-induced weight gain.
Abstract: The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients’ metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and −141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (−759−T/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients’ metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.
TL;DR: Results of a case–control WGA study in schizophrenia revealed a strong effect of a novel locus near the CSF2RA gene in the pseudoautosomal region, which may help explain prior epidemiologic data relating the risk for this illness to altered rates of autoimmune disorders, prenatal infection and familial leukemia.
Abstract: Schizophrenia is a strongly heritable disorder, and identification of potential candidate genes has accelerated in recent years. Genomewide scans have identified multiple large linkage regions across the genome, with fine-mapping studies and other investigations of biologically plausible targets demonstrating several promising candidate genes of modest effect. The recent introduction of technological platforms for whole-genome association (WGA) studies can provide an opportunity to rapidly identify novel targets, although no WGA studies have been reported in the psychiatric literature to date. We report results of a case–control WGA study in schizophrenia, examining B500 000 markers, which revealed a strong effect (P = 3.7 � 10 � 7 ) of a novel locus (rs4129148) near the CSF2RA (colony stimulating factor, receptor 2 alpha) gene in the pseudoautosomal region. Sequencing of CSF2RA and its neighbor, IL3RA (interleukin 3 receptor alpha) in an independent case–control cohort revealed both common intronic haplotypes and several novel, rare missense variants associated with schizophrenia. The presence of cytokine receptor abnormalities in schizophrenia may help explain prior epidemiologic data relating the risk for this illness to altered rates of autoimmune disorders, prenatal infection and familial leukemia. Molecular Psychiatry (2007) 12, 572–580; doi:10.1038/sj.mp.4001983; published online 20 March 2007
TL;DR: Epigenetic factors – inherited and acquired modifications of DNA and histones that regulate various genomic functions occurring without a change in nuclear DNA sequence – offer new insights about many of the non-Mendelian features of major depression, and provide a direct mechanistic route via which the environment can interact with the genome.
Abstract: Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder encompassing a spectrum of symptoms involving deficits to a range of cognitive, psychomotor and emotional processes. As is the norm for aetiological studies into the majority of psychiatric phenotypes, particular focus has fallen on the interplay between genetic and environmental factors. There are, however, several epidemiological, clinical and molecular peculiarities associated with MDD that are hard to explain using traditional gene- and environment-based approaches. Our goal in this study is to demonstrate the benefits of looking beyond conventional ‘DNA+environment’ and ‘DNA × environment’ aetiological paradigms. Epigenetic factors – inherited and acquired modifications of DNA and histones that regulate various genomic functions occurring without a change in nuclear DNA sequence – offer new insights about many of the non-Mendelian features of major depression, and provide a direct mechanistic route via which the environment can interact with the genome. The study of epigenetics, especially in complex diseases, is a relatively new field of research, and optimal laboratory techniques and analysis methods are still being developed. Incorporating epigenetic research into aetiological studies of MDD thus presents a number of methodological and interpretive challenges that need to be addressed. Despite these difficulties, the study of DNA methylation and histone modifications has the potential to transform our understanding about the molecular aetiology of complex diseases.
TL;DR: Fronto-limbic anatomical brain abnormalities in suicidal and non-suicidal adult female patients with unipolar depression find abnormalities in the orbitofrontal cortex and amygdala in suicidal patients may impair decision-making and predispose these patients to act more impulsively and to attempt suicide.
Abstract: Our knowledge about the neurobiology of suicide is limited. It has been proposed that suicidal behavior generally requires biological abnormalities concomitant with the personality trait of impulsivity/aggression, besides an acute psychiatric illness or psychosocial stressor. We investigated fronto-limbic anatomical brain abnormalities in suicidal and non-suicidal adult female patients with unipolar depression. Our sample consisted of seven suicidal unipolar patients, 10 non-suicidal unipolar patients and 17 healthy female comparison subjects. The criterion for suicidality was one or more documented lifetime suicide attempts. A 1.5T GE Signa Imaging System running version Signa 5.4.3 software was used to acquire the magnetic resonance imaging images. All anatomical structures were measured blindly, with the subjects' identities and group assignments masked. We used analysis of covariance with age and intracranial volume as covariates and the Tukey-Kramer procedure to compare suicidal patients, non-suicidal patients and healthy comparison subjects. Suicidal patients had smaller right and left orbitofrontal cortex gray matter volumes compared with healthy comparison subjects. Suicidal patients had larger right amygdala volumes than non-suicidal patients. Abnormalities in the orbitofrontal cortex and amygdala in suicidal patients may impair decision-making and predispose these patients to act more impulsively and to attempt suicide.
TL;DR: DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.
Abstract: Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder. It also has been reported that dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks in rats, increased their depression and aggression scores. Here, we show that n-3 PUFA deprivation for 15 weeks decreased the frontal cortex DHA level and reduced frontal cortex BDNF expression, cAMP response element binding protein (CREB) transcription factor activity and p38 mitogen-activated protein kinase (MAPK) activity. Activities of other CREB activating protein kinases were not significantly changed. The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor. DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.
TL;DR: Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory, and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.
Abstract: Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD(67)), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5' flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5' untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.
TL;DR: There is small but significant relationship between Val158Met genotype and executive function in healthy individuals but not in schizophrenia, and it is suggested that Val and Met alleles are codominant in their effects on cognition.
Abstract: The catechol-O-methyltransferase (COMT) Val158Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n=1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d=0.29; 95% confidence interval (CI) 0.02–0.55; P=0.03), but this was not supported in the patient sample (d=−0.07; 95% CI −0.40 to 0.26; P=0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val158Met genotype and executive function in healthy individuals but not in schizophrenia.
TL;DR: Evidence is focused on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and thatmuscarinic receptors may represent promising novel targets for the treatment of this disorder.
Abstract: Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including pre-clinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.
TL;DR: Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning.
Abstract: Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.
TL;DR: The association of the DRD2 Taq1A polymorphism with alcoholism is supported, qualified by the possibility of publication bias in the literature and the observed between-study heterogeneity, which indicates that the observed association may differ in strength between populations or may not exist at all in some populations.
Abstract: We investigated the association of the dopamine D2 receptor (DRD2) Taq1A polymorphism and alcoholism, using meta-analytic techniques, and specifically undertook an investigation of possible publication bias. Potential publication bias represents a genuine risk to the integrity of published research, but its impact has rarely been documented. We observed a small effect of the DRD2 Taq1A polymorphism on risk of alcoholism, indicating increased alcoholism in individuals possessing the A1 allele of the Taq1A polymorphism (OR=1.21, 95% CI 1.13-1.30, P<0.001). This association remained significant when data from samples of European and East Asian ancestry were analyzed separately. We did not find evidence for association in high-severity alcoholism compared to low-severity alcoholism. Removing the first published study significantly reduced the magnitude of the pooled effect size estimate, although the association remained significant. In addition, we observed evidence for possible publication bias and for the strength of individual study effect size to be inversely related to year of publication. These results support the association of the DRD2 Taq1A polymorphism with alcoholism. This conclusion is qualified by the possibility of publication bias in the literature and the observed between-study heterogeneity, which indicates that the observed association may differ in strength between populations or may not exist at all in some populations.
TL;DR: A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.
Abstract: Schizophrenia is associated with impairments in neurotransmitter systems and changes in neuronal membrane phospholipids. Several atypical antipsychotic drugs induce weight gain and hypertriglyceridemia. To date, there has not been a comprehensive evaluation and mapping of global lipid changes in schizophrenia, and upon treatment with antipsychotics. Such mapping could provide novel insights about disease mechanisms and metabolic side effects of therapies used for its treatment. We used a specialized metabolomics platform ‘lipidomics’ that quantifies over 300 polar and nonpolar lipid metabolites (across seven lipid classes) to evaluate global lipid changes in schizophrenia and upon treatment with three commonly used atypical antipsychotics. Lipid profiles were derived for 50 patients with schizophrenia before and after treatment for 2–3 weeks with olanzapine (n=20), risperidone (n=14) or aripiprazole (n=16). Patients were recruited in two cohorts (study I, n=27 and study II, n=23) to permit an internal replication analyses. The change from baseline to post-treatment was then compared among the three drugs. Olanzapine and risperidone affected a much broader range of lipid classes than aripiprazole. Approximately 50 lipids tended to be increased with both risperidone and olanzapine and concentrations of triacylglycerols increased and free fatty acids decreased with both drugs but not with aripiprazole. Phosphatidylethanolamine concentrations that were suppressed in patients with schizophrenia were raised by all three drugs. Drug specific differences were also detected. A principal component analysis (PCA) identified baseline lipid alterations, which correlated with acute treatment response. A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.
TL;DR: These findings may reflect a specific kind of vulnerability for the development of psychiatric affective disorders and suggest that trait anhedonia may be linked to a volumetric reduction in the basal ganglia and to a prefrontal functional abnormality during hedonic processing.
Abstract: Anhedonia, the reduced capacity to gain pleasure from pleasurable experiences, is a key symptom of major depression and schizophrenia. Reduced hedonic capacity can also be measured as an enduring trait in non-clinical subjects. Such altered hedonic capacity is likely the result of a basic neuropsychophysiological dysfunction and a vulnerability marker that potentially precedes and contributes to the liability of developing psychiatric disorders. The characterization of the structural and functional neural correlates of trait anhedonia in non-clinical individuals may provide new insights for the early detection of such psychiatric diseases. Twenty-nine non-clinical subjects were scanned at the Montreal Neurological Institute. Trait anhedonia was measured using the Chapman Revised Physical Anhedonia Scale. Semi-automated and automated structural MRI segmentation techniques were used to explore structural correlates of trait anhedonia. Seventeen of the 29 subjects also underwent a functional imaging task where responses to the viewing of affective stimuli were examined to identify the functional correlates of trait anhedonia. Trait anhedonia was inversely related to anterior caudate volume, but positively related to ventromedial prefrontal cortex activity during the processing of positive information. These findings may reflect a specific kind of vulnerability for the development of psychiatric affective disorders and suggest that trait anhedonia may be linked to a volumetric reduction in the basal ganglia and to a prefrontal functional abnormality during hedonic processing.
TL;DR: In vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD is provided, and MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls.
Abstract: The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age±s.d.=34.3±11.5 years) and 15 healthy comparison subjects (37.7±12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.
TL;DR: This updated meta-analysis covers all published studies using multiple research methods up to January 2006 and suggests a significant association with a P-value of 0.0068, which supports the involvement of the brain 5-HTT in the pathogenesis of suicidal behavior.
Abstract: Suicidal behavior, which ranks among the top 10 causes of death worldwide, is an important public-health problem and a psychiatric disorder, which has been the subject of considerable study. Studies have shown association between the serotonin transporter (5-HTT) gene and suicidal behavior, although a proportion of alternative studies have produced contrary results both in terms of positive and negative findings, possibly reflecting inadequate statistical power and the use of different populations. Using the cumulative data from recent years in both European and, more particularly, Asian populations, this updated meta-analysis seeks to examine whether the aggregate data provide evidence of statistical significance, and to clarify the contradictory findings suggested by previous studies. It covers all published studies using multiple research methods up to January 2006. Compared with a previous meta-analysis, which found no association between the 5-HTTLPR polymorphism and suicidal behavior (P=0.38), the current results (39 studies) suggest a significant association with a P-value of 0.0068 (overall odds ratio=0.88 (0.8,0.97)), and supports the involvement of the brain 5-HTT in the pathogenesis of suicidal behavior.
TL;DR: This study suggests that n-3 PUFA deprivation increases the half-live of brain DHA by downregulating iPLA2, opposite to what has been reported after chronic administration of anti-manic agents to rats and suggests thatn-3PUFA deprivation may increase susceptibility to bipolar disorder.
Abstract: The enzymes that regulate the brain arachidonic acid (AA) cascade have been implicated in bipolar disorder and neuroinflammation. Fifteen weeks of dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats decreases the concentration of docosahexaenoic acid (DHA) and increases its half-life within the brain. Based on this, we hypothesized that such dietary deprivation would decrease expression of enzymes responsible for the metabolic loss of DHA while increasing expression of those responsible for the metabolism of AA. Fifteen weeks of n-3 PUFA deprivation significantly decreased the activity, protein and mRNA expression of the DHA regulatory phospholipase A2 (PLA2), calcium-independent iPLA2, in rat frontal cortex. In contrast the activities, protein and mRNA levels of the AA selective calcium-dependent cytosolic phospholipase (cPLA2) and secretory sPLA2 were increased. Cyclooxygenase (COX)-1 protein but not mRNA was decreased in the n-3 PUFA-deprived rats whereas COX-2 protein and mRNA were increased. This study suggests that n-3 PUFA deprivation increases the half-live of brain DHA by downregulating iPLA2. The finding that n-3 PUFA deprivation increases cPLA2, sPLA2 and COX-2 is opposite to what has been reported after chronic administration of anti-manic agents to rats and suggests that n-3 PUFA deprivation may increase susceptibility to bipolar disorder.
TL;DR: Transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment, suggesting that both different regions and pathways account for fast onset but short lasting effects as compared to slow-onset but long-lasting effects.
Abstract: The significant proportion of depressed patients that are resistant to monoaminergic drug therapy and the slow onset of therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs)/serotonin/noradrenaline reuptake inhibitors (SNRIs) are two major reasons for the sustained search for new antidepressants. In an attempt to identify common underlying mechanisms for fast- and slow-acting antidepressant modalities, we have examined the transcriptional changes in seven different brain regions of the rat brain induced by three clinically effective antidepressant treatments: electro convulsive therapy (ECT), sleep deprivation (SD), and fluoxetine (FLX), the most commonly used slow-onset antidepressant. Each of these antidepressant treatments was applied with the same regimen known to have clinical efficacy: 2 days of ECT (four sessions per day), 24 h of SD, and 14 days of daily treatment of FLX, respectively. Transcriptional changes were evaluated on RNA extracted from seven different brain regions using the Affymetrix rat genome microarray 230 2.0. The gene chip data were validated using in situ hybridization or autoradiography for selected genes. The major findings of the study are: 1. The transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment. 2. The fast-onset, short-lived antidepressant treatments ECT and SD evoked transcriptional changes primarily in the catecholaminergic system, whereas the slow-onset antidepressant FLX treatment evoked transcriptional changes in the serotonergic system. 3. ECT and SD affect in a similar manner the same brain regions, primarily the locus coeruleus, whereas the effects of FLX were primarily in the dorsal raphe and hypothalamus, suggesting that both different regions and pathways account for fast onset but short lasting effects as compared to slow-onset but long-lasting effects. However, the similarity between effects of ECT and SD is somewhat confounded by the fact that the two treatments appear to regulate a number of transcripts in an opposite manner. 4. Multiple transcripts (e.g. brain-derived neurotrophic factor (BDNF), serum/glucocorticoid-regulated kinase (Sgk1)), whose level was reported to be affected by antidepressants or behavioral manipulations, were also found to be regulated by the treatments used in the present study. Several novel findings of transcriptional regulation upon one, two or all three treatments were made, for the latter we highlight homer, erg2, HSP27, the proto oncogene ret, sulfotransferase family 1A (Sult1a1), glycerol 3-phosphate dehydrogenase (GPD3), the orphan receptor G protein-coupled receptor 88 (GPR88) and a large number of expressed sequence tags (ESTs). 5. Transcripts encoding proteins involved in synaptic plasticity in the hippocampus were strongly affected by ECT and SD, but not by FLX. The novel transcripts, concomitantly regulated by several antidepressant treatments, may represent novel targets for fast onset, long-duration antidepressants.
TL;DR: The results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses.
Abstract: Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.
TL;DR: The current pipeline of drugs for schizophrenia is discussed, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs and highlighting the importance of developing new paradigms for drug discovery in schizophrenia.
Abstract: While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.
TL;DR: The data support possible differences of circulating proteins in autism, and should help stimulate the continued search for causes and treatments of autism by examining peripheral blood.
Abstract: Modern methods that use systematic, quantitative and unbiased approaches are making it possible to discover proteins altered by a disease. To identify proteins that might be differentially expressed in autism, serum proteins from blood were subjected to trypsin digestion followed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) on time-of-flight (TOF) instruments to identify differentially expressed peptides. Children with autism 4-6 years of age (n=69) were compared to typically developing children (n=35) with similar age and gender distributions. A total of 6348 peptide components were quantified. Of these, five peptide components corresponding to four known proteins had an effect size >0.99 with a P<0.05 and a Mascot identification score of 30 or greater for autism compared to controls. The four proteins were: Apolipoprotein (apo) B-100, Complement Factor H Related Protein (FHR1), Complement C1q and Fibronectin 1 (FN1). In addition, apo B-100 and apo A-IV were higher in children with high compared to low functioning autism. Apos are involved in the transport of lipids, cholesterol and vitamin E. The complement system is involved in the lysis and removal of infectious organisms in blood, and may be involved in cellular apoptosis in brain. Despite limitations of the study, including the low fold changes and variable detection rates for the peptide components, the data support possible differences of circulating proteins in autism, and should help stimulate the continued search for causes and treatments of autism by examining peripheral blood.