Identification of quantitative trait loci for prepulse inhibition in rats

Abstract Introduction. Schizophrenia is a common and debilitating psychiatric disorder that is partially under genetic control. Because of difficulties in mapping the genes that influence susceptibility to schizophrenia in humans, there has been substantial interest in mapping genes that control endophenotypes for schizophrenia in both human and rodent populations. Deficient prepulse inhibition (PPI) of the startle response has shown promise as an endophenotype for schizophrenia, as well as several other psychiatric disorders. Methods. Brown Norway (BN/SsNHsd) and Wistar Kyoto (WKY/lj-cr) rats were used because they show a large, unconfounded difference in PPI. We used interval mapping methods to identify quantitative trait loci (QTL) for PPI in a backcross population. Results. We identified a QTL on chromosome 2 with a LOD score of 3.63 and a suggestive QTL on chromosome 18 with a LOD score of 2.71. Conclusions. Both of the identified regions contain several candidate genes. Furthermore, the implicated rat chromosomes are syntenic with human chromosomal regions that have been reported to contain QTL for schizophrenia, bipolar disorder, and Tourette's syndrome. These results identify the chromosomal location of gene(s) that modulate an endophenotype for schizophrenia, and other psychiatric disorders, and may provide a shortcut to identifying specific genes and/or biochemical pathways involved in human psychiatric diseases. Electronic Publication     

The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations.

Schizophrenia is a complex psychiatric disorder with both genetic and environmental components and is thought to be in part neurodevelopmental in origin. The DISC1 gene has been linked to schizophrenia in two independent Caucasian populations. The DISC1 protein interacts with a variety of proteins including FEZ1, the mammalian homolog of the Caenorhabditis elegans unc-76 protein, which is involved in axonal outgrowth. Variation at the FEZ1 gene has been associated with schizophrenia in a large Japanese cohort. In this study, nine SNP markers at the FEZ1 locus were genotyped in two populations. A North American Caucasian cohort of 212 healthy controls, 178 schizophrenics, 79 bipolar disorder, and 58 with schizoaffective disorder, and an African American cohort of 133 healthy controls, 162 schizophrenics, and 28 with schizoaffective disorder. No association to schizophrenia, bipolar disorder or schizoaffective disorder was found for any of the nine markers typed in these populations at the allelic or the genotypic level. Additionally no association was found in either population between specific haplotypes and any of the psychiatric disorders. Variation at the FEZ1 locus does not play a significant role in the etiology of schizophrenia, bipolar disorder or schizoaffective disorder in North American Caucasian or African American populations.Neuropsychopharmacology (2007) 32, 190-196. doi:10.1038/sj.npp.1301177; published online 16 August 2006.     

The utility of biomarker discovery approaches for the detection of disease mechanisms in psychiatric disorders

Schizophrenia remains an elusive multifaceted disorder with all evidence of its onset and aetiology pointing to a complex interplay of genetic, nutritional, environmental and developmental factors. Although several molecular and structural abnormalities have been reported for schizophrenia, no diagnostic test or other application of clinical use has yet emerged from this research. The heterogeneity of schizophrenia symptoms and its similarity to other psychiatric disorders, the accessibility of appropriate samples and the complexity of molecular alterations have greatly slowed down research. Biomarker discovery approaches should ultimately facilitate objective diagnosis, allow the identification of at-risk individuals, predict treatment success and revolutionize drug-discovery approaches. For psychiatric disorders, large sample numbers are necessary if disease-intrinsic alterations are to be detected in an environment of high biological variability. Only recent technological advances facilitate the profiling of proteins and metabolites of large sample numbers. These approaches promise to provide interesting insights into disease mechanisms, as they enable capturing the dynamic nature of disease-related alterations. By means of parallel profiling using a multi-omics approach, we aim to disentangle the complex nature of schizophrenia's aetiology. Here, we will outline how this system-based analysis approach can contribute to the discovery of disease mechanisms in schizophrenia and in turn other psychiatric disorders.     

Genetics and Epigenetics in Major Psychiatric Disorders

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.     

Minocycline: therapeutic potential in psychiatry

Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialled in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry.     

A review of the possible relevance of inositol and the phosphatidylinositol second messenger system (PI-cycle) to psychiatric disorders--focus on magnetic resonance spectroscopy (MRS) studies

Myo-inositol is an important part of the phosphatidylinositol second messenger system (PI-cycle). Abnormalities in nerve cell myo-inositol levels and/or PI-cycle regulation has been suggested as being involved in the pathophysiology and/or treatment of many psychiatric disorders including bipolar disorder, major depressive disorder, panic disorder, obsessive-compulsive disorder, eating disorders and schizophrenia. This review examines the metabolism and biochemical importance of myo-inositol and the PI-cycle. It relates this to the current in vivo evidence for myo-inositol and PI-cycle involvement in these psychiatric disorders, particularly focusing upon the magnetic resonance spectroscopy (MRS) findings in patient studies to date. From this review it is concluded that while the evidence suggests probable relevance to the pathophysiology and/or treatment of bipolar disorder, there is much less support for a significant role for the PI-cycle or myo-inositol in any other psychiatric disorder. More definitive investigation is required before PI-cycle dysfunction can be considered specific to bipolar disorder.     

Epigenetics of psychoactive drugs

Objectives Epigenetics refers to the heritable, but reversible regulation of various biological functions. Changes in DNA methylation and chromatin structure derived from histone modifications are involved in the brain development, pathogenesis and pharmacotherapy of brain disorders. Key findings Evidence suggests that epigenetic modulations play key roles in psychiatric diseases such as schizophrenia and bipolar disorder. The analysis of epigenetic aberrations in the mechanisms of psychoactive drugs helps to determine dysfunctional genes and pathways in the brain, to predict side effects of drugs on human genome and identify new pharmaceutical targets for treatment of psychiatric diseases. Summary Although numerous studies have concentrated on epigenetics of psychosis, the epigenetic studies of antipsychotics are limited. Here we present epigenetic mechanisms of various psychoactive drugs and review the current literature on psychiatric epigenomics. Furthermore, we discuss various epigenetic modulations in the pharmacology and toxicology of typical and atypical antipsychotics, methionine, lithium and valproic acid.     

Chronic olanzapine treatment causes differential expression of genes in frontal cortex of rats as revealed by DNA microarray technique.

Recent emerging biochemical data indicate that several important neuroregulatory genes and proteins may be involved in the etiology of schizophrenia and bipolar disorder. Additionally, the same genes appear to be targets of several psychotropic medications that are used to treat these disorders. Recent DNA microarray studies show that genes involved in synaptic neurotransmission, signal transduction, and glutamate/GABA regulation may be differentially regulated in brains of subjects with schizophrenia. We hypothesized that chronic administration of olanzapine to rats would alter expression of various genes that may be involved in the etiology of schizophrenia and mood disorders. Rats were administered olanzapine (N=20, 2 mg/kg/day) or sterile saline intraperitoneally (N=20) daily for 21 days. Control and olanzapine-treated frontal cortices were analyzed using cDNA microarray technology. The results showed significant downregulation of 31 genes and upregulation of 38 genes by greater than two-fold in the drug-treated brains vs controls. Our results provide evidence for altered regulation of genes involved with signal transduction and cell communication, metabolism and energy pathways, transport, immune response, nucleic acid metabolism, and neuronal growth factors. Real-time quantitative RT-PCR analysis verified the direction and magnitude of change in six genes of interest: calbindin 3, homer 1, regulator of G-protein signaling (RGS) 2, pyruvate kinase, Reelin and insulin 2. Western blotting showed significant upregulation in protein products for Reelin 410 and Reelin 180 kDa and downregulation for NMDA3B and RGS2. Our results show for the first time that olanzapine causes changes in levels of several important genes that may be involved in the etiology and treatment of schizophrenia and other psychiatric disorders.     

Increased temporal cortex ER stress proteins in depressed subjects who died by suicide.

Regulation of ER stress proteins, such as the 78-kilodalton glucose regulated protein (GRP78) by chronic treatment with mood stabilizing drugs suggests that this family of proteins may be involved in the pathophysiology of mood disorders. Indeed, increased levels of GRP78, GRP94, and calreticulin, a third member of the ER stress protein family, were found in temporal cortex of subjects with major depressive disorder who died by suicide compared with controls and subjects who died by other means. No such differences were found in subjects with other psychiatric disorders such as bipolar disorder or schizophrenia. These data suggest a potential role for ER stress proteins in severe depression that merits further study.     

Oxidative Stress and Psychological Disorders

Oxidative stress is an imbalance between cellular production of reactive oxygen species and the counteracting antioxidant mechanisms. The brain with its high oxygen consumption and a lipid-rich environment is considered highly susceptible to oxidative stress or redox imbalances. Therefore, the fact that oxidative stress is implicated in several mental disorders including depression, anxiety disorders, schizophrenia and bipolar disorder, is not surprising. Although several elegant studies have established a link between oxidative stress and psychiatric disorders, the causal relationship between oxidative stress and psychiatric diseases is not fully determined. Another critical aspect that needs much attention and effort is our understanding of the association between cellular oxidative stress and emotional stress. This review examines some of the recent discoveries that link oxidative status with anxiety, depression, schizophrenia and bipolar disorder. A discussion of published results and questions that currently exist in the field regarding a causal relationship between oxidative and emotional stress is also provided.     

Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies

Many lines of evidence now support the hypothesis that inflammation-related pathways are involved in the pathophysiology of psychiatric disorders. Much of the data underpinning this hypothesis has come from the study of inflammation-related proteins in blood of individuals with mood disorders and schizophrenia. Significantly, recent data have emerged to suggest that changes in inflammation-related pathways are present in the CNS of subjects with psychiatric disorders. It is therefore timely to overview how such data, plus data on the role of inflammation-related proteins in CNS function, is contributing to understanding the pathophysiology of mood disorders and schizophrenia. In addition, it has been suggested that antidepressants, mood stabilizers and antipsychotic drugs act on inflammation-related pathways and therefore measuring levels of inflammation-related proteins in blood may be useful in monitoring treatment responsiveness. Despite these important neuropsychopharmacological discoveries, there is no clear understanding as to how inflammatory-related pathways can precipitate the onset of psychiatric symptoms. This review will focus on data suggesting that acute-reactive proteins and cytokines are affected by the pathophysiology of mood disorders and schizophrenia, that levels of blood inflammation-related proteins before and after treatment might be useful in the diagnosis of psychiatric disorders or measuring responsiveness to drug treatment. Finally, it will be postulated how changes in these proteins affect CNS function to cause psychiatric disorders.     

Comparing tolerability of olanzapine in schizophrenia and affective disorders: a meta-analysis

Background: Olanzapine is prescribed for a number of psychiatric disorders, including schizophrenia, bipolar mania, and unipolar and bipolar depression. Olanzapine treatment is associated with tolerability issues such as metabolic adverse effects (e.g. weight gain, increase in blood glucose, triglycerides and total cholesterol levels), extrapyramidal symptoms [EPS] (e.g. parkinsonism, akathisia, tardive dyskinesia) and sedative adverse effects. Metabolic issues lead to some long-term consequences, which include cardiovascular diseases (CVD) and type 2 diabetes mellitus, and these complications cause high rates of mortality and morbidity among patients with severe mental illnesses. The expanded indications of olanzapine in psychiatry suggest a need to investigate whether there is a difference in the incidence and severity of adverse effects related to category diagnosis. Are the adverse effects expressed differently according to phenotype? Unfortunately, there are no reported studies that investigated these differences in adverse effects associated with olanzapine treatment in psychiatric patients with different phenotypes. Objective: The aim of the present meta-analysis is to separately examine olanzapine-induced cardiometabolic adverse effects and EPS in patients with schizophrenia and affective disorders. Data Sources: A search of computerized literature databases PsycINFO (1967-2010), PubMed (MEDLINE), EMBASE (1980-2010) and the clinicaltrials.gov website for randomized clinical trials was conducted. A manual search of reference lists of published review articles was carried out to gather further data. Study Selection: Randomized controlled trials were included in our study if (i) they assessed olanzapine adverse effects (metabolic or extrapyramidal) in adult patients with schizophrenia or affective disorders; and (ii) they administered oral olanzapine as monotherapy during study. Data Extraction: Two reviewers independently screened abstracts for choosing articles and one reviewer extracted relevant data on the basis of predetermined exclusion and inclusion criteria. It should be mentioned that for the affective disorders group we could only find articles related to bipolar disorder. Data Synthesis: Thirty-three studies (4831 patients) that address olanzapine monotherapy treatment of adults with schizophrenia or bipolar disorder were included in the analysis. The primary outcomes were metabolic adverse effects (changes in weight, blood glucose, low-density lipoprotein, total cholesterol and triglyceride levels). The secondary outcomes of our study were assessing the incidence of some EPS (parkinsonism, akathisia and use of antiparkinson medication). The tolerability outcomes were calculated separately for the schizophrenia and bipolar disorder groups and were combined in a meta-analysis. Tolerability outcomes show that olanzapine contributes to weight gain and elevates blood triglycerides, glucose and total cholesterol levels in both schizophrenia and bipolar disorder patients. However, olanzapine treatment produced significantly more weight gain in schizophrenia patients than in bipolar disorder patients. In addition, increases in blood glucose, total cholesterol and triglyceride levels were higher in the schizophrenia group compared with the bipolar disorder group, even though these differences were not statistically significant. Based on our results, the incidence of parkinsonism was significantly higher in the schizophrenia group than in the bipolar disorder group. Subgroup analysis and logistic regression were used to assess the influence of treatment duration, dose, industry sponsorship, age and sex ratio on tolerability outcome. Conclusions: Our results suggest that schizophrenia patients may be more vulnerable to olanzapine-induced weight gain. The findings may be explained by considering the fact that in addition to genetic disposition for metabolic syndrome in schizophrenia patients, they have an especially high incidence of lifestyle risk factors for CVD, such as poor diet, lack of exercise, stress and smoking. It might be that an antipsychotic induces severity of adverse effect according to the phenotype.     

N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects

Introduction: N-acetylcysteine (NAC) is widely known for its role as a mucolytic and as an antidote to paracetamol overdose. There is increasing interest in the use of NAC in the treatment of several psychiatric disorders. The rationale for the administration of NAC in psychiatric conditions is based on its role as a precursor to the antioxidant glutathione, and its action as a modulating agent of glutamatergic, dopaminergic, neurotropic and inflammatory pathways.

Areas covered: This study reviews the available data regarding the use of NAC in different psychiatric disorders including substance use disorders, autism, obsessive-compulsive spectrum disorders, schizophrenia, depression, bipolar disorder. Promising results were found in trials testing the use of NAC, mainly as an add-on treatment, in cannabis use disorder in young people, depression in bipolar disorder, negative symptoms in schizophrenia, and excoriation (skin-picking) disorder. Despite initial optimism, recent findings regarding NAC efficacy in autism have been disappointing.

Expert opinion: These preliminary positive results require further confirmation in larger samples and with longer follow-ups. Given its high tolerability and wide availability, NAC represents an important target to investigate in the field of new adjunctive treatments for psychiatric conditions.     

Utilizing pharmacodynamic properties of second-generation antipsychotics to guide treatment

Second-generation antipsychotics (SGAs) are used for the treatment of multiple psychiatric disorders including schizophrenia, bipolar depression, bipolar mania, autism and major depressive disorder. Additionally, their off-label use has been expanding to include other disorders as well, including post-traumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, eating disorders and personality disorders. All SGAs share common properties; however, each individual SGA has a unique pharmacodynamic profile that may be utilized to guide and individualize treatment.     

The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence

Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer's disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder.     

The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration

The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for the discovery of previously unsuspected genes and molecular pathways. The successes of genetic studies of schizophrenia and bipolar disorder have been aided by the formation of a large-scale GWAS consortium: the Psychiatric Genomics Consortium (PGC). In contrast, only a handful of GWAS of PTSD have appeared in the literature to date. Here we describe the formation of a group dedicated to large-scale study of PTSD genetics: the PGC-PTSD. The PGC-PTSD faces challenges related to the contingency on trauma exposure and the large degree of ancestral genetic diversity within and across participating studies. Using the PGC analysis pipeline supplemented by analyses tailored to address these challenges, we anticipate that our first large-scale GWAS of PTSD will comprise over 10 000 cases and 30 000 trauma-exposed controls. Following in the footsteps of our PGC forerunners, this collaboration—of a scope that is unprecedented in the field of traumatic stress—will lead the search for replicable genetic associations and new insights into the biological underpinnings of PTSD.     

D2 receptor partial agonists: treatment of CNS disorders of dopamine function

A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinson's disease (PD), and restless legs syndrome (RLS). In such disorders, transmission in discrete DA pathways may range from hypoactivation to hyperactivation of DA receptors, particularly those of the D(2) subtype, providing the rationale for treatment approaches that activate or block D(2) receptors, respectively. However, full agonists or pure D(2) receptor antagonists may not be optimal therapeutic approaches for their respective disorders for a number of reasons, including an inability to restore the aberrant DA pathways to a normal level of basal tone. D(2) receptor partial agonists (D(2)PAs) are proposed to stabilize activity in DA pathways by dampening excessive (and/or by restoring deficient) D(2) receptor stimulation thereby shepherding DA neurons back to a desired level of basal activity. Stabilizing aberrant DA activity without disrupting non-dysfunctional DA neurons may provide a potentially improved approach for treating DA disorders. The status of DA D(2)PAs and their potential application to schizophrenia, BD, PD, and RLS is reviewed. Preclinical and clinical evidence supports the idea that dysfunctions of D(2) receptors contribute to these CNS disorders. Diseases in which both hyper- and hypofunction of DA pathways are present may be particularly promising, and challenging, targets for D(2)PAs. Furthermore, different DA disorders may respond optimally to D(2)PAs with differing levels of intrinsic activity, with "DA deficiency" diseases responding more effectively to higher intrinsic activity D(2)PAs than "DA hyperactivation" diseases. Overall, current evidence supports the conclusion that D(2)PAs have significant potential as improved CNS therapies relative to classic full agonists and antagonists at D(2) receptors.