The C/C Genotype of the C957T Polymorphism of the Dopamine D2 Receptor is Associated with Schizophrenia

The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in-vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and post-mortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention

Schizophrenia is a TH2 dominant autoimmune disease possibly against acetylcholine receptors of CNS

Schizophrenia is a very common psychiatric disorder. However, its etiology and pathogenesis is still unknown. Current theory saying that neurotransmitter imbalance such as serotonin or dopamine only provides limited effectiveness in schizophrenia treatment by drugs changing serotonin and dopamine concentration. Despite of such treatment, majority of schizophrenia patients still have very poor prognosis. Thus, the neurotransmitter imbalance theory is not correct. Here, I propose that schizophrenia is actually a TH2 dominant autoimmune disorder. The candidate of autoantigen could be acetylcholine receptors of CNS. My theory can explain the positive as well as negative symptoms of schizophrenia. By microarray analysis of PBMCS, one-tenth of the total 519 significantly expressed genes are immune-related genes. Among them, TH2 related genes are significantly up-regulated including IL-4, histidine decarboxylase, aldehyde dehydrogenase, CCR9, IgE Fc receptor, GATA2, serotonin receptor, phospholipase A2, and prostaglandin D2 synthase. Besides, TH1 and TH17 related genes are down-regulated including CXCL5, cathepsin C, and neutrophil related S100 binding proteins. The new theory sheds a light to better control this detrimental illness. Anti-inflammatory agents could be used to manage schizophrenia in the near future

A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset: HapMap tag-sincle-nucleotide polymorphism analysis

Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain which is known to be important in the aetiology of schizophrenia. It is therefore not surprising that most antipsychotic medication acts on the Dopamine D2 receptor. DRD2 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. Methods: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single nucleotide polymorphisms (SNPs) in DRD2 using a multiplex mass spectrometry method. SNPs were chosen using a haplotype block-based gene-tagging approach so the entire DRD2 gene was represented. Results: One polymorphism rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared to controls. Conclusions: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor age of onset

Novel psychoactive substances (NPS) – knowledge and experiences of drug users from Hungary, Poland, the UK and the USA

Submitted 19 September 2019; Accepted 29 November 2019; Proof received 29 November 2019; Published 18 February 2020. Note: No DOI allocated.Dopamine D 3 receptor partial agonists represent a new generation of atypical antipsychotics. Cariprazine, which has received centralized market authorization from the European Medicines Agency in 2017 for the treatment of adult patients with schizophrenia (including those with predominant negative symptoms of schizophrenia) differs from the other two partial agonist antipsychotics aripiprazole and brexpiprazole due to its unique features. Cariprazine is a dopamine D 3 preferring D 3/D2 partial agonist with very similar dopamine receptor sub-type selectivity as dopamine. It has proven efficacy in the treatment of positive and negative symptoms of schizophrenia, as well as for relapse prevention. Further phase-3 clinical studies proved the efficacy of cariprazine in the acute treatment of manic or mixed episodes associated with bipolar I disorder, as well as in bipolar depression. For the adjunctive treatment of major depressive disorder, phase 3 studies are in progress.Peer reviewedFinal Published versio

The role of genes, stress, and dopamine in the development of schizophrenia

The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients

Etiology of Schizophrenia

This literature review examines the biological and environmental risk factors in the etiology of schizophrenia. A well-researched theoretical framework behind the etiology of schizophrenia is the dopamine hypothesis which states the elevated levels of the brain chemical dopamine can contribute to the development of schizophrenia. Research has also shown genetic predispositions and obstetrical complications may contribute to the development of schizophrenia. The diathesis-stress model describes the heightened cortisol releasing the potential to intensify schizophrenia symptoms while amplifying dopamine activity in the environment. More recent findings show that genetics influences act in cohesion with environmental factors. Based upon the findings of this literature review; genetics, prenatal and postnatal factors, brain abnormalities, and environmental factors all have an impact on the etiology of schizophrenia. Further research should focus on how biological and environmental factors impact the etiology of schizophrenia to aid in better understanding of the illness’s development

Deep brain stimulation in schizophrenia

Deep brain stimulation (DBS) has successfully advanced treatment options of putative therapy-resistant neuropsychiatric diseases. Building on this strong foundation more and more mental disorders in the stadium of therapy-resistance are considered as possible indications for DBS. Especially schizophrenia with its associated severe and difficult to treat symptoms is gaining attention. This attention demands critical questions regarding the assumed mechanisms of DBS and its possible influence on the supposed pathophysiology of schizophrenia. Here we synoptically compare current approaches and theories of DBS and discuss the feasibility of DBS in schizophrenia as well as the transferability from other psychiatric disorders successfully treated with DBS. For this we consider recent advances in animal models of schizophrenic symptoms, results regarding the influence of DBS on dopaminergic transmission as well as data concerning neural oscillation and synchronization. In conclusion the use of DBS for some symptoms of schizophrenia seems to be a promising approach, but the lack of a comprehensive theory of the mechanisms of DBS as well as its impact on schizophrenia might void the use of DBS in schizophrenia at this point

The striatal dopamine transporter in first-episode, drug-naive schizophrenic patients: evaluation by the new SPECT-ligand[99mTc]TRODAT-1

Following the current hypothesis that acute schizophrenic psychotic illness is associated with a triatal ‘hyperdopaminergic state’, presynaptic integrity and dopamine transporter (DAT) density in first-episode, neuroleptic-naive schizophrenic patients was measured by single-photonemission- tomography (SPECT) and compared with that in healthy control subjects. A new SPECT-ligand for assessment of the striatal DAT, the Technetium-99m-labelled tropane TRODAT-1 ([99mTc]TRODAT-1), was used. Ten inpatients suffering from a first acute schizophrenic episode and 10 age- and sex-matched healthy control subjects underwent SPECT with [99mTc]TRODAT-1. On the day of SPECT, psychopathological ratings were performed with the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and Schedule for Assessment of Negative Symptoms (SANS). Patients had not previously received any neuroleptic or antidepressant medication. Mean specific TRODAT-1 binding in the striatum did not differ significantly between the patient and the age- and sex-matched control group (1.25 vs. 1.28). Variance was significantly higher in the patient group. The data obtained with the new ligand in first-episode, drug-naive schizophrenic patients are in line with the PET results from the group of Laakso et al. in a comparable patient sample. [99mTc]TRODAT-1 seems to be a valuable new SPECTligand in the evaluation of the presynaptic site of the striatal dopaminergic synapse in schizophrenia

Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.

Women exposed to a variety of viral and bacterial infections during pregnancy have an increased risk of giving birth to a child with autism, schizophrenia or other neurodevelopmental disorders. Preclinical maternal immune activation (MIA) models are powerful translational tools to investigate mechanisms underlying epidemiological links between infection during pregnancy and offspring neurodevelopmental disorders. Our previous studies documenting the emergence of aberrant behavior in rhesus monkey offspring born to MIA-treated dams extends the rodent MIA model into a species more closely related to humans. Here we present novel neuroimaging data from these animals to further explore the translational potential of the nonhuman primate MIA model. Nine male MIA-treated offspring and 4 controls from our original cohort underwent in vivo positron emission tomography (PET) scanning at approximately 3.5-years of age using [18F] fluoro-l-m-tyrosine (FMT) to measure presynaptic dopamine levels in the striatum, which are consistently elevated in individuals with schizophrenia. Analysis of [18F]FMT signal in the striatum of these nonhuman primates showed that MIA animals had significantly higher [18F]FMT index of influx compared to control animals. In spite of the modest sample size, this group difference reflects a large effect size (Cohen's d = 0.998). Nonhuman primates born to MIA-treated dams exhibited increased striatal dopamine in late adolescence-a hallmark molecular biomarker of schizophrenia. These results validate the MIA model in a species more closely related to humans and open up new avenues for understanding the neurodevelopmental biology of schizophrenia and other neurodevelopmental disorders associated with prenatal immune challenge

What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit.

The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms