Related Research Articles
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations, delusions, and disorganized thinking. Other symptoms include social withdrawal, and flat affect. Symptoms typically develop gradually, begin during young adulthood, and in many cases never become resolved. There is no objective diagnostic test; diagnosis is based on observed behavior, a psychiatric history that includes the person's reported experiences, and reports of others familiar with the person. To be diagnosed with schizophrenia, the described symptoms need to have been present for at least six months or one month. Many people with schizophrenia have other mental disorders, especially substance use disorders, depressive disorders, anxiety disorders, and obsessive–compulsive disorder.
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.
Schizotypal personality disorder, also known as schizotypal disorder, is a cluster A personality disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM) classification describes the disorder specifically as a personality disorder characterized by thought disorder, paranoia, a characteristic form of social anxiety, derealization, transient psychosis, and unconventional beliefs. People with this disorder feel pronounced discomfort in forming and maintaining social connections with other people, primarily due to the belief that other people harbor negative thoughts and views about them. Peculiar speech mannerisms and socially unexpected modes of dress are also characteristic. Schizotypal people may react oddly in conversations, not respond, or talk to themselves. They frequently interpret situations as being strange or having unusual meanings for them; paranormal and superstitious beliefs are common. Schizotypal people usually disagree with the suggestion that their thoughts and behaviors are a 'disorder' and seek medical attention for depression or anxiety instead. Schizotypal personality disorder occurs in approximately 3% of the general population and is more commonly diagnosed in males.
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder.
Prepulse inhibition (PPI) is a neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong reflex-eliciting stimulus (pulse), often using the startle reflex. The stimuli are usually acoustic, but tactile stimuli and light stimuli are also used. When prepulse inhibition is high, the corresponding one-time startle response is reduced.
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.
In genetic epidemiology, endophenotype is a term used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection. By seeing the EP notion as a special case of a larger collection of multivariate genetic models, which may be fitted using currently accessible methodology, it is possible to maximize its valuable potential lessons for etiological study in psychiatric disorders. The concept was coined by Bernard John and Kenneth R. Lewis in a 1966 paper attempting to explain the geographic distribution of grasshoppers. They claimed that the particular geographic distribution could not be explained by the obvious and external "exophenotype" of the grasshoppers, but instead must be explained by their microscopic and internal "endophenotype". The endophenotype idea represents the influence of two important conceptual currents in biology and psychology research. An adequate technology would be required to perceive the endophenotype, which represents an unobservable latent entity that cannot be directly observed with the unaided naked eye. In the investigation of anxiety and affective disorders, the endophenotype idea has gained popularity.
The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarisation and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.
Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.
Excitatory amino acid transporter 2 (EAAT2) also known as solute carrier family 1 member 2 (SLC1A2) and glutamate transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene. Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.
The GABAA beta-2 subunit is a protein that in humans is encoded by the GABRB2 gene. It combines with other subunits to form the ionotropic GABAA receptors. GABA system is the major inhibitory system in the brain, and its dominant GABAA receptor subtype is composed of α1, β2, and γ2 subunits with the stoichiometry of 2:2:1, which accounts for 43% of all GABAA receptors. Alternative splicing of the GABRB2 gene leads at least to four isoforms, viz. β2-long (β2L) and β2-short. Alternatively spliced variants displayed similar but non-identical electrophysiological properties. GABRB2 is subjected to positive selection and known to be both an alternative splicing and a recombination hotspot; it is regulated via epigenetic regulation including imprinting and gene and promoter methylation GABRB2 has been associated with a number of neuropsychiatric disorders, and found to display altered expression in cancer.
Fatty acid binding protein 7, brain, is a human gene.
The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.
Neurochondrin is a protein that in humans is encoded by the NCDN gene.
Mardepodect is a drug which was developed by Pfizer for the treatment of schizophrenia. It acts as a phosphodiesterase inhibitor selective for the PDE10A subtype. The PDE10A enzyme is expressed primarily in the brain, mostly in the striatum, nucleus accumbens and olfactory tubercle, and is thought to be particularly important in regulating the activity of dopamine-sensitive medium spiny neurons in the striatum which are known to be targets of conventional antipsychotic drugs. Older PDE10A inhibitors such as papaverine have been shown to produce antipsychotic effects in animal models, and more potent and selective PDE10A inhibitors are a current area of research for novel antipsychotic drugs which act through a different pathway to conventional dopamine or 5-HT2A antagonist drugs and may have a more favourable side effects profile. Mardepodect is currently one of the furthest advanced PDE10A inhibitors in development and has progressed through to Phase II clinical trials in humans. In 2017, development of mardepodect for the treatment of schizophrenia and Huntington's disease was discontinued.
SSR180711 is a drug that acts as a potent and selective partial agonist for the α7 subtype of neural nicotinic acetylcholine receptors. In animal studies, it shows nootropic effects and may be useful in the treatment of schizophrenia.
Sonepiprazole (U-101,387, PNU-101,387-G) is a drug of the phenylpiperazine class which acts as a highly selective D4 receptor antagonist. In animals, unlike D2 receptor antagonists like haloperidol, sonepiprazole does not block the behavioral effects of amphetamine or apomorphine, does not alter spontaneous locomotor activity on its own, and lacks extrapyramidal and neuroendocrine effects. However, it does reverse the prepulse inhibition deficits induced by apomorphine, and has also been shown to enhance cortical activity and inhibit stress-induced cognitive impairment. As a result, it was investigated as an antipsychotic for the treatment of schizophrenia in a placebo-controlled clinical trial, but in contrast to its comparator olanzapine no benefits were found and it was not researched further for this indication.
SHIRPA is a standardized set of experimental procedures used by scientists to characterize the phenotype of genetically modified laboratory mice. The protocols are designed to test muscle function, cerebellar function, sensory function and neuropsychiatric function.
Research into the mental disorder of schizophrenia, involves multiple animal models as a tool, including in the preclinical stage of drug development.
The epigenetics of schizophrenia is the study of how inherited epigenetic changes are regulated and modified by the environment and external factors and how these changes influence the onset and development of, and vulnerability to, schizophrenia. Epigenetics concerns the heritability of those changes, too. Schizophrenia is a debilitating and often misunderstood disorder that affects up to 1% of the world's population. Although schizophrenia is a heavily studied disorder, it has remained largely impervious to scientific understanding; epigenetics offers a new avenue for research, understanding, and treatment.
References
- ↑ Verma V, Tan CH, Ong WY, et al. (March 2008). "The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition". Neurosci. Res. 60 (3): 281–8. doi:10.1016/j.neures.2007.11.007. PMID 18164085. S2CID 207150983.
- ↑ Torres G, Meeder BA, Hallas BH, et al. (2005). "Ventricular size mapping in a transgenic model of schizophrenia". Developmental Brain Research. 154 (1): 35–44. doi:10.1016/j.devbrainres.2004.08.011. PMID 15617753.
- ↑ Dawe GS, Ratty AK (2007). "The chakragati mouse: A mouse model for rapid in vivo screening of antipsychotic drug candidates". Biotechnology Journal. 2 (11): 1344–52. doi:10.1002/biot.200700145. PMID 17886239. S2CID 24748043.
