Antipsychotic drugs (APDs) are best classified as typical or atypical. The distinction is based solely on their ability to cause extrapyramidal side effects (EPS), including tardive dyskinesia (TD). ...The two classes differ in mechanism of action, with atypical APDs providing important modulation of serotonergic neurotransmission. TD increases the death rate and can be minimized by limiting use of typical APDs. Clozapine is unique among the atypical APDs in its efficacy for ameliorating psychosis in patients with treatment-resistant schizophrenia (TRS), for reduction of suicide, and for improving longevity. The typical and atypical APDs do not differ in improving psychopathology in non-TRS. The atypicals vary in metabolic side effects: some have little burden. Cognitive benefits of the atypical APDs may be superior for some domains of cognition and require less use of anticholinergic drugs, which impair memory, for treatment of EPS. Overall, choosing among the atypical APDs as first-line treatment represents the best course for schizophrenia and most likely other disorders for which APDs are used.
This article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia ...treatments.
Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine- type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects are becoming appreciated. Typical APDs, e.g. haloperidol, are diminishing in favor because of their EPS, especially, tardive dyskinesia (T D) and appreciation that reducing D2 receptor stimulation is not the only means to treat psychosis. Some of the mechanisms inherent in various AAPDs, e.g. 5-HT2A inverse agonism, and D3 receptor partial agonism, are now recognized as effective treatments for psychosis. A new focus on treating the cognitive impairment associated with schizophrenia (CIAS) has emerged via mechanisms such as stimulation of acetyldraline receptor with muscarinic and nicotinic receptor agonists, but demonstrating their efficacy in trials is proving elusive. Pharmacogenetic strategies which may lead to personalized treatment of schizophrenia are emerging but have not yet succeeded in being widely reimbursable. Transcranial stimulation and cognitive enhancement therapy are more common but more evidence for their efficacy is needed.
The heterogeneity of the pathophysiology of the various domains of schizophrenia requires a diversity of treatments that are best met by the expert use of AAPDs at the current time. Pharmacogenetic efforts are consistent with new evidence that multiple genes are involved in the risk for schizophrenia and the effectiveness of AAPDs.
Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive ...impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.
A variety of serotonin (5-HT) receptors, especially 5-HT(2A), 5-HT(1A), 5-HT(6), 5-HT(7), and 5-HT(2C), have been postulated to contribute to the mechanism of action of atypical antipsychotic drugs ...(APDs), i.e., APDs which cause fewer extrapyramidal side effects (EPS) at clinically optimal doses, in contrast with typical APDs, which are more likely to cause EPS. This advantage, rarely disputed, has made such drugs the preferred treatment for schizophrenia and other indications for APDs. These 5-HT receptors are still of interest as components of novel multireceptor or stand-alone APDs, and potentially to remediate cognitive deficits in schizophrenia. Almost all currently available atypical APDs are 5-HT(2A) receptor inverse agonists, as well as dopamine (DA) D(2) receptor antagonists or partial agonists. Amisulpride, an exceptional atypical APD, has 5-HT(7) antagonism to complement its DA D(2/3) antagonism. Some atypical APDs are also 5-HT(1A) partial agonists, 5-HT(6), or 5-HT(7) antagonists, or some combination of the above. 5-HT(2C) antagonism has been found to contribute to the metabolic side effects of some atypical APDs, whereas 5-HT(2C) agonists have potential as stand-alone APDs and/or cognitive enhancers. This review will provide an update of current preclinical and clinical evidence for the role of these five 5-HT receptors in the actions of current APDs and for the development of novel psychotropic drugs.
Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly ...every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.
Co-infection with additional pathogens is a well-known feature of pandemics. We determined the prevalence and type of a wide variety of respiratory pathogens in 12,075 United States subjects tested ...for SARS-CoV-2 infection in March and April 2020. Infections with other respiratory pathogens, which on their own produce at least some SARS-CoV-2 symptoms including mortality, were present in both SARS-CoV-2 + and SARS-CoV-2- subjects. Non-SARS-CoV-2 infection rates were significantly higher in SARS-CoV-2 + (86%) patients than SARS-CoV-2– patients (76%) (
p
< 0.0001). Among the co-pathogens present in both subject groups were
K. pneumoniae
and
M. catarrhalis
which can produce serious respiratory illness on their own, Advanced age and nursing home status were associated with higher SARS-CoV-2 + and co-infection rates. Testing for the presence of co-pathogens going forward will assist in the diagnosis and optimal treatment of suspected SARS-CoV-2 respiratory infections in the current pandemic.
Abstract Biomarkers which predict response to atypical antipsychotic drugs (AAPDs) increases their benefit/risk ratio. We sought to identify common variants in genes which predict response to ...lurasidone, an AAPD, by associating genome-wide association study (GWAS) data and changes (Δ) in Positive And Negative Syndrome Scale (PANSS) scores from two 6-week randomized, placebo-controlled trials of lurasidone in schizophrenia (SCZ) patients. We also included SCZ risk SNPs identified by the Psychiatric Genomics Consortium using a polygenic risk analysis. The top genomic loci, with uncorrected p < 10 − 4 , include: 1) synaptic adhesion ( PTPRD , LRRC4C , NRXN1 , ILIRAPL1 , SLITRK1 ) and scaffolding ( MAGI1 , MAGI2, NBEA ) genes, both essential for synaptic function; 2) other synaptic plasticity-related genes ( NRG1/3 and KALRN) ; 3) the neuron-specific RNA splicing regulator, RBFOX 1; and 4) ion channel genes, e.g. KCNA10 , KCNAB1 , KCNK9 and CACNA2D3 ). Some genes predicted response for patients with both European and African Ancestries. We replicated some SNPs reported to predict response to other atypical APDs in other GWAS. Although none of the biomarkers reached genome-wide significance, many of the genes and associated pathways have previously been linked to SCZ. Two polygenic modeling approaches, GCTA-GREML and PLINK-Polygenic Risk Score, demonstrated that some risk genes related to neurodevelopment, synaptic biology, immune response, and histones, also contributed to prediction of response. The top hits predicting response to lurasidone did not predict improvement with placebo. This is the first evidence from clinical trials that SCZ risk SNPs are related to clinical response to an AAPD. These results need to be replicated in an independent sample.
Clozapine is often referred to as the gold standard for the treatment of schizophrenia and yet has also been described as the most underutilized treatment for schizophrenia supported by solid ...evidence-based medicine. In 2008, it was used to treat only 4.4% of patients with schizophrenia in the U.S., which is ~10-20% of those with approved indications for clozapine for which there is no alternative of equal efficacy. Its use is much higher in Scandinavian countries and China. The primary indications for clozapine are: 1) treatment-resistant schizophrenia or schizoaffective disorder, defined as persistent moderate to severe delusions or hallucinations despite two or more clinical trials with other antipsychotic drugs; and, 2) patients with schizophrenia or schizoaffective disorder who are at high risk for suicide. Concerns over a number of safety considerations are responsible for much of the underutilization of clozapine: 1) agranulocytosis; 2) metabolic side effects; and, 3) myocarditis. These side effects can be detected, prevented, minimized and treated, but there will be a very small number of fatalities. Nevertheless, clozapine has been found in two large epidemiologic studies to have the lowest mortality of any antipsychotic drug, mainly due to its very large effect to reduce the risk for suicide. Other reasons for limited use of clozapine include the extra effort entailed in monitoring white blood cell counts to detect granulocytopenia or agranulocytosis and, possibly, minimal efforts to market it now that it is largely generic. Awareness of the benefits and risks of clozapine is essential for increasing the use of this lifesaving agent.
Abstract Unlike the typical analysis of single markers in genome-wide association studies (GWAS), we incorporated Gene Set Enrichment Analysis (GSEA) and hypergeometric test and combined them using ...Fisher's combined method to perform pathway-based analysis in order to detect genes' combined effects on mediating schizophrenia. A few pathways were consistently found to be top ranked and likely associated with schizophrenia by these methods; they are related to metabolism of glutamate, the process of apoptosis, inflammation, and immune system (e.g., glutamate metabolism pathway, TGF-beta signaling pathway, and TNFR1 pathway). The genes involved in these pathways had not been detected by single marker analysis, suggesting this approach may complement the original analysis of GWAS dataset.
A genome-wide association study (GWAS) of response of schizophrenia patients to the atypical antipsychotic drug, lurasidone, based on two double-blind registration trials, identified SNPs from four ...classes of genes as predictors of efficacy, but none were genome wide significant (GWS). After inclusion of data from a third lurasidone trial, meta-analysis identified a GWS marker and other findings consistent with our first study. The primary end-point was change in Total Positive and Negative Syndrome Scale (PANSS) between baseline and last observation carried forward. rs4736253, a genetic locus near KCNK9, encoding the K2P9.1 potassium channel, with a role in cognition and neurodevelopment, was the top marker in patients of European ancestry (EUR) (n = 264), reaching GWS (p = 4.78 × 10−8). rs10180106 (p = 4.92 × 10−7), located at an intron region of CTNNA2, a SCZ risk gene important for dendritic spine stabilization, was one of other best response markers for EUR patients. SNPs at STXBP5L (rs511841, p = 2.63 × 10−7) were the top markers for patients of African ancestry (n = 158). The association between PTPRD, NRG1, and MAGI1 previously reported to be related to response to lurasidone in the first two trials, showed a trend of significant association in the third trial. None of these genetic loci showed significant associations with clinical response in the corresponding placebo groups (n = 107 for EUR; n = 58 for AFR). This meta-analysis yielded the first GWAS-based GWS biomarker for lurasidone response and additional support for the conclusion that genes related to synaptic biology and/or risk for SCZ are the strongest predictors of response to lurasidone in schizophrenia patients.
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