Modern antipsychotic drugs: a critical overview.
Ontology highlight
ABSTRACT:
SUBMITTER: Gardner DM
PROVIDER: S-EPMC1150265 | biostudies-literature | 2005 Jun
REPOSITORIES: biostudies-literature
Publications
Modern antipsychotic drugs: a critical overview.
Gardner David M DM Baldessarini Ross J RJ Waraich Paul P
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 20050601 13
Conventional antipsychotic drugs, used for a half century to treat a range of major psychiatric disorders, are being replaced in clinical practice by modern "atypical" antipsychotics, including aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone among others. As a class, the newer drugs have been promoted as being broadly clinically superior, but the evidence for this is problematic. In this brief critical overview, we consider the pharmacology, therapeutic effectiveness ...[more]
Similar Datasets
Project description:Mechanisms underlying antipsychotic cardiometabolic adverse effects are incompletely understood. This hampers the identification of high-risk patients, low-risk antipsychotics and preventive/ameliorative treatments. Recent clinical, molecular and genetic data suggest that: (i) antipsychotic-naïve samples provide the greatest power for mechanistic studies; (ii) weight and metabolic effects can be discordant, pointing to overlapping and distinct mechanisms; (iii) antipsychotics affect satiety and energy homeostasis signaling; (iv) the specific peptides mediating these effects are unknown but probably overlap with those involved in idiopathic obesity; and (v) single nucleotide polymorphisms in genes encoding known neurotransmitter receptors and metabolic proteins are promising pharmacogenomic targets for countering adverse affects. However, sophisticated molecular studies and genome-wide association studies, ideally in antipsychotic-naïve/first episode samples, are needed to further advance the field.
| S-EPMC3053585 | biostudies-literature
Project description:Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.
| S-EPMC4336924 | biostudies-literature
Project description:The beliefs that antipsychotic drugs (APDs) are 1) effective only to treat delusions and hallucinations (positive symptoms), 2) that typical and atypical APDs differ only in ability to cause extrapyramidal side effects, and 3) that their efficacy as antipsychotics is due solely to their dopamine D2 receptor blockade are outmoded concepts that prevent clinicians from achieving optimal clinical results when prescribing an APD. Atypical APDs are often more effective than typical APDs in treating negative symptoms, cognitive impairment, and mood symptoms as well as reducing the risk for suicide and decreasing aggression. This applies not only to those diagnosed with schizophrenia or schizoaffective disorder but also to bipolar disorder, major depression, and other psychiatric diagnoses. The greater advantage of an atypical APD is not evident in all patients for every atypical APD due, in part, to individual differences in genetic and epigenetic endowment and differences in the pharmacology of the atypical APDs, their mode of action being far more complex than that of the typical APDs. A common misconception is that among the atypical APDs, only clozapine is effective for reducing psychosis in treatment-resistant schizophrenia. Aripiprazole, lurasidone, olanzapine, and risperidone also can be more effective than typical APDs for treatment-resistant schizophrenia; clozapine is uniquely indicated for reducing the risk for suicide. The ability of the atypical APDs to improve cognition and negative symptoms in some patients together with lower propensity to cause tardive dyskinesia (an underappreciated advantage) leads to better overall outcomes. These advantages of the atypical APDs in efficacy and safety are due, in part, to initiation of synaptic plasticity via direct and indirect effects of the atypical APDs on a variety of proteins, especially G proteins, and release of neurotrophins (e.g., brain-derived neurotrophic factor). The typical APDs beneficial effects on psychosis are mainly the result of D2 receptor blockade, which can be associated with serious side effects and lack of tolerability.
| S-EPMC8412155 | biostudies-literature
Project description:BACKGROUND:Aripiprazole is a relatively new antipsychotic drug, said to be the prototype of a new third generation of antipsychotics; the so-called dopamine-serotonin system stabilisers. In this review we examine how the efficacy and tolerability of aripiprazole differs from that of typical antipsychotics. OBJECTIVES:To evaluate the effects of aripiprazole compared with other typical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY:We searched the Cochrane Schizophrenia Group Trials Register (November 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies for further trials. We contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. SELECTION CRITERIA:We included all randomised trials comparing aripiprazole with typical antipsychotics in people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS:We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model. We have contacted representatives of Bristol Myers Squibb pharmaceuticals (UK) for additional data. MAIN RESULTS:We included nine randomised trials involving 3122 people comparing aripiprazole with typical antipsychotic drugs. None of the studies reported on relapse - our primary outcome of interest. Attrition from studies was high and data reporting poor. Participants given aripiprazole were comparable to those receiving typical drugs in improving global state and mental state. Aripiprazole provided a significant advantage over typical antipsychotics in terms of fewer occurrences of extra-pyramidal symptom (n=968, 3 RCT, RR 0.46 CI 0.3 to 0.9, NNT 13 CI 17 to 10), and particularly akathisia (n=897, 3 RCT, RR 0.39 CI 0.3 to 0.6, NNT 11 CI 14 to 9). Fewer participants given aripiprazole developed hyperprolactinaemia (n=300, 1 RCT, RR 0.07 CI 0.03 to 0.2, NNT 2 CI 3 to 1). Aripiprazole presented a lesser risk of sinus tachycardia (n=289, 1 RCT, RR 0.09 CI 0.01 to 0.8, NNT 22 CI 63 to 13) and blurred vision (n=308, 1 RCT, RR 0.19 CI 0.1 to 0.7, NNT 14 CI 25 to 10); but enhanced risk of occurrence of dizziness (n=957, 3 RCT, RR 1.88 CI 1.1 to 3.2, NNH 20 CI 33 to 14) and nausea (n=957, 3 RCT, RR 3.03 CI 1.5 to 6.1, NNH 17 CI 25 to 13). Attrition rates were high in both groups, although significantly more participants in the aripiprazole group completed the study in the long term (n=1294, 1 RCT, RR 0.81 CI 0.8 to 0.9 NNT 8 CI 5 to 14). AUTHORS' CONCLUSIONS:Aripiprazole differs little from typical antipsychotic drugs with respect to efficacy, however it presents significant advantages in terms of tolerability. Clearly reported pragmatic short, medium and long term randomised controlled trials are required to replicate and validate these findings and determine the position of aripiprazole in everyday clinical practice.
| S-EPMC7052752 | biostudies-literature
Project description:The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.
| S-EPMC9465653 | biostudies-literature
Project description:BackgroundDose equivalents of antipsychotics are an important but difficult to define concept, because all methods have weaknesses and strongholds.MethodsWe calculated dose equivalents based on defined daily doses (DDDs) presented by the World Health Organisation's Collaborative Center for Drug Statistics Methodology. Doses equivalent to 1mg olanzapine, 1mg risperidone, 1mg haloperidol, and 100mg chlorpromazine were presented and compared with the results of 3 other methods to define dose equivalence (the "minimum effective dose method," the "classical mean dose method," and an international consensus statement).ResultsWe presented dose equivalents for 57 first-generation and second-generation antipsychotic drugs, available as oral, parenteral, or depot formulations. Overall, the identified equivalent doses were comparable with those of the other methods, but there were also outliers.ConclusionsThe major strength of this method to define dose response is that DDDs are available for most drugs, including old antipsychotics, that they are based on a variety of sources, and that DDDs are an internationally accepted measure. The major limitations are that the information used to estimate DDDS is likely to differ between the drugs. Moreover, this information is not publicly available, so that it cannot be reviewed. The WHO stresses that DDDs are mainly a standardized measure of drug consumption, and their use as a measure of dose equivalence can therefore be misleading. We, therefore, recommend that if alternative, more "scientific" dose equivalence methods are available for a drug they should be preferred to DDDs. Moreover, our summary can be a useful resource for pharmacovigilance studies.
| S-EPMC4960429 | biostudies-literature
Project description:The peptide transmitter neurotensin (NT) exerts diverse neurochemical effects that resemble those seen after acute administration of antipsychotic drugs (APDs). These drugs also induce NT expression in the striatum; this and other convergent findings have led to the suggestion that NT may mediate some APD effects. Here, we demonstrate that the ability of the typical APD haloperidol to induce Fos expression in the dorsolateral striatum is markedly attenuated in NT-null mutant mice. The induction of Fos and NT in the dorsolateral striatum in response to typical, but not atypical, APDs has led to the hypothesis that the increased expression of these proteins is mechanistically related to the production of extrapyramidal side effects (EPS). However, we found that catalepsy, which is thought to reflect the EPS of typical APDs, is unaffected in NT-null mutant mice, suggesting that NT does not contribute to the generation of EPS. We conclude that NT is required for haloperidol-elicited activation of a specific population of striatal neurons but not haloperidol-induced catalepsy. These results are consistent with the hypothesis that endogenous NT mediates a specific subset of APD actions.
| S-EPMC35465 | biostudies-literature
Project description:Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.
| S-EPMC8214668 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies.ResultA computational method based on ligand-protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski's rule.ConclusionThe present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.
| S-EPMC5660441 | biostudies-literature
Project description:Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments showed thioridazine and olanzapine constituted a robust cluster. K-means clustering separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups. Keywords: repeat sample
2004-09-24 | GSE1501 | GEO