New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics

Lobo, Maria C.; Whitehurst, Thomas; Kaar, Stephen; Howes, Oliver

doi:10.1016/j.neubiorev.2021.11.032

Cited by 43 publications

(65 citation statements)

References 143 publications

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“…Use of pimavanserin in conjunction with subtherapeutic doses of risperidone or haloperidol in psychosis in chronic schizophrenia did not show differences in motor AEs or as measured by SAS or BARS compared to placebo (n = 423) [ 84 ]. Very preliminary evidence (n = 403) for efficacy and similar tolerability in adjunctive treatment of negative symptoms in schizophrenia also exists without increase in DIMD while other studies are ongoing [ 88 89 90 91 ]. No studies have specifically cited or examined the risk of tardive syndromes with pimavanserin.…”

Section: Incidence Of Dimd With Novel Antipsychoticsmentioning

confidence: 99%

“…Roluperidone is a high-affinity 5-HT 2A antagonist and σ2R antagonist [ 91 ]. Early trials have shown modest clinical efficacy without increased DIMD which is unsurprising given its lack of D2R antagonism [ 144 ].…”

Section: Agents With Novel Mechanisms Under Investigationmentioning

confidence: 99%

“…Early trials have shown modest clinical efficacy without increased DIMD which is unsurprising given its lack of D2R antagonism [ 144 ]. Common side effects included headache, asthenia, and somnolence [ 91 ].…”

Section: Agents With Novel Mechanisms Under Investigationmentioning

confidence: 99%

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Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents

Kannarkat

Caroff

Morley

2022

Tremor and Other Hyperkinetic Movements

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Background: The last decade has seen development of numerous novel antipsychotic drugs with unique mechanisms including long-acting formulations for clinical use. A comparative assessment of these new drugs with each other and previous antipsychotics have not been performed with regards to risk for drug-induced movement disorders (DIMD). Methods: Medline was searched from January 2010 to February 2022 for primary research articles and review articles in English using the search terms “extrapyramidal” and “tardive” with individual drug names of novel antipsychotics. Results: We identified articles describing the risk of DIMD with 6 novel antipsychotics, 4 novel formulations, and 3 experimental antipsychotics. Both short- and long-term data generally showed comparable to lower risk of DIMD with novel antipsychotics and recent long-acting formulations compared to previously marketed antipsychotics. Discussion: Several novel antipsychotics, particularly lumateperone and pimavanserin, show promise in being able to treat psychosis while reducing the risk of DIMD. Long-acting paliperidone may reduce risk of DIMD while other long-acting injectable formulations of SGA have similar risk of DIMD compared to oral formulations. New drug targets for treating psychosis without dopamine blockade also show promise.

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Section: Incidence Of Dimd With Novel Antipsychoticsmentioning

confidence: 99%

Section: Agents With Novel Mechanisms Under Investigationmentioning

confidence: 99%

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Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents

Kannarkat

Caroff

Morley

2022

Tremor and Other Hyperkinetic Movements

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“…Schizophrenia is among the global most disabling health conditions ( Lee et al, 2016 ) and affects about 21 million people worldwide ( Vos et al, 2016 ; Li et al, 2018 ; Jung et al, 2021 ). People with schizophrenia have a life expectancy 15 years shorter than the general population ( Pillinger et al, 2019 ; Lobo et al, 2021 ). Antipsychotic drugs (ADs) and psychological consultation are commonly used to treat schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Total Barley Maiya Alkaloids Prevent Increased Prolactin Levels Caused by Antipsychotic Drugs and Reduce Dopamine Receptor D2 via Epigenetic Mechanisms

et al. 2022

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Background: The dopamine D2 receptor (DRD2) plays an important role in the increased prolactin (PRL) levels associated with the pathogenesis of antipsychotic drugs (ADs). Elevated prolactin levels can affect people’s quality of life. Maiya alkaloids has been used to treat diseases associated with high PRL levels. Maiya, is a processed product of the mature fruits of Hordeum vulgare L. (a gramineous plant) after sprouting and drying and also a common Chinese herbal drug used in the clinic, is traditionally used to treat abnormal lactation, and is currently used clinically for the treatment of abnormal PRL levels.Aims: Epigenetic mechanisms can be related to DRD2 expression. We investigated the role of DRD2 methylation in the induction of PRL expression by ADs and the mechanism underlying the effects of total barley maiya alkaloids (TBMA) on this induction.Methods: The methylation rate of DRD2 in 46 people with schizophrenia who took risperidone was detected by MassARRAY sequencing. Humans were long term users of Ris. Seventy Sprague Dawley female rats were divided into seven groups. A rat model of risperidone-induced PRL was established, and the potential protective effects of TBMA and its components [e.g., hordenine (Hor)] on these increased PRL levels were investigated. The PRL concentration was detected by Enzyme-linked immunosorbent assay. PRL, DRD2, and DNA methyltransferase (DNMT1, DNMT3α, and DNMT3β) protein and mRNA expression were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The positive rate of methylation in the DRD2 promoter region of rats was detected by MassARRAY sequencing.Results: Clinical studies showed that the positive rate of DRD2 methylation associated with increased PRL levels induced by ADs was significantly higher than in the normal prolactinemia (NPRL) group. In vivo and vitro, TBMA and Hor inhibited this induction of PRL expression and increased DRD2 expression by inhibiting the expression of the DNMTs.Conclusions: TBMA and hordenine increased DRD2 expression by inhibiting DNMT-dependent DRD2 methylation.

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“…9,10,[23][24][25]37 Animal research demonstrated that ulotaront does not produce significant D2 receptor occupancy at clinically relevant doses, suggesting that its therapeutic effect is not dependent on this mechanism of action. 10,38 Ralmitaront is another TAAR1 agonist and is also administered orally once daily. 9,11,31,35,36 These 2 drugs differ in that ralmitaront is a TAAR1 partial agonist, whereas ulotaront is a TAAR1 full agonist.…”

Section: Introductionmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

Vannabouathong¹,

Picheca²,

Dyrda³

2022

cjht

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TAAR1 agonists are an emerging drug class in the treatment of schizophrenia as they may offer a novel mechanism of action for symptom management without blocking dopamine D2 receptors, unlike currently available antipsychotic medications that act primarily via D2 binding. Two TAAR1 agonists are currently in clinical development for schizophrenia. The first is ulotaront, a TAAR1 full agonist with 5-hydroxytryptamine 1A agonist activity that is administered orally once daily, and the other is ralmitaront, a TAAR1 partial agonist that is also administered orally once daily. The published clinical trial evidence on TAAR1 agonists currently only pertains to ulotaront, which includes a 4-week, phase II, placebo-controlled randomized trial on patients with acute exacerbation of schizophrenia and a 26-week, open-label extension study of this same trial. These studies demonstrated improvements across disease-specific and global impression scales following treatment with ulotaront, with statistically significant differences compared to placebo, and no increased risk of the side effects (extrapyramidal symptoms and metabolic changes) associated with traditional D2-binding antipsychotic therapies. There is currently no cost information available for TAAR1 agonists. Ulotaront is currently undergoing phase III trials and, though it is not currently approved in any country and the date of Health Canada licensing and marketing in Canada is not yet known, it is expected to be the first TAAR1 agonist for schizophrenia in the Canadian market. Ulotaront received Breakthrough Therapy designation from the FDA in 2019 to expedite its development and the drug’s manufacturer is planning to file a New Drug Application with the FDA in 2023. Ralmitaront is currently in phase II trials, which are expected to be completed in 2023.

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New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics

Cited by 43 publications

References 143 publications

Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents

Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents

Total Barley Maiya Alkaloids Prevent Increased Prolactin Levels Caused by Antipsychotic Drugs and Reduce Dopamine Receptor D2 via Epigenetic Mechanisms

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

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