Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment

Lisoway, Amanda; Chen, Cheng C.; Zai, Clement C.; Tiwari, Arun; Kennedy, James L.

doi:10.1016/j.schres.2021.05.010

Cited by 36 publications

(24 citation statements)

References 137 publications

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“…It is plausible that part of the common genetic variance linked to schizophrenia might affect overlapping pathways involved in pharmacodynamics (40), the genomics of which are relatively unknown in psychopharmacology (48). It is also known that some of the genes identified in schizophrenia GWAS are related to neurodevelopment, synaptic biology, and immune response, pathways that have been linked to antipsychotic response and adverse effects (49,50). Given that studies suggest the efficacy of clozapine could be related to targeting TRS-specific biological pathways (16), an interesting perspective would be to analyze if future GWAS focused on TRS or antipsychotic treatment response are themselves associated with clozapine dose.…”

Section: Discussionmentioning

confidence: 99%

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

Kappel

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Hubbard

et al. 2022

Preprint

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BACKGROUND: Treatment-resistant schizophrenia (TRS) affects ~30% of individuals with the disorder. Clozapine is the medication of choice in TRS but optimizing administration and dose titration are complex. The identification of predictive factors that influence clozapine prescription and response, including genetics, is of clinical interest in a precision psychiatry framework. We aimed to determine if a polygenic risk score (PRS) for schizophrenia is associated with the highest drug dose an individual received during clozapine treatment. METHODS: We used generalized linear regression models accounting for demographic, pharmacological, and clinical covariates to determine the relationship between PRS and highest daily dose of clozapine. We used two independent multi-ancestry samples of individuals from the UK from a clozapine monitoring system, CLOZUK2 (N= 3133) and CLOZUK3 (N= 909). Schizophrenia PRS were calculated using the latest available GWAS summary statistics from the Psychiatric Genomics Consortium. In a secondary analysis of the two merged cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRS and clozapine doses classified as low, standard, or high (>600 mg/day). RESULTS: After controlling for relevant available covariates, schizophrenia PRS were correlated with the highest clozapine dose ever prescribed, in both CLOZUK2 (β= 12.217, s.e= 3.776, P= 0.001) and CLOZUK3 (β= 12.730, s.e= 5.987, P= 0.034). In the secondary analysis, the schizophrenia PRS was specifically associated with taking a clozapine dose greater than 600 mg/day (OR= 1.279, P= 0.006). CONCLUSIONS: Schizophrenia PRS is associated with the highest clozapine dose ever prescribed in two independent multi-ancestry samples from the UK, suggesting that the genetic liability to schizophrenia might index factors associated with therapeutic decisions in TRS cohorts.

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Section: Discussionmentioning

confidence: 99%

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

Kappel

Legge

Hubbard

et al. 2022

Preprint

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“…There is preliminary evidence of the potential utility of this approach in children and adolescents with other behavioral disorders [ 73 , 74 ]. Changes in the methylation of specific genes linked to these pathways, which have been identified in DBDs, could also serve as potential biomarkers of treatment response, though this approach has not yet been fully evaluated in young people [ 75 ]. Finally, antipsychotics acting through non-dopaminergic and non-serotonergic mechanisms have recently been evaluated and found effective in the management of adults with psychotic disorders.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotics in the Management of Disruptive Behavior Disorders in Children and Adolescents: An Update and Critical Review

Rajkumar

2022

Biomedicines

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Disruptive behaviour disorders (DBDs) in childhood include conduct disorder (CD) and oppositional defiant disorder (ODD). Though psychological therapies are considered to be the first-line treatment for DBDs, many patients require adjunctive pharmacotherapy for the control of specific symptoms, such as aggression. Three prior systematic reviews have examined the evidence for the use of antipsychotics in DBDs and have concluded that their efficacy is marginal and limited by adverse effects. This paper has two objectives: (i) to summarize the findings of existing systematic reviews of antipsychotics for the management of DBDs in children and adolescents (2012–2017), and (ii) to provide an update to these reviews by examining recent clinical trials of antipsychotics in this population, published in the period from 2 January 2017 to 10 October 2022. The PubMed, Scopus and ScienceDirect databases were searched for relevant citations using the search terms “disruptive behaviour disorder”, “oppositional defiant disorder”, “conduct disorder” and their variants, along with “antipsychotic”, “atypical antipsychotic” and the generic names of all currently approved atypical antipsychotics. Six relevant trials were identified during this period, including five randomized controlled trials and one naturalistic open-label trial. These trials were critically evaluated in terms of outcome measures, efficacy and safety. Overall, the data from these trials suggests that of all available antipsychotics, risperidone appears to be effective in the short-term management of DBDs. All available antipsychotics are associated with significant metabolic adverse effects in this population. These results are discussed in the light of global trends towards increasing off-label prescription of antipsychotic medication in children and adolescents and of recent literature on the neuropharmacology of aggression in this patient population. The need for rational, short-term use of these drugs is highlighted, as well as the importance of post-marketing surveillance for long-term or severe adverse events.

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“…Pituitary tumorigenesis often involves genetic mutations in classical oncogenes or tumor suppressor genes ( Asa and Ezzat, 2002 ; Thumfart et al, 2021 ). DRD2 methylation is closely related to children’s psychological trauma ( Cespedes et al, 2021 ) and alcohol dependence ( Shirvani-Farsani et al, 2021 ) and is a marker of schizophrenia ( Gangisetty et al, 2015 ; Molitch, 2020 ; Lisoway et al, 2021 ) showed that increased DRD2 promoter methylation is correlated with decreased DRD2 mRNA levels and increased PRL mRNA levels in the pituitary. Many studies have reported that the loss of DRD2 expression accelerates the increase in PRL levels caused by ADs ( Gao et al, 2021 ).…”

Section: Discussionmentioning

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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Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment

Cited by 36 publications

References 137 publications

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

Antipsychotics in the Management of Disruptive Behavior Disorders in Children and Adolescents: An Update and Critical Review

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

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