Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis

Nelson, Cara; Amsbaugh, Hayley M.; Reilly, James L.; Rosen, Cherise; Marvin, Robert; Ragozzino, Michael E.; Bishop, Jeffrey R.; Sweeney, John A.; Hill, S. Kristian

doi:10.1016/j.schres.2018.06.029

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…Catechol-O-methyltransferase gene has been shown to be related to multiple symptom domains as well as cognitive impairment in schizophrenia patients (82,83). Most of the relevant studies have consistently shown that patients with the Val allele (leading to low DA) have severe psychopathology or poor cognitive function (84)(85)(86)(87), although a meta-analysis did not support a relationship with working memory (88). In many areas of the human brain such as the striatum, thalamus, and hippocampus, both COMT and DAT provide DA clearance (89, 90), and it has been indicated that DAT could be involved more closely than COMT in the synaptic clefts (91-93).…”

Section: Discussionmentioning

confidence: 99%

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

Kogure,

Kanahara,

Miyazawa

et al. 2024

Front. Psychiatry

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BackgroundMost genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways.Patients and methodsTo examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489).ResultsThe distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology.ConclusionThe overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.

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Section: Discussionmentioning

confidence: 99%

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

Kogure,

Kanahara,

Miyazawa

et al. 2024

Front. Psychiatry

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“…Our review aimed to assess whether pharmacogenetic mechanisms underly the occurrence of olanzapine, clozapine, and loxapine ADRs in children and youth. Several included publications investigated the genes involved in neurotransmission (COMT [65,74,80], serotonin receptors/transporters [55,62,73], dopamine receptors [64,73]), and in energy and lipid homeostasis (AMP-K related genes [54,56], HSD11β1 [58,59]), mostly regarding weight gain (or MetS). However, findings regarding possible associations were sometimes conflicting.…”

Section: Discussionmentioning

confidence: 99%

“…The human leucocyte antigens HLA-DRB*12 (OR = 9.3 (95% CI 1-88.1), p = 0.05) and HLA-DQA*0102 (OR = 2.51 (95% CI 0.9-6.5), p = 0.058) were more commonly found in children presenting DILI. Using the Penn Conditional Exclusion Test (PCET), Nelson et al [80] investigated the relationship of performance errors (as a reflection of cognitive flexibility alteration) with COMT Val158Met (rs4680) genotype in patients treated with atypical APs. Met carriers displayed significant changes for error type (F(1,62) = 14.874, p < 0.001) and time (F(1,62) = 14.068, p < 0.001), characterized by a decrease in perseverative and regressive errors following AP treatment.…”

Section: Othersmentioning

confidence: 99%

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

Merino

Fernandez

Gérard³

et al. 2022

Pharmaceuticals

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Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs’ ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk–benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine.

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“…Many of these patients were then able to use active coping mechanisms to maintain their recovery. It may be that some patients suffering from schizophrenia have differing cognitive responses to antipsychotic medication depending on their genotype (Nelson et al, 2018).…”

Section: Recent Findings Associated With Cognition and Schizophreniamentioning

confidence: 99%

Schizophrenia: Epidemiology, Causes, Neurobiology, Pathophysiology, and Treatment

Volkan¹

2020

jhms

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Schizophrenia is a severe mental illness that has devastating consequences for those who suffer from the disorder. The epidemiology of schizophrenia indicates that it occurs relatively often, in many different contexts, and in conjunction with other disorders, decreasing quality of life and causing premature death. There has been an enormous amount of research into the causes of schizophrenia and there is now have a much better understanding of the genetic, environmental, and psychological factors that contribute to the disease. While there are numerous ways to understand and conceptualize schizophrenia, a unified picture of the neurobiology, changes in brain structure, cognitive and social-cognitive impairments related to the disorder has yet to emerge. Convulsive therapies and psychosurgery were used unsuccessfully, indiscriminately and without scientific validation in the past to treat schizophrenia. Medical advances including advanced imaging technology have now provided the ability to perform specifically focused neuromodulation and psychosurgery in severe and treatment resistant cases of schizophrenia. While still at a preliminary stage, these approaches have the potential to yield effective treatments in the future. For the last 70 years antipsychotic medication has become the prevailing treatment for schizophrenia. However, many people suffering from the disorder have trouble with side-effects and adhering to a regimen of antipsychotic medication. Newer pharmacological agents are being developed and include not only novel antipsychotic drugs, but anti-inflammatory and immunomodulating agents as well. These new agents, used either alone or in combination, have the potential to improve outcomes for people suffering from schizophrenia. Nevertheless, conclusively better pharmacotherapies will likely not arise until there is better understanding of the pathophysiology underlying schizophrenia. After the development of antipsychotic medication, psychotherapeutic methods for treating schizophrenia fell out of favor, but there is currently some reversal of this trend. The use of newer psychotherapies and modified forms of older therapeutic treatments are not only targeting the symptoms of schizophrenia but are also now focusing on recovery from the disorder. These newer approaches as well as efforts at preventing schizophrenia show promise in reducing the suffering caused by this disease.

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Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis

Cited by 8 publications

References 28 publications

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

Schizophrenia: Epidemiology, Causes, Neurobiology, Pathophysiology, and Treatment

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