Abstract
Treatment-resistant schizophrenia (TRS) continues to be a challenge. It was related to different factors, including alterations in the activity of brain dopaminergic system, which could be influenced by the dopamine-degrading enzyme, catechol-O-methyltransferase (COMT). Variants of the COMT gene have been extensively studied as risk factors for schizophrenia; however, their association with TRS has been poorly investigated. The aim of the present study was to determine the haplotypic and genotypic association of COMT rs4680 and rs4818 polymorphisms with the presence of TRS. Overall, 931 Caucasian patients diagnosed with schizophrenia (386 females and 545 males) were included, while 270 participants met the criteria for TRS. In males, no significant haplotypic and genotypic associations between COMT rs4680 and rs4818 polymorphisms and TRS were detected. However, genotypic analyses demonstrated higher frequency of COMT rs4680 AA genotype carriers compared to G-allele carriers (p = 0.033) and higher frequency of COMT rs4818 CC genotype carriers than G-allele carriers (p = 0.014) in females with TRS. Haplotype analyses confirmed that the presence of the G allele in females was associated with lower risk of TRS. In women with TRS, the high activity G-G/G-G haplotype was rare, while carriers of other haplotypes were overrepresented (p = 0.009). Such associations of COMT rs4680 and rs4818 high-activity (G variants), as well as G-G/G-G haplotype, with the lower risk of TRS in females, but not in males, suggest significant, but sex-specific influence of COMT variants on the development of treatment-resistance in patients with schizophrenia. However, due to relatively low number of females, those findings require replication in a larger sample.
Highlights
Patients were classified in Treatment-resistant schizophrenia (TRS) or non-TRS group according to criteria proposed by Suzuki et al (2012), which refer to the failure of at least two antipsychotics, given at ≥600 mg chlorpromazine equivalents (Inada and Inagaki, 2015) for more than consecutive 6 weeks, assessed retrospectively
This study used different methodology, such as the determination of TRS by a treatment-based proxy (Wimberley et al, 2017). Both male and female patients with TRS had significantly higher Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general psychopathology scores, as well as higher chlorpromazine equivalent doses in comparison to male and female patients in non-TRS group. This is in agreement with previous studies reporting that patients with TRS had more severe symptomatology as measured by PANSS (Moretti et al, 2018) and received higher total antipsychotic dose presented as chlorpromazine equivalents, compared to patients with non-TRS (Hotta et al, 2011; de Bartolomeis et al, 2018; Moretti et al, 2018)
Our findings reveal complex and gender-dependent genotypic and haplotypic associations between COMT rs4680 and rs4818 and TRS
Summary
Antipsychotics are the first-line agents in the treatment of schizophrenia, but the clinical response is highly variable. Between 23% (Demjaha et al, 2017) and 47% (Vlatkovic et al, 2018) of patients met the criteria for treatment-resistant schizophrenia (TRS), the definition has varied across different studies (Howes et al, 2017). There is an urgent need to distinguish TRS from non-TRS using genetic or other markers (Šagud, 2015; Lally et al, 2016; Gillespie et al, 2017) as early as possible, in order to provide the best possible treatment for an individual patient
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