AIM: Clozapine is still considered the gold standard for treatment-resistant schizophrenia patients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems. MATERIALS & METHODS: 107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMT rs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively. RESULTS: We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects. CONCLUSION: The findings support the hypothesis that COMT rs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system.
AIM: Clozapine is still considered the gold standard for treatment-resistant schizophreniapatients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems. MATERIALS & METHODS: 107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMTrs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively. RESULTS: We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects. CONCLUSION: The findings support the hypothesis that COMTrs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system.
Authors: Steven G Potkin; John M Kane; Christoph U Correll; Jean-Pierre Lindenmayer; Ofer Agid; Stephen R Marder; Mark Olfson; Oliver D Howes Journal: NPJ Schizophr Date: 2020-01-07
Authors: Eric Huang; Clement C Zai; Amanda Lisoway; Malgorzata Maciukiewicz; Daniel Felsky; Arun K Tiwari; Jeffrey R Bishop; Masashi Ikeda; Patricio Molero; Felipe Ortuno; Stefano Porcelli; Jerzy Samochowiec; Pawel Mierzejewski; Shugui Gao; Benedicto Crespo-Facorro; José M Pelayo-Terán; Harpreet Kaur; Ritushree Kukreti; Herbert Y Meltzer; Jeffrey A Lieberman; Steven G Potkin; Daniel J Müller; James L Kennedy Journal: Int J Neuropsychopharmacol Date: 2016-04-29 Impact factor: 5.176