COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine

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From: Pharmacogenomics(Vol. 16, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 6,480 words
Lexile Measure: 1790L

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Author(s): Marta Bosia aff1 aff2 , Cristina Lorenzi [*] aff1 , Adele Pirovano aff3 , Carmelo Guglielmino aff1 , Federica Cocchi aff1 , Marco Spangaro aff1 aff3 , Placido Bramanti aff4 , Enrico Smeraldi aff1 aff3 , Roberto Cavallaro aff1


clozapine; genetic polymorphisms; negative symptoms; PANSS; Positive and Negative Symptoms Scale; psychopharmacogenetics; psychosis; schizophrenia

Clozapine, the first atypical antipsychotic drug, is well established for the treatment of schizophrenia, especially in cases of patients who are refractory and/or intolerant to conventional antipsychotics [1 ]. Nevertheless, clozapine is not free of side effects, and can even produce severe side effects that have to be carefully considered before administration [2 ].

Although it is the gold standard in cases of refractory schizophrenia, unfortunately, only between 30 and 60% of treatment-resistant patients show a good clinical response to clozapine [3 ], and they represent a particular subgroup of patients characterized by a more homogeneous biological substrate. Thus, identifying potential predictors of clinical response to this last-line antipsychotic could advance our understanding of the pathophysiology and represent an important goal for treatment. Clozapine displays high affinity for multiple receptors, including serotoninergic, dopaminergic and muscarinic receptors [4 ], and it has been reported to increase dopamine (DA) release and neuronal activation in the prefrontal cortex (PFC) through a mechanism involving 5-HT1A-R binding [5-7 ]. Therefore, molecules that directly or indirectly regulate DA availability in the PFC may influence clozapine activity and genetic variability at this level could partially explain the heterogeneity observed in clinical response.

COMT, an enzyme that degrades DA, plays a major role in the regulation of DA levels in the PFC. The COMT gene presents a functional polymorphism (Val158Met, rs4680) consisting of an A to G substitution at codon 158, resulting in the presence of valine instead of methionine. This leads to a three- to four-times increase in enzymatic activity and therefore lower DA levels [8,9 ]. There is consensus in the literature of an association between the COMT Met allele and better PFC function, evaluated by both related performances through executive functions tests and regional activation through functional imaging studies [10,11 ]. Studies addressing symptom severity and clinical response to treatment in schizophrenia reported contradictory results, probably because of heterogeneity of the samples studied and variability of the assessments employed. The Val allele has been associated with more prominent negative symptoms [12-15 ], more severe psychotic symptoms and a poorer response to treatment [ 16 ]. By contrast, other studies have found an association between the Met allele and poor response to antipsychotics [17,18 ]. Furthermore, a lack of association between the COMT genotype and response to antipsychotic treatment has also been reported [ 19,20 ]. The COMT genotype has also been suggested to affect cognitive improvement after treatment, with the Met allele showing a better response [21-23 ].

At the crossroad between dopaminergic and serotoninergic transmission, the 5-HT1A-R contributes to clozapine activity at the PFC level [24 ] and has a direct effect on DA release [25 ]. The gene coding for 5-HT1A-R is located on the long arm of chromosome 5 (5q11.2-13)...

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Gale Document Number: GALE|A412067379