Interaction of COMT Val^108/158 Met Genotype and Olanzapine Treatment on Prefrontal Cortical Function in Patients With Schizophrenia

Abstract

These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine.

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

“…However, this difference in the response to the neuroleptic treatment was not identified in the remaining PANSS subscales, which could be explained by the sample size (20 and 30 patients, respectively; 8 weeks of treatment). Our results, using the GAF and the PANSS scales, and a longer period of treatment (6 months), although showing a small effect, are in good agreement with those obtained by Bertolino et al 36 and Weickert et al 37 In our sample, the Val/Val genotype was associated with a higher severity of psychotic symptoms measured by the PANSS scale ( Figure 1) and a smaller enhancement of the global functioning after period of treatment measured by the GAF scale than Met/Met and Val/Met patients ( Figure 2).…”

“…Thus, the effect of Val 158 Met in the response to treatment seems to be especially clear in terms of negative symptoms. These results, together with those obtained by Bertolino et al 36 and Weickert et al, 37 suggest that the advantage conferred by the Met allele in the response to the neuroleptic treatment is evident shortly after the administration of the neuroleptic drugs, and it seems to be still detectable after 6 months of treatment. It would be interesting to investigate this effect in larger series with longer periods of treatment to clarify the magnitude of this effect in the long-term prognosis.…”

“…Although our results need to be replicated to further clarify whether the presence of the Val/Val genotype is a risk factor for a higher severity of positive and negative symptoms, our findings are consistent with the model that explains positive and negative symptoms as the result of a cortical-subcortical dopaminergic imbalance, which originates a state in which a subcortical mesolimbic functional hyperdopaminergia (hyperstimulation of D 2 subcortical receptors; positive symptoms) coexists with a cortical functional hipodopaminergia (hypostimulation of D 1 cortical receptors; negative symptoms and cognitive impairment), 6 given the fact that the relatively high COMT activity conferred by the Val allele not only causes low prefrontal cortex dopamine levels, but also may enhance dopamine biosynthesis in the midbrain by means of greater tyrosine hydroxylase mRNA expression. 25 An important limitation of the results of this work concerning the influence of Val 158 Met genotype in the severity of symptoms and in the response to treatment is that given its observational and naturalistic design, and the fact that more than 25% of the patients were under treatment with more than one neuroleptic during the observational period, it was not possible to investigate interactions between specific neuroleptic drugs and the Val 158 Met genotype, as has been done with olanzapine in the work by Bertolino et al 36 However, given the limited statistical power of our study, the fact that a significant effect has been detected supports the idea that an increase of the number of patients treated homogeneously would lead to an enhancement of the differences detected herein.…”

“…The possible influence of the Val 158 Met genotype of the COMT gene in the response to the neuroleptic treatment has also been studied in two recent and concordant reports, 36,37 which detected a better outcome for Met allele carriers in terms of the performance in specific neuropsychological tests and of the PANSS-N rating subscale. However, this difference in the response to the neuroleptic treatment was not identified in the remaining PANSS subscales, which could be explained by the sample size (20 and 30 patients, respectively; 8 weeks of treatment).…”

Treatment with Olanzapine is Associated with Modulation of the Default Mode Network in Patients with Schizophrenia

“…Although some reports are questioning the size of the effect and specificity of the cognitive effects of second-generation antipsychotics (Goldberg et al, 2007;Keefe et al, 2007), some evidence shows that this treatment is associated with improvement of some of the cognitive deficits of schizophrenia including WM (Bertolino et al, 2004;Purdon et al, 2000). Furthermore, second-generation antipsychotic treatment appears to modulate brain physiology underlying WM function with reduced activation of dorsolateral prefrontal cortex (DLPFC) and parietal cortex for better levels of performance, suggesting increased neural efficiency (Bertolino et al, 2004). Moreover, other studies have indicated that systemic administration of levodopa and apomorphine in healthy humans or in patients with Parkinson's disease can modify the activity of the DMN (Argyelan et al, 2008;Nagano-Saito et al, 2009) further suggesting the potential relationship between dopamine signaling and DMN modulation.…”