D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine

Abstract

A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (Po0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, 5HT 2A , and 5HT 2C polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (Po0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype. Molecular Psychiatry (2003) an association between parietal lobe, but not other major brain regions, volumes, and brain-derived neurotrophic factor (BDNF) alleles. 6 Laruelle et al 7 failed to find an association between D2 receptor binding and alleles at the TaqI-A RFLP site in the D2 receptor gene using single-photon emission computed tomography (SPECT) imaging. Despite their small sample sizes, these preliminary studies provide intriguing data regarding the ability of brain imaging to serve as an intermediate phenotype in pharmacogenetic studies. These studies, however, did not examine the relationship between allelic variation, clinical response to pharmacological treatment, and the intermediate phenotypes as revealed by brain imaging. The relationship between dopamine and serotonin receptor genotypes, regional brain metabolism, and clinical response to clozapine treatment was the focus of this study.We report the changes in brain metabolism based on dopamine and serotonin alleles following treatment with clozapine. Positron emission tomography scanning using 18 F-fluorodeoxyglucose (FDG PET) has the ability to measure regional brain metabolic response while the subject is performing an activation task. PET has the ability to resolve individual gyri and distinguish subcortical regions from each other. PET can measure brain work because of the close coupling between glucose utilization and neuronal activity. 8,9 During the FDG uptake, the subject performed an attentional task, the degraded continuous performance task (CPT), activating brain systems related to essential elements of the illness. In this task, subjects view a series of blurred num...

Evidence for the Preferential Involvement of 5-HT2A Serotonin Receptors in Stress- and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex

“…An important area of future work would be to determine whether other atypical antipsychotic drugs that increase basal mPFC DA levels when administered systemically to animals (Meltzer et al, 2003) would also locally diminish mPFC DA release induced phasically by stress. Indeed, recent PET studies suggest that the highly efficacious drug clozapine may increase basal DA function in the PFC of schizophrenia patients (Cohen et al, 1997;Lahti et al, 2003;Molina et al, 2005a;Potkin et al, 2003). However, one exposure to amphetamine, which phasically increases cortical DA function in these patients, worsens their psychosis (Laruelle et al, 1999).…”

Exploring Genetic Influences on Cognition: Emerging Strategies for Target Validation and Treatment Optimization

“…Genetic polymorphisms in the serotonin system may mediate clozapine response [64]. PET studies have shown that polymorphisms in the dopamine D1 receptor (DRD1) gene influence baseline metabolic activity in the dorsolateral frontal cortex in response to clozapine treatment [65,66]. These polymorphisms showed significant associations with changes in attention and working memory; two cognitive functions that are disrupted in Schizophrenia [56] and which are thought to, at least in part, be dependent upon prefrontal cortical function.…”

Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study

“…15 In terms of functional neuroimaging, diminished cortical metabolism, particularly in the pre-frontal region, was found to be associated with poor response to Clozapine in a SPECT study, 16,17 whilst in a recent PET study, patients who were poor responders to Clozapine (less than 30% of improvement in the BPRS) had diminished cortical metabolism, predominantly in frontal areas. 9 Recently, we have presented preliminar y data on neuropsychological aspects comparing patients with SRS to patients with TRS and it was found that SRS patients presented worse performance than patients with TRS. However, the sample size was too small to detect significant statistical differences.…”

“…19 Moreover, to date only one study has found a correlation between pharmacogenetic data with neuroimaging parameters. 9 Thus, there is a paucity of data regarding super-refractory schizophrenic patients which have still not been adequately studied, especially in terms of demographic and psychopathological aspects. Such an investigation is necessary to establish predictive factors of response to Clozapine.…”

“…However, most of the studies have focused on the pharmacodynamics of Clozapine and found that an inadequate response was significantly associated with the polymorphisms of certain receptor genes such as D3, 5HT 2A , 5HT 2c , 5HT 6 8 and, more recently, also D1. 9 Three studies on structural neuroimaging consistently found an increased prefrontal sulcal prominence to be associated with a poorer response to Clozapine. [10][11][12] However, two MRI studies showed no association between brain abnormalities and treatment response to Clozapine, 13,14 but a recent MRI volumetric study did show that larger right prefrontal gray matter volume was associated with a favorable response to Clozapine.…”