COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia

Abstract

Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol-O-methyltransferase (COMT), a key enzyme involved in regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs). Specifically, several studies have identified an association between working memory and executive functions, and COMT val108/158met genotype in schizophrenia; although there have been several negative findings that are likely related to small sample sizes and, possibly, medication status of patients at the time of testing. The association between COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine was investigated in a relatively large prospective sample of patients with schizophrenia, most of whom were unmedicated at baseline. Patients were genotyped for the COMT val108/158met SNP after completing a cognitive battery consisting of tests of attention, working memory, verbal learning and memory, executive function, and verbal fluency at baseline and after 6 weeks and 6 months of treatment with clozapine. Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and val/met heterozygous patients demonstrated significantly greater improvement than val homozygous patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype, cognition, and cognitive improvement with atypical APDs in schizophrenia.

Introduction

Dopamine (DA) projections to the prefrontal cortex (PFC) comprising the mesocortical DA system are essential for normal cognition (Aalto et al., 2005, Brozoski et al., 1979). Reductions in mesocortical DA function, either by chemical ablation or disease, result in cognitive impairment, particularly in executive functions and working memory (Phillips et al., 2004, Brozoski et al., 1979, Roberts et al., 1994, Owen, 2004). Similarly, exogenous manipulation of DA under normal conditions enhances working memory and executive functions in primates and rodents. However, this effect is biphasic as either too little or too much DA impairs cognition (Mattay et al., 2000, Granon et al., 2000) suggesting that DA function in the PFC follows an inverted U-curve whereby increases or decreases from an optimal level result in cognitive impairment (Goldman-Rakic et al., 2000).

It has been hypothesized that the cognitive deficits observed in schizophrenia, especially those related to executive functions and working memory, arise to some extent from reduced DAergic transmission in the PFC (Doran et al., 1987, Davis et al., 1991, Weinberger et al., 1988). Post-mortem and in vivo imaging investigations have directly linked PFC DA function to cognitive impairment (Abi-Dargham et al., 2002, Weinberger et al., 1988), and pharmacological studies indicate that direct and indirect DA agonists improve PFC cognitive functions and cerebral neurophysiology in patients (Barch and Carter, 2005, Goldberg et al., 1991, Dolan et al., 1995). Recently, evidence that genetic polymorphisms related to DA function and susceptibility for schizophrenia influence cognitive functions related to PFC function has provided further evidence that mesocortical DA dysfunction is related to cognitive impairment in schizophrenia (for review see Weinberger et al., 2001). A single nucleotide polymorphism (SNP) in the gene that codes for catechol-O-methyltransferase (COMT), an enzyme that contributes to the removal of DA from the synapse, has attracted considerable attention due to the importance of COMT in regulating prefrontal DA flux (Axelrod and Tomchick, 1958). The substitution of met for val at codon 108/158 results in the transcription of a theromolabile variant of the COMT enzyme with approximately 40% less enzymatic activity in humans (Chen et al., 2004). The reduced activity associated with the met variant of the COMT gene presumably results in greater availability of DA in the PFC and, thus, may be linked to some aspects of cognition in humans, hypotheses supported by findings from a gene knockout investigation in mice (Gogos et al., 1998) and an imaging study in humans (Meyer-Lindenberg et al., 2005).

Numerous studies have identified associations between COMT genotype and cognition in humans. The first study to examine the link between COMT val108/158met genotype and cognition found that, as anticipated, schizophrenia patients and normal controls homozygous for the less effective met allele made fewer perseverative errors on the Wisconsin Card Sorting Test (WCST) than subjects homozygous for the val allele (Egan et al., 2001). Subsequent studies confirmed the association between COMT genotype and WCST, and identified novel associations between COMT genotype and other tests sensitive to PFC DA function including the N-back and letter–number span tests of working memory (Goldberg et al., 2003, Bruder et al., 2005, Joober et al., 2002, Malhotra et al., 2002). However, there have also been several negative findings in both patients and controls using the WCST and variants of the N-back test (Ho et al., 2005, Bilder et al., 2002b, Tsai et al., 2003, Stefanis et al., 2004). In some cases the failure to replicate the association between COMT genotype and performance on the WCST and other tests of executive functions and/or working memory is likely related to small sample sizes within genotype groups (Bilder et al., 2002b, Tsai et al., 2003), medication status of the patients at the time of testing, or differences in the sensitivity of the selected tests to PFC DA function (Goldberg et al., 2003, Stefanis et al., 2004). However, in other cases the reason for the discrepancy is not obvious. Moreover, there is a paucity of data on the specificity of the association between COMT genotype and cognition since most studies only included one or a few measures of cognition.

In addition to the cross-sectional studies supporting associations between COMT genotype and cognition, there is emerging evidence from longitudinal studies that COMT genotype might also interact with cognitive improvement with antipsychotic drugs (APDs), particularly atypical APDs, in schizophrenia. Atypical APDs including clozapine, olanzapine, risperidone, quetiapine, and, to a lesser extent, ziprasidone and amisulpride improve cognitive function in schizophrenia (Woodward et al., 2005, Wagner et al., 2005, Harvey et al., 2004). The improvements may be due to the unique ability of atypical APDs to increase DA and acetylcholine release in the PFC; although the exact mechanism(s) remains to be determined (Meltzer, 2002, Meltzer and Sumiyoshi, 2003). Preclinical and clinical data suggests that variation in COMT activity may influence the degree of cognitive improvement and cerebral physiological changes observed with atypical APDs, including clozapine (Tunbridge et al., 2004, Bertolino et al., 2004, Weickert et al., 2004). The results from two studies indicate that met homozygous schizophrenia patients demonstrate greater improvement in working memory, as measured using the N-back task, than val homozygous subjects after several weeks of treatment with a variety of atypical APDs (Weickert et al., 2004) or just olanzapine (Bertolino et al., 2004). Remarkably, in one case the improvement also corresponded with enhanced function of the dorsolateral PFC during performance of the N-back task suggesting that met homozygous patients may benefit more from enhanced cortical DA transmission as a result of treatment with atypical APDs than val homozygous subjects (Bertolino et al., 2004). An additional implication of the finding that COMT genotype interacts with cognitive improvement with atypical APDs is that the results from previous cross-sectional studies in patients might have been influenced by the medication status of patients at the time of neuropsychological testing and that this might explain some of the discrepant findings (e.g. Rosa et al., 2004, Ho et al., 2005).

Unfortunately the conclusions reached regarding the potential interactions between atypical APDs and COMT genotype must be considered preliminary until studies with larger sample sizes and more comprehensive neuropsychological batteries are carried out. The two prior investigations of interactions between COMT genotype and atypical APD related cognitive improvement included 30 patients or less, including 5 or less met homozygous subjects and employed relatively circumscribed neuropsychological test batteries (Bertolino et al., 2004, Weickert et al., 2004). It is plausible that interactions between COMT genotype and cognitive improvement are not limited to the N-back task given the relatively broad impact that atypical antipsychotics may exert on cognitive function. Similarly, it remains to be determined if the interactions are observed with the atypical APD clozapine specifically.

In order to address several questions relating to the relationship between COMT genotype, cognition, cognitive improvement with clozapine in schizophrenia, and methodological shortcomings of earlier studies, the associations between COMT genotype, cognitive function at baseline, and cognitive improvement with atypical APDs was examined in a relatively large sample of patients with schizophrenia who underwent neuropsychological evaluation at baseline when they were largely unmedicated and after 6 weeks and 6 months of treatment with clozapine. It was anticipated that the current study would 1) clarify the specificity of the association between COMT genotype and cognitive function at baseline in a largely unmedicated sample of patients; and 2) identify the interactions between COMT genotype and cognitive improvement with clozapine, a drug previously shown to increase cortical DA release in rodents and primates (Youngren et al., 1999, Kuroki et al., 1999).