Diverse Facets of COMT: From a Plausible Predictive Marker to a Potential Drug Target for Schizophrenia

Abstract

Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia.

A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

“…COMT is involved in the degradation of dopamine and is important in the regulation of dopaminergic prefrontal cortex dependent cognitive disturbances in schizophrenia (Gupta et al, 2011). The authors reported significant effects of COMT deletion to enhance WM performance in male, but not female, COMT -/-mice (Babovic et al, 2008) that could be related to higher prefrontal dopamine levels ( Table 2).…”

COMT polymorphism modulates the resting‐state EEG alpha oscillatory response to acute nicotine in male non‐smokers

“…That the nicotine‐induced electrocortical changes were evident in individuals with the COMT Met allele infers that the acute, nicotine‐modulated spontaneous oscillations reflect tonic cortical dopamine level and its potential functional role in cognitive tasks. These spectral EEG findings were observed with respect to α oscillatory activity, which is associated with cognitive processes and therefore may be of relevance to people diagnosed with schizophrenia – a disorder invariably linked with COMT polymorphism (Gupta et al ; Lewandowski ; Sagud et al ; Williams et al ), and is also associated with excessive smoking (Winterer ), aberrant dopamine neurotransmission (Brisch et al ), abnormalities in α rhythms (Knott et al ; Narayanan et al ; Venables et al ; Wix‐Ramos et al ), fMRI– (Whitfield‐Gabrieli et al ) and electrophysiologic–DMN (Kim et al ) and cognition (Nuechterlein et al ), with the latter being shown to improve both with smoking and nicotine administration (D'Souza & Markou ). Schizophrenia patients have shown increases in α 2 with the smoking of a single cigarette (Knott et al ), but the role of COMT in these oscillatory changes is not yet known and the cognitive changes accompanying these cortical rhythms require addressing.…”

Classical Neurotransmitters and Neuropeptides Involved in Schizophrenia: How to Improve the Therapeutic Effect of the Antipsychotic Drugs

“…The antipsychotic drug aripiprazol is a partial D2 agonist and improves cognitive functions, but impairs motor activities [19]. Dopamine hyperactivity is associated with polymorphisms of the catechol-O-methyl transferase gene and reduced dopamine degradation leads to dopamine hyperactivity and cognitive impairments [20]. The action of the enantiomers (-)-OSU-6,162 and (+)-OSU-6,162 has been reported, which are partial agonists at both D2 and 5-HT2A receptors.…”