In this work, we found an association between the GG genotype of COMT rs5993883 and SGA-treatment with these individuals with BD showing poorer cognitive performance than those with the GT or TT genotypes. Specifically, we observed significantly lower scores in areas of verbal cognition and cognitive control in this treatment population, indicating that individuals with BD who receive SGA treatment and have the GG genotype are at risk for greater difficulties in learning and remembering verbal or auditory information and they are less accurate when required to engage and disengage their attention to stimuli. Overall, they may be less efficient with learning, memory, and attentional capacity. Although the results of the PGNG Target Accuracy test was not significant when considering CPZ-equivalents, this may be due to non-dose dependent pharmacologic effects. This cohort also exhibited a significant interaction between the SGA-class of medication and COMT genotype in the same cognitive domains.

Neuropsychological studies of patients with brain injuries and neuroimaging work has indicated that dopamine action in the prefrontal cortex, dorsal striatum and hippocampus is critical for high level cognitive functioning [32–34]. O-methylation by COMT is one of the major degradative pathways for catecholamine neurotransmitters such as dopamine [15]. Consistent with its role in catecholamine metabolism in the prefrontal cortex, variation in this gene has been linked with decreased cognitive function in BD, schizophrenia and in healthy controls [14, 16, 35]. The most widely studied COMT variant allele is the COMT Val108/158Met polymorphism rs4680. This variant affects the stability and enzymatic activity of catechol-O-methyltransferase, which alters the enzyme's ability to methylate catecholamines in the pre-frontal cortex [36–38]. In previous work, Val allele load has been associated with detrimental effects in cognition for schizophrenia subjects and has also been linked to a further decrease in cognition in BD patients treated with SGAs [9].

The polymorphism COMT rs5993883 is located in intron 1 of the COMT gene and is not strongly linked to the rs4680 polymorphism (Distance = 13633 base pairs; r 2 = .327; d’ = 0.654; www.broadinstitute.org/mpg/snap/). In previous work, this mutation has been weakly associated with creativity, cocaine induced paranoia and modulation of certain personality traits including suicidal behavior [15, 39, 40]. Additionally, the rs5993883 G allele has been associated with cognitive manic symptoms in BD patients [41]. Intron variants are not in the protein-coding region of a gene but can generally affect function by altering processes such as transcription or alternative splicing, in which several splice variants have been noted for COMT [42–44]. Although no structural or transcriptional changes in function have been defined for COMT rs5993883, it’s possible that this variant could affect these types of processes.

Impairments in cognition are noted as being robustly evident in the schizophrenia literature but have also been noted in BD patients, although to a lesser degree. When compared to healthy controls, euthymic BD patients show deficiency in executive functioning, verbal memory, psychomotor speed and sustained attention [45]. It has also been observed that in first degree relatives, the cognitive domains of executive functioning and verbal memory are significantly different from healthy controls, which suggests these domains are bipolar endophenotypes reflecting a genetic link to BD [46]. Impaired inhibitory behavioral control in manic and euthymic BD subjects is a specific cognitive impairment that has also been described as distinct from the universal neuropsychological deficiency linked to other psychotic disorders [47, 48]. The overall cause of neurocognitive deficits in BD patients is likely multifactorial including genetic, medication and symptom considerations. Although deficiencies in verbal memory have been described in the BD population, we have observed further decrements in this domain due to an interaction between SGA-treatment and the GG genotype of the COMT rs5993883 variant. We also described a relationship between COMT rs5993883 and SGA-treatment on deficiencies in cognitive control as measured by a continuous performance test (PGNG).

Second generation antipsychotics have a role in the management of not only BD-associated mania but are also effective in BP-associated depression. Although the mechanistic basis for the efficacy of SGAs in mood disorders is not completely understood, the ability to block D2 and serotonin 5HT 2A receptors are likely to contribute. Dopamine dysregulation is thought have a role in the psychopathology of BD [49]. However, in contrast to the cognitive improvement observed in SGA-treated schizophrenia patients, SGAs use within the BD population has been associated with lower cognitive functioning. As a further complication for cognition in this group, our work and others have shown that treatment with SGAs may confer further decrements in cognition if the subject caries COMT variants [9]. In this report, we observe that a well-characterized large group of BD subjects show significantly lower cognitive performance in specific domains of verbal cognition and cognitive control that are associated with an SGA-treatment interaction with a GG genotype of COMT rs5993883.

Study limitations

As this study was cross-sectional in design, we miss looking longitudinally at cognitive measures in APP-treated subjects over time. In the future, as we accumulate more data in the Prechter longitudinal cohort, a longitudinal analytic approach will be informative. Additionally, we know that members of the SGA-class are not identical in either the mechanism of action or side effects. In this study, we did not distinguish between specific SGA-medications but this may be warranted in future work.

Greater severity of illness is associated with SGA treatment in the BD population, which can also result in reduced cognitive functioning. In an attempt to address this disparity, we adjusted our model for prior hospitalizations, as an indicator of disease severity, which showed a statistically significant increase in the SGA-treated population. However, it may also be important to consider other factors such as medication switching or chlorpromazine equivalents for SGA use to assess severity of illness. And finally, we also had a significantly under representation of the BD-II and schizoaffective BD type diagnoses when compared to subjects with a BD-I diagnosis. There may be differences in the effect of COMT variant alleles and interactions with SGA-treatment in the less-represented diagnosis in our subject cohort. As we accrue more subjects, this analysis may be possible using the Prechter cohort.