Introduction

Bipolar disorder (BD), especially in its softer expressions^{1 , 2}, is associated with professional success and increased creativity³. Although Jamison³ contends that the relationship between creativity and BD may be at the trait or temperament level⁴ and it is influenced by cognitive function and symptoms⁵. Little is known about the biological underpinnings of creativity in BD, although psychological, neuropsychological and functional imaging studies in healthy subjects have indicated the potential role of the dopaminergic system^{6 - 9}.

Dopaminergic pathways project into numerous brain areas implicated in the pathophysiology of BD¹⁰. Historically, dopaminergic models of BD have been dichotomous and support both dopamine (DA) excess in mania and deficiency in depression¹¹. However, most of these models were conceptualized based on indirect evidence drawn from pharmacological and animal studies¹⁰. DA has been strongly implicated in motivation and reward systems¹². Moreover, high DA has been reported to decrease inhibition of incoming stimuli from the surrounding environment^{13 , 14}, a trait characteristic of creative individuals of higher intelligence¹⁵. Also, the ability to generate many different ideas about a topic in a short period (divergent thinking), a key aspect of creativity¹⁶, is present in mania and influenced by dopaminergic function. Furthermore, a recent study has reported an association between divergent thinking and DA receptor polymorphisms¹⁷.

Catechol-O-methyltransferase (COMT) is one of the main enzymes involved in the catabolism of DA¹⁸ and thus constitutes an important regulator of prefrontal cortical (PFC) dopaminergic levels¹⁹. The COMT gene single nucleotide polymorphism (SNP) rs4680 (also known as Val¹⁵⁸Met) leads to a 35% to 50% reduction in the COMT enzyme in Met allele carriers (Met+)¹⁸. COMT SNP rs4680 Met+ has been linked to better performance on cognitive tests^{20 - 23} probably to an increment in PFC DA due to lower COMT activity. To our knowledge, only one study has investigated the association of COMT and creativity in healthy controls, and reported negative results¹⁷.

The objective of this research was to investigate the role of COMT functional polymorphism Val¹⁵⁸Met in creativity scores of healthy controls, and BD patients in euthymia and during mood episodes. We hypothesized that carriers of the Met allele would have higher creativity scores than Met non-carriers due to lower COMT activity in the PFC.

Material and methods

Results

The COMT genotype distribution in the experimental was in accordance with the Hardy-Weinberg equilibrium (χ ² = 0.79 p = 0.56) indicating that the samples were representative. Allelic distribution in the sample was 49.1% for allele Val and 50.8% for allele Met. Sociodemographic data of all four groups is presented in table 1.

Univariate analysis of variance (MANOVA) in which the total score BWAS was entered as a dependent variable and age, gender, education, rs4680 allele Met and WASI-IQ as covariates revealed an influence of age (B = -0.84 p = 0.05) and allele Met (B = 7.05 p = 0.03) in BWAS score in healthy controls (Table 2). No influence of gender, education or IQ in BWAS was observed in controls. The same MANOVA model in mania group revealed that gender influenced BWAS score (B = 9.8 p = 0.02). Females in the manic group presented higher creativity scores. In the same manic group a trend was observed for the influence of allele Met on BWAS scores (B = -6.4 p = 0.08). No influence of age, education or IQ on BWAS total score was observed on the manic group.

In the depression and euthymic groups the same MANOVA model revealed that none of the covariates influenced BWAS total score (Table 2).

Discussion

This is the first study investigating the role of COMT Val¹⁵⁸Met in creativity output in bipolar I disorder. Moreover, this is also the first study to report a positive association between COMT rs4680, specifically allele Met, and higher scores on the BWAS in the healthy population. Carriers of allele Met present lower COMT enzyme activity in PFC^{18 , 19}, and in the present study this same group was shown to have higher BWAS scores in the healthy control group. This finding confirms the recent hypothesis that COMT numbers among the candidate genes for creativity¹⁷. In the other hand, in BD the Met allele did not influence creativity in mood episodes or euthymia.

These findings reinforce the putative role of DA in creative abilities hypothesized based on pharmacological studies. In Parkinson’s disease (PD), the emergence of poetic talent³⁶ and “compulsive” augmentation of artistic productivity³⁷ have been reported in dopaminergic replacement therapy³⁶. Furthermore, DA antagonists, such as typical antipsychotics, are reported to suppress creativity³⁸. Functional imaging studies have shown that the creative thinking process is associated with increased PFC activity^{8 , 39}. These reports are consistent with findings of reviews of creativity studies suggesting that the dopaminergic system, including the PFC, is associated with creativity^{8 , 40}. Also, results of studies on COMT functional SNPs and the differential effects of D1 and D2 receptor binding, have clarified this association. The allele Met, associated with low-activity COMT, has been theoretically linked to decreases in phasic and increases in tonic DA transmission subcortically, and in increases DA concentrations cortically. This is associated with increased D1 and decreased D2 transmission in the PFC⁴¹, which have in turn been associated with higher creative achievement or psychosis¹⁵. Moreover this same SNP have been reported to modulate cognitive function in BD during mood episodes⁴².

Dopaminergic and other transmitter relationships to creativity have also been suggested in studies involving non-bipolar patients. A recent study reported an association between divergent thinking and dopamine receptor polymorphism. Higher creativity scores were observed in carriers of the A1 allele ¹⁷. The A1 allele of DRD2 (rs1800497) has a 30%-40% reduction in DA-D2 receptor density⁴³. In the same study, these authors reported that carriers of the A allele of the serotonin polymorphism TPH1 A779C also had higher creativity scores¹⁷. In another study involving a sample of healthy subjects, Kéri studied a polymorphism in the promoter region of neuregulin 1 and found that the T allele was associated with higher creative scores⁴⁴. Thus, further examination of the possible neurobiological underpinnings of the link between bipolar disorder and creativity are warranted, especially in those with lesser degrees of bipolarity at the trait level. Dopaminergic function should be investigated in cyclothymic and related temperaments, which the work of Akiskal et al. well as supportive evidence from Stanford⁴⁵, and supportive evidence from Italian work⁴⁶, suggest might be an underlying ingredient in creative work⁴. Andreasen and Canter’s early work had also implicated cyclothymic tendencies or disorder⁴⁷.

Andreasen and Powers’ work also raised the possibility that over-inclusive thinking is characteristic for both mania and schizophrenia⁴⁸. In bipolar disorder the thought processes are less extreme than in schizophrenia and might even be somewhat different qualitatively, and it may be that the overall thought impairment characteristic of schizophrenia restricts the execution of creativity.

There are many difficulties inherent to systematic studies of creativity, particularly methodological problems concerning the reliability and validity of creativity measures, and disagreements over the definition of creativity. The BWAS is not the only measure of creativity and other measures should be explored before drawing more definitive conclusions. In the present study, it was decided to examine the correlation between scores on a widely used scale for measuring creativity and the presence of functional polymorphism of COMT (rs4680), which likely influences PFC cognition, in a homogeneous sample of university students. Our results are also consistent with those reported in the literature investigating the role of DA and COMT in PFC function and cognition. However, no influence of COMT on IQ was evident, and BWAS and IQ scores were unrelated, further suggesting some degree of specificity in the association of COMT with creativity.

This study is the first to report findings that suggest the effects of COMT gene polymorphism may not be limited to isolated basal cognitive abilities, but could partially account for greater cognitive abilities related to creativity in healthy controls. In the other hand, we found evidence that creativity during BD episodes and euthymia is not associated with COMT DA catabolism activity in the PFC. Further studies involving larger samples should be conducted in an effort to replicate our findings. In addition, given the strong and consistent body of evidence indicating an association of bipolar spectrum disorders with creativity^{1 , 4 , 46}, examining the association of COMT polymorphism with creativity in this population is now warranted.