The influence of 5-HTTLPR, BDNF Rs6265 and COMT Rs4680 polymorphisms on impulsivity in bipolar disorder: the role of gender

Impulsivity has been proposed as an endophenotype for bipolar disorder (BD); moreover, impulsivity levels have been shown to carry prognostic significance and to be quality-of-life predictors. To date, reports about the genetic determinants of impulsivity in mood disorders are limited, with no studies on BD individuals. Individuals with BD and healthy controls (HC) were recruited in the context of an observational, multisite study (GECOBIP). Subjects were genotyped for three candidate single-nucleotide polymorphisms (SNPs) (5-HTTLPR, COMT rs4680, BDNF rs6265); impulsivity was measured through the Italian version of the Barratt Impulsiveness Scale (BIS-11). A mixed-effects regression model was built, with BIS scores as dependent variables, genotypes of the three polymorphisms as fixed effects, and centers of enrollment as random effect. Compared to HC, scores for all BIS factors were higher among subjects with euthymic BD (adjusted β for Total BIS score: 5.35, p < 0.001). No significant interaction effect was evident between disease status (HC vs. BD) and SNP status for any polymorphism. Considering the whole sample, BDNF Met/Met homozygosis was associated with lower BIS scores across all three factors (adjusted β for Total BIS score: -10.2, p < 0.001). A significant 5-HTTLPR x gender interaction was found for the SS genotype, associated with higher BIS scores in females only (adjusted β for Total BIS score: 12.0, p = 0.001). Finally, COMT polymorphism status was not significantly associated with BIS scores. In conclusion, BD diagnosis did not influence the effect on impulsivity scores for any of the three SNPs considered. Only one SNP-the BDNF rs6265 Met/Met homozygosis-was independently associated with lower impulsivity scores. The 5-HTTLPR SS genotype was associated with higher impulsivity scores in females only. Further studies adopting genome-wide screening in larger samples are needed to define the genetic basis of impulsivity in BD

Pituitary gland shrinkage in bipolar disorder: The role of gender

BACKGROUND: Hyperactivity of the Hypothalamic-Pituitary-Adrenal Axis (HPAA) has been consistently reported in mood disorders. However, only few studies investigated the Pituitary gland (PG) in Bipolar Disorder (BD) and the results are so far contrasting. Therefore, the aim of this study is to explore the integrity of the PG as well as the role of gender and the impact of clinical measurements on this structure in a sample of BD patients compared to healthy controls (HC). METHODS: 34 BD patients and 41 HC underwent a 1.5\u202fT MRI scan. PG volumes were manually traced for all subjects. Psychiatric symptoms were assessed by means of the Brief Psychiatry Rating Scale, the Hamilton Depression Rating Scale and the Bech Rafaelsen Mania Rating Scale. RESULTS: We found decreased PG volumes in BD patients compared to HC (F\u202f=\u202f24.9, p\u202f<\u202f0.001). Interestingly, after dividing the sample by gender, a significant PG volume decrease was detected only in female BD patients compared to female HC (F\u202f=\u202f9.1, p\u202f<\u202f0.001), but not in male BD compared to male HC (F\u202f=\u202f-0.12, p\u202f=\u202f0.074). No significant correlations were observed between PG volumes and clinical variables. CONCLUSIONS: Our findings suggest that BD patients have decreased PG volumes, probably due to the long-term hyperactivity of the HPAA and to the consequent strengthening of the negative feedback control towards the PG volume itself. This alteration was particularly evident in females, suggesting a role of gender in affecting PG volumes in BD. Finally, the absence of significant correlations between PG volumes and clinical variables further supports that PG disruption is a trait feature of BD, being independent of symptoms severity and duration of treatment

Temperament and character inventory in bipolar disorder versus healthy controls and modulatory effects of 3 key functional gene variants

Background: Bipolar disorder (BD) has been associated with temperamental and personality traits, although the relationship is still to be fully elucidated. Several studies investigated the genetic basis of temperament and character, identifying catechol-O-methyltransferase (COMT), brain derived neurotrophic factor (BDNF), and serotonin transporter (5-HTT) gene variants as strong candidates. Methods: In the GECO-BIP study, 125 BD patients and 173 HC were recruited. Subjects underwent to a detailed assessment and the temperament and character inventory 125 items (TCI) was administrated. Three functional genetic variants within key candidate genes (COMT rs4680, BDNF rs6265, and the serotonin-transporter-linked polymorphic region (5-HTTLPR)) were genotyped. Univariate and multivariate analyses were performed. Results: Compared to HC, BD patients showed higher scores in novelty seeking (NS; p = 0.001), harm avoidance (HA; p < 0.001), and self transcendence (St; p < 0.001), and lower scores in self directness (p < 0.001) and cooperativeness (p < 0.001) TCI dimensions. Concerning the genetic analyses, COMT rs4680 was associated with NS in the total sample (p = 0.007) and in the male subsample (p = 0.022). When performing the analysis in the HC and BD samples, the association was confirmed only in HC (p = 0.012), and in the HC male subgroup in particular (p = 0.004). BDNF rs6265 was associated with St in the BD group (p = 0.017). Conclusion: COMT rs4680 may modulate NS in males in the general population. This effect was not detected in BD patients, probably because BD alters the neurobiological basis of some TCI dimensions. BDNF rs6265 seems to modulate St TCI dimension only in BD patients, possibly modulating the previously reported association between rs6265 and BD treatment response. Further studies are needed to confirm our findings

Temperament and character influence on depression treatment outcome

Background: : personality features have been repeatedly associated with depression treatment outcome in Major Depressive Disorder (MDD), however conclusive results are still lacking. Moreover, as for Bipolar Disorder (BD), results are only few and preliminary. Aim: : the aim of the present study was to perform an exploratory investigation of the influence of personality traits as assessed by the Temperament and Character Inventory (TCI), on principal depression treatment outcomes (non remission, non response and resistance). Methods: : 743 mood disorders patients (455 MDD (61.24%) and 288 BD (38.76%)) were recruited in the context of 6 European studies. Generalized logit models were performed to test the effects of TCI dimensions on treatment outcomes, considering possible confounders such as age, gender and education. Positive results were controlled for comorbidities (anxiety and substance use disorders) as well. Results: : MDD Non-Remitters showed high Harm Avoidance (HA) and Self Transcendence (ST) (p = 0.0004, d = 0.40; p = 0.007, d = 0.36 respectively) and low Persistence (P) and Self Directedness (SD) (p = 0.05; d = 0.18; p = 0.002, d = 0.40, respectively); MDD Non-Responders showed a slightly different profile with high HA and low Reward Dependence (RD) and SD; finally, MDD Resistants showed low RD, P and Cooperativeness (C). In BD patients, only higher HA in non response was observed. Limitations: : the retrospective cross-sectional design, the TCI assessment regardless of the mood state and the small number of bipolar patients represent the main limitations. Conclusion: : specific TCI personality traits are associated with depression treatment outcome in MDD patients. The inclusion of such personality traits, together with other socio-demographic and clinical predictors, could ameliorate the accuracy of the prediction models available to date