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 ß 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 ß 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 ß 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 SNP­the BDNF rs6265 Met/Met homozygosis­was 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.

A scoping review of near infrared spectroscopy studies employing a verbal fluency task in bipolar disorder.

BACKGROUND: Deficits in cognitive functioning, including attention, memory, and executive functions, along with impairments in language production, are present in patients with bipolar disorder (BD) patients during mood phases, but also during euthymia.Verbal fluency tasks (VFTs), being able to evaluate integrity of a wide range of cognitive domains and represent, can be used to screen for these disturbances. Neuroimaging studies, including Near-InfraRed Spectroscopy (NIRS), have repeatedly showed widespread alterations in the prefrontal and temporal cortex during the performance of VFTs in BD patients. This review aims to summarize the results of NIRS studies that evaluated hemodynamic responses associated with the VFTs in prefrontal and temporal regions in BD patients. METHODS: We performed a scoping review of studies evaluating VFT-induced activation in prefrontal and temporal regions in BD patients, and the relationship between NIRS data and various clinical variables. RESULTS: 15 studies met the inclusion criteria. In BD patients, compared to healthy controls, NIRS studies showed hypoactivation of the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex and anterior temporal regions. Moreover, clinical variables, such as depressive and social adaptation scores, were negatively correlated with hemodynamic responses in prefrontal and temporal regions, while a positive correlation were reported for measures of manic symptoms and impulsivity. LIMITATIONS: The heterogeneity of the studies in terms of methodology, study design and clinical characteristics of the samples limited the comparability of the findings. CONCLUSIONS: Given its non-invasiveness, good time-resolution and no need of posturalconstraint, NIRS technique could represent a useful tool for the evaluation of prefrontal and temporal haemodynamic correlates of cognitive performances in BD patients.

Psychomotor Agitation Non-responsive to Treatment: A Case Report of Phenibut Withdrawal Syndrome.

Background and Objectives: Phenibut (4-amino-3-phenyl-butyric acid), acting as a GABA-B receptor agonist, has a beneficial effect on anxiety. Although its medical use is not approved in western countries, it can be easily obtained worldwide via the Internet, so it spread as a substance of abuse. In recent years, some case reports have, therefore, highlighted episodes of acute toxicity or withdrawal, but it is still a largely unknown phenomenon. Methods: In this case report, a 50-year-old woman was admitted to the emergency room with psychomotor agitation, psychotic symptoms, and insomnia, and was non-responsive to treatment. She was hospitalized at the psychiatry ward for 25 days and gave her consent for the publication of the present case report. Results: The suspicion of phenibut withdrawal allowed to establish the appropriate management, leading to the restitutio ad integrum of the psychopathological case. Conclusions: In the face of an incoercible psychomotor agitation case, the knowledge of the so-called novel psychoactive substances allows for more appropriate clinical management of intoxication and withdrawal syndromes. This is a scientifically significant report as it provides therapeutic and outcome data concerning a syndrome that is still quite unfamiliar.

The association of childhood trauma, lifetime stressful events and general psychopathological symptoms in euthymic bipolar patients and healthy subjects.

BACKGROUND: Psychopathological symptoms during euthymia in Bipolar Disorder (BD) affect quality of life and predispose to the occurrence of new acute episodes, however only few studies investigated potential risk-factors. This study aims to explore the association between childhood trauma (CT), lifetime stressful events (SLEs) and psychopathological symptoms in BD patients during euthymia and controls (HC). METHODS: A total of 261 participants (93 euthymic patients with BD, 168 HC) were enrolled. Generalized linear models and multiple logistic models were used to assess the association among the Symptom Check List-90-R (SCL-90-R), the Infancy Trauma Interview, the Paykel Life Events Scale. RESULTS: The rate of participants reporting CT was higher in BD (n=47; 53%) than HC (n=43; 30%) (p=0.001). The experience of neglect was strongly related to BD (OR 6.5; p=0.003). CT was associated to higher scores on the SCL-90-R subscales (all the subscales except Phobia). No effects of the interaction between CT and diagnosis were found on SCL-90-R. Finally, there was a main effect of CT on lifetime SLEs (p<.001), that was not associated with diagnosis (p=0.833), nor with the interaction between CT and diagnosis (p=0.624). LIMITATIONS: The cross-sectional design does not allow causal inferences; the exclusion of subjects reporting medical or psychiatric comorbidity limits generalizability. CONCLUSIONS: CT was associated both to psychopathological symptoms during euthymia and the lifetime SLEs, thus it may represent a vulnerability factor influencing the course of BD. Overall, these data contribute to overcome the limited evidences documenting the influence of environmental factors on euthymic phase in BD.

Brain Morphology of Cannabis Users With or Without Psychosis: A Pilot MRI Study.

Cannabis is the illicit drug most commonly used worldwide, and its consumption can both induce psychiatric symptoms in otherwise healthy subjects and unmask a florid psychotic picture in patients with a prior psychotic risk. Previous studies suggest that chronic and long-term cannabis exposure may exert significant negative effects in brain areas enriched with cannabinoid receptors. However, whether brain alterations determined by cannabis dependency will lead to a clinically significant phenotype or to a psychotic outbreak at some point of an abuser's life remains unclear. The aim of this study was to investigate morphological brain differences between chronic cannabis users with cannabis-induced psychosis (CIP) and non-psychotic cannabis users (NPCU) without any psychiatric conditions and correlate brain deficits with selective socio-demographic, clinical and psychosocial variables. 3T magnetic resonance imaging (MRI) scans of 10 CIP patients and 12 NPCU were acquired. The type of drug, the frequency, and the duration, as well socio-demographic, clinical and psychosocial parameters of dependency were measured. CIP patients had extensive grey matter (GM) decreases in right superior frontal gyrus, right precentral, right superior temporal gyrus, insula bilaterally, right precuneus, right medial occipital gyrus, right fusiform gyrus, and left hippocampus in comparison to chronic cannabis users without psychosis. Finally, in CIP patients, the results showed a negative correlation between a domain of the Brief Psychiatric Rating Scale (BPRS), BPRS-Activity, and selective GM volumes. Overall, the results suggest that cannabis-induced psychosis is characterized by selective brain reductions that are not present in NPCU. Therefore, neuroimaging studies may provide a potential ground for identifying putative biomarkers associated with the risk of developing psychosis in cannabis users.

The Role of the Subplate in Schizophrenia and Autism: A Systematic Review.

The subplate (SP) represents a transitory cytoarchitectural fetal compartment containing most subcortical and cortico-cortical afferents, and has a fundamental role in the structural development of the healthy adult brain. There is evidence that schizophrenia and autism may be determined by developmental defects in the cortex or cortical circuitry during the earliest stages of pregnancy. This article provides an overview on fetal SP development, considering its role in schizophrenia and autism, as supported by a systematic review of the main databases. The SP has been described as a cortical amplifier with a role in the coordination of cortical activity, and sensitive growth and migration windows have crucial consequences with respect to cognitive functioning. Although there are not enough studies to draw final conclusions, improved knowledge of the SP's role in schizophrenia and autism spectrum disorders may help to elucidate and possibly prevent the onset of these two severe disorders.

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.

Structural and metabolic cerebral alterations between elderly bipolar disorder and behavioural variant frontotemporal dementia: A combined MRI-PET study.

BACKGROUND: Elderly bipolar disorder (BD) and behavioural variant of frontotemporal dementia (bvFTD) may exhibit similar symptoms and both disorders are characterized by selective abnormalities in cortical and subcortical regions that are associated with cognitive and emotional impairments. We aimed to investigate common and distinct neural substrates of BD and bvFTD by coupling, for the first time, magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques. METHODS: 3-Tesla MRI and 18 fluorodeoxyglucose-PET scans were acquired for 16 elderly BD patients, 23 bvFTD patients with mild cognitive impairments and 68 healthy controls (48 for PET and 20 for MRI analyses). RESULTS: BD and bvFTD patients exhibit a different localization of grey matter reductions in the lateral prefrontal cortex, with the first group showing grey matter decrease in the ventrolateral prefrontal cortex and the latter group showing grey matter reductions in the dorsolateral prefrontal cortex as well as unique grey matter and metabolic alterations within the orbitofrontal cortex. The bvFTD group also displayed unique volumetric shrinkage in regions within the temporo-parietal network together with greater metabolic impairments within the temporal cortex and more extensive volumetric and metabolic abnormalities within the limbic lobe. Finally, while the BD group showed greater grey matter volumes in caudate nucleus, bvFTD subjects displayed lower metabolism. CONCLUSION: This MRI-PET study explored, for the first time to the best of our knowledge, structural and functional abnormalities in bvFTD and elderly BD patients, with the final aim of identifying the specific biological signature of these disorders, which might have important implications not only in prevention but also in differential diagnosis and treatment.

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 T 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 = 24.9, p < 0.001). Interestingly, after dividing the sample by gender, a significant PG volume decrease was detected only in female BD patients compared to female HC (F = 9.1, p < 0.001), but not in male BD compared to male HC (F = -0.12, p = 0.074). 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.