Altered brain creatine cycle metabolites in bipolar I disorder with childhood abuse: A 1H magnetic resonance spectroscopy study.

BACKGROUND: Childhood abuse (CA) is a risk factor for a number of psychiatric disorders and has been associated with higher risk of developing bipolar disorders (BD). CA in BD has been associated with more severe clinical outcomes, but the neurobiological explanation for this is unknown. Few studies have explored in vivo measurement of brain metabolites using proton magnetic resonance spectroscopy (1H-MRS) in CA and no studies have investigated the association of CA severity with brain neurometabolites in BD. OBJECTIVE: To investigate whether CA severity is associated with changes in anterior cingulate cortex (ACC) neurometabolite profile in BD and HC subjects. METHODS: Fifty-nine BD I euthymic patients and fifty-nine HC subjects were assessed using the Childhood Trauma Questionnaire (CTQ) and underwent a 3-Tesla 1H-MRS scan. Severity of childhood abuse (physical, sexual and emotional) and its association with levels of brain metabolites was analyzed within each group. RESULTS: BD patients had higher total scores on the CTQ and higher severity rates of sexual and physical abuse compared to HC subjects. Greater severity of physical and sexual abuse was associated with increased ACC PCr level and lower Cr/PCr ratio in the BD group only. CONCLUSION: Sexual and physical abuse in BD patients, but not in HC subjects, appeared to be associated with creatine metabolism in the ACC, which can influence neuronal mitochondrial energy production. Further studies should investigate whether this is the mechanism underlying the association between CA and worse clinical outcomes in BD.

Facial emotion recognition and its correlation with executive functions in bipolar I patients and healthy controls.

INTRODUCTION: The ability to recognize facial emotions is altered in patients with Bipolar Disorder (BD) during mood episodes and even in euthymia, while cognitive functioning is similarly impaired. This recognition is considered a fundamental skill for successful social interaction. However, it is unclear whether the ability to recognize facial emotions is correlated with the cognitive deficits observed in BD. OBJECTIVE: The objective of this study was to evaluate Facial Emotion Recognition (FER) and its correlation with executive function (EF) in BD I patients during mania, depression and euthymia compared to healthy controls. MATERIAL AND METHODS: A total of 110 patients with BD I, 18-40 years old were included (41 in manic episode; 31 in depressive episode and 38 euthymic). Patients were assessed for FER and EF (Wisconsin card sorting test - WCST), along with 96 healthy volunteers (18-40 years old) recruited from the University of São Paulo. RESULTS: The results showed that BD I patients had lower FER performance compared to controls on fear subtests, happiness, the surprise test, and FER total scores. Moreover, BD I manic patients showed poorer performance for EF compared to controls. Six out of the seven variables of the WCST correlated with FER in both healthy controls and BD euthymic subjects but not in BD patients during mood episodes. CONCLUSION: Cognitive deficits and difficulties recognizing facial emotions are present in all mood episodes in BD I patients, even during remission. Although FER is not considered a cognitive domain, these results suggest that, along with EF, it has a complementary function. Hence, further studies should investigate this issue in larger samples and verify whether these similarities also occur at a neurobiological level.

Gender effects of the COMT Val 158 Met genotype on verbal fluency in healthy adults.

Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol­O­methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender­specific effects of the COMT genotype on cognition in healthy young adults. Seventy­six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender.

The impact of limbic system morphology on facial emotion recognition in bipolar I disorder and healthy controls.

INTRODUCTION: Impairments in facial emotion recognition (FER) have been reported in bipolar disorder (BD) subjects during all mood states. This study aims to investigate the impact of limbic system morphology on FER scores in BD subjects and healthy controls. MATERIAL AND METHODS: Thirty-nine euthymic BD I (type I) subjects and 40 healthy controls were subjected to a battery of FER tests and examined with 3D structural imaging of the amygdala and hippocampus. RESULTS: The volume of these structures demonstrated a differential pattern of influence on FER scores in BD subjects and controls. In our control sample, larger left and right amygdala demonstrated to be associated to less recognition of sadness faces. In BD group, there was no impact of amygdala volume on FER but we observed a negative impact of the left hippocampus volume in the recognition of happiness while the right hippocampus volume positively impacted on the scores of happiness. CONCLUSION: Our results indicate that amygdala and hippocampus volumes have distinct effects on FER in BD subjects compared to controls. Knowledge of the neurobiological basis of the illness may help to provide further insights on the role of treatments and psychosocial interventions for BD. Further studies should explore how these effects of amygdala and hippocampus volumes on FER are associated with social networks and social network functioning.

The ARIQUELI study: potentiation of quetiapine in bipolar I nonresponders with lithium versus aripiprazole.

BACKGROUND: The treatment of bipolar disorder (BD) remains a challenge due to the complexity of the disease. Current guidelines represent an effort to assist clinicians in routine practice but have several limitations, particularly concerning long-term treatment. The ARIQUELI (efficacy and tolerability of the combination of lithium or aripiprazole in young bipolar non or partial responders to quetiapine monotherapy) study aims to evaluate two different augmentation strategies for quetiapine nonresponders or partial responders in acute and maintenance phases of BD treatment. METHODS/DESIGN: The ARIQUELI study is a single-site, parallel-group, randomized, outcome assessor-blinded trial. BD I patients according to the DSM-IV-TR, in depressive, manic/hypomanic or mixed episode, aged 18 to 40 years, are eligible. After diagnostic assessments, patients initiated treatment in phase I with quetiapine. Nonresponders or partial responders after 8 weeks are allocated into one of two groups, potentiated with either lithium (0.5 to 0.8 mEq/l) or aripiprazole (10 or 15 mg). Patients will be followed up for 8 weeks in phase I (acute treatment), 6 months in phase II (continuation treatment) and 12 months in phase III (maintenance treatment). Outcome assessors are blinded to the treatment. The primary outcome is the evaluation of changes in mean scores on the CGI-BP-M between baseline and the endpoint at the end of each study phase. DISCUSSION: The ARIQUELI study is currently in progress, with patients undergoing acute treatment (phase I), potentiation (phase II) and maintenance (phase III). The study will be extended until January 2015. Trials comparing lithium and aripiprazole with potentiate treatment in young BD I nonresponders to quetiapine in monotherapy can provide relevant information on the safety of these drugs in clinical practice. Long-term treatment is an issue of great importance and should be evaluated further through more in-depth studies given that BD is a chronic disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01710163.

Association of the COMT Met¹58 allele with trait impulsivity in healthy young adults.

Dopamine (DA) is considered to be an important neurotransmitter in the control of impulsive behavior, however, its underlying mechanisms have not been fully elucidated. Catechol-O-methyltransferase (COMT) is a key enzyme in the catabolism of DA within the prefrontal cortex (PFC) and has been suggested to play a role in the mediation of impulsive behavior. The COMT single nucleotide polymorphism (SNP) rs4680 (Val158Met) Met allele has been shown to decrease COMT enzyme activity and is associated with improved PFC cognitive function (intelligence and executive functions). Studies have associated the rs4680 genotype with impulsivity as a symptom in attention deficit hyperactivity disorder and substance abuse. However, only a few studies have assessed the effects of rs4680 on impulsiveness in healthy subjects, the results of which remain controversial. The Barratt Impulsiveness Scale (BIS-11) was applied to 82 healthy volunteers (including 42 females) who were genotyped for COMT rs4680. Subjects carrying the Met/Met genotype scored higher for the BIS-11 second-order factor Non-planning than carriers of the Val/Val genotype. No interaction between gender genotype was detected. Age, gender and education had no effect on the results. The COMT rs4680 Met/Met genotype was associated with higher impulsivity on the BIS-11 second-order factor Non-planning. These results suggest that COMT enzyme activity may be important in the regulation of impulsiveness among young adults. Further studies involving larger samples should be conducted to confirm the results of the present study.

Burden of maternal bipolar disorder on at-risk offspring: a controlled study on family planning and maternal care.

INTRODUCTION: Bipolar disorder (BD) is a highly incapacitating disease typically associated with high rates of familial dysfunction. Despite recent literature suggesting that maternal care is an important environmental factor in the development of behavioral disorders, it is unclear how much maternal care is dysfunctional in BD subjects. OBJECTIVE: The objective of this study was to characterize maternal care in DSM-IV/SCID diagnosed BD type I subjects compared to healthy controls with (PD) and without (NPD) other psychiatric diagnoses. MATERIALS AND METHODS: Thirty-four BD mothers and 106 controls underwent an interview about family planning and maternal care, obstetrical complications, and mother-child interactions. K-SADS-PL questions about violence exposure were used to ascertain domestic violence and physical/sexual abuse. RESULTS: BD mothers were less likely to have stable unions (45.5%; p<0.01) or to live with the biological father of their children (33.3%; p<0.01), but had higher educational level and higher rates of social security use/retirement. They also had fewer children and used less contraceptive methods than controls. Children of BD women had higher rates of neonatal anoxia, and reported more physical abuse (16.1%; p=0.02) than offspring of NPD mothers. Due to BD mothers' symptoms, 33.3% of offspring suffered physical and/or psychological abuse. LIMITATIONS: Post hoc analysis, and the use of questions as a surrogate of symptoms as opposed to validated instruments. CONCLUSION: This is one of few reports confirming that maternal care given by BD women is dysfunctional. BD psychopathology can lead to poor maternal care and both should be considered important environmental risk factors in BD, suggesting that BD psychoeducation should include maternal care orientation.

COMT Met (158) modulates facial emotion recognition in bipolar I disorder mood episodes.

BACKGROUND: One of the many cognitive deficits reported in bipolar disorder (BD) patients is facial emotion recognition (FER), which has recently been associated with dopaminergic catabolism. Catechol-O-methyltransferase (COMT) is one of the main enzymes involved in the metabolic degradation of dopamine (DA) in the prefrontal cortex (PFC). The COMT gene polymorphism rs4680 (Val158Met) Met allele is associated with decreased activity of this enzyme in healthy controls. The objective of this study was to evaluate the influence of Val158Met on FER during manic and depressive episodes in BD patients and in healthy controls. MATERIALS AND METHODS: 64 BD type I patients (39 in manic and 25 in depressive episodes) and 75 healthy controls were genotyped for COMT rs4680 and assessed for FER using the Ekman 60 Faces (EK60) and Emotion Hexagon (Hx) tests. RESULTS: Bipolar manic patients carrying the Met allele recognized fewer surprised faces, while depressed patients with the Met allele recognized fewer "angry" and "happy" faces. Healthy homozygous subjects with the Met allele had higher FER scores on the Hx total score, as well as on "disgust" and "angry" faces than other genotypes. CONCLUSION: This is the first study suggesting that COMT rs4680 modulates FER differently during BD episodes and in healthy controls. This provides evidence that PFC DA is part of the neurobiological mechanisms of social cognition. Further studies on other COMT polymorphisms that include euthymic BD patients are warranted. Clinicaltrials.gov identifier: NCT00969.

Creativity and executive function across manic, mixed and depressive episodes in bipolar I disorder.

INTRODUCTION: Creativity is a complex construct involving affective and cognitive components. Bipolar Disorder (BD) has been associated with creativity and is characterized by a wide range of affective and cognitive symptoms. Although studies of creativity in BD have tended to focus on creativity as a trait variable in medicated euthymic patients, it probably fluctuates during symptomatic states of BD. Since creativity is known to involve key affective and cognitive components, it is plausible to speculate that cognitive deficits and symptoms present in symptomatic BD could interfere with creativity. MATERIAL AND METHODS: Sixty-seven BD type I patients medication free, age 18-35 years and experiencing a maniac, mixed, or depressive episodes, were assessed for creativity, executive functioning, and intelligence. RESULTS: Manic and mixed state patients had higher creativity scores than depressive individuals. Creativity was influenced by executive function measures only in manic patients. Intelligence did not influence creativity for any of the mood episode types. CONCLUSION: We propose that creativity in BD might be linked to the putative hyperdopaminergic state of mania and be dependent on intact executive function. Future studies should further explore the role of dopaminergic mechanisms in creativity in BD.

Remissão sintomática e qualidade de vida em pacientes com depressão maior tratados com antidepressivo: um estudo prospectivo / Symptomatic remission and quality of life in patients with major depression treated with antidepressants: a prospective study

Este estudo teve como objetivo estimar a Qualidade de Vida (QV) em pacientes com transtorno depressivo maior antes e após tratamento antidepressivo eficaz. Participaram do estudo 26 indivíduos (18 a 65 anos) com episódio agudo de Transtorno Depressivo Maior, segundo critérios do DSM-IV. A duração do estudo foi de 8 semanas. Os instrumentos utilizados foram: escala de avaliação de depressão de Montgomery-Asberg (MADRS) e de Hamilton (HAMD-17). QV foi avaliada através da escala de qualidade de vida e satisfação (Q-LES-Q). Os resultados indicaram que sintomas depressivos e QV melhoraram significantemente com o tratamento (p<0,001). Sintomas de depressão e QV são significativamente correlacionados. Antes do tratamento, QV foi positivamente relacionada com o MADRS, mas não com o HAMD-17. Em todas as outras avaliações, a QV positivamente correlacionou-se com ambas as escalas, confirmando que a melhora sintomatológica traduz-se em melhora na qualidade de vida em pacientes com depressão maior.(AU)

This study aimed to estimate the QoL in individuals with severe Mood Depressive Disorder, before and after effective antidepressant treatment. The Sample consisted of 26 participants with MDD. Duration of study was 2 months. Symptoms were measured with the Montgomer-Asberg depression evaluations scale (MADRS) and the Hamilton Depression Scale (HAMD-17). QoL was measured using the Quality of Life and Satisfaction (Q-LES-Q). Treatment yielded significant improvement of depressive symptoms (HAM-D17: p<0.001 and MADRS: p< 0.001) and of quality of life (Q-LES-Q - p<0.001). As measured by the correlation coefficient, qualify of life and symptom scales were significantly correlated. At baseline, quality of life was positively correlated with MADRS (p=0.037), but not with HAMD (p=0.878). For all other time points, quality of life was positively correlated with MDRS and HAMD (p≤ 0.001); increased scores in the Q-LES-Q corresponded to decreased scores in the MADRS and HAMD scales. Symptomatic improvement is significantly correlated with improved QoL in individuals with MDD.(AU)

Remissão sintomática e qualidade de vida em pacientes com depressão maior tratados com antidepressivo: um estudo prospectivo / Symptomatic remission and quality of life in patients with major depression treated with antidepressants: a prospective study

Este estudo teve como objetivo estimar a Qualidade de Vida (QV) em pacientes com transtorno depressivo maior antes e após tratamento antidepressivo eficaz. Participaram do estudo 26 indivíduos (18 a 65 anos) com episódio agudo de Transtorno Depressivo Maior, segundo critérios do DSM-IV. A duração do estudo foi de 8 semanas. Os instrumentos utilizados foram: escala de avaliação de depressão de Montgomery-Asberg (MADRS) e de Hamilton (HAMD-17). QV foi avaliada através da escala de qualidade de vida e satisfação (Q-LES-Q). Os resultados indicaram que sintomas depressivos e QV melhoraram significantemente com o tratamento (p<0,001). Sintomas de depressão e QV são significativamente correlacionados. Antes do tratamento, QV foi positivamente relacionada com o MADRS, mas não com o HAMD-17. Em todas as outras avaliações, a QV positivamente correlacionou-se com ambas as escalas, confirmando que a melhora sintomatológica traduz-se em melhora na qualidade de vida em pacientes com depressão maior

This study aimed to estimate the QoL in individuals with severe Mood Depressive Disorder, before and after effective antidepressant treatment. The Sample consisted of 26 participants with MDD. Duration of study was 2 months. Symptoms were measured with the Montgomer-Asberg depression evaluations scale (MADRS) and the Hamilton Depression Scale (HAMD-17). QoL was measured using the Quality of Life and Satisfaction (Q-LES-Q). Treatment yielded significant improvement of depressive symptoms (HAM-D17: p<0.001 and MADRS: p< 0.001) and of quality of life (Q-LES-Q - p<0.001). As measured by the correlation coefficient, qualify of life and symptom scales were significantly correlated. At baseline, quality of life was positively correlated with MADRS (p=0.037), but not with HAMD (p=0.878). For all other time points, quality of life was positively correlated with MDRS and HAMD (p≤ 0.001); increased scores in the Q-LES-Q corresponded to decreased scores in the MADRS and HAMD scales. Symptomatic improvement is significantly correlated with improved QoL in individuals with MDD

Vocational rehabilitation improves cognition and negative symptoms in schizophrenia.

Several studies in schizophrenia found a positive association between cognitive performance and work status, and it has been reported that good cognitive performance at the outset does predict the success of vocational interventions. However little has been done to investigate whether vocational interventions itself benefit cognitive performance. To test this hypothesis we performed a randomized, placebo-controlled trial to investigate in remitted schizophrenic patients the effect of a 6-months vocational rehabilitation program on cognitive performance. We recruited 112 remitted and clinically stable schizophrenic patients who aimed to enter a vocational rehabilitation program. From these, 57 immediately entered a 6-months vocational rehabilitation program, whereas the remaining 55 were allocated to a waiting-list; the latter formed our control group, which received during the 6 months out-clinic follow-up treatment. Before and after the 6-months period we assessed changes in cognitive performance through a neuropsychological test battery, as well as changes in the psychopathological status and in quality of life. We found that vocational rehabilitation significantly improved patients' performance in cognitive measures that assess executive functions (concept formation, shifting ability, flexibility, inhibitory control, and judgment and critics abilities). Moreover, after 6 months the vocational group improved significantly in the negative symptoms and in quality of life, as compared to controls. Together with results from the literature, our findings reinforce the notion that the inclusion of vocational interventions may enhance the effectiveness of therapeutic strategies for schizophrenia patients.

SHORT COMMUNICATION: Apolipoprotein E genotype and cognition in bipolar disorder.

Apolipoprotein E (APOE) has been extensively studied as a risk factor for sporadic and late onset Alzheimer's Disease (AD). APOE allele (∗)3, the most frequent variant, is not associated to cognitive dysfunction (CD) or to increased AD risk. Differently, the (∗)4 allele is a well-established risk factor for CD, while the (∗)2 allele is associated with survival and longevity. CD is an important feature of Bipolar Disorder (BD) and recent data suggest that CD may be one of its endophenotypes, although controversial results exist. The aim of this research is to study the association of APOE genotype (APOE) and neurocognitive function in a sample of drug free young BD-type I patients. Sample consisted of 25 symptomatic BD (type I) patients (age 18-35 years old). They were submitted to an extensive neuropsychological evaluation and genotyped for APOE. Subjects with allele (∗)2 presented better cognitive performance. The presence of allele (∗)4 was associated with worse performance in a few executive tasks. APOE (∗)3(∗)3 was associated with overall severe dysfunction on cognitive performance. In young individuals with nontreated BD-type I, APOE may predict cognitive performance. Further and larger studies on APOE and cognition in BD are required to clarify whether APOE is a BD cognitive endophenotype.