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- A fundamental distinction in early neural processing of implicit social interpretation in schizophrenia and bipolar disorderPublication . Madeira, N; Martins, R; Valente Duarte, J; Costa, G; Macedo, A; Castelo-Branco, MBackground: Social cognition impairment is a key phenomenon in serious mental disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). Although genetic and neurobiological studies have suggested common neural correlates, here we hypothesized that a fundamental dissociation of social processing occurs at an early level in these conditions. Methods: Based on the hypothesis that key structures in the social brain, namely the temporoparietal junction, should present distinctive features in SCZ and BPD during low-level social judgment, we conducted a case-control study in SCZ (n = 20) and BPD (n = 20) patients and controls (n = 20), using task-based fMRI during a Theory of Mind (ToM) visual paradigm leading to interpretation of social meaning based on simple geometric figures. Results: We found opposite neural responses in two core ToM regions: SCZ patients showed social content-related deactivation (relative to controls and BPD) of the right supramarginal gyrus, while the opposite pattern was found in BPD; reverse patterns, relative to controls and SCZ, were found in the left posterior superior temporal gyrus, a region involved in inferring other's intentions. Receiver-operating-characteristic curve analysis showed 88% accuracy in discriminating the two clinical groups based on these neural responses. Conclusions: These contrasting activation patterns of the temporoparietal junction in SCZ and BPD represent mechanistic differences of social cognitive dysfunction that may be explored as biomarkers or therapeutic targets.
- Risk Calculators in Bipolar Disorder: A Systematic ReviewPublication . Silva Ribeiro, J; Pereira, D; Salagre, E; Coroa, M; Santos Oliveira, P; Santos, V; Madeira, N; Grande, I; Vieta, EIntroduction: Early recognition of bipolar disorder improves the prognosis and decreases the burden of the disease. However, there is a significant delay in diagnosis. Multiple risk factors for bipolar disorder have been identified and a population at high-risk for the disorder has been more precisely defined. These advances have allowed the development of risk calculators to predict individual risk of conversion to bipolar disorder. This review aims to identify the risk calculators for bipolar disorder and assess their clinical applicability. Methods: A systematic review of original studies on the development of risk calculators in bipolar disorder was performed. The studies' quality was evaluated with the Newcastle-Ottawa Quality Assessment Form for Cohort Studies and according to recommendations of the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis Initiative. Results: Three studies met the inclusion criteria; one developed a risk calculator of conversion from major depressive episode to bipolar disorder; one of conversion to new-onset bipolar spectrum disorders in offspring of parents with bipolar disorder; and the last one of conversion in youths with bipolar disorder not-otherwise-specified. Conclusions: The calculators reviewed in this article present good discrimination power for bipolar disorder, although future replication and validation of the models is needed.
- Personality, cognitive emotion regulation and insomniaPublication . Amaral, AP; Bos, SC; Soares, MJ; Pereira, AT; Marques, M; Madeira, N; Nogueira, V; Bajouco, M; Macedo, A
- Decrease in Stigma Towards Mental Illness in Portuguese Medical Students After a Psychiatry CoursePublication . Vilar Queirós, R; Santos, V; Madeira, NIntroduction: Stigma towards mental illness is considered a key obstacle to the provision of medical care to psychiatric patients. This is not only present in the general population but also among healthcare professionals. Therefore, medical students could be a target population for stigma prevention measures. The aim of this study is to assess the evolution of the attitudes of medical students from the Faculty of Medicine of the University of Coimbra towards psychiatric patients, before and after attending Psychology and Psychiatric courses. Material and Methods: Students from the third and fourth years of the integrated Master’s degree in Medicine in the Faculty of Medicine of the University of Coimbra were asked to complete four questionnaires. The surveys were distributed before and after the attendance of the courses. Results: There was a statistically significant decrease of the stigma scores (p = 0.025) between the two measurements (38.16 initially, 36.72 on the second moment). The baseline level of stigma was found to be negatively associated with empathy (rP = -0.477) and with the type of personality, with higher levels of openness to new experiences being associated with lower levels of initial stigma (rP= -0.357). Discussion: Overall, the students’ attitudes towards patients with mental illness were positive, with a decrease of the stigma value from the first to the second semester. This corroborates the hypothesis that education and contact with people with a mental condition could shape positive changes in attitudes and discrimination against those patients. Conclusion: Our results emphasise the importance of implementing programs inside medical schools in order to reduce stigma among future doctors.
- Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder PatientsPublication . Marques, AP; Resende, R; Silva, DF; Batista, M; Pereira, D; Wildenberg, B; Morais, S; Macedo, A; Pais, C; Melo, JB; Madeira, N; Pereira, CFThis study aims to evaluate whether mitochondrial changes occur in the early stages of bipolar disorder (BD). Using fibroblasts derived from BD patients and matched controls, the levels of proteins involved in mitochondrial biogenesis and dynamics (fission and fusion) were evaluated by Western Blot analysis. Mitochondrial membrane potential (MMP) was studied using the fluorescent probe TMRE. Mitochondrial morphology was analyzed with the probe Mitotracker Green and mitophagy was evaluated by quantifying the co-localization of HSP60 (mitochondria marker) and LC3B (autophagosome marker) by immunofluorescence. Furthermore, the activity of the mitochondrial respiratory chain and the glycolytic capacity of controls and BD patients-derived cells were also studied using the Seahorse technology. BD patient-derived fibroblasts exhibit fragmented mitochondria concomitantly with changes in mitochondrial dynamics and biogenesis in comparison with controls. Moreover, a decrease in the MMP and increased mitophagy was observed in fibroblasts obtained from BD patients when compared with control cells. Impaired energetic metabolism due to inhibition of the mitochondrial electron transport chain (ETC) and subsequent ATP depletion, associated with glycolysis stimulation, was also a feature of BD fibroblasts. Overall, these results support the fact that mitochondrial disturbance is an early event implicated in BD pathophysiology that might trigger neuronal changes and modification of brain circuitry.
- Défices Cognitivos na Perturbação Depressiva MajorPublication . Oliveira, J; Pestana-Santos, A; Madeira, N
- Inflamação na Doença Bipolar: Identificação de Novos Alvos TerapêuticosPublication . Oliveira, J; Madeira, N; Costa, MT; Pereira, CFIntrodução: A doença bipolar é um distúrbio mental com origem no conceito “mania”. Trata-se de uma patologia crónica, de natureza cíclica, caracterizada pelo aparecimento de episódios alternados de mania/hipomania com episódios de eutimia/depressão. Com este artigo pretendemos identificar novas abordagens terapêuticas para o tratamento da doença bipolar, tendo em consideração o envolvimento da inflamação na sua fisiopatologia. Métodos: Revisão da literatura que relaciona a doença bipolar com a inflamação e possíveis alvos terapêuticos, baseada em artigos de revisão. Pesquisa de ensaios clínicos que permitam avaliar as novas intervenções terapêuticas. Resultados: O tratamento farmacológico da doença bipolar é complexo, sendo periodicamente adaptado à fase de doença. Para a compreensão da fisiopatologia da doença bipolar são propostas várias hipóteses relacionadas com o processo inflamatório subjacente, como a ativação patológica da microglia, desvendando um vasto leque de alvos terapêuticos. Atualmente estão a decorrer alguns ensaios clínicos que avaliam a eficácia das novas estratégias terapêuticas. Conclusão: Distúrbios mentais como a doença bipolar têm suscitado preocupação na comunidade científica e médica devido ao seu impacto ao nível social e económico. Tendo em conta o envolvimento da inflamação na fisiopatologia da doença bipolar, o sistema imunitário constitui um novo alvo terapêutico. Assim, surgem novas opções de tratamento que incluem fármacos anti-inflamatórios não esteroides e antagonistas do glutamato. Estas novas abordagens requerem mais estudos, nomeadamente a realização de ensaios clínicos.
- Internamentos Psiquiátricos no Adulto Jovem: Um Estudo Observacional em 2006-2016Publication . Oliveira, P; Ribeiro, J; Morais, S; Santos, V; Madeira, N
- Lithium in Public Drinking Water and Suicide Mortality in Portugal: Initial ApproachPublication . Oliveira, P; Zagalo, J; Madeira, N; Neves, OINTRODUCTION: Lithium can be found naturally in drinking water. There is some evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality. The aim of this study is to evaluate if higher natural concentrations of lithium in public drinking water are associated with lower local rates of suicide in Portugal. MATERIAL AND METHODS: Suicide standardized mortality ratios at 54 Portuguese municipalities within the 6-year period from 2011 to 2016 was correlated with lithium concentrations in public drinking water and socioeconomic factors using Pearson's correlation coefficients (r) with one-tailed tests. Multivariate regression models were adjusted for well-known socioeconomic factors known to influence suicide mortality in Portugal (population density, average income per capita, unemployment rates and proportion of Roman Catholics). RESULTS: The average lithium level, as evidenced by raw values for 54 municipalities, was 10.88 μg/L (standard deviation = 27.18). There was no statistically significant correlation between lithium levels and suicide standardized mortality ratio (r = 0.001, p-value = 0.996). There was a statistically significant higher suicide standardized mortality ratio for males (p-value = 0.000). When analyzed separately for both sexes, no statistically significant correlation between suicide standardized mortality ratio and lithium levels was found (male r = 0.024, p-value = 0.862; female r = 0.000, p-value = 0.999). No association between suicide standardized mortality ratio and socioeconomic factors was found: population density (r = -0.144, p-value = 0.300), average income per capita (r = -0.112, p-value = 0.418), unemployment rates (r = -0.001, p-value = 0.994), and proportion of Roman Catholics (r =- 0.150, p-value = 0.278). DISCUSSION: Unlike most international studies regarding natural lithium levels and suicide risk, no inverse relation was found in Portugal. Factors such as the country's low suicide rate, confunding suicide risk variables, and unaccounted lithium intake might have influenced these findings. CONCLUSIONS: No association between lithium in public drinking water and suicide rates was found in Portugal.
- Morphometry and gyrification in bipolar disorder and schizophrenia: A comparative MRI studyPublication . Madeira, N; Duarte, JV; Martins, R; Costa, GN; Macedo, A; Castelo-Branco, MSchizophrenia is believed to be a neurodevelopmental disease with high heritability. Differential diagnosis is often challenging, especially in early phases, namely with other psychotic disorders or even mood disorders. such as bipolar disorder with psychotic symptoms. Key pathophysiological changes separating these two classical psychoses remain poorly understood, and current evidence favors a more dimensional than categorical differentiation between schizophrenia and bipolar disorder. While established biomarkers like cortical thickness and grey matter volume are heavily influenced by post-onset changes and thus provide limited possibility of accessing early pathologies, gyrification is assumed to be more specifically determined by genetic and early developmental factors. The aim of our study was to compare both classical and novel morphometric features in these two archetypal psychiatric disorders. We included 20 schizophrenia patients, 20 bipolar disorder patients and 20 age- and gender-matched healthy controls. Data analyses were performed with CAT12/SPM12 applying general linear models for four morphometric measures: gyrification and cortical thickness (surface-based morphometry), and whole-brain grey matter/grey matter volume (voxel-based morphometry - VBM). Group effects were tested using age and gender as covariates (and total intracranial volume for VBM). Voxel-based morphometry analysis revealed a schizophrenia vs. control group effect on regional grey matter volume (p < 0.05, familywise error correction) in the right globus pallidus. There was no group effect on white matter volume when correcting for multiple comparisons neither on cortical thickness. Gyrification changes in clinical samples were found in the left supramarginal gyrus (BA40) - increased and reduced gyrification, respectively, in BPD and SCZ patients - and in the right inferior frontal gyrus (BA47), with a reduction in gyrification of the SCZ group when compared with controls. The joint analysis of different morphometric features, namely measures such as gyrification, provides a promising strategy for the elucidation of distinct phenotypes in psychiatric disorders. Different morphological change patterns, highlighting specific disease trajectories, could potentially generate neuroimaging-derived biomarkers, helping to discriminate schizophrenia from bipolar disorder in early phases, such as first-episode psychosis patients.