Marsal Sanches

Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder

The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age±s.d.=34.3±11.5 years) and 15 healthy comparison subjects (37.7±12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.

Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder.

BACKGROUND In vivo imaging studies in adult bipolar patients have suggested enlargement of the amygdala. It is not known whether this abnormality is already present early in the illness course or whether it develops later in life. We conducted a morphometric MRI study to examine the size of specific temporal lobe structures in adolescents and young adults with bipolar disorder and healthy control subjects, as well as their relationship with age, to examine possible neurodevelopmental abnormalities. METHODS Subjects included 16 DSM-IV bipolar patients (16 +/- 3 years) and 21 healthy controls (mean age +/- SD = 17 +/- 4 years). Measures of amygdala, hippocampus, temporal gray matter, temporal lobe, and intracranial volumes (ICV) were obtained. RESULTS There was a trend to smaller left amygdala volumes in patients (mean volumes +/- SD = 1.58 +/- .42 mL) versus control subjects (1.83 +/- .4 mL; F = 3.87, df = 1,32, p = .06). Bipolar patients did not show significant differences in right or left hippocampus, temporal lobe gray matter, temporal lobe, or right amygdala volumes (analysis of covariance, age, gender, and ICV as covariates, p > .05) compared with healthy control subjects. Furthermore, there was a direct correlation between left amygdala volumes and age (r =. 50, p = .047) in patients, whereas in healthy controls there was an inverse correlation (r = -.48, p = .03). CONCLUSIONS The direct correlation between left amygdala volumes and age in bipolar patients, not present in healthy control subjects, may reflect abnormal developmental mechanisms in bipolar disorder.

Impulsivity and bipolar disorder

Impulsivity is frequently associated with bipolar disorder (BD) during manic episodes, but may also be present in euthymic bipolar patients. Aggression is an impulsivity-related behavior also found during manic episodes. The objective of this review is to further clarify the relationship between impulsivity and BD. A search in Medline and Psycinfo databases, combined with a manual search of selected references, was conducted to identify available literature on BD and impulsivity-related features. Although few studies have directly measured impulsivity in BD, available findings suggest that impulsivity is not only state-related, but also a trait component of BD, which could represent a core feature of the illness. Further research exploring the neurobiology of the impulsivity/BD relationship may contribute to elucidate the pathophysiology and to improve the diagnosis and treatment of this severe illness.

Neurodevelopmental basis of bipolar disorder: A critical appraisal

Neurodevelopmental factors have been implicated in the pathophysiology of mental disorders. However, the evidence regarding their role in bipolar disorder is controversial. We reviewed the pertinent literature searching for evidence regarding a neurodevelopmental origin of bipolar disorder. Findings from clinical, epidemiological, neuroimaging, and post-mortem studies are discussed, as well as the implications of the available data for a better understanding of the mechanisms involved in the genesis of bipolar disorder. While some evidence exists for developmental risk factors in bipolar disorder, further research is needed to determine the precise extent of their contribution to pathogenesis. The timing and course of such developmentally mediated neurobiological alterations also need to be determined. Of particular importance for further study is the possibility that bipolar disorder may be mediated by an abnormal maturation of brain structures involved in affect regulation.

Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone.

OBJECTIVE To compare the effectiveness of intramuscular olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone as the first medication(s) used to treat patients with agitation and aggressive behavior. METHOD One hundred fifty patients with agitation caused by psychotic or bipolar disorder were randomly assigned under double-blind conditions to receive olanzapine, ziprasidone, haloperidol plus midazolam, haloperidol plus promethazine or haloperidol alone. The Overt Agitation Severity Scale, Overt Aggression Scale and Ramsay Sedation Scale were applied within 12 hours after the first dosage. RESULTS All medications produced a calming effect within one hour of administration, but only olanzapine and haloperidol reduced agitation by less than 10 points, and only olanzapine reduced aggression by less than four points in the first hour. After twelve hours, only patients treated with haloperidol plus midazolam had high levels of agitation and aggression and also more side effects. Ziprasidone, olanzapine and haloperidol alone had more stable results for agitation control, while ziprasidone, haloperidol plus promethazine and olanzapine had stable results for aggression control. CONCLUSION Olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol were effective in controlling agitation and aggression caused by mental illness over 12 hours. Although all the drugs had advantages and disadvantages, haloperidol plus midazolam was associated with the worst results in all the observed parameters.OBJETIVO: Comparar a eficacia da olanzapina, ziprasidona, haloperidol associado ao midazolam, haloperidol associado a prometazina e haloperidol isoladamente por via intramuscular como primeira escolha no tratamento de pacientes em agitacao e agressividade. METODO: Cento e cinquenta pacientes com agitacao psicomotora por transtorno psicotico ou transtorno bipolar foram recrutados para estudo duplo-cego e receberam olanzapina, ziprasidona, haloperidol associado a midazolam, haloperidol associado a prometazina ou haloperidol isoladamente. Foram aplicadas as escalas Overt Agitation Severity Scale, Overt Aggression Scale e Ramsay Sedation Scale no periodo de 12 horas apos a primeira aplicacao. RESULTADOS: Todas as medicacoes foram capazes de acalmar os pacientes apos uma hora da administracao. Apenas a olanzapina e o haloperidol reduziram a agitacao para menos de 10 pontos e apenas a olanzapina reduziu a agressividade para menos de quatro pontos nesse periodo. Doze horas depois, apenas o haloperidol com midazolam apresentou valores altos para a agitacao e agressividade, e tambem esteve relacionado com maior proporcao de efeitos colaterais. A ziprasidona, a olanzapina e o haloperidol apresentaram resultados mais estaveis para o controle da agitacao e a ziprasidona, haloperidol associado a prometazina e olanzapina para o controle da agressividade. CONCLUSAO: A olanzapina, a ziprasidona, o haloperidol associado a prometazina, o haloperidol associado ao midazolam e o haloperidol isoladamente foram efetivos no controle da agitacao e da agressividade secundaria a transtornos mentais dentro de 12 horas. Todas as drogas apresentaram vantagens e desvantagens, exceto pela associacao haloperidol e midazolam que demonstrou os piores resultados em todos os parâmetros.

Lower N-Acetyl-Aspartate Levels in Prefrontal Cortices in Pediatric Bipolar Disorder: A 1H Magnetic Resonance Spectroscopy Study

OBJECTIVE The few studies applying single-voxel ¹H spectroscopy in children and adolescents with bipolar disorder (BD) have reported low N-acetyl-aspartate (NAA) levels in the dorsolateral prefrontal cortex (DLPFC), and high myo-inositol / phosphocreatine plus creatine (PCr+Cr) ratios in the anterior cingulate. The aim of this study was to evaluate NAA, glycerophosphocholine plus phosphocholine (GPC+PC) and PCr+Cr in various frontal cortical areas in children and adolescents with BD. We hypothesized that NAA levels within the prefrontal cortex are lower in BD patients than in healthy controls, indicating neurodevelopmental alterations in the former. METHOD We studied 43 pediatric patients with DSM-IV BD (19 female, mean age 13.2 ± 2.9 years) and 38 healthy controls (19 female, mean age 13.9 ± 2.7 years). We conducted multivoxel in vivo ¹H spectroscopy measurements at 1.5 Tesla using a long echo time of 272 ms to obtain bilateral metabolite levels from the medial prefrontal cortex (MPFC), DLPFC (white and gray matter), cingulate (anterior and posterior), and occipital lobes. We used the nonparametric Mann-Whitney U test to compare neurochemical levels between groups. RESULTS In pediatric BD patients, NAA and GPC+PC levels in the bilateral MPFC, and PCr+Cr levels in the left MPFC were lower than those seen in the controls. In the left DLPFC white matter, levels of NAA and PCr+Cr were also lower in BD patients than in controls. CONCLUSIONS Lower NAA and PCr+Cr levels in the PFC of children and adolescents with BD may be indicative of abnormal dendritic arborization and neuropil, suggesting neurodevelopmental abnormalities.

Common biological mechanisms between bipolar disorder and type 2 diabetes: Focus on inflammation.

INTRODUCTION Bipolar disorder (BD) patients present a 3-5 fold greater risk of developing type 2 diabetes (T2D) compared to general population. The underlying mechanisms for the increased prevalence of T2D in BD population are poorly understood. OBJECTIVES The purpose of this review is to critically review evidence suggesting that inflammation may have an important role in the development of both BD and T2D. RESULTS The literature covered in this review suggests that inflammatory dysregulation take place among many BD patients. Such dysregulated and low grade chronic inflammatory process may also increase the prevalence of T2D in BD population. Current evidence supports the hypothesis of dysregulated inflammatory processes as a critical upstream event in BD as well as in T2D. CONCLUSIONS Inflammation may be a factor for the development of T2D in BD population. The identification of inflammatory markers common to these two medical conditions will enable researchers and clinicians to better understand the etiology of BD and develop treatments that simultaneously target all aspects of this multi-system condition.

The medial forebrain bundle as a deep brain stimulation target for treatment resistant depression: A review of published data.

INTRODUCTION Despite a wide variety of therapeutic interventions for major depressive disorder (MDD), treatment resistant depression (TRD) remains to be prevalent and troublesome in clinical practice. In recent years, deep brain stimulation (DBS) has emerged as an alternative for individuals suffering from TRD not responding to combining antidepressants, multiple adjunctive strategies and electroconvulsive therapy (ECT). Although the best site for TRD-DBS is still unclear, pilot data suggests that the medial forebrain bundle (MFB) might be a key target to accomplish therapeutic efficacy in TRD patients. OBJECTIVE To explore the anatomic, electrophysiologic, neurocognitive and treatment data supporting the MFB as a target for TRD-DBS. RESULTS The MFB connects multiple targets involved in motivated behavior, mood regulation and antidepressant response. Specific phenomenology associated with TRD can be linked specifically to the superolateral branch (sl) of the MFB (slMFB). TRD patients who received DBS-slMFB reported high response/remission rates with an improvement in functioning and no significant adverse outcomes in their physical health or neurocognitive performance. DISCUSSION The slMFB is an essential component of a network of structural and functional pathways connecting different areas possibly involved in the pathogenesis of mood disorders. Therefore, the slMFB should be considered as an exciting therapeutic target for DBS therapy to achieve a sustained relief in TRD patients. CONCLUSION There is an urgent need for clinical trials exploring DBS-slMFB in TRD. Further efforts should pursue measuring baseline pro-inflammatory cytokines, oxidative stress, and cognition as possible biomarkers of DBS-slMFB response in order to aid clinicians in better patient selection.

Family Environment and Pediatric Major Depressive Disorder

Background: The risks for depression broadly include biological and environmental factors. Furthermore, having a family member suffering from major depression is also likely to have consequences for the family environment. Further research aimed at understanding the effects of having a child with major depression on family interaction patterns is warranted. Methods: We studied 31 families with an 8- to 17-year-old child (mean age ± SD = 12.9 ± 2.7 years) who met the DSM-IV criteria for major depressive disorder (MDD) and 34 families with no mentally ill children (mean age ± SD = 12.6 ± 2.9 years) or parents. Children and their parents were assessed with the K-SADS-PL (Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime Version) interview. Parents completed the Moos Family Environment Scale (FES) to assess their perceptions of current family functioning. Data were analyzed using the nonparametric Wilcoxon-Mann-Whitney test. Results: Families of MDD children showed significantly different patterns of family functioning on FES subscales representing relationships and personal growth dimensions. The families with MDD children showed higher levels of conflict (p < 0.001) and lower levels of cohesion (p < 0.001), expressiveness (p = 0.003) and active-recreational orientation (p = 0.02) compared to the families without mentally ill children. Conclusion: Families with MDD children show a lower degree of commitment, provide less support to one another, provide less encouragement to express feelings and have more conflicts compared to families with no mentally ill children or parents. Interventions aimed at improving family dynamics may be beneficial to MDD children and their families.

Changes in the corpus callosum in women with late-stage bipolar disorder.

This study investigated the differences in corpus callosum (CC) volumes between women with early‐stage and late‐stage bipolar I (BP I) disorder using the criteria previously described in the literature.