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.

Reduced medial prefrontal N-acetyl-aspartate levels in pediatric major depressive disorder: a multi-voxel in vivo(1)H spectroscopy study.

There is increasing evidence of a reciprocal fronto-limbic network in the pathogenesis of mood disorders. Prior in vivo proton ((1)H) spectroscopy studies provide evidence of abnormal neurochemical levels in the cingulate and dorsolateral prefrontal cortex (DLPFC) of adult subjects with major depressive disorder (MDD). We examined whether similar abnormalities occur in children and adolescents with MDD. We collected two-dimensional multi-voxel in vivo (1)H spectroscopy data at 1.5 Tesla to quantify levels of N-acetyl-aspartate (NAA), glycerolphosphocholine plus phosphocholine (GPC+PC), and phosphocreatine plus creatine (PCr+Cr) in the DLPFC, medial prefrontal cortex (MPFC), and anterior cingulate (AC) of children and adolescents aged 8-17 years with MDD (n=16) compared with healthy control subjects (n=38). Analysis of covariance with age and gender as covariates was performed. MDD subjects showed significantly lower levels of NAA in the right MPFC and right AC than controls. MDD subjects also had significantly lower levels of GPC+PC in the right AC than control subjects. There were no significant differences in other metabolites in the studied regions. Pediatric patients with MDD exhibit neurochemical alterations in prefrontal cortex regions that are important in the monitoring and regulation of emotional states.

Assessment of personality dimensions in children and adolescents with bipolar disorder using the Junior Temperament and Character Inventory.

OBJECTIVE: We compared temperament and character traits in children and adolescents with bipolar disorder (BP) and healthy control (HC) subjects. METHOD: Sixty nine subjects (38 BP and 31 HC), 8-17 years old, were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime. Temperament and character traits were measured with parent and child versions of the Junior Temperament and Character Inventory. RESULTS: BP subjects scored higher on novelty seeking, harm avoidance, and fantasy subscales, and lower on reward dependence, persistence, self-directedness, and cooperativeness compared to HC (all p < 0.007), by child and parent reports. These findings were consistent in both children and adolescents. Higher parent-rated novelty seeking, lower self-directedness, and lower cooperativeness were associated with co-morbid attention-deficit/hyperactivity disorder (ADHD). Lower parent-rated reward dependence was associated with co-morbid conduct disorder, and higher child-rated persistence was associated with co-morbid anxiety. CONCLUSIONS: These findings support previous reports of differences in temperament in BP children and adolescents and may assist in a greater understating of BP children and adolescents beyond mood symptomatology.

Rasgos del temperamento y carácter en pacientescon trastorno bipolar y asociaciones con elalcoholismo o trastornos de ansiedad comórbidos / Temperament and character traits in patients with bipolar disorder and associations with comorbid alcoholism or anxiety disorders

Los rasgos de temperamento y carácter pueden determinar diferencias en las presentaciones clínicas y el desenlace del trastorno bipolar. Comparamos los rasgos de personalidad en pacientes bipolares e individuos sanos utilizando el cuestionario de temperamento y carácter (Temperament and Character Inventory [TCI]) y tratamos de verificar si la comorbilidad con el alcoholismo o los trastornos de ansiedad se asocia con rasgos específicos de la personalidad. Se comparó a 73 pacientes con trastorno bipolar, basado en los criterios del Diagnostic and Statistical Manual of Mental Disorders,4.a edición (DSM-IV), con 63 individuos sanos usando el TCI. En una segunda fase, la muestra de pacientes bipolares se dividió en subgrupos según la comorbilidad psiquiátrica que tuvieran (alcoholismo, n = 10; trastornos de ansiedad, n = 23; alcoholismo más trastornos de ansiedad, n = 21; ausencia de comorbilidad, n = 19). Los pacientes bipolares obtuvieron puntuaciones significativamente más altas que los individuos sanos en la búsqueda de novedades, evitación de riesgos y autotrascendencia y puntuaciones más bajas en autodirección y cooperación. Los pacientes bipolares con alcoholismo comórbido exclusivo obtuvieron puntuaciones significativamente más bajas que aquellos sin ninguna comorbilidad en la perseverancia. Los pacientes bipolares con trastornos de ansiedad comórbidos exclusivos obtuvieron puntuaciones significativamente más altas en evitación de riesgos y más bajas en autodirección que aquellos sin ninguna comorbilidad. Las limitaciones de este estudio son el diseño transversal y el reducido tamaño de la muestra, específicamente en el análisis de subgrupos. Sin embargo, los resultados indican que los pacientes bipolares manifiestan una estructura de la personalidad diferente que los individuos sanos y quela comorbilidad psiquiátrica en este trastorno se asocia con rasgos específicos de personalidad. Estos hallazgos indican que la personalidad, al menos hasta cierto punto, media el fenómeno de la comorbilidad en el trastorno bipolar (AU)

Temperament and character traits may determine differences in clinical presentations and outcome of bipolar disorder. We compared personality traits in bipolar patients and healthy individuals using the Temperament and Character Inventory (TCI) and sought to verify whether comorbidity with alcoholism or anxiety disorders is associated with specific personality traits. Seventy-three DSM-IV bipolar patients were compared to 63 healthy individuals using the TCI. In a second step, the bipolar sample was subgrouped according to the presence of psychiatric comorbidity (alcoholism, n = 10; anxiety disorders; n = 23; alcoholism plus anxiety disorders, n = 21; no comorbidity, n = 19). Bipolar patients scored statistically higher than the healthy individuals on novelty seeking, harm avoidance and self-transcendence and lower on self-directedness and cooperativeness. Bipolar patients with only comorbid alcoholism scored statistically lower than bipolar patients without any comorbidity on persistence. Bipolar patients with only comorbid anxiety disorders scored statistically higher on harm avoidance and lower on self-directedness than bipolar patients without any comorbidity. Limitations of this study include the cross-sectional design and the small sample size, specifically in the analysis of the subgroups. However, our results suggest that bipolar patients exhibit a different personality structure than healthy individuals and that presence of psychiatric comorbidity in bipolar disorder is associated with specific personality traits. These findings suggest that personality, at least to some extent, mediates the comorbidity phenomena in bipolar disorder (AU)

Conceptualizing impulsivity and risk taking in bipolar disorder: importance of history of alcohol abuse.

BACKGROUND: Elevated levels of impulsivity and increased risk taking are thought to be core features of both bipolar disorder (BD) and addictive disorders. Given the high rates of comorbid alcohol abuse in BD, alcohol addiction may exacerbate impulsive behavior and risk-taking propensity in BD. Here we examine multiple dimensions of impulsivity and risk taking, using cognitive tasks and self-report measures, in BD patients with and without a history of alcohol abuse. METHODS: Thirty-one BD subjects with a prior history of alcohol abuse or dependence (BD-A), 24 BD subjects with no history of alcohol abuse/dependence (BD-N), and 25 healthy control subjects (HC) were assessed with the Barratt Impulsiveness Scale (BIS) and the computerized Balloon Analogue Risk Task (BART). RESULTS: Both BD groups scored significantly higher than controls on the BIS. In contrast, only the BD-A group showed impaired performance on the BART. BD-A subjects popped significantly more balloons than the BD-N and HC groups. In addition, subjects in the BD-A group failed to adjust their performance after popping balloons. Severity of mood symptomatology was not associated with performance on either task. DISCUSSION: The current study supports a primary role of prior alcohol abuse in risk-taking propensity among patients with bipolar disorder. In addition, findings suggest that impulsivity and risky behavior, as operationalized by self-report and experimental cognitive probes, respectively, are separable constructs that tap distinct aspects of the bipolar phenotype.

Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: To investigate whether the cox-2 inhibitor celecoxib has antidepressant effects in bipolar disorder (BD) patients during depressive or mixed phases. METHODS: We studied 28 DSM-IV BD patients who were experiencing a depressive or mixed episode and were on a stable dose of a mood stabilizer or atypical antipsychotic medication. Subjects were randomized to receive 6 weeks of double-blind placebo or celecoxib (400 mg/day) treatment. Current mood stabilizer or antipsychotic medication remained at the same doses during the trial. RESULTS: Intention-to-treat analysis showed that the patients receiving celecoxib had lower Hamilton Depression Rating Scale (HamD) scores after 1 week of treatment compared to the patients receiving placebo, but this difference was not statistically significant (p = 0.09). The improvement in the first week of treatment was statistically significant when the analysis included only the subjects who completed the full 6-week trial (p = 0.03). The two groups did not differ significantly on depressive or manic symptoms from the second week until the end of the trial. Celecoxib was well tolerated with the exception of two subjects who dropped out of the study due to rash. CONCLUSIONS: Our findings suggest that adjunctive treatment with celecoxib may produce a rapid-onset antidepressant effect in BD patients experiencing depressive or mixed episodes.

Family environment patterns in families with bipolar children.

BACKGROUND: We studied the characteristics of family functioning in bipolar children and healthy comparison children. We hypothesized that the family environment of bipolar children would show greater levels of dysfunction as measured by the Family Environment Scale (FES). METHODS: We compared the family functioning of 36 families that included a child with DSM-IV bipolar disorder versus 29 comparison families that included only healthy children. All subjects and their parents were assessed with the K-SADS-PL interview. The parents completed the FES to assess their current family functioning. Multivariate analysis of variance was used to compare the family environment of families with and without offspring with bipolar disorder. RESULTS: Parents of bipolar children reported lower levels of family cohesion (p<0.001), expressiveness (p=0.005), active-recreational orientation (p<0.001), intellectual-cultural orientation (p=0.04) and higher levels of conflict (p<0.001) compared to parents with no bipolar children. Secondary analyses within the bipolar group revealed lower levels of organization (p=0.031) and cohesion (p=0.014) in families where a parent had a history of mood disorders compared to families where parents had no history of mood disorders. Length of illness in the affected child was inversely associated with family cohesion (r=-0.47, p=0.004). LIMITATIONS: Due to the case-control design of the study, we cannot comment on the development of these family problems or attribute their cause specifically to child bipolar disorder. CONCLUSION: Families with bipolar children show dysfunctional patterns related to interpersonal interactions and personal growth. A distressed family environment should be addressed when treating children with bipolar disorder.

Temperament and character traits in patients with bipolar disorder and associations with comorbid alcoholism or anxiety disorders.

Temperament and character traits may determine differences in clinical presentations and outcome of bipolar disorder. We compared personality traits in bipolar patients and healthy individuals using the Temperament and Character Inventory (TCI) and sought to verify whether comorbidity with alcoholism or anxiety disorders is associated with specific personality traits. Seventy-three DSM-IV bipolar patients were compared to 63 healthy individuals using the TCI. In a second step, the bipolar sample was subgrouped according to the presence of psychiatric comorbidity (alcoholism, n=10; anxiety disorders; n=23; alcoholism plus anxiety disorders, n=21; no comorbidity, n=19). Bipolar patients scored statistically higher than the healthy individuals on novelty seeking, harm avoidance and self-transcendence and lower on self-directedness and cooperativeness. Bipolar patients with only comorbid alcoholism scored statistically lower than bipolar patients without any comorbidity on persistence. Bipolar patients with only comorbid anxiety disorders scored statistically higher on harm avoidance and lower on self-directedness than bipolar patients without any comorbidity. Limitations of this study include the cross-sectional design and the small sample size, specifically in the analysis of the subgroups. However, our results suggest that bipolar patients exhibit a different personality structure than healthy individuals and that presence of psychiatric comorbidity in bipolar disorder is associated with specific personality traits. These findings suggest that personality, at least to some extent, mediates the comorbidity phenomena in bipolar disorder.

Evidence for disruption in prefrontal cortical functions in juvenile bipolar disorder.

OBJECTIVES: Systematic parsing of executive function processes is critical for the development of more specific models of neurobiological processes mediating disturbed cognition in youth with bipolar disorder (BPD). METHODS: A sample of 33 children and adolescents with bipolar I disorder (BPD I) (mean age 12.1 +/- 3.0 years, 39% female) and 44 demographically matched healthy participants (mean age 12.9 +/- 2.8 years, 50% female) completed a neurocognitive battery including measures aimed at detection of disruption in prefrontal cortical circuitry (i.e., working memory, set shifting, and rule attainment). RESULTS: Compared to healthy controls, BPD I children exhibited significant deficits in spatial working memory, visual sequencing and scanning, verbal fluency and abstract problem solving, particularly when a memory component was involved. In our spatial delayed response task, memory set size was parametrically varied; the performance pattern in BPD I children suggested deficits in short-term memory encoding and/or storage, rather than capacity limitations in spatial working memory. Earlier age at onset of illness and antipsychotic medication usage were associated with poorer performance on speeded information-processing tasks; however, severity of mood symptomatology and comorbidity with disruptive behavior disorders were not associated with task performance. CONCLUSIONS: These results suggest impairment in measures of prefrontal cortical function in juvenile BPD I that are similar to those seen in the adult form of the illness, and implicate both the ventral and dorsolateral prefrontal cortex as loci of pathology in juvenile BPD. As these deficits were not associated with clinical state or comorbidity with other disorders, they may reflect trait-related impairments, a hypothesis that will be pursued further in longitudinal studies.

Medial temporal lobe abnormalities in pediatric unipolar depression.

In vivo anatomical magnetic resonance imaging (MRI) studies in adults with major depressive disorder (MDD) have implicated neurocircuitries involved in mood regulation in the pathophysiology of mood disorders. Specifically, abnormalities in the medial temporal lobe structures have been reported. This study examined a sample of children and adolescents with major depressive disorder to investigate anatomical abnormalities in these key medial temporal brain regions. Nineteen children and adolescents with DSM-IV major depression (mean age +/- S.D.=13.0 +/- 2.4 years; 10 unmedicated) and 24 healthy comparison subjects (mean age +/- S.D.=13.9 +/- 2.9 years) were studied using a 1.5T Philips MRI scanner. We measured hippocampus and amygdala gray matter volumes. MRI structural volumes were compared using analysis of covariance with age and total brain volumes as covariates. Pediatric depressed patients had significantly smaller left hippocampal gray matter volumes compared to healthy controls (1.89 +/- 0.16 cm(3) versus 1.99 +/- 0.18 cm(3), respectively; F=5.0, d.f.=1/39, p=0.03; effect size: eta2(p) =0.11). Unmedicated depressed patients showed a trend towards smaller left hippocampal volumes compared to medicated patients and healthy subjects (F=2.8, d.f.=2/38, p=0.07; effect size: eta2(p) =0.13). There were no statistically significant differences in mean volumes for left or right amygdala. Smaller left hippocampal volumes in children and adolescents with MDD are in agreement with findings from adult studies and suggest that such abnormalities are present early in the course of the illness. Amygdala volumes are not abnormal in this age group. Smaller hippocampal volumes may be related to an abnormal developmental process or HPA axis dysfunction.

Low levels of N-acetyl aspartate in the left dorsolateral prefrontal cortex of pediatric bipolar patients.

BACKGROUND: Increasing evidence suggests abnormalities in the structure, function, and neurochemistry of the frontal cortex in pediatric bipolar (BP) patients. We conducted a single-voxel proton magnetic resonance spectroscopy ((1)H MRS) of the left dorsolateral prefrontal cortex (DLPFC) of pediatric BP patients, expecting lower N-acetyl-aspartate (NAA) levels within that brain region compared to healthy comparison subjects. METHODS: We studied 35 pediatric BP (23 BP type I, 12 BP type II; mean age +/- SD = 13.2 +/- 2.9 years; 18 females) and 36 healthy controls (mean age +/- SD = 13.7 +/- 2.6 years, 17 females). A short echo time, single-voxel (1)H spectroscopy approach point-resolved spectroscopy (PRESS) sequence, measurements of metabolites was performed on a 1.5T Philips MR system. RESULTS: BP subjects had significantly lower NAA levels in the left DLPFC compared to healthy controls (F = 4.21, df = 1, 68, p = 0.04). There was not a significant difference between groups for phosphocreatine + creatine (PCr+Cr), glycerolphosphocholine + phosphocholine (GPC + PC), myo-inositol (mI), or glutamate. Further analyses revealed a significant reduction of NAA in our early puberty group compared to controls (Mann-Whitney U-test statistic = 52.00, p = 0.014), but not for BP versus controls in other pubertal groups. CONCLUSIONS: BP subjects have lower NAA levels in the left DLPFC compared to healthy subjects, suggesting neuronal dysfunction in this region.

An open trial of adjunctive escitalopram in bipolar depression.

OBJECTIVE: This study was designed to evaluate the efficacy and safety of a highly potent and selective serotonergic antidepressant, escitalopram, in the treatment of bipolar depression. METHOD: Twenty outpatients with DSM-IV bipolar depression types I and II were enrolled in a 12-week open trial of escitalopram, 10 mg daily, adjunctive to their ongoing mood stabilizer. Assessments were carried out using the Hamilton Rating Scale for Depression (HAM-D), the Young Mania Rating Scale (YMRS), and the Clinical Global Impressions for Severity (CGI-S) and Improvement (CGI-I) scales. The study was conducted from August 2003 to February 2004. RESULTS: Escitalopram was associated with significant improvement as measured by the HAM-D total score, which showed a mean reduction from baseline (mean = 20.9, SD = 4.2) to endpoint (mean = 8.9, SD = 3.6; p < .001) of 12 points. The mean CGI-S score decreased by 3.3 points (baseline: mean = 4.8, SD = 0.7; week 12: mean = 1.5, SD = 0.6; p < .001). Adverse events emerged in 75% of the patients (N = 15), usually of mild-to-moderate severity. Four dropouts took place due to manic switch (N = 1), hypomanic symptoms (N = 2), and hospitalization due to the emergence of suicidal ideation and psychosis (N = 1). CONCLUSION: These findings suggest that escitalopram in association with mood stabilizers may be an effective and reasonably well-tolerated treatment for patients with moderate-to-severe bipolar depression. The switch rate was similar to what is described in the literature for the selective serotonin reuptake inhibitors. Randomized controlled trials of escitalopram in bipolar depression are warranted.

Fronto-limbic brain abnormalities in juvenile onset bipolar disorder.

BACKGROUND: Advances in brain imaging techniques and cognitive neuropsychology have brought new possibilities for the in vivo study of the pathophysiology of neuropsychiatric disorders, including bipolar disorder (BD). Recently, such studies have been extended to the pediatric age range. Here we review the neuroimaging and neuropsychological studies conducted in BD children and adolescents. METHODS: A review of the peer-reviewed published literature was conducted in Medline for the period of 1966 to April 2005. RESULTS: Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies suggest abnormalities in fronto-limbic structures in pediatric BD patients, similar to those found in adults. A notable exception in pediatric BD patients is smaller amygdala volumes compared to healthy controls, contrary to what has been reported in most adult studies. CONCLUSIONS: Further research evaluating children and adolescents is needed to study the normal neurodevelopmental process and to answer how and when the illness processes that result in bipolar disorder exert their effects on the developing brain.

Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients.

The dorsolateral prefrontal cortex (DLPFC) plays an essential role in mood regulation and integration of cognitive functions that are abnormal in major depressive disorder (MDD). Few neuroimaging studies have evaluated the still maturing DLPFC in depressed children and adolescents. We conducted single voxel proton magnetic resonance spectroscopy ((1)H MRS) of the left DLPFC in 14 depressed children and adolescents (13.3 +/- 2.3 years old, 10 males) and 22 matched healthy controls (13.6 +/- 2.8 years old, 13 males). Depressed subjects had significantly lower levels of glycerophosphocholine plus phosphocholine (GPC + PC; or choline-containing compounds) and higher myo-inositol levels in the left DLPFC compared to healthy controls. In the depressed subjects, we found significant inverse correlations between glutamate levels and both duration of illness and number of episodes. In healthy controls there was a significant direct correlation between age and glutamine levels, which was not present in the patient group. Lower GPC + PC levels in pediatric MDD may reflect lower cell membrane content per volume in the DLPFC. Increased myo-inositol levels in MDD may represent a disturbed secondary messenger system. GPC + PC and myo-inositol abnormalities further demonstrate the involvement of DLPFC in pediatric MDD.

Declarative memory impairment in pediatric bipolar disorder.

OBJECTIVES: Impaired verbal declarative memory has been proposed as a trait marker for adult bipolar disorder. However, similar impairments in juvenile-onset bipolar disorder have not been yet documented. Here, we assessed declarative memory in a large sample of clinically well-characterized children with bipolar disorder. METHODS: Forty-one children and adolescents with bipolar disorder [21 bipolar I disorder (BP-I), 10 bipolar II disorder (BP-II), and 10 bipolar disorder, not otherwise specified (BP-NOS)] and 17 demographically matched healthy participants completed a standardized learning and memory test. RESULTS: BP-I children recalled and recognized significantly fewer words than healthy subjects, whereas children with BP-II and BP-NOS did not differ from controls. However, individuals with BP-NOS made more perseverative errors and intrusions than the other groups. Severity of mood symptomatology was not associated with memory performance in any bipolar subtype. CONCLUSIONS: Findings suggest that declarative memory impairments in juvenile BP-I are similar to those seen in the adult form of the illness. These impairments do not appear to be secondary to clinical state; rather, they may reflect trait-related impairments. Distinct performance patterns in BP-I, BP-II, and BP-NOS suggest that the broadly defined phenotype is significantly heterogeneous, and may not be informative for pathogenetic investigations of bipolar disorder.

Anormalidades neuropatológicas e neuroquímicas no transtorno afetivo bipolar / Neuropatological and neurochemical abnormalities in bipolar disorder

OBJETIVOS: Estudos pós-mortem, farmacológicos, de neuroimagem e em modelos animais têm demonstrado uma possível associação de mecanismos de sinalização intracelular na fisiopatologia do transtorno afetivo bipolar (TAB). Esse trabalho tem como objetivo revisar os achados em neuropatologia e bioquímica celular. MÉTODOS: Foi realizada uma pesquisa ao MEDLINE, entre 1980 e 2003, tendo sido utilizados os unitermos: bipolar disorder, signaling, second messengers e postmortem, além de referências cruzadas dos artigos selecionados. RESULTADOS: uropatológicos demonstraram uma diminuição do número de células neuronais e gliais, principalmente no córtex pré-frontal de pacientes bipolares. Estudos neuroquímicos demonstraram alterações nas vias do AMPc, fosfatidilinositol, Wnt/GSK-3beta e Ca++ intracelular nesses pacientes. CONCLUSÃO: Os achados de alterações neuropatológicas e neuroquímicas no TAB podem estar relacionados com a fisiopatologia deste transtorno e com os efeitos dos estabilizadores de humor. No entanto, mais estudos são necessários para esclarecer o papel das cascatas de sinalização intracelular na patogênese deste transtorno.

[Neuropatological and neurochemical abnormalities in bipolar disorder]. / Anormalidades neuropatológicas e neuroquímicas no transtorno afetivo bipolar.

OBJECTIVES: Postmortem, pharmacological, neuroimaging, and animal model studies have demonstrated a possible association of intracellular signaling mechanisms in the pathophysiology of bipolar disorder. The objective of this paper is to review the findings in neuropathology and cellular biochemistry. METHODS: We performed a MEDLINE research, between 1980-2003, using bipolar disorder, signaling, second messengers, and postmortem as keywords, and cross-references. RESULTS: Neuropathological studies reported a decrease in neuronal and glial cells, mainly in the prefrontal cortex of bipolar patients. Neurochemical studies reported dysfunction in cAMP, phosphoinositide, Wnt/GSK-3b, and intracellular Ca++ pathways in these patients. CONCLUSION: The neuropathological and neurochemical abnormalities demonstrated in BD may be related to the pathophysiology of this disorder and the effects of mood stabilizers. However, further studies are needed to clarify the role of the intracellular signaling cascade in the pathogenesis of this disorder.