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PubMed2005

When euthymia is just not good enough: the neuropsychology of bipolar disorder.

Bipolar disorder (BD) is a debilitating psychiatric illness that is uniquely characterized by switching between psychopathologically contrasting phases of mania and depression, often with intervening periods of euthymia. However, these periods of apparent clinical recovery (euthymia) are marked by subtle social, occupational, and cognitive impairments, profiled by recent neuropsychological investigations. Determining the cognitive changes across these three phases may help differentiate the disruptions that are mood state-dependent from those associated with underlying pathology. This article therefore critically reviews the reported neuropsychological impairments in BD and the methodological limitations facing such research. Integration of the available evidence, principally from the field of neuropsychology, when synthesized, implicates the prefrontal cortex in the etiopathogenesis of BD and posits cortical-subcortical-limbic disruption in recovered euthymic patients that manifests as cognitive dysfunction.

Bipolar Disorder↗

PubMed2006

Psychoeducational treatment for school-aged children with bipolar disorder.

Bipolar disorder (BPD) has received increasing attention from public and professional sources. Although pharmacologic treatments are considered the sine qua non in the treatment of youth with BPD, psychosocial interventions are critical to assist the child and family cope with symptoms that carry with them significant morbidity and mortality. Treatments developed to date are few in number; all are psychoeducationally based, using cognitive-behavioral and family systems interventions within a biopsychosocial framework. This paper reviews possible mediators of outcome, including caregiver concordance, children's social skills, hopelessness, and family stress. The author has developed two family-based psychoeducational interventions for the treatment of youth with BPD: multifamily psychoeducation groups (MFPG) and individual family psychoeducation (IFP). These treatments are both described and the results from a previously published randomized clinical trial (RCT) of MFPG are summarized. Then, new findings from an RCT of IFP are presented, along with preliminary pilot data from an expanded version of IFP. The paper concludes with recommendations for future research.

Adolescent↗

PubMed2005

A possible association between the -116C/G single nucleotide polymorphism of the XBP1 gene and lithium prophylaxis in bipolar disorder.

Bipolar disorder (BPD) is a severe, chronic, and life-threatening illness, and its pathogenesis remains unclear. Recently, a functional polymorphism (-116C/G) of the X-box binding protein 1 (XBP1) gene was reported to be a genetic risk factor for BPD. Moreover, the endoplasmic reticulum stress responses were impaired in cultured lymphocytes from BPD patients with the -116G allele and only valproate rescued such impairment among three major mood stabilizers. In this context, we hypothesized that BPD patients with different genotypes respond differently to mood stabilizers. We investigated the association between the -116C/G polymorphism of the XBP1 gene and lithium response in Japanese patients with BPD. We found that lithium treatment is more effective among BPD patients with the -116C allele carrier than in patients homozygous for the -116G allele. The association between the -116C/G polymorphism and clinical efficacy of mood stabilizers should be further investigated in a prospective study with a larger sample.

Adult↗

PubMed2005

Circadian genes and bipolar disorder.

Bipolar disorder (BD) is a chronic, potentially disabling illness with a lifetime morbid risk of approximately 1%. There is substantial evidence for a significant genetic etiology, but gene-mapping efforts have been hampered by the complex mode of inheritance and the likelihood of multiple genes of small effect. In view of the complexity, it may be instructive to understand the biological bases for pathogenesis. Extensive disruption in circadian function is known to occur among patients in relapse. Therefore, it is plausible that circadian dysfunction underlies pathogenesis. Evidence for such a hypothesis is mounting and is reviewed here. If circadian dysfunction can be established as an 'endophenotype' for BD, this may not only enable identification of more homogenous sub-groups, but may also facilitate genetic analyses. For example, it would be logical to investigate polymorphisms of genes encoding key proteins that mediate circadian rhythms. Association studies that analyzed circadian genes in BD have been initiated and are reviewed. Other avenues for research are also discussed.

ARNTL Transcription Factors↗

PubMed2004

Pharmacogenetics and bipolar disorder.

Bipolar disorder (BD) is a major psychiatric condition that commonly requires prophylactic and episodic treatment. There is important variability in the therapeutic response and side-effect profiles to currently available pharmacological agents. Pharmacogenetics have provided new hopes to develop more efficient treatment strategies tailored to the individual patient's needs. This review assesses nonsystematically studies using pharmacogenetic strategies in BD. Most of these studies have focused on patients selected according to lithium response, and more recently, a growing number of studies have been investigating genetic factors in mixed samples of patients classified according to response to antidepressant treatment. Although previous clinical and family studies support the use of pharmacogenetic strategies both to increase phenotype homogeneity as well as to identify genetic factors that may mediate response to treatment, most molecular studies carried out to date are still preliminary and in need of external validation. A major problem has been comparability between studies, in part, because of differences in the criteria used to define response. More attention should be paid to standardize the criteria for drug response definition.

Antidepressive Agents↗

PubMed2004

Perspectives for the development of animal models of bipolar disorder.

Bipolar disorder (BD) has been a particularly challenging illness for the development of adequate animal models for neurobiological studies. These difficulties are largely related to the peculiar clinical characteristics of this illness, with an intriguing alternation of mania, depression, euthymia, and mixed states. The etiology and brain mechanisms involved in this several mental illness remain unknown. Preclinical studies with animal models of mania or depression have been developed to evaluate the potential efficacy of new psychotropic drugs and generate information concerning the biochemical effects of these drugs on specific targets. These models try to mimic the behavioral components of mania and depression in human subjects and examine the pharmacological responses and mechanisms of action of potentially new therapeutic agents. The main limitation is that there is currently no model that would mimic mood cyclicity, which is a hallmark feature of BD. Thus, these models do not represent valid paradigms for the study of this illness, because they do not address key questions regarding cyclicity. In this review, we propose that new genetics approaches involving potential animal models of BD are a promising new area for further development.

Animals↗

PubMed2003

Association of a new polymorphism in ALOX12 gene with bipolar disorder.

Bipolar disorder (BPD) is characterised by episodes of excitement interspersed with periods of depression. The role of genetic factors in BPD is indicated by studies in monozygotic twins showing 40-70 % of concordance. Studies using genetic markers showed linkage of genes for affective disorders in different chromosome regions, emphasising the polygenic and multifactorial traits. The main goal of our research is to search non-synonymous SNPs (those that result in modifications in protein sequence) in genes that can be associated with psychiatric diseases as suggested by genomic mapping and/or by physiological function of the protein. Using DNA sequencing we could confirm a new non-synonymous SNP in the conservative domain of the ALOX12 gene (17p13.1), suggested by EST alignment. This SNP is an alteration from G to A that leads to a change of an arginine (A) to a glutamine in one of the most important domains of the protein. This SNP was evaluated by DNA sequencing in 182 patients with BPD and 160 control individuals. An increased presence of allele A among patients (60 % in controls and 73.1 % in cases; chi(2) = 6.581, P = 0.010; OR = 1.8095, 95 % CI = 1.1477-2.853) was found, suggesting an association of this polymorphism with the BPD in this Brazilian sample.

Adolescent↗

PubMed2018

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Adult↗

PubMed2004

[Genetics of bipolar disorder].

Bipolar disorder (BD) is a worldwide highly prevalent mental disease. This disorder has a genetic inheritance characterized by complex transmission mechanisms involving multiple genes. Many investigation strategies have been put forward in order to identify BD susceptibility genes. Linkage studies reveal markers and candidate genes for the association studies. Monoaminergic system genes and intracellular signaling pathway genes are also important candidates to be investigated in the etiology of this disorder. Recent techniques of gene expression mapping suggest novel genes whose mutations may be responsible for BD. Due to the complexity of the transmission pattern for BD and its phenotypic heterogeneity many difficulties have emerged to exactly define bipolar susceptibility genes. There is currently only preliminary results of genes associated with BD. However, the increasing understanding of gene expression regulation by epigenetic mechanisms and the dimensional approach to mental disorders can give directions for further research in psychiatric genetics.

Bipolar Disorder↗

PubMed2003

An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder.

BACKGROUND: Despite the increasing recognition of comorbid attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) in adults, there are no prospective trials of pharmacological agents to treat ADHD in these patients. Given the efficacy of bupropion for ADHD in adults, as well as its use in the management of bipolar depression, we studied the tolerability and efficacy of sustained-release (SR) bupropion in adults with ADHD plus BPD. METHODS: This was an open, prospective, 6-week trial of bupropion SR (up to 200 mg b.i.d.) in adults with DSM-IV ADHD plus historical bipolar I disorder (BPD I) (10%) or bipolar II disorder (BPD II) (90%). Adults receiving adjunct antimanic agents (mood stabilizers and antipsychotics) at baseline were included in the study. We used standardized psychiatric instruments for diagnosis and outcome. Efficacy was based primarily on the Clinical Global Impression Scale (CGI) for ADHD and the ADHD symptom checklist. RESULTS: Of 36 patients entered (75% male, mean age 34 years), 30 patients (83%) completed the protocol. At end point (last observation carried forward [LOCF]) compared to baseline, treatment with bupropion SR resulted in significant reductions in the ADHD symptom checklist (-55%, z = 5.63, p <.001) and CGI severity of ADHD (-40%, z = 6.285, p <.001). Bupropion was associated with reductions in ratings of mania and depression. CONCLUSIONS: The results from this open study of adults with ADHD plus BPD suggest that sustained-release bupropion may be effective in treating ADHD in the context of a lifetime diagnosis of BPD, without significant activation of mania. Further controlled trials are warranted.

Adult↗

PubMed1995

Comorbidity of obsessive compulsive disorder in bipolar disorder.

The comorbidity of OCD and bipolar disorder has not been systematically examined. Therefore, we determined the frequency of patients meeting DSM-III criteria for OCD syndrome in a sample of 149 inpatients with DSM-III major affective disorder who had received a clinically reviewed structured diagnostic interview. The frequency of OCD syndrome was not significantly different between subjects with major depression (35.2%, n = 105) and bipolar disorder (35.1%, n = 37). This suggests that OCD is equally common in bipolar as in unipolar patients.

Adult↗

PubMed2006

Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

ARNTL Transcription Factors↗

PubMed2003

Possible role of 3'(2')-phosphoadenosine-5'-phosphate phosphatase in the etiology and therapy of bipolar disorder.

Bipolar affective disorder (BPD) is a multifactorial, severe, chronic and disabling illness with 50% heritability that affects 1-2% of the population. Lithium ions (Li) are the drug of choice for BPD. Yet, 20-40% of patients fail to respond to Li. Although numerous biochemical and cellular effects have been attributed to Li, its therapeutic mechanism of action has not been elucidated. This review presents the possible involvement of 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase in the etiology of bipolar disorder and the mechanism of action of Li. Of the enzymes inhibited by Li, PAP phosphatase is inhibited with the lowest Ki (0.3 mM). At therapeutic concentrations of Li (0.5-1.5 mM), inhibition is greater than 80%. Therefore, PAP phosphatase is a strong candidate for Li's therapeutic mechanism of action. In yeast, a PAP phosphatase knockout mutation leads to the accumulation of PAP, which affects ribosomal-, transfer- and small nucleolar-RNA processing. PAP accumulation in the mammalian brain following Li inhibition of PAP phosphatase may very well account for the observed effects of Li on gene expression and behavior. Furthermore, we have reported significant changes in PAP phosphatase levels in postmortem frontal cortex of bipolar patients.

Adenine Nucleotides↗

PubMed1989

Bipolar disorder.

Bipolar illness is a serious heritable mood disorder characterized by recurrent episodes of depression and mania. The mean age of onset is under 25 years of age, but the period of risk extends from prepuberty to senescence. Fifteen percent of persons with the disorder commit suicide. Bipolar disorder carries an increased risk of cardiovascular disease.

Bipolar Disorder↗

PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Bipolar Disorder↗

PubMed1999

Antiretroviral antibodies: implications for schizophrenia, schizophrenia spectrum disorders, and bipolar disorder.

BACKGROUND: Some retroviral antigens share structural homology within a group of related retroviruses. It is possible that antibodies directed against one virus may cross-react with antigens from a different virus in the group. METHODS: Using this principle, the human immunodeficiency virus 1 (HIV-1) Western blot assay was used as an available source of human retroviral antigens to screen serum samples from an archived collection to ascertain whether there was an association between serum antiretroviral antibodies and mental illnesses. RESULTS: A statistically significant proportion (28/54, 52%) of patients suffering from psychiatric disorders had serum antibodies that recognized at least one antigen present on the blot, culminating in indeterminate HIV-1 tests. The majority of the reactive samples were directed against the HIV-1 group antigens p24 and p17. These findings contrast with those of nonpsychiatric patients, who had 4/16 (25%) indeterminate blots. CONCLUSIONS: The results suggest exposure to retroviral antigens related to those of HIV-1 in subpopulations of schizophrenic, schizophrenic spectrum disorder, and bipolar disorder patients.

Antibodies, Viral↗

PubMed2006

Comorbidity of eating disorders with bipolar disorder and treatment implications.

OBJECTIVES: To review the scientific evidence examining the comorbidity among eating disorders and bipolar disorder (BD). METHODS: We reviewed all published English-language studies addressing the comorbidity of anorexia nervosa, bulimia, bulimia nervosa, and binge eating disorder in patients with BD and studies of comorbidity of BD in patients with eating disorders. In addition, we discuss the pharmacologic treatment implications from reviewed studies of agents used in BD and eating disorders. RESULTS: Community and clinical population studies of the lifetime prevalence rates of eating disorders in patients with BD, and of BD in patients with eating disorders, particularly when subthreshold and spectrum manifestations of these disorders are included, indicate high rates of comorbidity among these illnesses. CONCLUSIONS: Pharmacologic treatment approaches to patients with BD and a co-occurring eating disorder require examination of the possible adverse effects of the treatment of each syndrome on the other and attempts to manage both syndromes with agents that might be beneficial to both.

Antidepressive Agents↗

PubMed2004

Prospective study of clinical predictors of suicidal acts after a major depressive episode in patients with major depressive disorder or bipolar disorder.

OBJECTIVE: The authors investigated the predictive potential of a stress-diathesis model for suicidal behavior based on correlates of past suicidal acts. In this model, suicidal acts are precipitated by stressors such as life events or a major depressive episode in the setting of a propensity for acting on suicidal urges. This diathesis is expressed as the tendency to develop more pessimism in response to a stressor and/or the presence of aggressive/impulsive traits. The predictive potential of the diathesis was tested by determining whether clinical correlates of past suicidal behavior predict suicidal acts during a 2-year follow-up of patients with a major depressive episode. METHOD: Patients with DSM-III-R major depressive disorder or bipolar disorder (N=308) were assessed at presentation for treatment of a major depressive episode. Potential predictors of suicidal acts in the 2 years after study enrollment were identified on the basis of an association with previous suicidal behavior and were tested by using Cox proportional hazards regression analysis. In addition, pessimism and aggression/impulsivity factors were generated, and their predictive ability was tested by using Cox proportional hazards regression analysis. RESULTS: The three most powerful predictors of future suicidal acts were a history of suicide attempt, subjective rating of the severity of depression, and cigarette smoking, each of which had an additive effect on future risk. The pessimism and aggression/impulsivity factors both predicted suicidal acts, and each factor showed an additive effect. CONCLUSIONS: In addition to obtaining a history of suicidal behavior, clinicians may find it useful to assess patients' current level of pessimism, aggressive/impulsive traits, and comorbidity with substance use disorders, including nicotine-related disorders, to help identify patients at risk for suicidal behavior after major depression. Interventions such as aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptoms may protect such at-risk individuals from future suicidal behavior.

Adult↗