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Tracking down the Footprints of Bipolar Disorder
(Released June 2005)

 
  by Jennifer A. Phillips  

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  1. Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation

    Hamid Mostafavi Abdolmaleky, Cassandra L. Smith and Stephen V. Faraone, et al.

    Am.J.Med.Genet.B., Vol. 127B, No. 1. pp. 51-59. , 2004.

    Fine-tuning of neuronal connections during development is regulated through environmental interactions. Some fine-tuning occurs through changes in gene expression and/or epigenetic gene-specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S-adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short-term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene-specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi-factorial psychiatric disorders. For example, l-methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This gene's protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimer's disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system.

  2. Association study of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and childhood-onset mood disorders

    Jennifer H. Adams, Karen G. Wigg and Nicole King, et al.

    Am.J.Med.Genet.B., Vol. 132B, No. 1. pp. 90-95. , 2005.

    Childhood-onset mood disorders (COMD) are often familial, and twin studies of COMD provide compelling evidence that genetic factors are involved. Deficits in neural plasticity have been suggested to underlie the development of depression. The receptor tropomyosin related kinase B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF), play essential roles in neural plasticity, and mRNA expression of both of these genes has been shown to be influenced by stress and chronic antidepressant treatment. In addition, TrkB knock-out mice display inappropriate stress coping mechanisms. Having previously shown that BDNF is associated with COMD, in this study we investigated the gene encoding TrkB, neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) as a susceptibility factor in COMD. We tested for association of NTRK2 with COMD in two independent samples: (a) a case-control sample matched on ethnicity and gender, consisting of 120 cases who met DSM III/ IV criteria for major depressive or dysthymic disorder before age 14 or bipolar I/ II before the age of 18, and controls, and (b) a family based control sample of 113 families collected in Hungary, identified by a proband between the age of 7 and 14 who met DSM IV criteria for major depressive disorder or bipolar I/ II disorder. There was no evidence for an allelic or genotypic association of three polymorphisms of NTRK2 with COMD in the case-control sample. Also, in the family based sample, using the transmission disequilibrium test (TDT), we did not identify any evidence of allelic association for each marker individually or when haplotypes were analyzed. Based on these results, using these three polymorphisms, we do not find support for NTRK2 as a susceptibility gene for COMD.

  3. Association study of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and childhood-onset mood disorders

    Jennifer H. Adams, Karen G. Wigg and Nicole King, et al.

    Am.J.Med.Genet.B., Vol. 132B, No. 1. pp. 90-95. , 2005.

    Childhood-onset mood disorders (COMD) are often familial, and twin studies of COMD provide compelling evidence that genetic factors are involved. Deficits in neural plasticity have been suggested to underlie the development of depression. The receptor tropomyosin related kinase B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF), play essential roles in neural plasticity, and mRNA expression of both of these genes has been shown to be influenced by stress and chronic antidepressant treatment. In addition, TrkB knock-out mice display inappropriate stress coping mechanisms. Having previously shown that BDNF is associated with COMD, in this study we investigated the gene encoding TrkB, neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) as a susceptibility factor in COMD. We tested for association of NTRK2 with COMD in two independent samples: (a) a case-control sample matched on ethnicity and gender, consisting of 120 cases who met DSM III/ IV criteria for major depressive or dysthymic disorder before age 14 or bipolar I/ II before the age of 18, and controls, and (b) a family based control sample of 113 families collected in Hungary, identified by a proband between the age of 7 and 14 who met DSM IV criteria for major depressive disorder or bipolar I/ II disorder. There was no evidence for an allelic or genotypic association of three polymorphisms of NTRK2 with COMD in the case-control sample. Also, in the family based sample, using the transmission disequilibrium test (TDT), we did not identify any evidence of allelic association for each marker individually or when haplotypes were analyzed. Based on these results, using these three polymorphisms, we do not find support for NTRK2 as a susceptibility gene for COMD.

  4. A linkage study between the GABAA beta2 and GABAA gamma2 subunit genes and major psychoses

    Ambrosio A.M., Kennedy J.L. and Macciardi F., et al.

    CNS spectrums, Vol. 10, No. 1. pp. 57-61. Jan, 2005.

    BACKGROUND: Alterations of the gamma-aminobutyric acid (GABA) system have been implicated in the pathophysiology of major psychoses. OBJECTIVE: Restriction fragment length polymorphisms associated with the human gamma-aminobutyric acid type A (GABAA) beta2 and GABAA gamma2 subunit genes on chromosome 5q32-q35 were tested to determine whether they confer susceptibility to major psychoses. METHODS: Thirty-two schizophrenic families and 25 bipolar families were tested for linkage. Results: Nonparametric linkage (NPL) analysis performed by GENEHUNTER showed no significant NPL scores for both genes in schizophrenia (GABAA beta2: NPL narrow= -0.450; NPL broad= -0.808; GABAA gamma2: NPL narrow=0.177; NPL broad= -0.051) or bipolar disorder (GABAA beta2: NPL narrow=0.834; NPL broad=0.783; GABAA gamma2: NPL narrow= -0.159; NPL broad=0.070). CONCLUSION: Linkage analysis does not support the hypothesis that variants within the GABAA beta2 and GABAA gamma2 genes are significantly linked to major psychoses in a Portuguese population.

  5. Schema-focused cognitive therapy for bipolar disorder: Reducing vulnerability to relapse through attitudinal change

    Jillian Ball, Philip Mitchell, Gin Malhi, Ashleigh Skillecorn and Meg Smith.

    Australian & New Zealand Journal of Psychiatry, Vol. 37, No. 1. pp. 41-48. Feb, 2003.

    A new model is presented highlighting the role of developmental experiences and temperament in determining reactions to bipolar disorder. The authors propose that by addressing reactions to the illness experiences and effects on self-concept through schema-focused cognitive therapy, functional recovery is more likely to occur among those patients functioning below expectation. A literature review was conducted, focusing on risk factors, cognitive vulnerabilities and triggers associated with bipolar disorder. Psychological treatments available for the treatment of bipolar disorder are reviewed and details of a novel schema-focused cognitive model for this condition are presented. Schema-focused cognitive therapy is proposed as an approach to help patients reduce cognitive vulnerability to relapse in addition to adopting effective mood management strategies. There is a need for psychological treatments which reduce the risks associated with poor functionality in patients with bipolar disorder. Schema-focused cognitive therapy specifically targets the temperament, developmental experiences and cognitive vulnerabilities that determine adjustment to illness. This proposed treatment, combined with pharmacotherapy, may offer new psychotherapeutic options for the future. (PsycINFO Database Record (c) 2004 APA, all rights reserved)

  6. Ticks and Lyme disease

    Clive E. Bennett.

    Advances in Parasitology 36 1995: 343-405, Vol. , No. . pp. . , 1995.

  7. Are measures of hypomanic personality, impulsive nonconformity and rigidity predictors of bipolar symptoms?

    Blechert J. and Meyer T.D.

    The British journal of clinical psychology / the British Psychological Society, Vol. 44, No. Pt 1. pp. 15-27. Mar, 2005.

    OBJECTIVES: It has been suggested that temperaments such as 'hypomanic personality' (HYP) have an explanatory role in affective disorders. Similarly, the impulsive nonconformity scale, originally designed to assess psychosis proneness, was recently found to augment the prediction of manic episodes. Conversely, research indicates that 'rigidity', a central feature of Typus Melancholicus (TMEL; von Zerssen, 1996), may characterize the premorbid personality of depressives. DESIGN: The present study combines these three scales to prospectively predict manic and depressive symptoms diagnosed 2 years later in a non-college student population. METHOD: Structured clinical interviews for DSM-IV were conducted with 114 individuals (60% female, mean age = 19 . 9 years), 2 years after an initial screening.RESULTS: It was found that none of the predictors predicted purely depressive symptoms. As expected, HYP emerged as the strongest predictor of (hypo-)manic symptoms. CONCLUSIONS: While rigidity did not predict depression, people with a hypomanic temperament are at risk of developing symptoms of bipolar disorder, especially (hypo-)manic ones. It is noteworthy that this was evident in our young sample, still in the earlier stages of the high-risk period.

  8. Lyme disease: Review from a Canadian perspective

    D. R. Burdge and D. O'Hanlon.

    Can.Fam.Physician, Vol. 38, No. . pp. 1426-1432. , 1992.

    Lyme borreliosis is an infectious disease caused by the tick-transmitted spirochete Borrelia burgdorferi. To date, the only known endemic focus of Lyme disease in Canada is Long Point, Ont. A national case definition for surveillance purposes, consensus statement regarding laboratory diagnosis, and treatment guidelines have recently been developed in an attempt to standardize the approach to surveillance, diagnosis, and management of Lyme borreliosis in Canada. (DBO)

  9. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system

    Cantorna M.T., Zhu Y., Froicu M. and Wittke A.

    The American journal of clinical nutrition, Vol. 80, No. 6 Suppl. pp. 1717S-20S. Dec, 2004.

    Vitamin D is an important immune system regulator. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to inhibit the development of autoimmune diseases, including inflammatory bowel disease (IBD). Paradoxically, other immune system-mediated diseases (experimental asthma) and immunity to infectious organisms were unaffected by 1,25(OH)2D3 treatment. There are similar paradoxical effects of vitamin D deficiency on various immune system functions. Vitamin D and vitamin D receptor (VDR) deficiency resulted in accelerated IBD. Experimental asthma was unaffected by 1,25(OH)2D3 treatment and was less severe among VDR-deficient mice. Vitamin D is a selective regulator of the immune system, and the outcome of 1,25(OH)2D3 treatment, vitamin D deficiency, or VDR deficiency depends on the nature of the immune response (eg, infectious disease, asthma, or autoimmune disease). An additional factor that determines the effect of vitamin D status on immune function is dietary calcium. Dietary calcium has independent effects on IBD severity. Vitamin D-deficient mice on low-calcium diets developed the most severe IBD, and 1,25(OH)2D3 treatment of mice on low-calcium diets improved IBD symptoms. However, the best results for IBD were observed when the calcium concentration was high and 1,25(OH)2D3 was administered. Both the type of immune response and the calcium status of the host determine the effects of vitamin D status and 1,25(OH)2D3 on immunity.

  10. Is there a relationship between Wolfram syndrome carrier status and suicide?

    Crawford J., Zielinski M.A., Fisher L.J., Sutherland G.R. and Goldney R.D.

    American journal of medical genetics, Vol. 114, No. 3. pp. 343-346. Apr 8, 2002.

    Wolfram syndrome (WFS) is a rare, autosomal recessive neurodegenerative disorder. An increased risk of psychiatric disorders and suicide has been reported for heterozygote carriers. In this study we investigated whether mutations in the WFS gene are associated with suicide in the general population. The gene for WFS (WFS1) has recently been mapped to chromosome 4p16.1, and its genomic structure has been characterized. We screened the entire WFS1 ORF in a panel of 100 completed suicides, 60 blood donors not known to have psychiatric illness, and 100 donors with a negative history of depression or suicidal behavior. We did not find evidence of an increased incidence of WFS carriers in the suicide panel and concluded that WFS1 carrier status is not a significant contributor to suicide in the general population. Screening of this highly polymorphic gene resulted in the detection of 33 variants, 13 of which cause amino acid changes. Seven of these changes have not been previously reported and six were unique to our suicide panel. (Copyright 2002 Wiley-Liss, Inc.)

  11. Screening for bipolar disorder in a primary care practice

    Das A.K., Olfson M. and Gameroff M.J., et al.

    JAMA : the journal of the American Medical Association, Vol. 293, No. 8. pp. 956-963. Feb 23, 2005.

    CONTEXT: Bipolar disorder consists of episodes of manic and depressive symptoms. Efforts to screen for depression in a primary care setting without assessment of past manic symptoms can lead to incorrect diagnosis and treatment of bipolar disorder. OBJECTIVES: To screen for bipolar disorder in adult primary care patients and to examine its clinical presentation and effect on functioning. DESIGN, SETTING, AND PARTICIPANTS: A systematic sample of 1157 patients between 18 and 70 years of age who were seeking primary care at an urban general medicine clinic serving a low-income population. The study was conducted between December 2001 and January 2003. MAIN OUTCOME MEASURES: Prevalence of bipolar disorder, its treatment and patient functioning. Study measures included the Mood Disorder Questionnaire, the PRIME-MD Patient Health Questionnaire, the Medical Outcomes Study 12-Item Short Form health survey, the Sheehan Disability Scale, data on past mental health treatments, and a review of medical records and International Classification of Diseases, Ninth Revision codes for each visit dating from 6 months prior to the screening day. RESULTS: The prevalence of receiving positive screening results for lifetime bipolar disorder was 9.8% (n = 112; 95% confidence interval, 8.0%-11.5%) and did not differ significantly by age, sex, or race/ethnicity. Eighty-one patients (72.3%) who screened positive for bipolar disorder sought professional help for their symptoms, but only 9 (8.4%) reported receiving a diagnosis of bipolar disorder. Seventy-five patients (68.2%) who screened positive for bipolar disorder had a current major depressive episode or an anxiety or substance use disorder. Of 112 patients, only 7 (6.5%) reported taking a mood-stabilizing agent in the past month. Primary care physicians recorded evidence of current depression in 47 patients (49.0%) who screened positive for bipolar disorder, but did not record a bipolar disorder diagnosis either in administrative billing or the medical record of any of these patients. Patients who screened positive for bipolar disorder reported worse health-related quality of life as well as increased social and family life impairment compared with those who screened negative. CONCLUSIONS: In an urban general medicine clinic, a positive screen for bipolar disorder appears to be common, clinically significant, and underrecognized. Because of the risks associated with treating bipolar disorder with antidepressant monotherapy, efforts are needed to educate primary care physicians about the screening, management, and pharmacotherapy of bipolar disorders.

  12. Polymorphisms in the Trace Amine Receptor 4 (TRAR4) Gene on Chromosome 6q23.2 Are Associated with Susceptibility to Schizophrenia

    J. Duan, M. Martinez and A. R. Sanders, et al.

    Am.J.Hum.Genet., Vol. 75, No. 4. pp. 624-638. Oct, 2004.

    Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia - and, more recently, for bipolar disorder - on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P = .0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples.

  13. Molecular diagnosis of Lyme disease: review and meta-analysis

    Dumler J.S.

    Molecular diagnosis : a.journal devoted to.the understanding of human disease through the clinical application of molecular biology, Vol. 6, No. 1. pp. 1-11. Mar, 2001.

    The diagnosis of Lyme disease is difficult because tests that reflect active disease or have reasonable sensitivity and specificity are lacking or not timely. Molecular methods are controversial because of differences in assays, gene targets, and limited clinical validation. This review summarizes published assays for Lyme disease diagnosis using skin, plasma, synovial fluid, cerebrospinal fluid (CSF), and urine. Meta-analyses show the strengths and weaknesses of these methods. Overall, assays for skin and synovial fluid (68% and 73%, respectively) have high sensitivity and uniformity. The low test sensitivity of CSF (18%) and plasma (29%), variable sensitivities among CSF and urine assays, and persistence of Borrelia burgdorferi DNA in urine and synovial fluid even with therapy and convalescence make these unsuitable for primary diagnosis. Molecular assays for Lyme disease are best used with other diagnostic methods and only in situations in which the clinical probability of Lyme disease is high.

  14. Good diagnoses require good diagnosticians: collecting and integrating the data

    Endicott J.

    American journal of medical genetics, Vol. 105, No. 1. pp. 48-49. Jan 8, 2001.

    The use of sets of diagnostic criteria and excellent structured clinical interviews will not result in data that is adequate for valid diagnoses or for dimensional measures if the rater collecting the data does not have adequate clinical skills. In the absence of biological measures or tests we are dependent on the rater's diagnostic and interviewing skills-both with subjects about themselves and with family informants asked to provide information about others. Best estimate diagnosticians (who usually have more experience and training) cannot compensate for inadequate or incorrect information and may even be misled by the information provided to them. In reviewing videotaped interviews sent by trained and experienced raters who were seeking certification, approximately 40% of the raters were judged to have failed to conduct an adequate diagnostic evaluation. Principal Investigators should make every effort to assure that their diagnostic data is being collected by experienced and well-trained professional raters and that the raters' ongoing work is subjected to close supervision and review.

  15. Good diagnoses require good diagnosticians: collecting and integrating the data

    Endicott J.

    American journal of medical genetics, Vol. 105, No. 1. pp. 48-49. Jan 8, 2001.

    The use of sets of diagnostic criteria and excellent structured clinical interviews will not result in data that is adequate for valid diagnoses or for dimensional measures if the rater collecting the data does not have adequate clinical skills. In the absence of biological measures or tests we are dependent on the rater's diagnostic and interviewing skills-both with subjects about themselves and with family informants asked to provide information about others. Best estimate diagnosticians (who usually have more experience and training) cannot compensate for inadequate or incorrect information and may even be misled by the information provided to them. In reviewing videotaped interviews sent by trained and experienced raters who were seeking certification, approximately 40% of the raters were judged to have failed to conduct an adequate diagnostic evaluation. Principal Investigators should make every effort to assure that their diagnostic data is being collected by experienced and well-trained professional raters and that the raters' ongoing work is subjected to close supervision and review.

  16. Bipolar disorder: I. Temperament and character

    Engstrom C., Brandstrom S., Sigvardsson S., Cloninger R. and Nylander P.O.

    Journal of affective disorders, Vol. 82, No. 1. pp. 131-134. Oct 1, 2004.

    BACKGROUND: The nature of the relationship between personality and bipolar affective disorders is an important but unanswered question. METHODS: We have studied personality in bipolar patients by using the Temperament and Character Inventory (TCI). TCI were administered to 100 euthymic bipolar patients and 100 controls from the normal population. RESULTS: Bipolar patients were significantly higher in harm avoidance (HA) and lower in reward dependence (RD), self-directedness (SD), and cooperativeness (CO) than controls. Bipolar patients are more fatigable, less sentimental, more independent, less purposeful, less resourceful, less empathic, less helpful, less pure-hearted, and have less impulse control than controls. Bipolar II patients are more impulsive, more fatigable, less resourceful, and have less impulse control than bipolar I patients. LIMITATIONS: Our results are limited to euthymic bipolar patients and cannot be generalized to affective disorders. CONCLUSIONS: Even when clinically euthymic on lithium maintenance, bipolar patients continue to have a characteristic cognitive deficit. This is in agreement with cognitive theories about cognitive deficits in depression that are regarded as important vulnerability factors in mood disorders.

  17. A genome-wide search for risk genes using homozygosity mapping and microarrays with 1,494 single-nucleotide polymorphisms in 22 eastern Cuban families with bipolar disorder

    H. Ewald, F. P. Wikman and B. M. Teruel, et al.

    Am.J.Med.Genet.B., Vol. 133B, No. 1. pp. 25-30. , 2005.

    Homozygosity mapping is a very powerful method for finding rare recessive disease genes in monogenic disorders and may also be useful for locating risk genes in complex disorders, late onset disorders where parents often are not available, and for rare phenotypic subgroups. In the present study, homozygosity mapping was applied to 24 persons with bipolar disorder from 22 inbred families. The families were selected irrespective of whether other affected family members were present or not. A genome wide screen using genotypes from only a single affected person in each family was performed using the AFFYMETRIX GeneChip HuSNP Mapping Assay, which contains 1,494 single nucleotide polymorphisms. At chromosome 17q24-q25 a parametric multipoint LOD score of 1.96 was found at WIAF-2407 and WIAF-2405. When analyzing 19 additional microsatellite markers on chromosome 17q the maximum parametric multipoint LOD score was 2.08, 1.5 cM proximal to D17S668. The present study replicates a recent significant linkage finding.

  18. Neurocognitive function in unaffected firstdegree relatives of patients with bipolar disorder: A preliminary report

    I. Nicol Ferrier, Rumana Chowdhury, Jill Maria Thompson, Stuart Watson and Allan H. Young.

    Bipolar Disord., Vol. 6, No. 4. pp. 319-322. Aug, 2004.

    Objective: Patients with remitted bipolar disorder (BD) have persistent impairments in neuropsychological function, particularly in the domains of executive control and declarative memory [Br J Psychiatry 180 (2002) 293]. If these were the phenotypic expression of genetic vulnerability to BD, then healthy subjects with a genetic predisposition to BD would be expected to display the same deficits. This study, therefore, examined neuropsychological function in healthy first-degree relatives of patients with BD. Method: A cross-sectional design was employed to compare the performance of 17 unaffected first-degree relatives of BD patients and 17 demographically matched controls on a range of neuropsychological tests. Results: Relatives were significantly impaired on Backward Digit Span, Spatial Span and on tasks of visuospatial declarative memory in comparison with controls. Psychomotor performance and verbal declarative memory were intact, as were non-working memory aspects of executive performance. Conclusion: The selective deficits in executive control and declarative memory exhibited by relatives in this study have previously been reported in euthymic BD patients suggesting they may be useful endophenotypic markers of genetic vulnerability to BD. (PsycINFO Database Record (c) 2004 APA, all rights reserved) (journal abstract )

  19. Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role for Topiramate

    P. L. Follett, W. Deng and W. Dai, et al.

    J.Neurosci., Vol. 24, No. 18. pp. 4412-4420. 5 May, 2004.

    Periventricular leukomalacia is a form of hypoxic-ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic-ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA-kainate-type glutamate receptor blockade in a rodent model of periventricular leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic-ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23-32 weeks gestation, the period of highest risk for periventricular leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic-ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA-kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA-kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f) quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA-kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.

  20. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog

    Fujiki N., Yoshida Y., Ripley B., Mignot E. and Nishino S.

    Sleep, Vol. 26, No. 8. pp. 953-959. Dec 15, 2003.

    STUDY OBJECTIVES: Using two different canine models of narcolepsy, we evaluated the therapeutic effects of hypocretin-1 on cataplexy and sleep. MEASUREMENTS AND RESULTS: Intracerebroventricular administration of hypocretin-1 (10 and 30 nmol per dog) but not intravenous administration (up to 6 microg/kg) induced significant wakefulness in control dogs. However, hypocretin-1 had no effect on cataplexy or wakefulness in hypocretin receptor-2 gene (Hcrtr2) mutated narcoleptic Dobermans. Only very high intravenously doses of hypocretin-1 (96-384 microg/kg) penetrated the brain, to produce a short-lasting anticataplectic effect in a hypocretin-ligand-deficient animal. CONCLUSIONS: Hypocretin-1 administration, by central and systemic routes, does not improve narcoleptic symptoms in Hcrtr2 mutated Dobermans. Systemic hypocretin-1 hardly crosses the blood-brain barrier to produce therapeutic effects. The development of more centrally penetrable and longer lasting hypocretin analogs will be needed to further explore this therapeutic pathway in humans.

  21. A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases

    R. A. Furlong, L. W. Ho and J. S. Rubinsztein, et al.

    Neurosci.Lett., Vol. 277, No. 2. pp. 123-126. Dec, 1999.

    A recent report has shown that Wolfram syndrome carriers (heterozygotes) are 26-fold more likely to require psychiatric hospitalization compared with non-carriers, and that Wolfram syndrome heterozygotes may constitute approximately 25% of individuals hospitalized with depression and suicide attempts. We analyzed a His611Arg polymorphism of the wolframin gene by the polymerase chain reaction (PCR) and HhaI restriction digestion, in 158 bipolar I and 163 unipolar major affective disorder cases, and 316 controls. Statistical analyses of allele or genotype frequencies do not support a major role for wolframin in affective disorder. HhaI restriction digestion and sequencing of PCR products from four affective disorder cases showed a heterozygous Ala559Thr change. The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder.

  22. Long-Term Lithium Therapy for Bipolar Disorder: Systematic Review and Meta-Analysis of Randomized Controlled Trials

    J. R. Geddes, S. Burgess, K. Hawton, K. Jamison and G. M. Goodwin.

    Am.J.Psychiatry, Vol. 161, No. 2. pp. 217-222. Feb, 2004.

    OBJECTIVE: The authors sought to determine the efficacy and acceptability of lithium for relapse prevention in bipolar disorder. METHOD: A systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo in the long-term treatment of bipolar disorders was conducted. Data were obtained from searching the registers of the Cochrane Collaboration; reviewing reference lists, journals, and conference abstracts; and contacting authors, experts, and pharmaceutical companies. Outcomes investigated included risk of relapse (manic, depressive, and total) as well as risk of specific adverse effects and total withdrawal rates. RESULTS: Five randomized controlled trials (770 participants) were included. Lithium was more effective than placebo in preventing all relapses (random effects relative risk=0.65, 95% CI=0.50 to 0.84) and manic relapses (relative risk=0.62, 95% CI=0.40 to 0.95). The protective effect of lithium on depressive relapses was smaller and was less robust (relative risk=0.72, 95% CI=0.49 to 1.07). CONCLUSIONS: Lithium treatment reduces the risk of relapse in bipolar disorder. The preventive effect is clear for manic episodes, although it is equivocal for depressive episodes.

  23. Long-Term Lithium Therapy for Bipolar Disorder: Systematic Review and Meta-Analysis of Randomized Controlled Trials

    J. R. Geddes, S. Burgess, K. Hawton, K. Jamison and G. M. Goodwin.

    Am.J.Psychiatry, Vol. 161, No. 2. pp. 217-222. Feb, 2004.

    OBJECTIVE: The authors sought to determine the efficacy and acceptability of lithium for relapse prevention in bipolar disorder. METHOD: A systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo in the long-term treatment of bipolar disorders was conducted. Data were obtained from searching the registers of the Cochrane Collaboration; reviewing reference lists, journals, and conference abstracts; and contacting authors, experts, and pharmaceutical companies. Outcomes investigated included risk of relapse (manic, depressive, and total) as well as risk of specific adverse effects and total withdrawal rates. RESULTS: Five randomized controlled trials (770 participants) were included. Lithium was more effective than placebo in preventing all relapses (random effects relative risk=0.65, 95% CI=0.50 to 0.84) and manic relapses (relative risk=0.62, 95% CI=0.40 to 0.95). The protective effect of lithium on depressive relapses was smaller and was less robust (relative risk=0.72, 95% CI=0.49 to 1.07). CONCLUSIONS: Lithium treatment reduces the risk of relapse in bipolar disorder. The preventive effect is clear for manic episodes, although it is equivocal for depressive episodes.

  24. Linkage Disequilibrium of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism in Children With a Prepubertal and Early Adolescent Bipolar Disorder Phenotype

    Barbara Geller, Judith A. Badner, Rebecca Tillman, Susan L. Christian, Kristine Bolhofner and Edwin H. Cook.

    Am.J.Psychiatry, Vol. 161, No. 9. pp. 1698-1700. 1 Sep, 2004.

    OBJECTIVE: Transmission of the brain-derived neurotrophic factor (BDNF) Val66 allele in children with a prepubertal and early adolescent bipolar disorder phenotype was examined. METHOD: The prepubertal and early adolescent bipolar disorder phenotype was defined as current DSM-IV bipolar I disorder (manic or mixed phase) with at least one cardinal mania criterion (i.e., euphoria and/or grandiosity) to ensure differentiation from attention deficit hyperactivity disorder. Probands (mean age=10.7 years, SD=2.7) were obtained by consecutive new case ascertainment from designated pediatric and psychiatric venues. Parents and probands were interviewed separately by research nurses who were blind to the probands' diagnoses. Genotyping was done with TaqMan Assay-on- Demand. Analysis was done with the Family Based Association Test program. RESULTS: There were 53 complete, independent trios. The BDNF Val66 allele was preferentially transmitted (Family Based Association Test: [Chi] super(2)=6.0, df=1, p=0.014). CONCLUSIONS: This finding in child bipolar disorder is consistent with data for adults with bipolar disorder that show preferential transmission of the Val66 allele.

  25. MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed

    E. Geuze, E. Vermetten and J. D. Bremner.

    Mol.Psychiatry, Vol. 10, No. 2. pp. 147-159. Feb, 2005.

    The advance of neuroimaging techniques has resulted in a burgeoning of studies reporting abnormalities in brain structure and function in a number of neuropsychiatric disorders. Measurement of hippocampal volume has developed as a useful tool in the study of neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. From this database, the methodology of all original manual tracing protocols were studied. These protocols differed in a number of important factors for accurate hippocampal volume determination including magnetic field strength, the number of slices assessed and the thickness of slices, hippocampal orientation correction, volumetric correction, software used, inter-rater reliability, and anatomical boundaries of the hippocampus. The findings are discussed in relation to optimizing determination of hippocampal volume.

  26. MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders

    E. Geuze, E. Vermetten and J. D. Bremner.

    Mol.Psychiatry, Vol. 10, No. 2. pp. 160-184. Feb, 2005.

    Magnetic resonance imaging (MRI) has opened a new window to the brain. Measuring hippocampal volume with MRI has provided important information about several neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. Smaller hippocampal volumes have been reported in epilepsy, Alzheimer's disease, dementia, mild cognitive impairment, the aged, traumatic brain injury, cardiac arrest, Parkinson's disease, Huntington's disease, Cushing's disease, herpes simplex encephalitis, Turner's syndrome, Down's syndrome, survivors of low birth weight, schizophrenia, major depression, posttraumatic stress disorder, chronic alcoholism, borderline personality disorder, obsessive-compulsive disorder, and antisocial personality disorder. Significantly larger hippocampal volumes have been correlated with autism and children with fragile X syndrome. Preservation of hippocampal volume has been reported in congenital hyperplasia, children with fetal alcohol syndrome, anorexia nervosa, attention-deficit and hyperactivity disorder, bipolar disorder, and panic disorder. Possible mechanisms of hippocampal volume loss in neuropsychiatric disorders are discussed.

  27. Hippocampal volumetrics differentiate patients with temporal lobe epilepsy and extratemporal lobe epilepsy

    Gilmore R.L., Childress M.D. and Leonard C., et al.

    Archives of neurology, Vol. 52, No. 8. pp. 819-824. Aug, 1995.

    OBJECTIVE: To determine whether the occurrence of hippocampal formation (HF) volumetric asymmetry can reliably discriminate between complex partial seizures (CPSs) of a temporal lobe origin and CPSs of an extra-temporal lobe origin in a prospective study of patients with intractable CPSs (approximately 70% of patients have electrographic foci in the temporal lobe [HF volumetric asymmetry on magnetic resonance imaging scans has been shown to lateralize such foci reliably)]. DESIGN: We examined HF volumetrics on magnetic resonance imaging scans that were acquired with a 1-T magnetic resonance imaging scanner (Siemens Magnetom, Siemens Medical Systems, Iselin, NJ) by using magnetization-prepared rapid gradient echo three-dimensional sequences (producing a gapless series of high-contrast 1.25-mm images). These data were compared with ictal, interictal, invasive, and noninvasive videoelectroencephalographic monitoring data, functional imaging data, and outcome data to define each patient's type of epilepsy. SETTING AND PATIENTS: Forty-one patients were recruited from a tertiary university comprehensive epilepsy program, and 22 control subjects were recruited from the neurologically normal university community. RESULTS: Among the control subjects, the difference in HF volumetrics (right-left HF volumetrics) was + 0.085 +/- 0.253 cm3. Of the 41 patients, 25 had temporal lobe epilepsy. When we set the upper limit of normal at the mean +/- 3 SDs, all patients beyond the upper limit had CPSs of a temporal lobe origin. Of the patients with temporal lobe epilepsy, only three fell within normal limits. No patient with CPSs of an extratemporal lobe origin fell beyond the upper limit. CONCLUSION: The presence of significant HF volumetric asymmetry makes it highly unlikely that a patient's CPSs are of an extratemporal lobe origin.

  28. Depression with versus without manic features in rapid-cycling bipolar disorder

    Goldberg J.F., Wankmuller M.M. and Sutherland K.H.

    The Journal of nervous and mental disease, Vol. 192, No. 9. pp. 602-606. Sep, 2004.

    Depression has been identified as a hallmark feature of rapid-cycling bipolar disorder, although less attention has been paid to the presence of manic features accompanying depression in rapid cyclers. To provide greater information about the extent to which depression arises with or without salient manic features in rapid cycling, we conducted a preliminary study of rapid cycling in outpatients seeking treatment at an academic specialty center for bipolar disorder. Forty DSM-IV affectively symptomatic bipolar outpatients with past year DSM-IV rapid cycling underwent systematic evaluation of symptoms and illness characteristics. Manic and depressive symptoms, treatments, and clinical features were rated by standardized scales. Major depression was present in most rapid cyclers (85%), but salient manic features were also evident in half of all depressed rapid cyclers. A lifetime history of suicide attempts was significantly more common in rapid cyclers who presented with major depression plus salient manic features than in those who presented with pure depression or pure mania (p = .033). Antidepressants were being prescribed for approximately one third of depressed rapid cycling patients regardless of the presence of concomitant manic features, whereas mood stabilizers tended to be used less often when manic features accompanied depression. Depression in conjunction with manic symptoms, rather than pure depression alone, may be more common among rapid-cycling bipolar patients who seek treatment. Lifetime suicide risk may be greater among rapid cycling patients whose depression occurs in tandem with manic symptoms. Prescribing habits in the community that favor antidepressants over mood stabilizers may promote further mood destabilization in this population. Further studies with larger sample sizes are needed to affirm these provisional findings.

  29. Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: evidence, limitations, and implications

    Green E. and Craddock N.

    Current psychiatry.reports, Vol. 5, No. 6. pp. 469-476. Dec, 2003.

    Brain-derived neurotrophic factor (BDNF) plays an important role in promoting and modifying growth, development, and survival of neuronal populations, and, in the mature nervous system, is involved in activity-dependent neuronal plasticity. Based on several lines of evidence, BDNF has been hypothesized to play an important role in the pathogenesis of mood disorder and the therapeutic action of at least some effective treatments. The gene encoding BDNF lies on the short arm of chromosome 11 in a region where some linkage studies of bipolar disorder have reported evidence for a susceptibility gene. BDNF can, thus, be considered as an attractive candidate gene for involvement in the pathogenesis of bipolar disorder, and two recent family-based association studies have provided evidence that one or more sequence variants within or near the BDNF gene show an association with disease susceptibility. These findings are of great interest and may open up a new chapter in the understanding of the causation and treatment of bipolar disorder. However, it is still early in the genetic investigation of BDNF in bipolar disorder, and it is important that these findings are replicated in large independent samples and that functional studies can confirm and characterize the pathogenic relevance of this genetic variation.

  30. Critical role of brain-derived neurotrophic factor in mood disorders

    K. Hashimoto, E. Shimizu and M. Iyo.

    Brain Res.Rev., Vol. 45, No. 2. pp. 104-114. May, 2004.

    The purpose of this review is to integrate what is currently known about the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Pre-clinical studies suggest that the expression of BDNF might be a downstream target of antidepressant treatments and mood stabilizers such as lithium and valproate, and that BDNF exerts antidepressant activity in animal models of depression. Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. Clinical studies have demonstrated that serum levels of BDNF in drug-naive patients with MDD are significantly decreased as compared with normal controls, and that BDNF might be an important agent for therapeutic recovery from MDD. Moreover, recent findings from family-based association studies have suggested that the BDNF gene is a potential risk locus for the development of BD. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders. New agents capable of enhancing BDNF levels may lead aid the development of novel therapeutic drugs for patients with mood disorders.

  31. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity

    R. Hashimoto, N. Takei, K. Shimazu, L. Christ, B. Lu and D. -M Chuang.

    Neuropharmacology, Vol. 43, No. 7. pp. 1173-1179. Dec, 2002.

    Mechanisms underlying the therapeutic effects of lithium for bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults in vitro and in vivo. This study was undertaken to investigate the role of the brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway in mediating neuroprotection of lithium against glutamate excitotoxicity in cortical neurons. Pretreatment with either lithium or BDNF protected rat cerebral cortical neurons from glutamate excitotoxicity. The duration of treatment required to elicit maximal neuroprotection by BDNF (1 day) was much shorter than that by lithium (6 days). K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody suppressed the neuroprotective effect of lithium. Treatment of cortical neurons with lithium increased the cellular BDNF content in 3 days and the phosphorylation of TrkB at Tyr490 in 5 days, suggesting that long-term lithium administration enhances BDNF expression/secretion, leading to the activation of TrkB receptor. Lithium failed to protect against glutamate excitotoxicity in cortical neurons derived from homozygous and heterozygous BDNF knockout mice, although lithium fully protected cortical neurons prepared from wild type mice littermates. Taken together, these data suggest that the BDNF/TrkB pathway plays an essential role in mediating the neuroprotective effect of lithium.

  32. Identification of an cysteine-to-arginine substitution caused by a single nucleotide polymorphism in the canine monoamine oxidase B gene

    Hashizume C., Masuda K., Momozawa Y., Kikusui T., Takeuchi Y. and Mori Y.

    The Journal of veterinary medical science / the Japanese Society of Veterinary Science, Vol. 67, No. 2. pp. 199-201. Feb, 2005.

    Monoamine oxidase B catalytically oxidizes biogenic amines such as phenylethylamine and dopamine, and its activity is presumed to be related to particular behavioral traits. In this study, we first identified a single nucleotide polymorphism (T199C) located on the putative third exon of the canine monoamine oxidase B gene, which causes an amino acid substitution from cysteine to arginine. We then examined the allelic frequencies in five dog breeds (Golden Retriever, Labrador Retriever, Maltese, Miniature Schnauzer, and Shiba) and found significant variation among them. The present results suggest that analysis of the monoamine oxidase B polymorphism could be a useful means of elucidating the genetic background of breed-specific behavioral characteristics in dogs.

  33. Disrupted in Schizophrenia 1 (DISC1): Association with Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder

    C. A. Hodgkinson, D. Goldman and J. Jaeger, et al.

    Am.J.Hum.Genet., Vol. 75, No. 5. pp. 862-872. Nov, 2004.

    Schizophrenia, schizoaffective disorder, and bipolar disorder are common psychiatric disorders with high heritabilities and variable phenotypes. The Disrupted in Schizophrenia 1 (DISC1) gene, on chromosome 1q42, was originally discovered and linked to schizophrenia in a Scottish kindred carrying a balanced translocation that disrupts DISC1 and DISC2. More recently, DISC1 was linked to schizophrenia, broadly defined, in the general Finnish population, through the undertransmission to affected women of a common haplotype from the region of intron 1/exon 2. We present data from a case-control study of a North American white population, confirming the underrepresentation of a common haplotype of the intron 1/exon 2 region in individuals with schizoaffective disorder. Multiple haplotypes contained within four haplotype blocks extending between exon 1 and exon 9 are associated with schizophrenia, schizoaffective disorder, and bipolar disorder. We also find overrepresentation of the exon 9 missense allele Phe607 in schizoaffective disorder. These data support the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders.

  34. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior

    Hong C.J., Huo S.J., Yen F.C., Tung C.L., Pan G.M. and Tsai S.J.

    Neuropsychobiology, Vol. 48, No. 4. pp. 186-189. , 2003.

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, has been implicated in both mood disorders and suicidal behavior. This study has examined the association between the BDNF gene Val66Met polymorphism and mood disorders, age of onset and suicidal behavior in a Chinese sample population. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing depression groups (total, bipolar disorder or major depression) and control subjects. Furthermore, it was not demonstrated that this BDNF polymorphism was associated with age of onset or suicidal history in our mood disorder patients. Based on these results, it seems reasonable to suggest that this polymorphism is unlikely to play a major role in the genetic susceptibility to mood disorders. Given the fact that the positive association between BDNF gene Val66Met polymorphism and bipolar disorder has only been demonstrated for a Caucasian population but not for a Japanese analog or our Chinese sample, it appears likely that this association is ethnicity dependent. (Copyright 2003 S. Karger AG, Basel)

  35. MRI-based hippocampal volumetrics: data acquisition, normal ranges, and optimal protocol

    Jack C.R., Theodore W.H., Cook M. and McCarthy G.

    Magnetic resonance imaging, Vol. 13, No. 8. pp. 1057-1064. , 1995.

    The process of producing magnetic resonance (MR) volume measurements can be divided into considerations of acquisition and postprocessing of the MR data. With careful attention to both of these, precise and reproducible measurements can be achieved. A statistical description of hippocampal measurements in normal volunteers must be available for comparison if volumetrics are employed either for clinical or research purposes. A wide range in normal hippocampal volume is present in the studies of normal young adults that have been reported to date. This variability is most probably due to interinstitutional differences in hippocampal boundary criteria, and in the software employed for counting pixels in a defined region of interest (ROI). Because the numeric output from the volume measurement procedure is highly technique-dependent, the statistical description of normal should be determined or calibrated at each institution wishing to use these techniques.

  36. Preclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson's disease

    Jenner P.

    Neurology, Vol. 63, No. 7 Suppl 2. pp. S13-22. Oct 12, 2004.

  37. Intravenously administered hypocretin-1 alters brain amino acid release: an in vivo microdialysis study in rats

    John J., Wu M.F., Kodama T. and Siegel J.M.

    The Journal of physiology, Vol. 548, No. Pt 2. pp. 557-62. Epub: 2003 Mar 07. Apr 15, 2003.

    We have reported that intravenous administration of hypocretin (Hcrt or orexin) reverses the symptoms of narcolepsy in genetically narcoleptic dogs. We have also reported that the onset of symptoms in canine genetic narcolepsy is accompanied by degenerative changes in forebrain regions, particularly the septal nucleus and amygdala. In the present in vivo microdialysis study we have investigated the effect of intravenous administration of Hcrt-1 (orexin-A) to anaesthetized rats on glutamate and GABA release in the amygdala, a region with moderate Hcrt innervation, and in the cerebellar cortex, a region with sparse or no Hcrt innervation. We found that intravenous Hcrt administration caused a marked (> 60 %) and sustained (> 50 min) increase in glutamate release within the amygdala, but no change in release in the cerebellar cortex. We did not detect a significant change in GABA release. When calcium-free artificial cerebrospinal fluid was used as the microdialysis perfusate, Hcrt-1 no longer produced an increase in glutamate release. Hcrt may act via the calcium-dependent regulation of glutamate release in certain nuclei of the central nervous system.

  38. Drug-induced decrease of protein kinase a activity reveals alteration in BDNF expression of bipolar affective disorder

    Karege F., Schwald M. and El Kouaissi R.

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Vol. 29, No. 4. pp. 805-812. Apr, 2004.

    Bipolar affective disorder (BAD) is a severe disease whose molecular and cellular bases are not well known. The aim of the present study was to probe the cAMP signaling downstream targets by pharmacologically manipulating the protein kinase A (PKA) enzyme, along with the assessment of brain-derived neurotrophic factor (BDNF) expression in lymphoblasts. The time course of lymphoblast PKA activity (up to 72 h) revealed optimal activity at 24 h. Then, the enzyme activity and protein levels of PKA Calpha subunit and phopsho-cAMP responsive element binding (CREB) were assayed in lymphoblasts derived from 12 BAD and 12 control (CT) subjects and cultured for 24 h in the presence of cAMP analog drugs. The results indicated that basal PKA activity and PKA Calpha subunit immunolabeling are increased in cells from BAD compared with controls. Enzyme activity was increased by Sp-isomer in BAD and in CT's cells, without change in protein levels. In contrast, the Rp-isomer decreased enzyme activity and protein levels. In drug-naive conditions, there was no change in BDNF expression of BAD cells compared with CT cells. Treatment with Sp-isomer induced increased BDNF in both groups, while treatment with Rp-isomer induced a significant decrease in BDNF expression of BAD compared with CT. The p-CREB changes followed changes in BDNF levels, with increased and decreased Sp-isomer and Rp-isomer treatment, respectively. Our results suggest that mood disorder is associated with PKA upregulation and this could mask alteration in BDNF expression, because slowing down of PKA signaling results in a decrease of BDNF expression. These findings, combined with previous reports, provide a new insight to explain pharmacological features in different diagnostic groups.

  39. Effects of depression, cigarette smoking, and age on monoamine oxidase B in amygdaloid nuclei

    Karolewicz B., Klimek V. and Zhu H., et al.

    Brain research, Vol. 1043, No. 1-2. pp. 57-64. May 10, 2005.

    Altered concentrations of dopamine transporter and D2/D3 receptors have been observed in the amygdaloid complex of subjects with major depression. These findings are suggestive of neurochemical abnormalities in the limbic dopamine system in depression. Monoamine oxidase-B (MAO-B) is a key enzyme in the catabolism of biogenic amines, including dopamine, and alterations in this enzyme may underlie dopaminergic abnormalities associated with depression. The specific binding of [(3)H]lazabemide to MAO-B was measured in the right amygdaloid complex of 15 major depressive subjects and 16 psychiatrically normal controls. Subjects of the two study groups were matched as close as possible for age, sex, and postmortem interval. Examination of the regional distribution of MAO-B revealed lower [(3)H]lazabemide binding to MAO-B in the lateral and basal nuclei of the amygdala and higher binding in the medial nucleus. A modest elevation in binding to MAO-B observed in all amygdaloid nuclei in major depressive subjects as compared to control subjects failed to reach statistical significance. A significant decrease in binding to MAO-B was observed when cigarette smokers were compared to nonsmoking subjects. The amount of MAO-B binding positively correlated with the age of subjects in all nuclei investigated. A decreased amount of MAO-B in smokers further validates the pharmacological effect of tobacco smoke on this enzyme.

  40. Association analysis of the dopamine transporter (DAT1)-67A/T polymorphism in bipolar disorder

    Keikhaee M.R., Fadai F., Sargolzaee M.R., Javanbakht A., Najmabadi H. and Ohadi M.

    American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, Vol. 135, No. 1. pp. 47-49. May 5, 2005.

    An imbalance in the dopaminergic system in humans has been hypothesized to contribute to the pathogenesis of a number of psychiatric illnesses, including bipolar disorder, schizophrenia, and attention deficit hyperactivity disorder. We performed a case/control study on the DAT1 (HUGO approved symbol SL6A3) gene core promoter polymorphism -67A/T to analyze the possible association of either allele of this polymorphism with bipolar disorder. The allele and genotype frequencies of the polymorphism were studied in 136 patients and 163 controls, which were matched on the basis of sex, age, and ethnicity. The genotype frequencies in the patients group were as follows: AA 30.9%; AT 55.1%; TT 14% versus the genotype frequencies in the control group: AA 49%; AT 41.8%; TT 9.2% [chi(2) = 10.3, df = 2, OR = 2.15 (95% CI 1.34-3.47, P [Lt]/= 0.006]. The T-allele of the -67A/T polymorphism revealed a approximately 1.4-fold excess in the patients group comparing with the controls (P [Lt]/= 0.003). For the first time, these findings provide tentative evidence of the contribution of the DAT1 gene core promoter polymorphism to the etiopathophysiology of bipolar disorder at least in the Iranian population that we have studied. Interestingly, no allelic or genotype association was observed in the female patients (P [Lt]/= 0.6 and P [Lt]/= 0.7, respectively). Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings. (c) 2005 Wiley-Liss, Inc.

  41. Memory and verbal learning functions in twins with bipolar-I disorder, and the role of information-processing speed

    Kieseppa T., Tuulio-Henriksson A. and Haukka J., et al.

    Psychological medicine, Vol. 35, No. 2. pp. 205-215. Feb, 2005.

    BACKGROUND: Euthymic bipolar-I disorder (BP I) patients and their siblings have shown impairments in verbal learning and memory functions compared with controls, suggesting that these impairments may be genetic in origin. Reduced information-processing speed has been associated with impaired memory in the elderly, and recently in schizophrenia. The authors compared verbal learning and memory functioning in twins with BP I and co-twins to control twins, and examined whether the observed deficits are related to information-processing speed. METHOD: Finnish Medical and Population Registers and Twin Cohorts were used to identify the BP I and control twins. Neuropsychological tests assessing verbal learning and memory, working memory, facial recognition, visual memory, and information-processing speed were administered to 26 BP I twins, 19 non-bipolar co-twins, and 114 controls. Group differences were analyzed by generalized estimation equation modeling. RESULTS: BP I patients, but not co-twins, showed impairments in all memory tests compared with controls. Female co-twins showed impairment in verbal learning and memory. Information-processing speed had a significant effect on encoding and learning efficiency. CONCLUSIONS: This study showed for the first time that information-processing speed is related to memory functioning and verbal learning in BP I in a population-based, representative and euthymic sample. Furthermore, the data support the view that defects in verbal memory may be related to the genetic factors predisposing to BP I in females.

  42. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells

    T. Kondo and M. Raff.

    Science (Wash.), Vol. 289, No. 5485. pp. 1754-1757. 8 Sep, 2000.

    During animal development, cells become progressively more restricted in the cell types to which they can give rise. In the central nervous system (CNS), for example, multipotential stem cells produce various kinds of specified precursors that divide a limited number of times before they terminally differentiate into either neurons or glial cells. We show here that certain extracellular signals can induce oligodendrocyte precursor cells to revert to multipotential neural stem cells, which can self-renew and give rise to neurons and astrocytes, as well as to oligodendrocytes. Thus, these precursor cells have greater developmental potential than previously thought.

  43. The Darwinian concept of stress: Benefits of allostasis and costs of allostatic load and the trade-offs in health and disease

    S. Mechiel Korte, Jaap M. Koolhaas, John C. Wingfield and Bruce S. McEwen.

    Neuroscience & Biobehavioral Reviews.Special Individual differences in behavior and physiology: causes and consequences, Vol. 29, No. 1. pp. 3-38. Feb, 2005.

    Why do we get the stress-related diseases we do? Why do some people have flare ups of autoimmune disease, whereas others suffer from melancholic depression during a stressful period in their life? In the present review possible explanations will be given by using different levels of analysis. First, we explain in evolutionary terms why different organisms adopt different behavioral strategies to cope with stress. It has become clear that natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves) within a population. The existence of these personality types (Hawks-Doves) is widespread in the animal kingdom, not only between males and females but also within the same gender across species. Second, proximate (causal) explanations are given for the different stress responses and how they work. Hawks and Doves differ in underlying physiology and these differences are associated with their respective behavioral strategies; for example, bold Hawks preferentially adopt the fight-flight response when establishing a new territory or defending an existing territory, while cautious Doves show the freeze-hide response to adapt to threats in their environment. Thus, adaptive processes that actively maintain stability through change (allostasis) depend on the personality type and the associated stress responses. Third, we describe how the expression of the various stress responses can result in specific benefits to the organism. Fourth, we discuss how the benefits of allostasis and the costs of adaptation (allostatic load) lead to different trade-offs in health and disease, thereby reinforcing a Darwinian concept of stress. Collectively, this provides some explanation of why individuals may differ in their vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and nonaggressive Doves in a population. A conceptual framework is presented showing that Hawks, due to inefficient management of mediators of allostasis, are more likely to be violent, to develop impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, chronic fatigue states and inflammation. In contrast, Doves, due to the greater release of mediators of allostasis (surplus), are more susceptible to anxiety disorders, metabolic syndromes, melancholic depression, psychotic states and infection. (PsycINFO Database Record (c) 2005 APA, all rights reserved) (journal abstract )

  44. Perspectives on MAO-B in Aging and Neurological Disease: Where Do We Go From Here?

    M. J. Kumar and J. K. Andersen.

    Mol.Neurobiol., Vol. 30, No. 1. pp. 077-090. Aug, 2004.

    The catecholamine-oxidizing enzyme monoamine oxidase-B (MAO-B) has been hypothesized to be an important determining factor in the etiology of both normal aging and age-related neurological disorders such as Parkinson's disease (PD). Catalysis of substrate by the enzyme produces H sub(2)O sub(2) which is a primary originator of oxidative stress which in turn can lead to cellular damage. MAO-B increases with age as does predisposition towards PD which has also been linked to increased oxidative stress. Inhibition of MAO-B, along with supplementation of lost dopamine via L-DOPA, is one of the major antiparkinsonian therapies currently in use. In this review, we address several factors contributing to a possible role for MAO-B in normal brain aging and neurological disease and also discuss the use of MAO-B inhibitors as drug therapy for these conditions.

  45. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study

    Kunugi H., Iijima Y. and Tatsumi M., et al.

    Biological psychiatry., Vol. 56, No. 5. pp. 376-378. Sep 1, 2004.

    BACKGROUND: Two previous studies reported a significant association between a missense polymorphism (Val66Met) in the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder; however, contradictory negative results have also been reported, necessitating further investigation. METHODS: We organized a multicenter study of a relatively large sample of 519 patients with bipolar disorder (according to DSM-IV criteria) and 588 control subjects matched for gender, age, and ethnicity (Japanese). Genotyping was done by polymerase chain reaction-based restriction fragment length polymorphism or direct sequencing. RESULTS: The genotype distributions and allele frequencies were similar among the patients and control subjects. Even if the possible relationships of the polymorphism with several clinical variables (i.e., bipolar I or II, presence of psychotic features, family history, and age of onset) were examined, no variable was related to the polymorphism. CONCLUSIONS: The Val66Met polymorphism of the BDNF gene is unrelated to the development or clinical features of bipolar disorder, at least in a Japanese population.

  46. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study

    Kunugi H., Iijima Y. and Tatsumi M., et al.

    Biological psychiatry., Vol. 56, No. 5. pp. 376-378. Sep 1, 2004.

    BACKGROUND: Two previous studies reported a significant association between a missense polymorphism (Val66Met) in the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder; however, contradictory negative results have also been reported, necessitating further investigation. METHODS: We organized a multicenter study of a relatively large sample of 519 patients with bipolar disorder (according to DSM-IV criteria) and 588 control subjects matched for gender, age, and ethnicity (Japanese). Genotyping was done by polymerase chain reaction-based restriction fragment length polymorphism or direct sequencing. RESULTS: The genotype distributions and allele frequencies were similar among the patients and control subjects. Even if the possible relationships of the polymorphism with several clinical variables (i.e., bipolar I or II, presence of psychotic features, family history, and age of onset) were examined, no variable was related to the polymorphism. CONCLUSIONS: The Val66Met polymorphism of the BDNF gene is unrelated to the development or clinical features of bipolar disorder, at least in a Japanese population.

  47. Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan

    Lai T.J., Wu C.Y., Tsai H.W., Lin Y.M. and Sun H.S.

    BMC medical genetics [electronic.resource], Vol. 6, No. 1. pp. 14. Epub: 2005 Mar 31. Mar 31, 2005.

    BACKGROUND: Disturbances in serotonin neurotransmission are implicated in the etiology of many psychiatric disorders, including bipolar affective disorder (BPD). The tryptophan hydroxylase gene (TPH), which codes for the enzyme catalyzing the rate-limiting step in serotonin biosynthetic pathway, is one of the leading candidate genes for psychiatric and behavioral disorders. In a preliminary study, we found that TPH1 intron7 A218C polymorphism was associated with BPD. This study was designed to investigate sequence variants of the TPH1 gene in Taiwanese and to test whether the TPH1 gene is a susceptibility factor for the BPD. METHODS: Using a systematic approach, we have searched the exons and promoter region of the TPH1 gene for sequence variants in Taiwanese Han and have identified five variants, A-1067G, G-347T, T3804A, C27224T, and A27237G. These five variants plus another five taken from the literature and a public database were examined for an association in 108 BPD patients and 103 controls; no association was detected for any of the 10 variants. RESULTS: Haplotype constructions using these 10 SNPs showed that the 3 most common haplotypes in both patients and controls were identical. One of the fourth common haplotype in the patient group (i.e. GGGAGACCCA) was unique and showed a trend of significance with the disease (P = 0.028). However, the significance was abolished after Bonferroni correction thus suggesting the association is weak. In addition, three haplotype-tagged SNPs (htSNPs) were selected to represent all haplotypes with frequencies larger than 2% in the Taiwanese Han population. The defined TPH1 htSNPs significantly reduce the marker number for haplotype analysis thus provides useful information for future association studies in our population. CONCLUSION: Results of this study did not support the role of TPH1 gene in BPD etiology. As the current studies found the TPH1 gene under investigation belongs to the peripheral serotonin system and may link to a cardiac dysfunction phenotype, a second TPH gene that functions predominantly in the brain (i.e., nTPH or TPH2) should be the target for the future association study.

  48. Bipolar disorder: A cognitive therapy approach

    Dominic Lam.

    Behaviour Research & Therapy, Vol. 41, No. 5. pp. 629. May, 2003.

    This is the long-awaited book (see record 2001-18264-000) on cognitive therapy for bipolar affective disorder from respected colleagues in Philadelphia and elsewhere. The book comprises 8 chapters: bipolar disorder--diagnostic and epidemiological issues; the role of cognition in bipolar disorder and its treatment; moderating mania and hypomania; clinical management of depression, hopelessness and suicidality; pharmacotherapy in the context of cognitive therapy for patients with bipolar disorder; the case of "Carlos". The chapters are clearly written and rich in case examples. This is a valuable practitioners' guide and adds to the existing books on cognitive therapy with this population. (PsycINFO Database Record (c) 2004 APA, all rights reserved)

  49. Quantitative MRI in outpatient childhood epilepsy

    Lawson J.A., Cook M.J., Bleasel A.F., Nayanar V., Morris K.F. and Bye A.M.

    Epilepsia, Vol. 38, No. 12. pp. 1289-1293. Dec, 1997.

    PURPOSE: In adult studies, MRI volumetrics is a proven technique in presurgical assessment of epilepsy. Hippocampal volume loss is maximal in the syndrome of mesial temporal lobe epilepsy. We aimed (a) to validate this methodology in a pediatric outpatient epilepsy population (b) to determine the relationship of hippocampal asymmetry (HA) to epileptic syndromes and risk factors. METHODS: Two neurologists classified the epileptic syndrome in 79 pediatric outpatients, according to the International Classification of Epilepsies and Epileptic Syndromes (ILAE). Hippocampal volumetrics were performed in all patients. HA was defined according to adult control values. RESULTS: Inter-rater variability on measurement of HA was very small (Correlation of test retest of 0.97 on 17 children [Lt]3 years old). The rate of HA was 44/79 (57%). In 21 patients, (27%) potentially epileptogenic lesions (other than HA) were identified (cerebral dysgenesis n = 11). HA was present in 9/15 (60%) of temporal lobe epilepsy and in 15/28 (54%) extratemporal onset epilepsy and 5/11 (46%) of generalized symptomatic epilepsy. Analysis confined to [Lt]13 years also showed HA was not specific for epileptic syndrome. There was no significant association of febrile convulsions (13%) with HA or temporal lobe epilepsy. CONCLUSIONS: There is a high incidence of HA in childhood epilepsy. HA was not confined to clinically defined temporal lobe epilepsy. The poor correlation of epileptic syndrome to quantitative MRI findings may be due to the inadequacies of epilepsy classification in the younger child, with the clinical semiology providing misleading localizing information. Normative childhood data for hippocampal volumes and symmetry is needed.

  50. MAO-B knockout mice exhibit deficient habituation of locomotor activity but normal nicotine intake

    Lee M., Chen K., Shih J.C. and Hiroi N.

    Genes, brain, and behavior, Vol. 3, No. 4. pp. 216-227. Aug, 2004.

    Low levels of monoamine oxidase-B (MAO-B) activity, such as those observed in smokers, are also associated with behavioral traits such as a heightened responsiveness to novelty. However, the exact mechanism by which low MAO-B activity influences smoking and heightened responsiveness to novelty is still poorly understood. We used MAO-B knockout (KO) mice to test the hypothesis that MAO-B concomitantly affects locomotor responses in a novel inescapable open field and nicotine intake. Male wild-type (WT) and MAO-B KO mice were placed in an inescapable open field and their horizontal locomotor activity was measured for 30 min per day for 5 days. MAO-B KO mice exhibited impaired within-session habituation of locomotor activity, as compared to WT mice. Separate groups of male WT and MAO-B KO mice were individually housed in their home cages with two water bottles. One of the bottles contained tap water and the other contained nicotine (0, 3.125, 6.25, 12.5, 25, 50 or 100 micro g/ml). The total amount of water and nicotine solution consumed was measured every three days for 16 days. MAO-B KO mice and WT mice consumed equal amounts of nicotine and exhibited comparable concentration-dependent nicotine preference and aversion over a period of 16 days. The data suggest that the absence of MAO-B impairs the ability of mice to habituate in the inescapable environment, but does not alter their nicotine intake.

  51. Bipolar disorder and substance abuse

    F. R. Levin and G. Hennessy.

    Biol.Psychiatry, Vol. 56, No. 10. pp. 738-748. 15 Nov, 2004.

    Substance use disorders are overrepresented in individuals with bipolar and bipolar spectrum disorders. Although awareness of this phenomenon has increased over the past 20 years, few empirically based treatment strategies have been developed for this challenging patient population. This review examines the relationship between bipolar and substance use disorders and treatment options that have been studied in this patient population. First, we examine the high prevalence rates of substance use disorders in individuals diagnosed with bipolar disorder, the common problems associated with establishing a bipolar disorder diagnosis in individuals who abuse substances, the possible explanations for the frequent coexistence of bipolar and substance use disorders, and the negative effect of substance abuse on the course of and treatment outcomes for bipolar disorder. The review then focuses on treatment approaches for this patient population, including integrated group therapy for co-occurring bipolar and substance use disorders and pharmacotherapies that target both disorders. Finally, we present suggestions for medications that might be tested for their efficacy in treating both disorders in specific subgroups of patients with bipolar and substance use disorders.

  52. Immunologic variables in acute mania of bipolar disorder

    Liu H.C., Yang Y.Y., Chou Y.M., Chen K.P., Shen W.W. and Leu S.J.

    Journal of neuroimmunology, Vol. 150, No. 1-2. pp. 116-122. May, 2004.

    Macrophages, lymphocytes and their products, may be involved in the pathophysiology of psychiatric disorders. The cell-mediated immune activation response of manic patients during pre-medication and medication stages remains unclear. The purpose of this case-control study was to investigate the plasma levels of immunologic variables, including interleukin (IL)-1 receptor antagonist (IL-1RA), soluble CD 4 (sCD4) and sCD8, and TH1 (interferon [IFN]-gamma and IL-2) and TH2 (IL-4 and IL-10) cytokines in patients with pre-medicated, medicated bipolar mania. The study subjects, aged 16-44 years, were physically healthy patients with Young Mania Rating Scale (YMRS) scores > or =26, and normal controls, aged 19-40 years, were matched for sex. The immune variables were measured in acute mania and in consequent remission (YMRS scores [Lt] or =12) among bipolar patients. The plasma levels of IL-1RA, sCD4, and sCD8 were found significantly increased in pre-medicated acute manic patients as compared to normal controls. But only IL-1RA and sCD8 were found different in remitted bipolar patients as compared to normal controls. For TH1 cytokines, culture supernatant level of IFN-gamma was found significantly lower in manic patients of both acute and remission stages as compared to normal controls. No significant difference was found in IL-2 level in pre-medicated acute manic patients compared to controls. For TH2 cytokines, no significant differences in IL-4 and IL-10 levels were observed. We showed that cell-mediated immune response was activated in patients with bipolar disorder during the pre-medication, medication, and the remission stages. Our study findings suggest that the immune-modulation in patients with bipolar disorder may be abnormal.

  53. Incidence of bipolar affective disorder in three UK cities: results from the AESOP study

    Lloyd T., Kennedy N. and Fearon P., et al.

    The British journal of psychiatry.: the journal of mental science, Vol. 186, No. . pp. 126-131. Feb, 2005.

    BACKGROUND: There has been a relative dearth of epidemiological research into bipolar affective disorder. Furthermore, incidence studies of bipolar disorder have been predominantly retrospective and most only included hospital admission cases. AIMS: To determine the incidence of operationally defined bipolar disorder in three areas of the UK and to investigate any differences in gender and ethnicity. METHOD: All patients who contacted mental health services with first-episode psychosis or non-psychotic mania between September 1997 and August 1999 were identified and diagnosed according to ICD-10 criteria. Incidence rates of bipolar affective disorder were standardised for age and stratified by gender and ethnic group across the three areas. RESULTS: The incidence rate per 100,000 per year in south-east London was over twice that in Nottingham and Bristol. There was no significant difference in the rates of disorder in men and women. Incidence rates of bipolar disorder in the combined Black and minority ethnic groups in all three areas were significantly higher than those of the comparison White groups. CONCLUSIONS: The incidence of bipolar disorder was higher in south-east London than in the other two areas, and was higher among Black and minority ethnic groups than in the White population.

  54. A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42

    Macgregor S., Visscher P.M. and Knott S.A., et al.

    Molecular psychiatry., Vol. 9, No. 12. pp. 1083-1090. Dec, 2004.

    In this study, we report a genome scan for psychiatric disease susceptibility loci in 13 Scottish families. We follow up one of the linkage peaks on chromosome 1q in a substantially larger sample of 22 families affected by schizophrenia (SCZ) or bipolar affective disorder (BPAD). To minimise the effect of genetic heterogeneity, we collected mainly large extended families (average family size >18). The families collected were Scottish, carried no chromosomal abnormalities and were unrelated to the large family previously reported as segregating a balanced (1:11) translocation with major psychiatric disease. In the genome scan, we found linkage peaks with logarithm of odds (LOD) scores >1.5 on chromosomes 1q (BPAD), 3p (SCZ), 8p (SCZ), 8q (BPAD), 9q (BPAD) and 19q (SCZ). In the follow-up sample, we obtained most evidence for linkage to 1q42 in bipolar families, with a maximum (parametric) LOD of 2.63 at D1S103. Multipoint variance components linkage gave a maximum LOD of 2.77 (overall maximum LOD 2.47 after correction for multiple tests), 12 cM from the previously identified SCZ susceptibility locus DISC1. Interestingly, there was negligible evidence for linkage to 1q42 in the SCZ families. These results, together with results from a number of other recent studies, stress the importance of the 1q42 region in susceptibility to both BPAD and SCZ.

  55. Brain-immune interactions and disease susceptibility

    A. Marques-Deak, G. Cizza and E. Sternberg.

    Mol.Psychiatry, Vol. 10, No. 3. pp. 239-250. Mar, 2005.

    Many studies have established the routes by which the immune and central nervous (CNS) systems communicate. This network of connections permits the CNS to regulate the immune system through both neuroendocrine and neuronal pathways. In turn, the immune system signals the CNS through neuronal and humoral routes, via immune mediators and cytokines. This regulatory system between the immune system and CNS plays an important role in susceptibility and resistance to autoimmune, inflammatory, infectious and allergic diseases. This review focuses on the regulation of the immune system via the neuroendocrine system, and underlines the link between neuroendocrine dysregulation and development of major depressive disorders, autoimmune diseases and osteoporosis. (PsycINFO Database Record (c) 2005 APA, all rights reserved) (journal abstract )

  56. Safety considerations in pharmacotherapy of bipolar disorder

    Masand P.S., Fazal F.S. and Patkar A.A.

    CNS spectrums, Vol. 9, No. 11 Suppl 12. pp. 16-26. Nov, 2004.

    Bipolar disorder is a chronic, frequently relapsing illness with a prevalence of 1.2% to 3.4% in the general population. It is associated with high disability, higher comorbidity due to medical illnesses, and significant social and economical consequences for patients, their families, and society. The episodic nature of this disease warrants rational use of medications and proper monitoring for adverse events. Various drug classes, such as mood stabilizers, antipsychotics, benzodiazepines, and antidepressants, are used for the acute and maintenance treatment of bipolar disorder. Each group of drugs is associated with wide array of adverse events and drug interactions, which are the main hurdles in treatment outcome and compliance. Common side effects seen with several agents, particularly antipsychotics, are somnolence, weight gain, extrapyramidal symptoms, dyslipidemia, type-2 diabetes, and hyperprolactinemia. Major drug interactions are seen with drugs such as carbamazepine, due to hepatic enzyme induction. Adverse effects such as somnolence are tolerability concerns and can be managed easily; others, such as diabetes mellitus, are safety concerns. It is prudent to have precise knowledge of the individual drug's side-effect profile, pharmacokinetics, and pharmacodynamics, to plan a treatment regimen. More research is needed to understand potential risks of various drugs and to devise and incorporate monitoring protocols in the treatment regimen.

  57. Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European multicenter association study of affective disorders

    Isabelle Massat, Daniel Souery and Jurgen Del-Favero, et al.

    Am.J.Med.Genet.B., Vol. 114, No. 2. pp. 177-185. , 2002.

    Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control [copyright] and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age (+/-five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P = 0.004) and allele 5 (P = 0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.

  58. Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study

    B. Meiser, P. B. Mitchell, H. McGirr, M. Van Herten and P. R. Schofield.

    Soc.Sci.Med., Vol. 60, No. 1. pp. 109-118. Jan, 2005.

    While major susceptibility genes for bipolar disorder are yet to be identified, the opportunity exists to systematically ascertain the important issues and societal implications of genetic risk determination for bipolar disorder prior to these technological advances becoming widely available. This study explores, in a sample of families with a high density of bipolar disorder: (i) attitudes to predictive genetic and prenatal testing, using different risk frames; (ii) attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed; and (iii) the impact of these attributions on the perceived stigma of bipolar disorder. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. Participants were ascertained through a molecular genetics study of bipolar disorder. In-depth interviews were conducted with 21 members of families with a high density of bipolar disorder. Most participants reported being interested in genetic testing if it gave a definitive answer, while expressed interest in testing was lower if it gave a probable answer only. Almost all stressed that a genetic susceptibility and environmental factors interacted. Most participants felt that a genetic explanation was likely to decrease the stigma associated with bipolar disorder as it shifted the locus of control and responsibility away from the individual towards the role of heredity. Findings indicate that expressed interest in genetic testing depends on the certainty imparted by the test. Results suggest that families with bipolar disorder are likely to benefit psychologically from information about the genetic basis of bipolar disorder.

  59. Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study

    B. Meiser, P. B. Mitchell, H. McGirr, M. Van Herten and P. R. Schofield.

    Soc.Sci.Med., Vol. 60, No. 1. pp. 109-118. Jan, 2005.

    While major susceptibility genes for bipolar disorder are yet to be identified, the opportunity exists to systematically ascertain the important issues and societal implications of genetic risk determination for bipolar disorder prior to these technological advances becoming widely available. This study explores, in a sample of families with a high density of bipolar disorder: (i) attitudes to predictive genetic and prenatal testing, using different risk frames; (ii) attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed; and (iii) the impact of these attributions on the perceived stigma of bipolar disorder. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. Participants were ascertained through a molecular genetics study of bipolar disorder. In-depth interviews were conducted with 21 members of families with a high density of bipolar disorder. Most participants reported being interested in genetic testing if it gave a definitive answer, while expressed interest in testing was lower if it gave a probable answer only. Almost all stressed that a genetic susceptibility and environmental factors interacted. Most participants felt that a genetic explanation was likely to decrease the stigma associated with bipolar disorder as it shifted the locus of control and responsibility away from the individual towards the role of heredity. Findings indicate that expressed interest in genetic testing depends on the certainty imparted by the test. Results suggest that families with bipolar disorder are likely to benefit psychologically from information about the genetic basis of bipolar disorder.

  60. Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of the Wolfram gene

    Middle F., Jones I. and McCandless F., et al.

    American journal of medical genetics, Vol. 96, No. 2. pp. 154-157. Apr 3, 2000.

    A number of linkage studies provide evidence consistent with the existence of a bipolar susceptibility gene on chromosome 4p16. The gene for Wolfram syndrome, a rare recessive neurodegenerative disorder, lies in this region and has recently been cloned. Psychiatric disturbances including psychosis, mood disorder, and suicide have been reported at increased frequency in Wolfram patients and in heterozygous carriers of a Wolfram mutation. In the current investigation we have undertaken a case-control association study using a single nucleotide polymorphism (causing an amino acid change) in exon 8 of the Wolfram gene in a UK Caucasian sample of 312 Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM IV) bipolar I probands and 301 comparison individuals. We found no evidence that variation at this polymorphism influences susceptibility to bipolar disorder. It remains possible that variation at other sites within or near the Wolfram gene plays important roles in determining susceptibility to affective illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:154-157, 2000. (Copyright 2000 Wiley-Liss, Inc.)

  61. Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder

    Nakata K., Ujike H. and Sakai A., et al.

    Neuroscience letters, Vol. 337, No. 1. pp. 17-20. Jan 30, 2003.

    Brain-derived neurotrophic factor (BDNF) belongs to a family of neurotrophic factors and has been demonstrated to promote the survival, differentiation, and maintenance of a broad variety of central nervous system neurons. Several reports have suggested that the BDNF gene is a plausible functional candidate gene underlying the predisposition for developing bipolar disorder (BPD). In the present study, we investigated the possible role of the BDNF gene in the etiology of BPD using a matched case-control association design in a Japanese population. There was no evidence for an allelic or genotypic association of two polymorphisms (-1360C>T and 196G>A) of the BDNF gene with BPD. Furthermore, no significant association was observed between these polymorphisms and either of two diagnostic subtypes (bipolars I and II disorder). The results suggest that the BDNF gene is unlikely to confer susceptibility to BPD.

  62. The Brain-Derived Neurotrophic Factor Gene Confers Susceptibility to Bipolar Disorder: Evidence from a Family-Based Association Study

    M. Neves-Pereira, E. Mundo, P. Muglia, N. King, F. Macciardi and J. L. Kennedy.

    Am.J.Hum.Genet., Vol. 71, No. 3. pp. 651-655. Sep, 2002.

    Bipolar disorder (BP) is a severe psychiatric disease, with a strong genetic component, that affects 1% of the population worldwide and is characterized by recurrent episodes of mania and depression. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of mood disorders, and the aim of the present study was to test for the presence of linkage disequilibrium between two polymorphisms in the BDNF gene and BP in 283 nuclear families. Family-based association test (FBAT) results for the dinucleotide repeat (GT) sub(N) polymorphism at position -1040 bp showed that allele A3 was preferentially transmitted to the affected individuals (Z = 2.035 and P = .042). FBAT results for the val66met SNP showed a significant association for allele G (Z = 3.415 and P = .00064). Transmission/disequilibrium test (TDT) haplotype analysis showed a significant result for the 3-G allele combination (P = .000394), suggesting that a DNA variant in the vicinity of the BDNF locus confers susceptibility to BP. Given that there is no direct evidence that either of the polymorphisms we examined alters function, it is unlikely that the actual risk-conferring allele is from these two sites. Rather, the causative site is likely nearby and in linkage disequilibrium with the 3-G haplotype that we have identified.

  63. Bipolar Disorder

    Cory F. Newman.

    , Vol. , No. . pp. 153-174. , 2003.

    (From the chapter ) Therapists who treat patients suffering from bipolar disorder can expect to have to deal with problematic episodes as a matter of course, as it is the exception to the rule that bipolar disorder is treated free of complications. For starters, bipolar disorder is difficult to diagnose accurately early in the course of the illness, when pharmacologic and psychosocial interventions may have their most positive, enduring impact. The purpose of this introduction is to convey that bipolar disorder is a serious adversary for patients, for important others in their lives, and for their treatment providers as well. Professionals who enter into a therapeutic relationship with patients with bipolar disorder need to find a way to maintain hope in the face of difficulties and to model optimism and perseverance in spite of setbacks. They must also be willing to deal with clinical crises, with patients' attempts at premature flight from therapy, with real and idiosyncratic difficulties with medications, and with other therapy-interfering behaviors. (PsycINFO Database Record (c) 2004 APA, all rights reserved)

  64. Pharmacotherapy in the context of cognitive therapy for patients with bipolar disorder

    Cory F. Newman, Robert L. Leahy, Aaron T. Beck, Noreen A. Reilly-Harrington and Laszlo Gyulai.

    , Vol. , No. . pp. 101-136. , 2002.

    (From the chapter ) It is of the utmost importance for cognitive therapy and pharmacotherapy to be partners in the battle against manic depression. The authors hope that pharmacologists are able to learn and use the principles of cognitive therapy to maximize patient adherence and to heighten their own sensitivity to the experiences and beliefs of bipolar patients that typically scare them away from their treatment. The authors have written this chapter in the hope that cognitive therapists will familiarize themselves with the state of the field of pharmacotherapy. This in the first half of the chapter they offer a brief, nonexhaustive summary of the current state of knowledge in the field. In the second half of the chapter, they explicate the use of cognitive therapy in the service of increasing the patient's ability to make optimal use of pharmacotherapy. (PsycINFO Database Record (c) 2005 APA, all rights reserved)

  65. Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: A Belgian patient-control study

    Pierre Oswald, Jurgen Del-Favero and Isabelle Massat, et al.

    Am.J.Med.Genet.B., Vol. 129B, No. 1. pp. 34-35. , 2004.

    This patient-control association study was conducted to investigate a possible association of two single nucleotide polymorphisms (SNPs), g.11757C > G and g.196G > A, in the brain-derived neurotrophic factor (BDNF) with bipolar affective disorder (BPAD). Two hundred seventy-five individuals of Belgian origin (at least two generations of Belgian ancestors) were genotyped (112 BPAD and 163 controls). No significant differences were found in the frequency of genotypes and alleles of g.196G > A (P = 0.37 and 0.94, respectively) and g.11757C > G (P = 0.49 and 0.59, respectively) between controls and BPAD patients. An haplotype analysis revealed no difference between patients and controls (P = 0.44). We failed to replicate previous findings implicating BDNF in the aetiology of BPAD. However, BDNF remains an interesting target for future genetic studies and should be tested in prospective pharmacogenetic therapeutic trials.

  66. Genetic linkage of bipolar disorder to chromosome 6q22 is a consistent finding in Portuguese subpopulations and may generalize to broader populations

    Carlos N. Pato, Frank A. Middleton and Karen L. Gentile, et al.

    Am.J.Med.Genet.B., Vol. 134B, No. 1. pp. 119-121. , 2005.

    We recently reported genome-wide significant linkage to chromosome 6q for bipolar disorder, in a study of 25 Portuguese families, using the Human Mapping Assay Xba 131 (HMA10K). To explore the generalizability of this finding, we reanalyzed our SNP linkage data according to the families' geographic origin. Specifically, the 25 families included 20 families from the Portuguese island collection (PIC; 15 families from the Azores Islands and 5 from the Madeira Islands) and 5 families from continental Portugal. Non-parametric linkage analysis (NPL) was performed as previously described and indicated that each of these subpopulations showed evidence of linkage for the same region. To further address the potential generalizability of these findings to other populations, we have also examined allelic heterozygosity in our subpopulations and in three reference populations (Caucasian, East Asian, and African-American). This analysis indicated that the PIC population is highly correlated to the Caucasian reference population (R = 0.86) for all of chromosome 6. In contrast allelic heterozygosity was more weakly correlated between PIC and both East Asian (R = 0.37) and African-American (R = 0.32) reference populations. Taken together these observations suggest a shared genetic liability among Portuguese populations for bipolar disorder on chromosome 6q, and that the PIC population is likely representative of Caucasians in general.

  67. The role of estrogen in mood disorders in women

    Payne J.L.

    International review of psychiatry.(Abingdon, England), Vol. 15, No. 3. pp. 280-290. Aug, 2003.

    Major depression is twice as common in women as men and depressive episodes appear to be more common in women with bipolar disorder. There is accumulating evidence that, in at least some women, reproductive-related hormonal changes may play a role in increasing the risk of depressive symptoms premenstrually, postpartum and in the perimenopausal period. In this review, the evidence for the role of hormonal fluctuations, specifically estrogen, in triggering depressive symptoms in a subgroup of women is summarized. In addition, the potential role of estrogen in triggering depressive symptoms via its effects on the serotonergic system, brain-derived neurotrophic factor and Protein Kinase C is reviewed.

  68. Novel aspects of signaling and ion-homeostasis regulation in immunocytes. The TRPM ion channels and their potential role in modulating the immune response

    Perraud A.L., Knowles H.M. and Schmitz C.

    Molecular immunology, Vol. 41, No. 6-7. pp. 657-673. Jul, 2004.

    In just a few years, the discovery and subsequent characterization of several members of the TRPM family of cation channels have provided us with surprising new insights into unknown aspects of cellular ion-homeostasis regulation. This includes reports about ADP-ribose functioning as a novel intracellular second messenger and gating molecule of the Ca(2+)-permeable TRPM2 channel, studies demonstrating the central role of mouse TRPM5 in taste signaling, as well as the unexpected involvement of TRPM6 and TRPM7 in regulating Mg(2+)-homeostasis, or the cool properties of TRPM8 acting as a cold and menthol sensor in sensory neurons. At least four of the eight known TRPM proteins have been shown to be present in the immune context: TRPM1 (melastatin), TRPM2, TRPM4 and TRPM7. Although we currently lack animal models allowing a detailed assessment of the potential involvement of TRPM family members in modulating the immune response, the powerful combination of molecular and cellular biology, biochemistry, and electrophysiology have provided the first clues as to how these molecules could contribute to immunity.

  69. Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients

    Rybakowski J.K., Borkowska A., Czerski P.M., Skibinska M. and Hauser J.

    Bipolar disorders, Vol. 5, No. 6. pp. 468-472. Dec, 2003.

    OBJECTIVES: The aim of the study was to test a possible association between the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and performance on a neurocognitive test, the Wisconsin Card Sorting Test (WCST), in bipolar patients. METHODS: Fifty-four bipolar patients were studied, 18 male and 36 female, aged 18-72 (mean 46 years). The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured in relation to the Val66Met genotypes of BDNF. RESULTS: The percentages of subjects with Val/Val, Val/Met and Met/Met genotypes were respectively 81.5, 16.7 and 1.8%. Subjects with Val/Val and Val/Met genotypes did not differ on clinical factors except for the age of onset of the illness, which was earlier in Val/Val than Val/Met genotype (27 years versus 38 years). The performance in all domains of WCST was significantly better in subjects with Val/Val BDNF genotype compared with Val/Met genotype. CONCLUSIONS: The results suggest a role of BDNF in prefrontal cognitive function in bipolar illness. The tests of prefrontal cognition may be considered as endophenotypic markers in bipolar illness.

  70. Morphine-induced alterations of immune status are blocked by the dopamine D2-like receptor agonist 7-OH-DPAT

    T. B. Saurer, K. A. Carrigan, S. G. Ijames and D. T. Lysle.

    J.Neuroimmunol., Vol. 148, No. 1-2. pp. 54-62. Mar, 2004.

    Morphine administration produces profound effects on the immune system, including reductions in natural killer cell activity, mitogen-induced lymphocyte proliferation, and cytokine production. Although it has been established that the activation of central nervous system (CNS) mu -opioid receptors by morphine induces immunomodulation, little is known about the neural mechanisms underlying such processes. Interestingly, it has been shown that the dopamine (DA) D2-like receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) blocks the effect of morphine on a number of behaviors that are mediated by central dopamine pathways. The present study examined whether dopamine is involved in the immunomodulatory effects of morphine. In separate experiments, 7-OH-DPAT was administered either systemically (subcutaneous, s.c.) or centrally (intracerebroventricularly, i.c.v.) prior to morphine treatment in male Lewis rats. The results demonstrate that both systemic and central administration of 7-OH-DPAT attenuate the suppressive effect of morphine on several measures of immune status. Overall, these findings provide the first evidence that CNS dopaminergic mechanisms are directly involved in morphine-induced immunomodulation.

  71. Bipolar disorders in children and adolescents

    Schapiro N.A.

    Journal of pediatric health.care.: official publication of National Association of Pediatric Nurse.Associates & Practitioners, Vol. 19, No. 3. pp. 131-141. May-Jun, 2005.

    In the past decade, 7 million children in the United States had a mental health problem, with higher rates of medication use, primary care visits, and specialty care visits than children without such problems. Children with bipolar disorders can present diagnostic and referral dilemmas for the primary care pediatric nurse practitioner, and frequently these children take multiple medications that interact with commonly used antibiotics, over-the-counter medications, and contraceptives. Diagnostic criteria for mania are controversial and coexisting attention deficit/hyperactivity disorder, conduct disorder, and anxiety disorders can complicate the diagnosis and treatment. The primary care pediatric nurse practitioner role includes referral, co-management, and advocacy for this vulnerable population.

  72. Cognitive Therapy of Bipolar Disorder

    Jan Scott.

    , Vol. , No. . pp. 228-243. , 2004.

    (From the chapter ) Until recently, bipolar disorder (BP) was widely regarded as a biological illness that should be treated with medication (Prien & Potter, 1990; Scott, 1995a). This view is gradually changing for two reasons. First, in the past three decades, there has been a greater emphasis on stress-vulnerability models. This has led to the development of new etiological theories of severe mental disorders, which emphasize psychosocial and particularly cognitive aspects of vulnerability and risk; it has also increased the acceptance of cognitive therapy (CT) as an adjunct to medication for individuals with treatment-resistant schizophrenia and with severe and chronic depressive disorders (Scott & Wright, 1997). Second, although medication is the mainstay of treatment in BP, there is a significant efficacy-effectiveness gap (Guscott & Taylor, 1994). Mood stabilizer prophylaxis protects about 60% of individuals against relapse in research settings, but protects only 25-40% of individuals against further episodes in clinical settings (Dickson & Kendall, 1986). The introduction of newer medications has not improved clinical or social outcomes for individuals with BP. This has also increased interest in other treatment approaches. This chapter explores why psychological treatment may be indicated, explores research into cognitive models of BP, and then gives an overview of CT in BP and the outcome studies available for it. (PsycINFO Database Record (c) 2005 APA, all rights reserved)

  73. Cognitive therapy for clients with bipolar disorder

    Jan Scott.

    , Vol. , No. . pp. 236-264. , 2002.

    (From the chapter ) The aims of therapy for bipolar disorder (BD) are to alleviate acute symptoms, restore psycho-social functioning, and prevent relapse and recurrence. The benefits of pharmacotherapy have dominated the literature on treatment. However, in day-to-day clinical settings, lithium prophylaxis protects only 25-50% of BD sufferers against further episodes (W. Dickson and R. Kendall, 1986) and the introduction of newer medications has not improved prognosis (J. Scott, 1995). In the past 2 decades there has been a greater emphasis on stress diathesis models, leading to the development of new etiological theories of severe mental disorders that emphasize psychological aspects of vulnerability and risk and has also increased the acceptance of cognitive therapy (CT) as an adjunct to medication for individuals with treatment-resistant schizophrenia and severe and chronic depressive disorders (J. Scott and J. Wright, 1997). Research on BD is limited, but there is evidence that CT may benefit this client group. This chapter explores current psychological models of BD. It comments on the clinical applicability of CT, and also reviews outcome research. A case example (male 37-yr-old) is used to outline the basic structure of the intervention and highlight how CT may be used with clients with BD. (PsycINFO Database Record (c) 2004 APA, all rights reserved)

  74. A pilot study of cognitive therapy in bipolar disorders

    Jan Scott, A. Garland and S. Moorhead.

    Psychol.Med., Vol. 31, No. 3. pp. 459-467. Apr, 2001.

    Explored the feasibility and efficacy of using cognitive therapy (CT) as an adjunct to usual psychiatric treatment in patients with bipolar disorders. Ss referred by general adult psychiatrists were assessed by an independent rater and then randomly allocated to immediate CT (N=21; mean age 37.8 yrs) or 6-mo waiting-list control, which was followed by CT (N=21; mean age 40.5 yrs). Observer and self-ratings of symptoms and functioning were taken immediately prior to CT, after a 6-mo course of CT and a further 6-mo later. Data on relapse and hospitalization rates in the 18 mo before and after commencing CT were also collected. At 6-mo follow-up, Ss allocated to CT showed statistically significantly greater improvements in symptoms and functioning as measured on the Beck Depression Inventory, the Internal State Scale, and the Global Assessment of Functioning than those in the waiting-list control group. In the 29 Ss who eventually received CT, relapse rates in the 18 mo after commencing CT showed a 60% reduction in comparison with the 18 mo prior to commencing CT. 70% of Ss who commenced therapy viewed CT as highly acceptable. (PsycINFO Database Record (c) 2004 APA, all rights reserved)

  75. Wolfram syndrome and suicide: Evidence for a role of WFS1 in suicidal and impulsive behavior

    Adolfo Sequeira, Caroline Kim and Monique Seguin, et al.

    Am.J.Med.Genet.B., Vol. 119B, No. 1. pp. 108-113. , 2003.

    There is evidence suggesting that subjects affected with the Wolfram syndrome (WFS) and normal carriers present an increased risk of psychiatric disorders, particularly depression and suicidal behavior. We investigated a possible role of the gene involved in WFS (WFS1) in the neurobiology of suicide and the potential modulatory effect on traits associated to suicidal behavior. Genetic variation at WFS1 (H611R, R456H, and I333V) was investigated in 111 suicide victims and 129 normal controls. Possible effects on psychopathology and behavioral traits were investigated in a subsample of suicide cases (N = 31) for whom phenotyping was carried out by means of structured psychiatric interviews and questionnaires adapted for psychological autopsies. We found a significantly higher frequency of the 611R/611R genotype in suicide completers as compared to controls ( Chi super(2) = 19.21, df=2, P = 0.001). Suicide completers with this genotype had higher scores on measures of impulsivity (t =-3.15, df = 15.3, P = 0.006); novelty seeking (NS) (t =-3.35, df = 13.8, P = 0.005); and conversely, lower scores of persistence (t = 2.4, df = 16.6, P = 0.028). Scores of impulsivity and NS remained higher in subjects with the associated genotype after adjusting for age, gender, and psychopathology. These results suggest a role for WFS1 in the pathophysiology of impulsive suicide, and are consistent with previous clinical reports suggesting an increased risk of suicidal behavior in WFS homozygotes and heterozygotes. However, these findings are preliminary and should be confirmed in independent samples.

  76. Inhibition of interleukin-12 expression in diltiazem-treated dendritic cells through the reduction of nuclear factor-kappa B transcriptional activity

    Severa M., D'Ambrosio A., Giordani L., Quintieri F. and Coccia E.

    Biochemical pharmacology, Vol. 69, No. 3. pp. 425-32. Epub: 2004 Dec 09. Feb 1, 2005.

    Diltiazem is a calcium channel blocker that suppresses the activation of a variety of immune cells, such as T and B cells, NK cells, monocytes and dendritic cells (DCs). It has been used in the treatment of cardiovascular disorders and has been widely included in clinical protocols to prevent rejection after kidney transplantation. In line with these data, we previously showed that diltiazem directly affects maturation of human DCs and the production of IL-12. Here, we extended our analysis studying the effect of diltiazem on the transcription of IL-12 p35 and p40 subunits focusing on the activity of nuclear factor-kappa B (NF-kappa B). A marked reduction of NF-kappa B binding to the kappa B sequences present within the p35 and p40 subunit promoters was observed in diltiazem-treated DCs following the stimulation with lipopolysaccharide (LPS) or CD40L. In order to examine the mechanisms by which NF-kappa B binding activity is reduced by diltiazem, we analyzed the NF-kappa B inhibitor, I kappa B alpha. No significant differences were observed in the phosphorylation and/or the degradation of I kappa B alpha. On the other hand, the subcellular distribution of NF-kappa B subunits was clearly affected in diltiazem-treated DCs following LPS stimulation, with a reduced nuclear translocation of p65, and RelB, and a nuclear accumulation of p50 subunit. Thus, all together, our data provided evidence that in addition to the inhibition of p65/p50 nuclear translocation, the selective induction and translocation of p50/p50 homodimers is an important mechanism by which diltiazem inhibits NF-kappa B activity, and in turn, IL-12 expression.

  77. Child maltreatment and HPA axis dysregulation: relationship to major depressive disorder and post traumatic stress disorder in females

    Alison Shea, Christine Walsh, Harriet MacMillan and Meir Steiner.

    Psychoneuroendocrinology, Vol. 30, No. 2. pp. 162-178. Feb, 2005.

    A history of child maltreatment increases the vulnerability to the development of Major Depressive Disorder (MOD) and/or Posttraumatic Stress Disorder (PTSD), especially in females. Both MOD and PTSD are associated with a dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. Dysregulation of the HPA axis may be an important etiological link between child maltreatment and subsequent psychiatric disorder, yet little is known about the relationship between exposure and outcome. The aim of this review is to explore the role of HPA axis dysregulation in the link between child maltreatment and MDD/PTSD among women. Studies of females with MOD frequently indicate a hyperactivity of the HPA axis, and contribute to our understanding of the underlying mechanisms involved in mood dysregulation. Evidence for HPA axis dysregulation in PTSD is less convincing and suggests that timing of the stressful experience as well as the type of the trauma may influence the outcome. The strongest evidence to date suggesting that the development of the HPA axis may be affected by early life stressful experiences comes from pre-clinical animal studies. Together these studies add to our understanding of the role of the HPA axis in psychiatric disorders in relation to stress. The literature on HPA axis function in both children and adults following child maltreatment further highlights the potential relevance of early stress to later onset of major psychiatric disorders. Such knowledge may also contribute to the development of early interventions targeted at primary prevention. (PsycINFO Database Record (c) 2004 APA, all rights reserved) (journal abstract )

  78. Analysis of microsatellite markers and single nucleotide polymorphisms in candidate genes for susceptibility to bipolar affective disorder in the chromosome 12Q24.31 region

    Shink E., Harvey M. and Tremblay M., et al.

    American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, Vol. 135, No. 1. pp. 50-58. May 5, 2005.

    Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers D12S86 and D12S378 on chromosome 12 was the most probable genomic region to contain a susceptibility gene for affective disorders. Here we present a more detailed genetic analysis of a 7.7 Mb genomic region located on 12q24.31. This region was saturated with 20 microsatellite markers to refine the candidate region and linkage analysis performed in 41 families from the Saguenay-Lac-St-Jean (SLSJ) region of Quebec. The results of two point parametric analysis using MFLINK supported the presence of a susceptibility locus on chromosome 12q24.31. Association studies with microsatellite markers using a case/control sample from the same population (n = 401) and analyzed with CLUMP revealed significant allelic associations between the bipolar phenotype and markers NBG6 (P = 0.008) and NBG12 (P [Lt] 10(-3)). According to these results, we investigated candidate genes in the NBG12 area. We analyzed 32 genes for the presence of polymorphisms in coding sequences and intron/exon junctions and genotyped 22 non-synonymous SNPs in the SLSJ case/control sample. Two uncommon polymorphisms (minor allele frequency [Lt]/= 0.03) found in KIAA1595 and FLJ22471 genes, gave P-values below 0.05 with the T1 statistic. Moreover, using haplotype analysis, a nearly significant haplotypic association was observed at the HM74 gene. These results do not give strong support for a role in the susceptibility to bipolar disorder of any of these genes analyzed. However, the significance of rare polymorphisms should be explored by further analyses. (c) 2005 Wiley-Liss, Inc.

  79. Genetic heterogeneity in a very large bipolar affective disorder pedigree from Quebec

    E. Shink, J. Morissette and N. Barden.

    Am.J.Med.Genet.B., Vol. 119B, No. 1. pp. 65-68. , 2003.

    We previously reported a genome-wide scan for bipolar affective disorder based on a multigenerational family sampled from a relatively homogeneous population derived from founding families that migrated to an isolated area of Quebec from the early 1830s onwards. For the genome scan, the pedigree was split into five branches to facilitate calculation and a second family was added to more specifically analyze chromosome 12 results. In the present study, we reanalyzed the undivided pedigree after genealogical links were reconstructed over ten generations to investigate a founder effect using an algorithm in the SIMWALK2 package. Our results do not lend support to the presence of a common haplotype shared among affected individuals.

  80. Genetic heterogeneity in a very large bipolar affective disorder pedigree from Quebec

    E. Shink, J. Morissette and N. Barden.

    Am.J.Med.Genet.B., Vol. 119B, No. 1. pp. 65-68. , 2003.

    We previously reported a genome-wide scan for bipolar affective disorder based on a multigenerational family sampled from a relatively homogeneous population derived from founding families that migrated to an isolated area of Quebec from the early 1830s onwards. For the genome scan, the pedigree was split into five branches to facilitate calculation and a second family was added to more specifically analyze chromosome 12 results. In the present study, we reanalyzed the undivided pedigree after genealogical links were reconstructed over ten generations to investigate a founder effect using an algorithm in the SIMWALK2 package. Our results do not lend support to the presence of a common haplotype shared among affected individuals.

  81. Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder

    Skibinska M., Hauser J. and Czerski P.M., et al.

    The world journal of biological psychiatry.: the official journal of the World Federation of Societies of Biological Psychiatry., Vol. 5, No. 4. pp. 215-220. Oct, 2004.

    Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar disorder. A functional polymorphism Val66Met of BDNF gene was studied in patients with schizophrenia (n=336), bipolar affective disorder (n=352) and healthy controls (n=375). Consensus diagnosis by at least two psychiatrists, according to DSM-IV and ICD-10 criteria, was made for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID). No association was found between the studied polymorphism and schizophrenia or bipolar affective disorder either for genotype or allele distribution (for genotype: p=0.210 in schizophrenia, p=0.400 in bipolar disorder; for alleles: p=0.260 in schizophrenia, p=0.406 in bipolar disorder). Results were also not significant when analysed by gender. For males genotype distribution and allele frequency were (respectively): p=0.480 and p=0.312 in schizophrenia, p=0.819 and p=0.673 in bipolar affective disorder. Genotype distribution and allele frequency observed in the female group were: p=0.258 for genotypes, p=0.482 for alleles in schizophrenia; p=0.432 for genotypes, p=0.464 for alleles in bipolar affective disorder. A subgroup of schizophrenic (n=62) and bipolar affective patients (n=28) with early age at onset (18 years or younger) was analysed (p=0.328 for genotypes, p=0.253 for alleles in schizophrenia; p=0.032 for genotypes, p=0.858 for alleles in bipolar affective disorder).

  82. BDNF polymorphism and association with bipolar disorder

    P. Sklar, E. S. Lander, J. R. DePaulo, M. G. McInnis and Whitehead Institute for Biomedical Research.

    , Vol. , No. US Patent: 6458541. pp. . , 2002.

    Methods for diagnosing and treating neuropsychiatric disorders, especially bipolar disorder, and to methods for identifying compounds for use in the diagnosis and treatment of neuropsychiatric disorders are disclosed. Also disclosed are novel compounds and pharmaceutical compositions for use in the diagnosis and treatment of neuropsychiatric disorders such as bipolar disorder.

  83. Role of Protein Kinase C- alpha in the Control of Infection by Intracellular Pathogens in Macrophages

    A. St-Denis, V. Caouras, F. Gervais and A. Descoteaux.

    J.Immunol., Vol. 163, No. 10. pp. 5505-5511. 15 Nov, 1999.

    The protein kinase C (PKC) family regulates macrophage function involved in host defense against infection. In this study, we investigated the role of macrophage PKC- alpha in the uptake and subsequent fate of Leishmania donovani promastigotes and Legionella pneumophila infections. To this end, we used clones of the murine macrophage cell line RAW 264.7 overexpressing a dominant-negative (DN) mutant of PKC- alpha . While phagocytosis of L. donovani promastigotes was not affected by DN PKC- alpha overexpression, their intracellular survival was enhanced by 10- to 20-fold at 48 h postinfection. Intracellular survival of a L. donovani mutant defective in lipophosphoglycan repeating units synthesis, which normally is rapidly degraded in phagolysosomes, was enhanced by 100-fold at 48 h postinfection. However, IFN- gamma -induced leishmanicidal activity was not affected by DN PKC- alpha overexpression. Similar to macrophages from genetically resistant C57BL/6 mice, control RAW 264.7 cells were not permissive for the intracellular replication of Legionella pneumophila. In contrast, DN PKC- alpha -overexpressing RAW 264.7 clones were phenotypically similar to macrophages from genetically susceptible A/J mice, as they allowed intracellular replication of L. pneumophila. Permissiveness to L. pneumophila was not the consequence of a general defect in the microbicidal capacities because killing of a temperature-sensitive mutant of Pseudomonas aeruginosa was normal in DN PKC- alpha -overexpressing RAW 264.7 clones. Collectively, these results support a role for PKC- alpha in the regulation of innate macrophage functions involved in the control of infection by intracellular parasites.

  84. Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder

    Strauss J., Barr C.L. and George C.J., et al.

    American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, Vol. 131, No. 1. pp. 16-19. Nov 15, 2004.

    Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals. BDNF gene polymorphisms have been associated with bipolar disorder. We tested two genetic polymorphisms of BDNF for their association with childhood-onset mood disorders (COMD) within the context of a case-control design. Two BDNF polymorphisms, a dinucleotide repeat (GT)(n), and a single nucleotide polymorphism (SNP) in the coding region, val66met, were genotyped in 99 adults with a history of COMD and matched psychiatrically healthy controls. A genomic control (GC) method was used to evaluate population substructure. Alleles at (GT)(n) were highly associated with COMD in this sample (chi(2) = 17.8; d.f. = 5; P = 0.0032). The odds of carrying the 168 bp allele were 3.94 times greater for cases than controls (CI = 1.72-9.04). Alleles of val66met were not significantly associated with COMD. GC analysis suggested population substructure was not a confounder of association. Analysis of haplotypes, in which (GT)(n) was treated as a binary variable (long vs. short alleles), provided significant evidence that the haplotype val/short contributes to liability to COMD. The BDNF (GT)(n) marker and the val/short haplotype are associated with COMD in this sample, in accordance with the previously described neurotrophic hypothesis of depression and some previous studies of association for bipolar disorder and neuroticism.

  85. Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder

    J. Strauss, C. L. Barr and C. J. George, et al.

    Am.J.Med.Genet.B., Vol. 131B, No. 1. pp. 16-19. , 2004.

    Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals. BDNF gene polymorphisms have been associated with bipolar disorder. We tested two genetic polymorphisms of BDNF for their association with childhood-onset mood disorders (COMD) within the context of a case-control design. Two BDNF polymorphisms, a dinucleotide repeat (GT) sub(n), and a single nucleotide polymorphism (SNP) in the coding region, val66met, were genotyped in 99 adults with a history of COMD and matched psychiatrically healthy controls. A genomic control (GC) method was used to evaluate population substructure. Alleles at (GT) sub(n) were highly associated with COMD in this sample ( Chi super(2) = 17.8; d.f. = 5; P = 0.0032). The odds of carrying the 168 bp allele were 3.94 times greater for cases than controls (CI = 1.72-9.04). Alleles of val66met were not significantly associated with COMD. GC analysis suggested population substructure was not a confounder of association. Analysis of haplotypes, in which (GT) sub(n) was treated as a binary variable (long vs. short alleles), provided significant evidence that the haplotype val/short contributes to liability to COMD. The BDNF (GT) sub(n) marker and the val/short haplotype are associated with COMD in this sample, in accordance with the previously described neurotrophic hypothesis of depression and some previous studies of association for bipolar disorder and neuroticism. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.mrw.interscience.wiley.com/suppmat/1552-4841/suppmat/in dex.html

  86. Not asleep, not quite awake

    J. G. Sutcliffe and L. de Lecea.

    Nat.Med., Vol. 10, No. 7. pp. 673-674. Jul, 2004.

    Narcoleptic individuals experience episodes of cataplexy, in which they retain consciousness but have no muscle tone. Consciousness and muscle tone are controlled by distinct brain regions, now delineated by research on narcoleptic dogs.

  87. Psychiatric disorders and mutations at the Wolfram syndrome locus

    Swift M. and Swift R.G.

    Biological psychiatry., Vol. 47, No. 9. pp. 787-793. May 1, 2000.

    Identifying genetic loci at which mutations predispose individuals to common psychiatric illnesses will have major impact on the diagnosis and treatment of mental illness. The available evidence indicates that mutations at the Wolfram syndrome locus contribute substantially to the prevalence of psychiatric illness in the general population. Patients with mutations at this locus on both parental chromosomes, called Wolfram syndrome homozygotes, have a distinctive and rare autosomal recessive syndrome characterized by juvenile onset diabetes mellitus and bilateral progressive optic atrophy. Diverse and serious psychiatric manifestations frequently have been observed in Wolfram syndrome patients; however, the population burden of mental illness attributable to mutations at this locus is almost entirely from individuals who carry a single mutation, called Wolfram syndrome heterozygotes, who have no distinguishing physical characteristics but constitute approximately 1% of the population. Molecular genotyping of blood relatives of Wolfram syndrome patients has shown that Wolfram syndrome heterozygotes are 26-fold more likely than noncarriers to have a psychiatric hospitalization. Severe depression was the predominant finding in the test group studied. The prediction that approximately 25% of all patients hospitalized for depression are Wolfram syndrome heterozygotes now can be tested by mutation screening of hospitalized patients from the general population. Many other behavioral and cognitive difficulties also have been observed in Wolfram syndrome families. For each specific psychiatric abnormality, a test group of blood relatives within Wolfram syndrome families with that abnormality can be formed. By comparing the number of Wolfram syndrome heterozygotes found in each test group by molecular genotyping with the number expected under the null hypothesis, the index-test method can determine which clinical phenotypes result from mutations at the Wolfram syndrome locus. This method can be utilized to identify other loci at which mutations predispose individuals to psychiatric illnesses.

  88. Predisposition of Wolfram syndrome heterozygotes to psychiatric illness

    Swift R.G., Polymeropoulos M.H., Torres R. and Swift M.

    Molecular psychiatry., Vol. 3, No. 1. pp. 86-91. Jan, 1998.

    Identification of specific genes that predispose to psychiatric illness will lead to more precise psychiatric diagnosis and more effective treatment. Heterozygous carriers of genes for many autosomal recessive syndromes may be 1% or more of the general population. Thus, if mutations at a specific locus produce psychiatric manifestations in homozygous affected individuals, it is important to determine whether mutations at such a locus also predispose heterozygous carriers to psychiatric disorders. The hypothesis that heterozygous carriers of the gene for the Wolfram syndrome (WS) are predisposed to psychiatric illness was supported previously by the finding of an excess of psychiatric hospitalizations and suicides in WS blood relatives compared to spouse controls. This hypothesis has now been tested further by comparing the number of psychiatrically hospitalized blood relatives with the specific marker haplotype associated with the Wolfram syndrome gene in their families to the number expected under the null hypothesis, calculated from Mendelian inheritance principles and the estimated haplotype frequency. The proportion of psychiatrically hospitalized relatives who were WS carriers (10/11) was much higher than expected (3.1/11), leading to the provisional estimate that WS gene carriers are 26-fold more likely to require psychiatric hospitalization than non-carriers.

  89. Psychiatric findings in Wolfram syndrome homozygotes

    R. G. Swift, D. B. Sadler and M. Swift.

    Lancet, Vol. 336, No. 8716. pp. 667-669. , 1990.

    Diabetes mellitus and bilateral optic atrophy are the defining characteristics of the autosomal recessive Wolfram syndrome. Diabetes insipidus, neurogenic bladder, deafness, and other neurological manifestations are frequent. A review was made of the medical records of 68 Wolfman syndrome patients, aged between 8 and 43 years, identified by casefinding throughout the USA. 41 of the patients (60%) had episodes of severe depression, psychosis, or organic brain syndrome, as well as impulsive verbal and physical aggression. These symptoms were very severe in 17 patients (25%), of whom 12 required admission to a psychiatric hospital and 11 attempted suicide. We conclude that the Wolfram syndrome gene predisposes homozygotes to psychiatric illness.

  90. Is mania caused by overactivity of central brain-derived neurotrophic factor?

    Tsai S.J.

    Medical hypotheses, Vol. 62, No. 1. pp. 19-22. , 2004.

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems, as well as the intracellular signal-transduction pathway. Recent studies had demonstrated that BDNF may play a role in the antidepressant mechanism and the pathogenesis of major depression. These findings implicated that BDNF may involve in mood regulation. In addition, (1). studies found positive association between BDNF genetic polymorphism and bipolar affective disorders; (2). agents which potentially induce manic states also increase BDNF, and (3). increase in mossy fibers were noted for bipolar affective disorder brain and BDNF is related to the induction of aberrant mossy fiber sprouting. From these finding, it is proposed that BDNF overactivity may be implicated in the manic state. The notion of BDNF overactivity in mania suggests that factors associated with increased BDNF activity may proffer the etiological fundamentals for bipolar affective disorder. Further, exploration of this hypothesis can provide a new direction in the treatment of the bipolar affective disorder.

  91. In psychosis, cortical interneurons overexpress DNA-methyltransferase 1

    Veldic M., Guidotti A., Maloku E., Davis J.M. and Costa E.

    Proceedings of the National Academy of Sciences of the United.States of America, Vol. 102, No. 6. pp. 2152-7. Epub: 2005 Jan 31. Feb 8, 2005.

    Cortical DNA-methyltransferase 1 (DNMT1) is preferentially expressed in interneurons secreting GABA where it very likely contributes to promoter CpG island hypermethylation, thus causing a down-regulation of promoter functions. To consolidate and expand on previous findings that, in the cortex of schizophrenia (SZ) brains, glutamic acid decarboxylase 67 (GAD67) expression is down-regulated whereas that of DNMT1 is up-regulated, we studied both parameters in Brodmann's area (BA) 9 from the McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center, Belmont, MA). In BA9 of SZ and bipolar disorder patients with psychosis, DNMT1 mRNA and protein expression preferentially increases in layer I, II, and IV interneurons, and this increase is paralleled by a decreased number of GAD67 mRNA-positive neurons. The increase in DNMT1 and the decrease in GAD67-expressing neurons were unrelated to postmortem interval, pH, RNA quality, or to the presence, dose, or duration of antipsychotic (APS) medication, with the exception of a subgroup of SZ patients treated with a combination of valproate and APS in which the expression of DNMT1 failed to change. The DNMT1 increase and the GAD67 decrease in BA9 interneurons are significant features of SZ and bipolar disorder with psychosis. Interestingly, the DNMT1 increase failed to occur when patients with psychosis received a combination of valproate and APS treatment but not APS monotherapy.

  92. Joint multi-population analysis for genetic linkage of bipolar disorder or "wellness" to chromosome 4p

    P. M. Visscher, C. S. Haley and H. Ewald, et al.

    Am.J.Med.Genet.B., Vol. 133B, No. 1. pp. 18-24. , 2005.

    To test the hypothesis that the same genetic loci confer susceptibility to, or protection from, disease in different populations, and that a combined analysis would improve the map resolution of a common susceptibility locus, we analyzed data from three studies that had reported linkage to bipolar disorder in a small region on chromosome 4p. Data sets comprised phenotypic information and genetic marker data on Scottish, Danish, and USA extended pedigrees. Across the three data sets, 913 individuals appeared in the pedigrees, 462 were classified, either as unaffected (323) or affected (139) with unipolar or bipolar disorder. A consensus linkage map was created from 14 microsatellite markers in a 33 cM region. Phenotypic and genetic data were analyzed using a variance component (VC) and allele sharing method. All previously reported elevated test statistics in the region were confirmed with one or both analysis methods, indicating the presence of one or more susceptibility genes to bipolar disorder in the three populations in the studied chromosome segment. When the results from both the VC and allele sharing method were considered, there was strong evidence for a susceptibility locus in the data from Scotland, some evidence in the data from Denmark and relatively less evidence in the data from the USA. The test statistics from the Scottish data set dominated the test statistics from the other studies, and no improved map resolution for a putative genetic locus underlying susceptibility in all three studies was obtained. Studies reporting linkage to the same region require careful scrutiny and preferably joint or meta analysis on the same basis in order to ensure that the results are truly comparable.

  93. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains

    Wang H.Y. and Friedman E.

    Biological psychiatry., Vol. 40, No. 7. pp. 568-575. Oct 1, 1996.

    Protein kinase C (PKC) activity and its redistribution were determined in the frontal cortices of postmortem brains of bipolar affective disorder subjects and age-, sex-, and postmortem time-matched controls. Membrane and cytosolic PKC activity was determined by histone phosphorylation using [32P]-adenosine triphosphate as substrate. Specific PKC isozyme levels were assessed by Western blot analysis using antipeptide antibodies. Brain membrane-associated PKC activity was higher in bipolar vs. control tissue. An examination of the specific PKC isozymes in cortical homogenates revealed that cytosolic alpha- and membrane-associated gamma- and zeta PKC isozymes were elevated in cortices of bipolar affective disorder subjects, whereas cytosolic epsilon PKC was found to be reduced. In control brain slices, incubation with 1 mumol/L phorbol 12-myristate 13-acetate (PMA) caused an increase in membrane PKC activity, whereas cytosolic enzyme activity was decreased. This redistribution of the enzyme by PMA was markedly potentiated in brain slices of bipolar subjects. The results suggest that PKC-mediated phosphorylation is increased in brains of subjects with bipolar affective illness.

  94. Phenotype definitions: some hidden issues in psychiatry

    Weissman M.M.

    American journal of medical genetics, Vol. 105, No. 1. pp. 45-47. Jan 8, 2001.

    Three hidden problems in phenotype definition in psychiatric genetic studies are described. 1. Data on physical conditions in family members are not routinely collected in genetic studies of psychiatric disorders. These data may reveal cosegregation with psychiatric disorders which can be included in genetic analysis when defining the phenotype. Data on physical conditions can be obtained by a combination of medical checklists, medical history, and medical records. 2. Detailed clinical narrative summaries should be prepared on family members even if the narratives are not part of the diagnostic data included in centralized cell repositories for future distribution to qualified genetic investigators. Means for retaining the narratives for future use, while protecting patient confidentiality, should be sought. The narratives include detailed information on the context, severity, and sequence of the symptoms and can provide phenotype descriptions for reconsideration of diagnosis in the future. 3. The selection of early onset psychiatric disorders for genetic studies does not automatically mean that affected children should be included in genetic studies for some psychiatric disorders. Screening for genetic studies among child psychiatric patients and inclusion of children as affected in pedigrees should proceed with caution until more data are available from longitudinal studies on the continuity between childhood and adult psychiatric disorders.

  95. Clinical Pharmacology of MAO Inhibitors: Safety and Future

    M. Yamada and H. Yasuhara.

    Neurotoxicology, Vol. 25, No. 1-2. pp. 215-221. Jan, 2004.

    In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson's disease, and Alzheimer's disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called 'cheese effect.' Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.

  96. Genome scan of a second wave of NIMH genetics initiative bipolar pedigrees: chromosomes 2, 11, 13, 14, and X

    Peter P. Zandi, Virginia L. Willour and Yuqing Huo, et al.

    Am.J.Med.Genet.B., Vol. 119B, No. 1. pp. 69-76. , 2003.

    As part of the on-going NIMH Genetics Initiative on Bipolar Disorder, we have ascertained 153 multiplex bipolar pedigrees and genotyped them in two waves. We report here the genome scan results for chromosomes 2, 11, 13, 14, and X in the second wave of 56 families. A total of 354 individuals were genotyped and included in the current analyses, including 5 with schizoaffective/bipolar (SA/BP), 139 with bipolar I disorder (BPI), 41 with bipolar II disorder (BP II), and 43 with recurrent unipolar depression (RUP). Linkage analyses were carried out with multi-point parametric and non-parametric affected relative pair methods using three different definitions of the affected phenotype: (model 1) SA/BP and BPI; (model 2) SA/BP, BPI, and BP II; and (model 3) SA/BP, BPI, BP II, and RUP. The best findings were on 11p15.5 (NPL = 2.96, P = 0.002) and Xp11.3 (NPL = 2.19, P = 0.01). These findings did not reach conventional criteria for significance, but they were located near regions that have been identified in previous genetic studies of bipolar disorder. The relatively modest but consistent findings across studies may suggest that these loci harbor susceptibility genes of modest effect in a subset of families. Large samples such as that being collected by the NIMH Initiative will be necessary to examine the heterogeneity and identify these susceptibility genes.