|
1
|
Paribello P, Isayeva U, Pisanu C, Squassina A, Manchia M. Pharmacogenomics and response to lithium in bipolar disorder. Pharmacogenomics 2025; 25:689-706. [PMID: 39998910 PMCID: PMC11901374 DOI: 10.1080/14622416.2025.2470605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 02/19/2025] [Indexed: 02/27/2025] Open
Abstract
AIMS The present review explores the existing evidence on pharmacogenomic tests for prediction of lithium response in the treatment of bipolar disorder. We focused our research article on reports describing findings from genome-wide association studies, polygenic risk scores, and gene expression analyses associated with lithium response. METHODS We conducted a non-systematic review of studies from PubMed/Medline by using terms such as "pharmacogenomics," "GWAS," "gene expression," and "lithium response." Inclusion criteria focused on original research involving human subjects and assessing lithium response outcomes as well as in vitro studies. An extensive pearl-growing strategy was employed to further enlarge the scope of the piece by capitalizing on the knowledge of study authors on the subject. RESULTS The observed results, albeit promising, remain preliminary in terms of clinical relevance. Machine learning combining genetic and clinical data appears associated with moderate success in predicting lithium responsiveness. Gene expression studies and genome-wide association studies have helped identify possible targets of lithium and have the potential to support target-specific drug research. CONCLUSIONS Pharmacogenomics may support further discoveries in precision medicine further enlarging our understanding of the underlying mechanisms of lithium for its efficacy. However, clinical applications currently appear out of reach in the near future.
Collapse
Affiliation(s)
- Pasquale Paribello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
| | - Ulker Isayeva
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Claudia Pisanu
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Alessio Squassina
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Mirko Manchia
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
| |
Collapse
|
|
2
|
Pisanu C, Squassina A. RNA Biomarkers in Bipolar Disorder and Response to Mood Stabilizers. Int J Mol Sci 2023; 24:10067. [PMID: 37373213 DOI: 10.3390/ijms241210067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023] Open
Abstract
Bipolar disorder (BD) is a severe chronic disorder that represents one of the main causes of disability among young people. To date, no reliable biomarkers are available to inform the diagnosis of BD or clinical response to pharmacological treatment. Studies focused on coding and noncoding transcripts may provide information complementary to genome-wide association studies, allowing to correlate the dynamic evolution of different types of RNAs based on specific cell types and developmental stage with disease development or clinical course. In this narrative review, we summarize findings from human studies that evaluated the potential utility of messenger RNAs and noncoding transcripts, such as microRNAs, circular RNAs and long noncoding RNAs, as peripheral markers of BD and/or response to lithium and other mood stabilizers. The majority of available studies investigated specific targets or pathways, with large heterogeneity in the included type of cells or biofluids. However, a growing number of studies are using hypothesis-free designs, with some studies also integrating data on coding and noncoding RNAs measured in the same participants. Finally, studies conducted in neurons derived from induced-pluripotent stem cells or in brain organoids provide promising preliminary findings supporting the power and utility of these cellular models to investigate the molecular determinants of BD and clinical response.
Collapse
Affiliation(s)
- Claudia Pisanu
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy
| | - Alessio Squassina
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy
- Department of Psychiatry, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 2E2, Canada
| |
Collapse
|
|
3
|
Saxena K, Kurian S, Kumar R, Arnold LE, Simkin DR. Mood Disorders in Youth: Complementary and Integrative Medicine. Child Adolesc Psychiatr Clin N Am 2023; 32:367-394. [PMID: 37147043 DOI: 10.1016/j.chc.2022.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Omega-3 polyunsaturated fatty acids, probiotics, vitamin C, vitamin D, folic acid and L-methyl folate, broad-spectrum micronutrients, N-acetylcysteine, physical activity, herbs, bright light therapy, melatonin, saffron, meditation, school-based interventions, and transcranial photobiomodulation are reviewed, with a focus on their use for treating mood disorders in children and adolescents. For each treatment, all published randomized controlled trials are summarized.
Collapse
Affiliation(s)
- Kirti Saxena
- Department of Child and Adolescent Psychiatry, Texas Children's Hospital, 8080 North Stadium Drive, Houston, TX 77054, USA; Department of Psychiatry, Baylor College of Medicine, 1 Moursund Street, Houston, TX 77030, USA.
| | - Sherin Kurian
- Department of Child and Adolescent Psychiatry, Texas Children's Hospital, 8080 North Stadium Drive, Houston, TX 77054, USA; Department of Psychiatry, Baylor College of Medicine, 1 Moursund Street, Houston, TX 77030, USA
| | - Reena Kumar
- Andrew Weil Center for Integrative Medicine, University of Arizona, 655 N Alvernon Way, Suite 120, Tuscon, AZ 85711, USA
| | - L Eugene Arnold
- Department of Psychiatry and Behavioral Health, The Ohio State University College of Medicine, 395E McCampbell Hall, 1581 Dodd Drive, Columbus, OH 43210, USA
| | - Deborah R Simkin
- Department of Psychiatry, Emory University School of Medicine, 8955 Highway 98 West, Suite 204, Miramar Beach, FL 32550, USA
| |
Collapse
|
|
4
|
Zhao XP, Li H, Dai RP. Neuroimmune crosstalk through brain-derived neurotrophic factor and its precursor pro-BDNF: New insights into mood disorders. World J Psychiatry 2022; 12:379-392. [PMID: 35433323 PMCID: PMC8968497 DOI: 10.5498/wjp.v12.i3.379] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 08/22/2021] [Accepted: 01/23/2022] [Indexed: 02/06/2023] Open
Abstract
Mood disorders are the most common mental disorders, affecting approximately 350 million people globally. Recent studies have shown that neuroimmune interaction regulates mood disorders. Brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF, are involved in the neuroimmune crosstalk during the development of mood disorders. BDNF is implicated in the pathophysiology of psychiatric and neurological disorders especially in antidepressant pharmacotherapy. In this review, we describe the functions of BDNF/pro-BDNF signaling in the central nervous system in the context of mood disorders. In addition, we summarize the developments for BDNF and pro-BDNF functions in mood disorders. This review aims to provide new insights into the impact of neuroimmune interaction on mood disorders and reveal a new basis for further development of diagnostic targets and mood disorders.
Collapse
Affiliation(s)
- Xiao-Pei Zhao
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Hui Li
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Ru-Ping Dai
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| |
Collapse
|
|
5
|
Pisanu C, Severino G, De Toma I, Dierssen M, Fusar-Poli P, Gennarelli M, Lio P, Maffioletti E, Maron E, Mehta D, Minelli A, Potier MC, Serretti A, Stacey D, van Westrhenen R, Xicota L, Baune BT, Squassina A. Transcriptional biomarkers of response to pharmacological treatments in severe mental disorders: A systematic review. Eur Neuropsychopharmacol 2022; 55:112-157. [PMID: 35016057 DOI: 10.1016/j.euroneuro.2021.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 10/18/2021] [Accepted: 12/16/2021] [Indexed: 11/04/2022]
Abstract
Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly investigated in patients treated with psychotropic drugs. Findings are promising, but reliable predictive biomarkers of response have yet to be identified. Here we conducted a PRISMA-compliant systematic search of PubMed, Scopus and PsycInfo up to 12 September 2020 for studies investigating RNA expression levels in cells or biofluids from patients with major depressive disorder, schizophrenia or bipolar disorder characterized for response to psychotropic drugs (antidepressants, antipsychotics or mood stabilizers) or adverse effects. Among 5497 retrieved studies, 123 (63 on antidepressants, 33 on antipsychotics and 27 on mood stabilizers) met inclusion criteria. Studies were either focused on mRNAs (n = 96), microRNAs (n = 19) or long non-coding RNAs (n = 1), with only a minority investigating both mRNAs and microRNAs levels (n = 7). The most replicated results include genes playing a role in inflammation (antidepressants), neurotransmission (antidepressants and antipsychotics) or mitochondrial function (mood stabilizers). Compared to those investigating response to antidepressants, studies focused on antipsychotics or mood stabilizers more often showed lower sample size and lacked replication. Strengths and limitations of available studies are presented and discussed in light of the specific designs, methodology and clinical characterization of included patients for transcriptomic compared to DNA-based studies. Finally, future directions of transcriptomics of psychopharmacological interventions in psychiatric disorders are discussed.
Collapse
Affiliation(s)
- Claudia Pisanu
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Giovanni Severino
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Ilario De Toma
- Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Mara Dierssen
- Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Paolo Fusar-Poli
- Early Psychosis: Intervention and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, King's College London, UK; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | - Massimo Gennarelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Pietro Lio
- Department of Computer Science and Technology, University of Cambridge, Cambridge, UK
| | - Elisabetta Maffioletti
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Eduard Maron
- Department of Psychiatry, University of Tartu, Tartu, Estonia; Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK
| | - Divya Mehta
- Queensland University of Technology, Centre for Genomics and Personalised Health, Faculty of Health, Kelvin Grove, Queensland, Australia
| | - Alessandra Minelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | | | - Alessandro Serretti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy
| | - David Stacey
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Roos van Westrhenen
- Parnassia Psychiatric Institute, Amsterdam, The Netherlands; Department of Psychiatry and Neuropsychology, Faculty of Health and Sciences, Maastricht University, Maastricht, The Netherlands; Institute of Psychiatry, Psychology&Neuroscience (IoPPN) King's College London, UK
| | - Laura Xicota
- Paris Brain Institute ICM, Salpetriere Hospital, Paris, France
| | | | - Bernhard T Baune
- Department of Psychiatry, University of Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Alessio Squassina
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
| |
Collapse
|
|
6
|
Karthikeyan S, Dimick MK, Fiksenbaum L, Jeong H, Birmaher B, Kennedy JL, Lanctôt K, Levitt AJ, Miller GE, Schaffer A, Young LT, Youngstrom EA, Andreazza AC, Goldstein BI. Inflammatory markers, brain-derived neurotrophic factor, and the symptomatic course of adolescent bipolar disorder: A prospective repeated-measures study. Brain Behav Immun 2022; 100:278-286. [PMID: 34896179 DOI: 10.1016/j.bbi.2021.11.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 11/15/2021] [Accepted: 11/29/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Numerous studies have found elevated pro-inflammatory markers and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD, or longitudinally in any BD age group. METHODS 79 adolescents, ages 13-19 years, were enrolled, including 43 symptomatic adolescents with BD and 36 age-matched healthy controls (HC). Blood samples were collected from all participants at intake, and repeatedly from BD participants at pre-specified intervals over the course of two years. Serum was assayed for levels of pro-inflammatory markers (c-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor alpha [TNF-α]), BDNF and the anti-inflammatory marker, IL-10. Week-by-week severity of mood symptoms was assessed using semi-structured interviews. RESULTS Adolescents with BD provided an average of 4.6 blood samples, on average every 5.0 months. During the most severe symptomatic interval (i.e., highest sum of mood symptom scores) among BD adolescents, levels of CRP (p = 0.01) and pro- to anti-inflammatory ratios (CRP/IL-10; p < 0.001 and IL-6/IL-10; p = 0.046) were significantly greater, and IL-10 levels (p = 0.004) were significantly lower, vs. HC. There were no differences between BD and HC in IL-6, TNF-α or BDNF. Within BD participants, higher BDNF (p = 0.01) and IL-10 levels (p = 0.001) significantly predicted greater burden of mood symptoms over the subsequent epoch. Moreover, higher CRP levels (p = 0.009) at intake predicted greater time to recovery from the index symptomatic episode. CONCLUSIONS In the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. Future larger studies are warranted.
Collapse
Affiliation(s)
- Sudhir Karthikeyan
- Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada
| | - Mikaela K Dimick
- Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada
| | | | - Hyunjin Jeong
- Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Boris Birmaher
- Department of Psychiatry, Western Psychiatric Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - James L Kennedy
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Krista Lanctôt
- Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Anthony J Levitt
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Gregory E Miller
- Institute for Policy Research & Department of Psychology, Northwestern University, Evanston, IL, USA
| | - Ayal Schaffer
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada
| | - L Trevor Young
- Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Eric A Youngstrom
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ana C Andreazza
- Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Benjamin I Goldstein
- Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
7
|
Kim S, Rush BS, Rice TR. A systematic review of therapeutic ketamine use in children and adolescents with treatment-resistant mood disorders. Eur Child Adolesc Psychiatry 2021; 30:1485-1501. [PMID: 32385697 DOI: 10.1007/s00787-020-01542-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/24/2020] [Indexed: 12/27/2022]
Abstract
Suicide is the second leading cause of death in the United States among individuals aged 10-24, and severe youth depression is often refractory to the current standards of care. Many studies have demonstrated the efficacy of ketamine in reducing depressive symptoms in adults with treatment-resistant mood disorders, though few studies utilizing ketamine in youth populations exist. This systematic review examines the current state of evidence for ketamine use in children with treatment-resistant mood disorders. We conducted a search utilizing two electronic databases for English-language studies investigating the therapeutic effects and side effect profile of ketamine in youth ≤ 19 years of age with a diagnosis of a treatment-resistant mood disorder. Analysis included subjects with treatment-resistant depression with and without psychotic features and with bipolar disorder. Primary outcome measures included the following scales: Montgomery-Asberg Depression Rating Scale, Children's Depression Rating Scale, Children's Depression Rating Scale Revised, Child Bipolar Questionnaire, Overt Aggression Scale, Yale-Brown Obsessive-Compulsive Scale, and Scale for Suicidal Ideation. Four published studies were identified that investigated therapeutic ketamine use in youth for the primary purpose of treating a treatment-resistant psychiatric disorder. Three additional studies that did not meet eligibility criteria were identified and discussed. Ketamine was shown in youth to generally improve depressive symptoms, decrease acute suicidality, and reduce mood lability, though a number of subjects remained resistant to its treatment. These findings substantiate the need for further longitudinal studies investigating ketamine's long-term safety, its efficacy, and abuse potential in the youth.
Collapse
Affiliation(s)
- Susan Kim
- Icahn School of Medicine at Mount Sinai, Babcock Building, 5 West, 1111 Amsterdam Avenue, New York, NY, 10025, USA
| | - Brittany S Rush
- Icahn School of Medicine at Mount Sinai, Babcock Building, 5 West, 1111 Amsterdam Avenue, New York, NY, 10025, USA
| | - Timothy R Rice
- Icahn School of Medicine at Mount Sinai, Babcock Building, 5 West, 1111 Amsterdam Avenue, New York, NY, 10025, USA.
| |
Collapse
|
|
8
|
Baykara B, Koc D, Resmi H, Akan P, Tunca Z, Ozerdem A, Ceylan D, Yalcın NG, Binici NC, Guney SA, Mesman E, Hillegers MHJ, Emiroglu NI. Brain-derived neurotrophic factor in bipolar disorder: Associations with age at onset and illness duration. Prog Neuropsychopharmacol Biol Psychiatry 2021; 108:110075. [PMID: 32798619 DOI: 10.1016/j.pnpbp.2020.110075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/21/2020] [Accepted: 08/11/2020] [Indexed: 01/09/2023]
Abstract
Bipolar disorder (BD) is a heterogeneous disorder that contains neurodevelopmental differences. Defining homogeneous subgroups of BD patients by using age at onset (AAO) as a specifier may promote the classification of biomarkers. This study compares peripheral BDNF levels between pediatric and adult BD patients to investigate the associations between BDNF levels, AAO, and illness duration. We enrolled two groups of euthymic patients, those with pediatric BD (n = 39) and those with adult BD (n = 31), as well as a group of healthy controls (HCs) (n = 90). Participants were assessed using clinical measures and BDNF serum levels were obtained using ELISA. We observed that BDNF levels were comparable between adult BD and HCs, but were clearly lower in pediatric BD than in HCs. In adult BD with AAO ≥30 years, BDNF levels were significantly higher than in adult BD with AAO <30 years. In pediatric BD, patients with prepubertal-onset had higher BDNF levels than those with pubertal-onset. BDNF levels demonstrated the accuracy of being able to distinguish pediatric BD from healthy controls in a receiver operating characteristic (ROC) curve analysis (area under the curve [AUC] = 0.792). In adult BD, higher BDNF levels were associated with later disease onset, but this was not the case in pediatric BD. Finally, reduced BDNF levels were associated with illness duration in adult BD. The findings indicate that BDNF levels in BD patients are associated with AAO. BDNF may, therefore, potentially serve as a developmental marker in BD, when AAO is taken into account.
Collapse
Affiliation(s)
- Burak Baykara
- Department of Child and Adolescent Psychiatry, Dokuz Eylul University, Izmir, Turkey
| | - Dogukan Koc
- Department of Child and Adolescent Psychiatry, Dokuz Eylul University, Izmir, Turkey.
| | - Halil Resmi
- Department of Biochemistry, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Pınar Akan
- Department of Biochemistry, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Zeliha Tunca
- Department of Psychiatry, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Aysegul Ozerdem
- Department of Psychiatry, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; Department of Neurosciences, Dokuz Eylul University, Health Sciences Institute, Izmir, Turkey
| | - Deniz Ceylan
- Department of Psychiatry, Izmir University of Economics, Faculty of Medicine, Izmir, Turkey
| | - Neslihan Gurz Yalcın
- Department of Psychiatry, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Nagihan Cevher Binici
- Department of Child and Adolescent Psychiatry, University of Health Sciences Dr. Behcet Uz Child Disease and Pediatric Surgery Training and Research Hospital, Izmir, Turkey
| | - Sevay Alsen Guney
- Department of Child and Adolescent Psychiatry, Dokuz Eylul University, Izmir, Turkey
| | - Esther Mesman
- Department of Child and Adolescent Psychiatry and Psychology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Manon H J Hillegers
- Department of Child and Adolescent Psychiatry and Psychology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, the Netherlands
| | | |
Collapse
|
|
9
|
Pandey GN, Rizavi HS, Bhaumik R, Zhang H. Chemokines gene expression in the prefrontal cortex of depressed suicide victims and normal control subjects. Brain Behav Immun 2021; 94:266-273. [PMID: 33571631 PMCID: PMC8231709 DOI: 10.1016/j.bbi.2021.01.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 01/03/2023] Open
Abstract
Abnormalities of neuroinflammation have been implicated in the pathogenesis of depression and suicide. This is primarily based on the observation that cytokines, which are major inflammatory molecules and play an important role in depression and suicide, are increased in both serum and in postmortem brain of depressed and suicidal subjects. Another class of immune mediators are chemokines which are primarily involved in chemotactic properties and trafficking of immune cells in the central nervous system (CNS). Chemokines also play an important role in CNS function. Whereas chemokines have been studied in the serum of depressed and suicidal patients, their role in brain of depressed or suicidal subjects is relatively unexplored. We studied the gene expression of several chemokines in the prefrontal cortex (PFC) obtained from depressed suicidal (DS) and normal control (NC) subjects. We determined the mRNA expression of several chemokines belonging to CXCL and CCL groups of chemokines using qPCR array technique and qPCR gene expression validation in 24 DS and 24 NC subjects. The postmortem brain samples were obtained from the Maryland Brain Collection. We found that the mRNA expression of chemokines CXCL1, CXCL2, CXCL3 and CCL2 was significantly decreased in the PFC of DS compared with NC subjects. No significant change was observed in CXCL5, CXCL6, CXCL10, CCL8 and CCL19 between DS and NC subjects. Since many of the chemokines are involved in mediating certain important CNS functions, such as neurotrophic effect, neurogenesis, anti-apoptotic growth factor release, modulation of synaptic transmission, brain development and neuronal loss, decreased levels of chemokines can reduce these functions which may be involved in the pathophysiology of depression.
Collapse
Affiliation(s)
- Ghanshyam N. Pandey
- Corresponding Author: Ghanshyam N. Pandey, Ph.D., University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA, Phone (312) 413-4540, Fax: (312) 413-4547,
| | | | | | | |
Collapse
|
|
10
|
Goldstein BI, Baune BT, Bond DJ, Chen P, Eyler L, Fagiolini A, Gomes F, Hajek T, Hatch J, McElroy SL, McIntyre RS, Prieto M, Sylvia LG, Tsai S, Kcomt A, Fiedorowicz JG. Call to action regarding the vascular-bipolar link: A report from the Vascular Task Force of the International Society for Bipolar Disorders. Bipolar Disord 2020; 22:440-460. [PMID: 32356562 PMCID: PMC7522687 DOI: 10.1111/bdi.12921] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVES The association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular-bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment. METHODS An international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps. RESULTS The association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular-bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets. CONCLUSIONS Further research focused on the vascular-bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.
Collapse
Affiliation(s)
- Benjamin I. Goldstein
- Centre for Youth Bipolar DisorderSunnybrook Health Sciences CentreTorontoONCanada,Departments of Psychiatry & PharmacologyFaculty of MedicineUniversity of TorontoTorontoONCanada
| | - Bernhard T. Baune
- Department of Psychiatry and PsychotherapyUniversity of MünsterMünsterGermany,Department of PsychiatryMelbourne Medical SchoolThe University of MelbourneMelbourneVICAustralia,The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleVICAustralia
| | - David J. Bond
- Department of Psychiatry and Behavioral ScienceUniversity of Minnesota Medical SchoolMinneapolisMNUSA
| | - Pao‐Huan Chen
- Department of PsychiatryTaipei Medical University HospitalTaipeiTaiwan,Department of PsychiatrySchool of MedicineCollege of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Lisa Eyler
- Department of PsychiatryUniversity of California San DiegoSan DiegoCAUSA
| | | | - Fabiano Gomes
- Department of PsychiatryQueen’s University School of MedicineKingstonONCanada
| | - Tomas Hajek
- Department of PsychiatryDalhousie UniversityHalifaxNSCanada,National Institute of Mental HealthKlecanyCzech Republic
| | - Jessica Hatch
- Centre for Youth Bipolar DisorderSunnybrook Health Sciences CentreTorontoONCanada,Departments of Psychiatry & PharmacologyFaculty of MedicineUniversity of TorontoTorontoONCanada
| | - Susan L. McElroy
- Department of Psychiatry and Behavioral NeuroscienceUniversity of Cincinnati College of MedicineCincinnatiOHUSA,Lindner Center of HOPEMasonOHUSA
| | - Roger S. McIntyre
- Departments of Psychiatry & PharmacologyFaculty of MedicineUniversity of TorontoTorontoONCanada,Mood Disorders Psychopharmacology UnitUniversity Health NetworkTorontoONCanada
| | - Miguel Prieto
- Department of PsychiatryFaculty of MedicineUniversidad de los AndesSantiagoChile,Mental Health ServiceClínica Universidad de los AndesSantiagoChile,Department of Psychiatry and PsychologyMayo Clinic College of Medicine and ScienceRochesterMNUSA
| | - Louisa G. Sylvia
- Department of PsychiatryMassachusetts General HospitalBostonMAUSA,Department of PsychiatryHarvard Medical SchoolCambridgeMAUSA
| | - Shang‐Ying Tsai
- Department of PsychiatryTaipei Medical University HospitalTaipeiTaiwan,Department of PsychiatrySchool of MedicineCollege of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Andrew Kcomt
- Hope+Me—Mood Disorders Association of OntarioTorontoONCanada
| | - Jess G. Fiedorowicz
- Departments of Psychiatry, Internal Medicine, & EpidemiologyCarver College of MedicineUniversity of IowaIowa CityIAUSA
| |
Collapse
|
|
11
|
Lin CC, Huang TL. Brain-derived neurotrophic factor and mental disorders. Biomed J 2020; 43:134-142. [PMID: 32386841 PMCID: PMC7283564 DOI: 10.1016/j.bj.2020.01.001] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 01/21/2020] [Accepted: 01/21/2020] [Indexed: 12/26/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that modulates neuroplasticity in the brain, and is one of the most widely investigated molecule in psychiatric disorders. The researches of BDNF emcompassed the advance of investigative techniques of past decades. BDNF researches ranged from protein quantilization, to RNA expression measurements, to DNA sequencing, and lately but not lastly, epigenetic studies. In this review, we will briefly address findings on BDNF protein levels, mRNA expression, Val66Met polymorphism, and epigenetic modifications, in schizophrenia, major depressive disorder (MDD), and bipolar disorder.
Collapse
Affiliation(s)
- Chin-Chuen Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tiao-Lai Huang
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Genomic and Proteomic Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| |
Collapse
|
|
12
|
Ai M, Wang J, Chen J, Wang W, Xu X, Gan Y, Li X, Gou X, Cao J, Lv Z, Chen X, Wang H, Ma Q, Kuang L. Plasma brain-derived neurotrophic factor (BDNF) concentration and the BDNF Val66Met polymorphism in suicide: a prospective study in patients with depressive disorder. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2019; 12:97-106. [PMID: 31308724 PMCID: PMC6614583 DOI: 10.2147/pgpm.s201187] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 05/18/2019] [Indexed: 12/20/2022]
Abstract
Purpose The relationship was investigated between brain-derived neurotrophic factor (BDNF) concentrations, a BDNF polymorphism (196G>A), and the response to selective serotonin reuptake inhibitors (SSRIs) among Chinese patients with major depressive disorder (MDD). Patients and methods A total of 125 patients and 91 healthy controls were enrolled. The disease progression and treatment responses were evaluated using the Hamilton depression rating scale (HAMD24), the Hamilton anxiety scale, the Beck depression index, and BDNF concentrations at the baseline, 4, 8, and 12 weeks after treatment. Responders were defined as patients with at least a 50% decrease in the HAMD24. Results The BDNF concentrations were significantly lower in MDD (947±297 vs 1187±236 pg/mL, p=0.019), in MDD with attempted suicide than those without (779±231 vs 993±298, p=0.024) at the baseline. The BDNF concentrations remarkably increased in response to SSRI treatment. Significant correlations were noted between the BDNF concentrations and suicide ideation or attempted suicide (p<0.01), but not with HAMD24 or depression. BDNF 196G>A correlated with neither suicide ideation nor treatment responses. Conclusion BDNF concentrations were significantly lower in patients with attempted suicide/ideation. BDNF concentrations could serve as a response marker for antidepressant treatment in MDD.
Collapse
Affiliation(s)
- Ming Ai
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jun Wang
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jianmei Chen
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Wo Wang
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xiaoming Xu
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Yao Gan
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xuemei Li
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xinyuan Gou
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jun Cao
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Zhen Lv
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xiaorong Chen
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Hengguang Wang
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Qing Ma
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Li Kuang
- Department of Psychiatry, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.,Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| |
Collapse
|
|
13
|
|
|
14
|
Gomez-Pinilla F, Yang X. System biology approach intersecting diet and cell metabolism with pathogenesis of brain disorders. Prog Neurobiol 2018; 169:76-90. [PMID: 30059718 PMCID: PMC6231047 DOI: 10.1016/j.pneurobio.2018.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 07/15/2018] [Indexed: 12/21/2022]
Abstract
The surge in meals high in calories has prompted an epidemic of metabolic disorders around the world such that the elevated incidence of obese and diabetic individuals is alarming. New research indicates that metabolic disorders pose a risk for neurological and psychiatric conditions including stroke, Alzheimer's disease, Huntington's disease, and depression, all of which have a metabolic component. These relationships are rooted to a dysfunctional interaction between molecular processes that regulate energy metabolism and synaptic plasticity. The strong adaptive force of dietary factors on shaping the brain during evolution can be manipulated to transform the interaction between cell bioenergetics and epigenome with the aptitude to promote long-lasting brain healthiness. A thorough understanding of the association between the broad action of nutrients and brain fitness requires high level data processing empowered with the capacity to integrate information from a multitude of molecular entities and pathways. Nutritional systems biology is emerging as a viable approach to elucidate the multiple molecular layers involved in information processing in cells, tissues, and organ systems in response to diet. Information about the wide range of cellular and molecular interactions elicited by foods on the brain and cognitive plasticity is crucial for the design of public health initiatives for curtailing the epidemic of metabolic and brain disorders.
Collapse
Affiliation(s)
- Fernando Gomez-Pinilla
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| |
Collapse
|
|
15
|
Goldstein BI, Birmaher B, Carlson GA, DelBello MP, Findling RL, Fristad M, Kowatch RA, Miklowitz DJ, Nery FG, Perez‐Algorta G, Van Meter A, Zeni CP, Correll CU, Kim H, Wozniak J, Chang KD, Hillegers M, Youngstrom EA. The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research. Bipolar Disord 2017; 19:524-543. [PMID: 28944987 PMCID: PMC5716873 DOI: 10.1111/bdi.12556] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 08/14/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. METHODS An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. RESULTS Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD. CONCLUSIONS As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.
Collapse
Affiliation(s)
- Benjamin I Goldstein
- Centre for Youth Bipolar DisorderSunnybrook Health Sciences CentreTorontoCanada,Departments of Psychiatry and PharmacologyUniversity of TorontoTorontoCanada
| | - Boris Birmaher
- Department of PsychiatryUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Gabrielle A Carlson
- Department of PsychiatryStony Brook University School of MedicineStony BrookNYUSA
| | - Melissa P DelBello
- Department of Psychiatry & Behavioral NeuroscienceUniversity of CincinnatiCincinnatiOHUSA
| | - Robert L Findling
- Department of Psychiatry & Behavioral SciencesThe Johns Hopkins UniversityBaltimoreMDUSA
| | - Mary Fristad
- Ohio State University Wexner Medical Center/Nationwide Children's HospitalColumbusOHUSA
| | - Robert A Kowatch
- Ohio State University Wexner Medical Center/Nationwide Children's HospitalColumbusOHUSA
| | | | - Fabiano G Nery
- Department of Psychiatry & Behavioral NeuroscienceUniversity of CincinnatiCincinnatiOHUSA
| | | | - Anna Van Meter
- Ferkauf Graduate School of PsychologyYeshiva UniversityBronxNYUSA
| | | | - Christoph U Correll
- The Zucker Hillside HospitalDepartment of PsychiatryNorthwell HealthGlen OaksNYUSA,Department of Psychiatry and Molecular MedicineHofstra Northwell School of MedicineHempsteadNYUSA
| | - Hyo‐Won Kim
- Department of PsychiatryUniversity of Ulsan College of MedicineAsan Medical CenterSeoulKorea
| | - Janet Wozniak
- Clinical and Research Program in Pediatric PsychopharmacologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Kiki D Chang
- Department of PsychiatryStanford UniversityPalo AltoCAUSA
| | - Manon Hillegers
- Department of Child and Adolescent Psychiatry and PsychologyErasmus Medical Center‐SophiaRotterdamThe Netherlands
| | - Eric A Youngstrom
- Department of Psychology and NeuroscienceUniversity of North CarolinaChapel HillNCUSA
| |
Collapse
|
|
16
|
Snijders G, Mesman E, de Wit H, Wijkhuijs A, Nolen WA, Drexhage HA, Hillegers MHJ. Immune dysregulation in offspring of a bipolar parent. Altered serum levels of immune growth factors at adolescent age. Brain Behav Immun 2017; 64:116-123. [PMID: 28392427 DOI: 10.1016/j.bbi.2017.04.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 03/20/2017] [Accepted: 04/05/2017] [Indexed: 10/19/2022] Open
Abstract
Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.
Collapse
Affiliation(s)
- G Snijders
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - E Mesman
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - H de Wit
- Erasmus Medical Center Rotterdam/Department of Immunology, Rotterdam, The Netherlands
| | - A Wijkhuijs
- Erasmus Medical Center Rotterdam/Department of Immunology, Rotterdam, The Netherlands
| | - W A Nolen
- University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - H A Drexhage
- Erasmus Medical Center Rotterdam/Department of Immunology, Rotterdam, The Netherlands
| | - M H J Hillegers
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Erasmus medical Center Rotterdam, Department of Child and Adolescent Psychiatry, Rotterdam, The Netherlands
| |
Collapse
|
|
17
|
Cevher Binici N, Inal Emiroğlu FN, Resmi H, Ellidokuz H. Serum Brain-derived Neurotrophic Factor Levels among Euthymic Adolescents with Bipolar Disorder Type I. Noro Psikiyatr Ars 2017; 53:267-271. [PMID: 28373806 DOI: 10.5152/npa.2015.8832] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 04/21/2015] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity and cellular resilience in brain regions that are involved in mood and that affect regulation. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that regulates neuroplasticity. The aims of the current study were to compare serum BDNF levels in euthymic adolescents with BD type I with those in controls and to investigate the relationship between clinical variables and serum BDNF levels in adolescents with BD type I. METHODS Twenty-five adolescents diagnosed with BD type I and 17 healthy control subjects within the age range of 15-19 years were recruited. Diagnoses were made by two experienced research clinicians using the Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version and the affective module of Washington University in St. Louis Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia-Present State and Lifetime. Blood samples were taken during euthymia, which was defined as Young Mania Rating Scale and Hamilton Depression Rating Scale scores below 7. RESULTS The comparison of BDNF serum levels between the case and healthy control groups revealed no significant differences. In the case group, BDNF levels were significantly lower in patients being currently treated with lithium. CONCLUSION Similar to normal BDNF levels in adult patients with BD, the normal BDNF serum levels that we found in the euthymic state in adolescents and early adulthood may be related to the developmental brain stage in our study group. It may also show a common neurobiological basis of pediatric and adult BD. Further investigations evaluating BDNF levels in different mood states could help identify the role of BDNF in the underlying pathophysiology of BD.
Collapse
Affiliation(s)
- Nagihan Cevher Binici
- Clinic of Child and Adolescent Psychiatry, Dr. Behçet Uz Pediatrics and Surgery Training and Research Hospital, İzmir, Turkey
| | | | - Halil Resmi
- Department of Medical Biochemistry, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Hülya Ellidokuz
- Department of Preventive Oncology, Dokuz Eylül University School of Medicine, İzmir, Turkey
| |
Collapse
|
|
18
|
Amodeo DA, Grospe G, Zang H, Dwivedi Y, Ragozzino ME. Cognitive flexibility impairment and reduced frontal cortex BDNF expression in the ouabain model of mania. Neuroscience 2017; 345:229-242. [PMID: 27267245 PMCID: PMC5136525 DOI: 10.1016/j.neuroscience.2016.05.058] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 05/25/2016] [Accepted: 05/27/2016] [Indexed: 11/26/2022]
Abstract
Central infusion of the Na+/K+-ATPase inhibitor, ouabain in rats serves as an animal model of mania because it leads to hyperactivity, as well as reproduces ion dysregulation and reduced brain-derived neurotrophic factor (BDNF) levels similar to that observed in bipolar disorder. Bipolar disorder is also associated with cognitive inflexibility and working memory deficits. It is unknown whether ouabain treatment in rats leads to similar cognitive flexibility and working memory deficits. The present study examined the effects of an intracerebral ventricular infusion of ouabain in rats on spontaneous alternation, probabilistic reversal learning and BDNF expression levels in the frontal cortex. Ouabain treatment significantly increased locomotor activity, but did not affect alternation performance in a Y-maze. Ouabain treatment selectively impaired reversal learning in a spatial discrimination task using an 80/20 probabilistic reinforcement procedure. The reversal learning deficit in ouabain-treated rats resulted from an impaired ability to maintain a new choice pattern (increased regressive errors). Ouabain treatment also decreased sensitivity to negative feedback during the initial phase of reversal learning. Expression of BDNF mRNA and protein levels was downregulated in the frontal cortex which also negatively correlated with regressive errors. These findings suggest that the ouabain model of mania may be useful in understanding the neuropathophysiology that contributes to cognitive flexibility deficits and test potential treatments to alleviate cognitive deficits in bipolar disorder.
Collapse
Affiliation(s)
- Dionisio A Amodeo
- Department of Psychology, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - Gena Grospe
- Department of Psychology, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - Hui Zang
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, United States
| | - Yogesh Dwivedi
- Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35209, United States
| | - Michael E Ragozzino
- Department of Psychology, University of Illinois at Chicago, Chicago, IL 60607, United States.
| |
Collapse
|
|
19
|
Brain-derived neurotrophic factor protein and mRNA levels in patients with bipolar mania - A preliminary study. Biomed J 2016; 39:272-276. [PMID: 27793269 PMCID: PMC6139608 DOI: 10.1016/j.bj.2016.08.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 12/28/2015] [Indexed: 12/15/2022] Open
Abstract
Background Brain-derived neurotrophic factor (BDNF) protein or mRNA levels may be involved in the pathophysiology of bipolar disorder. However, the results were inconsistent. We aimed to simultaneously investigate the relationship of BDNF protein and mRNA levels in peripheral blood of patients with bipolar mania. Methods Patients with bipolar mania (n = 30) and healthy controls (n = 30) were recruited during our one-year study. Psychiatric diagnoses were made according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria. The scores of the Young Mania Rating Scale (YMRS) of patients with bipolar mania were greater than 26. All participants had peripheral blood drawn to analyze the serum BDNF protein and mRNA levels. Results Using t-test, patients with bipolar mania had a lower BDNF protein and mRNA levels than did the healthy controls (p < 0.001 and 0.049, respectively), however, the statistical significances were lost after analysis of co-variance adjusted for age and body mass index. Twenty seven out of 30 patients with bipolar mania remained in the study after the 4 weeks of mood stabilizer treatment. Patients' BDNF protein and mRNA levels did not change significantly after 4-week treatment. Conclusions Our study found that serum BDNF protein and mRNA levels in patients with bipolar mania were lower than healthy controls, but a larger sample size will be needed to confirm this finding.
Collapse
|
|
20
|
Zeni CP, Tramontina S, Aguiar BW, Salatino-Oliveira A, Pheula GF, Sharma A, Stertz L, Moreira Maia CR, Hutz M, Kapczinski FP, Rohde LA. BDNF Val66Met polymorphism and peripheral protein levels in pediatric bipolar disorder and attention-deficit/hyperactivity disorder. Acta Psychiatr Scand 2016; 134:268-74. [PMID: 27209073 DOI: 10.1111/acps.12587] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/18/2016] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Frontiers between pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) are not well defined. Few studies have addressed potentially different neurobiological factors between the two disorders. Brain-derived neurotrophic factor (BDNF) has been increasingly recognized for its etiologic and prognostic role in adult bipolar disorder (BD) studies. This study aimed to examine the BDNF gene polymorphism and potential alterations in BDNF serum levels in the pediatric ADHD patients with or without comorbid BD illness. METHOD We assessed the non-synonymous single-nucleotide polymorphism in the BDNF gene (rs6265/Val66Met) and its serum levels in children and adolescents with BD comorbid with ADHD (BD + ADHD) and ADHD alone. Children and adolescents were assessed for psychiatric diagnoses using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). RESULTS Using Analysis of covariance (ancova) we detected a significant group effect (patients with BD + ADHD had higher serum levels than those with ADHD - F80,3 = 8.73, P = 0.005). CONCLUSION Although the Val66Met polymorphism at the BDNF gene does not seem to play a significant role in children and adolescents with BD or ADHD, BDNF serum levels deserve further attention in future research on neurobiological aspects of BD and ADHD.
Collapse
Affiliation(s)
- C P Zeni
- Juvenile Bipolar Disorder Outpatient Program (Programa para Crianças e Adolescentes com Transtorno Bipolar - ProCAB), Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - S Tramontina
- Juvenile Bipolar Disorder Outpatient Program (Programa para Crianças e Adolescentes com Transtorno Bipolar - ProCAB), Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - B W Aguiar
- Bipolar Disorder Unit, Molecular Psychiatry Unit, National Institute for Translational Medicine, CNPq, Porto Alegre, Brazil
| | - A Salatino-Oliveira
- Department of Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - G F Pheula
- Juvenile Bipolar Disorder Outpatient Program (Programa para Crianças e Adolescentes com Transtorno Bipolar - ProCAB), Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - A Sharma
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - L Stertz
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.,Bipolar Disorder Unit, Molecular Psychiatry Unit, National Institute for Translational Medicine, CNPq, Porto Alegre, Brazil
| | - C R Moreira Maia
- ADHD Outpatient Program (PRODAH), Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - M Hutz
- Department of Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - F P Kapczinski
- Bipolar Disorder Unit, Molecular Psychiatry Unit, National Institute for Translational Medicine, CNPq, Porto Alegre, Brazil
| | - L A Rohde
- Juvenile Bipolar Disorder Outpatient Program (Programa para Crianças e Adolescentes com Transtorno Bipolar - ProCAB), Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,ADHD Outpatient Program (PRODAH), Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,National Institute of Developmental Psychiatry for Children and Adolescents, Porto Alegre, Brazil
| |
Collapse
|
|
21
|
Inal-Emiroglu FN, Resmi H, Karabay N, Guleryuz H, Baykara B, Cevher N, Akay A. Decreased right hippocampal volumes and neuroprogression markers in adolescents with bipolar disorder. Neuropsychobiology 2016; 71:140-8. [PMID: 25925781 DOI: 10.1159/000375311] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 01/12/2015] [Indexed: 11/19/2022]
Abstract
OBJECTIVES The aim of the present study was to assess differences and correlations between the hippocampal volumes (HCVs), serum nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels in adolescents with bipolar disorder (BP) compared to healthy controls. METHODS Using structural magnetic resonance imaging, we compared HCVs of 30 patients with euthymic BP who were already enrolled in a naturalistic clinical follow-up. For comparison, we enrolled 23 healthy controls between the ages of 13 and 19. The boundaries of the hippocampus were outlined manually. The BDNF and NGF serum levels were measured with the sandwich ELISA. RESULTS The groups did not differ in the right or left HCVs or in the NGF or BDNF serum levels. However, negative correlations were found between the right HCVs and the duration of the disorder and medication and positive correlations were found between the duration of the medications and the NGF and BDNF levels in the patient group. Additionally, positive correlations were found between the follow-up period and left normalized HCVs in both the BP and lithium-treated groups. CONCLUSIONS The right HCVs may vary with illness duration and the medication used to treat BP; NGF and BDNF levels may be affected by long-term usage. Further research is needed to determine whether these variables and their structural correlates are associated with clinical or functional differences between adolescents with BP and healthy controls.
Collapse
Affiliation(s)
- F Neslihan Inal-Emiroglu
- Child and Adolescent Psychiatry Department, Dokuz Eylül University Medical School, Izmir, Turkey
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Nassan M, Croarkin PE, Luby JL, Veldic M, Joshi PT, McElroy SL, Post RM, Walkup JT, Cercy K, Geske JR, Wagner KD, Cuellar-Barboza AB, Casuto L, Lavebratt C, Schalling M, Jensen PS, Biernacka JM, Frye MA. Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder. Bipolar Disord 2015; 17:645-652. [PMID: 26528762 PMCID: PMC4672380 DOI: 10.1111/bdi.12323] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 04/03/2015] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association. METHODS DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects. RESULTS Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04). CONCLUSIONS These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder.
Collapse
Affiliation(s)
- Malik Nassan
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - Paul E Croarkin
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - Joan L Luby
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Marin Veldic
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - Paramjit T Joshi
- Department of Psychiatry and Behavioral Sciences, Children's National Medical Center, Washington, DC, USA
| | | | | | - John T Walkup
- Department of Psychiatry, Weil Cornell Medical College, New York, NY, USA
| | - Kelly Cercy
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Jennifer R Geske
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Karen D Wagner
- Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, TX, USA
| | | | | | - Catharina Lavebratt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | | | - Joanna M Biernacka
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Mark A Frye
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
23
|
The bipolar depression electrical treatment trial (BETTER): design, rationale, and objectives of a randomized, sham-controlled trial and data from the pilot study phase. Neural Plast 2015; 2015:684025. [PMID: 25878904 PMCID: PMC4387983 DOI: 10.1155/2015/684025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 01/11/2015] [Indexed: 02/06/2023] Open
Abstract
Background. Bipolar depression (BD) is a prevalent condition, with poor therapeutic options and a high degree of refractoriness. This justifies the development of novel treatment strategies, such as transcranial direct current stimulation (tDCS) that showed promising results in unipolar depression. Methods. We describe a randomized, sham-controlled, double-blinded trial using tDCS for refractory, acutely symptomatic BD (the bipolar depression electrical treatment trial, BETTER). Sixty patients will be enrolled and assessed with clinical and neuropsychological tests. The primary outcome is change (over time and across groups) in the scores of the Hamilton Depression Rating Scale (17 items). Biological markers such as blood neurotrophins and interleukins, genetic polymorphisms, heart rate variability, and motor cortical excitability will be assessed. Twelve anodal-left/cathodal-right 2 mA tDCS sessions over the dorsolateral prefrontal cortex will be performed in 6 weeks. Results. In the pilot phase, five patients received active tDCS and were double-blindly assessed, two presenting clinical response. TDCS was well-tolerated, with no changes in cognitive scores. Conclusion. This upcoming clinical trial will address the efficacy of tDCS for BD on different degrees of refractoriness. The evaluation of biological markers will also help in understanding the pathophysiology of BD and the mechanisms of action of tDCS.
Collapse
|
|
24
|
Pavuluri MN, Lee MS, Pandey G. Lithium response viewed as a biomarker to predict developmental psychopathology in offspring with bipolar disorder: a commentary. Bipolar Disord 2015; 17:224-32. [PMID: 25523965 DOI: 10.1111/bdi.12280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 09/15/2014] [Indexed: 12/27/2022]
Affiliation(s)
- Mani N Pavuluri
- Pediatric Brain Research and Intervention Center, University of Illinois at Chicago, Chicago, IL, USA
| | | | | |
Collapse
|
|
25
|
Mesman E, Hillegers MH, Ambree O, Arolt V, Nolen WA, Drexhage HA. Monocyte activation, brain-derived neurotrophic factor (BDNF), and S100B in bipolar offspring: a follow-up study from adolescence into adulthood. Bipolar Disord 2015; 17:39-49. [PMID: 25039314 DOI: 10.1111/bdi.12231] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 04/29/2014] [Indexed: 11/29/2022]
Abstract
OBJECTIVES There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder; however, their precise role remains unclear. In this study, we aimed to evaluate neuro-immune changes in a prospective study on children of patients with bipolar disorder. METHODS Bipolar offspring, from the prospective Dutch bipolar offspring study (n = 140), were evaluated cross-sectionally within a longitudinal context at adolescence, young adulthood, and adulthood. We examined the expression of 44 inflammation-related genes in monocytes, the cytokines pentraxin 3 (PTX3), chemokine ligand 2 (CCL2), and interleukin-1β (IL-1β), and brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B) in the serum of bipolar offspring and healthy controls. RESULTS During adolescence, bipolar offspring showed increased inflammatory gene expression in monocytes, high serum PTX3 levels, but normal CCL2 levels. BDNF levels were decreased, while S100B levels were normal. During young adulthood, monocyte activation remained, although to a lesser degree. Serum PTX3 levels remained high, and signs of monocyte migration became apparent through increased CCL2 levels. BDNF and S100B levels were not measured. At adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased. Both BDNF and S100B were now increased. Abnormalities were independent of psychopathology state at all stages. CONCLUSIONS This study suggests an aberrant neuro-immune state in bipolar offspring, which followed a dynamic course from adolescence into adulthood and was present irrespective of lifetime or future mood disorders. We therefore assumed that the aberrant neuro-immune state reflects a general state of vulnerability for mood disorders rather than being of direct predictive value.
Collapse
Affiliation(s)
- Esther Mesman
- Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | | | | | | |
Collapse
|
|
26
|
Lim CH, Zain SM, Reynolds GP, Zain MA, Roffeei SN, Zainal NZ, Kanagasundram S, Mohamed Z. Genetic association of LMAN2L gene in schizophrenia and bipolar disorder and its interaction with ANK3 gene polymorphism. Prog Neuropsychopharmacol Biol Psychiatry 2014; 54:157-62. [PMID: 24914473 DOI: 10.1016/j.pnpbp.2014.05.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 05/19/2014] [Accepted: 05/29/2014] [Indexed: 12/22/2022]
Abstract
Recent studies have shown that bipolar disorder (BPD) and schizophrenia (SZ) share some common genetic risk factors. This study aimed to examine the association between candidate single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) and risk of BPD and SZ. A total of 715 patients (244 BPD and 471 SZ) and 593 controls were genotyped using the Sequenom MassARRAY platform. We showed a positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population (P-value=0.001 and 0.009, respectively). Following stratification by ethnicity, variants of the ANK3 gene (rs1938516 and rs10994336) were found to be associated with BPD in Malays (P-value=0.001 and 0.006, respectively). Furthermore, an association exists between another variant of LMAN2L (rs2271893) and SZ in the Malay and Indian ethnic groups (P-value=0.003 and 0.002, respectively). Gene-gene interaction analysis revealed a significant interaction between the ANK3 and LMAN2L genes (empirical P=0.0107). Significant differences were shown between patients and controls for two haplotype frequencies of LMAN2L: GA (P=0.015 and P=0.010, for BPD and SZ, respectively) and GG (P=0.013 for BPD). Our study showed a significant association between LMAN2L and risk of both BPD and SZ.
Collapse
Affiliation(s)
- Chor Hong Lim
- The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
| | - Shamsul Mohd Zain
- The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Gavin P Reynolds
- Biomedical Research Centre, Sheffield Hallam University, City Campus, Howard Street, Sheffield S11WB, UK
| | - Mohd Aizat Zain
- The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Siti Norsyuhada Roffeei
- The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Nor Zuraida Zainal
- Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Sharmilla Kanagasundram
- Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Zahurin Mohamed
- The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
27
|
Spratt EG, Granholm AC, Carpenter LA, Boger HA, Papa CE, Logan S, Chaudhary H, Boatwright SW, Brady KT. Pilot Study and Review: Physiological Differences in BDNF, a Potential Biomarker in Males and Females with Autistic Disorder. ACTA ACUST UNITED AC 2014; 3:19-26. [PMID: 26866045 PMCID: PMC4746008 DOI: 10.9734/indj/2015/12118] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Aims There is a need for more biologic research in autistic disorder (AD) to determine if biomarkers exist that would be useful for correlating to symptom severity and/or clinical improvement during treatment. Given the fact that AD is 4 times more common in males than females, gender differences in physiological biomarkers may be present. One potential biomarker that has begun to be studied is brain-derived neurotropic factor (BDNF), a peptide involved in the regulation of neuronal cell survival, differentiation, and plasticity, and possessing an ability to influence neurotransmitter systems by modulating gene expression. This pilot study examined whether serum BDNF differed according to gender in children with AD and whether differences were associated with a behavioral phenotype or severity of illness. Study Design Data for this investigation were collected during the participants’ baseline visit of an intervention study. Participants were males (n=29) and females (n=7), aged 5 to 12 years diagnosed with AD. Baseline serum BDNF concentration was determined for comparison to clinical ratings using an autism severity measure and the Pervasive Developmental Disorder-Behavior Inventory (PDD-BI). Results BDNF serum concentrations were higher in females (p<0.049). The baseline BDNF value corresponded significantly to hyperactivity in females (p<0.0002) but not in males. BDNF did not correlate with severity of disease in either gender. Conclusion Although this is a small study, a better understanding of the central role of BDNF may provide insight into the pathophysiology of the disease and elucidate why gender differences exist in prevalence and behavioral phenotype of AD.
Collapse
Affiliation(s)
- Eve G Spratt
- Department of Pediatrics, Division of Developmental and Behavioral Pediatrics, Medical University of South Carolina, Charleston, SC, United States; Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Ann-Charlotte Granholm
- Department of Neuroscience and the Center on Aging, Medical University of South Carolina, Charleston, SC, United States
| | - Laura A Carpenter
- Department of Pediatrics, Division of Developmental and Behavioral Pediatrics, Medical University of South Carolina, Charleston, SC, United States
| | - Heather A Boger
- Department of Neuroscience and the Center on Aging, Medical University of South Carolina, Charleston, SC, United States
| | - Carrie E Papa
- Department of Pediatrics, Division of Developmental and Behavioral Pediatrics, Medical University of South Carolina, Charleston, SC, United States
| | - Sarah Logan
- Department of Healthcare Leadership and Management, Medical University of South Carolina, Charleston, SC, United States
| | - Humera Chaudhary
- Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Sarah-Wade Boatwright
- School of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Kathleen T Brady
- Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, United States
| |
Collapse
|
|
28
|
Severino G, Squassina A, Costa M, Pisanu C, Calza S, Alda M, Del Zompo M, Manchia M. Pharmacogenomics of bipolar disorder. Pharmacogenomics 2014; 14:655-74. [PMID: 23570469 DOI: 10.2217/pgs.13.51] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Bipolar disorder (BD) is a lifelong severe psychiatric condition with high morbidity, disability and excess mortality. The longitudinal clinical trajectory of BD is significantly modified by pharmacological treatment(s), both in acute and in long-term stages. However, a large proportion of BD patients have inadequate response to pharmacological treatments. Pharmacogenomic research may lead to the identification of molecular predictors of treatment response. When integrated with clinical information, pharmacogenomic findings may be used in the future to determine the probability of response/nonresponse to treatment on an individual basis. Here we present a selective review of pharmacogenomic findings in BD. In light of the evidence suggesting a genetic effect of lithium reponse in BD, we focused particularly on the pharmacogenomic literature relevant to this trait. The article contributes a detailed overview of the current status of pharmacogenomics in BD and offers a perspective on the challenges that can hinder its transition to personalized healthcare.
Collapse
Affiliation(s)
- Giovanni Severino
- Laboratory of Molecular Genetics, Section of Neuroscience & Clinical Pharmacology, Department of Biomedical Sciences, Sp 8, Sestu-Monserrato, Km 0.700 CA, University of Cagliari, Cagliari, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Pfaffenseller B, Fries GR, Wollenhaupt-Aguiar B, Colpo GD, Stertz L, Panizzutti B, Magalhães PVS, Kapczinski F. Neurotrophins, inflammation and oxidative stress as illness activity biomarkers in bipolar disorder. Expert Rev Neurother 2014; 13:827-42. [DOI: 10.1586/14737175.2013.811981] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
30
|
Jin L, Zhu W, Yu Y, Kou C, Meng X, Tao Y, Guo J. Nonparametric tests of associations with disease based on U-statistics. Ann Hum Genet 2013; 78:141-53. [PMID: 24328673 DOI: 10.1111/ahg.12049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 09/01/2013] [Indexed: 11/25/2022]
Abstract
In case-control studies, association analysis was designed to test whether genetic variants were associated with human diseases. To evaluate the association, analysing one genetic marker at a time suffered from weak power, because of the correction for multiple testing and possibly small genetic effects. An alternative strategy was to test simultaneous effects of multiple markers, which was believed to be more powerful. However, when the number of markers under investigation was large, they would be subjected to weak power as well, because of the greater degrees of freedom. To conquer these limitations in case-control studies, we proposed a novel method that could test joint association of several loci (i.e. haplotype), with only a single degree of freedom. In this research, we developed a nonparametric approach, which was based on U-statistics. We also introduced a new kernel for U-statistic, which could combine the haplotype structure information, and was expected to enhance the power. Simulations indicated that our proposed approach offered merits in identifying the associations between diseases and haplotypes. Application of our method to a study of candidate genes for internalising disorder illustrated its virtue in utility and interpretation, and provided an excellent result in detecting the associations.
Collapse
Affiliation(s)
- Lina Jin
- Key Laboratory for Applied Statistics of MOE and School of Mathematics and Statistics, Northeast Normal University, Changchun, Jilin, 130024, China; School of Public Health, Jilin University, Changchun, Jilin, 130021, China
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Toward clinically applicable biomarkers in bipolar disorder: focus on BDNF, inflammatory markers, and endothelial function. Curr Psychiatry Rep 2013; 15:425. [PMID: 24243532 PMCID: PMC3926699 DOI: 10.1007/s11920-013-0425-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The importance of biomarkers to many branches of medicine is illustrated by their utility in diagnosis and monitoring treatment response and outcome. There is much enthusiasm in the field of mood disorders on the emergence of clinically relevant biomarkers with several potential targets. While there are generally accepted criteria to establish a biomarker, such approaches are premature for our field as we acquire evidence on the most relevant candidates. A number of components of the inflammatory pathway are supported by published data together with an increasing focus on brain-derived neurotrophic factor. These markers may have measurable impacts on endothelial function, which may be particularly amenable to study in clinical samples. The adolescent population is a key focus as identifying biomarkers before the onset of comorbid medical conditions and which may help direct early intervention seem especially promising. A systematic approach to biomarker development in mood disorders is clearly warranted.
Collapse
|
|
32
|
Wu R, Fan J, Zhao J, Calabrese JR, Gao K. The relationship between neurotrophins and bipolar disorder. Expert Rev Neurother 2013; 14:51-65. [DOI: 10.1586/14737175.2014.863709] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
33
|
Frey BN, Andreazza AC, Houenou J, Jamain S, Goldstein BI, Frye MA, Leboyer M, Berk M, Malhi GS, Lopez-Jaramillo C, Taylor VH, Dodd S, Frangou S, Hall GB, Fernandes BS, Kauer-Sant'Anna M, Yatham LN, Kapczinski F, Young LT. Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Aust N Z J Psychiatry 2013; 47:321-32. [PMID: 23411094 DOI: 10.1177/0004867413478217] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.
Collapse
Affiliation(s)
- Benicio N Frey
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Lim CS, Baldessarini RJ, Vieta E, Yucel M, Bora E, Sim K. Longitudinal neuroimaging and neuropsychological changes in bipolar disorder patients: Review of the evidence. Neurosci Biobehav Rev 2013; 37:418-35. [PMID: 23318228 DOI: 10.1016/j.neubiorev.2013.01.003] [Citation(s) in RCA: 141] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 12/23/2012] [Accepted: 01/03/2013] [Indexed: 01/23/2023]
Affiliation(s)
- Chin Siang Lim
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | | | | | | | | | | |
Collapse
|
|
35
|
Min HJ, Cho HS, Kim SJ, Seok JH, Lee E, Jon DI. Association of the Brain-derived Neurotrophic Factor Gene and Clinical Features of Bipolar Disorder in Korea. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2012; 10:163-7. [PMID: 23430274 PMCID: PMC3569161 DOI: 10.9758/cpn.2012.10.3.163] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Revised: 06/15/2012] [Accepted: 06/26/2012] [Indexed: 01/19/2023]
Abstract
Objective Brain-derived neurotrophic factor (BDNF) plays an important role in cell survival, differentiation, and cell death as well as in neural plasticity. Recent studies have suggested that BDNF is involved in the pathogenesis of bipolar disorder. The aim of this study was to investigate the association of the genetic variations of the BDNF gene with bipolar disorder in Korea. We also studied the possible association of these genetic variants with clinical features. Methods The allelic and genotypic distributions of Val66Met polymorphism of the BDNF gene were analyzed using a polymerase chain reaction-based method in 184 bipolar patients and 214 controls. Analysis was performed to investigate an association of the Val66Met polymorphism of the BDNF gene and the clinical features in bipolar patients. Results No significant difference was found between bipolar patients and controls in the genotype and allele frequencies for the investigated BDNF polymorphism. However, the age of onset of bipolar disorder among the Val/Val (25.57), Val/Met (30.42) and Met/Met (32.45) genotype groups were significantly different (p=0.037). Conclusion This study suggests that Val66Met polymorphisms are unlikely to contribution to the genetic predisposition to bipolar disorder as a whole. But Val66Met polymorphism may be associated with age of onset of the disorder, further studies designed to investigate the relationship in a larger population may be warranted.
Collapse
Affiliation(s)
- Hye Ji Min
- Department of Psychiatry, Hallym University College of Medicine, Anyang, Korea
| | | | | | | | | | | |
Collapse
|
|
36
|
D'Addario C, Dell'Osso B, Palazzo MC, Benatti B, Lietti L, Cattaneo E, Galimberti D, Fenoglio C, Cortini F, Scarpini E, Arosio B, Di Francesco A, Di Benedetto M, Romualdi P, Candeletti S, Mari D, Bergamaschini L, Bresolin N, Maccarrone M, Altamura AC. Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology 2012; 37:1647-55. [PMID: 22353757 PMCID: PMC3358733 DOI: 10.1038/npp.2012.10] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 12/21/2011] [Accepted: 12/23/2011] [Indexed: 01/08/2023]
Abstract
The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.
Collapse
Affiliation(s)
- Claudio D'Addario
- Department of Biomedical Sciences, University of Teramo, Teramo, Italy
| | - Bernardo Dell'Osso
- Department of Clinical Psychiatry, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Mental Health, Department of Psychiatry, Milano, Italy
| | - Maria Carlotta Palazzo
- Department of Clinical Psychiatry, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Mental Health, Department of Psychiatry, Milano, Italy
| | - Beatrice Benatti
- Department of Clinical Psychiatry, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Mental Health, Department of Psychiatry, Milano, Italy
| | - Licia Lietti
- Department of Clinical Psychiatry, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Mental Health, Department of Psychiatry, Milano, Italy
| | - Elisabetta Cattaneo
- Department of Clinical Psychiatry, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Mental Health, Department of Psychiatry, Milano, Italy
| | - Daniela Galimberti
- Department of Neurological Sciences, Centro Dino Ferrari, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Neurology, Milano, Italy
| | - Chiara Fenoglio
- Department of Neurological Sciences, Centro Dino Ferrari, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Neurology, Milano, Italy
| | - Francesca Cortini
- Department of Neurological Sciences, Centro Dino Ferrari, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Neurology, Milano, Italy
| | - Elio Scarpini
- Department of Neurological Sciences, Centro Dino Ferrari, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Neurology, Milano, Italy
| | - Beatrice Arosio
- Geriatric Unit, Fondazione IRCCS Cà Granda Osp Maggiore Policlinico, University of Milan, Milano, Italy
| | | | | | | | | | - Daniela Mari
- Geriatric Unit, Fondazione IRCCS Cà Granda Osp Maggiore Policlinico, University of Milan, Milano, Italy
| | | | - Nereo Bresolin
- Department of Neurological Sciences, Centro Dino Ferrari, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Neurology, Milano, Italy
| | - Mauro Maccarrone
- Department of Biomedical Sciences, University of Teramo, Teramo, Italy
- European Center for Brain Research (CERC)/Santa Lucia Foundation, Rome, Italy
| | - A Carlo Altamura
- Department of Clinical Psychiatry, Università degli Studi di Milano, Fondazione IRRCS Cà Granda, Ospedale Maggiore Policlinico, Department of Mental Health, Department of Psychiatry, Milano, Italy
| |
Collapse
|
|
37
|
Ebstein RP, Knafo A, Mankuta D, Chew SH, Lai PS. The contributions of oxytocin and vasopressin pathway genes to human behavior. Horm Behav 2012; 61:359-79. [PMID: 22245314 DOI: 10.1016/j.yhbeh.2011.12.014] [Citation(s) in RCA: 200] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 12/20/2011] [Accepted: 12/21/2011] [Indexed: 01/23/2023]
Abstract
Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.
Collapse
Affiliation(s)
- Richard P Ebstein
- Department of Psychology, National University of Singapore, Singapore.
| | | | | | | | | |
Collapse
|
|
38
|
Yi Z, Li Z, Yu S, Yuan C, Hong W, Wang Z, Cui J, Shi T, Fang Y. Blood-based gene expression profiles models for classification of subsyndromal symptomatic depression and major depressive disorder. PLoS One 2012; 7:e31283. [PMID: 22348066 PMCID: PMC3278427 DOI: 10.1371/journal.pone.0031283] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 01/05/2012] [Indexed: 12/28/2022] Open
Abstract
Subsyndromal symptomatic depression (SSD) is a subtype of subthreshold depressive and also lead to significant psychosocial functional impairment as same as major depressive disorder (MDD). Several studies have suggested that SSD is a transitory phenomena in the depression spectrum and is thus considered a subtype of depression. However, the pathophysioloy of depression remain largely obscure and studies on SSD are limited. The present study compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD, and matched controls (8 subjects in each group). Support vector machines (SVMs) were utilized for training and testing on candidate signature expression profiles from signature selection step. Firstly, we identified 63 differentially expressed SSD signatures in contrast to control (P< = 5.0E-4) and 30 differentially expressed MDD signatures in contrast to control, respectively. Then, 123 gene signatures were identified with significantly differential expression level between SSD and MDD. Secondly, in order to conduct priority selection for biomarkers for SSD and MDD together, we selected top gene signatures from each group of pair-wise comparison results, and merged the signatures together to generate better profiles used for clearly classify SSD and MDD sets in the same time. In details, we tried different combination of signatures from the three pair-wise compartmental results and finally determined 48 gene expression signatures with 100% accuracy. Our finding suggested that SSD and MDD did not exhibit the same expressed genome signature with peripheral blood leukocyte, and blood cell-derived RNA of these 48 gene models may have significant value for performing diagnostic functions and classifying SSD, MDD, and healthy controls.
Collapse
Affiliation(s)
- Zhenghui Yi
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zezhi Li
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shunying Yu
- Department of Genetics, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengmei Yuan
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wu Hong
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zuowei Wang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Cui
- The Center for Bioinformatics and Institute of Biomedical Sciences, The College of Life Sciences, East China Normal University, Shanghai, China
| | - Tieliu Shi
- The Center for Bioinformatics and Institute of Biomedical Sciences, The College of Life Sciences, East China Normal University, Shanghai, China
- Shanghai Information Center for Life Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yiru Fang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
39
|
Goldstein BI, Collinger KA, Lotrich F, Marsland AL, Gill MK, Axelson DA, Birmaher B. Preliminary findings regarding proinflammatory markers and brain-derived neurotrophic factor among adolescents with bipolar spectrum disorders. J Child Adolesc Psychopharmacol 2011; 21:479-84. [PMID: 22040193 PMCID: PMC3205790 DOI: 10.1089/cap.2011.0009] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mood symptoms in adult bipolar disorder are associated with increased proinflammatory markers and decreased brain-derived neurotrophic factor (BDNF). We examined serum interleukin-6, high-sensitivity C-reactive protein (hsCRP), and BDNF among 30 bipolar disorder adolescents. Hypomanic/manic symptoms were positively associated with hsCRP. BDNF levels were negatively associated with interleukin-6. Forty percent had cardiovascular high-risk hsCRP levels. Larger longitudinal studies are warranted.
Collapse
Affiliation(s)
- Benjamin I. Goldstein
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Faculty of Medicine, University of Toronto, Toronto, Canada.,Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Katelyn A. Collinger
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Francis Lotrich
- Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anna L. Marsland
- Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mary-Kay Gill
- Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - David A. Axelson
- Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Boris Birmaher
- Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| |
Collapse
|
|
40
|
Are retinoids potential therapeutic agents in disorders of social cognition including autism? FEBS Lett 2011; 585:1529-36. [PMID: 21557943 DOI: 10.1016/j.febslet.2011.05.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2011] [Revised: 05/03/2011] [Accepted: 05/03/2011] [Indexed: 11/20/2022]
Abstract
Increasing evidence suggests that the nonapeptide, oxytocin (OT), helps shape social and affiliative behaviors not only in lower mammals but also in humans. Recently, an essential mediator of brain OT release has been discovered, ADP-ribosyl cyclase and/or CD38. We have subsequently shown that polymorphisms across the CD38 gene are associated with autism spectrum disorders (ASD). Notably, CD38 expression in lymphoblastoid cells (LBC) is reduced in cell lines derived from ASD subjects compared to parental cell lines. Intriguingly, a correlation was observed between CD38 expression and measures of social function in ASD. Finally, we have shown that all-trans retinoic acid (ATRA), a known inducer of CD38 transcription, can rescue low CD38 expressing LBC lines derived from ASD subjects and restore normal levels of transcription of this ectoenzyme providing 'proof of principle' in a peripheral model that retinoids are potential therapeutic agents in ASD.
Collapse
|
|
41
|
Gawryluk JW, Young LT. Signal transduction pathways in the pathophysiology of bipolar disorder. Curr Top Behav Neurosci 2011; 5:139-165. [PMID: 25236554 DOI: 10.1007/7854_2010_71] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Signal transduction pathways and genes associated with cellular life and death have received much attention in bipolar disorder (BPD) and provide scientists with molecular targets for understanding the biological basis of BPD. In this chapter, we describe the signal transduction pathways involved in the molecular biology of BPD and the indications for the mechanisms of disease and treatment. We discuss the BPD literature with respect to the disease itself and the effects of mood stabilizer treatment on cellular receptors, including G-protein-coupled receptors, glutamate receptors, and tyrosine receptor kinase. We also discuss the intracellular alterations observed in BPD to second messenger systems, such as cyclic adenosine monophosphate (cAMP), protein kinase A, phosphoinositide pathways, glycogen synthase kinase-3, protein kinase B, Wnt, and arachidonic acid. We describe how receptor activation and modulation of second messengers occurs, and how transcription factors are activated and altered in this disease (e.g., the transcription factors ?-catenin, cAMP response element binding protein, heat shock transcription factor-1, and activator protein-1). Abnormalities in intracellular signal transduction pathways could generate a functional discrepancy in numerous neurotransmitter systems, which may explain the varied clinical symptoms observed in BPD. The influence of mood stabilizers on transcription factors may be important in connecting the regulation of gene expression to neuroplasticity and cellular resilience.
Collapse
Affiliation(s)
- Jeremy W Gawryluk
- Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada, V6T 2A1,
| | | |
Collapse
|
|
42
|
Lee BH, Kim YK. BDNF mRNA expression of peripheral blood mononuclear cells was decreased in depressive patients who had or had not recently attempted suicide. J Affect Disord 2010; 125:369-73. [PMID: 20207421 DOI: 10.1016/j.jad.2010.01.074] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Revised: 01/30/2010] [Accepted: 01/31/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent reports have suggested a pathophysiological role for brain-derived neurotrophic factor (BDNF) in major depression and suicide. We evaluate BDNF mRNA in peripheral blood mononuclear cells (PBMCs) of patients with major depression who had or had not recently attempted suicide. METHODS BDNF mRNA expression was examined in PBMCs of 30 major depressed patients without recent suicide attempts, 30 major depressed patients with recent suicide attempts, and 30 healthy controls. All patients were diagnosed with major depressive disorder (MDD) and they were either medication-naïve or medication-free. BDNF mRNA expression was measured using real-time quantitative PCR. RESULTS BDNF mRNA expression was significantly decreased in PBMCs of MDD patients, with or without a history of suicide attempts, when compared with healthy controls (Z=-5.233, p<0.001). Suicidal MDD patients had more decrease in BDNF mRNA expression (chi(2)=45.881, df=2, p<0.001). LIMITATIONS The sample size of the present study was relatively small. Although suicidal MDD patients had higher HDRS scores than non-suicidal patients, the comparison of BDNF mRNA between them could not be adjusted for HDRS score. CONCLUSIONS Our study suggests that the BDNF mRNA expression is reduced in PBMCs of patients with major depression. This alteration of BDNF mRNA expression was noteworthy in recent suicide attempters. Such a decrease in BDNF mRNA might be associated with BDNF decrease in serum or plasma, and might also correspond to a BDNF decline in the brains of MDD patients.
Collapse
Affiliation(s)
- Bun-Hee Lee
- Department of Psychiatry, College of Medicine, Korea University, Ansan Hospital, 516, Gojan Dong, Ansan City, Kyunggi Province, 425-707 Seoul, Republic of Korea
| | | |
Collapse
|
|
43
|
Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Zhang H, Pavuluri MN. Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:645-51. [PMID: 20227453 DOI: 10.1016/j.pnpbp.2010.03.003] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Revised: 02/18/2010] [Accepted: 03/05/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) is a member of a neurotrophin family and is involved in many physiological functions, including cell proliferation, migration, and differentiation, and neuron survival in the human nervous system. Abnormalities of BDNF have been implicated in the pathophysiology of depression based on observations that antidepressant drugs cause increases in the levels of BDNF in rat brains and its abnormalities have appeared in the serum of depressed patients and in postmortem brains of suicide victims. METHODS We examined the gene expression of BDNF in the lymphocytes and protein expression in the platelets of adult and pediatric depressed patients during a drug-free period. We determined BDNF gene expression using a quantitative RT-PCR method and protein expression using the ELISA method. RESULTS We observed that the gene expression of BDNF was significantly decreased in the lymphocytes of adult and pediatric depressed patients compared with normal control subjects. Similarly, the protein expression of BDNF was significantly decreased in the platelets of adult and pediatric depressed patients compared with normal control subjects. CONCLUSIONS To our knowledge, this is the first study that reports a decrease in BDNF gene expression in the peripheral cells of depressed patients. Because of the bidirectional movement of BDNF between the periphery and the CNS, the reduced gene expression in the lymphocytes and the protein expression in the platelets may be an index of similar abnormalities in the brain and could be a target for antidepressant drugs.
Collapse
Affiliation(s)
- Ghanshyam N Pandey
- University of Illinois at Chicago, Department of Psychiatry (MC 912), 1601 West Taylor Street, Chicago, IL 60612, United States.
| | | | | | | | | | | |
Collapse
|
|
44
|
Barbosa IG, Huguet RB, Mendonça VA, Neves FS, Reis HJ, Bauer ME, Janka Z, Palotás A, Teixeira AL. Increased plasma levels of brain-derived neurotrophic factor in patients with long-term bipolar disorder. Neurosci Lett 2010; 475:95-8. [PMID: 20350583 DOI: 10.1016/j.neulet.2010.03.055] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2010] [Revised: 03/19/2010] [Accepted: 03/22/2010] [Indexed: 01/06/2023]
Abstract
Recent data indicate that neurotrophins may play a role in the physiopathology of bipolar disorder (BD) and may be useful as biomarkers of the disease. The aim of this study was to evaluate the plasma concentrations of brain-derived neurotrophic factor (BDNF) in BD patients, and to correlate their levels with clinical parameters. BDNF was measured in plasma from 53 BD type I subjects (34 during mania and 19 during euthymia) and 38 healthy controls by enzyme-linked immuno-sorbent assay (ELISA). Patients were assessed by a structured clinical interview (Mini-plus), Young mania and Hamilton depression rating scales. Plasma BDNF levels were significantly increased in patients with mania (P</=0.001) and euthymia (P</=0.001) when compared with controls, but did not correlate with any clinical parameters. BDNF concentration was higher in BD patients with 10 or more years of disease. BDNF plasma levels were increased in BD patients, mainly in those with a longer course of disease. In line with previous studies, it is conceivable that BDNF may play a role in the pathophysiology of BD.
Collapse
Affiliation(s)
- Izabela Guimarães Barbosa
- Programa de Neurociências, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, 31270-901 Campus Pampulha, Belo Horizonte, Minas Gerais, Brazil
| | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Reduced peripheral brain-derived neurotrophic factor mRNA levels are normalized by antidepressant treatment. Int J Neuropsychopharmacol 2010; 13:103-8. [PMID: 19835669 DOI: 10.1017/s1461145709990812] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Consistent data coming from biochemical studies have evidenced a brain-derived neurotrophic factor (BDNF) serum reduction in depressed patients compared to controls and a restoration following antidepressant treatment. However, to date, no study has evaluated whether BDNF synthesis in leukocytes could contribute to such modulation. Therefore, in this study, we analysed BDNF mRNA levels in leukocytes from 21 depressed patients prior to and during escitalopram treatment and from 23 control subjects showing that BDNF mRNA levels were decreased in drug-free depressed patients and that 12 wk escitalopram treatment was able to reverse this deficit. Interestingly, changes in BDNF mRNA levels paralleled BDNF serum increase during antidepressant treatment, and were correlated with symptoms improvement. Our results indicate that BDNF serum modulation observed in depressed patients is associated with BDNF synthesis alteration in leukocytes and suggest that these peripheral cells might play an active role in the mechanisms of action of antidepressants.
Collapse
|
|
46
|
Nakashima N, Yamagata T, Mori M, Kuwajima M, Suwa K, Momoi MY. Expression analysis and mutation detection of DLX5 and DLX6 in autism. Brain Dev 2010; 32:98-104. [PMID: 19195802 DOI: 10.1016/j.braindev.2008.12.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Revised: 12/25/2008] [Accepted: 12/30/2008] [Indexed: 11/26/2022]
Abstract
Linkage analysis has reported the chromosomal region 7q21 to be related with autism. This region contains an imprinting region with MECP2-binding sites, and DLX5 is reported to be modulated by MECP2. DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis. From these points, DLX5 and DLX6 are candidate genes for autism. Therefore, we analyzed the expression of DLX5 and DLX6, and also PEG10 as a control in the lymphoblasts of autistic spectrum disorder (ASD) patients by real-time PCR to identify potential abnormality of expression. And we also analyzed DLX5 and DLX6 on ASD patients for mutation by direct sequence. The expression level of DLX5 was not different between ASD and controls but was higher in four ASD patients compared to controls. Clinical features of these four patients were variable. DLX5 expression was biallelic in two ASD patients and two controls, indicating that DLX5 was not imprinted. There was no mutation in DLX5 in ASD. Although DLX5 was not likely to play major role in ASD, genes relating to DLX5 expression and downstream of DLX5 are considered to be candidate genes for some of the ASD patients. In DLX6, we detected a G656A base change (R219H) in two ASD patients who were male siblings. DLX6 may contribute to the pathogenesis of ASD.
Collapse
Affiliation(s)
- Naomi Nakashima
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | | | | | | | | | | |
Collapse
|
|
47
|
Lin PY. State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study. Neurosci Lett 2009; 466:139-43. [PMID: 19786073 DOI: 10.1016/j.neulet.2009.09.044] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2009] [Revised: 09/10/2009] [Accepted: 09/23/2009] [Indexed: 11/29/2022]
Abstract
Evidence has suggested a role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of bipolar disorder (BD). Recent studies have examined BDNF levels in BD patients, but showed inconsistent results. In current study, meta-analyses by random-effects model were performed to compare blood BDNF levels between BD patients and healthy controls, and examine patients based on different affective status (manic, depressed, or euthymic state). Fifteen studies from 10 citations were included into the analysis. Pooling of results from all studies indicated that, overall, patients with BD had a lower level of BDNF than healthy controls (p=1x10(-4)). But when separating these studies based on different affective status, it showed that the significance existed only when comparing patients in manic (p=0.0008) or depressed (p=0.02) state with controls, but not in euthymic state (p=0.25). In addition, BDNF level was significantly increased after pharmacological treatment of manic state (p=0.01). These findings indicate that BDNF levels are abnormally reduced in manic and depressed states of BD, and the reduced level in manic state increases after treatment. They suggest a role of blood BDNF level as a state-dependent biomarker of bipolar disorder.
Collapse
Affiliation(s)
- Pao-Yen Lin
- Department of Psychiatry, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung County 833, Taiwan.
| |
Collapse
|
|
48
|
Dias VV, Brissos S, Frey BN, Andreazza AC, Cardoso C, Kapczinski F. Cognitive function and serum levels of brain-derived neurotrophic factor in patients with bipolar disorder. Bipolar Disord 2009; 11:663-71. [PMID: 19689509 DOI: 10.1111/j.1399-5618.2009.00733.x] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVES Brain-derived neurotrophic factor (BDNF) is an important contributor to the pathophysiology of bipolar disorder (BD), and abnormalities in the BDNF-signaling system may be implicated in the cognitive decline observed in BD patients. We aimed to investigate serum BDNF levels in BD patients and its relation to neurocognitive function. METHODS We measured serum BDNF levels using an enzyme-linked immunosorbent assay method in 65 euthymic type I BD patients and 50 healthy controls, and administered a neuropsychological test battery to assess attention and mental control, perceptual-motor skills, executive functions, verbal fluency and abstraction, visuospatial attention, and memory. RESULTS We found no significant differences regarding serum BDNF levels in BD patients and healthy controls. We found significant positive associations between serum BDNF levels and illness duration, and manic and depressive episodes in female BD patients only. Serum BDNF levels were lower in patients medicated with antipsychotics and/or lithium, whereas patients on valproate and/or antidepressants showed higher serum BDNF levels. Patients performed significantly worse on 11 out of 16 neurocognitive tests as compared to controls. We found a significant positive association between serum BDNF levels and a test of verbal fluency in both BD patients and controls. CONCLUSIONS Present results support the hypothesis that BDNF normalizes with mood stabilization and pharmacological treatment. Our findings in young and physically healthy patients with short illness duration and few mood episodes may explain the lack of association between serum BDNF levels and neurocognitive performance, even though cognitive performance in patients was overall significantly worse as compared to healthy controls.
Collapse
|
|
49
|
Mick E, Faraone SV. Family and genetic association studies of bipolar disorder in children. Child Adolesc Psychiatr Clin N Am 2009; 18:441-53, x. [PMID: 19264272 DOI: 10.1016/j.chc.2008.11.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The risk of bipolar disorder (BPD) (15-42%) in first-degree relatives of children with BPD are consistently larger than the 8.7% estimate of recurrence risk of BPD in first-degree relatives of adult BPD cases. There have been no family linkage studies of pediatric BPD, but secondary analyses of adult linkage samples suggest that early-onset BPD both increases the strength of associations in linkage studies. Positive associations with pediatric BPD and the BDNF gene (Vall66), the GAD1 gene (4s2241165), and the dopamine transporter gene (rs41084) have been reported but none of these associations have been replicated in independent samples. The number of informative families examined so far is quite small and studies were vastly underpowered to detect small effects. An adequately powered sample will likely require collaborative ascertainment of cases and families from multiple sites using valid and accepted measures of pediatric BPD.
Collapse
Affiliation(s)
- Eric Mick
- Departments of Psychiatry, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
| | | |
Collapse
|
|
50
|
Mick E, Wozniak J, Wilens TE, Biederman J, Faraone SV. Family-based association study of the BDNF, COMT and serotonin transporter genes and DSM-IV bipolar-I disorder in children. BMC Psychiatry 2009; 9:2. [PMID: 19193231 PMCID: PMC2640390 DOI: 10.1186/1471-244x-9-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Accepted: 02/04/2009] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Over the past decade pediatric bipolar disorder has gained recognition as a potentially more severe and heritable form of the disorder. In this report we test for association with genes coding brain-derived neurotrophic factor (BDNF), the serotonin transporter (SLC6A4), and catechol-O-methyltransferase (COMT). METHODS Bipolar-I affected offspring triads (N = 173) were drawn from 522 individuals with 2 parents in 332 nuclear families recruited for genetic studies of pediatric psychopathology at the Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD at Massachusetts General Hospital. RESULTS We failed to identify an association with the val66 allele in BDNF (OR = 1.23, p = 0.36), the COMT-l allele (OR = 1.27, p = 0.1), or the HTTLPR short allele (OR = 0.87, p = 0.38). CONCLUSION Our study suggests that the markers examined thus far in COMT and SLC6A4 are not associated with pediatric bipolar disorder and that if the val66met marker in BDNF is associated with pediatric bipolar disorder the magnitude of the association is much smaller than first reported.
Collapse
Affiliation(s)
- Eric Mick
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Janet Wozniak
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Timothy E Wilens
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Joseph Biederman
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Stephen V Faraone
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
| |
Collapse
|