Brain‐derived neurotrophic factor as a biomarker for mood disorders: An historical overview and future directions

Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), are the most prevalent psychiatric conditions, and are also among the most severe and debilitating. However, the precise neurobiology underlying these disorders is currently unknown. One way to combat these disorders is to discover novel biomarkers for them. The development of such biomarkers will aid both in the diagnosis of mood disorders and in the development of effective psychiatric medications to treat them. A number of preclinical studies have suggested that the brain‐derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of MDD. In 2003, we reported that serum levels of BDNF in antidepressant‐naive patients with MDD were significantly lower than those of patients medicated with antidepressants and normal controls, and that serum BDNF levels were negatively correlated with the severity of depression. Additionally, we found that decreased serum levels of BDNF in antidepressant‐naive patients recovered to normal levels associated with the recovery of depression after treatment with antidepressant medication. This review article will provide an historical overview of the role played by BDNF in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Particular focus will be given to the potential use of BDNF as a biomarker for mood disorders. BDNF is initially synthesized as a precursor protein proBDNF, and then proBDNF is proteolytically cleaved to the mature BDNF. Finally, future perspectives on the use of proBDNF as a novel biomarker for mood disorders will be discussed.

[1]  B. Ravnkilde,et al.  Hippocampal volume and depression: a meta-analysis of MRI studies. , 2004, The American journal of psychiatry.

[2]  S. Soekadar,et al.  Increased plasma concentration of brain-derived neurotrophic factor with electroconvulsive therapy: a pilot study in patients with major depression. , 2007, The Journal of clinical psychiatry.

[3]  Wen-Wei Ho,et al.  A three‐year follow‐up study of the psychosocial predictors of delayed and unresolved post‐traumatic stress disorder in Taiwan Chi‐Chi earthquake survivors , 2010, Psychiatry and clinical neurosciences.

[4]  K. Hashimoto,et al.  Critical role of brain-derived neurotrophic factor in mood disorders , 2004, Brain Research Reviews.

[5]  K. Hashimoto,et al.  Role of brain-derived neurotrophic factor in eating disorders: Recent findings and its pathophysiological implications , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[6]  Barbara L. Hempstead,et al.  Regulation of Cell Survival by Secreted Proneurotrophins , 2001, Science.

[7]  T. Uzbay,et al.  Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  Ruoyan Chen,et al.  Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain , 2003, Biological Psychiatry.

[9]  K. Davis,et al.  Developing novel treatments for mood disorders: accelerating discovery , 2002, Biological Psychiatry.

[10]  Neil A. Ernst,et al.  Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. , 2009, Archives of general psychiatry.

[11]  M. Riva,et al.  BDNF Val66Met polymorphism and protein levels in Amniotic Fluid , 2010, BMC Neuroscience.

[12]  Chien-Te Lee,et al.  Serum brain-derived neurotrophic factor levels in patients with major depression: effects of antidepressants. , 2008, Journal of psychiatric research.

[13]  P. Buckley,et al.  Psychiatric comorbidities and schizophrenia. , 2009, Schizophrenia bulletin.

[14]  R. Lam,et al.  Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. , 2009, The international journal of neuropsychopharmacology.

[15]  C. Repérant,et al.  Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice , 2008, Neuropharmacology.

[16]  E. Nestler,et al.  A molecular and cellular theory of depression. , 1997, Archives of general psychiatry.

[17]  M. Schwald,et al.  Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets , 2002, Neuroscience Letters.

[18]  R. Duman,et al.  Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression , 2002, The Journal of Neuroscience.

[19]  R. Duman,et al.  Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  Y. Barde,et al.  Brain‐Derived Neurotrophic Factor Levels in the Nervous System of Wild‐Type and Neurotrophin Gene Mutant Mice , 1999, Journal of neurochemistry.

[21]  C. Martini,et al.  Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. , 2008, Journal of affective disorders.

[22]  Serge Nef,et al.  Brain-Derived Neurotrophic Factor Conditional Knockouts Show Gender Differences in Depression-Related Behaviors , 2007, Biological Psychiatry.

[23]  Gerty J. L. M. Lensvelt-Mulders,et al.  Brain volume abnormalities in major depressive disorder: A meta‐analysis of magnetic resonance imaging studies , 2009, Human brain mapping.

[24]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[25]  B. Woodside,et al.  Management of Psychiatric Comorbidity in Anorexia Nervosa and Bulimia Nervosa , 2006, CNS drugs.

[26]  Pao-Yen Lin.  State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: A meta-analytic study , 2009, Neuroscience Letters.

[27]  Petti T. Pang,et al.  The yin and yang of neurotrophin action , 2005, Nature Reviews Neuroscience.

[28]  M. Dietrich,et al.  Decreased Plasma Brain Derived Neurotrophic Factor Levels in Unmedicated Bipolar Patients During Manic Episode , 2007, Biological Psychiatry.

[29]  C. Gama,et al.  Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): A pilot study in drug resistant depressed patients , 2009, Neuroscience Letters.

[30]  R. Yoshimura,et al.  Effect of risperidone on plasma catecholamine metabolites and brain‐derived neurotrophic factor in patients with bipolar disorders , 2006, Human psychopharmacology.

[31]  S. Tsai,et al.  Association study of a brain‐derived neurotrophic‐factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[32]  E. Palazidou.  The neurobiology of depression. , 2012, British medical bulletin.

[33]  F. Holsboer,et al.  Combined Dexamethasone/Corticotropin Releasing Hormone Test Predicts Treatment Response in Major Depression–A Potential Biomarker? , 2007, Biological Psychiatry.

[34]  F. Lee,et al.  Neurotrophin signalling in health and disease. , 2006, Clinical science.

[35]  N. Yahata,et al.  Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia , 2008, Schizophrenia Research.

[36]  S M de la Monte,et al.  Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. , 1991, Genomics.

[37]  Markus Kosel,et al.  Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Affective Disorders , 2003, Neuropsychopharmacology.

[38]  G. Moore,et al.  Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers , 2001, British Journal of Psychiatry.

[39]  D. Chuang,et al.  Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity , 2002, Neuropharmacology.

[40]  R. Yoshimura,et al.  Effects of paroxetine or milnacipran on serum brain-derived neurotrophic factor in depressed patients , 2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[41]  Cesar Augusto Guevara-Cuellar,et al.  Electroconvulsive therapy for depression. , 2008, The New England journal of medicine.

[42]  N. Seidah,et al.  Biosynthesis and Post-translational Processing of the Precursor to Brain-derived Neurotrophic Factor* , 2001, The Journal of Biological Chemistry.

[43]  R. Yoshimura,et al.  Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: A pilot study , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[44]  J. Csernansky,et al.  Hippocampal atrophy in recurrent major depression. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Roy,et al.  Association of Polymorphism (Val66Met) of Brain-Derived Neurotrophic Factor with Suicide Attempts in Depressed Patients , 2008, Neuropsychobiology.

[46]  C. Caltagirone,et al.  Role of BDNF Val66Met functional polymorphism in Alzheimer's disease-related depression , 2009, Neurobiology of Aging.

[47]  P. Barker.  Whither proBDNF? , 2009, Nature Neuroscience.

[48]  G. Rajkowska,et al.  Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells , 2000, Biological Psychiatry.

[49]  H. Manji,et al.  Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression , 2003, Biological Psychiatry.

[50]  R. Lenox,et al.  Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks , 2003, Molecular Psychiatry.

[51]  M. Greenberg,et al.  New Insights in the Biology of BDNF Synthesis and Release: Implications in CNS Function , 2009, The Journal of Neuroscience.

[52]  H. Manji,et al.  New insights into BDNF function in depression and anxiety , 2007, Nature Neuroscience.

[53]  B. Frey,et al.  Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes , 2006, Neuroscience Letters.

[54]  M. Maj,et al.  Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge-eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables , 2004, Psychological Medicine.

[55]  C. Cotman,et al.  Exercise, Antidepressant Medications, and Enhanced Brain Derived Neurotrophic Factor Expression , 1999, Neuropsychopharmacology.

[56]  K. Hashimoto,et al.  Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are indistinguishable from controls , 2003, Neuroscience Letters.

[57]  G. MacQueen,et al.  Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression. , 2001, Behavioral neuroscience.

[58]  K. Hashimoto,et al.  Dietary restriction changes behaviours in brain‐derived neurotrophic factor heterozygous mice: role of serotonergic system , 2006, The European journal of neuroscience.

[59]  K. Hashimoto,et al.  Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants , 2003, Biological Psychiatry.

[60]  Michael Marriott,et al.  Lower hippocampal volume in patients suffering from depression: a meta-analysis. , 2004, The American journal of psychiatry.

[61]  B. Frey,et al.  Cognitive function and serum levels of brain-derived neurotrophic factor in patients with bipolar disorder. , 2009, Bipolar disorders.

[62]  S. Avissar,et al.  Toward molecular diagnostics of mood disorders in psychiatry. , 2002, Trends in molecular medicine.

[63]  Felipe Fregni,et al.  A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. , 2008, The international journal of neuropsychopharmacology.

[64]  S. Gabriel,et al.  Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus , 2002, Molecular Psychiatry.

[65]  A. Gershon,et al.  Transcranial magnetic stimulation in the treatment of depression. , 2003, The American journal of psychiatry.

[66]  Y. Okamoto,et al.  Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain , 2001, Psychopharmacology.

[67]  L. Reichardt,et al.  Neurotrophin-regulated signalling pathways , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[68]  M. Mattson,et al.  Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease , 2008, Annals of the New York Academy of Sciences.

[69]  Hongwei Song,et al.  The Val66Met polymorphism of the brain‐derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[70]  Yogesh K. Dwivedi,et al.  Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims. , 2008, The international journal of neuropsychopharmacology.

[71]  D. Matsuzawa,et al.  Serum brain-derived neurotrophic factor (BDNF) levels in patients with panic disorder: As a biological predictor of response to group cognitive behavioral therapy , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[72]  K. Hashimoto.  Emerging role of glutamate in the pathophysiology of major depressive disorder , 2009, Brain Research Reviews.

[73]  M. Egan,et al.  Brain-Derived Neurotrophic Factor val66met Polymorphism Affects Human Memory-Related Hippocampal Activity and Predicts Memory Performance , 2003, The Journal of Neuroscience.

[74]  Toshikazu Saito,et al.  Low serum BDNF and food intake regulation: A possible new explanation of the pathophysiology of eating disorders , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[75]  M. Barrot,et al.  Brain-derived neurotrophic factor in the ventral midbrain–nucleus accumbens pathway: a role in depression , 2003, Biological Psychiatry.

[76]  Ö. Aydemir,et al.  Serum brain-derived neurotrophic factor level in dysthymia: A comparative study with major depressive disorder , 2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[77]  M. Smith,et al.  Stress increases brain-derived neurotropic factor messenger ribonucleic acid in the hypothalamus and pituitary. , 1995, Endocrinology.

[78]  K. Hashimoto,et al.  Increased Levels of Glutamate in Brains from Patients with Mood Disorders , 2007, Biological Psychiatry.

[79]  L. Staib,et al.  Hippocampal volume reduction in major depression. , 2000, The American journal of psychiatry.

[80]  H. Lôo.  [On bipolar disorder]. , 2008, L'Encephale.

[81]  G. MacQueen,et al.  Increased hippocampal bdnf immunoreactivity in subjects treated with antidepressant medication , 2001, Biological Psychiatry.

[82]  R. Kessler,et al.  Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. , 1994, Archives of general psychiatry.

[83]  D. Ciraulo.  Neuropsychopharmacology: The Fifth Generation of Progress , 2003 .

[84]  H. Swartz,et al.  Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. , 2010, Bipolar disorders.

[85]  Abraham Zangen,et al.  Site-Specific Antidepressant Effects of Repeated Subconvulsive Electrical Stimulation: Potential Role of Brain-Derived Neurotrophic Factor , 2010, Biological Psychiatry.

[86]  N. Seidah,et al.  Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases , 1996, FEBS letters.

[87]  E. Gould,et al.  Preclinical models: status of basic research in depression , 2002, Biological Psychiatry.

[88]  K. Christian,et al.  BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory? , 2008, Neurobiology of Learning and Memory.

[89]  K. Hashimoto.  BDNF variant linked to anxiety-related behaviors. , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[90]  M. Maj,et al.  Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. , 2008, Bipolar disorders.

[91]  M. Baron,et al.  Manic-depression genes and the new millennium: poised for discovery , 2002, Molecular Psychiatry.

[92]  C. Wihler,et al.  Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[93]  J. Coyle,et al.  Finding the Intracellular Signaling Pathways Affected by Mood Disorder Treatments , 2003, Neuron.

[94]  C. Duarte,et al.  Role of the brain‐derived neurotrophic factor at glutamatergic synapses , 2008, British journal of pharmacology.

[95]  E. Taylor.  Managing bipolar disorders in children and adolescents , 2009, Nature Reviews Neurology.

[96]  Petti T. Pang,et al.  Cleavage of proBDNF by tPA/Plasmin Is Essential for Long-Term Hippocampal Plasticity , 2004, Science.

[97]  I. Fariñas,et al.  Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development , 1994, Cell.

[98]  Charles L. Raison,et al.  Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression , 2009, Biological Psychiatry.

[99]  J. Aubry,et al.  Decreased serum brain-derived neurotrophic factor levels in major depressed patients , 2002, Psychiatry Research.

[100]  M. Weissman,et al.  The relationship between panic disorder and major depression. A new family study. , 1993, Archives of general psychiatry.

[101]  Kimberly Hoagwood,et al.  Development and natural history of mood disorders , 2002, Biological Psychiatry.

[102]  R. Wynn,et al.  Neurotrophic factors in serum following ECT: A pilot study , 2009, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[103]  N. Seidah,et al.  Differential Sorting of Nerve Growth Factor and Brain-Derived Neurotrophic Factor in Hippocampal Neurons , 1999, The Journal of Neuroscience.

[104]  K. Hashimoto,et al.  Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders , 2003, Biological Psychiatry.

[105]  N. Lindefors,et al.  Spatiotemporal selective effects on brain-derived neurotrophic factor andtrkB messenger RNA in rat hippocampus by electroconvulsive shock , 1995, Neuroscience.

[106]  M. Bajbouj,et al.  Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: no effects on brain-derived neurotrophic factor (BDNF) concentrations in serum. , 2008, Journal of affective disorders.

[107]  P. Muglia,et al.  The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. , 2002, American journal of human genetics.

[108]  Kenji Hashimoto,et al.  Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: The possibility to explain ethnic mental traits , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[109]  J. Deakin,et al.  Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. , 2009, Journal of psychiatric research.

[110]  Yonggui Yuan,et al.  Plasma BDNF and tPA are associated with late‐onset geriatric depression , 2010, Psychiatry and clinical neurosciences.

[111]  J. Krystal,et al.  The NMDA receptor as a therapeutic target in major depressive disorder. , 2007, CNS & neurological disorders drug targets.

[112]  D. Ye,et al.  Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder , 2010, European Neuropsychopharmacology.

[113]  H. Ujike,et al.  Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder , 2003, Neuroscience Letters.

[114]  William A Banks,et al.  Transport of brain-derived neurotrophic factor across the blood–brain barrier , 1998, Neuropharmacology.

[115]  Shaheen E Lakhan,et al.  Biomarkers in psychiatry: drawbacks and potential for misuse , 2010, International archives of medicine.

[116]  F. Mosquera,et al.  Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients , 2006, Schizophrenia Research.

[117]  L. Parada,et al.  BDNF regulates eating behavior and locomotor activity in mice , 2000, The EMBO journal.

[118]  Jiing-Feng Lirng,et al.  The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression , 2006, Neurobiology of Aging.

[119]  S. Tsai,et al.  Association Study of a Brain-Derived Neurotrophic-Factor Genetic Polymorphism and Mood Disorders, Age of Onset and Suicidal Behavior , 2003, Neuropsychobiology.

[120]  F. Kapczinski,et al.  Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients. , 2009, Journal of psychiatric research.

[121]  M. Gurney,et al.  Human platelets contain brain-derived neurotrophic factor , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[122]  G. Moore,et al.  Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilizers. , 2001, The British journal of psychiatry. Supplement.

[123]  F. Taneli,et al.  Effect of treatment on serum brain–derived neurotrophic factor levels in depressed patients , 2005, European Archives of Psychiatry and Clinical Neuroscience.

[124]  Bai Lu,et al.  Pro-Region of Neurotrophins Role in Synaptic Modulation , 2003, Neuron.

[125]  F. Angelucci,et al.  Mapping the differences in the brain concentration of brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression , 2000, Neuroreport.

[126]  M. Schwald,et al.  Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. , 2005, Brain research. Molecular brain research.

[127]  N. Gervasoni,et al.  Partial Normalization of Serum Brain-Derived Neurotrophic Factor in Remitted Patients after a Major Depressive Episode , 2005, Neuropsychobiology.

[128]  Rudolf Jaenisch,et al.  Mice lacking brain-derived neurotrophic factor develop with sensory deficits , 1994, Nature.

[129]  S. Cichon,et al.  Evidence for a Relationship Between Genetic Variants at the Brain-Derived Neurotrophic Factor (BDNF) Locus and Major Depression , 2005, Biological Psychiatry.

[130]  Yogesh K. Dwivedi,et al.  Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. , 2003, Archives of general psychiatry.

[131]  A. Young,et al.  Changes in Brain-Derived Neurotrophic Factor Following Treatment with Mifepristone in Bipolar Disorder and Schizophrenia , 2007, The Australian and New Zealand journal of psychiatry.

[132]  P. Pasqualetti,et al.  Electroconvulsive Therapy (ECT) increases serum Brain Derived Neurotrophic Factor (BDNF) in drug resistant depressed patients , 2006, European Neuropsychopharmacology.

[133]  N. Toschi,et al.  Long-Term Repetitive Transcranial Magnetic Stimulation Increases the Expression of Brain-Derived Neurotrophic Factor and Cholecystokinin mRNA, but not Neuropeptide Tyrosine mRNA in Specific Areas of Rat Brain , 2000, Neuropsychopharmacology.

[134]  P. Skolnick,et al.  Glutamate-based antidepressants: 20 years on. , 2009, Trends in pharmacological sciences.

[135]  E. Castrén,et al.  Activation of the TrkB Neurotrophin Receptor Is Induced by Antidepressant Drugs and Is Required for Antidepressant-Induced Behavioral Effects , 2003, The Journal of Neuroscience.

[136]  J. Siuciak,et al.  Antidepressant-Like Effect of Brain-derived Neurotrophic Factor (BDNF) , 1997, Pharmacology Biochemistry and Behavior.

[137]  R. Duman,et al.  Serum Brain-Derived Neurotrophic Factor, Depression, and Antidepressant Medications: Meta-Analyses and Implications , 2008, Biological Psychiatry.

[138]  A. L. Mandel,et al.  Identification of pro- and mature brain-derived neurotrophic factor in human saliva. , 2009, Archives of oral biology.

[139]  T. Si,et al.  The Level of Serum Brain-Derived Neurotrophic Factor Is Associated With the Therapeutic Efficacy of Modified Electroconvulsive Therapy in Chinese Patients With Depression , 2010, The journal of ECT.

[140]  J. Lonnqvist,et al.  Suicide prevention strategies: a systematic review. , 2005, JAMA.

[141]  C. Siao,et al.  Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior , 2006, Science.

[142]  J. Gallinat,et al.  Acute exercise ameliorates reduced brain-derived neurotrophic factor in patients with panic disorder , 2010, Psychoneuroendocrinology.

[143]  Barbara L. Hempstead,et al.  ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin , 2005, The Journal of Neuroscience.

[144]  B. Bradley,et al.  Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients. , 2010, Archives of general psychiatry.

[145]  Idil Cavus,et al.  Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. , 2002, The American journal of psychiatry.

[146]  M. Wong,et al.  Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. , 2009, Archives of general psychiatry.

[147]  V. Lessmann,et al.  A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors. , 2003, Trends in pharmacological sciences.

[148]  Carlos A. Zarate,et al.  Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders , 2008, Nature Reviews Drug Discovery.

[149]  J. Siuciak,et al.  Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures , 1999, Neuroscience.

[150]  Bai Lu,et al.  Activation of p75NTR by proBDNF facilitates hippocampal long-term depression , 2005, Nature Neuroscience.

[151]  Emmanuel Mignot,et al.  Future of genetics of mood disorders research , 2002, Biological Psychiatry.

[152]  Mu-ming Poo,et al.  The neurotrophin hypothesis for synaptic plasticity , 2000, Trends in Neurosciences.

[153]  S. Radka,et al.  Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay , 1996, Brain Research.

[154]  M. Egan,et al.  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function , 2003, Cell.

[155]  T Bonhoeffer,et al.  Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[156]  D. Chuang.  Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? , 2004, Critical reviews in neurobiology.

[157]  C. Altar.  Neurotrophins and depression. , 1999, Trends in pharmacological sciences.

[158]  Hans-Jürgen Möller,et al.  Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. , 2007, Archives of general psychiatry.

[159]  N. Gervasoni,et al.  Low Brain-Derived Neurotrophic Factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity , 2005, Biological Psychiatry.

[160]  F. Taneli,et al.  Serum brain‐derived neurotrophic factor levels in conversion disorder: Comparative study with depression , 2007, Psychiatry and clinical neurosciences.

[161]  F. McMahon,et al.  Brain-derived neurotrophic factor ( BDNF) gene: no major impact on antidepressant treatment response. , 2009, The international journal of neuropsychopharmacology.

[162]  P. Sklar.  Linkage analysis in psychiatric disorders: the emerging picture. , 2002, Annual review of genomics and human genetics.

[163]  R. Duman,et al.  Repeated stress increases catalytic TrkB mRNA in rat hippocampus , 1999, Neuroscience Letters.

[164]  H. Möller,et al.  Neuroimaging genetics: new perspectives in research on major depression? , 2008, Acta psychiatrica Scandinavica.

[165]  R. Duman,et al.  Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[166]  Amelia Russo-Neustadt,et al.  Physical activity–antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model , 2001, Behavioural Brain Research.

[167]  Edward T. Bullmore,et al.  Plasma Protein Biomarkers for Depression and Schizophrenia by Multi Analyte Profiling of Case-Control Collections , 2010, PloS one.

[168]  R. Kvetňanský,et al.  Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[169]  R. Jaenisch,et al.  Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. , 2001, Molecular endocrinology.

[170]  M. Barrot,et al.  Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy , 2008, Biological Psychiatry.

[171]  Nanxin Li,et al.  The mood stabilizer lamotrigine produces antidepressant behavioral effects in rats: role of brain-derived neurotrophic factor. , 2010, Journal of psychopharmacology.

[172]  M. Weissman,et al.  RISK FACTORS FOR MAJOR DEPRESSION AND BIPOLAR DISORDER , 2002 .

[173]  V. Carli,et al.  Increased BDNF promoter methylation in the Wernicke area of suicide subjects. , 2010, Archives of general psychiatry.

[174]  Athina Markou,et al.  Assessing antidepressant activity in rodents: recent developments and future needs. , 2002, Trends in pharmacological sciences.

[175]  M. Leboyer,et al.  Association between brain-derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene. , 2008, Bipolar disorders.