Am J Hum Genet 2002 Sep;71(3):651-5 : The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study.
Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL.
Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8, Canada.

Bipolar disorder (BP) is a severe psychiatric disease, with a strong genetic component, that affects 1% of the population worldwide and is characterized by recurrent episodes of mania and depression. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of mood disorders, and the aim of the present study was to test for the presence of linkage disequilibrium between two polymorphisms in the BDNF gene and BP in 283 nuclear families. Family-based association test (FBAT) results for the dinucleotide repeat (GT)(N) polymorphism at position -1040 bp showed that allele A3 was preferentially transmitted to the affected individuals (Z=2.035 and P=.042). FBAT results for the val66met SNP showed a significant association for allele G (Z=3.415 and P=.00064). Transmission/disequilibrium test (TDT) haplotype analysis showed a significant result for the 3-G allele combination (P=.000394), suggesting that a DNA variant in the vicinity of the BDNF locus confers susceptibility to BP. Given that there is no direct evidence that either of the polymorphisms we examined alters function, it is unlikely that the actual risk-conferring allele is from these two sites. Rather, the causative site is likely nearby and in linkage disequilibrium with the 3-G haplotype that we have identified.
Mol Psychiatry 2002;7(6):579-93 : Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor.
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES.
Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3'. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm.
Mol Psychiatry 2002;7 Suppl 1:S29-34 : Synaptic plasticity and mood disorders.
Duman RS.
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA.

Recent studies demonstrate that the molecular elements known to regulate neuronal plasticity in models of learning and memory are also involved in the actions of drugs used for the treatment of depression and bipolar disorder. This includes up-regulation of transcription factors, such as the cAMP response element binding protein and neurotrophic factors, such as brain derived neurotrophic factor. These findings raise the possibility that regulation of neural plasticity in specific neuronal circuits is integrally involved in the therapeutic intervention of mood disorders. Atypical antipsychotic drugs, including clozapine and olanzapine, are also effective for the treatment of bipolar disorder, and are used as add-on medication for unipolar depression. The possibility that these atypical antipsychotic drugs also influence the molecular determinants of synaptic plasticity that are involved in the response to drugs used for the treatment of mood disorders, is discussed.
Biol Psychiatry 2001 Aug 15;50(4):260-5 : Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Department of Psychiatry and Behavioral Neuroscience, McMaster University, Hamilton, Ontario, Canada.

BACKGROUND: The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain. METHODS: Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. RESULTS: Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. CONCLUSIONS: These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.

Biol Psychiatry 2000 Oct 15;48(8):766-77 : Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells.
Rajkowska G.
Laboratory of Quantitative Neuroanatomy, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.

The influence of stress and glucocorticoids on neuronal pathology has been demonstrated in animal and clinical studies. It has been proposed that stress-induced changes in the hippocampus may be central to the development of depression in genetically vulnerable individuals. New evidence implicates the prefrontal cortex (PFC) in addition to the hippocampus as a site of neuropathology in depression. The PFC may be involved in stress-mediated neurotoxicity because stress alters PFC functions and glucocorticoid receptors, the PFC is directly interconnected with the hippocampus, and metabolic alterations are present in the PFC in depressed patients. Postmortem studies in major depression and bipolar disorder provide the first evidence for specific neuronal and glial histopathology in mood disorders. Three patterns of morphometric cellular changes are noted: cell loss (subgenual PFC), cell atrophy (dorsolateral PFC and orbitofrontal cortex), and increased numbers of cells (hypothalamus, dorsal raphe nucleus). The relevance of cellular changes in mood disorders to stress and prolonged PFC development and a role of neurotrophic/neuroprotective factors are suggested, and a link between cellular changes and the action of therapeutic drugs is discussed. The precise anatomic localization of dysfunctional neurons and glia in mood disorders may reveal cortical targets for novel antidepressants and mood stabilizers.
Psychopharmacol Bull 2001 Spring;35(2):5-49 : Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics.
Manji HK, Duman RS.
Laboratory of Molecular Pathophysiology,
NIMH, Building 49, Room B1EE16, 49 Convent Dr MSC 4405, Bethesda, MD 20892-4405, USA.

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggests that mood disorders are associated with impairments of structural plasticity and cellular resilience. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressants and mood stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP kinases, and may thus bring about some of their delayed long term beneficial effects via underappreciated neurotrophic effects. The future development of treatments that more directly target molecules involved in critical CNS cell survival and cell death pathways thus hold promise as novel, improved long-term treatments for mood disorders.
Med Hypotheses 2002 Aug;59(2):154-8 : Schizophrenia and other mental disorders require long-term adoptive immunotherapy.
Wank R.
Institute of Immunology, Klinikum Innenstadt, University of Munich, Goethestrasse 31, 80336 Munich, Germany.

Many different microbial factors seem to contribute to the pathogenesis of schizophrenic and other psychiatric disorders. Activation of all T lymphocytes reactivates those downregulated by low-grade chronic infections and restores equilibrium in immune cell subpopulations. Different immune cell subpopulations express different neurotrophin receptors and produce different cytokines, particularly brain-derived neurotrophin (BDNF) and neurotrophin 3 (NT3) [M. Besser, R. Wank, J. Immunol. 162 (1998) 6303-6306] that appear to play a key role in schizophrenic and bipolar disorders [E. Jonsson, S. Brene, X.R. Zhang, et al., Acta Psychiatr. Scand. 95 (1997) 414-419; R.S. Duman, Arch. Gen. Psychiatry 54 (1997) 597-606; J.A. Siuciak, D.R. Lewis, S.J. Wiegand, R.M. Lindsay, Pharmacol. Biochem. Be 56 (1997) 131-137]. The hypothesis that adoptive immunotherapy is effective in psychiatric disorders will be supported by three case reports, in a patient with bipolar disorder, a patient with schizophrenia, and a patient with autism.
Family-Based Association Study Of 76 Candidate Genes In Bipolar Disorder: BDNF Is A Potential Risk Locus August 6, 2002
Our study of 76 genes has narrowed down the search to BDNF but further studies will need to confirm our results," says Pamela Sklar, first author and researcher at the Whitehead and Psychiatric and Neurodevelopmental Genetics Unit at MGH. BDNF is a gene found on chromosome 11 and belongs to a family of so-called neurotrophins - nerve chemicals that promote the growth and survival of neurons.