Implication of BDNF in treatment and pathophysiology of depression
Final Report Abstract
The exact role of neurotrophins in pathophysiology and psychopharmacology treatment of depression remains unclear. Although there are many results promoting the neurotrophin hypothesis of depression, saying that especially the Brain-derived neurotrophin factor (BDNF) is reduced in depressive patients and must be restored to achieve antidepressant response, there are also contrary findings in clinical and preclinical studies so far. Even the widely accepted presumption, that in humans, low serum-BDNF is a state marker of depression, was not approved always. Studies also show, that individuals with a vulnerability for depression display lower serum-BDNF already in a healthy state. Finally not all studies can replicate a BDNF-increase in the course of antidepressant treatment and some even found a clinical response without a BDNF-serum increase at all. Procedure: We examined serum and plasma-BDNF in a sample of 76 depressed patients in the time course of eight weeks of antidepressant treatment. Patients were treated in a naturalistic setting, using individual indicated types of antidepressants. Besides that we took bloss samples to detect the phenotype of BDNFVal/Met-polymorphism in patiens. In part of the patients we measured a spectroscopy of NAA and glutamate before and after six weeks of antidepressant treatment. In neuro-imaging-measurements, we also assessed activation in the vmPC in association with self-referential thoughts. In addition to the sample of depressed patients serum/plasma-BDNF, genotype, MRI-measurments and demographic data were assessed in a group of 38 (24f/14m) healthy controls at time-point 0 and 6. Results: In contrast to most studies of BDNF-functioning and against the BDNF-hypotheses of depression, we found an overall serum-BDNF decrease in the time course of six weeks of antidepressant treatment. There was no association of symptom reduction in HAM-D and serum-BDNF-concentrations over the time-period of eight weeks of treatment. Though there was a slightly difference between male and female patients in the way that female patients showed more serum-BDNF decrease than men after six weeks of medical treatment. In line with our hypohtesis, NAA in the vmPFC increased over time an showed was associated with the serum-BDNF-concentration at this timepoint. Nevertheless, There was no association between the clinical indicators (HAM-D, BDI) an NAA. Associations between serum-BDNF and clinical data only showed a negative correlation between BDI-score at T0 and serum BDNF after two and four weeks of medical treatment. Whereas higher serum BDNF at T0 lead to higher HAM-D- scores at T7 and higher serum-BDNF at T2 lead to higher HAM-D at T8. In imaging measurments we found rising regional homogenity during resting state in depressed vs. healthy controls in the nucleus accumbes as well as more grey matter in the vmPFC of depressed patients after six weeks of medication in contras to healthy controls. Intersetingly there is an association between NAA in vmPFC and serum BDNF after, but not before medication. No difference so far could be found between depressed and HC before medication. So far, we cannot make a statement to the difference between patient and control- BDNF-altering, nor genetic influences. Conclusion: Our results question the BDNF-hypotheses of depression and the short -time influence of BDNF to depression-reduction. It would be more likely to assume, that BDNF-altering is not a forced precondition to depression-reduction and drug effectivity. In additional MRI-measurments though we found interesting results to the interaction of brain-funtioning and structural changes during medication.
Publications
- Acute exercise ameliorates reduced brain-derived neurotrophic factor in patients with panic disorder. Psychoneuroendocrinology. 2010 Apr;35(3):364-8
Ströhle A, Stoy M, Graetz B, Scheel M, Wittmann A, Gallinat J, Lang UE, Dimeo F, Hellweg R
(See online at https://doi.org/10.1016/j.psyneuen.2009.07.013) - Hyperactivity and enhanced curiosity of mice expressing PKB/SGK-resistant glycogen synthase kinase-3 (GSK-3). Cell Physiol Biochem. 2010;25(6):775-86
Ackermann TF, Kempe DS, Lang F, Lang UE
(See online at https://doi.org/10.1159/000315097) - Impairment of phosphatidylinositol 3-kinase signaling in schizophrenia: state or trait? Am J Psychiatry. 2010 Jun;167(6):719; author reply 719
Lang UE
(See online at https://doi.org/10.1176/appi.ajp.2010.10010103) - Met carriers of BDNF Val66Met genotype show increased N-acetylaspartate concentration in the anterior cingulate cortex. Neuroimage. 2010 Jan 1;49(1):767-71
Gallinat J, Schubert F, Brühl R, Hellweg R, Klär AA, Kehrer C, Wirth C, Sander T, Lang UE
(See online at https://doi.org/10.1016/j.neuroimage.2009.08.018) - Exploring the relationship between vitamin D and basic personality traits. Psychopharmacology (Berl). 2011 Jun;215(4):733-7
Ubbenhorst A, Striebich S, Lang F, Lang UE
(See online at https://doi.org/10.1007/s00213-011-2175-x) - (2013). Brain-derived neurotropic factor serum concentrations in acute depressive patients increase during lithium augmentation of antidepressants. Journal of Clinical Psychopharmacology, 33 (6), 806-809
Ricken, R., Adli, M., Lange, C., Krusche, E., Stamm, T.J., Gaus, S., Koehler, S., Nase, S., Bschor, T., Richter, C., Steinacher, B., Heinz, A., Rapp, M.A., Borgwardt, S., Hellweg, R., & Lang, U.E.
(See online at https://doi.org/10.1097/JCP.0b013e3182a412b8) - Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat Med. 2013 Jul;19(7):934-8
Gulbins E, Palmada M, Reichel M, Lüth A, Böhmer C, Amato D, Müller CP, Tischbirek CH, Groemer TW, Tabatabai G, Becker KA, Tripal P, Staedtler S, Ackermann TF, van Brederode J, Alzheimer C, Weller M, Lang UE, Kleuser B, Grassmé H, Kornhuber J
(See online at https://doi.org/10.1038/nm.3214) - Changes of serum concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine and mirtazapine: role of medication and response to treatment. Pharmacopsychiatry. 2013 Mar;46(2):54-8
Deuschle M, Gilles M, Scharnholz B, Lederbogen F, Lang UE, Hellweg R
(See online at https://doi.org/10.1055/s-0032-1321908) - Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem. 2013;31(6):761-77
Lang UE, Borgwardt S
(See online at https://doi.org/10.1159/000350094) - Regulation of mineral metabolism by lithium. Pflugers Arch. 2014 Mar;466(3):467-75
Fakhri H, Pathare G, Fajol A, Zhang B, Bock T, Kandolf R, Schleicher E, Biber J, Föller M, Lang UE, Lang F
(See online at https://doi.org/10.1007/s00424-013-1340-y)
