title: Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484).
abstract: Meta-analyses, published in 2008-2010, have confirmed abnormally low serum brain-derived neurotrophic factor (BDNF) concentrations in depressed patients and normalization of this by antidepressant treatment. These findings are believed to reflect peripheral manifestations of the neurotrophin hypothesis, which states that depression is secondary to an altered expression of BDNF in the brain. Since the publication of these meta-analyses, the field has seen a huge increase in studies on these topics. This motivated us to update the evidence on the aforementioned associations and, in addition, to compile the data on serum BDNF concentrations in relation to the symptom severity of depression. Using a manifold of data as compared with earlier meta-analyses, we find low serum BDNF concentrations in 2384 antidepressant-free depressed patients relative to 2982 healthy controls and to 1249 antidepressant-treated depressed patients (Cohen's d=-0.71 and -0.56, P-values <0.0000001). When publication bias is accounted for, these effect-sizes become substantially smaller (d=-0.47 and -0.34, respectively, P-values<0.0001). We detect between-study heterogeneity in outcomes for which only year of publication and sample size are significant moderators, with more recent papers and larger samples sizes in general being associated with smaller between-group differences. Finally, the aggregated data negate consistent associations between serum BDNF concentrations and the symptom severity of depression. Our findings corroborate the claim that altered serum BDNF concentrations are peripheral manifestations of depression. However, here we highlight that the evidence for this claim is slimmer as was initially thought and amidst a lot of noise.
authors: 1] Clinical, Health and Neuropsychology Unit, Leiden University, Leiden, The Netherlands [2] Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
authors: M L
authors: ML
authors: Molendijk
authors: 1] Clinical, Health and Neuropsychology Unit, Leiden University, Leiden, The Netherlands [2] Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands [3] Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
authors: P
authors: P
authors: Spinhoven
authors: Clinical, Health and Neuropsychology Unit, Leiden University, Leiden, The Netherlands.
authors: M
authors: M
authors: Polak
authors: Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: B A A
authors: BA
authors: Bus
authors: 1] Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands [2] Department of Psychiatry, EMGO Institute and Neuroscience Campus Amsterdam VU, Amsterdam, The Netherlands [3] University Center for Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: B W J H
authors: BW
authors: Penninx
authors: 1] Clinical, Health and Neuropsychology Unit, Leiden University, Leiden, The Netherlands [2] Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
authors: B M
authors: BM
authors: Elzinga
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood*; D016022:Case-Control Studies; D003863:Depression / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D011569:Psychiatric Status Rating Scales; D017594:Publication Bias / Q000706:statistics & numerical data
chemical_list: D000928:Antidepressive Agents; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor
references: Hum Psychopharmacol. 2009 Jul;24(5):409-13
references: 19548207
references: J Clin Psychiatry. 2009 Dec;70(12):1662-6
references: 19744406
references: J Affect Disord. 2006 Mar;91(1):83-6
references: 16448701
references: Int J Neuropsychopharmacol. 2010 Feb;13(1):1-4
references: 19995480
references: Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15;35(7):1623-30
references: 21749907
references: Prog Neuropsychopharmacol Biol Psychiatry. 2009 Mar 17;33(2):281-5
references: 19110026
references: World J Biol Psychiatry. 2012 Oct;13(7):535-43
references: 21888560
references: Eur Arch Psychiatry Clin Neurosci. 2005 Dec;255(6):381-6
references: 15809771
references: J Psychiatr Res. 2011 Aug;45(8):995-1004
references: 21550050
references: World J Biol Psychiatry. 2009;10(4):295-301
references: 19921971
references: Behav Res Methods. 2009 Nov;41(4):1149-60
references: 19897823
references: Psychoneuroendocrinology. 2006 Apr;31(3):388-94
references: 16289360
references: J Psychiatr Res. 2013 Feb;47(2):162-7
references: 23102630
references: Trends Genet. 2004 Sep;20(9):439-44
references: 15313553
references: Neurosci Lett. 2002 Aug 16;328(3):261-4
references: 12147321
references: Mol Psychiatry. 2007 Dec;12(12):1079-88
references: 17700574
references: Ann Intern Med. 2009 Aug 18;151(4):264-9, W64
references: 19622511
references: World J Biol Psychiatry. 2010 Sep;11(6):763-73
references: 20334574
references: PLoS One. 2012;7(11):e48046
references: 23133609
references: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1034-7
references: 17459550
references: Psychol Med. 1996 May;26(3):477-86
references: 8733206
references: Jpn J Clin Oncol. 2011 Oct;41(10):1233-7
references: 21926098
references: PLoS Med. 2005 Aug;2(8):e124
references: 16060722
references: J Psychiatr Res. 2012 Jul;46(7):966-72
references: 22551661
references: J Psychiatr Res. 2009 Jan;43(3):247-54
references: 18511076
references: Neurobiol Aging. 2007 Sep;28(9):1436-45
references: 16879899
references: Psychol Med. 2005 Jun;35(6):897-905
references: 15997610
references: Biol Psychiatry. 2003 Jul 1;54(1):70-5
references: 12842310
references: Neuropsychobiology. 2005;51(4):234-8
references: 15897674
references: J Psychiatr Res. 2012 Mar;46(3):285-9
references: 22244515
references: Mol Psychiatry. 2011 Sep;16(9):960-72
references: 20733577
references: BMC Med. 2013 May 15;11:129
references: 23672628
references: J Affect Disord. 2011 Dec;135(1-3):332-5
references: 21774990
references: Front Psychiatry. 2012 Feb 24;3:12
references: 22375129
references: World J Biol Psychiatry. 2010 Apr;11(3):550-5
references: 20109109
references: PLoS One. 2012;7(8):e42676
references: 22880079
references: Biol Psychiatry. 2006 Jun 15;59(12):1116-27
references: 16631126
references: Int J Epidemiol. 2007 Jun;36(3):666-76
references: 17470488
references: Brain Res Bull. 2010 Jan 15;81(1):61-5
references: 19589373
references: Mol Psychiatry. 2011 Nov;16(11):1088-95
references: 20856249
references: Psychiatry Res. 2002 Mar 15;109(2):143-8
references: 11927139
references: Psychoneuroendocrinology. 2011 Feb;36(2):228-39
references: 20702043
references: Hepatology. 2001 Jan;33(1):148-58
references: 11124831
references: Mol Psychiatry. 2013 Mar;18(3):332-9
references: 22158016
references: J Psychiatr Res. 2011 Oct;45(10):1301-6
references: 21641002
references: Biol Psychiatry. 2008 Sep 15;64(6):527-32
references: 18571629
references: Eur Neuropsychopharmacol. 2006 Dec;16(8):620-4
references: 16757154
references: Psychiatry Investig. 2009 Dec;6(4):299-305
references: 20140129
references: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1023-6
references: 17433517
references: Neuropsychobiology. 2013;67(1):33-40
references: 23221974
references: Pharmacopsychiatry. 2008 Mar;41(2):66-71
references: 18311687
references: Mol Psychiatry. 2010 Jan;15(1):80-92
references: 19621014
references: Psychopharmacology (Berl). 2011 Mar;214(1):319-28
references: 20703451
references: BMJ. 2001 Jan 27;322(7280):226-31
references: 11159626
references: Mol Psychiatry. 2012 Dec;17(12):1174-9
references: 22869033
references: Brain Res Bull. 2012 Aug 1;88(5):454-9
references: 22498307
references: JAMA. 1990 Mar 9;263(10):1385-9
references: 2406472
references: J Neurol Neurosurg Psychiatry. 1960 Feb;23:56-62
references: 14399272
references: Brain Res Bull. 2009 Sep 28;80(3):158-62
references: 19576267
references: BMJ. 1997 Sep 13;315(7109):629-34
references: 9310563
references: Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jul 1;32(5):1185-90
references: 18403081
references: Neurosci Lett. 2009 Apr 10;453(3):195-8
references: 19429034
references: Int J Neuropsychopharmacol. 2008 Dec;11(8):1169-80
references: 18752720
references: Neurochem Res. 2012 Mar;37(3):583-7
references: 22102172
references: Psychiatry Res. 2011 Sep 30;189(2):239-45
references: 21616544
references: World J Biol Psychiatry. 2011 Mar;12(2):110-8
references: 20726825
references: Nat Rev Neurosci. 2013 Jan;14(1):7-23
references: 23254191
references: Prog Neuropsychopharmacol Biol Psychiatry. 2006 Sep 30;30(7):1256-60
references: 16647794
references: Psychopharmacology (Berl). 2006 Jul;187(1):56-9
references: 16767416
references: Neuropsychopharmacology. 2011 Nov;36(12):2375-94
references: 21814182
references: Int J Neuropsychopharmacol. 2011 Apr;14(3):347-53
references: 20604989
references: Pharmacopsychiatry. 2013 Mar;46(2):54-8
references: 22961097
references: J ECT. 2010 Jun;26(2):121-5
references: 19935088
references: J Affect Disord. 2008 Jan;105(1-3):279-83
references: 17553570
references: Clin Chem Lab Med. 2011 Feb;49(2):185-9
references: 21143020
references: Psychosom Med. 2011 Oct;73(8):638-42
references: 21949427
references: Stat Med. 2007 Nov 10;26(25):4544-62
references: 17476644
references: J Psychiatr Res. 2012 Sep;46(9):1118-25
references: 22682508
references: J Psychiatr Res. 2008 Jun;42(7):521-5
references: 17585940
references: J Psychiatry Neurosci. 2011 May;36(3):195-203
references: 21223646
references: Eur Arch Psychiatry Clin Neurosci. 2010 Oct;260(7):527-33
references: 20306200
references: Biol Psychiatry. 2005 May 1;57(9):1068-72
references: 15860348
references: Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 1;35(4):1022-5
references: 21338649
references: Int J Psychiatry Med. 2011;42(3):211-26
references: 22439294
references: Arch Gen Psychiatry. 1997 Jul;54(7):597-606
references: 9236543
references: J Nutr Health Aging. 2008 Mar;12(3):183-5
references: 18309438
references: Biol Psychiatry. 2012 Oct 1;72(7):537-47
references: 22705040
references: Mol Psychiatry. 2007 Nov;12(11):981-3
references: 17957235
references: Annu Rev Public Health. 1996;17:1-23
references: 8724213
references: World J Biol Psychiatry. 2012 Jan;13(1):39-47
references: 21247257
references: Mol Psychiatry. 2014 Feb;19(2):151-2
references: 23399916