Background/Aims: In major depression cognitive impairment is common and may persist despite improvement in psychopathology. So far it is unclear how closely related improvement in cognitive functioning is to the clinical course of depression. Further, it is unclear whether recovery from cognitive impairment is linked to changes in serum brain-derived neurotrophic factor (sBDNF). The objectives of this study were (1) to explore the predictive value of cognitive impairment for therapeutic outcome, and (2) to assess the association between cognitive performance and sBDNF levels over a 6-week course of antidepressant treatment. Methods: Twenty-five adult patients suffering from major depression underwent standardized treatment with duloxetine. Both severity of depression as assessed by the Hamilton Depression Rating Scale and sBDNF levels were measured at baseline, and after 1, 2 and 6 weeks of treatment. Cognitive performance, i.e. alertness, working memory, and divided attention, was assessed at baseline, after 1 week, and at the end of treatment after 6 weeks. Results: Higher performance in alertness and divided attention at baseline correlated with less severe depression at week 6. During the first week of treatment, a greater increase in sBDNF was associated with a greater improvement in alertness at week 6. Conclusion: Greater alertness at baseline was a predictor of favorable antidepressive treatment outcome. Moreover, the early increase in sBDNF correlated with improvement in attention functioning. Thus, recovery from cognitive impairment and an early increase in sBDNF seem to be associated.

Castaneda AE, Tuulio-Henriksson A, Marttunen M, Suvisaari J, Lönnqvist J: A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. J Affect Disord 2008;106:1-27.
Kaymak SU, Demir B, Sentürk S, Tatar I, Aldur MM, Uluğ B: Hippocampus, glucocorticoids and neurocognitive functions in patients with first-episode major depressive disorders. Eur Arch Psychiatry Clin Neurosci 2010;260:217-223.
Lee RS, Hermens DF, Porter MA, Redoblado-Hodge MA: A meta-analysis of cognitive deficits in first-episode major depressive disorder. J Affect Disord 2012;140:113-124.
McClintock SM, Husain MM, Greer TL, Cullum CM: Association between depression severity and neurocognitive function in major depressive disorder: a review and synthesis. Neuropsychology 2010;24:9-34.
Porter RJ, Bourke C, Gallagher P: Neuropsychological impairment in major depression: its nature, origin and clinical significance. Aust NZ J Psychiatry 2007;41:115-128.
Den Hartog HM, Derix MM, Van Bemmel AL, Kremer B, Jolles J: Cognitive functioning in young and middle-aged unmedicated out-patients with major depression: testing the effort and cognitive speed hypotheses. Psychol Med 2003;33:1443-1451.
Farrin L, Hull L, Unwin C, Wykes T, David A: Effects of depressed mood on objective and subjective measures of attention. J Neuropsychiatry Clin Neurosci 2003;15:98-104.
Majer M, Ising M, Künzel H, Binder EB, Holsboer F, Modell S, Zihl J: Impaired divided attention predicts delayed response and risk to relapse in subjects with depressive disorders. Psychol Med 2004;34:1453-1463.
Oral E, Canpolat S, Yildirim S, Gulec M, Aliyev E, Aydin N: Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder. Brain Res Bull 2012;88:454-459.
Snyder HR: Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: a meta-analysis and review. Psychol Bull 2013;139:81-132.
Douglas KM, Porter RJ: Longitudinal assessment of neuropsychological function in major depression. Aust NZ J Psychiatry 2009;43:1105-1117.
Hasselbalch BJ, Knorr U, Kessing LV: Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J Affect Disord 2011;134:20-31.
Hasselbalch BJ, Knorr U, Hasselbalch SG, Gade A, Kessing LV: Cognitive deficits in the remitted state of unipolar depressive disorder. Neuropsychology 2012;26:642-651.
Paelecke-Habermann Y, Pohl J, Leplow B: Attention and executive functions in remitted major depression patients. J Affect Disord 2005;89:125-135.
Reppermund S, Ising M, Lucae S, Zihl J: Cognitive impairment in unipolar depression is persistent and non-specific: further evidence for the final common pathway disorder hypothesis. Psychol Med 2009;39:603-614.
Jaeger J, Berns S, Uzelac S, Davis-Conway S: Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res 2006;145:39-48.
Elgamal S, Denburg S, Marriott M, MacQueen G: Clinical factors that predict cognitive function in patients with major depression. Can J Psychiatry 2010;55:653-661.
Hasselbalch BJ, Knorr U, Hasselbalch SG, Gade A, Kessing LV: The cumulative load of depressive illness is associated with cognitive function in the remitted state of unipolar depressive disorder. Eur Psychiatry 2013;28:349-355.
Bhalla RK, Butters MA, Becker JT, Houck PR, Snitz BE, Lopez OL, Aizenstein HJ, Raina KD, DeKosky ST, Reynolds CF 3rd: Patterns of mild cognitive impairment after treatment of depression in the elderly. Am J Geriatr Psychiatry 2009;17:308-316.
Lee JS, Potter GG, Wagner HR, Welsh-Bohmer KA, Steffens DC: Persistent mild cognitive impairment in geriatric depression. Int Psychogeriatr 2007;19:125-135.
Panza F, Frisardi V, Capurso C, D'Introno A, Colacicco AM, Imbimbo BP, Santamato A, Vendemiale G, Seripa D, Pilotto A, Capurso A, Solfrizzi V: Late-life depression, mild cognitive impairment, and dementia: possible continuum? Am J Geriatr Psychiatry 2010;18:98-116.
Constant EL, Adam S, Gillain B, Seron X, Bruyer R, Seghers A: Effects of sertraline on depressive symptoms and attentional and executive functions in major depression. Depress Anxiety 2005;21:78-89.
Herrera-Guzmán I, Herrera-Abarca JE, Gudayol-Ferré E, Herrera-Guzmán D, Gómez-Carbajal L, Peña-Olvira M, Villuendas-González E, Joan GO: Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder. Psychiatry Res 2010;177:323-329.
Etkin A, Patenaude B, Song YJ, Usherwood T, Rekshan W, Schatzberg AF, Rush AJ, Williams LM: A cognitive-emotional biomarker for predicting remission with antidepressant medications: a report from the iSPOT-D Trial. Neuropsychopharmacology 2015;40:1332-1342.
Gorlyn M, Keilp JG, Grunebaum MF, Taylor BP, Oquendo MA, Bruder GE, Stewart JW, Zalsman G, Mann JJ: Neuropsychological characteristics as predictors of SSRI treatment response in depressed subjects. J Neural Transm 2008;115:1213-1219.
Kampf-Sherf O, Zlotogorski Z, Gilboa A, Speedie L, Lereya J, Rosca P, Shavit Y: Neuropsychological functioning in major depression and responsiveness to selective serotonin reuptake inhibitors antidepressants. J Affect Disord 2004;82:453-459.
Alexopoulos GS, Kiosses DN, Heo M, Murphy CF, Shanmugham B, Gunning-Dixon F: Executive dysfunction and the course of geriatric depression. Biol Psychiatry 2005;58:204-210.
Baldwin R, Jeffries S, Jackson A, Sutcliffe C, Thacker N, Scott M, Burns A: Treatment response in late-onset depression: relationship to neuropsychological, neuroradiological and vascular risk factors. Psychol Med 2004;4:125-136.
Dunkin JJ, Leuchter AF, Cook IA, Kasl-Godley JE, Abrams M, Rosenberg-Thompson S: Executive dysfunction predicts nonresponse to fluoxetine in major depression. J Affect Disord 2000;60:13-23.
Marcos T, Portella MJ, Navarro V, Gastó C, Rami L, Lázaro L, Salamero M: Neuropsychological prediction of recovery in late-onset major depression. Int J Geriatr Psychiatry 2005;20:790-795.
Pimontel MA, Culang-Reinlieb ME, Morimoto SS, Sneed JR: Executive dysfunction and treatment response in late-life depression. Int J Geriatr Psychiatry 2012;27:893-899.
Taylor BP, Bruder GE, Stewart JW, McGrath PJ, Halperin J, Ehrlichman H, Quitkin FM: Psychomotor slowing as a predictor of fluoxetine nonresponse in depressed outpatients. Am J Psychiatry 2006;163:73-78.
Duman RS, Monteggia LM: A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006;59:1116-1127.
Hallbook F: Evolution of the vertebrate neurotrophin and Trk receptor gene families. Curr Opin Neurobiol 1999;9:616-621.
Dijkhuizen PA, Ghosh A: BDNF regulates primary dendrite formation in cortical neurons via the PI3-kinase and MAP kinase signaling pathways. J Neurobiol 2005;62:278-288.
Gorski JA, Zeiler SR, Tamowski S, Jones KR: Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J Neurosci 2003;23:6856-6865.
Lu B, Chow A: Neurotrophins and hippocampal synaptic transmission and plasticity. J Neurosci Res 1999;58:76-87.
Bramham CR, Messaoudi E: BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 2005;76:99-125.
Lu B, Nagappan G, Lu Y: BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 2014;220:223-250.
Brunoni AR, Lopes M, Fregni F: A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008;11:1169-1180.
Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM: Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N = 9484). Mol Psychiatry 2014;19:791-800.
Sen S, Duman R, Sanacora G: Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008;64:527-532.
Brunoni AR, Machado-Vieira R, Zarate CA Jr, Vieira EL, Vanderhasselt MA, Nitsche MA, Valiengo L, Benseñor IM, Lotufo PA, Gattaz WF, Teixeira AL: BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation: results from a factorial, randomized, sham-controlled trial. Eur Neuropsychopharmacol 2014;24:1144-1151.
Deuschle M, Gilles M, Scharnholz B, Lederbogen F, Lang UE, Hellweg R: 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;46:54-58.
Gedge L, Beaudoin A, Lazowski L, du Toit R, Jokic R, Milev R: Effects of electroconvulsive therapy and repetitive transcranial magnetic stimulation on serum brain-derived neurotrophic factor levels in patients with depression. Front Psychiatry 2012;3:12.
Haghighi M, Salehi I, Erfani P, Jahangard L, Bajoghli H, Holsboer-Trachsler E, Brand S: Additional ECT increases BDNF-levels in patients suffering from major depressive disorders compared to patients treated with citalopram only. J Psychiatr Res 2013;47:908-915.
Hellweg R, Ziegenhorn A, Heuser I, Deuschle M: Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment. Pharmacopsychiatry 2008;41:66-71.
Lang UE, Hellweg R, Gallinat J, Bajbouj M: Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: no effects on brain-derived neurotrophic factor (BDNF) concentrations in serum. J Affect Disord 2008;107:255-258.
Matrisciano F, Bonaccorso S, Ricciardi A, Scaccianoce S, Panaccione I, Wang L, Ruberto A, Tatarelli R, Nicoletti F, Girardi P, Shelton RC: Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine. J Psychiatr Res 2009;43:247-254.
Mikoteit T, Beck J, Eckert A, Hemmeter U, Brand S, Bischof R, Holsboer-Trachsler E, Delini-Stula A: High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression. Psychopharmacology (Berl) 2014;231:2955-2965.
Kauer-Sant'Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT, Yatham LN: Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol 2009;12:447-458.
Komulainen P, Pedersen M, Hänninen T, Bruunsgaard H, Lakka TA, Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R: BDNF is a novel marker of cognitive function in ageing women: the DR's EXTRA Study. Neurobiol Learn Mem 2008;90:596-603.
Yu H, Zhang Z, Shi Y, Bai F, Xie C, Qian Y, Yuan Y, Deng L: Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han. J Clin Psychiatry 2008;69:1104-1111.
Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, Bartels M, Buchkremer G, Schott K: Stage-dependent BDNF serum concentrations in Alzheimer's disease. J Neural Transm 2006;113:1217-1124.
Laske C, Stellos K, Hoffmann N, Stransky E, Straten G, Eschweiler GW, Leyhe T: Higher BDNF serum levels predict slower cognitive decline in Alzheimer's disease patients. Int J Neuropsychopharmacol 2011;14:399-404.
Patanella AK, Zinno M, Quaranta D, Nociti V, Frisullo G, Gainotti G, Tonali PA, Batocchi AP, Marra C: Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients. J Neurosci Res 2010;88:1106-1112.
Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, Kauer-Sant'anna M, Grassi-Oliveira R, Post RM: Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 2008;32:675-692.
World Health Organization: ICD-10 Classification of Mental and Behavioural Disorders with Glossary and Diagnostic Criteria for Research ICD10: DCR-10. Edinburgh, Churchill Livingstone, 1994.
Zimmermann P, Fimm B: Testbattery for Attentional Performance (version 2.1) (in German). Herzogenrath, Psychologische Testsysteme, 2007.
Kupfer DJ: Management of recurrent depression. J Clin Psychiatry 1993;54(suppl):29 - 33.
Cohen J: Statistical Power Analysis for the Behavioural Sciences. Hillsdale, Lawrence Erlbaum Associates, 1988.
Zhu W: Sadly, the Earth is still round (p < 0.05). J Sport Health Sci 2012;1:9-11.
Manning KJ, Alexopoulos GS, Banerjee S, Shizuko Morimoto S, Seirup JK, Klimstra SA, Yuen G, Kanellopoulos T, Gunning-Dixon F: Executive functioning complaints and escitalopram treatment response in late-life depression. Am J Geriatr Psychiatry 2015;23:440-445.
McEwen BS, Stellar E: Stress and the individual mechanisms leading to disease. Arch Intern Med 1993;153:2093-2101.
Vieta E, Popovic D, Rosa AR, Solé B, Grande I, Frey BN, Martinez-Aran A, Sanchez-Moreno J, Balanzá-Martínez V, Tabarés-Seisdedos R, Kapczinski F: The clinical implications of cognitive impairment and allostatic load in bipolar disorder. Eur Psychiatry 2013;28:21-29.
Karlamangla AS, Singer BH, Greendale GA, Seeman TE: Increase in epinephrine excretion is associated with cognitive decline in elderly men: MacArthur studies of successful aging. Psychoneuroendocrinology 2005;30:453-460.
Mohlman J, Gorman JM: The role of executive functioning in CBT: a pilot study with anxious older adults. Behav Res Ther 2005;43:447-465.
Bus BA, Molendijk ML, Penninx BJ, Buitelaar JK, Kenis G, Prickaerts J, Elzinga BM, Voshaar RC: Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 2011;36:228-239.
Elzinga BM, Molendijk ML, Oude Voshaar RC, Bus BA, Prickaerts J, Spinhoven P, Penninx BJ: The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met. Psychopharmacology (Berl) 2011;214:319-328.
Lommatzsch M, Zingler D, Schuhbaeck K, Schloetke CZ, Schuff-Werner P, Virchow JC: The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 2005;26:115-123.
Tang SW, Chu E, Hui T, Helmeste D, Law C: Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects. Neurosci Lett 2008;431:62-65.
Jacobsen JP, Mørk A: The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels. Brain Res 2004;1024:183-192.
Musazzi L, Cattaneo A, Tardito D, Barbon A, Gennarelli M, Barlati S, Racagni G, Popoli M: Early raise of BDNF in hippocampus suggests induction of posttranscriptional mechanisms by antidepressants. BMC Neurosci 2009;10:48.
Duman RS, Aghajanian GK: Synaptic dysfunction in depression: potential therapeutic targets. Science 2012;338:68-72.
Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M: Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J Neurosci 2009;29:8688-8697.
Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS: BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 2014;18:pii.pyu033.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS: mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;329:959-964.
Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK: Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 2012;71:996-1005.
Giese M, Beck J, Brand S, Muheim F, Hemmeter U, Hatzinger M, Holsboer-Trachsler E, Eckert A: Fast BDNF serum level increase and diurnal BDNF oscillations are associated with therapeutic response after partial sleep deprivation. J Psychiatr Res 2014;59:1-7.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112:257-269.
Gong P, Zheng A, Chen D, Ge W, Lv C, Zhang K, Gao X, Zhang F: Effect of BDNF Val66Met polymorphism on digital working memory and spatial localization in a healthy Chinese Han population. J Mol Neurosci 2009;38:250-256.
Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P, Pendleton N, Horan M, Payton A: Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav 2008;7:411-417.
Alexopoulos GS, Glatt CE, Hoptman MJ, Kanellopoulos D, Murphy CF, Kelly RE Jr, Morimoto SS, Lim KO, Gunning FM: BDNF val66met polymorphism, white matter abnormalities and remission of geriatric depression. J Affect Disord 2010;125:262-268.
El-Hage W, Vourc'h P, Gaillard P, Léger J, Belzung C, Ibarguen-Vargas Y, Andres CR, Camus V: The BDNF Val66Met polymorphism is associated with escitalopram response in depressed patients. Psychopharmacology (Berl) 2015;232:575-581.
Erickson KI, Banducci SE, Weinstein AM, Macdonald AW 3rd, Ferrell RE, Halder I, Flory JD, Manuck SB: The brain-derived neurotrophic factor Val66Met polymorphism moderates an effect of physical activity on working memory performance. Psychol Sci 2013;24:1770-1779.
Zou YF, Ye DQ, Feng XL, Su H, Pan FM, Liao FF: Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder. Eur Neuropsychopharmacol 2010;20:535-544.
Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT: Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 2001;25:871-880.
Stahl SM, Zhang L, Damatarca C, Grady M: Brain circuits determine destiny in depression: a novel approach to psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry 2003;64(suppl 11):6-17.
Herrera-Guzmán I, Gudayol-Ferré E, Herrera-Guzmán D, Guàrdia-Olmos J, Hinojosa-Calvo E, Herrera-Abarca JE: Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res 2009;43:855-863.
Graf H, Abler B, Hartmann A, Metzger CD, Walter M: Modulation of attention network activation under antidepressant agents in healthy subjects. Int J Neuropsychopharmacol 2013;16:1219-1230.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.