The molecular basis of psychotherapy: Focus on BDNF in talking therapies
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Psychotherapy is effective in treating various types of mental disorders. However, the biological processes underlying its therapeutic efficacy in the relief of depression and anxiety remain unclear. An approach to investigating these therapeutic mechanisms derives from an understanding of disease pathogenesis, in which the dysfunction of brain-derived neurotrophic factor (BDNF) is strongly implicated. This study provides a review of various studies investigating the link between the efficacy of talking therapies in anxiety and depression and the measures of BDNF variability, the latter determined by plasma and serum BDNF concentrations, BDNF gene polymorphisms, and DNA methylation. Despite the few intriguing findings supporting the underlying hypothesis that reduced BDNF function results in poor response, many studies are limited by inadequate methodology and poor control of confounding factors. Thus, opportunities remain for further well-designed investigations, particularly utilizing the little-studied epigenetic factor of BDNF gene methylation.
- Carpenter JK, Andrews LA, Witcraft SM, Powers MB, Smits JAJ, Hofmann SG. Cognitive behavioral therapy for anxiety and related disorders: A meta-analysis of randomized placebo-controlled trials. Depress Anxiety. 2018;35(6):502-514. doi: 10.1002/da.22728
- Negt P, Brakemeier EL, Michalak J, Winter L, Bleich S, Kahl KG. The treatment of chronic depression with cognitive behavioral analysis system of psychotherapy: A systematic review and meta-analysis of randomized-controlled clinical trials. Brain Behav. 2016;6(8):e00486. doi: 10.1002/brb3.486
- Haram A, Fosse R, Jonsbu E, Hole T. Impact of psychotherapy in psychosis: A retrospective case control study. Front Psychiatry. 2019;10:204. doi: 10.3389/fpsyt.2019.00204
- Kappelmann N, Rein M, Fietz J, et al. Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry. BMC Med. 2020;18(1):170. doi: 10.1186/s12916-020-01623-9
- Dunlop BW, LoParo D, Kinkead B, et al. Benefits of sequentially adding cognitive-behavioral therapy or antidepressant medication for adults with nonremitting depression. Am J Psychiatry. 2019;176(4):275-286. doi: 10.1176/appi.ajp.2018.18091075
- Luong HK, Drummond SPA, Norton PJ. Elements of the therapeutic relationship in CBT for anxiety disorders: A systematic review. J Anxiety Disord. 2020;76:102322. doi: 10.1016/j.janxdis.2020.102322
- Goncalves L, Barbisan GK, Reboucas C, Da Rocha NS. Longitudinal investigation of psychotherapy outcomes (LIPO): Description of the study protocol. Front Psychiatry. 2019;10:212. doi: 10.3389/fpsyt.2019.00212
- Wang Y, Liang J, Xu B, Yang J, Wu Z, Cheng L. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury. Life Sci. 2024;336:122282. doi: 10.1016/j.lfs.2023.122282
- Xu L, Zhu L, Zhu L, et al. Moderate exercise combined with enriched environment enhances learning and memory through BDNF/TrkB signaling pathway in rats. Int J Environ Res Public Health. 2021;18(16):8283. doi: 10.3390/ijerph18168283
- Sharma V, Singh TG, Kaur A, Mannan A, Dhiman S. Brain-derived neurotrophic factor: A novel dynamically regulated therapeutic modulator in neurological disorders. Neurochem Res. Feb 2023;48(2):317-339. doi: 10.1007/s11064-022-03755-1
- Wang Y, Zhang H, Li Y, et al. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder. J Affect Disord. 2015;186:7-12. doi: 10.1016/j.jad.2015.07.023
- Lonsdorf TB, Kalisch R. A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment. Transl Psychiatry. 2011;1(9):e41. doi: 10.1038/tp.2011.36
- Piotrkowicz M, Janoska-Jazdzik M, Koweszko T, Szulc A. The influence of psychotherapy on peripheral brain-derived neurotrophic factor concentration levels and gene methylation status: A systematic review. J Clin Med. 2021;10(19):4424. doi: 10.3390/jcm10194424
- Wade PA. Dynamic regulation of DNA methylation coupled transcriptional repression: BDNF regulation by MeCP2. Bioessays. 2004;26(3):217-220. doi: 10.1002/bies.20018
- Casarotto P, Umemori J, Castren E. BDNF receptor TrkB as the mediator of the antidepressant drug action. Front Mol Neurosci. 2022;15:1032224. doi: 10.3389/fnmol.2022.1032224
- Zelada MI, Garrido V, Liberona A, et al. Brain-derived neurotrophic factor (BDNF) as a predictor of treatment response in major depressive disorder (MDD): A Systematic review. Int J Mol Sci. 2023;24(19):14810. doi: 10.3390/ijms241914810
- Zou Y, Zhang Y, Tu M, et al. Brain-derived neurotrophic factor levels across psychiatric disorders: A systemic review and network meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2024;131:110954. doi: 10.1016/j.pnpbp.2024.110954
- Dou SH, Cui Y, Huang SM, Zhang B. The role of brain-derived neurotrophic factor signaling in central nervous system disease pathogenesis. Front Hum Neurosci. 2022;16:924155. doi: 10.3389/fnhum.2022.924155
- Sha Z, Xu J, Li N, Li O. Regulatory molecules of synaptic plasticity in anxiety disorder. Int J Gen Med. 2023;16:2877-2886. doi: 10.2147/IJGM.S413176
- Nikolac Perkovic M, Gredicak M, Sagud M, Nedic Erjavec G, Uzun S, Pivac N. The association of brain-derived neurotrophic factor with the diagnosis and treatment response in depression. Expert Rev Mol Diagn. 2023;23(4):283-296. doi: 10.1080/14737159.2023.2200937
- Berry A, Bellisario V, Capoccia S, et al. Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice. Psychoneuroendocrinology. 2012;37(6):762-772. doi: 10.1016/j.psyneuen.2011.09.007
- Gomutbutra P, Srikhamjak T, Sapinun L, et al. Corrigendum to “Effect of intensive weekend mindfulness-based intervention on BDNF, mitochondria function, and anxiety. A randomized, crossover clinical trial” [Compr. Psychoneuroendocrinol. (2022) 100137]. Compr Psychoneuroendocrinol. 2022;11:100141. doi: 10.1016/j.cpnec.2022.100141
- Fujimura H, Altar CA, Chen R, et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost. 2002;87(4):728-734.
- Chimienti G, Mezzapesa A, Rotelli MT, Lupo L, Pepe G. Plasma concentrations but not serum concentrations of brain-derived neurotrophic factor are related to pro-inflammatory cytokines in patients undergoing major abdominal surgery. Clin Biochem. 2012;45(9):631-636. doi: 10.1016/j.clinbiochem.2012.02.025
- Sochal M, Ditmer M, Gabryelska A, Bialasiewicz P. The role of brain-derived neurotrophic factor in immune-related diseases: A narrative review. J Clin Med. 2022;11(20):6023. doi: 10.3390/jcm11206023
- Bruijniks SJE, Van Grootheest G, Cuijpers P, et al. Working memory moderates the relation between the brain-derived neurotropic factor (BDNF) and psychotherapy outcome for depression. J Psychiatr Res. 2020;130:424-432. doi: 10.1016/j.jpsychires.2020.07.045
- Guo H, Ren Y, Huang B, Wang J, Yang X, Wang Y. Psychological status, compliance, serum brain-derived neurotrophic factor, and nerve growth factor levels of patients with depression after augmented mindfulness-based cognitive therapy. Genet Res (Camb). 2022;2022:1097982. doi: 10.1155/2022/1097982
- Liu W, Yuan J, Wu Y, et al. A randomized controlled trial of mindfulness-based cognitive therapy for major depressive disorder in undergraduate students: Dose- response effect, inflammatory markers and BDNF. Psychiatry Res. 2024;331:115671. doi: 10.1016/j.psychres.2023.115671
- Orosz A, Federspiel A, Eckert A, et al. Exploring the effectiveness of a specialized therapy programme for burnout using subjective report and biomarkers of stress. Clin Psychol Psychother. 2021;28(4):852-861. doi: 10.1002/cpp.2539
- Xu L, Wang F, Yuan J, et al. A randomized controlled trial of mindfulness-based cognitive therapy (MBCT) for major depressive disorder in undergraduate students in China: The efficacy, serum proinflammatory cytokines and brain-derived neurotrophic factor. Asian J Psychiatr. 2023;88:103718. doi: 10.1016/j.ajp.2023.103718
- Kobayashi K, Shimizu E, Hashimoto K, 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. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(5):658-663. doi: 10.1016/j.pnpbp.2005.04.010
- Da Silva SK, Wiener C, Ghisleni G, et al. Effects of cognitive-behavioral therapy on neurotrophic factors in patients with major depressive disorder. Braz J Psychiatry. 2018;40(4):361-366. doi: 10.1590/1516-4446-2017-2357
- Koch JM, Hinze-Selch D, Stingele K, et al. Changes in CREB phosphorylation and BDNF plasma levels during psychotherapy of depression. Psychother Psychosom. 2009;78(3):187-192.doi: 10.1159/000209350
- Sadhasivam S, Alankar S, Maturi R, et al. Inner engineering practices and advanced 4-day isha yoga retreat are associated with cannabimimetic effects with increased endocannabinoids and short-term and sustained improvement in mental health: A prospective observational study of meditators. Evid Based Complement Alternat Med. 2020;2020:8438272. doi: 10.1155/2020/8438272
- Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112(2):257-269. doi: 10.1016/s0092-8674(03)00035-7
- Schosser A, Fischer-Hansal D, Swoboda MM, et al. BDNF gene polymorphisms predicting treatment response to CBT-based rehabilitation of depression: To be submitted to: European Neuropsychopharmacology. Eur Neuropsychopharmacol. 2022;58:103-108. doi: 10.1016/j.euroneuro.2022.03.005
- Peters RB, Xavier J, Mondin TC, et al. BDNF Val66Met polymorphism and resilience in major depressive disorder: The impact of cognitive psychotherapy. Braz J Psychiatry. 2020;43(1):22-28. doi: 10.1590/1516-4446-2019-0726
- Bakker JM, Lieverse R, Menne-Lothmann C, et al. Therapygenetics in mindfulness-based cognitive therapy: Do genes have an impact on therapy-induced change in real-life positive affective experiences? Transl Psychiatry. 2014;4(4):e384. doi: 10.1038/tp.2014.23
- Lester KJ, Hudson JL, Tropeano M, et al. Neurotrophic gene polymorphisms and response to psychological therapy. Transl Psychiatry. 2012;2(5):e108. doi: 10.1038/tp.2012.33
- Santacana M, Arias B, Mitjans M, et al. Predicting response trajectories during cognitive-behavioural therapy for panic disorder: No association with the BDNF gene or childhood maltreatment. PLoS One. 2016;11(6):e0158224. doi: 10.1371/journal.pone.0158224
- Hedman E, Andersson E, Ljotsson B, et al. Clinical and genetic outcome determinants of Internet- and group-based cognitive behavior therapy for social anxiety disorder. Acta Psychiatr Scand. 2012;126(2):126-136. doi: 10.1111/j.1600-0447.2012.01834.x
- Reynolds GP. Early life trauma, DNA methylation and mental illness. Epigenomics. 2021;13(11):825-827. doi: 10.2217/epi-2021-0128
- Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 1998;20(4):709-726. doi: 10.1016/s0896-6273(00)81010-7
- Li L, Wang T, Chen S, Yue Y, Xu Z, Yuan Y. DNA methylations of brain-derived neurotrophic factor exon VI are associated with major depressive disorder and antidepressant-induced remission in females. J Affect Disord. 2021;295:101-107. doi: 10.1016/j.jad.2021.08.016
- Gejl AK, Enevold C, Bugge A, Andersen MS, Nielsen CH, Andersen LB. Associations between serum and plasma brain-derived neurotrophic factor and influence of storage time and centrifugation strategy. Sci Rep. 2019;9(1):9655. doi: 10.1038/s41598-019-45976-5
- Brand SJ, Moller M, Harvey BH. A review of biomarkers in mood and psychotic disorders: A dissection of clinical vs. preclinical correlates. Curr Neuropharmacol. 2015;13(3):324-368. doi: 10.2174/1570159x13666150307004545
- Du D, Tang Q, Han Q, et al. Association between genetic polymorphism and antidepressants in major depression: A network meta-analysis. Pharmacogenomics. 2020;21(13):963-974. doi: 10.2217/pgs-2020-0037
- Bandelow B, Baldwin D, Abelli M, et al. Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition. World J Biol Psychiatry. 2017;18(3):162-214. doi: 10.1080/15622975.2016.1190867
- Cattane N, Vernon AC, Borsini A, et al. Preclinical animal models of mental illnesses to translate findings from the bench to the bedside: Molecular brain mechanisms and peripheral biomarkers associated to early life stress or immune challenges. Eur Neuropsychopharmacol. 2022;58:55-79. doi: 10.1016/j.euroneuro.2022.02.002
- Jin Y, Sun LH, Yang W, Cui RJ, Xu SB. The role of BDNF in the neuroimmune axis regulation of mood disorders. Front Neurol. 2019;10:515. doi: 10.3389/fneur.2019.00515
- Kishi T, Yoshimura R, Ikuta T, Iwata N. Brain-derived neurotrophic factor and major depressive disorder: Evidence from meta-analyses. Front Psychiatry. 2017;8:308. doi: 10.3389/fpsyt.2017.00308
- Kapfhammer HP. Somatic symptoms in depression. Dialogues Clin Neurosci. 2006;8(2):227-239. doi: 10.31887/DCNS.2006.8.2/hpkapfhammer
- Pius-Sadowska E, Machalinski B. BDNF-a key player in cardiovascular system. J Mol Cell Cardiol. 2017;110:54-60. doi: 10.1016/j.yjmcc.2017.07.007
- Matin S, Dadkhah M. BDNF/CREB signaling pathway contribution in depression pathogenesis: A survey on the non-pharmacological therapeutic opportunities for gut microbiota dysbiosis. Brain Res Bull. 2024;207:110882. doi: 10.1016/j.brainresbull.2024.110882
- Dinoff A, Herrmann N, Swardfager W, Lanctot KL. The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor in healthy adults: A meta-analysis. Eur J Neurosci. 2017;46(1):1635-1646. doi: 10.1111/ejn.13603
- Huang T, Larsen KT, Ried-Larsen M, Moller NC, Andersen LB. The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: A review. Scand J Med Sci Sports. 2014;24(1):1-10. doi: 10.1111/sms.12069
- Tsai CL, Pan CY, Chen FC, Wang CH, Chou FY. Effects of acute aerobic exercise on a task-switching protocol and brain-derived neurotrophic factor concentrations in young adults with different levels of cardiorespiratory fitness. Exp Physiol. 2016;101(7):836-850. doi: 10.1113/EP085682
- Gravesteijn E, Mensink RP, Plat J. Effects of nutritional interventions on BDNF concentrations in humans: A systematic review. Nutr Neurosci. 2022;25(7):1425-1436. doi: 10.1080/1028415X.2020.1865758
- Yan T, Wang L, Kuang W, et al. Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy: A systematic review and meta-analysis. Asia Pac Psychiatry. 2014;6(3):241-251. doi: 10.1111/appy.12148
- Shi Y, Luan D, Song R, Zhang Z. Value of peripheral neurotrophin levels for the diagnosis of depression and response to treatment: A systematic review and meta-analysis. Eur Neuropsychopharmacol. 2020;41:40-51. doi: 10.1016/j.euroneuro.2020.09.633
- Cubillos S, Engmann O, Brancato A. BDNF as a mediator of antidepressant response: Recent advances and lifestyle interactions. Int J Mol Sci. 2022;23(22):14445. doi: 10.3390/ijms232214445
- Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int J Mol Sci. 2020;21(20):7777. doi: 10.3390/ijms21207777
- Caldieraro MA, McKee M, Leistner-Segal S, et al. Val66Met polymorphism association with serum BDNF and inflammatory biomarkers in major depression. World J Biol Psychiatry. Aug 2018;19(5):402-409. doi: 10.1080/15622975.2017.1347713
- Fachim HA, Corsi-Zuelli F, Loureiro CM, et al. Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation. Prog Neuropsychopharmacol Biol Psychiatry. 2021;108:110188. doi: 10.1016/j.pnpbp.2020.110188