Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial

Raíssa Nóbrega de Almeida, Ana Cecília de Menezes Galvão, Flávia Santos da Silva, Erick Allan Dos Santos Silva, Fernanda Palhano-Fontes, João Paulo Maia-de-Oliveira, Lobão-Soares Barros de Araújo, Bruno Lobão-Soares, Nicole Leite Galvão-Coelho, Raíssa Nóbrega de Almeida, Ana Cecília de Menezes Galvão, Flávia Santos da Silva, Erick Allan Dos Santos Silva, Fernanda Palhano-Fontes, João Paulo Maia-de-Oliveira, Lobão-Soares Barros de Araújo, Bruno Lobão-Soares, Nicole Leite Galvão-Coelho

Abstract

Serotonergic psychedelics are emerging as potential antidepressant therapeutic tools, as suggested in a recent randomized controlled trial with ayahuasca for treatment-resistant depression. Preclinical and clinical studies have suggested that serum brain-derived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants, but the exact role of BDNF as a biomarker for diagnostic and treatment of major depression is still poorly understood. Here we investigated serum BDNF levels in healthy controls (N = 45) and patients with treatment-resistant depression (N = 28) before (baseline) and 48 h after (D2) a single dose of ayahuasca or placebo. In our sample, baseline serum BDNF levels did not predict major depression and the clinical characteristics of the patients did not predict their BDNF levels. However, at baseline, serum cortisol was a predictor of serum BDNF levels, where lower levels of serum BDNF were detected in a subgroup of subjects with hypocortisolemia. Moreover, at baseline we found a negative correlation between BDNF and serum cortisol in volunteers with eucortisolemia. After treatment (D2) we observed higher BDNF levels in both patients and controls that ingested ayahuasca (N = 35) when compared to placebo (N = 34). Furthermore, at D2 just patients treated with ayahuasca (N = 14), and not with placebo (N = 14), presented a significant negative correlation between serum BDNF levels and depressive symptoms. This is the first double-blind randomized placebo-controlled clinical trial that explored the modulation of BDNF in response to a psychedelic in patients with depression. The results suggest a potential link between the observed antidepressant effects of ayahuasca and changes in serum BDNF, which contributes to the emerging view of using psychedelics as an antidepressant. This trial is registered at https://ichgcp.net/clinical-trials-registry/NCT02914769" title="See in ClinicalTrials.gov">NCT02914769).

Keywords: BDNF; antidepressant; ayahuasca; biomarker; cortisol; depression; psychedelics; treatment-resistant.

Figures

FIGURE 1
FIGURE 1
Mean ± standard error of serum BDNF levels (pg/mL) at baseline for patients (MD, dark gray color n = 28) and controls (CG, light gray color n = 41). The curvilinear gray lines represent the density of sample distribution. The circles represent individuals in each group.
FIGURE 2
FIGURE 2
(A) Distribution of age (years old) for patients (MD, dark gray color n = 28) and healthy controls (CG, light gray color n = 41). (B) Box plot of age (years old) (median ± Q75% and Q25%) for the patients (MD, n = 28) and healthy controls (CG, n = 41). Mann–Whitney test, ∗p ≤ 0.05, statistically significant difference between-groups.
FIGURE 3
FIGURE 3
(A) Mean ± standard error of serum BDNF levels (pg/mL) at baseline for volunteers with hypocortisolemia (HC, n = 31) (serum cortisol < 15 mcg/dL) and eucortisolemia (EC, n = 38) (15 mcg/dL < serum cortisol < 43 mcg/dL). Independent Student T-test, ∗p ≤ 0.05, statistically significant difference between-groups. The curvilinear gray lines represent the density of samples distribution. The circles represent individuals in each group. (B) Significant negative correlation between serum BDNF and serum cortisol levels for eucortisolemic volunteers (MD and CG) at baseline (N = 38; Spearman test, p < 0.05, rho = –0.39).
FIGURE 4
FIGURE 4
Mean ± standard error of serum BDNF levels (pg/mL) for volunteers of ayahuasca (AYA: red color, n = 35) and placebo (PLA: blue color, n = 34) treatments at baseline (D0) and 48 h after dosing (D2). GLM test and Fisher post hoc, ∗p ≤ 0.05, statistically significant difference between-groups. The curvilinear gray lines represent the density of samples distribution. The circles represent individuals in each group.
FIGURE 5
FIGURE 5
Significant negative Spearman correlation between BDNF levels and MADRS scores at D2 for patients that were treated with ayahuasca (n = 14; Spearman test, p ≤ 0.05 rho = –0.55).

References

    1. Aherne D., Fitzgerald A., Aherne C., Fitzgerald N., Slattery M., Whelan N. (2017). Evidence for the treatment of moderate depression: a systematic review. Ir. J. Psychol. Med. 34 197–204. 10.1017/ipm.2017.10
    1. Allen A., Naughton M., Dowling J., Walsh A., Ismail F., Shorten G., et al. (2015). Serum BDNF as a peripheral biomarker of treatment-resistant depression and the rapid antidepressant response: a comparison of ketamine and ECT. J. Affect. Disord. 186 306–311. 10.1016/j.jad.2015.06.033
    1. Alves L. P. C., Rocha N. S. (2018). Lower levels of brain-derived neurotrophic factor are associated with melancholic psychomotor retardation among depressed inpatients. Bipolar Disord. 20 746–752. 10.1111/bdi.12636
    1. American Psychiatric Association (APA) (2013). Diagnostic, and Statistical Manual of (Mental)Disorders (DSM-V), 5th Edn. Arlington, VA: American Psychiatric Association.
    1. Anderson T., Petranker R., Rosenbaum D., Weissman C., Dinh-Williams L., Hui K., et al. (2019). Microdosing psychedelics: personality, mental health, and creativity differences in microdosers. Psychopharmacology 236 731–740. 10.1007/s00213-018-5106-2
    1. Angoa-Perez M., Anneken J. H., Kuhn D. M. (2017). The role of brain-derived neurotrophic factor in the pathophysiology of psychiatric and neurological disorders. J. Psychiatry Psychiatr. Disord. 1:17 10.26502/jppd.2572-519X0024
    1. Annane D., Maxime V., Ibrahim F., Alvarez J. C., Abe E., Boudou P. (2006). Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am. J. Respir. Crit. Care Med. 174 1319–1326. 10.1164/rccm.200509-1369OC
    1. Ardalan M., Wegener G., Rafati A. H., Nyengaard J. R. (2017). S-ketamine rapidly reverses synaptic and vascular deficits of hippocampus in genetic animal model of depression. Int. J. Neuropsychopharmacol. 20 247–256. 10.1093/ijnp/pyw098
    1. Aydemir O., Deveci A., Taneli F. (2005). The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 261–265. 10.1016/j.pnpbp.2004.11.009
    1. Brandl E. J., Walter H. (2017). From pharmacogenetics to imaging pharmacogenetics: elucidating mechanisms of antidepressant response. Pharmacogenomics 18 927–930. 10.2217/pgs-2017-0082
    1. Brierley D. I., Davidson C. (2012). Developments in harmine pharmacology — Implications for ayahuasca use and drug-dependence treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry 39 263–272. 10.1016/j.pnpbp.2012.06.001
    1. Brown G. M., McIntyre R. S., Rosenblat J., Hardeland R. (2018). Depressive disorders: processes leading to neurogeneration and potential novel treatments. Prog. Neuropsychopharmacol. Biol. Psychiatry 80(Pt C), 189–204. 10.1016/j.pnpbp.2017.04.023
    1. Brunoni A. R., Boggio P. S., De Raedt R., Benseñor I. M., Lotufo P. A., Namur V., et al. (2014). Cognitive control therapy and transcranial direct current stimulation for depression: a randomized, double-blinded, controlled trial. J. Affect. Disord. 162 43–49. 10.1016/j.jad.2014.03.026
    1. Brunoni A. R., Lopes M., Fregni F. (2008). 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. 11 1169–1180. 10.1017/S1461145708009309
    1. Brunoni A. R., Moffa A. H., Sampaio-Júnior B., Gálvez V., Loo C. K. (2017). Treatment-emergent mania/hypomania during antidepressant treatment with transcranial direct current stimulation (tDCS): a systematic review and meta-analysis. Brain Stimul. 10 260–262. 10.1016/j.brs.2016.11.005
    1. Cain S. W., Chang A. M., Vlasac I., Tare A., Anderson C., Czeisler C. A., et al. (2017). Circadian rhythms in plasma brain-derived neurotrophic factor differ in men and women. J. Biol. Rhythms 32 75–82. 10.1177/0748730417693124
    1. Carbonaro T. M., Gatch M. B. (2016). Neuropharmacology of N, N-dimethyltryptamine. Brain Res. Bull. 126(Pt 1), 74–88. 10.1016/j.brainresbull.2016.04.016
    1. Carhart-Harris R., Roseman L., Bolstridge M., Demetriou L., Pannekoek J., Wall M., et al. (2016). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci. Rep. 7:13187. 10.1038/s41598-017-13282-7
    1. Castren E., Rantamaki T. (2008). Neurotrophins in depression and antidepressant effects. Novartis Found. Symp. 289 43–52.
    1. Chou Y. H., Lirng J. F., Hsieh W. C., Chiu Y. C., Tu Y. A., Wang S. J. (2016). Neither cortisol nor brain-derived neurotrophic factor is associated with serotonin transporter in bipolar disorder. Eur. Neuropsychopharmacol. 26 280–287. 10.1016/j.euroneuro.2015.12.011
    1. Cipriani A., Furukawa T. A., Salanti G., Chaimani A., Atkinson L. Z., Ogawa Y., et al. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391 1357–1366. 10.1016/S0140-6736(17)32802-7
    1. Collo G., Pich E. M. (2018). Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression. Neural Regen. Res. 13 645–646. 10.4103/1673-5374.230288
    1. Dai T. T., Wang B., Xiao Z. Y., You Y., Tian S. W. (2018). Apelin-13 upregulates BDNF against chronic stress-induced depression-like phenotypes by ameliorating HPA axis and hippocampal glucocorticoid receptor dysfunctions. Neuroscience 390 151–159. 10.1016/j.neuroscience.2018.08.018
    1. Dakic V., Maciel R., Drummond H., Nascimento J., Trindade P., Rehen S. (2016). Harmine stimulates proliferation of human neural progenitors. Peerj 4:e2727. 10.7717/peerj.2727
    1. Dakic V., Minardi Nascimento J., Costa Sartore R., Maciel R., de Araujo D., Ribeiro S., et al. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Sci. Rep. 7:12863. 10.1038/s41598-017-12779-5
    1. Diniz C. R. A. F., Casarotto P. C., Resstel L., Joca S. R. L. (2018). Beyond good and evil: a putative continuum-sorting hypothesis for the functional role of pro BDNF/BDNF-propeptide/mBDNF in antidepressant treatment. Neurosci. Biobehav. Rev. 90 70–83. 10.1016/j.neubiorev.2018.04.001
    1. Duman R. S., Monteggia L. M. (2006). A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59 1116–1127. 10.1016/j.biopsych.2006.02.013
    1. Elfving B., Buttenschøn H. N., Foldager L., Poulsen P. H., Andersen J. H., Grynderup M. B., et al. (2012). Depression, the val66met polymorphism, age, and gender influence the serum BDNF level. J. Psychiatr. Res. 46 1118–1125. 10.1016/j.jpsychires.2012.05.003
    1. Fields D., Mitchell G. (2017). Divergent cAMP signaling differentially regulates serotonin-induced spinal motor plasticity. Neuropharmacology 113(Pt A), 82–88. 10.1016/j.neuropharm.2016.09.018
    1. Foltran R. B., Diaz S. L. (2016). BDNF isoforms: a round trip ticket between neurogenesis and serotonin? J. Neurochem. 138 204–212. 10.1111/jnc.13658
    1. Fortunato J., Réus G., Kirsch T., Stringari R., Fries G., Kapczinski F., et al. (2010). Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus. J. Neural Transm. 117 1131–1137. 10.1007/s00702-010-0451-2
    1. Galvão A. C. M., Almeida R. N., Silva E. A. S., Freire F. A., Palhano-Fontes F., Onias H., et al. (2018). Cortisol modulation by ayahuasca in patients with treatment resistant depression and healthy controls. Front. Psychiatry 9:185. 10.3389/fpsyt.2018.00185
    1. Gersner R., Gal R., Levit O., Moshe H., Zangen A. (2014). Inherited behaviors, BDNF expression and response to treatment in a novel multifactorial rat model for depression. Int. J. Neuropsychopharmacol. 17 945–955. 10.1017/s1461145714000030
    1. Gonul A., Akdeniz F., Taneli F., Donat O., Eker C., Vahip S. (2003). The effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur. Neuropsychopharmacol. 13:S203 10.1016/s0924-977x(03)91777-9
    1. Griffiths R., Johnson M., Carducci M., Umbricht A., Richards W., Richards B., et al. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J. Psychopharmacol. 30 1181–1197. 10.1177/0269881116675513
    1. Haile C., Murrough J., Iosifescu D., Chang L., Al Jurdi R., Foulkes A., et al. (2014). Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int. J. Neuropsychopharmacol. 17 331–336. 10.1017/s1461145713001119
    1. Halaris A., Sharma A., Meresh E., Pandey G., Kang R., Sinacore J. (2015). Serum BDNF: a potential biomarker for major depressive disorder and antidepressant response prediction. J. Depress. Anxiety 4:179 10.4172/2167-1044.1000179
    1. Hamilton M. (1960). A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23 56–62.
    1. Harmer C., Duman R., Cowen P. (2017). How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry 4 409–418. 10.1016/s2215-0366(17)30015-9
    1. Hashimoto K. (2016). Regulation of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain by serotonin. Eur. Arch. Psychiatry Clin. Neurosci. 266 195–197. 10.1007/s00406-016-0682-9
    1. Hellweg R., Ziegenhorn A., Heuser I., Deuschle M. (2008). Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment. Pharmacopsychiatry 41 66–71. 10.1055/s-2007-1004594
    1. Hengartner M., Plöderl M. (2018). Statistically significant antidepressant-placebo differences on subjective symptom-rating scales do not prove that the drugs work: effect size and method bias matter! Front. Psychiatry 9:517. 10.3389/fpsyt.2018.00517
    1. Ho R. C. M., Zhang M. W. B. (2016). Ketamine as a rapid antidepressant: the debate and implications. BJPsych Adv. 22 222–233. 10.1192/apt.bp.114.014274
    1. Horák M., Hasíková L., Verter N. (2018). Therapeutic potential ascribed to ayahuasca by users in the Czech republic. J. Psychoactive Drugs 50 430–436. 10.1080/02791072.2018.1511878
    1. Howland R. (2008). Sequenced treatment alternatives to relieve depression (STAR∗D). J. Psychosoc. Nurs. Ment. Health Serv. 46 21–24. 10.3928/02793695-20081001-05
    1. Huang X., Zhou Y., He H., Mei F., Sun B., Zhang X. Y. (2017). Association of serum BDNF levels with psychotic symptom in chronic patients with treatment-resistant depression in a Chinese Han population. Psychiatry Res. 257 279–283. 10.1016/j.psychres.2017.07.076
    1. Iimori T., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Noda Y. (2018). Effectiveness of the prefrontal repetitive transcranial magnetic stimulation on cognitive profiles in depression, schizophrenia, and Alzheimer’s disease: a systematic review. Prog. Neuropsychopharmacol. Biol. Psychiatry 88 31–40. 10.1016/j.pnpbp.2018.06.014
    1. Inserra A. (2018). Hypothesis: the psychedelic ayahuasca heals traumatic memories via a sigma 1 receptor-mediated epigenetic-mnemonic process. Front. Pharmacol. 9:330. 10.3389/fphar.2018.00330
    1. Jesulola E., Micalos P., Baguley I. J. (2018). Understanding the pathophysiology of depression: from monoamines to the neurogenesis hypothesis model - are we there yet? Behav. Brain Res. 341 79–90. 10.1016/j.bbr.2017.12.025
    1. Jevtović S., Karlović D., Mihaljević-Peleš A., Šerić V., Vrkić N., Jakšić N. (2011). Serum brain-derived neurotrophic factor (BDNF): the severity and symptomatic dimensions of depression. Psychiatr. Danub. 23 363–369.
    1. Jiang H., Chen S., Li C., Lu N., Yue Y., Yuan Y. (2017). The serum protein levels of the tPA-BDNF pathway are implicated in depression and antidepressant treatment. Transl. Psychiatry 7:e1079. 10.1038/tp.2017.43
    1. Johnstad P. G. (2018). Powerful substances in tiny amounts: an interview study of psychedelic microdosing. Nord. Stud. Alcohol Drugs 35 39–51. 10.1177/1455072517753339
    1. Kao C., Liu Y., Yu Y., Yang A., Lin E., Kuo P., et al. (2018). Gene-based analysis of genes related to neurotrophic pathway suggests association of BDNF and VEGFA with antidepressant treatment-response in depressed patients. Sci. Rep. 8:6983. 10.1038/s41598-018-25529-y
    1. Kavalali E., Monteggia L. (2015). How does ketamine elicit a rapid antidepressant response? Curr. Opin. Pharmacol. 20 35–39. 10.1016/j.coph.2014.11.005
    1. Khalin I., Alyautdin R., Wong T. W., Gnanou J., Kocherga G., Kreuter J. (2016). Brain-derived neurotrophic factor delivered to the brain using poly (lactide-co-glycolide) nanoparticles improves neurological and cognitive outcome in mice with traumatic brain injury. Drug Deliv. 23 3520–3528. 10.1080/10717544.2016.1199609
    1. Kowiañski P., Lietzau P. G., Czuba E., Waśkow M., Steliga A., Morys J. (2017). BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell. Mol. Neurobiol. 38 579–593. 10.1007/s10571-017-0510-4
    1. Kraus C., Castrén E., Kasper S., Lanzenberger R. (2017). Serotonin and neuroplasticity – links between molecular, functional and structural pathophysiology in depression. Neurosci. Biobehav. Rev. 77 317–326. 10.1016/j.neubiorev.2017.03.007
    1. Kreinin A., Lisson S., Nesher E., Schneider J., Bergman J., Farhat K., et al. (2015). Blood BDNF level is gender specific in severe depression. PLoS One 10:e0127643. 10.1371/journal.pone.0127643
    1. Kuehner C. (2017). Why is depression more common among women than among men? Lancet Psychiatry 4 146–158. 10.1016/s2215-0366(16)30263-2
    1. Kunugi H., Hori H., Adachi N., Numakawa T. (2010). Interface between hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor in depression. Psychiatry Clin. Neurosci. 64 447–459. 10.1111/j.1440-1819.2010.02135.x
    1. Lepack A., Fuchikami M., Dwyer J., Banasr M., Duman R. (2014). BDNF release is required for the behavioral actions of ketamine. Int. J. Neuropsychopharmacol. 18:pyu033. 10.1093/ijnp/pyu033
    1. Li Y. J., Li Y. J., Yang L. D., Zhang K., Zheng K. Y., Wu Y. M. (2018). Silibinin exerts antidepressant effects by improving neurogenesis through BDNF/TrkB pathway. Behav. Brain Res. 348 184–191. 10.1016/j.bbr.2018.04.025
    1. Lippmann M., Bress A., Nemeroff C. B., Plotsky P. M., Monteggia L. M. (2007). Long-term behavioural and molecular alterations associated with maternal separation in rats. Eur. J. Neurosci. 25 3091–3098. 10.1111/j.1460-9568.2007.05522.x
    1. Lopes C. D., Gonçalves N. P., Gomes C. P., Saraiva M. J., Pêgo A. P. (2017). BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury. Biomaterials 121 83–96. 10.1016/j.biomaterials.2016.12.025
    1. Lu Y., Ho C. S., Liu X., Chua A. N., Wang W., McIntyre R. S., et al. (2017). Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression. PLoS One 12:e0186700. 10.1371/journal.pone.0186700
    1. Lu Y., Ho C. S., McIntyre R. S., Wang W., Ho R. C. (2018a). Agomelatine-induced modulation of brain-derived neurotrophic factor (BDNF) in the rat hippocampus. Life Sci. 210 177–184. 10.1016/j.lfs.2018.09.003
    1. Lu Y., Ho C. S., McIntyre R. S., Wang W., Ho R. C. (2018b). Effects of vortioxetine and fluoxetine on the level of Brain Derived Neurotrophic Factors (BDNF) in the hippocampus of chronic unpredictable mild stress-induced depressive rats. Brain Res. Bull. 142 1–7. 10.1016/j.brainresbull.2018.06.007
    1. Lupien S. J., Maheu F., Tu M., Fiocco A., Schramek T. E. (2007). The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition. Brain Cogn. 65 209–237. 10.1016/j.bandc.2007.02.007
    1. Ly C., Greb A. C., Cameron L. P., Wong J. M., Barragan E. V., Duim W. C. (2018). Psychedelics promote structural and functional neural plasticity. Cell Rep. 23 3170–3182. 10.1016/j.celrep.2018.05.022
    1. Ma L., Xu Y., Wang G., Li R. (2019). What do we know about sex differences in depression: a review of animal models and potential mechanisms. Prog. Neuropsychopharmacol. Biol. Psychiatry 89 48–56. 10.1016/j.pnpbp.2018.08.026
    1. MacQueen G. M. (2009). Magnetic resonance imaging and prediction of outcome in patients with major depressive disorder. J. Psychiatry Neurosci. 34 343–349.
    1. Marek G. J. (2017). Interactions of hallucinogens with the glutamatergic system: permissive network effects mediated through cortical layer V pyramidal neurons. Curr. Top. Behav. Neurosci. 36 107–135. 10.1007/7854_2017_480
    1. Mizui T., Ishikawa Y., Kumanogoh H., Lume M., Matsumoto T., Hara T., et al. (2014). BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc. Natl. Acad. Sci. U.S.A. 112 E3067–E3074. 10.3390/ijms18051042
    1. Molendijk M., Molero P., Sánchez-Pedreño F. O., Van der Does W., Martínez-González M. A. (2018). Diet quality and depression risk: a systematic review and dose-response meta-analysis of prospective studies. J. Affect. Disord. 226 346–354. 10.1016/j.jad.2017.09.022
    1. Molendijk M. L., Bus B. A., Spinhoven P., Penninx B. W., Kenis G., Elzinga B. M. (2011). Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment. Mol. Psychiatry 16 1088–1095. 10.1038/mp.2010.98
    1. Montgomery S., Åsberg M. (1979). A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134 382–389. 10.1192/bjp.134.4.382
    1. Morales-García J., de la Fuente Revenga M., Alonso-Gil S., Rodríguez-Franco M., Feilding A., Perez-Castillo A., et al. (2017). The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro. Sci. Rep. 7:5309. 10.1038/s41598-017-05407-9
    1. Mowla S. J., Farhadi H. F., Pareek S., Atwal J. K., Morris S. J., Murphy R. A. (2001). Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J. Biol. Chem. 276 12660–12666. 10.1074/jbc.m008104200
    1. Numakawa T., Odaka H., Adachi N. (2017). Actions of brain-derived neurotrophic factor and glucocorticoid stress in neurogenesis. Int. J. Mol. Sci. 18:E2312. 10.3390/ijms18112312
    1. Nurden A. T. (2018). The biology of the platelet with special reference to inflammation, wound healing and immunity. Front. Biosci. 23 726–751. 10.2741/4613
    1. Osório F., Sanches R., Macedo L., dos Santos R., Maia-de-Oliveira J., Wichert-Ana L., et al. (2015). Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Rev. Bras. Psiquiatr. 37 13–20. 10.1590/1516-4446-2014-1496
    1. Ozan E., Okur H., Eker C., Eker Ö. D., Gönül A. S., Akarsu N. (2010). The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels. Brain Res. Bull. 81 61–65. 10.1016/j.brainresbull.2009.06.022
    1. Palhano-Fontes F., Barreto D., Onias H., Andrade K. C., Novaes M. M., Araujo D. B. (2018). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol. Med. 49 655–663. 10.1017/s0033291718001356
    1. Panagiotakopoulos L., Neigh G. N. (2014). Development of the HPA axis: where and when do sex differences manifest? Front. Neuroendocrinol. 35 285–302. 10.1016/j.yfrne.2014.03.002
    1. Papakostas G. I., Shelton R. C., Kinrys G., Henry M. E., Bakow B. R., Bilello J. A. (2011). Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a pilot and replication study. Mol. Psychiatry 18 332–339. 10.1038/mp.2011.166
    1. Phillips C. (2017). Brain-derived neurotrophic factor, depression, and physical activity: making the neuroplastic connection. Neural Plast. 2017:7260130. 10.1155/2017/7260130
    1. Piccinni A., Marazziti D., Catena M., Domenici L., Del Debbio A., Mariotti A. (2008). Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. J. Affect. Disord. 105 279–283. 10.1016/j.jad.2007.05.005
    1. Pius-Sadowska E., Machaliñski B. (2017). BDNF – a key player in cardiovascular system. J. Mol. Cell. Cardiol. 110 54–60. 10.1016/j.yjmcc.2017.07.007
    1. Polito V., Stevenson R. (2019). A systematic study of microdosing psychedelics. PLoS One 14:e0211023. 10.1371/journal.pone.0211023
    1. Porcher C., Medina I., Gaiarsa J. L. (2018). Mechanism of BDNF modulation in gabaergic synaptic transmission in healthy and disease brains. Front. Cell. Neurosci. 12:273. 10.3389/fncel.2018.00273
    1. Roody D. W., Farrell C., Doolin K., Roman E., Tozzi L., O’Hanlon E. (2018). The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression. Biol. Psychiatry 85 487–497. 10.1016/j.biopsych.2018.08.021
    1. Ross S., Bossis A., Guss J., Agin-Liebes G., Malone T., Cohen B., et al. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30 1165–1180. 10.1177/0269881116675512
    1. Rush A., Fava M., Wisniewski S., Lavori P., Trivedi M., Sackeim H., et al. (2004). Sequenced treatment alternatives to relieve depression (STAR∗D): rationale and design. Control. Clin. Trials 25 119–142. 10.1016/s0197-2456(03)00112-0
    1. Sackeim H. A. (2001). The definition and meaning of treatment-resistant depression. J. Clin. Psychiatry 62(Suppl. 16), 10–17.
    1. Sanches R. F., de Lima Osório F., Dos Santos R. G., Macedo L. R., Maia-de-Oliveira J. P., Wichert-Ana L., et al. (2016). Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J. Clin. Psychopharmacol. 36 77–81. 10.1097/JCP.0000000000000436
    1. Sanchez M. (2018). An Evaluation of Traditional and Non-Traditional Psychopharmacological Treatments for Major Depression. .
    1. Santos R., Osório F., Crippa J., Riba J., Zuardi A., Hallak J. (2016). Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Ther. Adv. Psychopharmacol. 6 193–213. 10.1177/2045125316638008
    1. Santos R., Valle M., Bouso J., Nomdedéu J., Rodríguez-Espinosa J., McIlhenny E., et al. (2011). Autonomic, neuroendocrine, and immunological effects of ayahuasca. J. Clin. Psychopharmacol. 31 717–726. 10.1097/jcp.0b013e31823607f6
    1. Schmidt H. D., Duman R. S. (2010). Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 35 2378–2391. 10.1038/npp.2010.114
    1. Schwabe L., Joëls M., Roozendaal B., Wolf O., Oitzl M. (2012). Stress effects on memory: an update and integration. Neurosci. Biobehav. Rev. 36 1740–1749. 10.1016/j.neubiorev.2011.07.002
    1. Sen S., Duman R., Sanacora G. (2008). Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol. Psychiatry 64 527–532. 10.1016/j.biopsych.2008.05.005
    1. Sheldrick A., Camara S., Ilieva M., Riederer P., Michel T. M. (2017). Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals – a proof of concept study. Eur. Psychiatry 46 65–71. 10.1016/j.eurpsy.2017.06.009
    1. Shirayama Y., Yang C., Zhang J., Ren Q., Yao W., Hashimoto K. (2015). Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist. Eur. Neuropsychopharmacol. 25 2449–2458. 10.1016/j.euroneuro.2015.09.002
    1. Silva F. S., dos Santos Silva E. A., de Sousa Junior G. M., Maia-de-Oliveira J. P., Rachetti V. D. P. S., Galvao-Coelho N. L. (2018). Acute effects of ayahuasca in a juvenile non-human primate model of depression. Brazil J. Psychiatry .
    1. Sodersten K., Palsson E., Ishima T., Funa K., Landén M., Agren H. (2014). Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: a study of two independent cohorts. J. Affect. Disord. 160 1–9. 10.1016/j.jad.2014.01.009
    1. Stapelberg N. J. C., Neumann D. L., Shum D., Headrick J. P. (2018). Health, pre-disease and critical transition to disease in the psycho-immune-neuroendocrine network: are there distinct states in the progression from health to major depressive disorder? Physiol. Behav. 198 108–119. 10.1016/j.physbeh.2018.10.014
    1. Strawn J., Mills J., Sauley B., Welge J. (2018). The impact of antidepressant dose and class on treatment response in pediatric anxiety disorders: a meta-analysis. J. Am. Acad. Child Adolesc. Psychiatry 57 235–244.e2. 10.1016/j.jaac.2018.01.015
    1. Tapia-Arancibia L., Rage F., Givalois L., Arancibia S. (2004). Physiology of BDNF: focus on hypothalamic function. Front. Neuroendocrinol. 25 77–107. 10.1016/j.yfrne.2004.04.001
    1. Teche S. P., Nuernberg G. L., Sordi A. O., de Souza L. H., Remy L., Ceresér K. M. M., et al. (2013). Measurement methods of BDNF levels in major depression: a qualitative systematic review of clinical trials. Psychiatr. Q. 84 485–497. 10.1007/s11126-013-9261-7
    1. Tharmaratnam T., Tabobondung T., Tabobondung T., Doherty S. (2018). Synergistic effects of brain-derived neurotrophic factor (BDNF) and exercise intensity on memory in the adolescent brain: a commentary. Environ. Health Prev. Med. 23:12. 10.1186/s12199-018-0701-8
    1. Tsai S., Su T. (2017). Sigma-1 receptors fine-tune the neuronal networks. Adv. Exp. Med. Biol. 964 79–83. 10.1007/978-3-319-50174-1_7
    1. Vamvakopoulos N. C., Chrousos G. P. (1993). Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimorphism of the stress response and immune/inflammatory reaction. J. Clin. Investig. 92 1896–1902. 10.1172/jci116782
    1. Vollenweider F. X., Kometer M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat. Rev. Neurosci. 11 642–651. 10.1038/nrn2884
    1. Wagner S., Kayser S., Engelmann J., Schlicht K. F., Dreimüller N., Lieb K. (2018). Plasma brain-derived neurotrophic factor (pBDNF) and executive dysfunctions in patients with major depressive disorder. World J. Biol. Psychiatry 10.1080/15622975.2018.1425478 [Epub ahead of print].
    1. Wilkinson S. T., Kiselycznyk C., Banasr M., Webler R. D., Haile C., Mathew S. J. (2018). Serum and plasma brain-derived neurotrophic factor and response in a randomized controlled trial of riluzole for treatment resistant depression. J. Affect. Disord. 241 514–518. 10.1016/j.jad.2018.08.075
    1. Winkelman M. J. (2017). The mechanisms of psychedelic visionary experiences: hypotheses from evolutionary psychology. Front. Neurosci. 11:539. 10.3389/fnins.2017.00539
    1. Wolkowitz O. M., Reus V. I., Mellon S. H. (2011). Of sound mind and body: depression, disease, and accelerated aging. Dialogues Clin. Neurosci. 13 25–39.
    1. Wright K. P., Drake A. L., Frey D. J., Fleshner M., Desouza C. A., Gronfier C., et al. (2015). Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain Behav. Immun. 47 24–34. 10.1016/j.bbi.2015.01.004
    1. Xing Y., Wen C. Y., Li S. T., Xia Z. X. (2016). Non-viral liposome-mediated transfer of brain-derived neurotrophic factor across the blood-brain barrier. Neural Regen. Res. 11 617–622. 10.4103/1673-5374.180747
    1. Yang C., Kobayashi S., Nakao K., Dong C., Han M., Qu Y., et al. (2018). AMPA receptor activation–independent antidepressant actions of ketamine metabolite (S)-Norketamine. Biol. Psychiatry 84 591–600. 10.1016/j.biopsych.2018.05.007
    1. Yip A. G., George M. S., Tendler A., Roth Y., Zangen A., Carpenter L. L. (2017). 61% of unmedicated treatment resistant depression patients who did not respond to acute TMS treatment responded after four weeks of twice weekly deep TMS in the brainsway pivotal trial. Brain Stimul. 10 847–849. 10.1016/j.brs.2017.02.013
    1. Yoshida T., Ishikawa M., Iyo M., Hashimoto K. (2012). Serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in healthy subjects. Open Clin. Chem. J. 5 7–12. 10.2174/1874241601205010007
    1. Zhao G., Zhang C., Chen J., Su Y., Zhou R., Fang Y. (2016). Ratio of mBDNF to proBDNF for differential diagnosis of major depressive disorder and bipolar depression. Mol. Neurobiol. 54 5573–5582. 10.1007/s12035-016-0098-6
    1. Zhao M., Chen L., Yang J., Han D., Fang D., Qiu X., et al. (2016). BDNF Val66Met polymorphism, life stress and depression: a meta-analysis of gene-environment interaction. J. Affect. Disord. 227 226–235. 10.1016/j.jad.2017.10.024
    1. Zhao X., Liu Q., Cao S., Pang J., Zhang H., Li H. (2017). A meta-analysis of selective serotonin reuptake inhibitors (SSRIs) use during prenatal depression and risk of low birth weight and small for gestational age. J. Affect. Disord. 241 563–570. 10.1016/j.jad.2018.08.061
    1. Zhou C., Zhong J., Zou B., Fang L., Chen J., Lei T. (2017). Meta-analyses of comparative efficacy of antidepressant medications on peripheral BDNF concentration in patients with depression. PLoS One 12:e0172270. 10.1371/journal.pone.0172270
    1. Zhou L., Xiong J., Lim Y., Ruan Y., Huang C., Zhu Y., et al. (2013). Upregulation of blood pro-BDNF and its receptors in major depression. J. Affect. Disord. 150 776–784. 10.1016/j.jad.2013.03.002

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere