O entendimento das bases biológicas da depressão, além de auxiliar no desenvolvimento de novos medicamentos, contribui também para a elucidação de biomarcadores que podem auxiliar no manejo clínico da DM (Dean & Keshavan, 2017).
Por definição, entende-se por biomarcador parâmetros laboratoriais controlados e padronizados a fim de auxiliar o médico em uma decisão clínica e que precisam ser validados nos seguintes aspectos: confiabilidade, sensitividade e custos. Podem ser classificados como
biomarcadores preditivos, aqueles estão relacionados aos riscos de contrair doenças; biomarcadores de diagnóstico, associados a uma doença presente ou biomarcadores de prognóstico, associado à evolução da doença. Além destes tipos, encontramos também os que estão associados aos tratamentos, responsáveis por relatar sua eficiência perante o paciente, mostrando de maneira mais clara ao médico, a resposta orgânica personalizada. De modo geral, podem ser considerados biomarcadores bioquímicos as amostras histológicas, anatômicas, células específicas, moléculas, genes, enzimas ou hormônios (Hutchinson & Lotan, 2017; Schmidt et al., 2011).
Apesar dos estudos apontarem que a concentração de BDNF encontra-se reduzido no soro/plasma de pacientes com DM, outros também apontam essa alteração em diferentes transtornos psiquiátricos (Cattaneo et al., 2016). Sendo assim, o BDNF de forma exclusiva não pode ser um biomarcador de diagnóstico da DM. Além disso, ainda há necessidade de discutir qual seria o limiar laboratorial para definir o estado fisiológico e alterado das concentrações de BDNF? As mudanças de baixo grau são clinicamente significativas? O quão forte é a associação entre BDNF e diagnostico/tratamento? (Polyakova et al., 2015).
Para consolidação do BDNF como biomarcador de tratamento da DM, ainda são necessários estudos adicionais que abordem principalmente a força da associação entre os níveis de BDNF sanguíneo e a eficiência do tratamento. Além disso, é necessário um maior foco na sensibilidade e especificidade do BDNF na resposta ao tratamento, que devem ser investigadas a partir da variação percentual do BDNF (Polyakova et al., 2015).
Ademais, o uso de métodos de mensuração sensíveis às diferentes isoformas do BDNF e com baixa reação cruzada abriria caminho para uma melhor compreensão do papel do BDNF como biomarcador da DM. Apesar dos estudos avançados na área, ainda não se sabe com precisão a razão fisiológica entre o pro-BDNF/m-BDNF (Polyakova et al., 2015; Foltran & Dias, 2016).
7. Conclusão
Diante do exposto, nota-se que o BDNF emerge como uma molécula com amplo envolvimento com a fisiopatologia da depressão maior. Além disso, a sugestão do aumento dos níveis de BDNF relacionados ao início dos efeitos antidepressivos, induzido por tratamentos farmacológicos, e ao mesmo tempo, associados ao aumento da neuroplasticidade cerebral, é um bom indicador de relação clínica entre BDNF e depressão maior. Porém, apesar dos avanços, ambas as áreas necessitam de mais estudos, principalmente no que concerne as
diferentes isoformas do BDNF, pois assim vias e mecanismos de ação mais precisos podem ser elucidados, auxiliando de maneira mais precisa na compreensão da fisiopatologia da DM e na busca por novos tratamentos.
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Artigo 2
Modulation of serum brain-derived neurotrophic factor by a single dose of ayahuasca: observation from a randomized controlled trial
Raíssa Nóbrega de Almeida1,2, Ana Cecília de Menezes Galvão1,2, Flávia Santos da Silva1,2, Erick Allan dos Santos Silva1, Fernanda Palhano-Fontes4,5, João Paulo Maia-de- Oliveira3,5,7, Dráulio Barros de Araújo4,5, Bruno Lobão Soares3,6, Nicole Leite Galvão- Coelho1,2,3*
1
Laboratory of Hormone Measurement, Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal- RN, Brazil.
2
Postgraduate Program in Psychobiology and Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal- RN, Brazil.
3
National Institute of Science and Technology in Translational Medicine, Brazil.
4
Brain Institute, Federal University of Rio Grande do Norte, Natal-RN, Brazil.
5
Onofre Lopes University Hospital, Federal University of Rio Grande do Norte, Natal-RN, Brazil.
6
Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal-RN, Brazil.
7
Department of Clinical Medicine, Federal University of Rio Grande do Norte, Natal- RN, Brazil. Pages: 22 Words: 4.624 Tables: 0 Figures: 6 Appendix: 2 References: 113 *Correspondence: Nicole L. Galvão-Coelho
Universidade Federal do Rio Grande do Norte, Departamento de Fisiologia e Comportamento.
Caixa Postal, 1511
59078-970 NATAL- RN, BRAZIL Phone: +55 84 3215-3410
E-mail: [email protected]
Abstract
Serotonergic psychedelics are emerging as potential antidepressant treatment tools, as suggested in a recent randomized controlled trial with ayahuasca for treatment-resistant depression. Preclinical and clinical studies have shown that serum brain-derived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants. However, the exact role of BDNF as a biomarker for diagnostic and treatment of major depression needs to be better explored. In this study, registered at http://clinicaltrials.gov (NCT02914769), we investigated serum BDNF levels in healthy controls (N= 45) and patients with treatment resistant depression (N = 28), before (baseline) and 48 hours after (D2) a single dose of ayahuasca or placebo. We found similar baseline levels of serum BDNF in both patients and healthy individuals. We detected lower levels of BDNF at baseline in a subgroup of subjects who also presented hypocortisolemia, with respect to individuals with eucortisolemia. Moreover, we found a baseline 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). Moreover, in 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 (MADRS scores). Few previous randomized controlled trials have evaluated serum BDNF levels in response to antidepressant treatments and their results are not conclusive. This is the first clinical trial to explore the modulation of BDNF in response to a psychedelic with antidepressant potential, and 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 psychedelic substances in the treatment of resistant depression.
Keywords: Ayahuasca, antidepressant, BDNF, biomarker, cortisol, psychedelics, treatment- resistant, depression.
1. Introduction
Most antidepressants act enhancing monoaminergic synaptic efficiency. This process, which can be specific or not to one monoamine, occurs by increasing the concentration of neurotransmitters in the synaptic cleft via the inhibition of their metabolism or reuptake, through the activation of post-synaptic monoamine receptors (Umukoro et al., 2018; Zhao et al., 2018), or by the antagonism of the pre-synaptic autoreceptors (Gram et al., 2013).
In spite of several reports of statistical differences between placebo and antidepressants in treatment efficacy of major depression, the effect size of this difference is low and the real relevance to clinical improvement is discussed (Hengartner & Plöderl, 2018). Large part of patients with mild or moderate depression has minimal or no antidepressant benefit after drug treatment (Aherne et al., 2017). Antidepressant drugs appear to act more efficiently than placebo mainly in severe major depression, but it is supposed to occur through a smaller response of placebo than by specifically an increase in antidepressant efficacy (Kirsch, 2014). Moreover, the latency between administration and the response of the antidepressants can take weeks (Strawn et al., 2018), and suicidal tendencies may arise within this critical period (Ferrari & Villa, 2016).
In this scenario, several research groups have intensified their search for new antidepressants, including psychedelics (Santos et al., 2016). Some serotonergic psychedelics, from natural or synthetic origin, present a similar action mechanism to those of certain commercial antidepressants (Sanchez, 2018). Therefore, there is an increasing number of studies testing the antidepressant effects of psychedelics in humans and animal models (Osório et al., 2015; Sanches et al., 2016; Carhart-Harris et al., 2017; Palhano-Fontes et al., 2018; Ross et al., 2016; Griffiths et al., 2016; Silva et al., 2018).
Despite of the peculiarity of each psychedelic, it is known that several pathways of neuronal plasticity are activated by these compounds (Winkelman, 2017). The induction of neuroplasticity and neurogenesis by psychedelics are relevant aspect of their action as potential antidepressants since several studies have shown that the efficacy of clinical antidepressants is related to an increase in hippocampal plasticity induced after monoaminergic enhancement (Ardalan et al., 2017; Dakic et al., 2016; Morales-García et al., 2017).
The activation of the serotonergic receptor 5-hydroxytryptamine 2A (5-HT2A) and tyrosine
kinase B receptor (TrkB) by some psychedelics induce neuroplasticity through rapamycin (mTOR) signaling pathway (Ly et al., 2018; Collo & Pich, 2018). On the other hand, the sigma-1 receptor (σ1R), which is involved in the modulation of several neurotransmitter systems, such as monoaminergic and glutamatergic pathways (Inserra, 2018), modulates neuroplasticity and neurogenesis by intracellular calcium-dependent signal (Tsai and Su, 2017). The elevation of glutamatergic activity in the prefrontal cortex by alpha-amino-3- hydroxy-methyl-5-4-isoxazolpropionic (AMPA) receptor increases in neuroplasticity by BDNF (Marek, 2017; Yang et al., 2018; Vollenweider & Kometer, 2010). Moreover, cortisol, the main stress hormone, also modulates a BDNF expression, as well as the activity of BDNF receptor, TrkB, in central nervous system (Kunugi et al. 2010).
Ayahuasca is a brew from Amerindians whose antidepressant effects have been recently tested in open label and randomized controlled clinical trials (Osório et al., 2015; Sanches et al., 2016; Palhano-Fontes et al., 2018). Its components act in several pathways involved in the etiology of depression (Carbonaro and Gatch, 2016): β-carbolines (tetrahydroharmine, harmine and harmaline) are reversible inhibitors of monoamine oxidase (MAOi) (Horák et al., 2018) and tetrahydroharmine also acts as a serotonin reuptake inhibitor, while N, N dimethyltryptamine (N,N-DMT) is a 5-HT2A and σ1R agonist (Carbonaro and Gatch, 2016).
Despite the agonistic action of ayahuasca on σ1R and 5-HT2A were already demonstrated,
there is still a demonstration of the direct relationship between ayahuasca and neuroplasticity or neurogenesis in humans. Some in vitro studies show that β-carbolines of ayahuasca induce proliferation, migration and differentiation of neurons (Morales-García et al., 2017) and 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) prompt formation of dendritic spines (Dakic et al., 2017). Moreover, one study with harmine showed increases in BDNF in the hippocampus of rodent animal models after treatment (Brierley and Davidson, 2012; Fortunato et al., 2010). Thus, taking these evidences into account, we postulate that a key molecule for establishing this direct link between ayahuasca and neuroplasticity may be BDNF.
BDNF is a neurotrophin synthesized by neurons and glial cells that has been strongly correlated with the alteration of the volume of brain areas in patients with major depression
(Foltran and Diaz, 2016). Depressive patients present neurodegeneration and smaller hippocampal and prefrontal cortex volume (Brown et al., 2018; Roody et al., 2018; Iimori et al., 2018) and these reductions are not only due to the increase of neuronal death, but also caused by decreased neuroplasticity and neurogenesis secondary to reduction in the expression of neurotrophic factors, such as BDNF (Jesulola et al., 2018; Kraus et al., 2017). On the other hand, recent studies show that there is an increase in the expression of BDNF in some brain areas, such as the amygdala and nucleus accumbens, which is related to changes in the normal functioning of these areas and possibly induce anxiety, negative emotional valence and anhedonia (Phillips, 2017).
In addition to these central alterations in BDNF expression, some preclinical and clinical studies show that depressive patients tend to present lower levels of serum BDNF (Ma et al., 2019; Wilkinson et al., 2018), which can be reversed after treatment with some antidepressant drugs (Molendijk et al., 2018; Brunoni et al., 2017). However, not all studies observed decreased levels of baseline serum BDNF in depressive patients (Elfving et al., 2012; Papakostas et al., 2011; Molendijk et al., 2011; Jevtovic et al., 2011) and changes in BDNF levels after treatment with antidepressants of different classes are not consensus in the literature (Kreinin et al., 2015; Sheldrick et al., 2017; Wilkinson et al., 2018). This inconsistency in results lead to a growing necessity for research in the field, in order to better explore the role of BDNF in the etiology and treatment of depression.
Therefore, this study investigated serum BDNF levels in a recent randomized placebo- controlled trial that tested the potential antidepressant effect of a single dose of ayahuasca in treatment-resistant depression patients (Palhano-Fontes et al., 2018). We expected that patients with major depression should disclose lower baseline levels of serum BDNF when compared to healthy volunteers. Moreover, as suggested in recent works, BDNF levels should be correlated with serum cortisol. In addition, we hypothesize that volunteers treated with ayahuasca could present higher levels of serum BDNF than those treated with placebo, and the improvement of depression symptoms would be correlated to BDNF levels after treatment.