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 http://clinicaltrials.gov (NCT02914769).
ABSTRACT
Major depression is a psychiatric disorder with high prevalence in the general population, with increasing expression in adolescence, about 14% in young people. Frequently, it presents as a chronic condition, showing no remission even after several pharmacological treatments and persisting in adult life. Therefore, distinct protocols and animal models have been developed to increase the understanding of this disease or search for new therapies. To this end, this study investigated the effects of chronic social isolation and the potential antidepressant action of nortriptyline in juvenile Callithrix jacchus males and females by monitoring fecal cortisol, body weight, and behavioral parameters and searching for biomarkers and a protocol for inducing depression. The purpose was to validate this species and protocol as a translational model of juvenile depression, addressing all domain criteria of validation: etiologic, face, functional, predictive, inter-relational, evolutionary, and population. In both sexes and both protocols (IDS and DPT), we observed a significant reduction in cortisol levels in the last phase of social isolation, concomitant with increases in autogrooming, stereotyped and anxiety behaviors, and the presence of anhedonia. The alterations induced by chronic social isolation are characteristic of the depressive state in non-human primates and/or in humans, and were reversed in large part by treatment with an antidepressant drug (nortriptyline). Therefore, these results indicate C. jacchus as a potential translational model of juvenile depression by addressing all criteria of validation.
