Modulation of serum brain-derived neurotrophic factor by a single dose of ayahuasca : observation from a randomized controlled trial

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)

Changes in cortisol but not in brain-derived neurotrophic factor modulate the association between sleep disturbances and major depression

Sleep disturbance is a symptom consistently found in major depression and is associated with a longer course of illness, reduced response to treatment, increased risk of relapse and recurrence. Chronic insomnia has been associated with changes in cortisol and serum brain-derived neurotrophic factor (BDNF) levels, which in turn are also changed in major depression. Here, we evaluated the relationship between sleep quality, salivary cortisol awakening response (CAR), and serum BDNF levels in patients with sleep disturbance and treatment-resistant major depression (n = 18), and in a control group of healthy subjects with good (n = 21) and poor (n = 18) sleep quality. We observed that the patients had the lowest CAR and sleep duration of all three groups and a higher latency to sleep than the healthy volunteers with a good sleep profile. Besides, low CAR was correlated with more severe depressive symptoms and worse sleep quality. There was no difference in serum BDNF levels between groups with distinct sleep quality. Taken together, our results showed a relationship between changes in CAR and in sleep quality in patients with treatment-resistant depression, which were correlated with the severity of disease, suggesting that cortisol could be a physiological link between sleep disturbance and major depression

Potential biomarkers of major depression diagnosis and chronicity

Background Molecular biomarkers are promising tools to be routinely used in clinical psychiatry. Among psychiatric diseases, major depression disorder (MDD) has gotten attention due to its growing prevalence and morbidity. Methods We tested some peripheral molecular parameters such as serum mature Brain-Derived Neurotrophic Factor (mBDNF), plasma C-Reactive Protein (CRP), serum cortisol (SC), and the salivary Cortisol Awakening Response (CAR), as well as the Pittsburgh sleep quality inventory (PSQI), as part of a multibiomarker panel for potential use in MDD diagnosis and evaluation of disease's chronicity using regression models, and ROC curve. Results For diagnosis model, two groups were analyzed: Patients in the first episode of major depression (MD: n = 30) and a healthy control (CG: n = 32). None of those diagnosis models tested had greater power than Hamilton Depression Rating Scale-6. For MDD chronicity, a group of patients with treatment-resistant major depression (TRD: n = 28) was tested across the MD group. The best chronicity model (p < 0.05) that discriminated between MD and TRD included four parameters, namely PSQI, CAR, SC, and mBDNF (AUC ROC = 0.99), with 96% of sensitivity and 93% of specificity. Conclusion These results indicate that changes in specific biomarkers (CAR, SC, mBDNF and PSQI) have potential on the evaluation of MDD chronicity, but not for its diagnosis. Therefore, these findings can contribute for further studies aiming the development of a stronger model to be commercially available and used in psychiatry clinical practice

ANÁLISE CARDÍACA DE RATOS SUBMETIDOS A EXPOSIÇÃO CRÔNICA DO HERBICIDA ÁCIDO DICLOROFENOXIACÉTICO (2,4-D)

One of the most commonly used herbicides in Brazil during the sugar cane harvest is dichlorophenoxyacetic acid (2,4-D). It is known that ingestion of this herbicide can cause cardiovascular damage. The objective of this study was to evaluate the oral use of 2,4-D on the heart of rats submitted to chronic exposure, using anatomical parameters and CKMB dosage. 30 male Wistar albino rats were divided into 3 groups: GCO (n=10), GBCO (n=10), and GACO (n=10). The animal feed was exposed to 2,4-D for 15 minutes/day and offered to the animals for 6 months. After this period, the animals were euthanized, the hearts dissected and weighed: atrium, left and right ventricle, the length of the tibia was used as the normalizer. Blood was collected through cardiac puncture for CKMB dosage. The results did not indicate atrial hypertrophy, right ventricular or left ventricular, or an increase in CKMB in the blood. We conclude that 2,4-D did not promote anatomical structural alterations or cardiac injury at the concentration evaluated.Um dos herbicidas mais utilizados nas colheitas de cana-de-açúcar do Brasil é o ácido diclorofenoxiacético (2,4-D). Sabe-se que sua ingestão pode causar danos cardiovasculares. O objetivo desse estudo foi avaliar o uso oral do 2,4-D no coração de ratos submetidos à exposição crônica, por meio de parâmetros anatômicos e dosagem da CKMB. 30 ratos Wistar albinos machos, divididos em 3 grupos: GCO (n=10), GBCO (n=10), e GACO (n=10). A ração foi exposta 15 minutos/dia e ofertada durante 6 meses aos animais. Após, foram eutanasiados, os corações dissecados e pesados: átrios, ventrículo esquerdo e direito e o comprimento da tíbia utilizado como normalizador. O sangue foi coletado por punção cardíaca para dosagem da CKMB. Não houve hipertrofia atrial, ventricular direita e esquerda, nem aumento da CKMB no sangue. Concluímos que o 2,4-D não promoveu alterações estruturais anatômicas, nem lesão cardíaca nas concentrações avaliadas

Subanesthetic Ketamine for Pain Management in Hospitalized Children, Adolescents, and Young Adults: A Single-Center Cohort Study.

BACKGROUND: Subanesthetic doses of ketamine, an N-methyl-d-aspartate receptor antagonist used as an adjuvant to opioid for the treatment of pain in adults with acute and chronic pain, have been shown, in some instances, to improve pain intensity and to decrease opioid intake. However, less is known about the role of ketamine in pain management in children, adolescents, and young adults. PURPOSE: We examined the effects of subanesthetic ketamine on pain intensity and opioid intake in children, adolescents, and young adults with acute and chronic pain syndromes treated in an inpatient setting. METHODS: This is a longitudinal cohort study of patients treated with subanesthetic ketamine infusions in regular patient care units in a tertiary pediatric hospital. Primary outcomes included changes in pain scores and morphine-equivalent intake. RESULTS: The study cohort included 230 different patients who during 360 separate hospital admissions received subanesthetic ketamine infusions for pain management. Overall, ketamine infusions were associated with significant reductions in mean pain scores from baseline (mean pain scores 6.64 [95% CI: 6.38–6.90]) to those recorded on the day after discontinuation of ketamine (mean pain scores 4.38 [95% CI: 4.06–4.69]), p<0.001. Importantly, the effect of ketamine on pain scores varied according to clinical diagnosis (p=0.011), infusion duration (p=0.004), and pain location (p=0.004). Interestingly, greater reductions in pain scores were observed in patients with cancer pain and patients with pain associated with pancreatitis and Crohn’s disease. There were no records of psychotomimetic side effects requiring therapy. CONCLUSION: These data suggest that administration of subanesthetic ketamine for pain management is feasible and safe in regular inpatient care units and may benefit children, adolescents, and young adults with acute and chronic pain. This study is informative and can be helpful in determining sample and effect sizes when planning clinical trials to determine the role of subanesthetic ketamine infusions for pain management in pediatric patients

Subanesthetic ketamine for pain management in hospitalized children, adolescents, and young adults: a single-center cohort study

BACKGROUND: Subanesthetic doses of ketamine, an N-methyl-d-aspartate receptor antagonist used as an adjuvant to opioid for the treatment of pain in adults with acute and chronic pain, have been shown, in some instances, to improve pain intensity and to decrease opioid intake. However, less is known about the role of ketamine in pain management in children, adolescents, and young adults. PURPOSE: We examined the effects of subanesthetic ketamine on pain intensity and opioid intake in children, adolescents, and young adults with acute and chronic pain syndromes treated in an inpatient setting. METHODS: This is a longitudinal cohort study of patients treated with subanesthetic ketamine infusions in regular patient care units in a tertiary pediatric hospital. Primary outcomes included changes in pain scores and morphine-equivalent intake. RESULTS: The study cohort included 230 different patients who during 360 separate hospital admissions received subanesthetic ketamine infusions for pain management. Overall, ketamine infusions were associated with significant reductions in mean pain scores from baseline (mean pain scores 6.64 [95% CI: 6.38–6.90]) to those recorded on the day after discontinuation of ketamine (mean pain scores 4.38 [95% CI: 4.06–4.69]), p<0.001. Importantly, the effect of ketamine on pain scores varied according to clinical diagnosis (p=0.011), infusion duration (p=0.004), and pain location (p=0.004). Interestingly, greater reductions in pain scores were observed in patients with cancer pain and patients with pain associated with pancreatitis and Crohn’s disease. There were no records of psychotomimetic side effects requiring therapy. CONCLUSION: These data suggest that administration of subanesthetic ketamine for pain management is feasible and safe in regular inpatient care units and may benefit children, adolescents, and young adults with acute and chronic pain. This study is informative and can be helpful in determining sample and effect sizes when planning clinical trials to determine the role of subanesthetic ketamine infusions for pain management in pediatric patients

Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca

Background: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45). Aims: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Ãsberg Depression Rating Scale. Results: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = –0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Ãsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Ãsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed. Conclusions: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression

Hormonal correlates of behavioural profiles and coping strategies in captive capuchin monkeys (Sapajus libidinosus)

In this study, we tested the hypothesis that individual differences in behavioural profiles correlate to differences in stress-related behaviours and hormonal levels in captive brown capuchin monkeys (Sapajus libidinosus). Based on a sample of 25 animals, 143 h of behavioural data collection and 518 faecal samples, principal component analyses indicated the existence of four components that characterize the individuals´ Genus Normative Behaviour (GNB) (KMO = 0.531, X2 = 127.672, p &lt; 0.001): ‘Feeding’ ‘Sociability’ ‘Exploration’ and ‘Activity’. Other four components are related to stress coping styles (based on Behaviour Potentially Indicative of Stress – BPIS) (KMO = 0.550, X2 = 329.303, p &lt; 0.001): ‘Self-directed’; ‘Restless’ ‘Ingestion/Self-Scratching’ and ‘Stereotyped’. More active individuals exhibit rapid stress-related behaviours (r = 0.443; p = 0.044) while less active individuals exhibit more stationary stress-related behaviours (r = -0.519; p = 0.013). Akaike information criteria indicated that the best linear regression model to predict the physiological profile (Faecal Glucocorticoid Metabolites - FGM) included three GNB and three BPIS components. ‘Sociability’ (p &lt; 0.05), ‘Exploration’ (p &lt; 0.05), and ‘Ingestion/Self-scratching’ (p &lt; 0.05) predicted lower FGM levels. ‘Activity’ (p &lt; 0.05), ‘Self-directed’ (p &lt; 0.05), and ‘Stereotyped’ (p &lt; 0.05) predicted higher FGM levels. ‘Feeding’ and ‘Restless’ factors were not included in the models. Our results support previous studies indicating that animals within the same population differ in the way they behave and react to stressful conditions, and these are correlated to different physiological profiles. Mapping inter-individual differences in stress coping strategies may help clarify the long-term reported incongruity between behavioural and physiological indicators of welfare in captive animals, supporting better management practices and assisting translational models of the development of psychopathologies