Classic serotonergic psychedelics for mood and depressive symptoms : a meta-analysis of mood disorder patients and healthy participants

Rationale: Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option. Objective: We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately). Results: Our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca (n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2–7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms. Conclusion: Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms

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

Default mode network modulation by psychedelics : a systematic review

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics

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

Factors associated with inflamm-aging in institutionalized older people

The increase in inflammatory cytokines associated with a reduction in the bioavailability of zinc has been used as a marker for inflammation. Despite the high inflammatory state found in institutionalized older individuals, few studies have proposed verifying the factors associated with this condition in this population. To verify the factors associated with inflamm-aging in institutionalized older people. A total of 178 older people (≥ 60 years old) living in nursing homes in Natal/RN were included in the study. Cluster analysis was used to identify three groups according to their inflammatory state. Analysis anthropometric, biochemical, sociodemographic, and health-related variables was carried out. In sequence, an ordinal logistic regression was performed for a confidence level of 95% in those variables with p < 0.20 in the bivariate analysis. IL-6, TNF-α, zinc, low-density lipids (LDL), high-density lipids (HDL), and triglycerides were associated with inflamm-aging. The increase of 1 unit of measurement of LDL, HDL, and triglycerides increased the chance of inflammation-aging by 1.5%, 4.1%, and 0.9%, respectively, while the oldest old (≥ 80 years old) had an 84.9% chance of presenting inflamm-aging in relation to non-long-lived older people (< 80 years). The association between biochemical markers and inflamm-aging demonstrates a relationship between endothelial injury and the inflammatory state. In addition, the presence of a greater amount of fat in the blood may present a higher relative risk of death

Pathophysiology of major depression by clinical stages

The comprehension of the pathophysiology of the major depressive disorder (MDD) is essential to the strengthening of precision psychiatry. In order to determine the relationship between the pathophysiology of the MDD and its clinical progression, analyzed by severity of the depressive symptoms and sleep quality, we conducted a study assessing different peripheral molecular biomarkers, including the levels of plasma C-reactive protein (CRP), serum mature brain-derived neurotrophic factor (mBDNF), serum cortisol (SC), and salivary cortisol awakening response (CAR), of patients with MDD (n = 58) and a control group of healthy volunteers (n = 62). Patients with the first episode of MDD (n = 30) had significantly higher levels of CAR and SC than controls (n = 32) and similar levels of mBDNF of controls. Patients with treatment-resistant depression (TRD, n = 28) presented significantly lower levels of SC and CAR, and higher levels of mBDNF and CRP than controls (n = 30). An increased severity of depressive symptoms and worse sleep quality were correlated with levels low of SC and CAR, and with high levels of mBDNF. These results point out a strong relationship between the stages clinical of MDD and changes in a range of relevant biological markers. This can assist in the development of precision psychiatry and future research on the biological tests for depression

Physiological and behavioral responses to routine procedures in captive common marmosets (Callithrix jacchus)

The effect of routine captive procedures on the welfare of species used as experimental models in biomedical research is of great interest, since stress may alter the generalization and interpretation of results. This study investigated behavioral and endocrine (fecal cortisol) reactivity patterns in common marmoset (Callithrix jacchus) adult males (N = 10) and females (N = 9) subjected to three types of routine procedures in captivity: (1) moving to a same-sized cage (P1), to a smaller cage (P2), and (2) first-time pair formation (P3). Sexually dimorphic cortisol responses were detected in animals submitted to a physical environmental stressor (cage change). Females showed an increased response throughout P1, in relation to baseline (BP) cortisol, and a trend during P2. Males increased cortisol only during P2. On the other hand, males and females showed a similar endocrine response when management involved social challenge (pair formation), with both sexes increasing cortisol levels, but females exhibited a more intense and longer-lasting cortisol increase. Males and females exhibited similar behavioral responses to cage change, except for autogrooming, with males decreasing this behavior in P1. Only females demonstrated a significantly higher increase in piloerection frequency than that of males during the pair formation phase. These endocrine and behavioral changes must be taken into account when interpreting research data that involve these types of procedures. Further studies on the impacts of routine colony management are required to devise and include protocols in official husbandry guidelines

The effects of successive soccer matches on the internal match load, stress tolerance, salivary cortisol and jumping performance in youth soccer players

The study aim was to analyze the effects of successive matches on the internal match load, stress tolerance, salivary cortisol concentration and countermovement vertical jump height in twelve youth soccer players (16.6 ± 0.5 yr; 175 ± 8 cm; 65 ± 8 kg) who performed four official matches within a four day-period with a 24-h recovery interval between the matches. The internal match load, monotony index and competitive strain, as well as stress tolerance were examined. Saliva samples were collected and countermovement vertical jump height was assessed 60 min pre and 30 min post each match; delta of salivary cortisol and countermovement vertical jump height for each match were analyzed. Salivary cortisol was analyzed using an enzyme-linked immunosorbent assay. The results of ANOVA with repeated measures showed no differences between matches for the internal match load (p > 0.05). The scores of the monotony index and competitive strain were 4.3 (±2.3) and 8104 (±6795) arbitrary units, respectively. There was no difference for stress tolerance between matches (p > 0.05). Delta values of salivary cortisol were not different among the assessed matches (F(3,33) = 1.397, p = 0.351, η2: 0.09); however, delta of countermovement vertical jump height decreased from match 1 to match 4 (F(3,33) = 8.64, p < 0.001, η2: 0.44). The current findings suggest that participating in four successive matches, with 24-h of recovery in between, may not lead to changes in stress tolerance and salivary cortisol of youth players, but it may induce a decrease in players' jumping performance after the fourth match

Stress, memory, and implications for major depression

The stress response comprises a phylogenetically conserved set of cognitive, physiological, and behavioral responses that evolved as a survival strategy. In this context, the memory of stressful events would be adaptive as it could avoid re-exposure to an adverse event, otherwise the event would be facilitated in positively stressful or non-distressful conditions. However, the interaction between stress and memory comprises complex responses, some of them which are not yet completely understood, and which depend on several factors such as the memory system that is recruited, the nature and duration of the stressful event, as well as the timing in which this interaction takes place. In this narrative review, we briefly discuss the mechanisms of the stress response, the main memory systems, and its neural correlates. Then, we show how stress, through the action of its biochemical mediators, influences memory systems and mnemonic processes. Finally, we make use of major depressive disorder to explore the possible implications of non-adaptive interactions between stress and memory to psychiatric disorders, as well as possible roles for memory studies in the field of psychiatry