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A substantial challenge in human brain aging is to find a suitable model to mimic neuronal aging in vitro as accurately as possible. Using directly converted neurons (iNs) from human fibroblasts is considered a promising tool in human aging since it retains the aging-associated mitochondrial donor signature. Still, using iNs from aged donors can pose certain restrictions due to their lower reprogramming and conversion efficacy than those from younger individuals. To overcome these limitations, our study aimed to establish an in vitro neuronal aging model mirroring features of in vivo aging by acute exposure on young iNs to either human stress hormone cortisol or the mitochondrial stressor rotenone, considering stress as a trigger of in vivo aging. The impact of rotenone was evident in mitochondrial bioenergetic properties by showing aging-associated deficits in mitochondrial respiration, cellular ATP, and MMP and a rise in glycolysis, mitochondrial superoxide, and mitochondrial ROS; meanwhile, cortisol only partially induced an aging-associated mitochondrial dysfunction. To replicate the in vivo aging-associated mitochondrial dysfunctions, using rotenone, a mitochondrial complex I inhibitor, proved to be superior to the cortisol model. This work is the first to use stress on young iNs to recreate aging-related mitochondrial impairments.
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Mitocondrias , Neuronas , Rotenona , Humanos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Rotenona/farmacología , Envejecimiento , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Hidrocortisona/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Donantes de Tejidos , Glucólisis/efectos de los fármacos , Adenosina Trifosfato/metabolismoRESUMEN
The translocator protein (TSPO) has been widely investigated as a PET-imaging biomarker of neuroinflammation and, more recently, as a therapeutic target for the treatment of neurodegenerative disease. TSPO ligands have been shown to exert neuroprotective effects in vivo and in vitro models of Alzheimer's disease (AD), by reducing toxic beta amyloid peptides, and attenuating brain atrophy. Recent transcriptomic and proteomic analyses, and the generation of TSPO-KO mice, have enabled new insights into the mechanistic function of TSPO in AD. Using a multi-omics approach in both TSPO-KO- and TSPO ligand-treated mice, we have demonstrated a key role for TSPO in microglial respiratory metabolism and phagocytosis in AD. In this review, we discuss emerging evidence for therapeutic and immunomodulatory functions of TSPO in AD, and new tools for studying TSPO in the brain.
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Enfermedad de Alzheimer , Receptores de GABA , Enfermedad de Alzheimer/metabolismo , Animales , Receptores de GABA/metabolismo , Humanos , Ratones , Microglía/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Ratones NoqueadosRESUMEN
PURPOSE: We recently demonstrated an additional oxytocin (OT) deficiency in patients with arginine vasopressin (AVP) deficiency (central diabetes insipidus) by using 3,4-methylenedioxy-methamphetamine (MDMA) as a novel provocation test. However, the implication of the MDMA provocation test in clinical practice might be challenging. Glucagon effectively stimulates vasopressinergic neurons with a strong increase in plasma copeptin. We therefore hypothesized that this provocation test might also stimulate OT. METHODS: This is a predefined secondary analysis of a prospective double-blind, randomised, placebo-controlled cross-over trial involving ten patients with AVP deficiency and ten sex- and body-mass index-matched healthy participants at the University Hospital Basel, Switzerland. Each participant underwent the glucagon test (s.c. injection of 1 mg glucagon) and placebo test (s.c. injection of 0.9% normal saline). Plasma OT levels were measured at baseline, 60, 120 and 180 min after injection. The primary objective was to determine whether glucagon stimulates OT and whether OT levels differ between patients with AVP deficiency and healthy participants. The primary outcome (maximum change in OT within 180 min) was compared between groups and conditions using a linear mixed effects model. RESULTS: In healthy participants, the median OT at baseline was 82.7 pg/ml [62.3-94.3] and slightly increased to a maximum of 93.3 pg/ml [87.2-121.1] after injection of glucagon, resulting in a change increase of 24.9 pg/ml [5.1-27.8]. Similarly, in patients with AVP deficiency, the median OT at baseline was 73.9 pg/ml [65.3-81.6] and slightly increased after glucagon injection to 114.9 pg/ml [70.9-140.9], resulting in a change increase of 36.8 pg/ml [-2.2 to 51.2]. The results from the mixed model showed no effect between glucagon compared to placebo on OT (difference: -0.5 pg/ml; 95%-CI [-25, 24]; p = 0.97) and no significant treatment-by-group interaction effect between patients compared to healthy participants (interaction: 28 pg/ml; 95%-CI [-7, 62]; p = 0.13). CONCLUSION: We found no effect of glucagon on plasma OT levels and no difference between patients with AVP deficiency and healthy participants.
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Over 300 million individuals worldwide suffer from major depressive disorder (MDD). Individuals with MDD are less physically active than healthy people which results in lower cardiorespiratory fitness (CRF) and less favorable perceived fitness compared with healthy controls. Additionally, individuals with MDD may show autonomic system dysfunction. The purpose of the present study was to evaluate the CRF, perceived fitness and autonomic function in in-patients with MDD of different severity compared with healthy controls. We used data from 212 in-patients (age: 40.7 ± 12.6 y, 53% female) with MDD and from 141 healthy controls (age: 36.7 ± 12.7 y, 58% female). We assessed CRF with the Åstrand-Rhyming test, self-reported perceived fitness and autonomic function by heart rate variability (HRV). In specific, we used resting heart rate, time- and frequency-based parameters for HRV. In-patients completed the Beck Depression Inventory-II (BDI-II) to self-assess the subjectively rated severity of depression. Based on these scores, participants were grouped into mild, moderate and severe MDD. The main finding was an inverse association between depression severity and CRF as well as perceived fitness compared with healthy controls. Resting heart rate was elevated with increasing depression severity. The time-based but not the frequency-based autonomic function parameters showed an inverse association with depression severity. The pattern of results suggests that among in-patients with major depressive disorder, those with particularly high self-assessed severity scores show a lower CRF, less favorable perceived fitness and partial autonomic dysfunction compared to healthy controls. To counteract these conditions, physical activity interventions may be effective.
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Major depressive disorder (MDD) is an increasingly common psychiatric illness associated with a high risk of insufficient physical activity, which in turn is associated with negative mental and physical health outcomes. Theory-based, individually tailored, in-person and remote physical activity counseling has the potential to increase physical activity levels in various populations. Given this, the present study investigated the effect of such a physical activity intervention on the physical activity behavior of in-patients with MDD. This was a multi-center, two-arm randomized controlled trial including initially insufficiently physically active adult in-patients with MDD from four study sites in Switzerland. The sample consisted of 220 participants (Mage = 41 ± 12.6 years, 52% women), 113 of whom were randomized to the intervention group and 107 to the control group. The main outcome, moderate-to-vigorous physical activity (MVPA), was assessed at three time points via hip-worn accelerometer. According to accelerometer measures, there was no significant difference in minutes spent in MVPA over a 12-month intervention period when comparing the intervention with the control group (ß = -1.02, 95% CI = -10.68 to 8.64). Higher baseline physical activity significantly predicted physical activity at post and follow-up. This study showed that it is feasible to deliver an individually tailored, theory-based physical activity counseling intervention to in-patients with MDD, however yielding no significant effects on accelerometer-based MVPA levels. Further efforts are warranted to identify efficacious approaches.Trial registration: ISRCTN, ISRCTN10469580, registered on 3rd September 2018, https://www.isrctn.com/ISRCTN10469580 .
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Trastorno Depresivo Mayor , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consejo , Trastorno Depresivo Mayor/terapia , Ejercicio Físico , Actividad Motora , SuizaRESUMEN
Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.
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COVID-19 , Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/psicología , Pandemias , Psicometría , Estudios Transversales , Neurobiología , Control de Enfermedades Transmisibles , Depresión/patologíaRESUMEN
Mitochondrial dysfunction has been widely implicated in the pathogenesis of Alzheimer's disease (AD), with accumulation of damaged and dysfunctional mitochondria occurring early in the disease. Mitophagy, which governs mitochondrial turnover and quality control, is impaired in the AD brain, and strategies aimed at enhancing mitophagy have been identified as promising therapeutic targets. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is upregulated in AD, and ligands targeting TSPO have been shown to exert neuroprotective effects in mouse models of AD. However, whether TSPO ligands modulate mitophagy in AD has not been explored. Here, we provide evidence that the TSPO-specific ligands Ro5-4864 and XBD173 attenuate mitophagy deficits and mitochondrial fragmentation in a cellular model of AD overexpressing the human amyloid precursor protein (APP). Ro5-4864 and XBD173 appear to enhance mitophagy via modulation of the autophagic cargo receptor P62/SQSTM1, in the absence of an effect on PARK2, PINK1, or LC3 level. Taken together, these findings indicate that TSPO ligands may be promising therapeutic agents for ameliorating mitophagy deficits in AD.
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Enfermedad de Alzheimer , Benzodiazepinonas , Mitofagia , Receptores de GABA , Proteína Sequestosoma-1 , Humanos , Mitofagia/efectos de los fármacos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Receptores de GABA/metabolismo , Proteína Sequestosoma-1/metabolismo , Benzodiazepinonas/farmacología , Ligandos , Línea Celular Tumoral , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Autofagia/efectos de los fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genéticaRESUMEN
Children in institutional care have a high risk to experience childhood adversities (CAs), with consequences for physical and mental well-being. The long-term effects of CAs on the brain, including consequences for neuronal plasticity and sleep, are poorly understood. This study examined the interplay between stress (including CAs), sleep, and brain-derived neurotrophic factor (BDNF), a prominent marker for neuronal plasticity. Participants (N = 131, mean age = 26.3±3.4 years, 40 females) with residential youth-care history completed questionnaires measuring CAs (Childhood Trauma Questionnaire, CTQ), psychological well-being (World Health Organization-Five Well-Being Index, WHO-5), and sleep disturbances (Pittsburgh Sleep Quality Inventory, PSQI). Hair cortisol and serum BDNF concentration were measured using enzyme-linked immunosorbent assays. The analyses were conducted by using bootstrap regression models. There was no association of stress parameters or sleep with BDNF concentration. However, we found a significant association of CAs and well-being with sleep disturbances. Last, we found an association between CAs and BDNF in sleep-healthy but not sleep-disturbed participants. Our findings indicated a role of sleep disturbance in the association between stress and BDNF. Still, further studies are warranted using vulnerable groups at-risk to understand long-term effects on mental health and sleep.
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Factor Neurotrófico Derivado del Encéfalo , Trastornos del Sueño-Vigilia , Adolescente , Adulto , Femenino , Humanos , Adulto Joven , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Sueño/fisiología , Trastornos del Sueño-Vigilia/complicaciones , MasculinoRESUMEN
Pathological abnormalities in the tau protein give rise to a variety of neurodegenerative diseases, conjointly termed tauopathies. Several tau mutations have been identified in the tau-encoding gene MAPT, affecting either the physical properties of tau or resulting in altered tau splicing. At early disease stages, mitochondrial dysfunction was highlighted with mutant tau compromising almost every aspect of mitochondrial function. Additionally, mitochondria have emerged as fundamental regulators of stem cell function. Here, we show that compared to the isogenic wild-type triple MAPT-mutant human-induced pluripotent stem cells, bearing the pathogenic N279K, P301L, and E10+16 mutations, exhibit deficits in mitochondrial bioenergetics and present altered parameters linked to the metabolic regulation of mitochondria. Moreover, we demonstrate that the triple tau mutations disturb the cellular redox homeostasis and modify the mitochondrial network morphology and distribution. This study provides the first characterization of disease-associated tau-mediated mitochondrial impairments in an advanced human cellular tau pathology model at early disease stages, ranging from mitochondrial bioenergetics to dynamics. Consequently, comprehending better the influence of dysfunctional mitochondria on the development and differentiation of stem cells and their contribution to disease progression may thus assist in the potential prevention and treatment of tau-related neurodegeneration.
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Células Madre Pluripotentes Inducidas , Proteínas tau , Humanos , Proteínas tau/genética , Proteínas tau/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Mitocondrias/metabolismo , Metabolismo EnergéticoRESUMEN
Introduction: Compared to the general population, individuals with depression have an increased risk for cardiovascular diseases. Nevertheless, little is known so far whether cardiorespiratory fitness (CRF) moderates this relationship. Therefore, we examined whether common physiological cardiovascular risk factors differ between patients with depression and healthy (non-depressed) controls, whether patients and controls differ in CRF, and whether higher CRF is associated with a lower cardiovascular risk in both patients and healthy controls. Additionally, we examined whether within the patient sample, cardiovascular risk factors differ between patients with mild, moderate and severe depression, and whether the relationship between symptom severity and cardiovascular risk is moderated by patients' CRF levels. Methods: Data from a multi-centric, two-arm randomized controlled trial (RCT) was analyzed, including 210 patients (F32, single episode: n = 72, F33, recurrent major depression: n = 135, F31-II, bipolar type II: n = 3) and 125 healthy controls. Waist circumference, body mass index, body fat, blood pressure, cholesterol levels, triglycerides, and blood glucose were considered as cardiovascular risk markers. CRF was assessed with a submaximal ergometer test. Differences between groups were examined via χ2-tests and (multivariate) analyses of covariance. Results: Compared to healthy controls, patients with depression had a higher cardiovascular risk as evident from about half of the examined indicators. In the total sample, participants with good CRF had more favourable scores across nearly all risk markers than counterparts with poor CRF. For most variables, no interaction occurred between group and fitness, indicating that in patients and controls, similar differences existed between participants with poor and good CRF. Few differences in risk markers were found between patients with mild, moderate and severe depression, and no interaction occurred between depression severity and CRF. Discussion: Patients with depression and healthy controls differ in several cardiovascular risk markers, putting patients at increased risk for CVDs. In contrast, people with good CRF show more favourable cardiovascular risk scores, a relationship which was observed in both healthy controls and patients with depression. Physical health of psychiatric patients should receive the clinical attention that it deserves. Lifestyle interventions targeting healthy diet and/or physical activity are recommended as a physically active and healthy lifestyle contributes equally to patients' mental well-being and cardiovascular health.
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Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3ß decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism.
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Mitocondrias , Proteínas tau , Proteínas tau/metabolismo , Mitocondrias/metabolismo , Retículo Endoplásmico/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Tirosina Fosfatasas/farmacología , Colesterol/metabolismoRESUMEN
BACKGROUND: Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus). METHODS: This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100âmg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137. FINDINGS: Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102â095 pg/mL (41â782-129â565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11â577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85â678 pg/mL [95% CI 63â356-108â000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia. INTERPRETATION: These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity. FUNDING: Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.
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Diabetes Insípida Neurogénica , Diabetes Mellitus , N-Metil-3,4-metilenodioxianfetamina , Humanos , N-Metil-3,4-metilenodioxianfetamina/efectos adversos , Oxitocina , Estudios Cruzados , Estudios de Casos y Controles , Método Doble Ciego , ArgininaRESUMEN
BACKGROUND: Patients with major depressive disorder (MDD) are characterized by neurocognitive impairments and show deficits in various cognitive performance indicators, including executive function. We examined whether sustained attention and inhibitory control differ between patients with MDD and healthy controls, and whether differences exist between patients with mild, moderate, and severe depression. METHODS: Clinical in-patients (N = 212) aged 18-65 years with a current diagnosis of MDD and 128 healthy controls were recruited. Depression severity was assessed using the Beck Depression Inventory, and sustained attention and inhibitory control were assessed using the oddball and flanker tasks. The use of these tasks promises insights into executive function in depressive patients that are not biased by verbal skills. Group differences were tested via analyses of covariance. RESULTS: Patients with MDD showed slower reaction times in both the oddball and flanker task, independent of the executive demands of the trial types. Younger participants achieved shorter reaction times in both inhibitory control tasks. After correcting for age, education, smoking, BMI, and nationality, only differences in reaction times in the oddball task were statistically significant. In contrast, reaction times were not sensitive to the symptom severity of depression. CONCLUSION: Our results corroborate deficits in basic information processing and specific impairments in higher-order cognitive processes in MDD patients. As difficulties in executive function underlie problems in planning, initiating, and completing goal-directed activities, they may jeopardize in-patient treatment and contribute to the recurrent nature of depression.
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N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus + low infusion (15 mg + 0.6 mg/min), and high bolus + high infusion (25 mg + 1 mg/min). Study sessions lasted for 5 h and were separated by at least 1 week. Participant's lifetime use of psychedelics was ≤20 times. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics of DMT, and plasma levels of brain-derived neurotropic factor (BDNF) and oxytocin. Low (15 mg) and high (25 mg) DMT bolus doses rapidly induced very intense psychedelic effects that peaked within 2 min. DMT infusions (0.6 or 1 mg/min) without a bolus induced slowly increasing and dose-dependent psychedelic effects that reached plateaus after 30 min. Both bolus doses produced more negative subjective effects and anxiety than infusions. After stopping the infusion, all drug effects rapidly decreased and completely subsided within 15 min, consistent with a short early plasma elimination half-life (t1/2α) of 5.0-5.8 min, followed by longer late elimination (t1/2ß = 14-16 min) after 15-20 min. Subjective effects of DMT were stable from 30 to 90 min, despite further increasing plasma concentrations, thus indicating acute tolerance to continuous DMT administration. Intravenous DMT, particularly when administered as an infusion, is a promising tool for the controlled induction of a psychedelic state that can be tailored to the specific needs of patients and therapeutic sessions.Trial registration: ClinicalTrials.gov identifier: NCT04353024.
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Alucinógenos , N,N-Dimetiltriptamina , Humanos , Voluntarios Sanos , Administración Intravenosa , AnsiedadRESUMEN
Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin. The tolerability of mescaline, LSD, and psilocybin was comparable, with mescaline at both doses inducing slightly more subacute adverse effects (12-24 h) than LSD and psilocybin. Clear distinctions were seen in the duration of action between the three substances. Mescaline had the longest effect duration (mean: 11.1 h), followed by LSD (mean: 8.2 h), and psilocybin (mean: 4.9 h). Plasma elimination half-lives of mescaline and LSD were similar (approximately 3.5 h). The longer effect duration of mescaline compared with LSD was due to the longer time to reach maximal plasma concentrations and related peak effects. Mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. None of the substances altered plasma brain-derived neurotrophic factor concentrations. In conclusion, the present study found no evidence of qualitative differences in altered states of consciousness that were induced by equally strong doses of mescaline, LSD, and psilocybin. The results indicate that any differences in the pharmacological profiles of mescaline, LSD, and psilocybin do not translate into relevant differences in the subjective experience. ClinicalTrials.gov identifier: NCT04227756.
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Alucinógenos , Psilocibina , Humanos , Psilocibina/farmacología , Mescalina/farmacología , Dietilamida del Ácido Lisérgico/farmacología , Estudios Cruzados , Voluntarios Sanos , Alucinógenos/farmacologíaRESUMEN
There is renewed interest in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. Although acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits. 3,4-Methylenedioxymethamphetamine (MDMA) produces marked positive subjective effects and is used recreationally with LSD, known as "candyflipping." The present study investigated whether the co-administration of MDMA can be used to augment acute subjective effects of LSD. We used a double-blind, randomized, placebo-controlled, crossover design with 24 healthy subjects (12 women, 12 men) to compare the co-administration of MDMA (100 mg) and LSD (100 µg) with MDMA and LSD administration alone and placebo. Outcome measures included subjective, autonomic, and endocrine effects and pharmacokinetics. MDMA co-administration with LSD did not change the quality of acute subjective effects compared with LSD alone. However, acute subjective effects lasted longer after LSD + MDMA co-administration compared with LSD and MDMA alone, consistent with higher plasma concentrations of LSD (Cmax and area under the curve) and a longer plasma elimination half-life of LSD when MDMA was co-administered. The LSD + MDMA combination increased blood pressure, heart rate, and pupil size more than LSD alone. Both MDMA alone and the LSD + MDMA combination increased oxytocin levels more than LSD alone. Overall, the co-administration of MDMA (100 mg) did not improve acute effects or the safety profile of LSD (100 µg). The combined use of MDMA and LSD is unlikely to provide relevant benefits over LSD alone in psychedelic-assisted therapy. Trial registration: ClinicalTrials.gov identifier: NCT04516902.
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Alucinógenos , N-Metil-3,4-metilenodioxianfetamina , Masculino , Humanos , Femenino , N-Metil-3,4-metilenodioxianfetamina/farmacología , Alucinógenos/farmacología , Voluntarios Sanos , Dietilamida del Ácido Lisérgico/farmacología , Método Doble Ciego , Estudios CruzadosRESUMEN
Objective: Psychiatric symptoms are common and bothersome in individuals with post-COVID-19 syndrome. Because they are often mixed and subthreshold, established treatment regimens cannot be applied. There is an urgent need to identify therapeutics for affected patients. Silexan, a proprietary essential oil from Lavandula angustifolia, has demonstrated efficacy against anxiety, comorbid symptoms, and subthreshold and mixed syndromes. The aim of the current narrative review is to examine the therapeutic potential of Silexan for psychiatric manifestations in patients with post-COVID-19 syndrome.Methods: We reviewed clinical evidence regarding the efficacy of Silexan and first clinical experience in patients with psychiatric symptoms attributable to the post-COVID-19 syndrome. Furthermore, we discussed potential modes of action based on nonclinical data.Results: Silexan has demonstrated therapeutic efficacy for the treatment of generalised anxiety disorder; subsyndromal anxiety disorders; comorbid depressive, somatic, and sleep disturbance symptoms; and mixed anxiety and depression. Emerging clinical experience also suggests the effectiveness and tolerability of Silexan for patients with post-COVID-19 syndrome. This can be explained by the fact that the therapeutic profile of Silexan overlaps with the spectrum of psychiatric symptoms in such patients.Conclusion: Preliminary findings indicate a promising potential of Silexan for the treatment of psychiatric manifestations in patients with post-COVID-19 syndrome.Key pointsAnxiety and mixed neuropsychiatric manifestations are commonly observed in patients with post-COVID-19 syndrome.Silexan has anxiolytic properties and can alleviate comorbid depressive, somatic, and sleep impairment symptoms.Silexan exhibits several biological mechanisms, such as neurotrophic and anti-inflammatory properties, which have the potential to positively impact post-COVID-19 disease.Silexan has a favourable safety profile and high acceptance among patients.Emerging data suggest that Silexan can alleviate neuropsychiatric symptoms in patients with post-COVID-19 syndrome.Silexan should be considered as a therapeutic in patients with psychiatric manifestations of post-COVID-19 syndrome.
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COVID-19 , Aceites Volátiles , Humanos , Síndrome Post Agudo de COVID-19 , COVID-19/complicaciones , Aceites de Plantas , Aceites Volátiles/farmacologíaRESUMEN
OBJECTIVES: Thus far, the diagnosis of insomnia is based on purely clinical criteria. Although a broad range of altered physiological parameters has been identified in insomniacs, the evidence to establish their diagnostic usefulness is very limited. Purpose of this WFSBP Task Force consensus paper is to systematically evaluate a series of biomarkers as potential diagnostic tools for insomnia. METHODS: A newly created grading system was used for assessing the validity of various measurements in establishing the diagnosis of insomnia; these measurements originated from relevant studies selected and reviewed by experts. RESULTS: The measurements with the highest diagnostic performance were those derived from psychometric instruments. Biological measurements which emerged as potentially useful diagnostic instruments were polysomnography-derived cyclic alternating pattern, actigraphy, and BDNF levels, followed by heart rate around sleep onset, deficient melatonin rhythm, and certain neuroimaging patterns (mainly for the activity of frontal and pre-frontal cortex, hippocampus and basal ganglia); yet, these findings need replication, as well as establishment of commonly accepted methodology and diagnostic cut-off points. Routine polysomnography, EEG spectral analysis, heart rate variability, skin conductance, thermoregulation, oxygen consumption, HPA axis, and inflammation indices were not shown to be of satisfactory diagnostic value. CONCLUSIONS: Apart from psychometric instruments which are confirmed to be the gold standard in diagnosing insomnia, six biomarkers emerge as being potentially useful for this purpose.
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Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/diagnóstico , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Sueño/fisiología , BiomarcadoresRESUMEN
Abnormal tau build-up is a hallmark of Alzheimer's disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal tau impairs almost every aspect of mitochondrial function, from mitochondrial respiration to mitophagy. The aim of our study was to investigate the effects of spermidine, a polyamine which exerts neuroprotective effects, on mitochondrial function in a cellular model of tauopathy. Recent evidence identified autophagy as the main mechanism of action of spermidine on life-span prolongation and neuroprotection, but the effects of spermidine on abnormal tau-induced mitochondrial dysfunction have not yet been investigated. We used SH-SY5Y cells stably expressing a mutant form of human tau protein (P301L tau mutation) or cells expressing the empty vector (control cells). We showed that spermidine improved mitochondrial respiration, mitochondrial membrane potential as well as adenosine triphosphate (ATP) production in both control and P301L tau-expressing cells. We also showed that spermidine decreased the level of free radicals, increased autophagy and restored P301L tau-induced impairments in mitophagy. Overall, our findings suggest that spermidine supplementation might represent an attractive therapeutic approach to prevent/counteract tau-related mitochondrial impairments.
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Enfermedad de Alzheimer , Neuroblastoma , Humanos , Proteínas tau/metabolismo , Mitofagia , Espermidina/farmacología , Enfermedad de Alzheimer/metabolismo , Metabolismo Energético , Adenosina Trifosfato/metabolismoRESUMEN
BACKGROUND: In major depressive disorder (MDD), cognitive dysfunctions strongly contribute to functional impairments but are barely addressed in current therapies. Novel treatment strategies addressing cognitive symptoms in depression are needed. As the gut microbiota-brain axis is linked to depression and cognition, we investigated the effect of a 4-week high-dose probiotic supplementation on cognitive symptoms in depression. METHODS: This randomized controlled trial included 60 patients with MDD, of whom 43 entered modified intention-to-treat analysis. A probiotic supplement or indistinguishable placebo containing maltose was administered over 31 days in addition to treatment as usual for depression. Participant scores on the Verbal Learning Memory Test (VLMT), Corsi Block Tapping Test, and both Trail Making Test versions as well as brain-derived neurotrophic factor levels were assessed at 3 different time points: before, immediately after and 4 weeks after intervention. Additionally, brain activation changes during working memory processing were investigated before and immediately after intervention. RESULTS: We found a significantly improved immediate recall in the VLMT in the probiotic group immediately after intervention, and a trend for a time × group interaction considering all time points. Furthermore, we found a time × group interaction in hippocampus activation during working memory processing, revealing a remediated hippocampus function in the probiotic group. Other measures did not reveal significant changes. LIMITATIONS: The modest sample size resulting from our exclusion of low-compliant cases should be considered. CONCLUSION: Additional probiotic supplementation enhances verbal episodic memory and affects neural mechanisms underlying impaired cognition in MDD. The present findings support the importance of the gut microbiota-brain axis in MDD and emphasize the potential of microbiota-related regimens to treat cognitive symptoms in depression. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02957591.