Effects of escitalopram on synaptic density in the healthy human brain: a randomized controlled trial.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a [11C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24-38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [11C]UCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.

Sexual function improves as depressive symptoms decrease during treatment with escitalopram: results of a naturalistic study of patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is closely associated with sexual dysfunction, which may worsen during treatment with selective serotonin reuptake inhibitors (SSRIs) due to the side effects of pharmacologic treatment. AIM: To examine the association between sexual function and severity of MDD in drug-naïve patients as compared with healthy controls and how treatment with SSRIs affects sexual function over time in individuals with MDD. Interaction with gender and treatment response was examined. METHODS: In 92 patients with MDD, we measured MDD severity with 6- and 17-item versions of the Hamilton Depression Rating Scale (HDRS6 and HDRS17) and the level of sexual function with the Changes in Sexual Functioning Questionnaire at baseline and 4, 8, and 12 weeks after initiating treatment with escitalopram. Baseline sexual function was compared with the sexual function of 73 healthy controls. Linear regression models were used to assess differences in sexual function between healthy controls and patients and change in sexual function from baseline to week 12. Linear mixed models were used to assess differences in change in sexual function between treatment response groups. OUTCOMES: Outcomes included total scores on the HDRS6, HDRS17, and Changes in Sexual Functioning Questionnaire and changes in total scores from baseline to week 12. RESULTS: Unmedicated patients with MDD reported impaired sexual function as compared with healthy controls. Level of sexual function was not associated with severity of MDD at baseline. Patients' sexual function improved significantly during treatment, which was coupled with amelioration of depressive symptoms. Treatment response groups (remitters, intermediate responders, nonresponders) did not predict change in sexual function. Gender had no effect on sexual dysfunction symptoms during treatment. CLINICAL IMPLICATIONS: Major depression is a risk factor for sexual problems, and improvement in sexual function was coupled with amelioration of depressive symptoms. STRENGTHS AND LIMITATIONS: Among its strengths, this was a naturalistic study reflecting real-world settings in clinical practice. It additionally included a baseline measurement of sexual function and MDD severity on drug-naïve patients prior to the initiation of treatment. Finally, the follow-up of 12 weeks extends beyond the acute phase of treatment in which previous research has observed a peak in sexual side effects. In terms of limitations, there was no placebo arm; thus, the study cannot attribute the effects on sexual function to treatment with antidepressants per se. Also, the patients were young, which may have served as a protective factor against sexual side effects. CONCLUSION: Sexual dysfunction was strongly associated with MDD and improved in parallel with overall symptoms of depression across a standard 12-week treatment with SSRI antidepressants. CLINICAL TRIAL REGISTRATION: NCT02869035 (https://clinicaltrials.gov/ct2/show/NCT02869035).

Psilocybin modulation of time-varying functional connectivity is associated with plasma psilocin and subjective effects.

BACKGROUND: Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state time-varying functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects. AIM: Evaluate the association between resting-state time-varying functional connectivity (tvFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans. METHODS: Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis. RESULTS: Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state partly associated with motion was positively associated with PPL and SDI. CONCLUSION: Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs. We apply and argue for a modified approach to modeling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics.

Brain serotonin transporter is associated with cognitive-affective biases in healthy individuals.

Cognitive affective biases describe the tendency to process negative information or positive information over the other. These biases can be modulated by changing extracellular serotonin (5-HT) levels in the brain, for example, by pharmacologically blocking and downregulating the 5-HT transporter (5-HTT), which remediates negative affective bias. This suggests that higher levels of 5-HTT are linked to a priority of negative information over positive, but this link remains to be tested in vivo in healthy individuals. We, therefore, evaluated the association between 5-HTT levels, as measured with [11 C]DASB positron emission tomography (PET), and affective biases, hypothesising that higher 5-HTT levels are associated with a more negative bias. We included 98 healthy individuals with measures of [11 C]DASB binding potential (BPND ) and affective biases using The Emotional Faces Identification Task by subtracting the per cent hit rate for happy from that of sad faces (EFITAB ). We evaluated the association between [11 C]DASB BPND and EFITAB in a linear latent variable model, with the latent variable (5-HTTLV ) modelled from [11 C]DASB BPND in the fronto-striatal and fronto-limbic networks implicated in affective cognition. We observed an inverse association between 5-HTTLV and EFITAB (ß = -8% EFITAB per unit 5-HTTLV , CI = -14% to -3%, p = .002). These findings show that higher 5-HTT levels are linked to a more negative bias in healthy individuals. High 5-HTT supposedly leads to high clearance of 5-HT, and thus, a negative bias could result from low extracellular 5-HT. Future studies must reveal if a similar inverse association exists in individuals with affective disorders.

Acute Traumatic Stress Screening Can Identify Patients and Their Partners at Risk for Posttraumatic Stress Disorder Symptoms After a Cardiac Arrest: A Multicenter Prospective Cohort Study.

BACKGROUND: Posttraumatic stress disorder (PTSD) is prevalent in patients who have had a cardiac arrest and their partners. Accordingly, acute traumatic stress screening is recommended, but its association with later PTSD symptoms has never been addressed in postresuscitation settings. OBJECTIVE: The aim of this study was to examine whether acute traumatic stress is associated with PTSD symptoms in patients who have had a cardiac arrest and their partners. METHODS: This multicenter longitudinal study of 141 patients and 97 partners measures acute traumatic stress at 3 weeks and PTSD symptoms at 3 months and 1 year after resuscitation, using the Impact of Event Scale. Linear regression models were used to evaluate the association between severity of acute traumatic stress and PTSD symptoms and post hoc to explore effects of group (patients/partners), age, and sex on acute traumatic stress severity. We categorized Impact of Event Scale scores higher than 26 at 3 months and 1 year as clinical severe PTSD symptoms . RESULTS: Higher acute traumatic stress severity is significantly positively associated with higher PTSD symptom severity at 3 months (patients and partners: P < .001) and 1 year (patients and partners: P < .001) postresuscitation, with the strongest association for women compared with men ( P = .03). Acute traumatic stress was higher in women compared with men across groups ( P = .02). Clinical severe PTSD symptoms were present in 26% to 28% of patients and 45% to 48% of partners. CONCLUSION: Experiencing a cardiac arrest may elicit clinical severe PTSD symptoms in patients, but particularly in their partners. Screening patients and partners for acute traumatic stress postresuscitation is warranted to identify those at increased risk of long-term PTSD symptoms.

Functional brain responses to emotional faces after three to five weeks of intake of escitalopram in healthy individuals: a double-blind, placebo-controlled randomised study.

Short-term intake of selective serotonin reuptake inhibitors (SSRIs) modulates threat-related amygdala responses in healthy individuals. However, how SSRI intake over a clinically relevant time period modulates threat-related amygdala responses is less clear. In a semi-randomised, double-blind, placebo-controlled study of 64 healthy individuals (SSRI n = 32, placebo n = 32), we examined the effect of 3-5 weeks of SSRI escitalopram (20 mg daily) on brain response to angry, fearful and neutral faces using BOLD fMRI. Data was analysed using a whole-brain region-wise approach extracting standardised effects (i.e., Cohen's D). The study was conducted at the Copenhagen University Hospital. A priori, we hypothesised that SSRI would attenuate amygdala responses to angry and fearful faces but not to neutral ones. Whether SSRI modulates correlations between amygdala responses to emotional faces and negative mood states was also explored. Compared to placebo, 3-5 weeks of SSRI intake did not significantly affect the amygdala response to angry, fearful, or neutral faces (|Cohen's D|< 0.2, PFWER = 1). Whole-brain, region-wise analyses revealed significant differences in frontal (|Cohen's D|< 0.6, PFWER < .01) and occipital regions (|Cohen's D|< 0.5, PFWER < .01). SSRI did not modulate correlations between amygdala responses to emotional faces and negative mood states. Our findings indicate that a 3-5 week SSRI intake impacts cortical responses to emotional stimuli, an effect possibly involved in SSRI's therapeutic efficacy.Trial registration Clinical Trials NCT04239339.

Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study.

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of 'cold' cognition (including inhibition, cognitive flexibility, memory) and 'hot cognition' including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on 'cold' or 'hot' cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the 'blunting' effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339 .

Lasting increases in trait mindfulness after psilocybin correlate positively with the mystical-type experience in healthy individuals.

Background: Psilocybin-induced mystical-type experiences are associated with lasting positive psychological outcomes. Recent studies indicate that trait mindfulness is increased 3 months after psilocybin intake, preceded by decreases in neocortical serotonin 2A receptor (5-HT2AR) binding. However, the association between psilocybin-induced mystical-type experiences and subsequent changes in trait mindfulness remains unexplored, as does the association between pre-drug trait mindfulness and 5-HT2AR binding in the healthy brain. Aim: We evaluated whether psilocybin induced lasting increases in trait mindfulness in healthy volunteers, and whether the mystical-type experience was associated with this increase. We further examined the association between pre-drug trait mindfulness and 5-HT2AR binding in neocortex and selected frontolimbic regions. Materials and methods: Forty-six medium-high dose psilocybin sessions were conducted in 39 healthy individuals. The mystical-type experience was measured with the Mystical Experience Questionnaire (MEQ) at the end of the session. Trait mindfulness was measured using the Mindful Attention and Awareness Scale (MAAS) at baseline and 3 months after the psilocybin session. Thirty-two of the participants completed pre-drug [11C]-Cimbi-36 positron emission tomography (PET) to assess 5-HT2AR binding in neocortex and, post-hoc, in the frontolimbic regions amygdala, frontal cortex, and anterior cingulate cortex. Results: The MAAS score was significantly increased at 3-month follow-up (p = 3.24 × 10-6), a change positively associated with the MEQ score (p = 0.035). Although the association between pre-drug MAAS score and neocortex 5-HT2AR binding was not significant (p = 0.24), post-hoc analyses revealed a significant negative association between MAAS and right amygdala 5-HT2AR binding (pFWER = 0.008). Conclusion: We here show that lasting changes in trait mindfulness following psilocybin administration are positively associated with intensity of the mystical-type experience, suggesting that the acute phenomenology of psilocybin facilitates a shift in awareness conducive for mindful living. We furthermore show that higher pre-drug trait mindfulness is associated with reduced 5-HT2AR binding in the right amygdala.

Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report.

Psychedelic drugs such as psilocybin have shown substantial promise for the treatment of several psychiatric conditions including mood and addictive disorders. They also have the remarkable property of producing persisting positive psychological changes in healthy volunteers for at least several months. In this study (NCT03289949), 35 medium-high doses of psilocybin were administered to 28 healthy volunteers (12 females). By the end of the dosing day, participants reported the intensity of their acute experience using the 30-item Mystical Experience Questionnaire (MEQ) and an open-form qualitative report from home. Persisting psychological effects attributed to the psilocybin experience were measured using the Persisting Effects Questionnaire (PEQ) 3-months after administration. Using a linear latent-variable model we show that the MEQ total score is positively associated with the later emergence of positive PEQ effects (p = 3 × 10-5). Moreover, the MEQ subscales "Positive Mood" (pcorr = 4.1 × 10-4) and "Mysticality" (pcorr = 2.0 × 10-4) are associated with positive PEQ whereas the subscales "Transcendence of Time and Space" (pcorr = 0.38) and "Ineffability" (pcorr = 0.45) are not. Using natural language pre-processing, we provide the first qualitative descriptions of the "Complete Mystical Experience" induced by orally administered psilocybin in healthy volunteers, revealing themes such as a sense of connection with the Universe, familial love, and the experience of profound beauty. Combining qualitative and quantitative methods, this paper expands understanding of the acute psilocybin induced experience in healthy volunteers and suggests an importance of the type of experience in predicting lasting positive effects.

Fear in groups: Increasing group size reduces perceptions of danger.

When we face danger or stress, the presence of others can provide a powerful signal of safety and support. However, despite a large literature on group living benefits in animals, few studies have been conducted on how group size alters subjective emotional responses and threat perception in humans. We conducted 5 experiments (N = 3,652) to investigate whether the presence of others decreases fear in response to threat under a variety of conditions. In Studies 1, 2 and 3, we experimentally manipulated group size in hypothetical and real-world situations and found that fear responses decreased as group size increased. In Studies 4 and 5 we again used a combination of hypothetical and real-world decisions to test whether increased anxiety in response to a potential threat would lead participants to choose larger groups for themselves. Participants consistently chose larger groups when threat and anxiety were high. Overall, our findings show that group size provides a salient signal of protection and safety in humans. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience.

The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive peroral dose of psilocybin (0.2-0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.

Cognitive impairment and psychopathology in out-of-hospital cardiac arrest survivors in Denmark: The REVIVAL cohort study protocol.

INTRODUCTION: Cognitive impairment and psychopathology caused by brain hypoxia and the traumatic impact of critical illness are common in cardiac arrest survivors and can lead to negative consequences of everyday life functioning, and further impact mental health in relatives. Most studies have dealt with the mere survival rate after cardiac arrest and not with long-term consequences to mental health in cardiac arrest survivors. Importantly, we face a gap in our knowledge about suitable screening tools in the early post-arrest phase for long-term risk prediction of mental health problems. This study aims to evaluate the efficacy of a novel screening procedure to predict risk of disabling cognitive impairment and psychopathology 3 months after cardiac arrest. Furthermore, the study aims to evaluate long-term prevalence of psychopathology in relatives. METHODS AND ANALYSES: In this multicentre prospective cohort study, out-of-hospital cardiac arrest survivors and their relatives will be recruited. The post-arrest screening includes the Montreal Cognitive Assessment (MoCA), the Hospital Anxiety and Depression Scale (HADS), the Impact of Event Scale-Revised (IES-R) and the Acute Stress Disorder Interview (ASDI) and is conducted during hospitalisation. In a subsample of the patients, functional MRI is done, and cortisol determination collected. At 3-month follow-up, the primary study outcomes for 200 survivors include the Danish Affective Verbal Learning Test-26 (VAMT-26), Delis-Kaplan Executive Function System tests (trail making, colour-word interference, word and design fluency), Rey's Complex Figure and Letter-number sequencing subtest of Wechsler Adult Intelligence Scale-IV, HADS and IES-R. For the relatives, they include HADS and IES-R. ETHICS AND DISSEMINATION: The study is approved by the local regional Research Ethics Committee (H-18046155) and the Danish Data Protection Agency (RH-2017-325, j.no.05961) and follows the latest version of the Declaration of Helsinki. The results will be published in peer-reviewed journals and may impact the follow-up of cardiac arrest survivors.

Psychometric Properties of the Verbal Affective Memory Test-26 and Evaluation of Affective Biases in Major Depressive Disorder.

We developed the Verbal Affective Memory Test-26 (VAMT-26), a computerized test to assess verbal memory, as an improvement of the Verbal Affective Memory Test-24 (VAMT-24). Here, we psychometrically evaluate the VAMT-26 in 182 healthy controls, examine 1-month test-retest stability in 48 healthy controls, and examine whether 87 antidepressant-free patients diagnosed with Major Depressive Disorder (MDD) tested with VAMT-26 differed in affective memory biases from 335 healthy controls tested with VAMT24/26. We also examine whether affective memory biases are associated with depressive symptoms across the patients and healthy controls. VAMT-26 showed good psychometric properties. Age, sex, and IQ, but not education, influenced VAMT-26 scores. VAMT-26 scores converged satisfactorily with scores on a test associated with non-affective verbal memory. Test-retest analyses showed a learning effect and a r ≥ 0.0.8, corresponding to a typical variation of 10% in recalled words from first to second test. Patients tended to remember more negative words relative to positive words compared to healthy controls at borderline significance (p = 0.06), and affective memory biases were negatively associated with depressive symptoms across the two groups at borderline significance (p = 0.07), however, the effect sizes were small. Future studies are needed to address whether VAMT-26 can be used to distinguish between depression subtypes in patients with MDD. As a verbal memory test, VAMT-26 is a well validated neuropsychological test and we recommend it to be used in Danish and international studies on affective memory.