European Neuropsychopharmacology

Anxiety disorders are the most common type of psychiatric disorders among Western countries. Evidence-based treatment modalities including pharmacological and cognitive-behavioral therapy result in relatively low response rates (average range: 51 - 58%). Historical and recent research suggests psychedelic drugs may be efficacious in alleviating anxiety-related symptoms among healthy and clinical populations. The main aim of the present study was investigation of the effects of psilocybin-containing truffles, when taken in a supportive group setting, on ratings of state and trait anxiety across self-reported healthy volunteers. Attendees of psilocybin ceremonies were asked to complete a test battery at three separate occasions: before the ceremony (baseline), the morning after, and one week after the ceremony. The test battery included questionnaires assessing state and trait anxiety (State-Trait Anxiety Inventory), mindfulness capacities (Five Facet Mindfulness Questionnaire), and personality (Big Five Inventory). Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire and the Ego Dissolution Inventory. The total amount of psilocybin-containing truffles consumed by each participant was recorded, and a sample of the truffles was analyzed to determine psilocin concentrations. Fifty-two attendees (males= 25; females= 25; others= 2) completed parts of the baseline assessment, 46 (males= 21; females= 24; others= 1) completed assessments the morning after the ceremony, and 23 (males= 10; females= 13) completed assessments at the one-week follow-up. Average psilocin consumption across individuals was 27.1 mg. We observed medium to large reductions in anxiety measures (both state and trait) compared to baseline which persisted over a one-week period post-ceremony. At one week post-ceremony, the non-judging facet of the mindfulness scale was increased, while the personality trait neuroticism decreased, when compared to baseline. Additionally, we found neuroticism and ratings of ego dissolution to be the strongest predictors of reductions in trait and state anxiety, respectively. In sum, results indicate rapid and persisting (up to one week) anxiolytic effects in psilocybin retreat attendees, which are related to the acute experience of ego dissolution, as well as lasting changes in trait neuroticism. To understand whether these effects extend to wider populations suffering from heightened anxiety, and the mechanisms involved, further experimental research is needed.

BackgroundThe endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses. MethodsThis post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-[A]sberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment. ResultsIn the placebo arm, baseline opioid use was associated with a 10-point increase (95% CI: 0.81-19.4) in MADRS scores across all post-treatment time points, indicating worse depression in this subgroup. In an alternative model using percent change in MADRS scores, the difference between opioid users and non-users was 38.4% (95% CI: 8.59-68.2), with opioid users experiencing less improvement. For ketamine-treated participants, baseline opioid use did not significantly impact MADRS scores or the percent change in MADRS scores. Pain intensity was not a significant predictor of MADRS outcomes, and the correlation between post-treatment MADRS scores and pain intensity was negligible (R=0.12). LimitationsThis analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies. ConclusionsOpioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

The majority of individuals receiving treatment for major depressive disorder (MDD) do not achieve remission from the first medication they try, and over 80% subsequently discontinue pharmacotherapy or switch to a different medication. SSRI discontinuation due to side effects is common. We evaluated the effect of CYP2C19 genotype on SSRI response using self-reported data from 114,627 direct-to-consumer genetics research participants who were prescribed an SSRI primarily metabolized by CYP2C19 (citalopram, escitalopram, or sertraline). Among participants taking citalopram or escitalopram, slower metabolizers experienced side effects significantly more often than faster metabolizers (OR=1.04 per grade, from 0 for poor metabolizers to 5 for ultrarapid metabolizers, 95%CI=[1.02-1.06] and OR=1.05 per grade, 95%CI=[1.02-1.07]) and were more likely to discontinue treatment due to side effects (OR=1.05, 95%CI=[1.03-1.08], e.g. 29.7% of poor vs. 21.6% of ultrarapid metabolizers, and OR=1.07, 95%CI=[1.04-1.11], e.g. 25.7% vs. 20.2%). Slower metabolizers taking escitalopram were more likely to suffer from sleep problems and sexual problems than faster metabolizers. Slower metabolizers taking sertraline reported tremor more often than faster metabolizers. Overall, we find substantial differences in side effect risk between individuals with different CYP2C19 genotypes in a large sample, supporting the notion that individuals seeking treatment for MDD may benefit from preemptive pharmacogenetic testing and genotype-guided dosing recommendations to minimize side effects and reduce discontinuations.

BackgroundRacemic ketamine and its enantiomer, esketamine, have emerged as fast-acting antidepressant options for individuals with treatment-resistant depression (TRD). Yet, despite growing clinical use, little is known about how sex assigned at birth shapes symptom-specific responses to these interventions, a critical gap in the move toward personalized psychiatry. MethodsWe conducted a pooled analysis of five randomized, double-blind, placebo-controlled trials in which adults with TRD received intranasal esketamine or placebo twice weekly for four weeks, alongside a newly initiated oral antidepressant. We evaluated the effects of sex assigned at birth on overall depression severity, measured via total Montgomery-[A]sberg Depression Rating Scale (MADRS) scores, and across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms. Rates of clinical response and remission were also analyzed by sex assigned at birth. FindingsOverall, esketamine treatment improved total MADRS scores in both sexes; however, significant sex-specific patterns emerged. Females showed greater improvement in total MADRS scores than males towards the end of the trials, in both the placebo and esketamine arms. Females also showed more pronounced reductions in the sadness and detachment factors at the end of the trials, as well as in the neurovegetative factor on day 15, regardless of the treatment group. On the other hand, males showed a significant reduction in sadness symptoms after esketamine on day 2 of the treatment. Females had higher odds of responding, regardless of treatment arm, during later time points. InterpretationThese findings reveal that sex assigned at birth influences overall antidepressant response and shapes the trajectory and symptom profile of improvement. Our findings emphasize the critical importance of incorporating sex assigned at birth as a key variable, essential for optimizing TRD treatment strategies and advancing individualized mental healthcare. FundingCanadian Institutes for Health Research.

The renin-angiotensin system (RAS), traditionally known for cardiovascular regulation, has increasingly been recognized as a modulator of cognitive and affective functions. However, whether the RAS regulates attentional control and whether such effects are sex-dependent remain unexplored. The present preregistered, randomized, double-blind, placebo-controlled pharmacological eye-tracking study (N = 79) examined the effects of transient angiotensin II type 1 receptor (AT1R) blockade via losartan (50 mg) on emotional attention control using a validated anti-saccade task with social (emotional faces) and non-social stimuli. Treatment effects on state anxiety and oculomotor responses were characterized using traditional performance metrics and a novel trial-history informed dynamic control (TIDC) framework for adaptive control. Losartan reduced state anxiety irrespective of sex and induced sexually dimorphic reconfiguration of attentional processing. In females, AT1R blockade enhanced performance by reducing endpoint error without altering latency. Conversely, in males, losartan increased endpoint error and prolonged latency of the first correct saccade. Trial-history analyses further revealed that losartan reduced error probabilities following error and repeat trials in both sexes. Yet, following correct trials, females receiving losartan maintained lower error probabilities, while males receiving losartan exhibited higher errors, potentially reflecting a failure to flexibly disengage from the effortful controlled mode. Findings indicate that the RAS modulates anxiety and attentional control, the latter in a sexdependent manner. AT1R blockade can reconfigure attentional processing and adaptive control, suggesting sex-specific therapeutic potential in disorders characterized by excessive anxiety and attentional dysregulation.

BackgroundThe neuropeptide oxytocin is proposed as a promising therapy for social dysfunction by modulating amygdala-mediated social-emotional behavior. Although clinical trials report some benefits of chronic treatment it is unclear whether efficacy may be influenced by dose frequency or genotype. MethodsIn a randomized, double blind, placebo-controlled pharmaco-fMRI trial (150 male subjects) we investigated acute and different chronic (every day or on alternate days for 5 days) intranasal oxytocin (24IU) effects and oxytocin receptor genotype-mediated treatment sensitivity on amygdala responses to face emotions. We also investigated similar effects on resting state functional connectivity between the amygdala and prefrontal cortex. ResultsA single dose of oxytocin reduced amygdala responses to all face emotions but for threatening (fear and anger) and happy faces this effect was abolished after daily doses for 5 days but maintained by doses given every other day. The latter dose regime also enhanced associated anxious-arousal attenuation for fear faces. Oxytocin effects on reducing amygdala responses to face emotions only occurred in AA homozygotes of rs53576 and A carriers of rs2254298. The effects of oxytocin on resting state functional connectivity were not influenced by either dose-frequency or receptor genotype. ConclusionsInfrequent chronic oxytocin administration may be therapeutically most efficient and its anxiolytic neural and behavioral actions are highly genotype-dependent in males.

ObjectiveDespite many decades of experimental studies and clinical trials involving a variety of psychedelic agents, we still lack a comprehensive understanding of the effects of these substances on psychological experiences. As such, we designed and conducted a study to comprehensively characterise the effects of both psilocybin and 3,4-Methylenedioxymethamphetamine (MDMA) on a range of psychological outcomes in a substantive non-clinical population. MethodsThis study involved a single dose administration of psilocybin or MDMA in healthy individuals in a group setting (2-4 people per session). All participants underwent a single preparation session, a drug exposure session, and an integration session within 72 hours of dosing. Outcome assessments were conducted at a pre-dosing baseline, 1-3 days post dose (side effects only), one week post dose and at 3 month follow up (the later time point data is not included here). ResultsOf 48 participants, 25 initially received MDMA and 23 psilocybin. Ten cross-over participants received MDMA and then psilocybin and six participants received both in the reverse order: making a total of 31 MDMA and 33 psilocybin dosing sessions. In the week after dosing, we found significant changes in personality (a reduction in neuroticism and increase in extraversion), mindfulness, and connectedness following the administration of psilocybin but not MDMA. Psilocybin also produced significantly stronger mystical experiences compared to MDMA, and there was a significant correlation between the magnitude of these mystical experiences and changes in connectedness and mindfulness (but not changes in personality). Of note, participants seemed more comfortable with, and preferred, larger group sizes when being administered MDMA than psilocybin. DiscussionOur results identified a range of short-term psychological effects in non-clinical participants following a single dose of psilocybin, that were not reported following a single dose of MDMA. Notably, our results indicate that these effects following psilocybin may be moderated through its induction of mystical experiences, as has been previously hypothesised. Although preliminary, our results also suggest that larger group dosing sessions seem more feasible with MDMA than psilocybin.

BackgroundAnesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial (NCT03684447) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. MethodsParticipants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. ResultsTreatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). ConclusionsThe medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Nicotine intake by cigarettes is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n=88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

BACKGROUNDKetamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. METHODSIn a triple-masked, randomized, placebo-controlled trial, 40 adult patients with major depressive disorder were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during anesthesia as usual for routine surgery. The primary outcome was depression severity measured by the Montgomery-[A]sberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. The secondary outcome was the proportion of participants with clinical response ([≥]50% reduction in MADRS scores) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. RESULTSMean MADRS scores did not differ between groups at screening or pre-infusion baseline. The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13). Clinical response rates were similar between groups (60% versus 50% on day 1) and comparable to previous studies of ketamine in depressed populations. Secondary and exploratory outcomes did not find statistical separation of ketamine from placebo. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. One serious adverse event occurred in each group, unrelated to ketamine administration. CONCLUSIONIn adults with major depressive disorder, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias. (ClinicalTrials.gov number, NCT03861988)

Sertraline is a common first-line pharmacological treatment of Major Depressive Disorder (MDD). There is no established consensus nor clinical guidelines for personalized dose adjustments, which imply risks of toxicity and lack of efficacy. To address these challenges, there is preliminary evidence of the clinical utility of the determination of blood levels of sertraline by means of therapeutic drug monitoring (TDM). Further evidence is needed regarding the optimal therapeutic range of sertraline in terms of an optimal efficacy/tolerability balance, with need of prospective studies on the association between blood concentration of sertraline and clinical outcomes. The PREDEP-SERT study (PREdictors of response in DEPression treated with SERTraline) is a single-center, observational, longitudinal, ambispective cohort study of patients with MDD to investigate the association between blood concentration of sertraline and its effectiveness and safety (pre-registered study in Spain, REec number: 0014-2022-OBS, https://reec.aemps.es/reec/observacional/0014-2022-OBS). It adopts wide inclusion and exclusion criteria in order to allow the inclusion of patients that are representative of real-world clinical practice. It includes an exploratory retrospective subcohort and a subsequent 6-month follow-up prospective subcohort, with repeated measures (blood concentrations of sertraline and clinical outcomes) at scheduled timepoints (15 days, 30 days, 60 days, 90 days and 6 months). Relevant clinical, pharmacogenetic and sociodemographic potential predictors, confounders and effect modifiers will be explored. Its primary objective is to prospectively assess the association between blood concentration of sertraline (and the ratio with its metabolite, N-desmethylsertraline) and the intensity of depressive symptoms measured by the Hamilton Depression Rating Scale at 6 months of treatment. Other secondary objectives are to assess the association between blood concentration of sertraline/N-desmethylsertraline and clinical variables of effectiveness (by means of validated clinical scales) and side effects at every timepoint. Its results may elucidate the clinical utility of TDM in the therapeutic management of MDD in a personalized fashion.

IntroductionN,N-Dimethyltryptamine (DMT), a naturally occurring psychedelic tryptamine contained in the indigenous ayahuasca brew has shown antidepressant effects. This Phase 2a clinical trial investigates for the first time the efficacy of isolated DMT in treatment-resistant depression (TRD). MethodsSix TRD patients participated in an open-label, fixed-order, dose-escalation study, receiving a lower (15 mg) and then a higher (60 mg) dose of vaporized DMT in a single-day session. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9) up to one-month post-dosing. ResultsSignificant reductions in MADRS and PHQ-9 scores were noted from Day 1 to M1. The mean MADRS score variation from baseline to D7 was -22 points and -17 points at M1. PHQ-9 scores also showed significant decreases, mirroring the MADRS results. By D7, 83.33% of patients responded to treatment, with 66.67% achieving remission. At M1, 66.67% maintained response, and 50% maintained remission. DiscussionThe rapid onset and sustained antidepressant effects of vaporized DMT align with the paradigm of rapid-acting antidepressants to be used in the scope of interventional psychiatry. The non-invasive route and short-acting nature of DMT offer practical advantages, potentially enhancing accessibility to psychedelic treatments. Clinical Trial registrationClinicaltrials.gov NCT06094907

Identifying biomarkers predicting therapy outcomes before treatment holds great promise for advancing precision medicine. Genetic variants such as the serotonin transporter gene linked polymorphic region (5-HTTLPR) may be associated with response to cognitive behavioral therapy in anxiety disorders, albeit results so far are controversial. Contributing to the ongoing debate, we investigated whether treatment response to a highly standardized one-session virtual reality exposure therapy (VRET) was predicted by 5-HTTLPR genotype. N=194 patients with arachnophobia (spider phobia) were genotyped for 5-HTTLPR and the functionally related single nucleotide polymorphism rs25531 and grouped into high-(LA/LA), and low-expression (S/S, S/LG, LG/LG, S/LA, LG/LA) genotype. At baseline, after VRET, and at a 6-month follow-up, participants underwent a standardized behavioral avoidance task (BAT) and the spider phobia questionnaire (SPQ) to assess symptom severity. Chi-square tests revealed a significant association between 5-HTTLPR/rs25531 and behavioral treatment outcome, that remained significant at the 6-month follow-up. No association was found between genotype and self-reported symptom severity measured with the SPQ. Our results support the idea that while LA/LAgenotype carriers might benefit from highly standardized treatment, lower 5-HTT expression may convey risk to poorer treatment response, likely necessitating more tailored psychotherapeutic interventions to promote sufficient response.

BackgroundReduced Environmental Stimulation Therapy via floatation (floatation-REST) is a behavioral intervention designed to attenuate exteroceptive sensory input to the nervous system. Pilot studies in anxious and depressed individuals demonstrated that single sessions of floatation- REST are safe, well-tolerated, and associated with acute anxiolysis. However, there is not sufficient evidence of the feasibility of floatation-REST as a repeated intervention. MethodsWe randomized 75 individuals with anxiety and depression to six sessions of floatation-REST in different formats (pool-REST or pool-REST preferred) or an active comparator (chair-REST). Feasibility was assessed via adherence rate to the assigned intervention, tolerability via duration of REST utilization and overall study dropout rate, and safety via incidence of serious or non-serious adverse events. ResultsSix-session adherence was 85% for pool-REST, 89% for pool-REST preferred, and 74% for chair-REST. Dropout rates did not differ significantly between the treatment conditions. Mean session durations were consistently above 50 minutes, and when allowed to choose the duration and frequency, participants opted to float for an average of 75 minutes. There were no serious adverse events associated with any intervention. Positive experiences were endorsed more commonly than negative ones and were also rated at higher levels of intensity. ConclusionsTaken together, six sessions of floatation-REST appear feasible, well-tolerated, and safe in anxious and depressed individuals. Floatation-REST induces positively-valenced experiences with few negative effects. Larger randomized controlled trials evaluating markers of clinical efficacy are warranted. Clinical Trial Registration IdentifierNCT03899090

Fibromyalgia is an increasingly prevalent condition resulting in high morbidity and economic burden for sufferers. Minimal to modest benefit has been achieved by pharmacotherapies, creating a strong rationale for novel therapies. Substantial evidence has implicated the endocannabinoid system in the modulation of fibromyalgia symptoms. However, the therapeutic potential and potential adverse effects of cannabis-based therapy in fibromyalgia are still under-reported, leading to clinicians hesitation to opt for such therapy. This systematic review examined the literature and provided a critical review of the safety and efficacy of cannabis-based therapy in fibromyalgia. It resulted that medical cannabis is a safe and effective treatment option for fibromyalgia, whilst further research in this area is needed.

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant minority of patients, slow onset, minimal cognitive benefit, and side effects. Preclinical studies suggest selective serotonin 4 receptor (5-HT4R) agonists may produce faster antidepressant effects via distinct mechanisms, however there has been no experimental research in clinical populations to date. AimsTo test whether the novel 5-HT4R partial agonist PF-04995274 produces early behavioural and neural changes in emotional cognition similar to SSRIs in patients with unmedicated major depressive disorder (MDD). MethodIn a double-blind, placebo-controlled trial, 90 participants with MDD were randomised to 7 days of PF-04995274 (15 mg), citalopram (20 mg), or placebo. Emotional processing was assessed using a behavioural facial expression recognition task and fMRI of implicit emotional face processing (days 6-9). Observer- and self-reported symptoms of depression were also measured at baseline and study end. ResultsAs anticipated, citalopram reduced accuracy and reaction time for negative faces, with corresponding fMRI changes (reduced left amygdala activation to emotional faces and valence-specific shifts in cortical regions). In contrast, PF-04995274 produced no change in behavioural negative bias or amygdala activity but increased medial-frontal cortex activation across valences. While this was not a clinical trial, both active treatments reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety, and negative affect. No major adverse events occurred. ConclusionsPF-04995274 was not associated with the typical antidepressant profile of negative bias reductions seen with citalopram but was associated with distinct medial-frontal activation during an emotional faces task and displayed preliminary evidence of early clinical improvement, suggesting a potential alternative mechanism for antidepressant effects. Findings support further clinical trials of 5-HT4R agonists and investigation of pro-cognitive and mood effects. Clinicaltrials.gov registration numberNCT03516604. Data set informationAnalysis scripts and selected data will be available on publication.

The neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear-regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. Moreover, OT has been proposed to modulate activity of the autonomic nervous system. Here, we conducted a double-blind, placebo-controlled study with 56 men, to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electro-dermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a naturalistic two-person social context. In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the autonomic arousal response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (increased steepness of recovery slope), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness and high attachment avoidance, indicating that person-dependent factors play a pivotal role in determining OT treatment-responses. Behaviorally, OT significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself. Together, these observations add further evidence to a role of OT in reducing subjective and autonomic stress responses, primarily by facilitating restoration of homeostatic balance after (social) stress-induced perturbation.

ObjectiveExacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device. MethodsUsing a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n=25) using noninvasive sensing modalities. Participants received either sham or active tcVNS after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated. ResultsRelative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted {beta}=-5.7%; 95% CI: {+/-}3.6%, effect size d=0.43, p<0.01), increased photoplethysmogram amplitude (peripheral vasodilation) (30.8%; {+/-}28%, 0.29, p<0.05), and increased pulse arrival time (vascular function) (6.3%; {+/-}1.9%, 0.57, p<0.0001). Similar (p < 0.05) autonomic, cardiovascular, and vascular effects were observed when tcVNS was applied after mental stress or without acute stress. ConclusiontcVNS attenuates sympathetic arousal associated with stress related to traumatic memories as well as mental stress in patients with PTSD, with effects persisting throughout multiple traumatic stress and stimulation testing days. These findings show that tcVNS has beneficial effects on the underlying neurophysiology of PTSD. Such autonomic metrics may also be evaluated in daily life settings in tandem with tcVNS therapy to provide closed-loop delivery and measure efficacy. ClinicalTrials.gov Registration # NCT02992899 O_LSTHighlightsC_LSTO_LIWe studied the effects of tcVNS on physiological responses to stress in patients posttraumatic stress disorder (PTSD). C_LIO_LItcVNS modulates physiologic reactivity to traumatic and mental stress in PTSD, and modulates autonomic tone when applied without acute stress. C_LIO_LIRepeated tcVNS enhances resilience in the face of repeated stress in PTSD as quantified by peripheral autonomic measures which potentially could serve as real-time measures to evaluate the therapy response in longitudinal settings. C_LI

Major depressive disorder (MDD) imposes significant disability on patients. In addition to antidepressants, brain stimulation modalities such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) have been helpful in treatment of MDD. Novel TMS paradigms like theta burst stimulation (TBS) have rapidly become popular due to their effectiveness. Given that both antidepressants and TMS are commonly used together and affect neuroplasticity, we reviewed studies that administered both these as treatments for MDD. Unlike ECT wherein previous trials have shown that continuing pharmacotherapy is useful while giving ECT, there are no consensus guidelines on what to do with antidepressants when starting TMS. So, we reviewed two groups of studies - 1) those that administered TMS and antidepressant pharmacotherapy concurrently and 2) those wherein TMS augmented antidepressants or were an adjunctive intervention to antidepressants. We performed a meta-analysis for randomized clinical trials (RCTs) that administered TMS and antidepressants concurrently. We found ten RCTs fulfilling criteria 1 and compared uniformly titrated antidepressant regimens combined with active versus sham TMS. We also found twenty studies fulfilling criterion 2, that used TMS as an augmenting or adjunctive intervention. Both groups of studies showed TMS combined with antidepressants had greater efficacy for treatment of MDD. We advocate for laboratory studies examining the interaction between TMS and antidepressants in a parametric fashion; in addition to randomized controlled trials that examine this combination to expedite remission in MDD.

In recent years there has been a resurgence of interest in the therapeutic potential of psychedelic substances such as 3,4-methylenedioxymethamphetamine (MDMA). This renaissance of psychedelic studies opens the door for a new paradigm in psychiatric medicine: drug-facilitated psychotherapy. In this study we report the findings of a randomized, double-blind, placebo-controlled, multi-site Phase 3 clinical trial (NCT03537014) to test the effects of MDMA-assisted therapy (MDMA-AT) on patients with severe PTSD. The vast majority (85%) of individuals in this study reported having suffered early childhood trauma, which is strongly associated with deficits in emotional coping skills /altered self-capacities, which have been shown to constitute major obstacles to successful completion of currently available evidence-based treatments. Partcicipants were randomized 1:1 to receive manualized therapy with either MDMA or placebo with three preparatory and nine integrative therapy sessions. Symptoms were measured at baseline and at 2{square} months after the last experimental session with the Clinician-Administered PTSD Scale for DSM-5, the Toronto Alexithymia Scale (TAS_20), the Self Compassion Scale (SCS) and the Inventory of Altered Self-Capacities (IASC). MDMA-AT, compared with psychotherapy alone, significantly altered the domains of alexithymia, self-compassion, and altered self-capacities. These findings suggest that MDMA-AT can substantially improve transdiagnostic mental processes associated with poor treatment response.