European Neuropsychopharmacology

Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel group design comprising of 60 healthy participants who received either placebo (n=30) or 0.17 mg/kg psilocybin (n=30). Blood samples were taken to assess acute changes in immune status, and 7 days after drug administration. Seven days post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor- (TNF-), while other inflammatory markers (interleukin (IL)-1, IL-1{beta}, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF- concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF- were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin blunted the cortisol response compared to placebo. Such acute and persisting changes may contribute to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Serotonin is known to have state-dependent modulatory influences on exteroceptive sensory processes and the processing of pain, but much less is known about its role in ordinary interoceptive processes and their relationships to affective states. This experiment compared the impact of a selective serotonin reuptake inhibitor (SSRI) (20mg CITALOPRAM), acutely increasing extracellular serotonin, to that of a PLACEBO on the neural processing of ordinary interoceptive sensations and the relationship of these influences to anxious states. Twenty-one healthy young volunteers completed the visceral interoceptive attention (VIA) task with each treatment, focusing attention on heart, stomach, or visual sensation control while scanned with functional magnetic resonance imaging (fMRI). The relative neural interoceptive response (IR) to heart sensation [heart minus visual] and stomach sensation [stomach minus visual] were compared between treatment conditions, controlling for general effects on sensory processing. CITALOPRAM reduced interoceptive processing in viscerosensory (bilateral posterior insular cortex, stomach-IR) and integrative/affective components (bilateral amygdala, stomach-IR and heart-IR) of known interoceptive pathways. We then searched for state-dependent modulatory effects of CITALOPRAM that varied with current levels of anxiety. The anterior insular cortex response to heart sensation increased with anxiety, replicating prior findings. This relationship disappeared on CITALOPRAM. Preliminary post hoc exploration found that CITALOPRAMS effects on amygdalae response to stomach sensation predicted acute increases and decreases in anxiety. Overall, this evidence of general and state-dependent serotonergic influence advances our understanding of interoception, its regulation, and its relationship to anxious states.

Serotonin (5-HT) has long been implicated in adaptive emotion regulation as well as the development and treatment of emotional dysregulations in mental disorders. Accumulating evidence suggests that a genetic vulnerability may render some individuals at a greater risk for the detrimental effects of transient variations in 5-HT signaling. The present study aimed to investigate whether individual variations in the Tryptophan hydroxylase 2 (TPH2) genetics influence susceptibility for behavioral and neural threat reactivity dysregulations during transiently decreased 5-HT signaling. To this end, interactive effects between TPH2 (rs4570625) genotype and acute tryptophan depletion (ATD) on reactivity towards angry, neutral and happy faces were examined in a within-subject placebo-controlled pharmacological fMRI trial (n = 51). An a priori genotype stratification approach of extreme groups (GG vs. TT) allowed balanced sampling. While no main effects of ATD on neural reactivity to threat-related stimuli and mood state were observed in the entire sample, accounting for TPH2 genotype revealed an ATD-induced increase in subjective anxious arousal in the GG but not the TT carriers. The effects were mirrored on the neural level, such that ATD specifically reduced ventromedial prefrontal cortex (vmPFC) reactivity towards threat-related stimuli in the GG carriers. Furthermore, the ATD-induced increase in subjective anxiety positively associated with the extent of ATD-induced changes in vmPFC activity in response to threat-related stimuli in GG carriers. Together the present findings suggest for the first time that individual variations in TPH2 genetics render individuals susceptible to the anxiogenic and neural effects of a transient decrease in 5-HT signaling.

Ketamines rapid acting symptom relief make it a promising intervention for PTSD. However, the mechanisms driving its long-term efficacy over weeks and months remain poorly understood. This study investigated the short-and long-term impacts on gene expression of a six-week subanesthetic oral ketamine trial in 23 PTSD participants (9 males, 14 females). Peripheral Blood Mononuclear Cells (PBMCs) were collected at baseline, one week (short-term), and four weeks (long-term) post oral ketamine for RNA sequencing and transcriptome analysis. Differential expression analysis identified substantial and persistent transcriptomic changes over time, with 533 genes upregulated and 621 downregulated across timepoints. Notably, there was a 37% increase in differential gene expression between the short-and long-term responses, accompanied by a 6.5-fold rise in expression magnitude and an 8.8-fold enhancement in pathway activity. Pathway analysis emphasised critical immune and inflammatory pathways that appear to be modulated by ketamine, including interferon alpha/beta signalling (z = 4), IL-17 signalling pathway (z = 3.36), and cytokine storm signalling (z = 4.26), neutrophil degranulation (z = 6.0) and antimicrobial peptide signalling (z = 1.63) which differed across timepoints. The findings suggest a transition from short-term inflammation suppression and antimicrobial activity to long-term sustained immune regulation, inflammation remodulation and tissue repair. Key cytokines, chemokines, interferons and antimicrobial peptides included, IL-6, IL-1{beta}, IFI27, IL-10 signalling, CXCL8, SOCS1/3 and CAMP which represent central regulators of immune and inflammatory pathways. These molecular changes offer novel insights into the short-and long-term therapeutic potential of ketamine for PTSD and highlight avenues for precision psychiatry and individualised maintenance therapy to prevent relapse.

BackgroundMost women experience hot flashes (hot flushes) during the menopause transition. Menopausal hot flashes typically persist for years. For a sizeable minority of women, hot flashes are severe and substantially impairing. It is worthwhile to further investigate the genetic underpinnings of hot flashes. MethodWe conducted the largest trans-ancestry genome-wide association study (GWAS) of hot flashes available to date (N=149,560). We used self-assessment of hot flashes in the Nurses Health Study, Nurses Health Study II, Womens Health Initiative, and Queensland Institute of Medical Research samples (total n=42,489). In one sample (UK Biobank, n=107,071) direct assessment of hot flashes was not available, so menopausal hormone therapy was used as a proxy variable. We estimated the heritability of hot flashes and genetic correlations with psychiatric phenotypes using linkage disequilibrium score regression (LDSR). ResultsIn component analyses and our trans-ancestry meta-analysis, the top locus was on chromosome 4 in the neurokinin 3 receptor gene (TACR3, position 104,556,732, trans-ancestry p=7.2x10-41). A second novel locus was identified (LINC02428, p=3.5x10-8). Gene results implicated TACR3, GRID1, NUDT4, and PHF21B. Using the hot flash GWAS meta-analysis (n=42,489; i.e., no proxy variable), SNP heritability was estimated: h2liab=.08 (h2SNP=.04, se=.02). Genetic correlations were statistically significant between hot flashes and posttraumatic stress disorder (PTSD, rg=0.25, p=0.01), schizophrenia (rg=0.17, p=0.02), and depression (rg=0.21, p=0.01). DiscussionThese genomic findings are consistent with independent, robust basic science research which led to a novel treatment for hot flashes, namely, neurokinin 3 receptor antagonists. This new class of hot flash drugs blocks the receptor (neurokinin 3 receptor) coded for by the top locus for hot flashes (TACR3). This GWAS of hot flashes provides an uncommonly clear example of how GWAS findings can point to potent treatment targets for complex brain phenotypes. We also found that the proxy variable (menopausal hormone therapy) pointed to the same target (TACR3), and that exclusively intronic and intergenic variants signaled this target.

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.

Major depressive disorder (MDD) impacts females and males differently and post-mortem gene expression profiling reveals distinct transcriptomic signatures of the disorder in each sex. Using genes that are transcriptionally altered in MDD in both sexes, we recently developed a novel transcriptome-based polygenic risk score (tPRS), which had sex-specific associations with brain structure and depressive symptoms in both adolescents and adults. Identifying the neurodevelopmental signatures of genetically-induced shifts toward a depression-like brain transcriptome in each sex during a crucial stage, when sex differences in MDD vulnerability initially manifest, could provide useful information about the developmental pathways of early MDD risk. Leveraging sex-specific MDD gene expression data, we sought to develop female- and male-specific tPRSs (tPRS-F and tPRS-M, respectively) and evaluate their impact on regional cortical thickness, cortical surface area, subcortical volume, and depressive symptoms at baseline and 2-year follow-up in a developmental sample of 5002 adolescents (46.6% female, aged 8.9-11.0). In males, tPRS-M was associated with higher depressive symptoms at both timepoints and thicker left posterior cingulate at follow-up. In females, tPRS-F was associated with lower volumes of the right accumbens area, right caudate, and bilateral hippocampi at follow-up. Subcortical volumes of the right caudate and right hippocampus further mediated an indirect effect of tPRS-F on depressive symptoms. For each sex-specific PRS, no effects emerged in the opposite sex. Our findings suggest that sex-specific depression-like shifts in gene expression may contribute to unique vulnerability phenotypes for future MDD risk via distinct mechanisms in each sex.

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.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood neuropsychiatric conditions. Both (epi)genetic and environmental factors are suggested to contribute to the aetiology of ADHD. In the last decade, nutrition has received considerable attention as potential environmental factor triggering ADHD behaviour. Studies applying a few-foods diet (FFD) can lead to behavioural improvements of at least 40% in 50-64% of children with ADHD. It is conceivable that the Microbiota-Gut-Brain (MGB) axis is involved in the mechanism of action underlying the behavioural improvements observed in children with ADHD after following the FFD. This study investigated potential associations between changes in ADHD symptoms in children that followed an FFD. We identified a significant association between microbiota composition and change in ADHD symptoms in food-associated ADHD.

BackgroundKetamine has emerged as a rapid-acting therapeutic option for post-traumatic stress disorder (PTSD); however, its ability to sustain long-term therapeutic outcomes remains poorly understood. Identifying molecular biomarkers predictive of a sustained response to ketamine may enhance personalised treatment strategies. This study investigates the epigenetic and transcriptomic precursors underpinning ketamines long-term therapeutic efficacy in PTSD. MethodsThis study utilised data from the Oral Ketamine Trial of PTSD (OKTOP), an open-label, dose-ranging clinical study conducted between 2021 and 2024. Baseline differential DNA methylation and gene expression profiles of sustained responders (clinical response >1 month post-ketamine treatment) were compared against non-responders. Epigenomic and transcriptomic analyses were performed to identify differentially regulated genes associated with ketamine response. ResultsBaseline molecular analyses revealed significant differential methylation and transcriptomic profiles across 112 genes. Key biomarkers included DENND5B (cg02046589), ZFY (cg00272582), PDGFRA (cg21309167), CPT1A (cg10098373), AHRR (cg26076054), RPH3AL (cg17316718), CHI3L1 (cg19081101), UTY (cg04790916), LDHD (cg00004883), TBC1D16 (cg26287152), FAM66A (cg23285059), NME8 (cg02531859), EIF1AY (cg13308744), PCBP3 (cg13695288), PAQR6 (cg03954786), KCNK17 (cg19475903), PLPP2 (cg24452451), ANK1 (cg23668222), LINC00200 (C10ORF139, cg19282259), ALAS2 (cg07471703), ZBP1 (cg06305758), TACSTD2 (cg01821018), and PLEKHH3 (cg24455236). These biomarkers were implicated in pathways related to metabolism, transcriptional regulation, cell signalling, neuronal development, immune response, synaptic plasticity, and cytoskeletal organisation. Non-responders exhibited persistent dysregulation across these pathways, suggesting potential biological barriers to treatment efficacy. Clinically, sustained responders presented with higher baseline PTSD severity and demonstrated a response at lower ketamine doses compared to non-responders. ConclusionsThis study highlights the potential of methylomic and transcriptomic profiling to identify functional biomarkers predictive of ketamine response in PTSD. The observed molecular distinctions between responders and non-responders suggest a complex interplay between clinical presentation and treatment outcomes. These findings contribute to advancing precision medicine approaches for PTSD by informing biomarker-driven treatment stratification and optimisation of ketamine therapy.

The hypothalamic-pituitary-adrenal axis (HPA axis) is an important part of the stress response. The HPA axis may adapt to the environment in part through epigenetics, including DNA methylation. This pre-registered (OSF), PRISMA-compliant systematic review and meta-analysis aimed to evaluate the level of evidence for an association between DNA methylation and the cortisol response to an acute psychological stressor, a key marker of HPA axis function, in humans. PsycINFO, MEDLINE, Scopus, and Web of Science were searched on the 1st of September 2025 and risk of bias was evaluated using an original rubric. Thirty-nine studies were included, with mixed results. Meta-analyses revealed support for an association between NR3C1 methylation and a stronger cortisol response in infants (r = .26, p = .01), but not other age groups (r = -.01, p = . 85). There was some tentative evidence for an association between SLC6A4 methylation and a weaker cortisol response (r = -.15, p = .056), but the effect was not significant. There was preliminary (non-meta-analytic) support for LEP, NR3C2, OXTR, and SKA2. The mixed results may be a product of confounding, small sample sizes, and candidate gene methods. They may also reflect a true but complex relationship, observable only in certain populations (e.g., infants) or in conjunction with other biological or environmental factors (e.g., antidepressants). We propose several directions for research, including a collaborative, pre-registered meta-analysis and a focus on genomic loci that may be more strongly correlated between brain and peripheral tissue. This review received no specific funding.

While nitrous oxide (N2O) has demonstrated antidepressant properties in treatment-resistant major depression (TRD), little is known about neural mechanisms mediating these effects. Employing serial resting-state functional magnetic resonance imaging (rs-fMRI), we compared spatiotemporal effects of inhaled N2O on brain functional connectivity in TRD patients (n=14) and non-depressed healthy controls (n=16, CNTL). Participants received sequential, one-hour inhalations of either 50% N2O/oxygen or air/oxygen (placebo), with sessions separated by at least one month in random cross-over order. BOLD-contrast rs-fMRI scans were acquired at three time points: pre-inhalation, 2 hours post-inhalation, and 24 hours post-inhalation. For the rs-fMRI functional connectivity analyses, five a priori seeds in medial limbic structures targeted cortical networks implicated in major depression - the salience, anterior and posterior default mode, reward, and cingulo-opercular networks - and a nexus in the dorsal paracingulate region previously identified in MDD ("dorsal nexus"). Depression, dissociation, and psychosis assessments were made before and after inhalations. In TRD patients, functional connectivity was reduced in all seeded networks and the voxel-wise global analysis after N2O exposure. N2O progressively decreased connectivity in patients with TRD but increased connectivity in healthy controls. In TRD patients, each seeded network demonstrated post-inhalation functional connectivity reductions in the dorsal paracingulate gyrus ("dorsal nexus"). This study further elucidates neural mechanisms underlying the antidepressant properties of N2O, supporting the notion that N2O specifically alters mood-associated brain regions in the depressed brain state by reducing functional connectivity within these brain networks. The trial was registered at ClinicalTrials.gov (NCT02994433). One sentence summaryNitrous oxide reduces long-range functional brain connectivity in treatment-resistant major depression, which may underlie its antidepressant action.

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.

Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT1A) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [carbonyl-11C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n=8 and n=3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted in excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere time and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group time and HAMD on 5-HT1A receptor specific binding VS. While post-hoc comparisons showed no significant changes of 5-HT1A VS in either group, higher 5-HT1A VS after treatment correlated with greater difference in HAMD (r=-0.62), indicative of potential effects of TBS on the 5-HT1A receptor. Due to the small sample size, all results, however, must be regarded with caution.

Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants. We performed genome-wide association meta-analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified two novel loci associated with non-response to antidepressants and showed significant polygenic prediction in independent samples. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants.

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.

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.

Classical psychedelics have regained interest for their potential to treat psychiatric and neurological disorders, and explore neural mechanisms supporting perception, cognition, and mood. Acute psychedelic effects have been linked to increases in brain complexity and entropy, but it is unclear if these changes are specific to psychedelics or reflect more general psychoactive effects. Here, we examined whether brain complexity and entropy metrics can identify features specific to the psychedelic state. Using resting-state fMRI from three placebo-controlled crossover trials (N=79; 255 sessions), we compared LSD, psilocybin, and mescaline with psychostimulants MDMA and d-Amphetamine. Compared to stimulants, psychedelics produced significant increases in meta-state complexity, short-timescale multiscale entropy, and dynamic conditional correlation entropy. Both drug classes increased Lempel-Ziv and spatial complexity, and decreased absolute modularity. Our findings highlight psychedelic-specific effects on brain signals that distinguish the acute psychedelic state from other psychoactive drug effects and may be relevant for understanding their therapeutic potential.

Antidepressant treatments are theorised to act by inducing a positive bias in information processing early on during treatment. Here, we tested for the first time whether this theory generalises to transcranial magnetic stimulation (TMS) treatment, an effective therapy for treatment-resistant depression. 49 patients with major depression received 20 sessions of open-label intermittent theta-burst stimulation applied to left dorsolateral prefrontal cortex. At baseline and after eight stimulation sessions, positive bias was assessed using behavioural and functional magnetic resonance imaging tasks presenting emotional faces. Clinical improvement at the end of treatment was related to an early increase in positive bias (1) in misclassification of emotional faces, (2) in the response of the default mode network (DMN) to emotional faces including rostral anterior cingulate cortex (ACC), and (3) in connectivity between rostral ACC and DMN. These neural changes predicted clinical improvement at the end of treatment beyond early symptom reduction. The results suggest that TMS treatment increases positive bias early on during treatment, and that the neural mechanisms might differ from that of antidepressant drugs.

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.