OBJECTIVE:This frequentist network meta-analysis was conducted to compare vornorexant (VOR) and lemborexant (LEM) in terms of efficacy, tolerability, and safety outcomes in adults with insomnia disorder. METHODS:Efficacy outcomes evaluated at weeks 1 and 2 included subjective time to sleep onset (sTSO), which served as the primary outcome at week 2, as well as subjective total sleep time (sTST), subjective wake after sleep onset (sWASO), and subjective sleep efficiency. Tolerability outcome was treatment discontinuation due to adverse events. Safety outcomes included the incidence of death, suicidal behavior or ideation, at least one adverse event, somnolence, fatigue, dizziness, falls, headache, nightmares, cataplexy, and sleep paralysis. RESULTS:This network meta-analysis included seven trials (n = 2805, average age = 55.14 years, 69.22% female). Treatment arms comprised VOR 5 mg/day (VOR5), VOR 10 mg/day (VOR10), LEM 5 mg/day (LEM5), LEM 10 mg/day (LEM10), and placebo. All active treatments were associated with significantly greater improvements in sTSO at week 2 than placebo. The mean differences in sTSO at week 2 were -11.997 min (95% CI, -15.236 to -8.757) for LEM5, -14.856 min (95% CI, -18.038 to -11.674) for LEM10, -11.364 min (95% CI, -14.733 to -7.996) for VOR5, and -9.758 min (95% CI, -13.186 to -6.330) for VOR10. LEM5, LEM10, and VOR5 demonstrated significant improvements across all efficacy outcomes at weeks 1 and 2 over placebo. However, although VOR10 did not demonstrate superiority over placebo for sWASO at weeks 1 and 2, it was superior to placebo for all other efficacy outcomes. LEM5 and LEM10 were associated with a higher incidence of at least one adverse event and somnolence compared with placebo, whereas no significant differences in tolerability or safety outcomes were observed for VOR5 or VOR10 versus placebo. CONCLUSIONS:Dosage variations could influence both the clinical efficacy and safety profile of these agents.
OBJECTIVE:To determine the effect that paliperidone palmitate 6-month long-acting injectable formulation (PP6M) had on metabolic parameters including body weight (BW), and blood lipid profiles, a post-hoc analysis was conducted to assess changes in BW from baseline to the end of study based on age, body mass index (BMI), and changes in blood lipid profiles during a 12-month, phase 3, double-blind (DB) clinical study. Long term effects of PP6M on BW and BMI were further explored during a 24-month extension study in which participants were treated exclusively with PP6M. METHOD:In the 12-month DB phase, participants were randomized to receive PP6M or paliperidone palmitate 3-month long-acting injectable formulation (PP3M). The mean change in BW and abnormal weight percent change from baseline were calculated at endpoint by age, gender, and BMI. Additionally, treatment-emergent shifts from baseline for the four key lipid parameters (fasting low density lipoprotein [LDL], fasting triglycerides [TG], fasting total cholesterol [TC], and fasting high density lipoprotein [HDL]) during DB were assessed. Following this study, participants were given the opportunity to transition to a 24-month extension study and be treated with PP6M. The mean change and percent change in BW, and the mean change in BMI from DB baseline to the end of the extension study (36 months total) were calculated. RESULTS:Participants who were treated with PP6M showed numerically less weight gain, BMI, waist circumference, and more weight decrease compared to PP3M group during 12-month DB phase, though the proportion of participants reporting an abnormal change (≥7% change) in BW did not significantly differ between PP3M and PP6M. The weight differences were more pronounced in the younger age group (18-25 years) and those who were overweight (BMI: 25 to <30 kg/m2. Numerical differences in favor of PP6M were found in fasting blood lipids (HDL, LDL, TG, and TC). The changes in BW and BMI over time remained consistent throughout the 24-month extension, favoring PP6M in each instance. CONCLUSIONS:This post-hoc analysis demonstrated that PP6M was comparable to PP3M in terms of metabolic parameters; however, it may have a beneficial effect on weight gain, especially in young patients. TRIAL REGISTRATION:Post-Hoc Analysis of Studies NCT03345342 and NCT04072575 (ClinicalTrials.gov). Significant outcomes The findings from this study have highlighted that participants who were treated with the 6-month long-acting injectable formulation of paliperidone exhibited less weight gain during treatment overall, and significantly less weight gain in adolescents and young adults. Importantly, this trend continued over the course of long-term treatment, regardless of age. Participants treated with the 6-month formulation also had fewer shifts in blood lipids outside of the normal range and had more favorable changes in body mass index and waist circumference. These results suggest that when considering metabolic dysregulation as a factor in choosing a long-acting injectable antipsychotic, the 6-month formulation is a viable alternative to the 3-month formulation, particularly in younger patients with schizophrenia. Limitations Because this is a post hoc analysis and the study was not powered to test weight and metabolic changes, most endpoints were summarized descriptively and the statistical test was limited to the main endpoint (abnormal percent weight gain and loss).
From early life to adulthood, stress shapes brain circuits by impacting vulnerable neuronal populations, with parvalbumin-expressing interneurons (PVIs) emerging as particularly sensitive targets. These fast-spiking interneurons orchestrate inhibitory control, maintain excitatory/inhibitory balance, and regulate network oscillations, all of which are crucial for cognitive and emotional function. In addition, PVIs play a central role in regulating stress vulnerability and resilience. Several cellular and molecular mechanisms have been implicated in stress-induced PVI deficits, including disrupted developmental trajectories, redox and metabolic vulnerabilities, inflammatory and microglia-associated signaling, and epigenetic modulation. Stress also remodels perineuronal nets (PNNs), specialized extracellular matrix structures that enwrap PVIs and contribute to their stabilization, the regulation of synaptic function, and protection against oxidative stress. This review synthesizes evidence from rodent models of stress, detailing putative mechanisms through which stress alters PVIs, their associated PNNs, and their circuit-level consequences across development and brain regions, including sex-dependent effects. It further discusses pharmacological and adjuvant interventions that may mitigate stress-induced PVI dysfunction, including monoaminergic modulators, ketamine and its derivatives, as well as anti-inflammatory and antioxidant strategies. By integrating mechanistic insights with potential strategies to protect or restore PVI function, we aim to provide a framework for understanding and reducing stress-induced psychiatric outcomes.
BACKGROUND:Major depressive disorder (MDD) is characterized by depressed mood, anhedonia, and loss of energy, which can be accompanied by associated symptoms and co-morbidities. Psychiatric scales such as the Montgomery Åsberg Depression Rating Scale (MADRS) must account for the complex nature of depression. METHODS:The MADRS total score change between baseline and week 8 was the primary outcome measure in a randomized, double-blind clinical trial investigating the antidepressant efficacy of 8 weeks' treatment with silexan compared to sertraline and placebo in patients with mild or moderate MDD. We report on a pre-planned, exploratory analysis of the individual MADRS items. Treatment effects were assessed using analyses of covariance with baseline adjustment, based on an estimand strategy. RESULTS:498 subjects (silexan 170, sertraline 171, placebo 157) were treated and analyzed. After 8 weeks, silexan was superior to placebo for 5 out of the 9 MADRS items analyzed ("apparent sadness", "reported sadness", "reduced appetite", "concentration difficulties", "lassitude"; P < .05) and showed clinically important adjusted mean value differences >0.2 points for 7 out of the 9 items. Item-level results for silexan and sertraline were mainly comparable. CONCLUSIONS:Silexan had a strong over-all antidepressant effect, with the most pronounced improvements affecting the cardinal symptoms of depression. TRIAL REGISTRATION:EudraCT2020-000688-22 first entered on 12/08/2020. Significance statement Patients with depressive disorders can show many different symptoms. To better characterize the clinical action of an antidepressant, it is therefore important to analyze not only the overall value of a depression scale but also the individual items that describe these symptoms. Silexan is a preparation from lavender oil whose antidepressant effect has been proven in a randomized, double-blind, placebo-controlled 8-week study in patients with mild or moderate major depressive disorder. Based on the individual items of the Montgomery Åsberg Depression Rating Scale that was used as the main outcome for efficacy, we found in an exploratory, hypothesis-generating analysis that silexan had a rather broad antidepressant effect in the participants of our study, with potentially clinically meaningful advantages over placebo for 7 out of the 9 individual items investigated. This applied in particular to the main symptoms of depression, namely sadness and lassitude. Our single-item analysis thus helps to understand the antidepressant effects of silexan in more detail. Significant outcomes In patients with mild to moderate major depressive disorder, lavender oil preparation silexan has a clinical profile similar to that of the selective serotonin re-uptake inhibitor sertraline based on an item-level analysis of the Montgomery-Åsberg Depression Rating Scale (MADRS). Silexan has a significant antidepressant effect that includes an alleviation of depressed mood, anhedonia, and loss of energy, the cardinal symptoms of depression. The broad improvement of symptoms of depression could not be explained by the proven anxiolytic efficacy silexan alone but indicates an independent, direct antidepressant effect. The present item-level analysis provides valuable and detailed additional insights into the therapeutic profiles of silexan and sertraline and may help clinicians to tailor antidepressant treatment to the specific symptoms of a patient. Limitations For item-level analyses of the MADRS, no validated thresholds for the assessment of the clinical importance of changes over time have been defined, taking into account that different items may have different thresholds. Even though our analyses were pre-defined, they were exploratory and did not include studywise type I error level control. Their generalizability beyond the study population is therefore limited.
Major depressive disorder (MDD) is frequently accompanied by residual symptoms such as anxiety and sleep disturbances, even after adequate antidepressant treatment. Brexpiprazole, a serotonin–dopamine activity modulator, has shown efficacy as adjunctive therapy for MDD. However, its mechanistic contribution to anxiety and sleep regulation remains unclear. This study aimed to evaluate the combined effects of brexpiprazole and paroxetine, a selective serotonin reuptake inhibitor (SSRI), on anxiety-like behavior and sleep architecture in mice. We used male Crl:CD1 and C57BL/6J mice. Anxiety-like behavior was assessed using the marble-burying behavior (MBB) test using Crl:CD1 mice. We also evaluated locomotor activity monitored to exclude sedative effects. Sleep architecture was evaluated via cortical electroencephalography and electromyography, quantifying Wake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep stages using C57BL/6J mice. In MBB test, paroxetine reduced buried marbles without affecting locomotor activity, whereas brexpiprazole alone was ineffective. The combination of brexpiprazole (0.1 mg/kg) and paroxetine (0.75 mg/kg) significantly decreased buried marbles. Next, to explore the role of α2C adrenoreceptor (AR) antagonism, JP-1302 (a selective α2C AR antagonist) was also tested. Similarly, JP-1302 (30 mg/kg) combined with paroxetine (0.75 mg/kg) decreased buried marbles. In sleep architecture, brexpiprazole dose-dependently decreased Wake and increased NREM sleep, while paroxetine primarily reduced REM sleep. Combined administration decreased Wake and REM sleep and increased NREM sleep. The combination showed effects comparable to each drug administered alone. In this study, we demonstrated that the combination of brexpiprazole and paroxetine produced anxiolytic-like effects and altered sleep architecture in mice. Furthermore, the anxiolytic-like effect of the combination suggests that brexpiprazole’s α2C AR antagonistic activity may be one of several plausible contributors. Adjunctive brexpiprazole may influence anxiety and sleep architecture, potentially contributing to the management of residual symptoms in MDD.
OBJECTIVE:Efficacy of viloxazine ER (extended-release capsules; Qelbree®) for attention-deficit/hyperactivity disorder (ADHD) is attributed to its ability to increase extracellular norepinephrine and dopamine in the medial prefrontal cortex by inhibiting norepinephrine transporters (NET); however, studies also suggest potentially relevant activity at serotonin (5-HT) receptors. In this study, we evaluated the target engagement by viloxazine at 5-HT2 receptor subtypes, in species with close similarities with humans, and whether viloxazine engages 5-HT2 receptor subtypes within a clinically relevant plasma concentration range. METHODS:This study utilized positron emission tomography (PET) and was conducted to measure the relationship between viloxazine plasma concentration and the changes in binding of the agonist radioligand [11C]CIMBI-36 to 5-HT2C/5-HT2A receptors in the brain of Macaca fascicularis monkeys. RESULTS:Viloxazine administration reduced the binding of [11C]CIMBI-36 at 5-HT2C receptors at a concentration 10- to 20-fold lower than at 5-HT2A receptors (EC50: 4.1 vs 45.1 μM, respectively), consistent with receptor binding affinities previously measured in vitro (Ki: 0.66 vs 16.0 μM, respectively). Unbound viloxazine plasma concentrations during these PET scans were compared to human unbound concentrations at doses used to treat ADHD. Our data suggest that at clinically relevant plasma concentrations, viloxazine occupies 60%-72% of 5-HT2C receptors. CONCLUSION:Our results demonstrate that at unbound viloxazine plasma concentrations comparable with those clinically relevant for the treatment of ADHD, viloxazine occupies a high proportion of 5-HT2C receptors. Occupancy of and potential functional activity at 5-HT2C receptors could therefore contribute to the therapeutic activity of viloxazine in addition to inhibition of NET.
BACKGROUND:This study was to explore how serum ghrelin levels modulate the relationship between interleukin-6 (IL-6) and outcomes of antidepressant treatment, specifically focusing on 12-week remission and 24-month relapse in patients with depressive disorders. METHODS:This investigation involved the analysis of baseline serum levels of ghrelin and IL-6 among 1086 patients enrolled in a naturalistic study of stepwise antidepressant therapy. Remission was determined by a Hamilton Depression Rating Scale (HAMD) score of 7 or less at 12 weeks. Those who responded (HAMD score ≤ 14) at this juncture were subsequently monitored for relapse (HAMD score > 14) quarterly over a 24-month period. The study employed logistic regression models, adjusted for various sociodemographic and clinical factors, to evaluate the interaction between these biomarkers and treatment outcomes. RESULTS:Findings revealed that while serum ghrelin levels did not independently affect treatment outcomes, they significantly influenced the association between elevated IL-6 levels and the risks of non-remission at 12 weeks and relapse at 24 months. Specifically, high IL-6 levels correlated with poorer outcomes predominantly in the presence of lower ghrelin levels, with these interactions reaching statistical significance in relapse outcomes post-adjustment. CONCLUSION:The study highlights the complex interplay between IL-6 and ghrelin in shaping the efficacy of antidepressant treatments, demonstrating divergent influences on remission and relapse. These results emphasize the importance of incorporating multiple biomarkers into predictive models to tailor antidepressant strategies more effectively. Continued research is needed to dissect the underlying dynamics of these biomarker interactions.
The therapeutic potential of psychedelics is currently being explored in a range of neuropsychiatric conditions. Nevertheless, their designation as Schedule 1 substances causes substantial regulatory and economic barriers to research. Rigorous human mechanistic studies are required to address the critical knowledge gaps surrounding the mechanisms underlying the putative treatment effects of psychedelics. This article presents practical guidance for navigating challenges relating to study design, legislation, and drug sourcing, to assist researchers in navigating the complex process of setting up human psychedelic studies, drawing on our experience of setting up non-clinical studies in the United Kingdom, while acknowledging that some of the content will be relevant for investigator-initiated studies more broadly.
OBJECTIVE:Secondary Restless Legs Syndrome (RLS) has repeatedly been associated with psychopharmacotherapy, especially antidepressants and antipsychotics. However, existing evidence is conflicting in terms of the magnitude of the association as well as the significance of substance classes or individual compounds. The objective of the present study was to evaluate secondary RLS linked to psychotropic medication in real-world, inpatient clinical routine treatment settings. METHODS:A large dataset from a multinational pharmacovigilance program in German-speaking countries (Arzneimittelsicherheit in der Psychiatrie, "Drug safety in Psychiatry") from January 2001 to December 2016 was retrospectively analyzed. RESULTS:In a total of 340 099 monitored inpatients, 67 cases of newly diagnosed and severe RLS related to psychotropic drug treatment were recorded equivalent to a relative frequency of 0.02%. Over 80% of the cases were attributable to two compounds: the antidepressant mirtazapine and the antipsychotic quetiapine. Mirtazapine was found in 39 patients, while quetiapine was found in 16 patients with secondary RLS. For both substances, drug dosages were generally low at onset of secondary RLS. Most cases exhibited an onset within 1 or 2 days after dosage start or change. CONCLUSION:Histamine neurotransmission may represent a crucial common denominator in terms of secondary RLS in association with psychopharmacotherapeutics, as both substances exhibit antihistamingeric effects at lower dosages.
BACKGROUND:Patients with chronic cluster headache (CCH) suffer from poor sleep, which may impact their brain microstructure and parenchymal clearance of waste products. Psilocybin has shown promise for the treatment of CCH and has been linked to increased neuroplasticity with possible influences on brain microstructure. AIMS:To investigate the effects of psilocybin on sleep, brain water diffusivity, and microstructure in CCH. METHODS:Eleven CCH patients underwent diffusion-weighted MRI and subjective sleep quality assessment with the Pittsburgh Sleep Quality Index (PSQI) before and 1 week after three psilocybin administrations (0.14 mg/kg) spaced 1 week apart. Measures taken prior to intervention were also compared to 24 healthy controls, and subjective sleep quality was related to brain microstructure and diffusivity across groups. RESULTS:We found that sleep was poor in CCH patients, but improved after psilocybin treatment (CCH mean PSQI change (SD) = -2.50 (2.1), pFWER = 0.015). When analyzing brain microstructure and water diffusivity in conjunction, we found differences between CCH patients and controls, which were primarily driven by differences in grey matter. On average, psilocybin intervention in CCH patients was not associated with statistically significant changes in brain microstructure or water diffusivity. However, most patients exhibited lower white matter diffusivity and neurite volume after intervention. Subjective sleep quality showed borderline significant correlations of moderate effect size with brain microstructure and water diffusivity. CONCLUSION:Subjective sleep quality improved in CCH patients after psilocybin and showed some evidence of an association with measures of brain microstructure and water diffusivity. CLINICALTRIALS:gov identifiers:Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH; NCT04280055) and The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2; NCT03289949).
INTRODUCTION:Clozapine is the gold-standard therapy for resistant schizophrenia. However, its use is limited by risks such as clozapine-induced agranulocytosis (CIA) and neutropenia (CIN), requiring strict monitoring. This study aimed to estimate the prevalence and mortality of CIA and CIN at GHU Paris Psychiatrie & Neurosciences and identify risk factors. METHODS:This retrospective study used data from the health data warehouse. We selected all patients treated with clozapine between January 1, 2019, and December 31, 2024. Based on the absolute neutrophil count (ANC), we identified cases of CIA (ANC < 500/mm3) and CIN, classified as mild (ANC = (1000-1499/mm3)) or moderate (ANC = (500-999/mm3)). We then investigated risk factors using ordinal adjacent categories regression. RESULTS:Among 1768 patients treated with clozapine, we identified 5 cases of CIA (prevalence: 0.28%), with no fatalities, and 163 cases of CIN (prevalence: 9.22%), including 36 moderate cases. African origins increased the risk of mild neutropenia (OR: 2.617; 95% CI: 1.327-5.163), while a higher ANC before treatment introduction decreased the risk (OR: 0.352; 95% CI: 0.229-0.542). Regarding the progression from mild to moderate neutropenia, receiving an anxiolytic treatment and being older than 49 years old significantly decreased the risk (OR: 0.189, 95% CI: 0.042-0.86; OR: 0.139, 95% CI: 025-0.772, respectively). Treatment was discontinued in 44% of the patients with neutropenia, and 53% were rechallenged with clozapine. CONCLUSION:Our study provides further evidence that CIA is a rare side effect. Given the benefits of clozapine and the rarity of agranulocytosis, our results suggest a looser approach to hematological monitoring and support the new French and US guidelines.
OBJECTIVE:Cannabis-nicotine co-use is common and may affect cessation outcomes, yet whether recent cannabis exposure alters nicotine's acute effects in humans remains unclear. We examined whether recent, non-daily cannabis exposure modulates the acute subjective effects of intravenous (IV) nicotine. METHODS:We pooled data from 2 randomized, double-blind, placebo-controlled studies using IV nicotine to isolate nicotine's pharmacodynamics in adults who smoke tobacco cigarettes (N = 60). Participants completed 3 sessions (placebo, 0.1 mg, 0.2 mg nicotine/70 kg). Recent cannabis exposure was defined a priori (past-30-day use with positive urine 11-nor-9-carboxy-delta-9-tetrahydrocannabinol vs no past-30-day use with negative screen). Primary outcomes were peak Drug Effects Questionnaire (DEQ) composites-stimulatory, pleasurable, aversive-within 10 minutes post-infusion. Secondary outcomes included nicotine self-administration behavior (proportion of nicotine choices) and cardiovascular responses (heart rate, blood pressure). Linear mixed-effects models included dose, cannabis exposure, sex, and FTND. RESULTS:Nicotine increased all DEQ domains dose-dependently (P < .0001). Aversive effects showed a significant dose x cannabis exposure interaction (χ2 = 13.31, P = .001): participants with recent cannabis exposure reported greater aversive responses at 0.2 mg (Cohen's d' = 0.83), with minimal between-group differences at placebo/0.1 mg. Nicotine self-administration did not differ by cannabis exposure status, and no dose x cannabis exposure interactions were observed for cardiovascular responses. CONCLUSIONS:Recent, non-daily cannabis exposure is thus associated with selectively greater aversive responses to a clinically relevant IV nicotine dose, without differential cardiovascular reactivity or altered nicotine choice. These findings support a shift in the aversive limb of nicotine's dose-response and inform mechanistic and clinical studies on how cannabis exposure shapes nicotine reinforcement and cessation outcomes. CLINICAL TRIAL REGISTRATION:NCT01495819, https://clinicaltrials.gov/study/NCT01495819.
Background: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent, short-acting psychedelic, induces profound shifts in cognition, affect, and self-awareness. Because language explicitly expresses these domains and voice implicitly conveys them, both may serve as potential ‘biomarkers’ of behavioural change. Aim: This study introduces a novel framework for analysing baseline language and vocal features, pre- to post-psychedelic changes, and assessing their potential to predict subjective experiences and psychological outcomes. Methods: Daily voice journals from 29 participants were collected via “RetreatBot” for 2 weeks before and after 5-MeO-DMT (1 × 12 mg). Transcripts were analysed using natural language processing (bag-of-words for vocabulary; transformer model for textual affect), and acoustic features (e.g. pitch, jitter, shimmer) were extracted to assess vocal dynamics. Results: Following 5-MeO-DMT, speech markers revealed increased cognitive language, decreased social words, and altered voice quality (increased jitter/shimmer). Baseline speech patterns predicted psychedelic preparedness, emotional breakthrough, and post-experience well-being. Conclusion: This first longitudinal analysis of speech markers surrounding a psychedelic retreat reveals a shift from external focus to introspection. Speech markers predicted and tracked psychological transformation surrounding the 5-MeO-DMT retreat experience, establishing vocal journaling as a valuable framework for monitoring changes during the “preparation” and “integration” periods.
BACKGROUND:Depression is a major global health problem, the pathogenesis of which remains to be elucidated, and current antidepressants exhibit limited efficacy. FK506-binding protein 51 (FKBP51) has been identified as a key modulator of stress-related psychiatric disorders, yet further research is required in depression. METHODS:We investigated the role of hippocampal FKBP51 using a chronic unpredictable mild stress rat model and stereotaxic FKBP5 overexpression. The antidepressant effect of the FKBP51 inhibitor, selective antagonist of FKBP51 by induced fit 2 (SAFit2), was evaluated in corticosterone-induced depression model both in vivo and in vitro. Molecular and structural changes were analyzed using quantitative polymerase chain reaction, Western blotting, Golgi-Cox staining, transmission electron microscopy, and immunofluorescence. SH-SY5Y cells were utilized to examine autophagic flux and dissect downstream pathways. RESULTS:Hippocampal FKBP51 was upregulated in chronic unpredictable mild stress-susceptible rats and correlated with depressive-like behaviors. Functionally, FKBP5 overexpression mimicked stress pathologies, inducing autophagic hyperactivation and suppressing AKT/mTOR signaling. Mechanistically, corticosterone enhanced the recruitment of the phosphatase PHLPP to FKBP51, thereby inhibiting the AKT/mTOR pathway. SAFit2 treatment disrupted the FKBP51-PHLPP interaction, reactivated the AKT/mTOR pathway, normalized autophagic flux, restored neuroplasticity, and attenuated depressive-like behaviors. CONCLUSIONS:Stress-induced FKBP51 upregulation drives depressive-like behaviors in male rats by impairing neuroplasticity and inducing autophagic hyperactivation via the PHLPP-AKT-mTOR pathway. SAFit2 exhibited antidepressant-like effects by targeting this axis, highlighting FKBP51 as a potential target for depression.
Background: Brain function is the dynamic output of coordinated excitatory and inhibitory (E-I) activity. E-I alterations, arising from differences in excitatory glutamate and inhibitory GABA pathways, are implicated in the development and heterogeneity of autism, and are consequently targets for pharmacological support options. Existing tools, such as Magnetic Resonance Spectroscopy, are limited in capturing the dynamic nature of E-I regulation. The aperiodic 1/f exponent of the EEG power spectrum has shown sensitivity to E-I perturbations in animals and neurotypical humans, but its applicability to neurodiverse populations remains underexplored. Methods: Therefore, as proof-of-concept, this study tested the hypotheses that (i) the aperiodic 1/f exponent of resting-state EEG changes following a pharmacological E-I challenge with arbaclofen (STX209), a GABAB receptor agonist; and (ii) dynamic responsivity to GABAergic challenge is different in autism. Participants were 40 adults, 15 autistic. EEG was recorded at rest after randomised, double-blind administration of a placebo, 15 mg of arbaclofen, and 30 mg of arbaclofen. Aperiodic 1/f exponents were extracted. Results: As predicted, in both groups the aperiodic 1/f exponent significantly increased following a high (30 mg) dose of arbaclofen, replicating the effect observed in animals. Furthermore, a lower (15 mg) dose showed a different response pattern across groups, with aperiodic exponents tending to increase in autistic individuals but decrease in non-autistic individuals, suggesting differences in GABAergic responsivity. Conclusions: These findings support the aperiodic 1/f exponent as a metric for dynamic E-I regulation and provide preliminary evidence of distinct homeostatic E-I dynamics in autism.
BACKGROUND:Methylphenidate can treat attention-deficit/hyperactivity disorders, which are frequently comorbid with bipolar disorders (BDs). Viktorin and collaborators (2017) reported that prescribing methylphenidate alone in adults with BD is associated with higher risk of manic relapse, whereas prescribing it in combination with mood-stabilizing medications is associated with lower risk. AIMS:We aimed to replicate these findings. METHODS:We identified adults with BD included in the French national healthcare claims database (SNDS) between 2008 and 2024. We compared the rate of manic relapse within 6 months before and after a new methylphenidate dispensation using self-controlled survival analysis. RESULTS/OUTCOMES:Among 2745 patients not receiving mood-stabilizing treatment, the rate of inpatient mania diagnoses was significantly higher within 3 months of methylphenidate dispensation compared to the pre-exposure period. This significance disappeared in self-controlled case-crossover analyses. Among 3526 patients receiving continuous mood-stabilizing treatment, there were no significant changes in the risk of an inpatient mania diagnosis after methylphenidate dispensation, except when administering >30 mg of methylphenidate. Treating the start of new antimanic therapy as an outcome event produced outlier results. CONCLUSIONS/INTERPRETATION:In patients with treated BD, methylphenidate is only associated with manic relapse at high dose. The strong significant risk of manic relapse we observed in untreated BD may be explained by natural progression of mania. This study highlights intrinsic limitations associated with self-controlled survival analysis.
BACKGROUND:Tobacco use disorder (TUD) is the largest premature cause of death in the world. While most adults with TUD have attempted to quit, only less than 10% quit for at least 6 months. Craving is one of the main causes of smoking relapses. Event-related potentials (ERPs) have been extensively studied using cue-provoked paradigms. However, little is known about ERPs related to resisting craving, which seems important to investigate since such activity might represent treatment targets to promote smoking cessation. AIMS:The goal of this work was to investigate the ERP correlates of resisting craving as compared to craving during a cue-provoked paradigm. METHODS:Fifty-three adults with TUD were assessed on urinary cotinine, tobacco dependence, anxiety, and impulsivity. They were presented with cigarette-related stimuli during two conditions (Crave and Resist craving). Craving ratings were collected on visual analog scales. EEG was recorded using 64 Ag-AgCl electrodes. RESULTS:Results revealed that P3 and early late positive potential (LPP) amplitudes were smaller during the Resist than the Crave conditions. P1 and late LPP amplitudes were also smaller but did not survive correction for multiple comparisons. Furthermore, anxiety level was related to the P3 amplitude during the Resist and Crave conditions, but did not survive correction for multiple comparisons. CONCLUSION:This line of work contributes to the identification of potential brain targets to help patients with TUD resist craving.
BACKGROUND:Lithium is the gold-standard mood stabilizer in bipolar disorder (BD) showing putative neuroprotective effects, but its association with cognition in older adults with BD (OABD) remains unclear. AIM:To examine the association of long-term lithium treatment with cognitive performance in euthymic OABD. METHODS:Forty outpatients aged 50-70 years with BD-I, without dementia or lifetime substance use disorder, completed a comprehensive neuropsychological battery. Participants were classified as lithium- (n = 19) or non-lithium-treated (n = 21). Test scores were converted to age- and education-adjusted Z-scores. We used t-tests/Mann-Whitney U tests, and Person's correlations were Bonferroni-corrected. A principal component analysis-generated general cognitive factor was entered into logistic regression models predicting lithium status, with sequential adjustment for various covariates. RESULTS/OUTCOMES:Lithium-treated patients showed large, widespread cognitive advantages in attention/working memory (Digit Symbol Forward Test (DSFT), d = 1.481; DSBT, d = 1.519), verbal learning and memory (Rey's Auditory Verbal Learning Test (RAVLT) recognition, d = 1.803), processing speed (Symbol Digit Modalities Test (SDMT), d = 2.147), executive function (Trail Making Test - Part B, d = 1.330), and verbal fluency (Controlled Oral Word Association Test (COWAT), d = 1.423). Higher lithium levels correlated with better DSFT and SDMT performance after correction. Antipsychotic dose was strongly and negatively correlated with Mini-Mental State Examination, particularly in the non-lithium group. The general cognitive factor distinguished lithium from non-lithium patients (R2 = 0.70), and its effect remained large and mostly significant across six adjusted models. CONCLUSION/INTERPRETATION:In euthymic OABD, chronic lithium treatment is associated with markedly better global cognition, independent of mood, illness severity, and polypharmacy. Our findings provide support for the role of lithium in cognitive preservation and are worthy of further investigation in larger longitudinal studies.
