Search

Sleep, constituting approximately one-third of the human lifespan, is a crucial physiological process essential for physical and mental well-being. Normal sleep consists of an orderly progression through wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep, all of which are tightly regulated. Melatonin, often referred to as the "hormone of sleep," plays a pivotal role as a regulator of the sleep/wake cycle and exerts its effects through high-affinity G-protein coupled receptors known as MT1 and MT2. Selective modulation of these receptors presents a promising therapeutic avenue for sleep disorders. This review examines research on the multifaceted role of melatonin in sleep regulation, focusing on selective ligands targeting MT1 and MT2 receptors, as well as studies involving MT1 and MT2 knockout mice. Contrary to common beliefs, growing evidence suggests that melatonin, through MT1 and MT2 receptors, might not only influence circadian aspects of sleep but likely, also modulate the homeostatic process of sleep and sleep architecture, or could be the molecule linking the homeostatic and circadian regulation of sleep. Furthermore, the distinct brain localization of MT1 and MT2 receptors, with MT1 receptors primarily regulating REM sleep and MT2 receptors regulating NREM sleep, is discussed. Collectively, sleep regulation extends beyond the circulating levels and circadian peak of melatonin; it also critically involves the expression, molecular activation, and regulatory functions of MT1 and MT2 receptors across various brain regions and nuclei involved in the regulation of sleep. This research underscores the importance of ongoing investigation into the selective roles of MT1 and MT2 receptors in sleep. Such research efforts are expected to pave the way for the development of targeted MT1 or MT2 receptors ligands, thereby optimizing therapeutic interventions for sleep disorders., (© 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.)

Mutations in the PRKN gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson's disease mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. To this end, we created a knock-in mouse carrying the homozygous PrknR275W mutation, which is the missense mutation with the highest allelic frequency in PRKN patients. We evaluated the anatomical and functional integrity of the nigrostriatal dopamine (DA) pathway, as well as motor behaviour in PrknR275W mice of both sexes. We report here that PrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that the PrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new Parkinson's disease model in which to study causative mechanisms of the disease and test therapeutic strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Psychedelics have shown promising effects in several psychiatric diseases as demonstrated by multiple clinical trials. However, no clinical experiments on patients with schizophrenia have been conducted up to date, except for some old semi-anecdotal studies mainly performed in the time-span '50s-'60s. Notably, these studies reported interesting findings, particularly on the improvement of negative symptoms and social cognition. With no doubts the lack of modern clinical studies is due to the psychomimetic properties of psychedelics, a noteworthy downside that could worsen positive symptoms. However, a rapidly increasing body of evidence has suggested that the mechanisms of action of such compounds partially overlaps with the pathogenic underpinnings of schizophrenia but in an opposite way. These findings suggest that, despite being a controversial issue, the use of psychedelics in the treatment of schizophrenia would be based on a strong biological rationale. Therefore, the aim of our perspective paper is to provide a background on the old experiments with psychedelics performed on patients with schizophrenia, interpreting them in the light of recent molecular findings on their ability to induce neuroplasticity and modulate connectivity, the immune and TAARs systems, neurotransmitters, and neurotropic factors. No systematic approach was adopted in reviewing the evidence given the difficulty to retrieve and interpret old findings. Interestingly, we identified a therapeutic potential of psychedelics in schizophrenia adopting a critical point of view, particularly on negative symptoms and social cognition, and we summarized all the relevant findings. We also identified an eligible subpopulation of chronic patients predominantly burdened by negative symptoms, outlining possible therapeutic strategies which encompass very low doses of psychedelics (microdosing), carefully considering safety and feasibility, to pave the way to future clinical trials., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Methamphetamine (METH) is an addictive drug that threatens human health. The supramammillary nucleus (SuM) and its neural circuits play key roles in the regulation of spatial memory retrieval, and hippocampal contextual or social memory. Melatonin (MLT), a pineal hormone, can regulate hypothalamic-neurohypophysial activity. Our previous study showed that MLT attenuates METH-induced locomotor sensitization. However, whether MLT regulates SuM function and participates in METH-induced contextual memory retrieval remains unclear. Using a mouse model of METH-conditioned place preference (CPP) and sensitization, we found that METH activated c-Fos expression and elevated calcium (Ca²⁺) levels in SuM neurons. Chemogenetic inhibition of SuM attenuates CPP and sensitization. Pretreatment with MLT decreased c-Fos expression and Ca 2+ levels in the SuM and reversed METH-induced addictive behavior, effects that were blocked with the selective MT 2 receptors antagonist 4P-PDOT and the MT 1 receptors antagonist S26131. Furthermore, MLT reduced SuM synaptic plasticity, glutamate (Glu) release, and neuronal oscillations caused by METH, which were blocked by 4P-PDOT. In conclusion, our data revealed that MLT regulates neuronal synaptic plasticity in the SuM, likely through the MLT receptors (MTs), and plays a role in modulating METH-addictive behavior., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mounting evidence points towards a crucial role of the kynurenine pathway (KP) in the altered gut-brain axis (GBA) balance in severe mental illness (SMI, namely depression, bipolar disorder, and schizophrenia) and cardiometabolic comorbidities. Preliminary evidence shows that serotonergic psychedelics and their analogues may hold therapeutic potential in addressing the altered KP in the dysregulated GBA in SMI and comorbidities. In fact, aside from their effects on mood, psychedelics elicit therapeutic improvement in preclinical models of obesity, metabolic syndrome, and vascular inflammation, which are highly comorbid with SMI. Here, we review the literature on the therapeutic modulation of the KP in the dysregulated GBA in SMI and comorbidities, and the potential application of psychedelics to address the altered KP in the brain and systemic dysfunction underlying SMI and comorbidities. Psychedelics might therapeutically modulate the KP in the altered GBA in SMI and comorbidities either directly, via altering the metabolic pathway by influencing the rate-limiting enzymes of the KP and affecting the levels of available tryptophan, or indirectly, by affecting the gut microbiome, gut metabolome, metabolism, and the immune system. Despite promising preliminary evidence, the mechanisms and outcomes of the KP modulation with psychedelics in SMI and systemic comorbidities remain largely unknown and require further investigation. Several concerns are discussed surrounding the potential side effects of this approach in specific cohorts of individuals with SMI and systemic comorbidities., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the last decade, the kynurenine pathway (KP) has gained attention in the pathogenesis of cognitive impairment in schizophrenia being at the croassroad between neuroinflammation and glutamatergic and cholinergic neurotransmission. However, clinical findings are scarse and conflicting, and the specific contributions of these two systems to the neurobiology of cognitive symptoms are far from being elucidated. Furthermore, little is known about the molecular underpinnings of non-pharmacological interventions for cognitive improvement, including rehabilitation strategies., Methods: The current study examined 72 patients with schizophrenia, divided in two clusters depending on the severity of the cognitive impairment, with the aim to evaluate the impact of inflammatory biomarkers and KP metabolites depending on cognitive functioning. Moreover, we studied their possible link to the cognitive outcome in relation to sessions of cognitive remediation therapy (CRT) and aerobic exercise (AE) in a longitudinal arm of 42 patients., Results: Neuroinflammation appeared to exert a more pronounced influence on cognition in patients exhibiting a higher cognitive functioning, contrasting with the activation of the KP, which had a greater impact on individuals with a lower cognitive profile. Cognitive improvements after the treatments were negatively predicted by levels of TNF-α and positively predicted by the 3-hydroxykynurenine (3-HK)/kynurenine (KYN) ratio, an index of the kynurenine-3-monooxygenase (KMO) enzyme activity., Conclusion: Overall, these findings add novel evidence on the biological underpinnings of cognitive impairment in schizophrenia pointing at a differential role of neuroinflammation and KP metabolites in inducing cognitive deficits depending on the cognitive reserve and predicting outcomes after rehabilitation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Inc.)

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT 1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT 1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT 1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT 1 receptors in the LC-NE neurons. In conclusion, MT 1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 López-Canul et al.)

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants., Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD ( DSM-5 ) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35)., Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant ( P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% ( P = .076), and response rates were 39.8% and 27.2% ( P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 ( P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups., Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies., Trial Registration: ClinicalTrials.gov identifier: NCT04688164., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Background and Objectives: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl- D -aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose)., Methods: Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment., Results: In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone C max and AUC 0-inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of C max and AUC 0-inf values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), C max and AUC 0-inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, C max and AUC 0-inf were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment., Conclusion: Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis., (© 2024. The Author(s).)

Two cardinal elements in the complex and multifaceted pathophysiology of schizophrenia (SCZ) are neuroinflammation and dysregulation of glutamatergic neurotransmission, with the latter being especially involved in treatment-resistant schizophrenia (TRS). Interestingly, the Kynurenine (KYN) pathway (KP) is at the crossroad between them, constituting a potential causal link and a therapeutic target. Although there is preclinical and clinical evidence indicating a dysregulation of KP associated with the clinical phenotype of SCZ, clinical studies investigating the possible relationship between changes in biomarkers of the KP and response to pharmacotherapy are still limited. Therefore, we have studied possible differences in the circulating levels of biomarkers of the metabolism of tryptophan along the KP in 43 responders to first-line treatments (FLR) and 32 TRS patients treated with clozapine, and their possible associations with psychopathology in the two subgroups. Plasma levels of KYN were significantly higher in TRS patients than in FLR patients, indicating a greater activation of KP. Furthermore, the levels of quinolinic (NMDA receptor agonist) and kynurenic acid (NMDA negative allosteric modulator) showed a negative and a positive correlation with several dimensions and the overall symptomatology in the whole sample and in FLR, but not in TRS, suggesting a putative modulating effect of clozapine elicited through the NMDA receptors. Despite the cross-sectional design of the study that prevents us from demonstrating causation, these findings show a significant relationship among circulating KP biomarkers, psychopathology, and response to pharmacotherapy in SCZ. Therefore, plasma KP biomarkers should be further investigated for developing personalized medicine approaches in SCZ., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms., Methods: Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined., Results: Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found., Conclusions: Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression., (© 2024. The Author(s).)

The brain circuit projecting from the ventral tegmental area (VTA) to the nucleus accumbens lateral shell (NAcLat) has a key role in methamphetamine (MA) addiction. As different dopamine (DA) neuron subpopulations in the VTA participate in different neuronal circuits, it is a challenge to isolate these DA neuron subtypes. Using retrograde tracing and Patch-seq, we isolated DA neurons in the VTA-NAcLat circuit in MA-treated mice and performed gene expression profiling. Among the differentially expressed genes, KCNQ genes were dramatically downregulated. KCNQ genes encode Kv7 channel proteins, which modulate neuronal excitability. Injection of both the Kv7.2/3 agonist ICA069673 and the Kv7.4 agonist fasudil into the VTA attenuated MA-induced conditioned place preference and locomotor sensitization and decreased neuronal excitability. Increasing Kv7.2/3 activity decreased neural oscillations, synaptic plasticity and DA release in the VTA-NacLat circuit in MA-treated mice. Furthermore, overexpression of only Kv7.3 channels in the VTA-NacLat circuit was sufficient to attenuate MA-induced reward behavior and decrease VTA neuron excitability. Activation of Kv7 channels in the VTA may become a novel treatment strategy for MA abuse., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT 1 and MT 2 , plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT 1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT 1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT 1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT 1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT 1 rs2165666 variant. Overall, this work lends support to the potentiality of MT 1 receptors as target for the treatment of BD., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose/background: Quetiapine is a first-line augmenting agent for treatment-resistant depression (TRD) and is used off-label in insomnia. Quetiapine and its active metabolite norquetiapine act mostly on 5-HT2A, 5-HT2C, H1, and D2 as antagonists and on 5-HT1A as partial agonists. Patients with TRD often have comorbid personality disorder (PD), and evidence suggests an association between sleep disturbance and recovery among patients with PD. Here, we aimed to evaluate the effects of quetiapine on sleep in TRD patients with and without PD (PD+/PD-)., Methods/procedures: We reviewed health records of 38 patients with TRD (20 TRD/PD+) who had been treated with a pharmacotherapy regimen including quetiapine. Clinical outcomes were determined by comparing changes in sleep items of the Hamilton Depression Rating Scale at the beginning (T0) and after 3 months of an unchanged treatment (T3)., Findings/results: Patients with TRD/PD+ and TRD/PD- taking quetiapine showed significant improvement in sleep items from T0 to T3 (P < 0.001, ηp2 ≥ 0.19). There was a significant personality × time interaction for sleep-maintenance insomnia (P = 0.006, ηp2 = 0.23), with TRD/PD+ showing a greater improvement at T3 compared with TRD/PD- (P = 0.01). While exploring other sleep items, no personality × time interaction was found. In the TRD/PD- group, improvement in sleep items was associated with an overall improvement in depressive symptoms (r = 0.55, P = 0.02)., Implications/conclusions: Quetiapine induced greater improvements in sleep-maintenance insomnia among TRD/PD+ patients than TRD/PD-. These findings suggest quetiapine could have a therapeutic role for insomnia in PD underscoring a distinct underlying neurobiological mechanism of sleep disturbance in people living with PD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders., (© 2023. The Author(s).)

Schizophrenia is a chronic psychotic disease burdened by cognitive deficits which hamper daily functioning causing disability and costs for society. Biological determinants underlying cognitive impairment are only partially understood and there are no convincing pharmacological targets able to improve cognitive outcome. Mounting evidence has shown the involvement of the kynurenine pathway in the pathophysiology of schizophrenia, also concerning cognitive symptoms. Therefore, the action of specific metabolites of kynurenine could affects cognition in schizophrenia. To evaluate the impact of the metabolites of kynurenine pathway on cognitive functions in schizophrenia spectrum disorders, with a focus on the modulating role of gender, to identify predictors of cognitive functioning and hypothetical pharmacological targets able to resize disability by improving cognition, thus functioning and quality of life. A systematic review was performed in PubMed/MEDLINE and Embase according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. All studies measuring the direct impact of kynurenine metabolites on cognitive performances in living individuals with schizophrenia spectrum disorders were included in the review. Six studies were included. The activation of the kynurenine pathway resulted associated with greater cognitive deficits in patients with schizophrenia and both elevations and reduction of metabolites seemed able to affect cognitive outcome. No modulating role of sex emerged. This systematic review provides evidence that the activation of the kynurenine pathway affects cognition in patients with schizophrenia and highlights this pathway as a possible future target for developing novel drugs toward this still unmet clinical need. However, evidence is still limited and future studies are needed to further clarify the relationship between kynurenine pathway and cognition in schizophrenia., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Smart Wearables are considered a very promising solution for monitoring and helping people affected by cognitive decline or dementia and, in particular, Alzheimer Disease (AD). Nonetheless, the acceptability and wearability of such devices for AD patients pose certain challenges. To address this, an empirical study has been conducted with a group of patients with mild to moderate AD, wearing wristbands E4 by Empatica for a duration of three months. The experiment has been integrated into the regular healthcare activities, with active involvement from nurses and physicians. The paper reports the feedbacks of the caregivers and discusses wearability and acceptability issues.

The synthesis of melatonin (MLT) physiologically decreases during aging. Treatment with MLT has shown anxiolytic, hypnotic, and analgesic effects, but little is known about possible age-dependent differences in its efficacy. Therefore, we studied the effects of MLT (20 mg/kg, intraperitoneal) on anxiety-like behavior (open field (OFT), elevated plus maze (EPMT), three-chamber sociability, and marble-burying (MBT) tests), and the medial prefrontal cortex (mPFC)-dorsal hippocampus (dHippo) circuit in adolescent (35-40 days old) and adult (three-five months old) C57BL/6 male mice. MLT did not show any effect in adolescents in the OFT and EPMT. In adults, compared to vehicles, it decreased locomotor activity and time spent in the center of the arena in the OFT and time spent in the open arms in the EPMT. In the MBT, no MLT effects were observed in both age groups. In the three-chamber sociability test, MLT decreased sociability and social novelty in adults, while it increased sociability in adolescents. Using local field potential recordings, we found higher mPFC-dHippo synchronization in the delta and low-theta frequency ranges in adults but not in adolescents after MLT treatment. Here, we show age-dependent differences in the effects of MLT in anxiety paradigms and in the modulation of the mPFC-dHippo circuit, indicating that when investigating the pharmacology of the MLT system, age can significantly impact the study outcomes.

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (E max ) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS E max compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS E max (p < 0.05). In the Ketamine Study, Drug Liking VAS E max scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses., (© 2023. The Author(s).)

Background and Objectives : Alterations in hot cognition and in the tryptophan metabolism through serotonin (5-HT) and kynurenine (KYN) pathways have been associated with an increased risk of suicidal behavior. Here, we aim at probing the association between Stroop test performances and tryptophan pathway components in a sample of individuals with bipolar disorder (BD). Materials and Methods : We explored the association between the Emotion Inhibition Subtask (EIS) performances of the Brief Assessment of Cognition for Affective Disorders (BAC-A) and plasmatic levels of 5-hydroxytriptophan (5-HTP), 5-HT, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KYNA) among subjects reporting lifetime suicide ideation (LSI) vs. non-LSI and subjects reporting lifetime suicide attempts (LSA) vs. non-LSA. Results : In a sample of 45 subjects with BD, we found a statistically significant different performance for LSA vs. non-LSA in the color naming (CN) and neutral words (NW) EIS subtasks. There was a significant association between CN performances and plasma 5-HTP levels among LSI and LSA subjects but not among non-LSI or non-LSA. Conclusions : In our sample, patients with LSA and LSI presented lower performances on some EIS subtasks compared to non-LSA and non-LSI. Moreover, we found an inverse correlation between plasma 5-HTP concentration and some EIS performances in LSA and LSI but not among non-LSA or non-LSI. This may represent an interesting avenue for future studies probing this complex association.

Brain injury and cerebral vasospasm during the 14 days after the subarachnoid hemorrhage (SAH) are considered the leading causes of poor outcomes. The primary injury induces a cascade of events, including increased intracranial pressure, cerebral vasospasm and ischemia, glutamate excitotoxicity, and neuronal cell death. The objective of this study was to monitor the time course of glutamate, and associated enzymes, such as glutamate-oxaloacetate transaminase (GOT1), glutamate-pyruvate transaminase (GPT) in cerebrospinal fluid (CSF) and serum, shortly after SAH, and to assess their prognostic value. A total of 74 participants participated in this study: 45 participants with SAH and 29 controls. Serum and CSF were sampled up to 14 days after SAH. SAH participants' clinical and neurological status were assessed at hospitalization, at discharge from the hospital, and 3 months after SAH. Furthermore, a logistic regression analysis was carried out to evaluate the ability of GOT1 and glutamate levels to predict neurological outcomes. Our results demonstrated consistently elevated serum and CSF glutamate levels after SAH. Furthermore, serum glutamate level was significantly higher in patients with cerebral ischemia and poor neurological outcome. CSF GOT1 was significantly higher in patients with uncontrolled intracranial hypertension and cerebral ischemia post-SAH, and independently predicted poor neurological outcomes., (© 2023. The Author(s).)

Suicide, a global health burden, represents the 17th leading cause of death worldwide (1.3%), but the 4th among young people aged between 15 and 29 years of age, according to World Health Organization (WHO), 2019. Suicidal behaviour is a complex, multi-factorial, polygenic and independent mental health problem caused by a combination of alterations and dysfunctions of several biological pathways and disruption of normal mechanisms in brain regions that remain poorly understood and need further investigation to be deciphered. Suicide complexity and unpredictability gained international interest as a field of research. Several studies have been conducted at the neuropathological, inflammatory, genetic, and molecular levels to uncover the triggers behind suicidal behaviour and develop convenient and effective therapeutic or at least preventive procedures. This review aims to summarise and focus on current knowledge of diverse biological pathways involved in the neurobiology of suicidal behaviour, and briefly highlights future potential therapeutic pathways to prevent or even treat this significant public health problem.

Background and Purpose: Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro-immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown., Experimental Approach: Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid-like mediators and metabolites were quantified via high-pressure liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Neurotransmitter levels were assessed via HPLC-UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing., Key Results: LSD increased social preference and novelty and decreased hippocampal levels of the N-acylethanolamines N-linoleoylethanolamine (LEA), anandamide (N-arachidonoylethanolamine) and N-docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2-docosahexaenoylglycerol (1/2-DHG); the prostaglandins D 2 (PGD 2 ) and F2α (PGF 2α ); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline-treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9., Conclusions and Implications: The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome., (© 2022 British Pharmacological Society.)

The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants.

Population aging requires innovative solutions to increase the quality of life and preserve autonomous and independent living at home. A need of particular significance is the identification of behavioral drifts. A relevant behavioral drift concerns sociality: older people tend to isolate themselves. There is therefore the need to find methodologies to identify if, when, and how long the person is in the company of other people (possibly, also considering the number). The challenge is to address this task in poorly sensorized apartments, with non-intrusive sensors that are typically wireless and can only provide local and simple information. The proposed method addresses technological issues, such as PIR (Passive InfraRed) blind times, topological issues, such as sensor interference due to the inability to separate detection areas, and algorithmic issues. The house is modeled as a graph to constrain transitions between adjacent rooms. Each room is associated with a set of values, for each identified person. These values decay over time and represent the probability that each person is still in the room. Because the used sensors cannot determine the number of people, the approach is based on a multi-branch inference that, over time, differentiates the movements in the apartment and estimates the number of people. The proposed algorithm has been validated with real data obtaining an accuracy of 86.8%.

Background: Women are nearly twice as likely as men to suffer from major depressive disorder. Yet, there is a dearth of studies comparing the clinical outcomes of women and men with treatment-resistant depression (TRD) treated with similar augmentation strategies. We aimed to evaluate the effects of the augmentation strategies in women and men at the McGill University Health Center., Methods: We reviewed health records of 76 patients (42 women, 34 men) with TRD, treated with augmentation strategies including antidepressants (AD) with mood stabilizers (AD+MS), antipsychotics (AD+AP), or in combination (AD+AP+MS). Clinical outcomes were determined by comparing changes on the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery-Åsberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology (QIDS-C16), and Clinical Global Impression rating scale (CGI-S) at the beginning and after 3 months of an unchanged treatment. Changes in individual items of the HAMD-17 were also compared between the groups., Results: Women and men improved from beginning to 3 months on all scales (P < .001, η p2 ≥ 0.68). There was also a significant sex × time interaction for all scales (P < .05, η p2 ≥ 0.06), reflecting a greater improvement in women compared with men. Specifically, women exhibited greater improvement in early (P = .03, η p2 = 0.08) and middle-of-the-night insomnia (P = .01, η p2 = 0.09) as well as psychomotor retardation (P < .001 η p2 = 0.16) and psychic (P = .02, η p2 = 0.07) and somatic anxiety (P = .01, η p2 = 0.10)., Conclusions: The combination of AD+AP/MS generates a significantly greater clinical response in women compared with men with TRD, supporting the existence of distinct pharmacological profiles between sexes in our sample. Moreover, they emphasize the benefit of augmentation strategies in women, underscoring the benefit of addressing symptoms such as insomnia and anxiety with AP and MS., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

In the last two years, the world has been overwhelmed by SARS-CoV-2. One of the most important ways to prevent the spread of the virus is the control of indoor conditions: from surface hygiene to ventilation. Regarding the indoor environments, monitoring the presence of the virus in the indoor air seems to be promising, since there is strong evidence that airborne transmission through infected droplets and aerosols is its dominant transmission route. So far, few studies report the successful detection of SARS-CoV-2 in the air; moreover, the lack of a standard guideline for air monitoring reduces the uniformity of the results and their usefulness in the management of the risk of virus transmission. In this work, starting from a critical analysis of the existing standards and guidelines for indoor air quality, we define a strategy to set-up indoor air sampling plans for the detection of SARS-CoV-2. The strategy is then tested through a case study conducted in two kindergartens in the metropolitan city of Milan, in Italy, involving a total of 290 children and 47 teachers from 19 classrooms. The results proved its completeness, effectiveness, and suitability as a key tool in the airborne SARS-CoV-2 infection risk management process. Future research directions are then identified and discussed.

The melatonin system and circadian disruption have well-established links with aggressive behaviors; however, the biological underpinnings have not been thoroughly investigated. Here, we aimed at examining the current knowledge regarding the neurobiological and psychopharmacological involvement of the melatonin system in aggressive/violent behaviors. To this end, we performed a systematic review on Embase and Pubmed/MEDLINE of preclinical and clinical evidence linking the melatonin system, melatonin, and melatoninergic drugs with aggressive/violent behaviors. Two blinded raters performed an independent screening of the relevant literature. Overall, this review included 38 papers distributed between clinical and preclinical models. Eleven papers specifically addressed the existing evidence in rodent models, five in fish models, and 21 in humans. The data indicate that depending on the species, model, and timing of administration, melatonin may exert a complex influence on aggressive/violent behaviors. Particularly, the apparent contrasting findings on the link between the melatonin system and aggression/violence (with either increased, no, or decreased effect) shown in preclinical models underscore the need for further research to develop more accurate and fruitful translational models. Likewise, the significant heterogeneity found in the results of clinical studies does not allow yet to draw any firm conclusion on the efficacy of melatonin or melatonergic drugs on aggressive/violent behaviors. However, findings in children and in traits associated with aggressive/violent behavior, including irritability and anger, are emerging and deserve empirical attention given the low toxicity of melatonin and melatonergic drugs., (© 2022 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd.)

Lysergic acid diethylamide (LSD) is a serotonergic psychedelic compound receiving increasing interest due to putative anxiolytic and antidepressant properties. However, the potential neurobiological mechanisms mediating these effects remain elusive. Employing in vivo electrophysiology, microionthophoresis, behavioral paradigms and morphology assays, we assessed the impact of acute and chronic LSD administration on anxiety-like behavior, on the cortical dendritic spines and on the activity of serotonin (5-HT) neurons originating in the dorsal raphe nucleus (DRN) in male mice exposed to chronic restraint stress. We found that while the acute intraperitoneal (i.p.) administration of LSD (5, 15 and 30 and 60 μg/kg) did not produce any anxiolytic or antidepressant effects in non-stressed mice, the dose of 30 µg/kg (daily for 7 days) prevented the stress-induced anxiety-like behavior and the stress-induced decrease of cortical spine densitiy. Interestingly, while LSD acutely decreased the firing activity of 5-HT neurons, repeated LSD increased their basal firing rate and restored the low 5-HT firing induced by stress. This effect was accompanied by a decreased inhibitory response of 5-HT neurons to microiontophoretic applications of the 5-HT 1A agonist 8-OH-DPAT (8-hydroxy-N,N-dipropyl-2-aminotetralin). In conclusion, repeated LSD prevents the exacerbation of anxiety-like behavior following chronic stress exposure, but has no behavioral effects in non-stressed mice. These effects are paralleled by increased cortical spinogenesis and an enhancement of 5-HT neurotransmission which might be due to 5-HT 1A receptors desensitization. Increased cortical spine density and enhancement of serotonergic neurotransmission may thus represent a candidate mechanism which mediate the therapeutic effects of serotonergic psychedelics on stress-induced anxiety., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Bipolar disorder is associated with an inflammation-triggered elevated catabolism of tryptophan to the kynurenine pathway, which impacts psychiatric symptoms and outcomes. The data indicate that lithium exerts anti-inflammatory effects by inhibiting indoleamine-2,3-dioxygenase (IDO)-1 activity. This exploratory study aimed to investigate the tryptophan catabolism in individuals with bipolar disorder ( n = 48) compared to healthy controls ( n = 48), and the associations with the response to mood stabilizers such as lithium, valproate, or lamotrigine rated with the Retrospective Assessment of the Lithium Response Phenotype Scale (or the Alda scale). The results demonstrate an association of a poorer response to lithium with higher levels of kynurenine, kynurenine/tryptophan ratio as a proxy for IDO-1 activity, as well as quinolinic acid, which, overall, indicates a pro-inflammatory state with a higher degradation of tryptophan towards the neurotoxic branch. The treatment response to valproate and lamotrigine was not associated with the levels of the tryptophan metabolites. These findings support the anti-inflammatory properties of lithium. Furthermore, since quinolinic acid has neurotoxic features via the glutamatergic pathway, they also strengthen the assumption that the clinical drug response might be associated with biochemical processes. The relationship between the lithium response and the measurements of the tryptophan to the kynurenine pathway is of clinical relevance and may potentially bring advantages towards a personalized medicine approach to bipolar disorder that allows for the selection of the most effective mood-stabilizing drug.

Purpose/background: There is a dearth of studies comparing the clinical outcomes of patients with treatment-resistant unipolar (TRD) depression and depression in bipolar disorder (BD) despite similar treatment strategies. We aimed to evaluate the effects of the pharmacological combinations (antidepressants [AD], mood stabilizers [MS], and/or antipsychotics [AP]) used for TRD and BD at the McGill University Health Center., Methods/procedures: We reviewed health records of 206 patients (76 TRD 130 BD) with TRD and BD treated with similar augmentation strategies including AD with MS (AD+MS) or AP (AD+AP) or combination (AD+AP+MS). Clinical outcomes were determined by comparing changes on the 17-time Hamilton Depression Rating Scale (HAMD-17), Quick Inventory of Depressive Symptomatology, and Clinical Global Impression-Severity of Illness at the beginning (T0) and after 3 months of an unchanged treatment (T3)., Findings/results: Baseline HAMD-17 scores in TRD were higher than in BD (P < 0.001), but TRD patients had a greater improvement at end point (P = 0.003). Antidepressants with AP generated greater reductions in HAMD-17 in TRD compared with BD (P = 0.02). Importantly, in BD patients, the addition of AD compared with other treatment strategies failed to improve the outcome. The limitations of this study include possibly unrepresentative subjects from tertiary care settings, incomplete matching of BD and TRD subjects, nonrandomized treatment with unmatched agents, doses, and times, unknown treatment adherence, and nonblinded retrospective outcome assessments. Nevertheless, the findings may reflect real-world interactions of clinically selected pharmacotherapies., Implications/conclusions: Combination of augmentation strategies such as AD+AP and/or MS showed a better clinical improvement in patients with TRD compared with BD suggesting a limited evidence for AD potentiation in BD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Bipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by altered levels of immune/inflammatory markers and disrupted white matter (WM) microstructure. A pro-inflammatory state was suggested to activate indoleamine 2,3-dioxygenase which, in turn, increases the amount of tryptophan (Trp) converted into kynurenine (Kyn). We investigated whether plasma levels of Trp, Kyn and Kyn/Trp ratio are associated with peripheral levels of immune/inflammatory markers and whether they are related to WM integrity in 100 MDD and 66 BD patients. Patients also underwent MRI, and fractional anisotropy (FA) was estimated as a measure of WM microstructure. BD patients showed higher Kyn levels and Kyn/Trp ratio than MDD patients, and lower FA in several WM tracts, including the corpus callosum and the inferior fronto-occipital fasciculus (IFO). Lower Trp levels associated with a more severe depressive symptomatology irrespective of diagnosis and with lower FA in the corpus callosum (CC) and external capsule (EC). We found an association of immune/inflammatory markers with Kyn/Trp ratio selectively in BD patients: IL-1β and TNF-α showed a positive relationship and IL-2 and IL-9 a negative relationship; in addition, higher IL-4 correlated with lower Kyn levels; higher Kyn/Trp ratio and IL-1β correlated with lower FA in the CC and IFO. Notably, the detrimental effect of IL-1β on the IFO was moderated by the Kyn/Trp ratio. These data suggest that in BD, cytokines and the conversion of Trp into Kyn may affect WM microstructure and support the idea that distinct mechanisms underlie the pathophysiology of BD and MDD., (Copyright © 2021. Published by Elsevier B.V.)

Melatonin (MLT) has been implicated in several pathophysiological states, including pain. MLT mostly activates two G protein-coupled receptors, MT 1 and MT 2 . MLT displays analgesic properties in several animal paradigms of acute, inflammatory, and neuropathic pain. Although the analgesic mechanism of action of MLT is not yet completely elucidated, there is strong preclinical evidence suggesting the pharmacological potential of melatonergic compounds for treating pain. Importantly, MLT and melatonergic compounds seem to have a favorable toxicological profile than currently approved analgesic drugs. These compounds may thus deserve to be further developed as novel analgesic drugs, but this process relies on the use of appropriate and standardized experimental procedures. Therefore, in this chapter, we present the methodology to study the analgesic properties of MLT and melatonergic drugs in a preclinical model of chronic and acute pain. In addition to technical details of the surgical technique, details of anesthesia and perioperative care are also included., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Melatonin is a potent neuroprotective agent which has shown therapeutic effects in animal models of brain injury such as stroke. Currently, there are few effective treatments for the therapeutics of stroke, the second leading cause of death and a major cause of disability worldwide. As demonstrated by the high number of publications during the last two decades, there is growing interest in understanding how and if melatonin could be a possible drug for stroke in humans, given also its very low and limited toxicity. Here, we describe the detailed protocol for performing the photothrombotic model of stroke which involves the occlusion of small cerebral vessels caused by the photoactivation of the previously injected light-sensitive dye Rose Bengal. Importantly, this model allows for the study of cellular and molecular mechanisms underlying the pathophysiology of stroke and thus can be used for investigating the neuropharmacological role of melatonin and the melatonin system in stroke. In particular, future research is warranted to demonstrate how and if melatonin impacts neurodegeneration, neuroprotection, and neuro-regeneration occurring after the brain injury caused by the occlusion of cerebral vessels., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The increased degradation of tryptophan (Trp) along the kynurenine (Kyn) pathway due to inflammation and/or activation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported among the biological factors involved in the pathophysiology of major depressive disorder (MDD) and suicide. However, the interaction among these multiple factors is not yet completely clarified., Methods: We studied plasma levels of Trp, Kyn, cortisol and proinflammatory cytokines (IL-1, IL- 6, IL-12, IL-20) and calculated the ratio Kyn/Trp as an index of the breakdown of Trp into Kyn in 31 suicidal MDD patients and 67 non-suicidal MDD patients., Result: We confirmed that suicidal MDD patients have reduced plasma Trp, higher Kyn and Kyn/Trp ratio, and no difference in cortisol levels than non-suicidal MDD patients. IL-1 and IL-12 levels were significantly higher in suicidal MDD than in non-suicidal MDD (p=0.034 and p=0.023, respectively), whereas Il-6 and IL-20 levels were equal in the two groups. The Kyn/Trp ratio was positively correlated with a pro-inflammatory cytokines index (r=0.309, p=0.002) and cortisol (r=0.368, p=0.001). Notably, the variance in the Kyn/Trp ratio explained by the model including both cortisol and inflammatory parameters as dependent variables, substantially improved compared with the models in which the two parameters were considered separately., Conclusion: These findings show that both cortisol and proinflammatory cytokines are involved in the enhanced breakdown of Trp into Kyn occurring in suicidal MDD patients, thus adding new knowledge on the biological mechanisms leading to the activation of the Kyn pathway in MDD and suicide., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Melatonin is a pleiotropic compound mostly acting through its two G protein-coupled receptors named MT 1 and MT 2 and known for its role in regulating the sleep/wake cycle and circadian rhythms. Although this is common belief, there has been long debate in the scientific community on whether melatonin or melatonergic compounds are endowed with hypnotic effects. One of the reasons for this debate relied on contrasting findings in the literature in part due to non-standardized methods across studies in examining at preclinical level the effect of melatonin or melatonergic compounds on the sleep/wake cycle. Here, we describe a method in mice and rats to evaluate the effect of melatonin or melatonergic compounds on the different stages of the sleep/wake cycle, providing details concerning the administration of the drug and the analytical procedure for scoring the electroencephalogram/electromyogram (EEG/EMG) recording., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A ( p = 0.018), FABP-2 ( p = 0.002), and 3-hydroxykynurenine ( p = 0.037) and lower levels of kynurenine ( p = 0.012) and serotonin ( p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine ( p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.

Recognizing Activities of Daily Living (ADL) or detecting falls in domestic environments require monitoring the movements and positions of a person. Several approaches use wearable devices or cameras, especially for fall detection, but they are considered intrusive by many users. To support such activities in an unobtrusive way, ambient-based solutions are available (e.g., based on PIRs, contact sensors, etc.). In this paper, we focus on the problem of sitting detection exploiting only unobtrusive sensors. In fact, sitting detection can be useful to understand the position of the user in many activities of the daily routines. While identifying sitting/lying on a sofa or bed is reasonably simple with pressure sensors, detecting whether a person is sitting on a chair is an open problem due to the natural chair position volatility. This paper proposes a reliable, not invasive and energetically sustainable system that can be used on chairs already present in the home. In particular, the proposed solution fuses the data of an accelerometer and a capacitive coupling sensor to understand if a person is sitting or not, discriminating the case of objects left on the chair. The results obtained in a real environment setting show an accuracy of 98.6% and a precision of 95%.

Purpose/background: The link between substances of abuse, impulsivity, and violence in psychotic patients remains unclear. This study aims at unraveling whether cannabis use disorder is associated with violent and/or psychotic behavior in patients who are hospitalized in a high-security hospital., Methods/procedures: We conducted a cross-sectional retrospective study in 124 patients with schizophrenia spectrum disorders admitted to a high-security hospital. Lifetime violent behavior was assessed using the History of Aggressive Behavior Form-Subject of the MacArthur Violence Risk Assessment Study and impulsivity using the Psychopathy Checklist-Revised (considering items: "proneness to boredom," "lack of self-control," and "impulsive thoughtless gestures"). Substance use disorder was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Positive and Negative Syndrome Scale was also administered., Findings/results: Violent and nonviolent psychotic patients showed similar prevalence of cannabis use disorder. Alcohol and cocaine use disorders were more prevalent among violent psychotic patients. Cannabis use disorder was not associated with any dimension of impulsivity, whereas alcohol use disorder was positively correlated to impulsive thoughtless gestures (standardized β = 0.213, P = 0.027) and cocaine use disorder with proneness to boredom (standardized β = 0.290, P = 0.002). Finally, logistic regression analysis revealed that, unlike cannabis and cocaine use disorders, alcohol use disorder (odds ratio, 3.964; 95% confidence interval, 1.729-9.087; P = 0.001) was a factor associated with violence., Implications/conclusions: These findings show that cannabis and alcohol are largely abused and coabused by psychotic patients with a propsensity for violence, but only alcohol is associated with impulsive and violent behavior. Therefore, especially alcohol abuse should be seriously considered by practitioners when evaluating the dangerousness of patients with schizophrenia spectrum disorders., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Mutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by early dysfunction and loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). No therapy is currently available to prevent or slow down the neurodegeneration in ARJP patients. Preclinical models are key to clarifying the early events that lead to neurodegeneration and reveal the potential of novel neuroprotective strategies. ParkinQ311X is a transgenic mouse model expressing in DA neurons a mutant parkin variant found in ARJP patients. This model was previously reported to show the neuropathological hallmark of the disease, i.e., the progressive loss of DA neurons. However, the early dysfunctions that precede neurodegeneration have never been investigated. Here, we analyzed SNc DA neurons in parkinQ311X mice and found early features of mitochondrial dysfunction, extensive cytoplasmic vacuolization, and dysregulation of spontaneous in vivo firing activity. These data suggest that the parkinQ311X mouse recapitulates key features of ARJP and provides a useful tool for studying the neurodegenerative mechanisms underlying the human disease and for screening potential neuroprotective drugs.

Background: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive., Methods: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose-response effects of cumulative LSD doses (5-160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex., Results: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose-response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D 2 ) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex., Conclusion: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D 2 -mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

The most frequent form of dementia is Alzheimer's Disease (AD), a severe progressive neurological pathology in which the main cognitive functions of an individual are compromised. Recent studies have found that loneliness and living in isolation are likely to cause an acceleration in the cognitive decline associated with AD. Therefore, understanding social behaviours of AD patients is crucial to promote sociability, thus delaying cognitive decline, preserving independence, and providing a good quality of life. In this work, we analyze the localization data of AD patients living in assisted care homes to gather insights about the social dynamics among them. We use localization data collected by a system based on iBeacon technology comprising two components: a network of antennas scattered throughout the facility and a Bluetooth bracelet worn by the patients. We redefine the Relational Index to capture wandering and casual encounters, these being common phenomena among AD patients, and use the notions of Relational and Popularity Indexes to model, visualize and understand the social behaviour of AD patients. We leverage the data analyses to build predictive tools and applications to enhance social activities scheduling and sociability monitoring and promotion, with the ultimate aim of providing patients with a better quality of life. Predictions and visualizations act as a support for caregivers in activity planning to maximize treatment effects and, hence, slow down the progression of Alzheimer's disease. We present the Community Behaviour Prediction Table (CBPT), a tool to visualize the estimated values of sociability among patients and popularity of places within a facility. Finally, we show the potential of the system by analyzing the Coronavirus Disease 2019 (COVID-19) lockdown time-frame between February and June 2020 in a specific facility. Through the use of the indexes, we evaluate the effects of the pandemic on the behaviour of the residents, observing no particular impact on sociability even though social distancing was put in place.

Synapsins (Syns) are a family of phosphoproteins associated with synaptic vesicles (SVs). Their main function is to regulate neurotransmitter release by maintaining a reserve pool of SVs at the presynaptic terminal. Previous studies reported that the deletion of one or more Syn genes in mice results in an epileptic phenotype and autism-related behavioral abnormalities. Here we aimed at characterizing the behavioral phenotype and neurobiological correlates of the deletion of Syns in a Syn triple knockout (TKO) mouse model. Wild type (WT) and TKO mice were tested in the open field, novelty suppressed feeding, light-dark box, forced swim, tail suspension and three-chamber sociability tests. Using in vivo electrophysiology, we recorded the spontaneous activity of dorsal raphe nucleus (DRN) serotonin (5-HT) and ventral tegmental area (VTA) dopamine (DA) neurons. Levels of 5-HT and DA in the frontal cortex and hippocampus of WT and TKO mice were also assessed using a High-Performance Liquid Chromatography. TKO mice displayed hyperactivity and impaired social and anxiety-like behavior. Behavioral dysfunctions were accompanied by reduced firing activity of DRN 5-HT, but not VTA DA, neurons. TKO mice also showed increased responsiveness of DRN 5-HT-1A autoreceptors, measured as a reduced dose of the 5-HT-1A agonist 8-OH-DPAT necessary to inhibit DRN 5-HT firing activity by 50%. Finally, hippocampal 5-HT levels were lower in TKO than in WT mice. Overall, Syns deletion in mice leads to a reduction in DRN 5-HT firing activity and hippocampal 5-HT levels along with behavioral alterations reminiscent of human neuropsychiatric conditions associated with Syn dysfunction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT 2A , but not N -methyl-D-aspartate (NMDA) and 5-HT 1A , synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons ( Raptor f/f :Camk2alpha-Cre ), the prosocial effects of LSD and the potentiation of 5-HT 2A /AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC ( Raptor f/f :Gad2-Cre ), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT 2A /AMPA receptors and mTOR signaling. The activation of 5-HT 2A /AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder., Competing Interests: Competing interest statement: G.G. is a consultant at Diamond Therapeutics Inc, Toronto, ON, Canada. G.G. and D.D.G. are inventors of a provisional patent regarding the use of LSD., (Copyright © 2021 the Author(s). Published by PNAS.)

Melatonin (MLT) is widely used to treat sleep disorders although the underlying mechanism is still elusive. In mice, using wheel-running detection, we found that exogenous MLT could completely recover the period length prolonged by N-methyl-D-aspartate receptor (NMDAR) impairment due to the injection of the NMDAR antagonist MK-801, a preclinical model of psychosis. The analysis of the possible underlying mechanisms indicated that MLT could regulate the homeostatic state in the ventrolateral preoptic nucleus (VLPO) instead of the circadian process in the suprachiasmatic nucleus (SCN). In addition, our data showed that MK-801 decreased Ca 2+ -related CaMKII expression and CREB phosphorylation levels in the VLPO, and MLT could rescue these intracellular impairments but not NMDAR expression levels. Accordingly, Gcamp6 AAV virus was injected in-vivo to further monitor intracellular Ca 2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca 2+ fluorescence compared with MK-801-injected mice. Additionally, using the selective melatonin MT 2 receptor antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT 2 receptors. Using electroencephalography/electromyography (EEG/EMG) recordings, we observed that the latency to the first nonrapid eye movement (NREM) sleep episode was delayed by MK-801, and MLT was able to recover this delay. In conclusion, exogenous MLT by acting upon melatonin MT 2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca 2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Depression and anxiety symptoms are highly prevalent among women during pregnancy and post-partum. Previous studies suggest that one of the pathophysiological underpinnings could be an enhanced metabolism of tryptophan (Trp) into kynurenine (Kyn) due to increased inflammation. However, the longitudinal changes in the Kyn pathway and the complex interplay with inflammation and stress in women with perinatal depressive or anxiety symptoms are incompletely understood. We examined a cohort of healthy women at 34-36 gestational weeks. One hundred and ten women were assessed for salivary cortisol and 97 participants were also assessed for serum levels of Trp, Kyn and Interleukin 6 (IL-6). Women filled in two screening questionnaires for depressive (Edinburgh Postnatal Depression Scale (EPDS)) and anxiety (State Trait Anxiety Inventory subscale (STAI-S)) symptoms at 34-36 gestational weeks, delivery, 3 and 12 months postpartum. Unexpectedly, lower prenatal Kyn levels were associated with higher depressive symptoms in late pregnancy. Furthermore, prenatal Trp levels and the Kyn/Trp ratio moderate the association between IL-6 levels and depressive symptoms during the perinatal and the post-partum period. We found no interactions between Trp and Kyn biomarkers and cortisol on depressive symptoms. The observed associations were more robustly found for depressive symptoms, whereas weak and non-significant effects were found for the trajectory of anxiety symptoms. Overall, our data support the involvement of the Trp to Kyn pathway and inflammation in the course of depressive but not anxiety symptoms in women from late pregnancy until one-year post-partum, providing new evidence on the mechanisms regulating emotions during pregnancy and after delivery in a low-risk sample., (Copyright © 2020 Elsevier Inc. All rights reserved.)