International Journal of Neuropsychopharmacology最新文献

Objective: Preclinical evidence suggests that modulating neural excitation through administration of diazepam, a positive allosteric modulator of GABAA receptors, can prevent the emergence of behavioral and neurobiological alterations relevant to psychosis in adulthood.

Design and participants: Here, we examine this neurochemical mechanism in individuals at clinical high risk for psychosis in a randomized, double-blind, placebo-controlled crossover study. Twenty-four individuals (15 female and 9 male) aged 18-35 were scanned twice using proton magnetic resonance spectroscopy to measure anterior cingulate cortex Glx (glutamate and glutamine) levels, once after a single dose of diazepam (5 mg) and once after placebo.

Results: Mixed-effects model analyses revealed that diazepam reduced anterior cingulate cortex Glx levels compared to placebo (t(20.8) = -2.14, P = .04). The effect of diazepam on Glx levels was greater in older individuals at clinical high risk for psychosis (t(12) = -4.36, P = .001).

Conclusion: These findings suggest that pharmacological modulation of GABAA receptors can alter Glx changes in and support a novel therapeutic mechanism of benefit for individuals at clinical high risk of psychosis.

Objective: Ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) act via the growth hormone secretagogue receptor (GHSR), which modulates feeding, alcohol use, and endocrine and immune system function. The GHSR blocker PF-5190457 has potential as a novel pharmacotherapy for alcohol use disorder (AUD). This study aimed to characterize the effects of PF-5190457 on endocrine and immune markers in individuals with AUD.

Methods: Pre-planned analyses used data from a randomized, double-blind, placebo-controlled, crossover human laboratory study in recently abstinent inpatients with AUD (N = 29; 8 females). Participants received PF-5190457 (100 mg twice daily) or matched placebo for 5+ days, separated by 2+ washout days. Blood was collected daily prior to dosing (T1). On days 4+, behavioral testing occurred post-dosing, followed by an additional blood collection ~2 hours post dosing (T2). Pharmacokinetic (PK: PF-5190457 and its active metabolite PF-6870961) and pharmacodynamic (PD: comprehensive panel of endocrine and immune markers) parameters were assessed over the course of dosing days. Additional exploratory analyses examined relationships between PK, PD, and behavioral measures.

Results: PF-5190457 and PF-6870961 concentrations peaked at T2 and were elevated at T1 under drug vs placebo. LEAP2 levels were reduced under drug vs placebo but rebounded on the first washout day. PF-5190457 dramatically reduced growth hormone (GH) at T2, followed by an elevation of GH at T1 the following day. No other endocrine or immune markers differed significantly between drug and placebo. GH at T1 negatively correlated with the number of calories selected during a cafeteria-like virtual reality buffet experiment under drug, but not placebo conditions.

Conclusions: GHSR blockade with repeated dosing of PF-5190457 changed LEAP2 and GH concentrations but produced overall negligible effects on the endocrine and immune systems. These results further characterize the ghrelin system in AUD and its potential as a therapeutic target.

Trial registration: ClinicalTrials.gov Identifier: NCT02707055; registered November 3, 2016.

Objective: Increasing evidence has suggested a potential role of glymphatic system function in the pathomechanisms underlying mood disorders and related cognitive impairment. However, this association in bipolar disorder remained unclear.

Design, participants, and measures: In all, 185 patients (mean age ~ 30 years) with bipolar disorder and 95 healthy individuals were enrolled for the assessment of the go/no-go task and the digit symbol substitution test (DSST). The Analysis Along the Perivascular Space (ALPS) index, an indicator of glymphatic system activity, was measured using diffusion tensor imaging within diffusion magnetic resonance imaging. All participants were divided into two subgroups (< vs. ≥ mean level) based on the mean ALPS index level. Additionally, participants were further categorized into quartiles based on ALPS index levels, ranging from Q1 (highest) to Q4 (lowest).

Results: Generalized linear model, after adjusting for age, sex, education years, and clinical symptoms, found no difference in the ALPS index levels between patients and controls. Patients with lower ALPS index levels-that is, those with values below the mean or in the lowest quartile (Q4)-performed the worst on the DSST and the go/no-go task.

Conclusions and relevance: Glymphatic system dysfunction appeared to play a critical role in cognitive impairment among patients with bipolar disorder, but not in healthy individuals. Further research is warranted to clarify the specific pathomechanisms underlying this bipolar disorder-specific association between glymphatic system dysfunction and cognitive deficits.

Background: Major depressive disorder (MDD) is a debilitating condition that is commonly treated with antidepressants. However, many people do not respond to treatment, and the molecular mechanisms underlying antidepressant response remain poorly understood. Baseline DNA methylation differences have been observed between individuals who respond to treatment compared to those who do not respond, however little is known regarding DNA methylation changes that occur during treatment or how they may relate to clinical response.

Methods: We assessed peripheral levels of DNA methylation and gene expression, at baseline, and after 8 weeks of treatment, in 154 individuals with MDD who were treated with escitalopram or desvenlafaxine, using the Infinium MethylationEPIC Beadchip and RNA sequencing. We identified methylation sites whose levels changed over time in relation to changes in depressive symptoms, as well as corresponding changes to gene expression levels after 8 weeks of treatment.

Results: We identified two sites, in SCN7A and IQANK1, whose methylation changes over time were correlated with changes in depressive symptoms at the epigenome-wide level. Gene ontology analyses of genes displaying response-related methylation changes highlighted several processes previously implicated in depression, including small GTPase-related signaling and the Wnt signaling pathway. Additionally, we identified methylation sites in 10 genes that displayed significant changes in methylation over time in relation to improvement of depressive symptoms, whose expression levels at week 8 were correlated with level of depressive symptoms, and for which methylation levels were functionally related to gene expression.

Conclusions: Antidepressant treatment response is associated with changes in peripheral DNA methylation over time, as well as corresponding alterations in gene expression.

Background: Response to naltrexone varies among individuals with alcohol use disorder (AUD). Studies in Western populations have linked the sweet-liking (SL) phenotype, reflecting an individual's hedonic response to sweet taste, to improved outcomes with naltrexone. However, cultural and ethnic variations in SL raise questions about the generalizability of this association. This exploratory investigation examined the relationship between SL phenotype and naltrexone treatment outcomes in Taiwanese patients with AUD.

Methods: Patients with DSM-5-defined severe AUD who had completed alcohol withdrawal were enrolled in an 8-week open-label naltrexone trial. Participants completed a sweet taste test and were categorized into SL or sweet-disliking (SDL) groups. Outcomes included alcohol consumption (drinking days per week, heavy drinking days per week, drinks per drinking day, abstinent days), alcohol craving, and depression and anxiety severity. Generalized estimating equations were used to assess the effects of time, group, and their interaction.

Results: Ninety-one patients were enrolled (SL: n = 44; SDL: n = 47). Baseline characteristics were comparable between groups, except for smoking-related variables. After adjusting for smoking, both groups showed improvements in alcohol use and psychological measures over time. A significant group-by-time interaction was found for drinks per drinking day, with the SL group showing more favorable outcomes than the SDL group (P = 0.03).

Conclusions: This is the first exploratory investigation in Asians to assess SL phenotype in relation to naltrexone response in AUD patients. The SL phenotype was associated with reduced alcohol consumption over 8 weeks of naltrexone treatment, supporting SL phenotype as a potential biomarker for personalized AUD treatment.

Background: Segmenting continuous experience into discrete units-event segmentation-is fundamental for situational awareness and adaptive action. Based on Event Segmentation Theory (EST), we used auricular transcutaneous vagus nerve stimulation (atVNS) to test whether the control of event segmentation is moderated by norepinephrine (NE) and/or GABAergic systems.

Methods: Healthy adults (n = 40) completed a double-blind, counterbalanced experiment in which they watched a narrative movie and indicated perceived event boundaries under active atVNS and sham stimulation while EEG was recorded. Multivariate pattern analysis (MVPA) quantified the decodability of boundary interval (BI) vs. no-boundary interval (NBI), and EEG source reconstruction assessed cortical activation.

Results: Relative to sham, active atVNS reduced the likelihood of segmentation. Converging neurophysiological evidence mirrored this behavioral effect: MVPA revealed lower decoding accuracy for BI and NBI, indicating less distinct neural representational patterns. Source reconstruction showed reduced activation in prefrontal cortex, a region involved in working memory.

Conclusions: Across behavioral and neural measures, atVNS stabilized ongoing event representation and restricted the updating of the current event working model, consistent with a GABAergic modulation of event segmentation. These findings extend prior work linking atVNS to working memory gating and demonstrate its impact on an ecologically relevant cognitive process-event segmentation.

The incidence of cognitive disorders is rising and medications to address cognitive impairments are limited. Phytochemical compounds have had some success in improving cognitive outcomes in preclinical studies. However, the evidence surrounding the implementation of these compounds routinely in (1) improving cognition in healthy individuals or (2) as prophylaxis and treatment against the cognitive sequelae of neurological insult, has not been collated. To address this, the evidence base surrounding the impact of phytochemical agents on cognitive function in healthy individuals were reviewed. Web of Science, PubMed, PsycNET, and AYUSH Research Portal were systematically searched for double-blind and single-blind randomized controlled trials assessing the efficacy of Curcuma longa, Bacopa monnieri, Ocimum tenuiflorum, Camellia sinensis, Centella asiatica, Ganoderma lingzhi, and Rosmarinus officinalis, on cognitive function. Seven studies met inclusion. These examined the impact of either B. monnieri, O. tenuiflorum or C. sinensis. No benefit of B. monnieri or C. sinensis processing speed, attention, working memory, language, psychomotor function or overall cognitive performance. O. tenuiflorum improved reaction times on an executive function task. Further, more methodologically robust trials are recommended of longer duration to investigate the efficacy of phytochemical supplementation for cognition.

Importance: Greater levels of treatment resistance in major depressive disorder (MDD) are associated with lower rates of initial benefit and higher rates of relapse (lower durability).

Objective: Characterize depressive symptoms, function, and quality of life (QoL) over 24 months of adjunctive vagus nerve stimulation (VNS) in participants with markedly treatment-resistant depression.

Design: Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025.

Setting: Outpatient.

Participants: Adults with moderate-severe MDD with ≥ 4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (n = 214).

Interventions: Vagus nerve stimulation and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, and ketamine/esketamine) were characterized over the 12-month extension.

Main outcomes and measures: The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression-Improvement (CGI-I) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in participants without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite measures with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori.

Results: Most participants with substantial benefit maintained their benefit (18-month median = 78.8%; 24-month median = 79.0% across 5 measures), as did participants with at least meaningful benefit at 12 months (18-month median = 83.1%; 24-month median = 81.3% across 7 measures). Furthermore, many participants with no meaningful benefit at 12 months achieved it at 18 (median = 30.6%) and 24 (median = 37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatric modalities.

Conclusions and relevance: Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of participants continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year.

Highlights:

Insomnia is a serious public health concern. As the widely prescribed hypnotics that positively modulate gamma-aminobutyric acid (GABA)A receptor activity have various safety concerns, there is a growing demand for the development of novel hypnotics that act on targets other than GABAA receptor signaling to overcome the drawbacks of current medications. As an alternative target to generate novel hypnotics, the orexin system has recently gained much attention, and 3 dual orexin receptor antagonists (DORAs)-suvorexant, lemborexant, and daridorexant-were launched. However, some doses of these DORAs are associated with a higher incidence of somnolence compared to placebo. Vornorexant is a novel DORA designed to have an improved pharmacokinetic profile-rapid absorption and the shortest half-life among existing DORAs to reduce the risk of residual activity, which has been confirmed in humans. Indeed, it has shown rapid sleep-promoting effects in patients with insomnia, maintaining its activity throughout the night but having a low incidence of next-day residual effects. In this review, we first provide an overview of the role of the orexin system in sleep/wake balance and then describe the profile of a newly developed DORA, vornorexant, from drug discovery to clinical results.