搜索结果：Neuropsychopharmacology

Transdiagnostic, dimensional frameworks such as the Research Domain Criteria (RDoC) are increasingly regarded as promising vehicles for precision neuropsychiatric drug development, yet no treatment has been approved that was explicitly developed according to such principles. This work, conducted under the aegis of the European College of Neuropsychopharmacology Thematic Working Group on Clinical Outcomes in Early-Phase Clinical Trials, synthesises seven structured multidisciplinary expert meetings supported by a narrative literature review to delineate opportunities and barriers for implementing RDoC in early-phase clinical development. We identify four key operational domains that condition the success of RDoC-aligned programmes: (1) terminology clarity and working definitions for RDoC-aligned trials and target constructs; (2) construct-enriched population selection methodologies; (3) selection, development or modification of construct-aligned clinical outcome assessments that are fit-for-purpose in transdiagnostic research settings; and (4) navigation of regulatory frameworks that remain anchored in categorical diagnoses. Through selected illustrative cases-most notably the aticaprant development program targeting anhedonia in mood and anxiety disorders-we demonstrate how early phase RDoC-aligned trial designs can be compromised at the pivotal stage by the absence of validated endpoints and regulatory constraints on labelling. On this basis, we propose pragmatic recommendations, including consensus-based definitions, registry tagging of RDoC-aligned trials, data-driven biomarker-based transdiagnostic enrichment strategies (i.e., biotyping), and early, iterative engagement with regulators and health technology assessment agencies. Systematic attention to these domains is required for enabling the development of neurobiologically RDoC informed treatments to be delivered to the right patients at the right time.

Introduction: Antipsychotic (AP) medications are widely prescribed beyond psychotic disorders, yet their long-term safety profile regarding breast cancer (BC) risk remains uncertain. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating the association between AP exposure and incident BC. Eligible studies reported adjusted odds ratios (ORs) with 95% confidence intervals for any AP, prolactin-increasing antipsychotics (PIAPs), or prolactin-sparing antipsychotics (PSAPs). Study quality was assessed using the modified Newcastle-Ottawa Scale (mNOS), and certainty of evidence was graded with the GRADE framework. Random-effect models were used to pool effect estimates by exposure category, duration, and cumulative Defined Daily Dose (DDD). Results: Nine high-quality observational studies encompassing 108 effect estimates were included. Most studies achieved mNOS scores of 9, yet GRADE certainty ranged from very low to moderate, with the overall body of evidence graded as low certainty due primarily to residual confounding. Any AP exposure was associated with a modestly increased BC risk, particularly with long-term use: use for >5 years yielded pooled ORs around 1.5-1.6, while short-to-medium duration (1-5 years) showed smaller increases (pooled ORs in the range 1.2-1.3). For PIAPs, both longer duration (>5 years) and higher cumulative exposure (>1000-2000 DDDs) were consistently associated with ORs/HRs in the 1.3-1.6 range, suggesting a possible dose-response pattern. Histological analyses indicated stronger associations for ductal than lobular BC, and elevated risks were observed across age strata, including women aged <55 and &#x2265;70 years. Discussion: This meta-analysis suggests that chronic exposure to prolactin-increasing antipsychotics is associated with a potentially clinically relevant increase in BC risk, whereas prolactin-sparing agents do not show a clear signal of harm. However, the certainty of this association is limited by inconsistently measured confounders and by the observational nature of the data. These findings support a cautious, individualized approach in which clinicians preferentially consider PSAPs when appropriate, discuss BC risk as part of shared decision-making, and integrate tailored screening strategies for women requiring long-term PIAP therapy. Further high-quality pharmacoepidemiologic studies with better confounder control and mechanistic integration are needed to refine risk estimates and inform preventive neuropsychopharmacology.

The serotonergic system remains a critical focus of neuropsychopharmacology due to its widespread influence on mood, cognition, and behavior. Despite the clinical success of selective serotonin reuptake inhibitors (SSRIs), their long-term efficacy is limited by receptor heterogeneity, desensitization, and compensatory adaptations. Recent advances suggest that ligands simultaneously modulating two serotonin (5-HT) receptor subtypes may offer superior therapeutic outcomes. This perspective summarizes progress in developing such dually acting compounds for CNS disorders, including Alzheimer's and Parkinson's disease, schizophrenia, and mood disorders. Clinically relevant examples include flibanserin (5-HT1A receptor agonist/5-HT2A receptor antagonist), pimavanserin (5-HT2A/5-HT2C receptors inverse agonist), and eltoprazine (5-HT1A/5-HT1B receptors partial agonist), alongside experimental 5-HT2A/5-HT6, 5-HT3/5-HT6 or TAAR1/5-HT2C receptors ligands. Integrating structure-activity insights and clinical findings, we discuss challenges of rational dual modulation. Advances in biased signaling, targeting distinctive conformational states, and optopharmacology utilizing photochromic ligands may further enable the design of innovative dually acting agents with improved efficacy and safety profiles.

Adolescence represents a critical neurodevelopmental period of high vulnerability to the onset of psychiatric conditions. Altered processing of uncertain reward outcomes likely contributes to this vulnerability, yet remains poorly understood. Addressing this knowledge gap, we sought to use the fMRI Reward Flanker Task, originally developed by our group, to examine neural responses to uncertain rewards and their clinical associations. To fully capture clinical correlates, we recruited adolescents with mood and anxiety symptoms ranging from low to high severity, including healthy controls (HC). Participants were 84 psychotropic-medication-free adolescents (15.3&#x2009;&#xb1;&#x2009;2.1 years; 62% female; 17 HC); all completed diagnostic and dimensional symptom assessments. Neuroimaging data were preprocessed using Human Connectome Project pipelines. Analyses examined participant-level neural responses to uncertain reward expectancy and attainment, adjusted for age, sex, and multiple comparisons. Across the whole sample, uncertain versus certain cues activated the default network and suppressed the fronto-parietal control network. Neural responses during expectancy to uncertain reward were intermediate between responses to certain reward and non-reward stimuli. Outcome attainment following uncertain cues activated stronger neural responses in reward and salience regions compared to reward cues. Anhedonia severity correlated with default network activation during uncertain outcome attainment. Anxiety severity correlated with blunted striatal responses during uncertain vs. certain non-reward expectancy. Exploratory group comparisons revealed that adolescents with mood and anxiety symptoms versus HC showed blunted striatal responses during uncertain versus non-reward expectancy and hyperactivation in visual and default network areas during attainment following uncertain cues. Together, these findings support the role of uncertain reward processing in adolescent mood and anxiety psychopathology.

The prevalence of obesity is rising worldwide in young people and is associated with poor long-term health outcomes. To counter obesity, weight loss strategies especially involve changes in feeding behaviors and food choice. However, the high level of relapse to unhealthy dietary habits represents an important challenge, suggesting long-term alterations of decision-making and food-seeking processes. Previous studies showed that adolescence is critical for the development of decision-making functions. Thus, it is essential to understand the precise impact of the exposure to obesogenic diets during this life stage on the different processes underlying flexible control of food-seeking actions. To address this, we gave mice access to high-fat diets (HFDs) with different fat contents during adolescence and investigated the long-lasting impact on action control at adulthood after a switch to a healthy diet. We uncovered important sex differences. In both males and females, exposure to HFD with very high-fat content (60%) promoted habitual behavior, which is less flexible to adapt to changes in outcome value or action-outcome relationships. In contrast, exposure to HFD with lower fat content (45%) impaired action control based on the updating of outcome value in males only, while impairing action control based on the updating of action-outcome relationships in females only. These findings highlight how the consumption of obesogenic diets during adolescence has long-lasting, diet- and sex-dependent effects on decision-making processes, promoting habitual responses to food. These changes may support long-term vulnerability for mental and physiological health conditions.

Suicide attempts (SA) and suicidal ideation (SI) are major public health concerns with incompletely understood underlying genetic and molecular mechanisms. We investigated the shared genetic architecture of SA and SI with 13 genetically correlated psychiatric, behavioural, and somatic phenotypes using summary statistics from 15 genome-wide association studies (N=46,350-975,353). Local Analysis of [co]Variant Association (LAVA) quantified locus-specific genetic covariance, while conjunctional false discovery rate (conjFDR) identified pairwise jointly associated genetic variants. Functional annotation and enrichment analyses characterised pathways and tissue-expression patterns. LAVA identified 16 loci with significant local correlations, mapping to 493 unique genes. After conditioning on depression and post-traumatic stress disorder, several locus-trait-pair correlations remained significant, including SI-ADHD, whose mapped genes were differentially expressed in hypothalamus, cortical regions, and peripheral tissues. Correlated loci implicated ion transport and transcriptional regulation. ConjFDR identified shared loci mapping to 798 unique genes, enriched for pathways involving cell adhesion, neurogenesis, signal transduction, chromatin regulation, immune processes, and protein secretion. Stratified analyses showed that SA pairs were enriched for gene sets related to brain morphology, cognition, and sleep regulation, whereas SI pairs for gene sets related to neuroticism, body mass index, and gastrointestinal traits. Shared loci displayed mixed effect directions. Both SA and SI were enriched for gene sets involving glycine, serine, and threonine metabolism, systemic lupus erythematosus, and DNA damage- and telomere stress-induced senescence. Recurrently mapped genes exhibited region- and developmental stage-specific brain expression. These findings refine the genetic architecture of suicide and implicate neurodevelopmental, immune, metabolic, and chromatin-related mechanisms in suicidal thoughts and behaviours.

Severe and/or repeated stress exposure can lead to a number of maladaptive physiological and behavioral changes that contribute to psychiatric illnesses. Recent work indicates that the neuropeptide pituitary-adenylate-cyclase-activating-polypeptide (PACAP) plays an important role in stress-related psychopathologies relevant to depression and trauma-related disorders such as PTSD. However, the specific neural circuits that mediate PACAP effects on stress function are not fully understood. One candidate area is the lateral septum (LS), a limbic structure where PACAP and its cognate PAC1 receptors are abundantly expressed. Despite this neuroanatomical evidence, direct functional data supporting a role for septal PACAP/PAC1 receptor signaling in stress regulation are lacking. Using quantitative PCR, we show that forced swim stress increases PACAP mRNA expression in several limbic areas, including the LS, bed nucleus of the stria terminalis and basolateral amygdala, while chronic variable mild stress reduced PACAP expression in the LS only. Providing functional evidence of a PACAP/stress interaction, local administration of PACAP38 into the LS potentiated stress-induced ACTH release and altered stress-coping behavior by increasing passive (floating) and reducing active (struggling) coping during a forced swim challenge. Moreover, intraseptal PACAP38 administration significantly increased anxiety-like behavior in the elevated plus-maze and reduced grooming behavior in the sucrose splashtest, indicating anxiogenic and motivationally disruptive effects following enhanced PACAP signaling in the LS. Importantly, to assess the contribution of endogenous PACAP signaling, intra-LS administration of the PACAP receptor antagonist PACAP(6-38) produced a robust anxiolytic phenotype in the elevated plus-maze. Collectively, these findings provide the first direct evidence that PACAP/PAC1 receptor signaling in the LS modulates emotional and motivational processes in response to stress, identifying this system as a potential target for neuromodulatory interventions in stress-related psychiatric disorders.

Posttraumatic stress disorder (PTSD) is a highly heterogeneous psychiatric disorder, complicating efforts to identify consistent biological markers and develop targeted treatments for individuals exposed to trauma. Recent research has identified a distinct intrusive-hypervigilant (IH) phenotype, which is characterized by heightened intrusive reexperiencing and hypervigilance symptoms along with elevated levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide involved in stress response via amygdala signaling. In an independent sample of 172 symptomatic trauma-exposed adults, we replicated this IH phenotype using latent profile analysis of Clinician-Administered PTSD Scale for DSM-5 symptom severity ratings and expanded its biological characterization using resting-state functional magnetic resonance imaging (rs-fMRI). Consistent with prior work, the identified IH group demonstrated more severe intrusive reexperiencing (Cohen's d's = 0.61-6.93) and hypervigilance symptoms (d's = 0.57-0.88) and higher PACAP levels compared to groups with generally High (d&#x2009;=&#x2009;0.35) or Low (d&#x2009;=&#x2009;0.44) symptom severity. Additionally, the IH phenotype exhibited stronger functional connectivity of the centromedial, but not basolateral, amygdala with regions in the occipital cortex (d's = 0.78-0.95), precuneus (d's = 1.20-1.21), and medial prefrontal cortex (d's = 0.81-1.18)-areas primarily within the Default Mode and Visual Networks. Meta-analytic decoding linked these regions to mental imagery, memory processing, fear, and threat perception. These findings support the existence of an IH phenotype of posttraumatic stress that may exhibit a distinct biological profile, characterized by exaggerated interactions between memory, threat, and arousal systems that may be mediated by PACAP and its effects on amygdala connectivity. This phenotype may serve as a promising target for precision psychiatry approaches, including pharmacological and neurotherapeutic interventions that modulate PACAP signaling and amygdala connectivity.

The present study determined the effectiveness of the glucagon-like peptide 1 agonist semaglutide to attenuate cocaine-vs-food choice in male and female rats. Repeated 5-day semaglutide treatment decreased cocaine choice and significantly reduced body weight. These preclinical results support the clinical evaluation of semaglutide as a candidate cocaine use disorder medication.

Antipsychotic drugs exert their therapeutic effects through dopamine D2-like receptor blockade but are also associated with clinically significant dysglycaemia. Whether these metabolic effects reflect consistent actions on peripheral dopaminergic targets, including pancreatic &#x3b2;-cell D2-like receptors, remains uncertain. We conducted a systematic review and meta-analysis of preclinical in vitro and ex vivo studies examining the effects of dopamine, D2-like receptor agonists and antagonists on insulin secretion in isolated pancreatic islets or &#x3b2;-cell lines. PubMed, Embase, and PsycINFO were searched from inception to Sept 22, 2025. Two reviewers independently screened studies, extracted data, and performed random-effects meta-analyses with subgroup and meta-regression analyses assessing glucose concentration, compound type, and dose. 39 studies met inclusion criteria, with 37 included in the metanalysis. Dopamine and D2-like receptor agonists showed no significant effect under low-glucose conditions but robustly inhibited glucose-stimulated insulin secretion (GSIS) in rodent and rabbit models (g = -2.36; 95% CI: -2.77 to -1.96; P&#x2009;<&#x2009;0.0001 & g = -1.98; 95% CI&#x2009;-&#x2009;2.88 to -1.09; p&#x2009;<&#x2009;0.0001 respectively), with greater GSIS suppression at higher glucose concentrations and dopamine doses. Though D2-like receptor antagonists alone had no significant effect (g = -0.25, 95% CI -0.68 to 0.18, P&#x2009;=&#x2009;0.25), these drugs blocked GSIS inhibiton by co-administered dopamine (g&#x2009;=&#x2009;1.59 [0.76 to 2.42]; p&#x2009;=&#x2009;0.0002). These findings demonstrate that D2-like receptor activation inhibits pancreatic &#x3b2;-cell insulin secretion in a glucose- and dose-dependent manner, whereas receptor blockade reverses this effect, identifying a peripheral dopaminergic mechanism that may contribute to antipsychotic drug-associated dysglycaemia independent of weight gain. Together, these findings highlight the need for metabolic monitoring beyond weight alone in response to treatment with antipsychotic medications.

Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease.

Attention-deficit/hyperactivity disorder (ADHD) is a disorder marked by inattentiveness and/or hyperactivity and increased impulsivity. A common treatment for ADHD is stimulant medications, with a formulation of methylphenidate or amphetamine. Although stimulant medication is effective in most patients, 40% show no response. There have been attempts to predict stimulant efficacy through neuroimaging and electroencephalograms; however, these methods are expensive and not sustainable in day-to-day clinical practices. This study aimed to identify clinical factors that could be used to predict which patients would best respond to stimulants. The reporting of this study conforms to the STROBE statement. This was a naturalistic prospective observational study. Thirty-six medication-na&#xef;ve adults with ADHD were prescribed stimulant medication and naturalistically followed for an average of 116&#x2009;days. Demographics, type of stimulant, and seven clinical rating scales were analyzed to identify response predictors. Truncated Poisson regressions, stepwise logistic regressions, receiver operating characteristic curve analysis, and Bonferroni corrections were performed. Executive function impairment and better quality of life were found to be the best indicators for stimulant response. Higher scores on Adult Self-Report (ASR) Thought Problems, Withdrawn Problems, Internalizing Problems, and Intrusive Thoughts were indicative of lower stimulant efficacy. Poorer working memory and task monitoring also predicted lower stimulant response. These clinical measures could aid clinicians and patients in predicting who would better respond to stimulant medications and reduce the time that patients wait before finding an effective treatment. Executive functioning, quality of life, and ASR profile measurements can be used to best manage ADHD symptomology.

Cannabidiol (CBD) is widely perceived as a safe and effective treatment for a growing list of health indications and use for general wellness. Evidence for its safety and efficacy comes from a variety of sources, including preclinical studies, clinical trials, and observational studies of real-world evidence. The challenge in interpreting these data is that CBD products are diverse with respect to format, formulation, intended route of administration, dose, and regulatory oversight with regard to quality assurance and labeling. This Circumspectives article presents two perspectives: one emphasizing CBD's potential as a pharmacologically diverse therapeutic agent with tremendous potential to treat debilitating health conditions for which there are limited alternative therapies and another highlighting concerns with the quality of existing evidence, misapplications of use, and risks related to both direct effects of CBD as well as quality control issues with retail products that lack proper regulatory oversight. Finally, these perspectives are integrated to provide guidance for reducing variability and improving clinical translation in CBD research.

We hypothesized that Restless Legs Syndrome (RLS) and the restlessness of opioid withdrawal share common neurobiological mechanisms based on the efficacy of &#x3bc;-opioid receptor (MOR) agonists in RLS and the common RLS-like phenotype of patients with opioid withdrawal. We also hypothesized this involves an increased sensitivity of the striatal striosomal neurons that co-express MORs and dopamine D1 receptors (D1Rs) and release GABA in the internal segment of the globus pallidus (GPi). This hypothesis was tested in mice with diet-induced brain iron deficiency (BID), a rodent model of RLS. Fiber-photometry experiments were performed in mice with BID using a viral GABA biosensor injected in the entopeduncular nucleus (EPN), the GPi equivalent in rodents. EPN GABA release was measured after the systemic administration of the D1R agonist SKF81297 and the MOR agonist methadone. Locomotor activation and striatal mRNA expression of D1Rs, MORs and adenosine A1 receptors (A1Rs) were also analyzed. A minimal locomotor-activating dose of SKF81297 induced a significant EPN GABA release in mice with BID but not controls, while a maximal locomotor-activating dose of the MOR agonist methadone significantly reduced EPN GABA release in mice with BID after saline or SKF81297 administration. BID was associated with a significant reduction in the striatal expression of MORs and A1Rs. The results indicate that BID induces an increased dopaminergic sensitivity of the opioid-responsive striatal-EPN pathway, which might represent a pivotal pathogenetic mechanism of the restlessness of RLS and opioid withdrawal.

暂无摘要（点击查看详情）

Mesolimbic dopamine (DA) neurons are central to cue-guided reward seeking and action sequence learning. Yet, the mechanisms by which cue-induced DA neural activity drives goal-directed or habitual sequence execution remain unknown. We designed two novel tasks to isolate the effect of sequence-delineating cues on DA-driven behavioral strategies and learning. In the lever insertion fixed-ratio 5 task (LI5), the lever insertion marked sequence initiation. In the lever retraction fixed-ratio 5 task (LR5), the lever retraction served as both sequence termination and reward-predictive cue. We found that sequence initiation and termination cues differentially affect reward expectation during action sequences, with only the termination cue contributing to greater outcome devaluation insensitivity, automaticity and behavioral chunking. Mesolimbic fiber photometry recording revealed that this habit-like behavior was associated with a rapid backpropagation in DA signals from the reward to the immediately preceding cue and with attenuated DA reward prediction error signals, which reflected greater behavioral inflexibility. Finally, in absence of external cues, brief optogenetic stimulation of VTA DA neurons at sequence termination was sufficient to drive automaticity and, to some extent, behavioral chunking. Our results highlight the critical role of cue-evoked DA signals at sequence termination in driving the development of automated, habit-like sequence execution.

Evolutionarily conserved neural circuits evolved that mediate switching between feeding and foraging for food, depending on environmental conditions such as food scarcity and internal state [1-3]. Activity-based anorexia is a phenomenon observed ubiquitously in normal mammals that emerges under conditions of time-restricted food availability and continuous access to running wheels. Under these experimental conditions, rodents progressively lose body weight and develop paradoxical hypophagia and compulsive wheel running, which can prove fatal if left unchecked. On the other hand, rodents survive indefinitely under conditions of either time-restricted food access or running wheel availability. In this review, we discuss preclinical studies within the past decade which used modern genetic circuit-dissecting tools including chemogenetic, optogenetic, and calcium imaging, to dissect the neural circuitry modulating activity-based anorexia. We highlight how circuits interconnecting the hypothalamus, prefrontal cortex, amygdala, mesolimbic system, and monoaminergic nuclei, interact to modulate animals' decision to feed or forage in the activity-based anorexia paradigm. We then highlight how these recent findings have aided in identifying pathophysiological mechanisms underlying neuropsychiatric disorders characterized by the maladaptive prioritization of exercise over feeding. Finally, we suggest approaches for the development of targeted therapeutics for anorexia nervosa, which has no approved pharmacological treatments.

Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in persons with ASD and related animal models, encouraging the idea that benefits might extend to cognitive function. We tested this possibility in male FXS model, Fmr1-knockout (KO) mice. Intranasal treatments with OXT or saline were given daily during the second or fifth postnatal week, and effects on social behavior, spatial and episodic memory, and hippocampal synaptic plasticity were assessed in adulthood. Saline-treated Fmr1-KOs exhibited profound deficits in social recognition, object location memory, what-when-where components of episodic memory and long-term potentiation (LTP) in both the CA3-CA1 and lateral perforant path (LPP) systems; NMDAR-mediated components of LPP responses were also impaired. OXT treatments during the second week postnatal normalized all of these functions in Fmr1-KOs assessed in adulthood; this included restoration of initial stages of CA3-CA1 LTP and granule cell NMDAR-mediated currents. In hippocampal slices from na&#xef;ve adult male Fmr1-KO mice, bath-applied OXT treatment restored LTP in CA1 but not the LPP, indicating pathway-specific effects. Intranasal OXT treatments during the 5th week postnatal did not have enduring effects in either genotype. The present evidence that early OXT treatment corrects a broad range of cognitive and synaptic plasticity deficits in Fmr1-KO mice identifies a clinically plausible strategy for normalizing hippocampal function in ASD and FXS, and highlights the presence of a critical developmental window for effective intervention.