International Journal of Neuropsychopharmacology最新文献

Classic psychedelics have shown promise in the treatment of various neuropsychiatric disorders. However, weak blinding integrity has been argued to limit the interpretability of therapeutic effects observed in psychedelic clinical trials, highlighting the need to explore alternative active placebos. Here, we aimed to describe the drawbacks of current placebo conditions used in classic psychedelic studies, propose criteria for suitable active placebos, and review interventions that may putatively fit these criteria. Considerations for the characteristics of ideal active placebos in classic psychedelic studies include (1) acute psychoactive effects, (2) acute physiological effects, (3) onset and duration of acute effects, (4) safety, and (5) lack of therapeutic effects in the target disease. We identified several pharmacological agents that may have potential as active placebos in trials involving moderate-to-high doses of certain short-acting and long-acting classic psychedelics, as well as low-dose administration and microdosing regimes. To accurately assess the safety and efficacy of classic psychedelics as therapeutics, future research should apply a thoughtful process for selecting active placebos and consider ancillary strategies to improve blinding in trials involving these substances.

Background: The global prevalence of dementia is significantly increasing. Early detection and prevention strategies, particularly for mild cognitive impairment (MCI), are crucial but currently hindered by the lack of established biomarkers. Here, we aimed to develop a high-precision screening method for MCI by combining D-amino acid profiles from peripheral blood samples with noninvasive subject information using nonlinear machine learning (ML) algorithms.

Methods: A cross-sectional study was conducted with 200 participants aged 50-89 years, classified into cognitively normal and MCI-suspected groups based on Mini-Mental State Examination scores. High-throughput techniques were used to analyze the D-amino acid profiles, specifically D-alanine (%) and D-proline (%), in peripheral blood. Correlation analysis was performed between D-amino acid levels in venous and fingertip blood. The predictive performance of various ML models, including Logistic Regression, Random Forest, kernel Support Vector Machine (SVM), and Artificial Neural Network (ANN), was compared.

Results: Nonlinear models (kernel SVM and ANN) that combined D-amino acid profiles with subject information achieved the highest area under the curve values of 0.78 and 0.79, respectively, demonstrating that the combination of D-amino acid profiles and noninvasive subject information is effective in detecting MCI.

Conclusions: Combining D-amino acid profiles with noninvasive subject information using nonlinear ML models, particularly kernel SVM and ANN, shows promise as a high-precision screening tool for MCI. This approach could serve as a cost-effective preliminary screening method before more invasive and expensive diagnostic tests and significantly contribute to the early detection and development of intervention strategies for dementia.

Background and hypothesis: The rate of antipsychotic polypharmacy is high. One risk factor for antipsychotic polypharmacy may be the severity of schizophrenia, including treatment-resistant schizophrenia (TRS). We hypothesized that the institutions that are able to prescribe clozapine present differences in pharmacological treatment even before TRS is diagnosed.

Study design: A total of 8155 patients with schizophrenia were divided into the clozapine-available institution (CAI) group and the clozapine-unavailable institution (CUI) group. The psychotropic prescription rates at discharge were compared between the two groups. Furthermore, to investigate whether the diagnosis of TRS subgroups influenced treatment efficacy, we compared CAIs and CUIs with descriptions of subgroups with TRS (DSTRS) and those without descriptions of subgroups with TRS (NDSTRS).

Results: Compared to the CUI group, the rates of both antipsychotic monotherapy (58.3% vs. 50.7%; P = 2.4 × 10-7) and antipsychotic monotherapy without the concomitant use of other psychotropics (20.4% vs. 15.6%; P = 3.8 × 10-5) were significantly higher in the CAI group. The rate of antipsychotic monotherapy in the CAI with DSTRS group (63.3%) was significantly higher than that in the CAI with NDSTRS group (54.5%; P = 1.4 × 10-12), the CUI with DSTRS group (49.6%; P = 4.9 × 10-9), and the CUI with NDSTRS group (50.9%; P = 2.0 × 10-8). The rate of antipsychotic monotherapy without the concomitant use of other psychotropics in the CAI with DSTRS group (22.6%) was also significantly higher than that in the CAI with NDSTRS group (18.7%; P = 4.7 × 10-4), the CUI with DSTRS group (15.9%; P = 5.5 × 10-4), and the CUI with NDSTRS group (15.2%; P = 8.0 × 10-5). There was no significant difference in these rates between the other groups.

Conclusions: Both the availability of clozapine prescriptions and the precise diagnosis of TRS subgroups at discharge can promote the development of an organizational culture that facilitates the treatment of patients with schizophrenia.

Importance: Driving under the influence of cannabis increases the risk of motor vehicle collisions. In some jurisdictions, deterrence rests on the ability to detect delta-9-tetrahydrocannabinol (THC) in blood. Recent evidence suggests that there may be a nuanced relationship of blood THC to driving.

Objective: The purpose of this systematic review was to summarize all published papers investigating the presence of a linear relationship between blood THC and driving, primarily measured by simulated driving in the lab.

Outcomes: The main outcomes assessed included "weaving"/lateral control (eg, standard deviation of lateral position), speed, car following (following distance; coherence), reaction time, and overall driving performance.

Results: Of the 4845 records from the literature search, only 12 met the inclusion criteria. Ten of these reported no significant linear correlations between blood THC and measures of driving (8 out of 9 for "weaving"/lateral control, 4 out of 5 for speed, 2 of 3 for car following tasks (coherence/headway maintenance task), 1/1 for reaction time, 3/3 for overall driving performance). The studies that did find an association between driving and blood THC employed complex driving situations.

Conclusions: This synthesis has important implications for road safety given driving situations can be complex due to challenging road situations and increases in potency of cannabis over the past years. Current methods of detection of impairment may be suited to some types of situations but more large-scale studies on the relationship of blood THC and driving are needed that systematically vary driving complexity and cannabis potency.

Since the 1950s, understanding of antipsychotic activity in schizophrenia has been largely grounded in the dopamine (DA) hypothesis. Most antipsychotics approved for schizophrenia interact with D2 DA receptors as an important part of their mechanism of action. While antipsychotics blocking D2 DA receptors can be effective for positive symptoms of schizophrenia, none are approved by regulatory authorities for predominant negative or cognitive symptoms. Moreover, many of these agents induce a range of problematic side effects related to D2 DA receptor blockade (eg, drug-induced parkinsonism, akathisia, tardive dyskinesia, hyperprolactinemia and related sexual side effects, sedation). This has prompted the search for novel mechanisms with improved efficacy and tolerability based on evidence supporting involvement of other neurotransmitter systems in schizophrenia pathophysiology, including acetylcholine, gamma-aminobutyric acid, and glutamate. Among these options, targeting muscarinic receptors emerged as a promising treatment strategy. In September 2024, the U.S. Food and Drug Administration approved xanomeline and trospium chloride for treatment of adults with schizophrenia based on results from three 5-week, randomized, double-blind, placebo-controlled trials and two 52-week open-label trials. In the placebo-controlled trials, xanomeline/trospium reduced symptoms of schizophrenia, was generally well tolerated, and was not associated with clinically meaningful motor symptoms, hyperprolactinemia, sexual side effects, or weight gain compared with placebo. The long-term safety of xanomeline/trospium was also confirmed in two 52-week, open-label trials. This paper reviews the preclinical and clinical rationale for muscarinic receptor activation as a treatment for schizophrenia and the efficacy, safety, and tolerability profile of xanomeline/trospium.

Background: Chronic, heavy alcohol use may lead to permanent brain damage, cognitive impairment, and dementia. One of the most serious consequences is alcoholic dementia (AlD). Phosphodiesterase-4 (PDE4) inhibitors have been shown to exhibit beneficial effects on cognition deficits and alcoholism. However, it is not known whether PDE4 inhibitors can be used to treat AlD. A33, a relatively selective PDE4B inhibitor, is absent of the emetic effect associated with PDE4D. The effect of A33 on memory and cognition in AlD remains unclear.

Methods: We investigated the effects of A33 and the PDE4 inhibitor rolipram on memory and cognition using an AlD animal model, that is, APP/PS1/Tau mice drinking alcohol in the 2-bottle choice test, with or without A33 or rolipram treatment for 3 weeks. The animal groups were compared in behavioral tests related to learning and memory. Neurochemical measures were conducted to explore the underlying mechanism of A33.

Results: Compared to wild-type controls, AlD mice showed impairments of learning ability and memory in the behavior tests; this was attenuated by treatment of rolipram or A33. In addition, administration of rolipram or A33 in AlD mice further alleviated neuropathological alterations in the hippocampus, including Aβ expression and deposition; rolipram or A33 also decreased the levels of inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as nuclear factor kappa-B (NF-κB). Further, rolipram or A33 decreased the activation of microglia while increased cyclic adenosine monophosphate (cAMP) levels in the hippocampus of AlD mice.

Conclusions: These results revealed that the alleviation of the cognitive impairment of AlD in APP/PS1/Tau triple transgenic mice by rolipram or A33 was linked to the action of the PDE4B/cAMP/PKA signaling pathway. A33 can be a promising therapeutic agent for AlD-related cognitive dysfunction.

Background: Depression is a therapeutic challenge with bipolar disorder (BD) patients and remains a major contributor to disability, comorbidity, and premature mortality. The efficacy and safety of antidepressants (ADs) for this indication remain particularly controversial, and optimally safe and effective treatment of bipolar (BP) depression remains uncertain.

Method: We summarized selected research findings on the treatment of depression in BD aimed at supporting practical guidelines for clinical treatment involving ADs.

Results: Growing research evidence indicates that ADs are probably effective in BP depression and possibly not less than in major depressive disorder. Tolerability of antidepressant (AD) treatment is greater with type II BD (BD-2) than with type I (BD-1), particularly when ADs are combined with a mood stabilizer or antipsychotic. For BP depression, preferred ADs are serotonin-reuptake inhibitors and bupropion given in moderate doses for limited times.

Conclusions: Optimal treatment of depression requires further investigation, particularly for long-term maintenance. Nevertheless, treatment for acute depressive episodes can usefully and safely include some ADs in moderate doses for limited duration, best combined with lithium, some anticonvulsants, or certain atypical antipsychotics, and more safely with BD-2 than BD-1 with close clinical supervision.

Background: Combination treatments based on pharmacological interactions at α7 nicotinic acetylcholine receptors (nAChRs) are promising therapeutic approaches for neurocognitive disorders.

Methods: Here, we tested the cognitive efficacy of combinations of memantine with an α7 nAChR-selective agonist (PHA-543613) in naturally aged rats. Age-related changes in the expression of some key genes and proteins were also measured using quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).

Results: Aged rats showed marked cognitive decline in the novel object recognition test, and they also exhibited cholinergic changes such as mRNA upregulation of α7 nAChRs. Upregulation of interleukin-1β, macrophage inflammatory protein 1α, CX3CL1, intercellular adhesion molecule 1, and ciliary neurotrophic factor mRNA was also detected in aged rats. Combination treatment of memantine and PHA-543613 successfully alleviated the age-related decline of recognition memory of rats by exceeding the effects of the corresponding monotreatments.

Conclusions: Results indicate a positive interaction between memantine and PHA-543613, which also reflects a putative role of α7 nAChRs in the cognitive enhancer effects of memantine. These findings may facilitate the development of combination therapies for age-related neurocognitive disorders.

Background: Suicide is among the severe outcomes of mental illness and has been reported to be associated with neurodegeneration and cognitive impairment. The blood neurofilament light chain (NfL) level is a biomarker of neuronal damage in neuropsychiatric disorders. This study investigated whether the NfL levels are associated with lifetime suicidal behaviors and whether this level is higher in patients with major depressive disorder (MDD) compared with healthy controls.

Methods: In this cross-sectional study, we included 73 patients with MDD and 40 age- and sex-matched controls. The blood NfL levels were measured using an enzyme-linked immunosorbent assay. We compared the NfL levels between patients with MDD and controls and performed regression analysis to evaluate the association between the NfL levels and suicidal behaviors.

Results: Nearly half of the patients with MDD (43.80%) reported lifetime suicide attempts. Those with MDD had higher blood NfL levels, but their levels did not significantly differ from those of the healthy controls. Logistic regression results revealed higher risks of lifetime suicide planning (Odds ratio [OR] = 1.64) and suicide attempts (OR = 1.94) with every 10 pg/mL increase in the NfL levels.

Conclusions: Our results demonstrate that higher serum NfL levels were associated with lifetime suicidal behavior.

Background: Event segmentation, the cognitive process of parsing continuous experiences into discrete events, plays a fundamental role in how humans perceive and interact with their environment. Guided by Event Segmentation Theory, this study investigates the modulation of event segmentation by the catecholaminergic system by methylphenidate (MPH).

Methods: Healthy adult participants (N = 52) engaged in a double-blind, counter-balanced, placebo-controlled experiment in which they watched a movie and identified event boundaries under placebo and MPH conditions.

Results: With the same information given, MPH increased the likelihood that the information was considered meaningful. Crucially, the number of situational changes and participant's prior experience had an interactive effect on the probability of event segmentation. There was a stronger relationship between environmental information and segmentation probability when catecholaminergic levels were elevated by MPH in addition to previous experience.

Conclusions: The catecholaminergic system modulates how incoming information is segmented to build meaningful episodes. Prior experience supports the effects of MPH to unfold. These findings underscore the complex interplay between neurochemical modulation and cognitive processes involved in event perception.