The International Journal of Neuropsychopharmacology最新文献

Background: Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression.

Methods: Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale score ≤10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session.

Results: In total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52).

Conclusion: Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.

Background: Prolonged forced abstinence from morphine can increase cue-induced cravings for the drug, contributing to a persistent vulnerability to relapse. Previous studies have identified the implications of aberrant microRNA (miRNA) regulation in the pathogenesis of morphine addiction, but the changes in miRNA expression during the incubation of morphine craving are still unknown.

Methods: Nucleus accumbens (NAc)-specific altered miRNA transcriptomics was determined in a mouse model of cue-induced incubation of morphine craving following a next-generation sequencing method and verified by RT-qPCR. Bioinformatics analysis was performed to predict the target gene of selected miRNA, and the protein expression of the target gene was detected by western blot. A dual-luciferase assay was performed to confirm the binding sites, and gain- and loss-of-function strategy was applied to understand the mechanism of miRNA and its target gene.

Results: The miR-592-3p observed to be downregulated in the NAc core was linked to the incubation of morphine craving, and a dual-luciferase assay was performed to confirm the binding sites of miR-592-3p in its target gene, tomoregulin-1 (TMEFF1). Also, gain- and loss-of-function analyses revealed that the inhibition of miR-592-3p expression in the NAc core negatively regulated TMEFF1 expression, thereby enhancing the incubation of morphine craving; however, the overexpression of miR-592-3p in the NAc core resulted in a decreased expression of TMEFF1, thereby reducing the incubation of morphine craving.

Conclusion: Our findings demonstrated that miR-592-3p can improve the incubation of morphine craving by targeting TMEFF1, and thus, it holds a therapeutic potential to inhibit opioid craving.

Background: Odor identification (OI) dysfunction is an early marker of Alzheimer's disease (AD), but it remains unclear how olfactory-related regions change from stages of subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to AD dementia.

Methods: Two hundred and sixty-nine individuals were recruited in the present study. The olfactory-related regions were defined as the regions of interest, and the grey matter volume (GMV), low-frequency fluctuation, regional homogeneity (ReHo), and functional connectivity (FC) were compared for exploring the changing pattern of structural and functional abnormalities across AD, MCI, SCD, and normal controls.

Results: From the SCD, MCI to AD groups, the reduced GMV, increased low-frequency fluctuation, increased ReHo, and reduced FC of olfactory-related regions became increasingly severe, and only the degree of reduced GMV of hippocampus and caudate nucleus clearly distinguished the 3 groups. SCD participants exhibited reduced GMV (hippocampus, etc.), increased ReHo (caudate nucleus), and reduced FC (hippocampus-hippocampus and hippocampus-parahippocampus) in olfactory-related regions compared with normal controls. Additionally, reduced GMV of the bilateral hippocampus and increased ReHo of the right caudate nucleus were associated with OI dysfunction and global cognitive impairment, and they exhibited partially mediated effects on the relationships between OI and global cognition across all participants.

Conclusion: Structural and functional abnormalities of olfactory-related regions present early with SCD and deepen with disease severity in the AD spectrum. The hippocampus and caudate nucleus may be the hub joining OI and cognitive function in the AD spectrum.

Backgrounds: Our recent studies reported that a single injection with lipopolysaccharide (LPS) before stress exposure prevents depression-like behaviors in stressed mice. Monophosphoryl lipid A (MPL) is a derivative of LPS that lacks the undesirable properties of LPS. We hypothesize that MPL can exert a prophylactic effect on depression.

Methods: The experimental mice were pre-injected with MPL before stress exposure. Depression in mice was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify depression-like behaviors. Real-time polymerase chain reaction and biochemical assays were performed to examine the gene and protein expression levels of pro-inflammatory cytokines.

Results: A single MPL injection 1 day before stress exposure at the dosages of 400, 800, and 1600 μg/kg but not 200 μg/kg prevented CSDS-induced depression-like behaviors in mice. This effect of MPL, however, vanished with the extension of the interval time between drug injection and stress exposure from 1 day or 5 days to 10 days, which was rescued by a second MPL injection 10 days after the first MPL injection or by a 4× MPL injection 10 days before stress exposure. A single MPL injection (800 μg/kg) before stress exposure prevented CSDS-induced increases in the gene expression levels of pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Pre-inhibiting the innate immune stimulation by minocycline pretreatment (40 mg/kg) abrogated the preventive effect of MPL on CSDS-induced depression-like behaviors and neuroinflammatory responses in animal brains.

Conclusions: MPL, through innate immune stimulation, prevents stress-induced depression-like behaviors in mice by preventing neuroinflammatory responses.

Major depressive disorder (MDD) is a common psychiatric illness that manifests in sex-influenced ways. Men and women may experience depression differently and also respond to various antidepressant treatments in sex-influenced ways. Ketamine, which is now being used as a rapid-acting antidepressant, is likely the same. To date, the majority of studies investigating treatment outcomes in MDD do not disaggregate the findings in males and females, and this is also true for ketamine. This review aims to highlight that gap by exploring pre-clinical data-at a behavioral, molecular, and structural level-and recent clinical trials. Sex hormones, particularly estrogen and progesterone, influence the response at all levels examined, and sex is therefore a critical factor to examine when looking at ketamine response. Taken together, the data show females are more sensitive to ketamine than males, and it might be possible to monitor the phase of the menstrual cycle to mitigate some risks associated with the use of ketamine for females with MDD. Based on the studies reviewed in this article, we suggest that ketamine should be administered adhering to sex-specific considerations.

Background: The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist.

Methods: Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design.

Results: The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported.

Conclusion: The salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.

Background: High placebo response in attention deficit hyperactivity disorder (ADHD) can reduce medication-placebo differences, jeopardizing the development of new medicines. This research aims to (1) determine placebo response in ADHD, (2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and (3) determine the covariates associated with placebo response.

Methods: A systematic review with meta-analysis of randomized, placebo-controlled clinical trial investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design-, intervention-, and patient-related covariates in predicting placebo response was studied by means of meta-regression and MetaForest.

Results: Ninety-four studies including 6614 patients randomized to placebo were analyzed. Overall, placebo response was -8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R2 = 0.0012 and root mean squared error = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response among ADHD patients increased by 63% between 2001 and 2020 and was larger in the United States than in other regions of the world.

Conclusions: Strong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last 2 decades and is greater in the United States than the rest of the world.

There is a large unmet need for effective treatment of major depressive disorder (MDD), an often chronic/recurrent disorder that affects 1 in 5 adults during their lifetime in the United States. Clinicians and individuals with MDD often rely on augmentation approaches given the low rate of remission with the initial antidepressant treatment. Therefore, the report by Savitz and colleagues on the safety and efficacy of seltorexant is of great interest because it provides initial evidence for the antidepressant potential of drugs targeting orexin neurotransmission. Findings of this study suggest that seltorexant 20 mg is more effective than placebo, especially in individuals with moderate or insomnia symptoms at baseline. Given that insomnia is a common feature of depression, orexin 2 receptor antagonists may serve as important new treatment alternatives for people with MDD.