International Journal of Neuropsychopharmacology最新文献

Opioid use disorder (OUD) affects over 40 million people worldwide, creating significant social and economic burdens. Medication for opioid use disorder (MOUD) is often considered the primary treatment approach for OUD. MOUD, including methadone, buprenorphine, and naltrexone, is effective for some, but its benefits may be limited by poor adherence to treatment recommendations. Immunopharmacotherapy offers an innovative approach by using vaccines to generate antibodies that neutralize opioids, blocking them from crossing the blood-brain barrier and reducing their psychoactive effects. To date, only 3 clinical trials for opioid vaccines have been published. While these studies demonstrated the potential of opioid vaccines for relapse prevention, there is currently no standardized protocol for evaluating their effectiveness. We have reviewed recent preclinical studies that demonstrated the efficacy of vaccines targeting opioids, including heroin, morphine, oxycodone, hydrocodone, and fentanyl. These studies showed that vaccines against opioids reduced drug reinforcement, decreased opioid-induced antinociception, and increased survival rates against lethal opioid doses. These studies also demonstrated the importance of vaccine formulation and the use of adjuvants in enhancing antibody production and specificity. Finally, we highlighted the strengths and concerns associated with the opioid vaccine treatment, including ethical considerations.

Objective: This study aims to quantitatively evaluate the efficacy and safety of various treatment regimens for treatment-resistant depression (TRD) across oral, intravenous, and intranasal routes to inform clinical guidelines.

Methods: A systematic review identified randomized controlled trials on TRD, with efficacy measured by changes in the Montgomery-Åsberg Depression Rating Scale (MADRS). We developed pharmacodynamic and covariate models for different administration routes, using Monte Carlo simulations to estimate efficacy distribution. Dropout and adverse event-related dropout rates were analyzed via single-arm meta-analysis.

Results: Involving 22 studies with 56 treatment arms and 3,059 patients, our findings suggest combination therapies outperform monotherapy, achieving an additional 6.5% reduction in MADRS scores over 12 weeks. The most effective combinations were olanzapine with fluoxetine and quetiapine with SSRIs/SNRIs. Injectable treatments, particularly ayahuasca, produced rapid effects, with a 77% reduction in MADRS scores at 15 days. Intranasal treatments reached efficacy sooner than oral ones, with 28-day efficacy similar to the 12-week efficacy of the olanzapine-fluoxetine combination. Dropout rates due to adverse events were similar across methods (4.5%-5.2%), but total dropouts were highest for oral (17.9%) and lowest for intranasal routes (10.6%). Additionally, there was considerable variation in the incidence of headache, dizziness, and nausea across different administration routes.

Conclusion: The quantitative evaluation of 22 TRD treatments illuminates key pharmacodynamic parameters, bolstering the development of clinical guidelines and aiding the design of clinical trials and medical decision-making.

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: Bipolar disorder (BD) has been associated with impaired cellular resilience. Recent studies have shown abnormalities in the unfolded protein response (UPR) in BD. The UPR is the cellular response to endoplasmic reticulum (ER) stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a trophic factor, decreases ER stress by modulating the UPR. The objective of this study is to investigate the MANF-ER stress pathway in BD and major depressive disorder (MDD) compared to healthy controls (HC).

Methods: MANF protein concentration and MANF and GRP78 gene expression were assessed in peripheral blood from individuals with BD, MDD and HC (protein: 40 BD, 55 MDD, 55 HC; gene expression: 52 BD, 61 MDD, 69 HC). MANF protein and gene expression along with GRP78 gene expression were also analyzed in postmortem brain tissue (20 BD, 20 MDD, 19 HC). MANF protein was quantified using an ELISA assay while quantitative polymerase chain reaction was used for MANF and GRP78 gene expression.

Results: Peripheral MANF protein levels were reduced in individuals with BD in a depressive state compared to controls (p=0.031) and euthymic BD participants (p=0.013). No significant differences in MANF or GRP78 gene expression were observed in BD irrespective of mood state, or MDD compared to HC (all p>0.05). No differences were observed regarding MANF/GRP78 protein or gene expression levels in postmortem tissue (p>0.05).

Conclusion: Individuals with BD who were in an acute depressive phase were found to have reduced peripheral MANF levels potentially signifying abnormal UPR and supporting the notion that BD is associated with increased ER stress.

Background: Alzheimer disease (AD) is a progressive neurodegenerative disorder primarily affecting the elderly, characterized by severe cognitive impairment and memory loss. Emerging evidence suggests that neuroinflammation plays a significant role in AD pathogenesis, with cytokines like interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL8) contributing to the disease progression.

Methods: We utilized Gene Expression Omnibus datasets to identify IL-6 and CXCL8 as pivotal inflammatory markers in AD. In vitro experiments were conducted using SK-N-BE(2)-M17 and THP-1 cell lines treated with IL-6 and CXCL8 to model AD. Additionally, in vivo tests on Amyloid Precursor Protein/Presenilin 1 (APP/PS1) AD mouse models were performed to assess the impact of these cytokines on cognitive functions and brain pathology.

Results: The results indicated a significant decrease in cell viability, increased apoptosis, and elevated inflammatory factor secretion following IL-6 and CXCL8 treatment in vitro. In vivo, AD mouse models treated with these cytokines exhibited exacerbated emotional distress, decreased social interaction, impaired cognitive functions, and increased amyloid protein deposition in neural tissues.

Conclusions: The study highlights the detrimental effects of IL-6 and CXCL8 on neuronal health and cognitive functions in AD. These findings suggest that targeting these cytokines could offer potential therapeutic interventions for improving patient outcomes in Alzheimer disease.

The results from a pilot, 1-year, randomized, open-label, add-on treatment study in treatment-resistant schizophrenia (TRS) with evenamide, a glutamate modulator, were not associated with any safety abnormalities at all doses (7.5-30 mg bid), with a high retention rate even at 6-month (~85%), and 1-year (~75%), and the absence of psychotic relapses during the 1-year treatment period. Overall, treatment with evenamide showed a gradual, sustained, and clinically important improvement up to 1 year in all efficacy measures (eg, PANSS mean change ~ -20%; CGI-S mean change ~ -1.0). In addition, compared to the results at Week 6, the responder rates generally more than doubled at 1-year (PANSS "≥20% improvement from baseline" = ~45%; CGI-S "2-category of improvement" = ~25%; CGI-C "much improved" = ~40%). These results, rarely replicated in other trials in TRS, support the use of evenamide as an add-on treatment in patients who are not benefiting from their current first- or second-generation antipsychotic medication.

Background: Recent interest in the clinical use of psychedelics has highlighted plant-derived medicines like ayahuasca showing rapid-acting and sustainable therapeutic effects in various psychiatric conditions. This traditional Amazonian plant decoction contains N,N-dimethyltryptamine (DMT) and β-carboline alkaloids such as harmine. However, its use is often accompanied by distressing effects like nausea, vomiting, and intense hallucinations, possibly due to complex pharmacokinetic/pharmacodynamic (PK-PD) interactions and lack of dose standardization.

Methods: This study addresses these limitations by testing a novel pharmaceutical formulation containing pure forms of DMT and harmine in a double-blind, randomized, placebo-controlled trial with 31 healthy male volunteers. We evaluated PK-PD by monitoring drug and metabolite plasma levels, subjective effects, adverse events, and cardiovascular parameters. Each participant received 3 randomized treatments: (1) 100 mg buccal harmine with 100 mg intranasal DMT, (2) 100 mg buccal harmine with intranasal placebo, and (3) full placebo, using a repeated-intermittent dosing scheme, such that 10 mg of DMT (or placebo) was administered every 15 minutes.

Results: N,N-dimethyltryptamine produced consistent PK profiles with Cmax values of 22.1 ng/mL and acute drug effects resembling the psychological effects of ayahuasca with a duration of 2-3 hours. Likewise, buccal harmine produced sustained-release PK profiles with Cmax values of 32.5 ng/mL but lacked distinguishable subjective effects compared to placebo. All drug conditions were safe and well tolerated, indicating the formulation's suitability for clinical applications.

Conclusions: This study underscores the potential of a patient-oriented pharmaceutical formulation of DMT and harmine to reduce risks and improve therapeutic outcomes in treating mental health disorders.

Clinical trial registration number: Neurodynamics of prosocial emotional processing following serotonergic stimulation with N,N-dimethyltryptamine (DMT) and harmine in healthy subjects (NCT04716335) https://clinicaltrials.gov/ct2/show/NCT04716335.

Background: The tachykinin substance P (SP) facilitates learning and memory processes after its central administration. Activation of its different receptive sites, neurokinin-1 receptors (NK1Rs), as well as NK2Rs and NK3Rs, was shown to influence learning and memory. The basal ganglia have been confirmed to play an important role in the control of memory processes and spatial learning mechanisms, and as part of the basal ganglia, the globus pallidus (GP) may also be involved in this regulation. SP-immunoreactive fibers and terminals, as well as NK1Rs and NK3Rs, were shown to be present in the GP.

Methods: The present study aimed to examine whether the SP administered into the GP can influence spatial memory consolidation in the Morris water maze (MWM). Therefore, male Wistar rats received a post-trial microinjection of 0.4 µLf 10 ng SP, 100 ng SP, or vehicle solution. The possible involvement of pallidal NK1Rs and NK3Rs in the SP effects was also studied by applying WIN51708 for NK1R antagonism and SR142801 as a selective NK3R antagonist.

Results: Our results showed that the lower dose of SP significantly decreased escape latency on the second day compared to control animals, while the higher dose was ineffective. Prior treatment with the NK1R antagonist WIN51708 could not block, while the NK3R antagonist SR142801 inhibited the effects of SP on memory consolidation in the MWM.

Conclusions: Our results are the first to demonstrate that SP improves consolidation of spatial memory in the GP, and this effect is mediated through NK3Rs but not NK1Rs.

Background: Negative symptoms of schizophrenia represent an unmet therapeutic need for many patients in whom pentoxifylline may be effective in terms of its dopaminergic, anti-inflammatory, and cerebral blood flow-increasing properties. This study aimed to evaluate pentoxifylline as a therapeutic agent for improving negative symptoms of schizophrenia.

Methods: Chronic schizophrenia outpatients experiencing significant negative symptoms were randomly allocated to receive pentoxifylline 400 mg or matched placebo every 12 hours for 8 weeks. All patients were clinically stable as they had received risperidone for at least 2 months, which was continued. The participants were assessed using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, Extrapyramidal Symptom Rating Scale, and side effect checklist.

Results: The patients' baseline characteristics were comparable between the groups. There was a significant time-treatment interaction effect on PANSS negative subscale scores (ηP2=0.075), with the pentoxifylline group showing significantly greater reductions until weeks 4 (Cohen d = 0.512) and 8 (Cohen d = 0.622). Also, this group showed a significantly better response by week 8. Other PANSS scores, Hamilton Depression Rating Scale scores, Extrapyramidal Symptom Rating Scale scores, and side effect frequencies were comparable between the groups. Pentoxifylline showed a nonsignificant higher remission of 37.1% compared with 14.7% in the placebo group.

Conclusions: Pentoxifylline was safely and tolerably beneficial for the primary negative symptoms of chronic schizophrenia.

Background: Understanding drug addiction as a disorder of maladaptive learning, where drug-associated or environmental cues trigger drug cravings and seeking, is crucial for developing effective treatments. Actin polymerization, a biochemical process, plays a crucial role in drug-related memory formation, particularly evident in conditioned place preference paradigms involving drugs like morphine and methamphetamine. However, the role of actin polymerization in the reconsolidation of heroin-associated memories remains understudied.

Methods: This study employed a rodent model of self-administered heroin to investigate the involvement of actin polymerization in the reconsolidation of heroin-associated memories. Rats underwent ten days of intravenous heroin self-administration paired with conditioned cues. Subsequently, a 10-day extinction phase aimed to reduce heroin-seeking behaviors. Following this, rats participated in a 15-minute retrieval trial with or without cues. Immediately post-retrieval, rats received bilateral injections of the actin polymerization inhibitor Latrunculin A (Lat A) into the nucleus accumbens core (NACc), a critical brain region for memory reconsolidation.

Results: Immediate administration of Lat A into the NACc post-retrieval significantly reduced cue-induced and heroin-primed reinstatement of heroin-seeking behavior for at least 28 days. However, administering Lat A 6-hour post-retrieval or without a retrieval trial, as well as administering Jasplakionlide prior to memory reactivation did not affect heroin-seeking behaviors.

Conclusions: Inhibiting actin polymerization during the reconsolidation window disrupts heroin-associated memory reconsolidation, leading to decreased heroin-seeking behavior and prevention of relapse. These effects are contingent upon the presence of a retrieval trial and exhibit temporal specificity, shedding light on addiction mechanisms and potential therapeutic interventions.