International Journal of Neuropsychopharmacology最新文献

Rationale: Classic psychedelics show promise as a treatment for various neuropsychiatric disorders. However, weak blinding integrity in trials has been argued to limit the capacity to definitively attribute therapeutic effects to the classic psychedelic and dose under investigation. This highlights the need to explore alternative active placebos.

Objectives: 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 fit these criteria.

Results: The active placebos that have typically been used in modern-day trials of classic psychedelics may not adequately blind participants, investigators, or raters. 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. Here, 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.

Conclusion: To accurately assess safety and efficacy of classic psychedelics as therapeutic drugs, future research should apply a thoughtful process for selecting active placebos and consider ancillary strategies to improve blinding in trials involving these drugs.

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 (e.g., standard deviation of lateral position (SDLP)), speed, car following (following distance; coherence), reaction time, and overall driving performance.

Results: Of the 4,845 records from the literature search, only 12 met the criteria. 10 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.

Background: Schizophrenia shortens the average lifespan by an estimated 15 years. This retrospective study evaluated whether relapse independently increases all-cause mortality risk in patients with stable schizophrenia.

Methods: Eligible adults had ≥2 outpatient claims on separate dates or ≥1 inpatient claim with a schizophrenia diagnosis code, had ≥12 months of continuous pre-index enrollment without a relapse, and received ≥1 antipsychotic medication during the baseline period. Occurrence and number of inpatient and non-inpatient relapses and all-cause mortality were evaluated during follow-up. A marginal structural model adjusting for both baseline and time-varying confounding was used to estimate hazard ratios (HRs) and 95% CIs.

Results: Mean age at index of the 32,071 patients included in the analysis was 57.6 (SD, 15.3) years; 51.0% of patients were male and 55.4% were White. During a mean follow-up of 40 (range, 1-127) months, 3974 (12.4%) patients died. Of the 9170 (28.6%) patients with relapse(s) during follow-up, most experienced one (53.4%) or two (20.0%) relapses. After adjustment for covariates, the HR for all-cause mortality was significantly higher for patients with one relapse versus no relapses (1.20 [95% CI: 1.14-1.26]). For the first five relapses, each subsequent relapse increased allcause mortality hazard by approximately 20%. Estimated 5-year survival was 78% in patients with one relapse and 58% in patients with 10 relapses.

Conclusions: The observed increase in all-cause mortality associated with schizophrenia relapse underscores the need for heightened attention to relapse prevention, including greater utilization of effective treatment strategies early in the course of disease.

Background: Insomnia is the most prevalent sleep disorder globally. Nuciferine (NF), a bioactive constituent extracted from Nelumbo nucifera leaves, is recognized for its diverse pharmacological activities. However, its sleep-regulating effects have not been investigated. This study aimed to delineate the therapeutic effects and underlying mechanisms of NF in mitigating insomnia.

Methods: The sedative-hypnotic effects of NF were assessed employing locomotor activity test, pentobarbital-induced sleep test, and electroencephalography (EEG)-based sleep profiling. Insomnia symptoms in rodents were induced by serotonin (5-HT) depletion and environmental stress. The potential mechanisms of NF's action through the regulation of central serotonin system were also explored.

Results: NF attenuated locomotor activity and extended pentobarbital-induced sleep duration in a dose-dependent manner. It also significantly augmented total and non-rapid eye movement (NREM) sleep time and enhanced delta power at frequencies of 0.5 Hz and 1 Hz in normal rats. Sleep analysis revealed that NF effectively reversed the reduction in total and NREM sleep time caused by environmental stress from cage changing. NF treatment also proved effective against insomnia induced by 5-HT depletion, as evidenced by increased sleep duration and reduced sleep latency. Further investigation revealed a synergetic effect of NF and 5-hydroxytryptophan, alone with increased 5-HT and 5-HT1A receptor levels in the hypothalamus of insomniac mice following NF administration.

Conclusion: The results demonstrate NF's hypnotic effects and its ability to alleviate insomnia, providing preclinical evidence for its potential as a naturally derived treatment for insomnia.

Background: SAPAP3-knockout (SAPAP3-KO) mice develop excessive self-grooming behavior at 4-6 months of age, serving as a model for obsessive-compulsive disorder (OCD). Given that anxiety often precedes OCD diagnosis in humans, this study investigated whether juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the self-grooming phenotype, and whether such behaviors respond to psilocybin treatment. The study also examined four key neuroplasticity-related synaptic proteins-GAP43, PSD95, synaptophysin, and SV2A - as SAPAP3 is a postsynaptic scaffold protein that interacts with PSD95 and may affect synaptic function.

Methods: Two studies were conducted using male and female juvenile (10-13 weeks) SAPAP3-KO mice. Study 1 compared behavioral phenotypes between homozygous (HOM), heterozygous (HET), and wild-type (WT) mice. Study 2 evaluated a different sample of HOM and WT mice and assessed the effect of psilocybin (4.4 mg/kg) on identified behavioral differences. Both studies included comprehensive behavioral testing focused on anxiety-like behavior, social interaction, and cognitive function. Additionally, levels of four synaptic proteins were measured by western blots in the frontal cortex, hippocampus, amygdala, and striatum of juvenile and adult SAPAP3-KO mice.

Results: In both studies, juvenile HOM SAPAP3-KO mice showed significant anxiety-like behaviors compared to WT mice, spending less time in open field center, and elevated plus maze open arms. They also buried fewer marbles and found fewer buried Oreos than WT mice. Psilocybin treatment did not improve these behavioral manifestations. Analysis of synaptic proteins revealed significant increases in GAP43, synaptophysin, and SV2A across multiple brain regions in adult male HOM mice and of SV2A in the frontal cortex of HOM females compared to WT, but not in juvenile mice of either sex.

Conclusions: Juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the characteristic excessive self-grooming phenotype, paralleling the prodromal anxiety often seen in human OCD. Unlike in adult SAPAP3-KO mice, these manifestations were not responsive to psilocybin treatment. The age-dependent increases in synaptic proteins observed in adult (but not juvenile) male SAPAP3-KO mice homozygous for the deletion and to a lesser extent in female homozygotes, may represent compensatory plasticity changes in response to the phenotype. These results provide insights into the developmental trajectory of OCD-like behaviors and associated neuroplastic adaptations.

Importance: Childhood Trauma (CT) worse the course of Bipolar Disorder (BD) and negatively impact treatment outcomes. Despite the recognized influence of CT on clinical trajectories, limited evidence exists on how it affects specific pharmacological responses in BD.

Objective: This study aimed to investigate the effectiveness of lurasidone in BD type I depression, with a focus on how CT exposure impact treatment response and remission.

Design: A multisite, observational, prospective, comparative effectiveness study over 8-week period was conducted.

Setting: A multisite in four clinical research sites in Colombia.

Participants: A total of 84 adults with BD type I depression were enrolled (lurasidone = 41, lurasidone with lithium = 43).

Intervention: For the lurasidone arm 41 participants were assigned, and for lurasidone plus lithium were 43 over 8-week period.

Exposure: Childhood trauma exposure was measured with the Childhood Trauma Questionnaire-Short Form (CTQ-SF) (BD-CT, n=40; BD-non-CT, n=44) were includedMain outcome and measures: The primary outcome was changes in Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Secondary outcomes included changes in Clinical Global Impression-Bipolar (CGI-BP) depression severity scores and responder rates.

Results: BD with CT exposure demonstrated a smaller mean reduction in MADRS scores compared to those without CT exposure for both treatments (monotherapy: LS -3.4, CI 95% -6.03, -0.76, p = 0.013; combination therapy: LS -3.1, CI 95% -5.36, -0.63, p = 0.014). The presence of CT exposure, particularly physical abuse, was associated with poorer response rates. Notably, lurasidone in combination with lithium showed superior outcomes compared to monotherapy, although effectiveness was attenuated in participants with documented CT exposure.

Conclusions: This study provides real-world evidence suggesting that CT exposure may modify treatment response in BD type I depression. Our findings underscore the importance of CT screening to guide personalized treatment strategies.

Relevance: This study provides evidence that childhood trauma (CT), particularly physical abuse, attenuates the antidepressant effects of lurasidone in bipolar disorder (BD) type I depression, leading to lower response and remission rates in both monotherapy and combination therapy with lithium. These findings underscore the clinical importance of screening for CT in BD to guide personalized treatment strategies. Identifying trauma history may help clinicians optimize treatment selection, considering the potential need for combination pharmacotherapy and adjunctive trauma-focused psychotherapeutic interventions to improve outcomes in this vulnerable population.

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.

Background: Neuropathic pain (NP) is a chronic and debilitating condition frequently comorbid with insomnia. However, the alterations in sleep architecture under NP conditions and the mechanisms underlying both pain and sleep disturbances remain poorly understood. The reticular thalamic nucleus (RTN) plays a crucial role in non-rapid eye movement sleep (NREMS) and pain processing, but its involvement in NP-related sleep disruptions has not been fully elucidated.

Methods: To investigate sleep-related electrophysiological changes in NP, we performed continuous 24-hour EEG/EMG recordings in rats exhibiting allodynia following L5-L6 spinal nerve lesions. Additionally, we assessed the in vivo neuronal activity of the RTN in both NP and sham-operated control rats. Spectral analyses were conducted to examine alterations in sleep oscillatory dynamics. RTN neuronal responses to nociceptive pinch stimuli were classified as increased, decreased, or unresponsive.

Results: NP rats exhibited a significant reduction in NREMS (-20%, p < 0.001) and an increase in wakefulness (+19.13%, p < 0.05) compared to controls, whereas rapid eye movement sleep (REMS) remained unchanged. Sleep fragmentation was pronounced in NP animals (p < 0.0001), with frequent brief awakenings, particularly during the inactive/light phase. Spectral analysis revealed increased delta and theta power during both NREMS and REMS. RTN neurons in NP rats displayed a higher basal tonic firing rate, along with increased phasic activity (number of bursts), although the percentage of spikes in bursts remained unchanged.

Conclusions: NP is characterized by disrupted sleep architecture, reduced NREMS, and heightened RTN neuronal firing activity with partial compensation of burst activity. Given that RTN burst activity is essential for optimal NREMS, its disruption may contribute to NP-induced sleep impairments. These findings suggest that altered EEG signals, alongside dysregulated RTN neuronal activity, may serve as potential brain markers for NP-related insomnia.

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.