Journal of Psychopharmacology最新文献

Rapid eye movement sleep (REMS) has historically been associated with anecdotal 'creative insights', possibly due to the fantastical and ostensibly illuminating nature of its associated phenomena (dreams). REMS, characterised by rapid eye movements, muscle atonia, and high-energy neuronal activity, has been linked to memory consolidation and information processing, particularly regarding the formation of novel associations or reintegration of consolidated memories into new cognitive networks. However, studies in these domains have largely used methodology which deprived subjects (animal or human) of REMS, rather than enhanced it. Assumptions about the positive effects of enhancing REMS have thus been largely theoretical since they are based on REMS inhibition rather than REMS stimulation. The present review aims to summarise the scientific perspective on the relationship between REMS and creativity, highlights its possible applications in neuropsychiatric disorders and outlines the potential clinical use of orexin receptor antagonists in this context. The orexin system plays a central role in the regulation of sleep/wakefulness physiology, and dual orexin receptor antagonists enhance REMS. This feature enables investigations into the effect of enhancing REMS on creativity and the associated potential therapeutic potential in neuropsychiatric disorders characterised by rigid thinking patterns and disruptions in cognitive flexibility.

Background: Clozapine has anti-suicidal properties and significant effects on sleep. Sleep disturbances are associated with suicide risk. Daytime somnolence and sedation are commonly reported adverse effects of clozapine treatment.

Aims: Systematic review and meta-analysis of somnolence in randomized controlled trials (RCTs) of patients with schizophrenia treated with clozapine.

Methods: We systematically searched PubMed, PsycINFO, and Web of Science databases. We included RCTs, in English, with data on somnolence in patients with schizophrenia treated with clozapine versus other antipsychotics. Data were pooled using a random effects model.

Results: Twenty-two RCTs (2991 patients: 1404 on clozapine and 1587 on other antipsychotics) met inclusion criteria. Patients treated with clozapine had a significantly increased odds of somnolence compared to other antipsychotics (36.3% vs 21.9%, OR = 2.06, 95% CI: 1.65-2.57, p < 0.01). Clozapine was also associated with significantly increased odds of somnolence compared to olanzapine and risperidone. In meta-regression analyses, clozapine dose, age, sex, race, and publication year were unrelated to the association.

Conclusions: Clozapine is associated with significantly more somnolence, compared to other antipsychotics. A greater mechanistic understanding of associations between sleep changes and suicide risk in patients treated with clozapine is needed.

Background: β-blockers (β-adrenoceptor antagonists), commonly used for cardiovascular conditions, may be linked to neuropsychiatric adverse events (AEs). However, many prevalent ones, including delirium and hallucinations, remain insufficiently studied.

Aims: To compare the neuropsychiatric risks of β-blockers with other antihypertensive drugs using data from the FDA Adverse Event Reporting System (FAERS) and differences between lipophilic and hydrophilic β-blockers.

Method: An active-comparator restricted disproportionality analysis was conducted using data from the FAERS (2004Q1-2023Q4). Neuropsychiatric AEs were analyzed using Preferred Terms and the System Organ Classes from the Medical Dictionary for Regulatory Activities for β-blockers compared to lisinopril and losartan. Adjusted Reporting Odds Ratios (aRORs) were calculated using logistic regression to account for potential confounders.

Results: β-blockers were linked to a significantly higher risk of nervous and psychiatric disorders, compared to lisinopril and losartan. Among the nine types of neuropsychiatric events studied, six-dizziness, nightmares, insomnia, hallucinations, somnolence, and disorientation-showed higher aRORs with β-blockers. Propranolol, a lipophilic β-blocker, exhibited the highest aRORs for psychiatric disorders and six types of neuropsychiatric events, including nightmares, delirium, hallucinations, disorientation, altered mental status, and somnolence, compared to lisinopril and losartan. Compared to atenolol, propranolol remained significantly associated with delirium, hallucinations, and disorientation.

Conclusion: β-blockers, especially propranolol, may be associated with a higher risk of neuropsychiatric AEs compared to lisinopril and losartan. These findings highlight the importance of considering the specific β-blocker prescribed, particularly in patients at risk for central nervous system side effects. Further population-based studies are warranted to confirm these results.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term illness with no treatment options that address the disease directly. Solriamfetol is a selective dual norepinephrine-dopamine reuptake inhibitor that promotes wakefulness in obstructive sleep apnea and narcolepsy.

Aims: This study evaluated the efficacy and safety of solriamfetol for fatigue symptoms in adults with ME/CFS over 8 weeks of treatment.

Methods: This was a phase 4, double-blind, randomized, placebo-controlled trial of solriamfetol in adults with ME/CFS. Eligible participants (N = 38) were randomly assigned to receive 75 mg (titrated to 150 mg as needed) solriamfetol or placebo. Participants completed a battery of assessments at weekly visits. The primary outcome was Fatigue Symptom Inventory (FSI) scores, and the secondary outcome measure was Behavioral Rating Inventory of Executive Function for Adults (BRIEF-A), at Weeks 6 and 8. T-tests assessed the differences in mean change from baseline between solriamfetol and placebo. Adverse events were monitored throughout the study.

Results: At Week 8 (p = 0.039), but not Week 6 (p = 0.270), solriamfetol improved FSI severity compared to placebo. On the BRIEF-A global executive composite, solriamfetol improved more than placebo at Week 8 (p = 0.012), driven by improved metacognition index (p = 0.004), but not behavioral regulation index (p = 0.574). Solriamfetol was well tolerated, with most common AEs being sleep loss and headaches.

Conclusions: Solriamfetol demonstrated good safety and efficacy in improving fatigue and executive functioning in patients with ME/CFS. As a dual norepinephrine-dopamine reuptake inhibitor and wakefulness-promoting factors, solriamfetol has the potential to improve fatigue symptoms of ME/CFS.

Clinical trial number: NCT04622293.

Objectives: Electroconvulsive shock (ES) can ameliorate psychotic symptoms and certain adverse effects of antipsychotics by inducing seizure activity via electrical brain stimulation. Although the relationship between ES and glial cells has been the focus of attention, the precise mechanisms underlying its effects remain unclear. This study aimed to investigate the effects of ES on astroglia in the drug-induced neurotoxicity rat model.

Methods: Haloperidol (HAL; 0.75 mg/kg/day for 28 days) or vehicle was administered to rats via an osmotic mini-pump, then received repeated seizure-inducing electrical stimulus (80 mA, 100 Hz, for 1 seconds with a pulse width of 0.5 mseconds) or sham operation twice daily for five consecutive days. The levels of glial fibrillary acidic protein (GFAP), glutamate transporter-1, and glutamine synthetase were determined in the brain regions.

Results: ES treatment led to GFAP expression, which is indicative of astrocyte activation. In the CA1 region, astrocytic changes associated with neurotoxicity were observed in the HAL-treated group. Furthermore, astroglial reactivity in this region was ameliorated following ES.

Conclusions: The present study suggests that ES could activate the astrocytic system. Furthermore, our results also showed that ES may mitigate neurotoxic damage induced by antipsychotics. In view of the need for therapeutic strategies for treatment-resistant psychiatric disorders, further investigations of our findings are warranted.

New treatments for schizophrenia are urgently needed because existing antipsychotic drugs mainly improve positive symptoms, with minimal effect on cognitive deficits and negative symptoms. The approval of Karuna Therapeutics (KarXT) in 2024 marked a significant milestone, as it became the first antipsychotic drug to target muscarinic acetylcholine receptors (mAChRs) rather than dopamine receptors. Here, we provide a perspective on how targeting mAChRs might improve the positive, negative and cognitive symptoms of schizophrenia. First, we revisit the prevailing view that xanomeline acts primarily as a M1 and M4 mAChR partial agonist. Next, we examine potential pharmacological overlap with clozapine, focusing on actions at 5-HT1A, 5-HT2A and 5-HT7 receptors and consider whether 5-HT receptor subtype agonism, inverse agonism or antagonism could be important for therapeutic efficacy. We then review the brain systems and networks impacted by muscarinic receptor subtypes in the context of Research Domain Criteria (RDoC) domains. We propose that, based on their cellular and regional expression, muscarinic receptor subtypes impact several cortico-striatal-thalamo-cortical loops and interrelated networks to improve RDoC-informed sensorimotor, positive valence, social processes, arousal and regulation, and cognitive systems. Taken together, these data suggest that there are neurobiological reasons for optimism for muscarinic agents to improve the classically described positive, negative and cognitive symptoms of schizophrenia, although the relative contribution of each mAChR subtype (M1-M5) remains unclear. We propose that a multi-targeted approach combining actions at 5-HT1A and 5-HT7 receptors could provide additional therapeutic benefits across a range of RDoC domains and hence be of clinical benefit trans-diagonistically beyond schizophrenia.

Clozapine is unique in being the only recourse for people with schizophrenia not responding to conventional pharmacotherapy with dopamine D2 antagonists and partial agonists. Yet, after half a century of use, the underlying mechanism of clozapine's relatively greater efficacy remains elusive. There have been many hypotheses relating to various neurotransmitter receptors that have not withstood further study, and some that have not been fully investigated. The recent introduction of the xanomeline-trospium combination for the treatment of schizophrenia has renewed interest in muscarinic receptor mechanisms; like xanomeline, clozapine and particularly its metabolite norclozapine reportedly have partial agonist actions at some muscarinic receptor subtypes. In their recent article, Morrison et al. draw attention to this by highlighting hypersalivation, a common feature of clozapine treatment that is not shared by other antipsychotic agents which they suggest to be a result of muscarinic receptor agonism. However the relatively weak muscarinic activity of clozapine, low brain availability of norclozapine and clinical findings from xanomeline combine to provide little support for muscarinic mechanisms underlying the greater efficacy of clozapine. An alternative hypothesis is that of alpha2 adrenergic receptor antagonism, a feature of clozapine pharmacology that may also contribute to clozapine-induced hypersalivation. Clinical findings with adjunctive alpha2 antagonists demonstrate clozapine-like improvements in antipsychotic efficacy, while both preclinical studies with specific alpha2C antagonists and the relatively high and selective antagonism of alpha2C receptors by clozapine provide support for this mechanism for clozapine's unique efficacy.