Journal of Psychopharmacology最新文献

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.

Background: Natural treatments may be used as an alternative or adjunct treatment for childhood neuropsychiatric disorders. Knowledge of benefits and harms is needed to inform use guidelines. We aimed to systematically identify how and which adverse events are monitored, assessed, and reported in pediatric trials that tested nutraceutical and phytoceutical treatments.

Methods: We searched MEDLINE, Embase, PsycINFO, ProQuest Dissertations and Theses Global, Cochrane Library, and Google Scholar from 2012 to 2024. Eligible studies included nutraceutical and phytoceutical trials, experimental or quasi-experimental in design, involving children or adolescents (age 4-19 years) with neuropsychiatric conditions.

Results: Ninety-eight trials were included with 75 reported as completed (77%). The most common natural treatment tested was polyunsaturated fatty acids (36%, 35/98). Most trials focused on treating attention-deficit/hyperactivity disorder (59%, 58/98) or autism spectrum disorder (21%, 21/98). Investigators from 74/98 trials (76%) reported methods that indicated adverse event monitoring. For these trials, events defined a priori for monitoring were identified in 43% (32/74), methods for collecting and recording events were described in 68% (50/74), and assessment of event severity and attribution was described in 49% (36/74) and 26% (19/74), respectively. Over 100 different adverse events were reported across completed trials. The most common events reported were gastrointestinal distress (65%, 49/75) and headache (33%, 25/75).

Conclusions: We found variability in monitoring, assessing, and reporting adverse events in pediatric trials of natural treatments. The adverse events identified in this review reinforces that specific events should be prospectively monitored in future trials.

Background: While some antipsychotics (APs) have been investigated with some controversy for insomnia associated with other mental disorders or off-label due to their sedative properties, evidence for their efficacy and safety remains inconclusive.

Aims: Our systematic review and meta-analysis have analysed comprehensively the impact of first- and second-generation (SGA) APs on subjective sleep measures.

Methods: A research string was used in PubMed, ISI Web of Science, Scopus, Cochrane and ClinicalTrials.gov databases, including both randomised clinical trials (RCTs) and non-RCTs.

Results: Overall, 43 studies were included in the systematic review, and 21 were included in the meta-analysis. APs were more effective than placebo in improving subjective measures of sleep quality and were associated with an improvement in sleep quality from the baseline to the end of the trial. We performed a meta-regression for possible moderators and found a significant effect of age and sex, with older subjects and males responding less to APs' effect on sleep. APs with higher antihistaminergic activity (e.g. quetiapine) improved sleep quality more than the dopaminergic/serotoninergic (e.g. risperidone) or simply serotonergic (e.g. pimavanserine) ones. Individuals with anxiety disorders reported greater effects of APs, especially SGAs with antihistaminergic activity, on sleep, and longer trials reported greater improvement in sleep quality.

Conclusions: APs, mostly SGAs, improved sleep quality more than placebo, and this effect was more pronounced in anxiety disorders, for anti-histaminergic APs, and in longer trials. These results could add another important tile to the mosaic of precision medicine for prescribing APs.

Background: The U.S. Food and Drug Administration approved three disease-modifying treatments for mild cognitive impairment and early Alzheimer's disease: aducanumab, lecanemab, and donanemab, which showed little efficacy, serious side effects, and are costly. Repetitive transcranial magnetic stimulation (rTMS) may overcome these difficulties by its safe, cheap, and potentially disease-modifying properties that extend beyond Aβ removal.

Aims: We aim to compare the efficacy on cognitive function, tolerability, and acceptability of rTMS with aducanumab, lecanemab, and donanemab in people with mild cognitive impairment and Alzheimer's disease.

Methods: We systematically reviewed relevant randomized placebo-controlled trials in PubMed, the CENTRAL, the CINHAL, and the ClinicalTrials.gov and performed a random-effect network meta-analysis.

Results: Nineteen randomized placebo-controlled trials with 6918 participants were included. rTMS was significantly more effective than placebo/sham stimulation. In addition, rTMS was significantly more effective than aducanumab, lecanemab, and donanemab. Furthermore, rTMS was not significantly inferior to placebo/sham stimulation in tolerability and acceptability, whereas aducanumab, lecanemab, and donanemab were significantly inferior to placebo/sham stimulation in tolerability and acceptability. rTMS was significantly superior to lecanemab and donanemab in acceptability. No significant differences were observed in the remaining comparisons.

Conclusions: rTMS may be more effective, tolerable, and acceptable than aducanumab, lecanemab, and donanemab. Long-term direct comparison studies are needed.

Background: Clozapine (CLZ) stands out for its unique receptor profile, making it more effective than other antipsychotics, especially in treatment-resistant schizophrenia (TRS). There is growing evidence supporting its use in schizoaffective disorder (SZD), although diagnostic challenges and drug characteristics have complicated the implementation of specific clinical trials.

Aim: Compare efficacy and tolerability of CLZ in real-world patients with TRS and SZD.

Methods: Prospective, pragmatic, three-month, evaluator-blinded clinical trial with two randomised controlled arms (TRS groups) and a third fixed arm (SZD group). The clinical response was assessed by monthly visits during which the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale (MADRS), Calgary Depression Scale for Schizophrenia (CDSS), Clinical Global Impression (CGI) and Udvalg für Kliniske Undersogelser were administered. One hundred twenty-seven participants (74.8% men, 25.2% women; 84 TRS, 42 SZD; mean age of 38.53) completed the follow-up.

Results: Patients treated with CLZ showed a greater reduction in all the PANSS subscales, MADRS and CDSS. In cases of SZD, there was a significant decrease in positive (F: 3.72, p < 0.05) and negative (F: 6.58, p < 0.01) symptoms, the overall score of PANSS (F: 5.64, p < 0.01) and YMRS (F: 12.01, p < 0.01). Patients using CLZ had a better subjective perception of their treatment (χ²: 17.29, p < 0.01). CLZ prescription was the only predictor of better outcomes across all the scales and improved substance use (dual disorders).

Conclusions: CLZ was effective in reducing psychotic and affective symptoms in patients with dual psychosis, with better outcomes in SZD compared with TRS.EudraCT protocol trial:2021-001278-44 (Comparative analysis of the effectiveness of clozapine in resistant schizophrenia and schizoaffective disorder; clinicaltrialsregister.eu/ctr-search/trial/2021-001278-44/ES).

Objective: The new drug KarXT targets muscarinic receptors to reduce the positive and negative symptoms of schizophrenia. Haloperidol is effective in treating the positive symptoms of schizophrenia, while sulpiride has shown modest efficacy in alleviating negative symptoms. The shared and distinct molecular mechanisms of these drugs are unclear. This study aimed to determine if the mechanism for KarXT overlaps with the benefits of haloperidol for positive symptoms and sulpiride for negative symptoms.

Methods: The putative target genes for the three drugs were identified, and a protein-protein interaction network was constructed to identify core targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the top 20 core targets were conducted. A drug-pathway-target-disease network was constructed.

Results: The search yielded 179 common targets for haloperidol against positive symptoms, 96 targets for sulpiride against negative symptoms, and 99 targets for KarXT against schizophrenia. Haloperidol affects positive symptoms by targeting the IL-17 signaling pathway via TNF, IL6, IL1B, MAPK3, and CASP3, and sulpiride affects negative symptoms by targeting the PI3K-AKT signaling pathway via BDNF, INS, AKT1, IGF1, and BCL2. KarXT affects schizophrenia by targeting the MAPK signaling pathway via AKT1, FOS, CASP3, NFKB1, and IGF1. Molecular docking revealed good binding affinities between the drugs and the potential core targets.

Conclusions: This study provides insights into the distinct molecular mechanisms by which haloperidol and sulpiride affect distinct symptoms of schizophrenia. KarXT integrates the partial effects of both drugs, including CASP3 with haloperidol and AKT1 and IGF1 with sulpiride. Our results provide a theoretical basis for clinical applications and new directions for drug development.

Background: Schizophrenia is a serious psychiatric disorder that affects over 24 million people worldwide. Current therapies treat positive symptoms but show little efficacy for negative and cognitive symptoms, which can impact quality of life. Development of effective medication for this unmet medical need is imperative. Phytocannabinoids, such as cannabidivarin (CBDV), show promising results for the treatment of neurological disorders and have demonstrated efficacy in preclinical models, including seizure, autism, Rett, and Fragile X syndromes.

Aim: To determine the effect of CBDV on cognitive and social deficits in a sub-chronic phencyclidine (scPCP) rat model of relevance to schizophrenia.

Methods: Female Lister Hooded rats received scPCP (2 mg/kg, intraperitoneally (i.p.)) or saline for 7 days, followed by a minimum 7-day drug-free washout. Rats were then treated with saline, CBDV (2, 10, and 20 mg/kg, i.p.), or risperidone (0.1 mg/kg, i.p.) 60 minutes before novel object recognition (NOR), social interaction (SI), and reversal learning (RL) testing.

Results: scPCP significantly impaired performance in all three behavioural tests. Deficits in the NOR and SI tests were significantly improved by CBDV (10 and 20 mg/kg), while 20 mg/kg was effective at reversing the deficits in RL. Risperidone also significantly reversed the scPCP-induced deficit in the NOR, RL, and SI paradigms.

Conclusion: Here, we are the first to demonstrate the ability of CBDV to ameliorate cognitive and social deficits in the scPCP rat model of relevance for schizophrenia, suggesting further research is justified into the potential therapeutic benefits of CBDV in patients.

Background: Lithium is an effective treatment for recurrent affective disorders, but it has a narrow therapeutic window and requires regular serum concentration monitoring, especially during periods of dose titration. Numerous attempts have been made to develop dose prediction methods to facilitate initiation and swift achievement of effective levels, but these typically lack sufficient accuracy and can be challenging to implement in practice.

Aims: Develop a pharmacokinetic model of lithium to enable accurate dose prediction which is adaptable for clinical practice.

Methods: The calculator was developed from a one-compartment model, which assumes that lithium distributes into total body water and requires only simple body measurements (age, sex, height and weight) as input variables. Its performance was compared to six commonly cited dose prediction methods in patients with bipolar disorder taking lithium, using two independent research samples from the United Kingdom (n = 40) and Germany (n = 18).

Results: Our one-compartment model performed better than the previous models, accurately predicting the required lithium dose within one 200 mg lithium carbonate tablet. The mean prediction error was 10 mg (SD = 148 mg) in this sample of euthymic subjects taking stable doses of lithium sampled at steady state.

Conclusions: This model sets a new benchmark for lithium dose prediction accuracy and requires only simple body measurements. Further validation work in larger, diverse samples and future developments, such as the ability of the model to back-calculate levels from samples taken outside the recommended 12-hour window, may support its translation and use in practice.