Journal of Psychopharmacology最新文献

{"title":"Six weeks open-label oral ketamine for patients with treatment-resistant depression, post-traumatic stress disorder, or obsessive-compulsive disorder.","authors":"Ben Beaglehole, Paul Glue, Shona Neehoff, Shabah Shadli, Neil McNaughton, Bridget Kimber, Chrissie Muirhead, Aroha de Bie, Rachel Day-Brown, Natalie J Hughes-Medlicott","doi":"10.1177/02698811251344710","DOIUrl":"10.1177/02698811251344710","url":null,"abstract":"<p><strong>Background: </strong>We previously completed a double-blind randomised crossover study assessing intramuscular ketamine for treatment-resistant depression (TR-D), post-traumatic stress disorder (TR-PTSD) and obsessive-compulsive disorder (TR-OCD). Here, we report an extension study to explore the ongoing benefits and tolerability of maintenance oral ketamine.</p><p><strong>Method: </strong>All participants from the original study were eligible to receive a 6-week open-label course of oral ketamine once-thrice weekly. Racemic ketamine for injection was diluted in orange juice and sipped over 30-60 min. Dose amount and frequency were adjusted individually to maximise benefits and tolerability. Effectiveness was assessed by disorder-specific scales. Side effects and tolerability were assessed using reported adverse events and scales for dissociation and urinary/bladder symptoms.</p><p><strong>Results: </strong>Seventeen participants with TR-D, 18 participants with TR-PTSD and 8 participants with TR-OCD commenced oral ketamine. Nine participants with TR-D, 16 participants with TR-PTSD and 5 participants with TR-OCD completed all 6 weeks of dosing. Ketamine dose increased over time from 1-1.5 mg/kg to 1.5-2.5 mg/kg, with a dosing frequency of 1-3 times/week, with an average total dose rising from 1.9 to 3.0 mg/kg/week over the first 3 weeks. Symptom rating scores for TR-D, TR-PTSD and TR-OCD were low at week 1 of oral dosing (compared to scores at entry into the original study) and remained low throughout the six-week course of oral ketamine. Oral ketamine was well tolerated with minimal side effects.</p><p><strong>Conclusion: </strong>The 6-week extension of oral ketamine appeared to sustain improvements for TR-D, TR-PTSD and TR-OCD. Oral ketamine was well tolerated and offers an alternative option for patients, researchers and clinicians.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"571-576"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A randomized, double-blind, placebo-controlled, Phase 1 study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of an immediate-release oral ketamine capsule in healthy volunteers.","authors":"Mutahira Qureshi, Daniel Silman, Romayne Gadelrab, Hans-Christian Stein, Pietro Carmellini, Graeme Duncan, Mitul A Mehta, Allan H Young, Carmel Reilly, Mario F Juruena","doi":"10.1177/02698811251340925","DOIUrl":"10.1177/02698811251340925","url":null,"abstract":"<p><strong>Background: </strong>Ketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist used as a therapeutic for treatment-resistant depression (TRD), is usually administered intravenously or intranasally.</p><p><strong>Aims: </strong>This randomized, double-blind, placebo-controlled, Phase 1 study investigated safety and tolerability (primary endpoint), pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release oral ketamine.</p><p><strong>Methods: </strong>Healthy volunteers (18-55 years) were randomized to each receive two single doses of oral ketamine (40-240 mg) and one oral placebo dose. Treatment-emergent adverse events (TEAEs) and PK and PD assessments (e.g., Bond and Lader visual analogue scale, Modified Observer's Assessment of Alertness/Sedation Scale) were assessed up to 24 h after dosing. Descriptive statistics were used.</p><p><strong>Results: </strong>Nineteen participants were randomized (mean age: 31 years; male, 68%); 18 completed the study. Eighty mild or moderate TEAEs were reported following oral ketamine (40-240 mg) and five following placebo. There were no TEAE-related discontinuations. Most TEAEs (86%) were considered probably related to study drug. The most common TEAEs with oral ketamine were dissociation (26 events), dizziness (nine events) and headache (nine events). A positive relationship between increasing ketamine doses and dissociation events was observed. PK parameters (<i>C</i>_max, AUC_inf) of oral ketamine and its primary metabolites (2S,6S;2R,6R-hydroxynorketamine, R/S-norketamine) were dose proportional. Transient changes in mood and dissociation were detected 1 h postdose with a return to predose values after ~4 h.</p><p><strong>Conclusions: </strong>There were no unexpected safety signals with oral ketamine. PK properties were consistent with those reported for other rapid-acting formulations. These findings warrant further investigation of oral ketamine capsules in TRD (EudraCT No. 2019-001019-22).</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"545-558"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression - comparison with ketamine, fluoxetine and lithium.","authors":"Yana Vella, Kateřina Syrová, Aneta Petrušková, Isis Koutrouli, Viera Kútna, Jan Pala, Klára Šíchová, Marek Nikolič, Vladimír Mazoch, Radek Jurok, Martin Kuchař, Zdeňka Bendová, Tomáš Páleníček","doi":"10.1177/02698811251338232","DOIUrl":"https://doi.org/10.1177/02698811251338232","url":null,"abstract":"<p><strong>Background: </strong>Recent evidence suggests that psychedelics can induce rapid and long-lasting antidepressant effects. The generally acknowledged explanation for these traits is the phenomenon of neuroplasticity, although the exact underlying molecular mechanisms remain unclear.</p><p><strong>Aims: </strong>This study investigates the effects of psilocin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) on synaptogenesis and immediate early genes (IEGs) expression in direct comparison with ketamine, fluoxetine and lithium after acute (1 h) and/or prolonged (24 h) treatment in vitro.</p><p><strong>Methods: </strong>Rat primary cortical cultures were treated with 10 µM psilocin, 1 µM LSD, 90 µM DMT, 1 µM ketamine, 10 µM fluoxetine and 5 mM lithium. Analysis of synaptic puncta was performed; puncta of presynaptic marker synapsin I/II, postsynaptic density protein 95 (PSD-95) and their co-localization (established synapse) were assessed 24 h after drug treatment. Next, expressions of IEGs encoding activity-regulated cytoskeleton-associated protein (<i>Arc</i>), early growth response 1 (<i>Egr1</i>), and neuronal PAS (Per-Arnt-Sim) domain protein 4 (<i>Npas4</i>) were analysed 1 and 24 h after drug treatments.</p><p><strong>Results: </strong>Psilocin increased synaptic puncta count and induced <i>Arc</i> expression. The effect to promote synaptogenesis was comparable to ketamine and lithium; ketamine additionally increased PSD-95 puncta count. LSD and DMT did not induce any significant effects. Interestingly, fluoxetine had no effect on synaptic puncta count, but upregulated <i>Egr1</i> and <i>Npas4</i>.</p><p><strong>Conclusions: </strong>Psilocin demonstrated synaptogenic effects comparable to those of ketamine and lithium, and acutely upregulated IEG <i>Arc</i> expression, adding another piece of evidence to its profile as a promising therapeutic agent.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251338232"},"PeriodicalIF":4.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What are set and setting: Reducing vagueness to improve research and clinical practice.","authors":"Kyle Patch, William R Smith","doi":"10.1177/02698811251337372","DOIUrl":"https://doi.org/10.1177/02698811251337372","url":null,"abstract":"<p><p>Research on the therapeutic potential of psychedelics has surged, prompting a re-examination of the role of set and setting in psychedelic-assisted therapy. Yet, these concepts are vague and typically defined over inclusively. We believe that set and setting research should be methodologically reductionist, focusing on specific components rather than set and setting as such. To that end, we propose the mechanism-first approach, which begins with specific, paradigmatic set and setting components, such as \"openness to the psychedelic experience\" or calming lighting and music. It seeks to understand the mechanisms through which these components affect psychedelic outcomes. Once the mechanisms in paradigmatic cases are understood, researchers can ask whether other mental and environmental factors play the same or similar mechanistic roles. As the process iterates over time, understanding of set and setting expands to include more components. Setting aside the vague, standard definitions of set and setting and focusing, instead, on specific components of set and setting, the mechanism-first approach encourages productive research agendas, focused on specific projects that are mutually informative. To defend it, we outline the problems with standard definitions of set and setting, describe the mechanism-first approach in detail, illustrate it by considering its implications for selected, active research projects, and respond to objections to our approach.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251337372"},"PeriodicalIF":4.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Centrally-acting opioid receptor antagonists as a treatment for antipsychotic-induced weight gain: A systematic review and meta-analysis of clinical trial data.","authors":"Kenn Lee, Matthew Twohig, Nguemo Pauline Idoko, Benjamin David Williams","doi":"10.1177/02698811251337374","DOIUrl":"https://doi.org/10.1177/02698811251337374","url":null,"abstract":"<p><strong>Background: </strong>Antipsychotic-induced weight gain (AIWG) is a major concern in psychiatry, where there is a mortality gap between those with mental illness, particularly schizophrenia, and the general population. One development proposed is using centrally-acting opioid receptor antagonists (CORAs) such as naltrexone and samidorphan.</p><p><strong>Objective: </strong>The systematic review and meta-analysis evaluated the available human clinical trial data on the effect of CORA on AIWG.</p><p><strong>Methodology: </strong>Four online databases (MEDLINE, EMBASE, PsycINFO, and Cochrane) were searched for randomized-controlled trials (RCTs) on the topic. The primary outcome was change in bodyweight. Secondary anthropometric outcomes included percentage bodyweight change, BMI change, and absolute risk of weight gain. Meta-analysis was conducted on primary outcome.</p><p><strong>Results: </strong>Nine RCT articles (samidorphan = 6, naltrexone = 3) and two extension studies from RCTs (both samidorphan) were identified. Meta-analysis of four RCTs (<i>n</i> = 1416) found olanzapine/samidorphan was associated with less weight gain than olanzapine alone (mean difference in bodyweight change: -1.18 kg; 95% CI: -1.67 to -0.68). Olanzapine/samidorphan was also superior to olanzapine for changes in BMI (-0.65 kg/m²; 95% CI: -1.1 to -0.28), waist circumference (-1.5 cm; 95% CI: -2.67 to -0.32), and risk reduction for gaining 7% body weight (-12.4%; 95% CI: -18.27 to -6.54) or 10% body weight (-10.8%; 95% CI: -16.21 to -5.45). Naltrexone did not separate from placebo for change in weight or BMI.</p><p><strong>Conclusion: </strong>CORA, specifically samidorphan, was effective at reducing weight gain in individuals prescribed olanzapine. The small effect sizes and discrepancy between samidorphan and naltrexone suggest effects may be timing dependent, not a class effect, or dependent on the antipsychotic combination.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251337374"},"PeriodicalIF":4.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychedelic-assisted psychotherapy: The need to monitor adverse events.","authors":"Krj Schruers, N K Leibold","doi":"10.1177/02698811251340929","DOIUrl":"https://doi.org/10.1177/02698811251340929","url":null,"abstract":"<p><p>The therapeutic use of psychedelics for mental health issues holds considerable promise. However, systematic assessment of adverse events associated with these substances has received relatively little attention. Here, we discuss several considerations concerning the assessment of adverse events in psychedelic-assisted therapies. We discuss the preference for using the term \"adverse effects\" over \"side effects\", as well as the ongoing debate regarding which substances are classified as psychedelic. We also provide recommendations on when and how to assess adverse effects, for example the importance to study them in any kind of therapy involving psychedelics, and using comprehensive monitoring of a wide range of physical parameters in combination with behavioral outcomes and the individual's experience, at baseline and throughout the study. Also, sex-specific differences should be considered. Furthermore, we highlight several significant studies that have addressed these aspects. In summary, psychedelics offer great promise as a potential treatment (add-on) option in psychiatry, but more rigorous assessment of adverse effects is needed to promote safe use and implementation in clinical practice.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251340929"},"PeriodicalIF":4.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping acute alcohol effects on bodily sensations: A cross-dimensional interoceptive approach.","authors":"Mateo Leganes-Fonteneau, Olivier Desmedt, Micah G Allen, Reinout W Wiers, Pierre Maurage","doi":"10.1177/02698811251338223","DOIUrl":"https://doi.org/10.1177/02698811251338223","url":null,"abstract":"<p><strong>Background: </strong>Interoceptive processes may underlie maladaptive patterns of alcohol use. Bodily sensations experienced during alcohol intoxication could therefore reveal distinct mechanistic components relevant for addiction theory and research. Here, we apply novel tools to examine how intoxication impacts somatic awareness using bodily maps and a cardiac interoception task.</p><p><strong>Methods: </strong>In a double-blind, within-subjects, placebo-controlled study, social drinkers (<i>n</i> = 37, 17 female) were administered 0.4 g/kg of alcohol. We measured changes in self-reported bodily sensations during the ascending and descending limbs of the blood-alcohol curves using the emBODY tool. Additionally, we recorded biphasic measures of subjective alcohol effects (sedation and stimulation), changes in heart rate, and assessed psychophysical measures of cardiac beliefs using the heart rate discrimination task.</p><p><strong>Results: </strong>Acute alcohol administration altered bodily sensations, reflected by strong sensations in the chest, limbs, and head, with lesser effects in the placebo condition. Linear-mixed models examined correlates of bodily sensations across conditions. Extent of bodily sensations correlated with heart rate changes and breath alcohol content. In the ascending limb, bodily sensations negatively correlated with subjective stimulation and positively with sedation. Finally, extent of bodily sensations correlated with the metacognitive sensitivity of cardiac beliefs, suggesting a cross-dimensional integration between sensations and interoceptive awareness.</p><p><strong>Discussion: </strong>These findings highlight the value of bodily mapping in psychopharmacology, as interoceptive components of alcohol intoxication may provide a somatic basis for addiction. We interpret our results through low-sensitivity models, suggesting individuals with reduced bodily sensations during intoxication may face elevated risk for alcohol use disorder, a hypothesis that will be examined in future research.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251338223"},"PeriodicalIF":4.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative efficacy, tolerability, and acceptability of aducanumab, lecanemab, and donanemab with repetitive transcranial magnetic stimulation on cognitive function in mild cognitive impairment and Alzheimer's disease: A systematic review and network meta-analysis.","authors":"Itsuki Terao, Wakako Kodama","doi":"10.1177/02698811251340901","DOIUrl":"https://doi.org/10.1177/02698811251340901","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>rTMS may be more effective, tolerable, and acceptable than aducanumab, lecanemab, and donanemab. Long-term direct comparison studies are needed.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251340901"},"PeriodicalIF":4.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotransmitter modulation of human facial emotion recognition.","authors":"Myrto Vlazaki, Catherine J Harmer, Philip J Cowen, Erdem Pulcu","doi":"10.1177/02698811251338225","DOIUrl":"https://doi.org/10.1177/02698811251338225","url":null,"abstract":"<p><p>Human facial emotion recognition (FER) is an evolutionarily preserved process that influences affiliative behaviours, approach/avoidance and fight-or-flight responses in the face of detecting threat cues, thus enhancing adaptation and survival in social groups. Here, we provide a narrative literature review on how human FER is modulated by neurotransmitters and pharmacological agents, classifying the documented effects by central neurotransmitter systems. Synthesising the findings from studies involving functional neuroimaging and FER tasks, we highlight several emerging themes; for example, noradrenaline promotes an overall positive bias in FER, while serotonin, dopamine and gamma-aminobutyric acid modulate emotions relating to self-preservation. Finally, other neurotransmitters including the cholinergic and glutamatergic systems are responsible for rather non-specific pro-cognitive effects in FER. With the ongoing accumulation of evidence further characterising the individual contributions of each neurotransmitter system, we argue that a sensible next step would be the integration of experimental neuropharmacology with computational models to infer further insights into the temporal dynamics of different neurotransmitter systems modulating FER.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251338225"},"PeriodicalIF":4.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: The effect of psychedelics on the level of brain-derived neurotrophic factor: A systematic review and meta-analysis.","authors":"","doi":"10.1177/02698811251341228","DOIUrl":"https://doi.org/10.1177/02698811251341228","url":null,"abstract":"","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251341228"},"PeriodicalIF":4.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}