Journal of Psychopharmacology最新文献

{"title":"Monoamine neurotransmitter-related gene-based genome-wide association study of low-dose ketamine in patients with treatment-resistant depression.","authors":"Chung-Feng Kao, Shih-Jen Tsai, Tung-Ping Su, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ya-Mei Bai, Pei-Chi Tu, Mu-Hong Chen","doi":"10.1177/02698811251326939","DOIUrl":"10.1177/02698811251326939","url":null,"abstract":"<p><strong>Background: </strong>Low-dose ketamine is an N-methyl-D-aspartate receptor antagonist that exerts an antidepressant effect on patients with treatment-resistant depression (TRD). This antidepressant effect may extend beyond the glutamatergic hypothesis. Nevertheless, the roles of genes encoding other monoamine neurotransmitters (i.e., serotonin and dopamine) in the neuromechanism of low-dose ketamine remain unknown.</p><p><strong>Methods: </strong>In this clinical trial, which involved 65 patients with TRD, 21 patients received 0.5 mg/kg ketamine, 20 received 0.2 mg/kg ketamine, and 24 received normal saline. All patients were genotyped for 684,616 single-nucleotide polymorphisms (SNPs). A total of 50 monoamine neurotransmitter-related candidate genes, including HTR2A and HTR2C from the serotoninergic system, CHRM4 and CHRNB1 from the cholinergic system, and DRD2 from the dopaminergic system, were selected to conduct a gene-based genome-wide association study of the antidepressant effects of ketamine.</p><p><strong>Results: </strong>Gene-set enrichment analysis revealed that the pathway underlying neuroactive ligand-receptor interaction (KEGG) played a pivotal role in the biomechanisms underlying ketamine's antidepressant effect. Specifically, the genes and SNPs related to the cholinergic system (e.g., rs2644247 in CHRM5), μ1 opioid receptor (e.g., rs2473546 in OPRM1), dopaminergic system (e.g., rs2617577 in SLC6A3), serotonergic system (HTR2A), cannabinoid receptor (CNR2), and σ1 receptor (SIGMAR1) were associated with the antidepressant effect of low-dose ketamine.</p><p><strong>Discussion: </strong>Low-dose ketamine has an antidepressant effect, which may be associated with multiple monoamine neurotransmitter systems and the σ1 receptor.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"593-602"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700583","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":"Acute subanesthetic ketamine-induced effects on the mismatch negativity and their relationship to early and sustained treatment response in major depressive disorder.","authors":"Sara de la Salle, Jennifer L Phillips, Pierre Blier, Verner Knott","doi":"10.1177/02698811251319456","DOIUrl":"10.1177/02698811251319456","url":null,"abstract":"<p><strong>Background: </strong>A sub-anesthetic dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, produces robust antidepressant effects in treatment-resistant major depressive disorder (MDD). The mismatch negativity (MMN) is reliant on glutamatergic neurotransmission and reduced by NMDAR antagonists. The MMN may characterise the neural mechanisms underlying ketamine's effects.</p><p><strong>Aims: </strong>This study examined the acute effects of ketamine and midazolam on the MMN and its relationship to early and sustained decreases in depressive symptoms.</p><p><strong>Methods: </strong>Treatment-resistant MDD patients (<i>N</i> = 24), enrolled in a multi-phase clinical ketamine trial, received two intravenous infusions within an initial double-blind crossover phase: ketamine (0.5 mg/kg) and midazolam (30 μg/kg). Three recordings were carried out per session (pre-, immediately post- and 2 h post-infusion). Peak MMN amplitude (μV), latency (ms), theta event-related oscillations (EROs), theta phase locking factor (PLF) and source-localised MMN generator activity were assessed. Relationships between changes in MMN indices and early (Phase 1: double-blind, cross-over phase) and sustained (Phases 2, 3: open-label repeated and maintenance phases, respectively) changes in depressive symptoms (Montgomery-Åsberg Depression Rating Scale score) were examined.</p><p><strong>Results: </strong>Ketamine reduced frontal MMN amplitudes, theta ERO immediately post- and 2 h post-infusion and source-localised peak MMN frontal generator activity. Select baseline and ketamine-induced MMN decreases correlated and predicted greater early (left frontal MMN decreases in amplitude and theta ERO, baseline left PLF) and sustained (baseline left PLF, right inferior temporal activity) symptom reductions.</p><p><strong>Conclusions: </strong>Acute NMDARs blockade reduced frontal MMN, with larger MMN reductions predicting greater symptom improvement. The MMN may serve as a non-invasive biomarker predicting antidepressant response to glutamatergic agents.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"577-592"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brexpiprazole augmentation and mitochondrial gene expression changes in major depressive disorder.","authors":"Kohei Kondo, Yuta Yoshino, Hiroshi Kumon, Mariko Okano, Hiroaki Mori, Jun-Ichi Iga, Shu-Ichi Ueno","doi":"10.1177/02698811251337365","DOIUrl":"10.1177/02698811251337365","url":null,"abstract":"<p><strong>Background: </strong>Overall, 20% of patients with major depressive disorder (MDD) are treatment-resistant and do not respond to multiple antidepressant monotherapies. For such patients, augmentation therapy with antipsychotics is one of the therapeutic options. However, the mechanism of augmentation therapy is essentially unknown.</p><p><strong>Aim: </strong>This study aimed to elucidate the mechanism of brexpiprazole (BREX) augmentation at gene expression levels.</p><p><strong>Methods: </strong>Vehicle, escitalopram (ES), BREX, and ES + BREX (augmentation therapy) were administered to mouse neuroblastoma (Neuro2a) cells and submitted to RNA-sequencing. Gene expressions were also measured in the whole blood of MDD patients and the frontal cortices and hippocampi of mice after treatment for 20 days.</p><p><strong>Results: </strong>On RNA-seq and gene ontology analyses, upregulation of mitochondria (MT)-related genes was confirmed by quantitative Polymerase Chain Reaction (PCR). These upregulated genes were successfully validated in both Neuro2a and Caco2 cells. Decreased <i>MT-ATP8</i> expression was found in the whole blood of MDD patients. Furthermore, changes in MT-mRNA expression were confirmed in the frontal cortices and hippocampi of mice with augmentation therapy.</p><p><strong>Conclusions: </strong>BREX augmentation modified MT-mRNA expressions in both in vitro and in vivo experiments. This may be a key finding in improving our understanding of MDD pathogenesis and clinical practice.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"603-611"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024853","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":"Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program.","authors":"Jolien Ke Veraart, Sanne Y Smith-Apeldoorn, Annemarie van der Meij, Jan Spijker, Robert A Schoevers, Jeanine Kamphuis","doi":"10.1177/02698811251332831","DOIUrl":"10.1177/02698811251332831","url":null,"abstract":"<p><strong>Background: </strong>Oral esketamine for patients with treatment-resistant depression (TRD) could offer certain advantages over other routes, such as intravenous or intranasal, but it has not been systematically studied in a real-world setting.</p><p><strong>Aims: </strong>Here we present results from a relatively large naturalistic study to evaluate the effectiveness, tolerability, and safety of oral esketamine in patients with TRD.</p><p><strong>Methods: </strong>One hundred eighty-five adults with severe TRD (average of 8.1 antidepressant trials plus electroconvulsive therapy in 63% without beneficial outcome) received oral esketamine treatment twice-weekly for 6 weeks with individually titrated doses ranging from 0.5 to 3 mg/kg. Outcome measures included change from baseline to week 6 on the Hamilton Depression Rating Scale (HDRS₁₇), Minimal Clinically Important Difference (MCID), response, remission, self-reported symptom improvement, functioning, and side effects.</p><p><strong>Results: </strong>Oral esketamine treatment improved depressive symptom severity on the HDRS₁₇ from 21.2 to 15.8 (<i>p</i> < 0.001). MCID, response, and remission rates were 47.1%, 26.8% and 15.6% respectively. In 45.9% of participants, treatment was continued after 6 weeks to maintain initial positive effects. Side effects were reported frequently but were overall well tolerated. The drop-out rate was 7.6%. We found no significant adverse effects associated with urinary tract or cognition.</p><p><strong>Conclusions: </strong>Repeated treatment with oral esketamine is effective in improving depressive symptom severity in highly treatment-resistant depressive patients. It is safe, well tolerated, and patient-friendly. Considering the level of treatment resistance, outcomes were in the range of studies investigating other routes of (es)ketamine administration.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"559-570"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting the pro-neurogenic effects of monoaminergic medications used to treat depression: a systematic review and meta-analysis.","authors":"Juliana A Bolzan, Tamires Martins, Karolina Domingues, Alexandre Surget, Catherine Belzung, Cilene Lino de Oliveira","doi":"10.1177/02698811251337382","DOIUrl":"10.1177/02698811251337382","url":null,"abstract":"<p><p>The neurogenic theory of depression proposes that chronic medications modulating monoaminergic neurotransmission may ameliorate symptoms of mood disorders by correcting stressor-induced disruptions in adult hippocampal neurogenesis. However, some controversial findings challenge this assertion. A systematic review and meta-analysis of all pertinent studies, corrected by publication bias, estimated a small, significant, and consistent pro-neurogenic effect of monoaminergic treatments in laboratory rodents. Nearly 30% of the literature exhibited low and 70% unclear risk of bias. In both naïve and stressed mice, pro-neurogenic effects occurred irrespective of strain, sex, stress, or behavioral testing experience. In rats, the effects were predominantly inconclusive due to the lower number of studies in this species. The available number of studies was also insufficient to yield definitive evidence for compounds acting as selective serotonin reuptake inhibitors (citalopram, escitalopram, fluvoxamine), serotonin-norepinephrine reuptake inhibitors (desvenlafaxine, duloxetine, venlafaxine), multimodal monoaminergic modulators (imipramine, desipramine), melatonergic compound (agomelatine), or norepinephrine-serotonin disinhibitory (mirtazapine). Subsequent updates of these reviews appear necessary to establish robust evidence regarding these compounds. Evidence was firm in favor of a robust pro-neurogenic effect of selective serotonin reuptake inhibitor fluoxetine, in both species, making updates of this review probably redundant.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"513-532"},"PeriodicalIF":5.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266469","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":"The anti-inflammation pharmacodynamics of lithium: Therapy of bipolar disorder.","authors":"Yuyang Zhou, Weizhi Zheng, Feichang Guo, Shijin Wu, Congjie Zhong","doi":"10.1177/02698811251326942","DOIUrl":"10.1177/02698811251326942","url":null,"abstract":"<p><p>Bipolar disorder is a severe mental disorder that necessitates effective long-term treatment strategies. Clinically, lithium has demonstrated favorable outcomes in managing this condition. The inflammatory theory posits that bipolar disorder is influenced by an inflammatory response, and lithium is thought to mitigate this disorder by inhibiting such responses. In terms of the pharmacodynamics of blocking inflammatory mediators, lithium mainly acts on GSK-3β. Upon interaction with GSK-3β, lithium can suppress the gene expression of inflammatory mediators, subsequently reducing their secretion. This mechanism influences multiple downstream pathways, ultimately contributing to the therapeutic effects observed in bipolar disorder. Specifically, these pathways include the arachidonic acid pathway, nitric oxide synthase pathway, neurotransmitter pathway, and so on. This article reviews the pharmacodynamic targets and mechanisms of lithium, offering insights into the appropriate clinical application of lithium and the advancement of lithium pharmacotherapies.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"533-544"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730691","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":"Repeated administration of L-alanine to mice reduces behavioural despair and increases hippocampal mammalian target of rapamycin signalling: Analysis of gender and metabolic effects.","authors":"Abdullah Aziz, Carolina Fernandes Ferreira Alves Costa, Erying Zhao, Daniel Radford-Smith, Fay Probert, Daniel Clive Anthony, Philip William John Burnet","doi":"10.1177/02698811251332838","DOIUrl":"10.1177/02698811251332838","url":null,"abstract":"<p><strong>Background: </strong>The amino acid L-alanine, has been shown to be elevated in biofluids during major depression but its relevance remains unexplored.</p><p><strong>Aim: </strong>We have investigated the effects of repeated L-alanine administration on emotional behaviours and central gene expression in mice.</p><p><strong>Methods: </strong>Mice received a daily, 2-week intraperitoneal injection of either saline or L-alanine at 100 or 200 mg/kg and were exposed to the open field, light-dark box and forced swim test. The expression of L-alanine transporters (asc-1, ASCT2), glycine receptor subunits (GlyRs), NMDA receptor subunits (GluNs) mRNAs were measured, together with western blots of the signalling protein mammalian target of rapamycin (mTOR). Since L-alanine modulates glucose homeostasis, peripheral and central metabolomes were evaluated with ¹H-NMR.</p><p><strong>Results: </strong>L-alanine administration at 100 mg/kg, but not at 200 mg/kg, to both male and female mice increased latency to float and reduced floating time in the forced swim test, but had no effect on anxious behaviour in the open field and light-dark box tests. There was a significant reduction in mRNAs encoding asc-1 and ASCT2 and GluN2B in the hippocampus of mice following 100 mg/kg L-alanine only. On western blots, hippocampal GluN2B immunoreactivity was reduced, but mTOR signalling was increased in the 100 mg/kg L-alanine group. 1H-NMR revealed gender-specific changes in the forebrain, plasma and liver metabolomes only at 200 mg/kg of L-alanine.</p><p><strong>Conclusions: </strong>Our data suggest that L-alanine may have antidepressant-like effect that may involve the modulation of glutamate neurotransmission independently of metabolism. In major depression, therefore, elevated L-alanine may be a homeostatic response to pathophysiological processes, though this will require further investigation.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"612-623"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recasting the role of electroconvulsive therapy and the electroconvulsive therapy practitioner: For severe illness, not necessarily treatment-resistant depression.","authors":"Randall T Espinoza, Charles H Kellner, Alexander Sartorius, Axel Nordenskjöld","doi":"10.1177/02698811251319469","DOIUrl":"10.1177/02698811251319469","url":null,"abstract":"","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"624-626"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433376","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205158/pdf/","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":"OA","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205163/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}