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Ansari M, Rhee TG, Santucci MC, Nikayin S. Does BMI matter when treating depression with esketamine? A retrospective analysis of real-world data. J Affect Disord 2025; 381:22-28. [PMID: 40185405 DOI: 10.1016/j.jad.2025.03.198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 03/15/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
OBJECTIVE Intranasal (IN) esketamine was approved as a therapy for treatment-resistant depression in March 2019. There continues to be interest in the field to better understand factors associated with response to treatment. The aim of the current study is to assess the association between BMI and response to esketamine. METHODS A retrospective analysis was conducted on all patients treated with intranasal esketamine at the Yale Interventional Psychiatry Service between January 2015 and May 2023. The primary outcome was the association between BMI (ctegorized as obese vs. non-obese) and response to treatment (≥50 % improvement) by Montgomery-Åsberg Depression Rating Scale (MADRS). Statistical models, including generalized linear mixed-effects models were employed. RESULTS A total of 190 patients met criteria for inclusion in the study, out of which 34.2 % were categorized as obese. Patients with obesity were significantly more likely to respond to esketamine treatment (RR = 1.63; p = 0.033) compared to non-obese patients. No linear association between BMI and treatment response was observed when BMI was treated as a continuous variable (RR = 1.02, p = 0.163). CONCLUSION Obesity appears to be associated with a higher response rate to intranasal esketamine treatment for depression. Although the underlying mechanisms of this association are still unknown, increased body fat may prolong the presence of lipid-soluble compounds such as ketamine/esketamine or their active metabolites.
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Affiliation(s)
- Mina Ansari
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; Yale Depression Research Program (YDRP), Yale University, New Haven, CT 06511, USA
| | - Taeho Greg Rhee
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Mia C Santucci
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; Yale Depression Research Program (YDRP), Yale University, New Haven, CT 06511, USA
| | - Sina Nikayin
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; Yale Depression Research Program (YDRP), Yale University, New Haven, CT 06511, USA; Interventional Psychiatry Services, Yale Psychiatry Hospital, New Haven, CT 06519, USA.
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Shen W, Yan Y, Zhang W, Xu J, Li Z, Yang L. Esketamine mitigates systemic inflammation via modulating phenotypic transformation of monocytes in patients undergoing thoracic surgery. Life Sci 2025; 371:123594. [PMID: 40164333 DOI: 10.1016/j.lfs.2025.123594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025]
Abstract
AIM To assess esketamine's anti-inflammatory effects during thoracic surgery and its modulation of immune responses. MATERIAL AND METHODS In a randomized trial, 64 of 73 patients undergoing thoracic surgery were allocated into the Control (not receiving esketamine) or the ES-KTM group (intraoperative esketamine infusion). Blood routine tests were conducted one day before (T0) and one day after the surgery (T3). Plasma levels of tumor necrosis factor-α (TNF-α) and interleukine-10 (IL-10) were analyzed by ELISA, and cell surface markers including CD14, CD16, CD163, CD40, CX3CR1, CD206 were tested by cytometry at the entry to the surgical room (T1) and the skin closure (T2). For the in vitro study, esketamine at 10 μM was employed to treat the lipopolysaccharide (LPS) stimulated macrophage cell line-Raw264.7, and its effects were tested by cytometry and RNA sequencing analysis. KEY FINDINGS Esketamine application reduces the count of neutrophils and monocytes, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and systemic inflammatory index (SII), and enhances the lymphocyte counting and lymphocyte to monocyte ratio (LMR). Then, esketamine application decreases the plasma TNF-α levels, while maintaining the IL-10 level in comparison with the Control group. Additionally, esketamine reduced the proportion of intermediate monocytes, downregulates the expressions of CD16, CD40 and CX3CR1, while upregulates the CD206 expression. Finally, in the in-vitro study, esketamine inhibits the M1 pro-inflammatory markers in LPS-challenged macrophages, and downregulates multiple immune-related pathways. SIGNIFICANCE Esketamine mitigates surgery-triggered inflammation by suppressing monocyte/macrophage proinflammatory activity and TNF-α release, offering dual anesthetic and immunomodulatory benefits.
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Affiliation(s)
- Weiyun Shen
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Anesthesia Clinical Medical Care Technology Research Center, Changsha, Hunan Province, China
| | - Yan Yan
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Anesthesia Clinical Medical Care Technology Research Center, Changsha, Hunan Province, China; Department of Anesthesiology, Xiamen Cardiovascular Hospital, Xiamen University, China
| | - Wenjuan Zhang
- Department of Laboratory, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Junmei Xu
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Anesthesia Clinical Medical Care Technology Research Center, Changsha, Hunan Province, China
| | - Zhijian Li
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Anesthesia Clinical Medical Care Technology Research Center, Changsha, Hunan Province, China.
| | - Lin Yang
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Anesthesia Clinical Medical Care Technology Research Center, Changsha, Hunan Province, China.
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3
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Lin Z, Xu X, Zhang K, Wang T, Cao L, Wang Z, Wang G. Correlations between major depressive disorder, splenic morphology, and immune function. BMC Psychiatry 2025; 25:477. [PMID: 40355817 PMCID: PMC12070695 DOI: 10.1186/s12888-025-06853-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/14/2025] [Indexed: 05/15/2025] Open
Abstract
To analyze the symptoms, courses, and severities of depressive disorder, as well as the morphological changes in the spleens and related immune mechanisms, we recruited patients with first-episode or recurrent major depressive disorder (MDD) (patient group) and healthy controls (normal group) matched in age and gender. We measured their plasma MICB (pg/ml), ULBP1 (ng/ml), and splenic volume (cm3) at baseline. The patient group was randomly assigned to receive (S)-ketamine (study group) or saline (control group), and the above indices were collected again on the 4th weekend after administration. At baseline, both MICB and splenic volume were significantly higher in the patient group than in the normal group. A positive correlation was observed between MICB and splenic volume in the patient group. After (S)-ketamine administration, the elevated splenic volume and MICB levels decreased. These results suggest that the pathogenesis of MDD may involve abnormal MICB expression and splenic morphology. (S)-ketamine may ameliorate inflammation and enhance splenic function, thereby relieving MDD symptoms.
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Affiliation(s)
- Zouqing Lin
- The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, 214151, China.
| | - Xiaoyan Xu
- Wuxi Affiliated Hospital of Nanjing, University of Chinese Medicine, Wuxi, China
| | - Kai Zhang
- Chaohu Hospital of Anhui Medical University, Hefei, China
| | - Tenglong Wang
- The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, 214151, China
| | - Leiming Cao
- The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, 214151, China
| | - Zhiqiang Wang
- The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, 214151, China
| | - Guoqiang Wang
- The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, 214151, China.
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Wei Q, Li M, Du Q, Zhang H, Liang Y, Cheng C, Mei B, Yang X, Fan Y, Zhu J, Zhang J, Yu Y, Shen Q, Liu X, Sessler DI. Effect of esketamine on postoperative depression in women with breast cancer and preoperative depressive symptoms: The EASE randomized trial. J Clin Anesth 2025; 103:111821. [PMID: 40153893 DOI: 10.1016/j.jclinane.2025.111821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 02/09/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
STUDY OBJECTIVE To determine whether intraoperative low-dose esketamine ameliorates depression in women having breast cancer surgery. DESIGN A prospective single-center double blind randomized placebo-controlled trial. SETTING Perioperative period, operating room, post anesthesia care unit and hospital ward. PATIENTS 108 women 18-65 years old who were scheduled for elective breast cancer surgery. All had preoperative depressive symptoms as defined by Montgomery-Åsberg depression scores ≥12 (range, 0-60; higher scores indicate more severe depression). INTERVENTIONS Eligible participants were randomized to esketamine 0.25 mg/kg or saline placebo. Blinded trial drugs were given intravenously over the initial 40 min of anesthesia. MEASUREMENTS Our primary outcome was the fraction of patients who had at least a 50 % reduction in the Montgomery-Åsberg depression score within 3 postoperative days. Secondary outcomes included the fraction of patients with depression remission defined as Montgomery-Åsberg scores ≤10, the numeric value of the Montgomery-Åsberg depression scores, postoperative severe pain, and anxiety as determined by the Generalized Anxiety Disorder 7-item score. Adverse events were monitored for 72 postoperative hours. MAIN RESULTS 54 women each were randomized to esketamine and saline, and 104 were available for our intent-to-treat analysis. The mean age was 50 years. Esketamine non-significantly doubled the fraction of patients who had a 50 % reduction in their depressions scores: 27 % vs 13 %, odds ratio 2.4, [95 % CI 0.9 to 6.6], P = 0.087. Montgomery-Åsberg depression scores were nearly a factor-of-two and significantly lower (better) on postoperative days 1 to 5 in patients given esketamine. Montgomery-Åsberg scores decreased significantly more from baseline in patients randomized to esketamine: mean difference - 2.5 [95 % CI -4.5 to -0.6], P = 0.010. Esketamine treatment had no significant effect on other secondary outcomes or on adverse events. CONCLUSIONS Intraoperative administration of 0.25 mg/kg esketamine did not significantly improve the fraction of depressed women having breast cancer patients who had a 50 % reduction in their depression scores at 3 days postoperatively. However, the observed factor-of-two treatment effect was clinically meaningful and esketamine significantly reduced short-term postoperative depression scores without provoking complications. Robust trials are warranted. Registration Trial registry:http://www.chictr.org.cn/; Identifier: ChiCTR2300071062.
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Affiliation(s)
- Qingfeng Wei
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mengmeng Li
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qiuling Du
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Huiwen Zhang
- Key Laboratory of Anesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Hefei, Anhui, China
| | - Yongjie Liang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Cen Cheng
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Bin Mei
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Anesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Hefei, Anhui, China
| | - Xiaowei Yang
- Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yinguang Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Jiajia Zhu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jingjie Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Yongqiang Yu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Qiying Shen
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Anesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Hefei, Anhui, China.
| | - Xuesheng Liu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Anesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Hefei, Anhui, China; OUTCOMES RESEARCH Consortium®, Houston, TX, USA.
| | - Daniel I Sessler
- OUTCOMES RESEARCH Consortium®, Houston, TX, USA; Center for OUTCOMES RESEARCH and Department of Anesthesiology, UTHealth, Houston, TX, USA; Population Health Research Institute, McMaster University, ON, Canada
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Elersič K, Banjac A, Živin M, Zorović M. Increased sensitivity to psychomotor effects of ketamine enantiomers in the Wistar-Kyoto depression model. J Psychiatr Res 2025; 184:307-317. [PMID: 40081264 DOI: 10.1016/j.jpsychires.2025.02.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/14/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
Ketamine, a fast-acting antidepressant, is a racemic mixture, composed of equal amounts of R- and S-ketamine. Preclinical studies are comparing them to better understand their role in therapeutic and undesirable effects. An important research gap is that studies do not use long clinically relevant protocols to compare the desired and undesired effects of ketamine enantiomers in modeled and control animals. In our preclinical study, we explored the behavioral effects of R- and S-ketamine at 10 mg/kg in clinically relevant treatment protocol using Wistar-Kyoto rats as a depression model and Wistar rats as a control. Undesirable psychomotor effects were evaluated with locomotor stimulation and sensitization, ataxia, and stereotypy. Persistent effects associated with therapeutic outcomes were evaluated by measuring working memory, anxiety, and behavioral despair. We found that S-ketamine has stronger acute psychomotor effects compared to R-ketamine and that Wistar-Kyoto rats are more sensitive to these effects compared to Wistar rats. After repeated treatment, sensitization to locomotor stimulating effects, and tolerance to ataxic effects of S-ketamine develops. We found no persistent changes due to ketamine treatments. Taken together, our results may indicate that depressed patients would be more prone to negative side effects of ketamine, compared to healthy controls. However, after repeated treatment, tolerance to side effects may develop and make the treatment more tolerable. Future preclinical and clinical studies are needed to address neurobiological mechanisms and clinical relevance of higher sensitivity to the psychomotor effects of ketamine, and the development of tolerance to psychomotor effects of ketamine in depressed individuals.
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Affiliation(s)
- Kristian Elersič
- Brain Research Laboratory, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000, Ljubljana, Slovenia.
| | - Anamarija Banjac
- Brain Research Laboratory, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000, Ljubljana, Slovenia.
| | - Marko Živin
- Brain Research Laboratory, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000, Ljubljana, Slovenia.
| | - Maja Zorović
- Brain Research Laboratory, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000, Ljubljana, Slovenia.
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Baldinger-Melich P, Spies M, Bozic I, Kasper S, Rujescu D, Frey R. Perspectives in treatment-resistant depression: esketamine and electroconvulsive therapy. Wien Klin Wochenschr 2025; 137:134-147. [PMID: 38662240 DOI: 10.1007/s00508-024-02358-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 02/23/2024] [Indexed: 04/26/2024]
Abstract
Modern electroconvulsive therapy (ECT) and the approval of nasal esketamine for clinical use have significantly improved the approach to treatment-resistant depression (TRD), which is defined as non-response to at least two different courses of antidepressants with verified adherence to treatment, adequate dosage, and duration of treatment. The goal of this literature review is to present the newest evidence regarding efficacy and safety. Furthermore, we aim to provide an overview of future perspectives in this field of research, for example, regarding structural and molecular effects. Both treatment methods will be critically evaluated for their individual advantages, disadvantages, and response rates. Firstly, we will discuss the well-established method of ECT and its different treatment modalities. Secondly, we will discuss the properties of ketamine, the discovery of its antidepressive effects and the route to clinical approval of the esketamine nasal spray. We will comment on research settings which have evaluated intravenous ketamine against ECT. The decision-making process between esketamine nasal spray or ECT should include the assessment of contraindications, age, severity of disease, presence of psychotic symptoms, patient preference and treatment accessibility. We conclude that both treatment options are highly effective in TRD. If both are indicated, pragmatically esketamine will be chosen before ECT; however, ECT studies in ketamine non-responders are missing.
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Affiliation(s)
- Pia Baldinger-Melich
- Department of Psychiatry and Psychotherapy, Clinical Division of General Psychiatry, Medical University Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Vienna, Austria
| | - Marie Spies
- Department of Psychiatry and Psychotherapy, Clinical Division of General Psychiatry, Medical University Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Vienna, Austria
| | - Ina Bozic
- Department of Psychiatry and Psychotherapy, Clinical Division of General Psychiatry, Medical University Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Vienna, Austria
| | - Siegfried Kasper
- Department of Molecular Neurosciences, Center for Brain Research, Vienna, Austria
| | - Dan Rujescu
- Department of Psychiatry and Psychotherapy, Clinical Division of General Psychiatry, Medical University Vienna, Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Vienna, Austria
| | - Richard Frey
- Department of Psychiatry and Psychotherapy, Clinical Division of General Psychiatry, Medical University Vienna, Vienna, Austria.
- Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Vienna, Austria.
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7
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Fountoulakis KN, Saitis A, Schatzberg AF. Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Am J Psychiatry 2025; 182:259-275. [PMID: 39876682 DOI: 10.1176/appi.ajp.20240515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
OBJECTIVE Intranasal esketamine has been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior. The authors conducted a systematic review and meta-analysis of the available data on its efficacy against depression and suicidality as well as its side effects. METHODS MEDLINE was searched with the keyword "esketamine" on March 24, 2024, using the PRISMA method. Data processing and statistical analysis were performed with R, version 4.3.3, and the meta-analysis was performed with the METAFOR package. RESULTS Of 1,115 articles initially identified, 87 were included for analysis and discussion. At weeks 2-4, randomized controlled trials were mostly negative or failed; however, the meta-analysis returned a weak but significant positive effect for depression (effect size range, 0.15-0.23 at weeks 2-4), similar to augmentation strategies with atypical antipsychotics for treatment-resistant depression. The effect size concerning suicidality was not significant at any time point. The sensitivity analysis produced the same results. CONCLUSIONS The study findings suggest that esketamine's efficacy as an add-on to antidepressants is modest in treatment-resistant depression (similar to augmentation strategies with atypical antipsychotics) and is absent against suicidality itself. These findings need to be considered in light of esketamine's abuse potential and the fact that long-term effects are still not fully known. Some alarming signs concerning deaths and emerging suicidality during the testing phase are discussed, along with other regulatory issues.
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Affiliation(s)
- Konstantinos N Fountoulakis
- 3rd Department of Psychiatry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece (Fountoulakis, Saitis); Stanford University Mood Disorders Center and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford (Schatzberg)
| | - Athanasios Saitis
- 3rd Department of Psychiatry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece (Fountoulakis, Saitis); Stanford University Mood Disorders Center and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford (Schatzberg)
| | - Alan F Schatzberg
- 3rd Department of Psychiatry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece (Fountoulakis, Saitis); Stanford University Mood Disorders Center and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford (Schatzberg)
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Zhang X, Zhao X, Xu J, Liu H, Yuan S, Zhang J. Efficacy and safety of esketamine for emergency endotracheal intubation in ICU patients: a double-blind, randomized controlled clinical trial. Sci Rep 2025; 15:6089. [PMID: 39972022 PMCID: PMC11840142 DOI: 10.1038/s41598-025-91016-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 02/18/2025] [Indexed: 02/21/2025] Open
Abstract
Emergency endotracheal intubation in critically ill patients are dangerous procedures with a greater risk of severe hypotension The efficacy and safety of esketamine with sympathoexcitatory effects for rapid sequence induction in critically ill patients remain unclear. In this prospective double-blinded randomized controlled trial, adult patients were randomly assigned to receive either esketamine or midazolam/sufentanil admixture for induction. The primary outcomes were the effects of induction with esketamine or midazolam/sufentanil admixture on hemodynamic responses (heart rate (HR) and mean arterial pressure (MAP) during and after induction). Secondary outcomes were the duration of ventilation support, length of intensive care unit (ICU) stay, 28-day mortality. We enrolled 80 patients, of whom 38 were assigned to the esketamine group and 42 to the midazolam/sufentanil admixture group. The MAP in group esketamine was significantly higher than that in group midazolam/sufentanil admixture during the induction, and at 1 min, 5 min and 10 min after intubation. No significant differences in HR between groups were observed. The duration of ventilation support [105.3 (interquartile range (IQR) 40.9 - 248.3) hours vs. 211.5 (IQR 122.1 - 542.1) hours, P = 0.002] and the length of ICU stay [7.0 (IQR 4.0 - 16.3) days vs. 15.0 (IQR 8.0 - 26.0) days, P = 0.002] were significantly decreased in group esketamine, compared to that in group midazolam/sufentanil admixture. In group esketamine, less norepinephrine [0.00 (IQR 0.00 - 0.10) µg/kg/min vs. 0.09 (IQR 0.00 - 0.29) µg/kg/min, P = 0.016] was needed. There was no significant difference in 28-day mortality between the two groups. No serious adverse events occurred. In conclusion, esketamine is a hemodynamically stable induction agent in critically ill patients, which could reduce the length of ICU stay and the duration of ventilation support.Trial registration: clinicaltrials.gov (19/07/2022; NCT05464979).
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Affiliation(s)
- Xue Zhang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Xin Zhao
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Jiaxin Xu
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Hong Liu
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Shiying Yuan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Jiancheng Zhang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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9
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Sajid S, Mann JJ, Grunebaum MF. Clinical trials since 2020 of rapid anti-suicidal ideation effects of ketamine and its enantiomers: a systematic review. Transl Psychiatry 2025; 15:44. [PMID: 39915491 PMCID: PMC11802767 DOI: 10.1038/s41398-025-03255-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 12/12/2024] [Accepted: 01/23/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Suicide is a global public health problem with few empirically supported treatments. METHODS We conducted a systematic review of clinical trials (CT) since 2020 of racemic ketamine or one of its enantiomers' (R/S) potential to reduce suicidal ideation or behavior (SIB). An initial PubMed search on April 15th, 2024 yielded 2483 results. 104 relevant CTs were identified. An additional search using other search engines on March 19th, 2024 yielded 52 sources. After screening, 14 RCTs met the inclusion criteria which required clinically significant SIB among participants, ketamine or one of its enantiomers as an anti-SIB treatment, and SIB as an outcome. We excluded neuroimaging studies, meta-analyses, reviews, and case reports. Open-label studies were also excluded except in the case of R-ketamine where we included 2 open trials due to limited published data for this enantiomer, yielding a total of 16 CTs. We used the Revised Cochrane risk-of-bias tool for the RCTs. CTs reviewed had suicidal ideation (SI) but none had suicidal behavior as an outcome. RESULTS The studies include ketamine augmentation of other treatments such as electroconvulsive therapy (ECT), various routes of administration - intravenous (IV), intramuscular (IM), and intranasal (IN) - and single versus multiple dose designs. Multiple doses of IV ketamine/S-ketamine produced reductions in SI for periods of several days to weeks, while single doses showed shorter, more variable effects. Multiple and single doses of IN ketamine/S-ketamine and single doses of IV ketamine produced less consistent anti-SI results. IN and IV ketamine/S-ketamine administration appears to be well tolerated. R-ketamine appears to produce fewer side effects, but additional clinical research is needed to clarify its antidepressant and anti-SI effects in humans. CONCLUSION This review affirms the time-limited, anti-SI effects of ketamine and the need for personalized treatment. Limitations include study heterogeneity, small samples, and paucity of data for suicidal behavior or R-ketamine.
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Affiliation(s)
- Sumra Sajid
- Columbia University Irving Medical Center and New York State Psychiatric Institute, New York, NY, USA
| | - J John Mann
- Columbia University Irving Medical Center and New York State Psychiatric Institute, New York, NY, USA
| | - Michael F Grunebaum
- Columbia University Irving Medical Center and New York State Psychiatric Institute, New York, NY, USA.
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10
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Tang Q, Chu H, Sun N, Fan X, Han B, Li Y, Yu X, Li L, Wang X, Liu L, Chang H. The effects and mechanisms of chai shao jie yu granules on chronic unpredictable mild stress (CUMS)-induced depressive rats based on network pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119268. [PMID: 39706355 DOI: 10.1016/j.jep.2024.119268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chai Shao Jie Yu Granules (CSJY) is a renowned and time-honored formula employed in clinical practice for the management of various conditions, notably depression. Depression, a prevalent psychiatric disorder, poses challenges with limited effective treatment options. Traditional herbal medicines have garnered increasing attention in the realm of combating depression, being perceived as safer alternatives to pharmacotherapy. AIM OF THE STUDY To explore the effects and mechanisms of CSJY in chronic unpredictable mild stress (CUMS)-induced depression. MATERIALS AND METHODS Rat models of CUMS-induced depression were established, and the rats were randomly allocated into six groups: Control, CUMS, CUMS + Paroxetine (PX), CUMS + CSJY-L, CUMS + CSJY-M, and CUMS + CSJY-H. Throughout the study, the rats' body weight was monitored. Depression-related behaviors were assessed using the sucrose preference test (SPT) and open field test (OFT). High-performance liquid chromatography-mass spectrometry (HPLC-MS) measured monoamine neurotransmitters in the rat cortex and hippocampus. We measured adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotropin-release hormone (CRH) levels in rat serum. Additionally, network pharmacology was employed to predict relevant molecular targets and potential mechanisms, followed by in vivo validation. Western blot analysis was conducted to evaluate the protein levels of 5-hydroxytryptamine/serotonin receptor 1A (5-HT1A) and Glutamate (Glu)-related proteins, such as p-GluA1, GluA1, p-GluN1, GluN1, p-GluN2A and GluN2A in the hippocampus. RESULTS In behavioral assessments, CUMS rats exhibited depressive behaviors, which were ameliorated by CSJY or PX treatment. Moreover, CSJY or PX treatment increased serotonin (5-HT) levels. It reduced the kynurenine/tryptophan (KYN/TRP) and gamma-aminobutyric acid/glutamate (GABA/Glu) in the hippocampus and cortex, as well as reduced serum levels of ACTH, CORT and CRH. Furthermore, CSJY or PX administration enhanced the decreased expression of p-GluN1/GluN1 while upregulating 5-HT1A and p-GluA1/GluA1 levels in the CUMS group. CONCLUSION CSJY demonstrated the ability to alleviate depressive behaviors in CUMS-induced depression rats, potentially through the inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, modulation of monoamine neurotransmitters, and glutamatergic neurons. These findings suggest that CSJY could serve as a promising treatment option for depression.
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Affiliation(s)
- Qin Tang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China; Pharmacy Department, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China.
| | - Haolin Chu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Nan Sun
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Xiaoxu Fan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Bing Han
- Heilongjiang Jiren Pharmaceutical Co., Ltd, Heilongjiang, 150025, China
| | - Yu Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xue Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Lina Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xiuli Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Liying Liu
- Heilongjiang Jiren Pharmaceutical Co., Ltd, Heilongjiang, 150025, China
| | - Hongsheng Chang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
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11
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Zang X, Zhang J, Hu J, Mo X, Zheng T, Ji J, Xing J, Chen C, Zhou S. Electroconvulsive therapy combined with esketamine improved depression through PI3K/AKT/GLT-1 pathway. J Affect Disord 2025; 368:282-294. [PMID: 39265873 DOI: 10.1016/j.jad.2024.08.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 07/18/2024] [Accepted: 08/23/2024] [Indexed: 09/14/2024]
Abstract
Neuron excitotoxic damage induced by extracellular glutamate accumulation pathologically is one of the main mechanisms of depression. Glutamate transporter-1 (GLT-1) expressed in astrocyte is responsible for glutamate clearance to maintain glutamate balance. Electroconvulsive therapy (ECT) is prevalently recommended for severe depression due to its significant anti-depressant effect. Esketamine could offer advantages of rapid anti-depressant effect and neuron protection. The aim of this study is to investigate the anti-depressant efficacy of esketamine plus ECT, and further to explore the mechanism. Firstly, total 12 patients were randomized into anesthesia with propofol (P) or propofol+esketamine (PK) before ECT. 24-Hamilton Depression Scale (HAMD) was used to evaluate the severity of depression after each ECT. Then, depressive rat model was built using chronic unpredictable mild stress method, and subsequently received infusion of esketamine (5 mg/kg) or saline before ECT treatment (0.5 mA; 100 V) for consecutive 10 days. Tests including sucrose preference test, open field test and forced swimming test were used to evaluate depression-like behaviors. In next experiments, rats were injected with RIL, DHK or LY294002 intracerebroventricularly for continuous 10 days before individual treatment. After the fifth and sixth ECT, PK group displayed lower HAMD score compared to P group. In rat model, we found that esketamine plus ECT could significantly improve depression-like behaviors and decrease glutamate level. Esketamine and ECT could both activate PI3K/Akt/GLT-1 pathway. The GLT-1 agonist RIL made equivalent effect as esketamine plus ECT. Furthermore, after using PI3K/Akt inhibitor LY294002 and GLT-1 inhibitor DHK, esketamine plus ECT could neither improve depression-like symptoms, nor upregulate GLT-1 level. Our present study suggested that esketamine plus ECT could dramatically improve depression symptom. The activation of PI3K/Akt/GLT-1 pathway may be the potential mechanism.
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Affiliation(s)
- Xiangyang Zang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China
| | - Jingting Zhang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China
| | - Jingping Hu
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China
| | - Xingying Mo
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China
| | - Tingwei Zheng
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China
| | - Jiaming Ji
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China
| | - Jibin Xing
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China.
| | - Chaojin Chen
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China.
| | - Shaoli Zhou
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China.
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12
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Chrobak AA, Siwek M. Drugs with glutamate-based mechanisms of action in psychiatry. Pharmacol Rep 2024; 76:1256-1271. [PMID: 39333460 PMCID: PMC11582293 DOI: 10.1007/s43440-024-00656-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 09/29/2024]
Abstract
Psychopharmacotherapy of major psychiatric disorders is mostly based on drugs that modulate serotonergic, dopaminergic, or noradrenergic neurotransmission, either by inhibiting their reuptake or by acting as agonists or antagonists on specific monoamine receptors. The effectiveness of this approach is limited by a significant delay in the therapeutic mechanism and self-perpetuating growth of treatment resistance with a consecutive number of ineffective trials. A growing number of studies suggest that drugs targeting glutamate receptors offer an opportunity for rapid therapeutic effect that may overcome the limitations of monoaminergic drugs. In this article, we present a review of glutamate-modulating drugs, their mechanism of action, as well as preclinical and clinical studies of their efficacy in treating mental disorders. Observations of the rapid, robust, and long-lasting effects of ketamine and ketamine encourages further research on drugs targeting glutamatergic transmission. A growing number of studies support the use of memantine and minocycline in major depressive disorder and schizophrenia. Amantadine, zinc, and Crocus sativus extracts yield the potential to ameliorate depressive symptoms in patients with affective disorders. Drugs with mechanisms of action based on glutamate constitute a promising pharmacological group in the treatment of mental disorders that do not respond to standard methods of therapy. However, further research is needed on their efficacy, safety, dosage, interactions, and side effects, to determine their optimal clinical use.
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Affiliation(s)
- Adrian Andrzej Chrobak
- Department of Adult Psychiatry, Jagiellonian University Medical College, Kopernika 21A, 31-501, Kraków, Poland
| | - Marcin Siwek
- Department of Affective Disorders, Jagiellonian University Medical College, Kopernika 21A, 31-501, Kraków, Poland.
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13
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Medeiros GC, Demo I, Goes FS, Zarate CA, Gould TD. Personalized use of ketamine and esketamine for treatment-resistant depression. Transl Psychiatry 2024; 14:481. [PMID: 39613748 PMCID: PMC11607365 DOI: 10.1038/s41398-024-03180-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 11/01/2024] [Accepted: 11/06/2024] [Indexed: 12/01/2024] Open
Abstract
A large and disproportionate portion of the burden associated with major depressive disorder (MDD) is due to treatment-resistant depression (TRD). Intravenous (R,S)-ketamine (ketamine) and intranasal (S)-ketamine (esketamine) are rapid-acting antidepressants that can effectively treat TRD. However, there is variability in response to ketamine/esketamine, and a personalized approach to their use will increase success rates in the treatment of TRD. There is a growing literature on the precision use of ketamine in TRD, and the body of evidence on esketamine is still relatively small. The identification of reliable predictors of response to ketamine/esketamine that are easily translatable to clinical practice is urgently needed. Potential clinical predictors of a robust response to ketamine include a pre-treatment positive family history of alcohol use disorder and a pre-treatment positive history of clinically significant childhood trauma. Pre-treatment versus post-treatment increases in gamma power in frontoparietal brain regions, observed in electroencephalogram (EEG) studies, is a promising brain-based biomarker of response to ketamine, given its time of onset and general applicability. Blood-based biomarkers have shown limited usefulness, with small-effect increases in brain-derived neurotrophic factor (BDNF) being the most consistent indicator of ketamine response. The severity of treatment-emergent dissociative symptoms is typically not associated with a response either to ketamine or esketamine. Future studies should ensure that biomarkers and clinical variables are obtained in a similar manner across studies to allow appropriate comparison across trials and to reduce the signal-to-noise ratio. Most predictors of response to ketamine/esketamine have modest effect sizes; therefore, the use of multivariate predictive models will be needed.
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Affiliation(s)
- Gustavo C Medeiros
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
- Advanced Depression Treatment (ADepT) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Isabella Demo
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Fernando S Goes
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Carlos A Zarate
- Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, NIMH-NIH, Bethesda, MD, USA
| | - Todd D Gould
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
- Advanced Depression Treatment (ADepT) Center, University of Maryland School of Medicine, Baltimore, MD, USA
- Departments of Pharmacology and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
- Veterans Affairs Maryland Health Care System, Baltimore, MD, USA
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14
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Magruder T, Isenhart M, Striepe MV, Mannisto A, Jannie KM, Smith J, McCarson KE, Christian DT, Duric V. Ketamine - An Imperfect Wonder Drug? Biochem Pharmacol 2024; 229:116516. [PMID: 39218043 PMCID: PMC11578541 DOI: 10.1016/j.bcp.2024.116516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/21/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
Ketamine is a potent sedative and dissociative anesthetic agent that has been used clinically for over 50 years since it was first developed in the 1960 s as an alternative to phencyclidine (PCP). When compared to PCP, ketamine exhibited a much lower incidence of severe side effects, including hallucinations, leading to its increased popularity in clinical practice. Ketamine was initially used as an anesthetic agent, especially in emergency medicine and in surgical procedures where rapid induction and recovery was necessary. However, over the last few decades, ketamine was found to have additional clinically useful properties making it effective in the treatment of a variety of other conditions. Presently, ketamine has a wide range of clinical uses beyond anesthesia including management of acute and chronic pain, as well as treatment of psychiatric disorders such as major depression. In addition to various clinical uses, ketamine is also recognized as a common drug of abuse sought for its hallucinogenic and sedative effects. This review focuses on exploring the different clinical and non-clinical uses of ketamine and its overall impact on patient care.
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Affiliation(s)
- Tanner Magruder
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
| | - Marielle Isenhart
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
| | - Maximillian V Striepe
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
| | - Andrew Mannisto
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
| | - Karry M Jannie
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
| | - Jolene Smith
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
| | - Kenneth E McCarson
- Department of Pharmacology, Toxicology and Experimental Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Daniel T Christian
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
| | - Vanja Duric
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA.
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15
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Song H, Luo Y, Fang L. Esketamine Nasal Spray: Rapid Relief for TRD and Suicide Prevention-Mechanisms and Pharmacodynamics. Neuropsychiatr Dis Treat 2024; 20:2059-2071. [PMID: 39502383 PMCID: PMC11536986 DOI: 10.2147/ndt.s486118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Esketamine nasal spray has emerged as a promising rapid-relief therapy for treatment-resistant depression (TRD) and suicide prevention. This review examines the chemical structure and pharmacodynamics of esketamine, highlighting its primary action on NMDA receptors and additional effects on AMPA receptors, opioid receptors, monoaminergic receptors, and inflammatory pathways. Despite the synergistic mechanisms contributing to its clinical benefits not being fully understood, future studies are essential to refine our understanding and optimize clinical use. Clinical research indicates that esketamine effectively alleviates depressive symptoms and prevents suicidal behavior in TRD patients, demonstrating good safety and efficacy over extended periods. Specifically, multiple randomized controlled trials have shown that esketamine reduces depressive symptoms within hours and maintains these benefits over several weeks, with a favorable safety profile and minimal side effects observed in long-term use. The approval of esketamine for TRD has significant implications for healthcare practices and policies, offering a new therapeutic option that addresses the urgent needs of patients with severe depression.
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Affiliation(s)
- Hui Song
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, People’s Republic of China
| | - Yang Luo
- Jiang You Third People Hospital, Mianyang, Sichuan, People’s Republic of China
| | - Lingzhi Fang
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, People’s Republic of China
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16
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Mathai DS, Hull TD, Vando L, Malgaroli M. At-home, telehealth-supported ketamine treatment for depression: Findings from longitudinal, machine learning and symptom network analysis of real-world data. J Affect Disord 2024; 361:198-208. [PMID: 38810787 PMCID: PMC11284959 DOI: 10.1016/j.jad.2024.05.131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/30/2024] [Accepted: 05/25/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Improving safe and effective access to ketamine therapy is of high priority given the growing burden of mental illness. Telehealth-supported administration of sublingual ketamine is being explored toward this goal. METHODS In this longitudinal study, moderately-to-severely depressed patients received four doses of ketamine at home over four weeks within a supportive digital health context. Treatment was structured to resemble methods of therapeutic psychedelic trials. Patients receiving a second course of treatment were also examined. Symptoms were assessed using the Patient Health Questionnaire (PHQ-9) for depression. We conducted preregistered machine learning and symptom network analyses to investigate outcomes (osf.io/v2rpx). RESULTS A sample of 11,441 patients was analyzed, demonstrating a modal antidepressant response from both non-severe (n = 6384, 55.8 %) and severe (n = 2070, 18.1 %) baseline depression levels. Adverse events were detected in 3.0-4.8 % of participants and predominantly neurologic or psychiatric in nature. A second course of treatment helped extend improvements in patients who responded favorably to initial treatment. Improvement was most strongly predicted by lower depression scores and age at baseline. Symptoms of Depressed mood and Anhedonia sustained depression despite ongoing treatment. LIMITATIONS This study was limited by the absence of comparison or control groups and lack of a fixed-dose procedure for ketamine administration. CONCLUSIONS At-home, telehealth-supported ketamine administration was largely safe, well-tolerated, and associated with improvement in patients with depression. Strategies for combining psychedelic-oriented therapies with rigorous telehealth models, as explored here, may uniquely address barriers to mental health treatment.
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Affiliation(s)
- David S Mathai
- The Johns Hopkins University School of Medicine, Center for Psychedelic and Consciousness Research, Department of Psychiatry and Behavioral Sciences, Baltimore, MD, United States of America; Sattva Medicine - Psychiatry/Psychotherapy Practice, Miami, FL, United States of America
| | - Thomas D Hull
- Institute for Psycholinguistics and Digital Health, United States of America
| | | | - Matteo Malgaroli
- NYU Grossman School of Medicine, Department of Psychiatry, New York, NY, United States of America.
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17
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Wen W, Wenjing Z, Xia X, Duan X, Zhang L, Duomao L, Zeyou Q, Wang S, Gao M, Liu C, Li H, Ma J. Efficacy of ketamine versus esketamine in the treatment of perioperative depression: A review. Pharmacol Biochem Behav 2024; 242:173773. [PMID: 38806116 DOI: 10.1016/j.pbb.2024.173773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 05/30/2024]
Abstract
Depression is a significant factor contributing to postoperative occurrences, and patients diagnosed with depression have a higher risk for postoperative complications. Studies on cardiovascular surgery extensively addresses this concern. Several studies report that people who undergo coronary artery bypass graft surgery have a 20% chance of developing postoperative depression. A retrospective analysis of medical records spanning 21 years, involving 817 patients, revealed that approximately 40% of individuals undergoing coronary artery bypass grafting (CABG) were at risk of perioperative depression. Patients endure prolonged suffering from illness because each attempt with standard antidepressants requires several weeks to be effective. In addition, multi-drug combination adjuvants or combination medication therapy may alleviate symptoms for some individuals, but they also increase the risk of side effects. Conventional antidepressants primarily modulate the monoamine system, whereas different therapies target the serotonin, norepinephrine, and dopamine systems. Esketamine is a fast-acting antidepressant with high efficacy. Esketamine is the S-enantiomer of ketamine, a derivative of phencyclidine developed in 1956. Esketamine exerts its effect by targeting the glutaminergic system the glutaminergic system. In this paper, we discuss the current depression treatment strategies with a focus on the pharmacology and mechanism of action of esketamine. In addition, studies reporting use of esketamine to treat perioperative depressive symptoms are reviwed, and the potential future applications of the drug are presented.
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Affiliation(s)
- Wen Wen
- Beijing Anzhen Hospital, Capital Medical University
| | - Zhao Wenjing
- Beijing Anzhen Hospital, Capital Medical University
| | - Xing Xia
- Beijing Anzhen Hospital, Capital Medical University
| | | | - Liang Zhang
- Beijing Anzhen Hospital, Capital Medical University
| | - Lin Duomao
- Beijing Anzhen Hospital, Capital Medical University
| | - Qi Zeyou
- Beijing Anzhen Hospital, Capital Medical University
| | - Sheng Wang
- Beijing Anzhen Hospital, Capital Medical University
| | - Mingxin Gao
- Beijing Anzhen Hospital, Capital Medical University
| | | | - Haiyang Li
- Beijing Anzhen Hospital, Capital Medical University.
| | - Jun Ma
- Beijing Anzhen Hospital, Capital Medical University.
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18
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Smith-Apeldoorn SY, Veraart JKE, Kamphuis J, Spijker J, van der Meij A, van Asselt ADI, Aan Het Rot M, Schoevers RA. Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension. Mol Psychiatry 2024; 29:2657-2665. [PMID: 38523183 DOI: 10.1038/s41380-024-02478-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/23/2024] [Accepted: 02/05/2024] [Indexed: 03/26/2024]
Abstract
About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.
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Affiliation(s)
- Sanne Y Smith-Apeldoorn
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Jolien K E Veraart
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Psychiatry, PsyQ Haaglanden, Parnassia Psychiatric Institute, The Hague, The Netherlands
| | - Jeanine Kamphuis
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Spijker
- Depression Expertise Center, Pro Persona Mental Health Care, Nijmegen, The Netherlands
- Behavioral Science Institute, Radboud University, Nijmegen, The Netherlands
| | | | - Antoinette D I van Asselt
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marije Aan Het Rot
- Department of Psychology, University of Groningen, Groningen, The Netherlands
- School of Behavioral and Cognitive Neurosciences, University of Groningen, Groningen, The Netherlands
| | - Robert A Schoevers
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- School of Behavioral and Cognitive Neurosciences, University of Groningen, Groningen, The Netherlands
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19
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Sackeim HA, Aaronson ST, Bunker MT, Conway CR, George MS, McAlister-Williams RH, Prudic J, Thase ME, Young AH, Rush AJ. Update on the assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form-2 (ATHF-SF2). J Psychiatr Res 2024; 176:325-337. [PMID: 38917723 DOI: 10.1016/j.jpsychires.2024.05.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 04/09/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024]
Abstract
All definitions of treatment-resistant depression (TRD) require that patients have experienced insufficient benefit from one or more adequate antidepressant trials. Thus, identifying "failed, adequate trials" is key to the assessment of TRD. The Antidepressant Treatment History Form (ATHF) was one of the first and most widely used instruments that provided objective criteria in making these assessments. The original ATHF was updated in 2018 to the ATHF-SF, changing to a checklist format for scoring, and including specific pharmacotherapy, brain stimulation, and psychotherapy interventions as potentially adequate antidepressant treatments. The ATHF-SF2, presented here, is based on the consensus of the ATHF workgroup about the novel interventions introduced since the last revision and which should/should not be considered effective treatments for major depressive episodes. This document describes the rationale for these choices and, for each intervention, the minimal criteria for determining the adequacy of treatment administration. The Supplementary Material that accompanies this article provide the Scoring Checklist, Data Collection Forms (current episode and composite of previous episodes), and Instruction Manual for the ATHF-SF2.
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Affiliation(s)
- Harold A Sackeim
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, USA.
| | - Scott T Aaronson
- Sheppard Pratt Health System and Department of Psychiatry, University of Maryland, Baltimore, MD, USA
| | | | - Charles R Conway
- Department of Psychiatry, Washington University, St. Louis, MO, USA
| | - Mark S George
- Departments of Psychiatry,Neurology,and Neuroscience, Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston, SC, USA
| | - R Hamish McAlister-Williams
- Northern Centre for Mood Disorders, Translational and Clinical Research Institute, Newcastle University, UK; Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Joan Prudic
- New York State Psychiatric Institute and Department of Psychiatry, Columbia University, New York, NY, USA
| | - Michael E Thase
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
| | - Allan H Young
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, and South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, UK
| | - A John Rush
- Duke-NUS Medical School, Singapore; Duke University, Durham, NC, USA; Texas Tech University, Permian Basin, TX, USA
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20
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Jiang Y, Dong Y, Hu H. The N-methyl-d-aspartate receptor hypothesis of ketamine's antidepressant action: evidence and controversies. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230225. [PMID: 38853549 PMCID: PMC11343275 DOI: 10.1098/rstb.2023.0225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/26/2023] [Accepted: 01/02/2024] [Indexed: 06/11/2024] Open
Abstract
Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an N-methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine's NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine's molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Affiliation(s)
- Yihao Jiang
- Department of Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou310058, People's Republic of China
- Nanhu Brain-Computer Interface Institute, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou311100, People's Republic of China
| | - Yiyan Dong
- Department of Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou310058, People's Republic of China
| | - Hailan Hu
- Department of Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou310058, People's Republic of China
- Nanhu Brain-Computer Interface Institute, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou311100, People's Republic of China
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21
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de Carvalho JF, de Sena EP. Ketamine in fibromyalgia: a systematic review. Adv Rheumatol 2024; 64:54. [PMID: 39075628 DOI: 10.1186/s42358-024-00393-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 07/15/2024] [Indexed: 07/31/2024] Open
Abstract
OBJECTIVE Fibromyalgia (FM) subjects are treated with antidepressant agents; in most cases, these drugs lose efficacy or have adverse effects. Ketamine is an anesthetic drug used in FM in some studies. This article aims to systematically review the safety and efficacy of ketamine in fibromyalgia (FM) patients. MATERIALS AND METHODS We systematically searched articles on FM and ketamine published at Pubmed from 1966 to 2021. This study was registered at PROSPERO. RESULTS There were only 6 articles published in this field, with a total of 115 patients. The female sex was predominant (88 to 100%). The age varied from 23 to 53 years old. Disease duration ranged from 1 month to 28 years. The dosage of ketamine changed from 0.1 mg/kg-0.3-0.5 mg/kg in intravenous infusion (4/5) and subcutaneous application (1/5). Regarding outcomes, the Visual analog scale (VAS) before ketamine was from 59 to 100 mm and after treatment from 2 to 95 mm. Most short-term studies had a good response. Only the study with 8 weeks of follow-up did not observe a good response. Side effects were common; all appeared during the infusion and disappeared after a few minutes of the ketamine injection. CONCLUSIONS The present study demonstrates the effectiveness and safety of ketamine in FM patients in the short term. Although, more studies, including long-term follow-up studies, are still needed.
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Affiliation(s)
- Jozélio Freire de Carvalho
- Instituto de Ciencias da Saude da Universidade Federal da Bahia, Rua das Violetas, 42, ap. 502, Pituba, Salvador, Bahia, Brazil.
| | - Eduardo Pondé de Sena
- Instituto de Ciencias da Saude da Universidade Federal da Bahia, Rua das Violetas, 42, ap. 502, Pituba, Salvador, Bahia, Brazil
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22
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Johnston JN, Zarate CA, Kvarta MD. Esketamine in depression: putative biomarkers from clinical research. Eur Arch Psychiatry Clin Neurosci 2024:10.1007/s00406-024-01865-1. [PMID: 38997425 PMCID: PMC11725628 DOI: 10.1007/s00406-024-01865-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 07/03/2024] [Indexed: 07/14/2024]
Abstract
The discovery of racemic (R, S)-ketamine as a rapid-acting antidepressant and the subsequent FDA approval of its (S)-enantiomer, esketamine, for treatment-resistant depression (TRD) are significant advances in the development of novel neuropsychiatric therapeutics. Esketamine is now recognized as a powerful tool for addressing persistent symptoms of TRD compared to traditional oral antidepressants. However, research on biomarkers associated with antidepressant response to esketamine has remained sparse and, to date, has been largely extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest that inflammation and mitochondrial function may play a role in esketamine's antidepressant effects, though these preliminary results require verification. In addition, neuroimaging research has consistently implicated the prefrontal cortex, striatum, and anterior cingulate cortex in esketamine's effects. Esketamine also shows promise in perioperative settings for reducing depression and anxiety, and these effects appear to correlate with increased peripheral biomarkers such as brain-derived neurotrophic factor and serotonin. Further indications are likely to be identified with the continued repurposing of racemic ketamine, providing further opportunity for biomarker study and mechanistic understanding of therapeutic effects. Novel methodologies and well-designed biomarker-focused clinical research trials are needed to more clearly elucidate esketamine's therapeutic actions as well as biologically identify those most likely to benefit from this agent, allowing for the improved personalization of antidepressant treatment.
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Affiliation(s)
- Jenessa N Johnston
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Carlos A Zarate
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Mark D Kvarta
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.
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23
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Chen X, Zhou R, Lan L, Zhu L, Chen C, Zhang X, Han J, Xia L. Comparison of Effects of Propofol Combined with Different Doses of Esketamine for ECT in the Treatment of Depression: A Randomized Controlled Trial Protocol. Neuropsychiatr Dis Treat 2024; 20:1107-1115. [PMID: 38774255 PMCID: PMC11108059 DOI: 10.2147/ndt.s463028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 05/10/2024] [Indexed: 05/24/2024] Open
Abstract
Objective Major depressive disorder (MDD) is a common mood disorder. Electroconvulsive therapy (ECT) has a significant effect on treatment-resistant MDD. Esketamine may have potential advantages in improving the efficacy of ECT, and the strong affinity of this compound for NMDAR renders it a viable therapeutic option for the management of depression. This study aims to compare the effects of different doses of esketamine combined with propofol anesthesia versus propofol anesthesia alone in ECT, aiming to provide further insights for optimizing ECT and enhancing comprehensive treatment outcomes for depression. Study Design and Methods This study was a prospective, randomized, controlled, double-blind trial involving subjects and evaluators. One hundred eleven patients scheduled for ECT were randomly assigned to three groups. In Group P, propofol at 1mg/kg was administered intravenously. In Group P+E, propofol at a dosage of 0.5mg/kg and esketamine at a dosage of 0.5mg/kg was administered intravenously. Patients in Group P+SE received propofol at a dosage of 0.75mg/kg and esketamine at a dosage of 0.25mg/kg. The same anesthesia protocol was used for the same patient until the end of the last treatment. The primary outcome measures were the Hamilton depression scale (HAMD) and the Patient Health Questionnaire-9 (PHQ-9), the Columbia-Suicide Severity Rating Scale (C-SSRS), and the Digit symbol substitution test (DSST). Secondary outcomes included length of hospital stay, readmission rate, hemodynamic status, recovery, and adverse events. Discussion This study aimed to compare the effects of propofol combined with different doses of esketamine for ECT. The results may provide a better choice for ECT anesthesia.
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Affiliation(s)
- Xuemeng Chen
- Department of Anesthesiology, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China
| | - Rui Zhou
- Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China
- Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434, People’s Republic of China
| | - Lan Lan
- Department of Anesthesiology, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China
| | - Ling Zhu
- Department of Psychosomatic Medicine, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China
| | - Cheng Chen
- Department of Psychosomatic Medicine, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China
| | - Xianjie Zhang
- Department of Anesthesiology, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China
| | - Jia Han
- Department of Anesthesiology, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China
| | - Leqiang Xia
- Department of Anesthesiology, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China
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Cao Y, Fu L, Zhang X, Xia L, Zhou R. The Relationship Between Perioperative Use of Esketamine and Postpartum Depression Risk: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Neuropsychiatr Dis Treat 2024; 20:1041-1048. [PMID: 38770534 PMCID: PMC11104439 DOI: 10.2147/ndt.s451930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 05/06/2024] [Indexed: 05/22/2024] Open
Abstract
PURPOSE To determine whether perioperative esketamine use decreases the risk of postpartum depression (PPD). METHODS Online search of PubMed, Web of Science, and Embase was conducted to identify relevant studies. Key words for search included, but were not limited to, postpartum depression, esketamine, and clinical trials. The mean and standard deviation of the Edinburgh Postnatal Depression Scale (EPDS) scores were extracted from the studies as primary parameters. RESULTS The literature search identified 226 articles, of which 5 met the criteria and were enrolled in the study. In total, 886 patients in the studies were taken into analysis. The EPDS scores in the esketamine group were lower than those of the control group at the early stage of puerperium (WMD=-2.05, 95% CI: -3.77, -0.34, p=0.019), whereas there was no significant difference at the middle and later stages (WMD=-1.41, 95% CI: -2.86, 0.04, p=0.056). The sensitivity analyses indicated that the result for the early stage was stable, whereas it was unreliable for the middle and later stages. The results of the Egger's test indicated no publication bias. CONCLUSION Perioperative use of esketamine contributes to a lower risk of PPD at the early stage of puerperium but not at the middle and later stages. To further verify this conclusion, more high-quality studies are required.
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Affiliation(s)
- Yuansheng Cao
- Department of Anesthesiology, Deyang People’s Hospital, Deyang, People’s Republic of China
| | - Lijuan Fu
- Department of Anesthesiology, Deyang People’s Hospital, Deyang, People’s Republic of China
| | - Xianjie Zhang
- Department of Anesthesiology, Deyang People’s Hospital, Deyang, People’s Republic of China
| | - Leqiang Xia
- Department of Anesthesiology, Deyang People’s Hospital, Deyang, People’s Republic of China
| | - Rui Zhou
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Clinical Research Center for Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
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25
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Lou XJ, Qiu D, Ren ZY, Hashimoto K, Zhang GF, Yang JJ. Efficacy and safety of esketamine for perioperative depression in patients undergoing elective surgery: A meta-analysis of randomized controlled trials. Asian J Psychiatr 2024; 95:103997. [PMID: 38492442 DOI: 10.1016/j.ajp.2024.103997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/25/2024] [Accepted: 03/06/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND Depression is a prevalent mood disorder during the perioperative period, with both preoperative concurrent depression and new-onset postoperative depression impacting postoperative recovery. Recent studies have indicated that the dissociative anesthetic esketamine may alleviate perioperative depressive symptoms. OBJECTIVE This meta-analysis aimed to assess the efficacy and safety of esketamine in treating perioperative depression. METHODS We selected randomized controlled trials comparing esketamine to placebo in terms of postoperative depressive symptoms. The primary outcome was postoperative depression scores, with secondary outcomes including the prevalence of postoperative depression, pain scores using the Visual Analogue Scale or Numeric Rating Scale, and incidences of adverse reactions such as nausea/vomiting, dizziness, dreams/nightmares, hallucinations. RESULTS We enrolled a total of 17 studies involving 2462 patients. The esketamine group demonstrated a significant reduction in postoperative depression scores within one week after surgery (SMD -0.47, 95% CI (-0.66, -0.27), P < 0.001) and over the long term (SMD -0.44, 95% CI (-0.79, -0.09), P = 0.01). Furthermore, esketamine significantly decreased the prevalence of postoperative depression both within one week (RR 0.46, 95% CI (0.33, 0.63), P < 0.001) and over the long term (RR 0.50, 95% CI (0.36, 0.70), P < 0.001). Additionally, esketamine effectively relieved pain on the first postoperative day compared to control. However, it also increased the risks of dizziness and hallucinations for a short time. CONCLUSION This meta-analysis suggests that the intraoperative or postoperative application of esketamine could be a potentially effective treatment for perioperative depression, although the increased risk of adverse reactions should be considered.
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Affiliation(s)
- Xue-Jie Lou
- Department of Anesthesiology, Pain and Perioperative Medicine, The first Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Di Qiu
- Department of Anesthesiology, Pain and Perioperative Medicine, The first Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Zhuo-Yu Ren
- Department of Anesthesiology, Pain and Perioperative Medicine, The first Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Kenji Hashimoto
- Department of Anesthesiology, Pain and Perioperative Medicine, The first Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba 260-8670, Japan.
| | - Guang-Fen Zhang
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
| | - Jian-Jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The first Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
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26
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Wang S, Deng CM, Zeng Y, Chen XZ, Li AY, Feng SW, Xu LL, Chen L, Yuan HM, Hu H, Yang T, Han T, Zhang HY, Jiang M, Sun XY, Guo HN, Sessler DI, Wang DX. Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ 2024; 385:e078218. [PMID: 38808490 PMCID: PMC11957566 DOI: 10.1136/bmj-2023-078218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/27/2024] [Indexed: 05/30/2024]
Abstract
OBJECTIVE To determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression. DESIGN Randomised, double blind, placebo controlled trial with two parallel arms. SETTING Five tertiary care hospitals in China, 19 June 2020 to 3 August 2022. PARTICIPANTS 364 mothers aged ≥18 years who had at least mild prenatal depression as indicated by Edinburgh postnatal depression scale scores of ≥10 (range 0-30, with higher scores indicating worse depression) and who were admitted to hospital for delivery. INTERVENTIONS Participants were randomly assigned 1:1 to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth once the umbilical cord had been clamped. MAIN OUTCOME MEASURES The primary outcome was prevalence of a major depressive episode at 42 days post partum, diagnosed using the mini-international neuropsychiatric interview. Secondary outcomes included the Edinburgh postnatal depression scale score at seven and 42 days post partum and the 17 item Hamilton depression rating scale score at 42 days post partum (range 0-52, with higher scores indicating worse depression). Adverse events were monitored until 24 hours after childbirth. RESULTS A total of 364 mothers (mean age 31.8 (standard deviation 4.1) years) were enrolled and randomised. At 42 days post partum, a major depressive episode was observed in 6.7% (12/180) of participants in the esketamine group compared with 25.4% (46/181) in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P<0.001). Edinburgh postnatal depression scale scores were lower in the esketamine group at seven days (median difference -3, 95% CI -4 to -2; P<0.001) and 42 days (-3, -4 to -2; P<0.001). Hamilton depression rating scale scores at 42 days post partum were also lower in the esketamine group (-4, -6 to -3; P<0.001). The overall incidence of neuropsychiatric adverse events was higher in the esketamine group (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than a day and none required drug treatment. CONCLUSIONS For mothers with prenatal depression, a single low dose of esketamine after childbirth decreases major depressive episodes at 42 days post partum by about three quarters. Neuropsychiatric symptoms were more frequent but transient and did not require drug intervention. TRIAL REGISTRATION ClinicalTrials.gov NCT04414943.
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Affiliation(s)
- Shuo Wang
- Department of Anaesthesiology, Peking University First Hospital, Beijing 100034, China
| | - Chun-Mei Deng
- Department of Anaesthesiology, Peking University First Hospital, Beijing 100034, China
| | - Yuan Zeng
- Department of Anaesthesiology, Peking University First Hospital, Beijing 100034, China
| | - Xin-Zhong Chen
- Department of Anaesthesiology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Ai-Yuan Li
- Department of Anaesthesiology, Hunan Province Maternal and Child Health Care Hospital, Changsha, Hunan Province, China
| | - Shan-Wu Feng
- Department of Anaesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, China
| | - Li-Li Xu
- Department of Anaesthesiology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Liang Chen
- Department of Anaesthesiology, Hunan Province Maternal and Child Health Care Hospital, Changsha, Hunan Province, China
| | - Hong-Mei Yuan
- Department of Anaesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, China
| | - Han Hu
- Department of Anaesthesiology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Tian Yang
- Department of Anaesthesiology, Hunan Province Maternal and Child Health Care Hospital, Changsha, Hunan Province, China
| | - Tao Han
- Department of Anaesthesiology, Hunan Province Maternal and Child Health Care Hospital, Changsha, Hunan Province, China
| | - Hui-Ying Zhang
- Department of Anaesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, China
| | - Ming Jiang
- Department of Anaesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, China
| | - Xin-Yu Sun
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Centre for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Hui-Ning Guo
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Centre for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Daniel I Sessler
- Department of Outcomes Research, Cleveland Clinic, Cleveland, OH, USA
- Outcomes Research Consortium, Cleveland, OH, USA
| | - Dong-Xin Wang
- Department of Anaesthesiology, Peking University First Hospital, Beijing 100034, China
- Outcomes Research Consortium, Cleveland, OH, USA
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Havlik JL, Wahid S, Teopiz KM, McIntyre RS, Krystal JH, Rhee TG. Recent Advances in the Treatment of Treatment-Resistant Depression: A Narrative Review of Literature Published from 2018 to 2023. Curr Psychiatry Rep 2024; 26:176-213. [PMID: 38386251 DOI: 10.1007/s11920-024-01494-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/05/2024] [Indexed: 02/23/2024]
Abstract
PURPOSE OF REVIEW We review recent advances in the treatment of treatment-resistant depression (TRD), a disorder with very limited treatment options until recently. We examine advances in psychotherapeutic, psychopharmacologic, and interventional psychiatry approaches to treatment of TRD. We also highlight various definitions of TRD in recent scientific literature. RECENT FINDINGS Recent evidence suggests some forms of psychotherapy can be effective as adjunctive treatments for TRD, but not as monotherapies alone. Little recent evidence supports the use of adjunctive non-antidepressant pharmacotherapies such as buprenorphine and antipsychotics for the treatment of TRD; side effects and increased medication discontinuation rates may outweigh the benefits of these adjunctive pharmacotherapies. Finally, a wealth of recent evidence supports the use of interventional approaches such as electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation for TRD. Recent advances in our understanding of how to treat TRD have largely expanded our knowledge of best practices in, and efficacy of, interventional psychiatric approaches. Recent research has used a variety of TRD definitions for study inclusion criteria; research on TRD should adhere to inclusion criteria based on internationally defined guidelines for more meaningfully generalizable results.
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Affiliation(s)
- John L Havlik
- Yale University School of Medicine, New Haven, CT, USA
| | - Syed Wahid
- The University of Chicago, Chicago, IL, USA
| | - Kayla M Teopiz
- Brain and Cognition Discovery Foundation, Toronto, Canada
| | - Roger S McIntyre
- Brain and Cognition Discovery Foundation, Toronto, Canada
- Department of Psychiatry, University of Toronto, Toronto, Canada
- Department of Pharmacology, University of Toronto, Toronto, Canada
| | - John H Krystal
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Taeho Greg Rhee
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
- Department of Public Health Sciences, University of Connecticut, Farmington, CT, USA.
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Vendrell-Serres J, Soto-Angona Ó, Rodríguez-Urrutia A, Inzoli B, González AL, Ramos-Quiroga JA. Treating Treatment-resistant Depression with Esketamine Nasal Spray When All Therapeutic Options Have Been Exhausted: Clinical Experience from a Spanish Cohort of Expanded Use. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE : THE OFFICIAL SCIENTIFIC JOURNAL OF THE KOREAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY 2024; 22:159-168. [PMID: 38247422 PMCID: PMC10811393 DOI: 10.9758/cpn.23.1097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/24/2023] [Accepted: 08/01/2023] [Indexed: 01/23/2024]
Abstract
Objective : Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more anti-depressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary objective consisted in researching the relationship between response and previous use of electroconvulsive therapy. Methods : A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were followed up to 4 months after the administration. Results : Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation between outcome and any demographic or clinical traits evaluated. No differences were found between patients that previously received Electroconvulsive Therapy, and those that didn't. 10 out of 16 patients responded (> 50% change in baseline MADRS scores), but only five achieved remission (< 12 points in the global MADRS score). We provide some recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects. Conclusion : Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed to properly assess predictors of response outcome.
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Affiliation(s)
- Júlia Vendrell-Serres
- Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Óscar Soto-Angona
- Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Amanda Rodríguez-Urrutia
- Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain
| | - Benedetta Inzoli
- Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | | | - Josep Antoni Ramos-Quiroga
- Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain
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Fang S, Yang X, Zhang W. Efficacy and acceptability of psilocybin for primary or secondary depression: A systematic review and meta-analysis of randomized controlled trials. Front Psychiatry 2024; 15:1359088. [PMID: 38426002 PMCID: PMC10902050 DOI: 10.3389/fpsyt.2024.1359088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/01/2024] [Indexed: 03/02/2024] Open
Abstract
Introduction Psilocybin is a classic psychedelics, which has been shown to have antidepressant effects by many studies in recent years. In this study, we aim to evaluate the efficacy, acceptability and tolerability of psilocybin in the treatment of primary (major depressive disorder) or secondary (experiencing distress related to life-threatening diagnoses and terminal illness) depression. Methods We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov for clinical trials of psilocybin for depression (updated to 4 October, 2023). Effect size Hedges' g was used as an indicator of efficacy, and other outcomes included response rate, drop-out rate, and adverse events. Results A total of 10 studies were finally included in systematic review. 8 studies were included in the meta-analysis, involving a total of 524 adult patients, and produced a large effect size in favor of psilocybin (Hedge's g =-0.89, 95% CI -1.25~-0.53, I² = 70.19%, P<0.01). The therapeutic effects of psilocybin increase with increasing doses. Adverse events caused by psilocybin are generally transient and reversible, but serious adverse events also may occur. Discussion Our study shows that psilocybin has both short-term and long-term antidepressant effects and holds promise as a potential complementary or alternative therapy for depression, probably. Further research may reveal more about its therapeutic potential.
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Affiliation(s)
- Shuping Fang
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
| | - Xin Yang
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
| | - Wei Zhang
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
- Med-X Center for Informatics, Sichuan University, Chengdu, China
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Kumari S, Chaudhry HA, Sagot A, Doumas S, Abdullah H, Alcera E, Solhkhah R, Afzal S. Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review. Cureus 2024; 16:e53987. [PMID: 38476783 PMCID: PMC10928016 DOI: 10.7759/cureus.53987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2024] [Indexed: 03/14/2024] Open
Abstract
The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters, mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indications of TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, and impact on cognition. An overview of the drug's origins, pharmacology, and standard treatment regimen are provided. The outcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlined to demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative to ketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD, propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, including ketamine, esketamine, treatment-resistant depression, and biomarkers, using automation tools along with selective search engine results. After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.
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Affiliation(s)
- Suneeta Kumari
- Psychiatry, Hackensack Meridian Ocean Medical Center, Brick, USA
| | - Hassan A Chaudhry
- Medical School, Medical University of Lublin, Lublin, POL
- Psychiatry and Behavioral Sciences, Youth Neuroscience Organization, Tbilisi, GEO
| | - Adam Sagot
- Psychiatry, Hackensack Meridian Ocean Medical Center, Brick, USA
| | - Stacy Doumas
- Psychiatry, Hackensack Meridian Ocean Medical Center, Brick, USA
| | - Hussain Abdullah
- Psychiatry, Hackensack Meridian Ocean Medical Center, Brick, USA
| | - Eric Alcera
- Psychiatry, Hackensack Meridian Ocean Medical Center, Brick, USA
| | - Ramon Solhkhah
- Psychiatry, Northshore University Health System, Evanston, USA
| | - Saba Afzal
- Psychiatry, Hackensack Meridian Ocean Medical Center, Brick, USA
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Rodolico A, Cutrufelli P, Di Francesco A, Aguglia A, Catania G, Concerto C, Cuomo A, Fagiolini A, Lanza G, Mineo L, Natale A, Rapisarda L, Petralia A, Signorelli MS, Aguglia E. Efficacy and safety of ketamine and esketamine for unipolar and bipolar depression: an overview of systematic reviews with meta-analysis. Front Psychiatry 2024; 15:1325399. [PMID: 38362031 PMCID: PMC10867194 DOI: 10.3389/fpsyt.2024.1325399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 01/03/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Unipolar and bipolar depression present treatment challenges, with patients sometimes showing limited or no response to standard medications. Ketamine and its enantiomer, esketamine, offer promising alternative treatments that can quickly relieve suicidal thoughts. This Overview of Reviews (OoR) analyzed and synthesized systematic reviews (SRs) with meta-analysis on randomized clinical trials (RCTs) involving ketamine in various formulations (intravenous, intramuscular, intranasal, subcutaneous) for patients with unipolar or bipolar depression. We evaluated the efficacy and safety of ketamine and esketamine in treating major depressive episodes across various forms, including unipolar, bipolar, treatment-resistant, and non-resistant depression, in patient populations with and without suicidal ideation, aiming to comprehensively assess their therapeutic potential and safety profile. METHODS Following PRIOR guidelines, this OoR's protocol was registered on Implasy (ID:202150049). Searches in PubMed, Scopus, Cochrane Library, and Epistemonikos focused on English-language meta-analyses of RCTs of ketamine or esketamine, as monotherapy or add-on, evaluating outcomes like suicide risk, depressive symptoms, relapse, response rates, and side effects. We included studies involving both suicidal and non-suicidal patients; all routes and formulations of administration (intravenous, intramuscular, intranasal) were considered, as well as all available comparisons with control interventions. We excluded meta-analysis in which the intervention was used as anesthesia for electroconvulsive therapy or with a randomized ascending dose design. The selection, data extraction, and quality assessment of studies were carried out by pairs of reviewers in a blinded manner. Data on efficacy, acceptability, and tolerability were extracted. RESULTS Our analysis included 26 SRs and 44 RCTs, with 3,316 subjects. The intervention is effective and well-tolerated, although the quality of the included SRs and original studies is poor, resulting in low certainty of evidence. LIMITATIONS This study is limited by poor-quality SRs and original studies, resulting in low certainty of the evidence. Additionally, insufficient available data prevents differentiation between the effects of ketamine and esketamine in unipolar and bipolar depression. CONCLUSION While ketamine and esketamine show promising therapeutic potential, the current evidence suffers from low study quality. Enhanced methodological rigor in future research will allow for a more informed application of these interventions within the treatment guidelines for unipolar and bipolar depression. SYSTEMATIC REVIEW REGISTRATION [https://inplasy.com/inplasy-2021-5-0049/], identifier (INPLASY202150049).
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Affiliation(s)
- Alessandro Rodolico
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
| | - Pierfelice Cutrufelli
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
| | - Antonio Di Francesco
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
| | - Andrea Aguglia
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Gaetano Catania
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
- University of Catania, Catania, Italy
| | - Carmen Concerto
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
| | - Alessandro Cuomo
- Department of Molecular Medicine, University of Siena, Siena, Italy
| | - Andrea Fagiolini
- Department of Molecular Medicine, University of Siena, Siena, Italy
| | - Giuseppe Lanza
- Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy
- Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Troina, Italy
| | - Ludovico Mineo
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
| | - Antimo Natale
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
- Department of Psychiatry, Adult Psychiatry Service (SPA), University Hospitals of Geneva (HUG), Geneva, Switzerland
| | - Laura Rapisarda
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy
| | - Antonino Petralia
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
| | - Maria Salvina Signorelli
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
| | - Eugenio Aguglia
- Department of Clinical and Experimental Medicine, Institute of Psychiatry, University of Catania, Catania, Italy
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Rodgers A, Bahceci D, Davey CG, Chatterton ML, Glozier N, Hopwood M, Loo C. Ensuring the affordable becomes accessible-lessons from ketamine, a new treatment for severe depression. Aust N Z J Psychiatry 2024; 58:109-116. [PMID: 37830221 DOI: 10.1177/00048674231203898] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
In this paper, the case study of ketamine as a new treatment for severe depression is used to outline the challenges of repurposing established medicines and we suggest potential solutions. The antidepressant effects of generic racemic ketamine were identified over 20 years ago, but there were insufficient incentives for commercial entities to pursue its registration, or support for non-commercial entities to fill this gap. As a result, the evaluation of generic ketamine was delayed, piecemeal, uncoordinated, and insufficient to gain approval. Meanwhile, substantial commercial investment enabled the widespread registration of a patented, intranasal s-enantiomeric ketamine formulation (Spravato®) for depression. However, Spravato is priced at $600-$900/dose compared to ~$5/dose for generic ketamine, and the ~AUD$100 million annual government investment requested in Australia (to cover drug costs alone) has been rejected twice, leaving this treatment largely inaccessible for Australian patients 2 years after Therapeutic Goods Administration approval. Moreover, emerging evidence indicates that generic racemic ketamine is at least as effective as Spravato, but no comparative trials were required for regulatory approval and have not been conducted. Without action, this story will repeat regularly in the next decade with a new wave of psychedelic-assisted psychotherapy treatments, for which the original off-patent molecules could be available at low-cost and reduce the overall cost of treatment. Several systemic reforms are required to ensure that affordable, effective options become accessible; these include commercial incentives, public and public-private funding schemes, reduced regulatory barriers and more coordinated international public funding schemes to support translational research.
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Affiliation(s)
- Anthony Rodgers
- The George Institute for Global Health, University of New South Wales, Newtown, NSW, Australia
| | - Dilara Bahceci
- The George Institute for Global Health, University of New South Wales, Newtown, NSW, Australia
| | - Christopher G Davey
- Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia
| | - Mary Lou Chatterton
- Health Economics Group, Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Nick Glozier
- Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Malcolm Hopwood
- Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia
| | - Colleen Loo
- School of Psychiatry, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
- Black Dog Institute, Randwick, NSW, Australia
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Hovda N, Gerrish W, Frizzell W, Shackelford R. A systematic review of the incidence of medical serious adverse events in sub-anesthetic ketamine treatment of psychiatric disorders. J Affect Disord 2024; 345:262-271. [PMID: 37875227 DOI: 10.1016/j.jad.2023.10.120] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/04/2023] [Accepted: 10/17/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND Limited published data exists that collates serious adverse outcomes involving ketamine as a psychiatric intervention. This systematic review assesses the reported incidence of medical serious adverse events (MSAEs), including but not limited to cardiovascular events, in patients receiving sub-anesthetic doses of ketamine for psychiatric disorders to guide practitioners during treatment planning, risk-benefit analyses, and the informed consent process. METHODS Pubmed database was searched for clinical trials of sub-anesthetic ketamine for psychiatric disorders in non-pregnant adult patients. Of the 2275 articles identified, 93 met inclusion criteria, over half of which were published in 2017 or later. Only studies that reported adverse events were included, and the incidence of MSAEs was calculated. RESULTS Of the 3756 participants who received at least one sub-anesthetic dose of ketamine, four participants experienced a MSAE, resulting in an incidence of approximately 0.1 % of individuals. The four MSAEs resolved without reported sequelae. Eighty-three percent of studies reported screening for medical illness and exclusion of high-risk patients. There were no serious cardiac adverse events or deaths observed in any participants; however, most trials' study designs excluded those with high cardiovascular complication risk. LIMITATIONS Most studies were small, underpowered for detecting rare MSAEs, at potential high-risk of bias of non-report of MSAEs, and limited mostly to intranasal and intravenous routes. CONCLUSIONS Findings suggest that with basic medical screening there is a very low incidence of MSAEs including adverse cardiac or cerebrovascular events in individuals receiving sub-anesthetic ketamine for psychiatric disorders.
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Affiliation(s)
- Nicholas Hovda
- Sojourn Psychotherapy, Boise, United States of America; University of Washington School of Medicine, Department of Psychiatry & Behavioral Sciences, United States of America; Boise VAMC, Psychiatry & Behavioral Sciences Department, United States of America.
| | - Winslow Gerrish
- University of Washington School of Medicine, Department of Psychiatry & Behavioral Sciences, United States of America; Family Medicine Residency of Idaho - Boise, Full Circle Health, United States of America.
| | - William Frizzell
- University of Washington School of Medicine, Department of Psychiatry & Behavioral Sciences, United States of America; Boise VAMC, Psychiatry & Behavioral Sciences Department, United States of America.
| | - Ryan Shackelford
- Sojourn Psychotherapy, Boise, United States of America; University of Washington School of Medicine, Department of Psychiatry & Behavioral Sciences, United States of America; Family Medicine Residency of Idaho - Boise, Full Circle Health, United States of America.
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34
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Alves-Pereira R, Fontes M, Cordeiro V, Bandeira ID, Faria-Guimarães D, Silva SS, Mello RP, Leal GC, Sampaio AS, Quarantini LC. Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: A Retrospective Chart Review. Clin Neuropharmacol 2024; 47:17-21. [PMID: 38194244 DOI: 10.1097/wnf.0000000000000578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
OBJECTIVE Converging evidence supports the role of the glutamate, an excitatory amino acid neurotransmitter, in the pathophysiology of obsessive-compulsive disorder (OCD). Ketamine and esketamine, both noncompetitive N -methyl- d -aspartate antagonists, have emerged as a promising medication for this psychiatric disorder, given its possible efficacy with faster onset and good tolerability. The purpose of this retrospective chart review is to evaluate whether unbiased clinical documentation supports formal clinical trials of esketamine for an OCD indication. METHODS A retrospective chart review of patients with treatment-resistant OCD receiving a single dose of esketamine (0.5mg/kg) added to standard therapy was conducted. The Yale-Brown Obsessive-Compulsive Scale and the Montgomery-Åsberg Depression Rating Scale were used to evaluate OCD and depressive symptoms respectively at baseline, 24 hours, and 7 days after esketamine administration. Descriptive statistics were used to analyze the data. RESULTS Eight subjects were identified in this retrospective chart review: esketamine was administered subcutaneously in 7 and intravenously in 1. One week after infusion, 25% of the sample met criteria for treatment response and 50% for partial response. Major depressive disorder was a comorbid diagnosis in 75% of the sample and 2 of these subjects showed a positive antidepressant response. CONCLUSIONS Our findings provide preliminary evidence that esketamine may reduce obsessive-compulsive symptoms in a subset of treatment-resistant OCD patients.
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Affiliation(s)
| | | | | | | | - Daniela Faria-Guimarães
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia
| | - Samantha S Silva
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia
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Johnston JN, Kadriu B, Kraus C, Henter ID, Zarate CA. Ketamine in neuropsychiatric disorders: an update. Neuropsychopharmacology 2024; 49:23-40. [PMID: 37340091 PMCID: PMC10700638 DOI: 10.1038/s41386-023-01632-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/08/2023] [Accepted: 06/01/2023] [Indexed: 06/22/2023]
Abstract
The discovery of ketamine as a rapid-acting antidepressant led to a new era in the development of neuropsychiatric therapeutics, one characterized by an antidepressant response that occurred within hours or days rather than weeks or months. Considerable clinical research supports the use of-or further research with-subanesthetic-dose ketamine and its (S)-enantiomer esketamine in multiple neuropsychiatric disorders including depression, bipolar disorder, anxiety spectrum disorders, substance use disorders, and eating disorders, as well as for the management of chronic pain. In addition, ketamine often effectively targets symptom domains associated with multiple disorders, such as anxiety, anhedonia, and suicidal ideation. This manuscript: 1) reviews the literature on the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; 2) describes similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; 3) discusses the day-to-day use of ketamine in the clinical setting; 4) provides an overview of ketamine use in other psychiatric disorders and depression-related comorbidities (e.g., suicidal ideation); and 5) provides insights into the mechanisms of ketamine and therapeutic response gleaned from the study of other novel therapeutics and neuroimaging modalities.
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Affiliation(s)
- Jenessa N Johnston
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
| | - Bashkim Kadriu
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
- Translational and Experimental Medicine, Neuroscience at Jazz Pharmaceuticals, San Diego, CA, USA
| | - Christoph Kraus
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
| | - Ioline D Henter
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | - Carlos A Zarate
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
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Aguilar AG, Beauregard BA, Conroy CP, Khatiwoda YT, Horsford SME, Nichols SD, Piper BJ. Pronounced Regional Variation in Esketamine and Ketamine Prescribing to US Medicaid Patients. J Psychoactive Drugs 2024; 56:33-39. [PMID: 36857284 PMCID: PMC10471778 DOI: 10.1080/02791072.2023.2178558] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 11/28/2022] [Accepted: 01/05/2023] [Indexed: 03/02/2023]
Abstract
Ketamine and esketamine are efficacious for treatment-resistant depression. Unlike other antidepressants, ketamine lacks a therapeutic delay and decreases the risk for suicide. This cross-sectional study geographically characterized ketamine and esketamine prescribing to United States (US) Medicaid patients. Ketamine and esketamine prescription rates and spending per state were obtained. Between 2009 and 2020, ketamine prescribing rates peaked in 2013 followed by a general decline. For ketamine and esketamine in 2019, Montana (967/million enrollees) and Indiana (425) showed significantly higher prescription rates, respectively, relative to the national average. A total of 21 states prescribed neither ketamine nor esketamine in 2019. There was a 121.3% increase in esketamine prescriptions from 2019 to 2020. North Dakota (1,423) and North Carolina (1,094) were significantly elevated relative to the average state for esketamine in 2020. Ten states prescribed neither ketamine nor esketamine in 2020. Medicaid programs in 2020 spent 72.7-fold more for esketamine ($25.3 million) than on ketamine (0.3 million). Despite the effectiveness of ketamine and esketamine for treatment-resistant depression and anti-suicidal properties, their use among Medicaid patients was limited and highly variable in many areas of the US. Further research to better understand the origins of this state-level variation is needed.
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Affiliation(s)
- Alexia G. Aguilar
- Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA, United States of America
| | - Burke A. Beauregard
- Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA, United States of America
| | - Christopher P. Conroy
- Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA, United States of America
| | - Yashoda T. Khatiwoda
- Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA, United States of America
| | - Shantia M. E. Horsford
- Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA, United States of America
| | - Stephanie D. Nichols
- Department of Pharmacy Practice, University of New England, Portland, ME, United States of America
| | - Brian J. Piper
- Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA, United States of America
- Center for Pharmacy Innovation & Outcomes, Forty Fort, PA, United States of America
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Zhen C, Wang C, Ma Y, Pang Y, Cai F, Meng J, He Y, Xiao P, Liu J, Mei X, Li S, Wu G, Jin G, Zheng B, Liang R, Tan Z. Mechanism of Antidepressant Action of (2R,6R)-6-Hydroxynorketamine (HNK) and Its Compounds: Insights from Proteomic Analysis. Mol Neurobiol 2024; 61:465-475. [PMID: 37632679 DOI: 10.1007/s12035-023-03555-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 08/02/2023] [Indexed: 08/28/2023]
Abstract
The effects of HNK, I5, and I6 on the expression of protein in hippocampus of depressed mice were studied by isobaric tags for relative and absolute quantitation (iTRAQ) to explore the mechanism of their antidepressant action. HNK, I5, and I6 were administered intragastric administration once a day in the morning for 7 days. The drug was subsequently discontinued for 7 days (without any treatment). On the 15th day, mice in each group were given the drug (1.0, 10.0, 30.0 mg/kg) intragastric stimulation and mouse hippocampal tissues were taken to perform iTRAQ to identify differentially expressed proteins, and bioinformatics was used to analyze the functional enrichment of the differentially expressed proteins. Compared with Ctr group, the number of differentially expressed proteins in HNK, I5, and I6 treatment groups was 158, 88, and 105, respectively. The three groups shared 29 differentially expressed proteins. In addition, compared with HNK group, the number of differentially expressed proteins in I5 and I6 groups was 201 and 203, respectively. A total of 47 and 56 differentially expressed proteins were co-expressed in I5 and I6 groups. Bioinformatics analysis showed that these differentially expressed proteins mainly had the functions of binding, biocatalysis, and transport, and mainly participated in cellular process, biological regulation process, biological metabolism process, and stress reaction process. GO and KEGG pathway analysis found that these differentially expressed proteins were involved long-term potentiation, G13 pathway, platelet activation pathway, and MAPK signaling pathway. HNK, I5, and I6 antidepressants are closely related to sudden stress sensitivity, stress resistance, neurotransmitter, and metabolic pathways. This study provides a scientific basis to further elucidate the mechanism and clinical application of HNK, I5, and I6 antidepressants.
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Affiliation(s)
- Chaohui Zhen
- Department of Surgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, 523000, Guangdong Province, China
| | - Chong Wang
- Department of Neurosurgery, Shenzhen Children's Hospital, Shenzhen City, 518026, Guangdong Province, China
| | - Yanjun Ma
- Shenzhen Ruijian Biotechnology Co., Ltd, Shenzhen City, 518057, Guangdong Province, China
| | - Yuli Pang
- Health Management Center, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen City, 518055, Guangdong Province, China
| | - Feiyue Cai
- Health Management Center, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen City, 518055, Guangdong Province, China
- General Practice Alliance, Shenzhen City, Guangdong Province, China
| | - Jiali Meng
- General Practice Alliance, Shenzhen City, Guangdong Province, China
- Department of General Practice, Shenzhen University General Hospital, Shenzhen University, Shenzhen City, 518055, Guangdong Province, China
| | - Yuefei He
- General Practice Alliance, Shenzhen City, Guangdong Province, China
- Department of General Practice, Shenzhen University General Hospital, Shenzhen University, Shenzhen City, 518055, Guangdong Province, China
| | - Ping Xiao
- Department of Otorhinolaryngology Head and Neck Surgery, Shenzhen Children's Hospital, Shenzhen City, 518026, Guangdong Province, China
| | - Jianxi Liu
- Shenzhen Ruijian Biotechnology Co., Ltd, Shenzhen City, 518057, Guangdong Province, China
| | - Xi Mei
- Zhuhai Pengkun Biomedicine Technology Co. Ltd, Zhuhai City, 519000, Guangdong Province, China
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen City, 518055, Guangdong Province, China
| | - Guanzheng Wu
- College of Textiles and Clothing, Yancheng Institute of Technology, Yancheng City, 224051, Jiangsu Province, China
| | - Guangzhen Jin
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Korea
| | - Biao Zheng
- Department of Surgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, 523000, Guangdong Province, China.
| | - Rui Liang
- Department of Surgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, 523000, Guangdong Province, China.
| | - Zhen Tan
- Department of Surgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, 523000, Guangdong Province, China.
- Health Management Center, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen City, 518055, Guangdong Province, China.
- General Practice Alliance, Shenzhen City, Guangdong Province, China.
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Nunez NA, Joseph B, Kumar R, Douka I, Miola A, Prokop LJ, Mickey BJ, Singh B. An Update on the Efficacy of Single and Serial Intravenous Ketamine Infusions and Esketamine for Bipolar Depression: A Systematic Review and Meta-Analysis. Brain Sci 2023; 13:1672. [PMID: 38137120 PMCID: PMC10741553 DOI: 10.3390/brainsci13121672] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 12/24/2023] Open
Abstract
Ketamine has shown rapid antidepressant and anti-suicidal effects in treatment-resistant depression (TRD) with single and serial intravenous (IV) infusions, but the effectiveness for depressive episodes of bipolar disorder is less clear. We conducted an updated systematic review and meta-analysis to appraise the current evidence on the efficacy and tolerability of ketamine/esketamine in bipolar depression. A search was conducted to identify randomized controlled trials (RCTs) and non-randomized studies examining single or multiple infusions of ketamine or esketamine treatments. A total of 2657 articles were screened; 11 studies were included in the systematic review of which 7 studies were included in the meta-analysis (five non-randomized, N = 159; two RCTs, N = 33) with a mean age of 42.58 ± 13.1 years and 54.5% females. Pooled analysis from two RCTs showed a significant improvement in depression symptoms measured with MADRS after receiving a single infusion of ketamine (1-day WMD = -11.07; and 2 days WMD = -12.03). Non-randomized studies showed significant response (53%, p < 0.001) and remission rates (38%, p < 0.001) at the study endpoint. The response (54% vs. 55%) and remission (30% vs. 40%) rates for single versus serial ketamine infusion studies were similar. The affective switch rate in the included studies approximated 2.4%. Esketamine data for bipolar depression are limited, based on non-randomized, small sample-sized studies. Further studies with larger sample sizes are required to strengthen the evidence.
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Affiliation(s)
- Nicolas A. Nunez
- Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; (N.A.N.)
- Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA
| | - Boney Joseph
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
| | - Rakesh Kumar
- Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; (N.A.N.)
| | - Ioanna Douka
- Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA
| | - Alessandro Miola
- Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; (N.A.N.)
- Department of Neuroscience (DNS), University of Padova, 35122 Padua, Italy
| | - Larry J. Prokop
- Mayo Medical Libraries, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Brian J. Mickey
- Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA
| | - Balwinder Singh
- Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; (N.A.N.)
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Vecera CM, C. Courtes A, Jones G, Soares JC, Machado-Vieira R. Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression. Pharmaceuticals (Basel) 2023; 16:1572. [PMID: 38004437 PMCID: PMC10675154 DOI: 10.3390/ph16111572] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/22/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.
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Affiliation(s)
- Courtney M. Vecera
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Alan C. Courtes
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Gregory Jones
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Jair C. Soares
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Rodrigo Machado-Vieira
- John S. Dunn Behavioral Sciences Center at UTHealth Houston, 5615 H.Mark Crosswell Jr St, Houston, TX 77021, USA
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Li Q, Gao K, Yang S, Yang S, Xu S, Feng Y, Bai Z, Ping A, Luo S, Li L, Wang L, Shi G, Duan K, Wang S. Predicting efficacy of sub-anesthetic ketamine/esketamine i.v. dose during course of cesarean section for PPD prevention, utilizing traditional logistic regression and machine learning models. J Affect Disord 2023; 339:264-270. [PMID: 37451434 DOI: 10.1016/j.jad.2023.07.048] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/29/2023] [Accepted: 07/08/2023] [Indexed: 07/18/2023]
Abstract
OBJECTIVE Increasing researches supported that intravenous ketamine/esketamine during the perioperative period of cesarean section could prevent postpartum depression(PPD). With the effective rate ranging from 87.2 % to 95.5 % in PPD, ketamine/esketamine's responsiveness was individualized. To optimize ketamine dose/form based on puerpera prenatal characteristics, reducing adverse events and improving the total efficacy rate, prediction models were developed to predict ketamine/esketamine's efficacy. METHOD Based on two randomized controlled trials, 12 prenatal features of 507 women administered the ketamine/esketamine intervention were collected. Traditional logistics regression, SVM, random forest, KNN and XGBoost prediction models were established with prenatal features and dosage regimen as predictors. RESULTS According to the logistic regression model (ain = 0.10, aout = 0.15, area under the receiver operating characteristic curve, AUC = 0.728), prenatal Edinburgh Postnatal Depression Scale (EPDS) score ≥ 10, thoughts of self-injury and bad mood during pregnancy were associated with poorer ketamine efficacy in PPD prevention, whilst a high dose of esketamine (0.25 mg/kg loading dose+2 mg/kg PCIA) was the most effective dosage regimen and esketamine was more recommended rather than ketamine in PPD. The AUCvalidation set of KNN and XGBoost model were 0.815 and 0.651, respectively. CONCLUSION Logistic regression and machine learning algorithm, especially the KNN model, could predict the effectiveness of ketamine/esketamine iv. during the course of cesarean section for PPD prevention. An individualized preventative strategy could be developed after entering puerpera clinical features into the model, possessing great clinical practice value in reducing PPD incidence.
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Affiliation(s)
- Qiuwen Li
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Kai Gao
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Siqi Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Shuting Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Shouyu Xu
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Yunfei Feng
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Zhihong Bai
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Anqi Ping
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Shichao Luo
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Lishan Li
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Liangfeng Wang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Guoxun Shi
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Kaiming Duan
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China.
| | - Saiying Wang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China.
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Yang SQ, Zhou YY, Yang ST, Mao XY, Chen L, Bai ZH, Ping AQ, Xu SY, Li QW, Gao K, Wang SY, Duan KM. Effects of different doses of esketamine intervention on postpartum depressive symptoms in cesarean section women: A randomized, double-blind, controlled clinical study. J Affect Disord 2023; 339:333-341. [PMID: 37442447 DOI: 10.1016/j.jad.2023.07.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 06/02/2023] [Accepted: 07/08/2023] [Indexed: 07/15/2023]
Abstract
BACKGROUND The optimal dosage and method of esketamine for postpartum depressive symptoms (PDS) are unclear. We conducted a randomized controlled trial (RCT) to investigate the effect of different doses of esketamine on PDS in women undergoing cesarean section, with evidence of prenatal depression. METHODS The three groups were high- (2 mg kg-1) and low-dose (1 mg kg-1) esketamine via patient controlled intravenous analgesia (PCIA), following an initial intravenous infusion of 0.25 mg kg-1 esketamine, compared to placebo (0.9 % saline infusion). All groups also received the sufentanil (2.2 μg kg-1). The primary outcome was the incidence of PDS at 7 and 42 days postpartum. The secondary outcomes were: the remission from depression and total EPDS scores at 7 days and 42 days postpartum; mean change from baseline in the EPDS score; postoperative analgesia. RESULTS i). 0.25 mg kg-1 of esketamine intravenous infusion combined with 1 mg kg-1 (n = 99) or 2 mg kg-1 (n = 99) esketamine PCIA reduces PDS incidence at 7 days postpartum (p < 0.05), with high-dose esketamine PCIA also reduces PDS incidence 42 days postpartum (p < 0.05), compared to placebo (n = 97). ii). Low- and high-dose esketamine PCIA lowers NRS scores at rest within 48 h postoperatively (p < 0.01), with high-dose esketamine also reducing the NRS score during movement at 48 h postoperatively (p = 0.018). iii). Neither high- nor low-dose esketamine PCIA increased postoperative adverse reactions (p > 0.05). CONCLUSIONS Esketamine (0.25 mg kg-1) intravenous infusion combined with 1 mg kg-1 or 2 mg kg-1 esketamine PCIA seems safe and with few adverse effects in the management of PDS and pain in women undergoing cesarean section. LIMITATIONS The tolerability and safety of esketamine requires further investigation based on more specific scales; the transient side effects of esketamine could have biased the staff and patients. TRIAL REGISTRATION ChiCTR-ROC-2000039069.
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Affiliation(s)
- Si Qi Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Ying Yong Zhou
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Shu Ting Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiao Yuan Mao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Liang Chen
- Department of Anesthesiology, The Maternal and Child Health Hospital of the Hu Nan Province, Changsha, China
| | - Zhi Hong Bai
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - An Qi Ping
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Shou Yu Xu
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Qiu Wen Li
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Kai Gao
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Sai Ying Wang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China.
| | - Kai Ming Duan
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China.
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Baldwin K, Wanson A, Gilecki LA, Dalton C, Peters E, Halpape K. Intranasal ketamine as a treatment for psychiatric complications of long COVID: A case report. Ment Health Clin 2023; 13:239-243. [PMID: 38131056 PMCID: PMC10732124 DOI: 10.9740/mhc.2023.10.239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 06/20/2023] [Indexed: 12/23/2023] Open
Abstract
Background Neuropsychiatric symptoms associated with long COVID are a growing concern. A proposed pathophysiology is increased inflammatory mediators. There is evidence that typical serotonergic antidepressants have limited efficacy in the presence of inflammation. Although ketamine has shown promise in MDD, there is limited evidence supporting the use of ketamine to treat depressive symptoms associated with long COVID. Case Report This case took place on an inpatient psychiatry unit in a Canadian hospital. The patient was admitted with a 10-month history of worsening depression and suicidality following infection with COVID-19. Depressive symptoms and suicidal ideation were assessed throughout treatment using the Montgomery-Asberg Depression Rating Scale (MADRS). Written informed consent was obtained prior to data collection. This patient received 4 doses of intranasal ketamine which resulted in rapid improvement of depressive symptoms and complete resolution of suicidality with no major adverse events. Discussion There is evidence to support long COVID symptoms result from dysregulated inflammatory processes. The presence of inflammation in patients with MDD has correlated to poor outcomes with first-line antidepressants. It has been demonstrated that IV ketamine is associated with decreased inflammatory mediators and proportional decrease in depressive symptoms. Conclusions Intranasal ketamine in this case was effective at treating depressive symptoms and suicidal ideation associated with long COVID. This is consistent with available data that demonstrates ketamine's efficacy in reducing inflammatory mediators associated with neuropsychiatric symptoms. Therefore, ketamine may be a potential therapeutic option to treat long COVID and persistent depressive symptoms.
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Affiliation(s)
- Kaitlyn Baldwin
- Pharmacy Resident, University of British Columbia, Lower Mainland Pharmacy Services, Vancouver, British Columbia
| | - Annabelle Wanson
- Psychiatrist and Area Department Lead (Interim), Saskatchewan Health Authority, Saskatoon, Saskatchewan
| | - Lee-Anne Gilecki
- Psychiatrist, Saskatchewan Health Authority, Saskatoon, Saskatchewan
| | - Courtney Dalton
- Psychiatrist, Saskatchewan Health Authority, Saskatoon, Saskatchewan
| | - Evyn Peters
- Psychiatrist, Saskatchewan Health Authority, Saskatoon, Saskatchewan
| | - Katelyn Halpape
- Pharmacy Resident, University of British Columbia, Lower Mainland Pharmacy Services, Vancouver, British Columbia
- Psychiatrist and Area Department Lead (Interim), Saskatchewan Health Authority, Saskatoon, Saskatchewan
- Psychiatrist, Saskatchewan Health Authority, Saskatoon, Saskatchewan
- Pharmacist, Saskatchewan Health Authority, Saskatoon, Saskatchewan
- Psychiatrist, Saskatchewan Health Authority, Saskatoon, Saskatchewan
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Liu LL, Hu JH, Pan JJ, Liu H, Ji FH, Peng K. An Intraoperative Sub-Anesthetic Dose of Esketamine on Postoperative Depressive Symptoms in Perimenopausal Women with Breast Cancer Undergoing Modified Radical Mastectomy: Protocol for a Randomized, Triple-Blinded, Controlled Trial. Int J Gen Med 2023; 16:3373-3381. [PMID: 37576915 PMCID: PMC10422984 DOI: 10.2147/ijgm.s421265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 08/02/2023] [Indexed: 08/15/2023] Open
Abstract
Background Depressive symptoms are common among perimenopausal women with breast cancer having modified radical mastectomy. Esketamine exerts antidepressant effects. This study aims to assess whether an intraoperative sub-anesthetic dose of esketamine prevents postoperative depressive symptoms in these patients. Methods In this randomized, triple-blinded, placebo-controlled trial, we will enroll 130 perimenopausal women (aged 45-60 years) with breast cancer undergoing unilateral modified radical mastectomy. Patients will be randomly assigned with a 1:1 ratio to receive either esketamine (0.25 mg/kg i.v.) or normal saline after anesthesia induction and before skin incision. The primary outcome is the incidence of depressive symptoms at day 30 postoperatively, assessed using the Beck's Depression Inventory (BDI). Secondary outcomes include incidence of depressive symptoms and BDI scores at day 1, 3, and 180 postoperatively, anxiety symptoms and scores at day 1, 3, 30, and 180 postoperatively, pain intensity and quality of recovery at day 1 and 2 postoperatively, nausea and vomiting within 48 hours postoperatively, length of postoperative hospital stay, and cancer-specific outcomes. Data will be analyzed in the modified intention-to-treat population. Discussion This is the first trial to evaluate the effects of a sub-anesthetic dose of esketamine on depressive symptoms in perimenopausal women after modified radical mastectomy. The results of this study will help to improve their mental health and recovery after breast cancer surgery. Trial Registration Chinese Clinical Trial Registry (ChiCTR2200064348).
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Affiliation(s)
- Lin-Lin Liu
- Departments of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, People’s Republic of China
| | - Jing-Hui Hu
- Departments of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, People’s Republic of China
| | - Jing-Jing Pan
- Departments of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Anesthesiology, Guanyun People’s Hospital, Lianyungang, Jiangsu, People’s Republic of China
| | - Hong Liu
- Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, CA, USA
| | - Fu-Hai Ji
- Departments of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, People’s Republic of China
| | - Ke Peng
- Departments of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, People’s Republic of China
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Nikolin S, Rodgers A, Schwaab A, Bahji A, Zarate C, Vazquez G, Loo C. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine 2023; 62:102127. [PMID: 37593223 PMCID: PMC10430179 DOI: 10.1016/j.eclinm.2023.102127] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 07/09/2023] [Accepted: 07/17/2023] [Indexed: 08/19/2023] Open
Abstract
Background Intranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated efficacy in severe depression. However, uncertainties remain regarding comparative efficacy, dosage, and the time course of response. Methods In this systematic review and meta-analysis, we searched Embase, Medline, Pubmed, PsycINFO, and CENTRAL up to April 13, 2023, for randomised controlled trials (RCTs) investigating ketamine for depression. Two investigators independently assessed study eligibility and risk of bias and extracted the data on depression severity scores, response and remission rates, and all-cause dropouts. Multivariable mixed-effects meta-regressions incorporated drug formulation (racemic (Rac) or esketamine (Esket)) and dose (Low or High) as covariates. Treatment effects were assessed: immediately following the first dose, during further repeated dosing, and follow-up after the final dose of a treatment course. This study is registered with PROSPERO (CRD42021221157). Findings The systematic review identified 687 articles, of which 49 RCTs were eligible for analysis, comprising 3299 participants. Standardised mean differences (95% confidence intervals) immediately following the first/single treatment were moderate-high for all conditions (Rac-High: -0.73, -0.91 to -0.56; Esket-High: -0.48, -0.75 to -0.20; Rac-Low: -0.33, -0.54 to -0.12; Esket-Low: -0.55, -0.87 to -0.24). Ongoing effects during repeated dosing were significantly greater than the control for Rac-High (-0.61; -1.02 to -0.20) and Rac-Low (-0.55, -1.09 to -0.00), but not Esket-Low (-0.15, -0.49 to 0.19) or Esket-High (-0.22, -0.54 to 0.10). At follow-up effects remained significant for racemic ketamine (-0.65; -1.23 to -0.07) but not esketamine (-0.33; -0.96 to 0.31). All-cause dropout was similar between experiment and control conditions for both formulations combined (Odds Ratio = 1.18, 0.85-1.64). Overall heterogeneity varied from 5.7% to 87.6. Interpretation Our findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose. Funding None.
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Affiliation(s)
- Stevan Nikolin
- Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, Australia
- Black Dog Institute, Sydney, Australia
| | - Anthony Rodgers
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
| | | | - Anees Bahji
- Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carlos Zarate
- Section Neurobiology and Treatment of Mood Disorders, Division of Intramural Research Program, National Institute of Mental Health, 10 Center Drive, MSC 1282, Building 10CRC, Room 7-5342, Bethesda, MD 20892, USA
| | - Gustavo Vazquez
- Section Neurobiology and Treatment of Mood Disorders, Division of Intramural Research Program, National Institute of Mental Health, 10 Center Drive, MSC 1282, Building 10CRC, Room 7-5342, Bethesda, MD 20892, USA
| | - Colleen Loo
- Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, Australia
- Black Dog Institute, Sydney, Australia
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
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45
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Chen CC, Wang XB. Acute Effects of Intravenous Sub-Anesthetic Doses of Ketamine and Intranasal Inhaled Esketamine on Suicidal Ideation: A Systematic Review and Meta-Analysis: Letter in Response [Response to Letter]. Neuropsychiatr Dis Treat 2023; 19:1623-1624. [PMID: 37484119 PMCID: PMC10361081 DOI: 10.2147/ndt.s429062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 07/11/2023] [Indexed: 07/25/2023] Open
Affiliation(s)
- Cheng-Chuan Chen
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China
| | - Xiao-Bin Wang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China
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Floriano I, Silvinato A, Bernardo WM. The use of esketamine in the treatment of patients with oral antidepressant-resistant depression: systematic review and meta-analysis. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:e2023D696. [PMID: 37377288 DOI: 10.1590/1806-9282.2023d696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 04/19/2023] [Indexed: 06/29/2023]
Abstract
The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field to standardize how to conduct, and to assist in the reasoning and decision-making of doctors. The information provided by this project must be critically evaluated by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical condition of each patient. Guideline conclusion: April 2023. Societies: Brazilian Medical Association.
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Affiliation(s)
- Idevaldo Floriano
- Cooperativa Baixa Mogiana, Evidence-Based Medicine - Mogi-Guaçu (SP), Brazil
| | - Antônio Silvinato
- Brazilian Medical Association, Evidence-Based Medicine - São Paulo (SP), Brazil
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Bandeira ID, Leal GC, Correia-Melo FS, Souza-Marques B, Silva SS, Lins-Silva DH, Mello RP, Vieira F, Dorea-Bandeira I, Faria-Guimarães D, Carneiro B, Caliman-Fontes AT, Kapczinski F, Miranda-Scippa Â, Lacerda ALT, Quarantini LC. Arketamine for bipolar depression: Open-label, dose-escalation, pilot study. J Psychiatr Res 2023; 164:229-234. [PMID: 37385001 DOI: 10.1016/j.jpsychires.2023.06.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/29/2023] [Accepted: 06/21/2023] [Indexed: 07/01/2023]
Abstract
There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart-0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression.
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Affiliation(s)
- Igor D Bandeira
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, United States
| | - Gustavo C Leal
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Fernanda S Correia-Melo
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Breno Souza-Marques
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Samantha S Silva
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Daniel H Lins-Silva
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Rodrigo P Mello
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Flávia Vieira
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Ingrid Dorea-Bandeira
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Daniela Faria-Guimarães
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Beatriz Carneiro
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Ana Teresa Caliman-Fontes
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Flávio Kapczinski
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada
| | - Ângela Miranda-Scippa
- Departamento de Neurociências e Saúde Mental, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
| | - Acioly L T Lacerda
- Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, Brazil; Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil; Instituto Sinapse de Neurociências Clínicas, Campinas, Brazil
| | - Lucas C Quarantini
- Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; Departamento de Neurociências e Saúde Mental, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil.
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48
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Johnston JN, Henter ID, Zarate CA. The antidepressant actions of ketamine and its enantiomers. Pharmacol Ther 2023; 246:108431. [PMID: 37146727 PMCID: PMC10213151 DOI: 10.1016/j.pharmthera.2023.108431] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/24/2023] [Accepted: 05/02/2023] [Indexed: 05/07/2023]
Abstract
Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist first developed as an anesthetic, has shown significant promise as a medication with rapid antidepressant properties in treatment-resistant depression. However, concerns such as adverse side effects and potential misuse liability have limited its widespread use. Racemic ketamine has two enantiomers-(S)- and (R)-ketamine-that appear to have disparate underlying mechanisms. This brief review summarizes some of the most recent preclinical and clinical research regarding the convergent and divergent prophylactic, immediate, and sustained antidepressant effects of (S)- and (R)-ketamine while addressing potential differences in their side effect and misuse liability profiles. Preclinical research suggests divergent mechanisms underlying (S)- and (R)-ketamine, with (S)-ketamine more directly affecting mechanistic target of rapamycin complex 1 (mTORC1) signaling and (R)-ketamine more directly affecting extracellular signal-related kinase (ERK) signaling. Clinical research suggests that (R)-ketamine has a milder side effect profile than (S)-ketamine and decreases depression rating scale scores, but recent randomized, controlled trials found that it had no significant antidepressant efficacy compared to placebo, suggesting that caution is warranted in interpreting its therapeutic potential. Future preclinical and clinical research is needed to maximize the efficacy of each enantiomer, either by optimizing dose, route of administration, or administration paradigm.
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Affiliation(s)
- Jenessa N Johnston
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MA, United States.
| | - Ioline D Henter
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MA, United States
| | - Carlos A Zarate
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MA, United States
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49
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Santos M, Lima L, Carvalho S, Mota-Pereira J, Pimentel P, Maia D, Correia D, Barroso MF, Gomes S, Cruz A, Medeiros R. The Impact of BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 Genetic Polymorphisms in Antidepressant Treatment Response Phenotypes. Int J Mol Sci 2023; 24:ijms24076758. [PMID: 37047730 PMCID: PMC10095078 DOI: 10.3390/ijms24076758] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/30/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023] Open
Abstract
This study aimed to investigate the influence of genetic variants in neuroplasticity-related genes on antidepressant treatment phenotypes. The BDNF-TrkB signaling pathway, as well as the downstream kinases Akt and ERK and the mTOR pathway, have been implicated in depression and neuroplasticity. However, clinicians still struggle with the unpredictability of antidepressant responses in depressed patients. We genotyped 26 polymorphisms in BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 in 80 patients with major depressive disorder treated according to the Texas Medical Algorithm for 27 months at Hospital Magalhães Lemos, Porto, Portugal. Our results showed that BDNF rs6265, PTEN rs12569998, and SYN1 rs1142636 SNP were associated with treatment-resistant depression (TRD). Additionally, MAPK1 rs6928 and GSK3B rs6438552 gene polymorphisms were associated with relapse. Moreover, we found a link between the rs6928 MAPK1 polymorphism and time to relapse. These findings suggest that the BDNF, PTEN, and SYN1 genes may play a role in the development of TRD, while MAPK1 and GSK3B may be associated with relapse. GO analysis revealed enrichment in synaptic and trans-synaptic transmission pathways and glutamate receptor activity with TRD-associated genes. Genetic variants in these genes could potentially be incorporated into predictive models of antidepressant response.
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Affiliation(s)
- Marlene Santos
- Centro de Investigação em Saúde e Ambiente (CISA), Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal
- Molecular Oncology & Viral Pathology, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072 Porto, Portugal
| | - Luis Lima
- Experimental Pathology and Therapeutics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072 Porto, Portugal
| | - Serafim Carvalho
- Hospital de Magalhães Lemos, 4149-003 Porto, Portugal
- Instituto Universitário de Ciências da Saúde, 4585-116 Gandra, Portugal
| | | | - Paulo Pimentel
- Trás-os-Montes e Alto Douro Hospital Centre, 5000-508 Vila Real, Portugal
| | - Dulce Maia
- Trás-os-Montes e Alto Douro Hospital Centre, 5000-508 Vila Real, Portugal
| | - Diana Correia
- Hospital de Magalhães Lemos, 4149-003 Porto, Portugal
| | - M. Fátima Barroso
- REQUIMTE/LAQV, Instituto Superior de Engenharia do Instituto Politécnico do Porto, 4200-072 Porto, Portugal
| | - Sofia Gomes
- Hospital de Magalhães Lemos, 4149-003 Porto, Portugal
| | - Agostinho Cruz
- Centro de Investigação em Saúde e Ambiente (CISA), Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology & Viral Pathology, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072 Porto, Portugal
- Research Department, Portuguese League Against Cancer (Norte), 4200-172 Porto, Portugal
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50
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Vasiliu O. Esketamine for treatment‑resistant depression: A review of clinical evidence (Review). Exp Ther Med 2023; 25:111. [PMID: 36793329 PMCID: PMC9922941 DOI: 10.3892/etm.2023.11810] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 01/13/2023] [Indexed: 01/26/2023] Open
Abstract
Treatment-resistant depression (TRD) is a challenge for psychiatrists, even after more than seven decades since the first antidepressants were used in clinical practice. Non-monoaminergic-based drugs with antidepressant properties have been developed, but to date, only esketamine and brexanolone have been approved for TRD and postpartum depression, respectively. A narrative review on the efficacy and safety of esketamine in the main categories of depressive disorders has been conducted through four electronic databases (Pubmed, Cochrane, EMBASE and Clarivate/Web of Science) The primary objective of the present review was to find evidence that may support the usefulness of esketamine for patients diagnosed with TRD as well as data about its potential adverse effects in the short and long term. A total of 14 papers were reviewed, and their results support the recommendation of esketamine for treatment of TRD as an add-on to antidepressants, but more data is needed in order to assess its long-term efficacy and safety. It must also be mentioned that there have been a few trials which did not report a significant effect on the severity of depressive symptoms with esketamine in TRD, therefore, caution is indicated for patients initiated on this adjuvant agent. There has been insufficient data to formulate specific guidelines about esketamine administration because evidence about favorable or negative prognostic factors of this treatment has been lacking, and the duration of its administration has not been unanimously accepted. Novel directions for research have been identified, especially in the case of patients with TRD and substance use disorders, geriatric or bipolar depression or in major depression with psychotic features.
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Affiliation(s)
- Octavian Vasiliu
- Department of Psychiatry, ‘Dr. Carol Davila’ University Emergency Central Military Hospital, Bucharest 010816, Romania,Correspondence to: Dr Octavian Vasiliu, Department of Psychiatry, ‘Dr. Carol Davila’ University Emergency Central Military Hospital, 88 Mircea Vulcanescu Street, Bucharest 010816, Romania
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