Single Dose Of Ketamine Research Articles

An evaluation of the efficacy and side effects of a single dose of ketamine in major depressive disorder.

This study aims to provide a comprehensive overview of the antidepressant and antisuicidal efficacy of ketamine in patients with unipolar depression, with a focus on the clinical evidence and safety profile. In our study, the data of 120 major depressive disorder patients who received single-dose ketamine infusion therapy were evaluated retrospectively, with Montgomery-Asberg Depression Rating Scale (MADRS) applied by the clinician before treatment and at the 4th and 24th hours after treatment and side effects at 4 and 24hours after treatment. There was a statistically significant difference between MADRS and MADRS-Suicide scores of all participants before the ketamine infusion (0th hour) and at the 4th and 24th hours after the ketamine infusion. Also, male and female, RAT(+) and RAT(-), and SA(+) and SA(-) participants have statistically significant differences on all three times for both MADRS and MADRS-S scores. The findings of this study are in line with those from previous research that demonstrated the rapid and robust antidepressant effects of ketamine, even in individuals with severe, treatment-resistant depression. Moreover, the observed reduction in suicidal ideation is particularly noteworthy, given the critical need for interventions that can provide rapid relief in acute suicidal crises. Key message What is already known on this topic - Ketamine is known for its rapid antidepressant and antisuicidal effects in treatment-resistant major depressive disorder, demonstrating significant symptom relief within hours of administration. What this study adds - This study provides additional evidence supporting ketamine's rapid efficacy in reducing depressive symptoms and suicidal ideation, highlighting statistically significant improvements observed at 4 and 24hours post-treatment. How this study might affect research, practice, or policy - The findings may encourage broader clinical adoption of ketamine for acute depressive episodes and suicidality, emphasizing the need for controlled medical settings to manage potential side effects, and could influence future research on optimizing dosing protocols and long-term safety.

Recent Interventions for Acute Suicidality Delivered in the Emergency Department: A Scoping Review

Introduction: Suicidality is a growing problem in the US, and the emergency department (ED) is often the front line for the management and effective treatment of acutely suicidal patients. There is a dearth of interventions that emergency physicians may use to manage and effectively treat acutely suicidal patients. To the extent that recently described interventions are available for ED personnel, no review has been conducted to identify them. This scoping review is intended to fill this gap by systematically reviewing the literature to identify recently described interventions that can be administered in the ED to reduce symptoms and stabilize patients. Methods: We conducted a search of PubMed, SCOPUS, and CINAHL in January 2024 to identify papers published between 2013–2023 for original research trialing recent interventions for the effective treatment of suicidality in the ED. We assessed 16 full-text articles for eligibility, and nine met inclusion criteria. Included studies were evaluated for features and characteristics, the fit of the intervention to the ED environment, and interventional efficacy. Results: Four studies assessed the efficacy of a single dose of the anesthetic/analgesic agent ketamine. Three studies assessed the efficacy of a brief psychosocial intervention delivered in the ED, two of which paired this intervention with the provision of follow-up care (postcard contact and referral assistance/case management, respectively). The remaining two studies trialed a brief, motivational interviewing-based intervention. Included studies had strong experimental designs (randomized controlled trials) but small sample sizes (average 57). Among the interventions represented across these nine studies, a single dose of ketamine and the brief psychosocial intervention Crisis Response Planning (CRP) show promise as ED-appropriate interventions for suicidality. Ketamine and CRP demonstrated the strongest fit to the ED environment and most robust efficacy findings. Conclusion: This review identified one drug (ketamine) and four unique psychological/behavioral interventions that have been used to treat acute suicidality in the ED. There is currently insufficient evidence to suggest that these interventions will prove efficacious and well-suited to be delivered in the ED environment. Future studies should continue to test these interventions in the ED setting to determine their feasibility and efficacy.

Optimizing the use of ketamine to reduce chronic postsurgical pain in women undergoing mastectomy for oncologic indication: study protocol for the KALPAS multicenter randomized controlled trial

BackgroundMastectomies are commonly performed and strongly associated with chronic postsurgical pain (CPSP), more specifically termed postmastectomy pain syndrome (PMPS), with 25–60% of patients reporting pain 3 months after surgery. PMPS interferes with function, recovery, and compliance with adjuvant therapy. Importantly, it is associated with chronic opioid use, as a recent study showed that 1 in 10 patients continue to use opioids at least 3 months after curative surgery. The majority of PMPS patients are women, and, over the past 10 years, women have outpaced men in the rate of growth in opioid dependence. Standard perioperative multimodal analgesia is only modestly effective in prevention of CPSP. Thus, interventions to reduce CPSP and PMPS are urgently needed. Ketamine is well known to improve pain and reduce opioid use in the acute postoperative period. Additionally, ketamine has been shown to control mood in studies of anxiety and depression. By targeting acute pain and improving mood in the perioperative period, ketamine may be able to prevent the development of CPSP.MethodsKetamine analgesia for long-lasting pain relief after surgery (KALPAS) is a phase 3, multicenter, randomized, placebo-controlled, double-blind trial to study the effectiveness of ketamine in reducing PMPS. The study compares continuous perioperative ketamine infusion vs single-dose ketamine in the postanesthesia care unit vs placebo for reducing PMPS. Participants are followed for 1 year after surgery. The primary outcome is pain at the surgical site at 3 months after the index surgery as assessed with the Brief Pain Inventory-short form pain severity subscale.DiscussionThis project is part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, a nationwide effort to address the opioid public health crisis. This study can substantially impact perioperative pain management and can contribute significantly to combatting the opioid epidemic.Trial registrationClinicalTrials.gov NCT05037123. Registered on September 8, 2021.

A pre-anesthetic bolus of ketamine versus dexmedetomidine for prevention of postoperative delirium in elderly patients undergoing emergency surgery: a randomized, double-blinded, placebo-controlled study

BackgroundWe aimed to evaluate whether a single dose of ketamine or dexmedetomidine before induction of general anesthesia could reduce the incidence of postoperative delirium (primary outcome) or cognitive dysfunction (secondary outcome) in elderly patients undergoing emergency surgery.Patients and methodsThis randomized, double-blinded, placebo-controlled trial included 60 elderly patients who were scheduled for emergency surgery. The patients were randomly assigned into one of three groups (n = 20): group I received 0.9% normal saline, group II received 1 µg/kg dexmedetomidine, and group III received 1 mg/kg ketamine right before anesthesia induction. Patients were observed for three days after surgery and tested for postoperative delirium and cognitive dysfunction using the delirium observation screening scale and the mini-mental state examination score, respectively.ResultsThe dexmedetomidine group had the lowest incidence of delirium (p = 0.001) and cognitive dysfunction (p = 0.006) compared to the ketamine and placebo groups. The multivariate logistic regression model revealed that dexmedetomidine reduced the incidence of postoperative delirium by 32% compared to placebo (reference) (OR = 0.684, 95% CI: 0.240–0.971, p = 0.025), whereas ketamine increased the risk by threefold (OR = 3.012, 95% CI: 1.185–9.681, p = 0.013). Furthermore, dexmedetomidine reduced the incidence of postoperative cognitive dysfunction by 62% (OR = 0.375, 95% CI: 0.091–0.543, p = 0.012), whereas ketamine increased the risk by 4.5 times (OR = 4.501, 95% CI: 1.161–8.817, p = 0.006).ConclusionA single pre-anesthetic bolus of dexmedetomidine is a practical choice for preventing postoperative delirium in elderly patients undergoing emergency surgery.Trial registrationThis study was approved by the Ethics Committee of Aswan University Hospital (approval number: aswu/548/7/2021; registration date: 06/07/2021) and registered on ClinicalTrials.gov (NCT05341154) (22/04/2022).

A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons.

A large amount of clinical evidence has revealed that ketamine can relieve fentanyl-induced hyperalgesia. However, the underlying mechanism is still unclear. In the current study, a single dose of ketamine (5 mg/kg or 10 mg/kg), TAK-242 (3 mg/kg), or saline was intraperitoneally injected into rats 15 min before four subcutaneous injections of fentanyl. Results revealed that pre-administration of ketamine alleviated fentanyl-induced hyperalgesia according to hind paw-pressure and paw-withdrawal tests. High-dose ketamine can reverse the expression of toll-like receptor-dimer (d-TLR4), phospho- nuclear factor kappa-B (p-NF-κB, p-p65), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) 1 d after fentanyl injection in the spinal cord. Moreover, fentany-linduced-hyperalgesia and changes in the expression of the aforementioned proteins can be attenuated by TAK-242, an inhibitor of TLR4, as well as ketamine. Importantly, TLR4, p-p65, COX-2, and IL-1β were expressed in neurons but not in glial cells in the spinal cord 1 d after fentanyl injection. In conclusion, results suggested that a single dose of ketamine can relieve fentanyl-induced-hyperalgesia via the TLR4/NF-κB pathway in spinal cord neurons.

Abstract OT3-20-01: Ketamine Analgesia for Long Lasting Pain Relief after Surgery (KALPAS) Study

Abstract Background: Post-mastectomy pain syndrome (PMPS) affects up to 60% of women undergoing mastectomy. Standard perioperative multimodal analgesia remains only moderately effective in preventing PMPS, and many patients continue to rely on opioids for their chronic pain. In the context of the opioid overdose crisis, alternative interventions are urgently needed. Ketamine targets risks factors for PMPS including acute pain and negative mood, making it an ideal candidate for the prevention of PMPS. Trial Design: This is a multisite, three-arm, double-blind, RCT to test the effectiveness of ketamine in reducing PMPS in women undergoing mastectomy for oncologic indication. Arm 1 consists of continuous perioperative ketamine infusion that begins during surgery and continues for 2 hours in the post-anesthesia care unit (PACU). Arm 2 consists of a single-dose of ketamine in the PACU given over 50-60 minutes. Arm 3 consists of placebo. Standard surgical and postsurgical care remain unchanged across all arms. Eligibility Criteria: Inclusion criteria are: women ≥18 years of age undergoing total mastectomy for oncologic indication +/- lymph node dissection and +/- immediate or delayed reconstruction with no distant metastases. Exclusion criteria include: (1) history of cognitive impairment (2) past ketamine or phencyclidine misuse or abuse, (3) schizophrenia or history of psychosis, (4) history of post-traumatic stress disorder, (5) known sensitivity or allergy to ketamine, (6) liver or renal sufficiency, (7) uncontrolled hypertension, chest pain, cardiac arrhythmia, stroke, head trauma, intracranial mass or hemorrhage, glaucoma, porphyria, uncontrolled thyroid disease, or other contraindication to ketamine, (8) lamotrigine alfentanil, physostigmine, or 4-aminopyridine use, (9) currently pregnant, (10) body mass index greater than 35, (11) non-English or non-Spanish speaker, (12) currently participating in another pain interventional trial, (13) patient has started or undergone hormone therapy for gender transition into male, or (14) patient is scheduled for bilateral (or greater) flap reconstruction. Specific Aims: The primary outcome is pain intensity on the Brief Pain Inventory short form scale at the surgical site three months after mastectomy. Secondary outcomes include pain severity and interference at the surgical site, incidence of PMPS, anxiety, and depression over 12 months after surgery. Tertiary outcomes include neuropathic symptoms, fatigue, sleep, physical function, and opioid use. Statistical Methods: We will test the differences in the primary outcome between 1) the continuous ketamine infusion and the control; and 2) the single-dose ketamine and the control, each at 0.025 significance level (adjusted for multiple comparisons using the Bonferroni correction), based on the two-sample t-tests (allowing unequal variances) if outcome variables are approximately normal, or Wilcoxon’s rank-sum tests otherwise. Accrual: The target accrual for this study is ~750. Recruitment began January 2022. Recruitment is expected to be complete by October 2025. As of July 14, 2022, 43 participants have been enrolled across all sites. If interested in the KALPAS Study, please contact kalpas@nyulangone.org, jing.wang@nyulangone.org, or lisa.doan@nyulangone.org This research is supported by the National Institutes of Health through the NIH HEAL Initiative under UH3CA261067. It is also supported by the NCATS Trial Innovation Network under award numbers U24TR001608 (CCC), U24TR001597 (DCC), U24TR001609 (SSC), U24TR001579 (RIC) Citation Format: Lisa Doan, Raven Perez, Jeana Chun, Randy Cuevas, Pabel Miah, Amber Guth, Karen Hiotis, Freya Schnabel, Michele Curatolo, Robert Edwards, Hyung Park, John Rotrosen, Deborah Axelrod, Jing Wang. Ketamine Analgesia for Long Lasting Pain Relief after Surgery (KALPAS) Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-20-01.

Subanaesthetic single-dose ketamine as an adjunct to opioid analgesics for acute pain management in the emergency department: a systematic review and meta-analysis

ObjectiveTo evaluate the effectiveness of a subanaesthetic single-dose ketamine (SDK) as an adjunct to opioids for acute pain in emergency department (ED) settings.DesignSystematic review and meta-analysis.MethodsA systematic search was performed...

Comparison of the Effect of Intravenous Fentanyl with Low-Dose Ketamine on Pain Relief in Patients Taking Methadone and Suffering from Limb Fractures.

Given the significance of pain control in addicted patients and the prominence of not using opioids due to patient's drug dependence, the present study aimed at comparing and evaluating the effect of intravenous fentanyl with low-dose ketamine on pain relief in patients taking methadone and suffering from limb fractures. The present double-blind randomized clinical trial was performed on 100 patients taking methadone and suffering from limb fractures. The patients were divided into two groups receiving 1 μg/kg single dose of fentanyl and 0.3 mg/kg single dose of ketamine (low-dose ketamine). Patients' pain scores and the incidence rate of complications were recorded before the intervention, and 15, 30, and 60 min after drug administration and were then compared between the two groups. The mean pain score of patients 15 min after the intervention was significantly lower in the low-dose ketamine group with a mean of 2.50 ± 1.34 as compared with the fentanyl group with a mean of 7.10 ± 1.43 (P < 0.001). However, the mean pain score was not significantly different between the two groups 30 and 60 min after the intervention (P > 0.05). In addition, the incidence rate of complications was not significantly different between the two groups (P > 0.05). According to the results of this study, low-dose ketamine as compared with fentanyl relieves pain in the mentioned patients with a faster effect and in a shorter time although no difference can be found between the pain scores of the two groups 30 and 60 min after the intervention.

Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression.

Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression.

Ketamine triggers rapid antidepressant effects by modulating synaptic plasticity in a new depressive-like mouse model based on astrocyte glutamate transporter GLT-1 knockdown in infralimbic cortex

ObjectiveRecently, we reported on a new MDD-like mouse model based on a regionally selective knockdown of astroglial glutamate transporters, GLAST/GLT-1, in infralimbic cortex (IL) which evokes widespread changes in mouse brain associated with the typical alterations found in MDD patients. To further characterize this new MDD-like mouse model, here we examine some transcriptional elements of glutamatergic/GABAergic neurotransmission and neuroplasticity in forebrain regions in the GLT-1 knockdown mice. Furthermore, we assess the acute ketamine effects on these transcriptional processes. Material and methodsWe used a small interfering RNA (siRNA) pool targeting GLT-1 mRNA to disrupt the GLT-1 transcription in mouse IL. Histological assays were performed to examine postsynaptic density protein-95 (PSD95), neuritin (NRN), glutamine acid descarboxilase-65 (GAD65), and GLT-1 mRNA expression in IL and hippocampus. ResultsKnockdown of GLT-1 in mouse IL leads to decreased expression of PSD95 and NRN neuroplasticity mRNAs in IL and hippocampus, which was reversed by an acute dose of ketamine antidepressant. Likewise, a single dose of ketamine also increased the mRNA levels of GAD65 and GLT-1 in IL of GLT-1 knockdown mice, reaching the basal values of control mice. ConclusionsThe glutamatergic neuronal hyperactivity and deficits in the GABA system resulting from siRNA-induced astroglial glutamate transporter knockdown in IL can compromise the integrity/plasticity of neurocircuits affected in MDD. Suitable depressive-like animal models to address the neurobiological changes in MDD are an unmet need and the development of the GLAST/GLT-1 knockdown mouse model may represent a better option to understand the rapid-acting antidepressant effects of ketamine.

Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex

BackgroundA key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. MethodsWe used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. ResultsCartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non–monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. ConclusionsThese data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience.

The Effects of Ketamine on Cognition in Unipolar and Bipolar Depression: A Systematic Review.

Objective: To determine the objective neurocognitive effects of (1) single-dose ketamine, (2) repeated-dose ketamine, (3) ketamine adjunct to electroconvulsive therapy (ECT), and (4) ketamine as the anesthetic for ECT in major depressive disorder (MDD) and depression in bipolar disorder (BD).Data Sources: Cochrane, MEDLINE, Embase, and PsycINFO databases were searched on March 19, 2020 (updated July 2, 2020), using the terms terms major depressive disorderbipolar disorder and ketamine and their synonyms. Clinical trial registries (search date May 4, 2020) and reference sections of included articles were also searched. There was no restriction on language or year of publication.Study Selection: Of 4,035 identified articles, 17 met inclusion criteria. Controlled and open-label studies of adults who received at least 1 ketamine treatment for a current major depressive episode, as part of MDD or BD, were included. Only studies measuring cognition using at least 1 validated, objective neurocognitive assessment were eligible.Data Extraction: Results are presented using a narrative review format. Data regarding change in cognitive performance from baseline to end-of-treatment and/or differences in cognition between ketamine and control groups were extracted.Results: There were no negative effects of single- or repeated-dose intravenous ketamine up to 2 weeks post-treatment in MDD. Limited data were available for BD populations, as well as on other routes of ketamine administration.Conclusions: Data to definitively answer the question of whether ketamine has substantive or persistent cognitive effects are insufficient; thus, larger controlled trials measuring cognition as the primary outcome are needed. Future research should focus on different routes of ketamine administration, ketamine enantiomers, and BD populations.

A single dose of ketamine cannot prevent protracted stress-induced anhedonia and neuroinflammation in rats

Worldwide, millions of people suffer from treatment-resistant depression. Ketamine, a glutamatergic receptor antagonist, can have a rapid antidepressant effect even in treatment-resistant patients. A proposed mechanism for the antidepressant effect of ketamine is the reduction of neuroinflammation. To further explore this hypothesis, we investigated whether a single dose of ketamine can modulate protracted neuroinflammation in a repeated social defeat (RSD) stress rat model, which resembles features of depression. To this end, male animals exposed to RSD were injected with ketamine (20 mg/kg) or vehicle. A combination of behavioral analyses and PET scans of the inflammatory marker TSPO in the brain were performed. Rats submitted to RSD showed anhedonia-like behavior in the sucrose preference test, decreased weight gain, and increased TSPO levels in the insular and entorhinal cortices, as observed by [11C]-PK11195 PET. Whole brain TSPO levels correlated with corticosterone levels in several brain regions of RSD exposed animals, but not in controls. Ketamine injection 1 day after RSD disrupted the correlation between TSPO levels and serum corticosterone levels, but had no effect on depressive-like symptoms, weight gain or the protracted RSD-induced increase in TSPO expression in male rats. These results suggest that ketamine does not exert its effect on the hypothalamic–pituitary–adrenal axis by modulation of neuroinflammation.

The role of the excitation:inhibition functional balance in the mPFC in the onset of antidepressants

Currently available antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), generally require weeks to months to produce a therapeutic response, but the mechanism of action underlying the delayed onset of antidepressant-like action remains to be elucidated. The balance between excitatory glutamatergic pyramidal neurons and inhibitory γ-aminobutyric acid (GABA) interneurons, i.e., the excitation:inhibition functional (E:I) balance, in the medial prefrontal cortex (mPFC) is critical in regulating several behaviors and might play an important mediating role in the mechanism of rapid antidepressant-like action reported by several studies. In the present study, the multichannel electrophysiological technique was used to record the firing activities of pyramidal neurons and interneurons and investigate the effects of a single dose of fluoxetine and ketamine (both 10 mg/kg, i.p.) on the E:I functional balance in the rat mPFC after 90 min or 24 h, and the forced swimming test (FST) was used to evaluate the antidepressant-like effects of fluoxetine and ketamine. The present study also explored the effects of chronic treatment with fluoxetine (10 mg/kg, i.g.) for 7 d or 21 d on the E:I functional balance in the mPFC. The present results suggested that a single dose of ketamine could both significantly increase the firing activities of pyramidal neurons and significantly decrease the firing activities of interneurons in the mPFC and exerted significant antidepressant-like action on the FST after 90 min and 24 h, but fluoxetine had no such effects under the same conditions. However, chronic treatment with fluoxetine for 21 d (but not 7 d) could significantly affect the firing activities of pyramidal neurons and interneurons in the mPFC. Taken together, the present results indicated that rapid regulation of the E:I functional balance in the mPFC might be an important common mechanism of rapid-acting antidepressants and the delayed onset of SSRIs might be partly attributed to their inability to rapidly regulate the E:I functional balance in the mPFC. The present study provided a new entry point to the development of rapid-acting antidepressants.

Fluoxetine and Ketamine Reverse the Depressive but Not Anxiety Behavior Induced by Lesion of Cholinergic Neurons in the Horizontal Limb of the Diagonal Band of Broca in Male Rat.

The basal forebrain cholinergic system is involved in cognitive processes, but the role of the basal forebrain cholinergic system in depression is unknown. We investigated whether a lesion of cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) produces depressive-like behavior and whether fluoxetine or ketamine inhibits such depressive-like behaviors. Here, in rats, we used 192 IgG-saporin to eliminate the cholinergic neurons of the HDB and evaluated depressive-like behaviors using a preference test for sucrose solution and the forced swimming test. Fourteen days after the injection of 192 IgG-saporin into the HDB, the rats exhibited a significantly fewer number of choline acetyltransferase positive cell density in HDB, accompanied with neuronal loss in the entire hippocampus. Meanwhile, these rats significantly reduced preference for sucrose solution, increased immobility time in the forced swimming test, reduced locomotor activity, decreased context dependent memory in fear conditioning and the time spent in the open arms of the plus-maze. A single dose of ketamine (10 mg/kg) increased the sucrose solution consumption, reduced the immobility time in the forced swim test (FST), and increased locomotor activity compared to vehicle-treated rats. Moreover, in rats that were continuously treated with fluoxetine (10 mg/kg/day for 11 days), the sucrose solution consumption increased, the immobility time in the FST decreased, and locomotor activity increased compared to vehicle-treated rats. The present results demonstrate that a lesion of HDB cholinergic neurons results in depressive-like and anxiety-like behaviors and that antidepressants such as fluoxetine or ketamine, can reverse these depressive-like behaviors but not anxiety-like behaviors, and suggest that a lesion of HDB cholinergic neurons and followed hippocampus damage may be involved in the pathogenesis of depression.

Rapid and long-lasting antidepressant-like effects of ketamine and their relationship with the expression of brain enzymes, BDNF, and astrocytes.

Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug’s sustained antidepressant-like effects.

Contribution of DNA methyltransferases to spared nerve injury induced depression partially through epigenetically repressing Bdnf in hippocampus: Reversal by ketamine

Long-lasting pain can induce depression, which seriously affects life quality of the patients, but little is known about the underlying mechanism. Chronic neuropathic pain can modulate DNA methylation in target genes related to neuroplasticity and mood regulation, which was induced by DNA methyltransferases (DNMTs). Methylation changes of brain-derived neurotrophic factor (Bdnf) in the hippocampus are critical for neuropathic pain and depression. Thus, we hypothesized that DNMTs are required for depression genesis, probably by repressing hippocampus Bdnf gene expression in rats with neuropathic pain, which can be rescued by ketamine. In the present study, rats were randomly subjected to spared nerve injury (SNI) or sham surgery. SNI upregulated DNMTs and downregulated Bdnf and exon I in the hippocampus and induced depression behaviors, whereas blocking the upregulation of DNMTs with RG108 alleviated SNI-induced depression by up-regulation of the expression of Bdnf and exon I. In addition, we showed that a single dose of ketamine could ameliorate SNI-induced depression-like behaviors, which was related to normalization of DNMTs and Bdnf. In conclusion, our study suggested that DNMTs-induced decreased expression of Bdnf may induce the comorbid of pain and depression, which can be prevented by ketamine.

Sex Differences in the Sustained Effects of Ketamine on Resilience to Chronic Stress.

Exposure to stress is recognized to be a triggering factor in several mood disorders, including depression and anxiety. There is very little understanding of why female subjects have a significantly higher risk for these conditions than males. Recent findings in male rodents indicated that prophylactic ketamine can prevent the development of a stress-induced depressive-like phenotype, providing a pharmacological tool to study the mechanisms underlying stress resilience. Unfortunately, none of these studies incorporated female subjects, nor did they provide a mechanistic understanding of the effects of ketamine on stress resilience. Our previous work identified the prefrontal glutamatergic and parvalbumin (PV) systems as potential molecular mechanisms underlying sex differences in susceptibility to stress-induced emotional deregulations. To further address this point, we treated male and female mice with a single dose of ketamine before exposure to a chronic stress paradigm to determine whether stress-resilience induced by a pre-exposure to ketamine is similar in males and females and whether modulation of the prefrontal glutamatergic and PV systems by ketamine is associated with these behavioral effects. Ketamine prevented chronic stress-induced changes in behaviors in males, which was associated with a reduction in expression of PV and the NMDA receptor NR1 subunit. Ketamine did not protect females against the effects of chronic stress and did not change significantly prefrontal gene expression. Our data highlight fundamental sex differences in the sustained effects of ketamine. They also further implicate prefrontal glutamatergic transmission and PV in resilience to chronic stress.

Subanesthetic Ketamine Reactivates Adult Cortical Plasticity to Restore Vision from Amblyopia

Subanesthetic ketamine evokes rapid and long-lasting antidepressant effects in human patients. The mechanism for ketamine's effects remains elusive, but ketamine may broadly modulate brain plasticity processes. We show that single-dose ketamine reactivates adult mouse visual cortical plasticity and promotes functional recovery of visual acuity defects from amblyopia. Ketamine specifically induces downregulation of neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons in mouse visual cortex. NRG1 downregulation in PV neurons co-tracks both the fast onset and sustained decreases in synaptic inhibition to excitatory neurons, along with reduced synaptic excitation to PV neurons invitro and invivo following a single ketamine treatment. These effects are blocked by exogenous NRG1 as well as PV targeted receptor knockout. Thus, ketamine reactivation of adult visual cortical plasticity is mediated through rapid and sustained cortical disinhibition via downregulation of PV-specific NRG1 signaling. Our findings reveal the neural plasticity-based mechanism for ketamine-mediated functional recovery from adult amblyopia.

Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

BackgroundDue to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains.MethodsElectronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed.ResultsA total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = − 0.89; 95% CI − 1.24; − 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2–3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = − 0.70; 95% CI − 1.15; − 0.25 or SMD = − 0.81; 95% CI − 1.41; − 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo.ConclusionsOur meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.