Ketamine Treatment Research Articles

Ketamine specifically reduces cognitive symptoms in depressed patients: An investigation of associated neural activation patterns

Major depressive disorder (MDD) is characterized by heterogeneous cognitive, affective and somatic symptoms. Hence, the investigation of differential treatment effects on these symptoms as well as the identification of symptom specific biomarkers might crucially contribute to the development of individualized treatment strategies.We here aimed to examine symptom specific responses to treatment with ketamine, which repeatedly demonstrated rapid antidepressant effects in severe MDD. Additionally, we investigated working memory (WM) related brain activity associated with changes in distinct symptoms in order to identify specific response predictors. In a sample of 47 MDD patients receiving a single sub-anesthetic dose of ketamine, we applied a three-factor solution of the Beck Depression Inventory (BDI) to detect symptom specific changes 24 h post-infusion. A subsample of 16 patients underwent additional fMRI scanning during an emotional working memory task prior to ketamine treatment. Since functional aberrations in the default mode network (DMN) as well as in the dorsolateral prefrontal cortex (DLPFC) have been associated with impaired cognitive and emotional processing in MDD, we investigated neural activity in these regions.Our results showed that ketamine differentially affects MDD symptoms, with the largest symptom reduction in the cognitive domain. WM related neuroimaging results indicated that a more pronounced effect of ketamine on cognitive symptoms is predicted by lower DMN deactivation and higher DLPFC activation. Findings thereby not only indicate that ketamine's antidepressant efficacy is driven by a pro-cognitive mechanism, but also suggest that this might be mediated by increased potential for adaptive adjustment in the circumscribed brain regions.

Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study

Recently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22–72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.

Efficacy of ketamine in relieving neuropathic pain: a systematic review and meta-analysis of animal studies.

In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.

Investigation of urinary components in rat model of ketamine-induced bladder fibrosis based on metabolomics

BackgroundKetamine abuse has been linked to the system's damage, presenting with lower urinary tract symptoms (LUTS). While the pathogenesis of ketamine-induced urinary damage is not fully understood, fibrosis is believed to be a potential mechanism. A metabolomic investigation of the urinary metabolites in ketamine abuse was conducted to gain insights into its pathogenesis.MethodsA rat model of ketamine induced bladder fibrosis was established through tail vein injection of ketamine hydrochloride and control group was established through tail vein injection of the equivalent normal saline. Hematoxylin and eosin (H&E) staining and Masson trichrome staining were performed to evaluated bladder pathology. Urinary components were detected based on a metabolomic approach using ultra-high performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOFMS platform). Orthogonal projections analyzed the data to latent structures discriminant analysis (OPLS-DA) and bioinformatics analysis.ResultsThe rat model of ketamine induced bladder fibrosis was confirmed through H&E and Masson trichrome staining. There were marked differences in the urinary metabolites between the experimental group and the control group. Compared to the control group, 16 kinds of differential metabolites were up-regulated and 102 differential metabolites were down-regulated in the urine samples of the ketamine group. Bioinformatics analysis revealed the related metabolic pathways.ConclusionsUsing a ketamine-induced bladder fibrosis rat model, this study identified the differential urinary metabolites expressed following ketamine treatment. These results provide vital clues for exploring the pathogenesis of ketamine-induced LUTS and may further contribute to the disease's diagnosis and treatment.

Kinetic Model Distinguishes Subanesthetic Doses of Ketamine Block on Single Channel N-Methyl-D-Aspartate Receptors from Effects of Protons

Ketamine, one of the most commonly used anesthetics world-wide, is also FDA-approved to treat major depressive disorder, when infused at sub anesthetic doses (0.3 to 0.5 mg/kg IV bolus). In these conditions, plasma levels of ketamine peak at 0.85 µM, and decay to 0.2 µM, within 230 minutes. In vitro, ketamine blocks NMDA receptor (NMDAR) currents, which are major contributors to excitatory post synaptic currents in the central nervous system, with a reported range of IC50, 0.7 - 50 µM. Moreover, this effect varies with pH due to both reduced activity of protonated NMDAR (IC50, 7.2), and increased inhibitory potency of protonated ketamine (pKa, 7.5). To ascertain the mechanisms by which low-dose ketamine treatment affects NMDAR signaling in physiologically relevant conditions, we examined in HEK293 cells macroscopic and single-molecule GluN1a/GluN2A currents, in the presence of several concentrations of ketamine, at several pH values. We found that when applied to steady-state whole-cell currents, ketamine inhibition varied strongly (IC50, 0.8 - 2.2 µM) with pH in physiologic ranges (pH, 6.8 - 7.6), being most potent at pH 7.2 (IC50, 0.5 µM). When applied onto individual channels at this pH (0.05 - 1 µM), we found that 0.1 µM ketamine halved the open probability (Po) of NMDARs. As reported previously, ketamine had negligible effects on mean open times, such that the decrease in Po was solely due to an increase in closed times. These data allowed detailed kinetic modeling of NMDAR activity in the presence of ketamine, to estimate channel gating rates. Upon further validation, these models will help to anticipate the effects of ketamine on synaptic NMDAR currents, a necessary step in ascertaining the mechanism by which ketamine exerts its antidepressant effects in patients.

Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment.

Intravenous (IV) ketamine has been shown to have rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD). Urological toxicity has been observed in chronic ketamine abusers as evidenced by dysuria, urgency, and hematuria. The foregoing observation provides the basis for evaluating whether ketamine-induced urological toxicity (KIUT) is associated with sub-anesthetic doses of ketamine (0.5-1.0 mg/kg) in adults with mood disorders. The overarching objective of this article is to identify potential mechanisms of KIUT which appears to be dose and frequency dependent. Available research indicates that high-frequency ketamine is associated with disruption of the urothelial barrier as well as direct ketamine toxicity (i.e., decreased expression of junction proteins) in KIUT of the bladder. Chronic and high-frequency ketamine use is also associated with bladder inflammation mediated via neurogenic and IgE inflammation. Other non-mutually exclusive causes are nerve hyperplasia, hypersensitivity, cell apoptosis, microvascular damage, and overexpression of carcinogenic genes. Notwithstanding the evidence of KIUT in ketamine abusers, there is no evidence that ketamine and/or esketamine treatment in adults with mood disorders is associated with KIUT. However, all patients receiving ketamine/esketamine for mood disorder treatment should be queried about genitourinary symptoms during acute and, where applicable, maintenance dosing.

A qualitative study of patients' experience of ketamine treatment for depression: The ‘Ketamine and me’ project

• Ketamine infusion causes an initial ‘high’, enhanced perception, and dissociation. • People may have a reduction in or removal of suicidal ideation & depression symptoms. • People can experience an increase in motivation, socialisation, and activity. • The treatment environment affects ketamine experience. • People who have experience of ketamine for depression advocate the treatment. There has been a lack of in-depth interviews investigating patient experience of ketamine treatment for depression. We examined participants’ pathways to receiving ketamine infusion to treat their depression, and their responses to, lived experiences of, and attitudes towards ketamine treatment. Qualitative methods were used to conduct in-depth interviews with 13 patients (6 male; 7 female) diagnosed with treatment resistant depression (TRD) with experience of receiving ketamine treatment for depression. Interpretative phenomenological analysis (IPA) was employed. For the majority of participants ketamine infusion causes a reported initial ‘high’, enhanced perception, and dissociative experience; followed by a lifting of mood and a reduction in or removal of suicidal ideation and depression symptoms lasting around 3–6 days. This leads to a reported increase in motivation, socialisation, and activity. All participants valued the therapeutic alliance with clinicians which enhanced the treatment experience and all advocated treatment access for those with depression who have not responded to other treatments. Small numbers, purposive sample, participant self-selection, and single site recruitment limit generalisability. Ketamine for depression can have many beneficial effects, and it is potentially life-transforming for some. Ketamine may be a source of hope for patients for whom other treatments have not been effective. For some, ketamine is not tolerated or does not have anti-depressive effects. Further qualitative in-depth exploration of patient experience and consideration of how ketamine depression treatment access can be appropriately made available are warranted.

Chronic lithium exposure attenuates ketamine-induced mania-like behavior and c-Fos expression in the forebrain of mice

Ketamine, a dissociative anaesthetic, has been used in the treatment of major depressive disorder (MDD) as a rapid acting antidepressant drug. Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in MDD patients. Lithium is a well-known mood stabilizer and has been widely used for the treatment of mania. It is not fully understood which forebrain regions are involved in ketamine- and lithium-induced expression of c-Fos. Therefore, our aim was to investigate the effect of chronic lithium treatment on mania-like behavior and c-Fos expression in the mouse forebrain activated by a single administration of ketamine. In the open field test, our results showed that ketamine significantly increased the total distance and total cumulative duration of movement in mice, while chronic lithium could attenuate these effects of ketamine. In addition, acute ketamine induced higher c-Fos expression in the lateral septal nucleus, hypothalamus, amygdala, and hippocampus of mice in the treatment group compared to those in the control group. However, chronic lithium inhibited the significant increase in c-Fos-immunoreactive neurons following acute ketamine administration in the dentate gyrus of the hippocampus, field CA1 of the hippocampus, dorsal subiculum, ventral subiculum, ventral subiculum, central amygdaloid nucleus and basolateral amygdaloid nucleus. In summary, our research shows that pretreatment with lithium moderates the effects of acute ketamine administration on mania-like behavior and c-Fos expression in the forebrain. These findings could be helpful in better understanding the episodes of mania related to ketamine treatment for MDD and bipolar disorder.

Ketamine Rapidly Enhances Glutamate-Evoked Dendritic Spinogenesis in Medial Prefrontal Cortex Through Dopaminergic Mechanisms

BackgroundKetamine elicits rapid onset antidepressant effects in patients with clinical depression through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity. MethodsHere, we used two-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex, directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combined pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes. ResultsWe found that ketamine rapidly enhances glutamate-evoked spinogenesis in the medial prefrontal cortex, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through dopamine Drd1 receptor (Drd1) activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic protein kinase A activity. Furthermore, ketamine’s behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals or postsynaptic Gαs-coupled cascades in the medial prefrontal cortex. ConclusionsOur findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.

Ketamine treatment for depression: qualitative study exploring patient views.

Ketamine is a new and promising treatment for depression but comes with challenges to implement because of its potential for abuse. We sought the views of patients to inform policy and practical decisions about the clinical use of ketamine before large-scale roll-out is considered. This qualitative study used three focus groups and three validation sessions from 14 patients with prior diagnoses of depression but no experience of ketamine treatment. Focus groups explored their views about clinical use of ketamine and the best way for ketamine to be administered and monitored. The qualitative data were analysed by three service-user researchers using thematic analysis. Five themes were generated: changing public perceptions, risks, monitoring, privacy and data protection, and practical aspects. Participants were conscious of the stigma attached to ketamine as a street drug and wanted better public education, and evidence on the safety of ketamine after long-term use. They felt that monitoring was required to provide evidence for ketamine's safe use and administration, but there were concerns about the misuse of this information. Practical aspects included discussions about treatment duration, administration and accessibility (for example who would receive it, under what criteria and how). Patients are enthusiastic about ketamine treatment but need more information before national roll-out. The wider societal impact of ketamine treatment also needs to be considered and patients need to be part of any future roll-out to ensure its success.

Association of plasma VEGF levels and the antidepressant effects of ketamine in patients with depression.

Aims:Growing evidence suggests that vascular endothelial growth factor (VEGF) may be involved in the neuronal mechanisms underlying both depression aetiology and the response to ketamine treatments. The aim of this study was to examine whether changes in plasma VEGF levels are associated with the antidepressant effects of repeated ketamine infusions in patients with depression.Methods:Ninety-six patients with depression were enrolled and received six ketamine infusions during a 12-day period. Depressive symptom severity and plasma VEGF levels were measured by the Montgomery–Åsberg Depression Rating Scale (MADRS) and an enzyme-linked immunosorbent assay (ELISA) respectively, at baseline, 13 days and 26 days.Results:Despite a significant improvement in MADRS scores after patients received six ketamine infusions (p < 0.001), no changes in plasma VEGF levels were observed at 13 days when compared with baseline. Moreover, no significant difference in plasma VEGF levels at baseline and 13 days was found between ketamine responders and nonresponders. No association was found between the antidepressant effects of repeated ketamine treatments and plasma VEGF levels.Conclusion:This study indicated that VEGF may not be a potential predictor of antidepressant response to repeated intravenous administration of ketamine in patients with depression.

Effects of Intranasal (S)-Ketamine on Veterans With Co-Morbid Treatment-Resistant Depression and PTSD

Objective: Ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal (S)-ketamine for treating patients with comorbid depression and PTSD. Methods: We retrospectively analyzed clinical outcomes in 35 patients with both depression and PTSD referred for (S)-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 to March 2021. Outcomes were calculated across the first 8 treatments (4 weeks, induction phase) using a repeated measures ANOVA to measure change in symptoms over treatments. In a smaller sub-group (n=19) we analyzed whether (S)-ketamine continued to show effects during the maintenance period (after 4 weeks. Sub-group analyses based on antidepressant response and general linear models were also performed to identify predictors of treatment response. Results: During the induction phase of treatment there was an absolute reduction of 4.6 +/- 0.9 on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.6 +/- 0.8 at treatment 1 to 14.9 +/- 0.9 at treatment 8 (week 4) (F(7,238)=6, p 50%) at treatment 8. There was an absolute reduction of 12.1 +/- 2.5 on the patient checklist 5 (PCL5) rating scale for PTSD, from 54.4 +/- 2 at treatment 1 down to 42.3 +/- 2.5 at treatment 8 (F(7,238)=10.8, p 30%) for PTSD at this time-point. After transitioning to maintenance treatments, depression and PTSD symptoms remained stable or improved. Conclusions: Our results show that (S)-ketamine can improve both depression and PTSD symptoms in Veterans with dual-diagnoses. The effects of (S)-ketamine on PTSD were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work warrants further research in studying intranasal (S)-ketamine for PTSD. Funding Information: This work was supported by awards from the Department of Veterans Affairs, Veterans Health Administration (Career Development Award: 7IK2BX003308 to D.S.R.), and funding from the Center of Excellence for Stress and Mental Health (CESAMH) at the San Diego VA Medical Center, as well as from the National Institute of Mental Health (K23 MH119375-01 to E.E.L.) Declaration of Interests: None of the authors have any competing interests to declare, financial or otherwise. Ethics Approval Statement: This study was approved as an IRB-exemption by the VA San Diego Medical Center IRB committee.

Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders.

Background:Anxiety disorders are common, associated with significant burden of disease, and have high levels of treatment resistance. Low-dose ketamine has been extensively studied in treatment-resistant depression, with fewer reports in treatment-resistant anxiety disorders.Aims:This systematic review and meta-analysis collected efficacy, safety, and tolerability data for ketamine as a treatment for anxiety spectrum disorders.Methods:We conducted a systematic search for randomized controlled trials (RCTs) of acute ketamine treatment for patients with anxiety disorders. Open-label trials of ketamine maintenance therapy were also considered. Qualitative and, where possible, quantitative syntheses of findings were performed using Review Manager software (RevMan). Acute dose-response and maintenance treatment data were also collected.Results:There were six eligible acute RCTs – two in social anxiety disorder (SAD), three in post-traumatic stress disorder (PTSD), and one in obsessive-compulsive disorder (OCD). Four of the six showed significant improvement in anxiety rating scores in ketamine compared with control groups. Pooled analysis showed ketamine was associated with an increased likelihood of treatment response for SAD (odds ratio (OR): 28.94; 95% confidence interval [CI]: 3.45–242.57; p = 0.002) but not for PTSD (OR: 2.03; 95% CI: 0.67–6.15; p = 0.21). A dose-response profile was observed for ketamine and changes in SAD symptoms, with doses ⩾0.5 mg/kg associated with greater reduction in anxiety rating scores than lower doses. Ketamine maintenance therapy was associated with sustained anxiolytic effects and improved social and/or work functioning.Conclusion:These preliminary analyses suggest that acute ketamine may be broadly effective across treatment-resistant anxiety spectrum disorders. These effects can be prolonged with maintenance treatment. Future studies will be needed to provide critical knowledge gaps around off-label use, side effects, and potential risks for abuse in clinical settings.

PROMs (Patient Reported Outcome Measures) after surgery for patients with chronic pain

In line with the new definition of chronic pain [1] outcome measures of pain treatment have shifted from unidimensional scales (NRS, VRS) to multidimensional patient reported outcome measures. The Patient Reported Outcome Measurement Information System (PROMIS) rates across seven domains (pain interference, physical functioning, anxiety, depression, fatigue, sleep disturbance, and the ability to participate in social roles and activities) with four questions in each domain. PROMIS have been shown to be adequate and cross-walks may replace disease specific legacy PROMS [2, 3]. In Europe, data for the general population are available online [4]. Opioids are an integral part of many chronic pain patients but are not associated with improvement of PROMIS PI (pain interference) and PF (physical function) scores [5]. A consensus group advocated against Buprenorphin tapering before surgery [6] but opioid weaning improves PROMIS profiles for patients undergoing spine surgery [7] and liver transplants [8]. Methadone may be more effective than conventional perioperative short acting opioids [9, 10] and may also prevent against chronic pain after surgery [11]. Perioperative low dose Ketamine treatment has been advocated for chronic pain patients [12, 13]. A combination of Methadone and Ketamine showed impressive results in spinal surgery patients [14]. Gabapentinoid treatment should be continued but not initiated for surgery [15, 16]. i.v Lidocaine currently has no clear beneficial impact [17]. Regional anesthesia is generally advocated as its opioid sparing effects are well documented. Whether it provides protection against chronic pain after surgery is less clear [18, 19].

Central nervous system-related safety and tolerability of add-on ketamine to antidepressant medication in treatment-resistant depression: focus on the unique safety profile of bipolar depression.

Background:There is evidence supporting the use of ketamine in treatment-resistant depression (TRD). However, there are some safety and tolerability concerns associated with ketamine. This study aimed to investigate ketamine’s safety and tolerability to the central nervous system and to assess the relationship between dissociative symptomology and psychometric outcomes during and after intravenous ketamine treatment concurrent with treatment by varying psychotropic medications in treatment-refractory inpatients with major depressive disorder (MDD) and bipolar disorder (BP).Methods:A total of 49 patients with MDD and BP were included in this study. The subjects were administered ketamine and were assessed for changes using an observational protocol.Results:No antidepressants were associated with psychomimetic symptomatology except for citalopram (p = 0.019). Patients treated with citalopram showed a higher intensity of psychomimetic symptomatology. The use of classic mood-stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the Brief Psychiatric Rating Scale (BPRS; lamotrigine p = 0.009, valproate p = 0.048, lithium p = 0.012). No sequelae were observed.Conclusions:Despite the limitations that this study may be underpowered due to the small sample size, the sample consisted of a heterogeneous TRD population in a single site, and there no blinding of who underwent only acute ketamine administration, our observations indicate ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients.ClinicalTrials.gov identifier: NCT04226963

A Prospective Study of Inpatient Ketamine Subanaesthetic Dose Infusion in Chronic Refractory Pain

Background: Inpatient subanaesthetic ketamine infusion for 5 days may improve pain and reduce oral opioid usage in patients with chronic pain. Objective: This study aims to investigate pain and psychological outcomes of ketamine parenteral infusion (0.1 - 0.35 mg/kg/h or maximum 24 mg/hour) for 5 days in patients with chronic refractory pain. The secondary objective is to explore any prognostic pain and psychological factors associated with the successful response to the ketamine treatment. Methodology: A prospective longitudinal study of a small cohort (N = 35) of patients with heterogenous chronic refractory pain conditions was conducted from one week to two months follow-up. Results: Pain Severity was significantly improved from mean 6.5 to 5.1 (t = 3.77, p &#87223.37, p = 0.002, d = &#87220.6) at 1-week and 23 (t =&#87222.60, p = 0.016, d =&#87220.5) at 2-month; Pain Catastrophizing (PCS) from 28 to 23 (t = 3.4, p = 0.002; d = 0.6) at 1-week and 21 (t = 2.45, p = 0.022, d = 0.5) at 2-month; Depression from mean 21 to 16 (t = 2.16, p = 0.038, d = 0.4) at 1-week and 16 (t = 3.53, p = 0.002, d = 0.7) at 2-month; and oral Morphine Equivalent Daily Dose (oMEDD) reduced from mean 191 mg/day on admission to 122 mg/day at 1-week (t = 2.38, p = 0.023; d = 0.4) and 93 mg/day at 2-month (t = 2.59, p = 0.016; d = 0.5). There was no significant difference between responders and non-responders on baseline psychological measures (t33 0.244) and pain classifications ( = 0.610, p = 0.894). Conclusion: Ketamine subanaesthetic dose infusion for 5 days was found to be effective in managing chronic refractory pain with significant opioid reduction and small improvements in all chronic pain outcomes, except anxiety, at 1-week and 2-month follow-up and with minimal severe adverse effects.

Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression.

Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery–Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.

Ketamine treatment for individuals with treatment-resistant depression: longitudinal qualitative interview study of patient experiences.

Ketamine has recently received considerable attention regarding its antidepressant and anti-suicidal effects. Trials have generally focused on short-term effects of single intravenous infusions. Research on patient experiences is lacking. To investigate the experiences over time of individuals receiving ketamine treatment in a routine clinic, including impacts on mood and suicidality. Twelve fee-paying patients with treatment-resistant depression (6 females, 6 males, age 21-70 years; 11 reporting suicidality and 6 reporting self-harm) who were assessed as eligible for ketamine treatment participated in up to three semi-structured interviews: before treatment started, a few weeks into treatment and ≥2 months later. Data were analysed thematically. Most participants hoped that ketamine would provide respite from their depression. Nearly all experienced improvement in mood following initial treatments, ranging from negligible to dramatic, and eight reported a reduction in suicidality. Improvements were transitory for most participants, although two experienced sustained consistent benefit and two had sustained but limited improvement. Some participants described hopelessness when treatment stopped working, paralleled by increased suicidal ideation for three participants. The transient nature and cost of treatment were problematic. Eleven participants experienced side-effects, which were significant for two participants. Suggestions for improving treatment included closer monitoring and adjunctive psychological therapy. Ketamine treatment was generally experienced as effective in improving mood and reducing suicidal ideation in the short term, but the lack of longer-term benefit was challenging for participants, as was treatment cost. Informed consent procedures should refer to the possibilities of relapse and associated increased hopelessness and suicidality.

MiRNA-429 alleviates ketamine-induced neurotoxicity through targeting BAG5.

Ketamine is a kind of anesthetic broadly applied in clinic. However, growing evidence has indicated that ketamine may induce neurotoxicity. Previous studies showed that mircoRNAs (miRNAs) participate in various aspects of biological regulations. In our work, we aimed to reveal the role of miR-429 in ketamine-induced neurotoxicity. The qRT-PCR was used to measure the miR-429 levels in ketamine-treated PC12 cells. TUNEL staining and caspase 3 activity detection assays were performed to assess cell apoptosis. A Cellular Reactive Oxygen Species Detection Assay Kit was utilized to detect ROS activity. A luciferase reporter assay was conducted in HEK-293T cells to test the binding between miR-429 and BAG5. Herein, we found that ketamine could induce the apoptosis and ROS activity in PC12 cells. The qRT-PCR results showed that miR-429 expression was downregulated by treatment of ketamine in a dose-dependent manner. Overexpression of miR-429 alleviated ketamine-induced neurotoxicity in PC12 cells. Mechanically, BAG5 was identified to be a target of miR-429 and negatively regulated by miR-429. Moreover, BAG5 expression was upregulated after ketamine treatment. Rescue assays revealed that overexpression of BAG5 reversed the suppressive effects of miR-429 upregulation on ketamine-induced neurotoxicity in PC12 cells. In summary, miR-429 attenuates ketamine-induced neurotoxicity in PC12 cells by the downregulation of BAG5.

Modulation of the functional connectome in major depressive disorder by ketamine therapy.

Subanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized. Data-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status. Significant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern. Results support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.