Plasma inflammatory cytokines and treatment-resistant depression with comorbid pain: improvement by ketamine

Abstract Background Treatment-resistant depression (TRD) and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in TRD patients with comorbid pain. Our aims were to determine the difference in ketamine’s antidepressant effects in TRD patients with or without pain and then to examine whether inflammatory cytokines might contribute to ketamine’s effect. Methods Sixty-six patients with TRD received six infusions of ketamine. Plasma levels of 19 inflammatory cytokines were assessed at baseline and post-infusion (day 13 and day 26) using the Luminex assay. Plasma inflammatory cytokines of sixty healthy controls (HCs) were also examined. Results TRD patients with pain had a higher antidepressant response rate (χ2 = 4.062, P = 0.044) and remission rate (χ2 = 4.062, P = 0.044) than patients without pain. Before ketamine treatment, GM-CSF and IL-6 levels were higher in the pain group than in the non-pain and HC groups. In the pain group, levels of TNF-α and IL-6 at day 13 and GM-CSF, fractalkine, IFN-γ, IL-10, MIP-3α, IL-12P70, IL-17α, IL-1β, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, MIP-1β, and TNF-α at day 26 were lower than those at baseline; in the non-pain group, TNF-α levels at day 13 and day 26 were lower than those at baseline. In the pain group, the changes of IL-6 were associated with improvement in pain intensity (β = 0.333, P = 0.001) and depressive symptoms (β = 0.478, P = 0.005) at day 13. Path analysis showed the direct (β = 2.995, P = 0.028) and indirect (β = 0.867, P = 0.042) effects of changes of IL-6 on improvement in depressive symptoms both were statistically significant. Conclusion This study suggested that an elevated inflammatory response plays a critical role in individual differences in TRD patients with or without pain. Ketamine showed great antidepressant and analgesic effects in TRD patients with pain, which may be related to its effects on modulating inflammation. Trial registration ChiCTR, ChiCTR-OOC-17012239. Registered on 26 May 2017

Download Full-text

Plasma Inflammatory Cytokines and Depressed Patients With Comorbid Pain: Improvement by Ketamine

10.21203/rs.3.rs-595708/v1 ◽

2021 ◽

Author(s):

Yanling Zhou ◽

Chengyu Wang ◽

Xiaofeng Lan ◽

Hanqiu Li ◽

Ziyuan Chao ◽

...

Keyword(s):

Depressive Symptoms ◽

Individual Differences ◽

Inflammatory Cytokines ◽

Pain Group ◽

Gm Csf ◽

Luminex Assay ◽

Analgesic Effects ◽

Depressed Patients ◽

Antidepressant Effects ◽

The Difference

Abstract Background: Depression and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in depressed patients with comorbid pain. Our aims were to determine the difference in ketamine’s antidepressant effects in depressed patients with or without pain and then to examine whether inflammatory cytokines might contribute to ketamine’s effect. Methods: Seventy-eight patients with major depressive disorder received six infusions of ketamine. Plasma levels of 19 inflammatory cytokines were assessed at baseline and post-infusion (day 13 and day 26) using the Luminex assay. Plasma inflammatory cytokines of sixty healthy controls (HCs) were also examined. Results: At baseline, the levels of GM-CSF, IL-1β and IL-6 were higher in pain group than in non-pain and HC groups. Pain group had better antidepressant outcomes than non-pain group. Pain group showed a greater decrease in IL-6 at day 13 and a greater decrease in IL-10, MIP-3α, IL-1β, IL-5 and IL-6 at day 26 than non-pain group. In the pain group, the changes in IL-6 levels were associated with improvement in pain intensity (β=0.347, t=2.159, P=0.038) and depressive symptoms (β=0.590, t=4.201, P<0.001) at day 13. The Sobel test showed indirect effects between decreases in IL-6 levels and improvement in depressive symptoms (Z=2.026, P=0.043).Conclusion: This study suggested that an elevated inflammatory response plays a key role in individual differences in depressed patients with or without pain. Ketamine showed great antidepressant and analgesic effects in depressed patients with pain, which may be related to its anti-inflammatory effect.

Download Full-text

Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

Psychopharmacology ◽

10.1007/s00213-021-05762-6 ◽

2021 ◽

Author(s):

Joshua S. Siegel ◽

Ben J. A. Palanca ◽

Beau M. Ances ◽

Evan D. Kharasch ◽

Julie A. Schweiger ◽

...

Keyword(s):

Depressive Symptoms ◽

Limbic System ◽

Anterior Cingulate ◽

Sustained Remission ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Subgenual Anterior Cingulate Cortex ◽

Post Infusion ◽

Resistant Depression

AbstractKetamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.ClinicalTrials.gov: Treatment Resistant Depression (Pilot), NCT01179009.

Download Full-text

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

Psychological Medicine ◽

10.1017/s0033291718001356 ◽

2018 ◽

Vol 49 (4) ◽

pp. 655-663 ◽

Cited By ~ 92

Author(s):

Fernanda Palhano-Fontes ◽

Dayanna Barreto ◽

Heloisa Onias ◽

Katia C. Andrade ◽

Morgana M. Novaes ◽

...

Keyword(s):

Rating Scale ◽

Remission Rate ◽

Controlled Trial ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Double Blind ◽

Therapeutic Value ◽

Antidepressant Effects ◽

Resistant Depression

AbstractBackgroundRecent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.MethodsTo test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.ResultsWe observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p= 0.04), and at D7 (p< 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen'sd= 0.84; D2: Cohen'sd= 0.84; D7: Cohen'sd= 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64%v.27%;p= 0.04). Remission rate showed a trend toward significance at D7 (36%v.7%,p= 0.054).ConclusionsTo our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered athttp://clinicaltrials.gov(NCT02914769).

Download Full-text

Baseline Working Memory Predicted Response to Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression

Pharmacopsychiatry ◽

10.1055/a-1589-6301 ◽

2021 ◽

Author(s):

Mu-Hong Chen ◽

Wei-Chen Lin ◽

Cheng-Ta Li ◽

Shih-Jen Tsai ◽

Hui-Ju Wu ◽

...

Keyword(s):

Working Memory ◽

Depressive Symptoms ◽

Treatment Response ◽

Low Dose ◽

Memory Function ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Ketamine Infusion ◽

Treatment Groups ◽

Resistant Depression

Abstract Introduction Pretreatment neurocognitive function may predict the treatment response to low-dose ketamine infusion in patients with treatment-resistant depression (TRD). However, the association between working memory function at baseline and the antidepressant efficacy of ketamine infusion remains unclear. Methods A total of 71 patients with TRD were randomized to one of three treatment groups: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HDRS) at baseline and after treatment. Cognitive function was evaluated using working memory and go-no-go tasks at baseline. Results A generalized linear model with adjustments for demographic characteristics, treatment groups, and total HDRS scores at baseline revealed only a significant effect of working memory function (correct responses and omissions) on the changes in depressive symptoms measured by HDRS at baseline (F=12.862, p<0.05). Correlation analysis further showed a negative relationship (r=0.519, p=0.027) between pretreatment working memory function and changes in HDRS scores in the 0.5 mg/kg ketamine group. Discussion An inverse relationship between pretreatment working memory function and treatment response to ketamine infusion may confirm that low-dose ketamine infusion is beneficial and should be reserved for patients with TRD.

Download Full-text

Sevoflurane augmentation in treatment-resistant depression: a clinical case study

Therapeutic Advances in Psychopharmacology ◽

10.1177/2045125320957126 ◽

2020 ◽

Vol 10 ◽

pp. 204512532095712

Author(s):

Shikai Wang ◽

Shanfei Cheng ◽

Min Feng ◽

Ping Guo ◽

Mincai Qian ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Case ◽

Efficacy And Safety ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Clinical Case Study ◽

Antidepressant Effects ◽

Mucous Membranes ◽

Resistant Depression

Compared with other inhaled anaesthetics, sevoflurane has a faster onset and offset, causes less irritation to the mucous membranes, and has a better safety profile. These characteristics warrant investigating the effect of sevoflurane in depression. In this Case Report, we describe that sevoflurane treatment was feasible and well tolerated by a patient with treatment-resistant depression (TRD). Sevoflurane had rapid and durable antidepressant effects, with few adverse effects. Moreover, the patient showed significant improvements in neurocognitive measurements. Our preliminary results suggest that further clinical trials are needed to determine the independent efficacy and safety of sevoflurane in patients with TRD.

Download Full-text

118 Use of Patient Health Questionnaire to Predict Relapses in Patients with Treatment-resistant Depression Treated With Esketamine + Oral Antidepressant

CNS Spectrums ◽

10.1017/s109285292000036x ◽

2020 ◽

Vol 25 (2) ◽

pp. 276-277

Author(s):

Carol Jamieson ◽

Nan Li ◽

Ella Daly ◽

Adam Janik ◽

Rosanne Lane ◽

...

Keyword(s):

Depressive Symptoms ◽

Patient Health Questionnaire ◽

Controlled Study ◽

Health Questionnaire ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Relapse Risk ◽

Total Score Range ◽

Patient Health ◽

Resistant Depression

Abstract:Objective:To assess the Patient Health Questionnaire (PHQ-9) as a predictor of relapse of depressive symptoms in treatment-resistant depression (TRD).Method:Analysis included maintenance phase data from SUSTAIN-1 (NCT02493868), a randomized, double-blind, active-controlled study in TRD patients that evaluated efficacy of intranasal esketamine (ESK) + oral antidepressant (AD) vs AD + intranasal placebo in delaying relapse of depressive symptoms. A ≥50% reduction in initial symptom score and total score of ≤12 were considered as response and remission, respectively, using the Montgomery-Asberg Depression Rating Scale. PHQ-9 total score (range, 0–27), PHQ-2 total score (0–6), and individual items of the PHQ-9 (0–3) were examined as predictors of relapse. Data were collected every 2 weeks. Association between time-varying PHQ-9 and event of depression relapse was evaluated in Andersen-Gill Cox model.Results:Of 176 stable remitters, 63 had a relapse event (ESK+AD [n=24]; AD+placebo [n=39]). Of 121 stable responders, 50 had a relapse event (ESK+AD [n=16]; AD+placebo [n=34]). Among stable remitters, PHQ-9 total score (HR; 95% CI [1.12; 1.04–1.21]) and PHQ-2 total score (1.58; 1.25–1.99) were associated with relapse risk. PHQ-9 items #1 (loss of pleasure, 2.07; 1.38–3.09), #2 (feeling down, 2.18; 1.51–3.15), #4 (feeling tired, 1.54; 1.13–2.11), and #6 (negative self-view, 2.27; 1.41–3.66) were associated with relapse risk. PHQ-2 total scale yielded the smallest Akaike’s Information Criterion among stable remitters and responders.Conclusion:PHQ-9, PHQ-2 total scores or individual items may be useful for predicting relapse of depressive symptoms among stable TRD patients.Funding Acknowledgements:This study was sponsored by Janssen Research and Development, LLC.

Download Full-text

S160. Antidepressant Effects of Single and Repeated Ketamine Infusions in Treatment-Resistant Depression

Biological Psychiatry ◽

10.1016/j.biopsych.2018.02.1052 ◽

2018 ◽

Vol 83 (9) ◽

pp. S410 ◽

Cited By ~ 1

Author(s):

Jennifer Phillips ◽

Sandhaya Norris ◽

Jeanne Talbot ◽

Abigail Ortiz ◽

Meagan Birmingham ◽

...

Keyword(s):

Treatment Resistant Depression ◽

Treatment Resistant ◽

Antidepressant Effects ◽

Resistant Depression

Download Full-text

Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: An open trial

European Psychiatry ◽

10.1016/j.eurpsy.2014.08.007 ◽

2015 ◽

Vol 30 (1) ◽

pp. 65-68 ◽

Cited By ~ 29

Author(s):

G. Scantamburlo ◽

M. Hansenne ◽

V. Geenen ◽

J.J. Legros ◽

M. Ansseau

Keyword(s):

Depressive Symptoms ◽

Rating Scale ◽

Open Trial ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Hamilton Depression Rating Scale ◽

Resistant Depression ◽

Synthetic Oxytocin

AbstractThe aim of this open trial was to assess the antidepressant/anxiolytic effects of oxytocin used as an adjunct to antidepressant in treatment-resistant depression. Fourteen patients, who have not responded to 40 mg of escitalopram, received intranasal synthetic oxytocin during 4 weeks, in association with antidepressant. This is the first open trial study suggesting OT in association with escitalopram significantly reduced scores on Hamilton Depression Rating Scale.

Download Full-text

Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects

Psychological Medicine ◽

10.1017/s0033291714002244 ◽

2014 ◽

Vol 45 (5) ◽

pp. 1073-1092 ◽

Cited By ~ 42

Author(s):

S. Kayser ◽

B. H. Bewernick ◽

A. Matusch ◽

R. Hurlemann ◽

M. Soehle ◽

...

Keyword(s):

Quality Of Life ◽

Depressive Symptoms ◽

Fdg Pet ◽

Metabolic Effects ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Magnetic Seizure Therapy ◽

Resistant Depression ◽

Pet Scans

Background.Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism.Method.Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed.Results.A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum.Conclusions.Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

Download Full-text