Real-world effectiveness of repeated intravenous ketamine infusions for treatment-resistant depression in transitional age youth.

BACKGROUND: Ketamine is an emerging treatment for treatment-resistant depression (TRD) associated with rapid and robust improvements in depressive symptoms and suicidality. However, the efficacy and safety of ketamine in transitional age youth (TAY; age 18-25) populations remains understudied. METHODS: In this retrospective analysis, TAY patients (n = 52) receiving ketamine for TRD were matched for sex, primary diagnosis, baseline depression severity, and treatment resistance with a general adult (GA) sample (age 30-60). Patients received four ketamine infusions over 2 weeks (0.5-0.75 mg/kg over 40 min). The primary outcome was the change in Quick Inventory of Depressive Symptomatology Self-Report 16-item (QIDS-SR16) over time. Secondary outcomes were changes in QIDS-SR16 suicidal ideation (SI) item, anxiety (Generalized Anxiety Disorder 7-item (GAD-7)), and adverse effects (ClinicalTrials.gov: NCT04209296). RESULTS: A significant main effect of infusions on reduction of total QIDS-SR16 (p < 0.001), QIDS-SR16 SI (p < 0.001), and GAD-7 (p < 0.001) scores was observed in the TAY group with moderate effect sizes, indicative of clinically significant improvements in depression, anxiety, and suicidality. There were no significant differences between TAY and GA groups on these measures over time, suggesting comparable improvements in both groups. Safety and tolerability outcomes were comparable between groups with only mild, transient adverse effects observed. CONCLUSION: Ketamine was associated with comparable clinical benefits, safety, and tolerability in a TAY sample as compared to a matched GA TRD sample.

Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder.

Borderline personality disorder (BPD) has high rates of comorbidity with mood disorders, including treatment-resistant depression (TRD). Comorbidity of BPD with depression is associated with poorer response to antidepressants. Intravenous ketamine is a novel treatment for TRD that has not been specifically evaluated in patients with comorbid BPD. In this retrospective analysis of data collected from participants who received care at the Canadian Rapid Treatment Centre of Excellence (CRTCE; Braxia Health; ClinicalTrials.gov: NCT04209296), we evaluated the effectiveness of intravenous ketamine in a TRD population with comorbid BPD (N=100; n=50 BPD-positive compared with n=50 BPD-negative). Participants were administered four doses of intravenous ketamine (0.5-0.75mg/kg over 40 minutes) over two weeks. The primary outcome measures were changes in depressive symptom severity (as measured by Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS-SR16)) and borderline symptom severity (as measured by Borderline Symptom List 23-item (BSL-23)). Both BPD-positive and BPD-negative groups improved significantly on the QIDS-SR16, QIDS-SR16 suicide ideation item, anxiety, and functionality scales with large effect sizes. There was no significant difference between groups. The BPD-positive group exhibited significant reduction of 0.64 on BSL-23 scores and a significant reduction of 5.95 on QIDS-SR16 scores. Patients with TRD and comorbid BPD receiving ketamine exhibited a significant reduction in symptoms of depression, borderline personality, suicidality, and anxiety.

Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression.

BACKGROUND: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. METHODS: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5-0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures. RESULTS: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16 ) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/-1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16 -Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. CONCLUSIONS: Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.

Real-World Effectiveness of Repeated Ketamine Infusions for Treatment-Resistant Bipolar Depression.

Background: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. Methods: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5-0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures. Results: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/-1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16-Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. Conclusions: Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.Reprinted from Bipolar Disord 2023; 25:99-109, with permission from John Wiley and Sons. Copyright © 2023.

Prevention and Management of Common Adverse Effects of Ketamine and Esketamine in Patients with Mood Disorders.

The emerging roles of ketamine and esketamine as effective rapid-acting antidepressants hold promise for patients suffering from treatment-resistant depression and/or major depressive disorder with suicidality. Practitioner familiarity with common tolerability/safety concerns along with pragmatic prevention and management strategies are needed to reduce patient burden and improve the acceptability and accessibility of these treatments. The most common treatment-emergent adverse events associated with ketamine/esketamine are dissociation, anxiety, nausea, increased blood pressure, and headache. The majority of side effects are mild, transient, dose dependent, and attenuate with subsequent treatments. Patient selection, baseline physical and psychiatric assessments, and an appropriate setting are critical first steps in the prevention and mitigation of adverse events. Patient education and supportive interventions play central roles in the prevention and management of select adverse events. Severe and/or clinically significant adverse effects may necessitate the judicious use of adjunctive medications. Moreover, practitioners must remain vigilant to the potential for abuse liability and long-term adverse events, for which there are insufficient data. This article succinctly reviews common treatment-emergent adverse events of ketamine and esketamine within the context of mood disorders, and provides practical suggestions for prevention and management at point-of-care.

Real-world effectiveness of repeated ketamine infusions for treatment resistant depression during the COVID-19 pandemic.

Herein we evaluate the impact of COVID-19 restrictions on antidepressant effectiveness of intravenous (IV) ketamine in adults with treatment-resistant depression (TRD). We conducted a case series analysis of adults with TRD (n = 267) who received four ketamine infusions at an outpatient clinic in Ontario, Canada, during COVID-19 restrictions (from March 2020 - February 2021; n = 107), compared to patients who received treatment in the previous year (March 2019 - February 2020; n = 160). Both groups experienced significant and comparable improvements in depressive symptoms, suicidal ideation, and anxiety with repeated ketamine infusions. Effectiveness of IV ketamine was not attenuated during the COVID-19 period.

The effectiveness of repeated intravenous ketamine on depressive symptoms, suicidal ideation and functional disability in adults with major depressive disorder and bipolar disorder: Results from the Canadian Rapid Treatment Center of Excellence.

BACKGROUND: The effectiveness, tolerability, and safety of intravenous (IV) ketamine in adults with treatment resistant depression (TRD) receiving care in real-word settings is insufficiently characterized. Herein, results from a naturalistic, retrospective study are presented from a Canadian outpatient IV ketamine clinic. METHODS: Adults (N = 213; Mage = 45) with Major Depressive Disorder or Bipolar Disorder, with a minimum of Stage 2 antidepressant resistance, received IV ketamine at a community-based multi-disciplinary clinic. The primary outcome measure was change from baseline to post-infusion 4 on the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16; n = 190). Secondary measures included QIDS-SR16-measured response and remission rates, changes from baseline to endpoint in Generalized Anxiety Disorder-7 Scale (GAD-7; n = 188) and the Sheehan Disability Scale (SDS; n = 168). RESULTS: Significant improvement in total depressive symptoms severity (p < 0.0001) was observed after four infusions of IV ketamine 0.5-0.75 mg/kg. Moreover, the response rate (QIDS-SR16 total score change ≥ 50%) was 27% and remission (QIDS-SR16 total score ≤5) rate was 13%. Patients receiving IV ketamine exhibited anxiolytic effects (p < 0.0001,), improved overall psychosocial function (p < 0.0001), and reduced suicidal ideation (p < 0.0001). Compared to the baseline infusion, dissociation severity significantly reduced in subsequent infusions. LIMITATIONS: This was a naturalistic, retrospective study, without a control group. CONCLUSIONS: IV ketamine was safe, well-tolerated, and effective at improving depressive, anxiety, and functional impairment symptoms in a well-characterized cohort of adults with TRD.

Sleep and Pathological Wakefulness at the Time of Liberation from Mechanical Ventilation (SLEEWE). A Prospective Multicenter Physiological Study.

Rationale: Abnormal patterns of sleep and wakefulness exist in mechanically ventilated patients. Objectives: In this study (SLEEWE [Effect of Sleep Disruption on the Outcome of Weaning from Mechanical Ventilation]), we aimed to investigate polysomnographic indexes as well as a continuous index for evaluating sleep depth, the odds ratio product (ORP), to determine whether abnormal sleep or wakefulness is associated with the outcome of spontaneous breathing trials (SBTs). Methods: Mechanically ventilated patients from three sites were enrolled if an SBT was planned the following day. EEG was recorded using a portable sleep diagnostic device 15 hours before the SBT. The ORP was calculated from the power of four EEG frequency bands relative to each other, ranging from full wakefulness (2.5) to deep sleep (0). The correlation between the right and left hemispheres' ORP (R/L ORP) was calculated. Measurements and Main Results: Among 44 patients enrolled, 37 had technically adequate signals: 11 (30%) passed the SBT and were extubated, 8 (21%) passed the SBT but were not deemed to be clinically ready for extubation, and 18 (49%) failed the SBT. Pathological wakefulness or atypical sleep were highly prevalent, but the distribution of classical sleep stages was similar between groups. The mean ORP and the proportion of time in which the ORP was >2.2 were higher in extubated patients compared with the other groups (P < 0.05). R/L ORP was significantly lower in patients who failed the SBT, and the area under the receiver operating characteristic curve of R/L ORP to predict failure was 0.91 (95% confidence interval, 0.75-0.98). Conclusions: Patients who pass an SBT and are extubated reach higher levels of wakefulness as indicated by the ORP, suggesting abnormal wakefulness in others. The hemispheric ORP correlation is much poorer in patients who fail an SBT.

Perioperative fluid management for pulmonary resection surgery and esophagectomy.

Perioperative fluid management is of significant importance during pulmonary resection surgery and esophagectomy. Excessive fluid administration has been consistently shown as a risk factor for lung injury after thoracic procedures. Probable causes of this serious complication include fluid overload, lung lymphatics and pulmonary endothelial damage. Along with new insights regarding the Starling equation and the absence of a third space, current evidence supports a restrictive fluid regimen for patients undergoing pulmonary resection surgery and esophagectomy. Multiple minimally invasive hemodyamic monitoring devices, including pulse pressure/stroke volume variation, esophageal Doppler, and extravascular lung water measurement, were evaluated for optimizing perioperative fluid therapy. Further research regarding the prevention, diagnosis, and treatment of acute lung injury after pulmonary resection and esophagectomy is required.

Serum bicarbonate level improves specificity of STOP-Bang screening for obstructive sleep apnea.

BACKGROUND: The STOP-Bang questionnaire is a validated screening tool for the identification of surgical patients with obstructive sleep apnea (OSA). A STOP-Bang score ≥ 3 is highly sensitive but only moderately specific. Apnea/hypopnea during sleep can lead to intermittent hypercapnia and may result in serum bicarbonate (HCO3⁻) retention. The addition of serum HCO3⁻ level to the STOP-Bang questionnaire may improve its specificity. METHODS: Four thousand seventy-seven preoperative patients were approached for consent and screened by the STOP-Bang questionnaire. Polysomnography was performed and preoperative HCO3⁻ level was collected in 384 patients. Study participants were randomly assigned to a derivation or validation cohort. Predictive parameters (sensitivity, specificity, positive and negative predictive values) for STOP-Bang score and serum HCO3⁻ level were calculated. RESULTS: In the derivation cohort, with a STOP-Bang score ≥ 3, the specificity for all OSA, moderate/severe OSA, and severe OSA was 37.0%, 30.4%, and 27.7%, respectively. HCO3⁻ level of 28 mmol/L was selected as a cutoff for analysis. With the addition of HCO3⁻ level ≥ 28 mmol/L to the STOP-Bang score ≥ 3, the specificity for all OSA, moderate/severe OSA, and severe OSA improved to 85.2%, 81.7%, and 79.7%, respectively. Similar improvement was observed in the validation cohort. CONCLUSION: Serum HCO3⁻ level increases the specificity of STOP-Bang screening in predicting moderate/severe OSA. We propose a two-step screening process. The first step uses a STOP-Bang score to screen patients, and the second step uses serum HCO3⁻ level in those with a STOP-Bang score ≥ 3 for increased specificity.

Obesity hypoventilation syndrome: a review of epidemiology, pathophysiology, and perioperative considerations.

Obesity hypoventilation syndrome (OHS) is defined by the triad of obesity, daytime hypoventilation, and sleep-disordered breathing without an alternative neuromuscular, mechanical, or metabolic cause of hypoventilation. It is a disease entity distinct from simple obesity and obstructive sleep apnea. OHS is often undiagnosed but its prevalence is estimated to be 10-20% in obese patients with obstructive sleep apnea and 0.15-0.3% in the general adult population. Compared with eucapnic obese patients, those with OHS present with severe upper airway obstruction, restrictive chest physiology, blunted central respiratory drive, pulmonary hypertension, and increased mortality. The mainstay of therapy is noninvasive positive airway pressure. Currently, information regarding OHS is extremely limited in the anesthesiology literature. This review will examine the epidemiology, pathophysiology, clinical characteristics, screening, and treatment of OHS. Perioperative management of OHS will be discussed last.

Fibrinogen decreases cardiomyocyte contractility through an ICAM-1-dependent mechanism.

INTRODUCTION: Cardiomyocytes exposed to inflammatory processes express intracellular adhesion molecule-1 (ICAM-1). We investigated whether fibrinogen and fibrinogen degradation products, including D-dimer, could alter cardiomyocyte contractile function through interaction with ICAM-1 found on inflamed cardiomyocytes. METHODS: In vivo, rats were injected with endotoxin to model systemic inflammation, whereas isolated rat cardiomyocytes were treated with tumor necrosis factor-alpha to model the inflammatory environment seen following exposure to bacterial products such as lipopolysaccharide. RESULTS: In vivo, endotoxin administration profoundly decreased cardiac contractile function associated with a large increase in intracardiac ICAM-1 and perivascular fibrinogen. Confocal microscopy with double-staining of isolated rat cardiomyocytes demonstrated colocalization of ICAM-1 and fibrinogen. This interaction was disrupted through pre-treatment of the cells with an ICAM-1-blocking antibody. Functionally, isolated rat cardiomyocyte preparations exhibited decreased fractional shortening when incubated with fibrinogen, and through the use of synthetic peptides, we determined that residues 117-133 of the fibrinogen gamma chain are responsible for this interaction with ICAM-1. Despite having crosslinked gamma chains, D-dimer retained the ability to decrease cardiomyocyte contractility. CONCLUSION: Site 117-133 of the fibrinogen gamma chain is able to depress cardiomyocyte contractility through binding ICAM-1.

Evaluation of small sample cDNA amplification for microdissected airway expression profiling in COPD.

Small airway obstruction and emphysematous destruction account for the airflow limitation that defines chronic obstructive pulmonary disease (COPD). While laser capture microdissection (LCM) allows gene expression studies in small airways separately from the surrounding parenchyma, tissue size limits the number of genes examined. The present study evaluates the Clontech SMART amplification to test the hypothesis that this amplification provides RNA in sufficient quantity and quality to evaluate large numbers of genes in airways < 2 mm diameter obtained by LCM. Commercial reference RNA was amplified 200-fold and the expression levels of 51 genes relative to the unamplified RNA had a correlation coefficient of 0.84. For two pairs of RNA preparations (commercial placenta versus commercial lung; lung sections prepared for LCM from GOLD 0 (at risk for COPD) versus GOLD 2 (moderate disease) patients linear regression of Delta Ct's (delta cycle thresholds) of unamplified versus amplified RNA gave correlation coefficients of R = 0.95. In RNA from microdissected small airways, expression patterns in all GOLD classes of COPD severity were very similar between unamplified and amplified RNA. We conclude that SMART amplification provides cDNA sufficient for studying large numbers of genes even in laser-captured small airways and this cDNA maintains the relative expression found in corresponding unamplified RNAs.

Cardiac ICAM-1 mediates leukocyte-dependent decreased ventricular contractility in endotoxemic mice.

OBJECTIVE: Binding of ICAM-1 expressed on cardiomyocytes decreases cardiomyocyte contractility in vitro by altering the intracellular Ca2+ transient. We tested the hypothesis that signaling via ICAM-1 contributes to decreased left ventricular contractility in an in vivo model of systemic inflammation. METHODS: C57B6 wild-type mice and ICAM-1 knock-out mice were treated with intraperitoneal lipopolysaccharide (LPS) then left ventricular contractility was measured 6 h later using a volume-conductance micromanometer catheter. We repeated this experiment in chimeric mice lacking ICAM-1 expression in bone marrow-derived cells (M-) and/or lacking ICAM-1 expression in the heart and other tissues (H-). RESULTS: In C57B6 wild-type mice LPS injection significantly increased cardiac ICAM-1 expression and decreased in vivo measures of left ventricular contractility (end-systolic elastance, Ees decreased 58 +/- 4%, p < 0.05, [dP/dtmax]/EDV decreased 60 +/- 6%, p < 0.05). Cyclophosphamide pretreatment to decrease leukocyte count prevented the LPS-induced decrease in contractility. In ICAM-1 knock-out mice LPS did not decrease any measure of contractility. LPS did not decrease left ventricular contractility in M+/H- mice but decreased contractility in M+/H+ and M-/H+ mice to the same extent as in C57B6 wild-type mice implicating the importance of cardiac ICAM-1. CONCLUSIONS: We conclude that signaling via cardiac ICAM-1 is necessary to mediate leukocyte-dependent decreases of left ventricular contractility in endotoxemic mice.