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.

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.