Patient-reported outcomes on sleep quality and circadian rhythm during treatment with intravenous ketamine for treatment-resistant depression.

Background: Intravenous (IV) ketamine is a rapid acting antidepressant used primarily for treatment-resistant depression (TRD). It has been suggested that IV ketamine's rapid antidepressant effects may be partially mediated via improved sleep and changes to the circadian rhythm. Objectives: This study explores IV ketamine's association with changes in patient-reported sleep quality and circadian rhythm in an adult population with TRD. Methods: Adult patients (18-64 years) with TRD scheduled for IV ketamine treatment were recruited to complete patient rated outcomes measures on sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and circadian rhythm using the Morningness-Eveningness Questionnaire (MEQ). Over a 4-week course of eight ketamine infusions, reports were obtained at baseline (T0), prior to second treatment (T1), prior to fifth treatment (T2), and 1 week after eighth treatment (T3). Results: Forty participants with TRD (mean age = 42.8, 45% male) were enrolled. Twenty-nine (72.5%) had complete follow-up data. Paired t tests revealed statistically significant improvements at the end of treatment in sleep quality (PSQI) (p = 0.003) and depressive symptoms (Clinically Useful Depression Outcome Scale-Depression, p < 0.001) while circadian rhythm (MEQ) shifted earlier (p = 0.007). The PSQI subscale components of sleep duration (p = 0.008) and daytime dysfunction (p = 0.001) also improved. In an exploratory post hoc analysis, ketamine's impact on sleep quality was more prominent in patients with mixed features, while its chronobiotic effect was prominent in those without mixed features. Conclusion: IV ketamine may improve sleep quality and advance circadian rhythm in individuals with TRD. Effects may differ in individuals with mixed features of depression as compared to those without. Since this was a small uncontrolled study, future research is warranted.

Patient-reported changes in sleep during treatment with intravenous ketamine for depression Intravenous ketamine is a fast acting treatment for depression that does not respond to more conventional antidepressant medications. Almost all people with depression have problems with sleep as a symptom of their illness. This can include things like difficulties falling asleep, problems staying asleep, sleeping more or less than usual, and shifting the sleep schedule to stay up later than usual. It has been previously suggested that improving sleep in people with depression may be part of how ketamine exerts its antidepressant effect. This study surveyed patients with depression who received eight intravenous infusions of ketamine (two per week for 4 weeks) to ask them about their sleep quality and patterns before treatment, part way through their course of treatment and after the treatments were completed. Symptoms of depression were also measured. Data were collected on 29 people. People reported overall that sleep quality did improve with ketamine treatments, and that timing of sleep shifted earlier. Sleep duration increased and people had less problems with daytime functioning. There is a subtype of depression called depression with "mixed features," meaning that these people, in addition to being depressed, may have some activating symptoms like irritability, restlessness, and agitation. It is thought that this type of depression may be biologically different from depression without these symptoms. In this study, around half (15/29) had mixed features. Sleep quality improved only in the group without mixed features. On the other hand, the group with mixed features had their sleep schedule shift earlier, but the group without mixed features did not. This supports the idea that these two types of depression may be biologically different, and ketamine treatment may exert different effects on the sleep of each group. This was a small study, but suggests a need for future research.

Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: A Systematic Review and Recommendations of Cannabis use in Bipolar Disorder and Major Depressive Disorder.

BACKGROUND: Given the increasing acceptability and legalization of cannabis in some jurisdictions, clinicians need to improve their understanding of the effect of cannabis use on mood disorders. OBJECTIVE: The purpose of this task force report is to examine the association between cannabis use and incidence, presentation, course and treatment of bipolar disorder and major depressive disorder, and the treatment of comorbid cannabis use disorder. METHODS: We conducted a systematic literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Embase, PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials from inception to October 2020 focusing on cannabis use and bipolar disorder or major depressive disorder, and treatment of comorbid cannabis use disorder. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach was used to evaluate the quality of evidence and clinical considerations were integrated to generate Canadian Network for Mood and Anxiety Treatments recommendations. RESULTS: Of 12,691 publications, 56 met the criteria: 23 on bipolar disorder, 21 on major depressive disorder, 11 on both diagnoses and 1 on treatment of comorbid cannabis use disorder and major depressive disorder. Of 2,479,640 participants, 12,502 were comparison participants, 73,891 had bipolar disorder and 408,223 major depressive disorder without cannabis use. Of those with cannabis use, 2,761 had bipolar disorder and 5,044 major depressive disorder. The lifetime prevalence of cannabis use was 52%-71% and 6%-50% in bipolar disorder and major depressive disorder, respectively. Cannabis use was associated with worsening course and symptoms of both mood disorders, with more consistent associations in bipolar disorder than major depressive disorder: increased severity of depressive, manic and psychotic symptoms in bipolar disorder and depressive symptoms in major depressive disorder. Cannabis use was associated with increased suicidality and decreased functioning in both bipolar disorder and major depressive disorder. Treatment of comorbid cannabis use disorder and major depressive disorder did not show significant results. CONCLUSION: The data indicate that cannabis use is associated with worsened course and functioning of bipolar disorder and major depressive disorder. Future studies should include more accurate determinations of type, amount and frequency of cannabis use and select comparison groups which allow to control for underlying common factors.

Use of ketamine for treatment resistant depression: updated review of literature and practical applications to a community ketamine program in Edmonton, Alberta, Canada.

Background: Though intravenous (IV) ketamine and intranasal (IN) esketamine are noted to be efficacious for treatment-resistant depression (TRD), access to each of these treatments within healthcare systems is limited due to cost, availability, and/or monitoring requirements. IV ketamine has been offered at two public hospital sites in Edmonton, Canada since 2015. Since then, demand for maintenance ketamine treatments has grown. This has required creative solutions for safe, accessible, evidence-based patient care. Objectives: Aims of this paper are twofold. First, we will provide a synthesis of current knowledge with regards to the clinical use of ketamine for TRD. Consideration will be given regarding; off-label racemic ketamine uses versus FDA-approved intranasal esketamine, populations treated, inclusion/exclusion criteria, dosing, assessing clinical response, concomitant medications, and tolerability/safety. Second, this paper will describe our experience as a community case study in applying evidence-based treatment. We will describe application of the literature review to our clinical programming, and in particular focus on cost-effective maintenance treatments, long-term safety concerns, routes of ketamine administration other than via intravenous, and cautious prescribing of ketamine outside of clinically monitored settings. Methodology: We conducted a literature review of the on the use of ketamine for TRD up to June 30, 2023. Key findings are reviewed, and we describe their application to our ketamine program. Conclusion: Evidence for the use of ketamine in resistant depression has grown in recent years, with evolving data to support and direct its clinical use. There is an increasing body of evidence to guide judicious use of ketamine in various clinical circumstances, for a population of patients with a high burden of suffering and morbidity. While large-scale, randomized controlled trials, comparative studies, and longer-term treatment outcomes is lacking, this community case study illustrates that currently available evidence can be applied to real-world clinical settings with complex patients. As cost is often a significant barrier to accessing initial and/or maintenance IV or esketamine treatments, public ketamine programs may incorporate SL or IN ketamine to support a sustainable and accessible treatment model. Three of such models are described.

A survey of drug liking and cravings in patients using sublingual or intranasal ketamine for treatment resistant depression: A preliminary evaluation of real world addictive potential.

Ketamine has gained rapid popularity as a treatment option for treatment resistant depression (TRD). Though seen only in limited contexts, ketamine is a potential drug of abuse, addiction and diversion. Clinical ketamine studies to date have not systematically evaluated factors relevant to addiction risk in patients with TRD, but in treating patients with ketamine, risks of potential harms related to addiction must be considered. As clinical access to intravenous ketamine programs is limited in much of Canada, these considerations become even more important for clinicians who elect to offer patients less supervised, non-parenteral forms of ketamine treatment. This study explores factors relevant to addiction risk in a real-world sample of 33 patients with TRD currently or previously treated with sublingual (SL) or intranasal (IN) ketamine in the community. First, patients were surveyed using a Drug Liking and Craving Questionnaire (DLCQ) to assess their level of drug liking and craving for ketamine, and to screen for symptoms of a ketamine use disorder. Second, the pharmacy records of these patients were reviewed for red flags for addiction such as dose escalation or early refills. Third, surveys were administered to the treating psychiatrists of patients who had discontinued ketamine to determine if abuse concerns contributed to reason for discontinuation. Though limited to a small sample, results indicate that ketamine is not a universally liked or craved substance in patients with TRD. Prescribers of non-parenteral ketamine should monitor patients and prescribe cautiously. Factors related to addiction (as in the DLCQ) should be explored for clinicians to consider individual risk/benefit for judicious use of ketamine in patients with TRD.

Intravenous ketamine for depression: A clinical discussion reconsidering best practices in acute hypertension management.

Ketamine is a versatile medication with an emerging role for the treatment of numerous psychiatric conditions, including treatment resistant depression. Current psychiatry guidelines for its intravenous administration to treat depression recommend regular blood pressure monitoring and an aggressive approach to potential transient hypertensive episodes induced by ketamine infusions. While this approach is aimed at ensuring patient safety, it should be updated to align with best practice guidelines in the management of hypertension. This review defines and summarizes the currently recommended approach to the hypertensive emergency, the asymptomatic hypertensive urgency, and discusses their relevance to intravenous ketamine therapy. With an updated protocol informed by these best practice guidelines, ketamine treatment for depression may be more accessible to facilitate psychiatric treatment.

Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judicious Prescribing.

Intravenous (IV) ketamine is increasingly used off-label at subanesthetic doses for its rapid antidepressant effect, and intranasal (IN) esketamine has been recently approved in several countries for treating depression. The clinical utility of these treatments is limited by a paucity of publicly funded IV ketamine and IN esketamine programs and cost barriers to private treatment programs, as well as the drug cost for IN esketamine itself, which makes generic ketamine alternatives an attractive option. Though evidence is limited, use of non-parenteral racemic ketamine formulations (oral, sublingual, and IN) may offer more realistic access in less rigidly supervised settings, both for acute and maintenance treatment in select cases. However, the psychiatric literature has repeatedly cautioned on the addictive potential of ketamine and raised caution for both less supervised and longer-term use of ketamine. To date, these concerns have not been discussed in view of available evidence, nor have they been discussed within a broader clinical context. This paper examines the available relevant literature and suggests that ketamine misuse risks appear not dissimilar to those of other well-established and commonly prescribed agents with abuse potential, such as stimulants or benzodiazepines. As such, ketamine prescribing should be considered in a similar risk/benefit context to balance patient access and need for treatment with concern for potential substance misuse. Our consortium of mood disorder specialists with significant ketamine prescribing experience considers prescribing of non-parenteral ketamine a reasonable clinical treatment option in select cases of treatment-resistant depression. This paper outlines where this may be appropriate and makes practical recommendations for clinicians in judicious prescribing of non-parenteral ketamine.

Effect of a Multilayer, Extended-Release Methylphenidate Formulation (PRC-063) on Sleep in Adolescents with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Fixed-Dose, Placebo-Controlled Trial Followed by a 6-Month Open-Label Follow-Up.

Objectives: We analyzed patient-reported sleep parameters for an extended-release methylphenidate formulation (PRC-063) in adolescents with attention-deficit/hyperactivity disorder. Methods: Clinical efficacy and long-term safety/tolerability data from a 4-week, double-blind, placebo-controlled, fixed-dose study (NCT02139111) and a subsequent 6-month, optimized-dose, open-label extension (OLE) study (NCT02168127) were used. In the double-blind study, participants were randomly assigned 1:1:1:1:1 to one of four doses of PRC-063 (25, 45, 70, or 85 mg/day) or placebo. In both the double-blind and OLE studies, sleep outcomes were assessed using the Pittsburgh Sleep Quality Index (PSQI). Results: During double-blind treatment, no statistically significant least-squares mean difference in change from baseline between PRC-063 (all doses combined; N = 293) and placebo (N = 74) was found for either global PSQI score (-0.3 vs. -0.5; p = 0.6110) or scores for any of the seven PSQI subscales. Compared with the placebo group, a marginally higher proportion of patients in the PRC-063 group (all doses combined) went from being poor to good sleepers (global PSQI score ≤5; 14.4% vs. 11.3%). In a logistic regression analysis, study treatment was not a predictor of poor sleep (p = 0.5368) at the end of the double-blind study. In the OLE study, there was a trend of improvement in sleep after 1 month of individualized dosing that was maintained through 6 months. Sleep efficiency (time asleep as a proportion of time in bed) showed improvement at the end of the OLE study. Conclusion: While individual patients may experience changes in sleep as an adverse event, group data evaluating sleep as an outcome found there were no differences between PRC-063 and placebo in self-reported sleep outcomes on the PSQI.

Down and High: Reflections Regarding Depression and Cannabis.

In light of the recent changes in the legal status of cannabis in Canada, the understanding of the potential impact of the use of cannabis by individuals suffering from depression is increasingly considered as being important. It is fundamental that we look into the existing literature to examine the influence of cannabis on psychiatric conditions, including mood disorders. In this article, we will explore the relationship that exists between depression and cannabis. We will examine the impact of cannabis on the onset and course of depression, and its treatment. We have undertaken a wide-ranging review of the literature in order to address these questions. The evidence from longitudinal studies suggest that there is a bidirectional relationship between cannabis use and depression, such that cannabis use increases the risk for depression and vice-versa. This risk is possibly higher in heavy users having initiated their consumption in early adolescence. Clinical evidence also suggests that cannabis use is associated with a worse prognosis in individuals with major depressive disorder. The link with suicide remains controversial. Moreover, there is insufficient data to determine the impact of cannabis use on cognition in individuals with major depression disorder. Preliminary evidence suggesting that the endogenous cannabinoid system is involved in the pathophysiology of depression. This will need to be confirmed in future positron emission tomography studies. Randomized controlled trials are needed to investigate the potential efficacy of motivational interviewing and/or cognitive behavioral therapy for the treatment of cannabis use disorder in individuals with major depressive major disorder. Finally, although there is preclinical evidence suggesting that cannabidiol has antidepressant properties, randomized controlled trials will need to properly investigate this possibility in humans.

Effect of a Multi-Layer, Extended-Release Methylphenidate Formulation (PRC-063) on Sleep in Adults with ADHD: A Randomized, Double-Blind, Forced-Dose, Placebo-Controlled Trial Followed by a 6-month Open-Label Extension.

BACKGROUND: The effects of stimulant treatment on sleep in adults with attention-deficit/hyperactivity disorder (ADHD) are complex and varied, with some individuals experiencing worsening of sleep but others experiencing improvement. METHODS: Data from previously reported trials of the clinical efficacy and safety of the long-acting methylphenidate formulation PRC-063 (Adhansia XR® in the USA; Foquest® in Canada) in adults with ADHD were used to evaluate patient-reported sleep outcomes, as captured using the Pittsburgh Sleep Quality Index (PSQI) and adverse events of insomnia. The trials comprised 4 weeks of randomized, forced-dose PRC-063 treatment at a dose of 0 (placebo), 25, 45, 70, or 100 mg/day followed by an optional 6 months of open-label PRC-063 treatment at an individually optimized dose of 25-100 mg/day. RESULTS: At the end of double-blind treatment, PRC-063 (all doses combined; N = 297) showed no significant difference versus placebo (N = 78) in least squares mean change in global PSQI score from baseline (- 0.7 vs. - 1.3; P = 0.0972) or in scores for each of the seven subscales of the PSQI. For patients enrolled in the open-label extension (N = 184), mean ± standard deviation global PSQI score improved from 7.8 ± 3.55 at the end of double-blind treatment to 5.8 ± 3.11 at 1 month and 5.4 ± 3.21 at 6 months (P < 0.0001). A greater proportion of patients were good sleepers (global PSQI score ≤ 5) at the end of the open-label extension (57.3%) than at baseline (20.9%) or at the end of double-blind treatment (26.0%). In a logistic regression analysis, baseline global PSQI score (odds ratio 1.491; P < 0.0001), but not randomized study treatment (P = 0.1428), was a significant predictor of poor sleep (global PSQI score > 5) at the end of double-blind treatment. Adverse event rates for insomnia (15.8 vs. 3.8%) and initial insomnia (6.1 vs. 1.3%) during double-blind treatment were higher for PRC-063 (all doses combined) than for placebo. Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events. CONCLUSIONS: Our findings indicate that, on average, PRC-063 had no significant impact on overall sleep quality in adults with ADHD. Although insomnia was observed as an adverse event, when sleep was measured over time as an outcome in its own right for patients receiving dose-optimized PRC-063 open-label, more patients showed improvement in sleep than deterioration. CLINICALTRIALS. GOV IDENTIFER: NCT02139124 and NCT02168127.

Bilateral ptosis: An unusual presentation of mid brain tuberculoma.

Central nervous system tuberculoma can have different clinical manifestations like headache, seizures, papilledema or other signs of raised intracranial pressure depending up on the site and number of tuberculoma. We report a case of 56 year old female reported with history of bilateral asymmetric ptosis of one month duration,with no other neurological defecit. Magnetic resonance imaging (MRI) brain revealed well defined ring enhancing lesion in the medial aspect of left hemi midbrain with diffuse disproportionate perilessional edema. Contrast Enhanced Computed Tomogram (CECT) of chest and abdomen revealed features of disseminated tuberculosis. She was diagnosed as a case of disseminated tuberculosis and started on antitubercular therapy with steroids and the ptosis almost resolved after 01 month of antitubercular therapy. Our case report is unique in the sense that only few cases of midbrain tuberculoma causing occulomotor abnormalities are reported in literature.

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers.

Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine's effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.

Correction.

This corrects the article DOI: 10.4088/JCP.20lcx13316.

Functional Recovery in Major Depressive Disorder: Focus on Early Optimized Treatment.

OBJECTIVE: This article presents the case that a more rapid, individualized approach to treating major depressive disorder (MDD) may increase the likelihood of achieving full symptomatic and functional recovery for individual patients and that studies show it is possible to make earlier decisions about appropriateness of treatment in order to rapidly optimize that treatment. DATA SOURCES: A PubMed search was conducted using terms including major depressive disorder, early improvement, predictor, duration of untreated illness, and function. English-language articles published before September 2015 were included. Additional studies were found within identified research articles and reviews. STUDY SELECTION: Thirty antidepressant studies reporting predictor criteria and outcome measures are included in this review. DATA EXTRACTION: Studies were reviewed to extract definitions of predictors, outcome measures, and results of the predictor analysis. Results were summarized separately for studies reporting effects of early improvement, baseline characteristics, and duration of untreated depression. RESULTS: Shorter duration of the current depressive episode and duration of untreated depression are associated with better symptomatic and functional outcomes in MDD. Early improvement of depressive symptoms predicts positive symptomatic outcomes (response and remission), and early functional improvement predicts an increased likelihood of functional remission. CONCLUSIONS: The approach to treatment of depression that exhibits the greatest potential for achieving full symptomatic and functional recovery is early optimized treatment: early diagnosis followed by rapid individualized treatment. Monitoring symptoms and function early in treatment is crucial to ensuring that patients do not remain on ineffective or poorly tolerated treatment, which may delay recovery and heighten the risk of residual functional deficits.

Procedural sedation associated displacement of sharp oesophageal foreign body.

Oesophageal foreign body is a common clinical problem. The therapeutic intervention varies from endoscopic removal to observation for spontaneous passage of foreign body. The authors illustrate a case of sharp board pin ingestion by a child, which stayed impacted at C(7)-T(1) level for 8 h with indentation of tracheal mucosa. However, upon administration of midazolam and ketamine for procedural sedation, the pin spontaneously advanced to stomach when muscle relaxation had set in. A few oesophageal mucosal erosions were noted on the endoscopy. The foreign body could not be retrieved by the procedure and was spontaneously egested impacted in faeces. This case presents a distinctive hazard associated with procedural sedation for a foreign body in aero-digestive tract, where the associated muscle relaxation can lead to complications due to spontaneous movement of foreign body.

Canadian Sleep Society/Canadian Thoracic Society position paper on the use of portable monitoring for the diagnosis of obstructive sleep apnea/hypopnea in adults.

The present position paper on the use of portable monitoring (PM) as a diagnostic tool for obstructive sleep apnea/hypopnea (OSAH) in adults was based on consensus and expert opinion regarding best practice standards from stakeholders across Canada. These recommendations were prepared to guide appropriate clinical use of this new technology and to ensure that quality assurance standards are adhered to. Clinical guidelines for the use of PM for the diagnosis and management of OSAH as an alternative to in-laboratory polysomnography published by the American Academy of Sleep Medicine Portable Monitoring Task Force were used to tailor our recommendations to address the following: indications; methodology including physician involvement, physician and technical staff qualifications, and follow-up requirements; technical considerations; quality assurance; and conflict of interest guidelines. When used appropriately under the supervision of a physician with training in sleep medicine, and in conjunction with a comprehensive sleep evaluation, PM may expedite treatment when there is a high clinical suspicion of OSAH.

An approach to managing depression. Defining and measuring outcomes.

OBJECTIVE: To provide family physicians with a contemporary approach to formulating a treatment model for major depressive disorder that integrates definitions of new therapeutic end points, familiarizes them with tools for assessing these end points, and describes newer methods for enhancing outcome. SOURCES OF INFORMATION: Canadian Psychiatric Association Guidelines for the Treatment of Depressive Disorders, relevant articles from a MEDLINE search using the MeSH headings"full remission" and "depression," and the authors' clinical experience. MAIN MESSAGE: Major depressive disorder is an episodic, relapsing, and sometimes chronic illness. Depressive symptoms in primary care settings are often vague reports of anhedonia, anxiety, and nonspecific somatic complaints. Therapeutic objectives in depression are full remission of depressive symptoms, prevention of recurrence, and restoration of function. Depression rating scales can be useful for monitoring and treating depression. CONCLUSION: The proposed therapeutic model anticipates the chronic course of illness, defines treatment end points, encourages longer duration of treatment, and includes both pharmacologic and lifestyle therapies. The 7-item Hamilton Depression Rating Scale can assist clinicians in determining when full remission has occurred.