Exploring psychedelic-assisted therapy in the treatment of functional seizures: A review of underlying mechanisms and associated brain networks.

Functional seizures (FS), the most common subtype of functional neurological disorder (FND), cause serious neurological disability and significantly impact quality of life. Characterized by episodic disturbances of functioning that resemble epileptic seizures, FS coincide with multiple comorbidities and are treated poorly by existing approaches. Novel treatment approaches are sorely needed. Notably, mounting evidence supports the safety and efficacy of psychedelic-assisted therapy (PAT) for several psychiatric conditions, motivating investigations into whether this efficacy also extends to neurological disorders. Here, we synthesize past empirical findings and frameworks to construct a biopsychosocial mechanistic argument for the potential of PAT as a treatment for FS. In doing so, we highlight FS as a well-defined cohort to further understand the large-scale neural mechanisms underpinning PAT. Our synthesis is guided by a complexity science perspective which we contend can afford unique mechanistic insight into both FS and PAT, as well as help bridge these two domains. We also leverage this perspective to propose a novel analytic roadmap to identify markers of FS diagnostic specificity and treatment success. This endeavor continues the effort to bridge clinical neurology with psychedelic medicine and helps pave the way for a new field of psychedelic neurology.

Ketamine-Assisted Group Psychotherapy for Frontline Healthcare Workers with COVID-19-Related Burnout and PTSD: A Case Series of Effectiveness/Safety for 10 Participants.

This study reports on 10 frontline healthcare workers, employed during the COVID-19 pandemic and experiencing symptoms of burnout and PTSD, treated with group ketamine-assisted psychotherapy (KAP) in a private outpatient clinic setting. Participants attended 6 sessions once weekly. These included 1 preparation session, 3 ketamine sessions (2 sublingual, 1 intramuscular), 2 integration sessions. Measures of PTSD (PCL-5), depression (PHQ-9), and anxiety (GAD-7) were administered at baseline and post-treatment. During ketamine sessions, the Emotional Breakthrough Inventory (EBI) and the 30-item Mystical Experience Questionnaire (MEQ-30) were recorded. Participant feedback was gathered 1-month post-treatment. We observed improvements in participants' average PCL-5 (59% reduction), PHQ-9 (58% reduction), and GAD-7 (36% reduction) scores from pre- to post-treatment. At post-treatment, 100% of participants screened negative for PTSD, 90% had minimal/mild depression or clinically significant improvement, and 60% had minimal/mild anxiety or clinically significant improvement. MEQ and EBI scores had large variations among participants at each ketamine session. Ketamine was well tolerated, and no significant adverse events were reported. Participant feedback corroborated findings of improvements observed in mental health symptoms. We found immediate improvements treating 10 frontline healthcare workers experiencing burnout, PTSD, depression, and anxiety using weekly group KAP and integration.

The implementation of value-based frameworks, clinical care pathways, and alternative payment models for cancer care in the United States.

BACKGROUND: Cancer treatment is a significant driver of rising health care costs in the United States, where the annual cost of cancer care is estimated to reach $246 billion in 2030. As a result, cancer centers are considering moving away from fee-for-service models and transitioning to value-based care models, including value-based frameworks (VBFs), clinical care pathways (CCPs), and alternative payment models (APMs). OBJECTIVE: To assess the barriers and motivations for using value-based care models from the perspectives of physicians and quality officers (QOs) at US cancer centers. METHODS: Sites were recruited from cancer centers in the Midwest, Northeast, South, and West regions in a 15/15/20/10 relative distribution. Cancer centers were identified based on prior research relationships and known participation in the Oncology Care Model or other APMs. Based on a literature search, multiple choice and open-ended questions were developed for the survey. A link to the survey was emailed to hematologists/oncologists and QOs at academic and community cancer centers from August to November 2020. Results were summarized using descriptive statistics. RESULTS: A total of 136 sites were contacted; 28 (21%) centers returned completed surveys, which were included in the final analysis. 45 surveys (23 from community centers, 22 from academic centers) were completed: 59% (26/44), 76% (34/45), and 67% (30/45) of physicians/QOs respondents had used or implemented a VBF, CCP, and APM, respectively. The top motivator for VBF use was "producing real-world data for providers, payers, and patients" (50% [13/26]). Among those not using CCPs, the most common barrier was a "lack of consensus on pathway choices" (64% [7/11]). For APMs, the most common difficulty was that "innovations in health care services and therapies must be adopted at the site's own financial risk" (27% [8/30]). CONCLUSIONS: The ability to measure improvements in cancer health outcomes was a large motivator for implementing value-based models. However, heterogeneity in practice size, limited resources, and potential increase in costs were possible barriers to implementation. Payers need to be willing to negotiate with cancer centers and providers to implement the payment model that will most benefit patients. The future integration of VBFs, CCPs, and APMs will depend on reducing the complexity and burden of implementation. DISCLOSURES :Dr Panchal was affiliated with the University of Utah at the time this study was conducted and discloses current employment with ZS. Dr McBride discloses employment with Bristol Myers Squibb. Dr Huggar and Dr Copher report employment, stock, and other ownership interests in Bristol Myers Squibb. The other authors have no competing interests to disclose. This study was funded by an unrestricted research grant from Bristol Myers Squibb to the University of Utah.

Case report: Intramuscular ketamine or intranasal esketamine as a treatment in four patients with major depressive disorder and comorbid anorexia nervosa.

Introduction: A comorbid diagnosis of a depressive disorder is a negative prognostic factor for individuals with AN, and novel treatments are needed to target depressive symptoms in this population. One emerging promising treatment for depressive disorders is ketamine, although there is less research investigating the use of ketamine for alleviating depression in people with AN. Case report: This study reports on four patients with a lifetime diagnosis of AN and a comorbid diagnosis of major depressive disorder who received either intramuscular ketamine (n = 2) or intranasal esketamine (n = 2) treatment from a private psychiatric clinic. Depressive symptomatology (PHQ-9) was measured prior to (es)ketamine administration on every dosing session and adverse effects were recorded during and after dosing. All patients reported a subjective decrease in depression, although only those administered intranasal esketamine showed a reduction in PHQ-9 depression scores over time. Number of doses ranged from 3 to 23. All patients tolerated treatment well and no serious adverse effects emerged, however nausea/vomiting was experienced by one patient on one dosing session. Weight remained stable in all cases, although notably across all patients, weight at the beginning of treatment was within a "healthy" range. Discussion: These findings suggest that (es)ketamine may reduce depressive symptoms in people with major depressive disorder and a comorbid diagnosis of AN. Future feasibility and pilot trials are warranted in order to elicit robust data on efficacy, acceptability, safety and tolerability.

Breathwork Interventions for Adults with Clinically Diagnosed Anxiety Disorders: A Scoping Review.

Anxiety disorders are the most common group of mental disorders, but they are often underrecognized and undertreated in primary care. Dysfunctional breathing is a hallmark of anxiety disorders; however, mainstays of treatments do not tackle breathing in patients suffering anxiety. This scoping review aims to identify the nature and extent of the available research literature on the efficacy of breathwork interventions for adults with clinically diagnosed anxiety disorders using the DSM-5 classification system. Using the PRISMA extension for scoping reviews, a search of PubMed, Embase, and Scopus was conducted using terms related to anxiety disorders and breathwork interventions. Only clinical studies using breathwork (without the combination of other interventions) and performed on adult patients diagnosed with an anxiety disorder using the DSM-5 classification system were included. From 1081 articles identified across three databases, sixteen were included for the review. A range of breathwork interventions yielded significant improvements in anxiety symptoms in patients clinically diagnosed with anxiety disorders. The results around the role of hyperventilation in treatment of anxiety were contradictory in few of the examined studies. This evidence-based review supports the clinical utility of breathwork interventions and discusses effective treatment options and protocols that are feasible and accessible to patients suffering anxiety. Current gaps in knowledge for future research directions have also been identified.

Safety and effectiveness of intranasal esketamine for treatment-resistant depression: a real-world retrospective study.

Aim: There is limited real-world evidence for patients with treatment-resistant depression (TRD) receiving esketamine nasal spray. Methods: This retrospective cohort study used data collected from a psychiatric clinic's EHR system. Results: A total of 171 TRD patients received esketamine July 2019-June 2021. This predominantly female, white population had several mental health comorbidities and high exposure to psychiatric medications. We observed significant reductions (p < 0.001) in average PHQ-9 and GAD-7 scores from baseline (PHQ-9: mean: 16.7; SD: 5.8; GAD-7: mean: 12.0; SD: 5.8) to last available treatment (PHQ-9: mean: 12.0; SD: 6.4; GAD-7: mean: 8.7; SD: 5.6). There were no reports of serious adverse events. Conclusion: This study found a significant disease burden for patients with TRD. Esketamine appears to be well tolerated and effective in improving depression and anxiety.

Real-world depression, anxiety and safety outcomes of intramuscular ketamine treatment: a retrospective descriptive cohort study.

BACKGROUND: Ketamine has emerged as a promising pharmacotherapy for depression and other mental illnesses, and the intramuscular (IM) administration of ketamine is now offered at many North American outpatient psychiatric clinics. However, a characterization of the outpatient population receiving IM ketamine treatment and an evaluation of the real-world depression, anxiety, and safety outcomes of long-term psychiatric IM ketamine treatment has not been reported. This study aimed to evaluate the clinical characteristics, treatment patterns, clinical outcomes, and adverse events of patients receiving IM ketamine treatment. METHODS: Patient data from the electronic health records of a private outpatient psychiatric clinic network in the United States were collected and analyzed retrospectively. Adults with any psychiatric diagnosis who received ketamine treatment only by IM administration from January 2018 to June 2021 were included. A total of 452 patients were included in the cohort. RESULTS: Patients receiving IM ketamine treatment had a mean of 2.8 (SD 1.4) psychiatric diagnoses. 420 (93%) patients had a diagnosis of major depressive disorder, 243 (54%) patients had a diagnosis of generalized anxiety disorder, and 126 (28%) patients had a diagnosis of post-traumatic stress disorder. Patients received a median of 4 (range 1-48) IM ketamine treatments. Median depression scores (PHQ-9) improved 38% from 16.0 (IQR 11.3-21.8) at baseline to 10.0 (IQR 6.0-15.0) at last treatment (p < .001). Median anxiety scores (GAD-7) improved 50% from 14.0 (IQR 8.0-17.0) at baseline to 7.0 (IQR 4.3-11.8) at last treatment (p < .001). With maintenance ketamine treatments, average improvements in depression (PHQ-9) and anxiety (GAD-7) scores of at least 4.7 and 4.9 points were maintained for over 7 months. An adverse event occurred during 59 of 2532 treatments (2.3%). CONCLUSIONS: IM ketamine is being utilized to treat psychiatric outpatients with multiple mental illnesses not limited to depression. Average depression and anxiety levels significantly improve throughout IM ketamine treatment and do not regress to baseline during patients' maintenance treatment phase. Prospective studies are recommended to confirm the long-term effectiveness and safety of IM ketamine.

Cost-effectiveness of esketamine nasal spray compared to intravenous ketamine for patients with treatment-resistant depression in the US utilizing clinical trial efficacy and real-world effectiveness estimates.

OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of esketamine nasal spray relative to intravenous ketamine for patients with treatment-resistant depression (TRD) in the US. METHODS: We used a Markov model with a 1-month cycle length, and we estimated quality-adjusted life years (QALYs), costs (2020 USD), and incremental cost-effectiveness ratios (ICER) of esketamine relative to ketamine over a 3-year time horizon, from both the healthcare sector and patient perspectives. We ran the model using efficacy estimates from both clinical trial and real-world effectiveness (RWE) data. One-way and probabilistic sensitivity analyses (PSAs) were performed to evaluate the robustness of findings. RESULTS: Over a 3-year time horizon, the use of esketamine yielded 1.98 QALYs (RWE/clinical trial efficacy), and the use of ketamine yielded 2.03 QALYs (clinical trial efficacy) or 1.99 QALYs (RWE). Esketamine was dominated by ketamine using the healthcare perspective. ICERs were above $150,000/QALY threshold with the patient perspective. Under the healthcare perspective, PSA showed there are no scenarios where esketamine was cost-effective compared to ketamine. With the patient's perspective, the probability that esketamine was cost-effective compared to ketamine was 0.0055 (clinical trial efficacy) and 0.35 (RWE). LIMITATIONS: The data utilized for efficacy have limitations. The time horizon may fail to capture longer-term costs and benefits. CONCLUSIONS: In this decision analytic model evaluating esketamine versus ketamine for TRD, we found esketamine unlikely to be cost-effective under a healthcare sector perspective. Under a patient perspective, esketamine had similar effectiveness and was less costly than ketamine due to insurance coverage.

A case series of group-based ketamine-assisted psychotherapy for patients in residential treatment for eating disorders with comorbid depression and anxiety disorders.

BACKGROUND: Depression and anxiety outcome measures, safety/tolerability, patient satisfaction, and ease of implementation of group-based ketamine-assisted psychotherapy (G-KAP) delivered to patients in intensive residential eating disorder (ED) treatment were assessed. CASE PRESENTATION: This study reports on five participants with a diagnosis of an ED and comorbid mood and anxiety disorders who received weekly intramuscular ketamine injections in a group setting over 4 weeks. Measures of anxiety (GAD-7) and depression (PHQ-9) were administered pre-dose, 4-h post-dose, and 24-h post dose. Four of the 5 participants experienced clinically significant improvements on the PHQ-9 score (i.e., change greater than 5) while 2 of the 5 participants experienced clinically significant improvements on the GAD-7 score (i.e., change greater than 4) from pre-dose to 24-h post-dose after the last ketamine session. Dosing sessions were well tolerated, and no serious adverse events were reported. Clinical observations and participant reports corroborated improvements in depression and anxiety symptoms, good tolerability of ketamine treatment, and practical implementation of the G-KAP protocol in a residential ED treatment center. CONCLUSIONS: This study suggests the potential utility of G-KAP as an adjunct to intensive, specialized ED treatment. Overall, this novel, cross-diagnostic intervention warrants future research to further explore its appropriateness in a treatment setting.

Ketamine as a Novel Psychopharmacotherapy for Eating Disorders: Evidence and Future Directions.

Eating disorders (EDs) are serious, life-threatening psychiatric conditions associated with physical and psychosocial impairment, as well as high morbidity and mortality. Given the chronic refractory nature of EDs and the paucity of evidence-based treatments, there is a pressing need to identify novel approaches for this population. The noncompetitive N-methyl-D-aspartate receptor (NMDAr) antagonist, ketamine, has recently been approved for treatment-resistant depression, exerting rapid and robust antidepressant effects. It is now being investigated for several new indications, including obsessive-compulsive, post-traumatic, and substance use disorder, and shows transdiagnostic potential for EDs, particularly among clinical nonresponders. Hence, the aim of this review is to examine contemporary findings on the treatment of EDs with ketamine, whether used as a primary, adjunctive, or combination psychopharmacotherapy. Avenues for future research are also discussed. Overall, results are encouraging and point to therapeutic value; however, are limited to case series and reports on anorexia nervosa. Further empirical research is thus needed to explore ketamine efficacy across ED subgroups, establish safety profiles and optimize dosing, and develop theory-driven, targeted treatment strategies at the individual patient level.

Comparative Safety and Efficacy of Therapeutic Options in Resectable and Advanced/Metastatic Pancreatic Cancer: A Systematic Review and Indirect Comparison.

OBJECTIVES: FOLFIRINOX, gemcitabine/nab-paclitaxel (gem-nab/P), and gemcitabine-capecitabine (gem-cap) demonstrated superiority over gemcitabine monotherapy for pancreatic cancer (PC). It is still unclear which chemotherapy regimen is the most optimal. This study aimed to conduct a systematic review (SR) and indirect comparison to compare safety and efficacy of FOLFIRINOX versus gem-nab/P and gem-cap in PC. METHODS: An SR was conducted in several databases from inception to November 2020. RCTs investigating resectable or advanced PC were included. Primary outcomes including overall survival (OS), disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS), and grade 3/4 adverse events (AEs) were pooled using a random effects model. Indirect comparisons were done to compare FOLFIRINOX versus gem-cap and gem-nab/P. Heterogeneity was evaluated using Cochran's Q test and I2 statistics. RESULTS: Nine studies were identified involving 6,564 patients. Indirect comparisons showed FOLFIRINOX had significantly better OS (resectable: HR 0.78 [0.61-0.99]; advanced: HR 0.71 [0.60-0.85]) and RFS/DFS/PFS (resectable: HR 0.67 [0.55-0.82]; advanced: HR 0.65 [0.57-0.74]) compared to gem-cap as well as OS (resectable: HR 0.78 [0.61-1.00]; advanced: HR 0.73 [0.54-0.98]) and DFS/PFS (resectable: HR 0.66 [0.53-0.82]; advanced: HR 0.64 [0.49-0.83]) compared to gem-nab/P. FOLFIRINOX increased grade 3/4 AE risk compared to gem-cap and gem-nab/P. CONCLUSIONS: FOLFIRINOX is associated with significant survival benefits compared to gem-nab/P and gem-cap. However, it is important to consider the increased grade 3/4 AE risk associated with FOLFIRINOX.