Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: II. Sensitivity to treatment effects.

OBJECTIVE: Characteristics of difficult-to-treat depression (DTD), including infrequent symptom remission and poor durability of benefit, compel reconsideration of the outcome metrics historically used to gauge the effectiveness of antidepressant interventions. METHODS: Self-report and clinician assessments of depression symptom severity were obtained regularly over a 2-year period in a difficult-to-treat depression registry sample receiving treatment as usual (TAU), with or without vagus nerve stimulation (VNS). Alternative outcome metrics for characterizing symptom change were compared in effect size and discriminating power in distinguishing the vagus nerve stimulation + treatment as usual and treatment as usual treatment groups. We expected metrics based on remission status to produce weaker between-group separation than those based on the classifications of partial response or response and metrics that integrate information over time to produce greater separation than those based on single endpoint assessment. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination in separating the treatment groups than metrics based on partial response or response classifications. Metrics that integrated information over the 2-year observation period had stronger performance characteristics than those based on symptom scores at single endpoint assessment. For both the clinician-rated and self-report depression ratings, the metrics with the strongest performance characteristics were the median percentage change in symptom scores over the observation period and the proportion of the observation period in partial response or better. CONCLUSION: In difficult-to-treat depression, integrative symptom severity-based and time-based measures are sensitive and informative outcomes for assessing between-group treatment effects, while metrics based on remission status are not.

Preoperative Opioid Use Disorder is Associated with Longer Length of Stay, Infection Rate, and Healthcare Expenditure Following Primary Shoulder Arthroplasty.

Recent research efforts have focused on the complications and outcomes associated with opioid use disorder (OUD). However, there is a lack of evidence on the associated risks respective to each primary shoulder arthroplasty procedure. After separating patients by total shoulder arthroplasty (TSA) and reverse shoulder arthroplasty (RSA) and matching to controls, our study demonstrated significant association with longer LOS in both groups, higher risk of SSI and PJI in the TSA group, PJI in the RSA group, and higher costs regardless of procedure. Efforts to appropriately recognize OUD, optimize patients pre-operatively, and apply targeted surveillance postoperatively should be made. (Journal of Surgical Orthopaedic Advances 33(2):117-121, 2024).

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: I. Association with change in quality of life.

BACKGROUND: In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. METHODS: Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. CONCLUSIONS: Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

How does sleep apnea impact outcomes following primary total hip arthroplasty for femoral neck fractures: a matched-control analysis.

BACKGROUND: Cross-sectional studies have demonstrated that the prevalence of sleep apnea (SA) to be increasing within the United States. While studies have shown the association of SA and its association on complications following elective orthopedic procedures, well-powered studies investigating its impact in a traumatic setting are limited. The purpose of this study was to determine whether SA patients undergoing primary total hip arthroplasty (THA) for femoral neck fractures have higher rates of: (1) hospital lengths of stay (LOS); (2) readmissions; (3) complications; and (4) healthcare expenditures. METHODS: The 100% Medicare Standard Analytical Files was queried from 2005 to 2014 for patients who sustained femoral neck fractures and were treated with primary THA. The study group consisted of patients with concomitant diagnoses of SA, whereas patients without SA served as controls. Study group patients were matched to controls in a 1:5 ratio by age, sex, and various comorbid conditions. Demographics of the cohorts were compared using Pearson's chi-squared analyses, and multivariate logistic regression analyses were used to calculate the odds (OR) of the effects of SA on postoperative outcomes. A p value less than 0.006 was considered to be statistically significant. RESULTS: The final query yielded 24,936 patients within the study (n = 4166) and control (n = 20,770) cohorts. SA patients had significantly longer in-hospital LOS (6 vs. 5 days, p < 0.0001) but similar readmission rates (24.12 vs. 20.50%; OR: 1.03, p = 0.476). SA patients had significantly higher frequency and odds of developing medical complications (72.66 vs. 43.85%; OR: 1.57, p < 0.0001), and higher healthcare costs ($22,743.79 vs. $21,572.89, p < 0.0001). CONCLUSION: SA is associated with longer in-hospital LOS, higher rates of complications and healthcare expenditures. This study is vital as it can allow orthopaedists to educate patients with SA on the potential complications which may occur following their procedure. LEVEL OF EVIDENCE: III.

Discovery of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.

Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.

The effects of the COVID-19 pandemic on elective unicompartmental knee arthroplasty in the USA: further evidence that outpatient arthroplasty is safe and effective.

PURPOSE: In response to COVID-19, elective surgeries including unicompartmental knee arthroplasties (UKA) decreased. We aimed to quantify and compare temporal trends in utilization and complications in the calendar year 2019 (pre-pandemic) to 2020 in the USA. METHODS: The 2019 to 2020 ACS-NSQIP database was queried for patients undergoing elective UKA. Patients prior to COVID-19 (2019 and 2020 Q1) were compared to those after (2020 Q2-Q4). Case volumes, patient demographics, complications, and lengths of stay (LOS) were compared between years. Pearson's chi-square test was used to compare patient demographics. Linear regression was conducted to evaluate the change in case volumes. P values less than 0.05 were significant. RESULTS: In total, 3361 patients underwent UKA: 1880 in 2019 and 1481 in 2020. The number of outpatient UKAs increased (56.4% vs. 65.6%; p < 0.001). There was no significant difference in the volume of cases in 2019Q1 through 2020Q1 (p = 0.424). Case volumes fell by 60% in 2020Q2 compared with the average quarterly volume in 2019. Comparing 2019 to 2020, there was no significant difference in rates of total complications (2.1% vs. 2.2%; p = 0.843), minor complications (1.2% vs. 0.9%; p = 0.529), major complications (1.1% vs. 1.4%; p = 0.447), infection complications (1.0% vs. 0.8%; p = 0.652), wound complications (0.1% vs. 0.1%; p = 1.0), cardiac complications (0.0% vs. 0.1%; p = 0.111), pulmonary complications (0.1% vs. 0.2%; p = 0.473), hematology complications (0.1% vs. 0.1%; p = 1.0), renal complications (0.1% vs. 0.0%; p = 1.0), and Clavien-Dindo IV complications (0.1% vs. 0.4%; p = 0.177). CONCLUSION: UKA case volumes declined during the second quarter of 2020. A significant proportion of surgeries were transitioned outpatient, despite no change in complication rates.

Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine. METHODS: We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9-12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638. FINDINGS: Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9-12. The change from the observation period in mean number of migraine days per month during weeks 9-12 was -4·3 days (95% CI -4·8 to -3·9) with rimegepant and -3·5 days (-4·0 to -3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died. INTERPRETATION: Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted. FUNDING: Biohaven Pharmaceuticals.

Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine.

BACKGROUND: Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment. METHODS: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered. RESULTS: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection. CONCLUSIONS: Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

How Did Coronavirus-19 Impact the Expenses for Medical Students Applying to an Orthopaedic Surgery Residency in 2020 to 2021?

BACKGROUND: Orthopaedic surgery is one of the most competitive specialties for residency applicants. For the 2021 residency match, the coronavirus-19 pandemic introduced complexity for programs and applicants because away rotations were limited and in-person interviews were cancelled. This may have changed the landscape in terms of expenses for candidates in important ways, but this topic has been insufficiently studied. QUESTIONS/PURPOSES: Given that in 2021, students did not attend away rotations and all interviews were held virtually, we asked (1) What were the financial savings associated with this change? (2) Was medical school geographic region associated with differences in expenses when applying to residency? METHODS: A retrospective, cross-sectional analysis of the 2020 and 2021 Texas Seeking Transparency in Application to Residency Dashboard database was performed. The data were derived from an online survey of a nationwide pool of applicants from 87% (123 of 141) of US allopathic medical schools upon conclusion of the match. The response percentage was 29% (521 of 1794). We believe this nationwide dataset represents the largest and most current data for this applicant group. Responses from applicants applying to orthopaedic surgery residency in the year before the COVID-19 pandemic application changes (2020) and during COVID-19 (2021) were queried and compared. After the orthopaedic surgery match, the database was evaluated for individual (application costs, away rotation expenses, and interview expenses) and total expenses for medical school seniors applying to orthopaedic surgery residency. Applicant characteristics were compared between application cycles. The 2020 to 2021 Texas Seeking Transparency in Application to Residency Dashboard database had 521 responses (n = 263 in 2020 and n = 258 in 2021) from applicants applying to orthopaedic surgery residency. Demographic and applicant characteristics were comparable between application cycles. Median expenses are reported with percentile distributions and geographic comparisons. A Mann-Whitney U test or Kruskal-Wallis H test was used to determine whether there were statistically significant differences in expenses between years and between medical school regions at a p value threshold of < 0.05. RESULTS: For all applicants, the median total expenses (USD 7250 versus USD 2250), application costs (USD 2250 versus USD 1750), away rotation expenses (USD 2750 versus USD 250), and interview expenses (USD 2250 versus USD 75) declined in 2021 compared with 2020 (all p < 0.001). The median total savings in expenses for all applicants in 2021 compared with 2020 was USD 5000. In 2021, median total expenses were lower in all geographic regions with the greatest savings from applicants in the West (USD 6000); in addition, the difference in median total expenses between the geographic region with the highest total expenses and the lowest total expenses was lower in the pandemic year than it was in the year prior (USD 1000 versus USD 1500; p < 0.001). In 2021, there were differences in total expenses between the Northeast (USD 1750), West (USD 1750), and Central (USD 2750) regions (p < 0.001). From 2020 to 2021, only application fees from Northeast applicants differed (USD 2250 versus USD 1250; p < 0.001). In 2020, interview expenses were not different between all regions (USD 2250 Northeast and West versus USD 2750 Central and South; p = 0.19); similarly in 2021, interview expenses were similar between all regions (USD 75 versus USD 75; p = 0.82). Finally, in 2020, Northeast (USD 3250) and Western (USD 3250) applicants spent more for away rotations than Southern (USD 2750) and Central (USD 2250) applicants (p = 0.01). In 2021, applicants from schools in the South (USD 250) and Central (USD 250) regions spent more than their counterparts (USD 0; p = 0.028). CONCLUSION: In the COVID-19 application cycle, the median expenditures of orthopaedic residency candidates were USD 5000 lower than they were in the previous year; the difference can be attributed to the use of virtual interviews and the lack of away rotations. There are geographic implications, with applicants from Western United States medical schools potentially saving the most. Despite the financial savings during the 2021 match, further study related to the long-term success of the current application process (both for applicants and programs) is needed. The recommendation in May 2020 by the AOA Council of Orthopaedic Residency Directors (CORD) to limit the number of applications submitted by candidates with USMLE Step 1 scores greater than 235 did not result in any considerable decline in applications submitted or expenses. A better understanding of how differences in these expenses may influence our specialty's ability to attract socioeconomically diverse candidates would be important, and we need to explore perceived and actual financial obstacles to obtaining this diversity in the application process. Finally, avenues should be explored by program directors and chairpersons to reduce the expenses of the traditional application process while maintaining recruitment of top candidates. LEVEL OF EVIDENCE: Level IV, economic analysis.

The resiliency of elective total shoulder arthroplasty case volumes in the United States during the COVID-19 pandemic: a nationwide temporal trends analysis.

BACKGROUND: Total shoulder arthroplasty (TSA) is one of the fastest growing procedures in terms of volume performed in hospitals in the United States. In 2020, elective surgery was suspended nationwide as a result of the SARS-CoV-2 (COVID-19) pandemic, and the use trends in the wake of the pandemic have yet to be evaluated substantially. Nationwide case volume reduction for TSA is unknown; therefore, the aim of this study is to compare patient demographics, complications, and temporal trends in case volume of elective TSA in the calendar year 2019 (prepandemic) to 2020 in the United States. METHODS: Using a multicenter, nationwide representative sample from 2019 to 2020, a retrospective query was conducted for all patients undergoing elective TSA. Patients undergoing surgery pre-COVID (2019 and 2020 Q1) were compared to those during COVID (2020 Q2-Q4). Temporal trends in case volumes were compared between time frames. TSA use, patient demographics, complications, and length of stay were compared between years. Linear regression was used to evaluate for changes in the case volume over the study period. A statistical significance threshold of P <.05 was used. RESULTS: In total, 9667 patients underwent elective TSA in 2019 (n = 5342) and 2020 (n = 4325). The proportion of patients who underwent outpatient TSA in 2020 was significantly greater than the year prior (20.6% vs. 13.9%; P < .001). Overall, elective TSA case volume declined by 19.0% from 2019 to 2020. There was no significant difference in the volume of cases in 2019 Q1 (n = 1401) through 2020 Q1 (n = 1296) (P = .216). However, elective TSA volumes declined by 54.6% in 2020 Q2. Elective TSA case volumes recovered to prepandemic baseline in 2020 Q3 and 2020 Q4. The average length of stay was comparable in 2020 vs. 2019 (1.29 vs. 1.32 days; P = .371), with the proportion of same-day discharge increasing per quarter from 2019 to 2020 (from 11.8% to 26.8% of annual cases). There was no significant difference in the total complication rates in 2019 (4.6%) vs. 2020 (4.9%) (P = .441). CONCLUSION: Using a nationwide sample, elective TSA precipitously declined during the second quarter of 2020. Patient demographics of those undergoing elective TSA in 2020 were similar in comorbidity burden. A large proportion of surgeries were transitioned to the outpatient setting, with rates of same-day discharge doubling over the study period despite no change in overall complication rates.

Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists.

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP Ki = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (FPO = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP Ki = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat FPO = 17%).

Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead.

In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.

Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. METHODS: In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. FINDINGS: Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3â€ˆ× the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2â€ˆ× the upper limit of normal were reported. Treated participants reported no serious adverse events. INTERPRETATION: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. FUNDING: Biohaven Pharmaceuticals.

Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With Depression.

OBJECTIVE: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). DESIGN: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. SETTING: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. PARTICIPANTS: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. INTERVENTION: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). OUTCOMES: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. RESULTS: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2 = 19.3, df = 2; p <0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities. CONCLUSIONS: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.

Safety of Rimegepant, an Oral CGRP Receptor Antagonist, Plus CGRP Monoclonal Antibodies for Migraine.

OBJECTIVE: Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine. BACKGROUND: The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs). METHODS: This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks. RESULTS: The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal. CONCLUSION: Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.

Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. RESULTS: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. CONCLUSIONS: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

Tricyclic Antidepressants and Monoamine Oxidase Inhibitors: Are They Too Old for a New Look?

Through unintentional discovery, monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were the first antidepressant classes to be used clinically and have been widely available for over half a century. From the 1950s to the 1980s, these two classes of antidepressants were the sole antidepressant tools available to psychiatrists. With the advent of the selective serotonin reuptake inhibitors (SSRIs) in the 1980s and 1990s, the prescribing of the MAOIs and TCAs has fallen significantly worldwide. In this chapter, we take a closer look at the arc of MAOI discovery and clinical use, and how these two classes of drugs compare to each other. This is important because relatively few studies compare these older classes of drugs to the newer classes of antidepressants. Finally, we argue that TCAs, and particularly MAOIs, should continue to play an important role in the modern treatment of depression, especially in the treatment-resistant patient.

Neurostimulation Therapies.

Depression is one of the most disabling conditions in the world. In many cases patients continue to suffer with depressive disorders despite a series of adequate trials of medication and psychotherapy. Neuromodulation treatments offer a qualitatively different modality of treatment that can frequently prove efficacious in these treatment-refractory patients. The field of neuromodulation focuses on the use of electrical/electromagnetic energy, both invasively and noninvasively, to interface with and ultimately alter activity within the human brain for therapeutic purposes. These treatments provide another set of options to offer patients when clinically indicated, and knowledge of their safety, risks and benefits, and appropriate clinical application is essential for modern psychiatrists and other mental health professionals. Although neuromodulation techniques hold tremendous promise, only three such treatments are currently approved by the United States Food and Drug Administration (FDA) for the treatment of major depressive disorder: electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and repetitive transcranial magnetic stimulation (rTMS). Additionally, numerous other neurostimulation modalities (deep brain stimulation [DBS], magnetic seizure therapy [MST], transcranial electric stimulation [tES], and trigeminal nerve stimulation [TNS]), though currently experimental, show considerable therapeutic promise. Researchers are actively looking for ways to optimize outcomes and clinical benefits by making neuromodulation treatments safer, more efficacious, and more durable.