Ketamine, an N-methyl-d-aspartate receptor antagonist, has been “repurposed” as a rapid-acting antidepressant for treatment-resistant depression (TRD). The s-enantiomer of ketamine, “esketamine,” was FDA approved for TRD and depressive symptoms in adults with major depressive disorder with suicidal ideations/behaviors. Intravenous (IV) ketamine, although financially less expensive, is often not covered by insurance and intranasal (IN) esketamine, although covered by insurance can be expensive. There is a paucity of literature on efficacy data comparing subanesthetic IV ketamine and IN esketamine for TRD in a real-world scenario. Thus, we conducted this study comparing the efficacy and the number of treatments required to achieve remission/response with repeated use of subanesthetic IV ketamine/IN esketamine among TRD patients.

This was an observational study where we included adults (≥18 years) with TRD who provided consent and had received up to 6 IV ketamine infusions (0.5 mg/kg, infused over 40 minutes) or up to 8 intranasal (IN) esketamine (56/84 mg) treatments for TRD at the Mayo Clinic Depression Center. Depression symptoms were measured utilizing the self-report 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale before and 24 hours after ketamine/esketamine treatment. Remission and response were defined as QIDS-SR 16 score ≤5 and ≥50% change in QIDS-SR 16, respectively. Continuous variables are reported as means ± SD and categorical variables as counts and percentages. The Wilcoxon rank-sum test was used to compare continuous variables. Chi-square and Fisher’s exact tests were used to compare categorical variables. The number of treatments to remission/response was calculated.

Sixty-three adults with TRD, middle-aged (47.0 ± 12.1 years), predominantly female (65%), of which 76% (n = 48) and 24% (n = 15) received IV ketamine and IN esketamine, respectively. Mean (SE) change in QIDS-SR 16 score was −8.7 ± 0.7 (P < .001), a significant reduction (improvement) from baseline (mean ± SD = 17.6 ± 3.7). Overall remission and response rates were 36.5% and 55.6%, respectively in the acute phase. Response (56.3% vs 53.3%) and remission rates (39.6% vs 26.7%) were similar among patients who received IV ketamine or IN esketamine, respectively (P > .05). The mean number of treatments received to achieve response (2.5 ± 1.6 vs 4.6 ± 2.1) and remission (2.4 ± 1.3 vs 6.3 ± 2.4) were significantly lower among patients who received IV ketamine compared to IN esketamine (P < .005). Most patients tolerated both treatments well.

Intravenous ketamine and intranasal esketamine showed similar response/remission in TRD patients but the number of treatments required to achieve response/remission was significantly lower with IV ketamine compared to IN esketamine. These findings need to be investigated in a randomized control trial comparing these two treatment interventions.

No funding

Prescription opioid dispensing patterns over time were assessed for individuals with bipolar disorder (BD) vs matched controls.

Health insurance claims data from the IBM MarketScan Commercial Database and Multi-State Medicaid Database were analyzed. Individuals aged 18 to 64 with ≥1 inpatient or ≥2 outpatient claims for BD during the year preceding the analysis year (2015-2019) were included, with age- and sex-matched controls. Baseline demographic and clinical characteristics were evaluated. Opioid dispensing during each analysis year was defined as either chronic (coverage for ≥70 days in any 90-day period, or ≥6 prescriptions dispensed during analysis year) or nonchronic (≥1 prescription dispensed, not meeting chronic definition).

BD patients had a higher prevalence of medical and psychiatric comorbidities, including pain diagnoses, vs controls. Among patients with BD in the Commercial database, chronic opioid dispensing decreased from 11% (controls: 3%) in 2015 to 6% (controls: 2%) in 2019, and in the Medicaid database, from 27% (controls: 12%) to 12% (controls: 5%). Among patients with BD in the Commercial database, nonchronic dispensing decreased from 26% (controls: 17%) in 2015 to 20% (controls: 12%) in 2019, and from 32% (controls: 26%) to 25% (controls: 14%) in the Medicaid database.

Between 2015 and 2019, there was a significant decrease in chronic and nonchronic prescription opioid dispensing among BD patients and controls across both the Commercial and Medicaid databases. Despite this finding, it is important to note that both chronic and nonchronic opioid dispensing was consistently higher for BD patients vs controls over time, across both databases.

Alkermes, Inc.

A combination of olanzapine and samidorphan (OLZ/SAM) that provides the efficacy of olanzapine while mitigating weight gain was recently approved by the FDA for the treatment of schizophrenia and bipolar I disorder. To improve communication of the OLZ/SAM benefit-risk profile, a structured framework was utilized.

The Benefit-Risk Action Team framework was used to evaluate OLZ/SAM, with analyses completed for each pivotal study. ENLIGHTEN-1 evaluated antipsychotic efficacy and safety. ENLIGHTEN-2 evaluated the weight profile of OLZ/SAM vs olanzapine. Benefit-risk outcomes were selected based on study outcome parameters, known risks of olanzapine and samidorphan, and public health importance. A subset of opioid antagonist risks was not assessed due to clinical trial exclusions; however, they were factored into the overall evaluation. Risk differences and confidence intervals were analyzed.

In ENLIGHTEN-1, OLZ/SAM had a lower risk of psychiatric discontinuation and nonresponse to treatment compared with placebo; higher risks of hyperprolactinemia, weight gain (≥7%), sedation, and worsening of fasting triglycerides and glucose, and no difference for fasting total and LDL cholesterol, neutropenia, orthostatic hypotension, and movement disorders. In ENLIGHTEN-2, OLZ/SAM had reduced risks of weight gain and waist circumference increase compared to olanzapine along with similar risks of relapse and psychiatric discontinuation and no difference in metabolic worsening, neutropenia, hyperprolactinemia, orthostatic hypotension, sedation, and movement disorders.

Based on this assessment, OLZ/SAM has comparable efficacy and a safety profile consistent with olanzapine, with reduced weight gain. A structured approach to assessing the benefit-risk profile of a product facilitates transparent evaluation and communication.

Alkermes, Inc.

MIND-TD is a collaboration of healthcare professionals (HCPs) who are committed to raising awareness of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. The MIND-TD questionnaire was developed to help HCPs screen for TD and facilitate discussion with patients.

In August 2020, an expert panel of 13 HCPs (4 psychiatrists, 6 neurologists/movement disorder specialists [MDSs], and 3 advanced practice providers [APPs]) met virtually to discuss potential screening questions for TD. This work was continued by 4 panelists (1 psychiatrist, 2 neurologists/MDSs, and 1 APP) who tested the questions in clinical practice for revision and refinement. The same group also worked with the sponsor to develop 2 additional sections that could be used to elicit more information from patients. The panel recognized the need for a tool that could facilitate telehealth screening for TD, including audio-only interactions. Therefore, practices from speech-language pathologists (eg, diadochokinetics) were used to refine the questionnaire.

Part 1 of the MIND-TD questionnaire includes a yes-or-no question for each of the 4 following topics: presence of extra or unwanted movements (Movement); feelings of embarrassment or self-consciousness (Impact); if anyone else has noticed the movements (Notice); and if movements interfere with everyday routines (Daily Activities). Part 1 can be administered by any trained medical staff, either in person or via telehealth (with video or audio-only). Routine administration is suggested in all patients who meet any of the following criteria: current or prior use of any first- or second-generation antipsychotic; use of an anticholinergic medication in conjunction with a current or past antipsychotic; or current diagnosis of TD. Part 2 of the MIND-TD questionnaire has 2 sections. The first (Thorough Interview) includes 9 items related to physical/functional difficulties (eg, eating, speaking, walking, and gripping objects) and 3 simple instructions for speech difficulties. The second section (Differentiate) includes checklists of characteristic movements for TD and drug-induced parkinsonism, along with an item related to akathisia and suggestions for observing abnormal or involuntary movements. Part 2 should be administered by the treating HCP in patients who have abnormal movements that may be related to TD. Part 2 requires visual observation of the patient, whether in-person or via video.

MIND-TD is a screening questionnaire that can facilitate a dialogue between HCPs and patients about the risks, symptoms, and impact of TD. The MIND questions can stand alone and be administered during in-person visits or telehealth visits (video or audio-only). The TD section can be used to gather more information about a patient’s abnormal movements.

Neurocrine Biosciences, Inc.

Older patients taking a dopamine receptor blocking agent (eg, first- or second-generation antipsychotic) have an increased risk for tardive dyskinesia (TD), a persistent and potentially disabling movement disorder. Valbenazine, a selective and potent vesicular monoamine transporter 2 inhibitor, is approved for once-daily treatment of TD with no dosing adjustments required for older patients. This analysis of valbenazine clinical trial data, which is the first to evaluate an approved TD medication in a population ≥65 years, was conducted to better understand treatment outcomes in older patients.

Data from two 48-week long-term studies (KINECT 3-extension, KINECT 4) were pooled and analyzed in older (≥65 years) and younger (<65 years) participants. Analyses based on the Abnormal Involuntary Movement Scale (AIMS) total score included: mean change from baseline (BL); clinically meaningful response (≥30% improvement from BL [AIMS-30%]); and protocol-defined response (≥50% improvement from BL [AIMS-50%]). Additional analyses included response thresholds for Clinical Global Improvement-Tardive Dyskinesia and Patient Global Impression of Change as follows: rating of “minimally improved” or better (score ≤3) at week 48 (CGI-TD≤3, PGIC≤3); rating of “much improved” or “very much improved” (score ≤2) at week 48 (CGI-TD≤2, PGIC≤2).

AIMS outcomes in the older subgroup were generally comparable to (or better than) outcomes in the younger subgroup and overall study populations. In participants ≥65 years, pooled AIMS results indicated substantial improvements in TD movements with valbenazine 40 mg (n = 8) and 80 mg (n = 20): mean change from BL (−6.4 and −9.8 [for 40 and 80 mg, respectively]); AIMS-30% (75% and 95%); AIMS-50% (75% and 85%). CGI-TD and PGIC response rates indicated that clinician- and patient-reported global improvements were also substantial in the older subgroup: CGI-TD = 3 (88% and 100% [for 40 and 80 mg, respectively]); CGI-TD = 2 (88% and 95%); PGIC = 3 (88% and 100%); PGIC = 2 (75% and 90%).

These analyses, which are the first to evaluate long-term valbenazine effects in patients ≥65 years, indicate that older study participants had clinically meaningful and substantial improvements in TD that were comparable to (or better than) those in younger participants.

Neurocrine Biosciences, Inc.

The purpose of this case study is to review the clinical presentation and medical workup of a young adult male presenting with rhabdomyolysis in the setting of suspected contributing factors, including treatment with mirtazapine and history of COVID-19 infection.

This case study involves a 19-year-old male in a residential setting with a psychiatric history of major depressive disorder and post-traumatic stress disorder who had been stabilized on mirtazapine for 9 months. Then, the patient exhibited fever, sore throat, cough, nausea, diarrhea, and malaise and was diagnosed with COVID-19 infection; he did not require hospitalization, was treated with supportive care, and signs and symptoms resolved uneventfully. Approximately 2 months later, in the winter, the patient presented for clinical assessment due to hematuria and painful urination. History revealed that he had been exercising excessively exercising over the past 24 hours, completing hundreds of push-ups and sit-ups. The patient presented to a nearby community hospital and was found to have creatine kinase of over 500,000. He was transferred to a large Midwestern university hospital for further evaluation and management.

The patient’s serum creatine kinase level was found to be 510,000 U/L. Patient’s ALT, AST, and alkaline phosphatase were 283, 79, and 76 IU/L, respectively, while creatinine was 0.92. Patient received vigorous hydration, supportive care, and further evaluation. Treatment with mirtazapine was discontinued. The following week he developed severe nausea and vomiting; creatine kinase had decreased to 920, while hepatic function tests remained mildly elevated. Evaluation for hepatitis, cytomegalovirus, and Epstein-Barr virus were negative, as was Wilson’s disease and hemochromatosis. Further medical workup for other potential causes of rhabdomyolysis was negative. The patient recovered and is asymptomatic with return to normal lab values. He remains in psychiatric follow-up.

The patient’s presentation of rhabdomyolysis may have been attributable to multiple factors. Independently, sustained excessive physical activity, COVID-19 infection, and treatment with mirtazapine have all been implicated in the development of rhabdomyolysis. Caution should be taken when prescribing mirtazapine in individuals at higher risk of developing rhabdomyolysis, including those engaged in excessive exercise or who have had COVID-19 infection.

No funding

Major depressive disorder (MDD) is the second leading cause of disability and chronic disease burden in the United States. The importance of improving functional outcomes in MDD is increasingly recognized. The Symptoms of Depression Questionnaire (SDQ), a patient-reported measure, was developed to capture the heterogeneity of symptoms of MDD. REL-1017 (esmethadone HCl; d-methadone), is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and potential rapid antidepressant currently in Phase 3 development. In a Phase 2a trial, REL-1017 showed robust, rapid, and sustained antidepressant efficacy as adjunctive treatment in patients with MDD. The objective of this study was to assess the effects of REL-1017 on SDQ subscales to better characterize the functional implications of its therapeutic effects.

A double-blind, placebo-controlled, inpatient, two-doses, 25 and 50 mg, three-arm, 1:1:1, randomized, phase 2a trial of REL-1017 was conducted at 10 centers in the United States. Least square (LS) mean scores and Cohen’s effect sizes of the total score of a 44-item of SDQ and its 5 subscales: lassitude, mood, cognitive/social functioning (SDQ-1); anxiety, agitation, anger, and irritability (SDQ-2); desire to be dead (SDQ-3); disruptions in sleep quality (SDQ-4); changes in appetite and weight (SDQ-5) were compared between REL-1017 and placebo.

A total of 62 adult male and female patients (18-65 years of age) diagnosed with MDD participated in the trial. On day 14, the last day of efficacy measurement, the difference from placebo of the LS mean (90% CI) for REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed improvement for both tested doses on SDQ total score (−23.2; P = .0066 [effect size: 0.9]; −26.8 P = .0014 [effect size: 1.1]). Additionally, for SDQ subscales, REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed significant improvement as compared with placebo: SDQ-1 (−13.9; P = .0025 [effect size: 1.0]; −15.0; P = .0009 [effect size: 1.1]), SDQ-2 (−4.6; P = .0398 [effect size: 0.7]; −7.2; P = .0012 [effect size: 1.1]) and SDQ-4 (−2.7; P = .0055 [effect size: 1.0]; −2.8; P = .0029 [effect size: 1.0]). No significant differences were observed between the treated groups and placebo in the SDQ-3 and SDQ-5 subscales.

In patients with MDD, aside from improving the overall CFB compared to placebo in SDQ total score, REL-1017 resulted in clinically meaningful and statistically significant improvements in cognitive/motivational, anxiety/irritability, and sleep-specific domains. The robust, rapid, and sustained efficacy of REL-1017 for MDD is not limited to improving mood, but potentially extends to cognitive, motivational, sleep, and social functions, with potentially meaningful therapeutic and socioeconomic implications. These results may signal disease-modifying effects of esmethadone for MDD that may offer potential advantages over symptomatic treatment with standard antidepressants.

Relmada Therapeutics, Inc.

Dissociative symptoms may be found in a subset of patients with major depressive disorders (MDD). The Clinician-Administered Dissociative States Scale (CADSS) is a 23-item scale for the measurement of present-state dissociative symptoms with good inter-rater reliability and construct validity that can discriminate patients with dissociative disorders. The total CADSS score is derived by adding the score for each of the 23 items. A score of 4 or more on the CADSS is considered abnormal and clinically meaningful. Uncompetitive N-methyl-d-aspartic acid receptor (NMDAR) channel blockers have been proposed as a treatment for post-traumatic stress disorder (PTSD). REL-1017 is a novel, low potency, NMDAR channel blocker currently in Phase 3 studies for MDD.

This retrospective case series describes a subset of patients from a double-blind, randomized, placebo-controlled, in-patient 7-day, phase 2 trial of oral, once daily, 25 mg (75 mg loading dose on day 1, first dose) and 50 mg REL-1017 (100 mg loading dose on day 1, first dose) as an adjunctive treatment for MDD. This subset of patients was selected based on abnormal CADSS score at baseline, pre-treatment with the study drug. As part of REL-1017 safety evaluation, the CADSS was administered at four timepoints to all study patients: (a) 30 to 60 minutes pre-treatment at baseline on day 1; (b) 2 hours post-treatment on day 1 (after the first dose of study drug); (c) 2 hours post-treatment on day 7 (after the last dose); and (d) prior to discharge on day 9 (2 days after the last dose).

Among the 62 randomized patients, four patients had a CADSS score of at least 4 on day 1 before study drug administration (2 patients in the 25 mg arm [CADSS score 22 and 4]; 1 patient in the 50 mg arm [CADSS score 35]; 1 patient in the placebo arm [CADSS score 6]). Among these 4 patients, starting on day 1, 2 hours post-treatment, the 2 subjects in the 25 mg subgroup (75 mg loading dose) and 1 subject in the 50 mg subgroup (100 mg loading dose) showed a clinically meaningful decrease in their CADSS score, while the single patient in the placebo group showed no change. CADSS scores on Day 1 pre-treatment, day 1 post-treatment, day 7 post last treatment, and on day 9 prior to discharge were 22-2-6-0; 4-0-0-0; 35-14-9-0, and 6-6-n/a-n/a, for the two patients in the 25 mg REL-1017 subgroup, the single patient in the 50 mg REL-1017 subgroup, and the single patient in the placebo group, respectively.

These retrospective case report data potentially signal that REL-1017 may determine rapid and sustained improvement in patients with MDD and concurrent clinically meaningful dissociative symptoms assessed by a CADSS score of 4 or above. Ongoing phase 3 trials with REL-1017 are expected to enroll a total of 1200 outpatients with MDD. These studies will potentially generate additional data that may support the initiation of controlled studies with REL-1017 for the treatment of PTSD.

Relmada Therapeutics

Adverse drug reactions (ADRs) are associated with increased morbidity, mortality, and resource utilization. Drug interactions (DDIs) are among the most common causes of ADRs, and estimates have cited that up to 22% of patients take interacting medications. DDIs are often due to the propensity for agents to induce or inhibit enzymes responsible for the metabolism of concomitantly administered drugs. However, this phenomenon is further complicated by genetic variants of such enzymes. The aim of this study is to quantify and describe potential drug-drug, drug-gene, and drug-drug-gene interactions in a community-based patient population.

A regional pharmacy with retail outlets in Arkansas provided deidentified prescription data from March 2020 for 4761 individuals. Drug-drug and drug-drug-gene interactions were assessed utilizing the logic incorporated into GenMedPro, a commercially available digital gene-drug interaction software program that incorporates variants of 9 pharmacokinetic (PK) and 2 pharmacodynamic (PD) genes to evaluate DDIs and drug-gene interactions. The data were first assessed for composite drug-drug interaction risk, and each individual was stratified to a risk category using the logic incorporated in GenMedPro. To calculate the frequency of potential drug-gene interactions, genotypes were imputed and allocated to the cohort according to each gene’s frequency in the general population. Potential genotypes were randomly allocated to the population 100 times in a Monte Carlo simulation. Potential drug-drug, gene-drug, or gene-drug-drug interaction risk was characterized as minor, moderate, or major.

Based on prescription data only, the probability of a DDI of any impact (mild, moderate, or major) was 26% [95% CI: 0.248-0.272] in the population. This probability increased to 49.6% [95% CI: 0.484-0.507] when simulated genetic polymorphisms were additionally assessed. When assessing only major impact interactions, there was a 7.8% [95% CI: 0.070-0.085] probability of drug-drug interactions and 10.1% [95% CI: 0.095-0.108] probability with the addition of genetic contributions. The probability of drug-drug-gene interactions of any impact was correlated with the number of prescribed medications, with an approximate probability of 77%, 85%, and 94% in patients prescribed 5, 6, or 7+ medications, respectively. When stratified by specific drug class, antidepressants (19.5%), antiemetics (21.4%), analgesics (16%), antipsychotics (15.6%), and antiparasitics (49.7%) had the highest probability of major drug-drug-gene interaction.

In a community-based population of outpatients, the probability of drug-drug interaction risk increases when genetic polymorphisms are attributed to the population. These data suggest that pharmacogenetic testing may be useful in predicting drug interactions, drug-gene interactions, and severity of interactions when proactively evaluating patient medication profiles.

Genomind, Inc.

Chronic insomnia affects the physical and mental health, quality of life, and productivity of 6 to 10% of the adult population (15-25 million U.S. adults). Available treatments include guideline-recommended first-line cognitive behavioral therapy for insomnia (CBT-I) and medications. However, limitations such as patient access to CBT-I and limited efficacy, the presence of significant side effects, as well as safety concerns about medications limit favorable outcomes. Somryst is an FDA-authorized prescription digital therapeutic for the treatment of chronic insomnia in adults. The purpose of this analysis is to compare the effectiveness of the digital therapeutic vs CBT-I and medications for primary insomnia.

Chronic insomnia trials focused on digital therapeutic, CBT-I, or medication were identified in a systematic literature review. Studies using a comparator arm that cannot be considered clinically equivalent to other treatments in the network were excluded (eg, meaningfully different definition of placebo arm). A Bayesian network meta-analysis was performed in R on the mean change from baseline and the proportion of remitters using the insomnia severity index (ISI) endpoint with follow-up timepoints between 6 and 12 weeks. Mean change in ISI score from baseline was analyzed as a continuous endpoint while comparisons of the proportion of remitters were performed using odds ratios. The analysis used a random-effects model for the base case analysis. A surface under the cumulative ranking curve (SUCRA) analysis was performed to rank the treatments on each endpoint.

In total, 13 studies reported ISI mean change from baseline data. Only the digital therapeutic and CBT-I were significantly different than placebo. The digital therapeutic had the greatest mean change from baseline in ISI from placebo (−5.77 points, 95% Credible Interval (CrI) [−8.53, −3.07]), followed by CBT-I (−4.3 points, 95% CrI [−6.32, −2.39]). In the SUCRA analysis, the digital therapeutic had the highest probability (56%) of being the most effective treatment based on ISI mean change from baseline. Only 8 studies reported the proportion of ISI remitters. Only the digital therapeutic showed a statistically significant difference in remission vs placebo and had the highest odds ratio for remission vs placebo (12.33 95% CrI [2.28, 155.91]). The odds ratio for remission vs placebo in CBT-I was not statistically significant (4.08 95% CrI [0.45, 45.58]). The digital therapeutic had the highest probability (64%) of being the most efficacious for inducing remission per ISI.

Somryst was projected to be the most effective therapy on both mean change in ISI and ISI remission within 6 to 12 weeks of treatment start vs either CBT-I or medications. Further investigation should be performed to demonstrate the long-term effectiveness of all chronic insomnia treatments.

Pear Therapeutics

The opioid epidemic in the United States is getting worse: in 2020 opioid overdose deaths hit an all-time high of 92,183. This underscored the need for more effective and readily available treatments for patients with opioid use disorder (OUD). Prescription digital therapeutics (PDTs) are FDA-authorized treatments delivered via mobile devices (eg, smartphones). A real-world pilot study was conducted in an outpatient addiction treatment program to evaluate patient engagement and use of a PDT for patients with OUD. The objective was to assess the ability of the PDT to improve engagement and care for patients receiving buprenorphine medication for opioid use disorder (MOUD).

Patients with OUD treated at an ambulatory addiction treatment clinic were invited to participate in the pilot. The reSET-O PDT is comprised of 31 core therapy lessons plus 36 supplementary lessons, plus contingency management rewards. Patients were asked to complete at least 4 lessons per week, for 12-weeks. Engagement and use data were collected via the PDT and rates of emergency room data were obtained from patient medical records. Data were compared to a similar group of 158 OUD patients treated at the same clinic who did not use the PDT. Abstinence data were obtained from deidentified medical records.

Pilot participants (N = 40) completed a median of 24 lessons: 73.2% completed at least 8 lessons and 42.5% completed all 31 core lessons. Pilot participants had significantly higher rates of abstinence from opioids in the 30 days prior to discharge from the program than the comparison group: 77.5% vs 51.9% (P < .01). Clinician-reported treatment retention for pilot participants vs the comparison group was 100% vs 70.9% 30 days after treatment initiation (P < .01), 87.5% vs 55.1% at 90 days post-initiation (P < .01), and 45.0% vs 38.6% at 180 days post-initiation (P = .46). Emergency room visits within 90 days of discharge from the addiction program were significantly reduced in pilot participants compared to the comparison group (17.3% vs 31.7%, P < .01).

These results demonstrate substantial engagement with a PDT in a real-world population of patients with OUD being treated with buprenorphine. Abstinence and retention outcomes were high compared to patients not using the PDT. These results demonstrate the potential value of PDTs to improve outcomes among patients with OUD, a population for which a significant need for improved treatments exists.

Trinity Health Innovation and Pear Therapeutics Inc.

Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with dopamine receptor blocking agents (eg, antipsychotics). Valbenazine is a highly selective vesicular monoamine transporter 2 inhibitor with several safe and effective dosing options now approved for once-daily (QD) treatment of TD in adults. Valbenazine 80 mg QD is the recommended dose for TD; however, 40 or 60 mg QD (newly approved dose) may be considered depending on response and tolerability. The recent approval of valbenazine 60 mg was based on results from an analysis that used the FDA’s model-informed drug development (MIDD) approach and leveraged existing data from the 6-week, phase 3 registration trial of valbenazine (KINECT 3).

A population pharmacokinetic (popPK) model was developed to describe plasma concentration-time profiles for valbenazine and its primary active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). An exposure-response (E-R) model was developed using the area under the concentration-time curve (AUC) of [+]-α-HTBZ (exposure) and change from baseline in the Abnormal Involuntary Movement Scale total score (AIMS-CFB) (response). Stepwise E-R model development evaluated various linear and nonlinear models to describe AIMS-CFB vs [+]-α-HTBZ AUC and time. E-R relationships established with the 40 and 80 mg data were used to predict AIMS-CFB for a 60 mg dose up to week 6, accounting for study-to-study, inter-individual, and residual variabilities.

Steady-state valbenazine and [+]-α-HTBZ concentrations were well described by a joint parent-metabolite popPK model. An Emax model with asymptotic exponential delay in the maximal valbenazine effect adequately characterized the E-R relationship between AIMS-CFB and [+]-α-HTBZ AUC. The simulated confidence intervals of response were consistent with the observed KINECT 3 results, demonstrating the utility of the model to predict efficacy results. The established E-R model was subsequently used to predict AIMS-CFB for valbenazine 60 mg QD at week 6. Mean AIMS scores decreased (improved) in a dose-dependent manner, with 60 mg QD predicted to result in least-squares mean (SEM) AIMS-CFB of −2.7 0.4, which is between the reported AIMS-CFB for 40 mg (−1.9 ± 0.4) and 80 mg (−3.2 ± 0.4). All simulated trials demonstrated valbenazine 60 mg to be significantly superior to placebo in AIMS-CFB after 6 weeks of treatment.

This analysis integrated and leveraged data from two previously approved valbenazine doses (40 and 80 mg QD) using an MIDD approach. The results provided key evidence that an intermediate dose (newly approved 60 mg QD) could be considered therapeutically beneficial without the need for an additional clinical trial. The availability of a valbenazine 60 mg dose to complement the previously approved doses fills an existing medical need for patients with TD who could benefit from this third effective dose.

Neurocrine Biosciences, Inc.

How can psychiatrists best provide care in complex, sometimes overwhelming disasters? COVID-19 strained every aspect of health care to the breaking point, from finances to pharmaceutical supply lines. We can expect more challenges to prescribing in the future, as shown by recent hurricanes in Puerto Rico, fires in California, and ice storms in Texas. When medications become scarce or inaccessible, then clinicians need to make difficult prescribing decisions. We suggest that a culture of deprescribing, a systematic approach to reducing or simplifying medications, could be applied to a wide variety of crises. Deprescribing is defined as the planned reduction of medications to improve patient health or to reduce side effects (see deprescribing.org). It has been used to reduce polypharmacy in geriatric and other complex populations. It provides evidence-based guidance for phasing out many classes of medications. It is part of the larger program to reduce waste in health care and to make pharmacy more rational. Disasters and resource scarcity, however, require a different approach. In contrast to routine care focused on individual patients, crisis standards of care (CSC) shift the clinical focus to the community. Instead of deprescribing guidelines for individual clinicians, CSC deprescribing would be national policies addressing shortages of important medications. We did a scoping review looking for studies of deprescribing in a crisis.

We extracted 1340 references in Google Scholar 2016 to 2021 using (deprescribing) AND (disaster OR crisis OR climate OR pandemic OR supply lines ). A scan of texts found 160 references matching our criteria, and only 19 of them addressed deprescribing as a strategy to strengthen health systems or providers in an emergency. Most of those were related to scarce supplies during COVID, and a few addressed the carbon impact of medications. We also reviewed related literatures on medication supply chain vulnerabilities, WHO Essential Medicines, and healthcare rationing.

Deprescribing gained attention during the COVID pandemic, responding to both disrupted supply lines and improving patient safety. Writers concerned with climate change support deprescribing to reduce the carbon impact of medications. Deprescribing as crisis policy could help streamline national stockpiles, supply chains, and manufacturing. Education could make deprescribing second nature for clinicians, potentially decreasing stress and increasing flexibility in future emergencies. Barriers to deprescribing generally include cultural inertia, industry lobbyists, education, and malpractice fears. In a crisis, deprescribing guidelines could provide clinicians with confidence and flexibility while conserving scarce resources. Research is needed to evaluate deprescribing guidelines for crises, especially ensuring equity in how they reduce polypharmacy and save money.

No funding

The mechanism of tardive dyskinesia (TD) is complex and not well understood. Dopamine-receptor blockade in the nigrostriatal pathway may lead to a hyperdopaminergic state that can interfere with mechanisms of movement control, leading to TD. Medications for the treatment of movement disorders, including TD, typically require fine-tuning of doses to optimize control of abnormal movements; however, doses are often not titrated sufficiently. The vesicular monoamine transporter 2 inhibitor deutetrabenazine is an FDA-approved treatment for TD in adults. This post hoc analysis examined dosing patterns in patients with TD according to baseline Abnormal Involuntary Movement Scale (AIMS) item 8 score, a clinician-rated global judgment of the overall severity of abnormal movements.

Patients who completed the pivotal 12-week studies, ARM-TD and AIM-TD, were eligible to enroll in the 3-year, open-label extension study. Deutetrabenazine was initiated at 12 mg/day and titrated in a response-driven manner on a weekly basis in intervals of 6 mg/day for 6 weeks, up to a maximum dose of 48 mg/day, based on dyskinesia control and tolerability. Further dose adjustments during the long-term maintenance period were permitted on a weekly basis. Subgroups were defined by AIMS item 8 scores of either 0/1/2 or 3/4 at baseline. Total daily dose categories and treatment exposure over time were evaluated in each subgroup.

A total of 336 patients were included in the analysis (baseline AIMS item 8 scores 0/1/2, n = 117; scores 3/4, n = 219). At week 15, the proportions of patients by deutetrabenazine total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 10% and 3%; ≥24 to ≤36, 41% and 48%; >36 to ≤48, 49% and 49%. At week 54, proportions by total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 11% and 4%; ≥24 to ≤36, 42% and 41%; >36 to ≤48, 46% and 55%; >48, 1% and 0. Similar patterns were observed at weeks 106 and 145 across total daily dose categories. For scores 0/1/2, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 36.9 ± 1.04 (n = 108), 37.1 ± 1.22 (n = 90), 37.7 ± 1.32 (n = 76), and 37.9 ± 1.44 (n = 64). For scores 3/4, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 39.2 ± 0.65 (n = 186), 39.8 ± 0.75 (n = 150), 40.3 ± 0.88 (n = 112), and 40.5 ± 0.99 (n = 97).

Dosing decisions in the treatment of TD are individualized, as treatment response is likely driven by complex factors. Findings from this analysis suggest that in order to achieve adequate control of TD symptoms, patients benefit from response-driven titration of deutetrabenazine to doses >24 mg/day, regardless of the baseline severity of abnormal movements assessed by AIMS item 8. These results highlight the importance of patient-driven titration of deutetrabenazine until adequate movement control is achieved, while maintaining safety/tolerability in the treatment of TD.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Clinically significant weight gain (CSWG) is associated with increased morbidity and mortality. This study describes CSWG and comorbidities observed in patients with bipolar I disorder (BD-I) and schizophrenia (SZ) after initiating select second-generation antipsychotics (SGAs).

Percent change in weight, CSWG (=7% weight increase), and incident comorbidities within 12 months of treatment were assessed among patients initiating oral SGAs of moderate-to-high weight gain risk using medical records/claims (OM1 Real-World Data Cloud; January 2013-February 2020). Oral SGAs included clozapine (SZ), iloperidone (SZ), paliperidone (SZ), olanzapine, olanzapine/fluoxetine (BD-I), quetiapine, and risperidone. Outcomes were stratified by baseline body mass index and reported descriptively.

Among patients with BD-I (N = 9142) and SZ (N = 8174), approximately three-quarters were overweight/obese at baseline. During treatment (mean duration = 30 weeks), average percent weight increase was 3.7% (BD-I) and 3.3% (SZ). Average percent weight increase was highest for underweight/normal weight patients (BD-I = 5.5%; SZ = 4.8%), followed by overweight (BD-I = 3.8%; SZ = 3.4%) and obese patients (BD-I = 2.7%; SZ = 2.3%). Within 3 months of treatment, 12% of all patients experienced CSWG. A total of 11.3% (BD-I) and 14.7% (SZ) of patients developed coronary artery disease, hypertension, dyslipidemia, or type 2 diabetes within 12 months of treatment; development of comorbidities was highest among overweight/obese patients and those with CSWG.

Patients who were underweight/normal weight at baseline had the greatest percent change in weight during treatment. Increased comorbidities were observed within 12 months of treatment, specifically among overweight/obese patients and those with CSWG. The magnitude of weight gain and development of comorbidities were similar for patients with BD-I and SZ.

Alkermes, Inc.

People with substance use disorders (SUDs) experience higher rates of depression and suicide and lack primary care providers (PCP).

Twenty chart audits at the St. Lawrence Addiction Treatment Center (SLATC) showed 65% (n = 11) of SUD patients lacked a PCP. Standardized screening tools and timely appointments were lacking. The aim was to increase timely scheduled psychiatric appointments for SUD patients at discharge by 80% within 90 days.

A 90-day rapid cycle improvement project with plan-do-study-act was the process for improvement. Data were collected with four interventions from screening, checklist, patient, and team engagement concurrently. Run charts, spreadsheets, and aggregate data were interpreted for timely care. Interventions: Screening tools evaluated risks for depression and suicide. If patients screened positive, a decision aid was used for patient education. Discharge Care Coordination Checklist was used as a quality tool tracking all patients. The Project Briefing Tool and team engagement activities were used to improve participation.

Screening tools were spread with 125 screenings showing 53 positives for depression and four positives for suicide. After using the decision aid, 24 (45.2%) chose depression medications, 29 (52.8%) chose complementary alternative medicine, and one patient chose neither. Of the 125 patients on the Discharge Care Coordination Checklist, 43.2% (n = 54) were scheduled with appointments, The Project Briefing Tool improved participation.

Standardized screening tools, CAM, and co-creation activities improved timeliness of care. A further study for the impact of mental health services for relapse prevention was recommended.

No funding

A combination of olanzapine and samidorphan (OLZ/SAM) that provides the efficacy of olanzapine while mitigating weight gain was recently approved by the Food and Drug Administration for the treatment of schizophrenia and bipolar I disorder. This exploratory population pharmacokinetic-pharmacodynamic analysis evaluated potential relationships between drug exposure and treatment effects.

Positive and Negative Syndrome Scale (PANSS) total score and/or bodyweight data from efficacy studies served as pharmacodynamic endpoints. Pharmacokinetic input came from predicted plasma drug concentrations using a population pharmacokinetic model for the corresponding studies. Regression and box plots were generated to investigate potential pharmacokinetic-pharmacodynamic relationships.

PANSS total score and/or bodyweight records were paired with olanzapine and/or samidorphan concentrations from 1464 patients with schizophrenia. Within the clinical dose range for olanzapine (10-20 mg/day) and samidorphan (5-20 mg/day), no significant correlation was noted between (a) olanzapine concentrations and change in PANSS total score, or % change in body weight, in patients treated with OLZ/SAM or olanzapine, and (b) samidorphan concentration or samidorphan-to-olanzapine concentration ratio and % change in body weight. No meaningful difference in olanzapine and samidorphan concentrations or samidorphan-to-olanzapine concentration ratios was observed between patients with <10% and ≥10% weight gain.

The antipsychotic efficacy of olanzapine was not affected by samidorphan at any concentration of olanzapine. Furthermore, olanzapine-associated weight gain did not correlate with olanzapine dose or plasma concentration. Finally, the effect of OLZ/SAM on mitigation of olanzapine-associated weight gain was not affected by intersubject variability in olanzapine and/or samidorphan plasma concentrations.

Alkermes, Inc.

Patients with schizophrenia may exhibit symptoms of hostility. HP-3070, a once-daily asenapine transdermal system, is the first antipsychotic patch approved by the FDA for use in adults with schizophrenia, and its efficacy in this indication has been demonstrated. This post hoc analysis of a phase 3 randomized study investigated the efficacy of HP-3070 in treating hostility in patients with schizophrenia.

In the pivotal phase 3 study, adults with schizophrenia were randomized 1:1:1 to once-daily treatment with HP-3070 3.8 mg/24 h, 7.6 mg/24 h, or placebo for 6 weeks. Least-squares mean (LSM) changes in the PANSS hostility item score (P7) and PANSS-Excited Component (PANSS-EC), the sum of items P4 (Excitement), P7 (Hostility), G4 (Tension), G8 (Uncooperativeness), and G14 (Poor impulse control), from baseline to week 6 were assessed post hoc. Efficacy was analyzed with a mixed-effects model for repeated measures (MMRM) adjusted for PANSS-positive symptoms, items P1 (Delusions), P2 (Conceptual disorganization), P3 (Hallucinatory behavior), P5 (Grandiosity), P6 (Suspiciousness/persecution), and G9 (Unusual thought content) and presence of somnolence (including hypersomnia, hypersomnolence, or sedation) or akathisia.

Among the 369 patients with a baseline PANSS hostility item score >1 and hostility scores collected at both baseline and week 6 (126 HP-3070 7.6 mg/24 h; 123 3.8 mg/24 h; 120 placebo), the week 6 LSM (95% CI) change from baseline in PANSS hostility item score was significantly better with HP-3070 than placebo for 7.6 mg/24 h (−0.4 [−0.6, −0.2]; P < .001) and 3.8 mg/24 h (−0.3 [−0.6, −0.1]; P < .01). Similar results were observed after adjusting for covariates (P < .01 for both doses). The week 6 PANSS-EC LSM change from baseline was also greater for HP-3070 7.6 mg/24 h (−1.1 [−1.9, −0.4]; n = 164; P < .01) and 3.8 mg/24 h (−1.3 [−2.0, −0.6]; n = 168; P < .001) compared with placebo (n = 165).

In this post hoc analysis, HP-3070 was superior to placebo in reducing hostility in patients with schizophrenia, even after adjusting for covariates, suggesting that these effects are at least partially independent of general antipsychotic effects or of effects on sedation or akathisia. These findings suggest that HP-3070 may have a specific anti-hostility effect in patients with schizophrenia.

Noven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical, Co.

BioXcel Therapeutics

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive impairment in symptoms of inattention, hyperactivity, and impulsivity. Psychopharmacologic treatment is targeted at the management of symptoms of ADHD, and evidence exists that ADHD persists into adulthood. Clinical practice guidelines recommend a combination of behavior therapy and psychostimulant medication for the treatment of ADHD in children, adolescents, and adults. Psychostimulants are often prescribed for ADHD in adults, and amphetamine long has been considered a mainstay of treatment for this population. As adult patients seek relief from ADHD symptoms early in the workday and into the early evening hours, with fewer required doses, extended-release formulations with an early onset of efficacy and an extended duration of effect are considered very desirable. The amphetamine-extended release tablet (AMPH ER TAB) was developed to provide a portable, easy-to-use amphetamine tablet dosage option that can be chewed or swallowed whole.

To evaluate the efficacy and safety of an Amphetamine Extended-Release Tablet (AMPH ER TAB) in adults with ADHD aged 18 to 60 years. Methods: In a 5-week forced dose-titration phase, eligible subjects were randomized to either oral double-blind AMPH ER TAB 5 mg starting dose or matching placebo, once daily in the morning beginning the day after the Baseline Visit. Subjects were titrated up (5 mg increments) each week. Safety and efficacy assessments were done weekly. After Visit 3, subjects received 20 mg for 14 (3) days before Visit 5 (V5). Subjects who could not tolerate study drugs discontinued. A Permanent Product Measure of Performance (PERMP) placement test was done at Screening or Baseline. At V5, efficacy assessments included the administration of serial PERMPs predose, 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP-T score across postdose time points during the Visit 5 serial PERMPs. Safety was monitored by AEs assessed at each visit, C-SSRS, vital signs, weight, and assessment of sleep, appetite, mood, and psychotic AEs.

The mean postdose PERMP-T score over all postdose time points at V5 was statistically significantly higher in the AMPH ER TAB group vs placebo (302.8 vs 279.6; P = .0043). Common adverse events were decreased appetite, insomnia, and dry mouth. The majority of TEAEs were mild to moderate in severity, and no SAEs were reported.

The AMPH ER TAB demonstrated efficacy in the treatment of symptoms of ADHD in adults, with an anticipated safety profile.

Tris Pharma, Inc.