Valbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.

Data from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.

Of the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with <50% AIMS improvement at Week 8, 81% achieved the ≥50% response threshold by end of treatment at Week 48. The proportion of participants meeting the threshold for CGI-TD response also increased over time, from 50% at Week 8 to 92% at Week 48. PGIC results were similar, with response rates of 53% and 88% at Weeks 8 and 48, respectively.

Post hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, >80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).

Neurocrine Biosciences, Inc.

Delayed access to mental health services (MHS) has become a crisis in the United States. Children have the highest disproportionate rates of delayed psychiatric services in comparison to adults. There are greater demands for mental health professionals than the workforce can supply. Social workers (SW) have been identified as essential stakeholders for children needing access to mental health services. The shortage of social workers is more profound than nurses, especially in rural and underserved areas. Therefore, the Institute of Medicine (IOM) has recommended all educational institutions incorporate telemental health (TMH) training into interprofessional students’ curriculums.

The delays in MHS are directly related to the shortage of mental health professionals especially for nursing but is it is more apparent in social work. The United States Health Resource and Service Administration (HRSA) have projected there is a greater demand for mental health clinicians than the workforce is able to supply. Social workers are essential providers for navigating our nation’s mental health system. They can also train to become licensed mental health therapists. HRSA predicts by 2025 the demand for SWs will be 157,760. However, the estimated supply will be 147,500 resulting in a shortage of approximately 10,260 social workers. Children have the greatest risk for lack of access amongst mental health patients in the U.S. An estimated 13–20 % of children in the United States have a diagnosable mental illness. Twenty-one percent of that amount are children who reside in rural or underserved areas. Strikingly, only 7% of children living in rural or underserved areas will receive a mental health appointment.

The purpose of the George Mason University initiative was to develop a telemental health training model that would be incorporated into social work students’ curriculum and meet the IOMs’ recommendation. The GMU Population Health Center Initiative sought to identify how SW students, trained as TMH providers could be the resolution to the workforce shortage crisis.

This project design was a quality improvement initiative to assess social work students’ perception of the telemental health training. The CTiBS framework was used to determine the level of competency SW students achieved upon completion of the TMH training. The Activity Theory was used as the methodological framework to assess social work students’ readiness of change, engagement, and TMH technology.

After reviewing quantitative data, 70% participants (n=7) declared novice competency. The remaining 30% (n=3) affirmed proficiency (SD= 0.46, V=0.21). Sixty percent (n=6) participants declared they would consider becoming TMH providers. Sixty percent (n=6) of the trainees stated they were satisfied with the training and would consider providing TMH services upon graduation (SD= 0.49, V=0.24). Ninety percent (n=9) of trainees stated they could successfully conduct a TMH visit and would consider working in rural and underserved areas (SD= 0.30, V=0.09). One hundred percent (n=10) of the participants stated the TMH training was a beneficial skill for their profession.

One hundred percent of the participants found TMH training beneficial and ninety percent would use it to conduct visits for children upon graduation. The workforce crisis will not improve unless the IOM recommendations are adapted by educational institutions. A telemental health-prepared labor force will help to reduce the rates of mental health disparities in children.

No Funding

Naloxone use has increased in recent years in response to the nation’s opioid crisis. Once only available to health care professionals, it is now obtainable by prescription for persons at risk for substance overdose and their families. Increasing its availability is seen by some as an “over-the-counter solution” to the opioid problem. However, while naloxone has been viewed as relatively safe, with a low side effect profile when appropriately dosed and monitored, it is not without safety concerns that may go unrecognized or misattributed to other causes.

Here we present a case study of a 41-year-old female who presented to our medication-assisted treatment (MAT) clinic complaining of sudden onset weight gain, shortness of breath, upper and lower extremity peripheral edema, tachycardia, insomnia, and nocturnal enuresis. These symptoms made it difficult for her to work at her housekeeping job, resulting in missed workdays. She had seen a primary care provider for her symptoms and been prescribed a rescue inhaler for her shortness of breath. This patient had previously been treated for opioid use disorder with buprenorphine/naloxone and experienced similar symptoms, which disappeared when she relapsed on opioids. However, symptoms reappeared upon resuming her prescribed treatment.

The patient was identified as experiencing side effects to naloxone, causing noncardiogenic edema. Her MAT medication was switched to buprenorphine. Within two weeks her heart rate had returned to normal, she had lost weight, and she no longer had nocturnal enuresis or needed the rescue inhaler. Her peripheral edema resolved so she was able to walk better and resume work. At the same time, buprenorphine continued to relieve her cravings.

There is a dearth of information related to naloxone-induced edema. Our patient had not received a formal evaluation of pulmonary edema, but her pulmonary and cardiac symptoms were consistent with that diagnosis. Although pulmonary edema is mentioned in the product literature, peripheral edema is not. A literature search indicates that the number of case studies on naloxone-induced pulmonary edema have increased since 2018, but only one other case of naloxone-induced peripheral edema was discovered.

Naloxone is used in a variety of settings by differing types of health care providers. As the number of persons treated with naloxone increases, there will likely be a corresponding increase in incidences of pulmonary and/or peripheral edema as side effects. Providers and patients who are not aware of these manifestations and their relationship to naloxone treatment may easily attribute presenting symptoms to cardiogenic or other causes, as this case illustrates. It is important for providers in all settings to consider new onset shortness of breath and edema within the context of the person’s whole health and to be aware of their implications for mental as well as physical health.

No Funding

DiGeorge Syndrome is a microdeletion of chromosome 22q11.2 and is most commonly de novo. Manifestations of DiGeorge are wide-spread including cardiac malformations, palatal abnormalities, intellectual disability, hypocalcemia, dysmorphic facial features, and psychiatric disorders (psychotic disorders, Autism, ADHD, etc). This case report highlights difficulties with diagnosis and treatment of psychosis in DiGeorge. This 29 yo male with history of DiGeorge and associated cardiac anomalies presented to the outpatient clinic with prior diagnoses of schizoaffective disorder, bipolar disorder, DMDD, autism, and ADHD. Patient denied all symptoms, though mother noted hallucinations for 5–6 years. He was previously on aripiprazole and divalproex and developed a resting tremor. With family history of Parkinson’s disease (PD), increased risk of PD in DiGeorge, and no improvement in tremor with dose reduction of aripiprazole or discontinuation of divalproex, neurology diagnosed PD, which was later negated when tremor resolved with complete discontinuation of aripiprazole. In our clinic we slowly increased divalproex and olanzapine, though parent concern of sedation limited higher doses. Patient had moderate improvement in symptoms per parents, but after several months on moderate-dose olanzapine, he developed a tremor. Sensitivity to extrapyramidal symptoms limits medication selection. Furthermore, QT prolongation in a population with cardiac abnormalities poses a unique risk. Given complexity and poor response, we researched pathogenesis and treatment of psychosis in DiGeorge.

We reviewed literature on PubMed with keywords including “DiGeorge,” “treatment,” “psychosis.” Specifically, we looked at articles addressing treatment response, efficacy, side effects, novel treatments, and the pathogenesis as it relates to treatment.

Literature indicates that psychotic symptoms are more treatment resistant compared to psychotic disorders not associated with DiGeorge and there is little consensus on which antipsychotics are more effective. The 22q11.2 deletion contains the gene segment for catechol-O-methyltransferase (COMT) and the resulting COMT deficiency leads to excess catecholamines. The presence of the low activity COMT variant on the remaining allele is associated with possibly more severe psychiatric symptoms. Metyrosine may be a potential medication in the treatment of psychosis in DiGeorge by interfering with dopamine synthesis. Overall there is sparse research on treatment of psychosis in DiGeorge and a lack of firm recommendations.

This case study exemplifies the need for further research on DiGeorge Syndrome and treatment of psychosis. Treatment is complicated by cardiac abnormalities, comorbid neuropsychiatric conditions confounding diagnosis, and little research on treatments that target the unique pathogenesis. Research is inconsistent concerning recommendations and novel treatments are primarily anecdotal.

No Funding

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I), versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with schizophrenia are reported here.

Patients with schizophrenia were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale [VAS] scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was evaluated at Week 32 using mean (standard deviation [SD]) Clinical Global Impression – Improvement (CGI-I) score, and mean (SD) change from baseline in Clinical Global Impression – Severity (CGI-S) score, Subjective Well-being under Neuroleptic Treatment – Short Form [SWN-S] Total score, and Positive and Negative Syndrome Scale (PANSS) Total score.

Study completion rate was 79.3% (73/92 patients) in the Ari 2MRTU 960 group and 67.7% (63/93 patients) in the AOM 400 group. Demographics and disease characteristics were well balanced between groups at baseline (mean [SD] PANSS Total score: Ari 2MRTU 960, 62.0 [13.5]; AOM 400, 61.8 [13.5]; mean (SD) CGI-S score: Ari 2MRTU 960, 3.3 [0.9]; AOM 400, 3.1 [0.9]). Treatment-emergent AE (TEAE) incidence was 66.3% with Ari 2MRTU 960 and 63.4% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 21.7%; AOM 400, 18.3%) and injection site pain (Ari 2MRTU 960, 15.2%; AOM 400, 9.7%). Mean (SD) VAS score for pain after last injection was 1.5 (4.58) with Ari 2MRTU 960 and 1.3 (2.79) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was similar between groups (Ari 2MRTU 960, 3.5 [1.0]; AOM 400, 3.6 [0.9]). Minimal change from baseline was seen at Week 32 in CGI-S score and SWN-S Total score. There was no clinically meaningful difference between the groups for PANSS Total score (difference of least squares mean change from baseline [95% confidence interval]: -0.9 [-3.5, 1.8]; p=0.5154).

In patients with schizophrenia, administration of Ari 2MRTU 960, as compared with AOM 400, was generally well tolerated, and clinical stability was maintained during the study.

Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder as monotherapy and as adjunctive therapy with lithium or valproate. This post hoc analysis investigated the efficacy and tolerability of lumateperone in patients with schizophrenia via number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).

Data were pooled from three late-phase 4–6 week placebo-controlled studies of lumateperone 42 mg/day in adults with schizophrenia and an acute exacerbation of psychosis (Study 005 [NCT01499563], Study 301 [NCT02282761], Study 302 [NCT02469155]). NNT and NNH were calculated vs placebo for several different Positive and Negative Syndrome Scale [PANSS] Total score response cutoffs (percent reduction from baseline) and for adverse events (AEs), respectively.

In the two informative studies (placebo, n=221; lumateperone, n=224), the NNT vs placebo for lumateperone was statistically significant for PANSS Total score reductions from baseline to 4 weeks/endpoint of ≥20% (NNT=9, 95% confidence interval [CI] 5–36) and ≥30% (NNT=8; 95%CI 5–21). In all studies pooled (placebo, n=412; lumateperone, n=406), study discontinuations due to AEs were uncommon and the NNH (389) was not statistically significant from placebo. The only AE with NNH vs placebo <10 was somnolence/sedation (NNH=8; 95%CI 6–12). With lumateperone treatment, weight gain ≥7% from baseline was similar to placebo (NNH=112) and fewer patients experienced akathisia than placebo. Lumateperone LHH ratios were >>1 for all AEs (range 13.6–48.6) except somnolence/sedation (LHH~1).

Lumateperone’s benefit-risk profile was favorable in late-phase schizophrenia trials.

Intra-Cellular Therapies, Inc.

HP-3070, a once-daily asenapine transdermal system, is FDA-approved for adults with schizophrenia. In a pivotal phase 3 randomized controlled study, patients with schizophrenia who were treated once daily with HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo. The PANSS score’s five-factor structure can also assess treatment efficacy across different domains. This post-hoc analysis of the pivotal study evaluated the efficacy of HP-3070 by examining these domains.

In the pivotal phase 3 study, adults with acute exacerbations of schizophrenia were randomized to 6 weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. Factor analysis of PANSS scores was performed using five domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates.

The analysis included 607 patients. Least-squares mean estimates (standard error) of the difference from placebo in change from baseline to Week 6 for each factor were as follows: negative symptoms, 3.8mg/24h, -0.9 (0.43), P=0.045, and 7.6mg/24h, -0.4 (0.43), P=0.41; positive symptoms, 3.8mg/24h, -2.3 (0.57), P<0.001, and 7.6mg/24h, -2.0 (0.57), P<0.001; disorganized thought, 3.8mg/24h, -1.5 (0.38), P<0.001, and 7.6mg/24h, -0.9 (0.38), P=0.03; uncontrolled hostility/excitement: 3.8mg/24h, -1.1 (0.30), P<0.001, and 7.6mg/24h -0.9 (0.30), P=0.002; anxiety/depression, 3.8mg/24h, -0.5 (0.31), P=0.14, and 7.6mg/24h, -0.6 (0.31), P=0.07.

HP-3070 demonstrated treatment effects on a PANSS five-factor model, with the results indicating impact on negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. These findings suggest that HP-3070 may address a broad range of symptoms in schizophrenia.

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

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or BP-I, versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole and maintenance monotherapy treatment of BP-I [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with BP-I are reported here.

Patients with BP-I were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale (VAS) scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was assessed at Week 32 by Clinical Global Impression – Improvement (CGI-I), Clinical Global Impression – Bipolar Version (CGI-BP), Subjective Well-being under Neuroleptic Treatment – Short Form (SWN-S), Montgomery–Åsberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS).

Study completion rate was 72.5% (29/40 patients) in the Ari 2MRTU 960 group and 70.7% (29/41 patients) in the AOM 400 group. Demographics and baseline disease characteristics were generally well balanced between treatment groups. Treatment-emergent AE (TEAE) incidence was 82.5% with Ari 2MRTU 960 and 87.8% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 25.0%; AOM 400, 26.8%) and injection site pain (Ari 2MRTU 960, 25.0%; AOM 400, 7.3%). Mean (standard deviation [SD]) VAS score for pain after last injection was 1.2 (2.07) with Ari 2MRTU 960 and 1.3 (2.19) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was 3.1 [1.2] with Ari 2MRTU 960 and 3.2 [1.5] with AOM 400, and there was minimal mean (SD) change from baseline in CGI-BP score (Ari 2MRTU 960, -0.2 [1.0]; AOM 400, -0.6 [1.2]). Mean (SD) change from baseline in SWN-S Total score was 10.3 (16.1) with Ari 2MRTU 960 and 3.4 (21.4) with AOM 400. There was no clinically meaningful difference between the groups in MADRS Total score or YMRS Total score (difference of least squares mean change from baseline [95% confidence interval]: MADRS Total score -2.1 [-6.3, 2.1], p=0.3185; YMRS Total score 0.1 [-1.8, 2.1], p=0.8995).

In patients with BP-I, Ari 2MRTU 960 was generally well tolerated, and clinical stability was maintained during the study.

Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Patients with major depressive disorder (MDD) often have inadequate response to antidepressant treatment (ADT) requiring augmentation with other treatments. Cariprazine is a D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat schizophrenia and manic, mixed, and depressive episodes of bipolar I disorder. The efficacy of cariprazine as an adjunctive treatment for patients with MDD and inadequate response to ADT alone has been evaluated in phase 2/3 randomized, double-blind, placebo-controlled trials. Post hoc analyses of one phase 3 trial (NCT03738215) evaluated cariprazine + ADT for improving depressive symptoms in subgroups of patients categorized by 1) the level of response to ongoing ADT at baseline and 2) the number of ADTs associated with inadequate response during the current episode.

Patients were randomized to placebo + ADT (n=254), cariprazine 1.5 mg/d + ADT (n=252), or cariprazine 3 mg/d + ADT (n=253) for 6 weeks of double-blind treatment. Post hoc analyses evaluated change from baseline to week 6 in MADRS total score in subgroups of patients who had ≥25%–<50% or <25% response to ongoing ADT at baseline, and in subgroups of patients who had inadequate response to 1 or ≥2 ADTs in the current episode. Analyses used a mixed-effects model for repeated measures; least squares mean differences (LSMD) versus placebo with 95% confidence interval (95% CI) were calculated.

At baseline, 65.1% (n=486) of patients had an ADT response level between 25%–<50% and 34.9% (n=261) of patients had an ADT response level <25%. Mean MADRS total score reductions were greater for cariprazine 1.5 mg/d + ADT versus placebo + ADT in both ADT response subgroups (25%–<50% ADT response: -14.8 vs -11.9, LSMD [95% CI]=-2.3 [-4.2, -0.3]; <25% response to ADT: (-14.7 vs -11.7, LSMD [95% CI]=-2.6 [-5.5, 0.3]). For cariprazine 3 mg/d + ADT, mean change in MADRS total score was numerically greater versus placebo in both response subgroups (25%–<50% response=-14.2, LSMD [95% CI]=-1.5 [-3.5, 0.4]; <25% response= -12.3, LSMD [95% CI]=-0.74 [-3.6, 2.1]). Approximately 86% (n=644) and 14% (n=105) of patients in this study had inadequate response to 1 ADT or ≥2 ADTs, respectively, during the current episode. The LSMD (95% CI) in MADRS total score change for cariprazine 1.5 mg/d + ADT versus placebo + ADT was -2.3 (-4.1, -0.6) in the subgroup of patients with 1 previous ADT and -3.2 [-7.1, 0.8]) in the subgroup of patients with ≥2 previous ADTs. For cariprazine 3 mg/d + ADT, the LSMD (95% CI) in MADRS total score change versus placebo was -0.7 (-2.5, 1.0) in the 1 previous ADT subgroup and -4.7 (-8.8, -0.6) in the ≥2 previous ADTs subgroup.

In these post hoc analyses, cariprazine + ADT was associated with greater reductions in MADRS total score versus placebo regardless of the level of response to ongoing ADT at baseline or number of prior ADT failures in the current episode.

AbbVie

Patients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.

Post hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).

Of the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).

In this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.

AbbVie

Glycolimia is observed in a plethora of medical conditions including burning mouth syndrome, opioid withdrawal, as well as from a variety of medications including vortioxetine, l-methylfolate, lisdexamfetamine, and gabapentin. While vilazodone, an antidepressant with agonist like effects on 5-HT1A receptors, has been found to induce hyperglycemia, it has not heretofore been reported to induce glycolimia. Such a case is described.

Case study: A 60-year-old, left-handed (pathological) male presented with a past history of depression, minimally responsive to a variety of antidepressant medications, was begun on vilazodone, initially 20 mg and gradually increased to 60 mg a day. On 60 mg a day he noticed severe cravings for sweets, which he had never experienced prior to starting vilazodone. He found he had increased consumption, craving sweet foods including cookies and candy. For instance, in a typical day, he would eat eight Oreos, chocolate-covered graham crackers, one pint of ice cream a day, and he would crave sweets even after feeling satiated after consuming a meal. Along with this increased eating, he gained 20 pounds over the 3 months while on the vilazodone. Upon discontinuing the vilazodone, although the weight didn’t change, the sweet cravings resolved.

Abnormalities on: Neurological examination: Mental status examination: Immediate recall: able to remember 6 digits forwards and 3 digits backwards. Motor examination: Drift testing: right inward drift. Gait examination: unstable tandem gait. Neuropsychiatric examination: Go-No-Go test: 6/6 (normal). Animal Fluency Test: 22 (normal).

There are myriad mechanisms whereby vilazodone may have induced glycolimia. Possibly due to its antidepressant effects, it increased hedonics, generating appetitive behaviors, including enhanced socialization, sexual, and other consumptive behaviors, including eating. Peradventure it may have enhanced motivation and socialization. Along with socialization, there is escalation in social intercourse, with accompanying commensalism. Along with such consumptive behaviors, we could anticipate glycolimia. As a 5-HT1A receptor agonist, possibly vilazodone may have acted on the arcuate pro-opiomelanocortin neurons associated with hyperphagia, with modulation of energy homeostasis in the serotonin pathway. Alternatively, vilazodone may have triggered an enhanced insulin response with secondary reduction in blood sugar, leading to a homeostatic behavioral response of increased glucose intake. In those who are treated with vilazodone, query as to glycolimia is warranted and warning as to potential manifestations of hyperglycemia should be entertained.

No Funding

The Dextroamphetamine Transdermal System (d-ATS) was developed as an alternative to oral amphetamine (AMP) formulations for ADHD. In a pivotal study, d-ATS met primary and secondary efficacy endpoints for ADHD in children and adolescents. Study subjects wore d-ATS for 9 hours, and an improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham scale (SKAMP) total score was observed from 2 through 12 hours after application. Patients with ADHD may need varying durations of treatment for symptoms from day to day. This analysis describes the exposure-response (E-R) relationship for d-ATS and explores possible outcomes for wear times ≤9 hours under varying assumptions.

A population pharmacokinetic (PK) model was developed to describe AMP disposition following d-ATS administration. This model was used to construct a population pharmacokinetic/pharmacodynamic (PK/PD) model from SKAMP total score data from two pediatric clinical studies to characterize onset and duration of effect after d-ATS administration. The integrated PK/PD model was used to describe the d-ATS E-R relationship and simulate the potential onset and duration of effect of d-ATS in response to various removal times (when <9 hours) by utilizing SKAMP scores as the efficacy measure. Subject-level AMP PK and SKAMP profiles were simulated for d-ATS removal at 4–9 hours post-application under different assumptions for AMP absorption after early patch removal. Modifications were made to the original population PK model to simulate patch removal.

Data from 81 children and 41 adolescents, 6–17 years old, were included. The model provided a reasonable description of the SKAMP score over time, showing an initial decline ~2 hours after patch application. In approximately 50% of children and adolescents, the maximum decline in SKAMP scores was observed within the first 4 hours after patch application. Earlier simulated d-ATS removal times were associated with reduced systemic exposure and earlier return to near-baseline scores across the range of assumptions tested.

Under different assumptions, the graphs changed modestly but not dramatically. For example, with moderate/conservative assumptions, following a 9-hour wear time, SKAMP scores returned to within 90% of baseline value in ~49% of subjects by 12 hours and ~80% of subjects by 16 hours. Following a 4-hour wear time, percentages were ~74% by 12 hours and ~95% by 16 hours.

Simulation results suggest that the duration of d-ATS efficacy may be related to wear time, which can be adjusted according to treatment needs, consistent with published observations for another transdermal stimulant. The d-ATS patch provides the ability to control medication exposure by shortening wear time, allowing treatment duration to be individualized and optimized in ADHD patients who have varying schedules and needs.

Noven Pharmaceuticals, Inc.

Demand for digital mental health tools has risen since the start of the COVID-19 pandemic; however, their evolving use in mental health care is not well understood. We surveyed mental health care professionals (HCPs) before and after the onset of the pandemic and assessed how use of and attitudes about digital technology changed.

We distributed a digital health survey to HCPs in the United States in 2019 (pre-pandemic; N = 141) and in 2021 (during the pandemic; N = 151). Both surveys recorded the respondents’ perceived barriers to integrating new digital health technologies and the tools they currently used in their practice.

HCP use of telemedicine increased from 47% of respondents in 2019 to 81% in 2021, as did the use of mHealth sensors (2% vs 10%). Patient comfort with technology remained one of the biggest barriers to implementing new digital tools (40% vs 43%), while difficulty integrating digital tools into clinical practice became less common (40% vs 32%). Data management (19% vs 10%) and patient acceptability (19% vs 13%) were cited less often as barriers in 2021. Respondents’ thoughts on what can be most improved by digital technology shifted substantially, with increased access to care rising from 27% of responses in 2019 to 46% in 2021.

The pandemic has changed how HCPs perceive digital health technologies and how they implement these tools in clinical practice. A growing number of HCPs believe increased access to care is the outcome that technology can most improve.

Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA

In STAR*D, following non-remission with an SSRI, remission rates for second-line treatments were ~ 25%, regardless of the switch strategy employed. Antidepressants with novel mechanisms may improve outcomes in MDD. AXS-05 (dextromethorphan HBr 45 mg- bupropion HCl 105 mg) is a novel, oral, investigational, NMDA receptor antagonist with multimodal activity. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan.

EVOLVE was an open-label study, in which patients were treated with AXS-05 twice daily for up to 15 months. Subjects had either rolled in after a prior AXS-05 study or were directly enrolled and had a DSM-5 diagnosis of MDD, a MADRS score of ≥25, and had been treated with ≥1 antidepressant in the current major depressive episode (MDE). A total of 186 patients were enrolled. Here we present the results for the directly enrolled patients (n =146).

Mean change in MADRS total score from a baseline of 32.2 were -9.1±7.64, -13.3±8.58, and -20.4±7.79 points at Weeks 1, 2, and 6, respectively (p< 0.001 for all). Remission (MADRS ≤10) was achieved by 5.7%, 16.2%, and 46.0% of patients at Weeks 1, 2, and 6, respectively. Improvement in functioning, measured by the SDS, was seen starting at Week 1 (p < 0.001). Improvements in MADRS and SDS were sustained at Month 12.

Long-term treatment with AXS-05 was generally well tolerated. The most commonly reported adverse events were COVID-19 infection (8.9%), nausea (8.9%), headache (7.5%), dry mouth (6.2%), insomnia (5.5%), and dizziness (5.5%).

AXS-05 improved depression and functioning in patients who failed one prior antidepressant in the current MDE.

Axsome Therapeutics

Treatments for bipolar disorder are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides ≥150mg/dL, high density lipoprotein cholesterol <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) ≥130mmHg or diastolic BP ≥85mmHg, fasting glucose ≥100mg/dL.

MetSy elevates the risk of developing type II diabetes, cardiovascular disease, and premature morbidity. Lumateperone (LUMA), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials.

LUMA 42-mg monotherapy was evaluated in 2 randomized, double-blind, placebo (PBO)-controlled studies (Study 401 [NCT02600494]; Study 404 [NCT03249376]) in patients with a major depressive episode (MDE) associated with bipolar I or bipolar II disorder. This post hoc pooled analysis of these studies compares rates of MetSy with LUMA 42 mg and PBO in the treatment of bipolar depression.

The incidence and shift in MetSy were analyzed in data pooled from 2 studies that recruited patients aged 18–75 years with a confirmed diagnosis of bipolar I or bipolar II disorder who were experiencing an MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4). Patients in these studies were randomized 1:1 to LUMA or PBO and treated for 6 weeks.

The safety population comprised 746 patients (LUMA, 372; PBO, 374). Rates of MetSy were similar between groups at baseline (LUMA, 20.7%; PBO, 22.2%) and at the end of treatment (EOT, LUMA, 21.8%; PBO, 23.8%). More LUMA patients (36.4%) compared with PBO patients (30.1%) improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. The individual criteria that shifted the most from meeting MetSy criteria at baseline to no longer meeting criteria at EOT was BP for LUMA (46.8%) and glucose for PBO (43.2%). The rate of MetSy developed during treatment was similar for LUMA (10.8%) and PBO (10.7%) with approximately half of these patients (LUMA, 43.8%; PBO, 45.2%) shifting due to a change in ≥2 criteria.

In this post hoc analysis of 2 randomized, PBO-controlled trials in patients with a MDE associated with bipolar I or bipolar II disorder, LUMA 42 mg had similar rates of MetSy compared with PBO. These results suggest that LUMA 42 mg is a promising new treatment for bipolar depression with a favorable metabolic profile.

Intra-Cellular Therapies, Inc.

Early onset of bipolar disorder is associated with high rates of psychiatric comorbidity (e.g., anxiety disorders, ADHD, PTSD), high rates of recurrence, and marked impairment in functioning and quality of life. The aim of this analysis was to evaluate the efficacy and safety of lurasidone in bipolar depression in youth and young adult patients (10–30 years old).

Data from two 6-week, double-blind, placebo-controlled studies of lurasidone monotherapy for bipolar I depression were pooled for this analysis. In the 1st study, patients 10–17 years old were evaluated using the Children’s Depression Rating Scale–Revised (CDRS-R) and the Clinical Global Impression-Bipolar Severity (CGI-BP-S) depression scale; in the 2nd study, a subgroup of adult patients (18–30 years old) were evaluated by CGI-BP-A, and the MADRS, with the latter being converted to a CDRS-R scores using a validated conversion algorithm.

The safety population consisted of 465 patients (mean age, 17.1 years; mean age of onset, 14.1; mean CDRS-R total score, 60.8). 400 patients (85.7%) completed the study. For lurasidone vs. placebo, LS mean Week 6 change was -21.4 vs. -15.3 for the CDRS-R total score (P<0.0001; ES, 0.46); and -1.6 vs. -1.1 for the CGI-BP-S score (P<0.0001; ES, 0.50). Adverse events (≥5%) on lurasidone vs. placebo were nausea (15.9% vs. 5.2%), headache (15.1% vs. 13.1%), somnolence (7.9% vs. 3.8%), vomiting (5.2% vs. 3.3%), and weight increase (5.2% vs. 2.3%). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin.

In this post-hoc analysis of two placebo-controlled trials, lurasidone demonstrated clinically meaningful improvement of depressive symptoms in youth and young adults with bipolar depression. Lurasidone was generally safe, well-tolerated, and associated with minimal effects on weight, metabolic parameters, and prolactin.

Servier Laboratories (Aust.) Pty. Ltd., and Sunovion Pharmaceuticals Inc.

Earlier onset of schizophrenia, which occurs more commonly in males, is characterized by greater illness severity, chronicity, and functional impairment with a less favorable prognosis than later-onset schizophrenia. The aim of this pooled analysis was to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia in adolescents (13–17 years) and young adults (18–25 years).

The 2 pooled studies used similar designs and outcome measures. Patients (13–25 years) with schizophrenia completed an initial double-blind 6-week trial of lurasidone (40 and 80 mg/d), and (80 and 160 mg/d) in the young adult trial. In the open-label long-term trials, adolescent patients were treated with 20-80 mg/d of lurasidone, and adults were treated with 40–160 mg/d of lurasidone. Efficacy was evaluated based on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity Scale (CGI-S).

The safety population consisted of 306 patients (mean age, 16.2 years; 208 patients (68.0%) who completed 12 months of treatment; 8.2% discontinued by 12 months due to an adverse event. Mean (SD) change in the PANSS total score from extension Baseline to Months 6 and 12 was -11.8 (13.9) and -15.3 (15.0), respectively (OC); and mean (SD) change in the CGI-S score was -0.8 (1.0) and -1.0 (1.1), respectively (OC). The most frequent adverse events were headache (17.6%), anxiety (11.4%), schizophrenia (9.8%), and nausea (9.8). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin.

In adolescents and young adults with schizophrenia, treatment with lurasidone was generally well-tolerated and effective. Long-term treatment was associated with continued reduction in symptoms of schizophrenia. Long-term treatment was associated with minimal effects on weight, metabolic parameters, and prolactin.

Angelini Pharma S.p.A. and Sunovion Pharmaceuticals Inc.

Psychosis is defined as the presence of false beliefs or false perceptions. In children some causes of psychosis include psychiatric diagnosis such as schizophrenia and autism. However, it may also be secondary to medical conditions like various forms of encephalitis. Studies have shown that IVIG has been efficacious in the treatment of psychosis in the setting of autoimmune encephalitis.

A 9-year-old girl with a past medical history of Turner Syndrome, developmental delay, epilepsy, growth hormone deficiency, metabolic bone disease, and autism (ASD) presented with auditory and visual hallucinations that began June 2020. She began with her hearing voices that repeated the word “dead” and told her that she would not live. The hallucination later took the form of a man that would mock her, laugh about her parents dying, and tell her to kill them. The patient had associated symptoms of insomnia, anxiety, sadness, and increased anger. On her initial admission, CSF studies including culture and gram strain were unremarkable. NMDA, VHKC, and GAD65 antibodies were negative. At this time the hallucinations were thought to be due to ASD and she was prescribed Risperdal 0.25mg twice a day. Unfortunately, this did not improve her symptoms and from the time period of June 2020 to May 2021 she subsequently underwent trials of Risperdal, Zyprexa, Invega, Abilify, Thorazine, Haldol, and Clozaril. However, the symptoms persisted. Zoloft was prescribed, which was efficacious for anger and dysphoria. Trazodone, melatonin, and Remeron were tried for the treatment of insomnia, but did not cause enough improvement to continue the medications. Due to progression of command hallucinations with “the man” instructing her to hurt others, the patient was admitted July 2021 for administration of IVIG. Repeat CSF studies and brain MRI were unremarkable. From July 29, 2021 to August 1, 2021 she received three doses of IVIG which resulted in improvement of psychosis. Prior to administration, she was seeing “the man” throughout the day every single day, was sleeping only 3–4 hours a night, and having nightmares everyday. On evaluation 2 weeks after IVIG, she was only seeing “the man” 1–2 time a day, sleeping 6–8 hours a night, having nightmares 1–2 times a week, and her mood had improved.

This case illustrates the potential use of IVIG for the treatment of treatment-resistant psychosis. Although the cause of this patient’s symptoms remains unclear, there were clear benefits from the administration of IVIG that were not seen with trials of antipsychotics.

No Funding

We sought to examine real-world treatment patterns and healthcare resource utilization (HCRU) for patients receiving an antipsychotic (AP) and subsequently prescribed benztropine.

A retrospective analysis was conducted among patients with evidence of benztropine initiation using claims data from IQVIA’s New Data Warehouse from January 2017–March 2020. Patients were indexed on the date of first pharmacy claim for benztropine and had continuous enrollment in the 6 months prior (pre-index) and minimum 12 months post-index date, up to 24 months. Patients also had ≥1 pharmacy claim for an AP either pre-index or on the index date.

A total of 112,542 patients were included; 59% were female with mean age of 46 years. The most common comorbidities were bipolar disorder (BD; 28.3%), schizophrenia (SCZ; 28.3%), and depression (26.3%). Over half of the cohort (54.1%) had ≥2 comorbid conditions. Nearly 20% of patients had ≥20 medications (median 10–14) and medications with anticholinergic (AC) properties were used by 87.9%. Approximately 80% of patients had mild AC burden at baseline (using AC burden calculator). The median number of benztropine prescription fills was 5 with treatment duration <3 months in 44.3% of patients and <6 months in 61.7%. All-cause mean healthcare costs in the 12-month cohort (24-month cohort) were $11,755 ($23,128), mean costs for pharmacy were $9,229 ($18,148), and mean costs for inpatient stays were $34,669 ($41,280). Emergency room (ER) visits occurred in 47.3% and physician office visits in 78.9% of the cohort. In patients with available inpatient 12-month data (n=33,717), inpatient stays occurred in 4.0% (13.3% when extrapolated to total cohort). In patients with 24-month data (n=73,836), ER visits occurred in 61% of the cohort and inpatient stays in 6.6% (21.9% when extrapolated to the total cohort). Multivariate analyses showed baseline SCZ was associated with a significantly increased risk of ER visit of 30% and inpatient stay of 50%. Similarly, substance abuse was associated with an increased risk of ER visit of 85% and inpatient stay of about 40%. Other significant associations with ER visits included falls/accidents at baseline (148% increased risk), abnormal movement disorders (38% increased risk), and orthostatic hypotension (38% increased risk).

In this real-world analysis of patients initiating benztropine, polypharmacy and AC burden were frequently observed. BD, SCZ, and depression were the most common comorbidities. Healthcare costs and HCRU were high for the entire cohort; inpatient stays contributed to high costs. Baseline SCZ, falls/accidents (ER only), and substance abuse were significantly associated with ER and inpatient admissions. The comorbidity and medication profiles of this cohort may have influenced the high healthcare costs and HCRU observed in the study.

Neurocrine Biosciences, Inc.

Patients with major depressive disorder (MDD) who have inadequate responses to antidepressants (ADs) can benefit from augmentation with atypical antipsychotics (AAs). Cariprazine, a D3/D2 receptor partial agonist, is approved for schizophrenia and for manic, mixed, or depressive episodes associated with bipolar I disorder. Cariprazine is also currently under investigation for the adjunctive treatment of MDD. The aim of this retrospective cohort study was to describe healthcare resource utilization (HCRU) and associated medical costs with cariprazine and other adjunctive AA therapies for MDD.

IBM® MarketScan Commercial Claims and Encounters, Medicare Supplemental, and Medicaid databases were searched for claims made from 01-Jan-2018 to 31-Mar-2021. The study population included adults (≥18 years) who met the following criteria: ≥1 inpatient claim with an MDD diagnosis or ≥2 outpatient claims that were >30 days apart; ≥1 AD therapy after MDD diagnosis; ≥1 branded or generic adjunctive AA (with AD); enrollment for ≥6 and ≥12 months for baseline and follow-up analyses, respectively. Branded AAs were analyzed individually; generic AAs were grouped. MDD-related HCRU outcomes per person over the 12-month follow-up period included inpatient stays, inpatient costs, office visits, and office visit costs, with adjusted pairwise comparisons between cariprazine and other AAs. Statistical significance was defined as the 95% confidence interval (CI) for the estimated mean ratio (EMR) of comparator AA to cariprazine not including 1 (i.e., value indicating no difference).

Analyses included 46,197 patients, with AA cohorts as follows: generics (n=39,410, including mostly aripiprazole and quetiapine); brexpiprazole (n=3,249); lurasidone (n=1,795); cariprazine (n=1,051); quetiapine-XR (n=644). A majority of patients across cohorts were women (range, 65.7% to 75.4%). Inpatient stays were statistically significantly fewer with cariprazine than all other AA therapies (EMR range [95% CI]: 1.7 [1.2–2.3] to 2.9 [2.1–3.9] for brexpiprazole and generics, respectively). Inpatient costs were lower for cariprazine than other branded AAs and statistically significantly lower compared to generics (2.4 [1.6–4.1]). Office visits were fewer with cariprazine than all other AAs and significantly lower than generics (1.1 [1.03–1.2]), lurasidone (1.3 [1.2–1.4]), and brexpiprazole (1.4 [1.2–1.5]). Office visit costs were also lower for cariprazine than all other AAs and statistically significantly lower than lurasidone (1.2 [1.03–1.5) and brexpiprazole (1.4 [1.2–1.6]).

The results of this study suggest that in patients with MDD, adjunctive treatment with cariprazine is associated with statistically significantly lower HCRU for certain outcomes and numerically lower medical costs compared to other branded AAs, along with statistically significantly lower HCRU and medical costs versus generic Aas.

AbbVie