Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) in development for ADHD. In 2 pivotal adult ADHD trials, CTN sustained-release (SR) 200 mg/d and 400 mg/d, administered twice daily (BID), significantly reduced Adult ADHD Investigator Symptom Rating Scale (AISRS) total score vs placebo, with favorable safety and tolerability. Long-term effects of CTN SR 400 mg/d in adult ADHD are reported here.

Adults meeting DSM-5 criteria for ADHD who completed a pivotal trial or enrolled de novo were eligible for the 52-week, phase 3, open-label trial. Uncontrolled comorbid psychiatric disorder, undifferentiated diagnosis of ADHD, prohibited medicines, or positive alcohol or drug screen were exclusionary. All patients (pts) received CTN SR BID, titrated to 400 mg/d by day 8, and fixed thereafter. Safety was primarily assessed by adverse events (AEs); laboratory results, physical examinations, vital signs, ECG, Study Medication Withdrawal Questionnaire (SMWQ), and Columbia-Suicide Severity Rating Scale (C-SSRS) were also assessed. Efficacy was assessed by AISRS, Clinical Global Impression-Severity (CGI-S) and ADHD Impact Module-Adult (AIM-A). Analyses were based on observed results using descriptive statistics. Baseline was relative to the first CTN dose in the open-label trial.

Of 662 pts enrolled (mean [SD] age 36.7 [10.1] years; 51.1% female; 82.9% White), 653 received CTN SR; 345 pts completed the trial. Common discontinuation reasons were pt withdrawal (119; 18%), AEs (81; 12.2%), and lost to follow-up (41; 6.2%); 22 (3.4%) pts discontinued for lack of efficacy. Treatment-emergent AEs (TEAEs) occurred in 401 pts (61.4%); 16 (2.5%) had severe TEAEs. Common TEAEs were insomnia (8.0%), nausea (7.7%), diarrhea, and headache (7.0% each). Serious TEAEs occurred in 12 pts (1.8%); none were CTN related. AEs of special interest (n=18; 2.8%) included rash (n=5; 1 severe), papule, rash erythematous, rash maculopapular, rash papular, and urticaria (n=1 each); 3 discontinued. Abuse potential–related AEs occurred in 31 pts (4.7%). No deaths occurred. SMWQ scores were low throughout. Suicidal ideation/behavior occurred in 13 pts (2.0%) per C-SSRS. There were no trends in laboratory, vital sign, or ECG changes. Baseline mean (SD) AISRS Total, Inattentive, and Hyperactive-Impulsive scores were 34.4 [10.3], 19.2 [5.6], and 15.2 [6.0], respectively; mean (SD) changes at week 52 were −20.4 (11.9), −11.2 (6.6), and −9.2 (6.2). Baseline mean (SD) CGI-S score was 4.2 (0.9); mean (SD) change at week 52 was −1.5 (1.1). Baseline mean (SD) AIM-A score was 6.5 (1.8); mean change at week 52 was 1.23 (2.0).

Safety, tolerability, and exploratory efficacy results from this trial demonstrate that CTN SR 400 mg is a safe and effective long-term treatment for ADHD in adults.

Study Registration: NCT03605849

Previous presentation: APA Annual Meeting, May 20–24, 2023, San Francisco, CA

Otsuka

Transcranial Magnetic Stimulation (TMS) is a Food and Drug Administration (FDA) approved treatment that induces neuronal activity in the left dorsolateral prefrontal cortex. TMS was initially developed to treat major depression after studies of patients with depression revealed hypometabolism in this brain region. Since it was first FDA approved in 2008, several types of TMS have been developed and its clinical indications expanded. Given the dearth of literature guiding clinicians in understanding different forms of TMS and their protocols, this poster will review the common and unique aspects of several forms of TMS in an effort to aid clinicians in appropriately utilizing this safe and effective neuromodulatory treatment.

Specific keywords were used to conduct a thorough but nonsystematic review of multiple databases, including PubMed, Google Scholar, and PsychInfo. Articles describing protocols rather than direct comparisons were selected. The outcomes regarding protocol guidelines, advantages, disadvantages, safety, and side effects were included in the review.

The FDA approved types of TMS include repetitive TMS (rTMS), deep TMS (dTMS), intermittent theta burst stimulation (iTBS), and accelerated TMS (aTMS). While rTMS is limited to cortical tissue, other forms of TMS reach subcortical neurons with aTMS using functional magnetic resonance imaging (fMRI) to specifically locate the target area. dTMS was approved in 2013 and its session time is half that of rTMS. Subsequently developed TMS types have even shorter sessions; iTBS sessions are only 3 minutes and aTMS is 9 minutes per session. Most TMS protocols require 8-9 weeks for full treatment, but aTMS only needs 5 days. All TMS protocols stimulate at 120% of resting motor thresholds except for aTMS which adjusts based on the patient using fMRI results. Efficacy is mostly similar with rTMS, dTMS, and iTBS demonstrating remission rates up to 30%, but aTMS had remission rates up to 90.5%. aTMS can also be used for suicidality, patients with severe or refractory depression, as well as those with comorbid anxiety, which have historically shown lower rates of success with other treatments. Overall, all forms of TMS produce minimal and temporary side effects with patients being able to return to normal activities the same day as treatment, although aTMS may cause side effects of greater intensity resulting in sleep dysregulation. Cost remains a barrier, with many insurances covering rTMS but not iTBS or aTMS.

TMS is an evidence based, efficacious, and safe treatment for depression. Most FDA-approved TMS protocols for depression have similar number of sessions, duration of treatment, common side effects, and remission rates, besides aTMS, which has dramatically greater remission rates and shorter treatment duration, making it a potentially rapid and effective treatment modality for acute and more severe cases of depression.

No Funding

The World Health Organization estimates depression affects 5% of the adult population and is the leading cause of disability and the 3rd cause of disease burden worldwide. Despite progress in therapies and pharmacology, 30% of patients have refractory symptoms. Patients with partial response and patients who do not want or are intolerant to medication can benefit from alternative treatment modalities such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). However, there is scant literature comparing these two neuromodulatory techniques. The authors provide an overview of rTMS and tDCS to guide clinicians.

A review of MEDLINE, Google Scholar, and EBSCOHost databases was conducted. Keywords used included “rTMS,” “tDCS,” and “depression.” All types of articles discussing or comparing the modalities were selected. The unique characteristics, indications, and side effects of rTMS and tDCS were included.

rTMS is a neurostimulator used in-clinic that induces depolarization and neuronal activity in the dorsolateral prefrontal cortex, where hypofunction has historically been associated with depressive symptoms. The treatment is Food and Drug Administration (FDA) approved, and the most common protocol consists of 36 sessions over 8-9 weeks. Side effects are mild and temporary, and patients can resume daily activities after sessions. Its absolute contraindications are limited to metallic objects or implanted stimulator devices in or near the head. The total cost varies from $6,000-$11,000 but is covered by most insurance.

In contrast, tDCS is a cost-effective, small, and portable neuromodulator self-administered by patients at home that either increases or decreases intrinsic neural firing in the primary motor cortex and dorsolateral prefrontal cortex. Multi-session tDCS is thought to promote or regulate information processing efficiency. The most common protocol uses a constant low current for 20-30 minutes applied daily for 10 to 15 days. Common side effects are mild and temporary, and there is no absolute contraindication. Some meta-analyses have found its efficacy comparable to rTMS or antidepressants. However, due to uncertainties about the specific mode of administration, number of treatments, and duration of effect, its status remains investigational by the FDA.

The efficacy and safety of rTMS for the treatment of depression have been demonstrated in numerous studies. However, the lack of adequately equipped clinics and large cost limits its availability in spite of FDA approval. In contrast, tDCS has some advantages, including safety, tolerability, ease of administration at home, and cost-effectiveness, but requires further research and more rigorous evidence.

No Funding

To examine the effectiveness of short-term progressive muscle relaxation therapy in reducing symptoms of depression, anxiety, and aggression/agitation, in patients on an inpatient psychiatric unit. Additionally, to determine the impact of clinical and sociodemographic factors on its effectiveness.

Psychiatric inpatients at a private, community-based psychiatric hospital were invited to participate in a progressive muscle relaxation activity and filled out pre- and post-activity surveys querying symptoms of depression, anxiety, and aggression/agitation, using a created Likert scale.

The 57 participants in this study showed an average decrease in every symptom domain, including -0.93 in agitation/aggressive symptoms (p<0.001), -2.14 in depressive symptoms (p<0.001), and -1.81 in anxiety symptoms (p<0.001). While diagnosis did not appear to be significantly related to change in score, patients with different primary diagnoses had changes in different symptom domains, with patients with Bipolar Disorder having statistically significant changes in aggression (-1.57, p=0.012) and depression (-2.36, p<0.001), but not in anxiety. Patients with Depression had significant changes in depression (-2.08, p<0.001) and anxiety (-1.96, p<0.001) but not in aggression/agitation, while patients with a Schizophrenia spectrum illness had changes in depression alone (-2.33, p=0.008). Sociodemographic variables had no significant impact.

The findings in this study indicate that a short-term progressive muscle relaxation intervention can lead to statistically and clinically significant changes across various symptom domains and in patients with a variety of psychiatric diagnoses, and support the implementation of this non-invasive and budget-friendly exercise.

No Funding

Although atypical antipsychotics have lowered the prevalence and severity of extrapyramidal symptoms (EPS), they still contribute to the overall side-effect burden of approved antipsychotics. Drugs with novel mechanisms without D2 dopamine receptor blocking activity have shown promise in treating schizophrenia without the side effects of currently available treatments. KarXT (xanomeline–trospium chloride) represents a possible alternative that targets muscarinic receptors. KarXT demonstrated efficacy compared with placebo in 3 out of 3 short-term acute studies and has not been associated with many of the side effects of D2 dopamine receptor antagonists. Here, we further characterize EPS rates with KarXT in these trials.

EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) were 5-week, randomized, double-blind, placebo-controlled, inpatient trials in people with schizophrenia experiencing acute psychosis. Data from the safety populations, defined as all participants who received ³1 dose of trial medication, were pooled. For this analysis, we used a broader definition of EPS-related adverse events (AEs) to encompass any new onset of dystonia, dyskinesia, akathisia, or extrapyramidal disorder reported any time after the first dose of medication. Additionally, EPS were assessed by examining change from baseline to week 5 on the Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS).

A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the analyses. The rate of treatment-emergent AEs (TEAEs) associated with EPS was 3.2% in the KarXT group vs 0.9% in the placebo group. The most commonly reported TEAE was akathisia (KarXT, 2.4%; placebo 0.9%); half of possible akathisia cases in the KarXT group (4/8 TEAEs) were from a single US site, considered by the investigator to be unrelated to trial drug, and resolved without treatment. Overall rates of akathisia TEAEs deemed related to trial drug were low (KarXT, 0.6%; placebo 0.3%). Dystonia, dyskinesia, and extrapyramidal disorder TEAEs were reported by only a single subject each (0.3%) in the KarXT arm. All reported TEAEs were mild to moderate in severity. KarXT was associated with no clinically meaningful mean±SD changes from baseline to week 5 on the SAS (-0.1±0.6), BARS (-0.1±0.9), or AIMS (0.0±0.7).

The incidence of EPS-related TEAEs with KarXT was low in comparison to those observed in similar trials of antipsychotics (D2 dopamine receptor antagonists), although head-to-head studies have not been completed. Moreover, KarXT was not associated with increased scores on EPS scales (SAS, BARS, AIMS) across 5 weeks of treatment. These results, combined with the robust efficacy of KarXT in trials to date, suggest that KarXT’s novel mechanism of action may provide therapeutic benefit in the absence of EPS frequently associated with currently available antipsychotics.

Karuna Therapeutics

Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotics (APs).

To estimate TD diagnosis rates across geographic regions of the United States (US) among adults who use APs.

In this retrospective cohort study, patients with ≥1 AP claim (≥30-day supply) followed by TD diagnosis (index date) aged ≥18 years at index date with ≥12 months of continuous insurance eligibility after index date and geographic location information were identified in the IBM MarketScan© commercial insurance database (2012– 2019). Additional information was collected from the US census, the Internal Revenue Service, and the Centers for Medicare & Medicaid Services. . Observed TD diagnosis rates were estimated by metropolitan statistical area (MSA; ie, a major city and surrounding geographic areas linked by socioeconomic factors with ≥50,000 individuals). A weighted multivariable linear regression model was used to calculate expected TD diagnosis rates per 1000 patients with an AP prescription at the MSA level. Estimated and expected TD diagnosis rates were aggregated at the state level. Underdiagnosis of TD was defined as the observed TD diagnosis rate being lower than the expected TD diagnosis rate.

Among 572,314 people who met inclusion criteria, the mean observed TD diagnosis rate across 341 MSAs was 3.10 per 1000 patients with an AP prescription; 86 (25.2%) MSAs had no patients with a TD diagnosis. Over 50% of MSAs and states had an underdiagnosis of TD. MSAs with the highest expected TD diagnosis rates were Missoula, MT (5.47), Billings, MT (5.39), and Madison, WI (5.16). MSAs with the highest observed TD rates were Chambersburg-Waynesboro, PA (18.52), Napa, CA (13.70), and San Angelo, TX (13.07). MSAs with the largest negative differences between observed and expected TD diagnosis rates (ie, highest underdiagnosis rates) were Missoula, MT (−5.47), Billings, MT (−5.39), and Gainesville, FL (−4.39). States with the highest expected TD rates were Montana (5.28), Idaho (4.52), and Alaska (4.32). States with the highest observed TD rates were North Dakota (7.09), Idaho (5.85), and New Mexico (5.67). States with the highest underdiagnosis rates were South Dakota (−3.72), Vermont (−3.57), and Montana (−3.21).

Overall, this study showed that TD was underdiagnosed in >50% of US geographic regions. This research highlights opportunities for improved TD recognition in areas with TD underdiagnosis.

Teva Branded Pharmaceutical Products R&D, Inc.

Co-occurrence of Obsessive compulsive symptoms (OCS)/Obsessive Compulsive disorder (OCD) and psychotic disorders is not uncommon affecting approximately 20% of the patients with psychotic disorders. The clinicians sometimes fail to recognize the comorbidity of these two conditions due to the overlapping symptoms and also due to under reporting by the patients until the symptoms become very severe. Timely recognition and treatment of obsessive symptoms are crucial for improving the outcomes of psychotic episodes. Our review aims to study the role of antipsychotics in causing OCD/OCS in schizophrenia. We also discuss the etiologies, pathophysiology, and treatment of OCD/OCS in schizophrenia.

A comprehensive literature search was conducted on PubMed and Google Scholar to identify relevant articles published between 2013-2023. The different search terms were “(Antipsychotics)”, “(OCD in schizophrenia)” with connector AND. All review, case control, cohort, cross sectional, observational studies were included for the literature review. Based on the relevance of the topic and removal of duplicates, we chose 61 articles.

The literature review revealed that several mechanisms could explain the temporal links between OCD/OCS and schizophrenia. Genetic factors, such as SLC1A1, BDNF, DLGAP3, and GRIN2B genes, have been studied. Serotonergic dysfunction in the cortical, striatal, and thalamic networks has been proposed by OCD pathogenic theories, supported by the therapeutic effects of SSRIs and CBT. Antipsychotic medications, particularly Clozapine, have been associated with a higher prevalence of OCS/OCD during treatment. Some second-generation antipsychotics, like risperidone and olanzapine, have also been linked to new-onset OCS. Treatment options for OCS/OCD in schizophrenia include SSRIs, atypical antipsychotics like Aripiprazole, Amisulpride, or Lamotrigine, CBT, and ECT.

Several studies have examined the link between the presence of OCS in relation to the use of antipsychotics. Among the APAs, the frequency of OCS/OCD is more in the patients using antipsychotics which have more anti serotonergic properties as compared to the ones having more anti dopaminergic properties. Of the second-generation antipsychotics, Clozapine, Olanzapine and Risperidone are the ones being documented most frequently, with clozapine being the most frequent. A dosage-dependent side effect may also be present based on correlations between OCS severity, dose, serum levels, and treatment duration. Various treatment approaches have been suggested, but further research is needed to determine the most effective strategies for managing OCS/OCD in schizophrenia. Clinicians must be aware of the potential comorbidity of these conditions to provide better care and improve patient outcomes.

No Funding

Pharmacogenomic (PGx) testing identifies individual genetic variation that may inform medication treatment. Lack of awareness and education may be barriers to implementing routine PGx testing. To characterize current PGx testing utilization and educational needs we conducted a survey of various provider types.

Healthcare providers in the primary care setting were targeted between November 2022 and February 2023 via the Medscape Members paid market research program. The survey included 5 demographic, 5 multiple-choice, and 4 multi-component five-point Likert scale questions to assess PGx sentiments, use, and education in mental health (e.g., depression) and primary care (e.g., cardiovascular disease) conditions. Responses were descriptively compared.

Of 305 U.S. provider respondents [40% nurse practitioners (NPs), 33% frontline MDs/DOs, 3% physician assistants (PAs), 24% other], most indicated that they “don’t use” (44-49%) or “have never heard of” (19-20%) PGx testing for mental health conditions. The most helpful sources to learn about PGx testing were accredited CE/CME activities (55-61%) and peer-reviewed publications (57-59%). Most NPs/PAs preferred webinars (62%) or online learning portal (57%) formats. MDs/DOs had no preference for webinars or learning portals over conferences, written materials, or academic presentations (45-47%). NPs/PAs were more interested in learning about PGx testing than MDs/DOs (4.29/5 vs. 3.96/5 average score).

These data reveal awareness level and desired learning opportunities for PGx testing between types of healthcare providers. Education should be tailored to meet providers’ preferred learning formats and information sources, such as offering CE/CME through an online learning portal.

Myriad Genetics, Inc.

Ketamine is used off-label for suicidality and mood disorders, whereas esketamine is FDA-approved for treatment-resistant depression in adults. However, many of these studies have excluded patients with a history of or currently presenting with psychosis. A significant number of patients who have primary mood disorders with psychotic features need novel psychopharmacological interventions. We conduct a systematic review of ketamine and esketamine usage in patients with treatment-resistant mood disorders (either depression or bipolar) with psychotic features to assess the safety and tolerability of these medications in this population.

PubMed, Google Scholar, and EBSCOHost databases were searched systematically using a curated search strategy involving keywords and subheadings. A total of 199 abstracts were reviewed after duplicates and 25 full text articles were screened. All selected publications were reviewed independently by three authors. We only included non-review articles in patients with primary mood disorder presenting with psychotic features measuring dissociative and psychotic outcomes with ketamine or esketamine administration.

A total of 12 articles were included: nine articles reported case reports/series and three reported observational studies. All combined, there was a total of 64 patients with depression and psychotic features and 19 adults with bipolar and psychotic features. The majority of case reports involved female adults and there was one pediatric patient of unknown sex. Either ketamine or esketamine was administered at a dose of 0.5 mg/kg for all patients, either intravenously, subcutaneously, or orally. Six articles mentioned dissociative symptoms, but only two used a validated scale, Clinician-Administered Dissociative States Scale (CADSS), to measure symptoms. While six articles reported a transient increase of dissociation during and within 2 hours of the medication infusion, no article reported sub-acute or chronic worsening of dissociative symptoms. Furthermore, one article reported a significant decrease in baseline CADSS over four weeks. 12 articles mentioned psychotic symptoms, but only three used a validated scale, Brief Psychiatric Rating Scale (BPRS), to measure symptoms. Every article reported that psychotic symptoms did not worsen. Furthermore, one article reported a significant decrease in baseline BPRS over four weeks and eight articles reported resolution of psychotic symptoms.

Ketamine and esketamine are being used for both depression and bipolar with psychotic features by some clinicians when other treatment modalities are not successful. This has usually resulted in fast recovery and maintained remission. Dissociative symptoms can be impactful near the time of infusions but resolves within a few hours in most cases. Psychotic symptoms often improve on repeated administration with none to minimal worsening during the short-term period.

No Funding

Long-acting injectable antipsychotics (LAIs) reduce relapses in schizophrenia; however, most healthcare professionals (HCPs) reserve LAIs for nonadherence to oral antipsychotics (OAs) or severe disease.

US HCPs were surveyed regarding attitudes and perceptions toward LAIs for schizophrenia and LAI selection preferences. Respondents were grouped by LAI use (high [≥31% of patients using LAIs], low [≤14% using LAIs]; mid not analyzed) and archetype based on response to, “Which of the following best fits the current way you view your use of [LAIs] for your patients with schizophrenia?” (see responses below).

Respondents (106 high, 130 low LAI use) were distributed across early LAI use (n=123), severity-reserved (n=88), adherence-reserved (n=113), and LAI-hesitant (n=56) archetypes.

Across all groups, HCPs estimated OA nonadherence in their practice (21%– 32%) to be lower than for patients nationwide (50%– 56%). Overall, 27% were dissatisfied with their LAI:OA use ratio, most thinking their OA use was too high. In all groups, side effects/tolerability was ranked as most important when choosing an LAI and “preference for the molecule” was ranked least important. Overall, 71%– 77% of HCPs were somewhat/much more likely to use a particular LAI based on multiple injection site options, small/on par needle, and price, and 63%– 82% of HCPs were somewhat/much more likely to select an LAI dosed once monthly or less often compared with an LAI dosed once every 2 weeks (8%). HCPs with high LAI use or early LAI use archetype were more likely to disagree that managing patients with schizophrenia increased their stress (64% and 63% vs 27%-45%, P<.05 each) and/or left them feeling “burned out” (77% and 79% vs 50%– 64%, P<.05 each).

Compared with other groups, greater proportions with high LAI use or early LAI use archetype consistently read new LAI publications (18% and 19% vs 0%– 5%, P<.01) and were confident in key aspects of LAI treatment (ie, dosing, managing side effects, access; 67%– 74% and 59%– 70% vs 11%– 57%, P<.05 each).

HCPs with low LAI use estimated the proportion of patients who initially refuse LAIs to be higher (mean, 55%) than those with low LAI use (44%, P<.01); there were no differences among archetypes (49%– 54%). HCPs with high LAI use or early LAI use archetype were more likely to “use any means necessary to ensure that a patient is on an LAI” vs other groups (44% and 51% vs 5%– 22%, P<.01 each) or had used guardianship to assist with treatment (70% and 69% vs 32%– 56%, P<.05 each); greater proportions with high LAI use or early LAI use archetype strongly agreed it was “worth [their] time to resolve issues with the insurance company” (42% and 45% vs 16%– 30%, P<.05 each) and were confident they would be able to do so (23% and 20% vs 2%– 11%, P<.05 each). Greater proportions of HCPs with early LAI use archetype vs the severity-reserved archetype strongly agreed that they attempt to determine the patient’s/caregiver’s preferred role before involving them (43% vs 27%, P<.05) and encourage them to participate (72% vs 57%, P<.05) in shared decision-making.

Comparing HCPs with high LAI use or early LAI use archetype vs other groups, multiple factors (eg, attitudes, preferences, training, knowledge base) combine to influence LAI use. These results highlight considerations for developing educational materials to increase LAI use in this population.

Teva Branded Pharmaceutical Products R&D, Inc.

Pharmacogenetic testing is becoming more common, especially to provide guidance for psychiatric medications. Over 17 psychotropic medications currently have a Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline. Several clinical trials have described PGx testing in specific patient populations, but various exclusion criteria create cohorts that may not represent real-world populations. Given the overall undefined characteristics of a real-world population utilizing commercial PGx testing, the clinical presentation of 15,198 patients that used a commercial PGx laboratory (Genomind) from October 15, 2018 through April 11, 2023 was assessed. These 15,198 patients include those whose provider conducted a clinical consultation with a Genomind psychopharmacologist, regardless of ICD diagnosis on the requisition form. Data were extracted from de-identified consult notes entered by the psychopharmacologist. Consultants made a total symptom severity assessment based on CGI-S (Clinician Global Impression Severity) criteria. Most patients were described as mildly (15%), moderately (59%), or markedly ill (21%). The most common presenting symptoms identified in the cohort were “Anxious” (61.6%), “Depressed” (61.1%), “Inattentive” (37.8%) and “Hyperactive” (11.4%). The most common co-occurring symptoms in patients with a depressive presentation were “Anxious” (68.1%), “Inattentive” (16.0%), “Manic/Hypomanic” (11.1%), “Insomnia” (9.8%) and “Irritable/Angry” (7.4%). The most common co-occurring symptoms in patients presenting with anxiety were “Depressed” (67.6%), “Inattentive” (20.9%), “Panic” (11.5%), “Worry/Rumination” (11.2%) and “Hyperactive” (11.1%). This analysis suggests that PGx testing is commonly being utilized in patients with symptoms of anxiety, mood lability and inattentiveness. Future PGx research should prioritize the selection of patients with these symptoms to generate evidence that matches the real-world users of commercial PGx services.

Genomind, Inc.

Pharmacogenomic (PGx) testing identifies individual genetic variation that may inform medication treatment. Sentiment and barriers may limit PGx testing. Here we compare confidence in utilizing PGx testing and barriers to implementation by type of provider and treatment condition as identified in a survey.

Healthcare providers in the primary care setting were targeted between November 2022 and February 2023 via the Medscape Members paid market research program. The survey included 5 demographic, 5 multiple-choice, and 4 multi-component five-point Likert scale questions to assess PGx sentiments, use, and education in mental health (e.g., depression) and primary care (e.g., cardiovascular disease) conditions. Responses were descriptively compared.

Of 305 U.S. provider respondents [40% nurse practitioners (NPs), 33% frontline MDs/DOs, 3% physician assistants (PAs), 24% other], 32% of NPs/PAs and 29% of MDs/DOs had used PGx testing for mental health conditions. The major barriers to adopt PGx testing were similar for mental health and primary care conditions yet differed by provider type. NPs/PAs (72-77%) were more concerned with patient cost than MDs/DOs (46-55%), whereas MDs/DOs were more concerned with evidence of clinical utility (54-59%) than NPs/PAs (40-42%). In respondents who use PGx testing, MDs/DOs reported slightly more confidence utilizing PGx than NPs/PAs. For both groups, confidence in using PGx for mental health conditions was somewhat greater than for non-mental health conditions.

These data illuminate the implementation barriers and confidence levels of clinicians utilizing PGx testing. Increasing awareness around patient cost and evidence of clinical utility for PGx testing may improve utilization.

Myriad Genetics, Inc.

In a recently published Phase 3 trial (KINECT™-HD; NCT04102579), once-daily treatment with valbenazine significantly improved chorea versus placebo in adults with Huntington disease (HD). Individuals who completed KINECT-HD, along with de novo participants, were allowed to enroll in KINECT™-HD2 (NCT04400331), the first long-term study of once-daily valbenazine for chorea associated with HD. Pre-planned interim analyses from this ongoing study were conducted to evaluate the maintenance of valbenazine’s effect on chorea and its long-term safety in adults with HD.

All KINECT-HD2 participants start valbenazine at 40 mg with increases to 60 mg (Week 2) and 80 mg (Week 4); target maintenance dose is 80 mg once daily until end of treatment (up to 156 weeks). Concomitant antipsychotic medications are allowed. Efficacy outcomes, analyzed by study visit, include mean changes from baseline in Unified Huntington’s Disease Rating Scale (UHDRS®) Total Maximal Chorea (TMC) score and response status for Clinical Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C). Responders are defined as participants with a score ≤2 (rating of “much improved” or better). Efficacy outcomes up to Week 50 (˜1 year) are reported. Treatment-emergent adverse events (TEAEs) are presented for all participants who received ≥1 dose of study drug, regardless of time in study (2 to 104 weeks). All interim outcomes were analyzed descriptively.

Of 127 participants enrolled at the time of analysis, 98 (77.2%) had completed KINECT-HD and 29 (22.8%) were newly enrolled. Of 125 participants who received treatment, 65 (52.0%) were female and 118 (94.4%) were white; mean age (±SD) was 54.8 (±11.5) years. A mean reduction in TMC score was observed by Week 2 with valbenazine 40 mg (-3.4 [±3.1], n=118); mean reductions were sustained from Week 8 (5.6 [±3.6], n=110) to Week 50 (-5.8 [±4.1], n=66) (all valbenazine doses). At Week 50, 76.9% (50/65) of participants met the pre-defined threshold for CGI-C response; 74.2% (49/66) met the threshold for PGI-C response. Analyses in participants taking concomitant antipsychotic medications are ongoing and will be presented at the meeting. Of the 125 participants who received treatment, 119 (95.2%) reported at least 1 TEAE and 17 (13.6%) discontinued due to a TEAE. The most commonly reported TEAEs were falls (30.4%), fatigue (24.0%), and somnolence (24.0%).

Interim TMC data from KINECT-HD2 indicated chorea improvement with once-daily valbenazine by Week 2 (3.4 [±3.1] with 40 mg), similar to KINECT-HD Week 2 results (-2.9 [±3.0]). The interim analyses also indicated that long-term treatment with valbenazine was well tolerated and provided clinically meaningful improvement in chorea severity for up to ˜1 year.

Neurocrine Biosciences, Inc.

Valbenazine is a highly selective vesicular monoamine transporter 2 inhibitor indicated for tardive dyskinesia (TD), a persistent and potentially debilitating movement disorder associated with prolonged antipsychotic exposure. Given the paucity of data regarding the course of TD in patients no longer taking antipsychotics, a meta-analysis of 3 long-term valbenazine studies was conducted in subgroups with and without concomitant antipsychotic use at baseline.

KINECTTM-3 (NCT02274558), KINECTTM-4 (NCT02405091), and JKINECT (NCT03176771) data were analyzed in study completers taking antipsychotics at baseline (AP+) and those who were not (AP-). The Abnormal Involuntary Movement Scale (AIMS) total score was used to measure TD severity at baseline, Wk48 (end of valbenazine treatment), and Wk52 (4 weeks after valbenazine withdrawal). The meta-analysis implemented a random-effects model that weighted each study based on inverse variance, adjusted for between-study variance.

Of 576 enrolled patients, 336 (58.3%) were study completers and included for analysis: AP+ (n=269); AP- (n=67). Mean baseline AIMS scores ranged from 7.9–14.9 (AP+) and 10.9–14.5 (AP-). Mean changes from baseline in AIMS scores indicated substantial TD improvements with valbenazine at Wk48 (AP+, 6.1; AP-, -6.5) and return towards baseline severity at Wk52 (AP+, -2.1; AP-, -1.4).

Once-daily valbenazine treatment resulted in substantial and sustained TD improvement through Wk48, with no meaningful differences between AP+ and AP- subgroups. The return towards baseline severity after valbenazine withdrawal shows TD is chronic and often irreversible, even in patients no longer taking antipsychotics. Continuous treatment with valbenazine may be warranted irrespective of antipsychotic therapy.

Neurocrine Biosciences, Inc.

Rates of psychiatric illness among the child and adolescent population have increased over the past several decades. As social and government agencies work to expand access to mental health treatment, more and more children and adolescents are receiving medications for their symptoms. However, many drugs used in this population are not approved for people under the age of 18, and have not been studied in terms of long-term impact on the developing brain. A significant proportion of these patients receive psychiatric polypharmacy, or the prescription of 2 or more psychotropic agents. This rate has increased from about 8% in 1996 to over 40% in 2005. Factors correlated with polypharmacy include older age, male gender, White race, and low socioeconomic status. Polypharmacy can increase the risk of drug-drug interactions, increase morbidity/mortality through cumulative toxicity, and cause decreased medication adherence.

Study Aims: This study aimed to examine psychiatric polypharmacy specifically among psychiatrically hospitalized patients in a New York City hospital, and to determine the impact of the COVID-19 pandemic.

This IRB-approved study reviewed the medical records of 1101 child and adolescent patients that were psychiatrically hospitalized between June 1 2018 and November 30 2021 at Mount Sinai Morningside. Sociodemographic and clinical information was collected and analyzed using SPSS.

In this sample, 29.4% of patients received psychotropic polypharmacy. The polypharmacy group contained a higher percentage of males, White patients, and fewer Asian/South Asian patients. They had on average more hospitalizations, a longer hospitalization period, and were more likely to be diagnosed with an impulsive/behavioral disorder, developmental disorder, or bipolar spectrum disorder. The polypharmacy group were twice as likely to receive medication for agitation while hospitalized. A regression model identified positive predictors of polypharmacy as having a history of violence and a higher number of psychiatric hospitalizations. Negative predictors included non-White race. White patients had the highest average number of medications and Asian/South Asian patients had the lowest. No impact of the COVID-19 pandemic was found.

Psychiatric polypharmacy is extremely common in the child and adolescent population that requires psychiatric hospitalization. Increased behavioral needs, such as episodes of violence, as well as greater illness severity, as indicated by greater number of hospitalizations, may be the driving factors behind polypharmacy. Further investigation is indicated to determine other contributing causal factors and to track long-term consequences of psychiatric polypharmacy.

No Funding

In prior studies, the dual M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic activity in people with schizophrenia and Alzheimer’s disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline’s beneficial central nervous system effects while mitigating adverse events (AEs) due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia was demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

The EMERGENT trials enrolled people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale total score ≥80, and Clinical Global Impression–Severity score ≥4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. Safety was assessed by monitoring for spontaneous AEs after administration of the first dose of trial drug until the time of discharge on day 35. Data from the EMERGENT trials were pooled, and all safety analyses were conducted in the safety population, defined as all participants who received ≥1 dose of trial drug.

A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the pooled safety analyses. Across the EMERGENT trials, 51.8% of people in the KarXT group compared with 29.4% in the placebo group reported ≥1 treatment-related AE. The most common treatment-relatedAEs occurring in ≥5% of participants receiving KarXT and at a rate at least twice that observed in the placebo group were nausea (17.1% vs 3.2%), constipation (15.0% vs 5.2%), dyspepsia (11.5% vs 2.3%), vomiting (10.9% vs 0.9%), and dry mouth (5.0% vs 1.5%). The most common treatment-related AEs in the KarXT group were all mild or moderate in severity.

In pooled analyses from the EMERGENT trials, KarXT was generally well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the efficacy results showing a clinically meaningful reduction in the symptoms of schizophrenia, support the potential of KarXT to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics.

Karuna Therapeutics

Healthcare professionals (HCPs) face unique challenges when managing patients with schizophrenia. Educational initiatives targeting common clinical dilemmas encountered by clinicians, such as unfamiliarity with prescribing information for long-acting injectable antipsychotics (LAIs), may assist clinicians when treating patients with schizophrenia.

Four experts in schizophrenia management used empirical evidence to identify 11 key clinical dilemmas where LAIs may be useful. These experts then developed a heuristic, educational tool (S.C.O.P.E.™: Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement) based on empirical evidence and expert opinion for clinicians to use when encountering similar scenarios to optimize schizophrenia care. S.C.O.P.E.™ also includes supportive elements such as an LAI selector.

S.C.O.P.E.™ is a freely available resource comprising an interactive digital platform providing educational materials for HCPs involved in continued care for patients with schizophrenia. To acquaint HCPs with characteristics of common LAIs used in schizophrenia treatment, S.C.O.P.E.™ offers a selector that filters LAIs by approved indication(s), initiation regimen, reconstitution, dosing strengths and frequency, injection volumes and routes, and supply and storage information based on approved product labels. The LAI selector does not provide LAI safety and efficacy data, so HCPs should visit individual product websites for this information. Therefore, S.C.O.P.E.™ will not replace clinical judgment, guidelines, or continuing medical education, and is not a platform for recording patient-level data, nor intended for payer negotiations or access-related questions by HCPs.

S.C.O.P.E.™ is an educational tool for HCPs to use alongside standard psychiatric evaluations to improve understanding of how to manage common clinical dilemmas when treating patients with schizophrenia, the role of LAIs in schizophrenia management, and the product characteristics of available LAIs.

Teva Branded Pharmaceutical Products R&D, Inc.

Healthcare professionals (HCPs) face unique challenges when managing patients with schizophrenia. Educational initiatives targeting common clinical dilemmas encountered by clinicians, including partial or nonadherence, may alleviate knowledge gaps and clarify the role of long-acting injectable antipsychotic agents (LAIs) in treating this population.

4 experts in schizophrenia management used empirical evidence to identify 11 key clinical dilemmas where LAIs may be useful. These experts then developed a heuristic, educational tool (S.C.O.P.E.™: Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement) based on empirical evidence and expert opinion for clinicians to use when encountering similar scenarios to optimize schizophrenia care.

S.C.O.P.E.™ is a freely-available resource comprising an interactive digital platform providing educational materials for HCPs involved in continued care for patients with schizophrenia. S.C.O.P.E.™ provides HCPs with considerations in common clinical scenarios met in inpatient and outpatient settings, as well as questions to consider when patients present to the emergency department. The potential usefulness of LAIs is explored in each scenario. Clinical education videos prepare nurse practitioners, social workers, and case managers to address patient concerns and communicate the benefits of LAI treatment. S.C.O.P.E.™ will not replace clinical judgment, guidelines, or continuing medical education, and is not a platform for recording patient-level data, nor intended for payer negotiations or access-related questions by HCPs.

S.C.O.P.E.™ is an educational tool for HCPs to use alongside standard psychiatric evaluations to improve understanding of how to manage common clinical dilemmas when treating patients with schizophrenia and the role of LAIs in schizophrenia management.

Teva Branded Pharmaceutical Products R&D, Inc.

Data gathered from previous studies has demonstrated the efficacy and safety of lamotrigine in the adult psychiatric population; however, it has not been well studied in children and adolescents with mood disorders (Watanabe & Hongo, 2017).

The objective of this study is to understand patients’ perspective of Lamotrigine efficacy and safety when prescribed for children and adolescents with mood disorders.

A proposal was approved by the University of Missouri-Columbia Internal Review Board to conduct this study. To answer a questionnaire, 20 patients were randomly selected who were taking lamotrigine for mood disorder. All 20 patients were seen in person at the University of Missouri Child and Adolescent Psychiatry Out-patient Clinic. A consent form was reviewed and signed by their respective legal guardian. The questionnaire consisted of yes or no, and free-response questions. Each participant was asked a series of questions about their symptoms before and after lamotrigine, whether or not the medication was helpful, and whether or not they experienced any side effects. Additional details were also obtained, including dosage, the length of their prescription, and any concomitant medications. Demographic information, including age, race, gender, and grade, was also obtained.

Among the participants, 65% were females and 35% were male patients who agreed to take the questionnaire. Fifty percent of the patients were between the ages of 16 and 18, 35% were between the ages of 11 and 15 and. 15% were between the ages of 8 and 10. Seventy present were Caucasian, 10% were African American, and 20% identified as belonging to another race. 35% of the patients were prescribed lamotrigine for less than a year, and 65% were prescribed lamotrigine for over a year. 30% of patients take 25-50mg daily, 25% take between 51-100mg daily, 40% take 101-200mg daily, and 5% take more than 200mg daily. Before lamotrigine was prescribed to the 20 patients in this study, collective reported symptoms included: anger, aggression, mood swings, irritability, depression, anxiety, and self-harm. Eighty percent of patients claimed lamotrigine improved their symptoms after taking the medication. Most improvement was claimed by patients with mood swings followed by patients with anger, aggression, and irritable mood. Seventy percent of patients reported no side effects with the medication. 10% of patients reported increased appetite, 5% reported rash, 5% GI issue, and other 10% reported various side effects, including fatigue, myalgia, and restlessness.

According to patients reports, this study provides data that lamotrigine may be effective in pediatric mood disorders and shows minimal adverse effects. Further larger clinical studies are needed to conclude the safety and efficacy of Lamotrigine in the treatment of pediatric mood disorder.

No Funding

Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) in development for treatment of attention-deficit/hyperactivity disorder (ADHD). The effect of CTN on cardiac repolarization from a thorough QT (TQT) trial is reported.

In this double-blind, placebo (PBO)- and active-controlled, 3-period crossover TQT trial, healthy adults (18-65 years) were randomized to dosing sequences including CTN (800 mg supratherapeutic dose: 4 x 100 mg tablets in the morning and 5 hours later), CTN PBO (4 PBO tablets in the morning and 5 hours later), and active control moxifloxacin (400 mg + CTN PBO in the morning and CTN PBO 5 hours later). Morning doses were separated by 72 hours. Plasma was collected and data were extracted from continuously recorded ECGs for 24 hours following dosing. Effects on ECG parameters (QT interval with Fridericia correction factor [QTcF], PR and QRS intervals, and T- and U-wave morphology), and heart rate (HR) were assessed. The primary analysis was C-QTc, the relationship between drug concentration and PBO-corrected change from baseline in QTcF (ΔΔQTcF). Categorical analyses of ECG parameters were conducted for changes in QTcF, PR, and QRS intervals and in HR.

Of 30 participants enrolled, 56.7% were male and 86.7% were White. Mean (SD) age was 37.6 (14.5) years; mean (SD) BMI was 26.4 (3.4) kg/m2. The slope (90% CI) of the C-QTc relationship for CTN was −0.001 (−0.003, 0.00002) msec/[ng/mL] and not significant. The predicted ΔΔQTcF (90% CI) at the geometric mean Cmax of CTN 800 mg was −2.72 (−6.92, 1.48) msec. A significant slope (90% CI) of the C-QTc relationship for moxifloxacin (0.004 [0.002, 0.006] msec/[ng/mL]) and a predicted ΔΔQTcF (90% CI) at the geometric mean Cmax of moxifloxacin 400 mg above 5 msec (11.75 [8.25, 15.24]) confirmed assay sensitivity. No ΔΔQTcF ≥10 msec was observed for CTN at any postdose time point; all upper limits of 90% CIs of ΔΔQTcF were <10 msec. The by-time-point analysis showed the maximum least squares mean difference in ΔQTcF (90% CI) between CTN and PBO was 1.64 (−1.40, 4.68) msec at 24 hours postdose. No CTN-treated participants had a QTcF increase of >30 msec; no relevant increases in PR or QRS interval or HR were observed. Four participants had >25% decrease in HR and <50 beats per minute. No abnormal U waves were observed; 1 participant had abnormal T-wave morphology. No serious TEAEs or deaths were reported. The most frequently reported TEAEs with CTN were nausea (24.1%), dizziness (24.1%), and decreased appetite (13.8%).

In this TQT trial, centanafadine, a potential first-in-class NDSRI in development for treatment of ADHD, had no clinically meaningful effect on cardiac repolarization and was generally safe and well tolerated.

Previous presentation: 2023 ACCP Annual Meeting, September 10–12, 2023, Bellevue, WA

Otsuka