Bipolar disorder (BD) is a lifelong mental disorder with a variable course, comprising one of the primary psychiatric illnesses warranting hospitalization due to its recurrent and chronic nature. Despite the existence of extensive evidence regarding factors influencing psychiatric hospitalization duration, limited scientific evidence establishes the duration of psychiatric hospitalization in patients with BD. The objective of this study is to assess the clinical characteristics and factors influencing the duration of hospital stay in patients with BD.

This is a retrospective observational and descriptive study. The protocol was approved by the ethics and research committee of the Hospital Universitario "Dr. José Eleuterio Gonzalez” in Monterrey, Nuevo León, México under the name "Factores predictores del tiempo de hospitalización psiquiátrica en pacientes con trastorno bipolar". Retrospective investigation was carried out of patients admitted between July 2015 and May 2022. Clinical and sociodemographic characteristics of 276 patients diagnosed with BD type 1 and type 2 were collected. Descriptive analyses were conducted for all variables using frequencies and percentages for categorical variables. Typical dispersion measures were applied to quantitative variables. Mann-Whitney U test was used to compare means between groups for dichotomous variables, and the Kruskal-Wallis test for variables with more than two categories. Spearman’s correlation coefficient was used for quantitative variables. Statistically significant values were considered at p < 0.05.

Factors associated with longer hospital stay included younger age (p < 0.001), being separated or divorced (p = 0.002), unemployment (x=27.94 vs. x=23.77; p=0.12), absence of medical comorbidity (x=27.21 vs. x=20.73; p=0.11), previous hospitalization history (x=28.50 vs. x=23.26; p=0.005), history of substance abuse (x=28.55 vs. 24.68; p=0.26), use of pharmacological restraint (p=0.28), and non-use of mood stabilizers during hospitalization (x=27.54 vs. x=24.11; p=0.27).

Overall, this study highlights the significance of comprehensive and personalized treatment approaches for patients with bipolar disorder. By addressing specific risk factors and optimizing therapeutic strategies, healthcare professionals can potentially reduce the length of hospital stays, leading to improved patient well-being and resource utilization within psychiatric care facilities. However, further research and intervention studies are warranted to validate and implement these findings in clinical practice.

No Funding

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.

Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI). The efficacy, safety, and tolerability of CTN sustained release (SR) for adults with ADHD was demonstrated in 2 pivotal phase 3 trials (Adler LA, et al. J Clin Psychopharmacol. 2022;42:429-39).

Adults (18–55 years) meeting DSM-5 criteria for ADHD enrolled in these double-blind, multicenter, placebo-controlled trials and randomized to treatment if ADHD Investigator Symptom Rating Scale (AISRS) score was ≥28 at screening (if not receiving pharmacologic treatment for ADHD) or ≥22 at screening and ≥28 at baseline (BL) (if receiving treatment). Having had no prior benefit from ≥2 ADHD therapies of 2 different classes, taking prohibited medications, and positive alcohol/drug screen were exclusionary. Trials had 4 periods: (1) screening and washout (≤28 days), (2) single-blind placebo run-in (1 week), (3) double-blind treatment (6 weeks), and (4) follow-up (10 days after last dose). Patients with ≥30% improvement in the Adult ADHD Self-report Scale (ASRS) from start to end of screening were screen failures; those with ≥30% ASRS improvement from start to end of placebo run-in were terminated early. Patients were randomized 1:1:1 to twice-daily CTN SR (200 or 400 mg total daily dose [TDD]) or matching placebo. The 200 mg/d group received CTN SR 200 mg TDD from days 1–42; the 400 mg/d group received 200 mg TDD on days 1–7, and increased to 400 mg TDD on day 8. This analysis assessed CTN SR effects based on median BL AISRS severity score (<38 or ≥38) using a mixed model for repeated measures analysis. Least squares mean (LSM) differences (95% CI) from BL at day 42 were compared between individual CTN SR dose groups and placebo, tested at a 2-sided significance level of 0.05.

In total, 859 patients were randomized (200 mg TDD, n=287; 400 mg TDD, n=287; placebo, n=285). Significant LSM differences on the AISRS were observed vs placebo in the overall population (200 mg TDD and 400 mg TDD, P<0.0001 for each), in the low BL severity (200 mg TDD [P=0.016]; 400 mg TDD [P=0.019]), and in the high BL severity (200 mg TDD [P=0.005]; 400 mg TDD [P=0.003]) populations at day 42. Significant LSM differences vs placebo (P<0.01) began at day 7 (200 mg) and day 14 (400 mg) overall, remaining significant to day 42. Significant LSM differences were observed vs placebo (P<0.05) from day 14 (400 mg TDD) and day 21 (200 mg) in the low severity populations, and from day 21 (400 mg TDD) and day 7 (200 mg TDD) in the high severity population, remaining significant (P<0.05) to day 42.

CTN SR, a potential first-in-class NDSRI, is efficacious for patients with adult ADHD of low or high BL symptom severity, with significant improvements observed vs placebo within the first 3 weeks.

Study Registration: NCT03605680, NCT03605836

Otsuka

The efficacy and safety of aripiprazole once-monthly 400 mg (AOM 400) as maintenance monotherapy treatment for bipolar I disorder (BP-I) were demonstrated in a double-blind, placebo-controlled, 52-week randomized withdrawal trial (NCT01567527). This post hoc analysis of data from NCT01567527 evaluated the efficacy of AOM 400 in the earlier BP-I population.

Patients within the first quartile of the dataset according to age (18–32 years: AOM 400, n=36; placebo, n=34) or disease duration (≤4.6 years: AOM 400, n=33; placebo, n=34) were considered to be in the earlier stages of BP-I, and were included. The primary outcome was time from randomization to recurrence of any mood episode, defined as meeting any one of several predetermined criteria, including Young Mania Rating Scale (YMRS) total score ≥15 or clinical worsening.

Time to recurrence of any mood episode was significantly delayed with AOM 400 versus placebo in patients aged 18–32 years (hazard ratio [HR]: 2.462 [95% confidence interval (CI): 1.092, 5.547]; p<0.05) and in patients with a disease duration ≤4.6 years (HR: 3.207 [95% CI: 1.346, 7.645]; p<0.01). Further analysis suggested that the benefit of AOM 400 versus placebo was driven by a significantly lower proportion of patients experiencing a YMRS total score ≥15 (18–32 years: 5.60% versus 44.10%, p<0.001; disease duration ≤4.6 years: 6.10% versus 41.20%, p<0.01) or clinical worsening (18–32 years: 8.30% versus 38.20%, p<0.01; disease duration ≤4.6 years: 6.10% versus 38.20%, p<0.01).

The efficacy of AOM 400 was demonstrated in the earlier BP-I population.

Study registration number: NCT01567527 (ClinicalTrials.gov)

The data in this poster were originally presented at Psych Congress, held on 6–10th September 2023 in Nashville, TN, USA.

Otsuka Pharmaceutical Development & Commercialization Inc. (Princeton, NJ, USA) and Lundbeck LLC (Deerfield, IL, USA).

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.

Fasedienol (PH94B; 3β-androsta-4,16-dien-3-ol) is a synthetic neuroactive nasal spray from the androstane family of pherines. Intranasal fasedienol activates receptors in peripheral nasal chemosensory neurons connected to subsets of neurons in the olfactory bulbs that in turn are neurally connected to neurons in the limbic amygdala involved in the pathophysiology of SAD and potentially other anxiety and mood disorders. Fasedienol is locally metabolized in the olfactory mucosa without systemic uptake or binding to CNS receptors. The objective of the present study was to compare fasedienol vs. placebo during a public speaking challenge in subjects with SAD.

This was a multi-center, double-blind, randomized, placebo-controlled study (NCT05011396). After screening (Visit 1), all subjects completed Visit 2 (V2, Baseline, placebo nasal spray administered to all subjects) and participated in a 5-minute public speaking challenge (PSC) during which Subjective Units of Distress Scores (SUDS) were recorded. Subjects with SUDS >= to 70 were invited back a week later for the Visit 3 (V3) treatment visit and randomly allocated to receive either fasedienol (3.2 μg intranasally) or placebo, then undergo a second 5-minute PSC, with SUDS scores recorded. After the V3 PSC, subjects completed a Patient Global Impression of Change (PGI-C) and trained raters completed a Clinical Global Impression of Improvement (CGI-I). CGI-I responders were defined as those assigned scores of 1 (very much improved) or 2 (much improved); PGI-C responders reported scores of 1 (very much less anxious) or 2 (much less anxious). ANCOVA with baseline SUDS as a covariate was used to compare change in mean SUDS from V2 to V3 for the subjects administered fasedienol at V3 vs those who received placebo at V3.

Fasedienol-treated patients (n=70) demonstrated a statistically significant greater change in mean SUDS score (least-squares (LS) mean = -13.8) compared with placebo (n=71, LS mean = -8.0), for a difference between groups of -5.8 (p=0.015). The proportion of CGI-I responders was higher in the fasedienol group 37.7% vs. placebo 21.4% (p=0.033), as was the proportion of PGI-C responders: fasedienol 40.6% vs. placebo 18.6% (p=0.003). Fasedienol was well-tolerated with no treatment-emergent adverse events above 1.5% occurrence.

The Phase 3 PALISADE-2 trial results demonstrated that a single dose of fasedienol prior to a stressful PSC produced efficacy on patient-rated SUDS and PGI-C, as well as the clinician-rated CGI-I. The results also confirmed the nasal-amygdala neural circuits as a new portal for administration of pharmaceuticals. The data support continued development of fasedienol as a first-in-class, rapid-onset, well-tolerated treatment option for SAD without addictive properties.

Vistagen Therapeutics

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

Parkinsonian symptoms seen with B12 deficiency have been described in five cases where B12 therapy has led to their elimination. Subacute combined degeneration (SCD) presenting with parkinsonian signs of cogwheel rigidity, unresponsive to B12 supplementation, has not heretofore been described.

Case Study: This 62-year-old right-handed woman with a past medical history of hypothyroidism presented with complaints of trouble with memory. Cogwheel rigidity and pernicious anemia with low intrinsic factor and B12 levels (165 pg/ml) were found. SCD was diagnosed and treated with monthly B12 injections over the past three years, providing symptomatic relief, yet the cogwheeling persisted. She described never developing trouble with gait, movement disorders, autonomic abnormalities, olfactory dysfunction, disorders of sleep, visual hallucinations, or other parkinsonian symptoms.

Abnormalities in Neurologic Examination: Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test: 9 (hyposmia). CN III, IV, VI: Bilateral ptosis. Motor Examination: 1+ Cogwheel rigidity both upper extremities. Drift Testing: Right pronator drift with left abductor digiti minimi sign. Reflexes: 3+ throughout other than 4+ ankle jerks. Quadriceps femoris bilaterally pendular. Bilateral Hoffman and Babinski reflexes present. B12 Level: 394 pg/ml (normal).

While predominantly affecting the posterior columns and the lateral corticospinal tract, the demyelination may further extend into adjacent fibers including the reticulospinal tract and the rubrospinal tract, the tracts which, in Parkinson’s Disease, have been cited for their role in maintenance of tone and thus cogwheeling. Additionally, low B12 and elevated homocysteine levels have been noted as potential contributory factors in the pathogenesis of Parkinson’s Disease. It is also possible that this is a violation of Occam’s razor, that this individual has two separate distinct diseases — the prominent subacute combined degeneration as well as a subclinical parkinsonism which was revealed on neurologic examination. The parkinsonian signs may have been present prior to the B12 deficiency, and if not for the examination findings, could have remained undiscovered for decades. In those that present with Subacute Combined Degeneration, evaluation for parkinsonism is warranted.

No Funding

Since COVID-19, mental healthcare telehealth services have increased. A 2021 online survey (TeleSCOPE 1.0 [T1]) identified challenges evaluating, diagnosing, and monitoring DIMDs with telehealth (via video or phone). TeleSCOPE 2.0 (T2) was conducted to understand the telehealth impact post-COVID restrictions.

T2 was fielded (5/18-6/9/2023) to neurologists (neuro), psychiatrists (psych), and nurse practitioners (NP)/physician assistants (PA) affiliated with neuro/psych practices who prescribed vesicular monoamine transporter 2 inhibitors or benztropine for DIMD in the past 6 months and saw ≥15% of patients via telehealth at peak and post-COVID.

100 neuros, 100 psychs, and 105 NP/PAs responded. More patients were seen in-person post-COVID (12-27% vs 31-53%), but percentage seen by video remained largely unchanged (54-62% vs 37-53%). Issues influencing appointment setting in T2 remained access to care, technology, and digital literacy although T2 clinicians reported less patients had issues connecting for a video visit. In T2, clinicians used multiple telehealth methods to evaluate DIMDs including personal phone videos (48-66%), telemedicine apps (36-45%), health/fitness trackers (6-13%), and other (2-5%). Common T2 diagnostic telehealth issues included determining signs of difficulty with gait, falls, walking, and standing; difficulty writing, using phone, computer; and painful movements. In patients evaluated for DIMD, more received an eventual diagnosis in T2 vs T1 both in-person (34-53% vs 26-46%) and video (32-51% vs 29-44%) but, on average, neuros and psychs required 1 more telehealth visit to confirm a DIMD diagnosis vs in-person. Over half of clinicians on average recommended patients come in-person to confirm a DIMD diagnosis. Most clinicians reported ongoing difficultly diagnosing patients via phone. Neuros were less comfortable than psychs/NP/PAs with telehealth visits due to risk of misdiagnosis and liability. While all clinicians saw telehealth advantages, neuros expect to see more of their patients in person post-COVID. However, in T2, the number of clinicians who found it difficult to manage DIMDs cases by video had significantly decreased (T1 52-54%; T2 28-36%). Half of clinicians reported the non-presence of a caregiver as a significant barrier to diagnosis and treatment via telehealth. Clear guidelines and provider education were the most feasible strategies to implement to improve telehealth quality of care.

T2 clinicians are more comfortable managing DIMDs via telehealth but require ˜1 more visit to confirm a diagnosis vs in-person. Significant barriers to telehealth remain including digital literacy, inconsistent caregiver presence, and lack of clear diagnosis guidelines. Clinicians see value in telehealth but it is still not as effective as in-person. Significantly more clinicians are in-office post-COVID and >50% recommend patients come in-person to confirm a DIMD diagnosis.

Neurocrine Biosciences, Inc.

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