During the initial weeks of the COVID-19 pandemic, the overall number of psychiatric consultations decreased; however, the consultations that were placed appeared to be heavily related to either COVID-19 infection or a stressor secondary to the pandemic. New onset neuropsychiatric symptoms have been seen and described in prior reports among patients with acute COVID-19 infection. This study aimed to examine the sociodemographic and clinical characteristics of psychiatric consultations in the early portion of the pandemic, and compare patients who were COVID-19-positive with those who were negative.

This IRB-approved retrospective chart review involved all psychiatric consultations for COVID-19-positive patients admitted to a medical floor at an academic medical center from March 1 2020 until May 31 2020. Sociodemographic, medical (including diagnoses and laboratory values), and psychiatric information was collected from all consultations, and patients who were COVID-19 positive were matched with a COVID-negative comparison group by age (+/- 3 years) and gender. Statistical analyses to compare these groups were performed.

There were 80 consultations for COVID-positive patients identified in the given time period. These were matched with a comparison group of 80 patients who had been listed as COVID-negative; however on review of medical records only 64 were truly negative, so 16 were excluded. Significant differences existed between groups in terms of reason for psychiatric consultation (p=0.04) and billing diagnosis (p<0.01), with COVID-positive patients appearing to have a greater likelihood of presenting with psychosis or delirium, and less likelihood for mood, anxiety, or substance use. D-dimer levels were higher in COVID-positive patients, and patients with COVID had a higher mortality rate. COVID-positive patients were more likely to receive a “second-generation antipsychotic”. Differences between groups in terms of specific psychiatric symptoms were explored. No other sociodemographic or medical differences were found between groups.

Discussion/Conclusion: Patients with COVID-19 infection may be at an increased rate for delirium and for symptoms of psychosis. Multiple studies have speculated on mechanisms for such symptoms, though findings are inconclusive. This study suggests that simply increased stress during the pandemic is not the driving factor for these symptoms. Patients admitted to medical floors with COVID-19 infection should be screened for delirium and for new-onset neuropsychiatric symptoms.

No Funding

IDgenetix is an advanced multi-gene pharmacogenomic (PGx) test that incorporates drug-gene interactions, drug-drug interactions, and lifestyle factors to guide medication management for patients diagnosed with major depressive disorder (MDD), anxiety, or other mental illnesses. In a previously published randomized controlled trial (RCT), IDgenetix significantly improved patient response and remission rates (Bradley et al., 2018). In this analysis, we aimed to compare the clinical outcome results from the RCT with real-world evidence from an open-label study (Cao et al., 2023).

Subjects with moderate to severe MDD at baseline per their HAM-D17 or PHQ-9 scores were included in the analysis for the RCT (n=261) and real-world data (n=242). In both studies, 8-week response and remission rates were analyzed for patients using IDgenetix-guided medication management (Guided) compared to patients receiving standard of care (Unguided).

Patient response and remission rates strongly aligned between both studies. Response rates for the IDgenetix-guided participants in the RCT were 49% compared to 58% in the real-world data. Remission rates in the Guided group were 31% in both the RCT and real-world study compared to 22% and 19%, respectively, for participants in the Unguided group.

Comparing the clinical outcome results from the RCT with real-world data demonstrated the consistent impact of IDgenetix on patient response and remission rates. This study provides robust evidence-based research that supports the clinical use of IDgenetix to guide medication management in patients with MDD.

Castle Biosciences (Friendswood, TX)

Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) that has demonstrated efficacy, safety, and tolerability vs placebo (PBO) in adults with ADHD in 2 pivotal phase 3 trials (Adler LA, et al. J Clin Psychopharmacol. 2022;42:429-39).

Pooled data from 2 double-blind, multicenter, PBO-controlled trials enrolling adults (18–55 years) meeting DSM-5 ADHD criteria were analyzed. Patients were randomized 1:1:1 to CTN sustained release (SR) 200 mg or 400 mg total daily dose (TDD) or matching PBO if Adult ADHD Investigator Symptom Rating Scale (AISRS) score was ≥28 at screening (if not receiving pharmacologic ADHD treatment) or ≥22 at screening and ≥28 at baseline (if receiving treatment). Having had no prior benefit from ≥2 ADHD therapies of different classes, use of prohibited medications, and positive alcohol/drug screens were exclusionary. Studies had 4 periods: (1) screening and washout (≤28 days), (2) single-blind PBO run-in (1 week), (3) double-blind treatment (6 weeks), and (4) follow-up (10 days after last dose). Patients with ≥30% Adult ADHD Self-report Scale (ASRS) improvement from start to end of screening were screen failures; those with ≥30% ASRS improvement from start to end of PBO run-in were terminated early. A mixed model for repeated measures analysis evaluated CTN SR vs PBO based on ADHD treatment history; least squares mean (LSM) change from baseline (BL) in AISRS at day 42 was the outcome of interest.

In total, 859 patients were analyzed (CTN SR 200 mg TDD, n=287; 400 mg TDD, n=287; PBO, n=285). LSM change from BL in AISRS score was significant at day 42 for each CTN SR TDD group (both, P<0.001) in the overall population vs PBO. Among patients with prior stimulant/nonstimulant treatment (n=542), LSM change from BL was significant at day 42 vs PBO in the CTN SR 200 mg (P=0.016) and 400 mg (P=0.008) TDD groups. Although cohort size was limited (n=47), LSM change from baseline with CTN SR 400 mg TDD was significant (P<0.05) from days 14 to 42 in those who took 2 prior stimulant/nonstimulant treatments, with P=0.030 at day 42. In those with no prior stimulant/nonstimulant treatment (n=317), LSM change from BL was significant at day 42 for the CTN SR 200 mg (P=0.007) and 400 mg (P=0.008) TDD groups vs PBO. When analyzed by history of any past stimulant use, LSM change from BL was significant at day 42 for CTN 200 mg (n=179; P=0.013) and 400 mg (n=166; P=0.006), with significance (P<0.05) noted at day 7 (200 mg TDD) and at day 21 (400 mg TDD), remaining significant to day 42.

This pooled analysis suggests that CTN SR treatment is efficacious in adults with ADHD, regardless of prior treatments, an encouraging finding given reported adult ADHD treatment patterns.

Study Registration: NCT03605680, NCT03605836

Otsuka

Psychogenic nonepileptic seizures (PNES) is a conversion disorder subtype that cause motor, sensory, autonomic, and cognitive symptoms that superficially resemble ictal epileptiform activity but without the electroencephalographic (EEG) activity that defines epilepsy. While 10-20% of patients referred to epilepsy centers are estimated to have PNES (1), diagnosing the condition is labor intensive as it requires seizure-like behavior observed during EEG monitoring. However, accurate diagnosis is essential as psychopharmacologic interventions have been shown to have limited utility in reducing seizure-like activity in PNES (2). Instead, case reports and small randomized clinical control trials have shown cognitive behavioral therapy (CBT) effective (3), and it is considered main stay of treatment.

We present the case of a 37-year-old woman who presented to our clinic with symptoms of depression including hypersomnia and anhedonia. Her most distressing symptoms were episodes of abnormal movements and shaking without loss of consciousness. She has a past medical history notable for EEG-confirmed PNES, major depressive disorder with psychotic features, generalized anxiety disorder, clipped-intracranial aneurysm. She had been taking Duloxetine for major depressive disorder and fibromyalgia, and Carbamazepine was initiated to manage abnormal movements and her depressive symptoms. She reported improvement in the frequency and severity of abnormal movements after initiating Carbamazepine. Unfortunately, her depression worsened, and she was admitted to the inpatient unit for suicidal ideation and auditory and visual hallucinations commanding her to end her life. She was initiated on Aripiprazole. She was admitted for four days and was discharged after she demonstrated improvement in mood and severity of auditory hallucinations.

No Funding

Craig Chepke, MD: Excel Psychiatric Associates, Huntersville, NC, and Atrium Health, Charlotte, NC; Andrew J. Cutler, MD: SUNY Upstate Medical University, and Neuroscience Education Institute, Syracuse, NY; Samantha Floam, DMD: Axsome Therapeutics, New York, NY; Gregory, Parks, PhD: Axsome Therapeutics, New York, NY; Russell Rosenberg, PhD: Neurotrials Research, Atlanta, GA

Solriamfetol (Sunosi®), a dopamine/norepinephrine reuptake inhibitor that has been shown to activate TAAR1, is approved (US and EU) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75-150 mg/day) or obstructive sleep apnea (OSA) (37.5-150 mg/day).Effect size, number needed to treat (NNT) and number needed to harm (NNH) are statistical representations of efficacy and tolerability that clinicians may find helpful in guiding treatment decisions. This analysis characterized these statistical parameters from two registrational studies.

Post-hoc analysis of data from two phase 3 studies in adults with excessive daytime sleepiness associated with narcolepsy (TONES 2) or obstructive sleep apnea (TONES 3). Effect size compared to placebo, NNT, and NNH were calculated based on previously published endpoints, post-hoc analyses, and adverse events.

On the maintenance of wakefulness test (MWT), effect size compared to placebo (Cohen’s d) was 0.29, 0.82, and 1.13 for 75mg, 150mg, and 300mg doses of solriamfetol in TONES 2 and 0.46, 0.89,1.08, and 1.28 for 37.5mg, 75mg, 150mg, and 300mg, respectively. On the Epworth sleepiness scale (ESS), d was 0.47, 0.80, and 1.02 for 75mg, 150mg, and 300mg doses in TONES 2, and 0.42, 0.37, 0.99, and 1.04 for 37.5mg, 75mg, 150mg, and 300mg doses in TONES 3. NNT for patients achieving an ESS ≤10 was 7, 5, and 3 for 75mg, 150mg, and 300mg doses in TONES 2 and 8, 6, 4, and 3 for 37.5mg, 75mg, 150mg, and 300mg doses in TONES 3. On the patient global impression of change (PGIc), NNT was 4, 3, and 3 for 75mg,150mg, and 300mg doses in TONES 2 and 16, 5, 3, and 3 for 37.5, 75mg, 150mg, and 300mg in TONES 3. Similar NNT were found for the clinician global impression of change (CGIc) as for the PGIc. In both TONES 2 and TONES 3, NNH pooled across doses for adverse events occurring in at least 5% of patients and greater than placebo were all >10, with the exception for headache in TONES 2 (NNH=6).

This post-hoc analysis demonstrates favorable effect size, NNT and NNH values for solriamfetol in the treatment of EDS associated with narcolepsy and OSA.

Axsome Therapeutics

Many potent antipsychotics, such as olanzapine (OLZ), can cause significant and rapid weight gain as a potential side effect. This can lead to medication non-adherence and recurrence of psychiatric outcomes, or developing cardiometabolic risk factors that increase the risk of heart disease. The olanzapine-samidorphan (OLZ/SAM) drug combination has demonstrated ability to mitigate the weight gain caused by OLZ. However, olanzapine-metformin (OLZ/MET) combinations have also been studied for weight gain problems before the introduction of OLZ/SAM. The authors will review the similarities and differences between OLZ/SAM and OLZ/MET combinations regarding weight gain.

In this literature review, we conducted a non-systematic search in PubMed and Google Scholar, utilizing specific key words, such as “Olanzapine”, “Metformin”, “Samidorphan”, and “Weight Gain.” Case reports/series and narrative reviews were excluded, and only English-language studies reporting weight change or rate of weight change outcomes were included. Data extraction and qualitative synthesis were performed for the selected studies.

OLZ/SAM has shown the ability to effectively reduce weight gain in non-obese populations, however, OLZ/MET has shown the ability to decrease weight gain in both obese and non-obese populations. Both drug combinations displayed these benefits after approximately 7 weeks. OLZ/MET’s weight mitigation was largely commensurate with increases in both dosage and duration of treatment. OLZ/SAM’s most efficacious dosage was not readily apparent. The maximum reduction in weight gain was achieved when MET was titrated to a daily dose of 2000 mg, although significant prevention of weight gain has been reported with lower doses as well. The mean weight change for OLZ/MET over 24 weeks was +5.5 lbs on 2000 mg per day. The mean weight change for OLZ/SAM over 24 weeks was +7.0 lbs., however, the average dose of OLZ/SAM was not reported. These results were seen in both adult and non-adult populations. OLZ/MET is considerably more affordable in comparison to OLZ/SAM. Other notable differences included dosage flexibility and scheduling, contraindications in select populations, and common side effects, among others.

Weight gain is a serious side effect of many antipsychotics and can greatly impair a patient’s quality of health and life. Drug combinations such as OLZ/SAM and OLZ/MET are crucial to help minimize the morbidity caused by medication-induced obesity. Both combinations showed effectiveness in reducing rates of weight gain but these effects were delayed until approximately 7 weeks. OLZ/MET’s effectiveness was positively correlated with increased dosages and duration, unlike OLZ/SAM in which no such relation could be convincingly established. OLZ/SAM’s relatively high cost is likely prohibitive for many persons, especially considering mental illness’ often devastating socioeconomic impact.

No Funding

Anhedonia characterizes major depressive episodes in bipolar depression and is associated with more severe illness/poor prognosis. These post hoc analyses assess effect of cariprazine 1.5 and 3 mg/d on anhedonia symptoms in patients with bipolar I depression.

Data were pooled from 3 randomized, double-blind, placebo-controlled bipolar I depression trials in cariprazine. Cariprazine 1.5 and 3 mg/d versus placebo were evaluated in patient subgroups stratified by median baseline MADRS anhedonia score (higher anhedonia=score ≥19; lower anhedonia=score <19). Outcomes included mean change from baseline to week 6 in MADRS total and anhedonia factor score (sum of apparent sadness, reported sadness, concentration, lassitude, and inability to feel items). The proportion of patients with week 6 anhedonia factor response (≥50% improvement from baseline) was also determined. Changes from baseline were analyzed using a mixed-effect model for repeated measures.

There were 760 patients in the higher anhedonia subgroup (placebo=249, cariprazine: 1.5 mg/d=261; 3 mg/d=250) and 623 patients in the lower anhedonia subgroup (placebo=211, cariprazine: 1.5 mg/d=200; 3 mg/d=212). Mean baseline MADRS total score was higher in the higher anhedonia subgroup (total=33.6) than in the lower anhedonia subgroup (total=27.6). Change from baseline to week 6 in MADRS total score was greater for both cariprazine doses versus placebo in the higher anhedonia subgroup (least squares mean difference [LSMD] and 95% confidence interval [CI]: 1.5 mg/d=-3.01 [-4.84, -1.19], P=.0012; 3 mg/d: -3.26 [-5.12, -1.40], P=.0006); in the lower anhedonia subgroup, cariprazine 1.5 mg/d was statistically significant versus placebo (-2.61 [-4.28, -0.93], P=.0024). In the higher anhedonia subgroup at week 6, change from baseline in anhedonia factor score was significant versus placebo for both cariprazine doses (1.5 mg/d=-1.97 [-3.13, -0.81], P=.0009; 3 mg/d=-2.07 [-3.26, -0.89], P=.0006); in the lower subgroup, the difference was significant versus placebo for cariprazine 1.5 mg/d (-1.70 [-2.77, -0.62], P=.0021). After adjusting for changes in other depressive symptoms, LSMDs versus placebo in the anhedonia factor score remained significant for cariprazine 1.5 mg/d (-1.21 [-2.05, -0.36], P=.0052) and 3 mg/d (-1.00 [-1.86, -0.14], P=.0233) in the higher anhedonia subgroup, and for 1.5 mg/d (-1.06 [-1.92, -0.19], P=.0164) in the lower subgroup. In the higher anhedonia subgroup, rates of anhedonia factor response were greater versus placebo (31.7%) for cariprazine 1.5 mg/d (44.8%, P=.0028) and 3 mg/d (45.6%, P=.0019); in the lower subgroup, response rates were 39.3% for placebo, 48.0% for 1.5 mg/d, and 46.7% for 3 mg/d. Adverse events in ≥5% cariprazine and twice placebo were nausea, akathisia, restlessness, and EPS.

Those with bipolar depression and anhedonia cariprazine demonstrated a potent antidepressant and antianhedonic effect in higher/lower anhedonia subgroups.

AbbVie

This data was previously presented at the European College of Neuropsychopharmacology (ECNP) Congress; Barcelona, Spain; October 7 – 10, 2023.

Assess effect of predominant polarity on efficacy of cariprazine in patients with bipolar I (BP-I) disorder. Predominant polarity may be an important clinical consideration in BP-I disorder, with predominant depressive episodes associated with delayed diagnosis and higher rates of suicidality, while predominant manic episodes are associated with younger onset, manic/psychotic first episode, and more substance abuse [1].

Data were pooled from 3 randomized, double-blind, cariprazine trials in BP-I depression and 3 trials in BP-I mania. Post hoc analyses were performed in subgroups from the bipolar depression studies with/without predominant depression (≥2:1 ratio of prior lifetime depressive to manic episodes), and in subgroups from the bipolar mania studies with and without predominant mania (≥2:1 ratio of prior lifetime manic to depressive episodes). Change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was evaluated for cariprazine 1.5 and 3 mg/d versus placebo (bipolar depression studies); change from baseline to week 3 in Young Mania Rating Scale total score was evaluated for cariprazine 3-12 mg/d versus placebo (bipolar mania studies). Change from baseline analyzed using mixed-effect model for repeated measures in pooled intent-to-treat population from each indication.

In bipolar depression studies, there were 624 patients (45% of total study population) in the predominantly depressive subgroup (placebo=197, cariprazine: 1.5 mg/d=217; 3 mg/d=210) and 750 patients (55%) in the subgroup without predominant depression (placebo=258, cariprazine: 1.5 mg/d=241; 3 mg/d=251). In the predominant depressive subgroup, LSMDs for MADRS total score change from baseline were significant versus placebo for cariprazine 1.5 mg/d (-2.49 [-4.30, -.68], P=.0071) and 3 mg/d (-2.48 [-4.31, -.65], P=.0079); in the subgroup without predominant depression, LSMDs were also significant versus placebo for both doses (1.5 mg/d=-3.30 [-5.06, -1.54], P=.0002; 3 mg/d=-2.53 [-4.29, -.77], P=.0049). In bipolar mania studies, there were 721 patients (73% of total study population) in the predominantly manic episode subgroup (placebo=307, cariprazine 3-12 mg/d =414) and 267 patients (27%) in the subgroup without predominant manic episodes (placebo=102, cariprazine 3-12 mg/d=165). In predominant mania subgroup, LSMD in YMRS total score change from baseline was significant for cariprazine 3-12 mg/d versus placebo (-4.65 [-6.29, -3.02], P<.0001); in subgroup without predominant mania, the LSMD for cariprazine versus placebo was also significant (-7.56 [-10.30, -4.82], P<.0001).

Cariprazine was efficacious in treating BP-I mood episodes regardless of predominant polarity for the presenting mood episode. Cariprazine was effective against symptoms of depression in patients with BP-I depression with/without predominant depressive episodes, and against symptoms of mania in patients with BP-I mania with/ without predominant manic episodes.

AbbVie

This data was previously presented at the Annual ECNP Congress; Barcelona, Spain; October 7-10, 2023.

Prior studies demonstrated the antipsychotic activity of the dual M1/M4 preferring muscarinic receptor agonist xanomeline 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 side effects due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia were demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

The EMERGENT trials randomized people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale (PANSS) total score ≥80, and Clinical Global Impression–Severity (CGI-S) score ≥4. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. In each trial, the primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Other efficacy measures included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scores. Data from the EMERGENT trials were pooled, and efficacy analyses were conducted in the modified intent-to-treat population, defined as all randomized participants who received ≥1 trial drug dose and had a baseline and ≥1 postbaseline PANSS assessment.

The pooled analyses included 640 participants (KarXT, n=314; placebo, n=326). Across trials, KarXT was associated with a significantly greater reduction in PANSS total score at week 5 compared with placebo (KarXT, -19.4; placebo, -9.6 [least squares mean (LSM) difference, -9.9; 95% CI, -12.4 to -7.3; P<0.0001; Cohen’s d, 0.65]). At week 5, KarXT was also associated with a significantly greater reduction than placebo in PANSS positive subscale (KarXT, -6.3; placebo, -3.1 [LSM difference, -3.2; 95% CI, -4.1 to -2.4; P<0.0001; Cohen’s d, 0.67]), PANSS negative subscale (KarXT, -3.0; placebo, -1.3 [LSM difference, -1.7; 95% CI, -2.4 to -1.0; P<0.0001; Cohen’s d, 0.40]), PANSS Marder negative factor (KarXT, -3.8; placebo, -1.8 [LSM difference, -2.0; 95% CI, -2.8 to -1.2; P<0.0001; Cohen’s d, 0.42]), and CGI-S scores (KarXT, -1.1; placebo, -0.5 [LSM difference, -0.6; 95% CI, -0.8 to -0.4; P<0.0001; Cohen’s d, 0.63]).

In pooled analyses from the EMERGENT trials, KarXT demonstrated statistically significant improvements across efficacy measures with consistent and robust effect sizes. These findings support the potential of KarXT to be first in a new class of medications to treat schizophrenia based on muscarinic receptor agonism and without any direct dopamine D2 receptor blocking activity.

Karuna Therapeutics

Multiple pharmaceutical technologies have been developed over the years and applied in the Attention-Deficit/Hyperactivity Disorder (ADHD) treatment space. While the base drugs are either the same or similar, these technologies lead to differences in the medications’ properties – including mechanism of release, timing of active drug release, and pharmacokinetic profiles. The technology differences also bring up clinical considerations applicable to patients, including delayed- or extended-release properties so that once daily dosing can be achieved.

This review seeks to make side-by-side comparisons of the technical features of the different technologies used in ADHD medications, not an efficacy comparison. The publication will focus on stimulant medications that use methylphenidate or amphetamine formulations. Gaining an understanding of the technologies’ properties and their implications will help clinicians to make more informed decisions when developing their patients’ treatment plans to fit their individual needs, and potentially improve adherence.

Sources including published literature, company websites, filed patents, and prescribing information were reviewed to extract data on the technology used for different ADHD medications. The comparison of the technology in ADHD medications included the drug delivery system, mechanism of drug release, and technology components such as use of resins, beads, complexes, coating or layers. Special considerations that come from these properties were elucidated and framed into a broader clinical context.

Although the medications evaluated were all stimulants containing methylphenidate or amphetamine as the active ingredient, they vary significantly in the technology used to deliver medication to patients. Differences in the technologies used to deliver the stimulants are significant and provide the platform to meet individual patient needs. This side-by-side comparison, describing the specific features and benefits of each technology, will better inform prescribers, leading to better treatment of patients’ ADHD.

Clarifying the technologies available among ADHD pharmacotherapies and discussing their implications on patient care may help healthcare professionals better understand the treatment landscape and assist them in clinical decision-making for appropriate ADHD treatment. Knowledge of the mechanism of the technology could improve patients’ medication adherence. Additionally, understanding the applications of the technology could also benefit research and clinical programs.

Tris Pharma

Although many patients respond equally well to both stimulant and nonstimulant medications for ADHD, some patients respond preferentially to one class over another. Currently, most patients receive a stimulant as first-line therapy; however, nonstimulants present fewer obstacles for prescribers and patients and have low abuse/misuse potential. Still, when patients have suboptimal response to stimulants, physicians may be reticent to switch to a nonstimulant medication due to concerns that the nonstimulant response will be less robust or less preferable for patients. Viloxazine ER (viloxazine extended-release capsules; Qelbree®) is a nonstimulant, FDA-approved treatment for ADHD in children (≥6 years) and adults. This post-hoc analysis of adult Phase 3 trial data (NCT04016779) evaluates response to viloxazine ER (200-600 mg/day) based on whether or not patients reported a history of previous stimulant use.

For patients randomized to viloxazine in this Phase 3, double-blind, placebo-controlled trial, the change from baseline (CFB) in Adult ADHD Investigator Symptom Rating Scale (AISRS) score (primary trial outcome) was analyzed for prior stimulant users vs. nonusers using MMRM. Prior stimulant use was based on patient-reported medication history recorded upon enrollment. Subjects using stimulants at the time of study screening were required to undergo a ≥1-week washout period prior to randomization.

Of 372 patients treated, 189 received viloxazine ER. Of the patients who received viloxazine ER, 40 reported prior stimulant use and 149 did not. Mean (SD) baseline AISRS scores for prior stimulant users and nonusers were 38.5 (7.40) and 38.3 (6.44), respectively. Response appeared similar in both patient groups. At Week 6/End of Study (EOS) the least squares (LS) mean (SE) CFB AISRS scores for prior stimulant users and nonusers were -15.8 (2.51) and -15.6 (1.08)]; treatment difference -0.2 (2.41); P=0.93. Though not significant, prior stimulant users showed a larger magnitude of improvement on the AISRS at early timepoints compared to those without prior stimulant use [Week 1, LS mean (SE) CFB AISRS Total scores: -9.2 (1.40) vs. -6.8 (0.70), respectively; treatment difference: -2.4 (1.56); P=0.12.]

A history of prior stimulant use did not appear to influence the magnitude of ADHD symptom response to viloxazine ER in this preliminary analysis of Phase 3 trial data in adults. Rather, subjects with prior stimulant use showed numerically larger reductions in AISRS scores at early timepoints that were not significantly different from those without prior stimulant use. Additional analysis should be undertaken to evaluate patterns of response in the pediatric population.

Supernus Pharmaceuticals, Inc.

Was Jackson Pollock “Jack the dripper” with paintings “that a dog or cat could have done better,” or did Pollock insert Polloglyphs – images that are encrypted that tell a story about Pollock’s inner being - into his paintings and then disguise them with drippings? On the one hand, some - especially art critics - have emphasized the formal elements of Pollock’s work, arguing that no images are present and the viewer can find whatever they are looking for because such images are artefacts of the “fractal” fuzzy edges to the drippings and are just fooling the eyes. Thus, maybe Pollock’s paintings are just a massive set of new Rorschach inkblots to provoke the viewer to project their own emotions onto the painting, whereas there is actually nothing at all in the painting from the artist. On the other hand, from a psychiatric point of view, given that Pollock had bipolar disorder, painted when he was euthymic or manic and not intoxicated nor depressed, had extensive exposure to Rorschach ink blots during his own psychiatric treatment, had visual images and hallucinations of images, clearly incorporated images into his pre-drip paintings (e.g., see Troubled Queen), and used repeatedly the same images in multiple drip paintings (e.g., booze bottles, images of himself, monkeys, clowns, elephants and more), the alternate point of view is that Pollock either consciously or unconsciously encrypted images in his drip paintings. His remarkable ability to do this with Polloglyphs hiding in plain sight may be part of Pollock’s creative genius and could have been enhanced by the endowment of extraordinary visual spatial skills that have been described in some bipolar patients. If so, painting could have been Pollock’s way to rapidly unspool his images and to do this onto canvas. Pollock himself stated that consciously “I try to stay away from any recognizable image; if it creeps in, I try to do away with it.” However, he also admitted “recognizable images are always there in the end.” If coming from his deep unconscious creativity and genius, such images may have appeared in spite of himself. Pollock thus may indeed not have been mindful of creating Polloglyphs as he stated “When I am in my painting, I’m not aware of what I am doing.” He painted in air, letting gravity make the picture, and dripping became not just another way of obscuring images but as well a new way of creating them. Ultimately, we may never know if there are Polloglyphs present in Jackson Pollock’s famous drip paintings, nor can we know for sure whether they are merely in the mind of the beholder or put there consciously or unconsciously by the artist. In the meantime, it can be fun and enlightening to view Pollock’s works and decide for yourself.

No Funding

Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication, FDA-approved for ADHD in children (≥6 years) and adults. Efficacy and safety for children and adolescents were evaluated in one phase 2 [NCT02633527]and four phase 3 [NCT03247517, NCT03247556, NCT03247530, and NCT03247543], double-blind (DB), placebo-controlled trials that fed into a long-term, open-label extension (OLE) trial [NCT02736656]. Here we report the findings from this OLE trial.

Participants completing the DB trials were eligible for the OLE. Viloxazine ER was initiated at 100 mg/day (children) or 200 mg/day (adolescents) and adjusted (if needed) over a 12-week Dose-Optimization Period (up to 400 mg/day [children] or 600 mg/day [adolescents]). Maintenance treatment then continued up to 72 months. Safety assessments included adverse events (AEs), clinical laboratory tests, vital signs, ECG (12-lead), and the Columbia Suicide Severity Rating Scale (C-SSRS). Efficacy assessments included the ADHD Rating Scale, 4th (Phase 2) or 5th (Phase 3) Edition (ADHD-RS-IV/5), and the Clinical Global Impression-Improvement (CGI-I) scale. Efficacy was assessed relative to DB baseline at study visits ˜ 3 months apart. Two response measures, 50% improvement in ADHD-RS-IV/5 Total score and CGI-I score of 1-2, were also evaluated.

1100 individuals (646 children; 454 adolescents; 66.5% male/33.5% female) received treatment. Median (range) exposure to viloxazine ER was 260 (1 to 1896) days. AEs were reported by 57.3% participants, most commonly (≥5%) nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%) decreased appetite (6.0%), and fatigue (5.7%). AEs were mostly mild or moderate in severity (3.9% reported any severe AE); AEs led to viloxazine ER discontinuation for 8.2%. The mean (SD) changes from DB baseline in ADHD-RS IV/5 Total score were -17.0 (14.18) (viloxazine ER) and -11.2 (13.19) (placebo) at the last DB study visit, 24.3 (11.96) at OLE Month 3, and 22.4 (13.62) at participants’ last OLE study visit. ADHD-RS-IV/5 and CGI-I responder rates each exceeded 65% at all OLE visits following Dose-Optimization.

The safety and efficacy of viloxazine ER were maintained with long-term use in children and adolescents with ADHD. No new safety concerns emerged, and efficacy results suggested potential for continued improvement over that seen during DB treatment.

Supernus Pharmaceuticals, Inc.

This study examined whether online continuing medical education (CME) could improve the knowledge, competence, confidence of psychiatrists regarding the diagnosis and management of tardive dyskinesia (TD).

Psychiatrists participated in a 30-minute online video-based lecture presented by an expert faculty. Educational effect was assessed using a repeated-pair design with pre-/post-assessment. 3 multiple choice questions assessed knowledge, and 1 question rated on a Likert-type scale assessed confidence. A paired samples t-test was conducted for significance testing on overall average number of correct responses and for confidence rating, and a McNemar’s test was conducted at the question level (5% significance level, P <.05). Data were collected from 4/14/2022 to 7/8/2022.

Psychiatrists (n=579) showed significant improvements in overall knowledge and competence (P<.001) as well as confidence.

• • There was a 9% relative improvement in knowledge among psychiatrists regarding the factors that differentiate TD from other motor symptoms associated with antipsychotic use

• • There was a 18% relative improvement in competence among psychiatrists regarding the selection of appropriate pharmacotherapy for TD

• • 38% of psychiatrists had measurable increases in confidence to diagnose and treat TD

This study demonstrated the success of online, video-based lecture CME on improving knowledge, competence, and confidence related to the diagnosis and management of TD. These findings suggest the benefits of education that addresses clinicians’ individual needs across the continuum of their professional development.

Medscape Education, Neurocrine Biosciences

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood disorder that can persist into adulthood in up to two-thirds of patients. ADHD is a heterogeneous disease, with a wide spectrum of symptoms and severity. Thus, ADHD presents diagnostic and treatment challenges for clinicians. This study utilized an online, virtual patient simulation (VPS)-based continuing medical education intervention to improve the ability of psychiatrists to diagnose, assess, and treat pediatric patients with ADHD.

A cohort of US-practicing psychiatrists who participated in the simulation-based education was evaluated. The simulation consisted of 2 patient cases that allowed learners to order lab tests, make diagnoses, and prescribe treatments in a manner matching the scope and depth of actual practice. Tailored clinical guidance (CG), based on current evidence and expert recommendation, was provided following each decision, followed by the opportunity for the learner to modify their decisions. Decisions were collected post-CG and compared with each user’s baseline (pre-CG) decisions using a McNemar’s test to determine P values (5% significance level, P <0.05). Data were collected from February 2022 through May 2022.

The assessment sample consisted of psychiatrists (n=420 for case 1, n=358 for case 2) who made clinical decisions within the simulation and proceeded to the concluding debrief section. As a result of clinical guidance provided through simulation, significant improvements (P<0.001) were observed in several areas of clinical care:

• • Assessing symptoms of ADHD using evidence-based tools/scales (70% relative improvement case 1; 100% relative improvement case 2)

• • Diagnosing ADHD and comorbidities across ages (162% relative improvement case 1; 370% relative improvement case 2))

• • Ordering evidence-based treatments for ADHD based on individual patient presentation (71% relative improvement case 1; 53% relative improvement case 2)

VPS that immerses and engages specialists in an authentic, patient-based, practical learning environment can significantly improve evidence-based clinical decision making for the assessment and appropriate management of patients with ADHD to improve patient outcomes.

Medscape Education, Supernus

Zuranolone is an investigational positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and a neuroactive steroid in clinical development as a once-daily, oral, 14-day treatment course for adults with major depressive disorder or postpartum depression (PPD). The randomized, double-blind, placebo-controlled SKYLARK Study (NCT04442503) demonstrated that zuranolone 50 mg significantly improved depressive symptoms (as assessed by 17-item Hamilton Rating Scale for Depression total score) at Day 15 (primary endpoint; p<0.001) and was generally well tolerated in adults with PPD.

In the SKYLARK Study, patients were randomized 1:1 to receive zuranolone 50 mg or placebo for 14 days. Safety and tolerability were assessed by the incidence and severity of treatment-emergent adverse events (TEAEs), rates of dose reduction and treatment discontinuation, as well as weight gain and sexual dysfunction.

The SKYLARK Study assessed safety data from 98 patients treated with zuranolone 50 mg and 98 patients treated with placebo. TEAEs were reported in 66.3% of zuranolone-treated patients and 53.1% of placebo-treated patients. In patients that experienced TEAEs, most reported mild (zuranolone, 50.8%; placebo, 75%) or moderate (zuranolone, 44.6%; placebo, 23.1%) events. The most common (≥5%) TEAEs were somnolence (26.5%), dizziness (13.3%), sedation (11.2%), headache (9.2%), diarrhea (6.1%), nausea (5.1%), urinary tract infection (5.1%), and COVID-19 (5.1%) with zuranolone, and headache (13.3%), dizziness (10.2%), nausea (6.1%), and somnolence (5.1%) with placebo. Dose reduction due to TEAEs was 16.3% in patients receiving zuranolone vs 1.0% in patients receiving placebo; the most common TEAEs (>1 patient) leading to zuranolone dose reduction were somnolence (7.1%), dizziness (6.1%), and sedation (3.1%). Treatment discontinuation due to TEAEs was 4.1% in patients receiving zuranolone vs 2.0% in patients receiving placebo; TEAEs leading to zuranolone discontinuation in >1 patient included somnolence (2.0%). Serious TEAEs were reported in 2.0% of zuranolone-treated and 0% of placebo-treated patients; these included upper abdominal pain (1.0%, [1/98]), peripheral edema (1.0%, [1/98]), perinatal depression (1.0%, [1/98]), and hypertension (1.0%, [1/98]). Per investigators, serious TEAEs were not related to zuranolone. No signals for weight gain or sexual dysfunction were identified.

In adults with PPD, zuranolone 50 mg was generally well tolerated. Most TEAEs were mild or moderate in severity. Dose reduction due to TEAEs mainly resulted from somnolence, dizziness, and sedation, while treatment discontinuation due to TEAEs was low. No signals for weight gain or sexual dysfunction were identified.

Sage Therapeutics, Inc., and Biogen Inc.

In RISE, TV46000 once monthly (q1m) or once every 2 months (q2m) significantly extended time to impending schizophrenia relapse. The current study (SHINE, NCT03893825) evaluated the long-term safety, tolerability, and effect of TV46000.

Patients completing RISE without relapse (rollover) or newly recruited (de novo) were eligible. The de novo and placebo rollover cohorts were randomized 1:1 to q1m or q2m for ≤56 weeks; the TV46000 rollover cohort continued assigned regimen. Exploratory efficacy endpoints included time to impending relapse and patient centered outcomes (PCOs) including Schizophrenia Quality of Life Scale (SQLS).

334 patients were randomized and received TV46000 q1m (n=172) or q2m (n=162), for 202.3 patient-years [PY] of TV-46000 treatment. Treatment-emergent adverse events (AEs) reported for ≥5% of patients were: overall–injection site pain (event rate/100 PY, n [%]; 23.23, 16 [5%]); de novo (n=109)–injection site pain (56.10, 11 [10%]), injection site nodule (16.03, 6 [6%]), blood creatine phosphokinase increased (16.03, 8 [7%]), urinary tract infection (10.69, 7 [6%]); placebo rollover (n=53)–tremor (18.50, 5 [9%]); TV46000 rollover (n=172)–headache (7.97, n=8 [5%]). Serious AEs reported for ≥2 patients were worsening schizophrenia and hyperglycemia. Kaplan– Meier estimates for remaining relapse-free at week 56 were 0.98 (2% risk; q1m) and 0.88 (12%; q2m). SQLS improved for q1m (least-squares mean change [SE], − 2.16 [0.98]) and q2m (− 0.43 [0.98]); other PCOs (5Level EuroQoL 5Dimensions Questionnaire, Personal and Social Performance Scale, Drug Attitudes Inventory 10-item version) remained stable.

TV-46000 had a favorable long-term benefit–risk profile in patients with schizophrenia.

Teva Branded Pharmaceutical Products R&D Inc.

Study Registration Number: NCT03893825

The prevalence of schizophrenia is relatively low, yet increasing globally, and the disorder imparts a substantial burden of disease on both individuals and health systems. With regard to schizophrenia treatments, including long-acting injectable antipsychotics (LAIs), social media listening provides a unique source of insight into the experiences and perceptions of healthcare professionals (HCPs), patients, and caregivers who live with and manage this disorder daily.

To gain insight into HCP and patient/caregiver perceptions of LAIs for the treatment of schizophrenia.

Publicly available online conversations in global English about LAIs for schizophrenia from May 2, 2022, to May 2, 2023, were analyzed. Posts were collected using customized search strings from social media analysis tools, including Talkwalker and Meltwater. Online forums, such as Reddit, were the main source for patient/caregiver conversations. Conversations among HCPs were examined using publicly available posts from Twitter about schizophrenia/LAIs. Random samples of posts on forums (100) and Twitter (100) were coded for primary topic, author type (patient, caregiver, or HCP), sentiment toward LAIs, and signs of LAI hesitancy. Additional topics in posts, such as barriers and benefits to LAI use, were also examined.

In the analyzed samples, some differences were observed between patients/caregivers (mostly patients) and HCPs (mostly psychiatrists) in lexicon, focus, and perspective. The most common terms for LAIs among patients/caregivers were “injection” or “shot,” while HCPs used the terms “LAIs” or “injectables.” The most frequent primary topic among patients/caregivers was treatment regimen, including impact of symptoms and side effects on quality of life. HCPs focused on drug efficacy, including broader health outcomes such as relapse, hospitalization, adherence, and mortality. Patients/caregivers expressed fewer positive sentiments (11% of posts) and more negative sentiments (35%) than HCPs (34% positive, 14% negative). Both groups noted reduced relapse and improved adherence among the top treatment benefits. Barriers to LAI use commonly cited by patients/caregivers included side effects and lack of effect on negative symptoms, while common barriers cited by HCPs included patient access/cost and limited knowledge around best prescribing practices. Treatment comparisons and/or switching were more commonly mentioned among patients/caregivers (51%) than HCPs (30%), suggesting a greater interest in optimizing treatment among patients. Patients/caregivers often compared individual LAIs with oral antipsychotics (OAs) or different LAIs, whereas it was more typical for HCPs to compare LAIs with OAs than to distinguish between different LAIs.

Based on social media posts, patients/caregivers and HCPs had different primary treatment goals/concerns and generally used different lexicons, which may affect communication. Overall, HCPs were more positive and less negative toward LAIs than patients/caregivers. Top benefits noted (relapse and adherence) were similar between groups, while top treatment barriers differed. These differences highlight the need to improve communication between patients/caregivers and HCPs in order to increase treatment satisfaction and potentially improve treatment outcomes.

Teva Branded Pharmaceutical Products R&D, Inc.

Emraclidine is a novel, highly selective positive allosteric modulator of M4 muscarinic acetylcholine receptors currently in development for the treatment of schizophrenia and Alzheimer’s disease psychosis. By selectively activating M4 receptors, emraclidine may reduce excess dopamine signaling in the striatum, potentially leading to a reduction in psychotic symptoms. Unlike current antipsychotics, emraclidine does not interfere with signaling at dopamine, serotonin, or histamine receptors, which can lead to adverse events. A previous phase 1b study supports further investigation of emraclidine. The phase 2 EMPOWER program will fully evaluate the efficacy, safety, tolerability, and dose-range of once-daily (QD) emraclidine in schizophrenia.

EMPOWER-1 and EMPOWER-2 are two adequately powered, multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week inpatient studies of emraclidine monotherapy (10 mg QD, 15 mg QD, 30 mg QD). The trials are enrolling adult participants with schizophrenia who are experiencing an acute exacerbation of psychosis. Eligible participants will have a Positive and Negative Syndrome Scale (PANSS) Total Score between ≥85 and ≤120 and a Clinical Global Impression – Severity (CGI-S) score ≥4 at baseline. Both de novo participants and those who complete EMPOWER-1 or EMPOWER-2 will be eligible to participate in EMPOWER-3, a 52-week open label extension trial to evaluate the long-term safety and tolerability of emraclidine in adult participants with stable schizophrenia.

Detailed study designs for the EMPOWER program will be presented. Primary outcome measure for EMPOWER 1 and 2 is change from baseline in PANSS total score at week 6. Other outcome measures include change from baseline in CGI-S score at week 6. Data from EMPOWER-3 will contribute to the overall evaluation of safety and tolerability of emraclidine in adult participants with schizophrenia.

The development of emraclidine is promising, as it selectively activates M4, a novel target that has been implicated in reducing psychotic symptoms while potentially avoiding many of the side effects currently associated with antipsychotics. The EMPOWER program aims to establish the efficacy, safety, tolerability, and appropriate dose-range of emraclidine in the treatment of schizophrenia.

Cerevel Therapeutics

Patient-reported outcomes (PROs) are increasingly collected in clinical trials and real-world studies as they provide valuable information on the impact of a treatment from the patient’s perspective. Studies in Parkinson’s disease psychosis (PDP) have focused on hallucination and delusions, however individuals with PDP also face functional limitations associated with worsening psychosis. Assessing activities of daily living (ADLs) and functioning of PDP patients can help inform PDP treatment. The International Parkinson and Movement Disorder Society has recommended the use of the Functional Status Questionnaire (FSQ) which has been infrequently utilized. Prior results were reported from a Phase 4 open-label study examining the impact of pimavanserin on ADLs and functioning in patients with PDP which utilized a modified version of the FSQ (mFSQ) as the primary outcome measure. In this analysis, we provide additional data on the patient-reported mFSQ within specific domains and correlation to the Schwab & England ADL scale.

Eligible patients entered a 16-week single-arm, open-label study of once-daily oral pimvanserin (34mg). The 6 domain FSQ was modified to assess 5 domains by removing the work/performance domain since this was not applicable to the patients in this study. The mean change from baseline to week 16 was evaluated in mFSQ domains (Basic ADL, Intermediate ADL, Psychological Function, Quality of Interaction, Social Activity). In addition, correlation between Schwab & England ADL scale and observed mFSQ value across post-Baseline visits were evaluated.

A total of 29 patients were enrolled in the study, mean age (70.2 years), 62% males. The MMRM LSM (SE) for mSFQ from baseline to Week 16 were the following within each domain: Basic ADL (n=22), 8.1 (2.41), p=0.0031; Intermediate ADL (n=21), 7.0 (3.00), p=0.0286; Psychological Function (n=22), 13.3 (1.94), p <.0001; Quality of Interaction (n=22), 12.3(2.07), p <.0001; and Social Activity (n=18), 25.8 (7.52), p=0.0026. All mFSQ domains were showing improvement at 16 weeks from baseline; however, the largest change was seen in Social Activity. The correlation of mFSQ and the Schwab & England ADL scales resulted in a correlation coefficient of r=0.6 (p <.0001) for patient total score and r=0.5 (p<.0001) for caregiver total score. There was a consistent trend among both scales which was demonstrating improvement among patients and caregivers.

This was the first open-label clinical trial to utilize the mFSQ in patients with PDP. In this small, proof-of-concept study, treatment with pimavanserin was associated with improvement across all mFSQ domains; most improvement was seen in social activity. Additionally, the mFSQ was significantly correlated with the Schwab & England ADL, thus this appears to be a promising scale deserving of further evaluation and use in clinical studies as well as in the clinic to complement other assessments.

Acadia Pharmaceuticals, Inc.