While physical activity has been shown to promote positive mental health and aid in treatment, the association between involvement in other activities and depressive symptoms among adolescents remains unclear. We sought to fill a gap in the literature by examining relationships between involvement in sports, art, and leadership activities during high school and depressive symptoms among adolescents. Hypothesis: We hypothesized that all types of involvement would be associated with lower levels of depressive symptoms.

We performed a secondary data analysis using the 2016 Minnesota Student Survey, a population-based survey of students in grades 9 and 11 (N=81,885). Descriptive sample statistics (e.g., frequencies) and chi-square tests, stratified by sex, were used to examine relationships between depressive symptoms and involvement in different extracurricular activities among males and females. Analyses were performed using SPSS.

For males and females, involvement in sports was associated with lower levels of depression, compared to non-involvement. Compared to males who did not participate in arts (16.6%), those who did were significantly more likely to report depressive symptoms (21.2%). In addition, females involved in leadership activities were significantly less likely to report depressive symptoms (21.9%) than those who were not involved in these activities (28.7%). Consistent with previous research, females were more likely to report depressive symptoms than males. Females also were more likely to participate in arts and leadership activities.

For males and females, sports participation, and for females, involvement in leadership activities, may represent protective factors against depressive symptoms during adolescence. However, clinicians might consider inquiring about depressive symptoms among adolescent males involved in art-related activities.

Typical amyotrophic lateral sclerosis (ALS) presents on neurological examination with specific signs of upper and lower motor neuron degeneration (Brooks et al, 1995), which can account for 85% of patients with ALS (Turner and Talbot, 2013). There are different types of clinical presentations, including progressive bulbar palsy (PBP), Limb-onset ALS, progressive muscular atrophy (PMA) and upper motor neuron (UMN) predominant ALS. PBP has mainly brainstem signs. There are a few case reports of dropped head syndrome in ALS, mainly in patients with the limb involvement variant.

Case report

A 56 year old right-handed male, presented to the clinic with four months of dysphagia to liquids and solids, neck pain and progressive neck weakness causing constant drop head. No dysarthria or other neurological symptoms, no dyspnea. Neurological examination: Cranial Nerve (CN) CN XII: Nasal voice, bilateral atrophy of the tongue with tremor and fasciculations. Motor: Diffuse atrophy and decreased tone of the sternocleidomastoid and trapezii bilaterally, strength: 2/5 in neck flexors and extensors. Sensory: Hypoesthesia of the tongue. The rest of his neurological examination was normal. Labs: Routine blood work, thyroid function tests, collagen vascular work-up, and protein electrophoresis were normal. Creatine Phosphokinase (CPK) and Acetylcholine Receptor Antibodies (AChR Ab) were negative. Brain and Spinal Cord MRI: Showed mild brainstem, cerebellar and cervical spinal atrophy.

Patients with ALS initially present with symptoms localized to the limbs or bulbar muscles. A very small percentage 1-2% of ALS patients had neck muscle weakness with head drop (Jokelainen et al, 1977; Gourie-Devi et al, 2003). However, in all the previously reported cases, the patients had limb involvement at the time of presentation which was absent in this case, and the head drop occurred after the onset of symptoms (Lange et al, 1986; Katz et al; 1996). Dropped head syndrome can be seen in inflammatory myopathies, myasthenia gravis, facioscapulohumeral muscular dystrophy, spinal muscular atrophy, nemaline myopathy and carnitine deficiency (Umapathy et al, 2003) but ALS should also be considered in patients with atypical presentations.

Early-onset schizophrenia is characterized by greater severity and more functional impairment than adult-onset schizophrenia. Few studies have prospectively evaluated short- or long-term antipsychotic efficacy in treatment-naïve (vs. previously treated) first-episode schizophrenia. The aim of this post-hoc analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naïve adolescents with schizophrenia.

Patients aged 13-17 years with schizophrenia were randomized to 6 weeks of double-blind (DB), fixed-dose treatment with lurasidone (40 mg/day or 80 mg/day) or placebo. Six-week completers were eligible to enroll in an open-label (OL), flexible dose 2-year lurasidone treatment study. Efficacy over 104 weeks of OL treatment with lurasidone was evaluated for 2 patient groups based on treatment status prior to entering the initial DB study (treatment-naïve [TN] vs. treated previously [TP]). Treatment-naïve was defined as never having received antipsychotic treatment prior to randomization. Efficacy measures included the PANSS total score and the Clinical Global Impressions-Severity (CGI-S) score. Treatment response was defined as ≥20% reduction from baseline in PANSS total score.

A total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. In the ITT population of the initial DB study, treatment with lurasidone (vs. placebo) yielded larger effects at DB endpoint on the PANSS total score in the TN group (-25.0 vs. -14.4; P<0.02; effect size [ES]=0.75) compared to the TP group (-17.3 vs. -10.0; P<0.001; ES=0.45); and in the CGI-S score in the TN group (-1.07 vs. -0.28; P=0.002; ES=0.97) compared to the TP group (-0.91 vs. -0.55; P=0.005; ES=0.38). During OL treatment with lurasidone, the magnitude of improvement from DB baseline continued to be somewhat larger in the PANSS total score for TN patients (n=38) vs. TP patients (151) at week 52 (-32.6 vs. -28.1) and week 104 (-33.6 vs. -29.2); and in the CGI-S score for TN vs. TP patients at week 52 (-2.1 vs. -1.5) and week 104 (-2.1 vs. -1.6). Responder rates during treatment with lurasidone were 72.0% (TN group) and 61.1% (TP group) at OL baseline (number-needed-to-treat [NNT]=10), 100% and 90.1% at week 52 [NNT=11], and 100% and 88.9% at week 104 [NNT=11]. During OL treatment, the most common adverse events for TN vs. TP patients were headache (26.0% vs. 23.5%), nasopharyngitis (24.0% vs. 5.4%), nausea (16.0% vs. 11.8%), and dizziness (16.0% vs. 4.1%).

In this post-hoc analysis of a 2-year OL extension study, antipsychotic-naïve adolescents with schizophrenia responded well to treatment with lurasidone at doses of 40 mg/day or 80 mg/day. TN patients achieved greater improvement than TP patients during acute treatment; and these greater treatment effects were largely maintained during 2 years of continued treatment with lurasidone.

Supported by funding from Sunovion Pharmaceuticals Inc

Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic use. RE KINECT, a real-world screening study of antipsychotic-treated outpatients, included patients with movements that were clinician-confirmed as possible TD (Cohort 2) and patients with no involuntary movements (Cohort 1). Baseline data from the patient rated EuroQoL 5-Dimension 5-Level questionnaire (EQ-5D-5L) and Sheehan Disability Scale (SDS) were analyzed to evaluate health related quality of life (Cohort 2 vs. Cohort 1) and the effects of possible TD on quality of life (Cohort 2).

Assessments included EQ-5D-5L utility score (0=equivalent to death to 1=perfect health); SDS total score (0=no impact to 30=highest impact); patient- and clinician-rated severity of possible TD in 4 body regions (0=none, 1=some, and 2=a lot; summary score, 0 to 8); and patient-rated impact of possible TD in 7 daily activities (0=none, 1=some, and 2=a lot; summary score, 0 to 14). Populations included Cohort 1 (N=450); full Cohort 2 (N=204); and limited Cohort 2 (N=111, patients who self-reported “some” or “a lot” of TD severity in ≥1 body region). Mean differences between Cohort 2 and Cohort 1 in EQ-5D-5L utility and SDS total scores were analyzed using a generalized linear regression model that was adjusted for potentially confounding factors (e.g., age, sex, psychiatric diagnosis). Associations between TD summary scores (severity, impact) and quality of life (EQ-5D-5L utility, SDS total) were analyzed using a regression model.

The mean score difference between full Cohort 2 (N=204) and Cohort 1 (N=450) was significant for EQ-5D-5L utility (-0.037; P<0.05 [adjusted analysis]) but not SDS total (0.267; P>0.05). However, when limited to Cohort 2 patients who self-reported “a lot” of TD severity (n=53) or impact (n=33), both EQ 5D 5L utility and SDS total scores were significantly worse than in Cohort 1 (P<0.05). Regression coefficients indicated significant associations between patient-rated impact and EQ 5D-5L utility in the full Cohort 2 (-0.021, P<0.001) and limited Cohort 2 (-0.024, P<0.001). A significant association was also found with patient rated severity in limited Cohort 2 (P<0.05), but not with clinician-rated severity. Similar results were found for SDS total score.

RE-KINECT patients were consistent in evaluating the severity and impact of TD, whether based on subjective assessments or standardized patient-reported instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD. Patient self-assessments (focused on symptom impact) can be clinically relevant; incorporating such measures into everyday practice may provide a more comprehensive approach to TD assessment and management.

Supported by Neurocrine Biosciences, Inc.

To present a case about a 12 year old with a movement disorder to educate the community about an uncommon side effect of a commonly utilized class of psychiatric medications. Simple statement of methods: Patient was seen in the context of a consultation-liaison psychiatry capacity during the first author’s general psychiatry residency. Information was obtained from an electronic medical record and interviews with other physicians that treated the patient. Research about the patient’s supposed diagnosis was conducted using a PubMed + OneSearch searches and articles were obtained under the guidance of a certified hospital librarian.

Withdrawal Emergent Dyskinesia is an uncommon, but debilitating condition that can occur after a rapid discontinuation/dosage change of a neuroleptic. This condition has been documented sparsely in the literature; more literature exists regarding its presence in children than in adults. The condition lasts for 2-3 months and resolves spontaneously in ~90% of cases. The literature that is available suggests (1) avoiding neuroleptic use in children if possible, (2) tapering off antipsychotics slowly, (3) using benzodiazepines and/or beta-blockers to treat symptoms of this condition, and (4) restarting the neuroleptic if symptoms do not improve.

Withdrawal Emergent Dyskinesia is an uncommon, poorly studied, debilitating condition that can occur after a rapid discontinuation/dosage change of a neuroleptic. Future research efforts could be focused on (a) the prevalence of neuroleptic withdrawal symptoms in both adults and children, (b) the complete neurochemical and neurobiological pathogenesis of WED, and (c) the differences in terms of diagnosis and treatment between dyskinesias associated with both neuroleptic use and/or withdrawal. In addition, the existence of such a condition is yet another reason to reconsider off-label use of neuroleptics to treat behavioral symptoms in the absence of clear psychiatric indications for their use.

The INSYTE study provides an understanding of the management of Parkinson disease psychosis (PDP) in actual practice settings, including use of antipsychotic (APs) and their impact on clinical, economic, and humanistic outcomes. Treatment paradigms or the benefits/consequences of various “real world” PDP treatment strategies have not been evaluated. Thus, providers may be using a wide range of AP treatment strategies that contrast with consensus recommendations.

The INSYTE study is enrolling up to 750 patients from up to 100 sites in the US. Data are compiled at the baseline (BL) visit and from standard-of-care follow up visits over 3 years. PDP treatment pathways are defined from 3 BL cohorts reflecting (1) no AP medication, (2) use of pimavanserin (PIM), or (3) other AP treatment. Information about APs used is collected at each follow-up visit: history, duration, dose, adjustment, and rationale for adjustment of treatment. Outcomes assessments (clinical, quality of life, disease burden) by the physician, patient, and caregiver are also collected. AP medication and outcomes data are analyzed for patients completing a BL and 1 follow up visit (FU1).

For 404 patients with BL and FU1 visits (mean 120.7 days from BL), 56.8% used no AP medications, 26.0% used PIM, and 13.6% used other APs at BL. The No Medication group was noted to be less severe in key BL disease parameters. Considering primary PDP treatments at BL and FU1 (including no treatment), 26 distinct pathways were being employed. 12.6% of patients had AP medication adjustments between BL and FU1 visits, most frequently from the non-PIM group. Adjustments of APs occurred in many forms: introduction of a single AP (64.7%%), introduction of multiple APs (5.9%), switching to another AP (3.9%), decreasing the number of APs (5.9%), and discontinuation (19.6%).

Multiple, divergent AP treatment strategies for PDP exist in actual practice. No identifiable BL characteristics correlated with the broad range of AP treatment pathways. The numerous distinct AP treatment pathways utilized (n=26) reflect discordance with the updated 2019 MDS evidence-based recommendations, which recognize only 2 APs as “efficacious” and “clinically useful”: pimavanserin and clozapine. Education of healthcare professionals remains a priority for PDP management.

ACADIA Pharmaceuticals Inc.

On June 14, 2018, the FDA approved generic buprenorphine/naloxone, as an alternative to the brand Suboxone (FDA,2018). A patient who developed acute withdrawal symptoms when switched from Suboxone to generic buprenorphine/naloxone at the same dosage, with resolution with replacement with brand name Suboxone, is presented. Induction of withdrawal with generic buprenorphine/naloxone has not heretofore been described.

Case Study: A 39-year-old right handed single male presented with a past medical history of intravenous heroin dependence. He was relapse free for 5 years and without change on Suboxone film 8mg/2mg twice daily, and was provided with prescriptions for the same, which was substituted to generic brand Dr. Reddy’s Lab SA buprenorphine HCl/naloxone HCl 8mg/2mg film. After two days on this, one hour after taking generic buprenorphine/naloxone film, symptoms of withdrawal began as manifest by hot flashes, diaphoresis, cold chills, leg cramping, and nausea without vomiting. These were the same symptoms he experienced during his past inpatient withdrawal from opioids. These symptoms recurred every day for an entire week until switching back to brand name Suboxone, whereupon his withdrawal symptoms resolved.

The mechanism whereby the generic buprenorphine/naloxone combination induced withdrawal symptoms is unclear. It appears that this generic version was either not effectively blocking the mu receptors or the naloxone was inducing a withdrawal state. Possibly the porous nature of the film was such that less of the buprenorphine was absorbed through the mucosa. As a result, less was transferred into the bloodstream, across the blood brain barrier, to the nucleus accumbens, and ultimately on kappa opioid/mu receptor (Centerwatch, 2002). Alternatively, a greater amount of naloxone may have been absorbed transmucosally, thus inducing withdrawal. The absorption may have been normal, but the exact milligram dosage may not be accurate with either too little buprenorphine or too much naloxone. On the other hand, this buprenorphine compound may have been pH sensitive, such that it became inactivated upon exposure to the mildly acidic salivary pH. He could have been malingering this response. Again this is unlikely since he was not given a higher dose of buprenorphine/naloxone, rather the same dose of Suboxone as previously prescribed. It is important that physicians be aware of the possibility for acute withdrawal and increased cravings, which can lead to relapse while using this agent. Further investigation of the efficacy of the generic variant and Suboxone as replacement therapy is warranted.

To describe the presence of psychotic symptomatology in a patient with hyperthyroidism

Psychiatric-spectrum symptoms associated with thyrotoxicosis has been well reported in the past. However, psychosis in a patient with a thyroid nodule is a rare find. Here, the case of twenty four-year-old, single, unemployed, Albanian American male with self-reported history of Attention Deficit Disorder (ADD) and Cannabis use disorder was brought in to the Comprehensive Psychiatric Emergency Program (CPEP) due to new onset psychosis. Patient was paranoid, disorganized with labile mood. He had poor insight, judgement and impulse control. The event coincided with a period of unemployment in his life and new onset of hallucinations from past few days. He was brought in to the hospital after he was found pacing and having lack of sleep. Patient was treated with antipsychotic for acute psychosis. He was started on Risperidone initially to which he did not respond to. Blood work showed low TSH and elevated T4. Physical exam was noted for palpable thyroid nodule. Further labs resulted in high thyroid peroxidase antibody. Ultrasound of thyroid with color flow showed single nodule in the left lobe and iodine uptake activity localized to the left lobe. Patient was started on Methimazole 5 mg along with Haldol 5mg orally twice a day which improved his symptoms tremendously. Patient was stabilized and after 1 week was discharged on Haldol 5 mg by mouth two times a day for Psychosis, Cogentin 1 mg by mouth two times a day for extrapyramidal system (EPS), and Methimazole 5 mg by mouth daily for overactive thyroid nodule.

Psychosis associated with thyroid nodule is rare but possible. The onset of psychotic syndrome is an important clinical element whose underlying medical cause must be promptly clarified. Psychosis can present in a number of ways and can have different causes. Apart from psychiatric causes, underlying medical causes should always be considered. In this case it was important to get a full clinical history of the patient as well as complete physical examination. The differential diagnosis of a psychotic disorder in light of a medical disease should always be considered in order to promptly diagnose and treat the underlying cause to reduce the morbidity and possibly the mortality associated with it.

To describe the initial results of implementing pharmacogenomics testing in a community-based psychiatry practice and potential impacts on medication management.

Retrospective chart review of prospectively maintained medical records of all adult patients with pharmacogenomics results from 9/01/2017 to 6/30/2019 under the care of psychiatrist and clinical pharmacist.

A total of 51 patients met inclusion criteria. A total of 7 pharmacokinetic genes and, due to changes in the test report over time, a range of 6-10 pharmacodynamic genes relevant to psychotropic medications were evaluated per patient. Every patient had genetic variations, with an average of 6.1 per patient (range 3-9; SD= 1.5). Patients were taking an average of 3.6 (range 1-8; SD=1.7) psychiatric medications at the time of the genetic test, to treat an average of 5 psychiatric conditions (range 1-9; SD=2.2). An average of 1.2 (range 0-4; SD=1.0) gene-drug interactions were uncovered per patient. Following review by psychiatrist and pharmacist, medication adjustments resulted in patients remaining on an average of 3.6 psychiatric medications, but decreasing the average number of gene-drug interactions per patient to 0.8 (range 0-3, SD=0.8).

The large number of genetic variations observed per patient is consistent with previous findings 1-2. The decrease in number of gene-drug interactions following testing demonstrates the practical utility of pharmacogenomics information to guide medication therapy. This study did not examine outcomes such as improvement in psychiatric condition or reduction in medication adverse effects; however, these endpoints have been evaluated in other trials 3-4.

Pharmacogenomics testing presents an opportunity for a personalized medicine approach in a community-based psychiatry practice.

SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P301) evaluated the efficacy and safety of once-daily SPN-812 at doses of 100 and 200 mg compared to placebo in children ages 6-11yrs with ADHD.

Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, a Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. This investigation was conducted at 34 study sites in the United States. Subjects (N=477) were randomized 1:1:1 to placebo:100 mg SPN-812:200 mg SPN-812. The 6-week treatment period included up to 1 week of titration and 5 weeks of maintenance (intent-to-treat population: N=460; placebo=155, 100 mg=147, 200 mg=158). The primary efficacy endpoint was the change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) scores at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and in Weiss Functional Impairment Rating Scale-Parent Version (WFIRS-P) total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical exams, electrocardiograms, and the Columbia-Suicide Severity Rating Scale.

Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 100 mg and 200 mg SPN-812 treatment groups beginning at week 1 (p=0.0004, p=0.0244; respectively) through EOS (p=0.0004, p<0.0001; respectively). Significant improvement at EOS for both 100 mg and 200 mg SPN-812 compared to placebo was also observed in CGI-I score (p=0.0020, p<0.0001; respectively), Connors 3-PS Composite T-score (p=0.0003, p=0.0002; respectively), and in WFIRS-P total average score (p=0.0019, p=0.0002, respectively). The most common (≥5%) treatment-related AEs reported were somnolence, decreased appetite, and headache.

In this study, SPN-812 at 100 mg and 200 mg doses met the primary and secondary objectives with statistical significance. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.

This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).

This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P302) evaluated the efficacy and safety of once-daily SPN-812 at doses of 200 and 400 mg compared to placebo in adolescents ages 12-17yrs with ADHD.

Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. This investigation was conducted at 34 study sites in the United States. Subjects (N=310) were randomized 1:1:1 to placebo:200 mg SPN-812:400 mg SPN-812. The treatment period included up to 1 week of titration and 5 weeks of maintenance (intent-to-treat population: N=301; placebo=104, 200 mg=94, 400 mg=103). The primary efficacy endpoint was change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) score at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and Weiss Functional Impairment Rating Scale-Parent Form (WFIRS-P) total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical exams, electrocardiograms, and the Columbia-Suicide Severity Rating Scale.

Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 200 mg and 400 mg SPN-812 treatment group at EOS (p=0.0232, p=0.0091; respectively). Significant improvement in CGI-I score at EOS for both 200 mg and 400 mg SPN-812 compared to placebo was also observed (p=0.0042, p=0.0003; respectively). No significant change was observed at either dose compared to placebo in the Conners 3-PS Composite T-score (p=0.6854, p=0.0518; respectively), or the WFIRS-P total average score (p=0.2062, p=0.0519; respectively). The most common (≥5%) treatment-related AEs were somnolence, decreased appetite, fatigue, headache, and nausea.

In this study, SPN-812 met the primary objective for both the 200 and 400 mg doses, and a key secondary objective (CGI-I) for both the 200 and 400 mg doses. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.

This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).

This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P303) evaluated the efficacy and safety of once-daily SPN-812 at doses of 200 and 400 mg compared to placebo in children ages 6-11yrs with ADHD.

Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. Subjects were enrolled at 31 study sites in the United States. Subjects (N=313) were randomized 1:1:1 to placebo:200 mg SPN-812:400 mg SPN-812. Treatment included up to 3 weeks of titration and 5 weeks of maintenance (intent-to-treat population: N=301; placebo=97, 200 mg=107, 400 mg=97). The primary efficacy endpoint was change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) score at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and in Weiss Functional Impairment Rating Scale-Parent Form (WFIRS-P) total average score. Safety assessments included adverse events (AEs) among other measures.

Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 200 mg and 400 mg SPN-812 treatment group at EOS (p=0.0038, p=0.0063; respectively). Significant improvement in CGI-I score at EOS for both 200 mg and 400 mg SPN-812 was also observed (p=0.0028, p=0.0099; respectively). Significant improvement was observed for the 200 mg SPN-812 dose compared to placebo in the Conners 3-PS Composite T-score (p=0.0064), but not for the 400 mg dose (p=0.0917). No significant improvement was observed in either dose group in the WFIRS-P total average score (p=0.0651, p=0.1680; respectively). The most common (≥5%) treatment-related AEs were somnolence, decreased appetite, fatigue, headache, and upper abdominal pain.

In this study, SPN-812 met the primary objective for both the 200 and 400 mg doses and the key secondary objective (CGI-I) for both the 200 and 400 mg doses with statistical significance. A second key secondary objective (Conners 3-PS) for the 200 mg dose was also met. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.

This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).

This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) under investigation as a treatment for attention-deficit/hyperactivity disorder (ADHD). One concern for any new drug is prolongation of the QT interval, which is associated with increased risk for potentially very harmful ventricular cardiac arrhythmias such as torsades de pointes (TdP). The objective of this study was to assess the effects of SPN-812 at a supratherapeutic dose (1800 mg once daily [QD]) on cardiac repolarization (QTc) in healthy adults.

This study was a Phase 1, double-blind (except for the positive control moxifloxacin), randomized, 3-period, 6-sequence crossover design in healthy adult male and female subjects evaluating the electrocardiographic effects of SPN-812. Subjects were randomized to receive a sequence of all 3 treatments – placebo, 400 mg moxifloxacin (positive control), and 1800 mg SPN-812 (supratherapeutic dose). Treatment was given for 2 consecutive days (separated by a washout of at least 4 days). The primary endpoint was based on concentration-QTc effect modeling, evaluating the relationship between plasma concentrations of SPN-812 and its metabolite 5-hydroxyviloxazine glucuronide (5-HVLX-gluc) with the placebo-adjusted change from baseline in QTcI, ΔΔQTcI (QT interval corrected for HR based on the individual-specific QT interval correction method). Secondary endpoints included time point change from baseline in QTcI, QTcF, HR, PR, and QRS; evaluation of the relationship between the plasma concentration of viloxazine and 5-HVLX-gluc and the placebo-adjusted change from baseline in HR, PR, QRS, and QTcF; evaluation of the relationship between the plasma concentration of moxifloxacin and ΔΔQTcI to demonstrate assay sensitivity; and changes in ECG morphology. Safety endpoints included assessment of adverse events and other parameters.

The relationship between ΔΔQTcI and viloxazine plasma concentration demonstrated a negative slope (p=0.0012). Predicted mean ΔΔQTcI (2-sided 90% CI) for SPN-812 was -9.7 ms (-11.3, -8.1) at the mean Cmax of 12.4 μg/mL. The relationship of 5-HVLX-gluc and ΔΔQTcI similarly demonstrated a predicted negative slope (p=0.0007) with a predicted mean ΔΔQTcI (2-sided 90% CI) of -9.2 ms (-10.8, -7.8) at the mean Cmax of 10.0 μg/mL. Assay sensitivity was confirmed. Concentration-effect modeling demonstrated no relationship between plasma concentrations of viloxazine and 5-HVLX-gluc and other ECG parameters. The secondary time point analyses demonstrated no effect of SPN-812 on QTcI or other ECG intervals. SPN-812 produced no changes in ECG T wave or U wave morphology.

Data from this Phase 1 thorough QT study demonstrate that a supratherapeutic dose of SPN-812, 1800 mg QD, has no effect on cardiac repolarization or other ECG parameters, and is thus not associated with a risk for cardiac arrhythmias such as TdP.

This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

To Evaluate the impact of mild-to-moderate orofacial tardive dyskinesia (TD) symptoms on the people and social lives of people with TD.

TD, a movement disorder affecting the face and extremities, may arise in patients taking antipsychotics. The impact of stigma on the professional and social lives of people with moderate-to-severe TD was previously examined, but has not been investigated in those with mild-to-moderate TD.

This study is an experimental, randomized digital survey of a general population sample. Three component surveys corresponding to employment, dating, and friendship domains were adopted from a prior study. For each domain, participants were randomized 1:1 into either a test group (who viewed a video of a scripted interview with an actor depicting mild-to-moderate TD movements) or a control group (who viewed the same actor but without TD movements) and asked about their impressions of the video subject. Actor simulations of the TD symptoms were validated by physicians familiar with TD and rehearsed to simulate orofacial movements with a total Abnormal Involuntary Movement Scale (AIMS) score of 3–6. Statistical comparison was made using Wilcoxon signed-rank or chi-squared tests for continuous and categorical variables.

A total of 800 respondents completed each survey. In all domains, respondents had more negative perceptions of actors portraying mild-to-moderate TD movements than of the same actors without movements. For employment, 41% fewer respondents in the test group versus the control group agreed that the actor would be suitable for client-facing jobs (P<0.001). For dating, the proportions of respondents who agreed that they would like to continue talking to the actor and who would be interested in meeting them for a coffee/drink were 23.2% and 26.0% lower, respectively, in the test group than in the control group (P<0.001). For friendship, the proportions of respondents who rated the actor as interesting and who would be interested in friendship with them were 13.0% and 12.2% lower in the test group than in the control group (P<0.001).

This study addresses the stigma faced by those with mild-to-moderate TD in professional and social situations. Consistent with previous results for moderate-to-severe TD, actors simulating mild-to-moderate orofacial TD movements were perceived to be less likely to move forward in a job interview, be considered as a potential romantic partner, or be a new friend.

This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.

Evaluate the impact of orofacial tardive dyskinesia (TD) symptoms on the professional and social lives of patients with TD.

TD, a movement disorder affecting the face and extremities, may arise in patients taking antipsychotics. The impact of social stigma on the professional and social lives of patients with orofacial manifestations of TD has not been thoroughly examined.

This study is an experimental, randomized digital survey of a general population sample. Three component surveys were developed, corresponding to employment, dating, and friendship domains. For each domain, participants were randomized 1:1 into either a test group (who viewed a video of a scripted interview with a standardized patient actor depicting TD movements) or a control group (who viewed the same actors but without TD movements), and asked about their impressions of the video subject. Actor simulations were validated by physicians familiar with TD and rehearsed to simulate a total Abnormal Involuntary Movement Scale score between 6 and 10. Statistical comparison was made using Wilcoxon sign-rank or chi-squared tests for continuous and categorical variables, respectively.

A total of 800 respondents completed each survey. In all domains, respondents had more-negative perceptions of actors portraying TD movements than of the same actors without movements. Regarding employment, 34.8% fewer respondents in the test group versus the control group agreed that the actor would be suitable for client-facing jobs (P<0.001). Regarding dating, the proportions of respondents who agreed that they would like to continue talking to the actor and who would be interested in meeting them for coffee/drink were 25.0% and 27.2% lower, respectively, in the test group than in the control group (P<0.001). Regarding friendship, the proportions of respondents who rated the actor as interesting and who would be interested in friendship with them were 18.8% and 16.5% lower, respectively, in the test group than in the control group (P<0.001).

Actors simulating orofacial TD movements were perceived to be statistically significantly less likely to move forward in a job interview, be considered as a potential romantic partner, or be a new friend. This is the first study to quantify the stigma faced by people with TD in a variety of professional and social situations.

This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.

To evaluate the risk of relapse for patients with schizophrenia (SZ), bipolar disorder (BP), and major depressive disorder (MDD) who switched antipsychotics compared with those who did not switch.

Antipsychotics are commonly used for maintenance treatment of SZ, BP, and MDD but can have significant side effects, such as extrapyramidal symptoms (EPS). Adherence to treatment is important for reducing the risk of relapse, but fear of side effects may prompt medication switching.

Medicaid claims from 6 US states spanning 6 years were retrospectively analyzed for antipsychotic switching versus non-switching. For all patients with SZ, BD or MDD and for the subset of patients who also had ≥1 EPS diagnosis during the baseline period, times to the following outcomes, during a 2-year study period were analyzed: underlying disease relapse, psychiatric relapse, all-cause emergency room (ER) visit, all-cause inpatient (IP) admission and EPS diagnosis.

Switchers (N=10,548) had a shorter time to disease relapse, other psychiatric relapse, IP admissions, ER visits, and EPS diagnosis (all, log-rank P<0.001) than non-switchers (N=31,644). Switchers reached the median for IP admission (21.50 months) vs non-switchers (not reached) and for ER visits (switchers, 9.07 months; non-switchers, 13.35 months). For disease relapse, other psychiatric relapse, and EPS diagnosis, <50% of patients had an event during the 2-year study period. Comparisons in a subgroup of patients with ≥1 EPS diagnosis revealed similar outcomes.

These results show that disease and other psychiatric relapse, all-cause ER visits, IP admissions, and EPS diagnosis occurred earlier for switchers than for non-switchers, suggesting that switching is associated with an increased risk of relapse in patients with SZ, BP and MDD.

This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.

To assess the Patient Health Questionnaire (PHQ-9) as a predictor of relapse of depressive symptoms in treatment-resistant depression (TRD).

Analysis included maintenance phase data from SUSTAIN-1 (NCT02493868), a randomized, double-blind, active-controlled study in TRD patients that evaluated efficacy of intranasal esketamine (ESK) + oral antidepressant (AD) vs AD + intranasal placebo in delaying relapse of depressive symptoms. A ≥50% reduction in initial symptom score and total score of ≤12 were considered as response and remission, respectively, using the Montgomery-Asberg Depression Rating Scale. PHQ-9 total score (range, 0–27), PHQ-2 total score (0–6), and individual items of the PHQ-9 (0–3) were examined as predictors of relapse. Data were collected every 2 weeks. Association between time-varying PHQ-9 and event of depression relapse was evaluated in Andersen-Gill Cox model.

Of 176 stable remitters, 63 had a relapse event (ESK+AD [n=24]; AD+placebo [n=39]). Of 121 stable responders, 50 had a relapse event (ESK+AD [n=16]; AD+placebo [n=34]). Among stable remitters, PHQ-9 total score (HR; 95% CI [1.12; 1.04–1.21]) and PHQ-2 total score (1.58; 1.25–1.99) were associated with relapse risk. PHQ-9 items #1 (loss of pleasure, 2.07; 1.38–3.09), #2 (feeling down, 2.18; 1.51–3.15), #4 (feeling tired, 1.54; 1.13–2.11), and #6 (negative self-view, 2.27; 1.41–3.66) were associated with relapse risk. PHQ-2 total scale yielded the smallest Akaike’s Information Criterion among stable remitters and responders.

PHQ-9, PHQ-2 total scores or individual items may be useful for predicting relapse of depressive symptoms among stable TRD patients.

This study was sponsored by Janssen Research and Development, LLC.

To assess health-related quality of life (HRQoL) and health status of patients with treatment resistant depression (TRD), treated with esketamine nasal spray+oral antidepressant (ESK+AD) vs oral antidepressant+placebo nasal spray (AD+PBO) using European Quality of Life Group-5-Dimension-5-Level (EQ-5D-5L). The EQ-5D-5L descriptive system consists of five domains relevant for patients with depression (mobility, self-care, usual activities, pain, anxiety/depression) and the EQ-Visual Analogue Scale (EQ-VAS).

Data from TRANSFORM-2 (NCT02418585), a randomized, double-blind short-term study were analyzed. Patients (18-64 years inclusive) with TRD were included. Patient reported health status change using EQ-5D-5L and EQ-VAS was measured from baseline to end of 4-week induction phase (endpoint). Each domain of EQ-5D-5L included 5 levels of perceived problems (L1: no problems; L5: extreme problems).

Full analysis set included 223 patients (ESK+AD: 114; AD+PBO: 109). At endpoint, mean (SD) change in health status index was 0.288 (0.2317) for ESK+AD group and 0.231 (0.2506) for AD+PBO group with higher score reflecting higher levels of functioning. At endpoint, percentage of patients reporting problems (grouped L2-L5 responses for each dimension) in ESK+AD vs AD+PBO group: mobility (13.5% vs 25.7%), self-care (16.2% vs 30.5%), usual activities (55.0% vs 71.4%), pain (38.7% vs 52.4%), and anxiety/depression (71.2% vs 78.1%). Mean (SD) change in EQ-VAS score at endpoint was 29.1 (26.32) for ESK+AD and 20.9 (26.60) for AD+PBO group.

Greater improvement in HRQoL and health status using EQ-5D-5L and EQ-VAS was observed among patients with TRD treated with ESK+AD vs AD+PBO.

This study was sponsored by Janssen Research and Development, LLC.