Patient preferences in schizophrenia (SCZ), including identification of key goals and outcomes for treatment and relative importance of certain treatment goals to patients, have been assessed by several studies. However, there continues to be a lack of sufficient evidence on US patient attitudes and perceptions towards treatment goals and pharmacotherapy options in SCZ, especially taking into context long-acting injectable antipsychotics (LAIs) in this disease area. This lack of evidence is further pronounced in caregivers of individuals with SCZ. The objective of this analysis was to characterize patients with SCZ on LAIs vs patients on oral antipsychotics (OAPs) and evaluate the treatment goals of patients in each group.

This was a real-world, cross-sectional survey of US psychiatrists, patients =18 years old with a diagnosis of SCZ, and caregivers. Data was collected using the Disease Specific Programme (DSP) methodology, which has been previously published. Psychiatrists (n=120) completed detailed record forms for next 8 consecutive outpatients and 2 inpatients matching inclusion criteria, including non-interventional clinical and subjective assessments. The same patients and their caregivers, if present, were invited by their psychiatrist to voluntarily complete a separate survey.

Of 1135 patients on treatment where the physician provided survey data; 251 were on an LAI, and 884 were on an OAP. Mean (SD) time to SCZ diagnosis for those on an LAI was 10.3 (12.0) years vs 7.8 (10.5) years for those on OAPs. More patients in the LAI vs OAP group were being treated as an inpatient (27.1% vs 15.7%, respectively; p<0.0001). Patients on an LAI reported being on their current medication regimen for less time (mean 1.7 years) vs those on OAPs (mean 2.5 years) (p=0.0093). More patients on LAIs were unemployed due to disability vs those on OAPs (56.1% vs 39.5%, respectively), and less patients on LAIs were able to work part-time or full-time (21.1% or 4.1%) vs those on OAPs (23.2% or 11.4%). More patients on an LAI had a caregiver vs those on OAPs (37.3% vs 26.1%, respectively; p=0.0011). Regarding the most important treatment goals reported by patients, both groups reported similar preferences for decrease in disease symptoms (62% on LAI vs 65% on OAPs) and thinking more clearly (53% on LAI vs 46% on OAPs); however, a numerically higher proportion of LAI patients reported that the current medication helped decrease hospitalizations due to relapse vs those on OAPs (38% vs 32%, respectively).

Given the characteristics of patients participating in this real-world survey, those on LAIs exhibited qualities which indicate a higher severity of illness vs those on OAPs. Results suggest that treatment with LAIs is still mainly being provided to patients later in the disease course and/or who have adherence problems, despite a growing body of evidence of utility in younger patients earlier in the course of illness.

Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck LLC

Carbamazepine, an anticonvulsant also used as a mood stabilizer and for trigeminal neuralgia, is associated with serious, sometimes fatal cutaneous adverse drug reactions, including Stevens Johnson Syndrome and toxic epidermal necrolysis1. Current literature demonstrates a genetic predisposition linked to specific class I and II human leukocyte antigen (HLA) types in various ethnic populations2. HLA-A*31:01 is one such HLA type, and is routinely identified by the tag SNP rs1061235. However, rs1061235 has poor specificity for HLA*31:01 due to interference of HLA-A*33 types3. We investigated the false positive rate in our population and developed a novel real-time PCR assay that distinguishes HLA-A*31:01 from other HLA-A types including HLA-A*33.

120 unique samples were tested in triplicate during the validation of this assay and were sent to a reference lab for HLA next generation sequencing (NGS) typing, including 89 in-house samples and 31 Coriell samples with documented HLA typing results. The results from our real-time PCR assay were compared to the HLA typing results. HLA typing results were also compared to the tag SNP rs1061235 results to calculate the false positive rate.

There was 100% concordance between our real-time PCR results and expected results based on HLA typing. 89 sample results for tag SNP rs1061235 were compared to HLA typing results. 75/89 samples had a rs1061235 variant, but 31/75 (41%) samples did not have the HLA-A*31:01 type, thus defining the false positive rate of the tag SNP for our population. We theorized there would be a small subset of rare HLA-A types that would interfere with the assay and we tested the three types available to us. We confirmed that 3 of the HLA types (HLA-A*31:04, 31:12, and 31:16) result falsely positive due to sequence homology with 31:01. There is no known literature indicating whether these rare HLA-A*31 subtypes are associated with cutaneous adverse reactions. These 3 HLA types and the other suspected interfering HLA types have limited frequency data sets and are expected to occur rarely in our patient population; we expect these HLA types make up less than 0.003% of the our population. Our assay specificity for the validation is >99%.

Our custom real-time PCR assay for detection of HLA-A*31:01 is significantly more specific than the commonly used tag SNP rs1061235. Clinicians considering carbamazepine therapy for their patients will have a better understanding of cutaneous adverse reaction risk and can make improved personalized treatment decisions. This quick, cost effective assay allows more patients in need of carbamazepine treatment to benefit from its use.

Genomind, Inc.

Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. Serotonin syndrome is underreported complication of pharmacotherapy. The Hunter Criteria for serotonin syndrome (SS) are fulfilled if the patient has taken a serotonergic agent and has one of the following symptoms: 1) spontaneous clonus, 2) inducible clonus and agitation or diaphoresis, 3) ocular clonus and agitation or diaphoresis, 4) tremor and hyperreflexia, 5) hypertonia, or 6) temperature above 38 C and ocular clonus or inducible clonus.

Patient A was a 16-year-old Caucasian male with history of major depressive disorder, social anxiety and OCD who presented to the emergency room with multiple complaints: twitching of bilateral cheeks, intermittent tremor of his hands and feet, mental fogginess/confusion, stuttering when attempting to speak, agitation, profuse sweating and headache. 3 weeks prior, his sertraline dose was increased from 25mg daily to 50 mg daily. His physical exam was remarkable for elevated blood pressure and heart rate as well as hyperreflexia noted on patellar reflex testing. No significant abnormalities were noted on routine labs. He was told his symptoms were likely due to medication side effects. The patient was discharged with instructions to decrease his sertraline dose from 50 mg to 25 mg daily and follow up with his outpatient psychiatrist. 2 days later the patient was seen at the outpatient child psychiatry clinic and he was advised to taper off sertraline completely by taking 12.5mg daily for 3 days before cessation. After stopping the medication, the patient’s symptoms resolved.

Patient B was a 16-year-old female with generalized anxiety disorder and major depressive disorder who presented to the general pediatric clinic with progressively worsening hand tremors and body shaking since her Zoloft dose was increased from 25mg to 50mg daily. She also felt it was more difficult to hold objects. At the physical exam she had an elevated heart rate to 93 and elevated blood pressure to 182/75. Her deep tendon reflexes were 4+ bilaterally. Upon consultation with child psychiatry, the patient was recommended to taper off sertraline. After the discontinuation of sertraline, her symptoms resolved.

These 2 patients developed mild to moderate symptoms of serotonin syndrome with low doses of sertraline. Symptoms resolved after the discontinuation of the SSRI.

In the pediatric patient population, serotonin syndrome can develop even with lower doses of an SSRI. To avoid a missed diagnosis, clinicians should familiarize themselves with the Hunter Criteria for serotonin syndrome. It is also vital to educate parents and caregivers about the toxicities of SSRIs, including serotonin syndrome, so they may monitor treatment and take appropriate action if needed.

Combination olanzapine and samidorphan (OLZ/SAM) is in development for treatment of schizophrenia and bipolar I disorder and is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This 52-week open-label extension study (NCT02873208; ENLIGHTEN-2-EXT) in schizophrenia assessed the safety and tolerability of OLZ/SAM. Methods: Patients completing the 24-week, randomized, double-blind, phase 3 ENLIGHTEN−2 study comparing weight gain with OLZ/SAM vs olanzapine were eligible for ENLIGHTEN-2-EXT enrollment. Initial OLZ/SAM doses were based on olanzapine dose (10 or 20 mg) received at the conclusion of ENLIGHTEN-2; subsequent olanzapine dose adjustments were allowed. The samidorphan dose (10 mg) remained fixed throughout. Assessments included adverse events (AEs), weight, waist circumference, metabolic laboratory parameters, and Positive and Negative Syndrome Scale (PANSS) scores. Analyses were based on observed results using descriptive statistics. Baseline was relative to the first OLZ/SAM dose in the extension study.

265 patients received OLZ/SAM; 167 (63.0%) completed the extension study. Common AEs (= 5%) were weight decreased (n=23; 8.7%), extra dose administered (n=21; 7.9%), headache (n=18; 6.8%), and weight increased (n=16; 6.0%). At week 52, mean (SD) change from baseline for weight and waist circumference was −0.03 (6.216) kg and −0.35 (6.115) cm, respectively. Changes in fasting lipid and glycemic parameters were generally small and remained stable over 52 weeks. PANSS total scores remained stable during the extension.

OLZ/SAM was generally well tolerated over 52 weeks. Weight, waist circumference, metabolic laboratory parameters, and schizophrenia symptoms remained stable throughout the study.

Alkermes, Inc.

There are no established treatment guidelines for tardive dyskinesia (TD) based on movement severity. The 12-week ARM-TD and AIM-TD studies in TD patients with baseline Abnormal Involuntary Movement Scale (AIMS) total score (items 1–7) ≥6 showed clinically significant improvements in AIMS score with deutetrabenazine versus placebo. Patients who completed these studies were eligible for the open-label extension (OLE) trial. This post-hoc analysis evaluated deutetrabenazine in TD patients with severe movements.

Subgroups were defined by upper quartile of baseline total AIMS score (local rating). Endpoints were: change and percent change from baseline in AIMS score, and percent of patients achieving ≥50% AIMS reduction from baseline.

337 patients were analyzed. The upper quartile of baseline total AIMS score was 14. Subgroups were defined as >14 and ≤14 at baseline, respectively (n=64 vs 273); data are presented at Week 145 (n=40 vs 120). Mean treatment duration was 880.5 and 760.8 days. Mean±SE daily doses were 41.1±1.6mg and 38.9±1.0mg. Mean±SE change from baseline in AIMS score was –11.0±0.8 versus –5.1±0.3; percent change from baseline was –60.1%±3.6% versus –55.9%±3.0%. More patients with AIMS score >14 had ≥50% AIMS reduction (73% vs 65%). Less patients discontinued (38% vs 51%); reasons included withdrawal by subject (16% vs 25%), adverse event (3% vs 11%), and lost to follow-up (6% vs 7%). Withdrawal due to lack of efficacy was uncommon (5% vs 2%).

Patients with baseline total AIMS score >14 had clinically meaningful reductions in AIMS score, suggesting deutetrabenazine has long-term benefit in these patients.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

An open-label extension study (NCT02873208) evaluated the long-term tolerability, safety, and efficacy of combination olanzapine/samidorphan (OLZ/SAM) treatment in patients with schizophrenia. This qualitative sub study explored perceptions of benefit, burden, and satisfaction with previous medications and OLZ/SAM.

Semi-structured interviews (60 minutes; audio-recorded) were conducted. Interviewer sensitivity training, senior interviewer oversight, and a list of common medications to aid recall supported data collection. Interview transcripts were content coded and analyzed (NVivo v11.0).

All 41 patients reported a lifetime burden with schizophrenia adversely impacting employment, relationships, emotional health, social activities, and daily tasks. Hospitalization for schizophrenia management was another reported aspect of disease burden. Although most (n=32) patients reported previous medication benefits, side effects affecting physical, emotional/behavioral, and cognitive functioning were reported by all (n=41). Following OLZ/SAM treatment, 39/41 patients (95%) reported improvements in symptoms including hallucinations, paranoia, depression, sleep, and concentration. Furthermore, patients described improvements in self-esteem, social activities, relationships, and daily activities. Twenty-three patients (56%) reported side effects attributed to OLZ/SAM; lack of energy (n=12 [29%]) and dry mouth (n= 5 [12%]) were most common. Twenty-four (59%) patients were “very satisfied” with OLZ/SAM; most (n=35 [85%]) preferred to continue OLZ/SAM vs switching to another medication. As most substudy patients (n=40; 98%) completed the extension study, satisfied patients may be overrepresented in this analysis.

This qualitative interview approach provided valuable insight into patients’ experiences with previous medications and OLZ/SAM. Overall, most patients reported treatment satisfaction and improvements in symptoms, function, and health-related quality of life with OLZ/SAM.

Alkermes, Inc.

Disease prevalence, comorbid conditions, and pharmacological treatments were examined in a large population of US commercial- or Medicaid-insured individuals with schizophrenia.

This retrospective, cross-sectional claims analysis sourced data from the IBM MarketScan Commercial and Medicare Supplemental Databases and the Multi-state Medicaid Database (01Jan2009 to 30Jun2016). Cases were defined by =1 diagnostic claim (ICD-9-CM/ICD-10-CM) for schizophrenia during the study period. Comorbidities (=1 ICD-9-CM/ICD-10-CM diagnosis code) were grouped according to Clinical Classifications Software (CCS) level 2 categories. For the per-database analysis of comorbidities, schizophrenia cases were matched with controls by demographic characteristics. Case-control comorbidity comparisons were performed using prevalence rate ratios (PRRs) and 95% CIs. Per-database medication exposure (=1 National Drug Code in outpatients grouped by Redbook classification) was also assessed.

Schizophrenia prevalence was 0.11% and 0.99% in commercially and Medicaid-insured patients, respectively. In both databases, comorbidity prevalence was higher among schizophrenia cases versus controls in approximately =80% of the CCS level 2 categories assessed. Common top categories of comorbidities for schizophrenia cases were mood disorders, anxiety disorders, other connective tissue disease, and diseases of the heart. Comorbidities with the highest case-control PRRs included personality disorders, suicide and intentional self-inflicted injury, and impulse control disorders. Across databases, the most commonly prescribed medications in cases were antipsychotics, antidepressants, and analgesics/antipyretics opiate agonists; the most highly prescribed antipsychotics were risperidone, quetiapine, aripiprazole, and olanzapine.

This large-scale analysis quantifies the high prevalence of medical and psychiatric comorbidity burden in patients with schizophrenia, highlighting the importance of integrated medical and psychiatric care.

Alkermes, Inc.

Tardive dyskinesia (TD) is an involuntary movement disorder that is more prevalent in older patients. However, there is limited information on TD treatment for this population. In two 12-week pivotal trials (ARM-TD and AIM-TD), TD patients demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) score with deutetrabenazine versus placebo.

Patients who completed ARM-TD or AIM-TD enrolled in an open-label extension (OLE) study. This post hoc analysis assessed change and percent change from baseline in AIMS score, response rates for ≥50% AIMS improvement, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety in younger (<55 years) and older (≥55 years) patients.

This analysis included 119 younger and 218 older patients enrolled in the OLE. Data presented at Week 145 (mean±SE): total deutetrabenazine dose was 39.4±1.39mg/day and 39.5±1.04mg/day in younger and older patients, respectively. Changes from baseline in AIMS score were –6.7±0.62 and –6.5±0.47, respectively (percent changes of –61.4%±4.10% and –54.6%±3.01%). The majority of younger and older patients achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%) and achieved ≥50% AIMS response (76% and 62%). Deutetrabenazine was generally well tolerated in both groups. Exposure-adjusted incidence rates (incidence/patient-years) were <0.01 and 0.02 for akathisia, 0.07 (both) for somnolence and sedation, 0.04 and 0.11 for parkinson-like events, and 0.06 and 0.09 for depression in younger and older patients, respectively.

Deutetrabenazine treatment was associated with sustained improvements in AIMS score and was well tolerated in both younger and older TD patients.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Objectives for this survey are to determine similarities or differences in treatment goals reported by psychiatrists, patients with schizophrenia (SCZ) and caregivers in the US, as well as whether goals differed by patients currently on an oral antipsychotic (OAP) or long-acting injectable (LAI), and whether goals differed by age.

This was a real-world, cross-sectional survey of US psychiatrists, patients =18 years old diagnosed with SCZ, and caregivers. Data was collected using the Disease Specific Programme (DSP) methodology. Psychiatrists (n=120) completed detailed record forms for next 8 outpatients and 2 inpatients matching inclusion criteria. The same patients and their caregivers, if present, were invited by their psychiatrist to voluntarily complete a separate survey.

Responses on treatment goals were collected from psychiatrists for all patients included in the analysis (n=1161), patients (n= 542) and caregivers (n=130). Among 3 top goals, psychiatrists, patients and caregivers concurred that “decrease in disease symptoms” is most important (63%, 64%, 68% respectively). For psychiatrists and caregivers, second was “decrease in hospitalization for relapse” (41%, and 38% respectively), whereas for patients, it was “thinking clearly” (47%). Of the 3 least important goals, psychiatrists, patients and caregivers agreed with “sexual problems” (59%, 43%, 44%, respectively) and “weight gain” (38%, 44%, 38%, respectively).

When asked which goals were met by current medication, patients responded “decrease in disease symptoms” (68%) and “thinking clearly” (39%). However, caregivers responded “thinking clearly” (30%) was not met by current medication. Caregivers most important goals, “decrease in disease symptom” (70%) and “decrease in hospitalization for relapse” (41%), were met. Additional analyses of patients on OAPs and LAIs, did not show differences in goals. However, “decrease in disease symptoms” was numerically more important for patients on LAIs vs OAPs according to psychiatrists (68% vs 62%) and caregivers (77% vs 70% respectively). Caregivers responded “decrease in hospitalization for relapse” was met for 63% patients currently on an LAI and 35% OAP. No major differences in treatment goals were observed by patient age (18–35 vs 36–65 vs >65 years).

There is consensus among US psychiatrists, patients and caregivers on the most important treatment goal “decrease in disease symptoms”, regardless of patients’ current medication or age. For patients, “thinking more clearly” was second, compared with “decrease in hospitalization due to relapse”, for psychiatrists and caregivers. All agreed that least important treatment goals, related to AEs, were “weight gain” and “sexual problems”. More caregivers agreed “decrease in hospitalization for relapse” was met by patients on LAIs vs OAPs. These findings may help with discussions between psychiatrists, patients and caregivers.

Lundbeck LLC and Otsuka Pharmaceutical Development & Commercialization, Inc.

Evaluate safety and tolerability of an aripiprazole lauroxil (AL) 2-month regimen using 1-day initiation in patients hospitalized for acute exacerbation of schizophrenia and transitioned to outpatient care.

In the 25-week, double-blind ALPINE study, adults hospitalized for an acute exacerbation of schizophrenia were randomized to AL (AL NanoCrystal Dispersion + oral aripiprazole 30 mg day 1; AL 1064 mg day 8 and q8wk) or the active control paliperidone palmitate (PP 234 mg day 1; PP 156 mg day 8 and q4wk), discharged after 2 weeks if clinically stable, and followed through the end of the study. Adverse events, including adverse events of special interest (AESIs; extrapyramidal symptoms [identified by non-mutually exclusive standardized MedDRA queries], sedation, hypotension, injection site reactions [ISRs], suicidal ideation and behavior) were monitored throughout the study.

In total, 200 patients were randomized (AL, n=99; PP, n=101); 99 patients (AL, n= 56; PP, n=43) completed the study. Rates of AESIs in AL-treated patients were akathisia, 10%; Parkinson-like events, 2%; dyskinesia, 3%; dystonia, 9%; sedation, 7%; hypotension, 6%; ISRs, 18 % (including placebo); and suicidal ideation and behavior, 2 %. In PP-treated patients, AESI rates were akathisia, 12%; Parkinson-like events, 4%; dyskinesia, 5%; dystonia, 11%; sedation, 7%; hypotension, 4%; ISRs, 27% (including placebo); and suicidal ideation and behavior, 3%.

No unexpected safety and tolerability findings were identified in patients treated with AL or PP who were hospitalized for acute schizophrenia exacerbation and transitioned to outpatient care in ALPINE. AESI profiles were consistent with each treatment’s respective known safety profile.

Alkermes, Inc.

All authors are employees of Alkermes, Inc., and may own stock/options in the company.

Deutetrabenazine is FDA approved for tardive dyskinesia (TD) based on two 12-week, placebo-controlled studies evaluating safety and efficacy in patients with baseline Abnormal Involuntary Movement Scale (AIMS) score ≥6. Deutetrabenazine reduced overall AIMS scores compared with placebo in ARM-TD (–3.0 vs –1.6, P=0.019) and AIM-TD (24 mg/day, –3.2 vs –1.4, P=0.003; 36 mg/day, –3.3 vs –1.4, P=0.001). This analysis assessed Minimal Clinically Important Difference (MCID) in AIMS score in patients with TD treated with deutetrabenazine.

MCID is the smallest change from baseline in AIMS score that is meaningful for patients. MCID analyses were performed based on Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) as anchors described by Hauser et al., where MCID is the difference between patients treated with deutetrabenazine who were minimally improved and patients treated with placebo who were unchanged. Additional MCID definitions were explored: difference between patients who demonstrated treatment improvement versus those who did not (Method 2); difference between patients who demonstrated treatment success versus those who did not (Method 3).

295 patients were analyzed. Based on PGIC, the suggested MCID was –2.8. Results were similar for Method 2 (75% of patients had treatment improvement; MCID = –2.8) and Method 3 (38% of patients had treatment success; MCID = –2.6). Based on CGIC, the suggested MCID was –2.6. Results were similar for Method 2 (76% of patients had treatment improvement; MCID = –2.8) and Method 3 (41% of patients had treatment success; MCID = –3.0). Therefore, the suggested MCID for deutetrabenazine is –3.

The MCID for change in AIMS score based on PGIC and CGIC for deutetrabenazine was –3 regardless of the analytical method. Findings suggest an AIMS score reduction of ~3 is associated with clinically meaningful improvement in TD symptoms.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Deutetrabenazine, a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. Dopamine-receptor antagonists (DRAs) are associated with worsening of metabolic parameters, including weight gain, hyperlipidemia, and elevated blood glucose. This post hoc analysis assessed the short- and long-term effects of deutetrabenazine treatment on weight and metabolic parameters in individuals treated for TD.

Two 12-week, randomized placebo-controlled trials (RCTs) of deutetrabenazine for patients with TD evaluated either fixed dosing (AIM-TD; 12, 24, or 36 mg) or dose titration (ARM-TD; max dose, 48 mg/day). Patients completing ARM-TD or AIM-TD were included in an open-label extension (OLE) study, in which all patients underwent response-driven titration of deutetrabenazine from 12 mg/day up to a maximum total dose of 48 mg/day. Weight, body mass index (BMI), serum glucose, serum total cholesterol, and serum triglycerides were evaluated at baseline and during treatment in the RCTs and in the OLE.

In the RCTs, 282 and 133 patients received deutetrabenazine or placebo. At baseline, 77% of patients used DRAs. At Week 12, no meaningful changes in weight were observed, with mean (standard error) weight changes of 0.9–1.2 (0.3–0.5) and 0.2 (0.3) kg in the deutetrabenazine and placebo groups, respectively, and mean BMI changes of 0.3–0.5 (0.1–0.2) and 0.1 (0.1) kg/m2. 337 patients were included in the analysis of the OLE study. No meaningful changes were observed in weight (mean change: 0.4 [0.4] kg at Week 54, –0.5 [0.6] kg at Week 106, and –1.1 [0.6] kg at Week 145) or BMI (mean change: 0.1 [0.2] kg/m2 at Week 54, –0.2 [0.2] kg/m2 at Week 106, and –0.3 [0.2] kg/m2 at Week 145). Across the studies, no meaningful changes were observed in triglyceride, cholesterol, or glucose levels.

Deutetrabenazine does not affect common metabolic parameters in patients with TD, even during long-term exposure.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Othello syndrome, also known as morbid jealousy, pathological jealousy, and conjugal paranoia, is a rare delusional disorder related to partner’s infidelity. There are no large scale or comprehensive studies on delusional jealousy, and only few case reports and cases series leave delusional disorder jealous type (DDJT) largely unknown. Herein, we report a case of DDJT, its possible etiology and describe its characteristics, comorbidities, and interventions.

A 65-year-old married, retired, and disabled Caucasian male with a history of closed traumatic brain injury and chronic pain presented for outpatient care accompanied by his wife with a chief complaint of paranoid delusions. The patient was a car racer when he sustained over 25% total body surface area burns after his motor vehicle crashed at the speed of almost 160 mph. The patient was in a coma for more than nine weeks, coded three times, and was resuscitated each time. Per imaging, the patient suffered subarachnoid hemorrhage to the right outer parietal and left front parietal lobes. The patient developed chronic pain from the extensive burns and has been on opioids for many years until he gradually tapered himself off about six years ago. For the last couple of years, the patient has experienced cognitive decline associated with disorientation and memory deficit. The patient has been perseverative on his wife’s trip two years ago during which the patient believed that she had an affair with one of their mutual acquaintances. The patient denied visual or auditory hallucinations and continued to express his love and affection toward his wife. Although his wife has continually provided reassurance, and multiple family members confirmed her faithfulness, the patient had minimal insight into his delusion and expressed disappointment in loss of sexual intimacy between him and his wife. The patient has been prescribed duloxetine 60mg and trazodone 150mg, and his mood, anxiety, and sleep have been stable. The patient has also started taking pimozide 1mg nightly since beginning of this year with good response.

The DSM estimates the prevalence of DDJT to be less than 1%. At least a third of cases show neurological basis involving frontal lobe dysfunction associated with strokes, Parkinson’s disease, brain trauma and tumors, neurodegenerative disorder, encephalitis, multiple sclerosis, and even normal pressure hydrocephalus. Association with alcohol, amphetamine, cocaine, and dopamine therapy (pergolide, ropinirole, levodopa, amantadine, and pramipexole) were reported. Finally, DDJT is known to be a risk factor of violent crimes including homicide. Treatment with pimozide shows the strongest evidence, and most patients show improvement with any antipsychotic medication along with CBT. Continued research and further clinical trials are warranted for DDJT considering patients’ positive response to interventions, and because DDJT can become a dangerous condition in forensic situations.

Dementia related psychosis (DRP), characterized by debilitating symptoms such as hallucinations and delusions, is estimated to affect 2.4M people with dementia in the US. Patients with DRP may have twice the rate of dementia progression compared to patients with no DRP. Given that dementia disproportionally impacts the elderly, a comprehensive cost of-illness analysis may add to the current understanding of the overall economic burden of DRP prevalence. The objective of this study was to estimate the cost of DRP from a Centers for Medicare and Medicaid Services (CMS) perspective.

A five state-transition Markov analysis, adapted from Green et al, was conducted to assess the annual direct DRP cost burden to CMS. Patients entering the model were allowed to transition between three at-home health-states (mild dementia plus psychosis, moderate dementia plus psychosis, severe dementia plus psychosis), one long-term care/nursing home (LTC/NH) stay, or death (absorbent health state) at any given time. Since the model accommodates tunnel health-states based on dementia, psychosis and functioning severity levels, patients stayed in the same health-state or transitioned to a more severe health-state or progressed to death (i.e., absorbent health-state) between each 30-day cycle. Prevalence, disease-severity, and state-transition probability estimates were derived from literature while direct costs of DRP were derived from a Medicare claims analysis. Costs were discounted at 3%. Model robustness was tested to check if results were sensitive to changes in inputs and assumptions.

Of the estimated 61.5M Medicare beneficiaries, about 6.87M may suffer from dementia. In the base-case scenario, an estimated total of 2.2M prevalent DRP patients enter the model based on dementia severity into one of the 4 non-absorbent health-states: three at-home (10% mild, 60% moderate, and 10% severe) and one LTC-NH (10%). Total Medicare annual direct DRP costs are estimated to be approximately $119.98B ($113.96B-$125.96B) and about $54K PPPY (Per-Patient-Per-Year) costs (2019 USD). NH costs and patient volume at higher severity levels are significant cost drivers. Sensitivity analysis results show that the model is sensitive to disease severity and disease progression.

These results suggest that DRP imposes a significant direct cost burden despite its low prevalence. In this analysis, per-patient per year (PPPY) cost of DRP prevalence was estimated to be slightly higher than incident PPPY DRP costs. These differences may be attributed to the number of patients at higher severity levels and the time spent in a severe health state as well as cost of LTC/NH stays. Especially given the ageing population in the US, DRP could become an increasing public health concern. There is a significant need for education and awareness about DRP cost burden.

Acadia Pharmaceuticals Inc.

The 12-week ARM-TD and AIM-TD studies in tardive dyskinesia (TD) patients showed statistically significant improvements in TD symptoms with deutetrabenazine. The completed open-label extension (OLE) study (SD-809-C−20) evaluated long-term efficacy and safety of deutetrabenazine in TD.

Patients who completed ARM-TD or AIM-TD enrolled in the OLE study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in Abnormal Involuntary Movement Scale (AIMS) score was assessed by local site raters. Treatment success was evaluated locally as patients being “much improved” or “very much improved” on Clinical Global Impression of Change (CGIC).

343 patients enrolled in the OLE study; 6 patients were excluded from analyses. At Week 54 (n=249; dose [mean±SE]: 38.7±0.66mg/day), mean change from baseline in AIMS score was –4.8±0.28; 66% of patients experienced treatment success. At Week 106 (n=194; dose: 39.3±0.75mg/day), mean change from baseline in AIMS score was –5.4±0.33; 65% of patients experienced treatment success. At Week 145 (n=160; dose: 39.4±0.83mg/day), mean change from baseline in AIMS score was –6.6±0.37; 73% of patients experienced treatment success. Treatment was generally well tolerated across 723 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) for akathisia/restlessness were 0.01, somnolence/sedation were 0.07, and symptoms which may represent parkinsonism or depression were 0.08 each.

Patients who received long-term treatment with deutetrabenazine achieved sustained improvement in AIMS scores. Findings from this open-label trial with response-driven dosing suggest the possibility of increasing benefit over time.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

In the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington’s disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.

Patient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.

All 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.

Based on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

This open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension (treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.

The crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%–125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.

Thirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80–125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.

The bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.

Tris Pharma, Inc.

This Phase 1, open-label, single-dose, one-period, one-treatment PK study enrolled 12 children 6–12 y with ADHD. PK parameters for d- and l-amphetamine in plasma (Cmax, tmax, AUC0–8, and t1/2) were calculated and expressed as means, geometric means, and standard deviations. The primary endpoint was all objective PK measurements at 28 hours post-dose. PK was evaluated for 2 cohorts (6 pts ages 6–9 y and 6 pts aged 10–12 y). Safety was monitored continuously and assessed based on occurrence of adverse events.

A single dose of 10 mg (4 ml) AMPH EROS (2.5 mg/ml) administered under fasted conditions resulted in a rapid rise in mean plasma concentration in d-amphetamine, reaching maximum concentrations within 5 hours. The overall study population mean (SD) plasma AUC0–8 (d-amphetamine) was 1061.2 (309) h*ng/mL, and for l-amphetamine was 380.5 (112) h*ng/mL. The mean maximum concentration (Cmax) for the overall study population was 54.91 ng/mL and 17.1 (5.2) ng/mL for d- and l-amphetamine, respectively. The overall study population median time to maximum concentrations (Tmax) for d-amphetamine were reached at 3.4 hours, and for l-amphetamine at 4.1 hours. The elimination half-life (t1/2) for the entire study cohort was 10.6 (2.0) hours for d-amphetamine, and 12.5 (3.2) hours for l-amphetamine. Directionally, a higher mean Cmax, AUC0–8, AUCt, and median Tmax were observed in the younger (6 to 9-year-old) age group, and this result was consistent with both the d- and l-amphetamine enantiomers. The mean elimination t1/2 for both d- and l-amphetamine was higher in the older cohort (10–12 years) than in the 6 to 12-year-olds. Study drug was well-tolerated by the subjects in this study. Two TEAEs were reported in one subject TEAEs (diarrhea and rash on legs) occurred approximately 12 hours postdose.

This study confirmed that the PK profile of AMPH EROS in 6 to 12-year-olds provided a consistent, predictable extended-release profile in a highly titratable liquid formulation, and this finding was relatively consistent and directionally predictable between the age groups assessed, with higher maximum concentrations and AUCs and shorter elimination half-lives noted in the younger population, with no anomalous parameters demonstrated, and no untoward or unexpected safety issues noted.

Tris Pharma, Inc.

Deutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance.

Safety was assessed during titration versus maintenance using integrated data from two 12-week placebo-controlled studies (ARM-TD and AIM-TD) and the open-label extension study. Rates were compared for overall and serious adverse events (AEs), AEs leading to discontinuation, treatment-related AEs, common AEs (≥4%), and specific AEs (parkinsonism, suicidal ideation, akathisia, restlessness).

In titration versus maintenance, AE rates with placebo (n=130) were: overall, 43.1% vs 25.4%; serious, 4.6% vs 2.3%; leading to discontinuation, 3.1% vs 0; treatment-related, 26.9% vs 10.0%. For placebo, common AEs during titration were somnolence, headache, nausea, fatigue, and dry mouth; none occurred during maintenance. In titration versus maintenance, AE rates in fixed-dose deutetrabenazine 12–36 mg (n=216) were: overall, 33.3–38.9% vs 22.2–29.2%; serious, 2.8–6.9% vs 0–1.4%; leading to discontinuation, 2.8–5.6% vs 0; treatment-related, 8.3–16.7% vs 8.3–13.9%. For fixed-dose deutetrabenazine, common AEs during titration were headache, diarrhea, nasopharyngitis, depression, hypertension, and dry mouth; headache was the only common AE during maintenance. In titration versus maintenance, AE rates with flexible-dose deutetrabenazine (n=168) were: overall, 49.4% vs 32.7%; serious, 3.6% vs 2.4%; leading to discontinuation, 2.4% vs 0.6%. For flexible-dose deutetrabenazine, the only common AE during titration was somnolence; none occurred during maintenance. Rates of parkinsonism, suicidal ideation, akathisia, and restlessness were low and comparable in titration and maintenance.

Deutetrabenazine was well-tolerated, with AE rates similar to placebo during both phases; AE rates were higher during titration and decreased during maintenance.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel