Chorea is a prominent motor dysfunction in Huntington’s disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.

Patients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.

Of 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119 [48] weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug–related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was –4.4 (3.1) and –2.1 (3.3) and change in TMS was –7.1 (7.3) and –2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.

The type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Tardive Dyskinesia (TD) refers to abnormal, involuntary, choreoathetoid movements of the tongue, lips, face, trunk, and extremities and is associated with long-term exposure to dopamine-blocking agents, such as antipsychotic medications. Once established, these movements usually persist. The movements are disfiguring and can bring unwanted attention to affected individuals. When severe, especially if the respiratory muscles are affected, the movements can be disabling, limit activity, and reduce quality of life. The prevalence is 7.2% in individuals on newer antipsychotics who have never been exposed to older neuroleptics. Until recently, there were no effective treatments for TD. In recent years, many new treatments have been investigated for the treatment of TD, including valbenazine, deutetrabenazine, and branched chain amino acids. Valbenazine first, followed by deutetrabenazine are FDA approved to treat TD. A virtual broadcast was developed to assess the ability of continuing medical education (CME) to improve awareness of the recognition and treatment of TD among psychiatrists.

The virtual broadcast (May 9, 2020) consisted of a two-hour, live-streamed discussion between two expert faculty. Impact of the educational activity was assessed by comparing psychiatrists’ responses to four identical questions presented before and directly after activity participation. A follow-up survey was sent to all participants six-weeks post-activity to measure performance in practice changes. A chi-square test was used to identify significant differences between pre- and post-assessment responses. Cohen’s d was used to calculate the effect size of the virtual broadcast.

Activity participation resulted in a noticeable educational effect among psychiatrists (n=621; d=6.12, P<.001). The following areas showed significant (P<0.05) pre- vs post-educational improvements: recognition of movements in patients with TD, rate of TD in SGA exposed patients, treatment options for TD (on and off-label), and treatment of TD using VMAT inhibitors. Additionally, 54% of psychiatrists reported a change in practice performance as a result of the education received in the activity, including utilization of a standard scale to evaluate movement disorders and educate patients and family members about potential for TD, how to recognize symptoms, and when to treat.

The results indicated that a CME-certified two-hour virtual broadcast was effective at improving knowledge among psychiatrists for the recognition and treatment of TD. This knowledge also resulted in positive changes in practice performance post-activity. Future education should continue to address best practices in the diagnosis, treatment and management of patients with TD, as there remains an increased need for tailored CME among psychiatrists.

Neurocrine Biosciences, Inc.

Approximately 70% of patients with bipolar disorder (BPD) are initially misdiagnosed, resulting in significantly delayed diagnosis of 7–10 years on average. Misdiagnosis and diagnostic delay adversely affect health outcomes and lead to the use of inappropriate treatments. As depressive episodes and symptoms are the predominant symptom presentation in BPD, misdiagnosis as major depressive disorder (MDD) is common. Self-rated screening instruments for BPD exist but their length and reliance on past manic symptoms are barriers to implementation, especially in primary care settings where many of these patients initially present. We developed a brief, pragmatic bipolar I disorder (BPD-I) screening tool that not only screens for manic symptoms but also includes risk factors for BPD-I (eg, age of depression onset) to help clinicians reduce the misdiagnosis of BPD-I as MDD.

Existing questionnaires and risk factors were identified through a targeted literature search; a multidisciplinary panel of experts participated in 2 modified Delphi panels to select concepts thought to differentiate BPD-I from MDD. Individuals with self-reported BPD-I or MDD participated in cognitive debriefing interviews (N=12) to test and refine item wording. A multisite, cross-sectional, observational study was conducted to evaluate the screening tool’s predictive validity. Participants with clinical interview-confirmed diagnoses of BPD-I or MDD completed a draft 10-item screening tool and additional questionnaires/questions. Different combinations of item sets with various item permutations (eg, number of depressive episodes, age of onset) were simultaneously tested. The final combination of items and thresholds was selected based on multiple considerations including clinical validity, optimization of sensitivity and specificity, and pragmatism.

A total of 160 clinical interviews were conducted; 139 patients had clinical interview-confirmed BPD-I (n=67) or MDD (n=72). The screening tool was reduced from 10 to 6 items based on item-level analysis. When 4 items or more were endorsed (yes) in this analysis sample, the sensitivity of this tool for identifying patients with BPD-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties represent an improvement over the Mood Disorder Questionnaire, while using >50% fewer items.

This new 6-item BPD-I screening tool serves to differentiate BPD-I from MDD in patients with depressive symptoms. Use of this tool can provide real-world guidance to primary care practitioners on whether more comprehensive assessment for BPD-I is warranted. Use of a brief and valid tool provides an opportunity to reduce misdiagnosis, improve treatment selection, and enhance health outcomes in busy clinical practices.

AbbVie Inc.

The COVID-19 crisis has severely stressed our healthcare system and pushed our economy to the brink. This long emergency will probably cause years of severe suffering in every region. Health expenses greatly increased, supply chains were disrupted, and governments coped with much less revenue. Good clinicians plan for ALL contingencies, and we need to consider that the current disaster may get much worse. How can we adapt psychiatry to a long emergency? This goes far beyond previous work on crisis standards of care because the emergency is severe, prolonged, and widespread. If we had to spend much less on psychotropics, which meds stay on the formulary? If we have to close hospitals, which patients get a bed? What adaptations could be used if demand exceeds the supply of providers? Very little is known about how to make severe, permanent cuts to healthcare. Our previous systematic review found no scholarship addressing the ethics of severe and prolonged healthcare rationing. Global catastrophes need a global health policy, but this one has no experts. The present study starts the project by surveying experts with related experience that could be useful in future plans.

We used purposive sampling to find 18 professionals with experience in healthcare rationing from underserved, indigenous communities, homeless programs, and African nations. We also interviewed ethicists, pharmacists, administrators, NGO clinicians, and military. Interviews were transcribed and coded using basic inductive techniques. Because so little is known about this topic, we used grounded theory, an iterative approach to guide further sampling, refine interviews, and make some preliminary conclusions.

Participants all agreed this crisis planning is extremely important and complex. They described diverse concerns regarding ethical decision making, with some having confidence with top-down government policy, and others recommending a grassroots approach. Minority participants had less confidence in government. There was no consensus on any best ethical framework. Most had confidence that clinicians will ultimately do the right thing. Native American leaders had confidence in a holistic, preventive approach. All agreed that social justice should be central in measuring economic impact of long emergencies and choosing ethical options. We collected suggestions for innovative approaches to rationing.

This research program illuminates the difficult ethical questions about adapting psychiatry to a prolonged, widespread, and severe emergency. Our interviews identify areas where severe but ethical cuts can be made in medications, hospitals, clinical staff, and administration. Next steps include evidence-based formularies, utilitarian staff cuts, and ethical standards for closing beds or revamping state hospitals. Underserved and diverse communities with rationing experience must have a voice in the discussion.

Extrapyramidal symptoms (EPS), including movement disorders, tremors, and muscle contractions are common side effects of atypical antipsychotic (AAP) drugs in patients with schizophrenia. This study examined the incidence and burden of EPS in patients with schizophrenia initiating AAPs.

Patients with schizophrenia initiating AAPs with no prior EPS were identified in the MarketScan Multi-state Medicaid database from 1/1/2012-12/31/2018. Incidence of EPS (identified via ICD-9/ICD-10 diagnoses and medications) was assessed during the 12-months following AAP initiation. Cohorts with and without EPS were defined. Demographics, clinical characteristics, and healthcare resource use and costs over 12 months following the first EPS claim (EPS) or randomly assigned index date (Non-EPS) were assessed.

A total of 11,642 patients with schizophrenia were identified; 21.2% developed EPS in the 12-months following AAP initiation. EPS and Non-EPS cohorts included 2,295 (mean age 38, 61% male, CCI 0.6) and 5,607 (mean age 39, 57% male, CCI 0.7) patients, respectively. Over the 12-month post-index period, EPS cohort had significantly higher rates of all-cause (30.2% vs. 24.6%, p<0.001) and schizophrenia-related hospitalizations (22.5% vs. 12.9%, p<0.001) and schizophrenia-related emergency room visits (25.5% vs. 16.7%, p<0.001) compared to Non-EPS cohort. All-cause ($25,911 vs. $21,550, p<0.001) and schizophrenia-related healthcare costs ($12,134 vs. $6,230, p<0.001) were significantly higher in EPS vs. Non-EPS cohort.

In the 12 months following AAP initiation, over 20% of schizophrenia patients developed EPS, which was associated with increased healthcare resource utilization and costs. Treatment options that minimize EPS may reduce the economic burden of schizophrenia.

Sunovion Pharmaceuticals Inc.

The internet allows easy access for the sales of psychoactive agents that are not regulated by the FDA. Some of those agents are used to help manage anxiety, depression and sleep, such as tianeptine, etizolam, and phenibut. These medications have the potential for abuse and potentially leading to altered mental status when intoxicated or withdrawing. This presents a challenge to clinicians who may not be aware of availability of such substances. Available literature has discussed the use of above substances individually, but how do you treat if there is use of more than one substance with different mechanisms of actions? Here we present a case of an adult male who has used all three agents simultaneously, leading to a hospital admission.

A 32-year-old male presented to the emergency department (ED) for altered mental status (AMS). He has a documented history of anxiety but was never treated with prescription medications. No history of substance use was documented. He was self-medicating with concurrent use of tianeptine (atypical antidepressant with mu agonist properties,) phenibut (GABA mimetic) and etizolam (a benzodiazepine-like agent). During his stay, he was agitated and delirious with reports of visual hallucinations. Neuroimaging and lab studies were within normal limits, EEG showed no seizure activity. Over the course of his hospital stay, he was started on Depakote for agitation, a Valium taper for suspected benzodiazepine withdrawal and prevention of seizures, Seroquel for delirium, and baclofen for suspected GABAergic withdrawal symptoms. The patient’s AMS improved and he was discharged on hospital day 10.

This case illustrates the difficulty managing poly-substance use/abuse and stresses the importance for physicians to screen for psychoactive agents purchased over the internet or over the counter to improve treatment outcomes. Continued discussions with patients regarding risks/benefits of use of such substances would be beneficial and help increase awareness.

Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).

Patients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.

Most patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41–2.83) and RR 2.25 (95% CI 1.39–3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15–0.99, p=0.048). No other significant differences in risk were observed at week 8.

These data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.

Myriad Neuroscience/Assurex Health

Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is hindered by significant weight gain. A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data.

The OLZ/SAM development program consists of 18 phase 1–3 clinical studies evaluating antipsychotic and weight mitigation efficacy of OLZ/SAM, along with pharmacokinetics, safety, and tolerability. Safety evaluation also included metabolic laboratory assessments.

OLZ/SAM significantly improved psychotic symptoms (measured by Positive and Negative Syndrome Scale); improvements were similar to that observed with olanzapine vs placebo. OLZ/SAM resulted in significantly less weight gain than olanzapine. Additionally, 2 long-term phase 3 extension studies confirmed the durability of antipsychotic effect, as well as stabilization of weight and metabolic parameters in those continuing treatment. Supporting the potential use of OLZ/SAM in BD-I, OLZ/SAM or olanzapine resulted in bioequivalent olanzapine plasma concentrations, and OLZ/SAM did not affect lithium or valproate pharmacokinetics. OLZ/SAM treatment had no clinically relevant effects on ECG parameters (including QTc interval). OLZ/SAM and olanzapine safety were similar, except for reduced weight gain with OLZ/SAM; no additional safety risks were identified.

Data across 18 OLZ/SAM studies in >1600 subjects support an antipsychotic efficacy and safety profile for OLZ/SAM that is similar to olanzapine, with significantly less weight gain than olanzapine. OLZ/SAM is a potential new treatment for schizophrenia and BD-I patients needing efficacious long-term treatment with reduced risk of weight gain.

Alkermes, Inc.

Repetitive transcranial magnetic stimulation (rTMS) is a safe, effective and non-invasive treatment for many psychiatric illnesses, including treatment-resistant depression (TRD). Ketamine, an NMDA receptor antagonist, is also an effective antidepressant. This retrospective review examined the clinical benefits of combining these two established treatments for patients suffering from TRD in a novel approach coined combination TMS with ketamine (CTK).

A group of 28 adult patients with a primary diagnosis of unipolar (n=18) or bipolar (n=10) depression received three CTK treatments a week at a private neuropsychiatric practice. Patients were given a concurrent treatment of rTMS (1Hz; 40 minutes; 130% of motor threshold) with bio-marker-determined IV ketamine infusions (0.2–4.7 mg/kg; 30 minutes). The TMS coil was positioned on the mid-prefrontal area. Frequency of treatment was dependent on patient responsiveness (10–30 sessions), which was measured as symptom reduction on the Clinical Global Impression (CGI) scale. CGI data was evaluated pre-treatment, post-treatment and at two-year follow-up.

Mean reduction in CGI severity for the patient group following CTK was 4.46 ± 0.54 at a 99% confidence interval and was deemed statistically significant using a paired t-test (a=0.01, t=22.81, p < 0.0001). This significant reduction in CGI severity was sustained for at least 2 years following treatment completion.

Despite years of unsuccessful treatments, all 28 patients in this trial obtained substantial and enduring reductions in their depressive symptoms following CTK therapy. Further research into method optimization and randomized controlled trials are warranted.

The randomized, controlled, phase 3b ALPINE study evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) initiated with a 1-day regimen during hospitalization for an acute exacerbation of schizophrenia; paliperidone palmitate (PP) was included as an active control. The primary efficacy outcome, within-group change from baseline in PANSS total score at 4 weeks, was previously reported. Here we report additional exploratory PANSS subscale endpoints and patient-reported outcomes (PROs).

Adults aged 18–65 years were enrolled as inpatients and randomized to AL 1064 mg q8wk or PP 156 mg q4wk and discharged after 2 weeks of study treatment if clinically stable. Patients were followed as outpatients through week 25. Exploratory efficacy endpoints were PANSS subscale (Positive, Negative, and General) and Clinical Global Impression-Severity (CGI-S) scores. The Burden Assessment Scale was administered to patients’ nonprofessional caregivers (family member or friend). Exploratory PROs (Quality of Life Enjoyment and Satisfaction Questionnaire Short Form [Q-LES-Q-SF] and Medication Satisfaction Questionnaire) were assessed during the outpatient period. Within-group changes in PANSS subscales and CGI-S scores from baseline through week 25 were analyzed for AL and PP using mixed models with repeated measures. PROs were summarized based on observed data.

In total, 200 patients were randomized (AL, n=99; PP, n=101); 99 (AL, n=56; PP, n=43) completed the 25-week study. PANSS Positive, Negative, and General subscale scores improved with AL treatment as measured by change from baseline to week 25 (least squares [LS] mean [95% CI]: Positive, −7.0 [−8.1, −6.0]; Negative, −3.7 [−4.7, −2.8]; General, −11.1 [−12.7, −9.5]), as did CGI-S scores (LS mean [95% CI] change at week 25: –1.2 [–1.4 –1.0]). Caregiver burden decreased over the treatment period, with the largest decline noted at week 9 for AL patients’ caregivers (mean change from baseline at week 9: −8.4; week 25: −8.9). Over weeks 5, 9, and 17, 70.8%−74.7% of AL-treated patients were somewhat or very satisfied with treatment. Mean Q-LES-Q-SF total scores were stable. With PP, PANSS subscale and CGI-S scores improved from baseline to study end (LS mean [95% CI] changes at week 25: Positive, −7.1 [−8.2, −5.9]; Negative, −3.5 [−4.6, −2.5]; General, −10.4 [−12.1, −8.6]; CGI-S, −1.2 [−1.5, −1.0]). Mean caregiver burden decreased (week 9: −8.8; week 25: −9.2). Most PP patients were satisfied or very satisfied with treatment (64.7%−69.3% at weeks 5, 9, and 17), and mean Q-LES-Q-SF total scores were stable.

In ALPINE, patients who initiated AL or PP in the hospital and continued treatment during outpatient care experienced improvement in schizophrenia symptoms and reported satisfaction with medication, decreased caregiver burden, and stable quality of life.

Alkermes, Inc.

Pediatric mania is difficult to distinguish from childhood hyperactivity. Both share 3 common symptoms: distractibility, motoric hyperactivity, and talkativeness. Oftentimes, children are referred from their pediatrician due to a lack of appropriate response to stimulant medication. Pediatricians have learned that merely raising the dose or changing the stimulant does not work. A thorough neuropsychological evaluation often reveals bipolar mania. They may have comorbid bipolar disorder and ADHD. This poster paper will examine measures that can assist in this important differential diagnosis as well as offer treatment options, including medication management.

This case study includes three pediatric patients diagnosed with childhood bipolar disorder and ADHD. A comprehensive psychoeducational assessment was conducted for each of the patients, which resulted in this comorbid diagnosis.

One of the most helpful measures was the TOVA (i.e., Test of Variables of Attention). When a child’s attention and impulsivity scores are normal, and response time and variability scores are abnormal, both on and off medication, that is an indication of a mood disorder, These children also performed poorly on measures of processing speed, and verbal learning and interference tasks. Measures of affect and personality were important diagnostically. A combination of amantadine and either clonidine HCL ER or propranolol, as prescribed by a medical psychologist, were found to be effective in controlling the symptoms of this comorbid diagnosis.

An evaluation of children’s intellectual, attentional, behavioral, mood, and personality functioning is crucial for a differential diagnosis. In cases of comorbidity, ADHD and childhood bipolar disorder, the sooner the child is on appropriate medications, the better. When just the surface diagnosis of ADHD is medicated, the outcome is often problematic. There may be a poor response to treatment and a higher rate of suicide.

To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder (BPD-I) when treated with lurasidone compared to other atypical antipsychotics (AAPs) as monotherapy.

Using IBM MarketScan Multi-State Medicaid Claims database, a retrospective cohort study was conducted on adult BPD-I patients who initiated an AAP (index date) between January 1, 2014 and June 30, 2019. Patients were required to be continuously enrolled during the 12-month pre- and 24-month post-index date. Marginal structural models were performed to estimate the risk of hospitalization (all-cause, BPD-I-related, and psychiatric-related) associated with each AAP and the average length of stay.

The analysis included 8262 adult BPD-I patients, of whom AAP use was divided between lurasidone (14%), aripiprazole (17%), olanzapine (8%), quetiapine (29%), risperidone (10%), no/minimal (1%) or other (21%) during each month of post-index period. The adjusted odds ratios (aORs) for all-cause hospitalization were significantly higher for olanzapine (aOR=1.60, 95% CI=1.09–2.10) and quetiapine (aOR=1.54, 95% CI=1.18–1.89), compared to lurasidone. The aORs for BPD-I-related hospitalization were significantly higher for quetiapine (aOR=1.57, 95% CI=1.10–2.04) and risperidone (aOR=1.80, 95% CI=1.04–2.56) compared to lurasidone. The average length of hospital stay was more than twice as high for quetiapine compared to lurasidone (aRR=2.12, 95% CI=1.32–2.92). The risk of psychiatric-related hospitalization was numerically lower for lurasidone compared to all other AAPs.

Over a 24-month follow-up period, lurasidone-treated adult BPD-1 patients had significantly lower risk of all-cause hospitalization than those treated with olanzapine and quetiapine, lower risk of BPD-I-related hospitalization than quetiapine and risperidone, and fewer hospital days than quetiapine in a Medicaid population.

Sunovion Pharmaceuticals Inc.

Opioid use disorder (OUD) continues to be the driving force behind drug overdoses in the United States, killing nearly 47,000 people in 2018 alone. The increasing presence of deadlier fentanyl analogues in the heroin drug supply are putting users at a greater risk for overdose than ever before. Admissions to treatment programs for OUD have also nearly doubled since 2006, yet relapse rates remain high. In response to these alarming statistics, developing approaches to reduce overdose deaths has become an area of high priority. As it is not yet known which patients are most likely to benefit from a specific treatment, there is a dire need to utilize new molecular tools to guide precision medicine approaches and improve treatment outcomes. Here we describe a proof-of-concept study evaluating plasma-derived extracellular vesicle (EV) signatures and how they differ in patients who responded to two pharmacologically contrasting treatments for OUD: the μOR agonist methadone, and the μOR antagonist naltrexone.

We obtained blood samples from patients with OUD who remained abstinent from illicit opioids for at least 3 months during treatment with methadone (n=5) and naltrexone (n=5), as well as matched healthy controls (n=5). EVs were isolated from plasma and histones were isolated from peripheral blood mononuclear cells (PBMCs). EVs were then analyzed for lipid and histone post-translational modification (PTM) content using liquid chromatography-mass spectrometry. EV miRNA cargo was determined by RNA sequencing.

We found one lipid class and six miRNAs that differed significantly between the naltrexone group and the methadone and control groups. We also found that histone H3acK9acK14 was increasingly acetylated in PMBCs from both the methadone and naltrexone groups compared to controls.

Naltrexone, which is used in treatment of OUD and other substance use disorders as well as disorders of impulse control, was found to have multiple potential corresponding molecular signatures that can be identified after long-term treatment. It remains to be seen if these markers can also be a good predictor for treatment response. In addition, significant gender differences in EV content are found between men and women with OUD, which supports the importance of examining changes in response to treatment in a gender informed way.

The population of patients with major depressive disorder (MDD) and suicidal ideation (SI) or behaviors/attempts (SA) is not well characterized. Electronic health records (EHR) may contain useful data elements that are unavailable in other routinely used population-level databases like insurance claims. For example, the Patient Health Questionnaire (PHQ)-9 is a disease severity metric in this population which may influence treatment choices and hence, outcomes. This study sought to describe the treatments, depression severity, and health resource utilization among this population prior to, during, and following a suicide-related event.

Adult patients enrolled in an integrated delivery network with a diagnosis code indicating MDD and without a diagnosis for bipolar or related disorders, dementia, intellectual disability, schizophrenia or other non-mood psychotic disorders between 10/31/2015 and 9/30/2019 were selected from the Optum de-identified EHR database. Only patients with a diagnosis code for SI or probable SA (SI/SA) between 10/31/2016 and 9/3/2019 and healthcare activity ≥12 months prior to their 1st observed SI/SA diagnosis were included. MDD-related treatments and PHQ-9 scores (obtained from physician notes using natural language processing) were described during 3 periods: the 1st SI/SA health care encounter (index period), 12 months before (pre-period), and 6 months after (follow-up period). For those with multiple PHQ-9 scores during a period, the latest one was used. All-cause and MDD-related healthcare utilization were assessed during follow-up period.

A total of 71,161 patients with MDD and SI/SA were included in the analysis; mean (SD) age was 39 years (16 years); 55% were female. Antidepressants were prescribed for 31.3% during the pre-period and 41.2% during the index period. The use of psychotherapy was 9.5% during the pre-period and 18.7% during the index period. In the subgroup with data at 6 months (N=40,261), 43.4% and 20.5% received an antidepressant prescription and psychotherapy, respectively. During follow-up, the percent with ≥1 all-cause (MDD-related) hospitalization, observation stay and ED visit were: 11.8% (7.0%), 5.0% (2.1%), and 33.1% (11.1%). More than half (61.0) had ≥1 outpatient visit, and about 1/3 (33.4%) had ≥1 MDD-related outpatient visit. Very few patients had PHQ-9 scores recorded: pre-period 4.4% (mean [SD] 13.0 [7.5]); index period 1.3% (mean [SD] 17.0 [7.2]); and follow-up period 7.6% (mean [SD] 12.1 [7.5]).

This study documents a high level of health care resource utilization among those with MDD and suicidal thoughts and behaviors. Only a small proportion had documented PHQ-9 scores. Given that sizable proportions did not receive any antidepressant therapy or psychotherapy, even after suicidality was noted in their medical record, continued efforts in screening and treatment intensification are warranted for this vulnerable population.

Janssen Scientific Affairs, LLC

To describe characteristics of veterans with MDD and the different treatment regimens received during the first observed and treated major depressive episode (MDE).

A retrospective study was performed using the Veterans Health Administration (VHA) database from 4/1/2015 to 2/28/2019 (study period), supplemented with Medicare Part A/B/D data from 4/1/2015 to 12/31/2017. Adult veterans with ≥1 MDD diagnosis in the VHA database between 10/1/2015 and 2/28/2017 (index date) were included if they received ≥1 line of therapy (LOT) within a complete MDE. An MDE was considered as starting on the date of the first observed MDD diagnosis preceded by ≥6 months depression-free period (i.e. a period without an MDD diagnosis or antidepressant (AD) use); an MDE was considered as ended on the date of the last MDD diagnosis or the end of the medication supply of the last AD/augmentation medication, whichever came last and then followed by ≥6 months depression-free period. An MDE was required to begin and end during the study period. A LOT was defined as ≥1 AD at adequate dose and duration (≥6 weeks of continuous therapy with no gaps longer than 14 days) with or without an augmenting medication. Patients were required to have VA benefit enrollment for ≥6 months before (baseline) and ≥24 months after index (follow-up). Patient baseline demographic and clinical characteristics as well as the number and type of LOTs (up to the first six LOTs) received during the first observed and treated MDE were evaluated.

Overall, 40,240 veterans with MDD were identified (mean ± standard deviation [SD] age: 50.9±16.3 years).The majority were male (83.9%), White (63.4%), and non-Hispanic (88.6%); 60.1% were unemployed or retired at some point during the study period. The most commonly observed baseline comorbidities included hypertension (27.5%), hyperlipidemia (20.8%), post-traumatic stress disorder (17.5%), and diabetes (14.8%). During the first observed and treated MDE (mean ± SD duration: 14.7 ± 8.6 months), patients received a mean of 1.6±1.0 LOTs, with 36.5% and 14.6% of patients receiving ≥2 and ≥3 LOTs, respectively; 0.8% of patients received ≥6 LOTs. The most commonly observed therapies were SSRI monotherapy (58.9%) followed by SNRI monotherapy (8.8%) in LOT1; SSRI monotherapy followed by AD augmented with anticonvulsants in LOT2 (SSRI monotherapy: 48.7%; AD augmentation with anticonvulsants:12.1%) and LOT3 (SSRI monotherapy: 43.5%; AD augmentation with anticonvulsants:15.0%).

This study used an episodic approach to evaluate the current standard of care among veterans with MDD. During the first observed and treated MDE, about one in seven veterans received ≥3 LOTs, suggesting presence of treatment-resistant MDD. Monotherapy with SSRIs or SNRIs and combination therapies of AD with anticonvulsants were the most common therapies in the first three LOTs.

Janssen Scientific Affairs, LLC

The purpose of this case study is to review the clinical presentation and medical workup of a young adult male presenting with acute behavior changes in the setting of undiagnosed ornithine transcarbamylase deficiency (OTCD)

This case study involves a 19-year-old male with a psychiatric history of depression and one previous suicide attempt, who presented to a large midwestern university hospital emergency department after being found by police naked in a neighbor’s yard. He displayed manic signs and symptoms, including euphoria, lack of sleep for five days, and attempting to purchase a new car and three large screen TVs. Family reported the patient uncharacteristically announced three weeks earlier that he was vegetarian and stopped eating his frequent customary cheeseburgers. Due to increased anxiety and inability to sleep, the patient received lorazepam 2 mg in the emergency department. Upon transfer to the psychiatric unit, therapy was initiated with aripiprazole 5 mg daily and valproate 1000 mg nightly on Day 1 of treatment. The patient refused medications on hospital Day 2, then received this combination again on Day 3. The next morning, the patient complained of lethargy, headache, nausea, and vomiting.

The patient’s ammonia level was found to be 204 micromol/L with ALT and AST of 714 and 647 IU/L respectively. Tests for infectious hepatitis were negative. Medical consultation recommended discontinuation of current medications, vigorous hydration, and further work up. On further investigation, the patient was found to have low plasma citrulline level of 8 micromol/L, undetectable plasma arginine, and high urinary orotic acid. The laboratory data showed a biochemical phenotype consistent with a diagnosis of partial OTCD, an X-linked urea cycle disorder resulting in toxic hyperammonemia. The patient was treated with a low protein diet modification as well as a combination of sodium benzoate and sodium phenylbutyrate to reduce serum ammonia concentration. With treatment the patient’s laboratory values normalized, and mental status improved.

In conclusion, partial ornithine transcarbamylase deficiency may manifest with psychiatric symptoms in early adulthood. In young patients with elevated ammonia and mental status change, OTCD is an important diagnosis to consider, as it is the most common inherited cause of hyperammonemia.