Outpatient benzodiazepine use can cause side effects including dependence (20–30%) and death from respiratory depression when used with alcohol or opioids. Benzodiazepine use is on the rise in the U.S., increasing 67% from 1996–2013. In this quality improvement project, two educational interventions were combined with the intent of decreasing benzodiazepine prescribing by providers (MDs, APRNs) in an urban university clinic.

When prescribers working in a low-income clinic receive an intervention to increase awareness of benzodiazepine dangers and promote harm reduction strategies compared to treatment as usual, do they write fewer benzodiazepine prescriptions in the month following the intervention?

A hybrid intervention combining academic detailing (educational outreach visits) and pharmaceutical industry detailing (merchandising, relationship building) was provided in two sessions to family practice providers (salaried and residents) working in a university outpatient clinic in Chicago. The subject matter included benzodiazepine risks, alternative treatments for anxiety & insomnia, and methods to deal with patient demand. All clinic providers (n=40) were invited to participate. Participants were self-selected to attend each session (although resident physicians were obligated to attend). A total of 20–24 providers attended each session.

Benzodiazepine prescription information was extracted by clinic information systems for two periods: 12months pre-intervention, and 30days post-intervention. For ease of comparison, each prescription was converted to a common denominator: the diazepam-equivalent dose. The pre-intervention monthly average (for one year) was compared to 30-day post-intervention data. The outcome measure was the numeric difference in the prescribed diazepam-equivalents pre- and post-intervention. This number was used as a measure of the effectiveness of the intervention. A decrease in prescribing post- compared to pre-intervention would indicate a successful intervention.

There was an 80% decrease in benzodiazepine prescribing in the 30-day post-intervention period compared to the 12-month pre-intervention monthly average. This result cannot be explained by personnel changes at the clinic. Although these did occur in 2017, the pattern of prescribing was stable throughout the year prior to this intervention.

The combination of academic and pharmaceutical industry detailing influenced family practice providers in an urban clinic setting to decrease benzodiazepine prescribing by 80%. Decreased benzodiazepine prescribing should decrease patient morbidity and mortality.

Tardive dyskinesia (TD) results from exposure to dopamine-receptor antagonists (DRAs), such as typical and atypical antipsychotics. Clinicians commonly manage TD by reducing the dose of or stopping the causative agent; however, this may cause psychiatric relapse and worsen quality of life. In the 12-week ARM-TD and AIM-TD trials, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores versus placebo and was generally well tolerated, regardless of baseline DRA use or comorbidities.

To evaluate the impact of underlying disease and current DRA use on efficacy and safety of long-term therapy of deutetrabenazine in patients with TD.

Patients with TD who completed ARM-TD or AIM-TD were eligible to enter this open-label, single-arm, long-term extension after completing the 1-week washout period and final evaluation in the blinded portion of the trial. Change in AIMS scores from baseline to Week 54 and patients “Much Improved” or “Very Much Improved” (treatment success) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) at Week 54 were analyzed by baseline psychiatric illness type, including mood disorders (bipolar disorder/depression/other) or psychotic disorders (schizophrenia/schizoaffective disorder), and presence or absence of current DRA use.

At Week 54, meaningful improvements from baseline in mean (standard error) AIMS scores were observed for patients with baseline mood disorders (–5.2[0.93]) and psychotic disorders (–5.0[0.63]), and in patients currently using DRAs (–4.6[0.54]) or not using DRAs (–6.4[1.27]). Most patients with mood disorders (73%) and psychotic disorders (71%) were “Much Improved” or “Very Much Improved” on CGIC at Week 54, similar to patients currently using (71%) or not using (74%) DRAs. The majority of patients with mood disorders (62%) and psychotic disorders (57%), as well as patients currently using (58%) or not using (63%) DRAs, were also “Much Improved” or “Very Much Improved” on PGIC at Week 54. Prior treatment in ARM-TD and AIM-TD did not impact the long-term treatment response. Underlying psychiatric disorder and concomitant DRA use did not impact the occurrence of adverse events (AEs). The frequencies of dose reductions, dose suspensions, and withdrawals due to AEs were low, regardless of baseline psychiatric comorbidities and DRAuse.

Long-term deutetrabenazine treatment demonstrated meaningful improvements in abnormal movements in TD patients, which were recognized by clinicians and patients, regardless of underlying psychiatric illness or DRAuse.

Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA

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

Tardive dyskinesia (TD) is an often-irreversible movement disorder that may intensify the stigma of patients with psychiatric disorders and worsen quality of life. In two randomized, double-blind, placebo (PBO)-controlled, 12-week trials, ARM-TD and AIM-TD (‘parent studies’), deutetrabenazine (DTB) demonstrated statistically significant improvements in centrally read Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with PBO and was generally well tolerated.

To evaluate the long-term efficacy of DTB in an open-label safety study following double-blind treatment using site-rated efficacy measures: AIMS, the Clinical Global Impression of Change (CGIC) and the Patient Global Impression of Change (PGIC), which may be used in real-world clinical practice settings.

Patients with TD who completed the parent studies were eligible to enter this open-label, long-term extension (OLE) after completing the 1-week washout period and final evaluation in the blinded portion of the trial. This extension comprised a 6-week titration period followed by a long-term maintenance phase. Patients began DTB at 12mg/day, titrating up to a maximum total dose of 48mg/day based on dyskinesia control and tolerability. Efficacy endpoints included in this analysis are the change in site-rated AIMS score (items 1–7) from parent study baseline, and the proportion of patients who were “Much Improved” or “Very Much Improved” (treatment success) on the CGIC and PGIC from OLE baseline.

At the end of the parent studies (Week 12), patients treated with DTB had experienced greater mean (standard error) improvements in site-rated AIMS score (–5.0[0.40]) than patients given PBO (–3.2[0.47]). With long-term DTB treatment, both groups experienced improvements in site-rated AIMS scores (prior DTB, –7.9[0.62]; prior placebo, –6.6[0.64]) compared with parent study baseline. Similarly, at the end of the parent studies, a greater proportion of patients treated with DTB had treatment success on the CGIC (DTB, 51%; PBO, 32%) and the PGIC (DTB, 46%; PBO: 33%); whereas at Week 54 of the OLE study, treatment success on CGIC and PGIC were similar in both the CGIC (prior DTB: 66%; prior PBO: 68%) and PGIC (prior DTB: 62%; prior PBO: 62%) groups. DTB was generally well tolerated.

Patients treated with DTB showed improvements in abnormal movements, as measured by site-rated AIMS, CGIC, and PGIC scores, which may be used in real-world clinical practice settings. These results corroborate the previously reported efficacy of DTB as observed in the 12-week, double-blind ARM-TD and AIM-TD trials, in which central raters were used to evaluate AIMS scores.

Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA

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

A hallmark of Parkinson’s disease is facial akinesia with decrease in blink frequency (Karson, 1984). A markedly decreased blink frequency from nyctophobia, a fear of the dark, has not heretofore been reported.

Case Study: A 26-year-old right handed male presented with a 20-year history of phantasmagoria. Visual hallucinations of strangers appeared several to a hundred times a day, seconds to minutes in duration. These morbid images were horrific, of dead people or ghosts, suddenly appearing in his visual space, actively attacking real people. Examples included a little girl, decapitated, cradling her head in her arm or Freddy Krueger like apparitions, shooting, stabbing, strangling or maiming actual people who were within the patient’s visual field. He was able to differentiate between the hallucinations and real people, either from the context (a non hallucination would not be murdering someone else), or he would wait for the hallucinations to vanish, allowing him to then interact with the person who is actually there. The images were so disturbing to him that he fled his home state to run away from the hallucinations, but to his chagrin, they persisted. There were diurnal variations to his hallucinations, which were more frequent at night, or when he closed his eyes, and the fear of these has induced nyctophobia. In order to avoid these, he attempted to curtail closing his eyes or blinking. He had been treated with 9 different psychotropic medications, which had no effect on his hallucinations. Phenytoin was begun, and once therapeutic levels were achieved, all of his hallucinations resolved, as did his nyctophobia, with return to normal blink frequency.

Physical examination: Bilateral palmar erythema. Facial expression with decreased blink frequency, approximately 1/per minute, but not otherwise hypomimetic. Neurological examination: Cranial Nerve (CN) Examination: CN III, IV and VI: bilateral ptosis. Motor Examination: Normal tone without cogwheel rigidity. No bradykinesia. Drift Testing: Right upward-outward drift, right cerebellar spooning, and Abductor Digiti Minimi sign. Gait: Normal without instability or retropulsion. Reflexes: 1+ throughout. Hoffman Reflex: positive bilaterally. Other: Magnetic Resonance Imaging of brain with/without infusion: Normal. Five-day Electroencephalogram: Temporal Lobe Status Epilepticus with bilateral foci.

In this individual, the sheer terror of phantasmagoria with his eyes closed, forced him to maintain them in the open position as long as possible, reducing his blink frequency to once a minute or less. The return to a normal rate of blink frequency with treatment using phenytoin, with resolution of his horrific hallucinations, further validates this as the origin for his infrequent blinking. In those with low nictation, without other manifestations of Parkinson’s disease, query as to volitional inhibition of blink frequency and nyctophobia is warranted.

Valbenazine (VBZ) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat tardive dyskinesia (TD) in adults. It has been evaluated in 2 long-term studies (KINECT 3, KINECT 4) in which participants received VBZ (40 or 80mg) for up to 48weeks. This long-term rollover study (NCT02736955) was conducted to evaluate global TD improvement and patient satisfaction with once-daily VBZ.

Key eligibility criteria: age 18 to 85 years; completion of KINECT 3 or KINECT 4; maintenance medications (for schizophrenia, schizoaffective disorder, or mood disorder) at stable doses; Brief Psychiatric Rating Scale score <50; no significant risk of active suicidal ideation or behavior. Following washout of prior VBZ treatment (Weeks 48 to 52 of KINECT 3 and KINECT 4), participants were re-initiated at 40mg (4weeks) and escalated to 80mg based on tolerability and clinical assessment of TD; dose was reduced to 40mg if 80mg was not tolerated (80/40mg). If unable to tolerate the 40mg dose, the participant was discontinued. Participants received open-label VBZ for up to 72weeks or until commercial availability. Assessments included Clinical Global Impression of Severity-TD (CGIS-TD: range, 1[“normal, not at all ill”] to 7[“among the most extremely ill patient”]) and Patient Satisfaction Questionnaire (PSQ: range, 1[“very satisfied”] to 5[“very dissatisfied”]).

160 participants with available data were included in analyses (40mg =35; 80mg =117; 80/40mg =8); 138 were receiving treatment when VBZ became commercially available. The percentages of participants who completed visits at Wks 12, 24, 36, and 48 were 96.3%, 78.1%, 56.9% and 35.0%, respectively. Few reached Wk 60 (n=4) or Wk 72 (n=0) due to commercial availability. The percentage of participants with CGIS-TD score ≤2 (“normal, not at all ill” or “borderline ill”) increased from baseline (before restarting VBZ) (40mg, 5.7%; 80mg, 18.1%) to Wk 48 (40mg , 41.7%; 80mg , 74.4%). At baseline, almost all participants rated their prior VBZ experience with a PSQ score ≤2 (“very satisfied” or “somewhat satisfied”) (40mg , 100%, 80mg , 99.1%). Similar results were seen at the Wk 48 visit, with most participants continuing to express satisfaction with VBZ (40mg , 100%; 80mg , 97.4%).

A clinician-based global assessment indicated ongoing, meaningful TD improvements in adults who received once-daily VBZ in the current study. In participants treated for >1 year, continued patient satisfaction rates with VBZ were high.

Funding Acknowledgements: Neurocrine Biosciences, Inc.

To evaluate the long-term safety and tolerability of once-dailyvalbenazine in adults with tardive dyskinesia(TD).

Data were pooled from KINECT 3 (NCT02274558: 6-week double-blind placebo-controlled period, followed by a 42-week double-blind extension and 4-week drug-free washout) and KINECT 4 (NCT02405091: 48-week open-label treatment period and 4-week drug-free washout). KINECT 3/4 study completers could enroll in a subsequent rollover study (NCT02736955: up to 72weeks of open-label treatment or until valbenazine became commercial available); data from this study were described separately for this analysis. Valbenazine dose groups (40 and 80mg) were pooled for analysis. Safety assessments included treatment-emergent adverse events (TEAEs) and the Columbia-Suicide Severity Rating Scale (C-SSRS). Psychiatric status was assessed in KINECT 3 and KINECT 4 using the following measures: Positive and Negative Syndrome Scale (PANSS) total score and Calgary Depression Scale for Schizophrenia (CDSS) in participants with schizophrenia/schizoaffective disorder; Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in participants with a mood disorder.

Analyses included 304 KINECT 3/4 participants and 160 rollover participants. In KINECT 3/4, the summary of TEAEs was as follows: any TEAE (71.7%), serious TEAE (16.8%), and discontinuation due to TEAE (15.5%). TEAEs reported in ≥5% of all KINECT 3/4 participants were headache (8.9%), urinary tract infection (8.9%), somnolence (7.9%), fatigue (6.3%), dizziness (5.9%), and suicidal ideation (5.6%). The summary of TEAEs from the rollover study was as follows: any TEAE (53.1%), serious TEAE (10.0%), and discontinuation due to TEAE (5.6%). The most common TEAEs in the rollover study were back pain and urinary tract infection (4.4%, each); no TEAE was reported in ≥5% of participants. Minimal changes in psychiatric status were observed in KINECT 3/4, as indicated by mean score changes from baseline to Week 48 in participants with schizophrenia/schizoaffective disorder (PANSS total, –3.2; CDSS total, –0.5) or a mood disorder (MADRS total, 0.3; YMRS total, –1.0). Over one-third of study participants had a lifetime history of suicidal ideation or behavior (KINECT 3/4, 41%; rollover, 38%). Most participants had no C-SSRS suicidal ideation at study baseline; of these, >90% had no emergence of suicidal ideation at any time during the study (KINECT 3/4, 93% [276/296]; rollover, 98% [153/156]).

Valbenazine was well tolerated and no unexpected safety signals were found in adults who received >1 year of once-daily treatment. Psychiatric stability was maintained, and few participants experienced any emergence of suicidal ideation during the studies despite 35–40% having a lifetime history of suicidality. These results indicate that once-daily valbenazine may be an appropriate treatment for the long-term management of TD.

Funding Acknowledgements: Neurocrine Biosciences, Inc.

Hyposmia refers to reduced ability to smell and hypogeusia is a partial loss of the ability to taste (Hummel, Basile, & Huttenbrink, 2016). Complaints of hyposmia and hypogeusia in the presence of normosmia and normogeusia has not heretofore been described. Three such cases are presented.

To explore the complaints of reduced smell and taste with normal objective olfaction and gustation.

All patients were given screening tests for smell and taste and obtained scores consistent with normosmia and normogeusia. The 12-item version of the Brief Smell Identification Test (B-SIT), using the odorants banana, chocolate, cinnamon, gasoline, lemon, onion, paint thinner, pineapple, rose, soap, smoke and turpentine was used. The Retronasal Olfactory Test was used to determine their perception of flavour and the Proplythiouracil Disc Taste Test used for gustation. Each patient also underwent a complete physical and neurological examination with any abnormalities mentioned.

Case 1: This 53 year old female, 8months prior to presentation, developed the flu followed by the inability to taste any foods and differentiate between smells, with everything smelling bitter.

Results: Chemosensory testing: Olfaction: Brief Smell Identification Test (B-SIT): 10 (normosmia). Retronasal Olfactory Test: Retronasal Smell Index: 9 (normal). Gustation: Propylthiouracil Disc Taste Test: 7 (normal).

Case 2: This 86 year old female, 6months prior to presentation, developed reduced taste, of gradual onset, to the point upon presentation was only 10% normal. She was able to taste lemons but very little else.

Results: B-SIT: 9 (normosmia). Retronasal Smell Index: 10 (normal). Propylthiouracil Disc Taste Test: 10 (normogeusia).

Case 3: This 63 year old female was nasute until 3months prior to presentation, when she developed an upper respiratory infection, followed by loss of smell and taste to 20% of normal.

Results: B-SIT: 10 (normosmia). Retronasal Smell Index: 7 (normal). Propylthiouracil Disc Taste Test: 10 (normogeusia).

Discordance between subjective and objective findings may be due to the wide distribution of normal in the general population in olfactory ability. The associated reduction in retronasal smell may then be interpreted by the patient as reduced ability to taste. Alternatively, complaints of hyposmia and hypogeusiamay be due to a non-organic need such as malingering or psychosomatic illness, or could represent a primary defect in the cortical integration of smell and taste, interpreted as reduction in perceived flavor, yet the primary sensory neurons and threshold as tested would appear to be normal. This disparity possibly indicates that the testing modalities are too insensitive to demonstrate more subtle sensory perception findings, and suggests the need for more refined testing methods for smell and taste.

Vesicular monoamine transporter 2 (VMAT2) inhibitors are the first class of drugs approved to treat tardive dyskinesia (TD). With the recent approval of these medications, a modified Delphi process was implemented to address the need for updated clinical guidelines for TD screening, diagnosis, and treatment.

A Steering Committee of 11 TD experts met in a Nominal Group meeting format to discuss/prioritize questions to be addressed about TD and identify individuals to be invited to serve as Delphi survey panelists. Two survey rounds were conducted anonymously; responses were collected, collated, and analyzed. Respondent agreement was defined a priori by the Steering Committee as unanimous (100%), consensus (75–99%), or majority (50–74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥4 (“agree completely” or “agree”). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with <25% agreement (deemed unlikely to achieve consensus) and some questions that already achieved consensus (>75% agreement).

Online surveys were sent to 60 individuals; 29 agreed to participate as panelists (23 psychiatrists; 6 neurologists). Respondents unanimously agreed (100%) that all patients currently taking dopamine receptor blocking agents (DRBAs) should be screened for TD, and that the Abnormal Involuntary Movement Scale (AIMS) is the standard structured assessment for monitoring severity of TD. There was consensus (76%) that a semi-structured assessment could be used for more frequent routine TD screening. Respondents unanimously agreed that treatment with first generation antipsychotics, older age, and longer cumulative exposure to antipsychotics were risk factors for TD. For TD diagnosis, consensus (89%) was reached that a patient with an AIMS score >2 (mild) affecting 1 body area should be considered as having possible TD; consensus (93%) was also reached that TD was most often evident in orofacial musculature, although other body areas may be affected and should not be neglected. Consensus was not reached on minimum cumulative duration of DRBA exposure for TD diagnosis, but a majority (70%) agreed that minimum cumulative exposure of 1month may be sufficient. For TD treatment, unanimity or consensus was reached on 4 strategies to consider: discussion of treatment options with patients/caregivers (100%), modification of antipsychotic regimen (100%), treatment with VMAT2 inhibitor (100%), and modification of anticholinergic regimen (86%).

Using a Nominal Group and modified Delphi process, consensus was reached within 1−2 rounds on several key aspects of TD screening, diagnosis, and treatment. This process may offer an expedient method to identify gaps in agreement and facilitate updated management guidelines.

Funding Acknowledgements: Sponsored by Neurocrine Biosciences,Inc.

Psychological risk factors that lead to impaired work performance, negatively impacting mental and physical health, have emerged as a concern across clinical settings. Although depression and anxiety are linked to poor physician mental health, physician burnout characterized by work related stress due to chronic exhaustion from clinical work, cynicism toward meaning of the medical profession, and feelings of inadequacy toward work related accomplishments, may be an even stronger indicator of well-being. Literature suggests that work satisfaction among physicians is rapidly deteriorating owing to high rates of burn out and poor mental health. Although the relationship between work burnout (WB) and negative affectivity has been well documented, the association with positive affect, such as trait forgiveness (TF) has been overlooked. On that note, research shows that lifetime stress severity and lower levels of forgiveness predict worse mental and physical health. Since TF has been linked strongly with healthy workplace relationships, positive occupational outcomes and general well-being, its association with WB remains to be investigated. Therefore, the aim of the present study was to explore the link between TF and WB among physicians. We hypothesized that TF would be associated with reduced levels of burnout.

A total of 62 (F=23) medical residents at a Teaching Hospital consented for the study. Residents were administered surveys on WB (Maslach BurnoutInventory), workplace bullying, personal bullying (PB), interpersonal rejection sensitivity (IRS), perceived stress scale (PSS), TF, anxiety, and depression, all of which were anonymously submitted via electronically. Hierarchical multiple regression (HMR) models were used to determine the associations between WB, work environment social factors and TF. A p-value of <0.05 was considered significant.

The mean age 33.1±SD 4.2 years. HMR analysis using WB as main outcome contained 6 predictors: Model 1 contained depression and anxiety, Model 2 added PB, Model 3 added IRS and PSS, Model 4 added TF. Anxiety and TF were the only significant predictors (p= >0.05) accounting for 10.4% and 17.5% of the variance in WB scores, respectively.

The novel finding of the present study is that TF was associated with low levels of burnout. Additionally, WB was found to be linked to anxiety and depression which is in line with previous research. These data suggest that TF could be a potential resolution to the deleterious influence of burnout. Further exploration is needed in order to understand the psychology of forgiveness as a potential adjuvant and/or therapeutic intervention for physicians’ burnout. These results suggest that strategies including forgiveness training aimed at decreasing WB while increasing job satisfaction among physicians warrant further exploration.

Funding Acknowledgements: no funding

To understand that tinnitus may be an aura for sleep paralysis.

Sleep paralysis is a transient-paralysis which occurs during awakening or falling asleep (Wilson, 1928). Those affected experience symptoms including visual, auditory, and haptic hallucinations, voluntary motor paralysis with intact ocular and respiratory motor movements, and diffuse or localized paresthesias. Sleep paralysis associated with tinnitus as an aura, has not heretofore been described.

A 34 year-old, right-handed female presented with a 13 year history of sleep paralysis. One month prior, she began to notice tinnitus prior to the onset of sleep paralysis. The tinnitus was bilateral, high-pitched, with a volume intensity of 5/10, lasting seven seconds prior to sleep initiation. She denied hearing loss, vertigo, dizziness, cataplexy, deja vu and jamais vu. After termination of tinnitus, she experienced paresthesia, “like at a dentist’s office” radiating from her posterior neck, to her tongue and down to her toes. She described seeing a white-shadowy male figure moving around her room, lasting seven seconds. Accompanied by a masculine “ahh” sound, lasting for three seconds. The sleep paralysis occurred after these events, lasting up to eight hours, or until her husband wakes her.

Abnormalities in Physical Examination: General Examination: right arm hemangioma 4 by 5cm. Reflexes: absent bilateral brachioradialis, 1+ bilateral quadriceps femoris and bilateral Achilles tendon. Neuropsychiatric Examination: Calibrated Finger Rub Auditory Screening Test: faint 70 AU (normal).

Tinnitus has been described as an aura for migraines (Schankin, 2014), temporal lobe epilepsy (TLE) (Florindo, 2006), and narcolepsy-cataplexy (Marco, 1978). These epochs may represent amigranous migraines, which initially present with tinnitus that occurs both during the day and night, forcing the patient to be partially awoken at night with induction of the sleep paralysis sequence. It would be worthwhile to query those with narcolepsy or sleep paralysis if tinnitus precedes the event.

Long-acting injectable antipsychotic therapies may offer benefits over oral antipsychotics in patients with schizophrenia. However, there is still a lack of real-world studies assessing the effectiveness of these therapies.

This study aimed to explore the safety, tolerability, and treatment response of aripiprazole monohydrate (AOM) once monthly in non-acute but symptomatic adult patients switched from previous therapy with frequently used oral or injectable atypical antipsychotics.

This was a post hoc analysis of a prospective, interventional, single-arm, open-label, 6-month study.

The patients (N=54) were switched to aripiprazole monohydrate once-monthly (AOM) from daily oral treatment or monthly injectable treatment with either aripiprazole (n=25), olanzapine (n=7), paliperidone extended-release (PP1M) (n=10), quetiapine (n=4), or risperidone (n=8). In all groups, mean Positive and Negative Syndrome Scale total (p=0.0001) and Clinical Global Impression-Severity scores improved significantly (p=0.0001). A reduction of ≥50% reduction of BPRS total-score and a CGI severity-score ≤4 in the Positive and Negative Syndrome Scale total score were observed in 16.7% (aripiprazole), 21.2% (olanzapine), 35.1% (PP1M), 27.3% (quetiapine), and 37.2% (risperidone) of patients. The patients showed significant improvements involving safety features as they experienced significant overall weight loss (p=0.0001) and prolactine decrease (risperidone p=0.0001, paliperidone extended-release p=0.0001). AOM once-monthly was well tolerated, presenting no new safety signals. Patient also reported an overall significant improvement on their quality of life measured with the Quality of Life Rating Scale (QLS) (p=0.0004) as well as in sexual functioning PRSexDQ-SALSEX (p=0.0001). In addition, the all cause treatment discontinuation rate after6-month follow-up was small (n=3; 5,55%)

These data illustrate that stable, non-acute but symptomatic patients either on oral antipsychotic therapy or under monthly antipsychotic treatment may show clinically meaningful improvement of psychotic symptoms, tolerability involving relevant side effects and quality of life perception. The findings are limited by the naturalistic study design; thus, further studies are required to confirm the current findings.

Keywords: Long-acting injectable antipsychotic therapy. Oral antipsychotic. Effectiveness- Tolerability-Quality oflife.

To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.

In the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.

Patients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.

343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.

Patients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.

Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.

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

To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.

In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.

Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).

343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.

These results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.

Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA

Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel

To report functional recovery, symptomatic remission, and sustained symptomatic remission rates after treatment with aripiprazole once-monthly 400mg (AOM 400) administered every 4weeks for up to 52weeks as maintenance treatment in a mixed cohort of AOM 400 naïve (de novo) and experienced adults (rollover) with bipolar I disorder (BP-I).

This open-label study (NCT01710709) enrolled de novo patients with a diagnosis of BP-I and ≥1 previous manic or mixed episode and rollover patients who completed a randomized, double-blind, placebo-controlled study assessing the efficacy and safety of AOM 400 (NCT01567527). Efficacy was assessed by mean changes from baseline in Young-Mania Rating Scale (YMRS), Montgomery-Asberg Depressive Rating Scale (MADRS), and Clinical Global Impression- Bipolar Version-Severity of Illness (CGI-BP-S) scores. Sustained functional recovery was defined as a total score of ≤11 on the Functioning Assessment Short Test (FAST) for ≥8 consecutive weeks. Remission was defined as YMRS and MADRS total scores ≤12, and sustained remission was defined as meeting criteria for remission for 8 consecutive weeks. The study included a screening phase (6weeks) for de novo patients, an oral aripiprazole conversion phase (4–6weeks), an oral stabilization phase (4–12weeks), and an AOM 400 maintenance phase (up to 52weeks). Rollover patients entered directly into the AOM 400 maintenance phase.

A total of 464 subjects entered the maintenance phase and 63% (291/464) completed the trial. Of patients entering the maintenance phase, 379 (82%) were de novo and 85 (18%) were rollover. The most frequent reasons for discontinuation were withdrawal of consent (11%) and adverse events (AEs) (10%). Weight increase (1.5%, 7/464) and BP-I (0.9%, 4/464) were the most common reasons for discontinuation due to AEs. Improvements in mean YMRS, MADRS, CGI-BP-S, and FAST scores achieved in previous phases were maintained over 52weeks. Treatment-emergent AEs experienced by >10% of the patients were akathisia (14.7%), weight increased (13.4%), nasopharyngitis (12.1%), and insomnia (11.0%). A high proportion of de novo patients met the criteria for symptomatic remission (87.2%, 328/376) and sustained remission (77%, 292/379) by last visit. Rollover patients’ remission rate remained stable (98.8%, 84/85) by last visit. Of the rollover patients, 35/85 (43%) and 35/116 (36%) of de novo subjects met the criteria for sustained functional recovery after study completion.

Patients treated with AOM 400 maintained symptomatic and functional stability for up to 52weeks. Importantly, more than one-third of patients achieved sustained functional recovery using a strict criterion. Overall, AOM 400 was safe and well tolerated in patients with BP-I. Results support AOM 400 as a viable once-monthlyoption for maintenance treatment of BP-I.

These data were previously presented at the 31st ECNP Congress, 2018, Barcelona,Spain.

Funding Acknowledgements: The study was supported by Otsuka Pharmaceutical Development & Commercialization, Inc.

Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.

1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.

At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.

Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.

Funding Acknowledgements: This study was supported by Assurex Health, Inc.

Buprenorphine/samidorphan (BUP/SAM), a combination of BUP (a µ-opioid receptor partial agonist and κ-antagonist) and SAM (a sublingually bioavailable µ-opioid antagonist), is an investigational opioid system modulator for depression. BUP/SAM has shown efficacy versus placebo as an adjunctive treatment for major depressive disorder (MDD) and a consistent safety profile in previously reported, placebo-controlled clinical studies.1,2

1. To characterize the safety profile following long-term treatment with BUP/SAM

2. To explore depression symptoms and remission rates in patients with MDD following long-term treatment with BUP/SAM

FORWARD-2 (Clinicaltrials.gov ID: NCT02141399) enrolled patients who had participated in 1 of 4 controlled studies as well as de novo patients. All patients had a confirmed diagnosis of MDD, had a history of inadequate response to standard antidepressant therapies (ADTs), and had been treated with an adequate dose of an established ADT for ≥8weeks before BUP/SAM initiation. ADT dosage could be titrated, but the ADT could not be changed. During the study, patients received open-label, sublingual BUP/SAM 2mg/2mg as adjunctive treatment for up to 52weeks. Safety (primary objective) was assessed via adverse events (AEs), vital signs, laboratory analytes, and electrocardiography. Suicidal ideation or behavior (SIB) was evaluated by the Columbia Suicide Severity Rating Scale. Abuse potential, dependence, and withdrawal were assessed by AEs and the Clinical Opiate Withdrawal Scale. Exploratory efficacy endpoints included mean Montgomery–Åsberg Depression Rating Scale (MADRS) scores and remission rate (MADRS ≤10).

Of 1454 total patients, 49% completed the 52-week study, 11% discontinued due to an AE, and 40% discontinued because of other reasons as of the interim data cutoff date (April 30, 2017). Most AEs were of mild/moderate severity. Serious AEs were reported in 3.2% of patients. AEs occurring in ≥10% of patients were nausea, headache, constipation, dizziness, and somnolence. There was no evidence of increased risk of SIB with BUP/SAM. Incidence of euphoria-related events was low (1.2%). After abrupt discontinuation of BUP/SAM, there was little evidence of withdrawal. BUP/SAM was not associated with meaningful changes in laboratory or metabolic parameters or in bodyweight. The mean MADRS score decreased from 22.9 (±9.7) at baseline to 9.8 (±8.8) after 52weeks. The remission rate at 52weeks was 52.5%.

Long-term treatment with BUP/SAM did not reveal any new safety findings and confirmed that the risk of abuse and dependence with BUP/SAM was low. BUP/SAM maintained an antidepressant effect for up to 52weeks of treatment in patients with MDD.

Funding Acknowledgements: Alkermes, Inc.

Facial expressivity in schizophrenia has been a topic of clinical interest for the past century. Besides the schizophrenia sufferers difficulty decoding the facial expressions of others, they often have difficulty encoding facial expressions. Traditionally, evaluations of facial expressions have been conducted by trained human observers using the facial action coding system. The process was slow and subject to intra and inter-observer variability. In the past decade the traditional facial action coding system developed by Ekman has been adapted for use in affective computing. Here we assess the applications of this adaptation for schizophrenia, the findings of current groups, and the future role of this technology.

We review the applications of computer vision technology in schizophrenia using pubmed and google scholar search criteria of “computer vision” AND “Schizophrenia” from January of 2010 to June of 2018.

Five articles were selected for inclusion representing 1 case series and 4 case-control analysis. Authors assessed variations in facial action unit presence, intensity, various measures of length of activation, action unit clustering, congruence, and appropriateness. Findings point to variations in each of these areas, except action unit appropriateness, between control and schizophrenia patients. Computer vision techniques were also demonstrated to have high accuracy in classifying schizophrenia from control patients, reaching an AUC just under 0.9 in one study, and to predict psychometric scores, reaching pearson’s correlation values of under 0.7.

Our review of the literature demonstrates agreement in findings of traditional and contemporary assessment techniques of facial expressivity in schizophrenia. Our findings also demonstrate that current computer vision techniques have achieved capacity to differentiate schizophrenia from control populations and to predict psychometric scores. Nevertheless, the predictive accuracy of these technologies leaves room for growth. On analysis our group found two modifiable areas that may contribute to improving algorithm accuracy: assessment protocol and feature inclusion. Based on our review we recommend assessment of facial expressivity during a period of silence in addition to an assessment during a clinically structured interview utilizing emotionally evocative questions. Furthermore, where underfit is a problem we recommend progressive inclusion of features including action unit activation, intensity, action unit rate of onset and offset, clustering (including richness, distribution, and typicality), and congruence. Inclusion of each of these features may improve algorithm predictive accuracy.

We review current applications of computer vision in the assessment of facial expressions in schizophrenia. We present the results of current innovative works in the field and discuss areas for continued development.

The spreading of pareidolia, the visualization of one image inside another image, from one member of a couple to another one is seen in a subtype of folie á deux called folie imposée.

A 27 year old right handed male started having delusions two years prior to presentation. He experienced marked hallucinations in which he saw faces imbedded in clothing and demon-like faces that would appear in curtain shades. During his visual hallucinations, “demonic-like angles would tell me how to get to heaven.” His pareidolia would be such that he would be looking at shadows on the walls or folds in clothing and see images within another. His fiancé, whom which he had been with for six years, also began to have pareidolia where she would be able to see facial images in furniture; for example, a chair would have an evil face or folds of material would have a jagged, folded distortion. These persisted more prevalently when she was with him.

General physical examination: Hypopigmented skin. Mental Status Examination: Feelings of unreality, blunted affect, disorganized and pressured speech, flight of ideas. Thought process: abnormal with circumstantiality. Cranial Nerve Examination: Cranial Nerve 2: Visual acuity 20/70 OD, 20/50 OS. Retinal freckles OS. Cranial Nerve 3, 4, 6: bilateral tortuosity. Cranial Nerve 9, 10: deviated to right. Motor Examination: Drift test: right abductor digiti minimi sign. Cerebellar Examination: decrease amplitude to move left upper extremity. Finger to nose with dysmetria bilaterally. Reflexes: Brachioradialis: right 1+, left 3+. Biceps: right 1+, left 2+. Triceps: 2+ bilaterally. Knee Jerk: right: 2+ and pendular. Ankle Jerk: 3+ bilaterally.

Healthy pareidolia where images inside clouds or images of constellations and star formations is a zeitgeist of imagination which is more intense in some cultures than others. Folie á deux is a shared delusional disorder and folie imposée is a subtype when the dominant or principal person forms a delusion and imposes it onto the secondary or associate person. If folie imposée pareidolia is spread from one member of a couple to the other, it suggests that the second individual may be overly empathic to the first due to the dominating nature of the principal individual; the associate individual may be passive and submissive and thus accepting these visual perceptions more willingly. Alternatively, the associate individual could already have pareidolia of visual images which subliminally influenced the principal individual to have them, and can be misinterpreted as the opposite. In this patient, the dominant person had a multitude of different delusions but the delusion of pareidolia was the one which transferred to the associate. It is unclear as to why it was this that transferred as opposed to the other delusions and further investigation in this realm is warranted.

Lithium remains to be the drug of choice for treating BPAD for the past few decades. There is extensive literature showing the effectiveness of Lithium when used as a mood stabilizing agent in bipolar spectrum disorders. However significant number of articles show that a third of the patients who receive lithium for their symptomology not only do not show any response but also may show deterioration of their clinical symptoms. (However, research shows that Lithium may negatively affect a third of the patients depending on various factors). The side effect profile of Lithium and especially its neurotoxic effects were discussed in depth in literature over the last decade. Although Lithium remains first choice as maintenance treatment for bipolar affective disorder, about half of all individuals may stop their treatment at some point, despite its proven benefits concerning the prevention of severe affective episodes and suicide.

The authors performed a systematic literature review to recognize the significance of negative effects of Lithium in a minority of patient population and also comment on the factors influencing patient compliance. We ran a literature search on Pubmed using the following terms: “Lithium” AND (“schizoaffective disorder [MeSH terms]” OR “Bipolar Affective disorder [MeSH terms]” ). Our inclusion criteria were studies which have observed effects of Lithium in schizoaffective patient population or bipolar affective patient population. Studies with other concurrent diagnoses were excluded.

We discuss a fifty nine year old male with a history of multiple admissions to a forensic hospital care setting. He initially endorsed a diagnosis of Psychotic disorder NOS which was later changed to schizoaffective disorder during his subsequent admissions. He presented with affective psychotic features where his mood was labile shifting from melancholic to euphoric and a concurrent history of auditory verbal hallucinations. He displayed paranoid non-bizarre persecutory delusions and also alleged that one of his doctors had hated him and put him on Lithium as a form of punishment. He claims that Lithium, as a result, has significantly affected him negatively and also damaged his nerves. This led the authors to explore the significance of use of Lithiumin people with schizoaffective disorders and also bipolar affective disorders. We also discuss the disease course in the patient and his clinical response to use of various psychotropic medications.

The case exemplifies the negative effects of Lithium when used as a mood stabilizer in patient population that is susceptible to its adverse effects due to various factors.