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

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.

There is a plethora of drugs available to psychiatrists for treatment of mental illness, which can vary in efficacy, tolerability, metabolic pathways and drug-drug interactions. Psychotropics are the second most commonly listed therapeutic class mentioned in the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling. Pharmacogenomic (PGx) assays are increasingly used in psychiatry to help select safe and appropriate medication for a variety of mental illnesses. Our commercial laboratory offers PGx expert consultations by PharmDs and PhDs to clinician-users. Our database contains valuable information regarding the treatment of a diverse and challenging population.

Genomind offers a PGx assay currently measuring variants of 24 genes relevant for selection of drugs with a mental illness indication. Since 2012 we have analyzed > 250,000 DNA samples. Between 10/18 - 8/20 6,401 reports received a consult. The data contained herein are derived from those consults. Consultants record information on prior meds, reason for failure or intolerability, potential risk-associated or useful drugs based on the genetic variants. Consultants only recommend specific drugs and doses consistent with a published PGx guideline.

The 5 most commonly discussed genes were SLC6A4, MTHFR, CACNA1C, COMT and BDNF. The 3 most commonly discussed drugs were fluoxetine, lithium and duloxetine. The most common reasons for drug failure were inefficacy and drug induced “agitation, irritability and/or anxiety”. SSRIs were the most common class of discontinued drug; sertraline, escitalopram and fluoxetine were the three most commonly reported discontinuations and were also the 3 most likely to be associated with “no improvement”. Aripiprazole was the most commonly reported discontinued atypical antipsychotic. The providers rated 94% of consultations as extremely or very helpful at the time of consult. An independent validation survey of 128 providers confirmed these ratings, with 96% reporting a rating of “very helpful” or “extremely helpful”. In addition, 94% reported that these consults were superior to PGx consults provided through other laboratories. Patient characteristics captured during consults via a Clinical Global Impressions-Severity (CGI-S) scale revealed that the majority of patients were moderately (54%) or markedly ill (23%). The most frequent symptoms reported were depression, anxiety, insomnia and inattentiveness.

The large variety of psychotropic drugs available to providers, and their highly variable response rates, tolerability, capacity for drug-drug interactions and metabolic pathways present a challenge for even expert psychopharmacologists. Consultation with experts in PGx provides additional useful information that may improve outcomes and decrease healthcare resource utilization. This database may provide future opportunities for machine learning algorithms to further inform implications of included gene variants.

Genomind, Inc.

Pixelated vision or visual snow has been associated with schizophrenia (Silverstein 2011). The impact of viewing a 3D motion picture on such a visualphenomenon has not heretofore been described.

Case Study: A 28 year old right handed single male three years prior to presentation noticed that all his vision was pixelated. The pixelated vision is panoramic, involving the entire visual field. The pixels are characterized by 10,000 flat white and gray dots measuring 1mm x 1mm. No changes in color, shape, or size were noted in high and low intensity light. White, dark, gray, or multicolored backgrounds had no effect on his vision. The visual distortions are not impacted by head movements, emotions, degree of tiredness, driving, or his hedonic perception of the object being visualized. The pixels were noted to disappear upon closure of both eyes but persisted during monocular vision with either eye. These visual hallucinations were sporadic during the first year and became continuous over the following two years. Two weeks after onset ofpixelated vision he developed auditory hallucinations and hyperacusis. These increased in intensity and frequency to 500-600 times per day. He denied palinopsia, migraines, tinnitus, and photophobia. These hallucinations persisted despite treatment with aripiprazole, paliperidone, lurasidone, olanzapine, clozapine, ziprasidone, benztropine, bupropion, lamotrigine, modafinil, trazodone, atomoxetine, and amphetamine.

Abnormalities in Examination: Hypoverbal, blunted affect, impaired concentration, preoccupied with racing thoughts. Admitted to actively having auditory and visualhallucinations, without suicidal or homicidal ideations. Memory testing: Able to recall 2 out of 4 objects in 3 minutes and 3 out of 4 with reinforcement. Similarities interpreted concretely. Visual Acuity: 20/20 OU. Retinal examination: Normal. Intraocular Pressure: 19 mm OD, 20 mm OS (normal). Automotive Perimetry Testing: Normal. Cover/Uncover: Normal. Near Convergence: 3 inches (normal). Lens or filtered prism have no effect on visual snow. MRI of his brain, EEG, BAER, liver function tests, CBC, vitamin B12, folate, and thyroid function tests were normal. MRA: mild hypoplasia of distal right vertebral artery.

Visual snow has been anecdotally described as static, continuous, and independent of the specific visual environment (McKendrick, 2017). However, thepersistence of visual snow in the presence of 3D movies has never been reported. The visual snow paralleled auditory hallucinations and hyperacusis in frequency and intensity, which suggests there may be generalized hyperexcitability of the brain inducing both auditory and visual hallucinations. Agents that reduce cortical hyperexcitability (i.e., anticonvulsants, anxiolytics) may have efficacy. Treatment with these agents has been described (Ghannam, 2017), warrants further investigation.

No funding.

The Dextroamphetamine Transdermal System (d-ATS) was developed as an alternative to oral amphetamine (AMP) formulations for ADHD. In a pivotal study, d-ATS met primary and secondary efficacy endpoints for ADHD in children and adolescents. Study subjects wore d-ATS for 9 hours, and an improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham scale (SKAMP) total score was observed from 2 through 12 hours after application. Patients with ADHD may need varying durations of treatment for symptoms from day to day. This analysis describes the exposure-response (E-R) relationship for d-ATS and explores possible outcomes for wear times ≤9 hours under varying assumptions.

A population pharmacokinetic (PK) model was developed to describe AMP disposition following d-ATS administration. This model was used to construct a population pharmacokinetic/pharmacodynamic (PK/PD) model from SKAMP total score data from two pediatric clinical studies to characterize onset and duration of effect after d-ATS administration. The integrated PK/PD model was used to describe the d-ATS E-R relationship and simulate the potential onset and duration of effect of d-ATS in response to various removal times (when <9 hours) by utilizing SKAMP scores as the efficacy measure. Subject-level AMP PK and SKAMP profiles were simulated for d-ATS removal at 4–9 hours post-application under different assumptions for AMP absorption after early patch removal. Modifications were made to the original population PK model to simulate patch removal.

Data from 81 children and 41 adolescents, 6–17 years old, were included. The model provided a reasonable description of the SKAMP score over time, showing an initial decline ~2 hours after patch application. In approximately 50% of children and adolescents, the maximum decline in SKAMP scores was observed within the first 4 hours after patch application. Earlier simulated d-ATS removal times were associated with reduced systemic exposure and earlier return to near-baseline scores across the range of assumptions tested.

Under different assumptions, the graphs changed modestly but not dramatically. For example, with moderate/conservative assumptions, following a 9-hour wear time, SKAMP scores returned to within 90% of baseline value in ~49% of subjects by 12 hours and ~80% of subjects by 16 hours. Following a 4-hour wear time, percentages were ~74% by 12 hours and ~95% by 16 hours.

Simulation results suggest that the duration of d-ATS efficacy may be related to wear time, which can be adjusted according to treatment needs, consistent with published observations for another transdermal stimulant. The d-ATS patch provides the ability to control medication exposure by shortening wear time, allowing treatment duration to be individualized and optimized in ADHD patients who have varying schedules and needs.

Noven Pharmaceuticals, Inc.

Pediatric psychiatric inpatients are among the most vulnerable individuals in society. While the use of seclusion and restraint is well chronicled in the field of research in this population, there is limited literature describing the effects, meaning, and attitudes of mandating the wear of clothing in hospital settings. This research explores the phenomenon of the practice of mandatory wear of hospital-issued clothing and its meaning to patients and the awareness and attitudes of this practice among staff caring for this population. This research aims to improve understanding of the experiences of patients regarding this practice at a large, urban hospital providing care for children using a mixed methods design. A qualitative, descriptive phenomenological analysis was conducted through individual interviews with adolescent patients (N = 5) on an inpatient psychiatric unit. Additionally, a cross-sectional self-reported questionnaire examined the awareness and attitudes toward this practice among unit staff (N = 41). The patients’ attitudes toward clothing restrictions was predominantly negative, noting a lack of self-expression, feeling like a mental health patient, desires to wear ones’ personal clothing, and feelings of shame and punishment. Among the staff there was a modest correlation between age, number of years practicing as a health professional, and years practicing in a pediatric setting with feelings of a need for a change in the clothing policy to allow patients to wear their own clothing on admission. Staff age and number of years working at the institution demonstrated a modest correlation between awareness of legal statutes regarding patients’ rights to their own clothing. This research found a readiness among staff to adopt a clothing policy that would permit patients to wear their own clothing on admission, which would improve the negative experiences described among the patients in the sample.

No Funding

Conventional treatment methods have limited effectiveness in addressing late-life depression (LLD) that does not respond well. While a new approach called priming repetitive transcranial magnetic stimulation (rTMS) has shown promise in treating depression in adults, its effectiveness in LLD has not been explored. This study aimed to investigate the impact of priming rTMS on LLD.

This study investigated the effectiveness of priming rTMS in 31 patients with LLD who did not improve after an adequate trial of antidepressants. Patients were randomly assigned to receive either active priming rTMS or sham priming rTMS. Active priming rTMS was delivered over the right dorsolateral prefrontal cortex for 10 sessions, lasting 31 minutes each, over a period of 2 weeks.

The group receiving active priming rTMS demonstrated greater improvements in scores on the Hamilton Rating Scale for Depression (p < 0.037; partial η2 0.141) and the Geriatric Depression Rating Scale (p < 0.045; partial η2 0.131) compared to the sham priming group, with a mild effect size. At the end of the second and fourth weeks, the priming rTMS group achieved a response rate of 50%, while the sham priming group had response rates of 26.7% and 6.7%, respectively. No adverse effects requiring intervention were observed.

Priming rTMS is well-tolerated for the treatment of LLD and not only reduces the severity of depression but also maintains the achieved response over time.

Chorea is defined as a hyperactive movement disorder associated with involuntary, quick, and unpredictable muscle contractions of the limbs, face, and trunk. The unpredictable nature of these movements includes variation in speed, timing, and direction of movement. A wide variety of medications, medical conditions and illicit drugs have been associated with movement disorders. Examples include a multitude of antipsychotic induced movement disorders and dyskinesia related to dopaminergic agents, like levodopa and metoclopramide. Dyskinesias have been associated with psycho-stimulant use, such as methylphenidate. However, most cases reported were associated with large doses or chronic use. Aside from dyskinesia, methylphenidate is known to be associated with tic disorder, tremor, and muscle spasm. However, this case reported is unlike any of the above described and involved the development of chorea after only 2 days of moderate doses of methylphenidate, in a patient on chronic methadone maintenance treatment, with successful arrest of symptoms following discontinuation of the methylphenidate.

A 47-year-old female was admitted to our hospital after presenting to the emergency department with 1 week of violent flailing movements. The ballistic flailing movements started acutely after 2 days of initiating methylphenidate in addition to her chronic methadone treatment and 2-week period of initiation of paroxetine. Lab work showed normal CBC, CMP, CRP, CK, and TSH. Urine drug screen, CT angiography of the head, and Huntington’s disease testing were all unremarkable, suggesting a decreased likelihood of illicit drugs, traumatic brain injury, or Huntington’s disease etiologies. Confirmation of the diagnosis was made as the chorea symptoms abruptly resolved upon discontinuation of methylphenidate and administration of intravenous Benadryl. The patient has been on methadone alone for 11 months and methylphenidate alone 2 years back with no involuntary movements or any similar presentation that shows the possibility of drug interaction through cytochrome P450 metabolism between Methylphenidate and methadone.

We are presenting a rare case report that adds on to the scarce literature on methylphenidate-induced chorea. It also challenges the consulting psychiatrists to broaden their differential diagnosis for acute onset of choreiform movement disorders. This unique case intrigues the thought process to consider the interaction of methylphenidate in the presence of cytochrome P450 2D6 and 3A4 inhibitors like methadone.

To examine the effect of esketamine nasal spray (ESK) plus newly initiated oral antidepressant (OAD) versus OAD plus placebo nasal spray (PBO) on the association between Montgomery–Åsberg Depression Rating Scale (MADRS) and 9-item Patient Health Questionnaire (PHQ-9) scores in adults with treatment-resistant depression (TRD).

Data from TRANSFORM-1 and TRANSFORM-2 (two similarly designed, randomized, active-controlled TRD studies) and SUSTAIN-1 (relapse prevention study) were analyzed. Group differences for mean changes in PHQ-9 total score from baseline were compared using analysis of covariance. Associations between MADRS and PHQ-9 total scores from TRANSFORM-1/TRANSFORM-2 were assessed using simple parametric, nonparametric, and multiple regression models.

In TRANSFORM-1/TRANSFORM-2 (ESK + OAD, n = 343; OAD + PBO, n = 222), baseline PHQ-9 mean scores were 20.4 for ESK + OAD and 20.6 for OAD + PBO (severe depression). At day 28, significant group differences were observed in least squares mean change (SE) in PHQ-9 scores from baseline (−12.8 [0.46] vs −10.3 [0.53], P < .001) and in clinically substantial change in PHQ-9 scores (≥6 points; 77.1% vs 64%, P < .001) in ESK + OAD and OAD + PBO groups, respectively. A nonlinear relationship between MADRS and PHQ-9 was observed; total scores demonstrated increased correlation over time. In SUSTAIN-1, 57.3% of patients receiving ESK + OAD (n = 89) versus 44.2% receiving OAD + PBO (n = 86) retained remission status (PHQ-9 score ≤4) at maintenance treatment end point (P = .044).

In adults with TRD, ESK + OAD significantly improved severity of depressive symptoms, and more patients achieved clinically meaningful changes in depressive symptoms based on PHQ-9, versus OAD + PBO. PHQ-9 outcomes were consistent with those of clinician-rated MADRS.

ClinicalTrials.gov: NCT02417064, NCT02418585, NCT02493868.