Post-traumatic dysgeusia with conversion of the taste of eggs rotten eggs has not heretofore been described.

Case Report: A 60 year old right handed female 6 months prior to presentation sustained head trauma. Three days later she noted reduced taste and smell dysgeusia to eggs. Eggs tasted distorted, like rotten eggs. Raw egg whites had no smell or taste. Cooked egg whites had faint sulfur smell for 2-3 seconds and the taste of sulfur. Yolk of soft-boiled eggs, had no smell or taste. The white had no smell but an unbearable sulfur taste. Raw eggs had no smell. The yolk of hardboiled eggs had no smell and taste, the whites smelled and tasted like sulfur. Sunny side up eggs with yolk and white segregated had no smell but tasted, as they should. Sunny side up eggs with yolk and white mixed together has no smell but strong sulfur taste. Scrambled eggs had no smell but mild sulfur taste, which changed over time to a rotten egg smell and taste. With nose clips, scrambled eggs had 0/10 taste, without the nose clips the smell of sulfur was 3/10.

Olfaction: Normosmia to threshold and Retronasal Smell Index: 2 (abnormal): Gustatation : Normogeusia to all. Mild hypogeusia to sodium chloride. MRI: Multiple foci of periventricular and deep white matter demyelization.

Rotten egg smell maybe mediated through retro-nasal pathways, since nasal obstruction eliminated the rotten egg taste. Eggs can possibly be developed as a home device to assess chemosensory function.

Parasitosis is a fixed belief of being infested with pathogens against all medical evidence [Freudenmann RW, Lepping P, 2009] Method: Case Report: A 53 year old right handed female presented with progressively severe BMS for 1 years. She noticed that aromas would project from her nose into her mouth and would experience this taste for days. Looking at the source of the odor would precipitate her to sense the smell of the product, immediately followed by the taste and then burning of the tongue, mouth and vagina. Fumes would eminent from her mouth, nose and anus. Five days prior she stopped eating and drinking. She had not brushed her teeth, showered, nor bathed for 3 weeks. Odors smell like ammonia and blood, which upon inhalation, effuse into her mouth which tastes like chemicals. Thereupon, she immediately experiences burning of her tongue and palate.

Abnormalities: Disheveled: Cacosmious. Personal hygiene poor. Facial expression odd and inappropriate. Loud but low quantity of speech. Unable to interpret similarities or proverbs. Calculation: poor.

In those who present with BMS, query as to the delusional nature of their symptoms is warranted and may suggest a treatment strategy.

Tardive dyskinesia (TD), a persistent and potentially disabling movement disorder, is associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Valbenazine (VBZ) is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults. Using data from two long-term phase 3 studies (KINECT 3 [K3], NCT02274558; KINECT 4 [K4], NCT02405091) and a rollover study (1506, NCT02736955), the long-term outcomes of once-daily VBZ on TD were examined in participants who received 40mg or had a dose reduction from 80 to 40mg.

The effects of VBZ 40mg (as well as VBZ 80mg) were evaluated in the following studies: the pivotal K3 study (6 weeks double-blind, placebo controlled), the extension phase of K3 (42 additional weeks of VBZ, 4 week discontinuation), and the open-label K4 study (48 weeks of VBZ, 4 week discontinuation). Completers from K3 extension and K4 were invited to participate in 1506 (up to 72 additional weeks of VBZ or until commercial availability of VBZ). Few participants reached Week 60 (n=4) or Week 72 (n=0) in the 1506 study before termination. Analyses focused on VBZ 40mg in two populations: pooled K3/K4 (participants who received VBZ 40mg throughout K3 or K4 or who had a dose reduction [80/40mg] during K3 or K4); and 1506 (participants who received VBZ 40mg from beginning of K3 or K4 to last visit in 1506 or who had a dose reduction [80/40mg] at any time). Outcomes for the K3/K4 population included mean change from baseline (CFB) in Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7) and AIMS response (≥50% total score improvement from baseline) at Week 48 of K3 or K4. Outcomes for the 1506 population included a Clinical Global Impression of Severity-Tardive Dyskinesia (CGIS-TD) score ≤2 (“normal, not at all ill” or “borderline ill”).

In the K3/K4 population, AIMS CFB to Week 48 indicated mean TD improvements in participants who received 40mg continuously (40mg, -5.7 [n=54]) and in those who had a dose reduction to 40mg (80/40mg, -6.2 [n=13]). In addition, a majority of these participants had an AIMS response after 48 weeks of treatment (40mg, 53.7%; 80/40mg, 53.8%). In the 1506 population, the percentage of participants who had a CGIS-TD score ≤2 (rating of “normal, not at all ill” or “borderline ill”) at Week 12 was 63.6% (7/11) in the 40mg group and 30.8% (4/13) in the 80/40mg group. Data from Weeks 24 to 60 of 1506 were limited by the small sample sizes (<10 participants each in 40mg or 80/40mg group at each of these visits).

Based on these analyses and results from published studies, VBZ 40mg may be an effective long-term option for some TD patients. Dose reductions from 80 to 40mg, if necessary, did not appear to compromise long-term benefit.

This study was sponsored by Neurocrine Biosciences, Inc.

Using the same DSM-5 criteria as in adults, BPD in adolescents is defined as a 1-year pattern of immature personality development with disturbances in at least 5 of the 9 domains listed in the DSM-5. BPD can now be reliably diagnosed as young as 13 using one of several standardized clinician, or self-rated diagnostic instruments. Unfortunately published US and Canadian positions regarding pharmacological treatment have been, With regard to evidence-based studies, pharmacological treatment is not recommended and, if ultimately required, should be limited to second-generation antipsychotics. Fortunately, the last decade s extensive advancements in brain-mapping have provided more clarity about the various brain dysfunctions underlying the symptoms/traits presenting in BPD, providing new opportunities to address these primarily Fronto-Limbic dysfunctions neuropharmacologically and potentially, significantly ameliorate. Thus, in turn, likely enhancing the effectiveness of the newer available therapies.

The current study explores the feasibility of more effectively managing BPD symptoms/traits with a unique medication protocol consisting of two medications; an anticonvulsant (oxcarbazepine) and a dopaminergic (amantadine HCl), without use of an antipsychotic medication.

Subjects were 147 females, ages 13-16, with the diagnosis of BPD treated with the described medication protocol in a residential facility. Positive outcome was described as achievement and maintenance of greater than 50% improvement from baseline admission state of functioning for 1 year. They were discharged when stable and having achieved greater than 50% improvement from baseline. Outpatient prescribers were requested to be compliant with the treatment protocol. However, some were non-compliant, substituting antipsychotic medication instead. Care givers were surveyed at 6 months and 1 year to determine whether their child was maintaining greater than 50% improvement.

The percent maintaining greater than 50% improvement was calculated for those whose caregivers reported continuation of the medications as prescribed, versus those whose prescribers changed the medications to the Community Standard. Of those compliant with the medication protocol, 61 of 86 (71%) maintained >50% improvement. Of those moved to the Community Standard approach, 19 of 61 (31%) maintained >50% improvement. Using Chi Square analysis, there was a significant relationship between maintenance of improvement and medication protocol compliance. Chi Square, Fisher’s exact test = p<0.001.

The results indicate that, for adolescents 1 year post-discharge from residential treatment for BPD, continuation of the above described medication protocol provides significantly higher rates of maintenance of achieved symptom improvement. Further controlled studies are needed.

None.

Antidepressant-induced hyponatremia/syndrome of inappropriate antidiuretic hormone (SIADH) can cause significant morbidity and mortality. Antidiuretic hormone release due to stimulation of central serotonin 5HT1C, 5HT2 and α-1 adrenergic receptors is thought to cause this adverse effect (Spigset, 1995). Evidence on which antidepressants are more likely to cause hyponatremia is inconsistent (Coupland, 2011; Leth-Moller, 2016). Owing to its uncommon use, there is limited and conflicting data on the risk of hyponatremia with Moclobemide, a reversible inhibitor of monoamine oxidase A (Mercier, 1997; Mazhar, 2019). There are few reports of hyponatremia induced by multiple antidepressant classes in the same patient.

To add to the literature on risk of hyponatremia with Moclobemide and other antidepressants.

We report a case of hyponatremia sequentially induced by multiple different antidepressant classes who was treated with Moclobemide with no recurrence of hyponatremia. We review existing literature on antidepressant-induced hyponatremia.

A 67-year-old man with a history of hypertension, dyslipidemia and gout was first diagnosed with major depressive disorder at age 50 after presenting with pervasive depressed mood, anhedonia, insomnia, poor concentration and feelings of worthlessness. Investigations found no medical causes of depression. His depression remitted on Venlafaxine 75mg/day with no hyponatremia induced. During a second depressive episode 4 years later, his serum sodium (Na) dropped from a normal baseline to 122mmol/L after Venlafaxine was restarted. He appeared euvolemic on physical examination. Investigations found no other causes of hyponatremia and were consistent with SIADH, which was attributed to Venlafaxine. His depression later remitted on Mirtazapine 30mg/day with no hyponatremia induced. During his third depressive episode at age 67, he developed hyponatremia (serum Na 123mmol/L) a week after restarting Mirtazapine. His clinical picture was consistent with SIADH. He later developed hyponatremia after initiating the following antidepressants sequentially: Fluvoxamine, Agomelatine, Nortriptyline, Bupropion. Hyponatremia resolved with fluid restriction and cessation of the implicated antidepressant each time before the next was initiated. He eventually tolerated Moclobemide 300mg/day with no recurrence of hyponatremia.

Agomelatine, Nortriptyline and Bupropion are reported to have a low risk of hyponatremia but were implicated in this case. Venlafaxine and Mirtazapine did not cause hyponatremia when first taken but were implicated when restarted after a period of cessation, underscoring the idiosyncratic nature of antidepressant-induced hyponatremia. Moclobemide can be considered for depressed patients with recurrent antidepressant-induced hyponatremia. Serum Na should be regularly monitored in patients taking antidepressants who are at high risk of hyponatremia.

In a study conducted in the database of a large commercial healthcare insurer, we previously demonstrated that use of a commercial pharmacogenetic assay for individuals with mood disorders was associated with decreased resource utilization and cost in the 6 month period following use compared to propensity-score matched controls. We conducted a post hoc analysis to understand variables associated with high cost savings.

The results and methods of the initial study have previously been described. Cases were individuals with mood and anxiety disorders who received a commercial pharmacogenetic assay (Genomind, King of Prussia PA) to inform pharmacotherapy. 817 tested individuals (cases) with mood and/or anxiety disorders were matched to 2745 controls. Overall costs were estimated to be $1,948 lower in the tested group. The differences were largely the result of lesser emergency room and inpatient utilization for cases. In the present analysis, cost difference for cases compared to their matched controls was rank ordered by decile. High cost savers were arbitrarily defined a priori as the top 20% of savers. Using multivariable modeling techniques, an ordinal logistic regression model was generated in which baseline or follow-up variables were statistically tested for independent associations with high, low, and no cost savings.

606 (74%) of cases were net cost savers compared to their controls (cost difference <0). High cost savers (n=121) saved on average $10,690 compared to their matched controls. They were statistically more likely to have been diagnosed with bipolar disorder (n=33/121) than low cost savers (n=57/485) or non-savers (n=31/211), and had a lower Charlson Comorbidity index. High cost savers had fewer mean number of antidepressants in the baseline period (mean=3.16) compared to non-savers (3.73) but more than low cost savers (2.72) (p<0.05 across groups). In a multivariable model, bipolar, count of antidepressants, outpatient visits, and inpatient visits were statistically associated with being a high cost saver; antidepressant count and all-cause inpatient and outpatient visits in the baseline period were inversely associated with cost savings.

Use of a pharmacogenetic assay was associated with cost-savings in the database of a large commercial insurer. Patients with bipolar disorder were more likely to be high cost savers than individuals with other mood and anxiety disorders.

Genomind

Is it in your differential diagnosis? Two Case Reports

Temporal Lobe Epilepsy (TLE), also referred as Complex Partial Seizures, is a medical diagnosis that must be considered in the pediatric, adolescent, and adult population presenting for psychiatric care. Mood disorders are common in people with epilepsy, with a prevalence rate of 20 to 50%. Scant literature exists that seeks specifically to enhance our knowledge of the similarities and subtle differences between TLE, Bipolar Disorder (BD) and Post Traumatic Stress Disorder (PTSD). Our objective is to describe an adolescent and adult case; one initially diagnosed as BD, the other PTSD, when in fact, it was TLE. We aim to illustrate that misdiagnosis and failure to diagnose are common. The provider must engage in a thorough review of systems and consider TLE in the differential diagnosis. A delay in the appropriate diagnosis and treatment can lead to a substantial amount of adverse effects and worsening of symptoms and negatively impact one’s quality of life.

Two case studies; an adolescent and one adult, diagnosed with BD and the other PTSD. Both endorsed a history of symptoms indicative of TLE. Key assessment findings and screening diagnostics alerted us to the differential diagnosis of TLE. The overlap of the symptom presentation is described.

TLE and many psychiatric conditions often present with overlapping symptoms. Patients have the potential to present with absence seizures, unprovoked irritability, oppositionality, aggression, anger, paroxysmal anxiety, somatic symptoms such as headaches, nausea, burning in the abdomen, stereotyped movements or behaviors, hypergraphia bizarre or incongruous affect, symptoms of fear, disturbed sleep, tearfulness, memory problems, déjà vu, fugue states, changes in cognition, inability to concentrate, fatigue, auditory and visual hallucination and bad temper.

Our differential diagnosis of TLE was confirmed with electroencephalogram (EEG). By prescribing the appropriate medications to these two individuals, they were able to experience improved moods, become more productive in society, working, attending church, family outings, etc. They were weaned off their antipsychotic medications, of which an abundance of troubling side effects is now a non-issue.

A delay in the proper diagnosis of TLE can have a significant negative impact on the adolescent and adult population. A need exists to educate mental health professionals on the overlap of symptoms of TLE and psychiatric disorders. The significant issue at hand is that they may not be receiving adequate or appropriate medications. Considering TLE in the differential diagnosis of presenting mood instability ensures our patients they are getting the basics of psychiatric care; which always emphasizes ruling out medical conditions first.

Choreaform movements provoked by opiates is an infrequent adverse event. Buprenorphine induction of chorea has not heretofore been described. Such a case is presented.

Case Study: A 38-year-old female presented with a decade long history of alcohol, cocaine, benzodiazepine, and heroin abuse. The patient was insufflating 1.5 grams of heroin daily. On presentation, she was actively withdrawing, scoring 17 on the Clinical Opioid Withdrawal Scale. Urine toxicology screening was positive for opiates, cocaine, and cannabinoids. Buprenorphine 4 mg sublingual was initiated. Within one hour, she observed, “My legs were moving uncontrollably as if I was a marionette.” These dance-like movements were isolated to both legs and gradually resolved after discontinuation of buprenorphine: most of the movements manifested in the first 8 hours, and dissipated over the next 2 days. She did have similar movements after treatment with quetiapine during a previous hospitalization, years earlier.

Abnormalities in physical examination: General: goiter, bilateral palmar erythema. Neurological examination: Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test: 2 (anosmia). Motor Examination: Drift testing: mild right pronator drift. Reflexes: 3+ bilateral lower extremities. Neuropsychiatric Examination: Clock Drawing Test: 3 (abnormal). Animal Fluency Test: 18 (normal). Go-No-Go Test 6/6 (normal).

Buprenorphine induced chorea could be a result of partial mu-opioid agonism, or kappa and delta receptor antagonism (Burke, 2018; Cowan, 1977). Mu-opioid receptor activation causes increased dopamine turnover in the nigrostriatum, which is responsible for locomotor sensitization (Campos-Jurado, 2017). With the addition of mu-opioid receptor modulation of dopamine release, kappa-opioid receptor alters various neurotransmitters in the basal ganglia, potentiating hyperkinetic movements. Buprenorphine’s choreiformogenic action may be due to kappa-opioid receptors ability to augment neurotransmission in the striatum (Escobar, 2017; Bonnet, 1998). The combination of simultaneous activity of these three opioid receptors may cause chorea, since they act to modulate dopamine, glutamate, and GABA in the direct and indirect pathways within the basal ganglia (Abin, 1989; Cui, 2013; Allouche, 2014; Trifilieff, 2013). This patient’s history of heroin and cocaine use may have caused supersensitization of dopamine receptors (Memo, 1981), provoking hyperkinesia. Involvement of substance-induced sensitization with concurrent kappa-opioid receptor neurotransmitter augmentation in direct and indirect pathways in the basal ganglia may have primed our patient to the development of chorea after buprenorphine administration. Further investigation for the presence of extrapyramidal movements in those undergoing buprenorphine treatment is warranted.

According to Nemeth et al. (2011), pediatric mania is difficult to distinguish from childhood hyperactivity. Both share 3 common symptoms: distractibility, motoric hyperactivity, and talkativeness (Biederman, 2000). 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. 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 (Nemeth et al., 2007). These children also performed poorly on measures of processing speed, and verbal learning and interference tasks (Henin et al., 2007). 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.

Anti-NMDA (N-methyl-D-aspartate) receptor encephalitis often presents itself in psychiatric settings as first-break psychosis. I present a case of a 31-year-old female who returned to the clinic one year after being treated for NMDA receptor antibody encephalitis.

Ms. C is a 31 y/o female who returned to the clinic after one year of being discharged from the hospital for NMDA-receptor encephalitis with positive serological NR1 antibodies. She was initially admitted to our inpatient psychiatric facility for an unspecified psychotic disorder complicated with seizure-like episodes. She was given various psychotropic medications without any improvement. She was moderately responsive to olanzapine and lorazepam. Her condition gradually worsened; she stopped communicating and became mute. Neurology consultation prompted work-up for encephalitis and the probable diagnosis of NMDA receptor encephalitis. She was subsequently treated with steroids, IVIG and then intrathecal rituximab and bortezomib. In addition to these aforementioned medications, she underwent a prophylactic oophorectomy and 10 ECT treatments for life threatening catatonia. After three weeks of this regimen, Ms. C recovered completely and was discharged home.

This case adds to literature that suggests prompt diagnosis and management of NMDA receptor encephalitis significantly improves prognosis. Treatment should be initiated if the patient meets probable diagnostic criteria for NMDA receptor encephalitis. Similar to other cases in the literature, our patient’s symptom of catatonia improved with ECT administration. During Ms. C one year follow-up, no evidence of psychotic symptoms were appreciated. Family members reported that she had returned to her baseline cognitive function.

In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The current open-label study evaluated the long-term efficacy and safety of deutetrabenazine in patients with TD.

Patients with TD who completed ARM-TD or AIM-TD could enroll in this open-label, single-arm extension study, titrating up over 6 weeks to a maximum total daily dose of deutetrabenazine 48 mg/day on the basis of dyskinesia control and tolerability. The proportion of Abnormal Involuntary Movement Scale (AIMS; items 1-7) responders was assessed based on response rates for achieving ≥50% improvement from baseline in the open-label extension study. AlMS score was assessed by local site raters for this analysis.

343 patients enrolled in the extension study. At Week 54 (n=249; total daily dose [mean ± standard error]: 38.6±0.66 mg), the mean percentage change from baseline in AIMS score was –40%; 48% of patients achieved a ≥50% response and 59% of those had already achieved a ≥50% response at Week 15. Further, 34% of those who had not achieved a ≥50% response at Week 15 achieved a ≥50% response at Week 54. At Week 106 (n=169; total daily dose: 39.6±0.77 mg), the mean percentage change from baseline in AIMS score was –45%; 55% of patients achieved a ≥50% response, 59% of those patients had already achieved a ≥50% response at Week 15, and 41% of those who had not achieved a ≥50% response at Week 15 but who reached Week 106 achieved a ≥50% response. At Week 132 (n=109; total daily dose: 39.7±0.97 mg), the mean percentage change from baseline in AIMS score was –61%; 55% of patients achieved a ≥50% response, 61% of those patients had already achieved a ≥50% response at Week 15, and 43% of those who had not achieved a ≥50% response at Week 15 but who reached Week 132 achieved a ≥50% response. Completer analysis suggests that long-term efficacy was not due to dose increases over time. Treatment with deutetrabenazine was generally well tolerated. There were 623 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) of adverse events of special interest were 0.01 for akathisia and restlessness, 0.07 for somnolence and sedation, 0.04 for parkinsonism, and 0.05 for depression.

Patients who received long-term treatment with deutetrabenazine achieved response rates that were indicative of clinically meaningful long-term benefit. Results from this open-label trial suggest the possibility of increasing benefit over time with individual dose titration of deutetrabenazine.

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

The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government.

Traumatic brain injuries (TBIs) have affected nearly 380,000 service members since 2000. Comorbid posttraumatic stress disorder (PTSD) may result from and/or exacerbate sequelae of mild TBI (mTBI) and is suspected to affect up to 65% of service members with TBI. Conventional treatments for mTBI/PTSD symptoms have limited efficacy and are associated with undesirable side effects. Repetitive transcranial magnetic stimulation (rTMS) has shown promise in treating PTSD symptoms and been identified as a potential mTBI therapy, but is untested as a therapy for comorbid mTBI/PTSD.

This double-blinded, prospective randomized, sham-controlled study consists of 30 treatment sessions 5 weeks of daily sessions followed by a two week taper of 3 and 2 sessions, respectively. Sessions consist of 3500 pulses administered to the left dorsolateral prefrontal cortex (dlPFC) at 10 Hz and 1500 pulses to the right dlPFC at 1 Hz. Approximately 60-80 participants will be randomized to receive active or sham rTMS. Primary outcome measures are the Posttraumatic Checklist 5 and the Rivermead Post-Concussion Questionnaire.

The study is ongoing, and 26 participants have been recruited to date. All patients were formally diagnosed with mTBI and reported moderate to severe PTSD symptoms. Preliminary data show no participants have withdrawn due to intolerability or indicated intolerability, despite the presence of minor discomforts such as headache. The majority of participants have been able to rest quietly or sleep during sessions, indicating high tolerability. Reported pain levels are low, with average ratings of 2.84/10.00 by week 2. One limitation was a high dropout rate.

This study aims to provide guidance as to whether rTMS is an efficacious therapy for comorbid mTBI/PTSD. Preliminary data indicates it to be a tolerable and safe therapy. Future research should consider decreasing the demand of the study on patients schedules, and performing a comparison to other mTBI/PTSD treatments to determine what treatment is more efficacious.

The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government.

Alzheimer s disease (AD) is a progressive neurodegenerative disease leading to cognitive decline and eventually death. Degradation of cortical neuroplasticity is thought to be a major catalyst of AD-related cognitive decline. Repetitive transcranial magnetic stimulation (rTMS), which uses pulsed magnetism to stimulate neurons, increases cortical plasticity and induces long-lasting neuroplastic changes. Patients have benefited from rTMS to treat AD, especially when done in conjunction with cognitive training exercises. This case report presents a 31-year-old male who tested positive for an autosomal dominant mutation implicated in early-onset AD. rTMS and cognitive training were employed to assist in the delay of early-onset AD manifestation in two cycles.

Prior to each treatment cycle, the patient completed questionnaires and interviews designed to test his cognitive functioning; his spouse was interviewed to provide a third-party assessment of his functioning. Following pre-treatment data collection, 30 daily rTMS/cognitive training sessions were completed in the first cycle and 35 daily rTMS/cognitive training sessions were completed in the second cycle. The bilateral dorsolateral prefrontal cortices each received 1,000 pulses (10 Hz, 110% SMT). Tolerability and side effect data were collected after each treatment. Immediately following rTMS, the patient played cognitive training games at our Brain Fitness Center. All pre-treatment assessments were repeated after completion of the 30 sessions in the first cycle and the 35 sessions in the second cycle for comparison of pre- to post-treatment cognitive functionality.

Pre-treatment testing indicated the patient was asymptomatic before each cycle. The patient completed 30 daily rTMS sessions in the first cycle and 35 daily rTMS sessions in the second cycle. Tolerability/side effect data showed he tolerated treatment well and experienced only minor pain. The patient also completed 30 cognitive training sessions in the first cycle and 35 cognitive training sessions in the second cycle and showed moderate improvement across all cognitive domains. Post-treatment assessments indicated no change in functioning except to note the patient s improved sleep. A third treatment cycle is scheduled to begin in February 2020.

This case report supports rTMS paired with cognitive training to be a safe and tolerable treatment for early-onset AD. However, more treatment cycles must be completed before conclusions about its efficacy can be determined.

Pharmacogenomics (PGx) testing, in particular combinatorial PGx testing, represents a potential means for delivering personalized treatment selection for patients with psychiatric disorders. The goal of this educational intervention was to educate clinicians about the role of PGx testing in neuropsychiatric conditions such as MDD, how these novel tests may be implemented into clinical practice, and how results may be used to inform decision-making.

Psychiatrists (n=830) participated in an online enduring CME activity on PGx testing in psychiatric disorders

• • The format was a 30-minute 2-person discussion (launched December 7, 2018)

• • Data from this activity were collected for 30 days after launch

• • Effectiveness of education for the CME activities was analyzed using 3 multiple-choice and 1 self-efficacy question (5-point Likert-type scale), presented as pre-/post-CME repeated pairs

• • A paired samples t-test was conducted to examine improvements in mean confidence pre and post

Participant knowledge, competence, and confidence change in pre- to post-CME responses were calculated

Overall, 72% of psychiatrists (n=830) had knowledge or competence that was reinforced or improved as a result of education.

• * 56% and 12% of psychiatrists had reinforcement and improvement, respectively, in knowledge related to the clinical benefits of PGx-guided treatment strategies

• • 61% and 8% of psychiatrists had reinforcement and improvement, respectively, in competence related to interpreting PGx tests for patients with neuropsychiatric disorders

• • Within the group of psychiatrists with reinforced and improved knowledge/competence, there was a 30% increase in their confidence using PGx tests to help guide treatment decisions for patients with major depressive disorder (MDD) (M pre=2.14, post=2.77, scale 1 to 5)

• • Confidence in the use of PGx testing was correlated with likelihood of considering PGx testing for patients with MDD

Online CME aided in psychiatrists’ knowledge, competence, and confidence in using pharmacogenomics testing in patients with psychiatric disorders.

Supported by an independent educational grant from Myriad Neuroscience, formerly Assurex Health

SEP-363856 is a novel psychotropic agent that has shown broad efficacy in animal models of schizophrenia and depression. Its antipsychotic effects appear to be mediated by agonist activity at both trace amine-associated receptor 1 (TAAR1) and 5-HT1A receptors. Notably, SEP-363856 does not bind to any dopaminergic, serotonergic (except 5-HT1A), glutamatergic, or other neuroreceptors thought to mediate the effects of currently available antipsychotics. The aim of this study was to evaluate the efficacy and safety of SEP-363856 in acutely symptomatic patients with schizophrenia.

Patients aged 18-40 years meeting DSM-5 criteria for schizophrenia (PANSS total score ≥80) were randomized, double-blind, to 4-weeks of flexible-dose SEP-363856 (50 or 75 mg/d) or placebo. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, and the Clinical Global Impressions-Severity (CGI-S) score. Change from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis.

Study treatment groups were similar at baseline: SEP-363856 (N=120; male, 64.2%; mean age, 30.0 years; PANSS total score, 101.4) and placebo (N=125; male, 63.2%; mean age, 30.6 years; PANSS total score, 99.7). Least-squares (LS) mean reduction from baseline to week 4 was significantly greater for SEP-363856 vs. placebo on the PANSS total score (-17.2 vs. -9.7; P=0.001; effect size, 0.45), PANSS positive subscale score (-5.5 vs. -3.9; P=0.019; effect size, 0.32), PANSS negative subscale score (-3.1 vs. -1.6; P=0.008; effect size, 0.37), PANSS general psychopathology subscale score (-9.0 vs. -4.7; P<0.001; effect size, 0.51), and the CGI-Severity score (-1.0 vs. -0.5; P<0.001; effect size, 0.52). Discontinuation rates for SEP-363856 vs. placebo were similar overall (21.7% vs. 20.8%) and due to an adverse event (8.3% vs. 6.4%). Change in weight, lipids, glucose and prolactin was similar in SEP-363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP-363856 or placebo (with SEP-363856 incidence higher than placebo) were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%). The proportion of patients who reported any extrapyramidal symptom was 3.3% on SEP-363856 and 3.2% on placebo.

In this placebo-controlled study, treatment with SEP-363856, a novel psychotropic agent, was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms as demonstrated by endpoint change in PANSS total and subscale scores, and CGI-Severity scores. Safety and tolerability findings for SEP-363856 were in general similar to placebo. In particular, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2 mechanism of action.

NCT02969382

Supported by funding from Sunovion Pharmaceuticals Inc.

Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults. Using data from a long-term study (KINECT 3; NCT02274558), the effects of once-daily valbenazine (40 mg, 80 mg) on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS) in participants who were early responders based on subjective measures, including patient self-report (Patient Global Impression of Change [PGIC]) or clinician judgment (Clinical Impression of Change-Tardive Dyskinesia [CGI-TD]).

Data from KINECT 3 (6-week double-blind, placebo-controlled [DBPC] period; 42-week double-blind extension) were analyzed post hoc. Long-term outcomes included mean change from baseline to Week 48 in AIMS total score (sum of items 1-7) and AIMS response (≥50% total score improvement from baseline) at Week 48. These AIMS outcomes were assessed in participants who achieved early improvement, defined as a PGIC or CGI-TD score of ≤3 (“minimally improved” or better) at Week 2 (first post-baseline visit of the DBPC period). Participants who initially received placebo were not included in the analyses.

In participants who received only valbenazine (40 or 80 mg) during KINECT 3 and had available Week 2 assessment, 50% (72/143) had early PGIC improvement (score ≤3) and 43% (61/142) had early CGI-TD improvement (score ≤3). Baseline characteristics were generally similar between participants who achieved early PGIC or CGI-TD improvement and those who did not. Based on available assessments at Week 48, mean AIMS total score change from baseline in participants with early PGIC improvement was similar to those who did not reach the early PGIC improvement threshold (-4.1 [n=35] vs -3.5 [n=41]). Mean AIMS total score change from baseline in participants with early CGI-TD improvement was similar to those who did not achieve early CGI-TD improvement (-4.2 [n=31] vs -3.5 [n=45]). AIMS response at Week 48 was also similar in those who achieved early PGIC and CGI-TD improvement (40% and 42%, respectively) compared to those who did not achieve early PGIC and CGI-TD improvement (39% and 38%, respectively).

Results from this long-term valbenazine trial indicate that many participants achieved at least minimal patient- and clinician-reported improvement at Week 2. AIMS outcomes at Week 48 demonstrated long-term reductions in TD severity regardless of early response. More research is needed to understand the association between early improvement and long-term treatment effects, but early non-improvement based on subjective measures may not be predictive of long-term treatment failure.

International Congress of Parkinson’s Disease and Movement Disorders; September 22-26, 2019; Nice, France.

This study was sponsored by Neurocrine Biosciences, Inc.

Valbenazine (VBZ) is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged antipsychotic exposure. Post hoc response and shift analyses were conducted using Abnormal Involuntary Movement Scale (AIMS) data from KINECT 4 (NCT02405091), a long-term open-label study in which participants received up to 48 weeks of open-label treatment with once-daily VBZ (40 or 80 mg).

KINECT 4 included participants who met the following criteria: ages 18 to 85 years; DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or mood disorder; neuroleptic-induced TD for ≥3 months prior to screening; stable psychiatric status (Brief Psychiatric Rating Scale score <50); no high risk of active suicidal ideation or behavior. Stable doses of concomitant medications to treat psychiatric and medical disorders were allowed. VBZ dosing was initiated at 40 mg, with escalation to 80 mg at Week 4 based on clinical assessment of TD and tolerability; a dose reduction to 40 mg was allowed if 80 mg was not tolerated. AIMS responses, ranging from ≥10% to 100% improvement from baseline in AIMS total score (sum of items 1-7), were analyzed at Week 48 based on scoring by site investigators. AIMS shift, conducted for each item (representing 7 different body regions), was defined as an improvement from a score ≥3 (moderate/severe) at baseline to a score ≤2 (none/minimal/mild) at Week 48.

103 participants had an available AIMS assessment at Week 48 (40 mg, n=20; 80 mg, n=83 [including 9 with a dose reduction]). At Week 48, 94.2% of participants had ≥30% total AIMS score improvement (40 mg, 90.0%; 80 mg, 95.2%) and 86.4% had ≥50% improvement (40 mg, 90.0%; 80 mg, 85.5%). The percentage of participants meeting the remaining AIMS response thresholds ranged from 9.7% (for 100% response) to 97.1% (for ≥10% response). In participants who had an AIMS item score ≥3 at baseline, shifts to a score ≤2 at Week 48 were as follows: 100% for lips, upper extremities, and lower extremities (VBZ 40 mg and 80 mg). Shift rates for the remaining regions were as follows (40 mg, 80 mg): face (100% [9/9], 96.9% [31/32]), jaw (100% [10/10], 97.6% [40/41]), tongue (100% [11/11], 97.9% [47/48]), trunk (87.5% [7/8], 88.9% [16/18]).

After 48 weeks of treatment with once-daily VBZ (40 or 80 mg), >85% of KINECT 4 participants had a clinically meaningful AIMS response (≥30% total score improvement), a robust AIMS response (≥50% total score improvement), or an AIMS shift (from item score ≥3 at baseline to score ≤2 at Week 48). These results suggest that VBZ is an appropriate long-term treatment for many adults with TD.

This study was sponsored by Neurocrine Biosciences, Inc.

SUSTAIN-2 (NCT02497287) was an open-label, phase III trial evaluating the safety of esketamine (ESK) nasal spray plus a newly initiated oral antidepressant (AD) for up to 1 year in adults with treatment-resistant depression (TRD). ESK is a schedule III drug that acts via glutamate receptor modulation. ESK is rapidly cleared from the plasma, and with intermittent dosing there is no accumulation. Thus, no withdrawal syndrome is expected. The current analysis assessed potential withdrawal symptoms in patients who discontinued ESK after long-term, intermittent use. In the absence of a glutamatergic-specific withdrawal scale, the Physicians Withdrawal Checklist1 (PWC-20) was used. The PWC-20 was designed to assess new or worsening benzodiazepine-like discontinuation symptoms after stopping non-SSRI anxiolytics.

ESK nasal spray was administered two times per week during a 4-week induction phase (IND). Responders entered the optimization/maintenance phase (O/M) where ESK nasal spray was dosed either weekly or every two weeks for up to 48 weeks. Patients entered a 4-week follow up period (F/U) after discontinuation from either phase, during which continuation of the AD was recommended. PWC-20 assessments were conducted at the last ESK dosing (endpoint of IND or O/M) and at weeks 1, 2 and 4 of F/U. Symptoms were rated using a 0-3-point scale (Not present = 0, Mild = 1, Moderate = 2, Severe = 3). To account for worsening of underlying depression, subset calculations were performed for depressive symptoms (PWC-DS: loss of appetite; anxiety or nervousness; irritability; dysphoric mood or depression; insomnia; fatigue, lethargy or lack of energy; restlessness or agitation; headaches; muscle aches or stiffness; weakness; difficulty concentrating or remembering; depersonalization-derealization) and withdrawal symptoms (PWC-WS: nausea and/or vomiting; diarrhea; poor coordination; diaphoresis; tremor or tremulousness; dizziness or light-headedness; increased acuity of sound, smell, or touch; paresthesias).

Data on 357 patients entering F/U were included in the analysis (91 completed treatment during the IND phase and 141 were treated during O/M). The mean (SD) PWC-20 total scores (range 0-60) at treatment endpoint, Week 1, 2 and 4 were 7.2 (6.8), 7.5(7.0), 7.4 (7.1) and 7.2 (6.9), respectively. At these same assessment times, mean PWC-WS scores (range 0-24) were 0.9 (1.7), 1.0 (1.7), 1.0 (1.8), and 0.9 (1.8). Mean PWC-DS scores (range 0-36) were 6.3 (5.6), 6.5 (5.7), 6.5 (5.8), and 6.3 (5.7), respectively. Complete analysis of data from the entire SUSTAIN-2 dataset will be presented.

No indication of drug-specific withdrawal symptoms was seen after stopping up to 1-year of intermittent treatment with ESK nasal spray for TRD.

Janssen Research and Development