The approval of valbenazine (INGREZZA; VBZ) for the treatment of tardive dyskinesia (TD) in adults was based on results from double-blind, placebo (PBO)-controlled trials. These studies demonstrated the efficacy of once-daily VBZ based on intent-to-treat analyses. However, because many different types ofpatients can develop TD, subgroup analyses describing treatment outcomes by various patient factors were also conducted.

Data were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558), with outcomes analyzed by VBZ dose (80 mg, 40 mg) and PBO. Descriptive analyses conducted using the Abnormal Involuntary Movement Scale (AIMS) total score included: mean change from baseline to Week 6; and AIMS response, defined as 50% improvement from baseline to Week 6. Subgroups were defined as follows: age (<55 years, ≥55 years), sex (male, female), psychiatric diagnosis (schizophrenia/schizoaffective disorder, mood disorder), CYP2D6 genotype (poor metabolizer [PM], non-PM), body mass index (BMI) (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2), concomitant antipsychotic (yes, no); type of antipsychotic (atypical, typical/both); lifetime history of suicidality (yes, no); concomitant anticholinergic (yes, no); TD duration (<7 years, ≥7 years).

The pooled population included 373 participants (VBZ 80 mg, n=101; VBZ 40 mg, n=114; PBO, n=158). Mean improvements from baseline to Week 6 in AIMS total score were greater overall with VBZ compared to PBO. Within subgroup categories, AIMS score improvement with VBZ 80 mg (recommended dose) was greater in CYP2D6 PMs (n=17; 80 mg, -6.8; 40 mg, 2.4; PBO, 0.5), participants taking no concomitant antipsychotics (n=64; 80 mg, -4.9; 40 mg, -3.0; PBO, 0.0), and overweight participants (BMI 25 to <30 kg/m2, n=115; 80 mg, -4.2; 40 mg, 2.7; PBO, -0.7). Overweight participants also had the highest AIMS response rates at Week 6 (80 mg, 57.7%; 40 mg, 31.6%; PBO, 11.8%), followed by participants taking typical/both antipsychotics (n=67; 80 mg, 57.1%; 40 mg, 20.0%; PBO, 25.0%), and those taking anticholinergics (n=126; 80 mg, 52.9%; 40 mg, 22.7%; PBO, 6.3%).

These preliminary analyses indicate that TD improvements were generally greater with VBZ than PBO across most subgroups. However, the small sizes of some subgroups may need to be considered when interpreting results. Additional analyses within subgroup categories are ongoing and will be presented at the meeting.

This study was funded by Neurocrine Biosciences, Inc.

Extrapyramidal symptoms (EPS), including tardive dyskinesia (TD), may result from exposure to antipsychotics. TD is often irreversible, may be debilitating, and cause additional burden to patients with underlying psychiatric conditions.

To assess the impact of developing TD, both with and without other EPS, on healthcare resource utilization (HRU).

Data on patients receiving antipsychotics who had schizophrenia, major depressive disorder, or bipolar disorder were extracted from a Medicaid claims database. Patients from the TD cohorts (TD+EPS and TD non-EPS) were matched to those in the non-TD/EPS cohort at ∼1:5 ratio. HRU outcomes associated with TD were assessed.

TD+EPS (n=289) and TD non-EPS (n=394) cohorts were matched with 1398 and 1922 control patients, respectively. The percentage of patients with all-cause and mental disorder-related inpatient admissions increased from baseline to follow-up in the TD+EPS (12.8% and 12.5%, respectively) and TD non-EPS (16.0% and 13.5%) cohorts, in contrast with slight decreases (∼3%) in matched controls. A higher percentage of patients in the TD cohorts had medical admissions/visits and claims for drugs that might be used to address TD or EPS than their matched controls at baseline and follow-up. The within-cohort change from baseline to follow-up in the use of potential drugs for TD or EPS was similar between the TD cohorts and their matched controls; however, both TD cohorts exhibited a larger increase in crisis–non-specific psychotherapy services versus matched controls.

Results demonstrated increased HRU in TD patients with or without other pre-existing EPS, compared with matched controls.

Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.

This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

Tardive dyskinesia (TD), an often-irreversible movement disorder typically caused by exposure to antipsychotics, most commonly affects the face, mouth, and tongue and may be debilitating

To investigate TD burden on patients’ quality of life and functionality

Adults with clinician-confirmed schizophrenia, bipolar disorder, or major depressive disorder participated in an observational study. Approximately half (47%) ofparticipants had a clinician-confirmed TD diagnosis. Participants completed the SF-12v2 Health Survey® (SF-12v2), Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), social withdrawal subscale of the Internalized Stigma of Mental Illness scale (SW-ISMI), and rated the severity of their TD symptoms. Group differences in SF-12v2 physical and mental component summaries (PCS and MCS), Q-LES-Q-SF, and SW-ISMI scores were analyzed.

TD (n=79) and non-TD (n=90) groups were similar in age, gender, and number of patients with schizophrenia, bipolar disorder, and major depressive disorder. TD patients reported significantly worse scores on PCS (P=0.003), Q-LES-Q-SF (P<0.001) and SW-ISMI (P<0.001) than non-TD patients. The difference in PCS exceeded the established minimal clinically important difference (MCID) of 3 points. When stratified by TD severity, those with more severe symptoms had significantly worse Q-LES-Q-SF (P<0.001) and SW-ISMI (P=0.006) scores than those with less severe symptoms. Differences in PCS (P=0.12) and MCS (P=0.89) were in the expected direction and exceeded the MCID.

Among patients with psychiatric disorders, TD is associated with significant physical health burden and incremental mental health burden. TD severity is also associated with lower overall quality of life and greater social withdrawal.

Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.

This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

To assess physicians’ current knowledge, skills, competence, and practice barriers regarding tardive dyskinesia (TD) and assess continuing medical education (CME) needs.

A 29-question clinical practice assessment survey instrument consisting of multiple-choice knowledge and case-based questions was administered online to gather abaseline “snapshot” of knowledge, skills, attitudes, and competence on TD epidemiology, risk factors, diagnosis, current guideline-based management, and emerging management strategies

The survey launched online on a website dedicated to continuous professional development on July 25, 2016, and was made available to healthcare providers without monetary compensation or charge. Data were collected through August 28, 2016

Confidentiality was maintained and responses were de-identified and aggregated prior to analyses

Data were collected for the 1157 psychiatrists and 177 neurologists who responded to all survey questions during the study period. The findings were:

• ∙ Epidemiology: 62% of psychiatrists and 68% of neurologists were aware that TD affects approximately 20% of patients treated with neuroleptic agents

• ∙ Risk factors: 63% of psychiatrists and 67% of neurologists were aware of risk factors for TD, such as older age

• ∙ Diagnosis: 93% of psychiatrists and 71% of neurologists were aware that Abnormal Involuntary Movement Scale (AIMS) can be used to support diagnosis of TD

• ∙ Guidelines: 21% of psychiatrists and 11% of neurologists were aware of the American Psychiatric Association guidelines for monitoring of TD, and 56% of psychiatrists and 42% of neurologists were aware of the American Academy of Neurology guidelines on treatment of TD

New/emerging treatments: 24% of psychiatrists and 34% of neurologists were aware of the mechanisms of action of new/emerging treatments for TD, and 54% and 44%, respectively, were aware of the clinical data for valbenazine

This educational research yielded important insights into clinical practice gaps in TD, indicating that both psychiatrists and neurologists would benefit from continuing medical education on epidemiology, risk factors, diagnosis, guideline-based care, and information on how to incorporate new/emerging treatments for TD into practice.

The educational activity and outcomes measurement were funded through an independent educational grant from Neurocrine Biosciences, Inc.

To determine if online continuing medical education (CME) could improve knowledge, competence, and confidence of psychiatrists and primary care physicians (PCPs) in managing patients with major depressive disorder (MDD) and co-occurring hypomanic/manic features.

• ∙ Physicians participated in a 1-hour text-based, online CME activity composed of 2 patient cases with interactive questions related to diagnosis, assessment, and management of various presentations of MDD

• ∙ Evidence-based educational feedback was provided following each answer

• ∙ Effects of CME were assessed using a repeated-question pairs pre- to post-assessment study design where individual participants served as his/her own control

• ∙ The assessment included 3 multiple-choice knowledge/competence questions and 1 self-efficacy question that rated confidence in managing MDD with mixed features on a 5-point Likert Scale

• ∙ For all questions combined, McNemar’s chi-square test assessed the differences from pre- to post-assessment

• ∙ P values measured significance; P values <.05 were considered statistically significant

• ∙ Effect size was calculated using Cramer’s V by determining the change in proportion of participants who answered questions correctly from pre- to post- assessment

• ∙ Survey data were collected from December 8th, 2016, to January 24th, 2017.

• ∙ Data set included responses from 1454 psychiatrists and 488 PCPs who completed all assessment questions during the study period

• ∙ Psychiatrists: Knowledge/competence improved (P<.001; V=0.54; large educational effect) following participation in the CME activity:

  1. ° While 5% answered all 3 questions correctly on pre-assessment, 70% answered them all correctly on post- assessment, with the largest increases on accurate differentiation between possible signs of mania and depression, accurate diagnosis of bipolar depression, and ability to select treatments for MDD with mixed features

  2. ° 20% reported being more confident in their ability to select treatments for various presentations of mood disorders

• ∙ PCPs: Knowledge/competence improved (P<.001; V=0.49; large educational effect) following participation in the CME activity:

  1. ° While 2% answered all 3 questions correctly on pre-assessment, 48% answered them all correctly on post-assessment, with the largest increases on accurate differentiation between possible signs of mania and depression, accurate diagnosis of bipolar depression, and ability to select treatments for MDD with mixed features

  2. ° 24% reported being more confident in their ability to select treatments for various presentations of mood disorders

Online CME in a clinically relevant interactive case-based format can improve knowledge, competence, and confidence in management of various presentations of mooddisorders and better equip physicians to recognize key features, accurately diagnose, and treat the complex spectrum of this patient population.

The educational activity and outcomes measurement were funded through an independent educational grant from Sunovion Pharmaceuticals Inc.

In this study the authors focus on reviewing imaging studies that used resting state functional magnetic resonance imaging for individuals with a history of heroin use. This review study compiled existing research addressing the effect of heroin use on decision making by reviewing available functional neuroimaging data. Systematic review ofthe literatures using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Eligible articles were retrieved through a computer-based MEDLINE and PsycINFO search from 1960 to December 2015 using the major medical subject headings “heroin, fMRI” (all fields). Only English language was included. Thirty-seven articles were initially included in the review. Sixteen were excluded because they did not meet the inclusion criteria. The results of 21 articles that met all the inclusion criteria were presented. Based on the 21 studies included in the current review, there is evidence that heroin use may have a direct and damaging effect on certain brain functions and that these changes may be associated with impulsive and unhealthy decision making. From the review of these studies, the authors understand that a longer duration of heroinuse may be associated with more damaging effects on brain functions. The authors also understand that these brain changes could last long after abstinence, which may increase the risk of relapse to heroin use. More research is needed to create a biomarker map for patients with heroin use disorder that can be used to guide and assess response to treatment.

No funding.

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.

Tardive dyskinesia (TD) is an involuntary movement disorder resulting from exposure to dopamine-receptor antagonists. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.

To evaluate the efficacy and safety of long-term deutetrabenazine therapy in patients with TD.

Patients with TD who completed the ARM-TD or AIM-TD studies were eligible to enter this open-label, single-arm, long-term safety study after they completed the 1-week washout period and final evaluation in the blinded portion of the trial. Efficacy endpoints included the change in AIMS score from baseline, and treatment success (defined as “much improved” or “very much improved”) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC). This analysis reports results up to Week 54.

304 patients enrolled in the extension study. At Week 54, the mean (standard error) change in AIMS score was –5.1 (0.52). After 6 weeks of deutetrabenazine treatment, the proportion of patients who achieved treatment success was 58% per the CGIC and 53% per the PGIC, and by Week 54 was 72% per the CGIC and 59% per the PGIC, thus demonstrating maintenance or enhancement of benefit over time. Deutetrabenazine was well tolerated for up to 54 weeks, and compared with the ARM-TD and AIM-TD studies, no new safety signals were detected.

54 weeks of deutetrabenazine treatment was generally efficacious, safe, and well tolerated in patients with TD.

Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.

This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

The efficacy of valbenazine (INGREZZA) in tardive dyskinesia (TD) was demonstrated in placebo-controlled clinical trials, based on the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). In these trials, mean changes in the AIMS total score were significantly greater with valbenazine 80 mg than with placebo. Currently, no minimal clinically important difference (MCID) has been established for the AIMS total score in patients with TD. Using valbenazine trial data, analyses were conducted to establish a MCID for AIMS total score in TD.

Data were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558). Using the Clinical Global Impression ofChange (CGI-TD) as an anchor comparison, AIMS total score changes from baseline to Week 6 were summarized for all study participants (pooled valbenazine and placebo groups) with a “minimal” CGI-TD score of ≤3 (minimally improved or better) or “robust” ≤2 (much improved or better) at Week 6.

In the pooled population (N=373), 72% and 29% of all participants had CGI-TD scores of ≤3 and ≤2, respectively. The median (maximum, minimum) change from baseline in AIMS total score at Week 6 was -2 (-13, 8) in participants with CGI-TD score ≤3 and -3 ( 13, 8) in participants with a score ≤2.

Pooled data from 3 randomized, double-blind, placebo-controlled trials suggest that a 2 point decrease in AIMS total score may represent the minimal clinically meaningful improvement. Larger AIMS score improvements were associated with “much improved” or “very much improved” CGI TD assessments.

This study was funded by Neurocrine Biosciences, Inc.

The purpose of this project was to systematize the use of pharmacogenetic testing (PGT) among psychiatric prescribers. The use of PGT in clinical practice is inconsistent despite the evidence supporting its efficacy (Burke, Love, Jones, & Fife, 2016). The question to be answered is: In patients with major depressive disorder (MDD), how is PGT currently used in clinical practice compared to use after implementation of practice change interventions?

This study was conducted among 4 psychiatric prescribers in a behavioral health clinic. 3 interventions were utilized to change practice. An educational in-service was delivered to address the PGT knowledge gap. A protocol for identifying patients that may benefit from PGT was developed, indicating PGT was warranted for patients with non-remitting moderate to severe MDD and at least 2 medication failures from 2 different classes. Next, a medication failure documentation template and the PGT report were integrated into the EHR. A baseline survey was administered before the in-service, assessing prescriber PGT perceptions and current parameters and barriers for use. Follow-up surveys were administered 3 months post-implementation. Project processes were measured by assessing the rate of medication failure template usage, as well as thePGT EHR upload rate.

A comparison of baseline and follow-up surveys indicated there was little change in prescriber view of test utility, receptiveness, and likelihood of use. This may be attributed to previous experience with testing and to PGT manufacturer education. View of parameters and barriers for use did change. Key parameter for use changes included patient experience of adverse reaction (increase) and only 2 medication failures from the same class (decrease). Key barrier to use changes included time to results (decrease). 3 PGT were completed during the project. All patients met the protocol criteria for testing. None of these patients had medication failures documented using theEHR template; all of the patients did have documentation using each prescriber’s preferred method. 2 of the 3 tests were uploaded to the EHR. The first test completed was not integrated, likely due to support staff becoming accustomed to the new workflow. 117 historical PGT were also integrated into the EHR.

While 16 to 20% of the population meets the criteria for MDD, available treatments achieve symptom remission only 40% of the time (Singh, 2014). Patients who do not achieve remission experience relapse more quickly and are more likely to develop chronic non-remitting MDD (Gaynes, 2016). While the PGT evidence base is still evolving, its use in clinical practice has the potential to improve depression treatment outcomes. This study highlighted continued barriers to PGT use in a practice setting, while implementing key interventions, including PGT use guidelines and EHR integration, to improve its systematic and appropriate use.

No funding.

Psychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.

NNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.

NNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are <10, and as robust as 4, denoting that PIM is a potentially efficacious intervention. NNH values for tolerability outcomes for PIM 34 mg/d (as well as for doses that range from 8.5 mg/d to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.

Using the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.

Clinical study was funded by ACADIA Pharmaceuticals Inc.

Cariprazine an atypical antipsychotic which acts as a dopamine D3-prefering partial agonist at dopamine D2/D3 receptors, as an antagonist at over stimulated dopamine receptors, as a partial agonist at serotonin 5-HT1A receptors, and as an antagonist of 5-HT2A receptors (Citrome, 2016; Kiss, 2010). While indicated for the treatment of schizophrenia and bipolar disorder, it has never been described to improve disorders of cranial nerve VIII. A patient with hearing loss associated with tinnitus, responsive to cariprazine, is reported.

Case Study: A 34 year old right handed married male 5 years prior to presentation developed bilateral auditory hallucinations of whispers, and one male disparaging voice. Approximately 6 months later it began belittling him, whereupon he was diagnosed with schizoaffective disorder, attention deficit hyperactivity disorder, and obsessive-compulsive disorder.

Three months prior to presentation he developed sepsis and became comatose. Upon awakening he experienced constant tinnitus, AS more than AD high pitched, without diurnal variation, which has been unrelenting. Coincident with the tinnitus was decreased hearing AS more than AD. Within a few days of treatment with cariprazine at 1.5 mg a day, the tinnitus transiently resolved and after raising the cariprazine to 3 mg per day the tinnitus abruptly stopped and his hearing returned to normal after 2 months. One and a half days after discontinuing the cariprazine the tinnitus and hearing loss returned. After reinstating the cariprazine to 3 mg a day the tinnitus and hearing loss resolved again.

Psychiatric evaluation: Disheveled with postural tremor of both upper extremities. Pharyngeal dysarthria. Irritable and with expansive and labile affect. Severely impaired attention. Slow tangential thoughts, preoccupied with paranoia and suspiciousness. Paranoid delusions. Mental status examination: Memory testing: Immediate recall: 5 digits forwards and 3 digits backwards. Able to recall none of 4 objects in 3 minutes and 1 with reinforcement. Unable to spell the word “world.” Similarities interpreted concretely. Calculation ability poor.

In the cochlea, as an inhibitory neurotransmitter, dopamine reduces sensitivity to auditory sensation (Langguth, 2009). Since ambient sounds are known to reduce tinnitus (masking), an antagonist at overstimulated dopamine receptors, cariprazine may act to reduce dopamine’s effectiveness, reducing inhibition and thus enhancing perceived external sound. It may act as a 5-HT1A serotonin agonist, directly reducing tinnitus. With reduced tinnitus there is less of a distraction and thus enhanced hearing. Or its function may be through its neuroleptic effects; the tinnitus could be a manifestation of auditory hallucinations, through reduction of this noise cariprazine secondarily causes enhanced hearing. Further investigation into the use of cariprazine in those with intractable tinnitus is worthwhile.

No funding.

Recognizing the importance not only of the clinician’s opinion but also of the patient’s experience and perspective, Sequenced Treatment Alternatives to Relieve Depression (STAR*D) utilized both clinician-reported and patient-reported outcomes in a large-scale multi-step study on antidepressant effectiveness in real-world settings. Both approaches indicate that <17% of Major Depressive Disorder (MDD) patients respond to novel oral treatments after two prior antidepressant failures. To address this low response rate and continue to investigate the use of patient-rated outcomes in clinical trials, an antidepressant with a new mechanism of action is being investigated for efficacy and safety utilizing both clinician-rated and patient-reported scales.

This is a post-hoc analysis of a Janssen R&D Phase 2a clinical trial (ESKETINTRD2003). Subjects aged 20-64 withMDD without psychotic features (DSM IV) and a history of inadequate response to ≥2 antidepressants were randomized [3:1:1:1] to 1 week of twice-weekly treatment with intranasal placebo (n=33), esketamine 28 mg (n=11), 56 mg (n=11), or 84 mg (n=12). Participants taking oral antidepressants at study entry continued treatment during the study. Changes in depression severitywere measured using the Clinical Global Impression Severity (CGI-S) and the Patient Global Impression Severity (PGI-S) scales.

At all esketamine doses (28 mg, 56 mg, 84 mg), subjects reported a one-point mean change in PGI-S from baseline to week one compared to no change on placebo (p-values 0.005, 0.001, 0.032 respectively). Similarly, mean CGI-S scores improved for subjects receiving esketamine at all doses (p-values 0.028, 0.004, 0.049 respectively) compared to no change inplacebo subjects. These data are consistent with previously reported data based on the Montgomery Åsberg Depression Rating Scale (MADRS) and support positive correlation between patient-reported and clinician-reported outcomes.

Initial results from this Phase 2a study suggest clinically relevant improvement in depression symptoms in as early as one week when treated with twice-weekly intranasal esketamine as reported by both clinicians and patients. This work will help guide future investigations of esketamine in larger populations to provide better therapeutic options for treatment resistantMDD patients.

Janssen

We present a case of a 66 year old Caucasian female with Bipolar type 1 disorder, status post right renal transplant (5/8/14) on maintenance immunosuppression who presented with mania and psychosis. The previous weeks had her being sleep deprived, talkative, making random calls to family members at odd hours, demonstrating pressured speech and also having erotomania regarding Joshua Bell, the violinist. She had recently been switched from Divalproex sodium (on which she had been stable for years) to Quetiapine due to thrombocytopenia attributed to the former. Quetiapine was optimized to 800 mg over two weeks without any improvement. She continued to be severely manic with new delusions of being in a World War II zone and the staff being NAZIs. She continued to be tangential with disorganized behavior and inability to care for self. She was then restarted on Divalproex sodium (for mood) with close monitoring of her counts along with Risperidone (for psychosis). Divalproex sodium was optimized to 1500mg and Risperidone to 6 mg over the next 2 weeks without much improvement. Risperidone was then cross tapered with Olanzepine. We also began to pursue other causes of treatment refractory mania withpsychosis, namely her immunosuppressant medications. She had been placed on maintenance immunosuppression withtacrolimus (Prograf) 3mg BID, Mycophenolic acid (Myfortic) 360 mg BID and Prednisone 5 mg. Though the most recent Tacrolimus level was within therapeutic range, they were still higher than her baseline levels. Based on few case reports of psychosis associated with Tacrolimus and per discussion with nephrology, we planned cross taper of Tacrolimus and Cyclosporin. Tacrolimus was eventually tapered off and Cyclosporine was maintained at 125 mg qam and 100 mg qpm. Prednisone was maintained at 5 mg daily. Her mania and psychosis improved and she was ultimately discharged on Olanzepine 20mg qhs, Divalproex sodium 1500mg qhs, The problems encountered during this case were plenty due to multiple comorbid conditions including a right adrenal adenoma, hypertension, impaired glucose tolerance, thyroid dysfunction, hyperlipidemia and having bio-prosthetic aortic valve due to Aortic stenosis (2013). In conclusion, psychosis can be precipitated in renal transplant patient with Bipolar disorder I with previously maintained stability on Tacrolimus with other comorbid conditions. So, It would be important to re-evaluate the use of Tacrolimus or the possibility of switching to another immunosuppressive agent withcareful consideration of risks versus benefits. Case management should include good coordination of care with Family medicine, Transplant/nephrology team and social services for efficacious and successful management of patient.

No funding.

In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.

To evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.

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 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.

304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.

Long-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.

Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.

This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

Optimizing TMS treatment for Depression - The 19 Minute Dash™ protocol

NeuroStar transcranial magnetic stimulation (TMS) is an effective treatment for patients with major depressive disorder. Due to the treatment session duration, a reduced treatment time would promote patients’ comfort and convenience. Also, shorter treatment sessions of retained efficacy and safety would increase access to treatment. This reduction could be accomplished by decreasing the time between TMS pulse sequences, the intertrain interval (ITI).

Meta-analysis of TMS delivered using varying treatment parameters, particularly the ratio of train duration (“on-time”) to ITI (“off-time”). PubMed and SCOPUS databases were searched through March 30, 2015 using the terms: “transcranial magnetic stimulation”, “TMS”, “rTMS”, “inter-train interval”, “inter-stimulus interval”, and “cortical spread”. Three hundred and one articles were identified comprising a total of 3359 patients. Clinical outcomes were reported as the proportion of patients achieving response defined as 50% reduction in baseline score on the primary outcome measure in each study. Treatment risk was assessed by the frequency of adverse events reported, and specifically considering the incidence of seizures.

This analysis confirms prior reports that the variables which impact treatment efficacy are the number of treatmentsessions, the number of pulses per session and the percent motor threshold. Varying the train duration/ITI (on-time/off-time) ratio over a broad range from 2.0 to 14 did not impact efficacy or safety.

Shortening the ITI to 11 seconds does not impact the safety and antidepressant effectiveness of the NeuroStar TMS and would result in shortening of each treatment session from approximately 37.5 to 19 minutes.

Neuronetics, Inc.

The NeuroStar Outcomes Registry

NeuroStar transcranial magnetic stimulation (TMS) is an effective acute treatment for patients with major depressive disorder (MDD). In order to further understand use of the NeuroStar in a clinical setting, Neuronetics has established a patient treatment and outcomes registry to collect and analyze utilization information on patients receiving treatment with the NeuroStar.

Individual NeuroStar providers are invited to participate in the registry and agree to provide their de-identified patient treatment data. The NeuroStar has an integrated electronic data management system (TrakStar) which allows for the data collection to be automated. The data collected for the registry include Demographic Elements (age, gender), Treatment Parameters, and Clinical Ratings. Clinical assessments are: Clinician Global Impression - Severity of Illness (CGI-S) and thePatient Health Questionnaire 9-item (PHQ-9). De-identified patient data is uploaded to Registry server; an independent statistical service then creates final data reports.

Over 500 patients have entered the NeuroStar Outcomes Registry since Sept 2016. Mean patient age: 48.0 (SD±16.0); 64% Female. Baseline PHQ-9, mean 18.8 (SD±5.0.) Response/Remission Rate, PHQ-9: 61%/33% CGI-S: 78%/59%.

For the initial 500 patients in the Outcomes Registry, approximately 2/3 patients achieve respond and 1/3 patients achieve remission with an acute course of NeuroStar. These treatment outcomes consistent with NeuroStar open-label study data (Carpenter, 2012). The TrakStar data management system makes large scale data collection feasible. The NeuroStarOutcomes Registry is ongoing, and expected to reach 6000 outpatients from more than 47 clinical sites in 36 months.

Neuronetics, Inc.

Clozapine is an atypical antipsychotic approved by the Food and Drug Administration for treatment-resistant schizophrenia and also indicated for the reduction in risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. The most serious side effect of clozapine treatment is agranulocytosis, which is defined as an absolute neutrophil count (ANC) < 0.50 × 109 per L. Benign ethnic neutropenia (BEN) is a condition found in members of African or Middle Eastern descent that is characterized by ANC < 1.50 × 109 per L in the absence of other causes. Filgrastim is a granulocyte colony-stimulating factor (G-CSF) that has shown efficacy in reducing the duration of agranulocytosis in some patients who develop clozapine-induced agranulocytosis. It is currently unknown whether filgrastim is beneficial in the treatment of neutropenia due to BEN. We here, for first the time report a case of a patient with BEN who developed agranulocytosis both during the first clozapine trial for schizophrenia and during the rechallenge, despite early stabilization with filgrastim treatment, which highlights the failure of filgrastim in treating BEN.

No funding.

To understand the effects of odor on anxiety.

Reduction of odor-induced anxiety through a presentation of an odor has not heretofore been described.

Case report: A 69-year-old right-handed male with a five year history of generalized anxiety disorder, presented with a one and a half month history of hypersensitivity to odors of multiple synthetic chemicals manifest by the perception that these odors were more intense and unpleasant inducing nausea, abdominal cramping, coughing, a need to “get away from the smell”, and panic with intense anxiety. These symptoms would occur whenever he was exposed to these smells, 20 to 25 times a day, and would persist for 10 to 15 minutes after the exposure. When odors induced the above symptoms, exposure to the aroma of cinnamon immediately alleviated these symptoms. He now continues using cinnamon odor whenever the odor induced anxiety and associated symptoms arise. This remedy has been effective over the course of treatment, for almost two years.

Abnormalities on examination: Three per second titubation. Archimedean Spiral Test: Saw tooth pattern with macrographia. Anxious, circumstantial, overly inclusive. Unable to determine how to put on shoe covers. Impaired voluntary upward gave, but intact vertical doll’s eyes. Left torticollis. Bilateral finger to nose dysmetria. Low amplitude, high frequency tremor on extension of both upper extremities. Areflexic. Olfactory Testing: hyposmic. MRI of brain with and without infusion: mild generalized volume loss.

There are myriad mechanisms whereby odor may have reduced the odor-induced anxiety. Since aroma induced anxiogeneis is usually confined to a specific odor, it does not preclude other odors from acting in an anxiolytic manner. The combination of exposure simultaneously of anxiolytic and anxiogenic odors may have acted to increase the threshold of the anxiety producing odor, inhibiting perception of the anxiogenic odor and thus precipitation of anxiety. The two odors could have combined in an additive fashion, changing the olfactory characteristics of the anxiety provoking odor such that it no longer was perceived as the same odor and thus no anxiety. The anxiolytic/anxiogenic odor mixture could have overwhelmed the anxiogenic odor, thus creating the perception of only anxiolytic odor. On a central basis, the anxiolysis and anxiogenesis may have been induced to occur coincidently with anxiolysis superseding anxiogenesis. Alternatively, the odors may have acted as a distractor, changing the focus of attention from anxiogenic odor to a different odor which does not have the same anxiety provoking effect. Maybe because the patient already has demonstrated a heightened odor emotion linkage, he may be more susceptible to any other odor emotion effects. Trial of odors in those with odor induced anxiety warrants consideration.

No funding.

Mental illness is one of the leading causes of disability, with direct and indirect costs posing a significant financial burden. Previously, a large prospective economic utility study (n>13,000) showed that the GeneSight® test, a psychiatric pharmacogenomic decision support tool powered by CPGx® technology, reduced medication costs, increased adherence, andreduced polypharmacy for patients who had failed monotherapy for psychiatric disorders. The current study, which is a sub-analysis of this larger study, assessed cost savings associated with combinatorial pharmacogenomic testing in patients with generalized anxiety disorder (GAD) and major depressive disorder (MDD). Medication costs were extracted using pharmacy claims data provided by Medco, a large pharmacy benefits manager, for patients with GAD (n=318) and MDD (n=459). Medication cost savings per member per year (PMPY) for 1 year following the test were compared between patients whose medication regimens were congruent with the test recommendations and those whose medication regimens were incongruent with these recommendations. When healthcare providers’ decisions were congruent with combinatorial pharmacogenomic testing, PMPY savings was $6,747 (p<0.004) for GAD patients and $3,738 (p<0.004) for MDD patients versus incongruent decisions within these disease states. Among the congruent group, GAD patients experienced greater savings in central nervous system (CNS) medications (2-fold) compared to MDD patients. Additionally, analysis of a subset of patients prescribed at least one benzodiazepine six months prior to testing (n=660) demonstrated a significant decrease in benzodiazepine drug counts (p<0.001) and refills (p<0.001) after testing. Using the GeneSight test as a treatment decision support tool for patients with GAD or MDD resulted in significant medication cost savings when HCPs made congruent decisions with the combinatorialpharmacogenomic results. Furthermore, use of the GeneSight test decreased the use of benzodiazepines.

Research was funded by Assurex Health, Inc.