The objective was to determine alterations in the care of people living with human immunodeficiency virus (PLHIV) with depressive disorder without and with apathy to determine differential parameters.

We studied 69 PLHIV, negativized viral load, of both sexes (19 women and 44 men), with depressive disorder (F32.9-DSM IV), 20 with apathy and 26 without apathy; negativized viral load, in highly effective antiretroviral treatment without therapeutic failure in the last 2 years and without protease inhibitors; without psychopharmacological treatment (except anxiolytics) or dementia due to HIV (American Academy of Neurology) or comorbidities (hepatitis C, CNS or central vascular infections). They were evaluated with MINI, Hamilton Depression Rating Scale, Apathy Evaluation Scale clinical version and Neuropsychiatric Inventory and neuropsychological tests were applied (Stroop, Trail Making A and B, digit-symbol substitution test, Visual and verbal direct digit span test, BTS−1 and BTS−3). Statistical tests were applied, and ethical-legal standards were met.

PLHIV with depressive disorder had a high prevalence of apathy. In patients with apathy, there was a greater significant alteration, according to decreasing differential involvement, in sustained and divided care. The processing speed was slowed down without significant difference in the apathy group. Selective attention did not show significant differences between groups.

Apathy in patients living with HIV with depression presents specific and differential alterations in the attention domain. The alterations of sustained and divided attention were specific in this group, with affectation of the previous attention circuit and would be related to the subsequent cognitive disruption as a prodrome. These characteristics must be taken into account as the basis for establishing interdisciplinary treatment strategies (psychopharmacological, psychotherapeutic and neurocognitive rehabilitation).

Hyperammonaemia (HA) is observed in decompensated liver disease. The picture of hyperammonemic encephalopathy in non-cirrhotic patients was reported mostly associated with valproic acid. There are few reports of hyperammonemia in people living with human immunodeficiency virus (PLHIV) and they are associated with other comorbidities and few with antiretrovirals (HAART), but not as adverse drug reactions associated with psychotropic drugs associated with the virus.

Report of cases of PLHIV in HARRT with hyperammonemia, its clinical impact and ammonium levels.

We report 67 PLHIV in treatment with HAART, negative viral loads, psychopharmacological treatment with valproic acid (n=45) or carbamazepine (n=22). Exclusion criteria were = HCV, HBV and alcohol consumption disorder (current or recent history) and decompensated liver pathology. We apply scales to evaluate side effects (UKU), subjective adherence (DAI), daily life activities (Barthel Index), liver severity (Child-Pugh Classification) and degrees of hepatic encephalopathy (West Haven Scale). The ethical-legal requirements were met. Results: 26.86% presented hyperammonemia, among which 38.88% was symptomatic. The clinical presentation was heterogeneous with a higher prevalence of gastrointestinal and cognitive alterations; the most severe cases presented alterations of the sensorium and 1 case of convulsions. We recorded a greater symptomatic severity with carbamazepine (average ammonia =104.4 pmol/L), but a higher prevalence of non-symptomatic hyperammonemia with valproic acid (62.3 pmol/L). The time of onset of symptoms was lower with carbamazepine, but the time until its decrease was higher with valproic acid.

We observed a higher prevalence of hyperammonemia and associated symptomatology in PLHIV with HAART medicated with carbamazepine. The significant percentage of this adverse drug reaction suggests a biochemical, perhaps preventive, control.

To discuss the psychiatric symptoms that are associated with CADASIL syndrome Abstract Cerebral:

Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare type of hereditary disease involving the small cerebral vessels. The clinical symptoms are various and include recurrent ischemic strokes, migraine with aura, seizures with epilepsy, psychiatric problems such as mood disturbances, and progressive cognitive decline leading to dementia. This disease needs awareness amongst the psychiatrists even though it is discussed much more in neurology literature. Psychiatric symptoms are seen in 20–41% of patients with CADASIL syndrome (1, 2). Psychiatric symptoms are actually the initial presentation in 15% of the cases. (3) The psychiatric disturbance most reported are mood disturbances (9–41%) especially depression. Here a 42-year-old African American female was brought to the hospital emergency room after she was found wandering in the streets. Psychiatry was consulted for altered mental status. Upon evaluation by the psychiatric consult service she was only oriented to person, depressed, anxious and complaining of headaches. Initial CT scan showed marked small vessel disease and old lacunar infarcts in the basal ganglia and right corona radiata. Magnetic Resonance Imaging (MRI) of the brain showed acute infarcts in the right posterior frontal and right parietal lobes along with old infarcts. Her symptoms and findings on imaging were consistent with CADASIL syndrome. Once the diagnosis was confirmed and prior records were obtained patient was resumed on an antidepressant and anxiolytic.

The purpose of this case report was to discuss psychiatric symptoms associated with CADASIL syndrome. Although there has been research showing a relationship between vascular disease and depression, a review of the literature suggests that there needs to be more research done to explore other psychiatric disturbances that may be seen with this syndrome. Psychiatric symptoms that are untreated can have the potential to further impact the quality of life therefore psychiatrists need to be aware of this syndrome in order to treat these patients promptly.

1 https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0778-8 2 http://dx.doi.org/10.32474/OJNBD.2018.01.000101 3 https://pdfs.semanticscholar.org/47f6/5952ee3c5dcf2a61345f704914b17fa8dc0d.pdf

Psychiatric prescribers typically assess adherence by patient or caregiver self-report. A new digital medicine (DM) technology provides objective data on adherence by using an ingestible event monitoring (IEM) sensor embedded within oral medication to track ingestion. Despite likely clinical benefit, adoption by prescribers will in part depend on attitudes toward and experience with digital health technology, learning style preference (LSP), and how the technology s utility and value are described.

is to identify attitudes, experiences, and proclivities toward DM platforms that may affect adoption of the IEM platform and provide direction on tailoring educational materials to maximize adoption. Methods A survey of prescribers treating seriously mentally ill patients was conducted to assess drivers/barriers to IEM adoption. Factor analysis was performed on 13 items representing prior experience with and attitudes toward DM. Factor scores were correlated with prescriber characteristics including attitude and experience with digital technologies, LSP, and level of focus on healthcare cost.

A total of 127 prescribers (56% female, 76% physicians, mean age 48.1yrs.) completed the survey. Over 90% agreed medication adherence is important, visits allow enough time to monitor adherence (84.1%), and tailoring treatment to level of adherence would be beneficial (92.9%). The majority (65.9%) preferred relying upon outcomes data as their learning style while 15.9% preferred opinion leader recommendations and 18.3% information about how the technology would affect practice efficiency. Factor analysis revealed four dimensions: Level of comfort with EHR; Concern over current ability to monitor medication adherence; Attitudes about value of DM applications; and Benefits vs cost of DM for payers. Women scored higher on attitudes about the value of digital applications (p<0.01). Providers who perceive non-adherence as costly, and those who believe DM could benefit providers and patients scored higher on the value of DM (p<.05). Those whose LSP focuses on improving efficiency and prescribers with a higher proportion of Medicaid/ uninsured patients displayed concern about their ability to monitor adherence (p<0.05). Willingness to be a Beta Test site for DM applications was positively correlated with concern about their ability to monitor adherence and attitudes about the value of DM (p <0.01).

Prescriber characteristics including LSP, focus on healthcare costs, and attitudes toward DM may be related to adoption of the IEM platform. Those with more Medicaid/ uninsured patients were more concerned about ability to monitor adherence while those focused-on cost and benefit to providers and patients viewed DM as part of a solution for managing outcomes and cost. Overall, LSP, patient panel size by payer type, and focus on healthcare cost containment should be considered when developing IEM provider training materials.

Otsuka Pharmaceutical Development & Commercialization, Inc.

The delusion of being a living animate non-animal object has not heretofore been reported.

A 21-year-old right-handed cisgender female, two months prior to presentation, noted stiffness and difficulty with ambulation. One-month prior to admission, she experienced recurrent depression with myriad vegetative and nonvegetative symptoms of depression. On admission her chief complaint was I am a tree, standing motionless and minimally responding to query. After treatment with quetiapine, mirtazapine and hydroxyzine for a one-week period, her perception of being a tree fully resolved.

Abnormalities in Mental Status Examination: Anxious mood repeatedly stating, I am a tree. Standing still for long periods of time, refusing blood pressure to be obtained and expressing fear of constricting flow. Neuropsychiatric Testing: Beck Depression Inventory Type II: 33 (severe depression)

The rapid response to risperidone is consistent with Cotard’s syndrome, which has been noted to respond rapidly to neuroleptics (Sharma, 2014). However, in Cotard’s syndrome, replacement by a living non-animal object has not hitherto been reported. Body infestation with animate objects, as in Ekbom syndrome, only includes animals not botanicals (Chaudhary, 2019). This could be viewed as Reverse Inanimate Capgras Syndrome: instead of an imposter replacing a close friend, who then is inserted into the sufferer; a tree has replaced the sufferer. Peradventure, this may fit into the construct of Intermetamorphosis, a misidentification syndrome associated with the belief that individuals have transformed into other persons (Jariwala, 2017). Botanical Intermetamorphosis, the belief by the sufferer that the other individual is transformed from a person into a plant has not been described. Reverse Intermetamorphosis is the projection of an external individual into the person suffering or a syndrome of altered physical and psychological identities of the self (Silva, 1990). However, in this situation, the objects are all human or animate animals not botanicals. In Fregoli syndrome, there is an altered physical identity of others. In Reverse Fregoli syndrome, the sufferer assumes the physical but not the psychological identity of the stranger (Silva, 1990). But in this instance, the stranger is human as opposed to a plant life form. In the current case there is only altered physical identity (into a tree) not psychological identity. The current case may also be interpreted as a Botanical Variant of Interparietal Syndrome. In this condition, parts of the body are perceived to be lifeless, due to lesions of the inferior parietal lobe including supramarginalis gyrus, angular gyrus and the basalis parietalis area (Angyal, 1935). Investigation for those whom have Intermetamorphosis, Fregoli syndrome, Capgras syndrome, Interparietal syndrome, and Cotard’s syndrome for the presence of delusions involving plant life is warranted.

The main objectives of this case study are 1. Clinicians facing symptoms that are difficult to interpret should exercise caution in diagnosing conversion disorder. 2. Increasing awareness about rare neurological conditions may appear as psychogenic illnesses. 3. Clinicians be advocate for their patients.

Conversion disorder is a mental condition in which a person present with one or more symptoms of altered voluntary motor or sensory function, or other neurologic symptoms that cannot be explained by medical evaluation. Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity, gait impairment, with superimposed painful spasms. SPS is commonly associated with high anti-glutamic acid decarboxylase (GAD) antibody titers. The dominant antigen recognized by these antibodies is the GABA-synthesizing enzyme GAD.

Patient X, a 17-year-old Hispanic American female who presented to the Child and Adolescent Psychiatry Clinic with the complaint of ataxia & aphasia associated with anxiety. Patient was referred by the neurology clinic after they could not establish any organic cause of her ataxia or aphasia. After thorough evaluation at the child psychiatry clinic she was given the diagnosis of anxiety secondary to ataxia and aphasia and r/o Conversion Disorder. She was initiated treatment with sertraline for her anxiety. Her sertraline dose was increased gradually up to 100 mg daily. From the beginning the patient also received counseling & physical therapy. With these combination of treatments, patient’s symptoms did not get any better. Her symptoms actually got worse over time. At this point, the Child Psychiatry Clinic sent a message to the neurology clinic for further evaluation of patient due to her progressive gait and speech impairments.

The neurology clinic saw the patient again and did further testing. The patient was positive for high titers of anti-glutamic acid decarboxylase antibodies (Anti-GAD). At this point, the patient was given the diagnosis of Stiff Person Syndrome. Patient was admitted to the hospital for further management. She was treated with benzodiazepines, IV immune globulin, & steroid. Soon after discharge from the hospital, the patient was seen at the Child Psychiatric Clinic. The patient’s mother reported, after the in-patient treatment, the patient’s symptoms improved.

It is essential for clinicians to look for neurologic & other general medical conditions while evaluating a patient with possible conversion disorder. A systematic review of 27 studies found that among 1466 patients initially diagnosed with conversion symptoms, the frequency of misdiagnosis was approximately 4 percent.

References. BMJ. 2005;331(7523):989. Epub Oct 13. Childhood onset of stiff-man syndrome. JAMA Neurol. 2013;70(12):1531. J Neurol Neurosurg Psychiatry. 2015 Aug; 86(8):840–8. Epub 2014 Dec 15.

Four medications are FDA approved for bipolar depression: lurasidone (LUR), cariprazine (CAR), quetiapine IR & XR (QUE), and olanzapine-fluoxetine combination (OFC). Indirect comparisons for efficacy using Number Needed to Treat (NNT) and for tolerability using Number Needed to Harm (NNH) can be useful clinical benchmarks to aid treatment decisions. Benefit and risk may also be examined using the Likelihood to be Helped or Harmed (LHH). In this post-hoc analysis, we examined the benefit-risk ratio of the four treatments using LHH.

Individual and pooled monotherapy data from short-term clinical registration trials of patients with bipolar depression were assessed for LUR, CAR, pooled QUE (300 and 600 mg), and pooled OFC (considered as monotherapy for this study at fixed doses of 6/25, 6/50, 12/50 mg) data. NNT estimates were calculated using the proportions of MADRS responders (defined as ≥ 50% improvement at study endpoint) and MADRS remitters (defined as a score of ≤ 10 [for LUR and CAR] and ≤ 12 [for QUE and OFC]) at study endpoint. NNH data were calculated for the proportions of patients who discontinued due to an adverse event (AE) and for individual AEs commonly associated with each treatment. LHH was calculated as the ratio of NNH/NNT to determine the benefit-risk ratio.

The NNT estimates for response vs. placebo were: 5 for both LUR 20–60 mg and 80–120 mg; 10 for both CAR 1.5 mg and 3.0 mg; 6 for QUE; and 4 for OFC. The NNTs for remission vs placebo were: 7 for LUR 20–60 mg and 9 for LUR 80–120 mg; 10 for CAR 1.5 mg and 13 for CAR 3.0 mg; 6 for QUE; and 5 for OFC. The NNH estimates for discontinuations due to AEs were: 642 for LUR 20–60 mg and −151 for LUR 80–120 mg; 298 for CAR 1.5 mg and 31 for CAR 3.0 mg; 10 for QUE; and −37 for OFC. NNH values that were negative were assigned a value of 1000 to permit LHH to be calculated. The LHHs for response vs discontinuation due to an AE were: 128.4 for LUR 20–60 mg and 200 for LUR 80–120 mg; 29.8 for CAR 1.5 mg and 3.1 for CAR 3.0 mg; 1.7 for QUE; and 250 for OFC. The LHHs for response vs akathisia were: 3.6 for LUR 20–60 mg and 2.4 for LUR 80–120 mg; 3.6 for CAR 1.5 mg and 1.3 for CAR 3.0 mg; 34 for QUE; and not available (NA) for OFC. The LHHs for response vs EPS were: 8 for LUR 20–60 mg and 3.2 for LUR 80–120 mg; 5 for CAR 1.5 mg and 2.5 for CAR 3.0 mg; NA for QUE; and NA for OFC. The LHH for response vs weight gain was 5.8 for LUR 20–60 mg and 1110 for LUR 80–120 mg; 5 for both doses of CAR; 2.7 for QUE; and 1.5 for OFC.

LHH can illustrate the trade-offs regarding potential benefits versus potential harms. Across a variety of measures, the lower-dose groups for both LUR and CAR generally evidenced a better benefit-risk profile than the higher-dose groups. While quetiapine and OFC demonstrated robust efficacy, their reduced tolerability resulted in a more marginal benefit-risk ratio for some of the outcomes.

Sunovion Pharmaceuticals Inc.

Few studies have examined treatment response in adolescents with schizophrenia who are treatment-naive; and there is no placebo-controlled study that we are aware of in first episode treatment-naive patients with schizophrenia. The aim of this analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naive adolescents with schizophrenia.

Patients aged 13–17 years with schizophrenia, and a PANSS total score ≥70 and <120, were randomized to 6 weeks of double-blind (DB) treatment with lurasidone (40 or 80 mg/day) or placebo. Six-week completers were eligible to enroll in a 2-year open-label extension phase receiving lurasidone flexibly dosed from 20–80 mg/day. In a post-hoc analysis, efficacy was evaluated for 2 patient groups based on treatment status prior to entering the initial 6-week DB study (treatment naïve [TN] vs. treated previously [TP]). Treatment-naïve was defined as never having received antipsychotic treatment. Efficacy measures included the PANSS total score and the Clinical Global Impression, Severity (CGI-S) score. Level of functioning was assessed using the Children’s Global Assessment Scale (CGAS), with a score of 70 representing normative levels of functioning.

A total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. During the initial 6 weeks of DB treatment, mean change in PANSS total score at endpoint was greater for lurasidone vs. placebo in both the TN group (−25.0 vs. −14.4; P<0.02; effect size, 0.75), and in the TP group (−17.3 vs. −10.0; P<0.001; effect size, 0.45). During OL extension phase treatment with lurasidone, mean change from DB baseline in the PANSS total score for TN and TP patients, at week 52 was −32.6 (n=38) and −28.1 (n=151), respectively; and at week 104 was −33.6 (n=30) and −29.2 (n=126), respectively. Mean change from DB baseline in CGI-S score at both weeks 52 and 104 was −1.8 for TN patients and −1.5 for TP patients. At DB baseline mean CGAS scores indicated significant functional impairment in both the TN and TP patients (CGAS=48 and 43, respectively). During OL treatment with lurasidone, mean change (from DB baseline) in the CGAS score at Weeks 52 and 104, respectively, was +22.0 and +22.9 in TN patients, and +21.1 and +22.9 in TP patients. During OL treatment with lurasidone, mean observed change from DB baseline in the weight (in kg,) at Weeks 52 and 104, respectively, was +4.2 and +4.8 in TN patients, and +4.0 and +5.0 in TP patients. These weight increases are consistent with expected weight gains in adolescents during a 2-year period (based on CDC growth charts).

In this post-hoc analysis of a 2-year study, adolescents with schizophrenia who had received no previous antipsychotic therapy showed greater improvement compared to previously treated patients during both short- and long-term treatment with lurasidone.

Sunovion Pharmaceuticals Inc.

Lurasidone is approved for the treatment of bipolar depression both as monotherapy and adjunctive therapy with lithium or valproate (Li/VPA). The aim of these analyses was to evaluate the prevalence of treatment-emergent mania (TEM) and worsening of mania symptom severity in clinical trials of both adult and pediatric patients with bipolar depression treated with lurasidone.

In these post-hoc analyses, TEM and change in manic symptom severity as measured by the Young Mania Rating Scale (YMRS) were evaluated in two double-blind (DB), 6-week studies in adults of lurasidone monotherapy, 20–60 mg/d (n=161) and 80–120 mg/d (n=162) vs. placebo (n=162), and adjunctive therapy of lurasidone 20–120 mg/d + Li/VPA (n=179) vs. placebo + Li/VPA (n=161). Prevalence of TEM was also evaluated in a 6-month, open-label (OL) extension study of adults treated with lurasidone monotherapy (n=316) or adjunctive therapy (n=497). In pediatric patients (ages 10–17) TEM and change in manic symptoms was evaluated in a DB 6-week study of lurasidone monotherapy (n=173) vs. placebo (n=170) and in a 24-month OL extension study. TEM was defined as an adverse event of mania or hypomania and/or having a YMRS score =16 at 2 consecutive post-baseline weekly visits (or the final assessment) in short-term studies or 1 post-baseline monthly visit in long-term studies.

Adult studies: In short-term studies, TEM rates were comparable in patients treated with lurasidone monotherapy 20–60 mg/d (3.7%) and 80–120 mg/d (1.9%) vs. placebo (1.9%). TEM rates were also comparable in patients treated with lurasidone 20–120 mg/d (1.1%) adjunctive to Li/VPA vs. placebo + Li/VPA (1.2%). In the monotherapy study, significant reduction in YMRS score was observed at study endpoint for the 20–60 mg/d group compared to placebo (−1.9 vs. −1.3; p<0.05) with similar improvement relative to placebo in the 80–120 mg/d group. Change for YMRS score was comparable for lurasidone and placebo in the adjunctive study. In long-term studies, 1.3% of adult patients treated with lurasidone monotherapy (n=316) met criteria for mania, and 3.8% of patients on adjunctive lurasidone therapy (n=497) met TEM criteria. Pediatric studies: TEM rates were comparable in patients treated with lurasidone vs. placebo (1.7% vs. 2.3%). LS mean reduction in symptoms of mania from baseline to week 6 was significantly greater for lurasidone vs. placebo on YMRS score (−2.0 vs. −1.1; p<0.05). Pediatric long-term studies: After two years of OL treatment with lurasidone, 5.2% of patients met TEM criteria. Mean change in YMRS total score from DB baseline to Month 24 continued to improve (−2.0).

Short-term and long-term treatment with lurasidone demonstrated significant improvement in manic symptoms and was not associated with an increased risk of TEM in either adult or pediatric patient populations compared to rates reported in clinical populations of patients.

Sunovion Pharmaceuticals Inc.

Bipolar disorder frequently has an early onset, with an estimated 1.8% prevalence of bipolar I disorder in children and adolescents. Childhood onset of bipolar disorder is typically associated with a chronic, severe, and disabling course of illness. Relatively few prospective studies are available that evaluate the long-term efficacy of atypical antipsychotics in achieving and sustaining response or remission in pediatric patients with bipolar depression. Lurasidone has been approved by the FDA as monotherapy for bipolar depression in pediatric patients ages 10–17 years. The aim of the current post-hoc analysis was to evaluate the long-term efficacy of lurasidone in achieving response or remission in children and adolescents with bipolar depression followed over a two-year period.

Patients 10–17 years with bipolar I depression who completed a 6-week double-blind (DB) study of lurasidone vs. placebo were eligible to enroll in a two-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (20–80 mg/d) or switched from placebo to lurasidone. Efficacy measures included the Children’s Depression Rating Scale, Revised (CDRS-R) and the Clinical Global Impression, Bipolar Depression Severity scale (CGI-BP-S). Functioning was evaluated utilizing the Clinician-rated Children’s Global Assessment Scale (CGAS) score, with a score >70 indicating no clinically meaningful functional impairment. Responder criteria were met if a patient achieved criteria = 50% reduction from DB baseline in the CDRS-R total score: remission criteria were met if a patient achieved a CDRS-R Total Score =28 and a YMRS total score =8 and CGI-BP-S depression score =3, and a patient was considered to have met recovery criteria if they achieved remission with a CGAS score >70. In addition, a more stringent outcome, sustained remission, was also analyzed, which required a patient to meet remission criteria for =24 consecutive weeks.

A total of 306 patients completed the 6-week DB study and entered the extension study; 195 (63.7%) patients completed one year of treatment and 168 (54.9%) patients completed two years of treatment. Responder rates at OL baseline, one year, and two years were: 51.0%, 88.4% and 91.1%, respectively; remission rates were 24.3%, 61.3%, and 75.6%, respectively; and recovery rates were 17.7%, 53.8%, and 73.8%. On a Pearson correlation analysis, there was a strong inverse relationship (r = −0.71) between CDRS-R total score, and global functioning as measured by the CGAS. Sustained remission was achieved by 37.2% of patients at one year and 57% of patients after two years.

In children and adolescents with bipolar depression, up to 2 years of treatment with lurasidone was associated with continued improvement in depressive symptoms, resulting in progressively higher rates of response, remission, recovery, and the more rigorously calculated outcome of sustained remission.

Sunovion Pharmaceuticals Inc.

SEP-363856 is a novel psychotropic agent without dopamine D2 receptor occupancy. Although its mechanism of action has not been fully elucidated, preclinical data suggest that agonism at trace amine receptor 1 (TAAR1) and the serotonin 5-H1A receptor contributes to its efficacy. In a double-blind (DB), placebo-controlled study, SEP−363856 demonstrated significant efficacy in the treatment of an exacerbation of schizophrenia (Koblan et al, NEJM 2020; 82:1497–1506). We present results of a 6-month extension study whose aim was to evaluate the safety and effectiveness of longer-term treatment with SEP−363856.

Patients with an acute exacerbation of schizophrenia who completed a 4-week, DB, placebo-controlled, flexible-dose (50 or 75 mg) study of SEP−363856 were given the option to enroll in an extension study in which they were treated, open-label (OL), with flexible doses (25/50/75 mg/d) of SEP−363856 for 26-weeks. The primary outcomes were safety measures; effectiveness outcomes were secondary and included the PANSS total score and the Brief Negative Symptom Scale (BNSS) total score.

A total of 193 patients completed the 4-week DB study, and 156 (80.8%) were dosed in the OL extension study and received at least one dose of SEP−363856 (safety population). Study completer rate was 66.9%; reasons for discontinuation consisted of adverse event (11.5%), withdrawal of consent (10.2%), lack of efficacy (5.1%), and other (6.4%). 15 patients experienced an SAE: schizophrenia (n=11); acute psychosis (N=1); uterine hemorrhage and suicidal ideation (N=1 each); there were no deaths in the study. Individual AEs with an incidence =2% were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decreased (3.2%), and prolactin increased (2.6%). On movement scales, minimal mean change from OL-baseline to Week 26 occurred on the Barnes total score (−0.1), AIMS total score (0.0) and SAS score (−0.1). Mean month 6 change from DB baseline in weight was −0.3 kg. No clinically meaningful median changes were observed at week 26 in metabolic laboratory parameters (total and LDL cholesterol, triglycerides, hemoglobin A1c) or in prolactin levels. During 6 months of OL treatment, one patient had an increase in QTcF =60 msec; no patients had a QTcF interval =480 msec. Treatment with SEP−363856 was associated with significant improvement from OL baseline to week 26 in PANSS total score (−22.6) and BNSS total score (−11.3).

Treatment with SEP−363856 was associated with continued improvement from open-label baseline in the PANSS total (−22.6) and BNSS total (−11.3) scores. The most frequently reported adverse events (= 5%) were schizophrenia, headache, insomnia and anxiety. SEP−363856 had minimal effects on weight, lipids, glycemic indices, prolactin, and was associated with minimal risk of extrapyramidal symptom.

Sunovion Pharmaceuticals Inc.

Approved treatments for bipolar depression are limited and associated with a spectrum of undesirable side effects. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia. Lumateperone is currently being investigated for the treatment of bipolar depression (major depressive episodes [MDE] associated with bipolar I and bipolar II disorder). This Phase 3 randomized, double-blind, parallel-group, placebo-controlled multinational study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a MDE.

Patients (18 75 years) with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing a MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score =20 and a Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score =4 at screening and baseline) were randomized to lumateperone 42mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS total score and CGI-BP-S scores, respectively. Secondary efficacy outcomes included response (MADRS improvement = 50%) and remission (MADRS total score =12) at Day 43. Safety assessments included treatment emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms (EPS), and suicidality.

In this study, 377 patients received treatment (placebo, n=189; lumateperone 42mg, n=188) and 333 completed treatment. Patients in the lumateperone 42-mg group had significantly greater mean improvement on MADRS total score change from baseline to Day 43 compared with placebo (least squares mean difference [LSMD]=-4.6; 95% confidence interval [CI]=-6.34, −2.83; effect size vs placebo [ES]=-0.56; P<.0001). Lumateperone treatment was associated with significant MADRS improvement in both patients with bipolar I (LSMD=-4.0; 95% CI=-5.92, −1.99; ES=-0.49; P<.0001) and bipolar II (LSMD=-7.0; 95% CI=-10.92, −3.16; ES=-0.81; P=.0004). The lumateperone 42-mg group also had significantly greater mean improvement in CGI-BP-S total score compared with placebo (LSMD=-0.9; 95% CI=-1.37, −0.51; ES=-0.46; P<.001). Lumateperone compared with placebo had significantly greater MADRS response rate (51.1% vs 36.7%; odds ratio=2.98; P<.001) and remission rates (P=.02) at Day 43. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin side effects.

Lumateperone 42 mg significantly improved depression symptoms in both patients with bipolar I and bipolar II depression. Lumateperone was generally well tolerated. These results suggest that lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.

Intra-Cellular Therapies, Inc.

Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Long-term safety of the approved TD medication, valbenazine, was demonstrated in 2 clinical trials (KINECT 3 [NCT02274558], KINECT 4 [NCT02405091]). Data from these trials were analyzed post hoc to evaluate the onset and resolution of adverse events (AEs).

Participants in KINECT 3 and KINECT 4 received up to 48 weeks of once-daily valbenazine (40 or 80 mg). Data from these studies were pooled and analyzed to assess the incidence, time to first occurrence, and resolution for the following AEs of potential clinical interest: akathisia, balance disorder, dizziness, parkinsonism, somnolence/sedation, suicidal behavior/ideation, and tremor.

In the pooled population (N=314), all AEs of potential clinical interest occurred in <10% of participants, with somnolence (9.6%), suicidal behavior/ideation (6.4%), and dizziness (5.7%) being the most common AEs. Mean time to first occurrence ranged from 36 days (akathisia [n=9]) to 224 days (parkinsonism [n=2]). By end of study (or last study visit), resolution of AEs was as follows: 100% (suicidal ideation/behavior, parkinsonism); >85% (somnolence/sedation, dizziness); >70% (akathisia, balance disorder, tremor).

In long-term clinical trials, the incidence of AEs of potential clinical interest was low (<10%) and most were resolved by end of treatment (>70–100%). All patients taking valbenazine should be routinely monitored for AEs, particularly those that may exacerbate the motor symptoms associated with TD.

Neurocrine Biosciences, Inc.

Vesicular monoamine transporter 2 (VMAT2) inhibitors including valbenazine are first-line therapies for tardive dyskinesia (TD), a persistent movement disorder associated with antipsychotic exposure. This real-world study was performed to assess the association between patient awareness of TD symptoms and clinician-assessed symptom severity.

Clinicians who treated antipsychotic-induced TD with a VMAT2 inhibitor within the past 24 months were asked to extract demographic/clinical data from patients charts and complete a survey for additional data, including patient awareness of TD (yes/no) and TD symptom severity (mild/moderate/severe).

Data for 601 patients were provided by 163 clinicians (113 psychiatrists; 46 neurologists; 4 primary care physicians). Patient demographics: 50% male; mean age 50.6 years; 55% schizophrenia/schizoaffective disorder; 29% bipolar disorder; 16% other psychiatric diagnoses. Positive relationships were seen between patient awareness and clinician-assessed symptom severity. Awareness was highest in patients with severe symptoms in specific body regions: face (88% vs 78%/69% [awareness by severe vs moderate/mild symptoms]); jaw (90% vs 80%/67%); wrists (90% vs 69%/63%). In other regions, awareness was similar in patients with severe or moderate symptoms: lips (85%/86% vs 68% [severe/moderate vs mild]); tongue (81%/80% vs 73%); neck (80%/78% vs 68%); arms (67%/66% vs 62%); knees (67%/67% vs 53%).

In patients prescribed a VMAT2 inhibitor for TD, patient awareness was generally higher in those determined to have moderate-to-severe symptom severity as assessed by the clinician. More research is needed to understand how awareness and severity contribute to TD burden, and whether different treatment strategies are needed based on these factors.

Neurocrine Biosciences, Inc.