The concept of dose equivalence is very useful when it comes to using drugs. In the case of antipsychotics, the first comparison was established by Davis in 1974, called the classical comparison method. Subsequently, other methods have appeared, such as the minimum effective dose method, the dose response method, the consensus among experts such as consensus method by Gardner, and the Daily Dose method of the World Health Organization. In 2016, Leucht et al performed the meta-analysis comparing the equivalence by the alternative methods of second-generation antipsychotics orally, based on Olanzapine. However, therapeutic equivalences between injectable antipsychotics have not yet been made.

The objective of the study is to establish a pattern of therapeutic equivalences between long-acting antipsychotics, based on the method of the Defined Daily Dose (DDD).

The DDD is the dose of the maintenance medium of a drug for its main indication in adults of 70kg. In the case of antipsychotics, psychosis is the most important indication. DDDs are different for each route of administration, especially if the bioavailability of the drug varies between one route and another. To establish the DDD of a drug, 3 measures are taken: firstly, the dose ranges of the drug approved by at least 1 major regulatory authority. Secondly, doses used in clinical trials. Thirdly, post marketing data on dose used in clinical practice when the drug is commercialized. Depot formulations are usually assigned the same DDDs as the ordinary oral dosage form. Based on the DDD according to the WHO classification at http://www.whocc.no/.

For comparison, Olanzapine 210mg was used as the main drug and equivalences were established from it. Therapeutic deposit of Aripiprazole (ARI), Flufenazine decanoate (FLU), Haloperidol Decanoate (HAL) Olanzapine pamoate (OLA), Paliperidone palmitate (PAL), Risperidone depot (RIS), and Zuclopenthixol decanoate (ZUC).

The results will be shown in a 8x8 table.

DDD is available for almost all antipsychotics and is an accepted method as well as a clinical level as a researcher. They are based on a wide variety of data from different sources. Several studies have found a strong correlation between this method and other methods of equivalence. This method also has limitations. First, the DDDs were not established for the purpose of therapeutic equivalences. Secondly, the daily dose can be applied mainly to the efficacy of the drug, when the dose could cause some adverse effects.

The establishment of therapeutic equivalences may help when a clinician needs to change one long-term antipsychotic. This could reduce psychotic relapses. It may enhance therapeutic adherence avoiding undesirable side effects. On the other hand, long-acting antipsychotics have corroborated the adherence and decrease of relapses, which is why it is increasingly used as a good alternative to oral drugs.

Aripiprazole once-monthly is an LAI formulation of aripiprazole that is currently approved in the USA and Europe for the treatment of schizophrenia. Some studies have reported a decline in hospital admissions and emergency use after initiation on long-acting injectable (LAI) antipsychotics, but the effects of using recently commercialised LAI aripiprazole remains uncertain.

To characterize the impact of ALAI initiation on number of hospitalizations and visits to the emergency service, among patients suffering from schizophrenia attending regularly to psychiatric consultations of Gregorio Marañón University General Hospital (Madrid, Spain).

Patients initiated on (ALAI) were studied in an observational mirror-image design to assess changes in number of hospitalizations and visits to the emergency service in the 12months pre- vs 12months post-depot initiation. Other sociodemographic, physical and clinical variables such as age, gender, weight, blood pressure and presence of dual disorders were also gathered. Variables were collected reviewing clinical records.

Wilcoxon test was used to assess hospitalizations and visits to the emergency. Paired t-tests were used to assess changes in weight and blood pressure. Non parametric Mann-Whitney U test was used to compare aripiprazole doses between genders and in order to assess de influence of dual disorders. In order to perform the statistical analysis, IBM SPSS statistics v.20 was used.

31 patients were included in the final analysis. Mean age was 44.67 (SD=15.57) years. Most of the patients were male (54.8% vs 45.2%). 71% were previously receiving oral antipsychotics treatment, whereas 29% were receiving other LAI antipsychotic: no significant differences were observed when comparing hospitalizations (p=0.74) or emergency use (p=0.98) in the 12months post-initiation between these groups. Mean dosage was 352.67mg/28days (SD=0.461), and 38.7% needed an adjustment during the first year of treatment (dosage increased in 76.9%). A combination of two or more antipsychotics was prescribed in 64.5% of the patients. Mean psychiatric number of hospitalizations a year declined from 0.483/year pre-initiation to 0.224/year post-initiation (P<0.05), whereas mean visits a year to the emergency psychiatric service declined from 1.419 pre-initiation to 1.032 post-initiation (P<0.1). No significant changes in weight (p=0.82), systolic (p=0.56) or diastolic (p=0.29) blood pressure were observed. No gender differences in dosage were observed (p=0.246). Suffering from dual disorders had no influence on dosage either (p=0.68).

LAI aripiprazole initiation appears to provide a benefit decreasing hospitalization needs and emergency services consumption and it was well tolerated. This data supports previous evidence indicating superiority of LAI antipsychotics.

Effective treatments for patients with high levels of negative symptoms of schizophrenia are lacking. Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all with subnanomolar potency. Long-term treatment with brexpiprazole demonstrated broad efficacy across all five Marder factor groupings, including positive, negative, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. This post-hoc analysis of long-term effects of brexpiprazole in patients with clinically relevant levels of negative symptoms of schizophrenia is based on data from two similarly designed short-term, placebo-controlled studies (Vector; NCT01396421 or Beacon; NCT01393613) for the brexpiprazole-treated patients who continued into an open-label extension study (Zenith; NCT01397786).

In the short-term studies, patients with acute schizophrenia were randomly assigned to fixed once-daily doses of brexpiprazole 0.25mg (Vector), 1mg (Beacon), 2mg , 4mg or placebo for 6weeks. The long-term study was an open-label, 52-week (amended to 26weeks), safety extension study with flexible-dose (1–4mg/day) brexpiprazole. The post-hoc analyses were performed on brexpiprazole-treated patients from the short-term studies who continued into the long-term study, and who had clinically relevant negative symptoms, defined as PANSS Factor Score for Negative Symptoms (PANSS-FSNS; N1, N2, N3, N4, G7, G16) of ≥24, and score of ≥4 on at least two of three core negative symptom PANSS items at randomization in the parent study. The outcome of the analysis included change from baseline to up to 58weeks in PANSS-FSNS, PANSS Total, and PSP. Safety was also assessed.

A total of 187 patients with clinically relevant levels of negative symptoms in the parent study rolled-over into the open-label extension study and were available for analysis. Eighty-three of these patients remained in the studies for 58weeks. Due to the study amendment, not all patients had the opportunity of complete 52weeks of open-label treatment. Baseline PANSS Total score was 104.4, while baseline PANSS-FSNS was 27.6 and baseline PSP Total score was 41.3. Mean change (SD) from baseline in PANSS-FSNS was –10.9 (5.0), and –44.2 (17.5) for PANSS Total score at Week 58. Change from baseline (SD) to Week 58 for PSP Total score was 24.8 (12.9) with improvement in all domains (socially useful activities, personal and social relationship, self-care, and disturbing and aggressive behaviors). The TEAEs reported ≥5% were schizophrenia (18.9%), insomnia (8.6%), weight increased (5.9%) and akathisia (5.9%).

This post-hoc analysis suggests that brexpiprazole has long-term effectiveness on negative symptoms and functioning in patients with schizophrenia and clinically relevant levels of negative symptoms.

Funding Acknowledgements: The study was funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S

Wearable sensors have become increasingly accurate in measuring various aspects of health monitoring in humans. Persons with dementia (PWD) often experience problematic behavioral and psychological symptoms of dementia (BPSD). These behaviors can include kicking, hitting, biting, screaming, pushing and are stressful and dangerous for the PWD as well as for caregivers both formal paid caregivers and informal family caregivers. There are many proven methods to intervene during agitated behavior outburst and the earlier these methods are used the better the results. Such methods include redirection, one-on-one socialization, music therapy, pet assisted therapy, etc. These types of effective methods are preferred over routine or as needed medications to control the behaviors. The medications currently used have well documented adverse side effects, especially in aging adults.

This IRB approved study used a convenience sample of eight PWD who had a history of BPSD in an assisted living facility specializing in the care of PWD. We evaluated the use of off-the-shelf smart watch technology to measure limb movements, vocalizations, heart rate and location in a facility. The research goal was to determine the feasibility of using this technology to accurately measure patient data which in turn will allow clinicians to promptly detect agitation and provide early intervention. Output data from the watch was compared to data recorded by trained observers using the Cohen-Mansfield Agitation Inventory (CMAI). Data was collected in four-hour blocks of time over a two-day period.

All the participants wore the devices without difficulty. Observations were then compared to the information obtained from the smart watch technology. Limb movements and heart rate increases correlated well with observers’ measurements of agitation. True positive measures were greater than 60% (data streams from devices correlated with observations). The voice measures of tone, volume and words used did not correlate well due to background noise in this communal environment.

Data streams did correlate with observations. This technology could be useful in quickly identifying, and potentially anticipate, agitation in PWD. Further research is pending that will fine tune our software developed to measure the data streams and enhance accuracy. Also, improvements are being made in the ability to use voice recognition technology to capture the vocalizations associated with agitation. This technology can be used to quickly identify and prevent escalation of some BPSD by allowing early application of non-pharmacologic methods to treat agitation. Further study will also evaluate the impact this may have on the quality of life for caregivers and PWD.

Funding Acknowledgements: Old Dominion University Office of Research, $2,500

Dopaminergic mechanisms are involved in addiction but few effective drugs have been developed to treat it. Recent research has highlighted dopamine D2 receptor partial agonists, like aripiprazole, as a potential treatment for different types of substance dependence. In this study we investigate the use of both oral or long-acting injectable (LAI) aripiprazole in the treatment of dual disorders, specifically focusing on patients with psychotic disorder and comorbid substance use disorder.

Retrospective mirror-image study was conducted at an adult psychiatry inpatient unit from a tertiary care center (Ramon y Cajal University Hospital, Madrid, Spain). Patients included were those with a comorbid psychotic disorder and substance-related disorders (excluding tobacco and caffeine), according to DSM-5 criteria, who started aripiprazole in 2017. The number of psychiatric acute inpatient admissions and psychiatric emergency room visits, six months before and after aripiprazole initiation, were obtained from patients’ records. Sociodemographic factors, average length of stay, antipsychotic polypharmacy, type of substance and change on clinical global impression (GCI) scale during hospitalization were also obtained. Data was analyzed using the IBM SPSS, v21. The Wilcoxon signed-rank test was used in the analysis.

11 patients were included; 7 (63.6%) were males, the mean age was 40.37 (SD:13.23) years and the average length of stay was 11.27 (SD:7.53) days. LAI aripiprazole was prescribed in 7 (63.6%) patients (all of them receiving 400mg monthly) and oral aripiprazole was prescribed in 4 (36.4%) patients (mean daily dose= 16.25mg; SD:10.30). Antipsychotic polypharmacy was observed in 6 (54.5%) patients: 4 with quetiapine (mean daily dose=75mg; SD:61.23), 1 with clotiapine 20mg daily and 1 olanzapine 15mg daily. There were 6 (54.5%) polysubstance users and the substances used were cannabis (63.7%), alcohol (36.4%), stimulants (27.3%), opioids (9.1%), hallucinogens (9.1%) and sedative-hypnotics (9.1%).

The mean of inpatient admissions before and after aripiprazole initiation was 1.00 (SD:1.00) and 0.18 (SD:0.60) (p=0.047). The mean of emergency room visits before and after aripiprazole initiation was 1.64 (SD:1.85) and 0.36 (SD:0.67) (p=0.026). With respect to CGI scale, the severity of illness score was 5.09 (SD:0.94) and the global improvement score was 2.00 (SD:0.63) (p=0.004).

These results suggest that aripiprazole could be an effective treatment in psychotic patients with comorbid substance use disorders. However, the results should be taken with caution due to some limitations in our study: a small sample, the short period of time studied, the retrospective design and the inherent biases associated with this type of research. Preliminary investigations on the topic and the results of our study allow clinicians to be optimistic about the use of D2 receptor partial agonist in the treatment of dual disorders.

The use of pharmacogenomics (PGx) testing has the potential to accelerate response to psychopharmacologic therapy (Rx) and improve outcomes; accordingly PGx use to select appropriate Rx is increasing. One such commercially available test is the Genecept Assay (the Assay [Genomind]) which measures variants of 18 genes (12 pharmacodynamic and 6 CYP450) for which response, tolerability or exposure to various Rx has been reported. Recent interest in genetics has led patients (pts) to be stewards of their own genetic data. In 2017 we launched a Patient Gateway to allow pts to retrieve their genetic results, have access to mental health information, and record outcomes following use of the Assay.

To assess the effectiveness of Rx recommendations following use of the Assay, as reported on a purpose-built patient portal.

Pts receiving the Assay were invited to visit an online, interactive portal. Pts providing informed consent (IC) were asked to record their baseline overall health using a 4- point modified patient global index (m-PGI) of severity. Pts also recorded their conditions, medications, and supplements, and various symptoms. Pts were invited to visit the portal ad libitum and re-rate their overall health using the m-PGI. These data were then combined with the pts’ genetic results using custom scripts in Python (v 3.6.4) and R (v 3.5.1). All identifying data were removed. Pts included in this analysis responded (at least) twice to the health questionnaire. New medications were subsequently scored as concordant, discordant, or indeterminate with the Assay’s recommendations, using predetermined criteria. We report the initial results for this subgroup herein.

Since launch 9,401 unique patient profiles were created on the Gateway; 5,207 (55%) of these provided IC. Of these, 410 provided at least 2 m-PGI scores. Seventy-three (73) of these pts reported scores at least 4weeks apart and started 222 medications in the interim. 69.4% of pts identified as female; 70.8% had a diagnosis of generalized anxiety disorder, while 50.0% and 31.9% had diagnoses of major depressive disorder and post-traumatic stress disorder, respectively. 60.2% of pts reported improvement on the m-PGI of ≥1 unit; 20% had a ≥2-unit improvement. Pts reporting improvement were more likely (77% vs 66%); to have been placed on medication that were concordant with the assay than those who were not improved, although this difference did not reach statistical significance.

In this naturalistic, virtual trial of a PGx assay to guide pharmacotherapy in individuals with mental health illness, most users reported improvement in overall health. More pts whose medication was reported as concordant with the Assay reported improvement than those with discordant medications. Data collection is ongoing and updated data will be provided.

Funding Acknowledgements: Genomind

This pilot study aims to explore the feasibility and proof of concept of triple chronotherapy (TCT) as a non-pharmacological, adjunctive intervention in the treatment of acute depression and suicidality in the adolescent population.

Thirty-one adolescents with moderate to severe depression were included in the study. Each participant underwent a 4-day intervention (TCT) which consisted of one night of sleep deprivation followed by three days of sleep phase advancement and daily bright light therapy. Primary outcomes were feasibility and depression, as measured by Hamilton Depression Scale-17 (HAMD-17) scores. Secondary outcomes included severity of illness, anxiety, self-harm, insomnia, and suicidality.

Twenty-nine (94%) adolescents completed the TCT protocol. Twenty-six (84%) of the 31 enrolled patients experienced a reduction in depressive symptoms of at least 50% from baseline; 24 (77%) achieved remission, defined as a HAMD-17 score less than 8. Secondary outcomes showed significant improvement following the 4-day TCT intervention; improvement was sustained through the 7–10 day and 1-month follow-up periods.

This pilot study determined TCT to be a feasible, safe, accelerated, and promising adjunctive treatment for acute depression in the adolescent population. This study has been submitted for publication and is currently under review.

Patient-reported outcomes and preferences rely on reports of the status of a patient’s health condition that comes directly from the patient, without interpretation or qualification by clinicians or investigators. Patient-reported outcomes and preferences have become an accepted approach in drug development. As part of this effort, we assessed the relative importance to patients with schizophrenia of trying a new antipsychotic that might improve symptoms in the context of common antipsychotic side effects, especially weight gain. Information from surveys such as this one can provide pilot guidance about what might be acceptable versus unacceptable trade-offs when considering new therapies for schizophrenia.

We prospectively administered a cross-sectional survey to 250 patients with clinical diagnoses of schizophrenia or schizoaffective disorder, aged ≥18 years, from five US outpatient community clinics, regarding the importance of efficacy and side effects on treatment decisions involving medications. Sixty-four percent (n=160) of the patients were male; mean age was 43 years (range: 18–72 years); mean weight was 91 kg (range: 49–182 kg); and mean body mass index was 30.3 kg/m2 (range: 15.3–63.3 kg/m2).

Patients rated both efficacy and side effects as important attributes of medication for schizophrenia treatment, with 88.5% identifying the ability to think more clearly as an important property of their medication. Patients identified efficacy and side effects as important drivers to take their prescribed medicine (endorsed as very or most important by 94.3% and 84.0% of patients, respectively). Patients identified weight gain, physical restlessness and somnolence as significant side effects of current treatments for schizophrenia (very/most important by 61.5%, 60.4%, and 58.9%, respectively). When asked about willingness to change antipsychotics, anticipated weight gain had a strong negative influence on willingness to try a new antipsychotic, with 44.9% of patients declining to try a medication that would lead to a weight gain of 3–5 kg, and 70.8% of patients declining for an anticipated weight gain of 5–9kg.

Patients living with schizophrenia or schizoaffective disorder are influenced by many factors when considering whether to take their prescribed medication, including efficacy and side effects. It is important for clinicians to assess patient-specific concerns and develop a comprehensive treatment plan to maximize adherence to prescribed therapies.

Funding Acknowledgements: This study was funded by Alkermes, Inc.

Major depressive disorder (MDD) is a highly prevalent and often debilitating condition with a vast impact on modern societies worldwide. Although it interferes significantly with functioning, MDD is frequently unresponsive to conventional treatment approaches and pharmacotherapy failure has been reported in approximately one third of patients. Current knowledge of the exact underlying disease mechanisms is insufficient, and may thus largely contribute to such therapeutic limitations. Optogenetics, a novel study field employing the expression of genetically-encodable light-sensitive proteins in specific cell types, circumvents the limitations of other forms of neuromodulation and enables temporally precise, bidirectional control of cellular activity in well-defined neuronal populations. This strategy has been used successfully to dissect neural pathways and circuitries involved in complex mental diseases such as MDD.

A systematic literature search was conducted using the terms “Optogenetics”, “Depression” and “Major depressive disorder” on the databases MEDLINE, LILACS, SciELO, Pubmed and BIREME. Inclusion criteria were adopted: articles published in the English language from 1971 (description of bacteriorhodopsin as a light-activated regulator of transmembrane ion flow) to 2017 and articles based on experimental studies were selected.

By using highly validated animal models based on the exposure of phenotypically susceptible rodents to different forms of chronic stress, researchers have been able to reproduce the hallmark symptoms of Depression as well as the histopathological abnormalities found in human brain specimens post-mortem. Several brain regions and neuron populations involved in MDD have been identified by use of a variety of molecular resources including viral vectors, genetically engineered animals, multiple promoters and bacterial opsins. Important areas of dysfunction underlying depression including the medial prefrontal cortex, the ventral tegmental area, the nucleus accumbens, the hippocampus and the basolateral amygdala have been investigated by using optogenetic neuromodulation, yielding new insights into the pathological processes underlying MDD. Researchers have been able to pinpoint affected circuitries and employ time-precise light modulation to successfully revert symptoms of MDD, restoring normal function. It is important to highlight that although promising, studies using optogenetics are controversial, largely due to the variable set tools, models and tests employed in research.

Light modulation using optogenetics has greatly aided to establish accurate models to unveil the neurobiological basis of Depression. Further research will continue to help build more complete pathophysiological constructs and pave the way for new treatment strategies.

The association of sleep disorders and post-traumatic stress disorder (PTSD) is almost universal. Nightmares are not only one of the most commonly associated but also featured as a diagnostic criterion for PTSD. PTSD-related nightmares are particularly distressing, may impair functioning and increase risk of suicide. No specific pharmacologic agent has been demonstrated to impair dreaming. Inhibition of PTSD-related nightmares with pramipexole has not heretofore been described. Such a case is presented.

Case study - This 60 year-old male with PTSD and trauma-related nightmares upon introduction of pramipexole 0.5mg PO qHS for Restless Leg Syndrome (RLS) had total elimination of dreams, which recurred upon discontinuation of this agent as a result of insomnia and increased anxiety. A lower dose of 0.375mg qHS provided optimal RLS-symptom control and overall improved tolerance despite nightmare recurrence.

Abnormalities on Neurological examination: Recent recall: 2 of 4 objects without improvement with reinforcement. Able to spell the word “world” forwards but not backwards. Abstract thought impaired. Chemosensory testing: Anosmia and normogeusia. Motor: Drift: mild right pronator drift with right cerebellar spooning and right abductor digiti minimi sign. Reflexes: 3+ brachioradialis and biceps bilaterally, absent ankle jerks. Other: CT scan with and without contrast: normal.

Nightmares related to PTSD may occur during Rapid Eye Movement (REM) sleep and non-REM sleep. Underlying sympathetic activation may lead to disruptive motor behavior similar to that seen in REM sleep behavior disorder. The exact mechanism of action by which inhibition of dreams occurred with use of pramipexole is unclear. Such a response is consistent with prior documented evidence of REM sleep suppression with low-dose pramipexole such as it‘s efficacy in reducing the intensity and frequency of nightmares and dream enactment related to REM sleep behavior disorder. Further research on therapeutic interventions that target nightmares directly may be beneficial for the management of patients with PTSD.

CerefolinNAC (CFLN-NAC) is a prescription medical food reported to help with mild to moderate cognitive impairment [Pamlab 2017]. It contains L-methylfolate calcium (6mg), methylcobalamin (2mg), Schizochytrium (90.3mg), and N-acetylcysteine (NAC) (600mg) [Pamlab 2017]. However, dysgeusia secondary to CFLN-NAC therapy has not heretofore been described.

A 64 year-old female presented with an eight year history of progressively decreased ability to smell and taste of unknown origin. CFLN-NAC was prescribed off-label to treat her hypogeusia and hyposmia. Three days after treatment initiation, her taste sensations gradually returned and she was able to describe food as bitter, salty, sour and sweet. Also, she was able to decipher the taste of different nuts, such as almonds, macadamia, pecans, and peanuts at baseline. However, her taste sensations became distorted and she was unable to distinguish specific foods. She reported that most food tasted bland, but she was still able to sense textures of various foods describing them as, “crunchy, but without taste.” She denied any oral pain, xerostomia, hot flashes, and psychological distress. CFLN-NAC was continued for three months and her hypogeusia improved from 20% to 80%. Her dysgeusia persisted, but remitted once CFLN-NAC was discontinued.

Abnormalities in physical examination: General: scalloped tongue, decreased blink frequency, and hypokinesia. Cranial Nerve (CN) Examination: Olfaction (CN I) Testing: Alcohol Sniff Test: 8 (hyposmia). Pocket Smell Test: 2 (hyposmia). Olfactometer Identification Test: Left: 5 (anosmia); Right: 12 (hyposmia). CN III, IV, VI: saccadization on horizontal eye movement. Motor Examination: hypokinetic movements and 1+ cogwheel rigidity in bilateral upper extremities. Drift Test: bilateral abductor digiti minimi signs with cerebellar spooning. Reflexes: absent patellar and Achilles bilaterally. Hoffman’s Reflex: present bilaterally. Other: Magnetic resonance imaging (MRI) of the brain with contrast was unremarkable.

When treating taste impairments, vitamins and minerals have been found to enhance the effect of non-injured nerves, but they do not repair damaged nerves. The presence of a scalloped tongue may suggest nerve injury of unknown proportion, and can either diminish or alter taste. CFLN-NAC may have enhanced the gustatory stimulus of the non-injured nerves. This transient increase could have either caused her dysgeusia or possibly unmasked the dysgeusia secondary to a scalloped tongue. Notable impairments found in her exam evince Parkinson’s disease as a possible etiology, but structural abnormalities were not seen on brain MRI, making this unlikely. Conversely, the relatively rapid resolution after terminating CFLN-NAC strongly suggests that this is not merely a coincidence, but rather an origin. Those initiated on CFLN-NAC should be queried for new onset of dysgeusia and warrant other treatment options.

Funding Acknowledgements: Smell & Taste Treatment and Research Foundation

Neurological conditions can be influenced by meteorological parameters. Some may predict weather changes, such as migraines [Marrelli 1988], burning mouth syndrome [Hirsch 2017], phantosmia [Hirsch 2013], and Bell’s Palsy [Danielides 2001]. However, climatic conditions inducing headaches in those with ventriculoperitoneal shunt (VPS) placements have not heretofore been described.

A 46-year-old female presented with epochs of headaches coinciding with climatic changes. She had hydrocephalus secondary to infantile meningitis that was treated with a Medtronics Strata II adjustable VPS. After multiple revisions, she noticed a headache occurring only before thunderstorms or snowstorms. These headaches were constant, bilateral, “halo-like” downward pressure located only around her parietal regions. It persists all day and does not dissipate after onset, regardless of the storm passing. She rates it 8/10 on the pain scale, and is exacerbated by jarring, sneezing, and bending forward. It is only alleviated with acetazolamide, diminishing to 0/10. She denies any pain relief when supine, pain radiation, rhinorrhea, auras, or correlating psychological distress.

Abnormalities in physical examination: General: hammer toes. Neurological Examination: Cranial Nerve (CN) Examination: CN III, IV, VI: saccadization on horizontal eye movement and bilateral ptosis (left > right). CN IX, X: right uvula deviation. Motor Examination: left upward-outward drift with a positive left abductor digiti minimi sign. Reflexes: 3+ bilateral biceps, brachioradialis, and patellar; 3+ right tricep and 4+ left tricep. Hoffman's Reflex: positive bilaterally (left > right). Neuropsychological Tests: Mental Status Examination: Recent Recall: 1/4 objects in three minutes without improvement with reinforcement. Go-No-Go Test: 6/6. Animal Fluency Test: 21 (normal). Center for Neurologic Study-Lability Scale: 23 (pseudobulbar affect).

How climatic changes induce VPS headaches remains unclear. Barometric changes have been reported to cause sinus engorgement [Kaliner 2009], somatic pain [Silove 2006] and can worsen anxiety and depression [Delyukov 1999]. Meteorological parameters may have induced or exacerbated her depression and anxiety, amplifying pain perception. Alternatively, barometric pressure can cause an increase in other somatic pains and stresses, which can augment awareness of additional, unrecognized somatic pains. It is also possible for barometric pressure to cause pain via nasal sinus or mucosal engorgement; thus, mimicking her VPS headache. Lastly, however unlikely, her pain may be a result of a transient VPS malfunction. The mechanism for such can be attributed to transient pressure changes caused by fluctuating blood pressure, inducing brief intrinsic intraperitoneal pressure changes. Nevertheless, querying patients suffering from VPS headacheswhether climatic changes play a role in their symptoms is warranted.

Funding Acknowledgements: Smell & Taste Treatment and Research Foundation

ALKS 3831, currently under development for the treatment of schizophrenia, is composed of olanzapine (OLZ) and a fixed dose of 10mg of samidorphan. In a Phase 2 study in stable patients with schizophrenia, ALKS 3831mitigated OLZ-associated weight gain while maintaining an antipsychotic efficacy profile similar to OLZ.

To assess the efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia.

This was a Phase 3, 4-week, randomized, double-blind, active and placebo (PBO)-controlled study of ALKS 3831 in patients with acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Eligible patients (N=403) were randomized 1:1:1 to receive ALKS 3831, OLZ, or PBO. Patients were treated in an inpatient setting for the first 2weeks of the study and could be treated as inpatients or outpatients for the remaining 2weeks. Patients were excluded if they received OLZ within 6months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression–Severity (CGI-S) and CGI–Improvement (CGI-I) scales. Safety and tolerability were assessed as adverse events (AEs).

Of 401 randomized patients who received ALKS 3831, OLZ, or PBO, 91%, 89%, and 83% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6% in both the ALKS 3831and PBO groups, and 7% in the OLZ group). Baseline characteristics were generally similar between groups; however, baseline mean body mass index was higher in the OLZ group than in the ALKS 3831 group. Baseline mean±standard deviation scores were 101.7±11.9 for PANSS total score and 5.1±0.7 for CGI-S scale score. The mean OLZ dose was 18.4mg/day in both active treatment arms. Least squares (LS) mean difference±standard error (SE) vs PBO from baseline to Week 4 in PANSS total score was –6.4±1.8 (P<.001) for the ALKS 3831 group and –5.3±1.8 (P=.004) for the OLZ group. LS mean difference±SE vs PBO from baseline to Week 4 in CGI-S scale score was −0.4±0.1 (P=.002) for the ALKS3831 group and −0.4±0.1 (P<.001) for the OLZ group. The percentage of patients with improvement in PANSS response (≥30% from baseline) at Week 4 was 60%, 54%, and 38% in the ALKS 3831, OLZ, and PBO groups, respectively. The percentage of patients with an improvement in CGI-I scale response (score of ≤2) at Week 4 was 58%, 51%, and 33% in the ALKS 3831, OLZ, and PBO groups, respectively. Discontinuation due to AEs was low in all groups. Common AEs (≥5% in any group) included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia.

Treatment with ALKS 3831 was more effective than PBO, as measured by the PANSS and CGI-S scale, and its antipsychotic efficacy was similar to the active control OLZ. The safety profile of ALKS 3831 was similar toOLZ.

Funding Acknowledgements: This study was funded by Alkermes, Inc.

Slow release is a fundamental feature of long-acting injectable (LAI) antipsychotics. This property allows continuous drug exposure between dosing intervals. However, there can be a significant delay between giving the first LAI dose and achievement of efficacious plasma concentrations. This time period requires additional pharmacologic intervention. Until now, this delay was addressed with one of two strategies: 1) continuing with supplemental oral antipsychotic, or 2) giving more LAI up front (e.g. loading dose). A third strategy has now been developed to reduce the time needed for oral supplementation when starting the LAI aripiprazole lauroxil (AL) from 21days to 1day. A nano-crystalline milled dispersion of AL (ALNCD; brand name ARISTADA INITIO™) was formulated by reducing the AL particle diameter from micron-size particles to nanometer- sized particles. ALNCD has faster dissolution and a shorter half-life than AL and is designed to be used as a single injection along with a single oral aripiprazole dose of 30mg as a 1-day alternative to the 21days of oral aripiprazole supplementation. Here we provide an overview of the new 1-day initiation regimen for starting AL treatment, and demonstrate the relative contributions of each of its components.

A blinded, randomized, phase 1, pharmacokinetic (PK), and safety study compared the 1-day initiation regimen with the 21-day oral aripiprazole regimen. A combination of observed data, and population pharmacokinetic model–based simulations were used to plot plasma aripiprazole concentrations of single doses of ALNCD, 30mg oral aripiprazole, and AL, individually, and all three combined.

The PK profiles of the 1-day and 21-day initiation regimens (both in conjunction with either 441mg or 882mg doses of AL) were comparable, with therapeutically relevant aripiprazole levels achieved within 4days of treatment initiation. The safety profile of the 1-day initiation regimen was similar to the 21-day initiation regimen, and consistent with that of AL. Aripiprazole concentration–time profiles demonstrated that each component delivered aripiprazole to the systemic circulation at different time periods, with the 30mg dose of oral aripiprazole predominant in the first week, followed by ALNCD, and then AL.

The 1-day initiation regimen is well-tolerated and a suitable alternative to 21days of oral aripiprazole supplementation for starting AL. Each component of the 1-day initiation regimen, together with AL, is necessary to provide continuous coverage from treatment initiation until the next regularly scheduled AL injection.

Funding Acknowledgements: This study was funded by Alkermes Inc.

The goal of this study was to determine physician performance in diagnosis and management of postpartum depression (PPD) and to provide needed education in the consequence free environment of a virtual patient simulation (VPS).

∙ A continuing medical education activity was delivered via an online VPS learning platform that offers a lifelike clinical care experience with complete freedom of choice in clinical decision-making and expert personalized feedback to address learner’s practice gaps

∙ Physicians including psychiatrists, primary care physicians (PCPs), and obstetricians/gynecologists (ob/gyns) were presented with two cases of PPD designed to model the experience of actual practice by including use of electronic health records

∙ Following virtual interactions with patients, physicians were asked to make decisions regarding assessments, diagnoses, and pharmacologic therapies. The clinical decisions were analyzed using a sophisticated decision engine, and clinical guidance (CG) based on current evidence-based recommendations was provided in response to learners’ clinical decisions

∙ Impact of the education was measured by comparing participant decisions pre- and post-CG using a 2-tailed, paired t-test; P <.05 was considered statistically significant

∙ The activity launched on Medscape Education on April 26, 2018, and data were collected through to June 17,2018.

∙ From pre- to post-CG in the simulation, physicians were more likely to make evidence-based clinical decisions related to:

∙ Ordering appropriate baseline tests including tools/scales to screen for PPD: in case 1, psychiatrists (n=624) improved from 34% to 42% on average (P<.05); PCPs (n=197) improved from 38% to 48% on average (P<.05); and, ob/gyns (n=216) improved from 30% to 38% on average (P<.05)

∙ Diagnosing moderate-to-severe PPD: in case 2, psychiatrists (n=531) improved from 46% to 62% (P<.05); PCPs (n=154) improved from 43% to 55% (P<.05); and, ob/gyns (n=137) improved from 55% to 73% (P<.05)

∙ Ordering appropriate treatments for moderate-to-severe PPD such as selective serotonin-reuptake inhibitors: in case 2, psychiatrists (n=531) improved from 47% CG to 75% (P<.05); PCPs (n=154) improved from 55% to 74% (P<.05); and, ob/gyns (n=137) improved from 51% to 78% (P<.05)

∙ Interestingly, a small percentage of physicians (average of 5%) chose investigational agents for PPD which were in clinical trials pre-CG, and this increased to an average of 9% post-CG

Physicians who participated in VPS-based education significantly improved their clinical decision-making in PPD, particularly in selection of validated screening tools/scales, diagnosis, and pharmacologic treatments based on severity. Given that VPS immerses physicians in an authentic, practical learning experience matching the scope of clinical practice, this type of intervention can be used to determine clinical practice gaps and translate knowledge into practice.

Funding Acknowledgements: The educational activity and outcomes measurement were funded through an independent educational grant from Sage Therapeutics, Inc.

Cryptococcal Meningitis is a fungal infectious disease of worldwide distribution, primarily associated with underlying immunosuppression conditions such as HIV infection, glucocorticoid treatment, status post organ transplantation and oncological treatments. Prevalence is particularly high in third-world countries where it constitutes one of the primary causes of central nervous system infections and may carry fatal outcomes. We present two cases of Cryptococcal Meningitis that portray the vast spectrum of clinical presentations associated with Cryptococcal Meningitis as well as relevant diagnostic and therapeutic implications.

Case study - These adult otherwise healthy patients presented at a public urban university hospital in southern Colombia. Both had an unusual clinical course and suffered fatal outcomes despite being seemingly immunocompetent at baseline. A diagnosis of hepatic cirrhosis could have been considered a cause of immunosuppression in one of the patients and the diagnostic work-up for the other patient revealed no evidence of immunological deficiency.

Cryptococcal Meningitis affecting immunocompetent individuals has been increasingly reported in recent years. Furthermore, outcomes in this population are particularly worse than those generally affected by the disease. A review of the literature related to the possible immunological mechanisms’ underlying the presented clinical course is included. We emphasize the importance of considering Cryptococcus spp. as a possible etiologic agent among differential diagnoses upon encountering suggestive meningeal conditions in immunocompetent patients.

Key words: Cryptococcus neoformans, Meningitis, Immunocompetent

Funding: None.

Lumateperone is a first-in-class agent in development for schizophrenia that acts synergistically through serotonergic, dopaminergic and glutamatergic systems. Lumateperone is a potent 5-HT2A antagonist, a mesolimbic/mesocortical dopamine phosphoprotein modulator (DPPM) with pre-synaptic partial agonist and post-synaptic antagonist activity at D2, a glutamate GluN2B receptor phosphoprotein modulator with D1-dependent enhancement of both NMDA and AMPA currents via the mTOR protein pathway and an inhibitor of serotonin reuptake.

Lumateperone was evaluated in 3 controlled clinical trials to evaluate efficacy in patients with acute schizophrenia. The primary endpoint was change from baseline on the PANSS total score compared to placebo. In Study ‘005, 335 patients were randomized to receive ITI-007 60mg or 120mg , risperidone 4mg (active control) or placebo QAM for 4weeks. In Study ‘301, 450 patients were randomized to receive ITI-007 60mg or 40mg , or placebo QAM for 4weeks. In Study ‘302, 696 patients were randomized to receive ITI-007 60mg or 20mg , risperidone 4mg (active control) or placebo QAM for 6weeks. Also, an open-label safety switching study was conducted in which 302 patients with stable schizophrenia were switched from standard-of-care (SOC) antipsychotics and treated for 6weeks with lumateperone QPM and then switched back to SOC.

In Studies ‘005 and ‘301, lumateperone (60mg ITI-007) met the primary endpoint with statistically significant superior efficacy over placebo at Day 28. In Study ‘302, neither dose of lumateperone separated from placebo on the primary endpoint; a high placebo response was observed in this study. Across all 3 efficacy trials, lumateperone improved symptoms of schizophrenia with the same trajectory and same magnitude of improvement from baseline to endpoint on the PANSS total score.

Lumateperone was well-tolerated with a favorable safety profile in all studies. In the two studies with risperidone included as an active control, lumateperone was statistically significantly better than risperidone on key safety and tolerability measures. In the open-label safety switching study statistically significant improvements from SOC were observed in body weight, cardiometabolic and endocrine parameters worsened again when switched back to SOC medication. In this study, symptoms of schizophrenia generally remained stable or improved. Greater improvements were observed in subgroups of patients with elevated symptomatology (comorbid symptoms of depression and those with prominent negative symptoms).

Lumateperone represents a novel approach to the treatment of schizophrenia with a favorable safety profile in clinical trials. The lack of cardiometabolic and motor safety issues presents a safety profile differentiated from standard-of-care antipsychotic therapy.

Funding Acknowledgements: Intra-Cellular Therapies, Inc.

To determine whether amphetamine extended-release oralsuspension (AMPH EROS) has an onset of effect at 30minutes postdose inchildren with ADHD.

This randomized, double-blind, 2-treatment, 2-sequence, placebo-controlled crossover pilot study enrolled subjects aged 6 to 12 years withattention-deficit/hyperactivity disorder (ADHD) and ADHD-Rating Scale-5 scores of ≥90th percentile for sex and age. A dose of 5 to 20mg/day of AMPH EROS was determined during a 1-week open-label phase based on medication history, symptom control, and tolerability. Subjects completed a practice laboratory classroom then received one day of double-blind active drug or placebo each in random sequence during 2 double-blind laboratory classroom days. Subjects completed the first double-blind laboratory classroom session, returned to open label drug for 5days then crossed over on day 6 during a second double-blind laboratory classroom session. DB dose was fixed at AMPH EROS 15, 17.5, or 20mg . The primary endpoint was change from predose in the Swanson, Kotkin, Agler, M-Flynn, Pelham rating scale-combined score (SKAMP-C) at 30minutes postdose on two DB days. The key secondary endpoint was change from predose in the SKAMP-C score at 3hours postdose for AMPH EROS compared with placebo. Safety assessments included vital signs and adverse events.

Eighteen subjects were enrolled in the study (14 males and 4 females) with a mean age of 9 years. At both 30minutes and 3hours postdose, changes from baseline in SKAMP-C for AMPH EROS vs. placebo were statistically significant (p<0.01 and p=0.0002, respectively) with corresponding effect sizes of 0.96 and 1.57. Adverse events (>10%) during the open-label phase included upper respiratory tract infection, fatigue, upper abdominal pain, headache, decreased appetite, and affect lability.

AMPH EROS was effective in reducing ADHD symptoms at 30minutes postdose. AEs were mild or moderate and consistent with those of other extended-release amphetamines.

Funding Acknowledgements: Support was provided by Tris Pharma, Inc.