Bipolar I disorder (BP-I) is associated with a high humanistic and economic burden. Evidence suggests that BP-I is often misdiagnosed as major depressive disorder (MDD), but the unmet needs associated with BP-I misdiagnosis are unknown. This study compares socioeconomic, healthcare-related quality of life (HRQoL), and healthcare resource utilization (HRU) burdens of participants diagnosed with BP-I vs participants who screened as probable for BP-I but were diagnosed only with MDD.

Using responses to the 2020 National Health and Wellness Survey, respondents were categorized into cohorts of potentially misdiagnosed BP-I (i.e., self-reported physician diagnosis of MDD but screened as probable BP-I [mBP-I]) or BP-I (i.e., self-reported physician diagnosis of BP-I, stratified by BP-I severity). Baseline characteristics were evaluated using bivariate analyses. HRQoL (Short Form-36v2 Health Survey [SF36v2] mental and physical component scores, EuroQol Five-Dimension Visual Analogue Scale [EQ-5D VAS]), HRU, were evaluated using multivariable analyses adjusting for key baseline differences.

There were 302 respondents in the mBP-I cohort and 818 in the BP-I cohort (mild=336, moderate=285, severe=197). Adults with mBP-I were similar in age and level of depression and anxiety to those with moderate and severe BP-I. With respect to HRQoL, the mBP-I cohort had significantly worse SF36v2 mental component scores and EQ-5D VAS scores vs the mild BP-I cohort (31.3 vs 40.3 [P<.001] and 60.6 vs 69.4 [P=.01], respectively) and statistically similar scores vs the moderate BP-I cohort. SF36v2 physical component scores were statistically similar to those of the mild BP-I cohort. Respondents with mBP-I reported similar rates of provider (5.5 vs 6.1 [P=.63]) and ER visits (.34 vs .40 [P=.59]) to patients with mild BP-I (but significantly fewer hospitalizations: .08 vs .19 [P=.03]).

Respondents with mBP-I exhibited similar HRQoL scores to those with mild to moderate BP-I. As expected for patients without a formal BP-I diagnosis, HRU was lower for mBP-I patients than moderate or severe BP-I, but comparable with mild BP-I. These results suggest that patients with potentially misdiagnosed BP-I may experience considerable HRQoL and HRU burdens akin to those of patients with mild to moderate BP-I.

AbbVie

Functional recovery is a treatment goal that goes beyond symptomatic remission and encompasses multiple aspects of schizophrenia patients’ lives, including quality of life, physical, and mental functioning. There is evidence that long-acting injectable (LAI) treatments promote adherence and reduce rehospitalisation and functional decline, which could facilitate patients’ ability to reach functional recovery. Despite this, LAIs are underused in the first-episode (FEP) and early-phase (EP) patient population, due to physician hesitancy and concerns around stigma. A Delphi panel was held to gain expert consensus on an approach to the domains and assessment of functional recovery elements in FEP and EP schizophrenia patients.

A literature review and input from a steering committee of 5 experts in psychiatry informed statements development for a three-round modified Delphi process. Round one was conducted via one-to-one video conference interviews, and the successive rounds were conducted via electronic surveys, which enabled international collaboration. Statements on the different domains and assessment for functional recovery were presented to 17 psychiatrists, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK), experienced in the treatment of schizophrenia with LAIs. Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists look at their previous responses in the context of the overall group.

A consensus was reached (defined a priori as ≥80% agreement) on all 27 statements covering the dimensions, assessment, and level of achieved functional recovery for FEP and EP patients. The following domains are important to consider when assessing functional recovery: depression, aggressive behaviour, social interaction, family functioning, education/employment, sexual functioning, and leisure activities. Additionally, panellists reached consensus that dimensions should be minimally impairing, if present (excluding sexual functioning) and asked about at every encounter with the patient (excluding sexual functioning and leisure activities). In summary, this Delphi panel yielded agreement that functional recovery is multidimensional and should be assessed regularly as part of usual care on an individual patient level in FEP and EP schizophrenia patients.

Lundbeck Otsuka Alliance

Schizophrenia is among the top ten causes of years lost due to disability. Goals of treatment are evolving beyond remission of psychotic symptoms to include physical and mental functioning, quality of life, and long-term functional recovery. Evidence has shown long-acting injectables (LAIs) are beneficial for schizophrenia patients by increasing treatment adherence and decreasing relapse and rehospitalisation. This potentially reduces disease progression and facilitates functional recovery. However, LAIs are underused and often seen as a last resort for first-episode (FEP) and early-phase (EP) patients, due to physicians’ lack of familiarity and stigma.

A three-round modified Delphi panel was held to gain expert consensus on an approach to functional recovery in FEP and EP patients with LAIs. A literature review and input from a steering committee of 5 experts in psychiatry informed the development of statements. Round one was carried out via one-to-one video conference interviews, and the subsequent rounds were conducted via electronic surveys, which enabled international collaboration. Delphi panellists were 17 psychiatrists with schizophrenia treatment experience, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK). Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendencies (mode, mean) and variability (interquartile range) of aggregated responses from the previous round were reported to panelists to understand their response in relation to the group.

There was consensus (defined a priori as ≥80% agreement) on the 8 statements relating to long-term treatment goals and LAI links to functional recovery. LAI treatment in FEP and EP patients increases adherence and reduces treatment burden and functional decline compared to the same and other oral medication. Additionally, there was consensus that LAIs lead to better treatment outcome and functional recovery. Other important factors to achieving functional recovery include patient attitude towards treatment and psychoeducation. Furthermore, consensus was reached that functional recovery and quality of life are linked. In summary, this Delphi panel yielded agreement that functional recovery is a reachable goal for FEP and EP patients and can be enhanced using LAIs.

Lundbeck Otsuka Alliance

Psychosis is a common feature of Parkinson’s Disease (PD), affecting approximately 50% of PD patients during their disease course. The INSYTE study was the first prospective, real-world, observational study examining the outcomes of both treated and untreated patients with PD Psychosis (PDP).

PDP patients were enrolled from 76 US academic centers and community sites from 03/21/2017 to 03/08/2021. Patients were included in the final analytical cohort if they had a baseline visit and at least 1 follow-up visit within 3 years; due to the variability of follow-up for each patient within the 3-year period, all study outcomes were assessed in patients with at least one baseline and two follow-up visits within 1 year. No specific visit schedule was imposed; all interactions were established by the investigators. Questionnaires were completed at follow-up visits and assessments focused on PDP treatment utilization, treatment patterns, clinical outcomes, caregiver burden, quality of life, and resource utilization.

760 patients were initially enrolled; 635 patients (84%) were included in the final study group, and 441 patients (69%) were included in the analysis. 281 patients (64%) had no antipsychotic treatment at enrollment (untreated group) vs 160 (36%) who had received an antipsychotic at enrollment (treated group). At enrollment, patients in the untreated vs treated group, respectively, had a mean PD duration of 8.05 vs 10.23 years, mean duration of PDP features of 2.20 vs 3.10 yrs, and had a PDP diagnosis for a mean of 1.42 vs 2.16 yrs. Most patients in the untreated group (n=221, 77%) received no antipsychotics through follow-up. The groups were balanced in terms of age (mean 73.9 vs 73.4 yrs) and sex (65.1% vs 63.1% male). The untreated group had higher rates of hypertension (44.5% vs 36.8%) and diabetes (12.8% vs 8.8%); however, the treated group had higher rates of depression (25.6% vs 41.3%) and anxiety (22.8% vs 26.9%). The percent change from baseline at 12 months in total psychosis, hallucination, and delusion scores for the untreated group showed greater worsening than the treated group: 32.3% vs 29.3%; 29.3 % vs 25.0%; and 29.3 % vs 25.0%, respectively, as did daytime sleepiness scores (51.6% vs 40.8%). Measures of PD severity (non-motor and motor MDS-UPDRS scores) and health-related quality of life showed less worsening for the untreated group vs treated group at 12 months. Caregiver burden (per the ZBI) was lower in the untreated group vs the treated group (81.5% vs 90.0%).

In this descriptive analysis, untreated patients had shorter duration of PD, fewer PDP symptoms at baseline, and lower rates of mental health comorbidities vs treated patients. The untreated PDP patients had greater worsening in their psychosis and sleepiness scores at 12 months versus the treated group, yet remained untreated. Future studies are needed to better understand clinicians’ rationale for withholding PDP treatment.

Acadia Pharmaceuticals, Inc

Psychosis is a common feature of Parkinson’s Disease (PD), with an estimated 50% of PD patients experiencing psychosis (i.e., hallucinations [H] or delusions [D]) at some time during the course of their illness. Pimavanserin (PIM) is the only medication approved in the US for the treatment of H&D associated with Parkinson’s disease psychosis (PDP); however, off-label atypical antipsychotics (AAP) are continuously used. Currently, there are very few real-world studies which evaluate the patient characteristics and clinical outcomes among PD patients residing in the long-term care (LTC) setting within the US, newly initiated on PIM or other AAPs to treat psychosis.

A national LTC database consisting of diagnoses (DX), pharmacy orders (RX), and EHR data linked with the Minimum Data Set (MDS) was used to identify PD patients with a PD DX and 1 PD RX from 01/01/2017 to 09/30/2021 retrospectively. Patient groups were created: PIM group (patients with a PIM RX); AAP group (patients with an AAP RX [and no PIM RX]); and no treatment (No Tx) group (no PIM or AAP RX). All patients were required to have at least 100 days in LTC to be labelled as a resident (≤7 days between discharge and admission were included as LTC stay). Psychosis diagnosis was required at any time for the AAP and No Tx groups. Other medical causes of psychosis beyond PD were not excluded. The index dates were the first RX identified during the study time period for the PIM and AAP groups; and the psychosis DX date for the No Tx group. Incident treatment patients were defined as having no history of PIM or AAP in the 6 months prior to the index date. Patient/clinical characteristics, treatment patterns, and study outcomes were reported using means (SD) and frequencies during the post index period.

There were: PIM group (N=3,120; N=870 incident), AAP group (N=5,880; N=2,396 incident), and No Tx group (N=1,802). The PIM and AAP groups had an average of 415 days and 383 days between the admitting date and the date of RX. The mean age among all groups was 76–77 years and 48–50% were female. PIM group patients were observed to be sicker with higher rates of concomitant dementia, depression, diabetes, and hypertension versus the AAP group or No Tx group. Initial treatments in the AAP group were mostly quetiapine (49%), risperidone (21%), or olanzapine (12%). The descriptive analysis during the 6 months post index showed the outcomes for the incident AAP group to have: higher proportion of falls and aggression events; higher incidence of new DX (physical changes, anxiety disorders, cognitive decline, insomnia, depression, and anticholinergic effects); and higher proportion of new medication orders (anticonvulsants, antidepressants, and benzodiazepines) compared with the incident PIM group.

In this descriptive LTC retrospective analysis, incident PIM patients were shown to have better outcomes versus the AAP group. These findings are subject to study limitations.

Acadia Pharmaceuticals Inc.

The purpose of this case study is to review the clinical presentation and medical work of an adult male who experienced symptomatic hyperammonemia and first-degree atrio-ventricular block in the setting of valproic acid toxicity.

This case involves a 28-year-old African American male with a past psychiatric history of bipolar 1 disorder with psychotic features, antisocial personality disorder, PTSD, and ASD, who was psychiatrically hospitalized for mania and psychosis at a large midwestern university hospital. At the time of evaluation in the emergency department, the patient endorsed suicidal ideation, religious/persecutory delusions, and auditory hallucinations of demons. Zyprexa Zydis was started and titrated to 20 mg every 12 hours, which did not sufficiently improve symptoms. Depakote EC/DR 1000 mg every 12 hours was then added for treatment of mania. Approximately 1 week later, the patient was observed to be somnolent and complained of malaise, nausea, and vomiting.

Labs were collected which showed an elevated ammonia level of 336 umol/L and free valproic acid level of 13.3 mcg/ml. An EKG was performed which showed first-degree atrio-ventricular block with fusion complexes. The patient’s baseline EKG displayed sinus bradycardia with no evidence of atrio-ventricular block. The patient’s CMP was unremarkable except total bilirubin of 1.5 mg/dL and glucose of 104 mg/dL. His lactate was elevated at 1.95 mmol/L. The patient’s troponin and CRP were unremarkable. The patient was medically transferred for management of hyperammonemia and EKG changes. Depakote was discontinued and lactulose 20 g TID was initiated. Patient was placed on telemetry and the first-degree atrio-ventricular block resolved within 24 hours after discontinuation of Depakote. Daily ammonia level, chem 7, and magnesium were collected. Ammonia decreased to 79 and 59 umol/L on consecutive days. Sodium was mildly elevated at 144 on day 2 of medical admission. Poison control was contacted and L-carnitine 990 TID was started for suspected carnitine deficiency. The patient medically recovered after several days and was readmitted to the psychiatric hospital for further psychiatric management.

The patient’s presentation of hyperammonemia and first-degree atrio-ventricular block were likely due to valproic acid toxicity. We suspect that carnitine deficiency contributed to the patient’s valproic acid toxicity at lower-than-expected blood levels. Although antipsychotics can cause prolonged QTc interval, conduction disorders are not typical abnormalities. Caution should be taken when prescribing Depakote to individuals at higher risk of developing toxicity, including those with potential nutritional deficiencies as well as those with limited self-advocacy abilities secondary to psychiatric illness. Rapid identification of side effects, such as valproic acid toxicity, remain crucial for favorable patient outcomes.

No Funding

Methylphenidate is a central nervous system stimulant used as first-line treatment for attention-deficit/hyperactivity disorder (ADHD). CNS stimulant use is associated with increased risk of cardiovascular events such as increased resting heart rate and blood pressure, sudden cardiac death, arrhythmia, and stroke. Its safety profile in recipients of cardiovascular transplants is unknown, and more research is warranted to determine the risk of adverse cardiac events due to stimulant medication in this population.

Clinical case report, n=1

A 19-year-old female with a history of restrictive cardiomyopathy, cardiac arrest, and orthotopic cardiac transplant has been treated with methylphenidate for ADHD for approximately 2 years without incident. The patient was diagnosed with ADHD between the ages of 8 and 10 and historically was treated with stimulant medication. At age 13, she experienced a cardiac arrest after a volleyball game with 4–6 minutes of pulselessness. She was successfully resuscitated and underwent defibrillator placement. It was concluded that the patient had restrictive cardiomyopathy undetected at birth, leading to the need for orthotopic cardiac transplantation at age 16. After her cardiac arrest, the patient’s memory and cognition worsened, and approximately 1 year after her transplant, she was prescribed amantadine. The patient remained untreated for her ADHD until approximately 1.5 years after her cardiac transplant, at which time she underwent neuropsychological testing that showed findings consistent with attention deficit disorder, and was restarted on stimulant medication. Her transplant cardiologist and psychiatrist have collaborated in her ongoing treatment with methylphenidate 40 mg daily and monitoring symptom response and cardiac stability. Because the patient had previously been stable on stimulant medication for many years, it is reasonable to conclude that stimulant medication did not lead to her cardiac arrest. The patient reports that methylphenidate has been helpful in improving her functioning as a college student, through reduction of her ADHD symptoms. The patient’s blood pressure and heart rate remain within an acceptable range and she has not experienced any adverse cardiac events to date while taking methylphenidate.

This case sheds light on the potential to treat cardiac transplant recipients with stimulant medication for ADHD. Although a careful evaluation of risk factors must be undertaken in cooperation with cardiology and other specialists, a role exists for the safe use of stimulant medications in the cardiac transplant population.

No Funding

Patients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy; adjunctive treatment is often used to address this unmet need. Cariprazine (CAR), a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with manic, mixed, or depressive episodes of bipolar I disorder, is under investigation as adjunctive therapy for patients with MDD.

This randomized, double-blind, phase 3 placebo (PBO)-controlled study assessed the efficacy, safety, and tolerability of CAR 1.5 and 3 mg/d as an adjunct to ADT in adult patients with MDD (18–65 years) and inadequate response to ADT alone (NCT03738215). The primary endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impressions (CGI) were also assessed. Treatment response was defined as at least 50% decrease in MADRS total score at week 6.

Patients (n=751) in the modified intent-to-treat population were randomly assigned to CAR 1.5 mg/d+ADT (n=250), CAR 3 mg/d+ADT (n=252), or PBO+ADT (n=249). Mean age was 44.8 years and 73.4% were female; mean baseline total scores were: MADRS=32.5, HAMD-17=25.9, HAM-A= 21.4. Overall, 89.7% of patients completed the study; rates of discontinuation due to adverse events (AEs) and lack of efficacy were 3.6% and 0.5%, respectively. The difference in MADRS total score change from baseline to week 6 was statistically significant after multiplicity adjustment for CAR 1.5 mg/d vs PBO (-14.1 vs -11.5; adjusted P=.0050), but not for CAR 3 mg/d (-13.1; P=.0727). Differences for CAR 1.5 mg/d vs PBO were observed by week 2 (nominal P=.0453) and maintained at weeks 4 (nominal P<.0001) and 6 (nominal P=.0025). At week 6, more CAR 1.5 mg/d patients (44%) than PBO patients (34.9%) responded to treatment (nominal P=.0446). Greater improvement in the CGI-I scores was observed for CAR 1.5 (nominal P=.0026) and 3 mg/d (nominal P=.0076) vs PBO. At week 6, improvement in HAMD-17 total score reached nominal significance for CAR 1.5 mg/d vs PBO (-13.1 vs -11.1; nominal P=.0017), but not for CAR 3 mg/day (-12.2; P=.0783). HAM-A improvement was greater for CAR 1.5 mg/d vs PBO (nominal P=.0370). There were no deaths; 2 serious AEs occurred in each group (CAR: kidney infection, social stay hospitalization; PBO: depression, multiple sclerosis). The most common CAR AEs (≥5% and twice PBO) were akathisia and nausea.

Cariprazine 1.5 mg/d was effective as adjunctive treatment in adults with MDD and inadequate response to ADT. Cariprazine was generally well tolerated, with a safety profile that was consistent with other indications. Together with results from a prior flex-dose study, these results suggest that adjunctive cariprazine may be an effective option for patients with inadequate response to ADT alone.

AbbVie

Cariprazine has been shown to be efficacious in placebo-controlled clinical trials. In this pooled analysis, the safety of cariprazine in patients with major depressive disorder (MDD) with inadequate response to antidepressants was evaluated using data from placebo-controlled studies of up to 8 weeks’ duration and a long-term open-label safety study.

The safety, tolerability, and efficacy of cariprazine as an adjunctive treatment for patients with MDD with inadequate response to antidepressant alone was assessed in five placebo-controlled studies (two 6-week fixed-dose studies [NCT03738215; NCT03739203] and three 8-week flexible-dose studies [NCT00854100; NCT01715805; NCT01469377]) and one 26-week open-label flexible-dose study (NCT01838876). Fixed doses of cariprazine 1.5 and 3 mg/d and flexible doses of 0.1-4.5 mg/d were evaluated. Safety assessments included adverse event (AE) reporting, clinical laboratory tests, weight and other vital signs, and suicide evaluation with Columbia-Suicide Severity Rating Scale (C-SSRS). Pooled analyses of the incidence of safety endpoints overall and within each treatment arm were performed using the most frequent (modal) daily dose taken by patients during the study.

A total of 2,222 MDD patients with an ongoing antidepressant received treatment with cariprazine, representing 370 patient-years of exposure in placebo-controlled and open-label studies. In the placebo-controlled studies, 1,969 patients were randomized to cariprazine (dose range, 0.1–4.5 mg/d) and 1,108 patients were randomized to placebo. Overall, treatment-emergent AEs occurred in 61% of cariprazine- and 48% of placebo-treated patients; discontinuation due to an AE occurred with 6% of cariprazine- and 2% of placebo-treated patients. The 2 AEs that occurred in at least 5% of cariprazine-treated patients and at a rate at least twice the rate in placebo-treated patients were akathisia (cariprazine=11%; placebo=2%) and restlessness (cariprazine=6%; placebo=2%). Changes in metabolic parameters, including shifts in fasting glucose and lipid parameters, were similar in cariprazine- and placebo-treated patients. In the long-term safety study, mean weight change was 1.6 kg over 6 months. In the placebo-controlled and long-term studies, other safety endpoints including laboratory and C-SSRS assessments of suicidality were generally consistent with the safety profile of cariprazine in approved indications of bipolar disorder and schizophrenia.

Cariprazine is generally safe and well-tolerated in MDD patients with inadequate response to antidepressant monotherapy. Safety analysis of 2,222 cariprazine-treated patients with MDD revealed no new safety signals, and the data is consistent with the currently approved prescribing information.

AbbVie

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months, intended for the treatment of schizophrenia and maintenance monotherapy treatment of bipolar I disorder (BP-I). This 32-week trial evaluated the safety, tolerability, and pharmacokinetic profile of multiple-dose administration of Ari 2MRTU 960 in clinically stable adult patients with a diagnosis of schizophrenia or BP-I, versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the treatment of schizophrenia and maintenance monotherapy treatment of BP-I).

This was an open-label, multiple-dose, randomized, parallel-arm trial conducted at 16 sites in the US. Patients were randomized to receive Ari 2MRTU 960 every 56±2 days (n=132) or AOM 400 every 28±2 days (n=134). The primary objective was to establish the similarity of aripiprazole concentrations on the last day of the dosing interval, as well as exposure during the dosing interval (area under the concentration-time curve [AUC]), between Ari 2MRTU 960 and AOM 400 following multiple doses. It was pre-specified that the lower bound of the 90% confidence interval (CI) of the geometric means ratio (GMR) for these parameters must be >0.8.

In the Ari 2MRTU 960 group, 102 patients (77.3%) completed the study; in the AOM 400 group, 92 patients (68.7%) completed the study. The GMR of C56 for Ari 2MRTU 960 to C28 for AOM 400 was 1.011 (90% CI: 0.893, 1.145). The GMR (90% CI) of AUC0–56 for Ari 2MRTU 960 to AUC0–28 for AOM 400 was 1.006 (90% CI: 0.851, 1.190). Mean (standard deviation) maximum aripiprazole plasma concentration was 342 (157) ng/ml after the fourth Ari 2MRTU 960 dose and 344 (212) ng/ml after the eighth AOM 400 dose.

Pharmacokinetic parameters were similar between Ari 2MRTU 960 and AOM 400.

Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Antipsychotic treatment can help improve outcomes in schizophrenia by reducing the risk of relapse and psychiatric hospitalization, and increasing rates of remission and recovery, particularly when used early in the disease course. However, adherence to oral antipsychotics is often poor. Long-acting injectable (LAI) antipsychotic formulations are associated with significant improvements in treatment adherence compared with oral medications, but LAIs are not widely used in early-phase schizophrenia.

An educational training program, called “Prevention in Practice,” was developed to offer clinicians a range of innovative, web-based, patient-centered resources, including virtual role-play and educational films, that aim to improve communication between clinicians and patients and help progress care for patients with early-phase schizophrenia. The program was based on findings from the PRELAPSE study, in which clinicians received training to improve communication with patients. The PRELAPSE trial was a cluster randomized study conducted in 39 mental health centers across 19 US states. Sites were randomized to encourage treatment with the LAI aripiprazole once-monthly 400 mg (AOM 400) or to provide treatment as usual. Eligible patients had a diagnosis of schizophrenia, <5 years of lifetime antipsychotic use, and were aged 18–35 years. The objective was to evaluate whether use of the LAI delayed time to first hospitalization in early-phase schizophrenia, compared with usual care. Clinicians received training on the rationale for LAI use in early psychosis, transitioning to LAIs, and discussing LAIs with patients and families. Communication training included the principles of shared decision-making, suggested responses to frequently asked questions, and role-playing.

In PRELAPSE, the sites randomized to encourage LAI treatment enrolled 234 patients and the sites randomized to usual care enrolled 255 patients. Training clinicians to improve their communication with patients made a difference—91% of patients with early-phase schizophrenia were willing to use LAI treatment at least once in the first 3 months of the study. Furthermore, the results showed that AOM 400 significantly prolonged time to first psychiatric hospitalization compared with usual care (hazard ratio: 0.56 [95% confidence interval: 0.34, 0.92]; p=0.02).

Offering clinicians training to improve their communication with patients, through techniques such as shared decision-making and motivational interviewing, may increase LAI use in early-phase schizophrenia. ”Prevention in Practice” is now available in in different countries and languages.

Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Schizophrenia is a debilitating mental illness that affects patient’s function and quality of life. Estimates indicate a lifetime prevalence of 0.48%, causing up to 13.4 million years of life burdened by disability. 30% of these patients are deemed as having treatment-resident schizophrenia (TRS), a subset of which do not respond to clozapine, the medication designated for TRS. Those that do not respond to clozapine are deemed to have clozapine-resistant schizophrenia (CRS), requiring further augmentation or multiple antipsychotics.

Clozapine only has limited formulations available (oral [PO] and dissolving [ODT]) and has a substantial side effect burden. Most serious among these side effects includes agranulocytosis, which in some cases can cause severe infections such as septicemia. Regular blood draws monitoring for this are vital to prevent this dangerous consequence, but place further burden on patients, requiring weekly to monthly lab work and visits. Other common and burdensome side effects include tachycardia, hypotension, sialorrhea, weight gain, and metabolic syndrome, to name a few. However, treatment for TRS is still needed, and further alternatives must be explored.

Among studies done on clozapine, few compare second-generation antipsychotics head-to-head, and those that do find similar improvement in overall symptom burden among multiple antipsychotics, especially olanzapine and paliperidone (in particular, paliperidone palmitate). Due in part to the improved receptor profile of these medications (especially 5-HT2A, 6, and 7) compared to clozapine, they can have similar or superior effect in patients with TRS without substantial patient side effect and functional burden. Paliperidone palmitate formulations are developing that can be spaced further and further apart, allowing for minimal impact on patient’s livelihood, while demonstrating similar overall effect with improved side effect profile. However, onset of action is slow, and an effective adjunct strategy may be to initially administer olanzapine for the first 6 months until peak effect is expected from paliperidone palmitate, at which point monotherapy with paliperidone is preferred.

Alternative therapies for patients with TRS may be more functional with fewer side effects, and this work indicates a particularly effective strategy may be to pursue paliperidone palmitate monotherapy long-term while utilizing the unique combination of paliperidone and olanzapine in the short-term (first 6 months) while awaiting peak efficacy.

No Funding

Delusions are defined as fixed false beliefs that are not within normal parameters of society, culture, or religion that can be part of psychotic or mood disorders. They can be difficult to treat and, for some inpatient individuals, persistent delusions can make safe discharge impossible. Ketamine is a dissociative agent that has shown promise in treating mood disorders. Despite this, clinicians hesitate to prescribe this when a patient presents with any type of psychotic symptom. There is proof that ketamine is safe to use with psychotic symptoms, and there is growing evidence that it may be a suitable treatment alternative for delusions resistant to other psychopharmacology.

A literature review using articles from multiple databases was conducted to gather supporting evidence on the use of ketamine in the context of psychosis. Since there has not been a reported conducted study specifically for ketamine and delusions, a look into its use for psychosis was done to find links between the neurobiology of delusions and the mechanism of action of ketamine.

Current literature does not demonstrate that ketamine within a therapeutic setting exacerbates psychotic symptoms in those with depression or bipolar disorder, regardless of the presence of psychotic features, nor does it reveal that predisposed patients experience lasting psychotic effects. Furthermore, although ketamine is often used to model schizophrenia, brain connectivity seen during ketamine-induced delusions is opposite to the connectivity seen in delusions in the context of chronic schizophrenia. Regardless of connectivity patterns, ketamine appears to act upon many of the same mechanisms that underlie delusions. There is evidence delusions are characterized by low belief flexibility, high prediction error, and high aberrant salience. An animal model of stress-induced cognitive dysfunction found that ketamine corrected the cognitive flexibility deficits. Ketamine has been shown to alter prediction error in those suffering from major depressive disorder, resulting in greater optimism bias when patients update maladaptive beliefs post-ketamine administration. In respect to aberrant salience, neural networks affecting this include midbrain dopaminergic neurons and their projections to striatal and frontal cortical regions. Studies have shown this effect was reduced by ketamine-induced plasticity in the orbitofrontal cortex.

Psychotic symptoms may not be an absolute contraindication for ketamine treatment. In fact, ketamine could be beneficial in the treatment of various mental illnesses with psychotic features that are not amenable to classical treatment. The dissociative properties may jump-start treatment while waiting for antipsychotics to work. This could significantly reduce hospital stays, especially for patients in long-term facilities.

No Funding

Gustatory sensation in response to tactile stimulation has been reported to occur in only 0.6% of synesthetes and has rarely been formally described.

Case Study: A 29-year-old female with schizoaffective disorder – depressed subtype, two months prior to presentation, began noticing that when she touched objects, she would experience an abnormal taste in her mouth. When she would touch specific items with her fingertips, for instance wood, bedsheets, tables, cups, plates, silverware, metal, trash cans, and toothpaste would induce a bitter taste. Touching wood caused the most intense bitter taste. Touching glass did not precipitate a taste.

Mental Status Examination: Disheveled and guarded with minimal eye contact. Anxious and agitated. She believes people are stalking her and that cell phones, radios, and computers emit radiation which makes her head burn as if it is on fire. She perceived that inanimate objects, such as furniture, were staring at her. Other: CT scan of brain with and without contrast: normal.

This could be due to neural overactivation between brain regions due to a neighborhood effect, with cross-firing of connecting fibers. The cortical taste area of the brain lies within the Brodmann area 43 of the parietal lobe which includes the pre- as well as post-central gyri extending into the parietal operculum. Brodmann areas 3, 1, and 2 in the postcentral gyrus is where the primary sensation for touch is mediated. The stimulation in adjacent and overlapping anatomical structures may be explained by ephaptic transmission with firing of one causing discharge of the second, yclept the adjacency principle.This co-localization hypothesis is further supported by the occurrence of pathological state of seizures which manifest both tactile and gustatory sensation. Such a hypothesis would be supported by Anderson’s 1886 observation discussing a peculiar sensation in the right arm and hand elicited concurrently with a bitter sensation in the mouth. Through an overflow phenomenon, touch may induce a diffuse serotonergic discharge to more remote regions of the brain that may mediate their functions through serotonin, such as taste. Possibly, other pathology may be invoked to explain this synesthesia. A deprived sensory system may be hyper-receptive to stray or overflow of sensations which are then interpreted within the sensorily deprived sensory system, as in Charles Bonnet syndrome. In the chemosensory sphere, sensory deprivation is associated with chemosensory hallucinations. If the patient manifests gustatory deficit, it may have predisposed her to sensitivity to such stray or overflowing sensory stimulus from touch manifesting as gustation. In those who present with synesthesia, investigation of pathology in the sensory system of the receiving concurrent sensation is warranted.

No Funding

Despite recognition in current and past versions of DSM, dissociative identity disorder (DID) remains a controversial psychiatric disorder which hampers its diagnosis and treatment. Factors that lead misdiagnosing of DID are the unfamiliarity with spectrum of dissociative disorders, the existence of feigned DID, the reluctance of individuals with DID to present their dissociative symptoms, and lack of knowledge and appreciation of its epidemiology which is shown to have 1.5% lifetime prevalence. An accurate diagnosis allows the appropriate interventions leading to fewer hospitalizations.

KC is 28 y.o. female with a psychiatric history significant for polysubstance use, PTSD, and GAD, who presented to the ED due concern for DID per mother. Prior to presentation, she had thrashed her mother’s home of which she denies recollection. She has a history of early sexual trauma by her own family. She screened 44 on the Dissociative Experiences Scale (DES). Throughout her hospitalization, she exhibited questionable lapses of disassociation, although there were no noted changes of posture, dress, speech, or acknowledgement of alters. She was discharged on Remeron 15 mg, Risperdal 2 mg, and Prazosin 2 mg with outpatient resources for trauma-based therapy.

DID is characterized by two or more distinct identities or personality that coincide with fluctuating states of consciousness and changing access to autobiographical memory. The neurological similarities between personality states in DID and PTSD subtypes support a trauma-related etiology of DID. Although there are many interviewing tools, the DES has been the most widely used clinically. Although collateral information, detailed history, and DES were concerning for DID, observation did not show distinct dissociative episodes as discussed by collateral (alter described as destructive and cold towards her own infant) although the hospital environment may not have provided enough stress for patient to transition from one personality to another.

The International Society for the Study of Trauma and Dissociation proposes a phase-oriented treatment approach: 1) establishing safety, stabilization, and symptom reduction; 2) confronting, working through and integrating traumatic memories; 3) identity integration and rehabilitation. From inpatient standpoint, phase 1 and 2 may be promptly addressed. Besides initiation of Remeron and Risperdal (consistent with treatment of DID in two prior case reports), implement grounding techniques and coping mechanisms against triggers for dissociative episodes. Inpatient screening can facilitate earlier accurate diagnosis, faster and more targeted interventions, prevent unnecessary direct and indirect societal costs, and, most importantly, improve quality of life for those with the disorder.

No Funding

Cotard is a syndrome characterized by ideas of damnation or rejection, anxious melancholia, and nihilistic delusions concerning one’s own body or existence. Capgras is a syndrome in which the patient believes that the identities of close relatives or friends are replaced by others. Capgras and Cotard delusion are rarely reported in one individual simultaneously, which we will describe in this poster.

DD is a 38-year-old female with history of schizoaffective disorder, bipolar type, PTSD, and reported TBI who presented to the ED exhibiting paranoia and delusions in the setting of medication non-adherence and increased psychosocial stressors. She endorsed her organs were rotting, and that she was stolen by imposters who claim to be her family from birth. Chart review revealed previous hospitalizations involving mania and paranoid delusions; however, these Cotard and Capgras delusions were new. She also had reported TBI injury from domestic abuse, as well as emotional and sexual trauma. Her Cotard delusions resolved with risperidone 6 mg daily and valproic acid 500 mg BID. However, her Capgras delusions were maintained after 22 days of inpatient hospitalization. On discharge, she continued to refuse reconnecting with her family and was subsequently set up with an intensive outpatient program.

Cotard and Capgras delusions are considered to reflect different interpretations of similar anomalous experiences. The persecutory delusions and suspiciousness often noted in Capgras contribute to the patient’s mistaking a change in themselves for a change in others, whereas people who are depressed in Cotard exaggerate the negative effects of the same change whilst attributing it to themselves. Although these two delusions are phenomenally distinct, they may therefore represent attempts to make sense of fundamentally similar experiences. The anatomical origin of these disorders have been reported to be from a disconnection between the temporal cortex and the limbic system as described in a patient with ischemic stroke. DD’s PTSD and TBI with possible damage to her left tempoparietal lobe may have predisposed her to comorbid delusions. Although DD’s Cotard delusions abated with antipsychotic treatment, her Capgras delusions were maintained. Recently losing custody of children may have contributed to the depression that precipitated her Cotard subtype 1 delusion. Her response to risperidone is consistent with a previous case report that highlighted the effectiveness of antipsychotics in the absence of ECT with Cotard delusion. In regards to her ongoing Capgras delusion, the chronic abuse by DD’s family may have led to a more persistent psychodynamically meaningful negation of DD’s sense of relationship to her family.

Capgras and Cotard syndromes, though rare, can present together. Additional studies are needed to understand the pathophysiology and treatment outcomes.

No Funding

Preclinical evidence has identified the trace amine-associated receptor 1 (TAAR1) as a novel regulator of metabolic control. Ulotaront is a TAAR1 and 5-HT1A agonist currently in Phase 3 clinical trials for the treatment of schizophrenia. Here we summarize preclinical results assessing the effects of ulotaront on weight and metabolic parameters.

Effects of ulotaront administration were evaluated on oral glucose tolerance (oGTT), gastric emptying, and in rodent models of weight gain (high-fat diet [HFD]-, corticosterone-, and olanzapine-induced).

Following 15-day oral administration of ulotaront, rats on HFD showed dose-dependent reduction in body weight, food intake, and liver triglyceride content compared to controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in rats switched to ulotaront (vs. vehicle). Consistent with weight-lowering effects in rats, chronic ulotaront treatment normalized corticosterone-induced weight gain in mice. Assessment of oGTT showed a dose-dependent reduction of glucose excursion in response to acute ulotaront administration in naive and diabetic db/db mice. Ulotaront administration also delayed gastric emptying in mice—a likely mechanism driving reductions in glucose excursions during the oGTT. Whole-brain c-fos imaging of ulotaront-treated mice revealed increased neuronal activity in several brain regions associated with regulation of food intake and metabolic signals.

The data indicate that ulotaront not only lacks metabolic liabilities typically associated with antipsychotics but can reduce body weight and improve glucose tolerance in rodent models. The underlying mechanisms may include TAAR1-mediated peripheral effects on glucose homeostasis and/or direct modulation of homeostatic and hedonic neurocircuits regulating energy balance. The beneficial metabolic effects of ulotaront may suggest a substantially improved risk-benefit profile compared to established antipsychotics.

Sunovion Pharmaceuticals Inc. and Otsuka Pharmaceutical Development & Commercialization, Inc.

Innovative therapies to treat individuals with MDD, especially those with comorbid anxiety, are urgently needed.

AXS-05 (dextromethorphan HBr 45 mg-bupropion HCl 105 mg) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan.

To evaluate the effects of AXS-05 on anxiety in MDD.

EVOLVE was an open-label study, in which patients were treated with AXS-05 twice daily for up to 15 months. Subjects had either rolled in after a prior AXS-05 study or were directly enrolled and had a DSM-5 diagnosis of MDD, a MADRS score of ≥25, and had been treated with ≥ 1 antidepressant in the current major depressive episode. A total of 186 patients were enrolled. Efficacy endpoints included MADRS and HAM-A. Here we present the results for the directly enrolled patients (n =146).

Mean baseline HAM-A scores were 15.6. Reductions from baseline to Weeks 1, 2, and 6 were 3.4±5.34 (p< 0.001), 5.5±5.81 (p< 0.001), and 8.6±5.75 (p< 0.001), respectively. Improvements on the HAM-A were durable through Month 12 (-10.2±6.33; p< 0.001). Remission (HAM-A ≤7) rates on the HAM-A at Weeks 1, 2, and 6 were 19.9%, 36.0%, and 58.1%, respectively. Remission at Month 12 was 78.3%.

Long-term treatment with AXS-05 was generally well tolerated. The most commonly reported adverse events were COVID-19 infection (8.9%), nausea (8.9%), headache (7.5%), dry mouth (6.2%), insomnia (5.5%), and dizziness (5.5%).

These data support the use of AXS-05 in patients with comorbid depression and anxiety.

Axsome Therapeutics

Major depressive disorder (MDD) is a heterogeneous condition characterized by depressed mood and/or loss of interest/pleasure in activities, among other symptoms. Most currently available treatments for depression were developed on the hypothesis that depressive symptoms arise from a depletion of monoamines within the central nervous system (CNS). However, clinical understanding has advanced to identify brain network dysregulation as the primary driver of depression, with monoamines playing a lesser role. Prolonged inability to regulate brain networks may lead to the core symptoms and clinical presentation of MDD. Depression has been linked to impaired neuronal activity in brain networks (e.g., central executive network [CEN], default mode network [DMN], and salience network [SN]). It is hypothesized that improvement in depressive symptoms may result from restoring balance in brain networks governing mood.

γ-aminobutyric acid (GABA) is critical for maintaining and restoring excitatory-inhibitory balance in the brain and regulating brain networks. Approximately one-third of neurons in the CNS are GABAergic, regulating network activity throughout the brain, including regions involved in mood, sleep, and cognition. GABA activates GABAA receptors (GABAAR), inhibiting neuronal activity through phasic (via synaptic GABAAR) and tonic (via extrasynaptic GABAAR) currents. Tonic GABA currents may play a particularly important role in regulating network activity, since they produce a large net inhibitory effect and are also involved in controlling the excitability of inhibitory interneurons, the key regulators of rhythmic brain network activity.

Zuranolone is an investigational oral GABAAR positive allosteric modulator and neuroactive steroid. In clinical trials, treatment with zuranolone has shown significant improvement over placebo in depressive symptoms in adults with MDD or postpartum depression, with a generally well-tolerated and consistent safety profile.

The hypothesized mechanism of zuranolone differs from monoamine-based antidepressants and from benzodiazepines. Unlike benzodiazepines, which bind to the α/γ subunit interface in synaptic GABAAR and enhance phasic inhibitory currents, zuranolone binds to the α/β subunit interface present in nearly all GABAAR, leading to enhanced phasic (synaptic) and tonic (extrasynaptic) inhibitory currents. Furthermore, in vitro evidence suggests that whereas benzodiazepines are associated with GABAAR downregulation, zuranolone upregulates the surface expression of GABAAR.

In conclusion, by upregulating GABAAR expression and increasing phasic and tonic inhibitory GABAergic signaling, zuranolone may rapidly restore and maintain excitatory-inhibitory balance in brain networks, thus allowing the brain to potentially respond appropriately to internal and external stimuli.

Sage Therapeutics, Inc., and Biogen Inc.

Opioid use disorder (OUD) is a serious public health threat. Pharmacotherapy, commonly known as medications for opioid use disorder (MOUD), is established as the cornerstone of OUD treatment. MOUDs reduce likelihood of relapse, promote recovery, and save lives. However, many clinicians are still reluctant to use these medications, in part due to inadequate training and experience. In light of the ongoing opioid overdose epidemic, it has become ever more important for clinicians to confidently and thoughtfully deploy these medications to help patients struggling with OUD. To aid busy clinicians, we have put together a review of the extant literature on three FDA-approved pharmacotherapy options—methadone, buprenorphine, and extended-release naltrexone—with a heavy focus on practical clinical application. We discuss how to effectively engage patients with OUD and initiate them on MOUDs—especially when their primary misused drug is fentanyl. We also review novel strategies, such as buprenorphine microinduction, as well as suggested best practice to effectively transition between MOUDs. Finally, we synthesize our review and recommendations in an algorithmic flowchart to provide visually compelling information.

No Funding