Treatment-resistant depression (TRD) is commonly defined as non-response to ≥2 antidepressant treatment courses of adequate doses and durations in the current episode in patients with major depressive disorder (MDD). Esketamine (ESK) nasal spray was approved by the Food and Drug Administration in March 2019 for the treatment of TRD in adults in conjunction with an oral antidepressant (AD). This study assessed changes in depressive symptoms following ESK initiation among patients with TRD in a real-world setting.

The study was a retrospective longitudinal observational cohort study of adults with TRD who initiated esketamine treatment between March 2019 and June 2022. Data were sourced from the PremiOM™ MDD Dataset (OM1, Boston, MA), a continuously updated cohort of over 440,000 patients with MDD in the United States with linked claims and electronic medical record data. Patients were classified as having TRD if they had ≥1 diagnosis of MDD during the 6 months prior to or on the index date (defined as ESK initiation) and a record of ≥2 unique ADs of adequate dose and duration at any time prior to the index date within the same major depressive episode (MDE; defined as no clean period of ≥180 days without ADs and/or MDD diagnoses). The Patient Health Questionnaire-9 (PHQ-9) was used to measure depressive symptoms. A machine learning model was used to estimate PHQ-9 scores for patients with no documented scores. The latest PHQ-9 score among questionnaires administered in the six months prior to or on the date of first ESK treatment was used as the baseline score. Baseline scores were compared to the latest scores in the 0-3-month and 3-6 month windows after first ESK treatment. A sensitivity analysis excluding the estimated scores was conducted. Marginal models were used to test for differences in post-treatment scores relative to baseline.

The study cohort included 163 patients with a mean age of 49.5 years (standard deviation [SD]=15.4). Most patients were female (58.3%). At baseline, the mean PHQ-9 score was 15.0 (SD=6.7) and 55.8% of patients had either moderately severe or severe depression (PHQ-9 ≥15). Patients experienced statistically significant reductions in PHQ-9 scores of 2.9 points (95% CI: 1.7 to 4.1, p<0.001) in the 0–3-month interval and 4.4 points (95% CI: 3.2 to 5.6, p<0.001) in the 3–6-month interval relative to baseline. The percentage of patients with moderately severe or severe depression (PHQ-9 ≥15) decreased to 34.4% at the 0-3 month interval and 20.9% at the 3-6 month interval. Results were consistent when estimated PHQ-9 scores were excluded.

Among patients with TRD in a real-world setting, PHQ-9 scores significantly decreased in the 6 months following initiation of ESK treatment. Further investigation of longer-term effectiveness of ESK and among key subgroups is warranted.

Janssen Pharmaceuticals, the manufacturer of esketamine

Tinnitus not heretofore been described as the only manifestation of delusional possession in Kandinsky-Clerambault syndrome. Such a case is presented.

Case Report: A 70-year-old left handed (pathological) man, eight years prior to presentation, noted gradual onset of decreased hearing and high- pitched constant tinnitus AU made worse with stress. Initially only present in quiet, it intensified, ultimately present in all situations, even with ambient background noise. He believed that the Devil was inside of his head, had been there for many years, and was making his life unbearable by subjecting him to the tinnitus. Other than the tinnitus, the devil did not cause any other symptoms, nor did it communicate with him in any fashion. In an effort to eliminate the Devil-induced tinnitus, he twice attempted suicide through self-strangulation. The tinnitus persisted despite treatment with mirtazapine and lumateperone.

Abnormalities in physical examination: General: Decreased blink frequency. Continuous fidgeting and generalized tremulousness. Neurological examination: Mental status examination: Hypoverbal. Able to remember 5 digits forwards and 3 digits backwards. Unable to remember any of four objects in 3 minutes with and without reinforcement. Presidents as follows: Biden, Obama, ?. Animal Fluency Test: 7 (Abnormal). Cranial Nerve (CN) Examination: CN I Alcohol Sniff Test: 0 (Anosmia). CN VIII Calibrated Finger Rub Auditory Screening Test: Strong 2 AU. Motor Examination: 1+ cogwheel rigidity in the right upper extremity. Gait Examination: Unstable tandem gait. Reflexes: 1+ throughout. Other: Tinnitus Severity Questionnaire : 38/40 (Severe tinnitus). Tinnitus Handicap Inventory: 94/100 (Grade 5- Catastrophic handicap).

While Kandinsky Clerambault Syndrome, Delusion of Possession Syndrome is uncommon in the United States (Dimkov, 2020; Enoch, 2020), 46% of Italians believe in the Devil (Marra, 1990) and 0.6% of Canadians believe that they have been possessed by a demon (Ross & Joshi, 1992). Although the most common neurological presentation of Kandinsky Clerambault syndrome is glossolalia, sensory phenomenon of anosmia (Chand et al, 2000; Medeiros De Bustos et al, 2014), ageusia (Chand et al, 2000), kinaesthesia (Gedevani et al, 2022), allochiria (Medeiros De Bustos et al, 2014), synesthetic neuralgia (Medeiros De Bustos et al, 2014), cenesthesia (Medeiros De Bustos et al, 2014), pain (Medeiros De Bustos et al, 2014) and anaesthesia (Yap, 1960) have also been described. While tinnitus has not been reported with Kandinsky Clerambault, it has been noted to occur with depression, anxiety (Zöger et al, 2006; Salviati et al, 2013), and psychosis (Frankenburg & Hegarty, 1994; Jain et al, 2017). Given the widespread belief in the general population of the Devil and possession by external entities, assessment of presence of Kandinsky Clerambault Syndrome in those with intractable tinnitus may be worthwhile.

No Funding

Postpartum depression (PPD) is a serious illness where patients (pts) experience depressive symptoms that start during or after pregnancy. Concurrent anxiety symptoms in PPD are common and are associated with poorer outcomes. The Edinburgh Postnatal Depression Scale (EPDS) is a patient-reported instrument used for PPD and may be used concurrently with the clinician-administered Hamilton Rating Scale for Anxiety (HAM-A). Zuranolone (ZRN) is an investigational oral positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid for the treatment of PPD and major depressive disorder in adults. The phase 3, double blind, randomized, placebo (PBO)-controlled SKYLARK study evaluating the efficacy and safety of ZRN 50 mg (ZRN50) in pts with severe PPD met its primary endpoint of change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day (D)15 (−15.6 vs −11.6 for placebo; p<0.001). The percentages of pts achieving HAMD-17 response (≥50% CFB in HAMD-17 total score) and remission (HAMD-17 total score ≤7) were higher in the ZRN group vs PBO. We report a post hoc analysis of the EPDS and HAM-A response and remission rates to assess the effects of ZRN50 on depressive and anxiety symptoms in the SKYLARK study.

Adults aged 18-45 years with severe PPD (baseline HAMD-17 ≥26) were randomized 1:1 to oral once-daily ZRN50 or PBO for 14 days and followed through D45. EPDS and HAM-A response (≥50% CFB in EPDS or HAM-A total score, respectively) and remission (EPDS total score <10 or HAM-A total score ≤7) rates were recorded at D3, D8, D15, D21, D28, and D45. Response and remission rates were modeled using generalized estimating equations for binary responses. Statistical testing was not adjusted for multiplicity; p values and statements of significance are considered nominal. D15 and D45 results are reported.

Among 196 pts randomized and dosed, 170 completed the 45-day study. Significantly greater percentages of pts treated with ZRN achieved EPDS response (52.7% vs 33.7%; p=0.0178) and remission (49.5% vs 33.7%; p=0.0192) at D15 vs PBO and achieved HAM-A response (54.3% vs 37.8%, p=0.0338) and remission (34.8% vs 15.6%; p=0.0050) at D15 vs PBO. Numerically greater percentages of pts achieved EPDS response (57.1% vs 50.6%; p=0.3020) and remission (56.0% vs 47.1%; p=0.0812) at D45 with ZRN vs PBO and achieved HAM-A response (65.5% vs 60.0%; p=0.3066) and remission (44.0% vs 37.6%; p=0.3662) at D45 with ZRN vs PBO.

ZRN50 was associated with improvements in both depressive and anxiety symptoms, which commonly co-occur in individuals with PPD. These results suggest treatment with ZRN may lead to improvements in measures of both depression and anxiety and support the potential role of ZRN as a novel, oral, rapid-acting, 14-day treatment course for PPD.

Sage Therapeutics, Inc. and Biogen Inc. Medical writing and editorial support were provided by Meditech Media, Ltd. and Parexel, and funded by Sage Therapeutics, Inc. and Biogen Inc.

Despite being the gold standard for long term treatment and mortality reduction, medications for opioid use disorder (mOUD) are under utilized despite ongoing efforts to reduce barriers to access, with only 18% of qualifying patients undergoing treatment. Approximately 38% of patients nationally with an opioid use disorder (OUD) have a co-occurring psychiatric diagnosis; however, treatment for these co-occurring illnesses frequently do not occur simultaneously, especially among acutely psychiatrically ill patients. Inpatient psychiatric units often do not initiate patients on mOUD, such as buprenorphine, possibly due to lack of national policy encouraging expanded access. This study involves a pilot mOUD consultation service for patients admitted to inpatient psychiatric units, and aimed to characterize the patients involved, and compare certain variables (such as length of stay (LOS)) to inpatients without an OUD.

This IRB-approved retrospective single-site (level 1 trauma in academic hospital just outside New York City) study examined the medical records of patients who received consultations from our service between January 1st 2018 and August 15th 2020. Demographic and clinical information was collected and analyzed for descriptive statistics. There were no interventions; the primary outcome gathered was average length of stay for patients consulted.

123 patients received consultations during this time period. Patients had an average age of 37 years, identified predominantly as male, and were mostly White. About one third of the population was undomiciled, and almost three quarters were unemployed. Over half of the patients had prior treatment with buprenorphine. The most common primary psychiatric diagnosis was depression (over 50%), followed by bipolar disorders and schizophrenia spectrum illness. About 40% of patients had co-occurring stimulant use, followed by about 30% with marijuana use, and 16% with benzodiazepine use. The average LOS among patients treated with mOUD was not significantly longer than the average LOS for the inpatient units overall. Over half of the patients were established with outpatient or inpatient substance use treatment following discharge from psychiatry.

Our data supports initiating patients with co-occurring OUD and psychiatric illness on mOUD, regardless of severity of acute psychiatric symptoms. Our study did not find that initiating substance use treatment prolonged LOS. Initiating treatment on the psychiatric unit may have increased engagement in outpatient addiction services. Further studies are required to characterize potential benefits.

No Funding

The tentative psychiatric disorder known as Internet Gaming Disorder (IGD) is characterized by persistent and repetitive engagement with video games, often resulting in notable disruptions in daily life, work, and/or education. The American Psychiatric Association (APA) has recognized the need for additional research in this area. The literature suggests a strong correlation between IGD and attention deficit hyperactivity disorder (ADHD), as a meta-analysis suggested an 85% correlation with symptoms of ADHD. In fact, both combined type ADHD and predominantly hyperactive/impulsive ADHD are linked to IGD. This study aims to understand the neurobiological overlap between these comorbid disorders in order to best understand which treatment modalities could best help patients with either symptoms of ADHD or IGD.

Google Scholar and PubMed were explored using search terms including “IGD,” “internet gaming disorder,” “ADHD,” “attention deficit hyperactivity disorder,” and “mechanism” in various permutations. Eighteen studies were included from 58 search results that addressed IGD’s connection to ADHD and their common biological mechanisms.

Findings suggest that In individuals with Internet Gaming Disorder (IGD), there is a decrease in the functional connectivity within brain networks associated with cognitive control, executive function, motivation, and reward. Additionally, structural changes such as reduced gray-matter volume and white-matter density have been observed. Furthermore, comorbidity studies suggest that the executive control networks affected in attention deficit-hyperactivity disorder (ADHD) may increase the vulnerability to developing IGD. Another meta-analysis found that , VBM (voxel-based morphometry) analysis showed disorder-specific GMV abnormality in the putamen among IGD subjects and orbitofrontal cortex in ADHD and shared GMV in the prefrontal cortex. Functionally, fMRI analysis discovered that IGD-differentiating increased activation in the precuneus and shared abnormal activation in anterior cingulate cortex, insular, and striatum. A 119 adolescent case-control study found that after a 6-week treatment period, both groups escitalopram and bupropion demonstrated improvement across all clinical symptom scales compared to the matched control group. Moreover, the bupropion group exhibited greater enhancements in scores on the Clinical Global Impression-Severity Scale, Young Internet Addiction Scale, ADHD Rating Scale, and Behavioral Inhibition Scale compared to the escitalopram group.

The literature findings suggest that individuals with IGD exhibit reduced functional connectivity and structural changes in brain networks associated with cognitive control and reward. Comorbidity studies indicate that executive control networks affected in ADHD may contribute to the vulnerability of developing IGD. These findings are helpful in the assessment and treatment of IGD which currently does not have any official treatment recommendations.

No Funding

The pandemic of coronavirus disease 2019 (COVID-19) has been associated with widespread myriad chemosensory dysfunction with smell loss as high as 99% and taste loss in 89% of those studied (Kim 2021, Paderno 2020, Renaud 2020). Other chemosensory problems, occur often in combination, including dysgeusia and hyposmia (3.2%), dysgeusia and anosmia (3.4%), ageusia and hyposmia (3.4%) and, ageusia and anosmia (8.5%) (Giacomelli, 2020). Hyperosmia has also been reported to be precipitated by COVID-19 infection (Di Stadio 2022, Kamali 2021). COVID-19 induced persistent hyposmia with resolution of smell and taste dysfunction with COVID-19 reinfection has not heretofore been described. Such a case is presented.

Two years prior to the presentation, a 26-year-old right-handed single male developed COVID-19 at which time his sense of smell and taste were totally eliminated. His smell gradually returned to 40-50% of normal whereby he was able to smell everything, but less intensively than he normally did. Furthermore, some odors he experienced in a hyperosmic fashion, such as smoke which was 200% more intense than normal. Prior to COVID-19 exposure, he experienced frequent flavorful eructations which were eliminated after COVID-19 exposure. His taste was initially absent after the COVID-19 exposure, but gradually returned to 60-70% of normal whereby he would taste everything but less intensively. Two years and one month after the initial COVID-19 infection despite being fully vaccinated, he contracted a recurrent COVID-19 infection. Prior to the infection, his smell and taste were 60% of normal. Acutely with the reinfection, his smell and taste ability abruptly dropped to 0% for 16 hours, after which his smell returned to 90% of normal and his taste returned to 100% of normal. During this time period, his other chemosensory problems including dysosmia, dysgeusia, cacogeusia, hyperosmia, and phantosmia all resolved, and his flavorful eructations returned. His sense of smell has remained normal for five months, but his sense of taste has gradually dropped down to 50% of normal.

Abnormalities in Physical Examination: General: Scalloped tongue. Neurological Examination: Cranial Nerve (CN) Examination: CN II: Visual acuity 20/25 OU. CN III, IV, VI: left ptosis. CN V: decreased light touch left V₁ and V₂ . CN IX and X: Uvula deviates to the right. Reflexes: Absent bilateral triceps. Neuropsychiatric Testing: Clock Drawing Test: 10/10 (normal). Animal Fluency Test: 26 (normal). Go-No-Go Test: 6/6 (normal). Center for Neurologic Study Lability Scale: 8/10 (normal). Chemosensory Testing: Olfaction: After the first infection prior to the second infection: Alcohol Sniff Test: 3 (Anosmia). Chemosensory Testing: 1 month after the recurrent COVID-19: Alcohol Sniff Test: 9 (hyposmia). Brief Smell Identification Test: 9 (normosmia). Retronasal Olfaction Test: Retronasal Index: 8 (normosmia). Gustation: Phenylthiocarbamide Taste Test: 9 (normogeusia). Waterless Empirical Taste Test: sweet: 6 (normogeusia) sour: 8 (normogeusia) salty: 6 (normogeusia) bitter: 4 (hypogeusia) brothy: 0 (ageusia) total: 37 (normogeusia).

COVID-19 induced smell loss has been observed to worsen after reinfection, improvement has not been described (Jain, Ear, Nose & Throat Journal, 2021, Lechien, Journal of Internal Medicine, 2021). Possibly the recurrent infection induced hyperosmia which superimposed upon the underlying COVID-19 induced anosmia caused an additive effect, combining together to induce normosmia as opposed to COVID-19 induced hyposmia. This may be due to persistent inflammation of the olfactory bulbs and frontal lobes, inducing excessive neuronal sprouting and associated hyperosmia (Di Stadio, European Review for Medical and Pharmacological Sciences, 2022). Alternatively, COVID-19 may have acted on not only the olfactory nerves but rather on a central basis, enhancing neuronal firings in the anterior insula and hippocampus, areas involved with the olfactory integration and which have enhanced gray matter volume in states of hyperosmia (Wabnegger, 2019). Even though COVID-19 vaccination has been noted to worsen the chemosensory function (Konstantinidis, International Forum of Allergy & Rhinology, 2021), COVID-19 immunization induced improvement in smell has also been reported (Plaza, Annals of Neurology, 2021). It is possible that such an improvement is through infection induced activation of inflammatory immune responses which then acts on the infected olfactory bulbs to reduce pathology. The current case of COVID-19 infection enhancing smell and taste strengthens such an autoimmune explanation. In those with recurrent COVID-19 infection, query and investigation as to presence of improvement of chemosensory dysfunction is warranted.

No Funding

The DSM V-TR places video game addiction, also known as Internet Gaming Disorder (IGD) within the section that suggests the need for additional research. Simultaneously, there has been a remarkable surge in the consumption of video games, with this medium attracting more funding than ever before. Additionally, as this disorder gains increased attention from the psychiatric world, there is a lack of any formal guidelines on the treatment of IGD, or for the superiority of any specific pharmaceutical treatment. The aim of this project focuses on reviewing the neurobiological mechanisms involved in IGD in order to garner a more robust understanding of the neural pathways involved.

Google Scholar and PubMed were explored using search terms including “Internet gaming disorder,” “neurology,” “imaging,” “mechanisms,” and “comorbid” in various permutations. Thirty-seven articles were included from 100 search results that addressed IGD neural and biological mechanisms, and their potential comorbidity with other mental disorders.

The literature suggests that some of the neural findings in IGD are similar to those found in other addiction disorders, which include the following mechanisms: (i) Activation of brain regions associated with reward, as observed in cue exposure and craving studies. Neurotransmitter system studies further suggest the involvement of dopamine-mediated reward mechanisms. (ii) Decreased activity in areas responsible for impulse control and impaired decision-making. (iii) Reduced functional connectivity in brain networks related to cognitive control, executive function, motivation, and reward. Another study suggested that the severity of IGD and depression symptoms predict each other reciprocally. Neurologically, individuals with IGD exhibited enhanced rsFC between the left amygdala and the right dorsolateral prefrontal cortex, inferior frontal gyrus, and precentral gyrus compared to control participants. The baseline amygdala-frontoparietal connectivity negatively predicted the reduction in depression symptoms following a psychotherapy intervention. Other studies suggest that altered executive control mechanisms in attention deficit hyperactivity disorder (ADHD) would be a predisposition for developing IGD. Furthermore, according to the literature, it was indicated that engaging in Internet game playing was linked to reduced white matter density in brain areas responsible for decision-making, inhibiting behavior, and regulating emotions.

The literature findings regarding IGD’s neural and biological pathways, as well as the association of these findings with other disorders such as depressive disorders and ADHD reflect behavioral patterns in individuals with IGD. These mechanisms can be utilized to maximize behavioral and pharmaceutical interventions.

No Funding

Late-onset mania presents as a diagnostic challenge given the interplay between psychiatry and neurology. Neurocognitive disorders, especially the behavioral subtype of Frontotemporal Dementia (FTD), are among one of the differential diagnoses in patients presenting later in life with manic-like symptoms. Here we discuss a case of new-onset manic symptoms in an elderly patient with no prior history of bipolar disorder and conduct a comprehensive literature review to assist with the diagnostic challenges of late-onset mania and dementia with behavioral disturbances.

Mrs. X is a 67-year-old female with bipolar disorder diagnosed 2 months prior to admission who presented to the hospital after a mechanical fall and witnessed seizure-like activity thought to be due to benzodiazepine withdrawal. She was found to have new atrial fibrillation that was stabilized, and clonazepam was resumed. Psychiatry was consulted to assist with manic behaviors. On initial evaluation, Mrs. X presented as anxious, distractible, tangential with pressured speech, increased psychomotor activity, and paranoid towards her husband. She was treated for a urinary tract infection but otherwise workup was unremarkable. Head imaging demonstrated gray matter volume loss that appeared more prominent in the temporal and frontal lobes. Once transferred to the inpatient psychiatry unit, she presented with elevated mood, excessive jocularity, disinhibition, and poor insight. SLUMS of 18 noted poor attention, processing, and short-term recall. She was started on divalproex sodium titrated to 1500 mg daily (VPA level 108 mcg/mL) and olanzapine 25 mg daily. Observations throughout this time included minimal change in affect, elevated mood, memory deficits and social disinhibition. She did have less aggression, minimal paranoia towards her husband and circumstantial thought process although noted with confabulation.

We completed a comprehensive literature review utilizing PubMed and Google Scholar. Search terms included combinations of “late-onset”, “bipolar disorder”, “mania”, “neurocognitive disorder”, “dementia”, “frontotemporal”, “behavioral disturbances”.

Once Mrs. X’s initial delirium resolved, she remained with manic-like symptoms. Collateral, brain imaging of reduced gray matter volume in the frontal and temporal lobes, and lack of response to high doses of a mood stabilizer and antipsychotic favor a probable neurocognitive disorder with behavioral disturbances. Literature reviewed helped to narrow down the differential diagnosis for Mrs. X and allowed for a more comprehensive treatment plan.

Diagnostic elucidation of late-onset mania relies on a comprehensive investigation into psychiatric and non-psychiatric etiologies, a detailed collateral history, and a neuropsychiatric lens. Neurocognitive disorders remain an important differential diagnosis.

No Funding

Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) being investigated for the treatment of attention-deficit/hyperactivity disorder (ADHD). In a phase 2a study in adult males with ADHD, CTN sustained release (CTN SR) treatment significantly improved ADHD Rating Scale-IV (ADHD-RS-IV) total and subscale scores and was well tolerated. Additional efficacy outcomes from this study are reported.

This flexible-dose (CTN SR 200–500 mg/d), single-blind, exploratory study enrolled males aged 18–55 years who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for ADHD and had a baseline ADHD-RS-IV total score ≥28 and Clinical Global Impression-Severity score of ≥4. The study had a screening period, a 1-week placebo run-in, and a 4-week CTN SR treatment phase. Previously unreported secondary outcomes of ADHD-RS-IV change from end of the single-blind placebo run-in and ADHD-RS-IV response (≥30% and ≥50% score reductions) at weeks 1, 2, 3 (on-treatment), and 6 (follow-up) are presented. Analyses were based on observed results using descriptive statistics.

Of 45 patients enrolled, 41 received ≥1 dose of study medication and 37 completed the 4-week treatment phase (mean [SD] age, 38.24 [11.88] years; 91.9% White). At baseline, mean (SD) ADHD-RS-IV total, Inattentive subscale, and Hyperactive/Impulsive subscale scores were 38.7 (6.19), 22.81 (2.55), and 15.89 (4.8), respectively. Mean (SD) changes in ADHD-RS-IV total scores were −11.14 (8.64), −16.14 (11.08), and −20.86 (11.11) at weeks 1, 2, and 3, and −11.53 (8.78) at week 6. Correspondingly, mean (SD) changes in Inattentive subscale scores were −6.32 (4.99), −9.76 (6.4), and −12.16 (6.61) at weeks 1, 2, and 3, and −6.36 (5.7) at week 6, and in Hyperactive/Impulsive subscale scores were −4.81 (4.74), −6.38 (5.94), and −8.7 (5.81) at weeks 1, 2, and 3, and −5.17 (4.33) at week 6. ADHD-RS-IV ≥30% response was observed in 13 (35.14%), 23 (62.16%), and 28 (75.68%) patients at weeks 1, 2, and 3, and in 12 (33.33%) patients at week 6. ADHD-RS-IV ≥50% response was observed in 6 (16.22%), 16 (43.24%), and 23 (62.16%) patients at weeks 1, 2, and 3, and in 8 (22.22%) patients at week 6. The pattern of ≥30% and ≥50% response in Inattentive and Hyperactive/Impulsive subscale scores was similar to that observed with ADHD-RS-IV total score response.

These secondary outcomes support published primary results showing that CTN SR improved ADHD-RS-IV total and subscale scores. CTN SR treatment improved total ADHD symptoms within the first 2 weeks and was well tolerated. These findings support the usefulness of CTN SR, a potential first-in-class NDSRI, in providing rapid treatment benefit to adults with ADHD.

Study Registration: NCT01939353

Previous presentation: ASCP 2023, May 30–June 2, 2023, Miami Beach, FL

Otsuka

Fasedienol (PH94B; 3β-androsta-4,16-dien-3-ol) is a synthetic neuroactive nasal spray from the androstane family of pherines. Intranasal fasedienol activates receptors in peripheral nasal chemosensory neurons connected to subsets of neurons in the olfactory bulbs that in turn are neurally connected to neurons in the limbic amygdala involved in the pathophysiology of SAD and potentially other anxiety and mood disorders. Fasedienol is locally metabolized in the olfactory mucosa without systemic uptake or binding to CNS receptors. The objective of the present study was to compare fasedienol vs. placebo during a public speaking challenge in subjects with SAD.

This was a multi-center, double-blind, randomized, placebo-controlled study (NCT05011396). After screening (Visit 1), all subjects completed Visit 2 (V2, Baseline, placebo nasal spray administered to all subjects) and participated in a 5-minute public speaking challenge (PSC) during which Subjective Units of Distress Scores (SUDS) were recorded. Subjects with SUDS >= to 70 were invited back a week later for the Visit 3 (V3) treatment visit and randomly allocated to receive either fasedienol (3.2 μg intranasally) or placebo, then undergo a second 5-minute PSC, with SUDS scores recorded. After the V3 PSC, subjects completed a Patient Global Impression of Change (PGI-C) and trained raters completed a Clinical Global Impression of Improvement (CGI-I). CGI-I responders were defined as those assigned scores of 1 (very much improved) or 2 (much improved); PGI-C responders reported scores of 1 (very much less anxious) or 2 (much less anxious). ANCOVA with baseline SUDS as a covariate was used to compare change in mean SUDS from V2 to V3 for the subjects administered fasedienol at V3 vs those who received placebo at V3.

Fasedienol-treated patients (n=70) demonstrated a statistically significant greater change in mean SUDS score (least-squares (LS) mean = -13.8) compared with placebo (n=71, LS mean = -8.0), for a difference between groups of -5.8 (p=0.015). The proportion of CGI-I responders was higher in the fasedienol group 37.7% vs. placebo 21.4% (p=0.033), as was the proportion of PGI-C responders: fasedienol 40.6% vs. placebo 18.6% (p=0.003). Fasedienol was well-tolerated with no treatment-emergent adverse events above 1.5% occurrence.

The Phase 3 PALISADE-2 trial results demonstrated that a single dose of fasedienol prior to a stressful PSC produced efficacy on patient-rated SUDS and PGI-C, as well as the clinician-rated CGI-I. The results also confirmed the nasal-amygdala neural circuits as a new portal for administration of pharmaceuticals. The data support continued development of fasedienol as a first-in-class, rapid-onset, well-tolerated treatment option for SAD without addictive properties.

Vistagen Therapeutics

Disruptions of antipsychotic therapy lead to greater symptoms and increased likelihood of relapse. One way to improve medication adherence has been with long-acting formulations, usually administered by injection. Implantable technology has been used to support medication continuity in a few therapeutic areas, e.g., contraception. Despite the potential benefits from implants, this modality is not yet available for maintenance treatment of schizophrenia. Delpor, Inc. is developing an investigational risperidone implant (DLP-114) that releases therapeutic drug levels for up to 12-months. Initial clinical findings are reported below.

The DLP-114 implant is a titanium cylinder approximately 4-5 cm long and 5 mm in diameter. It has membranes mounted on each end and is loaded with a proprietary formulation of risperidone.

The clinical study (NCT04418466) was an open-label study in stable schizophrenia patients to evaluate the safety, tolerability, and pharmacokinetics (PK) of switching from oral risperidone to DLP-114. Schizophrenia patients (N=28), stable on a 2-3 mg dose of oral risperidone for ≥2 weeks were randomized to receive either 6- or 12-month DLP-114 implant devices. Each patient received two DLP-114 devices implanted in the abdomen. Device placements were conducted through a 10-minute procedure using local anesthetic and a custom placement tool. Plasma levels of risperidone and 9-hydroxyrisperidone were tracked over the treatment period, and patients were clinically monitored for signs of relapse. Patient safety (including local tolerance and emergent AEs) and PK were the principal endpoints. Secondary clinical endpoints included PANSS and CGI scores.

The placement and removal procedures were well tolerated. Of 28 enrolled patients, two were lost to follow up and one asked to have the implant removed prior to the end of the dosing period. One nonrelated SAE (pulmonary embolism) was reported. Treatment-related AEs were generally mild, and included implant site pain/soreness/tenderness, drowsiness, ecchymosis, increased appetite, insomnia, and headache. The PK profile in both groups followed near zero-order kinetics with both dosing periods until the end of study. The average steady-state plasma concentration ranged between 7-13 ng/mL. One patient was removed from the study with signs of impending relapse. All other patients were clinically stable for the study duration, with average PANSS scores from 50-60 and CGI-I scores from 3-4. PANSS and CGI-I scores were comparable between the oral and the implant phases of the study.

DLP-114 was well tolerated for up to 12 months. Average PANSS and CGI-I scores were similar between the oral and implant treatment phases, suggesting that, for most patients, DLP-114 provided a comparable therapeutic benefit to 2-3 mg of daily oral risperidone over time. Plasma concentrations of risperidone and 9-hydroxyrisperidone were substantially constant for 6-12 months, but values for steady-state Cave fell slightly below the target of 10-14 ng/mL.

Research reported in this poster was supported by Delpor, Inc. and by the National Institute of Mental Health of the National Institutes of Health under award number R44MH094036.

This case discusses a 33-year-old transgender Army Veteran, diagnosed with co-occurring Bipolar Disorder Type 1 (Bipolar I) and Post-Traumatic Stress Disorder (PTSD), both with psychotic features. The patient exhibited recurrent mood swings, delusions, auditory hallucinations, and passive suicidal thoughts. Concurrent symptoms, such as disrupted sleep, irritability, and intrusive thoughts, complicated diagnosis and treatment. The patient’s medical history included migraines, chronic pain, medication-induced seizures, traumatic brain injury (TBI), and Borderline Personality Disorder.

During the assessment, the patient displayed mood fluctuations, cognitive issues, and intermittent tearfulness. They were averse to sedative medications and preferred non-pharmacological approaches. The Alpha-Stim (Cranial Electrical Stimulator – CES) was recommended for anxiety, depression, insomnia, and chronic pain.

Medication options (Aripiprazole, Lurasidone, and Risperidone) were discussed, and the patient chose Aripiprazole. The treatment plan included Dialectical Behavior Therapy for Borderline Personality Disorder and potential polysomnography to evaluate sleep disorders.

This case underscores the management challenges of co-occurring Bipolar I and PTSD with psychotic features, emphasizing the need for further research on their interplay, impact on functioning, and optimal treatments. It also explores CES as a potential intervention for psychosis during mood episodes.

No Funding

Long-acting injectable antipsychotics (LAIs) have demonstrated better rates of adherence among patients with schizophrenia than oral antipsychotics (OAs). While LAIs often cost more than OAs, better adherence can lead to cost offsets in other areas.

The purpose of this LAI Cost-Offset Value Calculator (LCVC) model is to provide an evidence-based model that estimates total costs and total cost offsets for a hypothetical population of adult patients with schizophrenia treated with atypical LAIs relative to second-generation oral antipsychotics (SGOAs) in the United States.

The model was derived based on studies included in a recent meta-analysis of patients who relapsed while taking an SGOA and were either switched to an atypical LAI or continued an SGOA. User inputs to the model include population size and payer archetype. The model then estimates the difference in adherence rates, relapse rates, hospitalizations, hospital days, hospital costs, emergency department (ED) visits, ED costs, and pharmacy costs, as well as cost offsets overall and by source (ie, hospitalization, ED, pharmacy).

In the base case, representing a hypothetical cohort of 1000 adult patients with schizophrenia in the United States and a composite payer archetype, 1-year pharmacy costs were higher for patients who switched to an LAI relative to patients who continued taking an SGOA ($14,561,971 vs $7,203,142). However, cost offsets were observed for other dimensions of direct costs, including lower ED costs ($1,664,808 vs $2,241,483) and substantially lower hospital costs ($23,623,612 vs $44,195,100) due to fewer relapses (409 vs 508). For some payer archetypes (ie, Medicare and Veteran Affairs), the cost offsets completely covered the higher pharmacy costs for LAIs; for others (ie, Commercial and Medicaid), the cost offsets partially covered the higher pharmacy costs for LAIs, though sometimes substantially.

Despite potential higher pharmacy costs for LAIs, this model supports the conclusion that those costs could be mitigated by cost offsets in other areas, with varying results depending on payer archetype. The LCVC model, parameterized using real-world data extracted from a recent systematic review and meta-analysis, may be helpful for payers in understanding the potential cost offsets of switching patients with schizophrenia who have relapsed while taking OAs to LAIs. To our knowledge, there are no similar studies for schizophrenia that calculate cost offsets based solely on empirical evidence of patients who failed on OAs.

Teva Branded Pharmaceutical Products R&D, Inc.

Treatment resistant depression (TRD) is linked to disproportionate unemployment and productivity burden in the US. Little is known about mental-health (MH)-related disability leave and costs of patients with TRD initiated on esketamine (ESK) versus conventional therapies including transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), or antipsychotic augmentation (AP) in the US.

Adults with evidence of TRD (≥2 unique antidepressants of adequate dose and duration within the same major depressive episode) were selected from Merative™ MarketScan® Commercial and Medicare Supplemental databases (01/2016-01/2023) and classified in four cohorts (ESK, ECT, TMS, and AP) based on therapy initiated (index date) on/after 03/05/2019 (ESK approval date for TRD). Patients had ≥12 months of health plan eligibility pre-index date and disability information available pre-and post-index in the Merative™ MarketScan® Health and Productivity Management database (01/2016-12/2021). MH-related disability days (i.e., short- or long-term) and associated costs (USD 2022) were reported per-patient-per-month (PPPM) for the 6 months pre- and post-index.

The ESK cohort included 107 patients (mean age=45.5 years; female=54.2%), ECT cohort included 55 patients (mean age=47.6 years; female=41.8%), TMS cohort included 443 patients (mean age=46.1 years; female=57.3%) and AP cohort included 4,374 patients (mean age=44.8 years; female=59.1%). At month 6 pre-index, ESK cohort had a mean of 1.7 MH-related disability days PPPM relative to 1.2 days in the TMS, 1.3 days in the ECT, and 0.8 days in the AP cohort while mean MH-related disability costs were $443 PPPM in the ESK cohort relative to $178 in the ECT, $339 in the TMS, and $143 in the AP cohort.

In all cohorts, mean MH-related disability days and costs peaked at month 1 after therapy initiation followed by a decreasing trend. At month 6 post-index versus month 6 pre-index, the mean number of MH-related disability days decreased by 0.4 days PPPM in the ESK cohort, remained the same in the TMS cohort, and increased by 1.6 and 0.1 days in the ECT and AP cohorts, respectively. In the same timeframe, MH-related disability costs decreased by $312 and $123 PPPM in the ESK and TMS cohorts and increased by $353 and $26 in the ECT and AP cohorts, respectively. MH-related disability days and costs were driven primarily by short-term disability.

In this descriptive analysis, mean MH-related disability days and costs trended higher at month 6 before therapy initiation in ESK relative to TMS, ECT, and AP cohorts. ESK initiation was associated with lower mean MH-related disability days and costs at month 6 after versus before initiation. This trend was either not observed or less pronounced among patients with TRD initiated on conventional therapies. Results suggest potential economic and societal gains associated with ESK treatment for TRD.

Janssen Scientific Affairs, LLC

In ESCAPE-TRD (NCT04338321), a randomized, open-label, rater-blinded, long-term, phase 3b trial, augmentation with esketamine nasal spray (ESK) demonstrated increased probability of achieving meaningful clinical benefit versus quetiapine extended release (QUE XR) in patients (pts) with treatment-resistant depression (TRD). This subgroup analysis of ESCAPE-TRD evaluated the incidence, duration, and impact of treatment-emergent adverse events (TEAEs) on treatment discontinuation in adults with TRD treated with ESK or QUE XR according to US prescribing information.

Pts aged 18-64 years were randomly assigned to receive flexibly dosed ESK (56 or 84 mg) or QUE XR (150-300 mg), both consistent with US label dosing and in combination with an ongoing oral antidepressant. The incidence and duration of the most commonly occurring TEAEs, as well as the most common TEAEs leading to treatment discontinuation, were summarized descriptively. All randomly assigned participants receiving ≥1 dose of study drug were included in the safety analyses.

Among the 636 pts included in the subgroup analysis, 316 and 320 were randomly assigned to ESK and QUE XR, respectively; 314 and 316 were included in the safety population. In the combined acute and maintenance phases, TEAEs occurred in 92.0% of pts in the ESK group and 78.5% of pts in the QUE XR group. The most commonly reported TEAEs with ESK or QUE XR in the combined acute and maintenance phases were dizziness (47.1% and 7.9%, respectively), headache (25.5% and 13.0%, respectively), somnolence (15.0% and 23.4%, respectively), and nausea (29.9% and 3.2%, respectively). Across all TEAE events reported in >5% of pts in either arm, 91.8% (5831 of 6351) resolved within 1 day in the ESK arm compared to 11.6% (90 of 776) with QUE XR. For specific TEAE events of clinical interest for ESK, same-day resolution rates for increased blood pressure, sedation, and dissociation in the ESK group were 93.5% (116 of 124), 96.2% (127 of 132), and 99.6% (740 of 743), respectively. The majority of TEAEs of clinical interest in the ESK group that occurred on the same day of dosing resolved within the first 2 hours after dosing. For the most frequently reported TEAEs with QUE XR, same-day resolution rates for somnolence, headache, and fatigue were 7.8% (8 of 103), 49.2% (29 of 59), and 9.5% (4 of 42), respectively. Fewer pts treated with ESK discontinued treatment due to TEAEs compared to QUE XR (4.4% versus 10.6%).

Safety data from this subgroup analysis were consistent with the overall study population as well as the known tolerability profile of each treatment. TEAEs were reported at higher incidence with ESK than with QUE XR; however, the majority of TEAEs occurring with ESK were transient in nature and did not result in a higher rate of treatment discontinuation compared to QUE XR.

Janssen Scientific Affairs, LLC

To compare the per-patient direct and indirect costs associated with achieving remission with esketamine nasal spray plus oral antidepressants (ESK NS+OAD) versus quetiapine extended release plus oral antidepressants (QTP XR+OAD) among patients with treatment-resistant depression (TRD). This comparison was based on a subanalysis of results from the ESCAPE-TRD Phase 3b trial (ex-US) comparing response and remission rates for ESK NS+OAD vs QTP XR+OAD in TRD patients over 32 weeks.

An Excel-based model was developed to estimate the cost-per-remitter for ESK NS+OAD and QTP XR+OAD from the perspective of a commercial insurance plan in the US. Remission rates, response rates, and relapse rates (among patients remitting or responding during the first 8 weeks of treatment) were estimated in 4-week intervals over 32 weeks using data from the ESCAPE-TRD Phase 3b clinical trial comparing ESK NS+OAD versus QTP XR+OAD in patients with TRD. Patients not remitting/responding (non-responders) or experiencing a relapse either stayed on current treatment (i.e., ESK NS+OAD or QTP XR+OAD) or discontinued current treatment and initiated either augmented therapy with antipsychotics (APS) or recurring transcranial magnetic stimulation (rTMS). For basecase analysis, equal proportions of non-responders off-treatment initiated rTMS or augmented therapy with APS. In a scenario analysis, all non-responders off-treatment initiated rTMS. Direct costs, including medical and drug costs, were derived from health economic literature and the RED BOOK® drug pricing database. Indirect costs attributed to work productivity loss from presenteeism and absenteeism were derived from a separate analysis of ESCAPE-TRD patients using the Work Productivity and Activity Impairment: Depression (WPAI:D) questionnaire and US Bureau of Labor Statistics survey results.

The cumulative relapse-free remission rate at 32 weeks was 50% for patients receiving ESK NS+OAD and 33% for patients receiving QTP XR+OAD. In the basecase analysis, the cost-per-remitter (including direct and indirect costs) for ESK NS+OAD was $3,102.17 lower than that of QTP XR+OAD. In the scenario where 100% of non-responders off-treatment were assumed to initiate rTMS, the cost-per-remitter (including direct and indirect costs) for ESK NS+OAD was $15,133.66 lower than that of QTP XR+OAD.

These findings suggest that esketamine nasal spray in conjunction with oral antidepressants is a cost-efficient alternative compared with quetiapine extended release for treatment of TRD for commercial insurance plans. The comparative benefits associated with ESK NS+OAD treatment are driven primarily by better short- and long-term efficacy observed in the trial and particularly pronounced when considering the costs associated with lost productivity.

Janssen Scientific Affairs, LLC

Major depressive disorder (MDD) is the second leading cause of disability in the US, and increases the risk of poor health outcomes. This analysis assessed the real-world benefit and availability of esketamine for patients with difficult-to-treat MDD.

Data were drawn from the Adelphi Real World Depression Disease Specific Programme XII (DSPTM), a cross-sectional retrospective survey of physicians and their patients in the United States in 2022. Physicians reported details for patients with MDD receiving esketamine regarding their prescribed medication (including access), daily functioning and disease improvement whilst receiving esketamine (reported by Clinical Global Impression Improvement Scale (CGI-I)),)) change in depression severity (reported by Clinical Global Impression Severity Scale (CGI-S)) and physician satisfaction. CGI-I responses measured level of disease improvement since the initiation of current depression treatment regimen (‘Very much worse=1’ to ‘Very much improved=7’). CGI-S response options were converted to numerics to measure level of severity change (‘Normal, not at all ill=0’ to ‘Among the most extremely ill patients=6’) and compared at time of esketamine initiation and currently. Physician satisfaction with medication’s ability to achieve patient treatment goals was derived from a numeric scale (where ’Not at all satisfied=1’ to ’Very satisfied=5’).

94 patients with MDD were currently receiving esketamine. Mean age was 44.3 (SD 13.26) and 47% were male. 26% of patients had been receiving esketamine for 0-3 months, 5% for 3-6 months, 15% for 6-12 months, 23% for 1-2 years and 30% for more than 2 years. CGI-I results showed physicians rated depression as improved in 98% of patients receiving esketamine >30 days. CGI-S results showed that patients receiving esketamine 1-30 days had a mean improvement of 1.2 while patients receiving esketamine for >30 days showed mean improvement of 0.9. 80% of physicians reported high satisfaction (score of 4 or 5) with esketamine’s ability to achieve patient treatment goals.

In patients receiving esketamine >30 days physicians reported that 62% could function better socially, 53% had a better quality of life, 41% had increased ability to work, 37% could better meet their own basic needs and 34% had an improvement in overall general health.

When prescribing esketamine, the treatment was only “available without restrictions” for 18% of patients, whilst 82% experienced at least some restrictions.

Physicians reported rapid and sustained clinical improvement among patients with MDD treated with esketamine in this real-world survey.

The analysis described here used data from Adelphi Real World Depression DSP. The DSP is a wholly owned Adelphi Real World product. Janssen is one of the multiple subscribers to the DSP.