To demonstrate that COVID-19-associated acute psychosis, though rare, can happen in the pediatric patient population. Patients with new-onset psychosis should be tested for COVID-19 infection, and other organic causes of psychosis should also be considered (e.g., delirium, medication-induced psychosis, and catatonia).

Patient X, a 14-year-old female with no known past psychiatric history, presented to the local emergency room following odd behavior for 3 days and having tested positive for COVID-19 2 weeks prior. The patient’s mother reported odd behaviors, including the patient claiming her fish was calling her name and her name was being repeated on TV. She had been moving slowly with occasional staring. The patient’s mother reported episodes in which the patient was repeating phrases over and over and where she would require redirection to a task. When the patient planned to have a bath, her mother noted that she was naked in her room while looking for something and then needed redirection to go take a bath. She did not have any episodes of agitation. A thorough psychiatric evaluation indicated she was experiencing visual hallucinations. Her vitals were within normal ranges, except for a mildly elevated heart rate. The patient was admitted for further testing, assessment, and management. She was started on chlorpromazine 10 mg daily as needed for psychosis.

A complete blood count with differential (CBC), complete metabolic panel (CMP), and thyroid function results were all within the normal range. Urine drug screening was negative. EKG, CSF analysis, chest X-ray, and brain MRI showed no significant abnormalities. Mild background slowing was noted on EEG, with no interictal/epileptiform discharges or any delta brushes. Therefore, a tentative diagnosis of COVID-19-associated psychosis was made. Treated with chlorpromazine 10 mg daily, the patient gradually improved with no hallucinations or bizarre behavior. She was discharged after 5 days and was not prescribed any medication at discharge. Nine days after discharge, the patient was seen by a pediatric neurologist. She did not report any hallucinations or delusions, but her mother reported that the patient moved slowly and had difficulty identifying common objects. An autoimmune panel, physical exam, and repeat EEG were all unremarkable. The neurologist concluded that her psychosis was most likely post-viral sequelae. The patient continued to improve and returned to school over the span of 2 months.

Acute psychosis after COVID-19 infection is a new and emerging diagnosis with no consensus on management strategies for pediatric or adult patient populations. This case highlights the need for clinicians to be vigilant of subtle, fluid psychotic symptoms, in addition to patients’ general mental well-being. We do not have research regarding the long-term consequences of acute psychosis episodes. Further studies are needed to investigate the neuropsychiatric etiology of post-COVID-19 psychosis and the optimum treatment for this group of patients.

No Funding

The study hypothesis is that regardless of "zero-tolerance policies," bullying is still occurring in schools. The study objective is to assess the prevalence of bullying in a child and adolescent psychiatric clinic patient population and gather information from students about their experiences with bullying, the response of school staff, and results of corrective actions taken.

A proposal was approved by the University of Missouri Internal Review Board to conduct this study. 101 randomly selected patients who are students in the mid-Missouri area were interviewed at the University of Missouri Child and Adolescent Psychiatry Clinic. All school districts in the surveyed area currently endorse a zero-tolerance bullying policy. After obtaining a guardian’s consent, each participant was asked a standard series of questions inquiring whether they had been bullied ever or in the past 12 months, bullied someone else, or witnessed bullying. Details including category, location, and action taken were also collected.

Of the 101 study participants, 80% reported having been bullied at some point in their lifetime and 49% in the past year. The most common form of bullying was emotional/verbal, which was reported by 77 participants. 43 participants reported they had been victims of physical bullying. 25 participants reported cyber bullying and 11 reported sexual bullying. Of the 81 patients who reported experiencing bullying, 52% were male and 48% were female. The study population was 75% Caucasian, 11% African American, 7% biracial, and 7% other. The bullied population was 80% Caucasian, 11% African American, 4% biracial, and 5% other. When asked where at school bullying occurs the most, responses were as follows: 23% playground, 21% classroom, 20% hallway, 13% lunchroom, 11% restroom, and 13% somewhere else. 66.3% of participants reported never having bullied someone and 74% of participants responded that they would intervene if they saw someone getting bullied. 67 participants reported that they had previously acted against bullying, and 37% of these stated nothing happened as a result of their action. 22% of participants got the bully to stop and 13% got them to stop temporarily. 16% reported that their bully got in trouble, but 9% reported they themselves got in trouble after taking action.

Despite zero-tolerance policies in place, a significant portion of bullied students reported that no action was taken even after reporting their bully. The threat of suspension or expulsion for the child accused may prevent school staff from taking these reports more seriously. Evidence-based methods, such as Positive Behavioral Interventions and Supports, are recommended to prevent bullying victimization. Many of these methods focus on creating a safe, inclusive environment by positively reinforcing expected behavior. There is also substantial evidence that educational programs can be successful in bullying reduction. As demonstrated by the results of this study, zero-tolerance policies alone are not sufficient bullying prevention. Revision to current policy is necessary to protect students in schools.

No Funding

This is a case report highlighting the side effect of suicidal ideation with lemborexant, a novel agent approved for the treatment of insomnia. A 22-year-old man received care at an outpatient psychiatrist for the treatment of major depressive disorder, persistent depressive disorder, generalized anxiety disorder, social phobia, and insomnia. The patient also has a diagnosis of Loeys-Dietz syndrome, a connective tissue disorder. Following numerous medication trials for both depression and insomnia that resulted in partial remission of mood symptoms without improvement in sleep, he was initiated on lemborexant to address insomnia. He was noted to be denying suicidal ideation at the appointment when lemborexant was prescribed. The patient did not take lemborexant until three days after the appointment, at which time he took the recommended dose of 5 mg at bedtime for insomnia. The patient experienced drowsiness immediately following taking this dose; however, he woke up two hours later with new-onset suicidal ideation. The patient was brought to the hospital for this complaint, and the following evening had attempted suicide by hanging in his hospital room. Laboratory investigations showed normal findings in blood chemistries, complete blood count, thyroid stimulating hormone, vitamin B12 level, vitamin D level, and urine illicit drug screening. Differential diagnosis includes acute reaction to insomnia, medication-induced side effect, and major depressive disorder. He had completed trials for insomnia with zolpidem, hydroxyzine, quetiapine, nortriptyline, and trazodone prior to beginning lemborexant. The patient had no history of suicide attempts in the past, but did experience suicidal ideation following a trial of nortriptyline. In the hospital, the lemborexant was discontinued, and clonidine and clonazepam were initiated at bedtime to address insomnia and ruminative thoughts. The patient was discharged with follow-up at his outpatient psychiatrist after his suicidal ideation was in remission, as well as noted improvement in insomnia. This case highlights new-onset suicidal ideation with subsequent suicide attempt after first use of lemborexant in a patient with major depressive disorder. This case is important given lemborexant is a new medication with limited information about its efficacy and safety in major psychiatric disorders.

No Funding

Recent research has highlighted the increasing ubiquity of smartphone ownership as well as the feasibility of digital interventions within schizophrenia. Digital therapeutics, a subset of digital interventions, have established standards for efficacy and safety and are subject to regulatory oversight as Software as a Medical Device. Here, we present data from a survey that assessed the opportunity and expectations that people with schizophrenia have for a digital therapeutic designed to be delivered on top of antipsychotic pharmacotherapy.

Seventy-five people with schizophrenia completed a 10-item survey. Participants were between 22 and 55 years of age, reported no hospitalizations or medication changes within the past 3 months, and were currently seeing a psychiatrist. For each question, participants were asked to rank responses to provide a clear understanding of their preferences.

Patients with schizophrenia reported the survey items that most impacted their daily life were: difficulty meeting new people (17%) and difficulty setting goals/completing activities in daily life and not being productive in their free time (both at 13%). The greatest unmet treatment needs reported by people with schizophrenia were: improving social skills (19%); reducing distress related to disease (19%); and being more productive in their free time (13%). In terms of expectations for what a digital therapeutic would include, the items reported as most important were: sharing progress with providers (13%); teaching ways to deal with symptoms (13%); and helping to set and achieve goals (12%).

Many of the top unmet needs that people with schizophrenia identified can be uniquely targeted by a digital therapeutic that augments their ongoing standard of care.

Boehringer Ingelheim International GmbH and CLICK Therapeutics, Inc.

AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational, NMDA receptor antagonist with multimodal activity being developed for MDD. 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.

AXS-05 was evaluated in two double-blind, randomized, controlled, 6-week trials. The GEMINI trial (N=327) was placebo-controlled and the ASCEND trial (N=80) used bupropion as the control. Here we focus on efficacy in the first 2 weeks of treatment and present a pooled analysis of the individual items of the MADRS for AXS-05 as compared to control.

In GEMINI, starting at Week 1, AXS 05 was superior (p < 0.05) to placebo on: mean MADRS improvement (7.3 vs. 4.9), MADRS response (15% vs. 7%), CGI-I (22% vs. 13%), CGI-S (0.7 vs. 0.4) and Q-LES-Q-SF (9.0% vs. 5.8%). At Week 2, AXS-05 was also statistically superior to placebo on MADRS remission (17% vs.8%) and on the SDS (6.8 vs. 4.5).

In ASCEND, from Week 2, AXS-05 was superior (p< 0.05) to bupropion on: mean MADRS improvement (12.5vs. 7.8), MADRS remission (26% vs. 3%), and CGI-S (1.41 vs. 0.9).

At Week 1, treatment with AXS-05 resulted in greater improvements (p< 0.05) in reported sadness, inner tension, inability to feel, pessimistic thoughts, and suicidal thoughts, as compared to control. At Week 6, AXS-05 demonstrated significant improvements over control on seven of the ten MADRS items.

In the GEMINI trial, the most commonly reported adverse events were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth.

Treatment with AXS-05 resulted in rapid and broad antidepressant efficacy.

Axsome Therapeutics

Long noncoding RNA nuclear-enriched abundant transcript 1 (lnc-NEAT1) is closely implicated in neurological or degenerative diseases, while its implication in AD is rarely reported. This study aimed to investigate the effect of lnc-NEAT1 knockdown on neuron injury, inflammation, and oxidative stress in AD, as well as its interaction with downstream targets and pathways.

APPswe/PS1dE9 transgenic mice were injected with negative control or lnc-NEAT1 interference lentivirus. Besides, AD cellular model was constructed by amyloid β treatment in mice primary neuron cells; then, knockdown of lnc-NEAT1 and microRNA-193a (miR-193a) was performed alone or in combination.

In vivo experiments revealed that Lnc-NEAT1 knockdown improved cognition in AD mice reflected by Morrison water maze and Y-maze assays. Besides, lnc-NEAT1 knockdown reduced injury and apoptosis, decreased TNF-α and IL-1β levels (indicating lower inflammation level), repressed ROS, MDA but promoted ATP and SOD levels (suggesting lower oxidative stress level), and activated CREB/BDNF and NRF2/NQO1 pathways in hippocampi of AD mice. Notably, lnc-NEAT1 down-regulated miR-193a both in vitro and in vivo; also, it acted as a decoy of miR-193a. In vitro experiments showed that lnc-NEAT1 knockdown decreased apoptosis and oxidative stress, improved cell viability, and also activated CREB/BDNF and NRF2/NQO1 pathways in AD cellular model. Meanwhile, miR-193a knockdown showed the opposite effects, which also attenuated lnc-NEAT1 knockdown-mediated reduction in injury, oxidative stress, and activation of CREB/BDNF and NRF2/NQO1 pathways of AD cellular model.

Lnc-NEAT1 knockdown reduces neuron injury, inflammation, and oxidative stress through activating miR-193a mediated CREB/BDNF and NRF2/NQO1 pathways in AD.

No Funding

Treatments for MDD that can improve both overall depressive and anhedonic symptoms are urgently needed.

AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity being developed for MDD. 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 effect of AXS-05 in improving anhedonic symptoms in MDD.

GEMINI (N=327) was a randomized, double-blind, placebo-controlled, 6-week study, which randomized adults with MDD to AXS-05 (dextromethorphan HBr 45 mg- bupropion HCl 105 mg) or placebo, twice daily. The primary endpoint was change from baseline in the MADRS total score at Week 6. A post-hoc analysis was conducted to determine the impact of AXS-05 versus placebo on the 5-item MADRS anhedonia subscale (MAS).

Baseline MAS scores were 19.8 and 19.6 in the AXS-05 and placebo group, respectively. At Week 1, AXS-05 treatment resulted in a significant mean reduction from baseline in the MAS score of 4.44 versus 2.69 points for placebo (p< 0.001). At Week 6, the mean reduction from baseline in the MAS was 9.70 for AXS-05 compared to 7.22 for placebo (p=0.001). Response rates (≥ 50% MAS improvement) were significantly greater for AXS-05 compared to placebo at Week 1 (p< 0.001) and at every time point thereafter.

Treatment with AXS-05 was generally safe and well tolerated. The most common adverse events being dizziness, nausea, headache, diarrhea, somnolence, and dry mouth.

Treatment with AXS-05 rapidly and significantly reduced anhedonic symptoms as well as overall depressive symptoms.

Axsome Therapeutics

To describe lemborexant and daridorexant for insomnia treatment using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).

Dichotomous outcomes were identified from the two registrational daridorexant randomized controlled trials. Analogous data were then extracted for lemborexant from the two lemborexant registration studies.

Using pooled dosage data, lemborexant had a clinically relevant magnitude of therapeutic effect, as evidenced by NNT values versus placebo <10, and NNH values for lemborexant versus placebo were >10, suggesting that lemborexant is relatively tolerable. When comparing response versus discontinuation because of an adverse event (AE) for Month 3, the LHH ranges 5.2 to 10.4 for lemborexant pooled 5 mg and 10 mg doses (a favorable result). For daridorexant, the efficacy outcomes for pooled 25 mg and 50 mg doses generally result in NNT values versus placebo ≥10; in all instances, doses of 50 mg yield more robust NNT estimates than for the 25 mg dose. The rate of discontinuation because of an AE at Month 3 was higher for placebo than for daridorexant, rendering favorable LHH calculations for daridorexant despite the less robust NNT estimates, with an LHH in the range of 90.9 to 125 for Month 3 when comparing response versus discontinuation because of an AE (a favorable result).

Benefit-risk ratio for lemborexant and daridorexant is favorable as measured by NNT, NNH, and LHH. Indirect comparisons suggest an efficacy advantage for lemborexant and a tolerability advantage for daridorexant.

Eisai Inc.