United States

Background: Since the FDA has mandated a boxed warning on all psychostimulants due to risks for misuse and death, coupled with nationwide shortages, clinicians have utilized non-stimulants, such as alpha-2-agonists for hyperactivity/impulsivity and the norepinephrine reuptake inhibitor atomoxetine for inattention, as safer alternatives. However, these agents lack comparable efficacy with delayed onset compared to psychostimulants. Insurers require generic atomoxetine prior to covering Viloxazine ER (VER), a novel 5-HT2B antagonist, 5-HT2C partial agonist, and 5-HT7 antagonist. We wanted to know whether patients taking atomoxetine would experience improvement in ADHD symptoms after switching to VER.
Methods: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to FDA guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine; 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; same protocol after treatment with VER. We conducted a retrospective chart review of these 50 patients. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p &lt; 0.05.
Results: From baseline total ADHD-RS-5 mean score (40.3+10.3), improvements were greater on VER (13.9+10.2) than atomoxetine (33.1+12.1) (t = -10.12, p &lt; 0.00001), in Inattention (t = -8.57, p &lt; 0.00001) and in Hyperactivity/Impulsivity (t = -9.87, p &lt; 0.00001). From baseline total AISRS mean score (37.3+11.8), improvements were greater on VER (11.9+9.4) than atomoxetine (28.8+14.9) (t = -4.18, p = 0.0009), in Inattention (t = -3.50, p &lt; 0.004) and in Hyperactivity/Impulsivity (t = -3.90, p &lt; 0.002). 86% of patients on VER reported positive response by 2 weeks versus 14% on atomoxetine. 36% discontinued atomoxetine for side effects, including GI upset (6 patients), irritability (6), fatigue (5), insomnia (1) versus 4% who discontinued VER due to fatigue. 96% preferred VER over atomoxetine with 85% (22/26) able to taper psychostimulants following stabilization on VER. 
Conclusion: Pediatric and adult ADHD patients, who have experienced less than optimal response to atomoxetine, demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on viloxazine extended-release, which deserves consideration as a new first-line ADHD treatment option

AMA Research Challenge 2023

Viloxazine Extended-Release As A Paradigm Shift In The Treatment Of ADHD

Background: Since the FDA has mandated a boxed warning on all psychostimulants due to risks for misuse and death, coupled with nationwide shortages, clinicians have utilized non-stimulants, such as alpha-2-agonists for hyperactivity/impulsivity and the norepinephrine reuptake inhibitor atomoxetine for inattention, as safer alternatives. However, these agents lack comparable efficacy with delayed onset compared to psychostimulants. Insurers require generic atomoxetine prior to covering Viloxazine ER (VER), a novel 5-HT2B antagonist, 5-HT2C partial agonist, and 5-HT7 antagonist. We wanted to know whether patients taking atomoxetine would experience improvement in ADHD symptoms after switching to VER.
Methods: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to FDA guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine; 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; same protocol after treatment with VER. We conducted a retrospective chart review of these 50 patients. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05.
Results: From baseline total ADHD-RS-5 mean score (40.3+10.3), improvements were greater on VER (13.9+10.2) than atomoxetine (33.1+12.1) (t = -10.12, p < 0.00001), in Inattention (t = -8.57, p < 0.00001) and in Hyperactivity/Impulsivity (t = -9.87, p < 0.00001). From baseline total AISRS mean score (37.3+11.8), improvements were greater on VER (11.9+9.4) than atomoxetine (28.8+14.9) (t = -4.18, p = 0.0009), in Inattention (t = -3.50, p < 0.004) and in Hyperactivity/Impulsivity (t = -3.90, p < 0.002). 86% of patients on VER reported positive response by 2 weeks versus 14% on atomoxetine. 36% discontinued atomoxetine for side effects, including GI upset (6 patients), irritability (6), fatigue (5), insomnia (1) versus 4% who discontinued VER due to fatigue. 96% preferred VER over atomoxetine with 85% (22/26) able to taper psychostimulants following stabilization on VER. 
Conclusion: Pediatric and adult ADHD patients, who have experienced less than optimal response to atomoxetine, demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on viloxazine extended-release, which deserves consideration as a new first-line ADHD treatment option

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Background 

Deposition of amyloid plaques in brain is considered as an index event in the pathophysiology of Alzheimer’s disease (AD) which leads to series of events resulting in cognitive impairment. AD commonly involves non-cognitive symptoms like depression, anxiety, etc. We attempted to explore whether amyloid burden is directly related to depressive symptoms, or this relationship is mediated by cognitive symptoms.

Methods 

We examined the relationship between quantitative amyloid PET data (Standardized Uptake Value Ratios), cognition measured with cognitive function instrument (CFI), and depression measured with geriatric depression scale among 4486 cognitively unimpaired older adults who were screened for a multisite secondary prevention trial (A4 study; Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). The relationships among the variables were assessed through path analysis using structural equation modeling (SEM).

Results 

Our path analysis showed that amyloid burden is not directly related to depression and this association is mediated by cognitive performance, objectively measured as well as subjectively reported. All variables were controlled for age and education. Our model showed good fit (Model 1; CFI= 0.0931, RMSEA= 0.058 & Model 2; CFI = 0.9205, RMSEA = 0.086). Greater amyloid burden correlated with greater subjective cognitive impairment (p < 0.001) and greater objective cognitive impairment (p < 0.001). In both models, increased cognitive impairment was associated with increased depression scores (p < 0.001) and (p = 0.03), respectively. 


Conclusion 

Our findings indicate that amyloid burden is not directly correlated with depression, but rather its relationship with depression is mediated through cognitive impairment. This mediation may also be secondary to intermediate steps between amyloid deposition and cognitive alteration. Identifying this relationship will have implications for targeted interventions to mitigate depressive symptoms and improve the quality of life for individuals in the preclinical stages of Alzheimer’s disease.

Associations Between Amyloid Burden, Cognitive Impairment, and Depression in Preclinical Alzheimer's

Background: Anxiety disorders have complex etiologies. However, several key risk factors have been identified, such sex, stress exposure and more recently neuroinflammation. In response to stress, the Hypothalamus-Pituitary-Adrenal (HPA) axis and the Locus coeruleus (LC)-Norepinephrine (NE) system are triggered. While beneficial in the short-term, chronic, and persistent stress exposure results in HPA axis and LC-NE system dysregulation and neuroinflammatory changes, often leading to anxiety-like phenotypes in animal models. Despite the current findings, the role of sex and the link between chronic stress exposure, neuroinflammation, and LC dysregulation in the development of anxiety disorders has not been elucidated.

Methods: This study demonstrates the sex-dependent neuroinflammatory and neuronal changes in the rodent LC using elevated plus maze (EPM), ex-vivo electrophysiology, and immunohistochemistry (IHC). To model chronic stress, male and female adolescent (8-week-old) Sprague Dawley rats were restrained and exposed to predator odorant for two hours per day for ten days over two consecutive weeks.

Results: Two-way ANOVA analysis of EPM reveals a main effect of stress in open arm time (F1,12=5.127, p=0.0429), suggesting increased anxiety-like behaviors in response to chronic stress. Likewise, a main effect of stress was also noted in LC spontaneous firing frequency (F1,73=6.394, p=0.0136) along with other measures of LC neuronal physiology such as Action potential (AP) threshold, afterhyperpolarization, and activation gap. IHC staining for IBA-1, a microglial marker, and Major histocompatibility II (MHC-II), an activation marker within the LC, reveals a reveal a significant increase in microglia (p=0.0001) and activated microglia (p=0.0351) in stressed males relative to control males. In contrast, an opposite trend was noted in females. Furthermore, correlation analysis between percent weight change, a measure of stress induction, and IBA-1 cell counts within the LC demonstrates a significant negative correlation in males (p=0.0113) and no correlations in females suggesting increased male LC neuroinflammation in response to chronic stress.

Conclusion: Our results indicate that chronic stress exposure induces sex-dependent LC neuroinflammation, which may lead to alterations in LC neuronal physiology and influence rodent anxiety-like behaviors. 


Chronic stress induces sex-dependent neuroinflammation and neuronal physiology alterations in the rodent Locus coeruleus

Background: Every year, over 3 million new concussions are diagnosed in the United States. The recovery from these concussions is not yet standardized as the post concussive symptoms (PCS) patients face are influenced by a myriad of medical, social, and psychological problems. Although recent studies have noted a correlation between premorbid psychological conditions and worsened PCS, there is not enough literature that studies a possible relationship between adverse childhood experiences (ACEs) and PCS. ACEs, traumatic events that occur to individuals during their childhood, have been shown to be associated with numerous negative health outcomes. This study aims to identify if higher ACE scores are correlated with worse PCS, or if patients with high ACEs develop a resiliency that is protective against PCS. 



Methods: This is a cross-sectional study of patients recruited from a concussion clinic at Saint Louis University Hospital. The inclusion criteria for this study: (1) patients between ages of 18-80, (2) diagnosed with a concussion or mild traumatic brain injury by their physician, (3) presenting as a new patient or a follow up for concussion care, (4) possess ability to speak and read English. Eligible participants, after completing appropriate consent and HIIPA authorization forms, complete assessments evaluating their ACEs and current PCS. Surveys for this study include: the Adverse Childhood Experiences questionnaire (ACEs), Adult Resilience Measure (ARM), Neuropsychiatric Symptom Inventory (NSI), Patient Healthcare Questionnaire (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7). The data from these assessments is compiled into a HIIPA-compliant spreadsheet. From there, statistical analyses are done to identify possible correlations between ACEs, PCS, ARM scores, depression, and anxiety. 



Results: Values from 66 patients were collected and Pearson Correlation values were subsequently calculated. The analyses yielded the following correlations: NSI and ACEs had a mild positive correlation of 0.19, NSI and ARM had a moderate negative correlation of -0.46, and ACE & ARM had a mild negative correlation of -0.13. Scatterplots with trendlines of these correlations were also created. 



Conclusion: Our results so far indicate a mild positive correlation between PCS and ACE and a moderate negative correlation between PCS and resiliency. There is not a strong correlation between ACE and resiliency.

Influence of Adverse Childhood Experiences on Postconcussive Symptoms

While studies have been performed to analyze the relationship between individuals who have committed sexual offenses and their levels of neuroticism, psychopathy, and narcissism, these three traits have not been analyzed in their relationship to paraphilia diagnoses. The Personality Assessment Inventory (PAI), Hare Psychopathy Checklist Revised (PCL-R), and calculated neuroticism and narcissism scores from the Alternative DSM-5 Model for Personality Disorders (AMPD) of 83 adult males charged with or convicted of sexual offending were reviewed and analyzed for a relationship between the three traits of interest and the presence of a paraphilic diagnosis. Each subject’s forensic evaluation report was reviewed for diagnoses of paraphilic disorders (pedophilic, sadism, exhibitionism, coercive paraphilic disorder/biastophilia), antisocial personality disorder, borderline personality disorder, narcissistic personality disorder, or other personality disorders given at the time of evaluation. The presence of neuroticism and narcissism could not be directly measured from an available inventory; thus, the AMPD was utilized to help approximate these traits. PAI T-score results were used to calculate the approximate equivalent AMPD B-Criterion scores for antisocial personality disorder, borderline personality disorder, and narcissistic personality disorder. While no significant relationship was found for paraphilic diagnoses in general, individuals diagnosed with pedophilic disorder displayed lower mean psychopathy scores. Individuals diagnosed with exhibitionism showed mixed results with higher scores in some facets of psychopathy and lower scores in others. Individuals diagnosed with narcissistic personality disorder displayed increased scores in measures of psychopathy and narcissism, but decreased scores in neuroticism measurements. Individuals diagnosed with paraphilic coercive disorder displayed higher scores in parts of psychopathy measurements. Individuals diagnosed with borderline personality disorder displayed higher levels of neuroticism, which is to be expected. Unsurprisingly, individuals diagnosed with antisocial personality disorder scored higher in measures of antisocial and psychopathic behavior. Individuals diagnosed with a personality disorder showed increased psychopathy and narcissistic scores. 


Neuroticism, Narcissism, and Psychopathy: An Analysis of Personality Traits in Convicted Sex Offenders

Background
Access to mental health services remains limited globally, and with increasing global needs remaining unmet, the need for rapid innovation in mental health care delivery continues to remain clear. Digital mental health apps and artificial intelligence, such as chatbots, have previously been proposed as a solution toward increased access to quality mental health care. Chatbots are digital tools capable of engaging in natural language conversations and mimicking human responses and behaviors, in addition to engaging in task-oriented dialogue with users. The widespread use of digital voice assistants coupled with low-cost availability of smartphone apps may uniquely position conversational agents as digital tools able to increase access to mental health care.
Methods
A systematic literature search was conducted in May 2023, using the PubMed, EmBase, PsychINFO, and Cochrane databases as well as ArXiv and IEEE Xplore. Included were studies that assessed the efficacy of a conversational agent on the treatment of serious mental illnesses (SMI), including mood disorders, anxiety disorders, psychotic disorders, and substance use disorders.
Results
Of the 677 papers reviewed, 21 were included and 656 were excluded. When compared to reviews of the chatbot landscape from 2018 and 2020, there continues to be a lack of standard measures to ensure ease of comparison between studies in this space. Some populations continued to lack representation, while others are now gaining representation. Overall, there were generally positive experiences with chatbots when measured across domains of usability, acceptability, and engagement. The continued degree of heterogeneity between studies in this space, however, makes direct comparison challenging.
Conclusion
Chatbots remain an important technology in consideration of increasing access to mental health services, gaining tremendous interest and popularity since the release of ChatGPT in November 2022. This literature review revealed areas of improvement in this space as well as increased need for standardization of scales used across studies, and the need to include clinician perspectives.

Chatbots in Mental Health Care: An Updated Systematic Review and Meta Analysis

Background:
Neuropsychiatric symptoms (NPS) emerging after the age of 50 may be a risk factor or an early clinical expression of AD dementia. Mild Behavioral Impairment (MBI) is a syndrome of new-onset and persistent NPS in older adults either with or without cognitive impairment. NPS in the context of race and ethnicity have not been studied and the influence of biology or culture on the expression of NPS is unknown.

Method:
Participants over the age of 60 ranging from cognitively normal to mild AD (N = 17,491) from the National Alzheimer’s Coordinating Center were categorized for MBI status (yes/no) using Neuropsychiatric Inventory-Questionnaire (NPI) scores and a published algorithm. MBI prevalence across White non-Hispanics, White Hispanics, African Americans, and Asians was compared using multivariable logistic regression with adjustment for a priori specified confounding factors including diagnostic group, age, sex, and other relevant factors. Among MBI negative participants at baseline, a Cox proportional hazards model was also fit to estimate the relative risk of progression to MBI across race/ethnicity groups.

Result:
After adjustment, White Hispanics were estimated to have a 2-fold higher odds of MBI when compared to White non-Hispanics (OR, 2.03; 95% CI, 1.65-2.50; p<0.001). In contrast, African Americans were less likely than White non-Hispanics to have MBI (OR, 0.79; 95% CI, 0.68-0.92; p<0.003). The odds of MBI were significantly higher among men when compared to women (OR, 1.28; 95% CI, 1.16-1.41; p<0.001). In the prospective analysis, African Americans were estimated to have 26% lower risk of progressing to MBI when compared to White non-Hispanics (RR, 0.74; 95% CI, 0.65-0.84; p<0.001). 

Conclusion:
These findings suggest there are racial/ethnic differences in the prevalence of MBI and the progression to MBI in older adults at risk for or with mild AD dementia. African Americans had a lower likelihood of having MBI and progression to MBI, while White Hispanics had a higher likelihood compared to White non-Hispanics. Future research is warranted to investigate potential biological features or cultural factors such as the differential expression or perception of NPS in older adults that explain these differences.

Neuropsychiatric Symptoms and Alzheimer’s Disease Risk Differences across Racial and Ethnic Groups

Background/Objective: Suicide is a public health crisis for children
and adolescents. Suicidal ideation and suicidal behavior are
important predictors of suicide risk. Peripheral biological correlates of
suicidal ideation and behavior can guide precision care of suicidality.
To assess the current literature landscape of the field, we conducted
a systematic review of peripheral biological correlates for suicidal
ideation and suicidal behavior of children and adolescents.

Method: We searched through 4 databases (PubMed, the Cochrane
Library, Embase, and PsychInfo) from the earliest date to April 2023.
We used MeSH terms with keyword synonyms related to children
and adolescents, suicidality, and peripheral biological correlates. We
excluded reviews, editorials, protocol papers, abstracts, conference
proceedings, abstracts, and non-English studies. We employed two
independent reviewers for the title/abstract screening and full-text
screening. We followed PRISMA guidelines for reporting systematic
review and used JBI risk of bias tool for the screened studies.

Results: A total of 27980 articles were screened by reviewers, and
133 full texts were extracted. The peripheral biological markers are
grouped into physiologic stress response, serotonin system,
neuromodulators, immune system/inflammation, lipid/metabolism,
HP Axis, genetics, and other.

Conclusion: This systematic review provides a valuable synthesis of
the current literature on peripheral biological correlates for suicidality
in children and adolescents. The review identifies potential
peripheral correlates that can serve as valued biomarkers for
suicidality, and areas of needed studies. The review also notes the
feasibility of meta-analysis of specific peripheral biological markers
on this topic. 


Peripheral biological correlates of suicidal ideation and suicidal behavior in children and adolescents: a systematic review

**Scoring is only possible in the semifinals hall**

**Abstract:**



The association between the accelerated pace of epigenetic aging in Bipolar Disorder
and underlying metabolic and inflammatory changes

Background and Objective: The complexities of the human psyche are tough to capture by a Cartesian system. Unfortunately, the medical enterprise takes pride in simplifying the human experience and disease into neatly organized diagnoses. While psychiatry as a field is much better than others in using the phenomenological approach to illness, this art has been slowly replaced with the rigid diagnostic criteria enshrined in the Diagnostic and Statistical Manual (DSM), now in its 5th edition. The phenomenological approach to diagnosis has been criticized for being overly subjective, lacking in theoretical framework, and relying on the metaphysical (spiritual or theological) aspects of the human self. 
However, experienced psychiatrists use their personal and clinical experiences to intuitively understand their patients’ mental-emotional struggles to arrive at the diagnoses without rigidly following the DSM. The objective is to fill the knowledge gap between the theory and the practice of the phenomenological approach to psychiatric diagnosis by the practice of empathic listening (EL). Additionally, we provide empirical and EEG (electroencephalographic) evidence for the theoretical framework and metaphysical aspects of EL. 
Methods and Results: Five detailed interviews were conducted using EL. Analytical autoethnography, a qualitative research method using Grounded Theory, was used to develop narratives. Verbal and non-verbal statements, the subjective thoughts and feelings of the interviewer, and the objective events in these narratives were open-coded to generate qualitative data, which are inductively analyzed to arrive at the Mindfulness-to-Transcendence (MT) framework of the EL process. Additionally, the neurofeedback/EEG recordings from the Brain-Computer-Interface (BCI) devices worn by the psychiatrist/provider and care recipients during their interviews revealed synchronized emergence of alpha/theta/gamma predominant waves which are reported as markers of mindfulness and Transcendence.
Discussion and Conclusion: The Transcendental state of mind is a metaphysical state that transpires during EL assessment. In such a state the psychiatrist’s assessment reaches beyond subjectivity, and their empathic understanding is free from self-identification and caregiver-burnout. Such a transcendental state empowers patients’ self-empathy, a first step in healing. 
This small pilot study serves as a proof of concept that EL assessment aides the phenomenological approach to psychiatric diagnosis. Without subjectivity, the diagnostic assessments may be more accurate than the currently prevalent Cartesian system. Additionally, EL care can prevent compassion burnout among clinical providers. In conclusion, the BCI-neurofeedback-informed EL assessment can be adapted to reinstate the phenomenological approach to psychiatric diagnostic assessment and care using DSM. Medical trainees may gain skills in EL assessments with BCI-evidence-based EL training in their curricula.


Brain-Computer-Interface Devices Informed Empathic Assessment in Psychiatry: Evidence from a Case Series Study

Background: Pulmonary nodules pose a significant diagnostic challenge in clinical practice. These small, often asymptomatic lesions can be benign or malignant, necessitating accurate localization and sampling for appropriate management decisions. Traditional bronchoscopic procedures have limitations in reaching peripheral lung nodules, particularly in challenging locations. Shape-sensing robotic-assisted bronchoscopy, utilizing the IonTM Endoluminal System, has emerged as a potential breakthrough in the field of pulmonary nodule management. This cutting-edge technology combines advanced imaging, robotic control, and shape-sensing capabilities to enhance the precision and efficacy of bronchoscopic procedures. By providing real-time 3D mapping and navigation guidance, it allows physicians to accurately locate and biopsy pulmonary nodules, even in challenging anatomical regions.
However, despite its promising potential, there is still a knowledge gap regarding the experience and outcomes of using shape-sensing robotic-assisted bronchoscopy for pulmonary nodules. This study aims to bridge this gap by investigating the real-world experiences and outcomes of this innovative technology as a solution for accurate pulmonary nodule management.
Methods: A retrospective analysis was conducted using NVivo software at Chandler Regional Medical Center. The analysis focused on patients who underwent shape-sensing robotic-assisted bronchoscopy for pulmonary nodules. Patient demographics, nodule characteristics, procedural details, diagnostic yield, complications, and overall effectiveness were assessed using NVivo.
Results: A total of 9 patients (5 males, 4 females) with suspected lung nodules were included in this NVivo retrospective analysis. The mean age of the patients was 71.3 years (range: 60-77). The commonly involved lobes were the left upper and lower lobes, and the right upper and middle lobes. The sizes of the nodules ranged from 0.3 cm to 3.2 cm. Needle and forceps biopsies were the most common techniques used for tissue sampling, followed by bronchoalveolar lavage (BAL). Positive findings included malignancy (adenocarcinoma), hamartoma, inflammation, infection, and cellular abnormalities. Negative findings indicated the absence of carcinoma, granulomas, malignancy, fungal organisms, and acid-fast bacteria. One rare case of Mantle cell lymphoma, presenting as a cavitary lesion in the lung, was also diagnosed.
Complications were observed in 2 cases, including small pneumothorax, which were appropriately managed. The analysis also revealed gender differences in complications, with females experiencing pneumothorax and minimal bleeding, while males only suffered minimal bleeding.
Conclusion: This study unveils the transformative potential of shape-sensing robotic-assisted bronchoscopy to enhance diagnostic accuracy and reduce complications. This cutting-edge approach
revolutionizes medical practice, empowering physicians with precise tools while minimizing interventions.

Next from AMA Research Challenge 2023

Associations Between Amyloid Burden, Cognitive Impairment, and Depression in Preclinical Alzheimer's