Neal D Ryan

• University of Pittsburgh

Introduction Post-Traumatic Stress Disorder (PTSD) entails behavioral changes with increased risk of suicide, and there is no consensus on the preferred antidepressants for treatment of those PTSD patients who are at elevated risk for suicide. Methods We conducted a clinical trial emulation study comparing suicide-related events (SREs) among those...

Background/Objectives: Comorbid post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) patients are at a significantly higher risk of adverse outcomes, including opioid use disorder, depression, suicidal behaviors, and death, yet limited treatment options exist for this population. This study aimed to build on previous research by inc...

Anhedonia emerges during adolescence and is characteristic of severe mental illness (SMI). To understand how anhedonia emerges, changes with time, and relates with other symptoms, there is a need to understand patterns of this symptom’s course reflecting change or stability—and associations with clinical symptoms and neural reward circuitry in adol...

Importance Suicide is a leading cause of death in US youths. Objective To assess whether screening with supplemental items 10 to 13 on the Patient Health Questionnaire–9 modified for teens (PHQ-9M) improves prediction of youth suicide attempts beyond the information provided by the first 9 items alone (the PHQ-9). Design, Setting, and Participant...

Background Extracting research of domain criteria (RDoC) from high-risk populations like those with post-traumatic stress disorder (PTSD) is crucial for positive mental health improvements and policy enhancements. The intricacies of collecting, integrating, and effectively leveraging clinical notes for this purpose introduce complexities. Methods...

Background Extracting research of domain criteria (RDoC) from high-risk populations like those with post-traumatic stress disorder (PTSD) is crucial for positive mental health improvements and policy enhancements. The intricacies of collecting, integrating, and effectively leveraging clinical notes for this purpose introduce complexities. Methods...

Background Identifying co-occurring mental disorders and elevated risk is vital for optimization of healthcare processes. In this study, we will use DeepBiomarker2, an updated version of our deep learning model to predict the adverse events among patients with comorbid post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD), a high-ris...

Prediction of high-risk events amongst patients with mental disorders is critical for personalized interventions. We developed DeepBiomarker2 by leveraging deep learning and natural language processing to analyze lab tests, medication use, diagnosis, social determinants of health (SDoH) parameters, and psychotherapy for outcome prediction. To incre...

Study objectives Healthy sleep is important for adolescent neurodevelopment, and relationships between brain structure and sleep can vary in strength over this maturational window. Although cortical gyrification is increasingly considered a useful index for understanding cognitive and emotional outcomes in adolescence, and sleep is also a strong pr...

Objective: Positive associations between therapeutic alliance and outcome (e.g. youth symptom severity) have been documented in the youth anxiety literature; however, little is known about the conditions under which early alliance contributes to positive outcomes in youth. The present study examined the relations between therapeutic alliance, sess...

Study objectives Healthy sleep is important for adolescent neurodevelopment, and relationships between brain structure and sleep can vary in strength over this maturational window. Although cortical gyrification is increasingly considered a useful index for understanding cognitive and emotional outcomes in adolescence, and sleep is also a strong pr...

Background Prediction of high-risk events in mental disorder patients is crucial. In our previous study, we developed a deep learning model: DeepBiomarker by using electronic medical records (EMR) to predict suicide related event (SRE) risk in post-traumatic stress disorder (PTSD) patients. Methods We applied DeepBiomarker2 through data integratio...

Objective To assess medication adherence and factors associated with poor adherence in youth with bipolar disorder followed from adolescence through young adulthood. Method Participants with bipolar disorder recruited through the Course and Outcome of Bipolar Youth (COBY) study were included in this study if they were prescribed psychotropic medic...

Introduction Prediction of high-risk events amongst patients with mental disorders is critical for personalized interventions. In our previous study, we developed a deep learning-based model, DeepBiomarker by utilizing electronic medical records (EMR) to predict the outcomes of patients with suicide-related events in post-traumatic stress disorder...

The goal of this study was to examine the relation between real-world socio-emotional measures and neural activation to parental criticism, a salient form of social threat for adolescents. This work could help us understand why heightened neural reactivity to social threat consistently emerges as a risk factor for internalizing psychopathology in y...

BACKGROUND Lack of quantifiable biomarkers is a major obstacle in diagnosing and treating depression. In adolescents, increasing suicidality during antidepressant treatment further complicates the problem. OBJECTIVE We sought to evaluate digital phenotypes for the diagnosis and treatment response of depression in adolescents through a newly develo...

Background: Lack of quantifiable biomarkers is a major obstacle in diagnosing and treating depression. In adolescents, increasing suicidality during antidepressant treatment further complicates the problem. Objective: We sought to evaluate digital biomarkers for the diagnosis and treatment response of depression in adolescents through a newly de...

The goal of this study was to examine the relationship between real-world socioemotional measures and neural activation to parental criticism, a salient form of social threat for adolescents. This work could help us understand why heightened neural reactivity to social threat consistently emerges as a risk factor for internalizing psychopathology i...

Purpose: We examined whether interindividual differences in naturalistic sleep patterns correlate with any deviations from typical brain aging. Methods: Our sample consisted of 251 participants without current psychiatric diagnoses (9-25 years; mean [standard deviation] = 17.4 ± 4.52 yr; 58% female) drawn from the Neuroimaging and Pediatric Slee...

Background Sexual minority youth (SMY) are 3x more likely to experience depression than heterosexual peers. Minority stress theory posits that this association is explained by sexual orientation victimization, which acts as a stressor to impact depression. For those vulnerable to the effects of stress, victimization may worsen depression by alterin...

Pediatric anxiety disorders are characterized by potentiated threat responses and maladaptive emotion regulation (ER). The Late Positive Potential (LPP) is a neural index of heightened attention to emotional stimuli. Anxious individuals typically exhibit a larger LPP to unpleasant stimuli, but the LPP may also be blunted to unpleasant and pleasant...

Objectives: To build a one-year risk calculator (RC) to predict individualized risk for suicide attempt in early-onset bipolar disorder. Methods: 394 youth with bipolar disorder who completed >2 follow-up assessments (median follow-up length=13.1 years) in the longitudinal Course and Outcome of Bipolar Youth (COBY) study were included. Suicide a...

Background Poor sleep and anxiety disorders are highly comorbid in youth, and each predicts altered ventral striatum (VS) response to rewards, which may impact mental health risk. Contrasting evidence suggests previously reported negative associations between sleep health and VS response may be stronger or weaker in youth with anxiety, indicating s...

Cognitive behavioral therapy (CBT) has been shown to be an efficacious treatment for youth anxiety, but we need to know more about the process of change. Affective network variability, or the “spread” of positive and negative emotions activated across a given time period, has been found to be positively associated with anxiety disorder symptomatolo...

Excessive monitoring of one's performance is a characteristic of anxiety disorders that has been linked to alterations in implicit emotion regulation (ER), including elevations in neural measures of performance monitoring (i.e., error- and correct-related negativity; ERN and CRN). Elevations in ERN and CRN amplitudes have been reported consistently...

Objective: The goal of this study was to examine whether neural sensitivity to negative peer evaluation conveys risk for depression among youth with a history of anxiety. We hypothesized that brain activation in regions that process affective salience in response to rejection, relative to acceptance, from virtual peers would predict depressive sym...

Background : To identify prospectively ascertained individual and family factors that are associated with improvement in Bipolar Disorder (BD) among youths who initially presented with poor course. Methods : 82 youths with BD with persistent poor mood symptomatology (“predominantly ill course”) were compared to 70 youths with BD who at intake had...

Objective Social determinants of health (SDOH) are non-medical factors that can profoundly impact patient health outcomes. However, SDOH are rarely available in structured electronic health record (EHR) data such as diagnosis codes, and more commonly found in unstructured narrative clinical notes. Hence, identifying social context from unstructured...

Background Childhood abuse negatively impacts the course of Bipolar Disorder (BD). Yet, no study has examined risk factors associated with prospectively evaluated physical/sexual abuse, specifically, those preceding first abuse among BD youth. We investigate past/intake/follow-up factors preceding first physical/sexual abuse among BD youth. Method...

Background Limited research has simultaneously focused on sociodemographic differences in who receives recommended adolescent depression screening in primary care and who endorses elevated depression and suicide risk on these screeners. We describe screening and risk rates in a large pediatric primary care network in the United States after the net...

Study Objectives Structural brain maturation and sleep are complex processes that exhibit significant changes over adolescence and are linked to many physical and mental health outcomes. We investigated whether sleep-gray matter relationships are developmentally-invariant (i.e., stable across age) or developmentally-specific (i.e., only present dur...

Objective Limited research exists in predicting first-time suicide attempts that account for two-thirds of suicide decedents. We aimed to predict first-time suicide attempts using a large data-driven approach that applies natural language processing (NLP) and machine learning (ML) to unstructured (narrative) clinical notes and structured electronic...

Objective: The goal of this study was to examine whether neural sensitivity to peer rejection, a potent form of social evaluative threat in adolescence, conveys risk for depression among anxious youth. We hypothesized that brain activation in regions that process affective salience in response to rejection from virtual peers would predict depressiv...

Objective: Identifying neural correlates of response to psychological treatment may inform targets for interventions designed to treat psychiatric disorders. This study examined the extent to which baseline functioning in reward circuitry is associated with response to psychotherapy in youths with anxiety disorders. Methods: A randomized clinica...

Importance: Structural brain maturation and sleep are complex processes that exhibit significant changes over adolescence and are linked to healthy physical and mental development. The precise timing and magnitude of these changes influence function throughout the lifespan. However, the relationships between gray matter structure and sleep patterns...

BACKGROUND Lack of quantifiable biomarkers is a major obstacle in making diagnosis and predicting treatment response in depression. In adolescents, increasing suicidality during antidepressant treatment further complicate the problems. Emerging healthcare systems based on digital technology are beginning to show promising results in dealing with me...

Objectives While adults with bipolar disorder (BD) often report symptoms starting in childhood, continuity of mania and/or hypomania (mania/hypomania) from childhood to adulthood has been questioned. Using longitudinal data from the Course and Outcome of Bipolar Youth (COBY) study, we assessed threshold mania/hypomania in young adults who manifeste...

Background Pediatric bipolar disorders are often characterized by disruptions in cognitive functioning, and exposure to child maltreatment (e.g., physical and sexual abuse) is associated with a significantly poorer course of illness. Although clinical and developmental research has shown maltreatment to be robustly associated with poorer cognitive...

Background Youth with bipolar disorder (BD) are at high risk for suicidal thoughts and behaviors and frequently experience interpersonal impairment, which is a risk factor for suicide. Yet, no study to date has examined the longitudinal associations between relationship quality in family/peer domains and suicidal thoughts and behaviors among youth...

Objective: Despite substantial literature on sex differences in adults with bipolar disorder (BD), little is known about this topic in youth; this study examines sex differences in mood symptomatology and psychiatric comorbidity in prospectively followed youth with BD. Methods: A subsample of the Course and Outcome of Bipolar Youth study (N = 37...

Background: Exposure to severe Traumatic Events (TEs) has been associated with poor course and outcomes among individuals with Bipolar Disorder (BD). However, there is limited research on TEs among youth with BD, and few studies are longitudinal. This study prospectively followed a large sample of BD youth, examining the associations of lifetime TE...

Suicidal ideation increases in adolescence, especially for anxious youth, and is a frequent precursor to suicide. This study examined whether neural processing of social rejection interacted with negative social experiences to predict suicidal ideation. Thus, to our knowledge this is the first study to examine how brain function may interact with t...

Objectives Compare longitudinal trajectories of youth with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV Bipolar Disorder (BD), grouped at baseline by presence/absence of increased energy during their worst lifetime mood episode (required for DSM-5). Methods Participants from the parent Course and Outcome of Bipolar Youth study (N...

Objectives : Few studies have examined domain-specific psychosocial functioning in Bipolar Disorder (BD) youths. This prospective study examines 1) Interpersonal Relationships with Family; 2) Interpersonal Relationships with Friends; 3) School/Work; 4) Recreation; 5) Life Satisfaction, in BD youths. Method : A Course and Outcome of Bipolar Youth s...

Anxiety is the most prevalent psychological disorder among youth, and even following treatment, it confers risk for anxiety relapse and the development of depression. Anxiety disorders are associated with heightened response to negative affective stimuli in the brain networks that underlie emotion processing. One factor that can attenuate the sympt...

Objective: With each recurrence the prognosis of bipolar disorder (BD) worsens, indicating the need to identify the factors associated with increased recurrence risk. The course of BD is heterogenous and although risk factors for recurrence for the group as a whole have been reported in the literature, identification of risk factors for a specific...

During adolescence, youth may experience heightened attention bias to socially relevant stimuli; however, it is unclear if attention bias toward social threat may be exacerbated for adolescents with a history of anxiety. This study evaluated attentional bias during the Chatroom-Interact task with 25 adolescents with a history of anxiety (18F, Mage...

Objectives: To compare the longitudinal clinical course of youths with bipolar spectrum disorders (BD) with lifetime (past,intake, and/or follow-up) psychosis (BDP+) to youths with BD without lifetime psychosis (BDP-). Also, to identify risk factors associated with increased risk of first onset of psychosis during prospective follow-up. Method:...

Objective: Sleep problems is the most common side effect of methylphenidate (MPH) treatment in ADHD youth and carry potential to negatively impact long-term self-regulatory functioning. This study aimed to examine whether applying machine learning approaches to pre-treatment demographic, clinical questionnaire, environmental, neuropsychological, g...

Objective: Despite abundant literature demonstrating increased metabolic syndrome (MetS) prevalence and important clinical correlates of MetS among middle-age adults with bipolar disorder, little is known about this topic among adolescents and young adults early in their course of bipolar disorder. We therefore examined this topic in the Course an...

Objective: Lithium (LI) is the mainstay for bipolar disorder (BD) treatment in adults, but evidence in youth is limited. We used data from the Course and Outcome of Bipolar Youth (COBY) study to assess whether LI vs. other mood stabilizing medication (OMS) was associated with improved outcomes, including mood symptoms and suicidality. Method: CO...

Objectives: Examine how relationship quality in family and peer domains are associated with suicidal ideation (SI) in youth with Bipolar Disorder (BP). Methods: 404 Course and Outcome of Bipolar Youth study participants were assessed for psychiatric disorders and SI at intake, and family/peer relationships the month after intake. Multivariate logis...

We aimed to predict an individual suicide risk level from lon-gitudinal posts on Reddit discussion forums. Through partic-ipating in a shared task competition hosted by CLPsych2019, we received two annotated datasets: a training dataset with 496 users (31,553 posts) and a test dataset with 125 users (9610 posts). We submitted results from our three...

Introduction Sleep-related problems are pervasive among youth with psychiatric symptoms, heterogeneous in nature, and vary by frequency, intensity, duration, and impairment. This poses a challenge for measurement of sleep problems in these populations. Although there are well-validated self-reports of sleep functioning in pediatric samples, we pres...

Objective: Children who are fearful and anxious are at heightened risk for developing depression in adolescence. Treating anxiety disorders in pre-/early adolescence may be one mechanism through which depressive symptoms later in adolescence can be prevented. We hypothesized that anxious youth who responded positively to cognitive-behavioral thera...

The ways parents socialize their adolescents to cope with anxiety (i.e., coping socialization) may be instrumental in the development of threat processing and coping responses. Coping socialization may be important for anxious adolescents, as they show altered neural threat processing and over reliance on disengaged coping (e.g., avoidance and dist...

Objectives: In a sample of participants diagnosed with Bipolar Disorder (BD) in youth, we aim: (1) to examine longitudinal psychosocial functioning; (2) to determine whether psychosocial impairment remains in those who remitted from mood disorders during later periods of follow-up; (3) to examine predictors of psychosocial impairment despite sympt...

Objective: Youth with subthreshold mania are at increased risk of conversion to bipolar disorder (BP) I/II. Predictors for conversion have been published for the group as a whole. However, risk factors are heterogeneous, indicating the need for personalized risk assessment. Method: One hundred forty youth with BP not otherwise specified (BP-NOS;...

Anxious youth often have trouble regulating negative affect (NA) and tend to over-rely on parents when faced with challenges. It is unclear how social interactions with parents or peers actually helps or hinders anxious youths’ success in regulating NA. The aim of this study was to examine whether the success of anxious youths’ emotion regulation s...

Background Anxiety disorders are associated with an overactive action monitoring system as indexed by a larger error‐related negativity (ERN). This study tests whether ERN magnitude changes following treatment, predicts response to treatment, and varies by treatment type. Methods The sample included 130 youth (9–14 years): youth with an anxiety di...

Background: Vigilant attention to threat is commonly observed in anxiety, undergoes developmental changes in early adolescence, and has been proposed to interfere with sleep initiation and maintenance. We present one of the first studies to use objective measures to examine associations between vigilant attention to threat and difficulties initiat...

Objective This study aims to document rates of sexual activity among youth with bipolar spectrum disorder (BD) and to examine demographic and clinical factors associated with first sexual activity and sexual risk behavior during follow-up. Method The sample was drawn from the Course and Outcome of Bipolar Youth (COBY) study of 413 youth 7 to 17 ye...

Objective There is substantial interest in delineating the course of cognitive functioning in bipolar (BP) youth. However, there are no longitudinal studies aimed at defining subgroups of BP youth based on their distinctive cognitive trajectories and their associated clinical variables. Method Cognitive functioning was measured in 135 participant...

Objectives: To identify mood symptoms that distinguishes bipolar disorder (BP) depression versus unipolar depression in youth during an acute depressive episode. Methods: Youth with BP (N = 30) were compared with youth with unipolar depression (N = 59) during an acute depressive episode using the depression and mania items derived from the Sched...

Anxious youth may experience altered positive affect (PA) relative to healthy youth, perhaps because of greater sensitivity to social experiences. Altered PA may be especially evident during the transition to adolescence, a period in which positive social events increase in salience and value. The current study evaluated whether anxious youth show...

Do day-to-day emotions, social interactions, and sleep play a role in determining which anxious youth respond to supportive child-centered therapy (CCT) versus cognitive behavioral therapy (CBT)? We explored whether measures of day-to-day functioning (captured through ecological momentary assessment, sleep diary, and actigraphy), along with clinica...

Objective: To provide the first longitudinal characterization of mood and psychosocial functioning in youth with comorbid bipolar (BD) and autism spectrum (ASD) disorders. Method: The Course and Outcome of Bipolar Youth study followed 368 youth (aged 7-17 years) with DSM-IV bipolar I (BP-I), BP-II, or Not Otherwise Specified (NOS) for, on averag...

Greater understanding of cognitive function in children and adolescents with bipolar disorder (BD) is of critical importance to improve our ability to design targeted treatments to help with real-world impairment, including academic performance. We sought to evaluate cognitive performance among children with either BD type I, II, or "not otherwise...

This study compared individual cognitive behavioral therapy (CBT) and a supportive child-centered therapy (CCT) for child anxiety disorders on rates of treatment response and recovery at posttreatment and 1-year follow-up, as well as on real-world measures of emotional functioning. Youth (N = 133; ages 9–14) with anxiety disorders (generalized, sep...

Vigilance and avoidance of threat are observed in anxious adults during laboratory tasks, and are posited to have real-world clinical relevance, but data are mixed in anxious youth. We propose that vigilance-avoidance patterns will become evident in anxious youth through a focus on individual differences and real-world strategic avoidance. Decrease...

Anxious youth exhibit heightened emotional reactivity, particularly to social-evaluative threat, such as peer evaluation and feedback, compared to non-anxious youth. Moreover, normative developmental changes during the transition into adolescence may exacerbate emotional reactivity to peer negative events, particularly for anxious youth. Therefore,...

Background: Childhood anxiety is associated with low levels of parental autonomy granting and child perceived control, elevated child emotional reactivity and deficits in child emotion regulation. In early childhood, low levels of parental autonomy granting are thought to decrease child perceived control, which in turn leads to increases in child...

Objective: Despite burgeoning literature in middle-aged adults, little is known regarding proinflammatory markers (PIMs) among adolescents and young adults with bipolar disorder. Similarly, few prior studies have considered potential confounds when examining the association between PIMs and bipolar disorder characteristics. We therefore retrospect...

Anxious youth are at heightened risk for subsequent development of depression; however, little is known regarding which anxious youth are at the highest prospective risk. Biased attentional patterns (e.g., vigilance and avoidance of negative cues) are implicated as key mechanisms in both anxiety and depression. Aberrant attentional patterns may dis...

Objective: Bipolar disorder (BP) frequently co-occurs with other psychiatric disorders. We examine whether course of anxiety disorders (ANX), attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), and substance use disorders (SUD) influence likelihood of recovery and recurrence of depression and mania in BP youth. M...

There are no objective, biological markers that can robustly predict methylphenidate (MPH) response in ADHD. This study aimed to examine whether applying machine learning approaches to pre-treatment demographic, clinical questionnaire, environmental, neuropsychological, neuroimaging, and genetic information can predict therapeutic response followin...

The ability to adaptively inhibit responses to tempting/distracting stimuli in the pursuit of goals is an essential set of skills necessary for adult competence and wellbeing. These inhibitory capacities develop throughout childhood, with growing evidence of important maturational changes occurring in adolescence. There also has been intense intere...

To determine the longitudinal impact of borderline personality disorder (BPD) on the course and outcome of bipolar disorder (BP) in a pediatric BP sample. Participants (N = 271) and parents from the Course and Outcome of Bipolar Youth (COBY) study were administered structured clinical interviews and self-reports on average every 8.7 months over a m...

The dot-probe task has been widely used in research to produce an index of biased attention based on reaction times (RTs). Despite its popularity, very few published studies have examined psychometric properties of the task, including test-retest reliability, and no previous study has examined reliability in clinically anxious samples or systematic...

The authors describe a model for teaching grant writing and other research survival skills to postdoctoral clinical-research fellows in psychiatry and for improving research mentoring. Over the past 4 years, the authors have developed a course on writing grant applications for postdoctoral clinical-research fellows, using peer-review processes mode...

Parkinson disease (PD) is a neurodegenerative disorder afflicting more than 1 million aging Americans, incurring $23 billion in annual medical costs in the U.S. alone. Approximately 90% Parkinson patients undergoing treatment have mobility related problems related to medication which prevent them doing their activities of daily living. Efficient ma...

Objective: The authors sought to identify and evaluate longitudinal mood trajectories and associated baseline predictors in youths with bipolar disorder. Method: A total of 367 outpatient youths (mean age, 12.6 years) with bipolar disorder with at least 4 years of follow-up were included. After intake, participants were interviewed on average 10...