Clinical decision support for bipolar depression using large language models.

Management of depressive episodes in bipolar disorder remains challenging for clinicians despite the availability of treatment guidelines. In other contexts, large language models have yielded promising results for supporting clinical decisionmaking. We developed 50 sets of clinical vignettes reflecting bipolar depression and presented them to experts in bipolar disorder, who were asked to identify 5 optimal next-step pharmacotherapies and 5 poor or contraindicated choices. The same vignettes were then presented to a large language model (GPT4-turbo; gpt-4-1106-preview), with or without augmentation by prompting with recent bipolar treatment guidelines, and asked to identify the optimal next-step pharmacotherapy. Overlap between model output and gold standard was estimated. The augmented model prioritized the expert-designated optimal choice for 508/1000 vignettes (50.8%, 95% CI 47.7-53.9%; Cohen's kappa = 0.31, 95% CI 0.28-0.35). For 120 vignettes (12.0%), at least one model choice was among the poor or contraindicated treatments. Results were not meaningfully different when gender or race of the vignette was permuted to examine risk for bias. By comparison, an un-augmented model identified the optimal treatment for 234 (23.0%, 95% CI 20.8-26.0%; McNemar's p < 0.001 versus augmented model) of the vignettes. A sample of community clinicians scoring the same vignettes identified the optimal choice for 23.1% (95% CI 15.7-30.5%) of vignettes, on average; McNemar's p < 0.001 versus augmented model. Large language models prompted with evidence-based guidelines represent a promising, scalable strategy for clinical decision support. In addition to prospective studies of efficacy, strategies to avoid clinician overreliance on such models, and address the possibility of bias, will be needed.

Neurocognitive risk phenotyping to predict mood symptoms in adolescence.

Predicting mood disorders in adolescence is a challenge that motivates research to identify neurocognitive predictors of symptom expression and clinical profiles. This study used machine learning to test whether neurocognitive variables predicted future manic or anhedonic symptoms in two adolescent samples risk-enriched for lifetime mood disorders (Sample 1, n = 73, ages = 13-25, M [SD] = 19.22 [2.49] years, 68% lifetime mood disorder) or familial mood disorders (Sample 2, n = 154, ages = 13-21, M [SD] = 16.46 [1.95] years, 62% first-degree family history of mood disorder). Participants completed cognitive testing and functional magnetic resonance imaging at baseline, for behavioral and neural measures of reward processing and executive functioning. Next, participants completed a daily diary procedure for 8-16 weeks. Penalized mixed-effects models identified neurocognitive predictors of future mood symptoms and stress-reactive changes in mood symptoms. Results included the following. In both samples, adolescents showing ventral corticostriatal reward hyposensitivity and lower reward performance reported more severe stress-reactive anhedonia. Poorer executive functioning behavior was associated with heightened anhedonia overall in Sample 1, but lower stress-reactive anhedonia in both samples. In Sample 1, adolescents showing ventral corticostriatal reward hypersensitivity and poorer executive functioning reported more severe stress-reactive manic symptoms. Clustering analyses identified, and replicated, five neurocognitive subgroups. Adolescents characterized by neural or behavioral reward hyposensitivities together with average-to-poor executive functioning reported unipolar symptom profiles. Adolescents showing neural reward hypersensitivity together with poor behavioral executive functioning reported a bipolar symptom profile (Sample 1 only). Together, neurocognitive phenotypes may hold value for predicting symptom expression and profiles of mood pathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Mood Symptom Dimensions and Developmental Differences in Neurocognition in Adolescence.

Adolescence is critical period of neurocognitive development as well as increased prevalence of mood pathology. This cross-sectional study replicated developmental patterns of neurocognition and tested whether mood symptoms moderated developmental effects. Participants were 419 adolescents (n=246 with current mood disorders) who completed reward learning and executive functioning tasks, and reported on age, puberty, and mood symptoms. Structural equation modeling revealed a quadratic relationship between puberty and reward learning performance that was moderated by symptom severity: in early puberty, adolescents reporting higher manic symptoms exhibited heightened reward learning performance (better maximizing of rewards on learning tasks), whereas adolescents reporting elevated anhedonia showed blunted reward learning performance. Models also showed a linear relationship between age and executive functioning that was moderated by manic symptoms: adolescents reporting higher mania showed poorer executive functioning at older ages. Findings suggest neurocognitive development is altered in adolescents with mood pathology and suggest directions for longitudinal studies.

Lithium and the living kidney donor: Science or stigma?

Nearly 10 000 people are removed from the kidney transplant waiting list each year either due to becoming too ill for transplant or due to death. Live donor kidney transplant (LDKT) provides superior outcomes and survival benefit relative to deceased donor transplant, but the number of LDKT has decreased over the past few years. Therefore, it is of paramount importance that transplant centers employ evaluation processes that safely maximize LDKT. Decisions about donor candidacy should be based on the best available data, rather than on processes prone to bias. Here, we examine the common practice of declining potential donors based solely on treatment with lithium. We conclude that the risk of end-stage renal disease related to lithium treatment is comparable to other generally accepted risks in LDKT. We present this viewpoint to specifically challenge the carte blanche exclusion of individuals taking lithium and highlight the importance of using the best available data relevant to any risk factor, rather than relying on biases, when evaluating potential living kidney donors.

Amygdala and nucleus accumbens activation during reward anticipation moderates the association between life stressor frequency and depressive symptoms.

BACKGROUND: Life stressors confer risk for depressive symptoms, but individuals vary in the extent of their sensitivity to life stressors. One protective factor may be an individual's level of reward sensitivity, e.g., a stronger neurobiological response to environmental rewards may mitigate emotional responses to stressors. However, the nature of neurobiological reward sensitivity that corresponds with stress resilience is unknown. Further, this model is untested in adolescence, when life stressor frequency and depression increase. METHODS: We tested the hypothesis that stronger reward-related activation in the left and right nucleus accumbens (NAc), amygdala, and medial prefrontal cortex (mPFC) attenuates the strength of the stress-depression relation. We measured BOLD activation throughout Win and Lose blocks of a monetary reward task, as well as during anticipation and outcome phases of the task. Participants (N = 151, ages 13-19) were recruited to be stratified on risk for mood disorders to enhance variance in depressive symptoms. RESULTS: Activation during anticipation of rewards in the bilateral amygdala and NAc, but not mPFC, buffered the association between life stressors and depressive symptoms. This buffering effect was not found for reward outcome activation or activation across Win blocks. CONCLUSIONS: Results highlight the importance of reward anticipation activation of subcortical structures in attenuating the stress-depression link, suggesting that reward motivation may be a cognitive mechanism through which this stress buffering occurs.

Early Family Intervention for Youth at Risk for Bipolar Disorder: Psychosocial and Neural Mediators of Outcome.

BACKGROUND: The impairing neurodevelopmental course of bipolar disorder (BD) suggests the importance of early intervention for youth in the beginning phases of the illness. OBJECTIVE: We report the results of a 3-site randomized trial of family-focused therapy for youth at high-risk (FFT-HR) for BD, and explore psychosocial and neuroimaging variables as mediators of treatment effects. METHODS: High-risk youth (<18 years) with major depressive disorder or other specified BD, active mood symptoms, and a family history of BD were randomly assigned to 4 months of FFT-HR (psychoeducation, communication and problem-solving skills training) or 4 months of enhanced care psychoeducation. Adjunctive pharmacotherapy was provided by study psychiatrists. Neuroimaging scans were conducted before and after psychosocial treatments in eligible participants. Independent evaluators interviewed participants every 4-6 months over 1-4 years regarding symptomatic outcomes. RESULTS: Among 127 youth (mean 13.2 ± 2.6 years) over a median of 98 weeks, FFT-HR was associated with longer intervals prior to new mood episodes and lower levels of suicidal ideation than enhanced care. Reductions in perceived family conflict mediated the effects of psychosocial interventions on the course of mood symptoms. Among 34 participants with pre-/post-treatment fMRI scans, youth in FFT-HR had (a) stronger resting state connectivity between ventrolateral PFC and anterior default mode network, and (b) increased activity of dorsolateral and medial PFC in emotion processing and problem-solving tasks, compared to youth in enhanced care. CONCLUSION: FFT-HR may delay new mood episodes in symptomatic youth with familial liability to BD. Putative treatment mechanisms include neural adaptations suggestive of improved emotion regulation.

Mood Instability in Youth at High Risk for Bipolar Disorder.

OBJECTIVE: Mood instability is associated with the onset of bipolar disorder (BD) in youth with a family history of the illness. In a clinical trial with youth at high risk for BD, we examined the association between mood instability and symptomatic, psychosocial, and familial functioning over an average of 2 years. METHOD: Youth (aged 9-17 years) with major depressive disorder or other specified BD, current mood symptoms, and a family history of BD were rated by parents on a mood instability scale. Participants were randomly assigned to 4 months of family-focused therapy or enhanced care psychoeducation, both with medication management as needed. Independent evaluators rated youth every 4-6 months for up to 4 years on symptom severity and psychosocial functioning, whereas parents rated mood instability of the youth and levels of family conflict. RESULTS: High-risk youth (N = 114; mean age 13.3 ± 2.6 years; 72 female) were followed for an average of 104.3 ± 65.8 weeks (range, 0-255 weeks) after randomization. Youth with other specified BD (vs major depressive disorder), younger age, earlier symptom onset, more severe mood symptoms, lower psychosocial functioning, and more familial conflict over time had higher mood instability ratings throughout the study period. Mood instability mediated the association between baseline diagnosis and mother/offspring conflict at follow-up (Z = 2.88, p = .004, αß = 0.19, 95% CI = 0.06-0.32). Psychosocial interventions did not moderate these associations. CONCLUSION: A questionnaire measure of mood instability tracked closely with symptomatic, psychosocial, and family functioning in youth at high risk for BD. Interventions that are successful in reducing mood instability may enhance long-term outcomes among high-risk youth. CLINICAL TRIAL REGISTRATION INFORMATION: Early Intervention for Youth at Risk for Bipolar Disorder; https://clinicaltrials.gov/; NCT01483391.

Effects of family intervention on psychosocial functioning and mood symptoms of youth at high risk for bipolar disorder.

OBJECTIVES: Family-focused therapy (FFT) is associated with reduced rates of mood episodes among youth at high risk for bipolar disorder (BD). In a randomized trial of FFT compared to a psychoeducation-only treatment (enhanced care, EC), we sought to determine if changes in psychosocial functioning mediate mood improvements among high-risk youth. METHOD: 119 youths with active mood symptoms and a family history of BD were randomized to either 4 months of FFT or EC. Participants were rated on mood symptom severity and provided self-ratings of psychosocial functioning across domains of family, social-emotional, and school functioning. Repeated measures mixed modeling and bootstrapped mediational analyses evaluated the effects of treatment conditions and psychosocial functioning on mood improvements immediately posttreatment and over 2 years of follow-up. RESULTS: Youths in FFT reported greater improvements in family functioning over 24 months compared to those in EC, F(5, 76.8) = 3.1, p < .05. Improvements in family functioning partially mediated participants' improvements in depressive symptoms, B = -0.22, p < .01; 95% CI [-0.55, -0.02]. The effects of FFT versus EC on family functioning were stronger among youth with comorbid anxiety and externalizing disorders than among youth without these comorbid disorders. CONCLUSIONS: The findings suggest a temporal link between changes in youths' perceptions of family functioning and improvements in depressive symptoms among high-risk youth in FFT. Family conflict and cohesion are important treatment targets for youth who present with early signs of BD. Future studies should examine whether changes in observational measures of family interaction precede improvements in mood among high-risk youth. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Social impairment in relation to clinical symptoms in youth at high risk for bipolar disorder.

AIM: Social impairment is common in individuals with bipolar disorder (BD), although its role in youths at high-risk for BD (i.e., mood symptoms in the context of a family history of BD) is not well understood. Social impairment takes many forms including social withdrawal, relational aggression, physical aggression, and victimization. The aim of this study was to explore the links between social impairment and clinical symptoms in youth at high-risk for BD. METHODS: The sample included 127 youths with elevations in mood symptoms (depression or hypomania) and at least one first and/or second degree relative with BD. Measures of youths' current psychopathology (i.e., depressive and manic severity, suicidality, anxiety, and attention-deficit/hyperactivity disorder [ADHD]) were regressed onto youths' self-reports of social impairment (i.e., social withdrawal, relational aggression, physical aggression, and victimization). RESULTS: Depressive symptoms, suicidal ideation, and anxiety symptoms were related to social withdrawal. Suicidal ideation was also related to reactive aggression. ADHD symptoms related to reactive and proactive aggression as well as relational victimization. Manic symptoms were not associated with social impairment in this sample. CONCLUSIONS: Although cross-sectional, study findings point to potential treatment targets related to social functioning. Specifically, social withdrawal should be a target for treatment of childhood depressive and anxiety symptoms. Treatments that focus on social skills and cognitive functioning deficits associated with BD may also have clinical utility.

Longitudinal relationship between maternal distress and pediatric mood symptoms in youth with mood disorders.

Parents of a child with a mood disorder report significant levels of distress and burden from caregiving. This study examined whether maternal distress varies over time with levels of mood symptoms in youth with mood disorders, and whether expressed emotion (EE) and family functioning moderate these associations. We recruited youth (ages 9-17 years) with mood disorders and familial risk for bipolar disorder (BD) for a randomized trial of family-focused therapy compared to standard psychoeducation. Participants were assessed every 4-6 months for up to 4 years. Using repeated-measures mixed effects modeling, we examined the longitudinal effects of youths' mood symptoms and maternal distress concurrently, as well as whether each variable predicted the other in successive study intervals. Secondary analyses examined the moderating effects of EE and ratings of family cohesion and adaptability on maternal distress. In sample of 118 youth-mother dyads, levels of self-reported parental distress decreased over time, with no differences between treatment conditions. Youths' depressive symptoms and, most strongly, mood lability were associated with greater maternal distress longitudinally; however, maternal distress did not predict youths' mood symptoms or lability. The effect of youth symptoms on maternal distress was greater among mothers who were high EE. Family cohesion was associated with reduced concurrent ratings of maternal distress, whereas family adaptability was associated with reduced maternal distress at successive follow-ups. While maternal distress decreases over time as youths' symptoms decrease, mothers of youth with mood disorders experience significant distress that is directly linked to the youths' depressive symptom severity and lability. Improved family functioning appears to be an important mechanism by which to intervene.

Rapid Conversion to Telemental Health Services in Response to COVID-19: Experiences of Two Outpatient Mental Health Clinics.

Background: The COVID-19 pandemic triggered changes across health care systems, with many sectors seeing significant drops in patient visits. Rapid transition to telemental health (TMH) allowed for the continued delivery of mental health care. Although several guidelines and best practices are available for the methodical development of a TMH service, there are few documented procedures on rapidly converting to fully virtualized services. We discuss how two outpatient mental health clinics at the University of Colorado Anschutz Medical Campus rapidly virtualized clinical services during the COVID-19 pandemic. Methods: All current clinical appointments were converted to virtual, and all new clinical intakes were scheduled as virtual visits starting March 16, 2020. Virtualization included a modified needs assessment, updated clinic procedures, focused patient and staff training on TMH, and increased frequency of team meetings. We conducted a retrospective evaluation of clinic log and electronic health record data to examine the number of appointments and no-shows before and after COVID-19 virtualization. Results: Virtualization was operational within two business days. Scheduled appointments decreased 10.6% immediately postvirtualization, followed by an increase of 17.8% across the 6 months postvirtualization. No-show rates dropped from 11.9% pre- to 6.8% postvirtualization, leading to a 26.2% increase in completed visits. Discussion: Rapid virtualization of mental health services can occur effectively. Wider use and acceptance of TMH, especially to patient-homes, is likely in the foreseeable future as health care providers and systems reconceptualize service delivery. Future research must include analyzing the impact such changes make on clinical outcomes and patient visit volumes.

Telemental Health Response to the COVID-19 Pandemic: Virtualization of Outpatient Care Now as a Pathway to the Future.

The use of telemental health (TMH) has fostered the continued provision of mental health care during the COVID-19 pandemic, and ultimately prevented the significant drop in clinical visits as experienced by other health care disciplines. Many health care providers and systems rapidly virtualized care to include visits occurring in what previously were defined as nontraditional locations such as provider and patient homes. Emerging data and reports suggest that this rapid virtualization of mental health services occurred safely and effectively. Although it is uncertain how long the full virtualization will remain, we envision a future wherein mental health services are delivered using a hybrid in-person/TMH approach. This opinion provides an overview of current lessons learned from rapid virtualization due to COVID-19 mitigation strategies and recommends that mental health providers and systems use these lessons to define and promote hybrid care delivery.

Advancing Treatment of Depression and Other Mood Disorders Through Innovative Models of Telepsychiatry.

Rapid changes in health care technology are advancing mental health care. Telepsychiatry, in the form of live interactive videoconferencing, has demonstrated its ability to improve access to high-quality mental health care, specifically in the treatment of patients with depression and mood disorders. This article reviews the advances in telepsychiatry in the treatment of depression and mood disorders. Telepsychiatry is significantly reconfiguring the structures and models of psychiatric care delivery. Such changes include direct-to-home services, blending telepsychiatry with other technologies, and using a team-based care approach. This article also examines the evolving and innovative models of care, synthesizes literature and lessons learned about telehealth, and considers current and future pragmatic implications for the treatment of depression and mood disorders in various clinical settings. Telepsychiatry has an important and expanding role in addressing the individual and societal psychiatric burdens of depression and mood disorders.

Neuropsychiatric effects of tamoxifen: Challenges and opportunities.

Epidemiological, clinical, and basic research over the past thirty years have described the benefits of estrogen on cognition, mood, and brain health. Less is known about tamoxifen, a selective estrogen receptor modifier (SERM) commonly used in breast cancer which is able to cross the blood-brain barrier. In this article, we review the basic pharmacology of tamoxifenas well as its effects on cognition and mood. The literature reveals an overall impairing effect of tamoxifen on cognition in breast cancer patients, hinting at central antiestrogen activity. On the other hand, tamoxifen demonstrates promising effects in psychiatric disorders, like bipolar disorder, where its therapeutic action may be independent of interaction with estrogen receptors. Understanding the neuropsychiatric properties of SERMs like tamoxifen can guide future research to ameliorate unwanted side-effects and provide novel options for difficult to treat disorders.

Longitudinal trajectories of mood symptoms and global functioning in youth at high risk for bipolar disorder.

BACKGROUND: Little is known about the longitudinal course of mood symptoms and functioning in youth who are at high risk for bipolar disorder (BD). Identifying distinct course trajectories and predictors of those trajectories may help refine treatment approaches. METHODS: This study examined the longitudinal course of mood symptoms and functioning ratings in 126 youth at high risk for BD based on family history and early mood symptoms. Participants were enrolled in a randomized trial of family-focused therapy and followed longitudinally (mean 2.0 years, SD = 53.6 weeks). RESULTS: Using latent class growth analyses (LCGA), we observed three mood trajectories. All youth started the study with active mood symptoms. Following the index mood episode, participants were classified as having a "significantly improving course" (n = 41, 32.5% of sample), a "moderately symptomatic course" (n = 21, 16.7%), or a "predominantly symptomatic course" (n = 64, 50.8%) at follow-up. More severe depression, anxiety, and suicidality at the study's baseline were associated with a poorer course of illness. LCGA also revealed three trajectories of global functioning that closely corresponded to symptom trajectories; however, fewer youth exhibited functional recovery than exhibited symptomatic recovery. LIMITATIONS: Mood trajectories were assessed within the context of a treatment trial. Ratings of mood and functioning were based on retrospective recall. CONCLUSIONS: This study suggests considerable heterogeneity in the course trajectories of youth at high risk for BD, with a significant proportion (32.5%) showing long-term remission of symptoms. Treatments that enhance psychosocial functioning may be just as important as those that ameliorate symptoms in youth at risk for BD.

Effects of family-focused therapy on suicidal ideation and behavior in youth at high risk for bipolar disorder.

BACKGROUND: Youth who are at clinical and familial risk for bipolar disorder (BD) often have significant suicidal ideation (SI). In a randomized trial, we examined whether family-focused therapy (FFT) is associated with reductions in SI and suicidal behaviors in high-risk youth. METHODS: Participants (ages 9-17 years) met diagnostic criteria for unspecified BD or major depressive disorder with active mood symptoms and had at least one relative with BD type I or II. Participants were randomly allocated to 12 sessions in 4 months of FFT or 6 sessions in 4 months of psychoeducation (enhanced care, EC), with pharmacotherapy as needed. Clinician- and child-rated assessments of mood, suicidal thoughts and behaviors, and family conflict were obtained at baseline and 4-6 month intervals over 1-4 years. RESULTS: Participants (N=127; mean 13.2±2.6 yrs., 82 female) were followed over an average of 105.9±64.0 weeks. Youth with high baseline levels of SI who received FFT had lower levels of (and fewer weeks with) SI at follow-up compared to youth with high baseline SI who received EC. Participants in FFT had longer intervals without suicidal behaviors than participants in EC. Youths' ratings of family conflict significantly mediated the effects of treatment on SI at follow-up. LIMITATIONS: Family conflict was based on questionnaires rather than observer ratings of family interactions. CONCLUSIONS: Family psychoeducation with skill training can be an effective deterrent to suicidal thoughts and behaviors in youth at high risk for BD. Reducing parent/offspring conflict should be a central objective of psychosocial interventions for high-risk youth with SI.

Characteristics of youth at high risk for bipolar disorder compared to youth with bipolar I or II disorder.

Significant efforts have been undertaken to characterize the phenomenology of the high-risk period for bipolar disorder (BD) through the examination of youth at familial risk (i.e., having a first- or second-degree relative with BD) or clinical high risk for the disorder (i.e., youth with BD Not Otherwise Specified [NOS] or major depressive disorder [MDD]). However, little is known about the phenomenology of youth at both familial and clinical high risk for BD. In this study, we examined the clinical and psychosocial characteristics of youth at familial and clinical high risk (HR) for BD, and compared these characteristics to those of youth with BD I and II. Both groups were recruited based on current, active mood symptoms from separate randomized trials of family therapy. A total of 127 HR youth were evaluated: 52 (40.9%) were diagnosed with BD-NOS and 75 (59.1%) were diagnosed with MDD. Compared to adolescents with BD I and II (n = 145), HR youth had higher rates of anxiety disorders, and comparable rates of attention-deficit/hyperactivity disorder and oppositional defiant disorder/conduct disorder. Manic symptom severity and psychosocial functioning were progressively more impaired consistent with diagnostic severity: BD I > BD II > BD-NOS > MDD. Nonetheless, HR youth exhibited depressive symptom severity that was comparable to adolescents with BD I. These results provide further support for the high rates of anxiety disorders and premorbid dysfunction in addition to active mood symptoms for youth at risk for BD, and suggest anxiety is an important phenomenological characteristic and treatment target in the high-risk period.