Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Facing Life in Old Age: Exploring Resilience in Older Adults with Bipolar Disorder.

Background: Older adults with bipolar disorder (OABD) are individuals aged 50 years and older with bipolar disorder (BD). People with BD may have fewer coping strategies or resilience. A long duration of the disease, as seen in this population, could affect the development of resilience strategies, but this remains under-researched. Therefore, this study aims to assess resilience levels within the OABD population and explore associated factors, hypothesizing that resilience could improve psychosocial functioning, wellbeing and quality of life of these patients. Methods: This study sampled 33 OABD patients from the cohort at the Bipolar and Depressive Disorders Unit of the Hospital Clinic of Barcelona. It was an observational, descriptive and cross-sectional study. Demographic and clinical variables as well as psychosocial functioning, resilience and cognitive reserve were analyzed. Resilience was measured using the CD-RISC-10. Non-parametric tests were used for statistical analysis. Results: The average CD-RISC-10 score was 25.67 points (SD 7.87). Resilience negatively correlated with the total number of episodes (p = 0.034), depressive episodes (p = 0.001), and the FAST (p < 0.001). Participants with normal resilience had a lower psychosocial functioning (p = 0.046), a higher cognitive reserve (p = 0.026), and earlier onset (p = 0.037) compared to those with low resilience. Conclusions: OABD individuals may have lower resilience levels which correlate with more psychiatric episodes, especially depressive episodes and worse psychosocial functioning and cognitive reserve. Better understanding and characterization of resilience could help in early identification of patients requiring additional support to foster resilience and enhance OABD management.

Cognitive reserve moderates the relationship between childhood maltreatment, objective and subjective cognition, and psychosocial functioning in individuals with first-episode psychosis.

OBJECTIVE: This study aimed to assess the relationship between childhood maltreatment (CM), objective and subjective cognition, and psychosocial functioning in adults with first-episode psychosis (FEP) by examining the moderating role of cognitive reserve (CR). A secondary objective was to explore whether unique CM subtypes (physical and/or emotional abuse, sexual abuse, physical and/or emotional neglect) were driving this relationship. METHOD: Sixty-six individuals with FEP (Mage = 27.3, SD = 7.2 years, 47% male) completed a comprehensive neuropsychological test battery, the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA), the Functioning Assessment Short Test (FAST), the Childhood Trauma Questionnaire (CTQ), and the Cognitive Reserve Assessment Scale in Health (CRASH). Linear regression analyses were conducted to evaluate the interaction effect of CR between CM and cognitive and psychosocial variables, controlling for age, sex, and social desirability (CTQ-denial-minimization). RESULTS: In adults with FEP overall CM interacted with CR to predict COBRA-subjective cognitive complaints, but not neurocognitive or psychosocial functioning. Sexual abuse and physical neglect interacted with CR to predict verbal memory. Most of the CM subtypes interacted with CR to predict FAST-leisure time, whereas only emotional neglect interacted with CR to predict FAST-interpersonal relationships. Overall, greater CR was related to better functioning. CONCLUSIONS: The current results indicate that associations between specific CM subtypes, subjective and objective cognition, and psychosocial domains are moderated through CR with greater functioning. Early interventions focused on CR seeking to improve cognitive and psychosocial outcomes, with emphasis on improving subjective cognitive functions would be beneficial for individuals with FEP and CM. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Emotional intelligence and neurocognition profiles in first-episode psychosis: A two-year follow-up study.

Emotional intelligence (EI) and neurocognition (NC) impairments are common in first-episode psychosis (FEP), yet their evolution over time remains unclear. This study identified patient profiles in EI and NC performance in FEP. 98 adult FEP patients and 128 healthy controls (HCs) were tested on clinical, functional, EI, and NC variables at baseline and two-year follow-up (FUP). A repeated-measures ANOVA compared the effects of group (patients and HCs) and time on EI. Significant EI improvements were observed in both groups. Four groups were created based on NC and EI performance at baseline and FUP in patients: impairment in NC and EI, impairment in NC only, impairment in EI only, and no impairment. At FUP, patients impaired in NC and EI showed less cognitive reserve (CR), greater negative and positive symptoms, and poorer functional outcomes. At FUP, three group trajectories were identified: (I) maintain dual impairment (II) maintain no impairment or improve, (III) maintain sole impairment or worsen. The maintain dual impairment group had the lowest levels of CR. EI and NC impairments progress differently in FEP. Greater CR may protect against comorbid EI/NC impairment. Identifying these patient characteristics could contribute to the development of personalised interventions.

Sex differences in prolactin levels and clinical outcomes in patients with a first psychotic episode.

AIM: To analyze the clinical, neurocognitive, and functional impact of prolactin levels according to sex in patients with a First Episode Psychosis (FEP). METHODS: We measured prolactin levels in 221 non-affective FEP patients treated with antipsychotics (AP) and 224 healthy controls, at baseline and 2-year follow-up. We examined whether the relationships between clinical and functional variables were mediated by prolactin, controlling for antipsychotic use, according to sex. RESULTS: Prolactin levels were higher in patients when compared to controls at both time points. Baseline factors associated with prolactin were chlorpromazine equivalents, attention, and executive functioning. In the FEP group, prolactin levels were associated with functioning and diminished expression in males, and with working memory in females. Prolactin levels (p=0.0134) played a role as a mediator between negative symptomatology (p=0.086) and functional outcome (p=0.008) only in FEP male patients at baseline. CONCLUSIONS: Prolactin plays a role in the functionality and clinical symptomatology of FEP patients. Our results suggest that pharmacological counselling in patients with hyperprolactinemia at baseline and negative symptomatology might improve their functional and clinical outcomes.

Identifying digital biomarkers of illness activity and treatment response in bipolar disorder with a novel wearable device (TIMEBASE): protocol for a pragmatic observational clinical study.

BACKGROUND: Bipolar disorder is highly prevalent and consists of biphasic recurrent mood episodes of mania and depression, which translate into altered mood, sleep and activity alongside their physiological expressions. AIMS: The IdenTifying dIgital bioMarkers of illnEss activity and treatment response in BipolAr diSordEr with a novel wearable device (TIMEBASE) project aims to identify digital biomarkers of illness activity and treatment response in bipolar disorder. METHOD: We designed a longitudinal observational study including 84 individuals. Group A comprises people with acute episode of mania (n = 12), depression (n = 12 with bipolar disorder and n = 12 with major depressive disorder (MDD)) and bipolar disorder with mixed features (n = 12). Physiological data will be recorded during 48 h with a research-grade wearable (Empatica E4) across four consecutive time points (acute, response, remission and episode recovery). Group B comprises 12 people with euthymic bipolar disorder and 12 with MDD, and group C comprises 12 healthy controls who will be recorded cross-sectionally. Psychopathological symptoms, disease severity, functioning and physical activity will be assessed with standardised psychometric scales. Physiological data will include acceleration, temperature, blood volume pulse, heart rate and electrodermal activity. Machine learning models will be developed to link physiological data to illness activity and treatment response. Generalisation performance will be tested in data from unseen patients. RESULTS: Recruitment is ongoing. CONCLUSIONS: This project should contribute to understanding the pathophysiology of affective disorders. The potential digital biomarkers of illness activity and treatment response in bipolar disorder could be implemented in a real-world clinical setting for clinical monitoring and identification of prodromal symptoms. This would allow early intervention and prevention of affective relapses, as well as personalisation of treatment.

Study protocol - elucidating the neural correlates of functional remediation for older adults with bipolar disorder.

Introduction: Beyond mood abnormalities, bipolar disorder (BD) includes cognitive impairments that worsen psychosocial functioning and quality of life. These deficits are especially severe in older adults with BD (OABD), a condition expected to represent most individuals with BD in the upcoming years. Restoring the psychosocial functioning of this population will thus soon represent a public health priority. To help tackle the problem, the Bipolar and Depressive Disorders Unit at the Hospital Clínic of Barcelona has recently adapted its Functional Remediation (FR) program to that population, calling it FROA-BD. However, while scarce previous studies localize the neural mechanisms of cognitive remediation interventions in the dorsal prefrontal cortex, the specific mechanisms are seldom unknown. In the present project, we will investigate the neural correlates of FR-OABD to understand its mechanisms better and inform for potential optimization. The aim is to investigate the brain features and changes associated with FROA-BD efficacy. Methods: Thirty-two individuals with OABD in full or partial remission will undergo a magnetic resonance imaging (MRI) session before receiving FR-OABD. After completing the FR-OABD intervention, they will undergo another MRI session. The MRI sessions will include structural, diffusion-weighted imaging (DWI), functional MRI (fMRI) with working memory (n-back) and verbal learning tasks, and frontal spectroscopy. We will correlate the pre-post change in dorsolateral and dorsomedial prefrontal cortices activation during the n-back task with the change in psychosocial functioning [measured with the Functioning Assessment Short Test (FAST)]. We will also conduct exploratory whole-brain correlation analyses between baseline or pre-post changes in MRI data and other clinical and cognitive outcomes to provide more insights into the mechanisms and explore potential brain markers that may predict a better treatment response. We will also conduct separate analyses by sex. Discussion: The results of this study may provide insights into how FROA-BD and other cognitive remediations modulate brain function and thus could optimize these interventions.

Safety intervention for improving functioning in suicidal attempters (STRONG): A secondary prevention study. Study rationale and research protocol.

BACKGROUND: Suicide is one of the most largely preventable causes of death worldwide. The aim of the STRONG study is to assess the effectiveness of a specific intervention (an extended Safety Planning Intervention) called iFightDepression-SURVIVE (iFD-S) in suicidal attempters by changes in psychosocial functioning. As secondary outcomes, quality of life, cognitive performance, clinical state and neuroimaging correlates will be considered. OBJECTIVE: To describe the rationale and design of the STRONG study, an extension of the SURVIVE study, a national multicenter cohort about on prevention in suicidal attempters. METHODS: The STRONG study is a two-year clinical trial. A total sample of 60 patients will be randomly allocated to two arms: a group will receive a iFD-S and treatment as usual (TAU) (n=30 treatment group), while another group will exclusively receive TAU (n=30 control group). There will be three study points: baseline; 3-month; and 6-month follow-up assessments, all of which will include rater-blinded evaluation of psychosocial functioning, quality of life, clinical state, cognitive performance and neuroimaging acquisition. RESULTS: It is expected to obtain data on the efficacy of iFD-S in patients who have committed a suicide attempt. CONCLUSION: Results will provide insight into the effectiveness of IFD-S in suicidal attempters with respect to improvements in psychosocial functioning, quality of life, cognition, and neuroimaging correlates. CLINICAL TRIALS ID: NCT05655390.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.

Validity and reliability of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) in Brazilian bipolar patients / Validade e fidedignidade da Escala de Disfunções Cognitivas no Transtorno Bipolar (COBRA) em pacientes bipolares brasileiros

Abstract Introduction: In Brazil, there is no valid instrument to measure subjective cognitive dysfunction in bipolar disorder. The present study analyzed the psychometric properties of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) in Brazilian bipolar patients. We further investigated the relationship between the COBRA, objective cognitive measures, and illness course variables. Methods: The total sample (N=150) included 85 bipolar disorder patients and 65 healthy controls. The psychometric properties of the COBRA (e.g., internal consistency, concurrent validity, discriminative validity, factor analyses, ROC curve, and feasibility) were analyzed. Results: The COBRA showed a one-factor structure with very high internal consistency (Cronbach's alpha=0.890). Concurrent validity was indicated by a strong correlation with the cognitive domain of the FAST (r=0.811, p<0.001). Bipolar patients experienced greater cognitive complaints (mean=14.69; standard deviation [SD]=10.03) than healthy controls (mean=6.78; SD=5.49; p<0.001), suggesting discriminative validity of the instrument. No significant correlations were found between the COBRA and objective cognitive measures. Furthermore, higher COBRA scores were associated with residual depressive (r=0.448; p<0.001) and manic (r=0.376; p<0.001) symptoms, number of depressive episodes (r=0.306; p=0.011), number of total episodes (r=0.256; p=0.038), and suicide attempts (r=0.356; p=0.003). Conclusion: The COBRA is a valid instrument to assess cognitive complaints, and the combined use of subjective-objective cognitive measures enables the correct identification of cognitive dysfunctions in bipolar disorder.

Resumo Introdução: No Brasil, não existem instrumentos válidos para medir a disfunção cognitiva subjetiva no transtorno bipolar. O presente estudo analisou as propriedades psicométricas da Escala de Disfunções Cognitivas no Transtorno Bipolar (COBRA) em uma amostra brasileira de pacientes bipolares. Adicionalmente, investigamos a relação entre a COBRA, medidas cognitivas objetivas e curso da doença. Métodos: A amostra total (n=150) incluiu 85 pacientes com transtorno bipolar e 65 controles saudáveis. As propriedades psicométricas da COBRA (consistência interna, validade concorrente, validade discriminativa, análise fatorial, curva ROC e fidedignidade) foram analisadas. Resultados: A COBRA apresentou estrutura de um fator com alta consistência interna (alfa de Cronbach=0,890). A validade concorrente ficou demonstrada pela forte correlação com o domínio cognitivo da FAST (r=0,811, p<0,001). Pacientes bipolares tiveram mais queixas cognitivas [média=14,69; desvio padrão (DP)=10,03] que os controles (média=6,78; DP=5,49; p<0,001), sugerindo a validade discriminativa do instrumento. Não houve correlação significativa entre a COBRA e medidas cognitivas objetivas. Além disso, escores mais altos na COBRA estiveram associados com sintomas residuais depressivos (r=0,448; p<0,001) e maníacos (r=0,376; p<0,001), número de episódios depressivos (r=0,306; p=0,011), número de episódios totais (r=0.256; p=0.038) e tentativas de suicídio (r=0,356; p=0,003). Conclusão: A COBRA é um instrumento válido para avaliar queixas cognitivas, e o uso combinado das medidas cognitivas subjetivas-objetivas possibilita a correta identificação das disfunções cognitivas no transtorno bipolar.