A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression.

OBJECTIVE: Antidepressants are commonly used to treat bipolar depression but may increase the risk of mania. The evidence from randomized controlled trials, however, is limited by short treatment durations, providing little evidence for the long-term risk of antidepressant-induced mania. The authors performed a target trial emulation to compare the risk of mania among individuals with bipolar depression treated or not treated with antidepressants over a 1-year period. METHODS: The authors emulated a target trial using observational data from nationwide Danish health registers. The study included 979 individuals with bipolar depression recently discharged from a psychiatric ward. Of these, 358 individuals received antidepressant treatment, and 621 did not. The occurrence of mania and bipolar depression over the following year was ascertained, and the intention-to-treat effect of antidepressants was analyzed by using Cox proportional hazards regression with adjustment for baseline covariates to emulate randomized open-label treatment allocation. RESULTS: The fully adjusted analyses revealed no statistically significant associations between treatment with an antidepressant and the risk of mania in the full sample (hazard rate ratio=1.08, 95% CI=0.72-1.61), in the subsample concomitantly treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.63-2.13), and in the subsample not treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.65-2.07). Secondary analyses revealed no statistically significant association between treatment with an antidepressant and bipolar depression recurrence. CONCLUSIONS: These findings suggest that the risk of antidepressant-induced mania is negligible and call for further studies to optimize treatment strategies for individuals with bipolar depression.

Sleep profiles of different psychiatric traits.

Disturbed sleep comes in many forms. While the key role of sleep in mental health is undisputed, our understanding of the type of sleeping problems that manifest in the early stages of psychiatric disorders is limited. A sample without psychiatric diagnoses (N = 440, 341 women, 97 men, 2 non-binaries; Mage = 32.1, SD = 9.4, range 18-77) underwent a comprehensive assessment, evaluating eight sleep features and 13 questionnaires on common psychiatric complaints. Results revealed that traits of affect disorders, generalized anxiety, and ADHD had the worst sleep profiles, while autism disorder, eating disorder, and impulsivity traits showed milder sleep issues. Mania was the only trait associated with an overall better sleep profile. Across traits, insomnia and fatigue dominated and sleep variability was least prominent. These findings provide support for both transdiagnostic and disorder-specific targets for prevention and treatment.

Sleep quality predicts future mood symptoms in adolescents with bipolar disorder.

BACKGROUND: Poor sleep is prevalent in adolescents with bipolar disorder, precedes illness onset, and is associated with worse mood symptoms. We examined interrelationships between sleep quality and mood symptoms in adolescents with bipolar disorder, particularly effects of sleep quality on emergent mood symptoms. METHODS: Adolescents with bipolar disorder participated in a two-year longitudinal treatment study. Sleep quality (Pittsburgh Sleep Quality Index, PSQI) was assessed quarterly during treatment (baseline, 3-, 6-, 9-, 12-month visits) and twice during follow-up (18-, 24-month visits). Mood symptoms (ALIFE Psychiatric Status Ratings) were retrospectively rated weekly by an independent clinician. Lag models tested whether sleep quality predicted next month's mood symptoms and whether mood symptoms predicted future sleep quality. RESULTS: Adolescents with bipolar disorder had poor sleep quality. Sleep quality initially improved but remained stable thereafter. Worse sleep quality at 6-months predicted worse depression, hypomania, and suicidal ideation the following month. Sleep quality was worse for adolescents who had a suicide attempt during the study compared to those who did not and was worse preceding months with a suicide attempt compared to months without attempts. Alternatively, worse depression predicted worse future sleep quality at baseline, 3-, and 18-months and worse suicidal ideation predicted worse future sleep quality at baseline, 12-, and 18-months. LIMITATIONS: Mood symptoms were rated retrospectively and the PSQI may not capture all dimensions of sleep important for mood symptoms. CONCLUSIONS: Targeted evidence-based sleep treatment in adolescents with bipolar disorder may alleviate sleep problems and have additional benefits on mood symptoms and suicidality risk.

Adaption and validation of the Rwandese version of the Young Mania Rating Scale to measure the severity of a manic or hypomanic episode.

BACKGROUND: Bipolar Disorder is one of the most incapacitating diseases among young persons, leading to cognitive and functional impairment and raised mortality, particularly death by suicide. Managing a manic episode and developing new and more effective treatment modalities requires sensitive and reliable instruments. This study aims to translate the English version of the YMRS questionnaire into Kinyarwanda, adapt it to the Rwandan context, and assess its validity. METHODS: The original English version of The Young Mania Rating Scale questionnaire was translated into Kinyarwanda. The translation process followed a standardized approach, including back-translation, cross-cultural adaptation, and final adjustments. A total of 130 inpatients with bipolar disorder in a manic episode from CARAES Ndera Teaching Hospital were included. The descriptive statistics and test-retest correlations were carried out, as well as the CFA for validation and Rasch-analysis. RESULTS: The Rwandese version of The Young mania rating scale had an adequate internal consistency (Cronbach's alpha = 0.90). Item 11 provided the lowest standardized loading in both ratings (0.51 and 0.55). The second lowest loading involved the highly correlated item pairs 5 & 9, with item 5 loading 0.51 in rating 1 and item 9 loading 0.57 in rating 2. The remaining loadings ranged from 0.59 to 0.79. This relatively narrow range indicated that a fit to a Rasch model was plausible if excluding item 11. CONCLUSION: The findings demonstrate that the translated YMRS, the R-YMRS, can be used as a reliable and valid instrument for assessing mania in the Rwandese population in clinical and research settings. However, the results supported using an unweighted total score of 32 and removing items 5, 9, and 11. Studies on this revised scale with an added interview guide for less-trained clinical staff are recommended.

The path from mood symptoms to substance use: A longitudinal examination in individuals with and at risk for bipolar spectrum disorders.

BACKGROUND: Adolescent substance use poses a critical public health challenge, intertwined with risk-taking behavior, criminality, functional impairment, and comorbid mental and physical health issues. Adolescents with bipolar spectrum disorders (BSD) exhibit heightened susceptibility to substance use, necessitating a nuanced exploration of the bipolar-substance use relationship. METHODS: This study addressed gaps in the literature by employing a prospective, longitudinal design with 443 Philadelphia-area adolescents, tracking BSD symptoms and substance use. We predicted that BSD symptoms would be associated with increases in substance use, and that these effects would be more pronounced for individuals with a BSD and those with high reward sensitivity. RESULTS: Hypomanic symptoms predicted subsequent substance use, with a stronger association observed in individuals diagnosed with BSD. Contrary to expectations, depressive symptoms did not exhibit a similar relationship. Although the hypothesized moderating role of reward sensitivity was not supported, higher reward sensitivity predicted increased substance use. LIMITATIONS: Symptoms and substance use are only captured for the month prior to each session due to the assessment timeline. This highlights the benefits of frequent assessments over a shorter time frame to monitor real-time changes. Alternative classification methods for reward sensitivity, such as brain or behavior-based assessments, might yield different results. CONCLUSIONS: This study's contributions include evaluating substance use broadly, utilizing a longitudinal design for temporal clarity, and shifting the focus from substance use predicting mood symptoms to the inverse. The findings underscore the need for continued exploration of mood symptom predictors of substance use, emphasizing the role of reward sensitivity.

Sex differences in neural responses to emotional facial expressions are associated with lifetime depression and mania risk.

INTRODUCTION: No studies systematically examined sex differences in neural mechanisms underlying depression and mania/hypomania risk. METHOD: 80 females and 35 males, n = 115(age21.6±1.90) were scanned using 3TfMRI during an implicit emotional-faces task. We examined neural activation to all emotional faces versus baseline, using an anatomical region-of-interest mask comprising regions supporting emotion and salience processing. Sex was a covariate. Extracted parameter estimates(FWE < 0.05,k > 15), age, IQ and their sex interactions were independent variables(IV) in two penalized regression models: dependent variable either MOODS-SR-lifetime, depressive or manic domain score as measures of mania and depression risk. Subsequent Poisson regression models included the non-zero variables identified in the penalized regression models. We tested each model in 2 independent samples. Test sample-I,n = 108(21.6 ± 2.09 years,males/females = 33/75); Test sample-II,n = 93(23.7 ± 2.9 years,males/females = 31/62). RESULTS: Poisson regression models yielded significant relationships with depression and mania risk: Positive correlations were found between right fusiform activity and depression(beta = 0.610) and mania(beta = 0.690) risk. There was a significant interaction between sex and right fusiform activity(beta = -0.609) related to depression risk, where females had a positive relationship than; and a significant interaction(beta = 0.743) between sex and left precuneus activity related to mania risk, with a more negative relationship in females than males. All findings were replicated in the test samples(qs < 0.05,FDR). LIMITATIONS: No longitudinal follow-up. CONCLUSION: Greater visual attention to emotional faces might underlie greater depression and mania risk, and confer greater vulnerability to depression in females, because of heightened visual attention to emotional faces. Females have a more negative relationship between mania risk and left precuneus activity, suggesting heightened empathy might be associated with reduced mania/hypomania risk in females more than males.

An algorithm for pharmacological treatment of mania during hospitalisation.

Current evidence for pharmacological treatment of mania during hospitalisation is insufficient as there are no larger well-designed randomised trials of comparative medical treatments of mania during inpatient stays. Moreover, there is considerable variation in pharmacological medication in clinical practice during hospitalisation for mania. Based on a hospital data overview, a systematic search of the literature and a three-day consensus meeting, this narrative review proposed an algorithm for optimised pharmacological treatment of mania during hospitalisation and its subsequent scientific evaluation.

Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study.

Testosterone has complex effects on psychological traits and behavior; it is associated with social dominance and competition and is a potential human sex pheromone. This study aimed to investigate the associations between testosterone levels, aggressive behavior, and manic symptoms using a network analysis among bipolar disorder (BD) patients in psychiatric emergency departments (PED). Data from January 2021 and March 2022 BD patients in PED were analyzed. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS). Aggression was assessed with subscale of the PANSS scale (PANSS-AG). The undirected network structures of testosterone levels, aggressive behavior, and manic symptoms were estimated, and centrality and bridge centrality indices were examined. Network stability was examined using the case-dropping procedure. The Network Comparison Test (NCT) was conducted to evaluate whether network characteristics differed by gender. We recruited a total of 898 BD patients, with the mean YMRS score as 13.30 ± 9.58. The prevalence of level II aggression was 35.6% (95%CI = 32.5%-38.7%), level III aggression was 29.5% (95%CI = 26.3%-32.6%), and level VI aggression was 7.0% (95%CI = 5.4%-8.8%). The male participants had a mean testosterone level of 391.71 (Standard Deviation (SD):223.39) compared to 36.90 (SD:30.50) for female participants in the whole sample. Through network analysis, "Increased motor activity-energy" emerged as the central symptom, with the highest centrality expected influence, followed by "Emotional Instability" and "Disruptive/aggression behavior". Notably, "Emotional Instability" appeared to be the bridge symptom linking manic symptoms to aggressive behavior. Within the flow network model, "Speech rate and amount" exhibited the strongest positive correlation with testosterone levels, followed closely by "Disruptive/aggression behavior". The constructed network model demonstrated robust stability, with gender showing no significant impact on the structure. In this study, "Increased motor activity-energy" stood out as the most influential symptom, and "Speech rate and amount" acted as the main bridge symptom linking testosterone levels, aggressive behavior, and manic symptoms. Targeting the central and bridge symptoms may improve the outcomes of aggression interventions implemented among BD patients in psychiatric emergency care.

Experiences of nurses providing care to hospitalized patients with acute mania in Türkiye: A phenomenological study.

The main purpose of this study was to determine the experiences of nurses who care for hospitalized patients experiencing an acute manic episode. This qualitative study was carried out with 15 nurses working in a psychiatric ward in Türkiye. Data were collected through semi-structured in-depth individual interviews and focus-group interviews in which the face-to-face interview technique was used. Two main themes emerged from the analysis of the qualitative data: (1) the difficulties experienced and (2) the most effective elements of care. Under the first main theme, the following sub-themes emerged: difficulties in setting boundaries, safety concerns, difficulties in managing the patient's demands, inability to choose the appropriate word(s), and the "emotional whirlwind" experienced. The second main theme, on the other hand, included the following sub-themes: meeting basic needs, ensuring treatment compliance, encouragement to engage in physical activity, and having a sufficient number of qualified personnel. The study revealed that the nurses had difficulties in caring for their manic patients. On the basis of these results, it is recommended that nurses be given counseling and training on setting boundaries, ensuring safety, managing the patient's demands, coping with their own emotions, and communicating better. In addition, the study identified the importance of nursing interventions to meet patients' basic needs, encourage them to engage in physical activity, and ensure treatment compliance, and the importance of there being an adequate number of qualified personnel. These results may help students and other nurses in terms of assessing and setting priorities in cases needing acute psychiatric care.

Association between electroconvulsive therapy and time to readmission after a manic episode.

OBJECTIVE: The majority of patients hospitalized for treatment of a manic episode are readmitted within 2 years despite maintenance treatment. Electroconvulsive therapy (ECT) has been associated with lower rehospitalization rates in some psychiatric conditions, but its association with readmission after a manic episode has not been investigated. Therefore, the aim of this study was to determine whether the time to readmission in patients with mania treated with ECT was longer than in patients not treated with ECT and whether there were subgroups of patients that benefited more. METHODS: This was a nationwide register-based, observational study. All patients diagnosed with bipolar disorder, manic episode, admitted to any hospital in Sweden between 2012 and 2021 were included. Patients contributed data to the study for every admission. All admissions were followed up until psychiatric readmission, death, or the end of the study (December 31, 2021). Association between ECT and time to readmission was analyzed. A paired samples model was performed for 377 patients with at least two admissions for mania, treated with ECT at one admission and without ECT at the other admission. Times to readmission were analyzed. RESULTS: A total of 12,337 admissions were included; mean (SD) age 47.7 (17.2), 5443 (44.1%) men. Readmission rate within 1 year was 54.6%. ECT was administered in 902 (7.3%) admissions. Within 30 days after admission, 182 out of 894 (20.4%) patients treated with ECT versus 2105 out of 11,305 (18.6%) patients treated without ECT were readmitted. There was no association between ECT and time to readmission (aHR 1.00, 95% CI 0.86-1.16, p = 0.992) in the model with all admissions. The paired samples model included 754 admissions (377 patients), mean (SD) age during admission without ECT was 45.6 (16.5), and with ECT 46.6 (16.4), 147 (39.0%) were men. In that model, readmission rate within 30 days for treatment with ECT was 19.0%, and for treatments without ECT, 24.1% (aHR 0.75, 95% CI 0.55-1.02, p = 0.067). CONCLUSION: Readmission rates after inpatient treatment of mania were high. ECT was not significantly associated with longer time to readmission, but there was a trend toward a protective effect of ECT when admissions with and without ECT were compared within the same patients.

Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine.

BACKGROUND: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. AIM: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). METHODS: Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. RESULTS: M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. CONCLUSION: These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.

Identifying tripartite relationship among cortical thickness, neuroticism, and mood and anxiety disorders.

The number of young adults seeking help for emotional distress, subsyndromal-syndromal mood/anxiety symptoms, including those associated with neuroticism, is rising and can be an early manifestation of mood/anxiety disorders. Identification of gray matter (GM) thickness alterations and their relationship with neuroticism and mood/anxiety symptoms can aid in earlier diagnosis and prevention of risk for future mood and anxiety disorders. In a transdiagnostic sample of young adults (n = 252;177 females; age 21.7 ± 2), Hypothesis (H) 1:regularized regression followed by multiple regression examined relationships among GM cortical thickness and clinician-rated depression, anxiety, and mania/hypomania; H2:the neuroticism factor and its subfactors as measured by NEO Personality Inventory (NEO-PI-R) were tested as mediators. Analyses revealed positive relationships between left parsopercularis thickness and depression (B = 4.87, p = 0.002), anxiety (B = 4.68, p = 0.002), mania/hypomania (B = 6.08, p ≤ 0.001); negative relationships between left inferior temporal gyrus (ITG) thickness and depression (B = - 5.64, p ≤ 0.001), anxiety (B = - 6.77, p ≤ 0.001), mania/hypomania (B = - 6.47, p ≤ 0.001); and positive relationships between left isthmus cingulate thickness (B = 2.84, p = 0.011), and anxiety. NEO anger/hostility mediated the relationship between left ITG thickness and mania/hypomania; NEO vulnerability mediated the relationship between left ITG thickness and depression. Examining the interrelationships among cortical thickness, neuroticism and mood and anxiety symptoms enriches the potential for identifying markers conferring risk for mood and anxiety disorders and can provide targets for personalized intervention strategies for these disorders.

Crocin (bioactive compound of Crocus sativus L.) potently restores REM sleep deprivation-induced manic- and obsessive-compulsive-like behaviors in female rats.

Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors including hyperlocomotion. On the other hand, crocin (one of the main compounds of Crocus sativus L. or Saffron) may be beneficial in the improvement of mental and cognitive dysfunctions. Also, crocin can restore the deleterious effects of SD on mental and cognitive processes. In this study, we investigated the effect of REM SD on female rats' behaviors including depression- and anxiety-like behaviors, locomotion, pain perception, and obsessive-compulsive-like behavior, and also, the potential effect of crocin on REM SD effects. We used female rats because evidence on the role of REM SD in modulating psychological and behavioral functions of female (but not male) rats is limited. REM SD was induced for 14 days (6h/day), and crocin (25, 50, and 75 mg/kg) was injected intraperitoneally. Open field test, forced swim test, hot plate test, and marble burying test were used to assess rats' behaviors. The results showed REM SD-induced manic-like behavior (hyperlocomotion). Also, REM SD rats showed decreased anxiety- and depression-like behavior, pain subthreshold (the duration it takes for the rat to feel pain), and showed obsessive compulsive-like behavior. However, crocin at all doses partially or fully reversed REM SD-induced behavioral changes. In conclusion, our results suggested the possible comorbidity of OCD and REM SD-induced manic-like behavior in female rats or the potential role of REM SD in the etiology of OCD, although more studies are needed. In contrast, crocin can be a possible therapeutic choice for decreasing manic-like behaviors.

Association of childhood trauma, social support, cognition, and suicidality in females with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a severe mental disorder with heavy disease burden. Females with BD are special populations who suffer a lot from childhood trauma, social support, cognitive deficits, and suicidality. In this study, the relationship among childhood trauma, social support, and clinical symptoms of BD was investigated and the risk factors for suicidality were explored in female patients with BD. METHODS: This study included 57 drug-naive female BD patients, 64 female BD patients with long-term medication, and 50 age-matched female healthy controls. Childhood trauma, social support, clinical symptoms, cognition, and suicidality (suicide ideation, suicide plan, suicide attempt, suicide frequency) were measured with scales. RESULTS: Compared with healthy controls, females with BD showed higher levels of childhood trauma and suicidality, and lower levels of social support and cognitive deficits. In the drug-naïve BD group, social support mediated the relationship between childhood trauma and insomnia symptoms (indirect effect: ab = 0.025). In the BD with long-term medication group, mania symptom was associated with suicide plan (OR = 1.127, p = 0.030), childhood trauma was associated with suicide attempt (OR = 1.088, p = 0.018), and years of education (OR = 0.773, p = 0.028), childhood trauma (OR = 1.059, p = 0.009), and delayed memory (OR= 1.091, p= 0.016) was associated with suicide frequency (OR = 1.091, p = 0.016). CONCLUSIONS: This study provides initial evidence that social support partially explains the relationship between childhood trauma and clinical symptoms in females with BD. Additionally, mania symptoms, childhood trauma, and delayed memory were risk factors for suicidality. Interventions providing social support and improving cognitive function may be beneficial for females with BD who are exposed to childhood trauma and with high suicide risk.

Effects of cariprazine on reducing symptoms of irritability, hostility, and agitation in patients with manic or mixed episodes of bipolar I disorder.

BACKGROUND: Hostility, irritability, and agitation are common in patients with bipolar I disorder. Post hoc analyses evaluated the effect of cariprazine on these symptoms in patients with bipolar I mania. METHODS: Data were pooled from three randomized, double-blind, placebo-controlled phase 3 cariprazine trials in adults with bipolar I manic/mixed episodes (NCT00488618, NCT01058096, NCT01058668); pooled cariprazine doses (3-12 mg/d) were analyzed. Patients were categorized into hostility/irritability and agitation subgroups by baseline scores: Young Mania Rating Scale (YMRS) irritability and disruptive-aggressive behavior items score ≥ 2; Positive and Negative Syndrome Scale (PANSS) hostility item ≥ 2; PANSS-Excited Component (PANSS-EC) total score ≥ 14 and score ≥ 4 on ≥ 1 individual item. Changes from baseline to week 3 in hostility/irritability- and agitation-related outcomes were evaluated. Adjustments were made for the presence of other manic symptoms, sedation, and akathisia. RESULTS: Most patients met subgroup inclusion criteria (YMRS hostility = 930; PANSS hostility = 841, PANSS-EC agitation = 486). In the YMRS subgroup, least squares mean differences in change from baseline were statistically significant for cariprazine versus placebo on YMRS hostility/irritability-related items (irritability [-0.93], disruptive-aggressive behavior [-0.79], combined [-1.75]; P ≤ 0.001 each), YMRS total score (-5.92, P ≤ 0.0001), and all individual YMRS items (-0.25 to -0.93, P ≤ 0.0001); differences remained significant after adjustment for other manic symptoms, sedation, and akathisia. Differences in PANSS hostility and PANSS-EC subgroups were significant for cariprazine versus placebo (P ≤ 0.001). LIMITATIONS: Post hoc analysis. CONCLUSION: Cariprazine demonstrated specific antihostility/irritability and anti-agitation effects in patients with manic/mixed episodes of bipolar I disorder and baseline hostility, irritability, or agitation.

Distinct global brain connectivity alterations in depressed adolescents with subthreshold mania and the relationship with processing speed: Evidence from sBEAD Cohort.

BACKGROUND: Bipolar disorder (BD) is a progressive condition. Investigating the neuroimaging mechanisms in depressed adolescents with subthreshold mania (SubMD) facilitates the early identification of BD. However, the global brain connectivity (GBC) patterns in SubMD patients, as well as the relationship with processing speed before the onset of full-blown BD, remain unclear. METHODS: The study involved 72 SubMD, 77 depressed adolescents without subthreshold mania (nSubMD), and 69 gender- and age-matched healthy adolescents (HCs). All patients underwent a clinical follow-up ranging from six to twelve months. We calculated the voxel-based graph theory analysis of the GBC map and conducted the TMT-A test to measure the processing speed. RESULTS: Compared to HCs and nSubMD, SubMD patients displayed distinctive GBC index patterns: GBC index decreased in the right Medial Superior Frontal Gyrus (SFGmed.R)/Superior Frontal Gyrus (SFG) while increased in the right Precuneus and left Postcentral Gyrus. Both patient groups showed increased GBC index in the right Inferior Temporal Gyrus. An increased GBC value in the right Supplementary Motor Area was exclusively observed in the nSubMD-group. There were opposite changes in the GBC index in SFGmed.R/SFG between two patient groups, with an AUC of 0.727. Additionally, GBC values in SFGmed.R/SFG exhibited a positive correlation with TMT-A scores in SubMD-group. LIMITATIONS: Relatively shorter follow-up duration, medications confounding, and modest sample size. CONCLUSION: These findings suggest that adolescents with subthreshold BD have specific impairments patterns at the whole brain connectivity level associated with processing speed impairments, providing insights into early identification and intervention strategies for BD.