This systematic review and meta-analysis aimed to synthesize the evidence from randomized trials of lithium, lamotrigine, and placebo for the treatment of bipolar II disorder (BDII) in terms of bipolar II depression, hypomania, and maintenance treatment.

A literature search was performed 20th November 2024 across PubMed, Embase and PsycINFO, and grey literature for studies of lithium, lamotrigine, and placebo in adults with BDII, across illness phases. Primary outcomes were efficacy and tolerability. We conducted random-effects pair-wise meta-analysis to provide a summary measure of effect, assessed the risk of bias, and assessed the certainty of the evidence using the GRADE framework.

Our search yielded 2326 records, including 10 randomized trials comprising 645 patients with BDII. The evidence was very uncertain regarding lithium's effect on the risk of new affective episodes, regardless of polarity, compared with placebo (RR 0.86, 95 % CI [0.66, 1.11], I2 = 0 %, four studies, very low certainty evidence). A quantitative synthesis could not be conducted to compare lamotrigine and placebo. The evidence was very uncertain regarding the effect of lithium on depression severity compared with lamotrigine (mean HAMD17 difference: 1.27, 95 % CI [-3.84, 6.38], I2 = 0 %, two studies, very low certainty evidence). The overall risk of bias was of 'some concern' for 84 % of outcomes assessed. For all outcomes, the certainty of the evidence was graded 'very low'.

The evidence for lithium and lamotrigine in treating BDII is scarce, and the certainty of the evidence is very low. Large, well-conducted RCTs of patients with BDII are needed.

Affective temperaments represent the substrate of personality that can influence the expression of chronic infectious diseases, including COVID-19 and its sequelae. However, research conducted so far on this topic focused on narrow aspects of psychopathology.

To investigate the effect of affective temperaments on the relationship between physical and psychiatric symptoms in patients with long-COVID.

The sample consisted of 1513 patients who have been hospitalized for COVID-19 and developed long-COVID. Participants performed a multidisciplinary assessment including psychiatric evaluation through the administration of rating scales. The psychiatric dimensions assessed included severity of depressive, anxiety, manic symptoms, anhedonia, hopelessness, suicidal risk, psychological distress, levels of well-being, resilience, emotion regulation, and levels of post-traumatic stress disorder (PTSD). Affective temperament was assessed through the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire (TEMPS-A). We used TEMPS-A subscales as moderators and sociodemographic and COVID-19/long-COVID-related clinical characteristics as predictors. Psychiatric rating scales total scores were outcome variables.

Cyclothymic, irritable, and depressive temperaments strengthened the relationship between number of long-COVID symptoms, levels of anhedonia and poor psychological well-being. Cyclothymic and irritable temperaments weakened the relationship between number of long-COVID symptoms and history of intensive care unit admission and PTSD severity. Depressive temperament strengthened the latter relationship.

The clinical variables included in the analyses do not represent the entire range of psychopathology.

Depressive temperament enhanced the relationship between physical and psychiatric symptoms in patients with long-COVID, whereas the effects of cyclothymic and irritable temperaments may depend on the psychiatric dimension assessed.

To assess the safety and efficacy of exenatide in overweight or obese patients treated with olanzapine.

Adults with stable major mood or psychotic disorders were randomized to double-blind exenatide or placebo for 16 weeks. Weight and body mass index (BMI) were monitored throughout the study. A secondary objective was to evaluate the tolerability of exenatide and its effects on mood and psychotic symptoms.

A significant difference in weight change was detected between the treatment groups. Participants in the exenatide group experienced on average a minor weight loss, while participants in the placebo group on average experienced weight gain (-0.5 kg [-0.6 %] vs. +2.6 kg [+2.8 %], both p < .01). The most common side effects in the exenatide group were gastrointestinal symptoms and headaches. There were no clinically meaningful differences between the groups in changes to mood or psychotic symptoms.

Exenatide is effective and well-tolerated for attenuating olanzapine-associated weight gain.

Exenatide for the Treatment of Weight Gain Associated with Olanzapine in Obese Adults. NCT00845507.

Traditional treatment for affective disorders primarily focuses on symptom management through pharmacotherapy and psychotherapy and rarely addresses co-existing physical impairments.

This randomized controlled trial assessed the impact of a six-month multimodal intervention (AWARE) on physical health in patients with bipolar and unipolar depressive disorders. A total of 103 patients, median age 40.75 years (65 % female), were randomized into the AWARE group (n = 50) or treatment as usual (TAU) group (n = 53). The AWARE intervention included five modules focused on activities of daily living, mood management, social relations, physical health, and cognition, with participants receiving approximately 12 sessions. TAU involved standard psychiatric care, Health outcomes were evaluated on sleep, metabolic markers, substance use, medication side effects, and perceived physical health. Statistical analyses used logistic regression for group comparisons and analysis of covariance for continuous outcomes.

The AWARE group had significant improvements in sleep onset latency and reported reduced physical pain affecting daily work compared to TAU. However, no statistically significant differences were found in other physical health outcomes, such as metabolic markers, substance use, medication side effects, or perceived physical health. Study limitations include a modest sample size and a relatively short intervention duration.

While the AWARE intervention improved sleep and pain management, it did not significantly affect other health markers. Future research should involve longer intervention periods, larger sample sizes, and a comprehensive approach to both mental and physical health.

Gender differences in non-suicidal self-injury (NSSI) among adolescents with major depressive episodes (MDE) may exist, but the underlying neurobiological mechanisms remain unclear.

171 unmedicated MDE adolescent patients with NSSI (NSSI group), 71 unmedicated MDE adolescent patients without NSSI (non-NSSI group), and 32 healthy controls (HC) were included. The 24-item Hamilton Depression Rating Scale (24-HDRS) was used to assess depressive symptoms. Bilateral metabolic ratios of N-acetyl aspartate (NAA) and choline-containing compounds (Cho) to creatine (Cr) in the prefrontal cortex (PFC), anterior cingulated cortex (ACC), lenticular nucleus (LN), and thalamus were obtained by proton magnetic resonance spectroscopy (1H-MRS) at 3.0 T.

A significant interaction effect between biological sex and the group can be found in the Cho/Cr of the right thalamus, in which males with NSSI showed significantly lower Cho/Cr than those without (p = 0.01), and males had higher Cho/Cr of the right thalamus than females in the non-NSSI group (p = 0.002). A significant correlation between the risk of NSSI and the Cho/Cr of the right thalamus can only be found in male MDE adolescents (p = 0.002), instead of in females. The binary logistic regression showed a significant negative association between the Cho/Cr of the right thalamus and the risk of NSSI in males (p = 0.02).

There is a sex-specific association between the neurochemical metabolisms and the NSSI risk. The Cho/Cr of the right thalamus may increase the risk of NSSI in MDE male adolescents, which can be a specific biomarker for NSSI risk the in MDE male adolescents.

Non-suicidal self-injury (NSSI) is associated with increased suicide risk and is prevalent among patients with mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). Structural alterations in cortical regions involved in emotional processing are linked to NSSI as well as suicide risk in mood disorders. Few studies have investigated the neurobiological substrates of NSSI and suicidal thoughts and behaviors (STB), particularly comparing youth with BD to those with MDD. There is a critical need to examine NSSI and STB in the context of MDD and BD separately, as risks differ between these populations.

This study investigated the relationship between anterior cingulate cortex (ACC) cortical thickness and volume and NSSI and STB in youth with mood disorders. One-hundred thirty-seven youth (86 with MDD and 51 with BD), ages 13 to 21, completed a diagnostic interview, clinical assessments, and 3 T magnetic resonance imaging. Morphometric analysis of brain images was performed to evaluate differences in cingulate regions of interest.

Seventy-five youth reported a NSSI. Youth with BD were more likely to report NSSI than youth with MDD. In addition, youth with BD and NSSI were more likely to have a suicide attempt and had significantly lower cortical thickness in the right caudal ACC (p = .009, η2 = 0.050) compared to youth with MDD and NSSI.

These structural alterations in the ACC, which impact emotional regulation and pain processing, may be linked to the increased NSSI and suicide risk observed in BD.

Approximately 50% of patients with psychiatric disorders do not fully adhere to the prescribed psychopharmacological therapy, significantly impacting the progression of the disorder and the patient's quality of life. The present study aimed to assess potential differences in terms of rates and clinical features of treatment adherence in a large cohort of psychiatric patients with different diagnoses attending various psychiatric services. The study included 307 psychiatric patients diagnosed with a primary major depressive disorder, bipolar disorder, anxiety disorder, schizophrenic spectrum disorder, or personality disorder. Patient's adherence to treatment was evaluated using the Clinician Rating Scale, with a cutoff of at least five defining adherence subgroups. One-third of the sample reported poor medication adherence. A lower rate of adherence emerged among patients with schizophrenic spectrum disorder and bipolar disorder. Subjects with poor adherence were more frequently inpatients and showed higher current substance use, a greater number of previous hospitalizations, and more severe scores at psychopathological assessment compared with patients with positive adherence. Poor adherence was associated with symptom severity and increased rates of relapses and rehospitalizations. In addition, substance use appears to be an unfavorable transdiagnostic factor for treatment adherence.

This study investigated whether having a familial risk of affective disorders, subclinical psychopathology, functioning, personality traits, stressful life events, and childhood trauma predict the onset or recurrence of affective episodes.

The present study is a 7-year follow-up study of a baseline sample of 204 monozygotic twins (MZ) with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk), and healthy twins with no personal or familial history of affective disorder (low-risk).

During the 7.0-year median follow-up time, 59.3 % of the affected twins had a recurrence of an affective episode, 33.3 % of high-risk twins, and 7.5 % of low-risk twins had an onset. Familial risk and being affected were predictors for onset and recurrence. Including the whole sample, subclinical symptoms, functioning, stressful life events, and the personality trait neuroticism were statistically significant predictors of onset and recurrence. Regarding the individual risk groups, increasing age was a significant predictor of increased hazard in the affected risk group and lower hazard in the low-risk group.

This follow-up study revealed that the most potent predictors for onset or recurrence were familial risk and having an affective disorder at baseline. Subclinical depressive symptoms, personality traits, stressful life events, and impaired functioning were significant contributors to onset risk and recurrence. These findings highlight the need to integrate relevant risk factors into daily clinical settings and integrate the most well-established factors as potential targets for primary care interventions.

Individuals with bipolar disorder (BD) frequently experience comorbid medical conditions, with migraine being among the most common. While research on migraine prevalence in BD is growing, the associated clinical features, comorbidities, and treatments remain underexplored and sometimes inconsistent. This study aimed to investigate the clinical features and comorbidities associated with migraine in a large cohort of adults with BD.

We assessed 4348 outpatients with BD attending FondaMental Advanced Centers of Expertise. Sociodemographic and clinical data were collected using a standardized procedure. Lifetime diagnoses for medical disorders, including migraine, were based on self-reports, clinician assessments, and medical history reviews. Multivariable logistic regression was used to assess associations between migraine and sociodemographic factors, clinical characteristics, comorbidities, and medications.

The prevalence of comorbid migraine in BD was 20 %, with 29.1 % in BD type II and 19.9 % in BD type I. Multivariable analysis found that migraine was associated with younger age (OR = 0.98, CI 95 % 0.97-0.99), females (OR = 2.15, CI 95 % 1.56-2.95), sleep disturbances (OR = 1.06, CI 95 % 1.02-1.11), childhood trauma (OR = 1.01, CI 95 % 1.00-1.02), hypertension (OR = 1.88, CI 95 % 1.13-3.15), psoriasis (OR = 1.61, CI 95 % 1.01-2.56), asthma (OR = 1.65, CI 95 % 1.02-2.67) and lower use of second-generation antipsychotics (OR = 0.65, CI 95 % 0.48-0.87).

Migraine is common in BD, especially in younger individuals, females, and those with sleep disturbances or a history of trauma, who also experience a higher clinical burden. These overlapping factors highlight the need for an integrated treatment approach, addressing mood stabilization, sleep management, and trauma support to reduce migraine burden in BD patients.

The clinical profiles of youth presenting to early intervention mental health services are heterogeneous, with various sub-groups proposed and little information about the longitudinal stability of profiles, especially those associated with bipolarity.

802 youth aged 12-25-years (Mean = 18.26; 66 % females) accessing primary-care based mental health clinics were assessed at baseline and 417 were re-assessed after 12-months. An exploratory factor analysis of 62 items from six validated rating scales of the severity of mental and physical ill-health was conducted. Seven factors (anxiety, sleep, depression, restlessness, distress, activation, somatic complaints) were derived and modelled using latent profile analysis. Associations between profile membership, clinical outcomes and functioning were examined. Conditional probabilities of shifting to a different profile longitudinally were computed.

Three profiles were revealed which were psychometrically invariant across baseline and follow-up: (1) 'High distress with high activation' (32 % baseline, 25 % follow-up); (2) 'High distress without activation' (31 % baseline, 26 % follow-up); and (3) 'Moderate distress' (37 % baseline, 33 % follow-up). A fourth profile, 'Low distress' (16 %), emerged at follow-up. Profiles did not differ by age at baseline or sex. 'High distress with high activation' was more likely to be impaired longitudinally, and to meet criteria for a full-threshold mental disorder at follow-up. About 39 % of youth retained the same profile longitudinally, while 16 % shifted to lower distress, and 13 % shifted to higher distress.

These findings suggest that activation is a marker of poorer clinical and functional outcomes in youth presenting for mental health care.

The study aimed at investigating the possible effects of early stressful experiences on chronotype and the clinical features associated with bipolar disorder (BD). A sample of 203 adults with BD depressive episode (mean age 46.7 + 13.5, females 57.1 %) was assessed by the Beck Depression Inventory-II (BDI-II), the Early Trauma Inventory Self Report-Short Form (ETISR-SF), the Difficulties in Emotion Regulation Scale (DERS), the Morningness-Eveningness Questionnaire (MEQ), the Resilience Scale for Adults (RSA), the Scale for Suicide Ideation (SSI) and the Young Mania Rating Scale (YMRS). Patients with evening chronotype showed greater early life stressors and greater severity of depressive symptoms, anxiety comorbidity, higher suicidal risk, emotional impulsivity and low resilience. In logistic regression models, evening chronotype (MEQ) was a significant predictor of depressive symptoms (BDI-II > 13; odds ratio [OR] = 4.41; 95 % CI 1.89-9.01; p < 0.001), mixed features (YMRS>5; OR = 2.60; 95 % CI 1.36-4.97; p = 0.004), a higher risk of suicidality (SSI > 6; OR = 2.27; p = 0.020), emotional dysregulation (DERS; OR = 2.01; 95 % CI 1.09-3.74; p = 0.027), and low resilience (RSA < 89; OR = 1.99; 95 % CI 1.12 = 3.93, p = 0.046). Mediation analyses revealed that an evening chronotype might play a mediating role in the relationship between early life stressors and high suicidal risk (Z = 2.0, SE = 0.62, p = 0.044), emotional impulsivity (Z = 2.07, SE = 0.33, p = 0.038), and low resilience in social competence (Z = 2.08, SE = 0.02, p = 0.037). Addressing circadian rhythm alterations in subjects exposed to early stressors may help preventing consequences of those stressors on BD.

In this study, it was aimed to investigate the relationship of circadian rhythm disorders with eating behavior and clinical features in patients diagnosed with Bipolar Disorder (BD).

The study included 95 patients with BD and a control group of 60 healthy individuals. Hamilton Depression Rating Scale (HDRS), Young Mania Rating Scale (YMRS), Eating Attitudes Test (EAT), and Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) were applied to the participants who volunteered to participate in the study.

In the study, patients diagnosed with BD were compared with the healthy individuals in the control group in terms of circadian rhythms and eating behaviors. In the comparison, it was found that the total and subscale scores of BRIAN scale were higher in patients diagnosed with BD (BRIAN total score: 33.31 ± 9.30) compared to the control group (BRIAN total score: 25.07 ± 5.70). In addition, it was also observed that EAT scores were also higher in patients diagnosed with BD (EAT total score: 18.42 ± 9.11) compared to the control group (EAT total score: 14.82 ± 4.86). In the analysis of the relationship between circadian rhythms and eating behavior and clinical characteristics, it was found that circadian rhythms were associated with clinical characteristics but not with eating behavior (p = 0.785).

In the study, it was found that circadian rhythm disorders and eating behavior disorders were higher in patients diagnosed with BD compared to the control group. It was also observed that the deteriorated circadian rhythm was associated with clinical features.

Differentiating Bipolar (BD) and depressive (DD) disorders remains challenging in clinical practice due to overlapping symptoms. Our study employs fixel-based analysis (FBA) to examine fiber-specific white matter differences in BD and DD and gain insights into the ability of FBA metrics to predict future spectrum mood symptoms.

163 individuals between 18 and 45 years with BD, DD, and healthy controls (HC) underwent Diffusion Magnetic Resonance Imaging. FBA was used to assess fiber density (FD), fiber cross-section (FC), and fiber density cross-section (FDC) in major white matter tracts. A longitudinal follow-up evaluated whether FBA measures predicted future spectrum depressive and hypomanic symptom trajectories over six months.

Direct comparisons between BD and DD indicated lower FD in the right superior longitudinal and uncinate fasciculi and left thalamo-occipital tract in BD versus DD. Individuals with DD exhibited lower FD in the left arcuate fasciculus than those with BD. Compared to HC, both groups showed lower FD in the splenium of the corpus callosum and left striato-occipital and optic radiation tracts. FD in these tracts predicted future spectrum symptom severity. Exploratory analyses revealed associations between FD, medication use, and marijuana exposure.

Our findings highlight distinct and overlapping white matter alterations in BD and DD. Furthermore, FD in key tracts may serve as a predictor of future symptom trajectories, supporting the potential clinical utility of FD as a biomarker for mood disorder prognosis. Future longitudinal studies are needed to explore the impact of treatment and disease progression on white matter microstructure.

Bipolar disorder (BD) is characterized by temporal instability of mood and energy, but the neural correlates of this instability are poorly understood. In previous cross-sectional studies, mood state in BD has been associated with differential functional connectivity (FC) amongst several subcortical regions and ventromedial prefrontal cortex. Here, we assess whether BD is associated with longitudinal instability within this mood-related network of interest (NOI). Young people with BD-I/II were scanned 4-6 times and healthy controls (HC) were scanned 4 times over 9 months. Following preprocessing of 20-min resting-state scans, we assessed across-scan correlation of FC, focusing on FC between regions previously associated with BD mood state. Utilizing Bayesian models, we assessed the relationship between diagnostic group and within-person, across-scan correlation, adjusting for motion, time-of-day, and inter-scan interval; prediction intervals (PI) are reported. In a sample of 16 youth (11 BD, 5 HC; 16.3-23.3 years old) with 70 scans (50 BD, 20 HC), across-scan NOI stability was higher within- than between-person (0.70 vs. 0.54; p < 0.0001). BD (vs. HC) within-person scan-pairs showed lower NOI stability (mean -0.109; 95% PI -0.181, -0.038), distinguishing BD vs. HC with excellent accuracy (AUC = 0.95). NOI instability was more pronounced with manic symptoms (mean -0.012; 95% PI -0.023, -0.0002) and in BD-II (vs. BD-I; mean -0.071; 90% PI -0.136, -0.007). Results persisted after accounting for medications, comorbidity, and sleep/arousal measures. Within this pilot sample, BD is characterized by less within-person stability of a mood-related NOI. While preliminary, these results highlight a possible role for precision imaging approaches to elucidate neural mechanisms underlying BD.

An important aim in psychiatry is to establish valid and reliable associations linking profiles of brain functioning to clinically relevant symptoms and behaviors across patient populations. To advance progress in this area, we introduce an open dataset containing behavioral and neuroimaging data from 241 individuals aged 18 to 70, comprising 148 individuals meeting diagnostic criteria for a broad range of psychiatric illnesses and a healthy comparison group of 93 individuals. These data include high-resolution anatomical scans, multiple resting-state, and task-based functional MRI runs. Additionally, participants completed over 50 psychological and cognitive assessments. Here, we detail available behavioral data as well as raw and processed MRI derivatives. Associations between data processing and quality metrics, such as head motion, are reported. Processed data exhibit classic task activation effects and canonical functional network organization. Overall, we provide a comprehensive and analysis-ready transdiagnostic dataset to accelerate the identification of illness-relevant features of brain functioning, enabling future discoveries in basic and clinical neuroscience.

Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of bipolar disorder. We performed a PubMed search for microRNA biomarkers in bipolar disorder and found 18 original research articles on studies performed with human patients and published from January 2011 to June 2023. These studies included microRNA profiling in blood- and brain-based materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for bipolar disorder in adults could be miR-140-3p, -30d-5p, -330-5p, -378a-5p, -21-3p, -330-3p, -345-5p in whole blood, miR-19b-3p, -1180-3p, -125a-5p, let-7e-5p in blood plasma, and miR-7-5p, -23b-5p, -142-3p, -221-5p, -370-3p in the blood serum. Two of the studies had investigated the changes in microRNA expression of patients with bipolar disorder receiving treatment. One showed a significant increase in plasma miR-134 compared to baseline after 4 weeks of treatment which included typical antipsychotics, atypical antipsychotics, and benzodiazepines. The other study had assessed the effects of prescribed medications which included neurotransmitter receptor-site binders (drug class B) and sedatives, hypnotics, anticonvulsants, and analgesics (drug class C) on microRNA results. The combined effects of the two drug classes increased the significance of the results for miR-219 and -29c with miR-30e-3p and -526b* acquiring significance. MicroRNAs were tested to see if they could serve as biomarkers of bipolar disorder at different clinical states of mania, depression, and euthymia. One study showed that upregulation in whole blood of miR-9-5p, -29a-3p, -106a-5p, -106b-5p, -107, -125a-3p, -125b-5p and of miR-107, -125a-3p occurred in manic and euthymic patients compared to controls, respectively, and that upregulation of miR-106a-5p, -107 was found for manic compared to euthymic patients. In two other studies using blood plasma, downregulation of miR-134 was observed in manic patients compared to controls, and dysregulation of miR-134, -152, -607, -633, -652, -155 occurred in euthymic patients compared to controls. Finally, microRNAs such as miR-34a, -34b, -34c, -137, and -140-3p, -21-3p, -30d-5p, -330-5p, -378a-5p, -134, -19b-3p were shown to have diagnostic potential in distinguishing bipolar disorder patients from schizophrenia or major depressive disorder patients, respectively. Further studies are warranted with adolescents and young adults having bipolar disorder and consideration should be given to using animal models of the disorder to investigate the effects of suppressing or overexpressing specific microRNAs.

Transcranial direct current stimulation (tDCS) is a potential home-based treatment for major depressive disorder (MDD). In our double-blind randomised controlled trial (RCT) (n = 174; UK and USA), a 10-week course of home-based tDCS demonstrated clinical efficacy (clinical response: 58.3 % active treatment arm and 37.8 % sham (p = 0.017). tDCS was delivered in a bifrontal montage, with anode over left dorsolateral prefrontal cortex (DLPFC) and cathode over right DLPFC. Each session was 30 min, with active stimulation at 2 mA and sham at 0 mA, incorporating brief ramp-up and ramp-down phased. Following the 10-week RCT, all participants were offered active tDCS in a 10-week open-label treatment phase, with 111 participants completing this phase. UK cohort (n = 77 MDD) were invited for additional 3-month and 6-month follow-ups, extending the total study period to 11 months post-randomisation. Participants were able to continue using the tDCS device during follow-up. At least one follow-up visit was attended by 42 MDD participants (27 women). Device usage rates were 59 % at 3-month follow-up and 55 % at 6-month follow-up. Clinical response rate was 64 % at 3-month follow-up and 76 % at 6-month follow-up. Among participants who had shown a clinical response after the open-label phase, 90 % maintained their response at the 6-month follow-up. In summary, long-term follow-up showed high and sustained clinical response rates regardless of continued tDCS device use.

The B-SNIP consortium validated neurobiologically defined psychosis Biotypes (BT1, BT2, BT3) using cognitive and psychophysiological measures. B-SNIP's biomarker panel is not practical for most settings. Previously, B-SNIP developed an efficient classifier of Biotypes using only clinical assessments (called ADEPT-CLIN) with acceptable accuracy (~.81). Adding cognitive performance may improve ADEPT's performance.

Clinical assessments from ADEPT-CLIN plus 18 cognitive measures from 1907 individuals with a B-SNIP psychosis Biotype were used to create an additional diagnostic algorithm called ADEPT-COG. Extremely randomized trees were used to create this low burden classifier.

Total Biotype classification accuracy peaked at 94.6 % with 65 items. A reduced set of 18 items showed 90.5 % accuracy. Only 9-10 items achieved a one-vs-all (e.g., BT1 or not) accuracy of ~.95, considerably better than using clinical assessments alone. The top discriminators of psychosis Biotypes were antisaccade proportion correct, BACS total, symbol coding, antisaccade correct response latency, verbal memory, digit sequencing, stop signal reaction times, stop signal proportion correct, Tower of London, and WRAT Reading. Except for anti-saccade proportion correct and Tower of London, there was no overlap of the top discriminating items for B-SNIP Biotypes and DSM psychosis categories.

This low-burden algorithm using clinical and cognitive measures achieved high classification accuracy and can support Biotype-specific etiological and treatment investigations in clinical and research environments. It may be especially useful for clinical trials.

Distinguishing between unipolar depression (UD) and bipolar disorder (BD) during periods of remission presents a significant clinical challenge. To mitigate the potential confounding effects of depressive episodes, our study compares the white matter networks of individuals with UD and BD in remission, aiming to explore the differentiation between these two affective disorders. Our cohort included 69 individuals with remitted UD, 55 with remitted BD, and 78 healthy controls (HC). We employed diffusion tensor imaging (DTI) to assess the white matter (WM) network. Additionally, we utilized a comprehensive set of connectome and five communication models to characterize the alterations within the whole-brain WM network. Compared to HC, both UD and BD patients showed reduced connectivity in the frontal orbital region, with BD patients exhibiting a more pronounced decrease. BD patients demonstrated superior navigation ability and higher shortest path metric values in key brain region connections compared to UD. Conversely, UD patients showed greater diffusion efficiency in certain brain regions. Communicability and search information analyses revealed distinct patterns of connectivity between the two patient groups, with potential implications for emotion regulation and information processing. Our findings highlight distinct brain connectivity patterns in BD and UD during remission, suggesting that these patterns could serve as neuroimaging biomarkers for differentiating between the two disorders. The study provides insights into the enduring effects of mood disorders on brain connectivity and has potential clinical implications for diagnosis and treatment.

Pediatric mood disorders, including Major Depressive Disorder (MDD) and Bipolar Disorder (BD), exhibit overlapping symptomatology and complex neurodevelopmental trajectories, necessitating a comprehensive investigation of their neuroanatomical underpinnings. This study aimed to characterize structural brain differences in children with MDD and euthymic BD using high-resolution structural magnetic resonance imaging (MRI). A total of 51 children (aged 10-14 years) were categorized into MDD, euthymic BD, and typically developing (TD) controls. Utilizing advanced surface-based morphometry, we examined four cortical features: fractal dimension, gyrification, sulcal depth, and cortical thickness, to delineate disorder-specific and shared neuroanatomical alterations. Additionally, we explored the interaction between white matter volumetrics and these surface-based metrics to assess its modulatory role in structural brain differences. Our results revealed significant cortical alterations, with distinct and overlapping patterns in both MDD and BD. The findings demonstrated disruptions in cortical complexity, folding patterns, and sulcal morphology, particularly in regions implicated in emotion regulation and cognitive processing. These structural variations provide critical insights into the neurodevelopmental alterations associated with pediatric mood disorders. By integrating multiple morphometric parameters, this study offers a comprehensive framework for understanding the neuroanatomical changes in MDD and BD, contributing to more precise diagnostic biomarkers. The results underscore the importance of incorporating surface-based morphometry and white matter interactions in future research to refine early diagnosis and targeted interventions for mood disorders in children.

Increased oxidative stress-generated tissue damage seems to play a pivotal role in the pathophysiology and progression of bipolar disorder (BD). Malondialdehyde (MDA), a product of lipid oxidation, may represent a trait marker in BD associated with familial risk. However, MDA is scarcely studied in patients with newly diagnosed bipolar disorder (BD) and their unaffected relatives (UR).

In this prospective "the Bipolar Illness Onset study", we investigated repeated measurements of MDA in a cohort of 371 patients with newly diagnosed/first-episode BD (1016 visits), 139 of their unaffected first-degree relatives (307 visits) and 199 healthy control individuals (HC) with no personal or first-degree family history of affective disorder (537 visits) with a median follow-up time of 2.0. [0.1; 3.8] years for patients with BD, 1.4 [0; 2.4] years for UR, and 2.5 [1.1; 3.9] years for HC. Amongst patients with BD, we further investigated associations of MDA with affective phases and medicine- and illness variables over a period of 7 years.

Unaffected relatives had 42.3 % higher levels of MDA at baseline compared with HC in analyses adjusted for sex and age corrected for multiple comparisons (B = = 1.423, 95 % CI = 1.139, 1.777, p = <0.044). However, this difference did not persist over time. No statistically significant differences in MDA levels were observed over time between BD patients and either HC or UR. Additionally, MDA levels were not associated with psychotropic use, illness variables, or affective phase alterations.

Against expectations, our findings did not support increased lipid oxidation being a trait phenomenon in BD.

Cognitive dysfunction is a core dimension in psychotic disorders and among the strongest predictors of disability and poor quality of life. Cognitive impairments are highly heterogeneous, and cross-sectional studies have consistently found evidence of distinct cognitive profiles both within diagnoses and transdiagnostically. Findings regarding the course of cognitive impairments over time have been mixed. We hypothesized that subgroups of patients in the early course of psychosis show distinct cognitive trajectories that can be identified using data-driven methods, and that these subgroups differ on clinical and functional outcomes over time. Persons with schizophrenia-spectrum disorders or mood disorders with psychosis in the early course of illness (N=127) were assessed using clinical, functional and cognitive measures at three timepoints: baseline, 8 and 16 months. Group-based trajectory modeling was used to identify cognitive subgroups, which were then compared on clinical and functional measures using multilevel models. We identified three distinct cognitive subgroups: an Impaired group, an Average group, and a High-Functioning group. Cognition was stable over the follow-up period in the Impaired and High-Functioning groups, whereas the Average group showed cognitive improvement. Groups did not differ in terms of diagnostic distribution, baseline clinical symptoms, and most baseline functional and demographic measures. However, over the follow-up, group membership predicted changes in negative symptoms, social functioning, and patient-reported outcomes, with the Impaired group showing the most severe illness course. We conclude that patients in the early course of psychosis show distinct cognitive trajectories that predict future symptoms and social functioning, despite presenting no clinical differences at baseline. These findings have implications for understanding biology-cognition associations, which may be related to heterogeneity; developing predictive models for clinical and functional outcomes; and personalizing treatment to support patients' cognitive, clinical and functional needs towards improving illness course.

Numerous studies have revealed that patients with major depressive disorder (MDD) suffer from insomnia symptoms. However, the dysfunction pattern in specific insomnia symptoms in patients with MDD remains unclear. The present study aimed to examine the regional brain neuroimaging activity features of difficulty falling asleep (DFA) and early awakening (EA) in patients with MDD. The resting-fMRI by applying the amplitude of low-frequency fluctuation (ALFF) method was estimated in 50 MDD patients with DFA, 36 patients with EA, 46 patients without insomnia symptoms, and 60 matched healthy controls. The Pearson correlation analysis was used among the ALFF with significant difference brain regions, the 17-item Hamilton Depression Rating Scale factor scores, and the Pittsburgh Sleep Quality Index scores. Patients with DFA showed lower ALFF values in the left precentral gyrus than those with EA and higher ALFF values in the left insula than those without insomnia symptoms. Patients with EA showed higher ALFF values in the left precentral gyrus than those without insomnia symptoms. This study revealed distinct neural mechanisms underlying specific insomnia symptoms, identifying the left insula as a potential pathological region in DFA patients and the left precentral gyrus as a characteristic neuropathological region in EA patients.

Cognitive dysfunction is a well-documented feature of schizophrenia (SZ) and bipolar (BD) disorder. The person's subjective experience of cognitive difficulties is less investigated. Here we investigated subjective cognition in SZ and BD compared to healthy controls (HC). Subjective and objective cognition were assessed in 91 SZ participants, 55 BD participants and 55 HC, applying a novel measure of subjective cognition, the self-assessed cognitive complaints scale (SACCS) and a clinically relevant neuropsychological test battery. The psychometric properties of SACCS were investigated. The relationship between subjective and objective cognition, and subjective cognition and clinical variables were explored in SZ and BD. The SACCS showed adequate psychometric properties. Clinical groups reported significantly more cognitive complaints than HCs, without differences between SZ and BD. There were no significant associations between subjective and objective cognitive measures. There was a small trend association between subjective cognition and insight in SZ participants, and moderate sized associations between subjective cognition and general psychopathology and functioning in BD participants. Although SZ participants are more cognitively impaired than BD participants, the two groups report similar levels of subjective cognitive complaints, with no association between subjective and objective cognition. Our results suggest that the expression of subjective cognition is associated with different clinical factors in SZ and BD.

Aging is a multilevel process of gradual decline that predicts morbidity and mortality. Independent investigations have implicated senescence of brain and peripheral physiology in psychiatric risk, but it is unclear whether these effects stem from unique or shared mechanisms.

To address this question, we analyzed clinical, blood chemistry, and resting-state functional neuroimaging data in a healthy aging cohort (n = 427; ages 36-100 years) and 2 disorder-specific samples including patients with early psychosis (100 patients, 16-35 years) and major depressive disorder (MDD) (104 patients, 20-76 years).

We identified sex-dependent coupling between blood chemistry markers of metabolic senescence (i.e., homeostatic dysregulation), functional brain network aging, and psychiatric risk. In females, premature aging of frontoparietal and somatomotor networks was linked to greater homeostatic dysregulation. It also predicted the severity and treatment resistance of mood symptoms (depression/anxiety [all 3 samples], anhedonia [MDD]) and social withdrawal/behavioral inhibition (avoidant personality disorder [healthy aging], negative symptoms [early psychosis]). In males, premature aging of the default mode, cingulo-opercular, and visual networks was linked to reduced homeostatic dysregulation and predicted the severity and treatment resistance of symptoms relevant to hostility/aggression (antisocial personality disorder [healthy aging], mania/positive symptoms [early psychosis]), impaired thought processes (early psychosis, MDD), and somatic problems (healthy aging, MDD).

Our findings identify sexually dimorphic relationships between brain dynamics, peripheral physiology, and risk for psychiatric illness, suggesting that the specificity of putative risk biomarkers and precision therapeutics may be improved by considering sex and other relevant personal characteristics.

The aim of this study was to determine the effects of anxiety levels and emotion dysregulation on each other and their effects on psychosocial functioning in remitted BD patients.

Sixty-six patients with BD and 38 healthy controls were included in this study. All the patients were assessed with the Hamilton Depression Rating Scale, the Young Mania Rating Scale, the Bipolar Disorder Functioning Questionnaire, the State-Trait Anxiety Inventory (STAI) and the Difficulties in Emotion Regulation Scale (DERS). Healthy controls were only assessed with the STAI and the DERS.

STAI and DERS scores were significantly higher in the patient group than in the control group. Higher scores of STAI and DERS were found to be associated with lower functionality in the patient group. The trait anxiety scores explained 22% of the variance in the psychosocial functionality scores of the patients while the total DERS score explained 51.5% of the variance in the trait anxiety scores. Patients on lithium treatment had less difficulty in regulating their emotions than those on valproic acid treatment.

In light of these findings, planning interventions for emotion regulation difficulties during the management of patients would reduce anxiety levels and contribute to improving patients' psychosocial functionality.

Clinical heterogeneity is a major problem in mental health, referring to wide clinical variability among people with the same diagnosis. In bipolar disorders (BD), an heterogeneity was found both in global remission (symptomatic and functional) and in personal recovery during euthymia. This heterogeneity is a challenge for clinicians, who have to adapt their care to the individuals' characteristics. This preliminary study aimed at identifying profiles of experiences during euthymia by considering global remission (manic and depressive symptomatology, and functional impairment) and personal recovery, and exploring personal and contextual correlates associated with the heterogeneity of experiences.

A convenience sample of 58 participants in euthymia of BD was recruited. Data were collected using self-report questionnaires. Consistent with a person-oriented approach, clustering was performed to identify profiles by simultaneously considering symptomatology, functional impairment, and personal recovery. Associations between the identified profiles and socio-demographic, clinical, and family characteristics were explored using analysis of variance, Fisher's exact tests, and post hoc tests.

Five profiles were identified when considering both global remission and personal recovery: adverse experience (20.69%), slightly adverse experience (22.41%), unbalanced experience (10.34%), positive experience (22.14%), and hyperthymic positive experience (24.14%). Among the correlates, only current family functioning was significantly associated with the identified profiles through cohesion, communication, and satisfaction dimensions.

These results highlight that personal recovery and family dynamics of people with BD should be more considered in the clinical practice to better understand their experience during euthymia and adapt therapeutic care accordingly.

Alterations in glial cell function and cytokine levels in the central nervous system may be influenced by neuroinflammatory processes, which have a pathogenic role in psychiatric disorders. Variability in genes that encode inflammatory mediators is associated with risk of developing mental disorders. Therefore, by analyzing data from the transdiagnostic PsyCourse Study, we aimed to investigate whether variations in inflammatory mediator genes are associated with current symptom severity. We used cross-sectional data from 1320 individuals with a psychiatric disorder and 466 neurotypical individuals. Outcome variables were the psychopathological data from various rating scales and questionnaires that measured depressive, psychotic, and manic symptoms. Furthermore, from a whole-genome SNP array dataset, we extracted single nucleotide polymorphisms (SNPs) in the loci of genes related to inflammatory mediators, and we performed an association analysis by considering covariates. False discovery rate (FDR) was used to adjust the results for multiple comparisons. A total of 1594 individuals and 1336 SNPs were included in the analyses. The results of regression analysis showed a significant positive association of six SNPs located on the interleukin (IL)-1 receptor type 1 (IL-1R1) gene locus with Altman Self-Rating Mania Scale scores (FDR-adjusted p value < 0.05). Our findings show that genetic variations in IL-1R1 may influence the pathophysiology of psychiatric disorders by affecting brain cytokine profiles associated with manic episodes. IL-1R1 encodes a membrane-bound receptor for IL-1. Several physiological functions, including inflammation, are linked to the IL-1/IL-1R1 signaling pathway. Replication of our findings is warranted.

There is a lack of information about factors associated with Bipolar disorder (BD), Rapid Cycling (RC) course in the Indian context.

This study aimed to evaluate the prevalence and factors associated with BD-RC course using data from the Bipolar Disorder Course and Outcome study from India (BiD-CoIN study).

This was a secondary analysis of data obtained from the BiD-CoIN study to evaluate the factors associated with RC in bipolar disorder.

Out of the 773 patients, about 6 % of BD patients have RC in their lifetime. Factors associated with RC included: being unemployed/homemakers (p < 0.001), being non-Hindus (p = 0.001), longer duration of episodes (p < 0.001), higher number of total and depressive episodes (in a lifetime, per year of illness, first five years, and per year of illness in first five years) (p < 0.001), higher number of manic, hypomanic, and mixed episodes (in the lifetime and per year of illness), shorter duration of current remission (p = 0.01), higher severity of depressive episodes in a lifetime, higher depressive affective morbidity index (p < 0.001), lower severity of manic episodes (p = 0.003), higher level of overall disability (p = 0.01) and in the interpersonal relationship domain, more frequent first-lifetime episode of depressive polarity, more frequent breakthrough episodes (p = 0.001), seasonality of episodes (p < 0.001), suicidal attempts (p = 0.003), relapses due to poor medication adherence (p = 0.003), indeterminate predominant polarity, psychotic symptoms during episodes in a lifetime, higher likelihood of receiving lithium.

The prevalence of BD-RC course is lower compared to Western countries, but there are many similarities in the factors associated with RC in bipolar disorder between India and Western countries.

The aim herein was to investigate mitochondrial cytochrome B (MT-CYB) mutations in individuals with bipolar disorder. Stanniocalcin-1 ( STC1 ) and uncoupling protein 2 ( UCP2 ) mRNA expressions and their relationship with clinical data and each other were also investigated.

The blood samples of 100 individuals were included in this study. Real-time PCR was used to evaluate mRNA expressions of STC1 and UCP2 . Genetic alterations were investigated via Sanger DNA sequencing. An in silico analysis was performed to reveal the phenotypic effects of MT-CYB mutations.

In the MT-CYB gene of the bipolar disorder patients, the most seen mutations were the T194A A>G mutation at position 1532, G deletion at position 15498, and C>A L236I mutation at position 15452. Most of the mutations appeared to be neutral or benign. The UCP2 and STC1 mRNA expression levels were significantly higher in the patients than in the healthy controls ( P  = 0.0124 and P  < 0.0001, respectively). The area under the curve values of the receiver operating characteristic curve analysis for UCP2 and STC1 were 0.6631 ( P  = 0.0123) and 0.8059 ( P  < 0.0001), respectively. No significant relationship was observed between the gene expressions and the routine laboratory findings. There was a positive correlation between the UCP2 and STC1 mRNA expressions in the bipolar disorder patients ( r  = 0.03559, P  = 0.0306).

Expression of UCP2 and STC1 may be important parameters in bipolar disorder. MT-CYB mutations may be related to gene expressions. Comprehensive studies on bipolar disorder will help better understand UCP2 and STC1 gene functions.

It is unclear if lithium and quetiapine have neuroprotective effects, especially in early stages of bipolar and schizoaffective disorders. Here, an age-related multivariate brain structural measure (i.e., brain-PAD) at baseline and changes in response to treatment after a first-episode mania (FEM) were examined. FEM participants were randomized to lithium (n=21) or quetiapine (n=18) monotherapy. T1-weighted scans were acquired at baseline, 3-months (FEM participants only) and 12-months. Brain age predictions for healthy controls (n=29) and young people with bipolar or schizoaffective disorder (15-25 years) were derived using a deep learning model trained on one of the largest datasets (N=53,542) to date. Notably, a higher brain-PAD value (predicted brain age - age) signifies an older-appearing brain. Baseline brain-PAD was higher in young people with FEM compared to controls (+1.70 year, p=0.04; Cohen's d=0.53 [SE=0.25], CI 95% [0.04 to 1.01]). However, no significant effects of time or treatment group, nor an interaction between the two, were observed throughout the course of the study. Baseline brain-PAD did not predict any change in symptomatic, quality of life or functional outcome scores over 12 months. In young individuals with FEM, baseline findings show their brains appeared older than controls. However, brain-PAD remained stable over time across treatment groups and neither baseline values nor treatment predicted 12-month outcomes. A longer follow-up with a larger sample is warranted to determine if treatment effects emerge later in bipolar and schizoaffective disorders. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry - ACTRN12607000639426.

While circadian disruptions are common in some sub-groups of youth with mood disorders, skin temperature rhythms in these cohorts are understudied. We examined 24-h wrist skin temperature rhythms in youth with emerging mood disorders, exploring associations with clinical stage and proposed illness subtypes. Youth (n = 306, 23.42 ± 4.91 years, 65% females) accessing mental health care and 48 healthy controls (23.44 ± 3.38 years, 60% females) were examined. Skin temperature parameters including rhythm-adjusted mean temperature, inter-daily stability (day-to-day consistency), intra-daily variability (rhythm fragmentation), and peak temperature time were derived from a wearable sensor. Based on our illness trajectory-pathophysiology model, participants were classified by mood disorder subtypes ("hyperarousal-anxious" [n = 209], "neurodevelopmental-psychosis" [n = 40], or "circadian-bipolar spectrum" [n = 43]), as well as by clinical stage (subthreshold disorders classed as 1a or 1b [n = 47, 173, respectively], and full-threshold disorders as 2+ [n = 76]). Compared to controls, youth with mood disorders had delayed, less stable, and more variable skin temperature rhythms, indicated by lower rhythm-adjusted mean skin temperature (29.94 ± 0.10 °C vs 31.04 ± 0.25 °C, p < 0.001), delayed peak timing (0533 ± 0014 vs 0332 ± 0036, p = 0.002), reduced inter-daily stability (p = 0.009), and increased intra-daily variability (p = 0.020). Peak skin temperature also occurred later relative to sleep midpoint (0.31 ± 0.14 vs -0.48 ± 0.35 radians, p = 0.037). The "circadian-bipolar spectrum" subtype exhibited lower relative amplitude (0.07 ± 0.005 vs 0.08 ± 0.002 [hyperarousal-anxious] and 0.09 ± 0.005 [neurodevelopmental-psychosis], p = 0.039), with no delay in sleep midpoint. Clinical stages were not associated with differences in skin temperature parameters. These findings highlight the potential of use of 24-h skin temperature rhythms as a non-invasive biomarker of circadian disturbances in youth with emerging mood disorders. The observed disruptions in temperature patterns and rhythmicity support the notion that disrupted circadian rhythms may mediate the onset or illness course of some subgroups of youth with emerging major mood disorders.

The brain age gap (BAG) quantifies the difference between predicted brain age and chronological age. Prior research implicates higher BAG in psychotic disorders, suggesting accelerated brain aging. We hypothesized distinct brain aging profiles among biological subtypes of psychosis and intermediate BAG in their relatives.

Brain age gap values were quantified in 348 healthy controls (HCs), 950 psychosis probands classified by both DSM diagnoses of psychotic bipolar disorder, type I (BP, n = 247), schizoaffective disorder (SAD, n = 313), and schizophrenia (SZ, n = 390), and Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Biotypes (301 Biotype 1, 304 Biotype 2, and 345 Biotype 3), and 491 of their non-psychotic first-degree relatives. We calculated brain age values from structural T1-weighted images using the pre-trained, open-source brain age package, brainageR. In probands, we assessed associations between BAG and clinical characteristics, comorbid disorders, medications, and polygenic risk scores for SZ (PRS-SZ).

All DSM diagnosis and Biotype groups had higher BAG than HC. While no significant differences were observed between BP, SAD, or SZ, Biotypes 1 and 2 had significantly higher BAG compared to Biotype 3. Relatives exhibited intermediate BAG values between HC and probands, with the highest BAG in relatives of those with SAD. Brain age gap was not linked to comorbid disorders or PRS-SZ, but was associated with symptom severity, cognition, functioning, and psychotropic medication use.

Bipolar-Schizophrenia Network for Intermediate Phenotypes Biotypes better captured age-related brain structural differences in psychosis than DSM diagnoses. Associations between BAG and medication underscore the potential influence of pharmacotherapy on brain aging in psychosis.

Exposure to severe stressful life events (e.g., physical, sexual, emotional abuse and/or physical or emotional neglect) is common among adults with bipolar disorder (BD) and is associated with poor prognosis and clinical outcomes. This systematic review aims to evaluate the prevalence, clinical impact, and therapeutic considerations of trauma in adults with BD.

A systematic review of primary research was conducted using Embase, PsycInfo, MEDLINE, and PubMed databases from inception to January 2025, following PRISMA criteria. Sixteen human studies evaluating the prevalence, clinical impact, and therapeutic considerations of trauma in adults with BD were included.

Prevalence rates of trauma range from approximately 40-60 % of adults with BD. Childhood physical maltreatment is highly associated with comorbidities and symptom severity in adults with BD. Childhood emotional maltreatment is associated with an earlier age of onset, greater illness severity, comorbidity and suicidality in BD. The moderating effects of trauma in BD treatment response across disparate modalities of treatment are not adequately characterized.

Trauma, particularly childhood trauma, is prevalent and has a severe negative clinical impact on the presentation, progression, treatment, and outcomes of adults with BD. The research strategic priority is to characterize the biosignature of trauma in BD, the impact of trauma on treatment outcomes, and to empirically evaluate integrated models of care in persons with BD with a history of trauma.