Brain morphological alterations in bipolar disorder are well documented, particularly in chronic cases. This study focuses on first-episode mania (FEM) to quantify neuroanatomical changes at early stages of the disorder.

To assess deviations from normative brain morphometry and age-related brain changes in patients with FEM.

Pretrained models, based on large, independent healthy samples, were applied to structural brain images from FEM patients (n = 83) and healthy individuals (n = 61). Normative deviation z-scores were computed for regional brain morphometry, along with global and voxel-level brain–age-gap estimates (G-brainAGE and L-brainAGE, respectively). The proportions of infranormal (z < −1.96) and supranormal (z > 1.96) deviations were measured for both groups. Ridge regression and support vector machine models were used to evaluate whether z-scores predicted symptom severity, IQ or diagnosis. Case-control differences in L-brainAGE and correlations between G-brainAGE and clinical features were analysed.

Both FEM and healthy individuals showed similar proportions of infra- and supranormal deviations in regional measures. Morphometric data, whether observed or normative, did not significantly predict clinical outcomes or diagnosis. Mean G-brainAGE in FEM was −1.04 (s.d. 3.26) years and negatively correlated with age of onset, while L-brainAGE did not differ significantly between groups.

Regional morphometry and local brain-ageing metrics in FEM patients aligned with normative ranges, suggesting minimal abnormalities in early bipolar disorder. However, subtle delays in global brain ageing may reflect variation based on the age of onset, highlighting a potential area for further exploration.

The duration of undiagnosed or untreated bipolar disorder (DUBD) has become a focus of research interest. However, its relationship with clinical characteristics and outcomes remains poorly understood.

The objective of this systematic review and meta-analysis was to examine DUBD and explore its relationships with clinical characteristics and outcomes in bipolar disorder.

We conducted a systematic search of the literature to identify studies reporting on DUBD and its relationships with clinical characteristics and outcomes including frequency of relapse into mood episodes, severity and persistence of mood symptoms, functional and cognitive measures, suicidality, hospital admission rate, and comorbidities such as substance use disorders.

Thirty articles met inclusion criteria for the systematic review, and 23 studies were included in the three different sets of meta-analyses. The pooled mean DUBD across all studies was 9.10 years. Early onset, depression as the polarity of the first mood episode, lifetime suicide attempts, comorbid anxiety and alcohol use disorders, and family history of bipolar disorder were associated with significantly longer DUBD, whereas diagnosis of bipolar I disorder and lifetime psychotic symptoms were associated with shorter DUBD. Studies that investigated outcomes subsequent to the diagnosis of bipolar disorder yielded conflicting results.

DUBD may be associated with certain adverse outcomes. This association indicates the importance of adopting a more comprehensive approach to assessing mood disorders, with an emphasis on prioritising early screening for bipolar disorder. The significant heterogeneity among included studies suggests a need for improved methodological rigour in future research.

Lamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks in healthy volunteers, previously shown to be sensitive to antidepressant drug action in similar experimental designs.

Healthy volunteers (n = 36) were randomized in a double-blind design to receive a single dose of placebo or 300 mg lamotrigine. Mood and subjective effects were monitored throughout the study period, and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post-administration.

Participants receiving lamotrigine showed increased accurate recall of positive versus negative self-descriptors, compared to those in the placebo group. There were no other significant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience.

Lamotrigine did not induce widespread changes in emotional processing. However, there was increased positive bias in emotional memory, similar to the effects of antidepressants reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.

Offspring of parents with bipolar disorder (BD offspring) face elevated risks for emotional dysregulation and cognitive deficits, particularly in working memory. This study investigates working memory deficits and their neural correlates in BD offspring.

We assessed 41 BD offspring and 25 age-matched healthy controls (HCs) using a spatial N-back task and task-related functional magnetic resonance imaging (fMRI).

Compared to HCs, BD offspring exhibit reduced accuracy and lower signal-detection sensitivity (d′) on the 1-back task. fMRI reveals hyperactivation in the right intracalcarine cortex/lingual gyrus (ICC/LG) in BD offspring, particularly during the 1-back condition. Psychophysiological interaction (PPI) analyses show reduced connectivity between the right ICC/LG and the left postcentral gyrus in BD offspring as task load increases from 0-back to 1-back. This connectivity positively correlates with 1-back task performance in HCs but not in BD offspring. Additionally, using bilateral dorsolateral prefrontal cortex (DLPFC) as regions of interest, PPI analyses show diminished condition-dependent connectivity between the left DLPFC and the left superior frontal gyrus/paracingulate cortex, and between the right DLPFC and the left postcentral gyrus/precentral gyrus in BD offspring as the task load increases.

These findings suggest that BD offspring exhibit working memory deficits and impaired neural connectivity involving both sensory processing and higher-order cognitive systems. Such deficits may emerge at a genetically predisposed stage of bipolar disorder, underscoring the significance of early identification and intervention strategies.

The identification of early warning signs is of great importance for identifying individuals at risk for mental disorders. Especially in the case of bipolar disorder, these research endeavours are imperative considering that the frequently delayed diagnoses and longer illness duration are associated with symptom exacerbation and lower recovery rates.

To multimodally investigate associations between hypomanic personality traits and altered social affect and social cognition to probe their role as early warning signs of bipolar disorder.

In a community sample (n = 140; 50.71% female), we investigated associations between hypomanic personality traits and both behavioural and neural activity measures of empathy and theory of mind (ToM) based on data from a functional magnetic resonance imaging paradigm.

Although analyses revealed no significant associations between behavioural or neural correlates of empathy and hypomanic personality traits, these traits were significantly associated with elevated ToM-related neural activity in the anterior rostral medial prefrontal cortex and anterior cingulate cortex. These neural activation differences were not accompanied by differences in behavioural ToM performance, suggesting more intense recruitment of task-relevant brain regions but unaffected behavioural outcomes.

Our findings indicate hypomanic personality traits to be positively associated with ToM-related neural activity but not with behavioural ToM performance. Prospectively, our study contributes to driving towards a more comprehensive and potentially neurobiologically grounded phenotype of bipolar disorder risk that contributes to a more differential understanding of risk and resilience mechanisms.

A systematic review and meta-analysis was conducted to investigate the prevalence and antecedents/outcomes of loneliness and social isolation among individuals with severe mental disorders (SMD), such as schizophrenia, schizoaffective disorder, bipolar disorder or major depressive disorder.

Five well-known electronic databases (PubMed, PsycINFO, CINAHL, Web of Science and Scopus) were searched (plus a hand search). Observational studies that report the prevalence and, if available, antecedents and consequences of loneliness/isolation among individuals with SMD were included. Key characteristics were extracted, and a meta-analysis was performed. Our systematic review was preregistered on PROSPERO (ID: CRD42024559043). The PRISMA guidelines were followed. The Joanna Briggs Institute (JBI) standardized critical appraisal tool developed for prevalence studies was applied to assess the quality of the included studies.

The initial search yielded 4506 records, and after duplicate removal and screening, a total of 10 studies were finally included. The studies included used data from Europe, Asia, North America, and Oceania. Two studies employed a longitudinal design, while all other studies had a cross-sectional design. Most of the studies included between 100 and 500 individuals with SMD. All studies involved both male and female participants, with women typically comprising about 40% of the sample. The average age of participants often ranged from approximately 30 to 40 years. The estimated prevalence of loneliness was 59.1% (95% CI: 39.6% to 78.6%, I2 = 99.3, P < .001) among individuals with any diagnosis of SMD. Furthermore, the estimated prevalence of objective social isolation was 63.0% (95% CI: 58.6% to 67.4%) among individuals with schizophrenia or schizophrenia spectrum disorder. The quality of the studies was moderate to good. Subjective well-being and depressive symptoms in particular were found to contribute to loneliness in the included studies.

The present systematic review with meta-analysis identified high levels of loneliness and objective social isolation among those with SMD. These findings stress the importance of monitoring and addressing social needs in this vulnerable group, which may have a positive effect on the life quality of individuals with SMD. Future research in neglected regions (e.g. South America and Africa) is recommended. Different diagnoses within severe mental disorders should be distinguished in future studies. Furthermore, additional longitudinal studies are required to explore the antecedents and consequences of loneliness and social isolation among individuals with SMD.

It is widely known that people with a severe and persistent mental illness (SPMI) are more at risk of poor physical health outcomes because of disparities in healthcare access and provision. Less is known about the quality of end-of-life (EoL) care in people with SPMI who have a life-limiting disease.

A comprehensive and systematic literature search in PubMed, Embase, Web of Science, Scopus, and CINAHL electronic databases (from inception to November 2023) was conducted, without language restriction, for reviews on EoL care and/or palliative sedation for people with SPMI and a life-limiting disease. A critical appraisal of the selected reviews was performed. Data were analyzed according to the four principles of biomedical ethics.

Ten reviews were included. These show that people with SPMI are at risk of suboptimal EoL care. Stigma among healthcare professionals, lack of integrated care policies, absence of advanced care planning, and insufficient expertise and training in palliative care of psychiatrists have been identified as key challenges to the provision of adequate EoL care for people with SPMI. No data were found about palliative sedation.

To optimize palliative and EoL care for SPMI patients with a life-limiting disease, a policy of coordinated and integrated mental and physical healthcare is needed. Moreover, education and training initiatives to reduce stigma and discrimination among all healthcare workers and to enhance palliative care skills in psychiatrists should be offered. Finally, more research is needed on EoL particularly on palliative sedation for people with SPMI and a life-limiting disease.

Impairment in both psychosocial functioning and neurocognition (NC) performance is present in bipolar disorder (BD) yet the role of sex differences in these deficits remains unclear. The present systematic review and meta-analysis examined whether males and females with BD demonstrate differences in psychosocial functioning and NC performance.

The Cochrane Library, EMBASE, PsycINFO, PubMed, Scopus, and Web of Science databases were systematically searched from inception until November 20, 2023.

Twenty studies published between 2005 and 2023 with a total sample size of 2286 patients with BD were included. A random effects meta-analysis revealed a statistically significant result with a small effect (SMD = 0.313) for sex differences in verbal learning and memory as well as visual learning and memory (SMD = 0.263). Females outperformed males in both domains. No significant sex differences were observed for any other NC outcome or psychosocial functioning. High heterogeneity and differences in assessment scales used should be considered when interpreting these findings, given their potential impact on results.

Future research should adopt a more homogenous, standardized approach using longitudinal designs to gain a clearer insight into sex differences in this population. This approach so may increase the use of preventative therapeutic options to address the difficult clinical challenge of reaching cognitive and functional recovery.

Preliminary evidence suggests that a ketogenic diet may be effective for bipolar disorder.

To assess the impact of a ketogenic diet in bipolar disorder on clinical, metabolic and magnetic resonance spectroscopy outcomes.

Euthymic individuals with bipolar disorder (N = 27) were recruited to a 6- to 8-week single-arm open pilot study of a modified ketogenic diet. Clinical, metabolic and MRS measures were assessed before and after the intervention.

Of 27 recruited participants, 26 began and 20 completed the ketogenic diet. For participants completing the intervention, mean body weight fell by 4.2 kg (P < 0.001), mean body mass index fell by 1.5 kg/m2 (P < 0.001) and mean systolic blood pressure fell by 7.4 mmHg (P < 0.041). The euthymic participants had average baseline and follow-up assessments consistent with them being in the euthymic range with no statistically significant changes in Affective Lability Scale-18, Beck Depression Inventory and Young Mania Rating Scale. In participants providing reliable daily ecological momentary assessment data (n = 14), there was a positive correlation between daily ketone levels and self-rated mood (r = 0.21, P < 0.001) and energy (r = 0.19 P < 0.001), and an inverse correlation between ketone levels and both impulsivity (r = −0.30, P < 0.001) and anxiety (r = −0.19, P < 0.001). From the MRS measurements, brain glutamate plus glutamine concentration decreased by 11.6% in the anterior cingulate cortex (P = 0.025) and fell by 13.6% in the posterior cingulate cortex (P = <0.001).

These findings suggest that a ketogenic diet may be clinically useful in bipolar disorder, for both mental health and metabolic outcomes. Replication and randomised controlled trials are now warranted.

Extant literature implicates the role of glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs) on modulating alcohol-associated behaviours, with a particular emphasis of these agents on neural circuits subserving reward and appetite control. Herein, we explore the potential effects of GLP-1RAs on alcohol-associated behaviours in brain regions implicated in reward processing facilitating the repurposing of these agents for the treatment and prevention of problematic drinking. Understanding how GLP-1’s analogues interact with alcohol-related behaviours may underscore the development of therapeutic strategies for alcohol use disorder (AUD) and those with comorbid metabolic disorders.

A systematic review was conducted, wherein relevant literature was identified through Web of Science, PubMed, and OVID (MedLINE, Embase, AMED, PsycInfo, JBI EBP) from database inception to October 27th, 2024. Preclinical and clinical studies examining the association between GLP-1RAs and alcohol-related behaviours were assessed.

Preclinical studies (n = 19) indicate that GLP-1RAs attenuate alcohol-related behaviours, with exenatide demonstrating significant dose-dependent effects in high alcohol-consuming phenotypes. Semaglutide and liraglutide are associated with reduced alcohol intake, though their effects were often transient. In human studies (n = 2) with AUD, semaglutide significantly reduced alcohol consumption, while exenatide showed mixed results, with reductions in alcohol drinking within high BMI subpopulations.

Extant preclinical and clinical literature provides preliminary support for the potential therapeutic role of GLP-1RAs in attenuating alcohol consumption and preference. There is a need for large well controlled studies evaluating the effect of GLP-1RAs as a treatment strategy for behavioural modifications in individuals living with alcohol use disorder.

Impaired emotion regulation has been proposed as a putative endophenotype in bipolar disorder (BD). Functional magnetic resonance imaging (fMRI) studies investigating this in unaffected first-degree relatives (UR) have thus far yielded incongruent findings. Hence, the current paper examines neural subgroups among UR during emotion regulation.

71 UR of patients with BD and 66 healthy controls (HC) underwent fMRI scanning while performing an emotion regulation task. Hierarchical cluster analysis was performed on extracted signal change during emotion down-regulation in pre-defined regions of interest (ROIs). Identified subgroups were compared on neural activation, demographic, clinical, and cognitive variables.

Two subgroups of UR were identified: subgroup 1 (39 UR; 55%) was characterized by hypo-activity in the dorsolateral, dorsomedial, and ventrolateral prefrontal cortex and the bilateral amygdalae, but comparable activation to HC in the other ROIs; subgroup 2 (32 UR; 45%) was characterized by hyperactivity in all ROIs. Subgroup 1 had lower success in emotion regulation compared to HC and reported more childhood trauma compared to subgroup 2 and HC. Subgroup 2 reported more anxiety, lower functioning, and greater attentional vigilance toward fearful faces compared to HC. Relatives from both subgroups were poorer in recognizing positive faces compared to HC.

These findings may explain the discrepancy in earlier fMRI studies on emotion regulation in UR, showing two different subgroups of UR that both exhibited aberrant neural activity during emotion regulation, but in opposite directions. Furthermore, the results suggest that impaired recognition of positive facial expressions is a broad endophenotype of BD.

Accelerated ageing indexed by telomere attrition is suggested in schizophrenia spectrum- (SCZ) and bipolar disorders (BD). While inflammation may promote telomere shortening, few studies have investigated the association between telomere length (TL) and markers of immune activation and inflammation in severe mental disorders.

Leucocyte TL defined as telomere template/amount of single-copy gene template (T/S ratio), was determined in participants with SCZ (N = 301) or BD (N = 211) and a healthy control group (HC, N = 378). TL was analysed with linear regressions for associations with levels of 12 immune markers linked to SCZ or BD. Adjustments were made for a broad range of potential confounding variables. TL was measured by quantitative polymerase chain reaction (qPCR) and the immune markers were measured by enzyme immunoassays.

A positive association between levels of soluble tumour necrosis factor receptor 1A (sTNF-R1) and TL in SCZ (β = 0.191, p = 0.012) was observed. Plasma levels of the other immune markers were not significantly associated with TL in the BD, SCZ or HC groups.

There was limited evidence of association between immune markers and TL in SCZ and BD. The results provide little support for involvement of immune dysregulation, as reflected by current systemic markers, in telomere attrition-related accelerated ageing in severe mental disorders.

Time distortions characterise severe mental disorders, exhibiting different clinical and neurobiological manifestations. This systematic review aims to explore the existing literature encompassing experimental studies on time perception in patients with bipolar disorder (BD), considering psychopathological and cognitive correlates.

Studies using an experimental paradigm to objectively measure the capacity to judge time have been searched for. Selected studies have been described based on whether i) explicit or implicit time perception was investigated, ii) the temporal intervals involved were sub-second or supra-second, and iii) a perceptual or motor timing paradigm was used.

Only 11 met the criteria for inclusion in the review. The available literature shows that the performance of BD patients mostly aligns with controls within sub-second timeframes (six articles), while a different pattern emerges within supra-second intervals based on the clinical phase of the disease (seven articles). Specifically, for longer temporal spans, BD patients tend to overestimate the duration during manic states and underestimate it during depressive states. Notably, no studies have directly investigated the neurobiological mechanisms associated with time perception.

This review indicates that BD patients exhibit time perception similar to controls within sub-second intervals, but tend to overestimate time and underestimate it based on the clinical phase within supra-second intervals. Expanding the understanding of time perception in BD, particularly in relation to clinical phases and cognitive function, is of great importance. Such insights could deepen our understanding of the disorder, refine diagnostic processes, and guide the development of innovative therapeutic interventions.

Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).

We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.

Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.

Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.

We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.