Impaired autophagy has been implicated in the pathophysiology of neurodegenerative disorders, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Consistent and replicated evidence indicate that Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) exert treatment and preventative effects across disparate neurologic and mental disorders, potentially through mechanisms involving autophagy. This systematic review examined the effects of GLP-1RAs on autophagy in cell and animal models of AD and PD, as a proof of concept, to determine if these agents can be repurposed for the prevention and treatment of neurodegenerative and other mental disorders.

A systematic search on PubMed, Web of Science, and OVID (Medline, Embase, and APA PsycInfo databases) was conducted from inception to June 17, 2025. Screening was performed independently by two reviewers (MCS and IH) using predefined inclusion and exclusion criteria. Subsequently, a quality assessment was conducted.

The search yielded 142 studies, of which 14 were included. Across studies, GLP-1RAs (e.g., liraglutide, semaglutide, and exendin-4) autophagy-specific markers, including beclin-1, LC3-II/LC3-I, ATG7, ATG3, and LAMP1, while normalizing p62 levels.

In addition to promoting neurogenesis, neuroplasticity, and reducing inflammation, GLP-1RAs appear to modulate molecular and cellular systems contributing to autophagy, potentially mediating their broad therapeutic effects. Collectively, these studies present promising findings of GLP-1RAs for neurodegenerative and mental disorders; however, further studies are required to establish their translatability to human populations.

Seeking to clarify the parent-offspring transmission of Major Depression (MD) and type I Bipolar Disorder (BD), we examined offspring MD and BD risk in five informative parental pairs: Unaffected x MD, Unaffected x BD, MDxMD, MDxBD and BDxBD.

We identified 289,637 individuals born in Sweden 1970-1990, followed through 2018, from parents with MD and/or BD identified from Swedish medical registers. We quantified the MD→MD, BD→BD, MD→BD and BD→MD parent-offspring transmission and explored effects of parental illness on MD→BD conversions.

The risk for MD was modestly and similarly increased in offspring of Unaffected x MD (HR=1.64) and Unaffected x BD parents (HR=1.53), higher in MDxMD and MDxBD pairings (HRs=2.39 and 2.47) and slightly lower in BDxBD matings (HR=2.29). By contrast, risk for BD was much higher in Unaffected x BD versus Unaffected x MD matings (HRs = 5.59 vs. 1.70), further elevated modestly in MDxBD matings (HR=6.26) and very high in BDxBD matings (HR=13.61). The rate of offspring MD→BD conversions was substantially increased by parental BD but not parental MD. Offspring BD was equally predicted by paternal and maternal affective illness while offspring MD was more strongly predicted by maternal than paternal affective illness.

Examining risk for MD and BD in offspring of different parental mating types of MD and BD is an informative strategy for further clarifying the cross-generational transmission of these two partially related and partially distinct mood disorders.

Bipolar disorder (BD) is associated with impairments in facial emotion recognition (FER), affecting social functioning and quality of life. Understanding FER deficits in BD is crucial for tailoring interventions and improving treatment outcomes. This systematic review and meta-analysis aims to evaluate FER differences among individuals with BD, unaffected first-degree relatives (FDRs), and healthy controls (HCs), exploring predictors related to patient and study characteristics.

We systematically searched PubMed/MEDLINE, Scopus, EMBASE, and PsycINFO databases from inception to March 28, 2024. Random-effects meta-analyses were conducted to explore differences in accuracy and reaction time during FER identification and discrimination tasks.

A total of 100 studies were included, comprising 4920 individuals with BD (females = 56%, mean age = 34.1 ± 9.1), 676 FDRs (females = 55%, mean age = 36.1 ± 12), and 4909 HCs (females = 53.2%, mean age = 32.5 ± 9.5). Compared to HCs, adults with BD exhibited significantly lower accuracy (SMD = −0.47; 95% CIs = −0.56, −0.38) and higher reaction time (SMD = 0.57; 95%CIs = 0.33, 0.81) during facial emotion identification tasks. During facial emotion discrimination tasks, adults with BD had significantly lower accuracy than HCs (SMD = −0.59; 95%CIs = −0.78, −0.4), but similar speed. No significant differences were observed between BD and FDRs. Meta-regressions identified several predictors of FER performance, including manic symptom severity, stimulus duration, and presence of practice before task.

FER deficits appear to be a core feature of BD and require specialized, systematic assessment. Identifying these deficits may help guide interventions aimed at improving affective cognition and social outcomes in individuals with BD.

Structural brain alterations in bipolar disorder (BD) have been widely reported, yet the hierarchical organization of cortical morphometric networks and their molecular and cognitive underpinnings remain unclear.

We applied the morphometric inverse divergence (MIND) network approach to structural MRI data from 49 BD patients and 119 healthy controls. Principal MIND gradients were derived using diffusion map embedding, followed by multiscale analyses linking gradient alterations to neurotransmitter systems, cognitive-behavioral domains, and transcriptomic profiles from the Allen Human Brain Atlas. Validation was performed in three independent, cross-scanner, cross-race, and cross-age validation datasets.

Bipolar disorder patients showed significant principal gradient alterations in the left rostral middle frontal and lateral occipital cortices, with network-level decreases in the ventral attention and motor networks and increases in frontoparietal and visual networks. Gradient alterations spatially correlated with acetylcholine (VAChT) and GABA (GABAA/BZ) systems, and were associated with cognitive processes involving executive control and visual attention. Transcriptomic analyses identified gene sets enriched for BD-related GWAS loci, expressed predominantly in excitatory and inhibitory neurons, astrocytes, and oligodendrocytes, with preferential enrichment in cortical layers III-IV and developmental windows spanning early fetal to young adulthood.

These findings reveal disrupted hierarchical cortical organization in BD and link macroscale morphometric alterations to specific neurotransmitter systems and transcriptional architectures. The MIND gradient emerges as a potential biomarker bridging structural disruptions with molecular and cognitive mechanisms in BD.

Cognitive impairment varies widely in bipolar disorder. Identifying cognitive subgroups and their biological correlates may improve understanding of the disorder. Brain-derived neurotrophic factor (BDNF) and C-reactive protein (CRP) are key candidates due to their roles in neuroplasticity and inflammation.

The aim was to investigate cognitive subgroups in patients with bipolar disorder and their association with serum levels of BDNF and CRP.

A cross-sectional study was conducted on 149 bipolar disorder patients and 48 healthy controls. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests. Cluster analysis was performed to identify cognitive subgroups, followed by discriminant function analysis to validate the classification. Serum levels of BDNF and CRP were measured and compared across cognitive subgroups.

Cluster analysis identified three cognitive subgroups: intact cognition, selectively impaired cognition (SIC) and globally impaired cognition (GIC). SIC exhibited the highest BDNF levels, while GIC demonstrated the highest CRP levels. CRP levels were negatively associated with performance across all cognitive domains. BDNF showed a negative correlation with verbal fluency, short-term memory and working memory. CRP levels exceeding 4.3 mg/L predicted global cognitive impairment with a sensitivity of 72.41% and specificity of 73.63%.

Cognitive impairments in bipolar disorder patients can be classified into distinct subgroups, which are associated with serum levels of BDNF and CRP. These findings suggest that inflammation and neuroplasticity play key roles in the pathophysiology of cognitive decline in bipolar disorder, providing potential biomarkers for identifying patients at risk for severe cognitive impairments.

Deficits in working memory (WM) and attention have a considerable functional impact on people with bipolar disorder (PBD). Understanding the neurocognitive underpinnings of these cognitive constructs might facilitate the discovery of more effective pro-cognitive interventions. Therefore, we employed a paradigm designed for jointly studying attentional control and WM encoding.

We used a visuospatial change-detection task using four Gabor Patches with differing orientations in 63 euthymic PBD and 76 healthy controls (HCS), which investigated attentional competition during WM encoding. To manipulate bottom-up attention using stimulus salience, two Gabor patches flickered, which were designated as either targets or distractors. To manipulate top-down attention, the Gabor patches were preceded by either a predictive or a non-predictive cue for the target locations.

Across all task conditions, PBD stored significantly less information in visual WM than HCS (significant effect of group). However, we observed no significant group-by-salience or group-by-cue interactions. This indicates that impaired WM was not caused by deficits in attentional control.

While WM was disturbed in PBD, attentional prioritization of salient targets and distractors, as well as the utilization of external top-down cues, were not compromised. Thus, the control of attentional selection appears to be intact at least for our specific manipulation of this cognitive construct. These findings provide valuable clues for models of WM dysfunction in PBD by suggesting that later stages of WM encoding, such as WM consolidation, are likely primarily impaired, while selective attention is not a main source of impairment.

The population with a serious mental illness (SMI) shows a high risk of premature mortality. Overexposed to multiple health risks throughout life, their main threat is physical illness, which starts earlier and is not diagnosed in time. Developing preventive actions is a public health priority.

This longitudinal prospective study evaluated the predictive value of lung function on all-cause mortality in patients with schizophrenia (SCHIZ) or bipolar disorder. Patients aged 40–70 years, active smokers, and without preexisting respiratory disease underwent spirometry following American Thoracic Society/European Respiratory Society 2021 standards. Mortality data were collected through December 2022. Cox proportional hazards models and Kaplan–Meier survival curves analyzed the association between lung function, specifically forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and mortality, adjusting for relevant confounders (age, gender, abdominal circumference, and comorbidities).

Of 107 participants (mean age 49.3 years, 63.3% male) with SMI (72% SCHIZ) and active smokers, 8 (7.5%) died during the 6-year follow-up (5 cardiovascular and 3 cancer). Mean z-scores were −1.41 (SD = 1.22) for FEV1 and −0.99 (SD = 1.16) for FVC. Lower FEV1 and FVC z-scores were significantly associated with increased mortality risk (p = 0.002 and p = 0.009, respectively). Kaplan–Meier analysis confirmed this association for FEV1 (p = 0.039) and FVC (p = 0.007) but not for gender, comorbidities (hypertension, diabetes, and dyslipidemia), or FEV1/FVC. A multivariate Cox regression model, adjusting for age and abdominal circumference, confirmed the independent predictive value of lower FEV1 z-score for mortality (hazard regression = 0.473, 95% confidence interval: 0.220–0.979, p = 0.044).

Poorer lung function, especially lower FEV1, was independently associated with all-cause mortality in SMI. Spirometry, an easily implementable technique, could help to detect at-risk individuals and favor prevention initiatives.

How psychotic symptoms, depressive symptoms, cognitive deficits, and functional impairment may interact with one another in schizophrenia or bipolar disorder is unclear.

This study explored these interactions in a discovery sample of 339 Chinese, of whom 146 had first-episode schizophrenia and 193 had bipolar disorder. Psychotic symptoms were assessed using the Positive and Negative Symptom Scale; depressive symptoms, using the Hamilton Depression Rating Scale; cognitive deficits, using tests of processing speed, executive function, and logical memory; and functional impairment, using clinical assessments. Network models connecting the four types of variables were developed and compared between men and women and between disorders. Potential causal relationships among the variables were explored through directed acyclic graphing. The results in the discovery sample were compared to those obtained for a validation sample of 235 Chinese, of whom 138 had chronic schizophrenia and 97 had bipolar disorder.

In the discovery and validation cohorts, schizophrenia and bipolar disorder showed similar networks of associations, in which the central hubs included ‘disorganized’ symptoms, depressive symptoms, and deficits in processing speed during the digital symbol substitution test. Directed acyclic graphing suggested that disorganized symptoms were upstream drivers of cognitive impairment and functional decline, while core depressive symptoms (e.g. low mood) drove somatic and anxiety symptoms.

Our study advocates for transdiagnostic, network-informed strategies prioritizing the mitigation of disorganization and depressive symptoms to disrupt symptom cascades and improve functional outcomes in schizophrenia and bipolar disorder.

Sleep disorders are closely linked to the onset, progression and severity of psychiatric disorders, yet large-scale data from real-world inpatient settings remain limited. Evaluating the impact of chronic sleep disorders (CSD) in this context is essential for improving care.

We conducted an analysis of adult inpatients hospitalized from January 1, 2021, to December 31, 2023, using data from the Paris Psychiatry Hospital Group’s health data warehouse. Sleep disorders were identified via ICD-10 codes, hypnotic prescriptions, or mentions in medical record. CSD was defined using an Index of Length of Stays with Disorders (ILSD) >0.5, and no sleep disorders (NSD) with an ILSD of zero.

Among 13,913 psychiatric inpatients, 81% were classified as having CSD. Compared to NSD patients, those with CSD had a higher number of hospitalizations (1.84 vs 1.33, p<0.001) and increased use of seclusion (17.6% vs 13.3%, p<0.001) and physical restraint (6.6% vs 5.3%, p=0.003). Individuals with CSD were more frequently hospitalized than the NSD group for depressive disorders (15.6% vs13.1%, p<0.001), bipolar disorders (11.4% vs5.6%, p<0.001), personality disorders (5.3% vs4.3%, p=0.009), alcohol abuse (3.3% vs2.4%, p=0.005), other substance use disorders (2.9% vs2.2%, p=0.018), manic episode (2.0% vs0.9%, p<0.001), and anxiety disorders (1.4% vs0.9%, p=0.012). Hypnotics were prescribed in 50.5% of SD-related stays. The CSD group had more psychiatric and non-psychiatric comorbidities.

CSD are highly prevalent in psychiatric inpatients and associated with more severe clinical profiles, greater hospitalization burden, and increased restraint use. Targeted sleep management strategies may help improve outcomes and care.

The nosology of mania has long been a conundrum. Prior studies have alternately concluded that it is an internalizing disorder, a thought disorder, or a unique condition. Unfortunately, nearly all existing studies assessed symptoms cross-sectionally. This is problematic for syndromes that follow a more episodic course, such as mania. Here, we test whether including a history of episodes, not simply current symptoms, can help resolve the placement of mania in the meta-structure of psychopathology.

First-admission patients with psychosis from the Suffolk County Mental Health Project (N = 337) were followed across 20 years. Internalizing, thought disorder, and mania symptoms were assessed at year 20, whereas corresponding episodes (i.e. depressive, psychotic, and manic) were assessed across three intervals spanning the previous 20 years. We tested five models to determine whether mania (current and past) loaded onto the internalizing factor, the thought disorder factor, or an independent factor. A final model was validated against established markers of bipolar disorder.

For depression and psychosis, current and past markers were congruent in loading onto internalizing and thought disorder factors, respectively. However, current and past markers of mania diverged: current mania was most strongly related to the thought disorder dimension, whereas past mania formed an independent factor. Classic correlates of mania – including family history, genetic risk, and neuropsychological function – were associated only with the history of mania dimension.

Including illness course in structural models of psychopathology suggests that mania is distinguished from internalizing and thought disorder factors, whereas assessments of current symptoms place it with psychosis. These findings require independent validation, but if replicated, they would support a separate spectrum of mania defined by the occurrence of episodes across the lifetime.

In this study, a classifier (hyperplane) is determined to distinguish the neural responses during emotion regulation versus viewing images in healthy adults and then applied to determine (i) the effectiveness of the emotion regulation response (defined as emotion regulation distance from the hyperplane [DFHER]) in independent samples of healthy adults, patients with BD, and the patients’ unaffected relatives (URs) and (ii) the association of DFHER with the duration of future (hypo)manic and depressive episodes for patients with BD over a 16-month follow-up period.

Study participants (N = 226) included 65 healthy adults (35 used for support vector machine [SVM] learning [HCTrain] and 30 kept as an independent test sample [HCTest]), 87 patients with newly diagnosed BD (67% BD type 2) and 74 URs. BOLD response data came from an emotion regulation task. Clinical symptoms were assessed at baseline fMRI and after 16 months of specialized treatment.

The SVM ML analysis identified a hyperplane with 75.7% accuracy. Patients with BD showed reduced DFHER relative to the HCTest and UR groups. Reduced DFHER was associated with reduced improvement in psychosocial functioning during the 16-month follow-up time (B = −1.663, p = 0.02).

The neural response during emotion regulation can be relatively well distinguished in healthy adults via ML. Patients with newly diagnosed BD show significant disruption in the recruitment of this emotion regulation response. Disrupted may indicate a reduced capacity for functional improvement during specialized treatment in a mood disorder clinic.

Euthymic bipolar disorder (BD) is associated with general and domain-specific cognitive impairment, which predicts poor occupational and social functioning.

We searched Embase, Medline, and PsycInfo for articles published between database inception and June 2024, examining cognitive domains in euthymic BD. We conducted meta-analysis, meta-regressions, including premorbid IQ, demographic, and clinical variables. Newcastle Ottawa Scale, I2 statistic, and funnel plots/Egger’s and Begg’s Test were used to assess quality, heterogeneity, and publication bias, respectively. The Benjamini-Hochberg (BH) procedure was utilised for multiple comparisons.

We identified 95 groups from 75 studies (N = 4,404 BD & 4,037 HC). BD showed significant impairment in general cognitive functioning (Hedge’s g = −0.58, 95%CI: −0.79, −0.37, p <.01), verbal memory (Hedge’s g = −0.70, 95%CI: −0.79, −0.60, p <.01), executive function (Hedge’s g = −0.69, 95%CI: −0.78, −0.60, p <.01), visuo-spatial memory (Hedge’s g = −0.68, 95%CI: −0.83, −0.53, p <.01), attention/processing speed (Hedge’s g = −0.64, 95%CI: −0.75, −0.54, p <.01), working memory (Hedge’s g = −0.61, 95%CI: −0.74, −0.49, p <.01), and premorbid IQ (Hedge’s g = −0.24, 95%CI: −0.36, −0.12, p <.01). Demographic and clinical factors were not associated with cognitive performance, except for a statistically significant, but small positive correlation between years of education and lower impairment in verbal memory, β = .066, adjusted p <.05.

Our findings highlight cognitive domains impaired in euthymic BD, indicating targets for interventions. Substantial variance is unexplained, warranting focus on larger samples of individual-level data.

Among the clinical features of bipolar disorder (BD), sleep disturbances are highly prevalent and persist across all phases of the illness, from onset to acute and inter-episodic periods. Substantial evidence suggests that sleep disturbances may function as proximal triggers for suicidal behavior, independent of other underlying psychiatric conditions. Although suicide is a major clinical concern in BD, the interplay between sleep disturbances and suicidality remains incompletely understood.

We conducted a systematic review and meta-analysis (SRMA) following the PRISMA guidelines. We performed a comprehensive search across PubMed, PsycINFO, and SCOPUS, including all studies reporting an association between sleep disturbances and suicidal behavior in BD. A total of 16 reports, comprising 14 cross-sectional studies and two longitudinal studies, were included in this SRMA.

Among individuals with BD, sleep disturbances were associated with increased odds of lifetime suicidal behaviors (OR = 1.51, 95% CI = 1.23, 1.86), and a history of suicide attempts was associated with significantly elevated odds of experiencing sleep disturbances (OR = 1.37, 95% CI = 1.21, 1.55). In addition, poor sleep quality as measured by the Pittsburgh Sleep Quality Index positively correlated with suicidality (r = 0.24, 95% CI = 0.10, 0.36).

These results highlight the link between sleep disturbances and suicidal tendencies in individuals with BD. Prompt recognition and treatment of sleep disturbances could be crucial for averting or reducing suicidal behaviors in this population.

Euthymic bipolar disorder (euBD) patients exhibit deficits in neurocognitive and social cognitive functioning compared to healthy controls (HCs). Our prior research has shown that the excitatory/inhibitory (E/I) imbalance in the default mode network (DMN) is linked to executive function in euBD. Neurocognitive impairments are associated with social cognition deficits in individuals with mental disorders. Given this connection, this study posits E/I imbalance within the DMN is associated with social cognition, with executive function as a mediator.

Seventy-five HCs and 49 euBD individuals were recruited. Using the emotion recognition task, Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW) and cognitive flexibility task, Wisconsin Card Sorting Test (WCST), we assessed emotion recognition and prefrontal function. Proton magnetic resonance spectroscopy (1H-MRS) measured metabolites in the posterior cingulate cortex (PCC) and medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), quantifying excitatory glutamate+glutamine (Glx) and inhibitory GABA to calculate the E/I ratio.

euBD patients showed poorer emotion recognition (p = 0.020) and poorer cognitive flexibility (fewer WCST categories completed, p = 0.002). A negative association was found between emotion recognition and the E/I ratio in the mPFC/ACC of the BD patients (r = −0.30, p = 0.034), which was significantly mediated by cognitive flexibility (Z = −2.657, p = 0.007).

The BD patients demonstrate deficits in emotion recognition, linked to an altered E/I balance in the prefrontal cortex, and the cognitive flexibility, a key aspect of executive function, mediates the impact of the E/I ratio on emotion recognition accuracy in euBD patients.

There is preliminary evidence that childhood trauma (e.g., abuse) is associated with subclinical hypomania reported in adolescence. These findings need replicating in early adulthood, as clinical conditions emerge, and the mechanisms underlying this association need elucidating. This study aimed to examine the magnitude of shared genetic and environmental underpinnings of the association between childhood trauma with hypomanic symptoms and high-risk status for bipolar disorder (BD) using a twin design. Gene–environment correlations and interactions between childhood trauma and polygenic scores (PGS) for psychiatric and neurodevelopmental conditions were also investigated.

Childhood trauma was reported using the Avon “Life at 22+” questionnaire by 8,464 individuals from a community twin sample. Self-reported hypomanic symptoms were assessed using the Mood Disorder Questionnaire at age 26 by 7,748 participants. PGS for psychiatric and neurodevelopment conditions were derived from independent published discovery samples.

Childhood trauma was significantly associated with hypomanic symptoms (β = 0.23, 95% CI: 0.20–0.25) and being at high-risk for BD (OR = 1.77, 95% CI: 1.59–1.98). These associations were strongly influenced by genetic factors (bivariate heritability range: 0.51–0.90). Gene–environment correlations were found between childhood trauma and the PGS for six conditions: Major Depressive Disorder (MDD), schizophrenia, Attention-Deficit Hyperactivity Disorder, anxiety disorders, Post-Traumatic Stress Disorder, and BD II (β range = −0.19–0.11). The MDD-PGS was found to significantly interact with childhood trauma in hypomania (β = 0.01, p < .05).

The associations between childhood trauma and subclinical hypomania and high-risk for BD were partially attributed to shared genetic factors. These associations were also moderated by MDD-PGS. Gene–environment correlations were detected between childhood trauma and polygenic vulnerability to psychiatric and neurodevelopmental conditions. The etiology of hypomania and BD is likely the result of a confluence of genetic and environmental factors, and research in this area should account for potential genetic confounding.

Bipolar disorder often goes unrecognised for several years, leading to delayed treatment and negative outcomes. To help address this, we have developed a novel telehealth-based group psychoeducational and resilience enhancement programme for individuals at high risk for bipolar disorder (PREP-BD), aimed at improving help-seeking among adolescents and young adults at risk of developing bipolar disorder.

The purpose of the current study was to explore the perspectives of at-risk youth, their families and group facilitators who participated in the feasibility trial of PREP-BD.

Group and individual semi-structured feedback sessions were conducted with the participants (n = 21) of the programme, their family members and the facilitators of PREP-BD. The questions covered their experiences, opinions on the programme’s structure and content and suggestions for improvement. Feedback sessions were transcribed and analysed qualitatively using inductive content analysis.

Overall feedback was positive, with participants and facilitators appreciating the informative and engaging nature of the sessions. Some participants desired more actionable resources and complex content. Family members sought greater involvement and information about the programme. The online format was valued for convenience, but was also viewed as a barrier by some to fostering deeper connections.

PREP-BD shows promise as a psychoeducational intervention for individuals at high risk for bipolar disorder. To enhance the programme’s effectiveness, future iterations should incorporate more nuanced content, provide additional practical guidance and address the limitations of the virtual setting. Continued evaluation and optimisation are crucial for ensuring the programme’s effectiveness as a tool for early intervention in bipolar disorder.