Background:Electroconvulsive therapy (ECT) is the most effective treatment for severe and treatment-resistant depression, but its biological mechanisms remain poorly understood. Given the pivotal role of mitochondria in cellular energy metabolism and their proposed involvement in the pathology of depression, we aimed to investigate whether ECT alters mitochondrial metabolism. Methods:We included 102 patients with major depressive disorder referred for ECT at 7 Swedish hospitals. Fasting serum samples were collected at 3 time points: immediately before the first ECT session (T0), 30 minutes after the first session (T1), and before the sixth session (T2). Proton nuclear magnetic resonance spectroscopy was used to quantify metabolites related to the tricarboxylic acid cycle and amino acid metabolism. Results:Acutely (T0→T1), serum levels of citrate, glucose, glutamine, and pyruvate increased significantly, while formate and phenylalanine decreased. Across the treatment course (T0→T2), alanine and pyruvate levels increased, whereas the ketone bodies acetoacetate, acetone, and 3-hydroxybutyrate decreased significantly. An exploratory analysis indicated that the reduction in ketone bodies (T0→T2) was confined to patients showing clinical improvement, as defined by the Clinical Global Impressions-Improvement scale. Conclusions:ECT induces both acute and sustained alterations in mitochondrial energy metabolism. These findings suggest that ECT modulates systemic mitochondrial function, warranting further investigation into how these metabolic changes relate to clinical improvement.

Abstract Synaptic dysfunction is increasingly recognized as a core feature of psychiatric disorders, yet fluid biomarkers that reflect such changes in vivo are lacking. Here, we applied targeted mass spectrometry to quantify low-abundant synaptic proteins in cerebrospinal fluid from 672 individuals with anorexia nervosa, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ + ), and healthy controls. Synaptic protein levels were markedly reduced in SCZ + , with intermediate reductions in BD and ADHD. Using a data-driven approach to model transdiagnostic contrasts—psychotic experience, cognitive and functional impairment—a shared two-biomarker signature emerged: elevated LAMP1, a phagolysosomal marker, and reduced NPTX2, a synaptic activity marker which inhibits complement-dependent synapse elimination. Combining this ratio with polygenic scores improved diagnostic classification. Key findings were extended to an independent cohort at first-episode psychosis. These results support synaptic pathology as a measurable and transdiagnostic feature across several psychiatric disorders and highlight the potential of integrating fluid and genetic biomarkers.

Background Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psychotic MDD and elucidates its position within the mood- psychotic spectrum. Methods This population-based cohort study used Swedish and Danish registry data for over 5.1 M individuals born between 1958 and 1993/1996. Specialist-diagnosed psychotic MDD was defined using ICD-10 sub-codes of MDD, F32.2/F32.3. We estimated familial aggregation/coaggregation using generalised estimating equations, heritability and genetic correlations using structural equation modelling. We also analysed similar to 30,000 genotyped MDD cases from the UK Biobank and a Swedish cohort to explore which polygenic risk score (PRS) may predispose individuals to psychotic MDD. Findings With over 10,000 psychotic MDD identified from the two nationwide patient registers, this study highlights the familial aggregation of psychotic MDD, co-aggregation with mood and psychotic disorders, and its stronger genetic correlation with schizophrenia compared to non-psychotic MDD. The familial risks increased with closer biological relatedness, suggesting genetic influence. Pedigree-heritability of psychotic MDD was 30.17% (95% CI 23.53-36.80%). While the genetic correlation between psychotic and non-psychotic MDD was high (0.82, 95% CI 0.73-0.92), the psychotic subgroup showed a higher genetic correlation with schizophrenia than non-psychotic MDD (0.67 vs 0.46, p-value 7.55*10-4). Within 30,000 genotyped MDD cases, individuals with psychotic MDD had higher mean PRS for schizophrenia and BD but a lower MDD PRS than non-psychotic MDD. PRS for BD type-I was associated with increased odds of psychotic MDD, while BD type-II PRS showed no significant association with psychotic MDD. Interpretation This study provides evidence for the genetic basis of psychotic MDD, underscoring its unique position bridging the spectrum of mood and psychotic disorders. These findings advance our understanding of the aetiology of psychotic MDD and contribute to the limited body of evidence on this phenotype by utilising large-scale population-based data. Copyright (c) 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND AND OBJECTIVE:Post-infectious sequelae can increase burden on healthcare systems. We aimed to assess the long-term effect of COVID-19 on healthcare utilization across all levels of care. METHODS:In this register-based cohort study, we included all adult (≥18 years) residents in Sweden's two largest counties with a registered COVID-19 index date between 31 January 2020 and 9 February 2022. Each exposed individual was matched 1:1 to a control without registered COVID-19 on index date based on gender, birth year, vaccination status and the change in number of healthcare contacts between 2018 and 2019. We counted the number of healthcare contacts across all levels of care during the pre-index (13-1 months) and post-index (4-15 months) full-year periods. A difference-in-difference (DID) analysis was used to assess changes in the number of healthcare contacts and specific diagnoses, between each individual's pre- and post-periods, as well as comparing individuals with and without COVID-19. RESULTS:The study included 753,905 matched pairs, comprising 1,415,432 unique individuals. Trends in healthcare contacts were parallel between the matched groups prior to the index date. The DID analysis revealed a mean increase of 0.33 (95%CI 0.30-0.36) healthcare contacts following COVID-19, mainly observed from a smaller proportion of the population (5%) and by contacts with primary healthcare. The largest diagnosis-specific difference was observed for reactions to severe stress (0.02, 0.01-0.03). The estimate varied across gender, acute COVID-19 severity, virus variant period and vaccination status. CONCLUSION:This study demonstrates increased healthcare utilization after COVID-19 in a smaller proportion of the population.

Individuals with bipolar disorder (BD) have an elevated risk of dementia, but the underlying etiology is unclear. Examining the genetic risk for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is crucial to understanding this increased risk and uncovering underlying mechanisms, which are essential for improving patient outcomes. We included 2,238 genotyped individuals with bipolar disorder (BD) from the Swedish Bipolar Collection (SWEBIC). Dementia diagnoses were identified using ICD-10/9/8 codes from Swedish national patient register. APOE genotype was divided into ε4 carriers and non-carriers. Non-APOE polygenic score (PGS) for AD (Bellenguez, 2022) and DLB (Chia, 2021) was calculated using PRS-CS. In BD patients, Cox regression analyses examined PGS and APOE ε4 carriership in relation to dementia risk, adjusted for age, sex, and ancestry ( N dementia=76, N controls=2162). A total of 76 participants developed dementia (mean age of 71.5 years, range: 53–84 years). Among individuals with bipolar disorder, APOE ε4 carriership (HR: 1.88, 95% CI: 1.19–2.98, p  = 0.007) and AD-PGS (HR: 1.34, 95% CI: 1.06–1.68, p  = 0.01) were associated with an increased risk of dementia. However, DLB-PGS was not associated with risk of dementia (HR: 1.17, 95% CI: 0.91-1.47, p  = 0.2). The findings indicate that genetic risk for AD contributes to dementia development in individuals with bipolar disorder. These results provide insights into the etiology of dementia in bipolar disorder, highlighting the genetic interplay between the two conditions and informing strategies for risk stratification and targeted prevention.

BACKGROUND:Long-term effects of COVID-19 can place burden on individuals, healthcare, and society. We aimed to evaluate the importance of a wide range of potential risk factors for being diagnosed with post-COVID-19 condition (PCC). METHODS:We used data from national and regional registers and databases for all adult residents in the two largest regions in Sweden. Individuals with a first COVID-19 between 1 August 2020 and 9 February 2022 were included and followed until PCC diagnosis, censoring (death or migration), or 30 November 2023. Using Cox proportional hazards models and backwards stepwise selection, we evaluated a large set of risk factors including sociodemographic data, comorbidities, healthcare contact behaviors, COVID-19-related factors, as well as PCC in family and cohabitants (as proxies for genetics and shared environment). RESULTS:We include 810,851 individuals (age range 18-106 years and 53.3% women), of whom 1.4% are diagnosed with PCC during follow-up. Female sex, older age, being born outside Sweden, higher educational attainment, essential workers, having comorbidities such as thromboembolic disease, asthma, fibromyalgia, depression/anxiety, and stress-related disorders, being infected earlier in the study period, experiencing severe acute COVID-19, not being vaccinated before COVID-19, and having a relative or a cohabitant with PCC are associated with an increased risk of being diagnosed with PCC. CONCLUSIONS:In this large population-based cohort study, our exploratory analysis reveals several risk factors for being diagnosed with PCC. Our findings can serve as a basis for future targeting of preventive measures against PCC.

Treatment-resistant depression (TRD), defined as major depressive disorder (MDD) with multiple failed responses to antidepressant treatments, has been suggested to be heritable, but identifying its genetic component is challenging. Using a restrictive TRD definition based on antidepressant medication followed by electroconvulsive therapy (ECT), which may represent a severe subset of TRD cases, we investigated both common variants and rare copy number variations (CNVs) associated with a) TRD risk (2 062 TRD vs. 441 037 healthy controls) and b) treatment resistance in MDD (2 062 TRD vs. 38 544 non-TRD) across three Nordic countries. We observed a significant SNP-based heritability for TRD risk at 26% (SE = 5%). Genome-wide association analysis identified one locus on chromosome 3 (intronic region of SPATA16) for TRD risk and one suggestive locus for treatment resistance in MDD. TRD risk showed positive genetic correlations (rg) with other psychiatric disorders, with notably rg with bipolar disorder (0.86, SE = 0.20) and schizophrenia (0.57, SE = 0.13), as well as a negative rg with intelligence (−0.13, SE = 0.07). Analyses using PRS showed that TRD had higher common-variant burdens of various psychiatric disorders compared to non-TRD. Furthermore, TRD carried a higher CNV deletion burden in total and average lengths than healthy controls or non-TRD cases and was associated with a group of 54 known neuropsychiatric CNVs (ORs = 1.74–2.86). Given that our definition of TRD involves the use of ECT, our findings may reflect a severe form of treatment resistance. This work adds evidence on a genetic basis and provides insights into the genetic architecture of TRD, underscoring the need for further genomic research into this ‘difficult-to-treat’ condition.

BACKGROUND:Individuals with bipolar disorder (BD) have an elevated risk of dementia, but the underlying etiology is unclear. Examining the genetic risk for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is crucial to understanding this increased risk and uncovering underlying mechanisms, which are essential for improving patient outcomes. METHOD:We included 2,238 genotyped individuals with bipolar disorder (BD) from the Swedish Bipolar Collection (SWEBIC). Dementia diagnoses were identified using ICD-10/9/8 codes from Swedish national patient register. APOE genotype was divided into ε4 carriers and non-carriers. Non-APOE polygenic score (PGS) for AD (Bellenguez, 2022) and DLB (Chia, 2021) was calculated using PRS-CS. In BD patients, Cox regression analyses examined PGS and APOE ε4 carriership in relation to dementia risk, adjusted for age, sex, and ancestry (N dementia=76, N controls=2162). RESULT:A total of 76 participants developed dementia (mean age of 71.5 years, range: 53-84 years). Among individuals with bipolar disorder, APOE ε4 carriership (HR: 1.88, 95% CI: 1.19-2.98, p = 0.007) and AD-PGS (HR: 1.34, 95% CI: 1.06-1.68, p = 0.01) were associated with an increased risk of dementia. However, DLB-PGS was not associated with risk of dementia (HR: 1.17, 95% CI: 0.91-1.47, p = 0.2). CONCLUSION:The findings indicate that genetic risk for AD contributes to dementia development in individuals with bipolar disorder. These results provide insights into the etiology of dementia in bipolar disorder, highlighting the genetic interplay between the two conditions and informing strategies for risk stratification and targeted prevention.

BACKGROUND:The Swedish Bipolar Collection (SWEBIC) was launched to investigate the genetic basis of bipolar disorder. Here, we provide a detailed overview of the procedures and assessment tools used during the SWEBIC data collection. METHODS:The SWEBIC collection occurred in two waves, the first from 2009 to 2013, followed by the second wave from 2017 to 2022. Recruitment primarily relied on the Swedish National Quality Register for Bipolar Disorders (BipoläR). Additional sources included the Hospital Discharge Register, an online questionnaire, and identification of individuals with bipolar disorder from other cohort studies. We assessed the diagnostic validity of the BipoläR entries by reviewing randomly selected medical records from the study participants. RESULTS:Across the two waves, SWEBIC recruited 8580 individuals diagnosed with bipolar disorder, 89 percent from BipoläR. The bipolar disorder diagnoses in BipoläR showed high agreement with medical records (positive predictive value of 0.90). The response rate in BipoläR was higher during the first (61%) than the second wave (23%). Further, the proportion of individuals with subtype 1 was higher in the first wave. Including individuals from other cohort studies, the total number of DNA samples from individuals with bipolar disorder in SWEBIC exceeds 10,000. CONCLUSIONS:Using quality registries to identify patients for large cohort studies facilitates genetic research with high recruitment efficiency and throughput combined with rich phenotypic data. The extensive data and biological samples collected in SWEBIC will continue to be a valuable resource for future studies, advancing our understanding of the genetic basis of bipolar disorder.

Importance Hypochondriasis, also known as health anxiety disorder, is a prevalent, yet underdiagnosed psychiatric disorder characterized by persistent preoccupation about having serious and progressive physical disorders. The risk of mortality among individuals with hypochondriasis is unknown. Objective To investigate all-cause and cause-specific mortality among a large cohort of individuals with hypochondriasis. Design, Setting, and Participants This Swedish nationwide matched-cohort study included 4129 individuals with a validated International Statistical Classification of Diseases and Related Health Problems, Tenth Revision ( ICD-10 ) diagnosis of hypochondriasis assigned between January 1, 1997, and December 31, 2020, and 41 290 demographically matched individuals without hypochondriasis. Individuals with diagnoses of dysmorphophobia (body dysmorphic disorder) assigned during the same period were excluded from the cohort. Statistical analyses were conducted between May 5 and September 27, 2023. Exposure Validated ICD-10 diagnoses of hypochondriasis in the National Patient Register. Main Outcome and Measures All-cause and cause-specific mortality in the Cause of Death Register. Covariates included birth year, sex, county of residence, country of birth (Sweden vs abroad), latest recorded education, civil status, family income, and lifetime psychiatric comorbidities. Stratified Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% CIs of all-cause and cause-specific mortality. Results Of the 4129 individuals with hypochondriasis (2342 women [56.7%]; median age at first diagnosis, 34.5 years [IQR, 26.3-46.1 years]) and 41 290 demographically matched individuals without hypochondriasis (23 420 women [56.7%]; median age at matching, 34.5 years [IQR, 26.4-46.2 years]) in the study, 268 individuals with hypochondriasis and 1761 individuals without hypochondriasis died during the study period, corresponding to crude mortality rates of 8.5 and 5.5 per 1000 person-years, respectively. In models adjusted for sociodemographic variables, an increased rate of all-cause mortality was observed among individuals with hypochondriasis compared with individuals without hypochondriasis (HR, 1.69; 95% CI, 1.47-1.93). An increased rate was observed for both natural (HR, 1.60; 95% CI, 1.38-1.85) and unnatural (HR, 2.43; 95% CI, 1.61-3.68) causes of death. Most deaths from unnatural causes were attributed to suicide (HR, 4.14; 95% CI, 2.44-7.03). The results were generally robust to additional adjustment for lifetime psychiatric disorders. Conclusions and Relevance This cohort study suggests that individuals with hypochondriasis have an increased risk of death from both natural and unnatural causes, particularly suicide, compared with individuals from the general population without hypochondriasis. Improved detection and access to evidence-based care should be prioritized.

The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.

Despite electroconvulsive therapy (ECT) being recognized as an effective treatment for major depressive episodes (MDE), its application is subject to controversy due to concerns over cognitive side effects. The pathophysiology of these side effects is not well understood. Here, we examined the effects of ECT on blood-based biomarkers of neuronal injury and astrocytic reactivity. Participants with a major depressive episode (N = 99) underwent acute ECT. Blood was sampled just before (T0) and 30 min after (T1) the first ECT session, as well as just before the sixth session (T2; 48-72 h after the fifth session). Age- and sex-matched controls (N = 99) were recruited from the general population. Serum concentrations of neurofilament light chain (NfL), total tau protein, and glial fibrillary acidic protein (GFAP) were measured with ultrasensitive single-molecule array assays. Utilizing generalized least squares regression, we compared baseline (T0) biomarker concentrations against those of our control group, and calculated the shifts in serum biomarker concentrations from baseline to immediately post-first ECT session (T1), and prior to the sixth session (T2). Baseline analysis revealed that serum levels of NfL (p < 0.001) and tau (p = 0.036) were significantly elevated in ECT recipients compared with controls, whereas GFAP levels showed no significant difference. Relative to T0, serum NfL concentration neither changed at T1 (mean change 3.1%, 95%CI -0.5% to 6.7%, p = 0.088) nor at T2 (mean change -3.2%, 95%CI -7.6% to 1.5%, p = 0.18). Similarly, no change in total tau was observed (mean change 3.7%, 95%CI -11.6% to 21.7%, p = 0.65). GFAP increased from T0 to T1 (mean change 20.3%, 95%CI 14.6 to 26.3%, p < 0.001), but not from T0 to T2 (mean change -0.7%, 95%CI -5.8% to 4.8%, p = 0.82). In conclusion, our findings suggest that ECT induces a temporary increase in serum GFAP, possibly reflecting transient astrocytic activation. Importantly, we observed no indicators of neuronal damage or long-term elevation in any assessed biomarker.

OBJECTIVES:Electroconvulsive therapy (ECT) is effective in treating late-life depression. There is limited research on suicidal behavior and all-cause mortality in the oldest old after ECT. METHODS:Older adults aged 75 years and above who had been inpatients for moderate to severe depression between January 1, 2011, and December 31, 2017, were included in the study. We used exact and propensity score matching to balance groups. We compared suicidal behavior (fatal and non-fatal) and all-cause mortality in those who had received ECT and those with other depression treatments. RESULTS:Of the study population, 1802 persons who received ECT were matched to 4457 persons with other treatments. There were no significant differences in the risk of suicidal behavior between groups, (within 3 months: odds ratio 0.73; 95% confidence intervals (CI), 0.44-1.23, within 4 months to 1 year: aOR 1.34; 95% CI, 0.84-2.13). All-cause mortality was lower among ECT recipients compared to those who had received other treatments, both within 3 months (aOR, 0.35; 95% CI, 0.23-0.52), and within 4 months to 1 year (aOR 0.65; 95% CI, 0.50-0.83). CONCLUSIONS:Compared to other depression treatments, ECT is not associated with a higher risk of suicidal behavior in patients aged 75 and above. ECT is associated with lower all-cause mortality in this age group, but we advise caution regarding causal inferences.

ObjectivesNon-fatal self-harm (SH) is a major risk factor for late-life suicide. A better knowledge of the clinical management of older adults who self-harm is needed to establish where improvements could be made for the implementation of effective suicide prevention interventions. We therefore assessed contacts with primary and specialised care for mental disorders and psychotropic drug use during the year before and after a late-life non-fatal SH episode.MethodLongitudinal population-based study in adults aged >= 75 years with SH episode between 2007 and 2015 retrieved from the regional database VEGA. Healthcare contacts for mental disorders and psychotropic use were assessed during the year before and after the index SH episode.ResultsThere were 659 older adults who self-harmed. During the year before SH, 33.7% had primary care contacts with a mental disorder, 27.8% had such contacts in specialised care. Use of specialised care increased sharply after the SH, reaching a maximum of 68.9%, but this figure dropped to 19.5% by the end of the year. Use of antidepressants increased from 41% before to 60% after the SH episode. Use of hypnotics was extensive before and after SH (60%). Psychotherapy was rare in both primary and specialised care.ConclusionThe use of specialised care for mental disorders and antidepressant prescribing increased after SH. The drop in long-term healthcare visits should be further explored to align primary and specialised healthcare to the needs of older adults who self-harmed. The psychosocial support of older adults with common mental disorders needs to be strengthened.

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate the genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) and non-TRD within ~4500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores (PRS) of antidepressants and lithium response for individuals with MDD and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1778 ECT-treated MDD cases, nearly all (94%) used antidepressants before their first ECT and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We did not observe a significant difference in the mean PRS of antidepressant response between TRD and non-TRD; however, we found that TRD cases had a significantly higher PRS of lithium response compared to non-TRD cases (OR = 1.10–1.12 under various definitions). The results support the evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.

Objectives: To investigate potential differences in the strength of associations between different levels of passive and active suicidal ideation and all-cause mortality in older adults. Design: Prospective cohort study. Setting: Population-based samples of older adults in Gothenburg, Sweden. Participants: Older adults aged 79 and above who participated in any wave of the Gothenburg H70 Birth Cohort Studies or the Prospective Population Study of Women between 1986 and 2015 (n = 2,438; 1,737 women, 701 men; mean age 86.6). Measurements: Most intense level of passive or active suicidal ideation during the past month: life-weariness, wish to die, or active suicidal ideation. The outcome was all-cause mortality over 3 years. Results: During follow-up, 672 participants (27.6%) died. After adjustments for sex, age, and year of examination, participants who reported a wish to die (HR 2.01; 95% CI 1.55-2.60) as the most intense level of ideation, but not participants who reported life-weariness (HR 1.40; 95% CI 0.88-2.21) or active suicidal ideation (HR 1.10; 95% CI 0.69-1.76) were at increased risk of all-cause mortality. Reporting a wish to die remained associated with mortality in a fully adjusted model, including somatic conditions, dementia, depression, and loneliness (HR 1.70; 95% CI 1.27-2.26). Conclusion: In older adults, reporting a wish to die appears to be more strongly associated with all-cause mortality than either life-weariness or active suicidal ideation (Am J Geriatr Psychiatry 2023; 31:267-276)