Introduction
The term “neuroprogression” imply that bipolar disorder (BD) progressively worsens for some patients and accompanying neuroanatomical changes. BD has indeed been associated with cortical ...and subcortical brain abnormalities. But cross-sectional studies cannot determine whether the observed brain alterations reflect static premorbid traits or whether they result from progressive changes during the course of illness.
Objectives
The aims of this series of studies were to determine if progressive brain changes occur in bipolar disorder, and if so, what the drivers of these changes are.
Methods
We addressed these questions in the St. Göran cohort – a longitudinal study where patients and controls undergo structural magnetic resonance imaging (MRI) scans at baseline and after 7 years. We have also conducted a longitudinal multicenter study within the ENIGMA consortium including 307 patients and 925 healthy controls scanned at two time points.
Results
We addressed these questions in the St. Göran cohort – a longitudinal study where patients and controls undergo structural magnetic resonance imaging (MRI) scans at baseline and after 7 years. We have also conducted a longitudinal multicenter study within the ENIGMA consortium including 307 patients and 925 healthy controls scanned at two time points.
Conclusions
BD is associated with some (accelerated ventricular enlargement) but not global progressive brain changes (change in cortical structures do not differ from controls). Occurrence of manic episodes is, however, associated with accelerated cortical thinning over time. These results highlight the importance of preventing the potentially toxic effects of manic episodes and might explain why some patients experience worsening cognitive function.
Disclosure
ML has received lecture honoraria (unrelated to this topic) from Lundbeck pharmaceuticals.
Introduction
Postpartum psychosis is a rare psychiatric emergency, occurring days to weeks after 1-2 per 1000 deliveries. Its low prevalence makes it difficult to recruit enough participants to ...investigate the underlying pathophysiology. It is epidemiologically linked to bipolar disorder, which one study also found it to resemble in genetic susceptibility for psychiatric disorders (Di Florio
et al
. Lancet Psych 2021; 8: 1045–52).
Objectives
In this study we aim to investigate polygenic liability for psychiatric disorders in two new Swedish postpartum psychosis cohorts.
Methods
Cases with postpartum psychosis, defined as a psychiatric hospitalization within 6 weeks after delivery, and/or receiving a diagnosis of F53.1 (ICD 10) or 294.40 (ICD 8.), parous women with severe mental illness without postpartum psychosis, and healthy parous controls were identified in two Swedish genetic studies: the Swedish bipolar collection (SWEBIC) and Predictors for ECT (PREFECT). Polygenic risk scores (PRS) were calculated from summary statistics from genome wide studies on bipolar disorder (Mullins
et al.
Nat Genet 2021; 53 817-829), schizophrenia (Trubetskoy
et al.
Nature 2022; 604 502-508) and major depression (Wray
et al
. Nat Genet. 2018; 50 668-681). The p-value thresholds best predicting their respective phenotype were used in logistic regression analyses with the first six principal components and genotyping platform as confounders.
Results
We identified 176 patients with postpartum psychosis and genetic information (N(SWEBIC)=126, N(PREFECT)=50). Compared with healthy parous women, patients with postpartum psychosis had significantly higher PRS for bipolar disorder (SWEBIC: odds ratio OR 2.6 (95% confidence interval CI 1.9-3.5), PREFECT: OR 2.4 (95% CI 1.8-3.2), Figure 1.) and schizophrenia (SWEBIC: OR 1.6 (95% CI 1.2-2.2), PREFECT: OR 1.8 (95%; CI 1.3-2.5)). Patients with postpartum psychosis had significantly higher PRS for bipolar disorder (SWEBIC: OR 1.4 (95% CI 1.2-1.8), PREFECT: OR 1.5 (95% CI 1.1-2)) compared with parous women with severe mental illness without postpartum psychosis. We found no associations with major depression PRS in either cohort.
Image:
Conclusions
We replicated previous findings of significantly higher PRS for bipolar disorder and schizophrenia in postpartum psychosis compared with healthy controls. In contrast to previous research, we find postpartum psychosis cases to have higher PRS for bipolar disorder than bipolar disorder cases. Our findings highlight the genetic influence in postpartum psychosis and support previous genetic and epidemiological evidence that postpartum psychosis lies on the bipolar spectrum.
Disclosure of Interest
None Declared
Aim
The aim of this systematic review was to assess the effects on psychosocial and mental health, cognition, body composition, and metabolic markers of hormone treatment in children with gender ...dysphoria.
Methods
Systematic review essentially follows PRISMA. We searched PubMed, EMBASE and thirteen other databases until 9 November 2021 for English‐language studies of hormone therapy in children with gender dysphoria. Of 9934 potential studies identified with s reviewed, 195 were assessed in full text, and 24 were relevant.
Results
In 21 studies, adolescents were given gonadotropin‐releasing hormone analogues (GnRHa) treatment. In three studies, cross‐sex hormone treatment (CSHT) was given without previous GnRHa treatment. No randomised controlled trials were identified. The few longitudinal observational studies were hampered by small numbers and high attrition rates. Hence, the long‐term effects of hormone therapy on psychosocial health could not be evaluated. Concerning bone health, GnRHa treatment delays bone maturation and bone mineral density gain, which, however, was found to partially recover during CSHT when studied at age 22 years.
Conclusion
Evidence to assess the effects of hormone treatment on the above fields in children with gender dysphoria is insufficient. To improve future research, we present the GENDHOR checklist, a checklist for studies in gender dysphoria.
Cross-sectional neuroimaging studies show that bipolar disorder is associated with structural brain abnormalities, predominantly observed in prefrontal and temporal cortex, cingulate gyrus, and ...subcortical regions. However, longitudinal studies are needed to elucidate whether these abnormalities presage disease onset or are consequences of disease processes, and to identify potential contributing factors. Here, we narratively review and summarize longitudinal structural magnetic resonance imaging studies that relate imaging outcomes to manic episodes. First, we conclude that longitudinal brain imaging studies suggest an association of bipolar disorder with aberrant brain changes, including both deviant decreases and increases in morphometric measures. Second, we conclude that manic episodes have been related to accelerated cortical volume and thickness decreases, with the most consistent findings occurring in prefrontal brain areas. Importantly, evidence also suggests that in contrast to healthy controls, who in general show age-related cortical decline, brain metrics remain stable or increase during euthymic periods in bipolar disorder patients, potentially reflecting structural recovering mechanisms. The findings stress the importance of preventing manic episodes. We further propose a model of prefrontal cortical trajectories in relation to the occurrence of manic episodes. Finally, we discuss potential mechanisms at play, remaining limitations, and future directions.
Psychological constructs related to health outcomes and well-being, such as metacognitive beliefs, have been linked to executive functions in general, and cognitive flexibility more specifically. ...However, such effects have previously only been discussed on a theoretical level and behavioral flexibility has most often been measured through self-report, only approximating information processing capacities. Objectively measured executive functions may be a more potent predictor of health outcomes. We set out to test whether cognitive flexibility capacity was associated with sick leave in a medium sized company. We included 111 subjects of widely different occupations and assessed their executive functions using Delis-Kaplan Executive Function System test battery (D-KEFS). To assess cognitive flexibility capacity, we included Design Fluency (DF) and Verbal Fluency (VF) and computed these into an index of cognitive flexibility (DFVF). Detailed information on sick leave for the last 5 years was gathered from the company. Our results showed that there was a significant negative correlation between DFVF and sick leave r
(109) = -0.23,
= 0.015 in the full group as well as in the group that had at least 1 day of sick leave r
(72) =
0.25,
= 0.03. The results withstood adjustment for sex, age, occupation, and several core executive functions as well as autistic and ADHD-traits. The results remained for separate analyses using DF or VF. Our main findings were conceptually replicated in a group of bipolar disorder patients. This study shows that objectively measured capacity of cognitive flexibility is associated with key health outcomes such as sick leave.
Objective
Electroconvulsive therapy (ECT) is used in patients with severe forms of bipolar depression. ECT is effective but not all patients respond. The aim of this study was to determine prognostic ...factors for response to ECT in patients hospitalized for bipolar depression.
Methods
Data were obtained from several national Swedish registers. All patients with bipolar depression treated with ECT in any hospital in Sweden between 2011 and 2016 for whom information about ECT response was available were included (n = 1251). Response was defined as a score on the Clinical Global Impression – Improvement scale of one or two. Univariate and multivariate logistic regression were conducted to investigate associations between socio‐demographic and clinical factors and response.
Results
Response was achieved in 80.2% patients. Older age was associated with higher response rate to ECT. Patients with comorbid obsessive‐compulsive disorder or personality disorder, and patients previously treated with lamotrigine had lower response rate.
Conclusion
Electroconvulsive therapy for bipolar depression was associated with very high response rates. The strongest prognostic factors were higher age, absence of comorbid obsessive‐compulsive disorder or personality disorder, and less prior pharmacologic treatment.
Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric ...patients may be particularly vulnerable to this adverse outcome.
To estimate whether pediatric patients treated with antidepressants have an increased incidence of mania/hypomania compared with patients not treated with antidepressants and to identify patient characteristics associated with the risk of mania/hypomania.
In a cohort study applying the target trial emulation framework, nationwide inpatient and outpatient care in Sweden from July 1, 2006, to December 31, 2019, was evaluated. Follow-up was conducted for 12 and 52 weeks after treatment initiation, with administrative follow-up ending December 31, 2020. Data were analyzed between May 1, 2022, and June 28, 2023. Individuals aged 4 to 17 years with a diagnosis of depression, but without a prior diagnosis of mania/hypomania, bipolar disorder, or psychosis or treatment with mood stabilizer (lithium, valproate, or carbamazepine), prescriptions were included.
The treatment group included patients who initiated any antidepressant medication within 90 days of diagnosis. The control group included patients who did not initiate antidepressants within 90 days.
Diagnosis of mania/hypomania or initiation of mood stabilizer therapy. Incidences were estimated with Kaplan-Meier estimator, and inverse probability of treatment weighting was used to adjust for group differences at baseline.
The cohort included 43 677 patients (28 885 66% girls); 24 573 in the treatment group and 19 104 in the control group. The median age was 15 (IQR, 14-16) years. The outcome occurred in 96 individuals by 12 weeks and in 291 by 52 weeks. The cumulative incidence of mania was 0.26% (95% CI, 0.19%-0.33%) in the treatment group and 0.20% (95% CI, 0.13%-0.27%) in the control group at 12 weeks, with a risk difference of 0.06% (95% CI, -0.04% to 0.16%). At 52 weeks, the cumulative incidence was 0.79% (95% CI, 0.68%-0.91%) in the treatment group and 0.52% (95% CI, 0.40%-0.63%) in the control group (risk difference, 0.28%; 95% CI, 0.12%-0.44%). Hospitalizations, parental bipolar disorder, and use of antipsychotics and antiepileptics were the most important predictors of mania/hypomania by 12 weeks.
This cohort study found no evidence of treatment-emergent mania/hypomania by 12 weeks in children and adolescents. This corresponds to the time frame for antidepressants to exert their psychotropic effect. A small risk difference was found only with longer follow-up. Certain patient characteristics were associated with mania/hypomania, which warrants clinical attention.
Objective
Bipolar disorder carries a high risk of suicide. Identification of risk factors is important. The aim of this study was to study risk factors for suicide in a large cohort of men and women ...with bipolar disorder.
Method
A prospective cohort study using clinical data from the Swedish National Quality Register for Bipolar Affective Disorder (BipoläR). The outcome variable was suicide captured in the Cause of Death Register between 2004 and 2014. Hazard ratios (HR) were calculated using Cox proportional hazards models.
Results
Of 12 850 persons (4844 men and 8006 women) with bipolar disorder, 90 (55 men and 35 women) died by suicide during the follow‐up period (between 1 and 10 years). Male sex (HR 2.56), living alone (HR 2.45), previous suicide attempts (HR 4.10), comorbid psychiatric disorder (HR 2.64), recent affective episodes (HR 2.39), criminal conviction (HR 4.43), psychiatric inpatient care (HR 2.79), and involuntary commitment (HR 3.50) were significant risk factors for suicide. Several of the statistically significant risk factors for suicide in bipolar disorder differed between men and women.
Conclusions
Risk factors for suicide in bipolar disorder include factors associated with suicide in general, but also diagnosis‐specific factors.
Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel ...biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n=54) and age-matched male healthy controls (n=40). Subsequently, post-mortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.
PDF