COVID-19-associated mortality in individuals with serious mental disorders in Sweden during the first two years of the pandemic- a population-based register study.

BACKGROUND: Reports at the beginning of the COVID-19 pandemic suggested differences in COVID-19-associated mortality between individuals with serious mental disorders (SMD) and the population at large. AIM: To compare the pattern of COVID-19-associated mortality in individuals with and without SMD in Sweden over the two main pandemic years. METHODS: We compared the pattern of COVID-19-associated mortality in individuals with and without SMD in Sweden during 2020 and 2021. For SMD, we included psychotic disorder, bipolar disorder, and severe depression. The analysis was based on summary data from the Swedish Board of Health and Welfare covering the entire adult Swedish population. RESULTS: The overall relative risk (RR) for experiencing a COVID-19-associated death was 1.66 (CI 1.50-1.83; p < 0.001) for individuals with SMD versus individuals without SMD. The corresponding RRs were 3.25 (CI 2.84-3.71; p < 0.001) for individuals with psychotic disorder, 1.06 (CI 0.88-1.26; p = 0.54) for individuals with bipolar disorder, and 1.03 (CI 0.80-1.32; p = 0.80) for individuals with severe depression. Compared to their respective counterparts in the non-SMD group, in the psychotic disorder and severe depression group, the RR were higher in women than in men. In the bipolar disorder group, the RR was higher in men than in women. The RR of COVID-19-associated death was generally higher in younger individuals with SMD. Individuals with psychosis between 18 and 59 years had the highest RR of COVID-19-associated death with 7.25 (CI 4.54-11.59; p<0.001). CONCLUSIONS: Individuals with SMD, and particularly those with psychotic disorders, had a higher risk of COVID-19-associated death than the general population. As this is a pattern also seen with other infections, people with SMD may be similarly vulnerable in future pandemics.

Longitudinal neuropsychological trajectories in idiopathic normal pressure hydrocephalus: a population-based study.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a progressive syndrome affecting gait, incontinence, and cognition in a significant number of older adults. Still, prospective studies on early development of symptoms are scarce. AIM: To investigate how neuropsychological functions develop before and in already diagnosed iNPH over a two-year period in a population-based material. METHOD: A sample of 104 participants (median [IQR] 75 [72-80] years old) from the general population underwent CT-imaging and clinical assessment at baseline and follow-up. We used the iNPH symptom scale covering four domains (Neuropsychology, Gait, Balance, Incontinence) and additional tests of executive functions. Morphological signs were rated with the iNPH Radscale. Non-parametric statistics with Bonferroni corrections and a significance-level of p < 0.05 were used. RESULTS: Median (IQR) time to follow-up was 25 (23-26) months. Effect size (ES) for individuals who developed iNPH (n = 8) showed a large (ES r = -0.55) decline in the Gait domain and on the Radscale (ES r = -0.60), with a medium deterioration in declarative memory (ES r = -0.37). Those having iNPH at baseline (n = 12) performed worse on one executive sub-function i.e., shifting (p = 0.045). CONCLUSION: Besides deterioration in gait and radiology, our results suggest that a neuropsychological trajectory for those developing iNPH includes a reduction in declarative memory. Executive dysfunction was limited to those already having iNPH at baseline. These findings could suggest that memory impairments are included in the early development of iNPH.

Medical residents' and teachers' perceptions of the digital format of nation-wide didactic courses for psychiatry residents in Sweden: a survey-based observational study.

BACKGROUND: This study aimed to explore residents' and teachers' perceptions of the digital format of Metis (a national education network in Sweden) didactic courses for psychiatry residents in Sweden to guide post-pandemic curriculum development. METHODS: An online attitude survey was developed and sent out to 725 residents in psychiatry and 237 course directors/teachers. Data were examined descriptively and group differences were analysed with independent sample t-tests. RESULTS: The survey was completed by 112 residents and 72 course directors/teachers. Perceptions of digital formats were quite similar between the two groups with some significant differences i.e., residents agreed more strongly than directors/teachers with the statement that Metis courses in digital format were of the same quality (or better) than the classroom-based format. Residents perceived the positive effects of using interactive tools more than directors/teachers. More than 40% of the responders in both groups preferred a return to classroom-based course meetings. Responders in both groups suggested that different forms of digital elements (e.g., video-based and sound-recorded lectures, digital-group discussions, virtual patients) could be incorporated into different phases in the courses. CONCLUSIONS: The study represents the current largest survey among residents in psychiatry and a teaching faculty in Sweden, to understand the impact of digitalization on the quality of residents' education during the pandemic. The results point towards applying a mixed format for training and education going forward, incorporating digital aspects into the national curriculum.

Serious adverse drug events associated with psychotropic treatment of bipolar or schizoaffective disorder: a 17-year follow-up on the LiSIE retrospective cohort study.

Introduction: Mood stabilisers and other psychotropic drugs can lead to serious adverse drug events (ADEs). However, the incidence remains unknown. We aimed to (a) determine the incidence of serious ADEs in patients with bipolar or schizoaffective disorders, (b) explore the role of lithium exposure, and (c) describe the aetiology. Methods: This study is part of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. Between 2001 and 2017, patients in the Swedish region of Norrbotten, with a diagnosis of bipolar or schizoaffective disorder, were screened for serious ADEs to psychotropic drugs, having resulted in critical, post-anaesthesia, or intensive care. We determined the incidence rate of serious ADEs/1,000 person-years (PY). Results: In 1,521 patients, we identified 41 serious ADEs, yielding an incidence rate of 1.9 events per 1,000 PY. The incidence rate ratio (IRR) between ADEs with lithium present and causally implicated and ADEs without lithium exposure was significant at 2.59 (95% CI 1.20-5.51; p = 0.0094). The IRR of ADEs in patients <65 and ≥65 years was significant at 3.36 (95% CI 1.63-6.63; p = 0.0007). The most common ADEs were chronic lithium intoxication, oversedation, and cardiac/blood pressure-related events. Discussion: Serious ADEs related to treatment of bipolar (BD) or schizoaffective disorder (SZD) were uncommon but not rare. Older individuals were particularly at risk. The risk was higher in individuals exposed to lithium. Serum lithium concentration should always be checked when patients present with new or unclear somatic symptoms. However, severe ADEs also occurred with other mood stabilisers and other psychotropic drugs.

Dual-Task Performance in Older Adults With and Without Idiopathic Normal Pressure Hydrocephalus.

Two of the main features of idiopathic normal pressure hydrocephalus (iNPH) are disturbed gait and cognition. These features are typically investigated separately, but here we combined walking with a cognitive task to investigate if older adults with iNPH were more susceptible to dual-task interference on walking than those without iNPH. In total, 95 individuals from the general population participated in our study. Of these, 20 were classified as Possible iNPH (median [interquartile range, IQR] 80 years [75-82.5]) and 75 as Unlikely iNPH (74 years [72-78]). Conversation, 10-m walking, semantic and phonemic verbal fluency were performed either combined or independently. "Stopping walking while talking" was noted. Pairwise comparisons and multiple logistic regression analyses were used. We found that the Possible iNPH group was older, stopped walking more frequently during the conversation, and had a slower single-task pace. The dual-task pace was slower for both groups. Only single-task walking pace could predict Possible iNPH when adjusted for age. We could establish a dual-task cost on gait performance in this sample of older adults from the general population, but the cost was not exclusive for individuals with Possible iNPH. To further assess the value of dual-task testing in iNPH, including observations of stopping walking while talking, a study of a clinical iNPH material with more severe symptoms would be valuable.

Bipolar Disorder and Bone Mineral Density Z-Scores in Relation to Clinical Characteristics and Lithium Medication.

Bipolar disorder is associated with a long range of medical comorbidities, including migraine, diabetes, and cardiovascular disease. Bipolar disorder has also been associated with an increased risk of bone fractures. Osteoporosis is a reduction in bone mineral density, which leads to an increased risk for fragility fractures. Currently there is limited research on the association between bipolar disorder and osteoporosis. We aimed to study the association between high and low bone mineral density in relation to disease and treatment history in a sample of bipolar patients. We found that bipolar patients with high bone mineral density were more often on lithium medication, had a more active lifestyle and expressed lower current disease burden. Low mineral density was not associated with any of the addressed aspects of disease and treatment history. In conclusion our results support that patients on lithium treatment have higher bone mineral density; further studies are needed to address if lithium medication causes an increase in bone mineral density, and lowers the risk of bone fractures in bipolar disorder.

Effects of Toxic Lithium Levels on ECG-Findings from the LiSIE Retrospective Cohort Study.

(1) Background: Few studies have explored the impact of lithium intoxication on the heart. (2) Methods: We examined electrocardiogram (ECG) changes associated with lithium intoxication in the framework of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. We analysed ECGs before, during, and after intoxication. (3) Results: Of the 1136 patients included, 92 patients had experienced 112 episodes of lithium intoxication. For 55 episodes, there was an ECG available at the time; for 48 episodes, there was a reference ECG available before and/or after the lithium intoxication. Lithium intoxication led to a statistically significant decrease in heart rate from a mean 76 beats/min (SD 16.6) before intoxication to 73 beats/min (SD 17.1) during intoxication (p = 0.046). QTc correlated only weakly with lithium concentration (ρ = 0.329, p = 0.014). However, in 24% of lithium intoxication episodes, there were QT prolongations. In 54% of these, QTc exceeded 500 ms; patients with chronic intoxications being more affected. (4) Conclusions: Based on summary statistics, effects of lithium intoxication on HR and QTc seem mostly discrete and not clinically relevant. However, QT prolongation can carry a risk of becoming severe. Therefore, an ECG should always be taken in patients presenting with lithium intoxication.

Increased Risks of Death and Hospitalization in Influenza/Pneumonia and Sepsis for Individuals Affected by Psychotic Disorders, Bipolar Disorders, and Single Manic Episodes: A Retrospective Cross-Sectional Study.

Individuals with severe mental disorders (SMDs) such as psychotic disorders, bipolar disorders, and single manic episodes have increased mortality associated with COVID-19 infection. We set up a population-based study to examine whether individuals with SMD also had a higher risk of hospitalization and death from other infectious conditions. Anonymized and summarized data from multiple Swedish patient registers covering the entire Swedish population were supplied by the Swedish National Board of Health and Welfare. The frequencies of hospitalizations and deaths associated with influenza/pneumonia and sepsis in individuals with SMD were compared with the rest of the population during 2018-2019. Possible contributing comorbidities were also examined, of which diabetes, cardiovascular disease, chronic lung disease, and hypertension were chosen. A total of 7,780,727 individuals were included in the study; 97,034 (1.2%) cases with SMD and 7,683,693 (98.8%) controls. Individuals with SMD had increased risk of death associated with influenza/pneumonia (OR = 2.06, 95% CI [1.87-2.27]) and sepsis (OR = 1.61, 95% CI [1.38-1.89]). They also had an increased risk of hospitalization associated with influenza/pneumonia (OR = 2.12, 95% CI [2.03-2.20]) and sepsis (OR = 1.89, 95% CI [1.75-2.03]). Our results identify a need for further evaluation of whether these individuals should be included in prioritized risk groups for vaccination against infectious diseases other than COVID-19.

Death Associated With Coronavirus (COVID-19) Infection in Individuals With Severe Mental Disorders in Sweden During the Early Months of the Outbreak-An Exploratory Cross-Sectional Analysis of a Population-Based Register Study.

Background: Individuals with severe mental disorder (SMD) have a higher risk of somatic comorbidity and mortality than the rest of the population. We set up a population-based study to assess whether individuals with SMD had a higher risk of death associated with a COVID-19 infection (COVID-19 associated death) than individuals without SMD. Methods: Exploratory analysis with a cross-sectional design in the framework of a population-based register study covering the entire Swedish population. The Swedish Board for Health and Welfare (Socialstyrelsen) provided anonymized tabulated summary data for further analysis. We compared numbers of COVID-19 associated death in individuals with SMD (cases) and without SMD (controls). We calculated the odds ratio (OR) for the whole sample and by age group and four comorbidities, namely diabetes, cardiovascular disease, hypertension, chronic lung disease. Results: The sample comprised of 7,923,859 individuals, 103,999 with SMD and 7,819,860 controls. There were 130 (0.1%) COVID-19 associated deaths in the SMD group and 4,945 (0.06%) in the control group, corresponding to an OR of 1.98 (CI 1.66-2.35; p < 0.001). The odds were 4-fold for the age groups between 60 and 79 years and 1.5-fold for cardiovascular diseases. Individuals with SMD without any of the risk factors under study had 3-fold odds of COVID-19 associated death. Conclusion: Our preliminary results identify individuals with SMD as a further group at increased risk of COVID-19 associated death. In regard to comorbidities, future studies should explore the potential confounding or mediation role in the relationship between SMD and COVID-19 associated deaths.

Hyper- and hypocortisolism in bipolar disorder - A beneficial influence of lithium on the HPA-axis?

BACKGROUND: A hyperactive hypothalamic-pituitary-adrenal axis (HPA-axis) is a well-known phenomenon in bipolar disorder (BD). However, hypocortisolism has also been described and found associated with depression, low quality of life and cardiovascular risk factors in BD patients. Although the pathophysiology related to hypocortisolism in BD is largely unknown, hypocortisolism is associated with chronic stress exposure and after inducing an initial rise in cortisol long-term stress may result in a transition to hypocortisolism. BD patients are throughout life often exposed to chronic stress. We therefore hypothesized that higher age would be associated with lower HPA-axis activity especially among patients without previous mood stabilizing treatment. METHODS: This cross-sectional study consisted of 159 bipolar outpatients and 258 controls. A low-dose-dexamethasone-suppression-test (DST) was used to measure HPA-axis activity. RESULTS: Patients with BD showed a negative association between post DST cortisol and age (-3.0 nmol/l per year; p=0.007). This association gradually increased in subgroups that were naïve to lithium (-7.7 nmol/l per year; p=0.001) and "all mood stabilizers" (-11.4 nmol/l per year; p=0.004). Patients exhibiting hypercortisolism were characterized by younger age and female gender, whereas patients exhibiting hypocortisolism were characterized by long disease duration without prophylactic lithium treatment as well as absence of current lithium medication. LIMITATIONS: Cross sectional study design. CONCLUSIONS: There was a negative association between HPA-axis activity and age in BD, rendering BD patients at risk for developing hypocortisolism. This association was most pronounced among patients without previous or current lithium prophylaxis.

Relative hypocortisolism is associated with obesity and the metabolic syndrome in recurrent affective disorders.

BACKGROUND: Cardiovascular disease (CVD) is one of the main causes of excess deaths in affective disorders. Affective disorders are associated with increased frequencies of CVD risk-factors such as obesity, dyslipidemia, and metabolic syndrome. Stress-induced chronic cortisol excess has been suggested to promote obesity and metabolic syndrome. Chronic stress with frequent or persisting hypothalamic-pituitary-adrenal-axis (HPA-axis) hyperactivity may, over time, lead to a state of low HPA-axis activity, also denoted hypocortisolism. A low-dose weight-adjusted dexamethasone-suppression-test (DST) is considered to be a sensitive measure of hypocortisolism. METHODS: 245 patients with recurrent depression or bipolar disorder and 258 controls participated in a low-dose DST and were also examined with regard to metabolic status. RESULTS: Patients with hypocortisolism (low post-DST cortisol) compared with patients without hypocortisolism (normal or high post-DST cortisol) exhibited increased odds ratios (OR) for obesity (OR=4.0), overweight (OR=4.0), large waist (OR=2.7), high LDL (OR=4.2), low HDL (OR=2.4), high LDL/HDL ratio (OR=3.3), high TC/HDL ratio (OR=3.4) and metabolic syndrome (OR=2.0). A similar pattern but less pronounced was also found in the control sample. LIMITATIONS: The cross sectional study design and absence of analyses addressing lifestyle factors. CONCLUSIONS: Our findings suggest that a substantial portion of the metabolic disorders and cardiovascular risk factors seen in recurrent affective disorders are found among individuals exhibiting hypocortisolism. This might indicate that long-term stress is a central contributor to metabolic abnormalities and CVD mortality in recurrent affective disorders.

Association between gastrointestinal symptoms and affectivity in patients with bipolar disorder.

AIM: To study if anxiety, depression and experience of stress are associated with gastrointestinal (GI) symptoms in patients with bipolar disorder. METHODS: A total of 136 patients with bipolar disorder (mean age 49.9 years; 61% women) and 136 controls from the general population (mean age 51.0 years; 60% women) were included in the study. GI symptoms were assessed with The Gastrointestinal Symptom Rating Scale-irritable bowel syndrome (GSRS-IBS), level of anxiety and depression with The Hospital Anxiety and Depression Scale (HADS) and stress-proneness with Perceived Stress Questionnaire. Over a ten year period, all visits in primary care were retrospectively recorded in order to identify functional GI disorders. RESULTS: In subjects with low total HADS-score, there were no significant differences in GI-symptoms between patients and controls (GSRS-IBS 7.0 vs 6.5, P = 0.513). In the patients with bipolar disorder there were significant correlations between all GSRS and HADS subscores for all symptom clusters except for "constipation" and "reflux". Factors associated to GI symptoms in the patient group were female sex (adjusted OR = 2.37, 95%CI: 1.07-5.24) and high HADS-Depression score (adjusted OR = 3.64, 95%CI: 1.07-12.4). These patients had also significantly more visits for IBS than patients with low HADS-Depression scores (29% vs 8%, P = 0.008). However, there was no significant differences in consulting behaviour for functional GI disorders between patients and controls (25% vs 17%, P = 0.108). CONCLUSION: Female patients and patients with high HADS depression score reported significantly more GI symptoms, whereas patients with low HADS scores did not differ from control subjects.

Relative hypo- and hypercortisolism are both associated with depression and lower quality of life in bipolar disorder: a cross-sectional study.

BACKGROUND: Depression in unipolar and bipolar disorders is associated with hypothalamic-pituitary-adrenal-axis (HPA-axis) hyperactivity. Also, unipolar disorder has recently been shown to exhibit HPA-axis hypoactivity. We studied for the first time how HPA-axis hypo- and hyperactivity relate to depression and disease burden in bipolar disorder. We were interested in studying hypocortisolism; characterized by increased HPA-axis negative feedback sensitivity and lower basal cortisol levels together with the opposite HPA-axis regulatory pattern of hypercortisolism. METHODS: This cross-sectional study includes 145 type 1 and 2 bipolar outpatients and 145 matched controls. A dexamethasone-suppression-test (DST) measures the negative feedback sensitivity and a weight-adjusted very-low-dose DST was employed, which is sensitive in identifying hypocortisolism and hypercortisolism. The 25th and 75th percentiles of control post-DST values were used as cut-offs identifying patients exhibiting relative hypo-, and hypercortisolism. Self-report questionnaires were employed: Beck-Depression-Inventory (BDI), Montgomery-Åsberg-Depression-Rating-Scale (MADRS-S), World-Health-Organization-Quality-of-Life-Assessment-100 and Global-Assessment-of-Functioning. RESULTS: Patients exhibiting relative hypocortisolism expectedly exhibited lowered basal cortisol levels (p = 0.046). Patients exhibiting relative hypercortisolism expectedly exhibited elevated basal levels (p<0.001). Patients exhibiting relative hypocortisolism showed 1.9-2.0 (BDI, p = 0.017, MADRS-S, p = 0.37) and 6.0 (p<0.001) times increased frequencies of depression and low overall life quality compared with patients exhibiting mid post-DST values (eucortisolism). Adjusted Odds Ratios (OR:s) for depression ranged from 3.8-4.1 (BDI, p = 0.006, MADRS-S, p = 0.011) and was 23.4 (p<0.001) for life quality. Patients exhibiting relative hypercortisolism showed 1.9-2.4 (BDI, p = 0.017, MADRS-S, p = 0.003) and 4.7 (p<0.001) times higher frequencies of depression and low overall life quality compared with patients exhibiting eucortisolism. Adjusted OR:s for depression ranged from 2.2-2.7 (BDI, p = 0.068, MADRS-S, p = 0.045) and was 6.3 (p = 0.008) for life quality. LIMITATIONS: The cross-sectional design and lack of pre-established reference values of the DST employed. CONCLUSIONS: Relative hypocortisolism and relative hypercortisolism were associated with depression and lower life quality, providing novel insights into the detrimental role of stress in bipolar disorder.

Short telomeres in depression and the general population are associated with a hypocortisolemic state.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls. METHODS: Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires. RESULTS: TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, short TL was associated with a hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control subjects but more pronounced among patients. This state, which was overrepresented among patients, was characterized by high familial loading of affective disorders among patients (p = .001) and high C-reactive protein levels among control subjects (p = .040). TL was also inversely associated with stress measured with the Perceived Stress Questionnaire (r(s) = -.258, p = .003). CONCLUSIONS: Short TL is associated with depression and hypocortisolism. Because hypocortisolism has been shown to develop from chronic stress exposure, our findings corroborate the concept of TL as a cumulative measure of stress and provide novel insights into the detrimental role of stress in depressive illness and the general population.