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.

Kidney function in patients with bipolar disorder with and without lithium treatment compared with the general population in northern Sweden: results from the LiSIE and MONICA cohorts.

BACKGROUND: The clinical relevance of lithium nephropathy is subject to debate. Kidney function decreases with age and comorbidities, and this decline might lead to attribution bias when erroneously ascribed to lithium. We aimed to investigate whether patients with bipolar or schizoaffective disorder had faster decline in estimated glomerular filtration rate (eGFR) compared with the general population, whether observed differences in the steepness of the decline were attributable to lithium, and whether such changes depended on the length of lithium exposure. METHODS: In this cross-sectional cohort study, we used clinical data from the Lithium-Study into Effects and Side-effects (LiSIE) retrospective cohort study, which included patients with bipolar disorder or schizoaffective disorder whose medical records were reviewed up to Dec 31, 2017, and the WHO Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, covering a representative sample of the general population in northern Sweden aged 25-74 years. The primary outcome was the age-associated decline of creatinine-based eGFR, assessed using linear regression. We adjusted for sex and grouped for different lengths of lithium exposure (never or <1 year, 1-5 years, >5-10 years, and >10 years). For patients with moderate-to-severe kidney disease we identified the underlying nephropathy in the case records. FINDINGS: From LiSIE, we included 785 patients (498 [63%] female and 287 [37%] male), with a mean age of 49·8 years (SD 13·2; range 25-74). From MONICA, we included 1549 individuals (800 [52%] female and 749 [48%] male), with a mean age of 51·9 years (13·8; 25-74). No ethnicity data were collected. Adjusted for duration of lithium exposure, eGFR declined by 0·57 mL/min/1·73 m2/year (95% CI 0·50-0·63) in patients with bipolar disorder or schizoaffective disorder and by 0·57 mL/min/1·73 m2/year (0·53-0·61) in the reference population. Lithium added 0·54 mL/min/1·73 m2 (0·43-0·64) per year of treatment (p<0·0001). After more than 10 years on lithium, decline was significantly steeper than in all other groups including the reference population (p<0·0001). Lithium nephropathy was judged to be the commonest cause of moderate-to-severe chronic kidney disease, but comorbidities played a role. The effect of lithium on eGFR showed a high degree of inter-individual variation. INTERPRETATION: Steeper eGFR decline in patients with bipolar disorder or schizoaffective disorder can be attributed to lithium, but the trajectory of kidney function decline varies widely. Comorbidities affecting kidneys should be treated assertively as one possible means to affect the trajectory. In patients with a fast trajectory, a trade-off is required between continuing lithium to treat mental health problems and discontinuing lithium for the sake of renal health. FUNDING: Norrbotten County Research and Learning Fund Sweden, Visare Norr (Northern County Councils Regional Federation Fund), Swedish Kidney Foundation (Njurfonden), Swedish Kidney Association (Njurförbundet), Norrbotten section. TRANSLATION: For the Swedish translation of the Summary see Supplementary Materials section.

Patterns of Thyroid Hormone Prescription in Patients with Bipolar or Schizoaffective Disorder: Findings from the LiSIE Retrospective Cohort Study.

The prescription of thyroid hormone replacement therapy (THRT) has increased in the general population; the thyroid stimulating hormone (TSH) threshold to initiate THRT has decreased. It remains unclear whether a similar trend has occurred in patients with bipolar disorder (BD). In this work we explore patterns and trends of prescribing THRT in patients with BD or schizoaffective disorder (SZD) with an observational study and time-trend analysis in the framework of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. In most patients, THRT was initiated for subclinical hypothyroidism. The median TSH at which THRT was started was 6.0 (IQR 4.0) mIU/L and the median free serum thyroxine (fT4) at which THRT was started was 11.8 (IQR 3.9) pmol/L. The median TSH concentration at the start of THRT decreased annually with 0.10 mIU/L (p = 0.047) and was higher in patients treated with lithium than in patients treated with other mood stabilisers (p = 0.02). In conclusion, THRT was typically initiated in the context of mild or absent alterations of thyroid function tests with a decreasing TSH threshold. As THRT is rarely reversed once initiated, clinicians need to weigh up potential benefits and risks when prescribing THRT for subclinical hypothyroidism in patients with BD or SZD.

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.

Suicidal and non-suicidal self-injurious behaviour in patients with bipolar disorder and comorbid attention deficit hyperactivity disorder after initiation of central stimulant treatment: a mirror-image study based on the LiSIE retrospective cohort.

BACKGROUND: Currently, our understanding regarding treatment of adult attention deficit hyperactivity disorder (ADHD) co-occurring with bipolar disorder (BD) remains limited. The aim of this study was to evaluate the impact of central stimulant (CS) treatment on suicidal and non-suicidal self-injurious behaviour in patients with a pre-existing diagnosis of BD or schizoaffective disorder (SZD). Specifically, we tested the hypothesis that CS treatment significantly decreased the number of suicide attempts and non-suicidal self-injury events. METHODS: A mirror-image study in patients with a dual diagnosis of BD or SZD and ADHD, comparing suicide attempts and non-suicidal self-injury events within 6 months and 2 years before and after CS initiation. This study was part of a retrospective cohort study (LiSIE) into effects and side-effects of lithium for maintenance treatment of BD as compared with other mood stabilisers. RESULTS: Of 1564 eligible patients, 206 patients met the inclusion criteria. Within the 6 months after CS initiation, suicide attempts and non-suicidal self-injury events decreased significantly, both in terms of numbers of patients having such events (p = 0.013) and numbers of events experienced (p = 0.004). These effects were preserved 2 years after CS initiation. CONCLUSIONS: CS treatment may reduce the risk of suicide attempts and non-suicidal self-injury events in patients with a dual diagnosis of BD or SZD and ADHD. Based on our findings, clinicians should not withhold CS treatment from patients with concomitant ADHD for fear of deterioration of the underlying BD. However, to minimise the risk of manic episodes concomitant mood stabiliser treatment and close monitoring remains warranted.

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.

Lithium-associated hypothyroidism and potential for reversibility after lithium discontinuation: Findings from the LiSIE retrospective cohort study.

BACKGROUND: The association between lithium and thyroid dysfunction has long been known. However, it remains unknown if lithium-associated hypothyroidism is reversible once lithium treatment has been stopped. AIMS: To determine whether lithium-associated hypothyroidism was reversible in patients who subsequently discontinued lithium. METHODS: A retrospective cohort study in the Swedish region of Norrbotten into the effects and side- effects of lithium treatment and other drugs for relapse prevention (Lithium - Study into Effects and Side Effects). For this particular study, we reviewed medical records between 1997 and 2015 of patients with lithium-associated hypothyroidism who had discontinued lithium. RESULTS: Of 1340 patients screened, 90 were included. Of these, 27% had overt hypothyroidism at the start of thyroid replacement therapy. The mean delay from starting lithium to starting thyroid replacement therapy was 2.3 years (SD 4.7). In total, 50% of patients received thyroid replacement therapy within 10 months of starting lithium. Of 85 patients available for follow-up, 41% stopped thyroid replacement therapy after lithium discontinuation. Only six patients reinstated thyroid replacement therapy subsequently. Of these, only one had overt hypothyroidism. CONCLUSIONS: Lithium-associated hypothyroidism seems reversible in most patients once lithium has been discontinued. In such cases, thyroid replacement therapy discontinuation could be attempted much more often than currently done. Based on the limited evidence of our study, we can expect hypothyroidism to recur early after thyroid replacement therapy discontinuation, if at all.

Clinical course and need for hospital admission after lithium discontinuation in patients with bipolar disorder type I or II: mirror-image study based on the LiSIE retrospective cohort.

BACKGROUND: Currently, the evidence for lithium as a maintenance treatment for bipolar disorder type II (BD-II) remains limited. Guidelines commonly extrapolate recommendations for BD-II from available evidence for bipolar disorder type I (BD-I). Comparing the impact of lithium discontinuation is one way of assessing effectiveness in both groups. AIMS: To compare the impact of lithium discontinuation on hospital admissions and self-harm in patients with BD-I or schizoaffective disorder (SZD) and patients with BD-II or other bipolar disorder. METHOD: Mirror-image study, examining hospital admissions within 2 years before and after lithium discontinuation in both patient groups. This study was part of a retrospective cohort study (LiSIE) into effects and side-effects of lithium for maintenance treatment of bipolar disorder as compared with other mood stabilisers. RESULTS: For the whole sample, the mean number of admissions/patient/review period doubled from 0.44 to 0.95 (P<0.001) after lithium discontinuation. The mean number of bed days/patient/review period doubled from 11 to 22 (P = 0.025). This increase in admissions and bed days was exclusively attributable to patients with BD-I/SZD. Not having consulted with a doctor prior to lithium discontinuation or no treatment with an alternative mood stabiliser at the time of lithium discontinuation led to more admissions. CONCLUSIONS: The higher relapse risk in patients with BD-I/SZD suggests a higher threshold for discontinuing lithium than for patients with BD-II/other bipolar disorder. In patients with BD-II/other bipolar disorder, however, judged on the impact of discontinuation alone, lithium did not appear to prevent more severe depressive episodes requiring hospital admission.

Correction to: Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study.

Following publication of the original article [1], the authors reported an error in Fig. 1 and Table 1, concerning the number of female participants. The correct number is 283, instead of 238 that was originally published.

Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study.

BACKGROUND: Lithium remains first choice as maintenance treatment for bipolar affective disorder. Yet, about half of all individuals may stop their treatment at some point, despite lithium's proven benefits concerning the prevention of severe affective episodes and suicide. METHODS: Retrospective cohort study in the Swedish region of Norrbotten into the causes of lithium discontinuation. The study was set up to (1) test whether patients with bipolar affective disorder or schizoaffective disorder, treated with lithium maintenance therapy, were more likely to discontinue lithium because of adverse effects than lack of therapeutic effectiveness, (2) explore gender differences, (3) understand the role of diagnosis and (4) identify who, patient or doctor, took the initiative to stop lithium. Review of medical records for all episodes of lithium discontinuation that had occurred between 1997 and 2013 with the intent to stop lithium for good. RESULTS: Of 873 patients treated with lithium, 54% discontinued lithium, corresponding to 561 episodes of lithium discontinuation. In 62% of episodes, lithium was discontinued due to adverse effects, in 44% due to psychiatric reasons, and in 12% due to physical reasons interfering with lithium treatment. The five single most common adverse effects leading to lithium discontinuation were diarrhoea (13%), tremor (11%), polyuria/polydipsia/diabetes insipidus (9%), creatinine increase (9%) and weight gain (7%). Women were as likely as men to take the initiative to stop lithium, but twice as likely to consult a doctor before taking action (p < 0.01). Patients with type 1 BPAD or SZD were more likely to discontinue lithium than patients with type 2 or unspecified BPAD (p < 0.01). Patients with type 1 BPAD or SZD were more likely to refuse medication (p < 0.01). Conversely, patients with type 2 or unspecified BPAD were three times as likely to discontinue lithium for lack or perceived lack of effectiveness (p < 0.001). CONCLUSIONS: Stopping lithium treatment is common and occurs mostly due to adverse effects. It is important to discuss potential adverse effects with patients before initiation and continuously during lithium treatment, to reduce the frequency of potentially unnecessary discontinuations.