Acta Psychiatrica Scandinavica最新文献

Aims: Both inflammation and smoking are known to affect clozapine metabolism. However, the impact of inflammation on clozapine metabolism in relation to smoking status is unclear. Therefore, we investigated correlations between C-reactive protein (CRP) and clozapine levels in smokers and non-smokers separately.

Methods: Patients were included retrospectively from a therapeutic drug monitoring (TDM) service in Oslo, Norway, during January 2005-April 2022. Inclusion criteria were known smoking status and CRP measurements no longer than 7 days before or after clozapine TDM. Exclusion criteria were confirmed blood sampling for TDM outside 10-30 h after the last clozapine intake. Information about clozapine dosing was retrieved from the requisition forms.

Results: In 126 patients fulfilling the criteria (47% smokers), dose-adjusted serum concentration (CD) of clozapine correlated significantly with CRP in non-smokers (R = 0.492; p < 001) but not in smokers (R = 0.191; p = 0.166). When subgrouping non-smoking patients into low CRP (< 5 mg/L; reference [51% of the population]), mid CRP (5-50 [37%]) and high CRP (> 50 [12%]), clozapine CD gradually increased in mid- (+48%, p = 0.004) and high-CRP groups (+204%, p < 0.001) compared with the low-CRP group. No significant differences in clozapine CD were found between CRP groups among smokers (p > 0.15).

Conclusions: We report a significant correlation between CD of clozapine and CRP levels in non-smoking patients only. In these patients, clozapine CD is more than 3-fold higher at CRP > 50 versus CRP < 5. This suggests that non-smokers are most susceptible to clozapine side effects during inflammation or infection and represent patients where TDM analyses are especially important for guiding clozapine dosing.

Background: Mental disorders are associated with excess risk of death from unnatural and natural causes, but few studies have differentiated causes of death among patients with major depression. We examined cumulative and relative risks of all-cause and cause-specific mortality in individuals with major depression up to 50 years after diagnosis according to sex, age, and time since depression diagnosis.

Methods: In this nationwide matched-cohort study, we included individuals diagnosed with major depression in Danish National Patient registries from 1970 through 2021 and a 1:5 matched sample of the general population (reference population). Individuals were followed for their underlying cause of death in the Danish Cause of Death Registry up to 2022, and we estimated cumulative risk and hazard ratios for all-cause and 10 specific causes of death.

Results: The study included 330,577 adults diagnosed with major depression in Denmark (median age at first diagnosis, 45 years; 63.4%women) and 1,652,885 members of the matched reference population (median age, 45 years; 63.4%women). During the study period, 116,628 (35.2%) individuals with depression and 389,135 (23.5%) matches from the reference population died. Individuals with depression had considerably higher mortality risk at all time periods and ages compared to the reference population, and the increased risk was most pronounced in the first year after diagnosis. The lifetime risk of suicide was 11.2% in individuals with depression compared with 1% in the reference population, and before age 65 years, suicide was the leading cause of death in patients with depression. When compared with the reference population, individuals with depression also exhibited a higher risk of various specific natural causes of death before the age of 85 years.

Conclusions: The risk of death from suicide and medical disorders is elevated in individuals with depression, especially the first year after diagnosis. Because a large number of deaths can be attributed to depression shortly after onset, clinicians should be aware of this risk.

Background: Metformin shows potential in combating clozapine-induced weight gain (CIWG). However, current evidence for its use remains limited. Through an audit we determined the prevalence of metformin use among clozapine-treated patients and its impact on weight and waist circumference (WC).

Methods: This retrospective cohort study examined electronic medical records of community-based clozapine patients under the care of metropolitan community mental health teams within the Central Adelaide Local Health Network (CALHN) from January 2014 to June 2023. We included patients treated with clozapine both with and without metformin, above 18 years of age, with complete physical monitoring data at baseline, 6, and 12 months.

Results: There were 357 patients, who met study criteria. Metformin was prescribed to 23% of patients, of whom 78% had diabetes. At baseline, WC was > 101 cm in 71% of males and > 87 cm in 86% of females, placing them at increased risk of weight-related comorbidities, including cardiovascular disease, cancer, and death. After 1 year, males and females in the highest risk group for WC-related comorbidities increased to 76.3% and 95.4%, respectively. Co-prescription of metformin with clozapine was associated with unadjusted mean weight loss (-1.67 kg) and decrease in WC (-1.00 cm). Patients not using metformin gained weight (0.68 kg) and WC (2.49 cm). Using a linear mixed-effects models adjusting for repeated measurements, age, sex, and type 2 diabetes, over 12 months, patients treated with metformin were 3.08 kg lighter than those not taking metformin (95% confidence interval [CI]: 0.54-5.62, p = 0.018). Similar models suggested patients treated with metformin showed an average 2.83 cm decrease in WC compared with those not taking metformin (CI: 0.26-5.40, p = 0.03). There was no significant interaction between difference from baseline in weight or WC and metformin dose (p > 0.05).

Discussion/conclusion: The prevalence of metformin use for CIWG appears low in this cohort, where over 84% of patients were overweight or obese. Metformin use was associated with a significantly lower incidence of weight and WC gain over 12 months. Pharmacists are crucial for educating clinicians and patients about the benefits of metformin for reducing CIWG.

Objectives: Recurrent [hypo]mania without major depressive episodes ("unipolar mania" [UPM]) is an uncommon form of major affective disorder related to bipolar disorder (BD). We characterized UPM patients and estimated the prevalence of their characteristics based on prolonged times-at-risk.

Methods: Using standard bivariate and multivariate statistics, we compared the characteristics of 63 consecutive UPM patients to 1210 other BD patients over prolonged, close, prospective follow-up at expert mood disorder centers.

Results: UPM was uncommon (4.95% of 1273 BD cases during 18.2 years at risk) with a 2.5-fold excess of men and 93.4% considered type I BD. UPM cases had earlier initial clinical interventions than other BD patients, more psychotic features with first episodes, and fewer UPM patients were married but did not have fewer children and were more unemployed. UPM cases experienced more morbidity (episodes and hospitalizations/year and %-time ill) than other BD patients and made more follow-up clinic visits/year. They were less likely to be suicidal and had less general medical comorbidity but did not differ in substance abuse. They had lower ratings of depressive symptoms, used mood stabilizers more, and as expected, received antidepressants 27 times less than other BD patients. Observed rates of UPM declined with longer observation times.

Conclusions: UPM was uncommon (4.95% of BD cases; 0.31% with hypomania only). Compared to ordinary BD, UPM had significantly greater morbidity and unemployment but a lower risk of suicidal behavior or general medical disorders associated with bipolar depression. This unusual disorder needs greater recognition, clarification of its nosological status, and efforts to optimize its treatment.

Introduction: Gestational exposure to valproate has been associated with a wide range of adverse pregnancy outcomes, including major congenital malformations in offspring. However, to date, no meta-analysis has comprehensively examined the risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children gestationally exposed to valproate.

Methods: We searched MEDLINE, Embase, and Scopus from inception until 15 May 2024 for relevant English-language articles. Primary outcomes of interest were the risk of ASD and ADHD, two independent primary outcomes, in children exposed to valproate anytime during pregnancy relative to unexposed children. Secondary outcomes were trimester-wise analyses of risk. We used a random effects model to pool the overall and trimester-wise hazard ratios (HRs) and obtained 95% confidence intervals (CIs), separately for the risks of ASD and ADHD. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist.

Results: Eight cohort studies (pooled N = 6,033,300) met our search criteria. Anytime gestational exposure to valproate was associated with a large increase in the risk of ASD (adjusted HR [aHR], 3.10; 95% confidence interval [CI], 2.24-4.28; N = 1,841,198) and a modest increase in the risk of ADHD (aHR, 1.62; 95% CI, 1.30-2.01; N = 24,295). The findings in sensitivity analyses for both outcomes were generally consistent with those of the main analyses. Notably, anytime gestational exposure to high-dose valproate (> 1.0 to 1.1 g/day) was associated with a substantially elevated risk of ASD (aHR, 6.32; 95% CI, 3.12-12.80, N = 1,719,825). Likewise, in monotherapy (aHR, 4.21; 95% CI, 2.97-5.95; N = 1,745,253) and discordant sibling pair (aHR, 6.42; 95% CI, 2.02-20.42; N = 1133) analyses, the risk of ASD was substantially elevated.

Conclusion: Gestational exposure to valproate was associated with an increased risk of ASD and ADHD; the risks for ASD were greater at doses ≥ 1000 mg/day. These findings add to the literature that strongly discourages the use of valproate by women of childbearing age, especially during pregnancy.

Introduction: Depressive disorders are a leading cause of global disease burden, particularly with the challenge of treatment-resistant depression (TRD). Research points to a complex bidirectional relationship between cardiovascular (CV) risk factors and TRD, with CV risk negatively impacting brain structure and potentially influencing antidepressant resistance. Moreover, the association between depression and the genetic vulnerability to cardiovascular disease suggests a shared pathophysiological process between the two. This study investigates the mediating role of brain structural alterations in the relationship between CV and cerebrovascular (CeV) risk and treatment resistance in depression.

Methods: We assessed 165 inpatients with Major depressive disorder. Each patient's CV risk was assessed via the QRISK 3 calculator. For a subset of patients, CV and CeV disease polygenic risk scores (PRS) were obtained. All patients underwent a 3 T MRI scan, and white matter hyperintensities estimates and indicators of brain trophic state were obtained.

Results: Both CV risk and CV disease PRSs are associated with treatment resistance status, white matter hyperintensities, and indicators of brain atrophy. Mediation analyses suggested that CV-induced brain alterations might underlie the relation between CV genetic and phenotypic risk and antidepressant treatment resistance.

Conclusion: These results underscore the need to explore cardiovascular risk management as part of treatment strategies for depression, pointing toward a shared pathophysiological process linking heart and brain health in treatment-resistant depression.

Introduction: Changes in psychotropic drug use relative to suicidal behavior could potentially inform the timing of preventive efforts. We aimed to describe the initiation and discontinuation of psychotropic drugs relative to suicide and suicide attempts.

Methods: The Danish registries were used to describe incidents and prevalent use of psychotropic drugs 2 years before and after a suicide attempt and before suicide. Discontinuation of psychotropic drugs in the 6-month period prior to suicide and suicide attempts was estimated. Analyses were stratified by drug groups, sex, and age.

Results: Among 5.8 million Danish citizens(2021), 6374 died by suicide, and 29,332 had a first-ever suicide attempt from 2010 to 2021. Use of psychotropic drugs increased markedly in the 6 months prior to suicide and suicide attempt, e.g., up to 18 incident drug redemptions and 92 prevalent drug redemptions per 100 persons in the month before suicide. The highest rates of both incident and prevalent drug redemptions were observed immediately after the suicide attempt. Psychotropic drug use was generally lower among men. Immediately after the suicide attempt, however, men exhibited a slightly higher level of incident use than women. Ten percent discontinued psychotropic drugs completely in the 6-month period before suicide, while 48% discontinued drugs used in alcohol abuse.

Conclusion: We found a marked increase in psychotropic drug use before suicide and before and after attempted suicide. Complete pre-attempt discontinuation of psychotropic drugs was low, though approximately half discontinued drugs used for alcohol abuse. The process of prescribing psychotropic drugs may represent an opportunity for prevention.

Introduction: Patients with mood disorders, especially, major depressive disorder (MDD) and bipolar disorder (BD), are at heightened risk of relapse and psychiatric rehospitalizations. Therefore, there is an urgent need to identify modifiable biomarkers to inform personalized and intensified prevention strategies for those at the greatest risk of relapse and hospital readmissions. Brain structural measures subserving cognitive function hold particular promise among potential predictive biomarkers.

Methods: In the present study, structural magnetic resonance imaging scans were obtained from 319 patients with MDD (n = 241) or BD (n = 78). Longitudinal data on psychiatric hospitalization for up to 10 years were available from the Danish National population-based registers. Interhemispheric hippocampal asymmetry, a putative marker of cognitive function and brain reserve, was calculated for each patient. The association between hippocampal asymmetry and future psychiatric hospitalization was assessed using a cause-specific Cox regression model. Exploratory analyses, also using a cause-specific Cox model, assessed the association of prefrontal and hippocampal gray matter volume and whole-brain white matter volume with hospitalizations.

Results: The results indicated a negative association between rightward hippocampal asymmetry (i.e., left

Conclusion: The findings suggest a role for hippocampal and, additionally, prefrontal morphological features in the risk of future psychiatric hospitalizations in mood disorders.