Tapio Paljärvi

Background: Despite uncertain benefits, antidepressants are used in the management of personality disorders (PDs). We investigated the association between antidepressants and two adverse outcomes - suicidal behaviour and violent crimes - in individuals with PDs. Methods: We used nationwide Danish healthcare registries to identify all individuals with a diagnosed PD aged 18–64 years from 2007 to 2016. Antidepressant use was identified using dispensed prescriptions. Individuals were followed up for healthcare presentations of suicidal behaviour and separately for police-recorded charges of violent crimes. We applied a within-individual design comparing rates of suicidal behaviour and violent crimes during time periods of antidepressant treatment with periods without treatment. Subgroup analyses were performed according to PD clusters, individual antidepressants, specific PDs, psychiatric comorbidities, and history of suicidal behaviour and violent crime. Results: The cohort included 167,319 individuals with a diagnosed PD, 19,519 (12%) of whom were prescribed antidepressants and presented at least one outcome event during follow-up, making them eligible for within-individual analyses. Overall, we found an association with lower rates of suicidal behavior during periods of antidepressant treatment, compared with periods when individuals were not on antidepressants (incidence rate ratio 0.86, 95% CI 0.84–0.89). However, this association was modified by specific PDs, individual antidepressants, comorbidities, and past history. For violent crimes, we did not observe consistent associations in any direction. Conclusions: Antidepressants were associated with lower rates of suicidal behaviour, but less clearly in violent crimes. Types of PDs, individual antidepressants, and comorbidities modified these associations.

Background The evidence base on montelukast-associated adverse outcomes is inconclusive in children and young persons (CYP) with asthma. We aimed to investigate 1-year incidence of neuropsychiatric diagnoses after initiation of montelukast as an adjunct therapy to inhaled corticosteroids (ICSs) in CYP aged 3–17 years with asthma. Methods This propensity score matched cohort study was conducted using electronic health records between 2015 and 2019 in the TriNetX Analytics Network patient repository in the USA. Neuropsychiatric diagnoses were identified using the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. We estimated risk ratios (RRs), absolute risk increase (ARI) and number needed to harm (NNH) with 95% CIs. Findings The mean age (SD) at index prescription in the 107 384 CYP with asthma was 8.7 (4.0) years (93 461 (87%) mild to moderate asthma; 62 301 (58%) male; 53 485 (50%) white; 33 107 (31%) black/African American). Montelukast was associated with excess incidence of any neuropsychiatric outcome (71 per 1000 persons with montelukast and 54 per 1000 persons with no montelukast; RR 1.32 (95% CI 1.25 to 1.39); ARI per 100 persons, 1.71 (95% CI 1.44 to 1.98); 1-year NNH, 58 patients (95% CI 51 to 69)). The highest excess risk in the montelukast group was for sleep disorders (RR 1.63 (95% CI 1.50 to 1.77); ARI per 100 persons 1.17 (95% CI 1.00 to 1.33); NNH, 85 patients (95% CI 75 to 100)). Montelukast use was also associated with excess incidence of anxiety disorders (RR 1.16 (95% CI 1.08 to 1.24)) and mood disorders (RR 1.16 (95% CI 1.05 to 1.29)). Conclusions In CYP with asthma who were treated with ICSs, adjunct treatment with montelukast was associated with a higher incidence of neuropsychiatric outcomes compared with those who were not exposed to montelukast.

Background: Limited evidence base on cause‐specific excess cardiovascular disease (CVD) mortality in bipolar disorder (BD) is a barrier to developing preventive interventions aimed at reducing the persistent mortality gap in BD.Objective: To investigate cause‐specific CVD mortality in BD.Methods: We identified all individuals aged 15+ years during 2004–2018 with a diagnosis of BD using Finnish nationwide routine data. Standardised mortality ratios (SMR) with 95% confidence intervals (CI) were calculated using the mortality rates in the general population as weights.Results: 53,273 individuals with BD (57% women; median age at BD diagnosis, 40 years), were followed up for 428,426 person‐years (median, 8.2 years). There were 5988 deaths due to any cause, of which 26% were due to CVD. The leading cause of absolute excess CVD mortality was coronary artery disease (CAD). The leading causes of relative excess mortality were cardiomegaly (SMR, 4.51; 95% CI, 3.58–5.43), venous thromboembolism (3.03; 2.26–3.81), cardiomyopathy (2.46; 1.95–2.97), and hypertensive heart disease (2.12; 1.71–2.54). The leading causes of absolute CVD mortality showed markedly lower relative excess, including CAD (1.47; 1.34–1.61), ischaemic stroke (1.31; 1.06–1.54), and acute myocardial infarction (1.12; 0.98–1.25). Due to the higher relative excess mortality, structural and functional heart disorders contributed as much as atherosclerotic and ischaemic disorders to the absolute excess mortality.Conclusions: Cardiomyopathy and hypertensive heart disease as the leading causes of relative excess mortality emphasise the contribution of structural and functional heart disorders to the overall excess mortality alongside coronary artery disease. Interventions targeted at these modifiable causes of death should be priorities in the prevention of premature excess CVD mortality in BD.

Background: Pharmacological treatment patterns for bipolar disorder have changed during recent years, but for better or worse?Aims: To investigate the comparative real-world effectiveness of antipsychotics and mood stabilisers in bipolar disorder.Method: Register-based cohort study including all Finnish residents aged 16–65 with a diagnosis of bipolar disorder from in-patient care, specialised out-patient care, sickness absence and disability pensions registers between 1996 and 2018, with a mean follow-up of 9.3 years (s.d. = 6.4). Antipsychotic and mood stabiliser use was modelled using the PRE2DUP method and risk for hospital admission for psychiatric and non-psychiatric reasons when using versus not using medications was estimated using within-individual Cox models.Results: Among 60 045 individuals (56.4% female; mean age 41.7 years, s.d. = 15.8), the five medications associated with lowest risk of psychiatric admissions were olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37–0.80), haloperidol LAI (aHR = 0.62, 0.47–0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52–0.85), lithium (aHR = 0.74, 95% CI 0.71–0.76) and clozapine (aHR = 0.75, 95% CI 0.64–0.87). Only ziprasidone (aHR = 1.26, 95% CI 1.07–1.49) was associated with a statistically higher risk. For non-psychiatric (somatic) admissions, only lithium (aHR = 0.77, 95% CI 0.74–0.81) and carbamazepine (aHR = 0.91, 95% CI 0.85–0.97) were associated with significantly reduced risk, whereas pregabalin, gabapentin and several oral antipsychotics, including quetiapine, were associated with an increased risk. Results for a subcohort of first-episode patients (26 395 individuals, 54.9% female; mean age 38.2 years, s.d. = 13.0) were in line with those of the total cohort.Conclusions: Lithium and certain LAI antipsychotics were associated with lowest risks of psychiatric admission. Lithium was the only treatment associated with decreased risk of both psychiatric and somatic admissions.

Background Bipolar disorder (BD) is associated with increased mortality, but evidence on cause-specific mortality is limited. Objective To investigate cause-specific premature excess mortality in BD. Methods Finnish nationwide cohort study of individuals with and without a diagnosis of BD who were aged 15–64 years during 2004–2018. Standardised mortality ratios (SMRs) with 95% CIs were calculated for BD using the mortality rates in the Finnish general population without BD as weights. Causes of death were defined by the International Classification of Diseases, 10th revision codes. Findings Of the included 47 018 individuals with BD, 3300 (7%) died during follow-up. Individuals with BD had sixfold higher mortality due to external causes (SMR: 6.01, 95% CI: 5.68, 6.34) and twofold higher mortality due to somatic causes (SMR: 2.06, 95% CI: 1.97, 2.15). Of the deaths due to external causes, 83% (1061/1273) were excess deaths, whereas 51% (1043/2027) of the deaths due to somatic causes were excess. About twice the number of potential years of life were lost in excess due to external causes than due to somatic causes. Alcohol-related causes contributed more to excess mortality than deaths due to cardiovascular disease. Conclusion External causes of death contributed more to the mortality gap than somatic causes after controlling for age-specific background general population mortality. Clinical implication A balanced consideration between therapeutic response, different treatment options and risk of cause-specific mortality is needed to prevent premature mortality in BD and to reduce the mortality gap.

Background: Evidence on the role of co-occurring psychiatric disorders in mortality associated with psychotic depression is limited.Aims: To estimate the risk of cause-specific mortality in psychotic depression compared with severe non-psychotic depression while controlling for comorbid psychiatric disorders.Method: This cohort study used routine data from nationwide health registers in Finland. Eligible participants had their first diagnosis for psychotic depression or for severe non-psychotic depression between the years 2000 and 2018, had no pre-existing diagnoses for schizophrenia spectrum disorders or bipolar disorder, and were aged 18–65 years at the index diagnosis. Causes of death were defined by ICD-10 codes. The follow-up time was up to 18 years.Results: We included 19 064 individuals with incident psychotic depression and 90 877 individuals with incident non-psychotic depression. Half (1199/2188) of the deaths in those with psychotic depression occurred within 5 years from the index diagnosis and the highest relative risk was during the first year after the diagnosis. Compared with individuals with non-psychotic depression, those with psychotic depression had a higher risk of all-cause mortality (adjusted hazard ratio, aHR = 1.59, 95% CI 1.48–1.70), suicides (aHR = 2.36, 95% CI 2.11–2.64) and fatal accidents (aHR 1.63, 95% CI 1.26–2.10) during the subsequent 5-year period after the index diagnosis.Conclusions: Psychotic symptoms markedly added to the mortality risk associated with severe depression after controlling for psychiatric comorbidity. Prompt treatment and enhanced monitoring for psychotic symptoms is warranted in all patients with severe depression to prevent deaths because of suicides and other external causes.

Background Severe neuropsychiatric outcomes have been reported in individuals exposed to isotretinoin, but the evidence is inconclusive and complicated by several methodological limitations. Objectives To establish and quantify the association between isotretinoin and one-year incident neuropsychiatric adverse outcomes. Methods Propensity score matched cohort study of electronic medical records between years 2013 and 2019 with patients followed up for one year after their index dispensed prescription. Over 12 million patients aged 12 to 27 years from 56 healthcare organizations. Patients aged 12 to 27 years with a dispensed prescription for isotretinoin or control prescription. International Classification of Diseases Clinical Modification 10^th revision diagnoses of any incident sleep or mental health disorder, or non-fatal self-harm within one year of the index prescription. Odds ratios (OR) with 95% confidence intervals (95%CI). Results We included 30866 acne patients in the isotretinoin cohort, 44748 patients in the oral antibiotics cohort, 108367 in the topical anti-acne agents cohort, and 78666 in the cohort of acne patients without anti-acne prescription medicines. After propensity score-matching for baseline confounders, the OR for any incident neuropsychiatric outcomes in acne patients exposed to isotretinoin was 0.80 (95%CI: 0.74 to 0.87) compared to acne patients with oral antibiotics, 0.94 (95%CI: 0.87 to 1.02) compared to acne patients with topical anti-acne medicines, and 1.06 (95%CI: 0.97 to 1.16) compared to acne patients without prescription anti-acne medicines. Patients exposed to isotretinoin experienced significantly more incident physical symptoms than patients in any of the three comparison cohorts. Conclusions Isotretinoin was not independently associated with excess adverse neuropsychiatric outcomes at the population level. In monitoring potential adverse outcomes during isotretinoin treatment, clinicians should also consider the high mental health burden associated with treatment-resistant acne and the potential contribution of physical side effects of the prescribed medication on mental health.