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Background: Long-term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking., Aims: To present systematic population-based nation-wide register data on comparative 2-year non-response within six antidepressant drug classes and 17 different antidepressants in patients with MDD., Method: The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non-response to first antidepressant within a 2-year study period was defined as switch to or add-on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders., Results: Compared with sertraline, there was no difference for citalopram (RR: 1.00 [95% CI: 0.98-1.02]) but fluoxetine (1.13 [95% CI: 1.10-1.17]), paroxetine (1.06 [95% CI: 1.01-1.10]) and escitalopram (1.22 [95% CI: 1.18-1.25]) were associated with higher risk ratio of non-responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin-norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non-response, whereas there was no difference for imipramine., Conclusions: These analyses emulating a randomized trial of "real world" observational register-based data show that 2-year long-term non-responses to some antidepressants within six different drug classes are increased over others., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Few studies have estimated the lifetime incidence of mental health disorders and the association with socioeconomic functioning., Objective: To investigate whether the lifetime incidence of treated mental health disorders is substantially higher than previously reported and estimate associations with long-term socioeconomic difficulties., Design, Setting, and Participants: This nationwide population-based register linkage study includes a randomly selected sample of 1.5 million individuals from the population of Denmark from 1995 to 2018. Data were analyzed from May 2022 to March 2023., Main Outcomes and Measures: Lifetime incidence of any treated mental health disorder in the general population was estimated from birth to age 100 years taking into account the competing risk of all-cause death and associations with socioeconomic functioning. Register measures were (1) from hospitals, a diagnosis of any mental health disorder at an inpatient/outpatient hospital contact; (2) from hospitals and prescription statistics, any mental health disorder/psychotropic prescription, including a hospital-contact diagnosis, or any psychotropic medication prescribed by physicians, including general practitioners or private psychiatrists; and (3) socioeconomic functioning as indicated by highest educational achievement, employment, income, residential status, and marital status., Results: Among a sample of 462 864 individuals with any mental health disorder, the median (IQR) age was 36.6 years (21.0-53.6 years), 233 747 (50.5%) were male, and 229 117 (49.5%) were female. Of these, 112 641 were registered with a hospital-contact mental health disorder diagnosis and 422 080 with a prescription of psychotropic medication. The cumulative incidence of a hospital-contact mental health disorder diagnosis was 29.0% (95% CI, 28.8-29.1), 31.8% (95% CI, 31.6-32.0) for females, and 26.1% (95% CI, 25.9-26.3) for males. When also considering psychotropic prescriptions, the cumulative incidence of any mental health disorder/psychotropic prescription was 82.6% (95% CI, 82.4-82.6), 87.5% (95% CI, 87.4-87.7) for females, and 76.7% (95% CI, 76.5-76.8) for males. Socioeconomic difficulties were associated with mental health disorder/psychotropic prescriptions, including lower income (hazard ratio [HR], 1.55; 95% CI, 1.53-1.56), increased unemployment or disability benefit (HR, 2.50; 95% CI, 2.47-2.53), and a greater likelihood of living alone (HR, 1.78; 95% CI, 1.76-1.80) and being unmarried (HR, 2.02; 95% CI, 2.01-2.04) during long-term follow-up. These rates were confirmed in 4 sensitivity analyses with the lowest being 74.8% (95% CI, 74.7-75.0) (1) by using varying exclusion periods, (2) by excluding prescriptions of anxiolytics and quetiapine that may be used for off-label indications, (3) by defining any mental health disorder/psychotropic prescription as any hospital-contact mental health disorder diagnosis or any psychotropic medication prescribed at least 2 times, and (4) by excluding individuals with somatic diagnoses for which psychotropics may be prescribed off-label., Conclusions and Relevance: This registry study of data from a large representative sample of the Danish population showed that the majority of individuals either received a diagnosis of a mental health disorder or were prescribed psychotropic medication during their lifetime, which was associated with subsequent socioeconomic difficulties. These findings may help change our understanding of normalcy and mental illness, reduce stigmatization, and further prompt rethinking the primary prevention of mental illness and future mental health clinical resources.

Background: Neurocognitive impairments are associated with poor clinical and employment outcomes in individuals with affective disorders. However, little is known about their associations with long-term clinical outcomes such as psychiatric hospitalizations, and with socio-demographic indicators other than employment. In the largest longitudinal study of neurocognition in affective disorders to date, we investigate the role of neurocognitive impairments on psychiatric hospitalizations and socio-demographic conditions., Methods: The study included 518 individuals with bipolar or major depressive disorder. Neurocognitive assessments covered executive function and verbal memory domains. Longitudinal data on psychiatric hospitalization and socio-demographic conditions (employment, cohabitation, and marital status) for up to 11 years were obtained using National population-based registers. The primary and secondary outcomes were psychiatric hospitalizations (n = 398) and worsening of socio-demographic conditions (n = 518), in the follow-up period since study inclusion, respectively. Cox regression models were used to examine the association of neurocognition with future psychiatric hospitalizations and the worsening of socio-demographic conditions., Findings: Clinically significant impairment in verbal memory (z-score ≤ -1; defined by the ISBD Cognition Task Force), but not in executive function, was associated with a higher risk of future hospitalization, when adjusted for age, sex, hospitalization in the year preceding inclusion, depression severity, diagnosis, and type of clinical trial (HR = 1.84, 95% CI:1.05-3.25, p = 0.034; n = 398). The results remained significant even after accounting for illness duration. Neurocognitive impairments were not associated with the worsening of socio-demographic conditions (p ≥ 0.17; n = 518)., Interpretation: Promoting neurocognitive function, especially verbal memory, may mitigate the risk of future psychiatric hospitalization in individuals with affective disorders., Funding: Lundbeckfonden (R279-2018-1145)., Competing Interests: Dr. Knudsen has received honoraria as expert advisor for Sage Therapeutics, and Sanos, and as expert supervisor for Onsero, and Gilgamesh. Dr. Frokjaer has served as consultant for SAGE therapeutics, H. Lundbeck and Janssen-Cilag. Dr. Miskowiak has received consultancy fees from Lundbeck, Janssen and Angelini Pharma in the past three years. All other authors declare no conflict of interest., (© 2023 The Authors.)

Background: Few studies have reported real-life data on socio-economic functioning in patients with bipolar disorder and their unaffected first-degree relatives., Methods: We used Danish nation-wide population-based longitudinal register linkage to investigate socio-economic functioning in 19 955 patients with bipolar disorder, their 13 923 siblings and 20 sex, age and calendar-matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Patients with a diagnosis of bipolar disorder had lower odds of having achieved the highest educational level [OR 0.75 (95% confidence interval (CI) 0.73-0.77)], being employed [OR 0.16 (95% CI 0.159-0.168)], having achieved the 80% highest quartile of income [OR 0.33 (95% CI 0.32-0.35)], cohabitating [OR 0.44 (95% CI 0.43-0.46)] and being married [OR 0.54 (95% CI 0.52-0.55)] at first contact to hospital psychiatry as inpatient or outpatient compared with control individuals from the general population. Similarly, siblings to patients with bipolar disorder had a lower functioning within all five socio-economic areas than control individuals. Furthermore, patients and partly siblings showed substantially decreased ability to enhance their socio-economic functioning during the 23 years follow-up compared to controls., Conclusions: Socio-economic functioning is substantially decreased in patients with bipolar disorder and their siblings and does not improve during long-term follow-up after the initial hospital contact, highlighting a severe and overlooked treatment gap.

Objective: In a nation-wide population-based longitudinal register linkage study for the first time 1) to investigate long-term response to lithium in patients with bipolar disorder with and without comorbid epilepsy, and 2) within patients with bipolar disorder and comorbid epilepsy to compare differences in responses between lithium, valproate and lamotrigine., Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 154 patients with bipolar disorder and comorbid epilepsy and 8381 patients with bipolar disorder without comorbid epilepsy during a study period from 1995 to 2017. Response was defined as continuous monotherapy with lithium, valproate or lamotrigine without switch to or add-on of an antipsychotic drug or an antidepressant or hospitalization during an up to ten-year follow-up period. We calculated standardized absolute risks and differences thereof with respect to age, gender, socioeconomic status and comorbidity with other physical disorders than epilepsy., Results: Response to lithium was decreased in patients with bipolar disorder with versus without comorbid epilepsy during the ten-year follow-up period and the difference remained after standardization for comorbidity with other physical disorders than epilepsy. Within patients with bipolar disorder and comorbid epilepsy, response to lithium was decreased compared with responses to valproate and lamotrigine., Conclusions: The findings suggest that valproate and lamotrigine should be given priority in patients with comorbid bipolar disorder and epilepsy. The study highlights the need for closely clinical monitoring and psychological support for patients with bipolar disorder and comorbid epilepsy and emphasize the need for further long-term studies of effect of interventions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: In a nation-wide population-based longitudinal register linkage study to investigate long-term response to antidepressants in patients with depression with and without comorbid epilepsy., Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 1487 patients with depression and comorbid epilepsy and 71,163 patients with depression without comorbid epilepsy during a study period from 1995 to 2017. Response was defined as continuous monotherapy with an antidepressant drug without switch to or add-on of another antidepressant drug, an antipsychotic drug or lithium or hospitalization during an up to ten-year follow-up period. We calculated standardized absolute risks and differences thereof with respect to age, gender, socioeconomic status and comorbidity with other physical disorders than epilepsy., Results: In patients with depression, response to antidepressants was decreased with versus without comorbid epilepsy during the ten-year follow-up period. One year after start of antidepressant treatment the proportion of responders was 12% (CI: 10%-14%) lower in patients with versus without comorbid epilepsy in the standardized population. Response to antidepressants were specifically decreased among younger and unemployed patients with depression and comorbid epilepsy., Limitations: We did not include sub-analyses according to subtypes of epilepsy., Conclusions: Response to antidepressants was decreased in patients with comorbid epilepsy versus without comorbid epilepsy at all time points during a ten-year follow-up period. The study highlights the need for closely clinical monitoring and psychological support for patients with depression and comorbid epilepsy and emphasize the need for further long-term studies of effect of interventions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Mortality is increased in bipolar disorder due to both suicide and death by physical disorders, but it has never been investigated whether these mortalities translate into relatives to patients with bipolar disorder. The aim was to present the life expectancy and the overall mortality and mortality due to suicide and physical disorders among patients with bipolar disorder and their unaffected full siblings, respectively, compared with control individuals from the general population., Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 19.955 patients with bipolar disorder, their 13.923 siblings and 20 sex, age and calendar matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Bipolar disorder was associated with a decreased life expectancy of 7.7 (95% CI: 7.4-8.1) years and increased mortality overall (hazard ratio (HR): 2.11 (95% CI: 2.04-2.18)) and due to suicide (HR: 18.23 (95% CI: 15.81-21.02) and physical disorders (HR: 2.01 (95% CI: 1.94-2.08). In contrast, siblings to patients with bipolar disorder who were unaffected by bipolar disorder did not have decreased life expectancy (0.45 (95% CI: -6.62-2.46)) or increased mortality overall (HR: 1.00 (95% CI: 0.88-1.14) or due to suicide (HR: 1.50 (95% CI: 0.95-2.36) or physical disorders (HR: 0.99 (95% CI: 0.87-1.34)., Conclusions: Increased mortality in bipolar disorder is mainly due to the impact of bipolar psychopathology and to a lesser degree to familial transmitted factors, highlighting the urgent need for preventive intervention studies in relation to suicide and physical disorders following onset of bipolar disorder., (Copyright © 2021. Published by Elsevier B.V.)

Objective: The aim was to map rates and cumulative incidences of psychiatric disorders during lifetime for siblings to patients with a diagnosis of bipolar disorder compared with the general population., Methods: Danish nationwide population-based longitudinal register linkage study including 13,923 unaffected siblings to 19,955 patients with bipolar disorder and 278,460 unaffected control individuals from the general population matched according to year of birth and sex. Follow-up covered 22 years from 1995 to 2017., Results: Rates of 'any psychiatric disorder' among siblings compared with control individuals were constantly around twofold increased throughout lifespan whereas there was a bimodal age distribution of hazard ratios of bipolar disorder, unipolar disorder and use of alcohol or psychoactive drugs with the highest hazard ratios up to age 20 and above 60 years of age. Cumulative incidences from age 15 years of any psychiatric disorder were 44.2% at age 80 years for siblings versus 27.6% for control individuals and the corresponding numbers for bipolar disorder was 8.7% for siblings compared with 1.6% for control individuals., Conclusion: Strategies to prevent onset of psychiatric illness in individuals with a first-generation family history of bipolar disorder should not be limited to adolescence and early adulthood but should be lifetime, likely with differentiated age-specific strategies., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with bipolar disorder may have increased risk of physical diseases due to genetic and environmental factors, but no study has systematically mapped all physical comorbidities in such subjects. The aim was to map rates of all physical diseases among patients and siblings to patients with bipolar disorder., Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 19.955 patients with bipolar disorder, their 13.923 siblings and 20 sex, age and calendar matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Bipolar disorder was associated with increased rates of all physical disease categories compared with rates for control individuals, except for cancer. Further, bipolar disorder was associated with increased rates of separate disorders including ischemic heart disease, diabetes, dementia, hypertension, hypercholesterolemia and hyperlipidemia, hypothyroidism and infections. In contrast, siblings to patients with bipolar disorder who were unaffected by bipolar disorder had increased rates of certain disorders, only, comprising infectious and parasitic diseases, and diseases of the nervous system, digestive system and genitourinary system., Limitations: Underdetection of physical disorders is likely because data are not available for persons who do not seek help for their disorders., Conclusions: Bipolar disorder was associated with increased rates of all physical diseases categories, except cancer, and with separate disorders, likely involving inflammatory components in the pathogenesis. In contrast, unaffected siblings to patients with bipolar disorder had increased rates of certain disorders, only., (Copyright © 2020. Published by Elsevier B.V.)