Sedative drug prescription patterns in Danish adults from 2002 through 2021. A register-based cohort study.

OBJECTIVE: Pharmacological treatment strategies for insomnia seem to vary, and there is lack of knowledge about how sedative drugs are used in a real-world setting. We investigated changes in sedative drug prescription patterns in Danish adults who initiated treatment between 2002 and 2016. METHODS: All adults with a first-time purchase of a sedative drug registered in the Danish National Prescription Register from 2002 through 2016 were followed for five years between 2002 and 2021 for subsequent prescriptions of sedative drugs, death, or emigration. Sedative drugs were classified into anxiolytic benzodiazepines (N05BA), hypnotic benzodiazepines (N05CD), Z-drugs (N05CF), melatonin (N05CH01), promethazine (R06AD), and low-dose quetiapine (N05AH04). Analyses were stratified on time: 2002-2006, 2007-2011, and 2012-2016. RESULTS: A total of 842,880 individuals purchased their first sedative drug between 2002 and 2016. Most of them (40.0%) initiated treatment between 2002 and 2006, whereas 29.2% initiated treatment in 2012-2016. In 2002-2006, anxiolytic benzodiazepines (46.4%), Z-drugs (42.8%), and hypnotic benzodiazepines (5.4%) were the most common first treatment. This pattern changed over time with a gradual increase in the use of melatonin, promethazine, and low-dose quetiapine, which in 2011-2016 accounted for 27% of all first treatments. During the five years from first prescription, around 27% shifted to a different sedative drug. This percentage increased slightly over time, but over time the first shift to another drug class was most often to a Z-drug or anxiolytic benzodiazepine. Few individuals (5.8%) had more than one shift and the third choice seemed randomly distributed across all other drug classes. CONCLUSION: Sedative drug prescriptions are distributed on different drug classes, with Z-drugs and anxiolytic benzodiazepines as the most frequent first treatment, and second choice in case of shift.

Association of Familial Aggregation of Major Depression With Risk of Major Depression.

Importance: Major depression (MD) aggregates within families, but how family history of MD confers risk of MD over the life course is unclear. Such knowledge is important to identify and prevent possible depressogenic effects of family environment. Objective: To examine the association between family MD history and risk of MD including association with age, sex, type of kinship, and age of the affected family member. Design, Setting, and Participants: This cohort study included all Danish citizens born from 1960 to 2003 with known parental identity followed up from their 15th birthday until time of MD, censoring, or December 31, 2018. Analysis took place between April 2022 and December 2022. Exposures: Family members with first-time MD using International Classification of Diseases, Eighth Revision codes 296.09, 296.29, 298.09, and 300.49 or 10th Revision codes F32.0-F33.9, family members' age at MD onset, and individuals' age at exposure to family MD. Main Outcomes and Measures: Multivariable Poisson regression was applied to estimate the incidence rate ratio (IRR) with 95% CI of first-time MD. Results: Of 2 903 430 individuals (1 486 574 [51.2%] men), 37 970 men (2.6%) and 70 223 women (5.0%) developed MD during follow-up. For men, exposure to maternal, paternal, or full sibling MD were associated with a 2-times higher risk of MD (IRR, 2.10 [95% CI, 2.02-2.19]; IRR, 2.04 [95% CI, 1.94-2.14]; IRR, 2.08 [95% CI, 1.97-2.19]) and the associated risk increased with number of affected family members. This pattern was similar for women. For men, family members' age at MD onset was not associated with MD. For women, maternal MD onset at 69 years or younger was associated with higher IRRs of MD (age <40 years: IRR, 1.64 [95% CI, 1.28-2.10]; age 40-49 years: IRR, 1.62 [95% CI, 1.27-2.07]; age 50-59 years: IRR, 1.56 [95% CI, 1.22-2.00]; and age 60-69 years: IRR, 1.67 [95% CI, 1.28-2.16]) compared with women with maternal MD onset at 70 years or older. For men, exposure to maternal MD younger than 30 years (age <1 year: IRR, 1.95 [95% CI, 1.70-2.25]; age 1 to <12 years: IRR, 2.31 [95% CI, 2.16-2.47]; age 12 to <19 years: IRR, 2.18 [95% CI, 2.03-2.35]; age 19 to <30 years: IRR, 1.42 [95% CI, 1.32-1.53]) was associated with increased IRRs, while exposure to maternal MD at 30 years or older was associated with a lower IRR (0.77 [95% CI, 0.70-0.85]). The findings were similar across type of kinships and for women. Conclusions and Relevance: In this study, risk of MD was associated with increased numbers of affected family members but did not vary by gender or type of kinship. Exposure to family MD during childhood and adolescence was associated with increased risk.

Healthcare resource utilization in patients with treatment-resistant depression-A Danish national registry study.

OBJECTIVES: To investigate healthcare resource utilization (HRU) and associated costs by depression severity and year of diagnosis among patients with treatment-resistant depression (TRD) in Denmark. METHODS: Including all adult patients with a first-time hospital contact for major depressive disorder (MDD) in 1996-2015, TRD patients were defined at the second shift in depression treatment (antidepressant medicine or electroconvulsive therapy) and matched 1:2 with non-TRD patients. The risk of utilization and amount of HRU and associated costs including medicine expenses 12 months after the TRD-defining date were reported, comparing TRD patients with non-TRD MDD patients. RESULTS: Identifying 25,321 TRD-patients matched with 50,638 non-TRD patients, the risk of psychiatric hospitalization following TRD diagnosis was 138.4% (95%-confidence interval: 128.3-149.0) higher for TRD patients than for non-TRD MDD patients. The number of hospital bed days and emergency department (ED) visits were also higher among TRD patients, with no significant difference for somatic HRU. Among patients who incurred healthcare costs, the associated HRU costs for TRD patients were 101.9% (97.5-106.4) higher overall, and 55.2% (50.9-59.6) higher for psychiatric services than those of non-TRD patients. The relative differences in costs for TRD-patients vs non-TRD patients were greater for patients with mild depression and tended to increase over the study period (1996-2015), particularly for acute hospitalizations and ED visits. LIMITATIONS: TRD was defined by prescription patterns besides ECT treatments. CONCLUSION: TRD was associated with increased psychiatric-related HRU. Particularly the difference in acute hospitalizations and ED visits between TRD and non-TRD patients increased over the study period.

Treatment-resistant depression and labor market affiliation in the Danish welfare society: a register-based study.

PURPOSE: We explored if patients with treatment-resistant depression (TRD) go through different states of labor market affiliation during their course of illness before they return to work or obtain early retirement as compared to patients without TRD. METHODS: All adults between 18 and 58 years with a first-time hospital contact due to depression in Danish patients' registers from 2000 to 2014 were followed in a nationwide labor market database. At time of TRD (index week), TRD patients were matched with patients without TRD in a 1:2 ratio. Sequence analysis and logistic regression were applied to explore the association of TRD and labor market affiliation and measures of transitions between labor market states 52 weeks before and after the index week. RESULTS: At the index week, 14.1% of patients with TRD were in employment, whereas the proportion was 26.4% among non-TRD patients. Over time, the proportion of patients in employment increased slightly to 25.5% for TRD and 33.7% for non-TRD patients. The proportion of TRD patients with sickness absence at index was 47.0%, while the proportion was 26.2% for non-TRD patients. The adjusted odds of a below mean volatility of labor market transitions, characterized by more episodes in passive social transfer payments and disability pension, were higher among patients with TRD compared with non-TRD patients (OR 1.63, 95% CI [1.56-1.69]). Similarly, the adjusted odds of a below mean integration into employment were 1.63 higher among TRD patients compared with non-TRD patients (95% CI [1.56-1.70]). CONCLUSION: Patients with TRD have higher levels of sickness absence and lower levels of reintegration into the labor market after meeting the criteria for TRD compared with patients without TRD.

Treatment patterns in patients with treatment-resistant depression in Danish patients with major depressive disorder.

OBJECTIVE: To describe treatment patterns in patients with treatment-resistant depression (TRD) and major depressive disorder (MDD) stratified by depression severity and year of diagnosis. Patterns of treatment were also compared to country-specific guidelines. METHODS: All adults registered first time with a hospital contact due to MDD from 1996 through 2015 were identified and followed for all dispensed prescriptions of antidepressants, antipsychotics, lithium, initiation of electroconvulsive therapy (ECT), and psychotherapy in Danish registers 12 months before and after their hospital MDD diagnosis. TRD was characterized by two shifts in treatment. RESULTS: We identified 197,615 patients of whom 15% developed TRD. In total, 88% of patients started treatment with antidepressants or ECT. Selective serotonin reuptake inhibitors (SSRIs) were the most frequently used treatment during the study period and more than half (50.7%) of patients changed treatment at least once. Among patients with TRD, serotonin and noradrenaline reuptake inhibitors (SNRIs) were the most frequently used treatment (55.9%), and 37.0% initiated a new treatment the following year. SSRIs and SNRIs were part of most combinations of treatment, regardless of depression severity, year of diagnosis, or presence of TRD. CONCLUSION: 15% of patients met the criteria for TRD. Irrespective of patient characteristics and year of diagnosis, SSRIs and SNRIs are the most used treatments for depression, even after patients met the criteria for TRD. We confirm that guidelines for first treatment were followed for most patients diagnosed with MDD in Denmark, but for patients with TRD, choice of treatment was arbitrary.

Treatment-resistant depression and risk of all-cause mortality and suicidality in Danish patients with major depression.

OBJECTIVE: Treatment-resistant depression (TRD) has been associated with higher mortality and risk of suicide, but this has mainly been showed in few studies which did not include self-harm. The aim was to investigate the association of TRD with all-cause mortality, suicide and self-harm in a nationwide cohort of patients with major depression and explore any differences in relation to patient characteristics. METHODS: First-time hospital contacts for major depression between January 1, 1996 and December 31, 2014 were identified in Danish patient registers (ICD-10: F32 and F33). TRD was defined as two shifts in antidepressant treatment, assessed from one year prior depression diagnosis until one year after. Information on mortality, suicide and self-harm was obtained from Danish registers and associations between TRD and the three prognostic outcomes were analyzed using Cox Proportional Hazard Regression. RESULTS: TRD was not associated with all-cause mortality the first year of follow-up (adjusted HR (aHR) 1.04, 95% confidence interval (CI) [0.98-1.11]), and the HR for mortality was lower the following 1-5 years. However, TRD was associated with higher rates of suicide (0-1 year: aHR 2.20, 95% CI [1.77-2.74]; 1-5 years: aHR 1.70, 95% CI [1.42-2.03]) and self-harming behavior (0-1 year: aHR 1.51, 95% CI [1.36-1.66]; 1-5 years: aHR 1.59, 95% CI [1.48-1.70]). The above risk estimates varied only slightly across sociodemographic and clinical patient characteristics. CONCLUSIONS: Patients with TRD have higher rates of suicide and self-harm compared with non-TRD patients, whereas there seems to be no increase overall in all-cause mortality - in fact, there was a lower rate at follow-up after 1 year. We found only a few differences in HRs for mortality or suicidality across patient characteristics.

Socio-demographic and clinical risk factors of treatment-resistant depression: A Danish population-based cohort study.

BACKGROUND: Knowledge of risk factors of treatment-resistant depression (TRD) contributes to understand the underlying mechanisms and to identify patients at risk. However, there is still a lack of studies on how different risk factors associate with TRD. The objective of this study was to determine the independent association of several socio-demographic and clinical risk factors with TRD. METHODS: 194.074 patients with a first-time hospital contact for depression identified in the Danish National Patient Registry (DNPR) from 1996 through 2014 were followed for TRD for 12 months after diagnosis. Socio-demographic and clinical risk factors were identified in nation-wide registries. Data were analyzed using Cox Proportional Hazard Regression and Fine-Gray model for competing mortality risk. RESULTS: Indicators of disease severity (recurrent depression (adjusted HR (aHR) 1.17 (1.14-1.20)), severity of depression (aHR 2.01 (1.95-2.08)), admission to a psychiatric ward (aHR 2.03 (1.96, 2.10)) were strong risk factors. Aged 65-84 (aHR 1.96 (1.83-2.10)), lost labor market affiliation ((aHR 1.12 (1.08, 1.16)), cohabiting (aHR 1.27 (1.23, 1.30)), comorbid anxiety (aHR 1.18 (1.10-1.27)), insomnia (aHR 1.27 (1.06-1.51)), migraine (aHR 1.42 (1.16-1.73)) and use of psychotropic drugs was also associated with higher rates of TRD. LIMITATIONS: Information on drug use during hospitalization was not available. Information on rating scales could have provided a more precise assessment of symptom severity and treatment response. CONCLUSIONS: Besides indicators of disease severity, other important risk factors associated with TRD are age, lost labor market affiliation, cohabiting with a partner as well as anxiety, insomnia, migraine and the use of psychotropic medications.

Incidence of, Risk Factors for, and Changes Over Time in Treatment-Resistant Depression in Denmark: A Register-Based Cohort Study.

OBJECTIVE: Varying definitions of treatment-resistant depression (TRD) across studies make it difficult to estimate the size of the problem and to identify patients at increased risk. The aim of this cohort study was to examine the incidence of TRD, disease-related risk factors, and changes over time using different definitions of TRD. METHODS: From 1996 through 2014, all patients with a first-time hospital contact for depression (ICD-10 codes F32 and F33) were identified in Danish National Patient Registries. A total of 211,689 patients were followed for shifts in antidepressant treatment in the Danish Patient and Prescription Registries. TRD was defined at the second shift in treatment during the first 12 months after diagnosis. The associations of year and type of hospital contact, depression subtype, and severity of TRD were analyzed using Cox proportional hazard regression. RESULTS: A total of 14.0% of patients experienced a second shift in antidepressant treatment during the first year after admission. When applying 3 other common TRD definitions, the proportion varied from 13% to 31%. Psychiatric inpatients and patients with recurrent or severe depression had the highest incidence of TRD. The incidence of TRD was also slightly higher in patients diagnosed after 2001. All associations were replicated when data were reanalyzed using the alternative definitions of TRD. CONCLUSIONS: About 14% of patients with depression developed TRD during the first year after first hospital contact. The incidence was highest in patients with severe depression and was relatively stable over time. Various definitions of TRD provided different estimates of the frequency of TRD but were all associated with disease severity.