Seasonality and sun exposure in incidence of major depression, bipolar disorder, and first-time use of antidepressant medication.

INTRODUCTION: Seasonality in depressive and bipolar disorders, are recognized in the ICD-10/11 and DSM-5 diagnostic systems. The existence of a seasonal pattern of hospital diagnosis of major depression, bipolar disorder and prescription of antidepressant medications has not been evaluated in the Danish population. METHODS: We retrieved date and year for all first-time hospital contacts with depression or bipolar disorder between 1999 and 2019, registered in the Danish National Patient Registry. Depression was defined using the ICD-10 F32-F33 codes, and for bipolar disorder the F30 or F31 codes. Date and year of all first-time purchases of antidepressant medications with ATC codes (N06A) between 1999 and 2021 were retrieved from the Danish National Prescription Registry, containing information on all prescribed drugs dispensed at pharmacies since 1995. Data on sunlight hours from 2012 to 2021 were retrieved from the Danish Metrological Institute. RESULTS: Incidences of hospital diagnoses as well as purchases of medication varied with month and season. The monthly variations were larger for antidepressant medication and smallest for bipolar disorder. The multiple linear regression analysis showed that number of first-time diagnoses of depression or bipolar disorder did not correlate with season. For antidepressant medication the number of first-time prescriptions was significantly lower in summer compared to the winter season. CONCLUSION: This study found a seasonal variation of first-time prescriptions of antidepressant medication. We did not find a seasonal variation in first-time hospital diagnoses. Further research looking into depression severity, polarity of bipolar illness episodes, lag-time for sunlight exposure, and specific parts of the yearly photoperiods should be conducted.

Cognitive ability, education, height and body mass index in relation to risk of schizophrenia and mortality following its diagnosis.

This study examines the hypotheses that the traits of higher IQ, longer education and taller height are associated with lower risk of death as compared to traits of low IQ, short education, and short height in men with schizophrenia compared to men without schizophrenia. In total, 937,919 men born 1939-59 and 1983-1997 with information from conscription were followed for incident schizophrenia in Danish registries. Higher levels of cognitive ability, longer education, and taller height were associated with fewer cases of schizophrenia. In a sub-sample of 652,368 men with information on body mass index, underweight was associated with more and overweight and obesity were associated with fewer cases of schizophrenia compared with normal weight. Higher cognitive ability, longer education, and taller height were associated with fewer deaths from both natural and unnatural causes in both men with and without schizophrenia. Underweight was associated with more deaths from natural and unnatural causes, whereas overweight and obesity were associated with more deaths from natural causes and fewer deaths from unnatural causes in both groups of men. Due to interaction, tall height and long educational duration were associated with fewer deaths from natural causes, and obesity was associated with fewer deaths from unnatural causes among men with schizophrenia compared to men without. In conclusion, traits in young adulthood are associated with higher mortality in men with and without schizophrenia, but traits of long educational duration and obesity seem to be especially important for lower mortality in men with schizophrenia.

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.

Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation.

OBJECTIVE: The authors investigated the frequency and determinants of long-term use and risk of dose escalation of benzodiazepines and benzodiazepine-related drugs (benzodiazepine receptor agonists, or BZRAs). METHODS: All adults ages 20-80 years living in Denmark on January 1, 2000 (N=4,297,045) were followed for redeemed prescriptions of BZRAs in the Danish National Prescription Registry from January 1, 2000, to December 31, 2020. For each drug class, we calculated long-term use for more than 1 or 7 years, and dose escalation measured as increase in dose to a level above the recommended level. Associations were examined using logistic regression. RESULTS: The authors identified 950,767 incident BZRA users, of whom 15% and 3% became long-term users for more than 1 or 7 years, respectively. These percentages were highest for individuals who initiated Z-drugs (17.8% and 4%). Among the 5% of BZRA users who had at least 3 years of continuous use, there was no indication of dose escalation, as the median dose remained relatively stable. However, 7% (N=3,545) of BZRA users escalated to doses above the recommended level. Psychiatric comorbidity, especially substance use disorder, was associated with higher risk of long-term use and dose escalation. CONCLUSIONS: A limited portion of the population that received BZRA prescriptions were classified as continuous users, and only a small proportion of this group escalated to doses higher than those recommended in clinical guidelines. Thus, this study does not, under the current regulations, support the belief that BZRA use frequently results in long-term use or dose escalation.

Use of hypnotic-sedative medication and risk of falls and fractures in adults: A self-controlled case series study.

OBJECTIVE: To evaluate the risk of falls and fractures in users of benzodiazepines, Z-drugs, or melatonin. METHODS: We followed 699,335 adults with a purchase of benzodiazepines, Z-drugs, or melatonin in the Danish National Prescription Registry between 2003 and 2016 for falls and fractures in the Danish National Patient Registry between 2000 and 2018. A self-controlled case-series analysis and conditional Poisson regression were used to derive incidence rate ratios (IRR) of falls and fractures during six predefined periods. RESULTS: In total 62,105 and 36,808 adults, respectively, experienced a fall or fracture. For older adults, the risk of falls was highest during the 3-month pre-treatment period (IRRmen+70 , 4.22 (95% confidence interval, 3.53-5.05), IRRwomen + 70 , 3.03 (2.59-3.55)) compared to the baseline (>1 year before initiation). The risk continued to be higher in the later treatment periods. Contrarily, in men and women aged 40-69 years, the risk was only higher in the 3-month pre-treatment period. The incidence of falls among young men and women was slightly lower after initiation of sedating medication (treatment period, IRRmen15-39 , 0.66 (0.50-0.86), IRRwomen15-39 , 0.65 (0.51-0.83)). Analyses with fractures as outcome yielded similar results. CONCLUSIONS: Although falls and fractures occur more often in persons using sedative-hypnotic medication, the higher risk of falls and fractures in the pre-treatment period relative to the period directly after treatment, suggests that this association is better explained by other factors that elicited the prescription of this medication rather than the adverse effects of the sedative-hypnotic medication.

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.

Sedative drug-use in Denmark, 2000 to 2019: a nationwide drug utilization study.

AIM: To describe trends in and characteristics of sedative drug use from 2000 through 2019 in relation to the introduction of central regulations and new drugs. METHODS: In this descriptive study, we used individual prescription data on the entire Danish population from the Danish National Prescription Registry to calculate yearly incidence and prevalence of use of benzodiazepines, benzodiazepine-related drugs (Z-drugs), melatonin, olanzapine, low-dose quetiapine, mianserin/mirtazapine, pregabalin, and promethazine from 2000 through 2019. From the Danish National Patient Registry, we obtained data on drug users' psychiatric and somatic comorbidity. RESULTS: The use of benzodiazepines and Z-drugs declined gradually from 2000 through 2019, whereas the newer alternatives, melatonin, low-dose quetiapine, pregabalin and promethazine, increased in use, while the use of olanzapine and mianserin/mirtazapine was relatively stable. This development was seen in both men and women and across all age groups except for hypnotic benzodiazepines which showed a steep increase in the oldest age group from 2010. For all sedative drugs depression, anxiety, alcohol and misuse disorder, pain and cancer were the most prevalent comorbidities. During our study period, the number of individuals without any of the selected diagnoses increased. CONCLUSION: In Denmark different central regulations have influenced prescription practice toward more restrictive use of Z-drugs and benzodiazepines, except for hypnotic benzodiazepine prescriptions increased after the introduction of special palliative care. An increase in use of newer sedative drugs, however, indicates that the regulations do not remove the need for sedative drugs in the population.

Use of GLP-1 receptor agonists and subsequent risk of alcohol-related events. A nationwide register-based cohort and self-controlled case series study.

Animal studies have related glucagon-like peptide 1 receptor agonists (GLP-1) to lower alcohol intake. We examined whether GLP-1 was associated with risk of alcohol-related events in a nationwide cohort study and a self-controlled case series analysis including all new users of GLP1 (n = 38 454) and dipeptidyl peptidase 4 inhibitors (DPP4) (n = 49 222) in Denmark 2009-2017. They were followed for hospital contacts with alcohol use disorder or purchase of drugs for treatment of alcohol dependence in nationwide registers from 2009 to 2018. Associations were examined using Cox proportional hazard and conditional Poisson regression. During follow-up of median 4.1 years, 649 (0.7%) of participants were registered with an alcohol-related event. Initiation of GLP-1 treatment was associated with lower risk of an alcohol-related event (Hazard ratio = 0.46 (95%CI: 0.24-0.86) compared with initiation of DPP4 during the first 3 months of follow-up. Self-controlled analysis showed the highest risk of alcohol-related events in the 3-month pretreatment period (incidence rate ratio [IRR] = 1.25 (1.00-1.58)), whereas the risk was lowest in the first 3-month treatment period (IRR = 0.74 (0.56-0.97). In conclusion, compared with DPP4 users, individuals who start treatment with GLP-1 had lower incidence of alcohol-related events both in cohort and self-controlled analyses. Thus, there might be a transient preventive effect of GLP1 on alcohol-related events the first months after treatment initiation.

Diabetes, sleep disorders and risk of depression - A Danish register-based cohort study.

AIMS: We examined the influence of comorbid sleep disorder on the association between type 2 diabetes (T2D) and risk of incident depression. METHODS: The study population (N = 232,489) was based on all individuals registered aged ≥40 years with a T2D diagnosis between January 1, 2000 to December 31, 2012 in the Danish National Diabetes Register and a matched reference population. The risk of incident depression (diagnosis or anti-depressant medication) following T2D and possible effect modification of comorbid sleep disorder was estimated using adjusted Cox proportional hazards regression. Sleep disorder was defined as a diagnosis of insomnia, hypersomnia or sleep-wake schedule disorders or use of sleep medication (z-drugs or melatonin) in the Danish National Patient Registry or the Danish National Prescription Registry. RESULTS: At study entry, 15.3 % of the participants had a sleep disorder. During follow-up, 2.6 % were diagnosed with depression and 32.1 % received antidepressant medication. The unadjusted hazard ratio (HR) for depression was 1.54 (95%CI 1.52-1.56) for patients with diabetes, which attenuated to 1.50 (1.48-1.52) after adjustment for sleep disorders, which further attenuated to 1.27 (1.26-1.29) in the model further adjusted for psychiatric and somatic comorbidities. The analyses of T2D and sleep disorder as independent and combined variables compared with none of the conditions on risk of depression, showed a HR of 1.27 (95 % CI 1.19-1.35) for T2D without sleep disorder, 1.46 (95 % CI 1.33-1.59) for sleep disorders without T2D, and 1.49 (95%CI 1.37-1.63) for both conditions. CONCLUSIONS: T2D and sleep disorders were independently associated with subsequent risk of depression and individuals with both conditions experienced the greatest relative risk. Sleep disorders neither explained nor amplified the relation between diabetes and depression.

The association between birth weight, ponderal index, psychotropic medication, and type 2 diabetes in individuals with severe mental illness.

BACKGROUND: Impaired fetal growth may increase vulnerability towards metabolic disturbances associated with some medications. We examined whether birth weight and ponderal index modify the association between psychotropic medication and type 2 diabetes among young adults with severe psychiatric diagnosis. METHODS: A total of 36,957 individuals born in Denmark between 1973 and 1983 with a diagnosis of schizophrenia, bipolar disorder, or depression were followed from first diagnosis until 2018. Cox proportional hazard models were applied to analyse risk of type 2 diabetes with use of psychotropic medications and interactions between psychotropic medication and birth weight and ponderal index, respectively. RESULTS: During follow-up, 1575 (4.2%) individuals received a diagnosis of type 2 diabetes. Use of antipsychotic, mood stabilizing and antidepressant medications were associated with higher hazard ratios (HRs) of type 2 diabetes (HRantipsychotics 1.68 [95%CI 1.49-1.90]; HRmood stabilizing medication 1.41 [95%CI 1.25-1.59]; HRantidepressants 2.00 [95%CI 1.68-2.37]), as were a birth weight below 2500 g (HR 1.13 [95%CI 1.01-1.28]), and high ponderal index (HR 1.26 [95%CI 1.11-1.43]). The highest rates of type 2 diabetes for each psychotropic medication category were found in medication users with low birth weight or high ponderal index. However, neither birth weight nor ponderal index significantly modified the association between psychotropic medication and diabetes risk. CONCLUSION: Psychotropic medication use, birth weight, and ponderal index were risk factors for type 2 diabetes in patients with severe mental illness, but neither birth weight nor ponderal index modified the association between psychotropic medication and type 2 diabetes.

Diabetes, antidiabetic medications and risk of depression - A population-based cohort and nested case-control study.

OBJECTIVE: Diabetes type 2 is associated with depression, but the impact of antidiabetic drugs is not clear. The objective was to analyze the association between diabetes type 2, antidiabetic drugs, and depression. METHODS: This register-based study included 116.699 patients with diabetes type 2 diagnosed from 2000 to 2012 and an age, gender, and municipality matched reference group of 116.008 individuals without diabetes. All participants were followed for a diagnosis of depression or prescription of antidepressant medication. Based on this, a case-control study was nested within the cohort, using risk set sampling. Antidiabetic medication was categorized into insulin, metformin, sulfonylureas and glinides combined, glitazones, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose. The association between diabetes and depression was analyzed using Cox proportional hazards regression, whereas conditional logistic regression was used to analyze the association between use of antidiabetic drugs and depression. RESULTS: Patients with diabetes had higher risk of depression compared to individuals without diabetes (hazard ratio 1.14 (95% confidence interval 1.14-1.15)). Low doses of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower risk of depression in patients with diabetes compared to non-users, with the lowest risk for sodium-glucose transport protein 2 inhibitor users (odds ratio 0.55 (0.44-0.70)). Use of insulin, sulfonylurea and high doses of metformin were associated with higher risk of depression. CONCLUSION: Patients with diabetes had increased risk of depression. However, users of specific antidiabetic drugs had lower risk of depression compared to non-users.

Familial risk and heritability of ischemic heart disease and stroke in Danish twins.

Aim: Our aim was to explore whether familial factors influence the risk of ischemic heart disease, stroke, and their co-occurrence. Methods: In total, 23,498 monozygotic and 39,540 same-sex dizygotic twins from the Danish Twin Registry were followed from 1977 to 2011 in the Danish National Patient Registry for ischemic heart disease and stroke. Time-to-event analyses accounting for censoring and competing risk of death were used to estimate familial risk (casewise concordance relative to the cumulative incidence) and heritability of ischemic heart disease, stroke, and the co-occurrence by age. Results: During follow-up, we observed 5561 and 4186 twin individuals with ischemic heart disease and stroke respectively, with 936 twin pairs concordant for ischemic heart disease and stroke. Familial risks were significant for both, with higher cumulative risks in monozygotic than in dizygotic twins. Estimates for heritability were significant for ischemic heart disease as well as for stroke diagnosed after the age of 80. The casewise concordance of ischemic heart disease in twins whose co-twin was diagnosed with stroke did not differ for monozygotic and dizygotic twins; however, from age 55 it was 10% higher than the cumulative risk in the overall twin cohort and was 25% higher at age 90. A similar pattern was seen for stroke following the co-twin's ischemic heart disease. Conclusions: As in previous studies, we found a higher heritability of ischemic heart disease than of stroke. There was a significant familial risk but no heritability for the co-occurrence of ischemic heart disease and stroke. The co-occurrence is therefore likely due to other shared familial than genetic factors, highlighting that preventive initiatives should target families rather than individuals.

Body mass index and height in young adult men in relation to subsequent risk of mood disorder.

Adolescence represents an important period in brain and mental development, which raises the question of whether measures of body size at entry into adult life influence the risk of developing mood disorders. We examined the association of BMI and height in a cohort of young men with risk of mood disorders throughout life. The study included 630,807 Danish men born 1939-1959 and 1983-1997 with measures of height and weight at conscription board examinations. Psychiatrist's diagnosis of mood disorders was obtained from national patient registries from 1969 to 2016. The associations of BMI and height with mood disorders were estimated by Cox proportional hazard regression analyses adjusting for education, cognitive ability, migration status drug and alcohol misuse. During a mean follow-up of 26.3 years, 2,608 (0.6%) and 19,690 (3.1%) men were diagnosed with bipolar disorder and depression, respectively. We found an inverse linear association of BMI with risk of bipolar disorder, whereas the association of BMI with depression was curve-linear with a decline in risk until BMI around 25 kg/m2, and an almost constant risk across the BMI range above 25 kg/m2. Height was not associated with bipolar disorder or depression. Comparison of brothers, assumed to share family factors of possible influence on the risk of mood disorders, showed similar results although with wider confidence intervals. BMI in the lower range at men's entry into adulthood is inversely associated with risk of bipolar disorder and depression throughout adult life, whereas height is not related.

Use of register- and survey-based measures of anxiety in a population-based Danish cohort.

OBJECTIVE: We explored the comparability of anxiety measures from register- and survey-based data including analyses of prevalence and associations with selected psychiatric and somatic diseases. METHODS: We measured anxiety using Danish registers (hospital diagnosis and anxiolytic drug prescriptions), self-reports, symptom checklist (SCL) scores, and a clinical interview in 7493 adults with mean age 52 (SD 13.3) years who participated in a health survey between 2012 and 2015. We estimated the prevalence of anxiety, agreement between different measures and performed quantitative bias analysis. RESULTS: The lifetime prevalence of hospital diagnosed anxiety, anxiolytic drug prescriptions, and self-reported anxiety were 4.4%, 6.2%, and 5.1%, respectively, after adjusting for selective participation. The agreement between the different anxiety measures was low. Thus, 25% with an anxiety diagnosis and 20% with anxiolytic drug prescriptions also had a high SCL score. Anxiolytic drugs were the only measure significantly associated with higher odds of heart disease. Hospital diagnosis and self-reported anxiety were associated with depression with odds ratio (OR) above 15, whereas anxiolytic drug prescriptions were less strongly associated (OR = 2.2(95% confidence interval: 1.26-3.91)). The risk estimates attenuated considerably when correcting for measurement error, whereas the ORs became slightly higher when the selective participation in the survey was accounted for. CONCLUSION: Anxiety diagnosed in hospitals and self-reported anxiety showed low level of agreement but provide comparable results regarding frequency measures and associations with disease outcomes.

An analysis of the relative and absolute incidence of somatic morbidity in patients with affective disorders-A nationwide cohort study.

BACKGROUND: Patients with affective disorder seem to experience higher risks of several somatic diseases, but no studies have provided estimates of both absolute and relative risks for these diseases in the same population. METHODS: A prospective cohort of all patients age ≥18 years old with a hospital contact with affective disorder between 1997-2014 (n=246,282) and a random sample from the background population (n=167,562) was followed for hospitalizations with cardiovascular disease, diabetes, cancers, chronic obstructive pulmonary disease (COPD), asthma, inflammatory bowel disease, hip fracture, psoriasis, migraine, or dementia. Adjusted absolute and relative risk estimates were calculated using multivariable adjusted Aalen's additive and Cox proportional hazard regression models. RESULTS: After adjustments, the absolute risk difference was 130.6 (95% confidence interval [CI] 125.5-135.7) additional cases per 10,000 person-years among affective disorder patients compared to the reference population. The corresponding hazard ratio for any somatic disease was 1.50 (95% CI 1.48-1.52). The strongest associations were found for dementia, hip fracture, COPD, and stroke on both the relative and absolute scale. The patients did not have higher risk of cancers except for lung cancer and brain tumors. Risk estimates tended to be slightly higher for individuals with depression or other affective disorder compared to bipolar disorder. LIMITATIONS: Limitations include use of register-based data, risk of reverse causation and Berkson's bias. CONCLUSIONS: Patients with affective disorder have both higher absolute and relative risk of most somatic diseases except for cancers. Further identification of the shared mechanisms will facilitate the development of targeted interventions.

Longitudinal association between CRP levels and risk of psychosis: a meta-analysis of population-based cohort studies.

Meta-analyses of cross-sectional studies suggest that patients with psychosis have higher circulating levels of C-reactive protein (CRP) compared with healthy controls; however, cause and effect is unclear. We examined the prospective association between CRP levels and subsequent risk of developing a psychotic disorder by conducting a systematic review and meta-analysis of population-based cohort studies. Databases were searched for prospective studies of CRP and psychosis. We obtained unpublished results, including adjustment for age, sex, body mass index, smoking, alcohol use, and socioeconomic status and suspected infection (CRP > 10 mg/L). Based on random effect meta-analysis of 89,792 participants (494 incident cases of psychosis at follow-up), the pooled odds ratio (OR) for psychosis for participants with high (>3 mg/L), as compared to low (≤3 mg/L) CRP levels at baseline was 1.50 (95% confidence interval [CI], 1.09-2.07). Evidence for this association remained after adjusting for potential confounders (adjusted OR [aOR] = 1.31; 95% CI, 1.03-1.66). After excluding participants with suspected infection, the OR for psychosis was 1.36 (95% CI, 1.06-1.74), but the association attenuated after controlling for confounders (aOR = 1.23; 95% CI, 0.95-1.60). Using CRP as a continuous variable, the pooled OR for psychosis per standard deviation increase in log(CRP) was 1.11 (95% CI, 0.93-1.34), and this association further attenuated after controlling for confounders (aOR = 1.07; 95% CI, 0.90-1.27) and excluding participants with suspected infection (aOR = 1.07; 95% CI, 0.92-1.24). There was no association using CRP as a categorical variable (low, medium or high). While we provide some evidence of a longitudinal association between high CRP (>3 mg/L) and psychosis, larger studies are required to enable definitive conclusions.

The familial and genetic contribution to the association between depression and cardiovascular disease: a twin cohort study.

Depression and cardiovascular disease (ischemic heart disease and stroke) are associated in a bidirectional manner. Their relatively high heritability has led to the hypothesis that this co-occurrence is related to shared familial and genetic factors; this study aims to test this hypothesis. We included 23,498 monozygotic and 39,540 same-sex dizygotic twins from the Danish Twin Registry followed from January 1977 until December 2011 in nationwide Danish registries. We used survival analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of the co-occurrence of depression and cardiovascular disease by age using monozygotic and same-sex dizygotic twin pairs. The casewise concordance of ischemic heart disease or stroke in twins whose co-twin was diagnosed with depression was at all ages similar for the monozygotic and dizygotic twin pairs and to the cumulative incidence of ischemic heart disease or stroke, respectively, in the entire twin population. A similar pattern was seen in analyses of depression risk given the co-twin being diagnosed with ischemic heart disease or stroke. Relative recurrence risk and heritability estimates were also of modest size and with confidence intervals including unity. Results were similar after stratification by gender as well as when redefining depression to include the use of antidepressant medication from 1995. Our findings do not support that co-occurrence between depression and cardiovascular disease is explainable by shared genetic factors, nor did we find strong evidence of a familial effect.

The impact of mental vulnerability on the relationship between cardiovascular disease and depression.

BACKGROUND: The mechanisms linking cardiovascular disease (CVD) and depression are still not established. We investigated the impact of mental vulnerability on the relationship between CVD and depression. METHODS: A total of 19,856 individuals from five cohorts of random samples of the background population in Copenhagen were followed from baseline (1983-2011) until 2017 in Danish registries. Additive hazard and Cox proportional hazard models were used to analyze the effects of confounding by mental vulnerability as well as interactions between mental vulnerability and CVD on the risk of depression. RESULTS: During follow-up, 15.3% developed CVD, while 18.1% experienced depression. A strong positive association between CVD and depression (hazard ratio: 3.60 [95% confidence intervals (CI): 3.30; 3.92]) corresponding to 35.4 (95% CI: 31.7; 39.1) additional cases per 1,000 person-years was only slightly attenuated after adjustment for mental vulnerability in addition to other confounders. Synergistic interaction between CVD and mental vulnerability was identified in the additive hazard model. Due to interaction between CVD and mental vulnerability, CVD was associated with 50.9 more cases of depression per 1,000 person-years among individuals with high mental vulnerability compared with individuals with low mental vulnerability. CONCLUSIONS: Mental vulnerability did not explain the strong relationship between CVD and depression. CVD was associated with additional cases of depression among individuals with higher mental vulnerability indicating that this group holds the greatest potential for intervention, for example, in rehabilitation settings.

An attempt to explain the bidirectional association between ischaemic heart disease, stroke and depression: a cohort and meta-analytic approach.

BACKGROUND: Depression and cardiovascular diseases (CVDs) are common diseases and associated in a bidirectional manner. AIMS: To examine whether a bidirectional association between CVD and depression could be explained by shared risk factors, misclassification of disease measures or non-response. METHOD: A total of 10 population-based cohorts including 93 076 men and women (mean age 54.4 years, s.d. = 9.2) and an additional 10 510 men (mean age 51.2 years, s.d. = 0.3) were followed for subsequent depression, ischaemic heart disease (IHD) and stroke in the Danish National Patient Registry from health examinations between 1982 and 2015 and until end of follow-up in 2017-2018. Exposures were physicians' diagnoses of IHD, stroke, depression or self-reported chest pain, depression, use of antidepressant medication and the Major Depression Inventory at the time of study entry in the Metropolit study. Associations were analysed using Cox proportional hazard regression with disease as time-dependent variables. RESULTS: IHD and stroke were associated with subsequent depression (hazard ratio (HR) for IHD: 1.79, 95% CI 1.43-2.23 and HR for stroke: 2.62, 95% CI 2.09-3.29) and the associations were present in both men and women. Adjustment for the shared risk factors socioeconomic status, lifestyle, body mass index, statin use and serum lipids did not change the risk estimates. Furthermore, depression was associated with higher risk of subsequent IHD (HR = 1.63, 95% CI 1.36-1.95) and stroke (HR = 1.94, 95% CI 1.63-2.30). The associations were also present when the analyses were based on self-reported disease measures or restricted to include non-responders. CONCLUSIONS: The bidirectional association between CVD and depression was not explained by shared risk factors, misclassification or non-response.