Proton pump inhibitors and dementia: A nationwide population-based study.

INTRODUCTION: Proton pump inhibitors (PPIs) may increase dementia risk. However, it is currently unknown whether timing of exposure or age at dementia diagnosis influence the risk. METHODS: We assessed associations between cumulative PPI use and dementia at different ages in a nationwide Danish cohort of 1,983,785 individuals aged 60 to 75 years between 2000 and 2018. RESULTS: During follow-up, there were 99,384 all-cause dementia incidences. Incidence rate ratio (IRR) of dementia with PPI ever-use compared with never-use was 1.36 (95% CI, 1.29 to 1.43) for age 60 to 69 years at diagnosis, 1.12 (1.09 to 1.15) for 70 to 79 years, 1.06 (1.03 to 1.09) for 80 to 89 years, and 1.03 (0.91 to 1.17) for 90+ years. Longer treatment duration yielded increasing IRRs. For cases below 90 years, increased dementia rate was observed regardless of treatment initiation up to >15 years before diagnosis. DISCUSSION: Regardless of timing of treatment initiation, PPI use was associated with increased dementia rate before age 90 years. Dementia rates increased with younger age at diagnosis. HIGHLIGHTS: After following 1,983,785 individuals for a median of 10 years, 99,384 developed dementia PPIs were used by 21.2% of cases and 18.9% of controls PPI use was associated with increased dementia rate regardless of time of treatment onset Magnitude of associations increased with younger age at diagnosis PPI use was not associated with dementia occurring after age 90 years.

Antidepressant treatment initiation and public sick-leave compensation in the following year: a register-based prospective cohort study in Denmark.

OBJECTIVES: Mental disorders have caused increasing sickness absence and related benefit claims in the OECD countries. This study investigates the association between antidepressant treatment initiation and public sick leave compensation (PLSC) in the following year in Denmark. METHODS: The study was designed as a register-based prospective cohort study. We included 39,401 adults (aged 18-65 years) with at least 12 consecutive months of full-time labour market attachment who had initiated first-time antidepressant monotherapy for depression or anxiety between 1 January 2015 and 31 December 2018. PLSC was estimated for the year following the incident prescription of various antidepressants for depression or anxiety disorders. RESULTS: The most frequently prescribed antidepressant medication was SSRIs (66.8%), with sertraline being the leading choice. Compared with sertraline, mirtazapine and mianserin were associated with the highest risks of PSLC in the year following initiation, with IRRs of 2.74 (95% CI: 2.63 to 2.86) and 5.79 (95% CI: 5.18 to 6.47), respectively. Compared with sertraline, citalopram (IRR 1.22, 95%CI 1.17-1.28), venlafaxine (IRR 1.34, 95%CI 1.23-1.45) and duloxetine (IRR 1.48, 95%CI 1.35-1.62) were all associated with increased PSLC. In contrast, paroxetine (IRR 0.85, 95% CI 0.74-0.98), fluoxetine (IRR 0.51, 95%CI 0.42-0.62) and vortioxetine (IRR 0.78, 95% CI 0.63-0.97) were all associated with a significantly lower risk of PSLC compared with sertraline. CONCLUSIONS: Antidepressant treatment initiation was associated with PLSC. The highest risk of PLSC was seen for antidepressants with sedative side effects. Some types of antidepressants were associated with a lower risk of PLSC in the year following treatment initiation.

Treatment History Characteristics Associated With Use of Isocarboxazid: A Nationwide Register-Based Study.

PURPOSE/BACKGROUND: The monoamine oxidase inhibitor isocarboxazid (Marplan) is occasionally used in the treatment of depression, but there is only little knowledge on the nature of the use of isocarboxazid in clinical practice. We aimed to identify treatment history characteristics associated with this use. METHODS/PROCEDURES: Via the nationwide Danish registers, we identified all adult incident users of isocarboxazid in the period from 2001 to 2018, as well as up to 5 matched controls using another antidepressant (matched on date of redeemed prescription, age, sex, and region of residence). The 5-year treatment history of the isocarboxazid users and the controls was assessed via the Danish registers. The association between treatment history characteristics and isocarboxazid use was examined by multivariate conditional logistic regression. FINDINGS/RESULTS: We identified 1455 isocarboxazid users and 7045 controls using another antidepressant. The following characteristics were associated with statistically significant increased likelihood of receiving isocarboxazid treatment: Prior treatment with a selective serotonin reuptake inhibitor (odds ratio [OR], 1.80 with 95% confidence interval [CI], 1.46-2.23), a serotonin-norepinephrine reuptake inhibitor (OR, 4.90; 95% CI, 4.08-5.89), a noradrenergic and specific serotonergic antidepressant (OR, 1.56; 95% CI, 1.30-1.88), a tricyclic antidepressant (OR, 5.05; 95% CI, 4.19-6.08), other antidepressants (OR, 4.74; 95% CI, 3.74-6.01), lithium (OR, 6.70; 95% CI, 5.08-8.83), an antipsychotic (OR, 1.43; 95% CI, 1.19-1.73), and each diagnosis of depression received in relation to psychiatric hospital treatment (OR, 1.31; 95% CI, 1.23-1.39). Forty percent of those initiating isocarboxazid had received treatment with drugs from 5 or more different psychopharmacological classes in the 5 preceding years. IMPLICATIONS/CONCLUSIONS: These findings suggest that isocarboxazid is typically used for treatment-resistant depression, consistent with guideline recommendations.

Treatment indications and potential off-label use of antidepressants among older adults: A population-based descriptive study in Denmark.

OBJECTIVES: Off-label prescriptions of antidepressants may be of special concern in older-adults. We aimed to study the potential off-label use of antidepressants among adults ≥65 years by describing the patterns, trends, and factors associated with missing and unspecified treatment indications. METHODS: We used registry data to describe indications of all antidepressant prescriptions (N = 13.8 million) redeemed by older-adults in 2006-2019. We investigated factors associated with off-label use by considering prescriptions with missing and unspecified indications of the first antidepressant prescription using a multinomial logistic regression with the 'depression' indication as a reference category and reported odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: Overall, 18.1% of all antidepressant prescriptions had missing indications, and 9.9% had unspecified indications. The proportion of potential off-label use based on missing and unspecified prescriptions remained mostly consistent during 2006-2019. We identified similar associations in user characteristics whether considering missing or unspecified first prescription. ORs with 95% CI were raised in non-western ethnicity (vs. Danish, 1.12 (0.99-1.26) for missing indication and 1.28 (1.11-1.48) for unspecified indication) and female sex (vs. male, 1.05 (1.02-1.07) and 1.05 (1.02-1.07) respectively). ORs were reduced for shorter educational attainment (vs. long, 0.90 (0.87-0.94) and 0.92 (0.88-0.96)), older age (≥81 vs. 67-70 years, 0.66 (0.65-0.71) and 0.73 (0.70-0.76)) and hospital psychiatric diagnosis (per diagnosis 0.76 (0.73-0.78) and 0.88 (0.86-0.91)). CONCLUSIONS: Nearly one-third of all antidepressant prescriptions redeemed by older-adults in Denmark had either missing or unspecified treatment indications. Whether these prescriptions were actual off-label use needs to be validated. Clinicians should pay special attention to patients' characteristics linking missing and unspecified indications and maintain adequate documentation while prescribing medication.

Life-time Actionable Pharmacogenetic Drug Use: A Population-based Cohort Study in 86 040 Young People With and Without Mental Disorders in Denmark.

OBJECTIVE: To describe life-time use of current actionable pharmacogenetic (PGx) somatic and psychotropic drugs according to international PGx consortia in people with and without hospital-diagnosed mental disorders in the Danish population. METHODS: Population- and register-based observational drug utilization study in 56 065 individuals with mental disorders, i. e. attention-deficit/hyperactivity disorder, autism, bipolar disorder, depression and schizophrenia, and a random, representative sample of 29 975 individuals of the Danish population, born between 1981 and 2005. Individuals were followed from 1995 or birth until 2016 (for a maximum of 22 years). We report prevalence and incidence rates of PGx drug use by age, sex and mental disorders based on redeemed prescriptions between 1995 and 2016. RESULTS: Of the 69 PGx drugs, prescriptions of 39 drugs had been redeemed by the study population by 35 years of age. The use of at least 1 PGx drug varied between 23.1% in males without mental disorders and 97.2% in females with schizophrenia. Males with ADHD or autism were the youngest first-time PGx drug users at a mean of 11.6 years. The mean number of different PGx drugs used was 1.2 in males without mental disorders and 5.6 in individuals with schizophrenia. The prevalence of different PGx drugs linked to more than one gene was 25.3% in males without mental disorders to 94.1% in females with schizophrenia. CONCLUSION: PGx drugs are commonly used by younger people, more often by individuals with mental disorders and by females. Panel-based PGx testing could contribute to treatment decisions at a very young age.

Cerebrospinal fluid test results and associations with subsequent mental disorders, neurological diseases, and CNS infections: A population-based cohort study.

BACKGROUND: Cerebrospinal fluid (CSF) immune alterations have been associated with mental disorders, neurological disease, and CNS infections; however, comprehensive large-scale longitudinal CSF studies are lacking. METHODS: By using the Clinical Laboratory Information System (LABKA) Research Database in the Central Denmark Region (1994-2012), we included 15,030 individuals tested for CSF WBC, CSF/serum albumin ratio, IgG index, total protein, albumin, or IgG with follow-up for the risk of mental disorders, psychotropic prescriptions, neurological diseases, or CNS infections, estimated by Cox regression. RESULTS: Among individuals receiving a mental disorder diagnosis (N = 1,147) after a CSF test, 30·0% had an abnormal CSF test result, while for those with a neurological disease (N = 3,201), 39·9% had abnormal test results, and among individuals with CNS infections (N = 1,276), 73·0% had abnormal test results. Individuals with abnormal CSF test results had an increased risk of mental disorders (HR = 3·20; 95%CI = 2·86-3·59), neurological diseases (HR = 12·40; 95%CI = 11·65-13·20), and CNS infections (HR = 338·59; 95%CI = 299·06-383·35) compared to individuals not registered with a CSF test. However, the risk of mental disorders was higher (P < 0·001) after CSF test results within the normal range (HR = 4·45; 95%CI = 4·08-4·86), whereas for neurological diseases (HR = 9·72; 95%CI = 9·19-10·29) and CNS infections (HR = 55·17; 95%CI = 47·12-64·60), the risk was highest after abnormal CSF test results (all P < 0·001). The risk of organic mental disorders tended to be highest in individuals with abnormal CSF test results (HR = 19·30; 95%CI = 13·44-27·71) even though not significantly different from the risk in the group of individuals with CSF test results in the normal range (HR = 13·55; 95%CI = 9·36-19·60) (P ≥ 0·05). Abnormal CSF test results were associated with an elevated risk of psychotropic prescriptions (HR = 3·91; 95%CI = 3·66-4·18), as were CSF test results within the normal range (HR = 4·26; 95%CI = 4·03-4·51) (P < 0·05). CONCLUSIONS: Immunological CSF abnormalities are associated with an increased risk of mental disorders, neurological disease, and particularly CNS infections; however, the included CSF parameters were not specific for mental disorders and the relevant CSF biomarkers in psychiatry are yet to be discovered.

Pre-diagnostic and post-diagnostic psychopharmacological treatment of 16 288 patients with bipolar disorder.

OBJECTIVES: The aim was to describe the pre-diagnostic and post-diagnostic psychopharmacological treatment of bipolar disorder over the past two decades. METHODS: We identified all 16 288 individuals aged ≥ 18 years, who received their first diagnosis of bipolar disorder at a psychiatric hospital in Denmark between 1997 and 2014. For each calendar year, we calculated the proportion of patients (with index date in the respective calendar years) who were prescribed psychopharmacological treatment in the 2 years preceding and the 2 years following the date of the first diagnosis of bipolar disorder. For patients diagnosed with bipolar disorder from 2007 to 2010 (n = 3949), we described the psychopharmacological treatment from 1995 to 2016, that is, from up to 16 years prior to and up to 10 years after the diagnosis. RESULTS: Concomitant use of ≥ 2 antidepressants in the 2 years preceding the bipolar disorder diagnosis increased over the study period. In the 2 years following the diagnosis, the use of lithium decreased, while use of atypical antipsychotics (particularly quetiapine), valproate, and lamotrigine increased over the study period. During the 10 years following the diagnosis, 53%-90% of the patients received any psychotropic drug while 12%-26% received treatment with an antidepressant without overlapping treatment with a mood-stabilizing drug. CONCLUSION: The increased use of two or more antidepressants suggests more focus on bipolar disorder as a differential diagnosis to treatment-resistant unipolar depression. The decreased use of lithium (consistent with international trends) and the prevalent use of antidepressants without overlapping treatment with a drug with mood-stabilizing properties are concerning.

Cumulative incidence and relative risk of sleep problems among children and adolescents with newly diagnosed neurodevelopmental disorders: A nationwide register-based study.

We estimated the absolute and relative risk of sleep problems in children and adolescents with newly diagnosed neurodevelopmental disorders. This was a population-based cohort study of individuals born in Denmark in 1993-2014 and followed in nationwide registers in 2011-2016. We estimated the 5-year cumulative incidence of sleep problems in incident cases of attention-deficit/hyperactivity disorder (ADHD; n = 12,844), autism spectrum disorder (ASD; n = 8,073), oppositional defiant disorder/conduct disorder (ODD/CD; n = 2,234) and epilepsy (n = 3,709). Hazard ratios (HRs) for sleep problems were estimated by Cox regression. The 5-year risk of sleep problems was highest in ADHD (29.2%; 95% CI, 28.4-30.1), ASD (24.2%; 95% CI, 23.1-25.3) and ODD/CD (27.1% 95% CI, 25.0%-29.2%) and lowest in epilepsy (11.3%; 95% CI, 10.2%-12.6%). For ADHD and ASD, sleep problems were more common in females than in males. Furthermore, sleep problems were predicted by high parental socioeconomic status and varied with the geographical region of residence, suggesting that different clinical practices exist across Denmark and that sleep problems may be more likely to go undetected in families of lower socioeconomic position. Compared with individuals without these disorders, the likelihood of sleep problems was increased in individuals with ADHD (HR, 33.81; 95% CI, 32.78-34.87), ASD (HR, 16.77; 95% CI, 16.15-17.41), ODD/CD (HR, 14.73; 95% CI, 13.88-15.64) and epilepsy (HR, 6.01; 95% CI, 5.67-6.37). After mutual adjustment for comorbidity, HRs were attenuated, especially in ASD, ODD/CD and epilepsy when adjusted for ADHD, suggesting that the increased risk of sleep problems in individuals with ASD, ODD/CD and epilepsy is driven largely by comorbid ADHD.

Risk of hospitalization and hip fracture associated with psychotropic polypharmacy in patients with dementia: A nationwide register-based study.

OBJECTIVE: To investigate the association of benzodiazepines and antidepressants on the risk of hospitalization and hip fracture in patients with dementia initiating antipsychotic drug treatment. METHODS: A register-based retrospective cohort study using data on all incident dementia cases (≥65 years) initiating antipsychotic treatment as monotherapy or in combination with benzodiazepines and/or antidepressants in Denmark from 2000 to 2015. The outcomes of interest were all-cause hospitalization and hip fracture. Cox proportional hazards models with adjustment for multiple variables were used to investigate risk of hospitalization and hip fracture within 180 days. RESULTS: The risk of all-cause hospitalization during 180-days follow-up was significantly increased by 55% (adjusted HR: 1.55, 95% CI: 1.29-1.86, p < 0.0001), when antipsychotic use was combined with benzodiazepines, when compared to antipsychotic monotherapy. The association between the combination of antipsychotics and benzodiazepines with the risk of hip fracture did not reach statistical significance (adjusted HR: 1.50, 95% CI: 0.99-2.26, p = 0.0534). CONCLUSIONS: The observed increased risk of all-cause hospitalization and hip fracture may indicate increased drug-related adverse events. Thus, careful and regular monitoring is needed to assess response to treatment and decrease the risk of adverse events, when antipsychotics are combined with BZDs, albeit confounding cannot be fully excluded within the current design.

Survival Rate Following Involuntary Electroconvulsive Therapy: A Population-Based Study.

OBJECTIVE: Involuntary electroconvulsive therapy (ECT) can be a lifesaving intervention for patients suffering from potentially lethal conditions who are unable to give informed consent. However, its use is not widespread, probably partly because of the scarce data on hard outcomes following involuntary ECT. In Denmark, involuntary ECT is only used when patients are at imminent/potential risk of dying if not receiving ECT. Here, we aimed to estimate the 1-year survival rate after the administration of involuntary ECT as a proxy for the effectiveness of this treatment. METHODS: We conducted a register-based cohort study involving (i) all patients receiving involuntary ECT in Denmark between 2008 and 2019, (ii) age- and sex-matched patients receiving voluntary ECT, and (iii) age- and sex-matched individuals from the general population. One-year survival rates were compared via mortality rate ratios. RESULTS: We identified 618 patients receiving involuntary ECT, 547 patients receiving voluntary ECT, and 3080 population-based controls. The survival rate in the year after involuntary ECT was 90%. For patients receiving involuntary ECT, the 1-year mortality rate ratios were 3.1 (95% confidence interval, 1.9-5.2) and 5.8 (95% confidence interval, 4.0-8.2) compared with those receiving voluntarily ECT and to the population-based controls, respectively. Risk factors for early death among patients receiving involuntary ECT were male sex, being 70 years or older and having organic mental disorder as the treatment indication. CONCLUSIONS: Treatment with involuntary ECT is associated with a high survival rate, suggesting that the intervention is effective. However, patients receiving involuntary ECT constitute a high-risk population that should be monitored closely after this treatment.

Antiepileptic Drugs and Suicide: Role of Prior Suicidal Behavior and Parental Psychiatric Disorder.

OBJECTIVE: To examine whether prior suicidal behavior and familial predisposition to psychiatric disorders modify the association between antiepileptic drug use and completed suicide. METHODS: Using the Danish National Prescription Register, we identified all incident users of antiepileptic drugs aged 15 years or older in Denmark between July 1997 and December 2015. We carried out a nested case-control study and defined exposure to antiepileptic drugs at the index date (ie, time of suicide). Conditional logistic regressions were used to estimate mortality rate ratios (MRRs) of suicide in current versus previous users of antiepileptic drugs. We also analyzed suicide risk associated with the 9 most commonly used antiepileptic drugs. RESULTS: We identified 1,759 individuals completing suicide. Current versus previous use of any antiepileptic drug was associated with an increased risk of suicide (MRR = 1.26, 95% confidence interval [CI] = 1.13-1.40). This excess risk was observed in individuals with a history of suicidal behavior (MRR = 1.28, 95% CI = 1.07-1.54) and in those without (MRR = 1.26, 95% CI = 1.11-1.43), and in individuals with a familial predisposition to psychiatric disorders (MRR = 1.48, 95% CI = 1.18-1.87) and in those without (MRR = 1.21, 95% CI = 1.07-1.35). INTERPRETATION: Use of antiepileptic drugs was associated with an increased risk of suicide. The findings do not support that the risk of suicide following treatment with antiepileptic drugs identified in randomized trials is explained by prior suicidality or familial predisposition to psychiatric disorders. The additional risk of suicide associated with use of antiepileptic drugs was generally low and should be balanced against benefits of treatment. ANN NEUROL 2019;86:951-961.

Incidence of direct oral anticoagulant use in patients with nonvalvular atrial fibrillation and characteristics of users in 6 European countries (2008-2015): A cross-national drug utilization study.

AIMS: To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries. METHODS: Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed. RESULTS: A total of 186 405 new DOAC users (age ≥18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany). CONCLUSION: Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH).

Use of attention-deficit/hyperactivity disorder medication among older adults in Denmark.

AIMS: Knowledge on the use of attention-deficit/hyperactivity disorder (ADHD) medication among older adults is limited. We hypothesized that ADHD medication is used off-label in adults aged ≥50 years as part of palliative care in e.g. cancer patients. The aim of this study was to describe the use of ADHD medication among adults aged ≥50 years in Denmark. METHODS: Using the Danish health registries, we identified new users ≥50 years of ADHD medication during 2000-2012. We estimated the annual incidence of ADHD medication use and ADHD diagnoses. We described new users of ADHD medication according to co-medication, comorbidities and assessed the 1-year cumulative mortality rate. A posthoc analysis allowed us to include new users until 2015. RESULTS: We identified 6690 new users of ADHD medication from 2000 to 2012. From 2000 to 2015 we observed an increase in the incidence of ADHD medication use from 12.5 to 30.3 per 100 000 person-years. However, the incidence rate decreased from 2010 to 2015. Throughout the study period, the incidence rate of ADHD diagnoses was low (overall prevalence among new users ≤2%). Opioids were the most frequent comedication used (used by 54%), while cancer was the most frequent diagnosis preceding treatment (prevalence of 52%). The 1-year cumulative mortality was 50%, primarily driven by patients with a preceding cancer diagnosis. CONCLUSION: There was an increase in the incidence of ADHD medication use in adults aged ≥50 years from 2000-2010 and a decreasing incidence from 2010-2015. Our results suggest that ADHD medication is used off-label in older adults as part of palliative care.

Prescription drug use in pregnancy and variations according to prior psychiatric history.

PURPOSE: Prescription drug use during pregnancy has increased during the past decades. However, little is known about prescription drug use for high-risk pregnancies. We aimed to estimate the prevalence of redeemed prescriptions in Danish pregnant women with and without previous psychiatric history. METHODS: A Danish population-based descriptive study of 981 392 pregnancies ending in live-born singletons by 586 988 women aged 15 to 55 years between 1997 and 2012, of which 113 449 (11.6%) pregnancies were by women with a psychiatric history prior to the index pregnancy. All prescription drugs redeemed during pregnancy were identified, and dispensing patterns among the women were reported by therapeutic classes of drugs, calendar year of childbirth, and trimester. RESULTS: Overall, women with psychiatric history prior to pregnancy were more likely to fill a prescription (75.8%; 95% confidence interval [CI], 75.5-76.0%), compared with women with no psychiatric history (64.5%; 95% CI, 64.4-64.6%). The difference was observed even when psychotropic drug use was excluded and in all therapeutic classes except for antineoplastic and immunomodulating drugs. The most commonly prescribed drugs were anti-infectives. Approximately 44.7% (95% CI, 44.5-45.0%) of women with psychiatric history and 31.3% (95% CI, 31.2-31.4%) of women with no psychiatric history redeemed more than one therapeutic class of drugs. CONCLUSIONS: Women with a psychiatric history were more likely to redeem prescriptions during pregnancy across almost all drug classes, especially anti-infectives. Two thirds of all women redeemed at least one prescription drug during pregnancy and one third more than one drug class. KEY POINTS We mapped prescription drug use of almost 600 000 women during almost one million pregnancies with focus on women with a history of psychiatric disorder before conception compared with women with no such history. Pregnant women with a previous psychiatric disorder were more likely to redeem prescription drugs compared with pregnant women without a previous psychiatric disorder. The observed overall difference was not due to obvious differences in psychotropic drug use. The difference was evident across calendar years, all trimesters, and almost all drug classes, but to a large extent in anti-infectives, among those mainly antibiotics. Two thirds of pregnant women redeemed prescription drugs during pregnancy, and one third redeemed more than one drug class. Health professionals should be aware of comorbid conditions requiring multiple drug use during pregnancy with the risk of unknown fetal effects.

Positive predictive value of a register-based algorithm using the Danish National Registries to identify suicidal events.

PURPOSE: It is not possible to fully assess intention of self-harm and suicidal events using information from administrative databases. We conducted a validation study of intention of suicide attempts/self-harm contacts identified by a commonly applied Danish register-based algorithm (DK-algorithm) based on hospital discharge diagnosis and emergency room contacts. METHODS: Of all 101 530 people identified with an incident suicide attempt/self-harm contact at Danish hospitals between 1995 and 2012 using the DK-algorithm, we selected a random sample of 475 people. We validated the DK-algorithm against medical records applying the definitions and terminology of the Columbia Classification Algorithm of Suicide Assessment of suicidal events, nonsuicidal events, and indeterminate or potentially suicidal events. We calculated positive predictive values (PPVs) of the DK-algorithm to identify suicidal events overall, by gender, age groups, and calendar time. RESULTS: We retrieved medical records for 357 (75%) people. The PPV of the DK-algorithm to identify suicidal events was 51.5% (95% CI: 46.4-56.7) overall, 42.7% (95% CI: 35.2-50.5) in males, and 58.5% (95% CI: 51.6-65.1) in females. The PPV varied further across age groups and calendar time. After excluding cases identified via the DK-algorithm by unspecific codes of intoxications and injury, the PPV improved slightly (56.8% [95% CI: 50.0-63.4]). CONCLUSIONS: The DK-algorithm can reliably identify self-harm with suicidal intention in 52% of the identified cases of suicide attempts/self-harm. The PPVs could be used for quantitative bias analysis and implemented as weights in future studies to estimate the proportion of suicidal events among cases identified via the DK-algorithm.

Predictors of Nonhospitalization and Functional Response in Clozapine Treatment: A Nationwide, Population-Based Cohort Study.

BACKGROUND: Clozapine remains the only evidence-based treatment for treatment-resistant schizophrenia, and prediction of clozapine response is important in developing stratified treatment. We studied potential predictors of clozapine response, applying functional assessments as well as service use. PROCEDURES: We performed a nationwide cohort study among all individuals diagnosed with schizophrenia in Denmark after 1995 (age, ≥18 years) who initiated clozapine treatment between 2004 and 2011 with a Global Assessment of Functioning (GAF-F) score registered at clozapine initiation. During up to 2-year follow-up, clinical response was defined as (a) no further hospitalization with schizophrenia or (b) improvement in GAF-F score (moderate improvement: increase, ≥10; substantial improvement: increase, ≥20; and GAF-F, ≥50). We performed Cox regression analysis and report adjusted hazard rate ratios (HRRs; 95% confidence intervals [95% CIs]). RESULTS: Among 502 clozapine users with a registered GAF-F score, 232 (46.2%) remained out of hospital, 96 (19.1%) achieved moderate functional improvement, and 29 (5.8%) substantial functional improvement. Of all potential predictors, voluntary status at clozapine initiation showed borderline statistical significance with nonhospitalization (HRR, 1.61; 95% CI, 0.97-2.67). Regarding functional improvement, living with a partner was the strongest predictor with an almost threefold increased HRR (2.78; 95% CI, 1.07-7.23). Female sex was only nonsignificantly associated with functional improvement, whereas the chance of substantial improvement decreased by 15% (HRR, 0.85; 95% CI, 0.72-1.00) for each year delay in clozapine initiation among females. CONCLUSIONS: Living with a partner was the strongest predictor of functioning after clozapine initiation in this study. Although potentially indicating better premorbid functioning, this finding stresses the need and importance of social support during the course of the treatment independent of clinical factors.

Psychopharmacological treatment of psychotic mania and psychotic bipolar depression compared to non-psychotic mania and non-psychotic bipolar depression.

OBJECTIVES: An evidence base for the treatment of mania and bipolar depression with psychotic symptoms is lacking. Nevertheless, clinicians may have a preference for treating episodes of bipolar disorder with or without psychotic symptoms in different ways, which is likely to reflect notions of differential efficacy of treatments between these subtypes. This study aimed to investigate whether the psychopharmacological treatment of psychotic and non-psychotic episodes of mania and bipolar depression, respectively, differs in clinical practice. METHODS: We conducted a register-based study assessing the psychopharmacological treatment of all individuals receiving their first diagnosis of mania or bipolar depression between 2010 and 2012. The psychopharmacological treatment within 3 months following the time of diagnosis was considered. Potential differences in psychopharmacological treatment between the psychotic and non-psychotic subtypes of mania and bipolar depression, respectively, were investigated by means of Pearson's χ2 test and logistic regression adjusted for sex and age at diagnosis of bipolar disorder. RESULTS: A total of 827 patients were included in the analyses. The adjusted odds ratio (aOR) for treatment with an antipsychotic was 1.71 (95% confidence interval [CI]: 1.18-2.48, P<.01) for psychotic mania and 3.89 (95% CI: 1.95-7.76, P<.001) for psychotic bipolar depression. The aOR for treatment with the combination of an antipsychotic and an anticonvulsant was 1.60 (95% CI: 1.06-2.43, P<.05) for psychotic mania. The aOR for treatment with the combination of an antipsychotic and an antidepressant was 2.50 (95% CI: 1.43-4.37, P<.01) for bipolar psychotic depression. CONCLUSIONS: It would be of interest to conduct studies evaluating whether antipsychotics represent the superior pharmacological treatment for psychotic mania and psychotic bipolar depression.

C-reactive protein levels and treatment resistance in schizophrenia-A Danish population-based cohort study.

OBJECTIVE: Schizophrenia is associated with increased levels of inflammatory markers. However, it remains unclear whether inflammatory markers are associated with treatment-resistant schizophrenia. METHODS: We conducted a population-based follow-up study among individuals with a first-time schizophrenia diagnosis and a baseline C-reactive protein measurement (a commonly available marker of systemic inflammation) from 2000 to 2012. We defined treatment resistance as the earliest observed instance of either clozapine initiation or hospital admission due to schizophrenia after having received at least 2 prior antipsychotic monotherapy trials of adequate duration. We used adjusted Cox regression analysis to calculate hazard ratios. RESULTS: We identified 390 individuals with a C-reactive protein measurement at first-time schizophrenia diagnosis. A nonsignificant higher median C-reactive protein (4.0 vs. 3.1 mg/L, p = .13) was observed among the 52 (13.3%) treatment-resistant individuals. Increased levels of C-reactive protein (above 3 mg/L) at baseline were not associated with treatment resistance (adjusted hazard ratio = 0.99, 95% confidence interval [0.56, 1.73]). CONCLUSIONS: C-reactive protein, as a single inflammatory marker, appears insufficient to detect treatment-resistant schizophrenia.

Postoperative Treatment of Pain after Hip Fracture in Elderly Patients with Dementia.

BACKGROUND/AIMS: Prior studies have shown that patients with dementia are at risk of receiving insufficient treatment for pain after a hip fracture. We therefore hypothesized that elderly hip fracture patients with dementia received less postoperative pain treatment than those without dementia. METHOD: All patients (age ≥65 years) who had been operated on for a hip fracture in the Copenhagen University Hospital region in 2009 were included. Data about analgesic use for the first 72 h after surgery were acquired from the hospitals' electronic medication system and linked with information about dementia, comorbidity, and prior drug use. RESULTS: A total of 1,507 patients were included, of which 296 (19.6%) suffered from dementia. Both groups were equally likely to receive paracetamol and opioids. Patients with dementia received lower doses of oral morphine equivalents during the first [dementia vs. no dementia: 29.0 (26.4-31.8) vs. 34.7 (33.1-36.4) mg, p = 0.001] and second [27.8 (25.4-30.5) vs. 31.2 (29.9-32.4) mg, p = 0.019] but not on the third postoperative day (p = 0.10). CONCLUSION: The lower doses of opioids may reflect uncertainty about how to treat pain patients with dementia. Further guidance is needed, as inadequate treatment of pain may have adverse consequences.