Real-world effectiveness of mood stabilizer use in schizophrenia.

OBJECTIVE: Mood stabilizers (MS) are often used as adjunctive medication in patients with schizophrenia. The aim of this study was to investigate the real-world effectiveness of MS use in persons with schizophrenia. METHODS: The study cohort included all persons treated in inpatient care due to schizophrenia during 1972-2014 in Finland (N = 61,889). Drug purchase data were obtained from the national Prescription register and modeled with the PRE2DUP method. The follow-up period covered the years 1996-2017. Mood stabilizers included carbamazepine, valproic acid, lamotrigine, and lithium. The main outcome was psychosis hospitalization. We utilized within-individual design to compare the risk of outcome between time-periods of MS use and non-use within the same person. Stratified Cox regression analyses were conducted with adjusted hazard ratios (aHR) and 95% confidence intervals (CIs). RESULTS: Mean age at cohort entry was 46.2 years (SD 16.0) and 50.3% were male. During the follow-up (maximum of 22 years, median 14.8 years, interquartile range 7.5-22.0), 28.1% (N = 17,370) of the study cohort used MS, valproic acid being the most often used one (60.4%, N = 10,483). Risk of psychosis hospitalization was lower during MS use than non-use (aHR 0.88, 95% CI 0.86-0.90). Use of lithium (0.84, 0.81-0.87), valproic acid (0.87, 0.85-0.90), and lamotrigine (0.90, 0.85-0.95) were associated with lower risk of psychosis hospitalization compared with their non-use, whereas carbamazepine use was not. CONCLUSIONS: Mood stabilizers were relatively often used as adjunctive treatments in schizophrenia and their use was associated with a 12% decreased risk of psychosis rehospitalization, a marker of relapse in schizophrenia.

Automated multi-dose dispensing in persons with and without Alzheimer's disease-impacts on pharmacotherapy.

PURPOSE: We investigated the drug use before and after transition to automated multi-dose dispensing (MDD) service among persons with Alzheimer's disease (AD) and compared whether the changes were similar in persons without AD. METHODS: The register-based Finnish nationwide MEDALZ cohort includes 70,718 community-dwelling persons diagnosed with AD during 2005-2011. Each person who initiated MDD was matched in both groups with a comparison person without MDD by age, gender and for persons with AD, also time since AD diagnosis at the start of MDD. The study cohort included 15,604 persons with AD in MDD and 15,604 no-MDD, and 5224 persons without AD in MDD and 5224 no-MDD. Point prevalence of drug use was assessed every 3 months, from 1 year before to 2 years after the start of MDD and compared between persons in MDD to those who did not have MDD. RESULTS: MDD was started on average 2.9 (SD 2.1) years after AD diagnosis. At the start of MDD, the prevalence of drug use increased especially for antipsychotics, antidepressants, opioids, paracetamol and use of ≥ 10 drugs among persons with and without AD. Prevalence of benzodiazepine use (from 12% 12 months before to 17% at start of MDD), memantine (from 29 to 46%) and ≥ 3 psychotropics (from 3.2 to 6.0%) increased among persons with AD. Decreasing trend was observed for benzodiazepine-related drugs, urinary antispasmodics and non-steroidal anti-inflammatory drugs. CONCLUSION: MDD seems to be initiated when use of psychotropics is initiated and the number of drugs increases.

Association between different diabetes medication classes and risk of Parkinson's disease in people with diabetes.

PURPOSE: Diabetes has been associated with increased risk of Parkinson's disease (PD). Diabetes medications have been suggested as a possible explanation, but findings have been inconsistent. More information on the role of exposure in different time windows is needed because PD has long onset. We assessed the association between use of different diabetes medication categories and risk of PD in different exposure periods. METHODS: A case-control study restricted to people with diabetes was performed as part of nationwide register-based Finnish study on PD (FINPARK). We included 2017 cases (diagnosed 1999-2015) with PD and 7934 controls without PD. Diabetes medication use was identified from Prescription Register (1995-2015) and categorized to insulins, biguanides, sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues and glinide. Exposure for each medication class was determined as none, at least 3 years before outcome and only within the three-year lag time before PD outcome. RESULTS: The use of insulins, biguanides, sulfonylureas, DPP-4 inhibitors, GLP-1 analogues or glinides was not associated with PD. Use of TZDs before lag time compared to non-use of TZDs (adjusted odds ratio (OR) 0.78; 95% Confidence interval (CI) 0.64-0.95) was associated with decreased risk of PD. CONCLUSIONS: Our nationwide case-control study of people with diabetes found no robust evidence on the association between specific diabetes medication classes and risk of PD. Consistent with earlier studies, TZD use was associated with slightly decreased risk of PD. The mechanism for this should be verified in further studies.

Treatment initiation for parkinson's disease in Australia 2013-2018: a nation-wide study.

BACKGROUND: Guidelines highlight the importance of an individualized approach to treatment initiation for Parkinson's disease. Our aim was to investigate initiation of anti-Parkinson medication in Australia from 2013-2018, and to determine factors predicting choice of initial treatment. METHODS: Cohort of new-users (N = 4,887) of anti-Parkinson medication aged ≥ 40 years were identified from a 10% random representative sample of national medication dispensing data from July-2013 to June-2018. Changes in treatment initiation were examined across the whole cohort and stratified by age and sex. RESULTS: Treatment initiation was most frequent with levodopa followed by non-ergot dopamine agonists (DAs) and anticholinergics. Two thirds initiated with levodopa across the study period. Initiation with non-ergot DAs increased from 22 to 27% (rate ratio, RR 1.23, 95% confidence interval, CI 1.02-1.47) and initiation with anticholinergics decreased from 6.9% to 2.4% (RR 0.34, 95% CI 0.21-0.55) from 2013-2018. Among persons aged ≥ 65 years, one third of women and one fourth of men initiated on levodopa. Among women aged < 65 years, rates of treatment initiation with DAs (37%) and levodopa (37%) were similar in 2013/2014 but initiation with DA exceeded levodopa thereafter. Among men aged < 65 years, treatment initiation with levodopa (44%-49%) remained more frequent than initiation with DAs (29%-32%) throughout the study period. CONCLUSIONS: Treatment initiation with levodopa was most frequent among persons aged ≥ 65 years, consistent with current guidelines. Whilst the value of levodopa sparing strategies is unclear, treatment initiation with DA has become increasingly common relative to levodopa among women but not among men aged < 65 years.

Prevalence of oral anticoagulant use among people with and without Alzheimer's disease.

BACKGROUND: Although cardio- and cerebrovascular diseases are common among people with Alzheimer's disease (AD), it is unknown how the prevalence of oral anticoagulant (OAC) use changes in relation to AD diagnosis. We investigated the prevalence of OAC use in relation to AD diagnosis in comparison to a matched cohort without AD. METHODS: Register-based Medication use and Alzheimer's disease (MEDALZ) cohort includes 70 718 Finnish people with AD diagnosed between 2005-2011. Point prevalence of OAC use (prescription register) was calculated every three months with three-month evaluation periods, from five years before to five years after clinically verified diagnosis and compared to matched cohort without AD. Longitudinal association between AD and OAC use was evaluated by generalized estimating equations (GEE). RESULTS: OAC use was more common among people with AD until AD diagnosis, (OR 1.17; 95% CI 1.13-1.22), and less common after AD diagnosis (OR 0.87; 95% CI 0.85-0.89), compared to people without AD. At the time of AD diagnosis, prevalence was 23% and 20% among people with and without AD, respectively. OAC use among people with AD began to decline gradually two years after AD diagnosis while continuous increase was observed in the comparison cohort. Warfarin was the most common OAC, and atrial fibrillation was the most common comorbidity in OAC users. CONCLUSION: Decline in OAC use among people with AD after diagnosis may be attributed to high risk of falling and problems in monitoring. However, direct oral anticoagulants (DOACs) that are nowadays more commonly used require less monitoring and may also be safer for vulnerable people with AD.

Increased Risk of Parkinson's Disease in Patients With Schizophrenia Spectrum Disorders.

BACKGROUND: PD comorbid with schizophrenia has been considered rare because these diseases associate with opposite alterations in the brain dopamine system. The objective of this study was to investigate the risk of PD after a diagnosis of a schizophrenia spectrum disorder. METHODS: Regionally, this was a retrospective record-based case-control study. The cohort included 3045 PD patients treated 2004-2019 in southwestern Finland. Nationally this was a nested case-control study using registers to examine Finnish patients who received a clinically confirmed PD diagnosis 1996-2015 (n = 22,189). PD patients with previously diagnosed schizophrenia spectrum disorder (separate analysis for schizophrenia) were included. Comparable non-PD control groups were derived from both data sets. All PD diagnoses were based on individual clinical examinations by certified neurologists. RESULTS: In PD patients, the prevalence of earlier schizophrenia spectrum disorder was 0.76% in regional data and 1.50% in nationwide data. In age-matched controls, the prevalence in the regional and national data was 0.16% and 1.31%, respectively. The odds ratio for PD after schizophrenia spectrum disorder diagnosis was 4.63 (95% CI, 1.76-12.19; P < 0.01) in the regional data and 1.17 (95% CI, 1.04-1.31; P < 0.01) in the national data. CONCLUSIONS: Schizophrenia spectrum disorder increases the risk of PD later in life. This association was observed in both individual patient data and nationwide register data. Therefore, despite the opposite dopaminergic disease mechanisms, schizophrenia spectrum disorder increases rather than decreases the risk of PD. The increased PD risk could be related to risk-altering effects of dopamine receptor antagonists or to the increased vulnerability of the dopamine system induced by illness phase-dependent dopamine dysregulation in schizophrenia/schizophrenia spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association of recent hospitalisation with antidepressant initiation among community dwellers with Alzheimer's disease.

OBJECTIVES: Antidepressant are commonly prescribed to persons with cognitive disorders to treat depressive and other neuropsychiatric symptoms despite the inconclusive evidence on their effectiveness on this indication. We studied whether recent hospitalisation was associated with antidepressant initiation in people with Alzheimer's disease (AD). METHODS: The register-based Finnish nationwide Medication use and Alzheimer's disease cohort includes community-dwelling persons diagnosed with AD during 2005-2011 in Finland (n = 70,718). This study was restricted to people who initiated antidepressant use after AD diagnosis and had no active cancer treatment and schizophrenia or bipolar disorder diagnoses. We performed a nested case-control study with antidepressant initiators as cases. A matched noninitiator (sex, age and AD duration), was identified for each initiator (15,360 matched pairs). Recent hospitalisation was defined as hospital discharge within the past 14 days of initiation. RESULTS: Antidepressant initiators were four times more likely (adjusted odds ratio: 4.41, 95% confidence interval: 4.06-4.80) to have been hospitalised within the past 2 weeks before initiation (21.2%, n = 3250) than matched noninitiators (5.4%, n = 831) and the duration of hospital stay was significantly longer among initiators. Dementia was the most common main discharge diagnosis among both initiators (43.8%, n = 1423) and noninitiators (24.8%, n = 206). CONCLUSION: Recent hospitalisation was strongly associated with antidepressant initiation in persons with AD. Further studies are needed to investigate whether this is due to neuropsychiatric symptoms leading to hospital admission, inpatient care triggering or worsening neuropsychiatric symptoms or other indications. Nonpharmacological treatments for neuropsychiatric symptoms should be prioritised and the threshold for prescribing antidepressants should be high.

Changes in the use of diabetes drugs among community-dwelling people with Alzheimer's disease.

BACKGROUND: Type 2 diabetes is common in persons with Alzheimer's disease (AD). Management of diabetes in persons with AD is challenging due to changing goals of care and susceptibility to adverse drug events including hypoglycemia. The aim of this study was to investigate the prevalence of diabetes drug use from 5 years before to 5 years after the time of AD diagnosis among persons with and without AD. METHODS: This was a nationwide register-based study of persons with and without AD and diabetes in Finland. We analyzed data from the Medication Use and Alzheimer's disease (MEDALZ) study that included 70,718 community-dwelling people diagnosed with AD from 2005 to 2011. The study population included 8418 persons with AD and 6666 matched persons without AD who were diagnosed with diabetes 5 years before AD diagnosis (index date). We defined the prevalence of diabetes drug use in three-month evaluation periods from 5 years before until 5 years after the index date. RESULTS: Nearly all people with diabetes (94% in both cohorts) used one or more diabetes drugs on the index date. The most prevalent drug metformin was used by 60.9% of people with AD and 59.1% of people without AD. The next most prevalent drugs were sulfonylureas and insulin. The prevalence of diabetes drug use was similar in people with and without AD but began to decline 1 year after AD diagnosis in the AD cohort compared to non-AD cohort. CONCLUSIONS: The decline in diabetes drug use after AD diagnosis may be attributed to clinicians and patients seeking to avoid serious adverse drug events including hypoglycemia. In addition, the findings may reflect personalized glycemic control and unintentional weight loss in persons with AD reducing the need for diabetes drugs.

Use of antidepressants and mood stabilizers in persons with first-episode schizophrenia.

PURPOSE: Antipsychotics are first-line treatment of schizophrenia. They are often accompanied by adjunctive treatments, such as antidepressant (AD) or mood stabilizer (MS), although there is only limited information of their use in first-episode schizophrenia. This study aimed to investigate AD and MS initiation and factors associated with initiation in persons with first-episode schizophrenia. METHODS: Register-based data was utilized to identify persons who received inpatient care due to schizophrenia during 1996-2014 in Finland and who did not use AD or MS at the time of first inpatient care diagnosis of schizophrenia (N = 7667, mean age 40.2, SD 18.2). Drug purchase data (1995-2017) was obtained from the National Prescription register and modelled with PRE2DUP method. Initiations of AD and MS use were followed up 3 years from first schizophrenia diagnoses. Cox proportional hazard models were used to investigate factors associated with AD or MS initiation. RESULTS: Among persons with first-episode schizophrenia, 35.4% initiated AD and 14.1% initiated MS use within three years from diagnoses. Female gender, younger age, and benzodiazepine use were associated with higher risk of AD and MS initiation. The number of previous psychoses was associated with decreased risk of AD and increased risk of MS initiation. CONCLUSION: Clinical guidelines rarely recommend the use of AD or MS as adjunctive treatment in persons with schizophrenia. However, this population is often treated with AD or MS. More studies are needed to evaluate benefits and risks of these medications as adjunctive treatment of schizophrenia.

Causes of death in a nationwide cohort of community-dwellers with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is related to higher mortality but it is not entirely evident which causes of death explain this. The objective of this study was to assess the causes of death in a nationwide cohort of clinically verified AD cases and compare the causes to a matched comparison cohort without AD. METHODS: Cohort of all community-dwellers with clinically verified AD residing in Finland on 31 December 2005 (n = 27,948) and a matched comparison cohort without AD (n = 27,948). Mortality (2006-2012, n = 30,641, 54.8%) and causes of death were obtained from register. Cause of death was ascertained with clinical examination (87.3% of deaths), forensic (8.0%) or medical autopsy (4.7%). RESULTS: In AD cohort, the most common causes were diseases of the nervous system (49.9%), circulatory system (31.7%) and neoplasms (7.7%), while diseases of circulatory system (53.5%), neoplasms (19.1%) and mental and behavioral disorders (7.3%) contributed for majority of deaths in the comparison cohort. There were no sex-wise differences. People with AD were over 20 times more likely to die due to diseases of the nervous system (OR, 95% CI 22.06, 19.87-24.25) than the comparison cohort, while other causes, e.g., diseases of the circulatory system (0.40, 0.38-0.42), neoplasms (0.35, 0.33-0.38), mental and behavioral disorders (0.27, 0.24-0.30) and external causes of morbidity and mortality (0.72, 0.62-0.81) were less common in the AD cohort. CONCLUSIONS: Although half of the people with AD died due to diseases of the nervous system, cancers and especially cardio/cerebrovascular diseases were still important contributors to the overall mortality among them. This should be acknowledged when planning their terminal care.

Length of hospital stay after hip fracture and readmission rates of persons with and without Alzheimer's disease: a matched cohort study.

BACKGROUND: Hospital length of stays (LOS) for incident of hip fracture are decreasing, but it is unknown if these changes have negative impacts on vulnerable older patient populations, like those with Alzheimer's disease (AD). We aimed to assess if persons with and without AD have different hospital LOS for hip fracture, and is the LOS associated with hospital readmissions. METHODS: Utilizing register-based data for a matched cohort study nested in the Medication use and Alzheimer's disease study (MEDALZ), we collected all community-dwelling persons in Finland diagnosed with AD during 2005-2012, had incident of first hip fracture between 2005 and 2015 after AD diagnosis, and were discharged alive from an acute care hospital. Hospital LOS and hospital readmissions within 30-days and 90-days were compared between those with and without AD and risk of readmission was assessed using binary logistic regression analysis. RESULTS: In this matched cohort study of 12,532 persons (mean age 84.6 years (95% CI: 84.5-84.7), 76.8% women), the median LOS in an acute care hospital was 1 day shorter for those with AD (median 4 days, IQR 3-7) than those without AD (median 5 days, IQR 3-7) (P < 0.001). However, the AD cohort had respectively 6 days and 5 days longer median LOS in a community hospital, and total hospital stay compared to the non-AD cohort (P < 0.001 for all comparisons). Those with AD had fewer readmissions within 30-days (10.7%) and 90-days (16.9%) compared to those without AD (13.3% 30-days and 20.7% 90-days) (P < 0.001 for all comparisons). Both cohorts had a reduced readmission risk within 30-days when the LOS in an acute care hospital was 4-14 days, compared to a LOS less than 4 days. CONCLUSIONS: Persons with AD had shorter acute care hospital LOS, but had longer LOS in a community hospital setting compared to those without AD, which is similar to other findings when comparing total hospital LOS. These findings imply that short LOS in acute care hospitals may be associated with poor health outcomes for vulnerable older populations after hip fracture.

Maternal use of drugs and preeclampsia.

AIMS: The aim was to compare and describe maternal use of drugs between women with preeclampsia and controls and to estimate the possible association with preeclampsia. METHODS: The study cohort was collected from the Kuopio University Hospital Birth Register, which includes information about all women who gave birth in Kuopio University Hospital during the years 2002-2016, including information from approximately 36 000 parturients, of whom 1252 had preeclampsia. Maternal use of 16 groups of drugs during pregnancy was analysed from all women with preeclampsia and 1256 controls. RESULTS: Every second woman had used at least 1 drug during pregnancy but those with preeclampsia had used significantly more than the controls (cases 59.5% vs controls 35.5%; p < 0.001). In both study groups, the most commonly used drugs were antibiotics (cases 19.5%, controls 17.0%), antihypertensives (cases 29.0%, controls 7.6%) and paracetamol (cases 13.1%, controls 5.9%). Women with preeclampsia had used significantly more benzodiazepines, paracetamol, antihypertensives and acid-suppressive drugs than the women in the control group (p < 0.05). CONCLUSIONS: Women with preeclampsia were more likely to use medicines during pregnancy. While the association between benzodiazepines, antihypertensives and acid-suppressive drugs and preeclampsia may be explained by reverse causation, the association of paracetamol with preeclampsia remains to be clarified. Because paracetamol is a frequently used drug, more information about its safety during pregnancy including its role in preeclampsia is urgently needed.

Duration of new antidepressant use and factors associated with discontinuation among community-dwelling persons with Alzheimer's disease.

PURPOSE: To study how long antidepressants initiated after diagnoses of Alzheimer's disease (AD) were used and factors associated with discontinuation of use among persons with Alzheimer's disease (AD). In addition, differences in duration of use between the antidepressants groups were compared. METHODS: Register-based Medication use and Alzheimer's disease (MEDALZ) cohort included 70,718 community-dwelling people with AD who were diagnosed during the years 2005-2011. For this study, the new antidepressant users were included after 1-year washout period (N = 16,501; 68.6% females, mean age 80.9). The duration of antidepressant use was modeled with the PRE2DUP method. Factors associated with treatment discontinuation were assessed with Cox proportional hazard models and included age, gender, comorbid conditions and concomitant medications. RESULTS: Median duration of the new antidepressant use period was 309 days (IQR 93-830). For selective serotonin reuptake inhibitor (SSRI) use, the median duration was 331 days (IQR 101-829), for mirtazapine 202 days (IQR 52-635), and for serotonin and norepinephrine reuptake inhibitors (SNRIs) 134 days (IQR 37-522). After 1-year follow-up, 40.8% had discontinued antidepressant use, 54.6% after 2 years and 64.1% after 3 years. Factors associated with treatment discontinuation were age over 85, male gender, diabetes, and use of memantine, opioids, and antiepileptics whereas benzodiazepines and related drugs and antipsychotic use were inversely associated with discontinuation. CONCLUSIONS: Antidepressants are used for long-term among people with AD. Need and indication for antidepressant use should be assessed regularly as evidence on their efficacy for behavioral and psychological symptoms of dementia is limited.

Antipsychotic Use and the Risk of Initiating Medication for Benign Prostate Hyperplasia in Persons With Alzheimer Disease: A Matched Cohort Study.

BACKGROUND: Antipsychotics (APs) are known to exacerbate symptoms of benign prostate hyperplasia (BPH) and may even cause urinary retention. The anticholinergic effects of APs and their dopamine D2- and α-receptor blockade may lead to voiding dysfunction of BPH patients. The objective of our study was to investigate whether the use of APs is associated with an increased risk of initiating medication for BPH in men with Alzheimer disease (AD). METHODS: Data from the nationwide MEDALZ (MEDication use and ALZheimer's disease) cohort, including all community-dwelling persons diagnosed with AD in Finland, were utilized. Register-based data included medication dispensing, comorbidities, and hospital discharge diagnoses. Men who initiated APs (n = 4579) were 1:1 matched with men who did not initiate APs (n = 4579), according to time since AD diagnoses and age. The risk of starting BPH medication was investigated with Cox regression. RESULTS: Among AP users, BPH medication was initiated to 345 persons (7.5%). Antipsychotic use was not associated with risk of initiating BPH medication (comorbidity-adjusted hazard ratio, 0.92; 95% confidence interval, 0.74-1.15) compared with no use of APs. In addition, no risk was found when AP drug substances were analyzed separately. CONCLUSIONS: Use of APs did not increase the risk of initiating medication for BPH in men with AD.

Risk of death associated with new benzodiazepine use among persons with Alzheimer disease: A matched cohort study.

OBJECTIVE: To investigate the risk of death associated with new benzodiazepine and related drug (BZDR) use in a nationwide cohort of persons with Alzheimer disease (AD). METHODS: The register-based MEDALZ cohort, including all community-dwelling Finns diagnosed with AD during 2005 to 2011 (n = 70 718), was used. Clinically verified AD diagnoses were obtained from the Special Reimbursement Register. Drug use periods were modeled from BZDR purchases, derived from the Prescription Register. To study new users, persons who had any BZDR use during the year preceding the AD diagnosis were excluded. For each person initiating BZDR use (n = 10 380), 2 nonusers (n = 20 760) were matched on age, gender, and time since AD diagnosis. The outcome was 180-day mortality, and BZDR use was compared with nonuse with Cox regression. Multivariable analyses were adjusted for Charlson comorbidity index, socioeconomic position, hip fractures, psychiatric disorders, substance abuse, stroke, and other psychotropic drug use. RESULTS: During the follow-up, 5 excess deaths per 100 person-years occurred during BZDR use in comparison to nonuse, and mortality rates were 13.4 (95% confidence interval [CI], 12.2-14.5) and 8.5 (95% CI, 7.9-9.1), respectively. Benzodiazepine and related drug use was associated with an increased risk of death (adjusted hazard ratio = 1.4 [95% CI, 1.2-1.6]), and the association was significant from the initiation of use. Benzodiazepine use was associated with an increased risk of death, whereas benzodiazepine-related drug use was not. CONCLUSIONS: Benzodiazepine and related drug use was associated with an increased risk of death in persons with AD. Our results support treatment guidelines stating that nonpharmacological approaches should be the first-line option for symptomatic treatment of AD.

Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease.

BACKGROUND: Knowledge regarding whether benzodiazepines and similarly acting non-benzodiazepines (Z-drugs) are associated with an increased risk of pneumonia among older adults is lacking. We sought to investigate this association among community-dwelling adults with Alzheimer disease, a condition in which both sedative/hypnotic use and pneumonia are common. METHODS: We obtained data on all community-dwelling adults with a recent diagnosis of Alzheimer disease in Finland (2005-2011) from the Medication use and Alzheimer disease (MEDALZ) cohort, which incorporates national registry data on prescriptions, reimbursement, hospital discharges and causes of death. Incident users of benzodiazepines and Z-drugs were identified using a 1-year washout period and matched with nonusers using propensity scores. The association with hospital admission or death due to pneumonia was analyzed with the Cox proportional hazards model and adjusted for use of other psychotropic drugs in a time-dependent manner. RESULTS: Among 49 484 eligible participants with Alzheimer disease, 5232 taking benzodiazepines and 3269 taking Z-drugs were matched 1:1 with those not taking these drugs. Collectively, use of benzodiazepines and Z-drugs was associated with an increased risk of pneumonia (adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.05-1.42). When analyzed separately, benzodiazepine use was significantly associated with an increased risk of pneumonia (adjusted HR 1.28, 95% CI 1.07-1.54), whereas Z-drug use was not (adjusted HR 1.10, 95% CI 0.84-1.44). The risk of pneumonia was greatest within the first 30 days of benzodiazepine use (HR 2.09, 95% CI 1.26-3.48). INTERPRETATION: Benzodiazepine use was associated with an increased risk of pneumonia among patients with Alzheimer disease. Risk of pneumonia should be considered when weighing the benefits and risks of benzodiazepines in this population.

Incidence of antidepressant use in community-dwelling persons with and without Alzheimer's disease: 13-year follow-up.

OBJECTIVES: The study aimed to investigate the incidence of antidepressant use in persons with and without Alzheimer's disease (AD) from 9 years before to 4 years after AD diagnosis and to examine the incidence of different antidepressant groups. METHODS: We used register-based data from the Medication use and Alzheimer's disease cohort including all Finnish persons diagnosed with AD in 2005-2011 with their age-matched and gender-matched comparison persons without AD. In this study, 62,104 persons with AD and 62,104 comparison persons were included. Data on dispensed antidepressants during 1995-2012 were collected from the Prescription Register. A 1-year washout period was utilized to measure the rate of new antidepressant users every 6-month period starting from 9 years before and until 4 years after the AD diagnoses. The incidence rate between persons with and without AD was compared with Poisson regression. RESULTS: The incidence of antidepressant use in persons with AD was higher during the whole study period compared with that in persons without AD. The incidence rate was highest at 6 months after AD diagnosis (incidence rate ratio = 5.22, 95% confidence interval 4.77-5.72). Selective serotonin reuptake inhibitors were the most frequently initiated group (61.3% of initiations in persons with AD). CONCLUSIONS: The incidence of antidepressant use was higher in persons with AD than in comparison persons, and it was not explained by history of hospital-treated psychiatric disorders. Widespread use of antidepressants in persons with AD is concerning as their efficacy is controversial and their use is associated with adverse events. Copyright © 2016 John Wiley & Sons, Ltd.

Antidepressant use and risk of hip fractures among community-dwelling persons with and without Alzheimer's disease.

OBJECTIVE: To study whether antidepressant use is associated with an increased risk of hip fracture among community-dwelling persons with and without Alzheimer's disease (AD), and to compare the risk according to duration of use and between antidepressant groups. METHODS: Retrospective cohort study, including 50,491 persons with AD (mean age 80) and 100,982 comparison persons without AD from Finnish register-based MEDALZ cohort. Antidepressant use was compared with nonuse with Cox proportional hazard models. Incident users were identified with a one year washout period from Prescription register data. Main outcome was hospitalization due to hip fracture. RESULTS: During antidepressant use, the age-adjusted rate of hip fractures per 100 person-years was 3.01 (95% CI 2.75-3.34) among persons with and 2.28 (1.94-2.61) among persons without AD. Antidepressant use was associated with an increased risk of hip fracture among persons with and without AD (adjusted HR 1.61, 95% CI 1.45-1.80 and 2.71, 2.35-3.14, respectively) compared with nonuse. The risk was most prominent in the beginning of use and was elevated even up to 4 years. The risk was increased with all of the most frequently used antidepressants. CONCLUSION: Antidepressant use is associated with an increased risk of hip fracture among older persons. Copyright © 2017 John Wiley & Sons, Ltd.

Screening approach for identifying candidate drugs and drug-drug interactions related to hip fracture risk in persons with Alzheimer disease.

PURPOSE: To assess whether a "drugome-wide" screen with case-crossover design is a feasible approach for identifying candidate drugs and drug-drug interactions. METHODS: All community-dwelling residents of Finland who received a clinically verified Alzheimer disease diagnosis in 2005 to 2011 and experienced incident hip fracture (HF) afterwards (N = 4851). Three scenarios were used to test the sensitivity of this approach (1) hazard period 0 to 30 and control period 31 to 61 days before HF, (2) hazard period 0 to 30 and control period 336 to 366 days before HF, and (3) hazard period 0 to 14 and control period 16 to 30 days before HF. RESULTS: Nine, 44, and 5 drugs were associated with increased HF risk and 8, 23, and 4 with decreased risk in scenarios 1, 2, and 3, respectively. Six drugs were identified with scenario 1 only and 54 and 1 with scenarios 2 and 3, respectively. Only six drugs (metoprolol, simvastatin, trimethoprim, codeine combinations, fentanyl, and paracetamol) were associated with HF in all scenarios, four with 1 and 2 (cefalexin, buprenorphine, olanzapine, and memantine), and one with 1 and 3 (enalapril) or 2 and 3 (ciprofloxacin). The direction of associations was the same in all/both scenarios. The interaction results were equally versatile, with hydroxocobalamin*oxazepam being the only interaction observed in all scenarios. CONCLUSIONS: Case-crossover analysis is a potential approach for identifying candidate drugs and drug-drug interactions associated with adverse events as it implicitly controls for fixed confounders. The results are highly dependent on applied hazard and control periods, but the choice of periods can help in targeting the analyses to different phases of drug use.

Drug use in persons with and without Alzheimer's disease aged 90 years or more.

BACKGROUND: increasing number of persons reach very high age but few studies have investigated their drug use patterns. OBJECTIVE: to compare drug use among persons with Alzheimer's disease (AD) aged ≥90 years to persons without AD with similar age and to younger persons with AD. DESIGN: register-based data were from the MEDALZ cohort including all community-dwelling persons diagnosed with AD 2005-11 in Finland. They were identified from Special Reimbursement register. One comparison person without AD was matched with age-, gender- and region of residence. Persons with AD were divided to those aged ≥90 years (N = 3,319) and <90 years (N = 63,896) at the time of AD diagnoses. Drug use was analysed during a 6-month period after AD diagnosis. Logistic regression models were constructed to compare prevalence of drug use. RESULTS: compared to comparison persons without AD with similar age, persons with AD aged ≥90 years were more likely to use antipsychotics (comorbidity adjusted odds ratio [aOR] 4.84, 95% CI 4.07-5.75; CI, confidence intervals) and antidepressants (aOR 2.45, 95% CI 2.14-2.80). In addition, persons with AD used more likely preventive drugs such as statins (aOR 1.20, 95% CI 1.04-1.38) and bisphosphonates (aOR 1.33, 95% CI 1.13-1.57). Compared to younger persons with AD, those aged ≥90 years were more likely to use psychotropic drugs (55.6% vs. 48.4%, aOR 1.30, 95% CI 1.21-1.39), including antipsychotics (aOR 1.40, 95% CI 1.28-1.52) and BZDRs (aOR 1.34, 95% CI 1.25-1.45). CONCLUSIONS: the vulnerable oldest persons with AD receive a substantial burden of psychotropics.