Long-Term Risk of Dementia in Persons with Schizophrenia a Danish Population-Based Cohort Study

Research

Original Investigation Long-term Risk of Dementia in Persons With Schizophrenia A Danish Population-Based Cohort Study

† Anette Riisgaard Ribe, MD; Thomas Munk Laursen, PhD; Morten Charles, MD, PhD; Wayne Katon, MD ; Morten Fenger-Grøn, MSc; Dimitry Davydow, MD, MPH; Lydia Chwastiak, MD, MPH; Joseph M. Cerimele, MD, MPH; Mogens Vestergaard, MD, PhD

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IMPORTANCE Although schizophrenia is associated with several age-related disorders and Supplemental content at considerable cognitive impairment, it remains unclear whether the risk of dementia is higher jamapsychiatry.com among persons with schizophrenia compared with those without schizophrenia.

OBJECTIVE To determine the risk of dementia among persons with schizophrenia compared with those without schizophrenia in a large nationwide cohort study with up to 18 years of follow-up, taking age and established risk factors for dementia into account.

DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study of more than 2.8 million persons aged 50 years or older used individual data from 6 nationwide registers in Denmark. A total of 20 683 individuals had schizophrenia. Follow-up started on January 1, 1995, and ended on January 1, 2013. Analysis was conducted from January 1, 2015, to April 30, 2015.

MAIN OUTCOMES AND MEASURES Incidence rate ratios (IRRs) and cumulative incidence proportions (CIPs) of dementia for persons with schizophrenia compared with persons without schizophrenia.

RESULTS During 18 years of follow-up, 136 012 individuals, including 944 individuals with a history of schizophrenia, developed dementia. Schizophrenia was associated with a more than 2-fold higher risk of all-cause dementia (IRR, 2.13; 95% CI, 2.00-2.27) after adjusting for age, sex, and calendar period. The estimates (reported as IRR; 95% CI) did not change substantially when adjusting for medical comorbidities, such as cardiovascular diseases and diabetes mellitus (2.01; 1.89-2.15) but decreased slightly when adjusting for substance abuse (1.71; 1.60-1.82). The association between schizophrenia and dementia risk was stable when evaluated in subgroups characterized by demographics and comorbidities, although the IRR was higher among individuals younger than 65 years (3.77; 3.29-4.33), men (2.38; 2.13-2.66), Author Affiliations: Research Unit individuals living with a partner (3.16; 2.71-3.69), those without cerebrovascular disease (2.23; for General Practice, Department of 2.08-2.39), and those without substance abuse (1.96; 1.82-2.11). The CIPs (95% CIs) of Public Health, Aarhus University, Aarhus, Denmark (Ribe, Fenger-Grøn, developing dementia by the age of 65 years were 1.8% (1.5%-2.2%) for persons with Vestergaard); National Centre for schizophrenia and 0.6% (0.6%-0.7%) for persons without schizophrenia. The respective CIPs Register-Based Research, for persons with and without schizophrenia were 7.4% (6.8%-8.1%) and 5.8% (5.8%-5.9%) Department of Economics and by the age of 80 years. Business, Aarhus University, Aarhus, Denmark (Laursen); Section for General Medical Practice, CONCLUSIONS AND RELEVANCE Individuals with schizophrenia, especially those younger than Department of Public Health, Aarhus 65 years, had a markedly increased relative risk of dementia that could not be explained by University, Aarhus, Denmark (Charles, Vestergaard); Department established dementia risk factors. of Psychiatry and Behavioral Sciences, School of Public Health, University of Washington, Seattle (Katon, Davydow, Chwastiak, Cerimele). Corresponding Author: Anette Riisgaard Ribe, MD, Research Unit for General Practice, Department of Public Health, Aarhus University, JAMA Psychiatry. 2015;72(11):1095-1101. doi:10.1001/jamapsychiatry.2015.1546 Bartholins Allé 2, Aarhus C, Jutland Published online October 7, 2015. 8000, Denmark ([email protected]).

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ementia is one of the major challenges for modern health care1 and places a substantial financial burden Methods D on society.2 The disorder is a clinical syndrome characterized by cognitive decline and impairment in activities of A population-based cohort study was conducted from Janu- daily living.1 In the Western world, dementia affects 5% to 6% ary 1, 1995, to January 1, 2013, using information on Danish citi- of persons older than 60 years.3 The prevalence of dementia zens from nationwide registries. All data are recorded with ref- is expected to double every 20 years through 2040 owing to erence to a civil registration number, which is a unique personal changes in population demographics and increased life identification number assigned to all Danish residents. This expectancy.3 number permits accurate linkage of recorded information at Schizophrenia affects approximately 1% of the population.4 the personal level.21 Until December 31, 1993, the diagnostic The disorder is associated with disturbances in perception, system used in the Danish registers was the Danish version of communication, and thought process as well as abnormali- the International Classification of Diseases, Eighth Revision ties in behavior.5 These disturbances often lead to substantial (ICD-8).22 From January 1, 1994, the Danish version23 of the functional impairment and social disability.6 Historically, ICD-10 was used. Analysis was conducted from January 1, 2015, schizophrenia was named dementia praecox by Kraepelin,7 as to April 30, 2015. deficits in memory, attention, and visuospatial orientation The study was approved by the Danish Data Protection are hallmarks of the disorder.8 Mounting evidence supports a Agency and the Danish Health and Medicine Authority. No in- neurodevelopmental origin for schizophrenia (ie, genetic vul- formed consent from participants was needed as data were ana- nerabilities interact with prenatal or perinatal exposures) as lyzed anonymously. Since the study was entirely based on reg- well as a neurodegenerative origin for schizophrenia (ie, pro- ister data, no ethical permission was required according to gressive deterioration of the central nervous system).9,10 Fur- Danish law. thermore, it has been proposed that individuals with schizophrenia experience an “accelerated aging” that contributes to Procedures their reduced life expectancy.11 This theory is biologically Study Population plausible as schizophrenia is associated with premature We used the Danish Civil Registration System21 to establish a death owing to age-related disorders, such as diabetes melli- population-based cohort consisting of all persons who were tus, cancer, and cardiovascular disease,12-14 but also because born in Denmark; alive on January 1, 1995; and aged 50 years of shared risk factors between schizophrenia and age-related or older at some point between 1995 and 2013. The Civil Reg- disorders (ie, advanced paternal age, low birth weight, and istration System includes information on sex and date of birth specific genes).11 as well as continuously updated information on vital status and Nevertheless, the association between schizophrenia and migration since 1968. the risk of subsequent dementia remains unclear. Four prior studies have compared the risk of dementia among persons Schizophrenia with vs those without schizophrenia using clinical dementia Information on schizophrenia was obtained from the Danish diagnoses, and their findings ranged from a 2.4-fold to a Psychiatric Central Research Register (DPCR),24 which con- 16-fold higher risk of developing dementia.15-18 However, those tains information on all admissions to psychiatric hospitals in studies were limited because they did not include individu- Denmark since 1969 and outpatient mental health contacts (ie, als with onset of schizophrenia before the age of 30 years16-18 psychiatric ambulatory care) since 1995. All inpatient admis- (potentially effecting generalizability, as the majority of per- sions to and outpatient contacts (excluding emergency con- sons with schizophrenia are diagnosed before the age of 30 tacts) with a psychiatric hospital for schizophrenia between years19) or had an insufficient duration of follow-up for the co- 1969 and 2013 were identified (eTable 1 in the Supplement). hort to display a clinically significant risk of developing dementia.15 Furthermore, a recent review of 20 longitudinal Dementia studies using cognitive screening tools or neuropsychological Information on dementia was obtained by combining data re- tests to examine the risk of cognitive decline (ie, beyond corded in the Danish National Patient Register (DNPR),25 the what can be attributed to the pathophysiologic factors of DPCR, and the Danish National Prescription Registry.26 The schizophrenia itself) in persons with schizophrenia found DNPR contains information on all medical hospital admis- inconsistent results: 12 studies suggested significant cogni- sions in Denmark since 1977 and outpatient medical contacts tive decline, whereas 8 studies did not find a significant since 1995. The Danish National Prescription Registry con- association.20 tains information on all prescriptions dispensed at Danish phar- Using administrative data, we aimed to estimate the risk macies since 1995, including information on day of purchase of dementia in all persons with schizophrenia compared with and classification of drugs according to the Anatomical Thera- persons without schizophrenia using a population-based co- peutic Chemical Classification System.27 The diagnostic hort with sufficient sample size and follow-up time and a suf- workup of dementia is considered a specialist task in Den- ficient induction period for the cohort to display a clinically mark, which includes cognitive testing, assessment of activi- significant risk of dementia. This study also takes into ac- ties of daily living, psychiatric evaluation, neuroimaging, physi- count established risk factors of dementia, such as cardiovas- cal examination, and laboratory testing.28 Approximately cular disease, diabetes, and substance abuse (SA). two-thirds of dementia cases are diagnosed within the sec-

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ondary care setting and recorded in the registries.29 Hospital- Table 1. Entry Into Study, Exit From Study, Onset of Schizophrenia, based outpatient clinics from the disciplines of psychiatry, geri- Onset of Dementia, and Mean Follow-up Time atrics, and neurology assess patients with cognitive deficits as Characteristic Years, Mean (SD) part of their general service,29 and 74% of dementia diagno- Age ses in the registries are made by health care professionals from Entry into study 58.7 (11.2) 1 of these 3 specialties.28,29 All inpatient or outpatient con- Exit from study 69.7 (12.1) tacts with a medical or psychiatric hospital for dementia a between 1969 and 2013 were identified according to a vali- Onset of schizophrenia 44.6 (14.6) dated algorithm.29 In addition, we included information on Onset of dementia 80.6 (8.6) prescriptions for anti-dementia drugs (ie, cholinesterase Follow-up time in study 11.0 (6.0) inhibitors, memantine) filled between 1995 and 2013 (eTable a This analysis was carried out in a subgroup of persons diagnosed with 2intheSupplement). All persons with a dementia diagnosis schizophrenia after 1975 (n = 15 581) to ensure that these were incident cases. before January 1, 1995, were excluded to ensure inclusion of only incident cases. cal comorbidity, and SA. Second, we evaluated the association between schizophrenia and dementia after restricting our Comorbid Illnesses dementia definition to diagnoses from the registers and diag- Information on comorbid chronic conditions known to be risk noses from the DPCR. Finally, we compared the effect of early- factors for dementia but also known to occur with higher in- and late-onset schizophrenia (before or after the age of 40 cidence in persons with schizophrenia included diabetes years, respectively) in the subgroup of persons diagnosed with mellitus,30,31 ischemic heart disease (IHD),32-34 congestive heart schizophrenia after 1975 or at an age younger than 40 years. failure (CHF),33,35 atrial fibrillation or flutter,35,36 peripheral vas- We stratified the follow-up on persons younger than 65 years cular disease (PVD),33,34 cerebrovascular disease,30,33 and vs older than 65 years to account for the correlation between SA.30,37 Information on medical comorbidities other than dia- age at onset of schizophrenia and age under risk in the study. betes was obtained from the DNPR for the period between 1977 All IRRs were adjusted for age, sex, and calendar period. All and 2013 (eTable 3 in the Supplement). Information on diabe- variables, with the exception of sex, were treated as time- tes was obtained from the Danish National Diabetes Register38 dependent variables. Adjustments for age and calendar pe- for the period between 1990 and 2013 using a validated algo- riod were performed using 2-year age bands and 1-year time rithm (eTable 4 in the Supplement).14,38 Information on SA bands, respectively. We used 2-sided significance tests for all (excluding tobacco abuse) was obtained from the DPCR or the analyses, with P < .05 considered signficant. DNPR for the period between 1969 and 2013 (eTable 5 in the Cumulative incidence proportions (CIPs) for the out- Supplement). come of all-cause dementia were estimated between the ages of 50 and 90 years for persons with and without schizophre- Civil Status nia. Aalen-Johansen curves were used with age as the time scale Information on civil status between 1995 and 2013, dichoto- and competing risk of death was taken into account. Point es- mized into living with a partner (ie, marriage, registered part- timates with corresponding 95% CIs were calculated for the nership, or cohabitation) or living alone (ie, living without a risk of dementia at the ages of 65 and 80 years. Analyses were partner, including widows and widowers), was obtained performed with appropriate components of the STATA, ver- from Statistics Denmark,39 which provides a data bank with sion 13, statistical software program (StataCorp). societal information on all residents in Denmark from 1980 onward. Results Statistical Analysis Follow-up started on January 1, 1995, or the person’s 50th birth- We observed 2 845 440 individuals for up to 18 years (mean, day, whichever came last, and ended on January 1, 2013, on 11.0 years) (Table 1), of whom 20 683 had or developed the date of a diagnosis of dementia, on the person’s 100th birth- schizophrenia. Overall, 136 012 individuals developed day, on the day of emigration, or on the day of death, which- dementia, including 944 individuals with a history of schizo- ever came first. phrenia (Table 2). Incidence rate ratios (IRRs) for dementia, comparing per- Schizophrenia was associated with a more than 2-fold sons with and without schizophrenia, were calculated using higher risk of dementia (IRR, 2.13; 95% CI, 2.00-2.27) when log-linear Poisson regression analysis with the logarithm of the compared with persons without schizophrenia (Figure 1). person-years as an offset variable. We fitted 4 survival analy- Adjusting this estimate for civil status and medical comor- sis models to the dementia outcome and adjusted stepwise for bidities did not change the estimate substantially (civil demographics (ie, age, sex, and calendar period), civil status, status: IRR, 1.98; 95% CI, 1.86-2.12; comorbidities: IRR, 2.01; medical comorbidity (ie, a diagnosis of diabetes, IHD, CHF, 95% CI, 1.89-2.15), whereas the adjustment for SA attenuated atrial fibrillation or flutter, PVD, and cerebrovascular the association (IRR, 1.71; 95% CI, 1.60-1.82). disease), and SA. We conducted 3 subanalyses. First, we evalu- The association between schizophrenia and dementia risk ated the association between schizophrenia and dementia in was stable when evaluated in subgroups characterized by de- subgroups characterized by demographics, civil status, medi- mographics and comorbidities, although the IRR was higher

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2.2%) for persons with schizophrenia compared with 0.6% Table 2. Number of Incident Cases of Dementia and Person-years at Risk (95% CI, 0.6%-0.7%) for persons without schizophrenia, Incident Dementia, Person-years whereas the corresponding CIPs by the age of 80 years were Variable No. (%) at Risk Total dementia cases 136 012 (100) 31 347 186 7.4% (95% CI, 6.8%-8.1%) and 5.8% (95% CI, 5.8%-5.9%), Age for dementia onset, y respectively (Figure 2). <65 8750 (6.4) 18 341 908 ≥65 127 262 (93.6) 13 005 278 Sex Discussion Men 52 901 (38.9) 14 763 666 This large, population-based cohort study showed that the risk Women 83 111 (61.1) 16 583 520 of dementia was more than 2-fold higher in persons with Calendar period schizophrenia compared with those without schizophrenia. 1995-1998 20 828 (15.3) 6 521 515 The relative risk of dementia was almost 4-fold higher among 1999-2002 29 109 (21.4) 6 812 298 individuals younger than 65 years. In absolute numbers, 7.4 2003-2006 34 422 (25.3) 7 026 506 of 100 persons with schizophrenia developed dementia be- 2007-2010 34 261 (25.2) 7 261 185 fore the age of 80 years compared with 5.8 of 100 persons with- 2011-2012 17 392 (12.8) 3 725 682 out schizophrenia. Civil status Persons with schizophrenia may be at higher risk of de- Living with a partnera 50 581 (37.2) 20 657 637 veloping dementia for several reasons. First, persons with Living aloneb 85 309 (62.7) 10 562 712 schizophrenia are at increased risk of developing several Missing 122 (0.1) 126 837 chronic conditions, which are also well-established risk fac- Schizophrenia tors for dementia, including diabetes mellitus,30,31 IHD,32-34 No 135 068 (99.3) 31 170 435 CHF,33,35 atrial fibrillation or flutter,35,36 PVD,33,34 cerebrovas- 30,33 30,37 Yes 944 (0.7) 176 751 cular disease, and SA. The risk of dementia in per- Comorbidity sons with schizophrenia decreased when adjusted for Diabetes mellitus 19 935 (14.7) 2 492 805 SA, which suggested that comorbid SA is an important con- Ischemic heart disease 25 709 (18.9) 2 931 237 founder or an intermediate variable for the association. In con- Congestive heart failure 12 731 (9.4) 866 699 trast, the association was unaffected when adjusting for other Atrial fibrillation or flutter 16 273 (12.0) 1 148 610 comorbidities or for civil status. However, the excess risk ac- counted for by comorbidity could be underestimated, as physi- Peripheral vascular disease 8834 (6.5) 908 392 cal conditions may be underdiagnosed among persons with Cerebrovascular disease 30 496 (22.4) 1 916 734 schizophrenia.32,40 Because the IRR estimate varied when Substance abuse 8193 (6.0) 1 131 903 evaluated for age, civil status, SA, and cerebrovascular dis- a Living with a partner included persons living in marriage, registered ease, these factors seem to modify the association between partnership, or cohabitation. schizophrenia and dementia risk. We were unable to include b Living alone included widows and widowers. information on educational level or adverse health risk factors (ie, smoking, sedentary lifestyle, and high body mass among individuals younger than 65 years (IRR, 3.77; 95% CI, index) that might be associated with risk of dementia, 3.29-4.33), men (IRR, 2.38; 95% CI, 2.13-2.66), those living with which introduced the possibility of residual confounding. In a partner (IRR, 3.16; 95% CI, 2.71-3.69), those without cere- summary, potentially modifiable factors such as comorbid- brovascular disease (IRR, 2.23; 95% CI, 2.08-2.39), and those ity or adverse health risk factors cannot be excluded as without SA (IRR, 1.96; 95% CI, 1.82-2.11) (Figure 1). important opportunities to prevent dementia in persons The IRR estimate was unaffected by restricting the de- with schizophrenia. mentia definition to the 129 546 diagnoses recorded in the reg- More recently, some researchers have proposed acceler- isters (ie, DNPR and DPCR) (IRR, 2.19; 95% CI, 2.05-2.34), but ated aging as one of the explanations for the reduced the estimate was slightly higher after restricting the demen- longevity in persons with schizophrenia.11 In line with this tia definition to the 63 323 diagnoses from the DPCR (IRR, 2.57; hypothesis, a recent British study identified patterns of 95% CI, 2.37-2.80). The risk of dementia was lower for per- macrostructural abnormalities in magnetic resonance sons with early- vs late-onset schizophrenia among persons images of the brain that are seen in both schizophrenia and younger than 65 years (early-onset: IRR, 2.83; 95% CI, 2.31- Alzheimer disease, revealing a connection between the 3.48; late-onset: IRR, 4.19; 95% CI, 3.49-5.02; P = .005) and 2 disorders.41 These findings indicate that both neurobio- among persons older than 65 years (early-onset: IRR, 1.40; 95% logical and environmental factors could contribute to the CI, 1.14-1.74; late-onset: IRR, 1.86; 95% CI, 1.70-2.04; P =.02). excess risk of dementia in persons with schizophrenia. Among persons with dementia, the diagnosis was made Four previous longitudinal studies identified a total of 196 before the age of 65 years for 22.4% (211 of 944) of persons with persons with schizophrenia who developed a clinical demen- schizophrenia and for 6.3% (8539 of 135 068) of persons with- tia diagnosis15-18; the studies found relative risks for the de- out schizophrenia (Figure 1). The absolute risk of developing velopment of dementia ranging from 2.4 to 16. As the median dementia (ie, CIP) by the age of 65 years was 1.8% (95% CI, 1.5%- age at onset is 28 years for schizophenia19 and 81 years for

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Figure 1. Incident Rate Ratios (IRRs) for Dementia in Persons With Schizophrenia Compared With Persons Without Schizophrenia

Dementia, No. Persons Without Persons With Variable Schizophrenia Schizophrenia IRR (95% CI) Calendar period 1995-199820 697 131 1.91 (1.61-2.27) 1999-200228 933 176 1.81 (1.56-2.09) 2003-200634 188 234 2.11 (1.86-2.40) 2007-201033 981 280 2.58 (2.29-2.90) 2011-201217 269 123 2.21 (1.85-2.64) Age, y <658539 211 3.77 (3.29-4.33) ≥65126 529 733 1.89 (1.76-2.04) Sex Women82 486 625 2.02 (1.86-2.18) Men52 582 319 2.38 (2.13-2.66) Civil status Living with a partner50 418 163 3.16 (2.71-3.69) Living alone84 530 779 1.71 (1.59-1.83) Diabetes mellitus No115 309 768 2.12 (1.98-2.28) Yes19 759 176 1.95 (1.68-2.26) IHD No109 486 817 2.12 (1.98-2.28) Yes25 582 127 2.27 (1.91-2.71) CHF No122 414 867 2.15 (2.01-2.29) Yes12 654 77 1.82 (1.45-2.27) AF The IRRs were adjusted for age, sex, No118 850 889 2.16 (2.02-2.31) and calendar period and were Yes16 218 55 2.10 (1.61-2.74) stratified for age, sex, calendar PVD period, civil status, medical No126 267 911 2.16 (2.02-2.30) comorbidity, or substance abuse. The Yes8801 33 1.75 (1.24-2.47) estimates differed significantly when Cerebrovascular disease evaluated for age (P < .001), sex No104 731 785 2.23 (2.08-2.39) (P = .02), civil status (P < .001), Yes30 337 159 1.71 (1.47-2.00) cerebrovascular disease (P = .002), Substance abuse and substance abuse (P < .001). The No127 099 720 1.96 (1.82-2.11) vertical dotted line represents the Yes7969 224 1.09 (0.95-1.24) overall estimate without stratification Total135 068 944 2.13 (2.00-2.27) (IRR, 2.13). AF indicates atrial fibrillation or flutter; CHF, congestive 1.0 2.0 3.0 4.0 5.0 heart failure; IHD, ischemic heart IRR (95% CI) disease; IRR, incidence rate ratio; and PVD, peripheral vascular disease. dementia,42 it is difficult to establish studies with sufficient Our study was also limited by a lack of important clinical size and follow-up time to include all persons with schizo- information. Most important, the validity of a dementia diag- phrenia and allow for a sufficient induction period between a nosis among persons with schizophrenia is unknown. It can diagnosis of schizophrenia and a diagnosis of dementia. Three be a challenge to diagnose dementia in persons with schizo- of the previous studies included only persons with onset of phrenia owing to preexisting cognitive dysfunction, negative schizophrenia after the age of 30 years,16-18 which may im- symptoms, and behavioral problems.5,8,45 However, the diag- pede generalizability of the results for most persons with nosis of dementia has high validity for other disorders with pre- schizophrenia who are diagnosed before the age of 30 years,19 existing cognitive impairments, such as Down syndrome.46 In and the fourth study was limited by a small sample size.15 Denmark, neurologists, psychiatrists, and geriatricians make Our study used a large population-based cohort with com- most dementia diagnoses, and their diagnoses of dementia plete follow-up and sufficient observation time for most of the have a PPV of 95%.28 It is most likely that persons with schizo- cohort to display a clinically significant risk of dementia. There- phrenia are referred to a psychiatrist if dementia is suspected fore, selection bias and loss to follow-up cannot explain our owing to the patient’s preexisting psychiatric disease. The as- findings. Information on schizophrenia and dementia has high sociation between schizophrenia and dementia was slightly validity, which minimized the risk of information bias. The stronger when the analysis was restricted to a subgroup of per- positive predictive value (PPV) has been shown to be 87% for sons diagnosed by psychiatrists. Because schizophrenia is schizophrenia in the DPCR43 and 86% for all-cause dementia associated with preexisting cognitive impairment, such indi- in the DPCR and the DNPR,42 although the PPV for dementia viduals might experience dementia-like symptoms at an ear- diagnoses has been shown to be as low as 59% among indi- lier age compared with persons without schizophrenia. How- viduals younger than 65 years.44 ever, according to the definition of a dementia diagnosis, a loss

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the cross-sectional diagnosis of a physician seeing the pa- Figure 2. Cumulative Incidence Proportions of Risk of Dementia in Persons With and Without Schizophrenia as a Function of Age tient for a diagnostic workup. Because approximately two-thirds of all cases of demen- 15 tia in Denmark are diagnosed within the secondary health care system,29 some cases of dementia diagnosed in primary care or private psychiatric and neurologic practices are not referred to the secondary health care system. Consequently, 10 some of these cases are not included in our study, unless With schizophrenia these cases are registered with dementia at a subsequent hospitalization or if they fill prescriptions for anti-dementia 5 drugs. In addition, this study was conducted in a country with free and equal access to health care, and the association Without schizophrenia

Cumulative Incidence Proportion,Cumulative % may not apply to other types of health care systems. How-

0 ever, this scenario limits potential bias induced by incentives 50 55 60 65 70 75 80 85 90 for diagnosing dementia in persons with schizophrenia to Age, y improve their access to health care. Persons with schizophrenia die, on average, 15 to 20 years The cumulative probability of dementia and corresponding 95% CIs (dashed prematurely compared with the general population.48 Conse- lines) are presented as a function of age for persons with and without schizophrenia, taking competing risk of all-cause mortality into account. The quently, those who live long enough to develop dementia 95% CIs are very narrow for persons without schizophrenia owing to the large would represent a selected group of more healthy persons, and sample size and thus are not discernible in this graph. our results could thereby underestimate the true risk of dementia in persons with schizophrenia. This theory was also supported by our finding of a lower CIP of dementia for per- of cognitive function compared with baseline is required. sons with schizophrenia after their mid-80s (compared with Therefore, we expect that physicians, and in particular psy- persons without schizophrenia at the same age) owing to the chiatrists, diagnose only severe cognitive impairment, be- reduced life expectancy of this population. yond that which can be attributed to schizophrenia in and of itself, as dementia. Moreover, there is the risk that even subtle cognitive deficits or behavioral problems in persons with Conclusions schizophrenia could be interpreted as signs of dementia by physicians with less knowledge of the psychopathological Persons with schizophrenia may be at high risk of developing features of schizophrenia, which would overestimate the as- dementia. The relative risk appears to be particularly high in sociation. On the other hand, dementia may also be underdi- persons younger than 65 years with schizophrenia. The re- agnosed in persons with schizophrenia owing to misattribu- sults did not change substantially after adjusting for estab- tion of dementia symptoms to the schizophrenia in and of lished risk factors of dementia, such as cardiovascular dis- itself (ie, diagnostic overshadowing47) and owing to under- ease and diabetes, although the association attenuated slightly diagnosing of comorbidity in general in persons with after adjusting for SA. Thus, additional studies are warranted schizophrenia,32,40 which would underestimate the associa- to elucidate the pathophysiologic factors of the link between tion. Finally, the data here are strongly suggestive but require schizophrenia and dementia, and more knowledge is needed longitudinal verification of decline in function well beyond age to develop targeted interventions to prevent dementia in this expectation to confirm that these are true dementias and not high-risk population.

ARTICLE INFORMATION intellectual content: All authors. REFERENCES †Died March 1, 2015. Statistical analysis: Ribe, Laursen, Fenger-Grøn. 1. van der Flier WM, Scheltens P. Epidemiology and Obtained funding Ribe, Vestergaard. Submitted for Publication: May 12, 2015; final risk factors of dementia. J Neurol Neurosurg Administrative, technical, or material support: Ribe. Psychiatry. 2005;76(suppl 5):v2-v7. revision received July 18, 2015; accepted July 19, Study supervision: Ribe, Laursen, Charles, Katon, 2015. Davydow, Vestergaard. 2. Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs of dementia in the Published Online: October 7, 2015. Conflict of Interest Disclosures: None reported. doi:10.1001/jamapsychiatry.2015.1546. United States. N Engl J Med. 2013;368(14):1326-1334. Funding/Support: This study was supported by Author Contributions: Dr Ribe had full access to all 3. Reitz C, Brayne C, Mayeux R. Epidemiology of unrestricted grant R155-2012-11280 from the Alzheimer disease. Nat Rev Neurol. 2011;7(3):137-152. the data in the study and takes responsibility for the Lundbeck Foundation, the Augustinus Foundation, integrity of the data and the accuracy of the data and the Reinholdt W. Jorck and Wife Foundation. 4. Laursen TM, Agerbo E, Pedersen CB. Bipolar analysis. disorder, schizoaffective disorder, and Study concept and design: Ribe, Laursen, Charles, Role of the Funder/Sponsor: The funding sources schizophrenia overlap: a new comorbidity index. Katon, Chwastiak, Vestergaard. had no role in the design and conduct of the study; J Clin Psychiatry. 2009;70(10):1432-1438. Acquisition, analysis, or interpretation of data: Ribe, collection, management, analysis and interpretation of the data; preparation, review, or 5. Flaum M, Schultz SK. The core symptoms of Laursen, Charles, Katon, Fenger-Grøn, Davydow, schizophrenia. Ann Med. 1996;28(6):525-531. Cerimele, Vestergaard. approval of the manuscript; and decision to submit Drafting of the manuscript: Ribe. the manuscript for publication. 6. Viertiö S, Tuulio-Henriksson A, Perälä J, et al. Critical revision of the manuscript for important Activities of daily living, social functioning and their

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