Treatment with antidepressants in patients with ...

C 2006 International Psychogeriatric Association International Psychogeriatrics (2007), 19:5, 902–913 doi:10.1017/S1041610206004376 Printed in the United Kingdom

Treatment with antidepressants in patients with dementia – a nationwide register-based study ..............................................................................................................................................................................................................................................................................

Lars Vedel Kessing,1 Mette Harhoff2 and Per Kragh Andersen2 1 2

Department of Psychiatry, Rigshospitalet, University of Copenhagen, Denmark Department of Biostatistics, University of Copenhagen, Denmark

ABSTRACT

Background: Depression and anxiety is prevalent among patients with dementia but the extent to which these conditions are treated with antidepressants has not previously been investigated. Methods: Nationwide register-based data in Denmark were used to identify all patients diagnosed with dementia or osteoarthritis at hospital admission or at first outpatient contact during the period 1995–2000. Rates of subsequent purchase of antidepressants from pharmacies were then calculated. Further, the rate of antidepressant use for patients with dementia was compared with the rate in a gender-, age-, and calendar-matched sample of the general population. Results: In total, 24,137 patients with a main diagnosis of dementia and 100,378 patients with a main first diagnosis of osteoarthritis were incorporated in the study. A total of 43.2% of patients with dementia received antidepressants during follow-up compared to 16.0% of patients with osteoarthritis. Among patients with a diagnosis of dementia, the rate of subsequently purchasing antidepressants was 4.17 times higher (95% CI = 4.05–4.29) than that of patients with a first diagnosis of osteoarthritis, and 8.85 times higher (95% CI = 8.68–9.03) than that of a gender-, age- and calendar-matched sample of the general population. The rate was increased in all subgroups of patients regardless of gender, age, socio-economic group and time since diagnosis. Conclusions: The findings challenge the widely held contention that depression and anxiety in patients with dementia is underdiagnosed and undertreated in clinical practice. Key words: dementia, depressive disorder, antidepressants, chronic illness

Correspondence should be addressed to: Lars Vedel Kessing, Department of Psychiatry, Rigshospitalet, Blegdamsvej 9, DK 2100 Copenhagen Ø, Denmark. Phone: +45 3545 6237; Fax: +45 3545 6218. Email: lars.kessing@rh.dk. Received 10 Apr 2006; revision requested 6 Jul 2006; revised version received 24 Aug 2006; accepted 25 Aug 2006. First published online 23 October 2006.

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Introduction Dementia is often associated with depression that may lead to increased disability, impaired quality of life and higher mortality (Burns et al., 1990; Pearlson et al., 1990; Rovner et al., 1991). The prevalence of major and minor depression among patients with dementia ranges from 30% to 50% (Lee and Lyketsos, 2003). Besides major and minor depression, other “affective syndromes” such as dysphoria, irritability and anxiety disorders may be prevalent in dementia. Diagnosing depression in patients with dementia can be difficult. Denial, aphasia, anosognosia, cognitive impairment and confusion may compromise the self-reporting of depressive symptoms, and non-verbal manifestations such as demanding behavior and clinging may be more apparent than depressed mood (Bains et al., 2002). Moreover, neurocognitive symptoms such as poor concentration and anhedonia are features of both dementia and depression, making it difficult to diagnose depression in patients with dementia. Thus, it is likely that depression and anxiety in patients with dementia are underdiagnosed and undertreated (Cohen et al., 1998; Evers et al., 2002; Fernandez et al., 1995). However, no larger study has investigated the actual rate of antidepressant treatment in patients with dementia in clinical practice. We carried out a nationwide case register study of admission and pharmacological data and compared the rate of antidepressants prescribed for patients previously discharged with a diagnosis of dementia with the rate for patients discharged with a diagnosis of osteoarthritis and with the rate for a matched sample of the general population. Patients with osteoarthritis were chosen as a control group because it is a chronic and progressive disease and because the disease and the treatment do not, as far as is known, cause any biological effect on the brain or on mood (Creamer et al., 1999). In earlier case register studies we included patients with osteoarthritis as a control group (Nilsson et al., 2002a; 2002b; Kessing et al., 2003).

Methods The Danish registers Data were obtained by linking four Danish population-based registers that use the unique personal identification number assigned to each of the 5.3 million inhabitants of Denmark, thus ensuring accurate linkage of information between registers, irrespective of changes in name or other personal details (Malig, 1996). In this way, the Danish National Hospital Register (DNHR: Andersen et al., 1999), the Danish Psychiatric Central Register (DPCR: Munk-Jorgensen and Mortensen, 1997), the Medicinal Product Statistics (Danish National Board of Health, 2002) and the Danish Medical Register on Vital Statistics (Juel and Helweg-Larsen, 1999) were linked. The DNHR contains data on all patients treated at all somatic hospitals either as inpatients or outpatients in Denmark since 1 January 1977 as part of the official Danish health survey (World Health Organization, 1993). Likewise, all

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psychiatric admissions have been registered in a nationwide register, the DPCR, since 1 April 1970, and since 1 January 1994, the ICD-10 has been used in both registers (World Health Organization, 1993). Since there are no private psychiatric hospitals or clinics in Denmark, all admissions for the 5.3 million inhabitants are included in the DPCR. There are very few somatic private hospitals in Denmark, and they have the same obligation as public hospitals to provide entries in the public registers. Thus, all admissions are included in the DNHR and the DPCR and it can be established with great certainty whether a patient has been admitted previously, irrespective of changes in name or address. The Medicinal Product Statistics register contains data on all prescribed medication purchased at pharmacies since 1 January 1995 (Danish National Board of Health, 2002). In Denmark, all medication prescribed by doctors, such as antidepressants, can only be purchased at pharmacies. Information on the indications for the drug is not available, but antidepressants are mainly prescribed for depressive and anxiety disorders. The Danish Medical Register on Vital Statistics (Juel and Helweg-Larsen, 1999) contains data on deaths. The study period for the present study was from 1 January 1995 to 31 December 2000. The study sample The study sample consists of two cohorts that were defined according to the diagnoses of dementia or osteoarthritis at discharge in the DNHR or the DPCR after an admission or outpatient contact during the study period. Dementia was defined as a main diagnosis of ICD-10 codes: G30.0–G30.9 as recorded in the DNHR or as F.00–F00.9 + F0.1–F01.9 as recorded in the DPCR. Osteoarthritis was defined as a main diagnosis of ICD-10 code DM15.0–DM19.9. Statistical analysis In initial analyses, the rate ratios of antidepressants were compared for patients with a diagnosis of Alzheimer’s disease (ICD-10 codes: G30.0–G30.9 and F00– F00.9) and for patients with a diagnosis of vascular dementia (ICD-10 codes: F01–F01.9). In subsequent analyses, patients with a diagnosis of Alzheimer’s disease and patients with a diagnosis of vascular dementia were analysed together as patients with a diagnosis of dementia. Using Poisson regression analyses (Clayton and Hills, 1993), the cohort of patients with dementia was compared with the cohort of patients with osteoarthritis. Since there is a major hazard of death (see Table 1), death and the purchase of antidepressants were both treated as outcomes in a model of competing risks. When estimating the intensity of purchasing antidepressants, an individual was censored at the time of death, of emigration, diagnosis of the opposite cohort (i.e. patients with dementia were censored at the time of a diagnosis of osteoarthritis and vice versa), or at the end of follow-up (31 December 2000). Event time was defined as the date when the prescribed antidepressants were first purchased. When estimating the death intensity, an individual was censored at the time of purchasing an antidepressant, of emigration, diagnosis of the opposite cohort,


and at the end of follow-up. Thus, separate models were fitted for the agespecific intensities for death and for purchasing antidepressants assuming these to be constant within the age intervals 0–34, 35–49, 50–64, 65–79, 80+ years. Gender was included in both models as a fixed covariate while socio-economic status (working, unemployed, disability or age pension, student, and other: Statistics Denmark 1997), calendar time (1995–6, 1997–8, 1999–2000) and time since diagnosis (0–0.5, 0.5–1, >1 year) were included as time-dependent covariates. We used the estimated intensities of purchasing antidepressants and death in a competing risks model to calculate the probability of purchasing antidepressants before a given age for various combinations of the covariates (Clayton and Hills. 1993). These probabilities were presented graphically. In separate analyses, the rate for patients with a main diagnosis of dementia was compared with the rate for the general population using indirect standardization. The standardized ratios were calculated as the observed number of patients who purchased antidepressants divided by the expected number. The expected number was calculated on the basis of the number of patients with a diagnosis of dementia divided according to gender, five-year age groups and two-calendar-year categories multiplied by the corresponding rates in the general Danish population of first purchase of antidepressants. These rates were derived from the Medicinal Product Statistics. Confidence limits of the rate ratios were calculated assuming the observed number of cases to be Poisson distributed using exact P-values and confidence limits (Clayton and Hills, 1993).

Results The study comprised 24,137 patients who received a main diagnosis of dementia at discharge from hospital or as an outpatient, and 100,378 patients who received a main diagnosis of osteoarthritis at discharge from hospital or as an outpatient in the period from 1 January 1995 to 31 December 2000. Table 1 presents the gender and age distribution at first discharge, the median follow-up and events and reasons for censoring. As can be seen, the gender composition was similar in the cohort of patients with dementia and the cohort with osteoarthritis but the median age was higher for patients with dementia. However, within each age span, the number of patients with osteoarthritis was greater than the number of patients with dementia, making comparison between the cohorts appropriate for a fixed age. A total of 43.2% of patients with a diagnosis of dementia subsequently purchased antidepressants compared to 16.0% of patients with a diagnosis of osteoarthritis. It can be seen further that the proportion of deaths was very different for the two cohorts, which is why the method of competing risks was used in the analyses. Censoring due to emigration or due to the occurrence of the opposite index diagnosis was rare. Initially, the rate of purchasing antidepressants was compared for the 6,117 patients with a main diagnosis of Alzheimer’s disease and the 18,020 patients with a main diagnosis of vascular dementia. Patients with a diagnosis of

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Table 1. Gender, age at ﬁrst discharge, events and reasons for censoring the two patient cohorts DEMENTIA

OSTEOARTHRITIS

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N Female (%) Age (median, quartiles) < 35 years (%) 35–49 50–64 65–79 > 80 Follow-up in years (median, quartiles)

24,137 60.6 81.0 (75.0–86.0) 42 (0.2) 324 (1.3) 1542 (6.4) 9065 (37.6) 13164 (54.5) 0.39 (0.07–1.51)

100,378 58.8 65.0 (53.9–75.2) 3427 (3,4) 13674 (13.6) 33051 (32.9) 37029 (36.9) 13197 (13.2) 2.48 (0.97–4.22)

Event Antidepressants (%) Death (%)

10426 (43.2) 7419 (30.7)

16096 (16.0) 6710 (6.7)

Censoring End of follow-up (%) Other reasons (%)∗

6168 (25.6) 124 (0.52)

76827 (76.5) 745 (0.74)

Note: ∗ Other reasons for censoring: emigration and opposite index diagnosis.

Alzheimer’s disease had a slightly increased rate of purchasing antidepressants compared with patients with vascular dementia (1.09 (95% CI 1.04–1.14)). However, as the difference in the rate of antidepressants was so small, patients with a diagnosis of Alzheimer’s disease and patients with a diagnosis of vascular dementia were analyzed together as patients with a diagnosis of dementia in subsequent analyses. Thus, taken together, the rate of subsequently purchasing antidepressants among patients with a diagnosis of dementia was 4.17 times higher (95% CI = 4.05–4.29) than that of patients with a first diagnosis of osteoarthritis patients. Table 2 shows that for all patient subgroups, patients with dementia had a greater rate of purchasing antidepressants than patients with osteoarthritis. There were significant interactions of gender, age, socio-economic group and time since diagnosis on the effect of diagnosis (dementia versus osteoarthritis). The rate ratio (RR) was greater for men than for women (df = 1, χ 2 = 209.4, p < 0.0001) and for patients who were between 50 and 79 years old (df = 4, χ 2 = 333.6, p < 0.0001) and for patients who were employed or student (df = 3, χ 2 = 92.0, p < 0.0001). The rate of purchasing antidepressants was significantly greater for patients with dementia in all periods following the diagnosis, but greatest in the first half-year period. Figure 1 shows the estimated probabilities of purchasing antidepressants at the age of 65 and at the age at 80 for men and women, respectively. As can be seen, in both age groups, the probability of antidepressant use was substantially greater for the dementia patients than for those with osteoarthritis.


Table 2. Effects of gender, age, socio-economic group and duration of illness on the rate of purchasing antidepressants, adjusted for calendar time and the other variables in the table VA L U E

RR

95%

CI

df χ 2 p

...............................................................................................................................................................................................................................................

Diagnosis × gender

Diagnosis × age

Diagnosis × socio-economic group

1 209.4 < 0.0001 D women OA women D men OA men

3.67 1 5.49 1

D < 34 OA 0–34 D 35–49 OA 35–49 D 50–64 OA 50–64 D 65–79 OA 65–79 D 80+ OA > 80

3.10 1 3.51 1 5.09 1 5.19 1 3.07 1

D unemployed OA unemployed D disability age pension OA disability age pension D employed / student OA employed / student D other OA other

5.54 1 4.05

3.55–3.80 5.24–5.75 4 333.6 < 0.0001 1.52–6.29 2.93–4.22 4.69–5.51 4.99–5.41 2.94–3.21 3 92.0 < 0.0001

4.14–7.40 3.93–4.17

1 7.51 1 3.73 1

6.68–8.44 3.04–4.58

Diagnosis × time since diagnosis (years)

2 462.3 < 0.0001 D 0–0.5 OA 0–0.5 D 0.5–1 OA 0.5–1 D 1+ OA 1+

5.13 1 3.52 1 2.60 1

4.96–5.31 3.25–3.80 2.46–2.76

Note: D = dementia; OA = osteoarthritis.

Finally, compared with the rate for a gender-, age- and calendar-matched sample of the general population, the rate of purchasing antidepressants increased 8.85 times (95% CI: 8.68–9.03) for patients with a diagnosis of dementia.

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0.6

Dementia

0.4

Osteoarthritis

0.0

0.2

0.4

Osteoarthritis

0.2

Probability of antidepressants

0.6

Dementia

0.0


Men, 65 years

65

66

67 68 Age (years)

69

70

80

Women, 65 years

83

84

85

0.6

Dementia Osteoarthritis

0.4

0.4

Osteoarthritis

0.0

0.2


Dementia 0.6

82

Women, 80 years

0.2


81

Age (years)

0.0

908

65

66

67 68 Age (years)

69

70

80

81

82 83 Age (years)

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Figure 1 The probability of patients with a diagnosis of dementia or osteoarthritis purchasing antidepressants.

Discussion There are two main findings in the study. First, as stated above, patients who received a first diagnosis of dementia had a 4.17 times higher rate of subsequently purchasing antidepressants than those with patients with a first diagnosis of osteoarthritis (and a rate 8.85 times higher than the general population). These rates were higher in all subgroups of dementia patients regardless of gender, age, socio-economic group and time since diagnosis. Secondly, the rate of antidepressant purchasing was not only higher in the first period following diagnosis of dementia, but also remained elevated in the long run. A total of 43.2% of the approximately 24,000 patients with dementia purchased antidepressants during a median of 0.5 years (quartiles 0.1–1.6) of follow-up compared with 16.0% of patients with osteoarthritis during 2.5 years (quartiles 1.0–4.2). No other study has investigated the prevalence of antidepressant use following diagnosis of dementia. The figure of 43.2% may be compared with the estimated prevalence rates in


dementia of major depression, minor depression and other affective syndromes such as dysphoria, irritability and anxiety disorders which vary between 30% to 50% (Lee and Lyketsos, 2003; Lyketsos and Lee, 2004). Depression and other affective syndromes may respond to antidepressant treatment in various degrees (Bains et al. 2002, Lyketsos and Lee 2004). The present study does not include data on the diagnoses or indications for treatment because this information is not available in the Danish Medicinal Product Statistics or elsewhere. It is possible that a proportion of the antidepressants may have been prescribed for unspecific psychological and behavioral symptoms related to dementia but it is likely that such conditions also have their origin in an affective or anxiety syndrome. An antidepressant such as trazodone, which in clinical practice in some countries is prescribed to persons with dementia for the treatment of insomnia or nocturnal wandering, is not available in Denmark. Thus, it is most likely that the major proportion of antidepressants are prescribed for affective and anxiety syndromes. The results from the present study challenge the widely held contention that depression and anxiety in patients with dementia are underdiagnosed and undertreated conditions (Evers et al., 2002; Fernandez et al., 1995). The widespread use of antidepressants underscores the pressing need for investigating whether antidepressants effectively reduce depression and other neuropsychiatric symptoms in patients with dementia (Bains et al., 2002, Sink et al., 2005). Choice of control groups Those patients who have been admitted and diagnosed with a disorder (e.g. dementia) have greater chances of being diagnosed with a second disorder compared with subjects for whom no diagnosis has been made, because they are seen more often by a doctor, resulting in the so-called Berkson’s bias (Berkson, 1946). The rate of antidepressant treatment may be greater for patients with osteoarthritis than for individuals from the general population for two reasons: (1) living with a chronic disorder in general is associated with increased risk of depressive and anxiety symptoms; and (2) the diagnosis of depression/anxiety is made more frequently in patients with osteoarthritis simply because, as noted above, they visit a doctor more often than subjects in the general population. To reduce Berkson’s bias in the present study, patients with osteoarthritis were chosen as the primary control group instead of the general population. Thus, our findings emphasize the importance of comparing dementia with another chronic illness and not just with the general population. Osteoarthritis was chosen because the disease and its treatment do not, as far as is known, cause any biological affection on the brain or on mood. Patients with osteoarthritis may have been treated with non steroid anti-inflammatory drugs (NSAID). Long-term treatment with NSAID has been supposed to reduce the risk of dementia (Klegeris and McGeer, 2005), although findings from case control and cohort studies and a few randomized trials have been controversial (de Craen et al., 2005). However, these drugs do not affect mood. There is no increased comorbidity between osteoarthritis and dementia and both disorders have a late first onset with a rather similar prevalence in the two sexes (Table 1). In earlier case register studies we included patients with osteoarthritis as

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a control group (e.g. Nilsson et al., 2002a; 2002b; 2003; Nilsson and Kessing, 2004). Thus, we believe that, in relation to dementia, patients with osteoarthritis constitute the best control group of patients with a chronic illness when pathophysiological, epidemiological and demographic aspects are considered. Other potential biases Whereas recall bias and other kinds of information bias are often a problem in longitudinal studies of patients with dementia (due to aphasia, anosognosia and other cognitive dysfunction) (Lee and Lyketsos 2003; Lyketsos and Lee 2004), the problem was reduced in this study because data on the purchase of antidepressants are collected routinely and electronically by pharmacies in Denmark. Validity of the diagnoses It should be emphasized that the diagnoses in the register originate from different clinicians throughout Denmark and are not standardized for research purposes. The validity of diagnoses in the DNHR has been evaluated in earlier studies (Jurgensen et al. 1986, Mosbech et al. 1995) but the diagnosis of dementia has not been specifically validated. Nevertheless, we previously conducted a minor validation study in which 30 patients with a diagnosis of dementia were randomly selected from the register (Kessing, unpublished data). The majority of these patients scored within the demented range on two different scales of cognitive assessment: 70% of patients scored below 100 on the CAMCOG rating scale (Roth et al., 1986; range: 0–120, with an average of 89.5 ± 19.7) and 96.2% of patients scored 1 on the GDS scale (Reisberg et al., 1988); range: 1–6, with an average of 3.9 ± 1.0). The diagnosis of osteoarthritis recorded in the DNHR has not been validated. The effect of socio-demographic variables Overall, predictors of antidepressant treatment were the same as the usual predictors of depression and anxiety – i.e. being female, being old and being on disability or age pension – which increases the validity of our findings. The effect of dementia was greater among men than among women and among middle-aged patients and among persons who were employed or students at the time of discharge. We are not aware of any study that has looked at the association with socio-economic status. Advantages of the study It is a major advantage that this study comprises an observation period of some six years for the whole Danish population and that this population is ethnically and socially homogeneous and with a very low migration rate. Hospital care is well developed in Denmark and, being free of charge, encourages everyone to use its services, irrespective of their socio-economic status. Using survival statistics estimates were made of time to purchase of antidepressants and the competing risks of purchase of antidepressants and death. During the study period, 30.7% of patients with dementia died compared with 6.7% of patients with osteoarthritis.


Patients with dementia also had an increased risk of purchasing antidepressants after correction for different death intensities in competing risks models, as illustrated in Figure 1.

Conclusion Patients who received a diagnosis of dementia had an increased rate of subsequently purchasing antidepressants compared with patients with a diagnosis of osteoarthritis and compared with the general population. The rate was increased in all subgroups of patients regardless of gender, age, socio-economic group and time since diagnosis. Thus, dementia is associated with increased rate of treatment with antidepressants and the rate remains elevated in the long run. The findings challenge the widely held contention that depression and anxiety in patients with dementia are underdiagnosed and undertreated in clinical practice. This widespread use of antidepressants underscores the pressing need to investigate whether antidepressants effectively reduce depression and other neuropsychiatric symptoms in patients with dementia (Bains et al., 2002, Sink et al., 2005). Further, it emphasizes the need for an investigation of the pathogenesis behind the association between dementia and depression.

Conﬂict of interest None.

Description of authors’ roles Lars Vedel Kessing formulated the research question, designed the study and the analyses, and wrote the paper. Mette Harhoff designed and carried out the analyses, and participated in writing the paper. Per Kragh Andersen designed the study and the analyses, and participated in writing the paper.

Acknowledgments The authors wish to acknowledge the Lundbeck Foundation and the Foundation for Psychiatric Research.

References Andersen, T. F., Madsen, M., Jorgensen, J., Mellemkjaer, L. and Olsen, J. H. (1999). The Danish National Hospital Register: a valuable source of data for modern health sciences. Danish Medical Bulletin, 46, 263–268. Bains, J., Birks, J. S. and Dening, T. R. (2002). The efficacy of antidepressants in the treatment of depression in dementia. Cochrane Database of Systematic Reviews 4, CD003944.

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L. V. Kessing et al. Berkson, J. (1946). Limitations of the application of fourfold table analysis to hospital data. Biometrics Bulletin, 2, 126–135. Burns, A., Jacoby, R. and Levy, R. (1990). Psychiatric phenomena in Alzheimer’s disease. III: Disorders of mood. British Journal of Psychiatry, 157, 81–84. Clayton, D. and Hills, M. (1993). Statistical Models in Epidemiology. Oxford: Oxford University Press. Cohen, C. I., Hyland, K. and Magai, C. (1998). Depression among African American nursing home patients with dementia. American Journal of Geriatric Psychiatry, 6, 162–175. Creamer, P., Lethbridge-Cejku, M., Costa, P., Tobin, J. D., Herbst, J. H. and Hochberg, M. C. (1999). The relationship of anxiety and depression with self-reported knee pain in the community: data from the Baltimore Longitudinal Study of Aging. Arthritis Care and Research, 12, 3–7. Danish National Board of Health (2002). Medicinal Product Statistics. Copenhagen. (www. laegemiddelstyrelsen.dk). de Craen, A. J., Gussekloo, J., Vrijsen, B. and Westendorp, R. G. (2005). Meta-analysis of nonsteroidal antiinflammatory drug use and risk of dementia. American Journal of Epidemiology, 161, 114–120. Evers, M. M., Samuels, S. C., Lantz, M., Khan, K., Brickman, A. M. and Marin, D. B. (2002). The prevalence, diagnosis and treatment of depression in dementia patients in chronic care facilities in the last six months of life. International Journal of Geriatric Psychiatry, 17, 464–472. Fernandez, F., Levy, J. K., Lachar, B. L. and Small, G. W. (1995). The management of depression and anxiety in the elderly. Journal of Clinical Psychiatry, 56 (Suppl. 2), 20–29. Juel, K. and Helweg-Larsen, K. (1999). The Danish registers of causes of death. Danish Medical Bulletin, 46, 354–357. Jurgensen, H. J., Frolund, C., Gustafsen, J., Mosbech, H., Guldhammer, B. and Mosbech, J. (1986). Registration of diagnoses in the Danish National Registry of Patients. Methods of Information in Medicine, 25, 158–164. Kessing, L. V., Nilsson, F. M., Siersma, V. and Andersen, P. K. (2003). No increased risk of developing depression in patients with diabetes compared to other chronic illness. Diabetes Research and Clinical Practice, 113–121. Klegeris, A. and McGeer, P. L. (2005). Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Current Alzheimer Research, 2, 355–365. Lee, H. B. and Lyketsos, C. G. (2003). Depression in Alzheimer’s disease: heterogeneity and related issues. Biological Psychiatry, 54, 353–362. Lyketsos, C. G. and Lee, H. B. (2004). Diagnosis and treatment of depression in Alzheimer’s disease: a practical update for the clinician. Dementia and Geriatric Cognitive Disorders, 17, 55–64. Malig, C. (1996). The Civil Registration System in Denmark. Technical Paper no.66, Bethesda, MD: International Institute for Vital Registration and Statistics. Mosbech, J., Jorgensen, J., Madsen, M., Rostgaard, K., Thornberg, K. and Poulsen, T. D. (1995). [The national patient registry. Evaluation of data quality. In Danish]. Ugeskrift for Læger, 157, 3741–3745. Munk-Jorgensen, P. and Mortensen, P. B. (1997). The Danish Psychiatric Central Register. Danish Medical Bulletin, 44, 82–84. Nilsson, F. M. and Kessing, L. V. (2004). Increased risk of developing stroke for patients with major affective disorder: a registry study. European Archives of Psychiatry and Clinical Neuroscience, 254, 387–391.

Antidepressants in dementia Nilsson, F. M., Kessing, L. V., Sørensen, T. M., Andersen, P. K. and Bolwig, T. G. (2002a). Enduring increased risk of developing depression and mania in patients with dementia. Journal of Neurology, Neurosurgery and Psychiatry, 73, 40–44. Nilsson, F. M., Kessing, L. V., Sørensen, T. M., Andersen, P. K. and Bolwig, T. G. (2002b). Major depressive disorder in Parkinson’s disease: a register-based study. Acta Psychiatrica Scandinavica, 106, 202–211. Nilsson, F. M., Kessing, L. V., Sørensen, T. M., Andersen, P. K. and Bolwig, T. G. (2003). Affective disorders in neurological diseases: a case register-based study. Acta Psychiatrica Scandinavica, 108, 41–50. Pearlson, G. D., Ross, C. A., Lohr, W. D., Rovner, B. W., Chase, G. A. and Folstein, M. F. (1990). Association between family history of affective disorder and the depressive syndrome of Alzheimer’s disease. American Journal of Psychiatry, 147, 452–456. Reisberg, B., Ferris, S. H., Deleon, M. J. and Crook, T. (1988). Global Deterioration Scale (GDS). Psychopharmacology Bulletin, 24, 661–663. Roth, M. et al. (1986). CAMDEX: a standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British Journal of Psychiatry, 149, 698–709. Rovner, B. W., German, P. S., Brant, L. J., Clark, R., Burton, L. and Folstein, M. F. (1991). Depression and mortality in nursing homes. JAMA, 265, 993–996. Sink, K. M., Holden, K. F. and Yaffe, K. (2005). Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA, 293, 596–608. Statistics Denmark (1997). SOCIO. Danmarks Statistiks Socioøkonomiske Klassifikation. Copenhagen. World Health Organization (1993). Klassifikation af Sygdomme. International Statistical Classification of Diseases and Health Related Problems. 10th revision (Danish edn). Geneva: World Health Organization.

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