Psychotropic and Analgesic Drug Use Among Old People

UMEÅ UNIVERSITY MEDICAL DISSERTATION New Series No. 1157 - ISSN 0346-6612 - ISBN 978-91-7264-504-2

From the Department of Community Medicine and Rehabilitation, Geriatric Medicine Umeå University, Sweden

PSYCHOTROPIC AND ANALGESIC DRUG USE AMONG OLD PEOPLE

WITH SPECIAL FOCUS ON PEOPLE LIVING IN INSTITUTIONAL GERIATRIC CARE

HUGO LÖVHEIM

UMEÅ 2008

Detta verk skyddas enligt lagen om upphovsrätt (URL 1960:729) ISSN 0346-6612 - ISBN 978-91-7264-504-2 Printed in Sweden by Umeå Universitet, Print & Media, Umeå 2008

3 CONTENT

CONTENT

ABSTRACT 7 SVENSK SAMMANFATTNING 9 ABBREVIATIONS 12 LIST OF ORIGINAL PAPERS 13 INTRODUCTION 15 Old and very old people 15 DEMENTIA DISORDERS 15 Prevalence of dementia disorders 16 The course of a dementia disorder 16 Measuring cognitive impairment 17 Behavioral and Psychological Symptoms of Dementia 17 DEPRESSION 18 Depression and dementia 19 PAIN 19 Pain treatments 20 GERIATRIC CARE 21 Characteristics of different types of institutional geriatric care 22 facilities in Sweden Time trends in the organization of institutional care of old 23 people in Sweden The county of Västerbotten 23 Healthcare and institutional geriatric care in the county of 24 Västerbotten NERVOUS SYSTEM DRUGS 24 The central nervous system 24 Prevalence of psychiatric disorders in a general population 24 and among old people An exposé of the history of psychotropic drugs and analgesics 25 The nerve cells, synapses and receptors 27 Transmitter systems 28 Nervous system drug classes 28 Main effects of different nervous system drugs 28 Effects and side effects of nervous system drugs among old 31 people Prevalence and time trends in psychotropic drug use among 34 old people RATIONALE 37 AIM 38 SPECIFIC AIMS 38 METHODS 39 PARTICIPANTS 39 AC1982 and AC2000 data collections 39

4 CONTENT

GERDA/Umeå 85+ data collection 41 PROCEDURES 41 AC1982 and AC2000 data collections, the MDDAS 41 Basic characteristics 41 ADL 41 Pain 42 Cognitive function, Gottfries’ cognitive scale 43 Behavioral and Psychological Symptoms of Dementia 43 Workload 43 Additional data 43 Drug data 43 Terminology notes 44 GERDA/Umeå 85+ data collection 44 Drug data coding procedures 45 Drug data coding and terminology notes 45 ETHICS 46 STATISTICS 46 Selection procedures 46 Descriptive statistics 46 Regression statistics 47 Factor analysis 47 Computer programs 47 RESULTS 49 PAPER I, Poor staff awareness of analgesic treatment jeopardizes 50 adequate pain control in the care of older people PAPER II, Relationship between antipsychotic drug use and 53 Behavioral and Psychological Symptoms of Dementia in old people with cognitive impairment living in geriatric care PAPER III, Symptoms of mental health and psychotropic drug use 57 among old people in geriatric care, changes between 1982 and 2000 PAPER IV, On depression in dementia 59 PAPER V, The use of central nervous system drugs and analgesics 62 among very old people with and without dementia ADDITIONAL RESULTS 65 Mini Mental State Examination versus Gottfries’ cognitive 65 scale Evaluation of the questions about pain included in the 65 AC2000 and GERDA/Umeå 85+ data collections A calculation of the numbers needed to treat based on data 66 from Paper III DISCUSSION 69 THE MAIN FINDINGS 69 PREVALENCE OF PSYCHOTROPIC AND ANALGESIC DRUG USE 69 Time trends in psychotropic drug use 70 APPROPRIATENESS OF NERVOUS SYSTEM DRUG USE 70

5 CONTENT

Appropriateness of nervous system drug use in relation to 71 indications for treatment Appropriateness of nervous system drug use in relation to 72 treatment results Appropriateness of nervous system drug use in relation to 75 differences between various groups of people Appropriateness of nervous system drug use in relation to 76 known potentially inappropriate medications ETHICAL CONSIDERATIONS 77 METHODOLOGICAL CONSIDERATIONS 78 Cross-sectional epidemiological studies 78 Study population 79 Procedures in data collection 79 Reliability of the MDDAS 79 Characteristics of Gottfries’ cognitive scale 80 Reliability of the pain questions 80 Reliability and validity of drug data 81 Reliability of the scales included in the GERDA/Umeå 85+ 82 data collection Participation rate and missing values 82 Statistical considerations 82 Power issues 82 Selection procedures 83 Statistical tests 83 Risk of mass significance effects of multiple tests 83 Risk of type I-errors with post-hoc analyses 84 Representativeness and transferability of the results 84 CLINICAL IMPLICATIONS 85 IMPLICATIONS FOR FURTHER RESEARCH 86 CONCLUSIONS 87 ACKNOWLEDGEMENTS 88 REFERENCES 90 APPENDIX 1, The Multi-Dimensional Dementia Assessment Scale, 105 Behavioral and Psychological Symptoms, including English translation APPENDIX 2, The Gottfries’ Cognitive Scale, including English 108 translation ORIGINAL PAPERS I-V DISSERTATIONS FROM THE DEPARTMENT OF COMMUNITY MEDICINE AND REHABILITATION, GERIATRIC MEDICINE 1983- 2008

6 ABSTRACT

PSYCHOTROPIC AND ANALGESIC DRUG USE AMONG OLD PEOPLE

WITH SPECIAL FOCUS ON PEOPLE LIVING IN INSTITUTIONAL GERIATRIC CARE

Hugo Lövheim, the Department of Community Medicine and Rehabilitation, Geriatric Medicine, Umeå University, Umeå, Sweden

ABSTRACT

Old people in general, and those affected by dementia disorders in particular, are more sensitive to drug side effects than younger people. Despite this, the use of nervous system drugs and analgesics among old people is common, and has increased in recent years. Institutional geriatric care accommodates people who need round-the-clock supervision and care, due to somatic, psychiatric, cognitive or behavioral symptomatology. A majority of those living in institutional geriatric care suffers from dementia disorders. This thesis is based on three different data collections. Two large cross-sectional studies, the AC1982 and AC2000 data collections, including all those living in institutional geriatric care in the county of Västerbotten in May 1982 and 2000 respectively (n=3195 and n=3669) and one study, the GERDA/Umeå 85+ data collection, including a sample of very old people, living at home and in institutions (n=546), in the municipalities of Umeå, Sweden and Vaasa and Mustasaari, Finland, in 2005-2006. The use of psychotropic drugs and analgesics was common among old people living in geriatric care and among very old people in general. A higher proportion of people with dementia received certain nervous system drugs, such as antipsychotic drugs. The use of antipsychotic drugs among people with cognitive impairment living in geriatric care was found to be correlated to several behaviors and symptoms that are not proper indications for antipsychotic drug use, and also factors related more to the staff and the caring situation. Over the course of eighteen years, from 1982 to 2000, there has been a manifold increase in the use of antidepressants, anxiolytics and hypnotics in geriatric care, but the use of antipsychotics had decreased slightly. During the same time, the prevalence of several depressive symptoms decreased significantly, correcting for demographical changes. One analysis of calculated numbers needed to treat, however, indicated poor remission rates, suggesting that even better results might be achievable. The prevalence of depressive symptoms among people with moderate cognitive impairment remained unchanged between 1982 and 2000, despite the fact that about 50% were receiving treatment with antidepressants in 2000. One possible explanation might be that depressive symptoms have different etiologies in different stages of a dementia disorder. Approximately a quarter of the people experiencing pain in geriatric care were not receiving any regular analgesic treatment. One possible reason might be misconceptions among the caring staff regarding whether or not the residents were receiving analgesic treatment. Such misconceptions were found to be common.

7 ABSTRACT

In conclusion, psychotropic and analgesic drug use among old people in geriatric care, and very old people in general, was found to be common and in many cases possibly inappropriate. The use of antipsychotics among people with dementia deserves particular concern, because of the high risk of severe adverse events and the limited evidence for positive effects. The use of antidepressants, on the other hand, might have contributed to a lower prevalence of depressive symptoms among old people.

Keywords

Dementia, Alzheimer’s Disease, Depression, Pain, Nursing Home, Residential Care, Old, Very old, Psychotropic drugs, Analgesics, Antidepressants, SSRI, Benzo- diazepines, Anxiolytics, Hypnotics, Antipsychotics, BPSD, Behavioral and Psychological Symptoms of Dementia, Inappropriate drugs, Sex difference.

8 SAMMANFATTNING

ANVÄNDNING AV PSYKOFARMAKA OCH SMÄRTSTILLANDE LÄKEMEDEL BLAND ÄLDRE

MED SÄRSKILT FOKUS PÅ PERSONER SOM BOR INOM INSTITUTIONELL ÄLDREVÅRD

Hugo Lövheim, Institutionen för Samhällsmedicin och Rehabilitering, Enheten för Geriatrik, Umeå Universitet, Umeå, Sverige

SAMMANFATTNING

Det är mycket vanligt att äldre använder psykofarmaka och smärtstillande läkemedel. Till gruppen psykofarmaka räknas antidepressiva läkemedel, sömnmedel, lugnande medel och neuroleptika (antipsykotiska läkemedel). Jämfört med yngre personer har dock äldre, och särskilt de med demenssjukdom, en ökad risk för läkemedels- biverkningar, vilket kräver särskild försiktighet vid läkemedelsbehandling. Samtidigt är depression, smärta och demenssjukdomarna betydande orsaker till psykiskt lidande bland äldre personer, och ett optimalt användande av de läkemedel som står till buds kan sannolikt minska detta lidande. En person med demenssjukdom drabbas mycket ofta av olika psykiska symptom eller beteendestörningar någon gång under sjukdomsförloppet. Vanliga symptom är ångest, oro, nedstämdhet, hallucinationer, aggressivitet, vandringsbeteende, plockbeteende och apati. När de här beteendestörningarna tillstöter händer det inte sällan att läkemedelsbehandling med neuroleptika sätts in, även om behandlingen inte är särskilt effektiv och många gånger förenad med biverkningar, eller risk för mycket allvarliga biverkningar, som stroke och förtida död. Alternativet till läkemedelsbehandling är att personalen på boendena tränas i att hantera beteendestörningar hos en person med demens, och lär sig hur de kan minska dessa till exempel genom sitt sätt att kommunicera med personen med demenssjukdom. Syftet med den här avhandlingen var att beskriva användningen av psykofarmaka och smärtstillande läkemedel bland äldre. Syftet inbegrep beskrivning av förekomsten av olika läkemedelsgrupper, förändringar över tid, förekomsten av symptom relaterade till läkemedelsbehandlingen samt jämförelser mellan olika grupper, till exempel personer med demenssjukdom jämfört med personer som inte har demens. Ett särskilt fokus är på personer som bor inom institutionell äldrevård (sjukhem, servicehus, gruppboenden för dementa och korttidsboenden), eftersom denna grupp av människor, på grund av att de har en högre förekomst av olika sjukdomstillstånd, ofta använder psykofarmaka och smärtstillande läkemedel. En majoritet av personerna som bor på särskilda boenden för äldre har en demenssjukdom. I avhandlingen ingår dels två datainsamlingar från alla särskilda boenden i Västerbotten, genomförda i maj 1982 och 2000, baserade på enkäter ifyllda av vårdpersonal. I dessa datainsamlingar finns uppgifter från 3195 respektive 3669 personer. Dels ingår data från insamlingen GERDA/Umeå 85+ som baseras på journaluppgifter från sjukvård och äldreomsorg samt hemintervjuer med de allra äldsta - 85, 90 och 95 år och äldre i Umeå kommun och Vasa och Korsholms kommuner i

9 SAMMANFATTNING

Finland. I det delmaterial från GERDA/Umeå 85+-insamlingen som ingår i den här avhandlingen finns uppgifter från 546 personer, insamlade under 2005 och 2006. I det första delarbetet visas att smärta är vanligt bland äldre på särskilt boende, och att underbehandling förefaller vara ett problem. Av personerna som bedömdes ha smärta, var det 28% som inte hade någon regelbunden smärtstillande medicinering. Dessutom påvisades att personalen i en majoritet av fallen då den boende hade smärta och inte fick behandling, felaktigt trodde att den boende hade behandling. Betydelsen av detta diskuteras, och det konstateras att förbättrad kommunikation mellan olika personalgrupper sannolikt behövs för att förbättra behandlingen av smärta hos äldre på särskilt boende. I det andra delarbetet undersöks vilka faktorer som hänger samman med att en person med kognitiv nedsättning, som är ett tecken på demenssjukdom, får läkemedel av typen neuroleptika. Dessa läkemedel användes av 26% av personerna med kognitiv nedsättning som bodde i särskilt boende. Neuroleptika används för att behandla beteendestörningar och psykiska symptom, men behandlingen är högst tveksam med tanke på att effekten sällan är särskilt god och de möjliga biverkningarna är allvarliga. I arbetet visas att manligt kön, att kunna resa sig från en stol utan hjälp, personalens skattade psykiska arbetsbörda och att bo på ett gruppboende för dementa sammanhänger med en ökad risk att få neuroleptika, liksom om personen har aggressivt beteende, vandringsbeteende, verbalt aggressivt/ uppmärksamhetssökande beteende och depressiva symptom. Lägre ålder och större självständighet i ADL (det dagliga livets aktiviteter) befanns också vara förenat med en högre risk att ha neuroleptikabehandling. Trots vissa svårigheter att veta vad som är orsak och verkan konstateras att neuroleptikabehandling sammanhänger med flera faktorer som inte är giltiga behandlingsindikationer, och med flera faktorer som mer hör samman med personalen och vårdsituationen än personen själv. Med tanke på vilken farlig behandling det gäller väcker resultaten en hel del tankar om kvalitén på vården och huruvida personernas livskvalitet verkligen sätts i första rummet. I det tredje delarbetet jämförs användningen av neuroleptika, lugnande medel, sömnmedel och antidepressiva läkemedel bland äldre på särskilt boende 1982 med 2000. Det konstateras att andelen personer som har behandling med antidepressiva hade ökat från 6% till 40% och för sömnmedel och lugnande medel från 13% till 39%. Neuroleptika hade minskat något, från 25% till 21%. När förekomsten av olika psykiska symptom undersöktes visade det sig att flera minskat från 1982 till 2000. ”Ledsen” hade minskat med 28%, ”gråter” med 33%, ”orolig och rastlös” med 16%, ”ängslig och rädd” med 27% och ”initiativlös” med 33%. Eftersom andelen personer med kognitiv nedsättning hade ökat mycket mellan 1982 och 2000 är ovanstående siffror justerade för förändringarna i gruppens sammansättning. Anledningen till den lägre förekomsten av depressiva symptom 2000 är troligen den ökade behandlingen med antidepressiva. Omkring 1990 kom de så kallade selektiva serotoninåterupptagshämmarna, SSRI, vilka har avsevärt mindre biverkningar än äldre antidepressiva, och därför kan användas även av äldre personer. Två symptom var dock vanligare 2000 jämfört med 1982, ”överaktiv/manisk”, som var 44% vanligare, och ”synhallucinationer”, som var 27% vanligare. Intressant nog är båda dessa kända biverkningar av antidepressiva, och detta visar på vikten av att följa upp insatt behandling. Fjärde delarbetet följer upp resultaten i delarbete tre och undersöker hur före- komsten av depressiva symptom har förändrats mellan 1982 och 2000 bland personer

10 SAMMANFATTNING

med olika grad av kognitiv nedsättning. Resultatet var att förekomsten var lägre år 2000 i alla grupper förutom bland dem som hade måttlig grad av kognitiv nedsättning. I den gruppen var förekomsten av depressiva symptom lika hög år 2000 som 1982, trots att 51% hade behandling med antidepressiva år 2000 jämfört med 7% 1982. I arbetet diskuteras olika möjliga orsaker till detta och konstateras att en anledning skulle kunna vara att depressiva symptom har olika orsak vid olika grad av demenssjukdom, och att de därför kräver olika behandling. I arbetet spekuleras i om de depressiva symptomen hos personer med måttlig kognitiv nedsättning är ett resultat av en stressfylld vardag, eftersom personer med denna grad av besvär har svårigheter att tolka intryck, känna igen personer, att hitta och att förstå vad det är som händer. Behandlingen skulle i så fall behöva inriktas främst på att förbättra omvårdnadssituationen, och göra den mer förståelig, lugnare och mindre stressande. Femte delarbetet baseras på GERDA/Umeå 85+-materialet och jämför förekomsten av olika läkemedelsbehandlingar bland personer med respektive utan demenssjukdom. I detta arbete, till skillnad från de övriga fyra, ingår även personer som bor i eget boende, utöver de som bor på olika typer av äldreboenden. Resultatet visade att användningen av psykofarmaka och smärtstillande läkemedel var vanlig även bland de allra äldsta. Personer med demens fick oftare behandling med neuroleptika, lugnande medel, antidepressiva och smärtstillande läkemedel. Det var ingen skillnad vad gäller användningen av sömnmedel. Mest anmärkningsvärt var den höga andelen som hade behandling med lugnande medel och sömnmedel, liksom att många personer med demenssjukdom fick neuroleptika. I arbetet visades även att endast 50% av personerna med smärta hade regelbunden smärtstillande behandling. Sammanfattningsvis visar avhandlingen att behandling med psykofarmaka och smärtstillande läkemedel är vanligt bland äldre som bor på särskilt boende och bland de allra äldsta. Vidare påvisades att personer som hade demens eller kognitiv nedsättning i högre utsträckning fick behandling med psykofarmaka och smärtstillande, samt tecken på att behandlingen inte var optimal, med både möjlig över- och underbehandling av olika tillstånd. Särskilt behandlingen av personer med demenssjukdom med neuroleptika med potentiellt allvarliga biverkningar och dåligt dokumenterad effekt och det omfattande bruket av sömnmedel och lugnande medel kräver eftertanke, likaså tecknen till dåliga behandlingsresultat med antidepressiva och smärtstillande, som tyder på bristfällig uppföljning av behandlingen.

11 ABBREVIATIONS

ABBREVIATIONS

5-HT 5-Hydroxy Tryptamine MDDAS Multi-Dimensional Dementia (Serotonin) Assessment Scale AC Västerbotten County, Sweden MNA Mini-Nutritional Assessment AC1982 The survey Institutionsvård av MMSE Mini-Mental State äldre i AC län, (May 1982) Examination AC2000 The survey Äldre vårdade på M01A ATC-code for NSAID institution i Västerbottens län N02A ATC-code for opioid år 2000, (May 2000) analgesics ACh Acetylcholine N02B E ATC-code for paracetamol AD Alzheimer’s Disease N05A ATC-code for antipsychotic ADL Activities of Daily Living drugs AM404 N-arachidonoyl-phenolamine N05B ATC-code for anxiolytics ATC Anatomical Therapeutical N05C ATC-code for hypnotics and Chemical sedatives BEHAVE-AD The Behavioral N06A ATC-code for antidepressant Pathology in Alzheimer’s drugs Disease Scale N06D ATC-code for anti-dementia BPSD Behavioral and Psychological drugs Symptoms of Dementia NA Noradrenaline CB1 Cannabinoid receptor type 1 NMDA N-methyl D-aspartic acid CI Confidence Interval NNT Numbers Needed to Treat CNS Central Nervous System NPI Neuro-Psychiatric Inventory COX Cyclo-Oxygenase NSAID Non-Steroidal Anti- DA Dopamine Inflammatory Drug DDD Defined Daily Doses OBS Organic Brain Syndrome scale DSM-III-R Diagnostic and Statistical OR Odds Ratio Manual of Mental Disorders- PGCM Philadelphia Geriatric Centre 3rd Edition- Revised Morale scale DSM-IV Diagnostic and Statistical PRN Pro Re Nata, as needed Manual of Mental Disorders- SD Standard Deviation 4th Edition SNRI Serotonin and Noradrenaline ECT Electro-Convulsive Therapy Reuptake Inhibitor EPS Extra-Pyramidal Side effects SPSS® Statistical Package for Social FE Fisher’s exact test Science® GABA γ-Amino Butyric Acid SSRI Selective Serotonin Reuptake GDS Geriatric Depression Scale Inhibitor H Histamine TCA Tri-Cyclic Antidepressant L-dopa Levodopa (precursor of TRPV1 Transient receptor potential dopamine, used in Parkinson’s vanilloid 1 disease) GERDA/Umeå 85+ The GERDA/ MADRS Montgomery-Åsberg Umeå 85+ data collection of Depression Rating Scale 2005-2006 MAO Mono-Amine Oxidase VAS Visual Analogous Scale WHO World Health Organisation

12 ORIGINAL PAPERS

ORIGINAL PAPERS

This thesis is based on the following papers, which in the text will be referred to by their Roman numerals:

I Lövheim H, Sandman PO, Kallin K, Karlsson S and Gustafson Y. Poor staff awareness of analgesic treatment jeopardises adequate pain control in the care of older people. Age and Ageing 2006; 35: 257-261.

II Lövheim H, Sandman PO, Kallin K, Karlsson S and Gustafson Y. Relationship between antipsychotic drug use and behavioral and psychological symptoms of dementia in old people with cognitive impairment living in geriatric care. International Psychogeriatrics 2006; 18: 713-726.

III Lövheim H, Sandman PO, Kallin K, Karlsson S and Gustafson Y. Symptoms of mental health and psychotropic drug use among old people in geriatric care, changes between 1982 and 2000. International Journal of Geriatric Psychiatry 2008; 23: 289-294.

IV Lövheim H, Bergdahl E, Sandman PO, Karlsson S, Gustafson Y. On depression in dementia. Submitted.

V Lövheim H, Karlsson S, Gustafson Y. The use of nervous system drugs among very old people with and without dementia. Pharmacoepidemiology and Drug Safety 2008; Accepted for publication.

14 INTRODUCTION

INTRODUCTION

The use of drugs that act on the nervous system is common among old people, despite an increased sensitivity to adverse drug effects compared to younger people. There are, furthermore, indications of an increased use of nervous system drugs among old people in recent years. This thesis comprises studies on the use of nervous system drugs, particularly psychotropic drugs and analgesics, among old people. First, some general concept will be introduced, as well as the results of previous research, subsequently the aim of the thesis will be outlined in more detail.

Old and very old people

The World Health Organization’s definition of being old is to be aged 60 or more, and very old to be aged 80 or more [1]. In Sweden, the term old people usually refer to people aged 65 years or more, which is also the usual age of retirement on a pension [2]. In this thesis the term old people will refer to people aged 65 years or more and very old to people who are aged 85 years or older. The number of old and very old people is expected to increase in the future, due to improvements in life expectancy. In 2005, 17.3% of the Swedish population was aged 65 years or older and 5.4% 80 years or older. The estimation for 2050 is 23.6% and 8.7% respectively [3].

DEMENTIA DISORDERS

The Diagnostic and Statistical Manual of Mental Disorders, DSM [4] by the American Psychiatric Association provides diagnostic criteria for mental disorders, and is used throughout the world. The current edition of the manual is the fourth, published in 1994, with a text revision published in 2000. According to the DSM-IV dementia disorders are characterized by the development of multiple cognitive deficits including memory impairment. The disorders share a common symptom presentation but are differentiated based on etiology. The symptoms that are essential for the diagnoses are multiple cognitive deficits, which must include memory impairment and at least one of the following - aphasia (impaired language function), apraxia (impaired ability to perform learned purposeful movements), agnosia (impaired ability to recognize objects, persons, sounds et cetera), or disturbances in executive functioning (ability to plan and perform complex tasks). The symptoms have to severely impair occupational or social functioning or represent a significant decline from previous level of function. The symptoms should also not be present exclusively during the course of a delirium, or be the result of another Axis I disorder e.g. major depressive disorder or schizophrenia. The diagnosis of the various dementia disorders requires a number of specific criteria to be fulfilled which target the etiology of the different disorders. For example, the diagnosis of dementia of Alzheimer’s type requires a gradual onset and continuing cognitive decline and the exclusion of other nervous system or systemic conditions known to cause progressive memory deficits [4].

15 INTRODUCTION

Prevalence of dementia disorders

The prevalence of dementia disorders increases with advancing age. A meta-analysis of 36 studies from Europe, North America, Asia and Africa found the following age- related prevalences of dementia: 1.5% in the age group 65-69 years old, 3% in ages 70- 74, 6% in ages 75-79 and 12% in age 80-84 [5]. Among people aged 85 years or older, the prevalence is approximately 25%-30% [6-8]. Dementia disorders also appear to be more common among women than among men [7]. The most common type of dementia is Alzheimer’s type dementia, which accounts for approximately half of all people suffering from dementia. Vascular dementia is the second most common type of dementia, found to account for about 15% of all dementia cases [7]. However, in many cases, dementia is of mixed type, with pathological features of both Alzheimer’s type dementia and vascular dementia, and prevalence numbers are therefore uncertain [9]. Finally other types of dementia, which has been investigated to a much more limited extent than Alzheimer’s dementia and vascular dementia, account for approximately 11% [9]. Included in this group are Lewy-body dementia, frontal lobe dementia, Parkinson’s disease with dementia and numerous others.

The course of a dementia disorder

There is wide intra-individual variation concerning the survival time for Alzheimer’s type dementia. The survival time after diagnosis may range from 2 to 16 years. The median survival time also varies in different studies, probably due mostly to differences in the severity of the disorder when the diagnoses were set. However, most studies have reported median survival times ranging from 3-6 years [9]. For vascular dementia, the cognitive outcome is often fairly comparable to that of Alzheimer’s disease, but the survival time is often shorter, due to the underlying vascular disorders [9]. When the dementia disorder is mild, a majority of those affected is taken care of in their homes, by their spouse or other relatives and/or home-help services. In later stages, the decision is taken at some point for the person to move into an institutional care facility. The time point for institutionalization has been described as largely dependent on the commitment and willingness of relatives to take care of the person suffering from dementia at home, and certain factors are often associated with this decision. Such factors are: the sufferer needs the support of more then one person in activities of daily living, loses the ability to recognize relatives or becomes incontinent for urine or faeces [9]. Severe psychological distress, such as depression, in the carer might also lead to institutionalization. Behavioral and Psychological Symptoms of Dementia (BPSD) have also been found to hasten the transfer to a geriatric care facility [9, 10]. In a Swedish context, where many people with dementia receive home-help services [11], the decision is also influenced by the possibility of providing for all the person’s care needs in their own home. When the person with dementia needs care around the clock or continuous supervision to prevent them from going out and getting lost, institutionalization is hastened [12], as it is when other BPSD set in.

16 INTRODUCTION

Measuring cognitive impairment

The Mini Mental State Examination [13] is a widely used screening instrument for cognitive impairment. It includes questions and tasks covering the cognitive domains of orientation to time and place, registration, attention and calculation, recall (short-term memory) and language, and scores 0-30 points. A score of 23 or below is generally considered to indicate cognitive impairment. The MMSE score correlates with more comprehensive cognitive instruments such as the WAIS (Wechsler Adult Intelligence Scale) [13]. The MMSE has been found to have a sensitivity of 86% and a specificity of 92%, for differentiating between people with dementia and normal controls [14] (referred to in [9]). A dementia diagnosis cannot be set on an MMSE score alone, but the instrument is usually one part of the investigation. Another scale measuring cognitive impairment is the Gottfries’ cognitive scale [15, 16], used in Papers I-IV in this thesis. This scale is presented in Appendix 1 and comprises 27 items measuring a person’s cognitive function. A score of less than 24 is considered to indicate cognitive impairment. This has been found to correlate with a sensitivity of 90 % and a specificity of 91% [17] to the cut-off 24/30 in the MMSE.

Behavioral and Psychological Symptoms of Dementia

A person suffering from a dementia disorder might exhibit not only cognitive decline but also a range of non-cognitive symptoms and behaviors [18, 19]. The point prevalence of such behaviors and symptoms among people with dementia living in geriatric care facilities has been estimated to be between 79% and 92% [20, 21], and these symptoms often cause much suffering for both the person afflicted and their relatives and caregivers [22-24]. The non-cognitive features of a dementia disorder are not covered by the diagnostic criteria in the DSM-IV, except for the additional code “with behavioral disturbances” [4]. Some of the non-cognitive symptoms and behaviors are covered by other diagnoses such as anxiety, depression, delusions and hallucinations but the overall utility of the DSM-IV for diagnosis of BPSD is limited. The grouping of the symptoms and behaviors into the four main categories of hyperactivity, psychosis, mood disturbances and apathy is fairly consistent in earlier research [25, 26]. A Nordic state-of-the-art document lists delusions, hallucinations, activity disturbances (including wandering behavior), aggression, diurnal disturbances, affective disturbances, anxiety and phobias, misidentifications and catastrophe reactions as the main BPSD areas [27]. There is some evidence for specific symptoms to be more common in certain dementia disorders, e.g. hallucinations in Lewy-body dementia and depression and emotional lability in vascular dementia [28, 29]. Commonly-used rating scales for BPSD are the BEHAVE-AD scale [30] and the Neuropsychiatric Inventory [31]. The group of symptoms and behaviors should not be regarded as one disorder, and the term BPSD has been questioned [32]. The treatment of people with different behaviors and symptoms should be individualized and the various conditions should receive specific, and evidence-based, treatment. In many cases, however, people with behavioral disturbances such as aggression and agitation receive antipsychotics [19, 33-35], despite their, at best, modest effect [36- 38], and potentially severe side effects, for example the increased risk of stroke [38-42]. Old people receiving antipsychotics have an increased mortality rate compared to those

17 INTRODUCTION

who do not receive antipsychotics, and the risk seems to be about equally severe for both conventional and atypical antipsychotics [42-48]. There is some evidence for a correlation between serotonergic deficits and aggression in dementia [49-55], which would intuitively suggest that a heightening of serotonin levels, as for example with SSRI:s, would be more appropriate than a blockade, as with the atypical antipsychotics. Three studies have found beneficial effects on behavioral disturbances with citalopram [56-58], and two of these studies have compared it with antipsychotic drugs, perphenazine (a conventional antipsychotic) and risperidone (an atypical antipsychotic) respectively. Compared to perphenazine, citalopram had a better effect [58], and compared to risperidone there were no differences between the two treatments, either for agitation or for psychosis (sic!) [57]. There were fewer side effects with citalopram than with risperidone [57]. Other studies, however, have not found any effects from antidepressants compared to placebo on the behavioral and psychological symptoms of dementia other than depression [38, 59]. As an alternative to the use of psychotropic drugs for people with dementia, some studies have identified potentially modifiable risk factors for developing behavioral disturbances [60, 61] and evaluated various non-pharmacological interventions with promising results [62-68].

DEPRESSION

One major source of emotional suffering in both the general population and among old people is depression. According to the DSM-IV, a major depressive episode is diagnosed if, during at least a two-week period, at least five of the following symptoms have been present. One of the first two symptoms must also have been present.

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report or observations made by others. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day. 3. Significant weight loss when not dieting or weight gain (>5% of body weight in a month), or decrease or increase in appetite nearly every day. 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day. 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day. 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day. 9. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide [4].

According to the DSM-IV, minor depressive disorder is one or more episodes of depressive symptoms, similar to major depressive disorder in duration, but not in intensity, typically fulfilling between two and five of the criteria, including at least one of the first two. Dysthymic disorder is diagnosed when depressive symptoms have been present most days for at least two years [4]. In old, community-dwelling people the prevalence of major depression has been estimated to be between 1-2% when the DSM-IV criteria have been strictly followed. If, on the other hand, depressive symptoms, which might be regarded as signs of

18 INTRODUCTION

subsyndromal or atypical depression, are measured, the prevalence is much higher, approximately 13%-27% [69-72]. In geriatric care, the prevalence has been found to be even higher, possibly as high as 40%-50% [70, 73]. Depressive symptoms should not be regarded as a normal consequence of problems related to aging such as physical illnesses and social problems (loss of spouse and isolation for example). It has been found that old people with depression or depressive symptoms have an increased mortality rate [69, 72, 74], suggesting that depressive symptoms, even if the DSM criteria for major depression are not fulfilled, are clinically relevant, and should be considered a serious health problem [75]. In old people, depression often co-occurs with general medical or dementia disorders, making the diagnosis and treatment more complicated [69, 71]. Yet, if properly diagnosed, depression in old age can often be treated, and the treatment results are not in general worse than among young or middle-aged people [76, 77]. As many as 80% have been reported to respond to antidepressant treatment [78], and SSRI are generally better tolerated than tricyclic antidepressants [70, 77, 79]. There are, however, indications of both under diagnosis and suboptimal treatment of depression among old people, such as too low doses and poor follow-up, resulting in low remission rates [72, 80, 81]. There is also a relative lack of clinical trials of antidepressants in old and very old people, compared to young and middle-aged people [82]. More about antidepressant drugs is presented in the section on nervous system drugs.

Depression and dementia

Depressive symptoms and depression seems to be more common among people suffering from dementia, than among those without dementia. Among those suffering from Alzheimer’s disease it has been estimated that around 50% will suffer from depression sometime during the course of the disease [83]. Depression seems to be at least as common in vascular dementia as in AD [84, 85]. The exact relationship between dementia and depression is still not known. It has been proposed both that depression is a reaction to the awareness of functional decline and the very knowledge that one has a progressive dementia disorder, and on the other hand, that depression is caused by the neurodegenerative changes in the brain associated with the dementia disorder [86, 87]. There is more evidence today to support the latter hypothesis [83]. White matter changes [77, 88], and possibly sleep apnea [89] are probably of special importance for depression in vascular dementia. In mild cognitive impairment, depression might imitate the symptoms of dementia and to differentiate between the two can sometimes be difficult [9]. Many authors have not found any relationship between the level of dementia and the prevalence of depressive symptoms [29, 33, 90-94]. In some studies, however, mood symptoms have been found to decrease in prevalence among people with severe cognitive impairment [95, 96], supposedly related more to the increased difficulty in assessing depressive symptoms, than to any real decrease [83].

PAIN

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [97]. Pain is common among old people, especially

19 INTRODUCTION

among people living in geriatric care facilities [98-101]. One large study in nursing homes in the USA estimates the prevalence of persistent pain to be 48.5% [102]. The prevalence of pain seems to increase with age [101-103], and it seems to be somewhat higher in women than men [99, 102, 104-107]. The most common source of pain among old people is the musculoskeletal system [100, 101, 106, 108, 109], for example as in osteoarthritis. If not properly treated pain might lead to a lower quality of life and perceived health, as well as sleep disturbances and depression [98, 99, 103, 104, 110]. There are indications that pain among old people is poorly recognized and treated, around 20%-25 % of all those in geriatric care experiencing daily pain might not receive any treatment [102, 106, 111]. Some studies have reported even higher estimates of under-treatment [98]. It seems that people with dementia experience pain to about the same extent as people without dementia [112-114], and that their reports in general are valid [115]. Especially in people with moderate to severe dementia, however, recognition of pain might be more difficult, due to their reduced ability to properly communicate their symptoms [114, 116-120]. There are indications that pain among people with dementia might lead to behavioral disturbances [121] and it is of course of the utmost importance to then identify pain as the cause, to treat the pain or, if possible, the underlying causes of the pain and not the behavioral symptoms. Some promising results exist regarding pain treatment for people with dementia and behavioral disturbances, showing improvements in behavior or participation in various activities [122-124]. Different authors have proposed educational programs [125-129] and the regular use of structured pain assessments [130-135] as two ways of improving the recognition and treatment of pain in geriatric care.

Pain treatments

The most common pharmacological pain treatments are paracetamol, opioid analgesics and NSAID [102, 109, 136]. Paracetamol is generally well tolerated among old people, and often rather effective for mild to moderate pain [137]. It has long been discussed whether or not paracetamol inhibits cyclooxygenase to a clinically significant extent, but the side-effect profile and the relative lack of anti-inflammatory effect suggest that COX-inhibition is not the principal mechanism of its analgesic activity [138]. The involvement of inhibition of COX type 2 is still being debated, and specific action onto the prostaglandin synthesis within the CNS has also been proposed [139-141]. It has, however, recently been demonstrated that paracetamol probably acts through the endocannabinoid system, which might explain its effects [138]. The endocannabinoid system has many properties, some of which are suppression of pain transmission and thermal regulation [138, 142]. The mechanism is that some of the paracetamol is deacetylated to p-aminophenol and conjugated to arachidonic acid in the central nervous system to form N-arachidonoylphenolamine (AM404) [143], a compound previously described as acting onto the cannabinoid system [138, 142]. AM404 is a potent activator of vanilloid subtype 1 receptors (TRPV1) [144]. The effect of the activation of this receptor is an inhibition of the reuptake of the endogenous cannabinoid enandamide, and hence an increased activity onto the receptor CB1 [138, 145, 146]. The exact mechanism of this reuptake-inhibiting effect of AM404 is not yet known, and more than one principal pathway might be involved [146].

20 INTRODUCTION

Substances that directly stimulate CB1 receptors, such as Δ9-tetra-hydro- cannabinol, have undesirable psychotropic side effects [147]. Such side effects are not seen with paracetamol, which can probably be explained by the reuptake-inhibiting mechanism, thought to result in an enhancement only at synapses where cannabinoids are currently released [142]. The analgesic effect of paracetamol is totally inhibited if the CB1 receptor is blocked [148], but also when the serotonin receptor 5-HT3 is blocked [149, 150], suggesting a downstream activation of descending inhibitory pain pathways [149, 151]. With this new knowledge, paracetamol can no longer be considered a peripheral-acting analgesic, as has previously been thought. Opioid analgesics are strong analgesics with some known side effects such as constipation, sedation, nausea and confusion. Despite the side effects, their effectiveness makes opioid analgesics an invaluable element in the therapeutic arsenal, especially for moderate to severe pain. Opioids bind to and activate opioid receptors, particularly receptors of µ-type. The endogenous opioid system inhibits pain signal transmission, both from somatic and visceral pain nerve fibers [152, 153]. NSAID inhibit the enzyme COX and thereby the formation of prostaglandins, which are pro-inflammatory substances. NSAID have analgesic, antipyretic and anti- inflammatory effects [153]. They have some potentially severe adverse effects such as gastrointestinal bleeding, nephrotoxicity, heart failure and depression [153-155] and are in general not very much more effective than paracetamol regarding their analgesic effect [156], hence their use is more seldom warranted in old people. Non-pharmacological pain treatment such as warm or cold rice bags, massage, physiotherapy or acupuncture might be effective in some cases and generally have a very advantageous side-effect profile. It is, therefore, often justifiable to try such a strategy before pharmacological treatment is initiated, or use it as a complementary treatment. For neuropathic pain, low dose tricyclic antidepressants or GABA-analogues such as gabapentin and pregabalin can be alternatives [137, 153, 157, 158].

GERIATRIC CARE

It is important to stress that old people do not need care just because they are old, but some of them, as well as some younger people, need care because of somatic, psychiatric or cognitive disorders or conditions. Geriatric care is provided in various forms. A large part of the care of old people is carried out by other old people, namely their close relatives. Many old women especially take major responsibility for the care of their husbands. The municipalities provide home-help services for old people. Home-help services can comprise both help in ADL such as dressing, eating and personal hygiene as well as services such as transportation, shopping and food distribution. Home medical care is also an alternative [2]. When the need for care cannot be met by home-help services and home medical care, institutional geriatric care is introduced [2]. In Sweden, 8.9% of all people aged 65 years or older and 20.9% of all people aged 80 years or older receive home-help services. Another 6.2% of those aged 65 years or more and 16.2% of those aged 80 years or more live in institutional geriatric care [12].

21 INTRODUCTION

Characteristics of different types of institutional geriatric care facilities in Sweden

Old peoples’ homes and senior citizens’ apartments are grouped together under the term residential care facilities in this thesis, and correspond to the terms ålderdomshem and servicehus in Swedish. Ålderdomshem is an obsolete term and is no longer in use. The term seniorboende has recently begun to be used in Sweden and refers to apartments specially adjusted for old people but without any ordinary nursing staff. Instead the residents can receive home-help services if they are warranted. This kind of dwelling is not included in the term institutional geriatric care facilities. Psychogeriatric and somatic long-stay wards were caring facilities that resembled hospitals. This kind of facility is no longer in use in Sweden. The psychogeriatric long- stay wards were for people with dementia or other chronic psychiatric disorders while the somatic long-stay wards were for people with chronic disabilities or somatic disorders. The long-term care facilities, often centralized near hospitals, did not focus so much on rehabilitation as today’s hospital wards, but more on providing good long-term care and care at the end of life. The people often lived in shared rooms, and the meals were served in a dining room. There was not so much space for private things. Registered nurses and licensed practical nurses or nursing aids were available round the clock. The division between somatic long-stay wards and nursing homes was not so clear. However, people with the most need of medical care lived in the long-stay wards and some efforts of rehabilitation were made. Today there are no somatic long-stay wards so people with extensive care needs, who would previously have been living in these facilities, now live in nursing homes. The people living in nursing homes also have their own rooms or share rooms with up to three other people and, as in the somatic long-term care, there is a generally high staffing rate and staff available round the clock. Nursing homes are organized to provide full-time care. Today the geriatric hospital wards focus mainly on rehabilitation, for example after hip fractures or strokes, or investigations prior to geriatric care placement for various medical conditions. Psychogeriatric hospital wards now focus on the investigation and treatment of BPSD. In residential care, people have their own apartments, with their own toilet and small kitchen, and the rooms can be furnished with their own things. Meals are often served in common rooms. Registered nurses are available on site during the day and licensed practical nurses or nursing aids around the clock. The facilities and staffing are adjusted to providing an intermediate level of care, and are generally less well suited to those with dementia or extensive care needs. Group dwellings for those with dementia are small units for 8 to 12 people, providing specialized dementia care. The people have their own rooms and share a kitchen and living room. Staff are available at all times, and staffing rate is somewhat higher than in residential care. The facilities are usually locked to prevent the residents from going out without supervision. Short-stay or rehabilitation units are dwellings that provide intermediate care, i.e. until a person can be assigned to a permanent geriatric care unit, is so improved that they can return to their own house or apartment or need intermediate relief care.

22 INTRODUCTION

Time trends in the organization of institutional care of old people in Sweden

Geriatric care in Sweden is financed through taxes and municipal authorities run most facilities. An increasing number of private geriatric care facilities, still however financed through taxes, have started up in recent years. The proportion of people living in private geriatric care facilities has increased from 11% in 2000 to 14% in 2006 [2]. A large reform (Ädelreformen) was carried out in 1992, which transferred the responsibility for long-term care facilities and nursing homes from the county councils to the municipalities. Before that time, the county councils were responsible for the nursing homes and somatic geriatric and psychogeriatric long-stay wards and the municipalities for residential care facilities, including homes for the aged [159]. There has been a trend over the last thirty years or so towards a deinstitutionalization of geriatric care, aimed at providing more home-like environments in geriatric care. The closure of long-stay wards and the opening of group dwellings for people with dementia could be regarded as a manifestation of this trend, as can the expansion of the home- help services.

The county of Västerbotten

The county of Västerbotten covers 59,284 square kilometers, is situated in northern Sweden, and comprises about one eighth of the country’s total area, see Figure 1. The county is divided into 15 municipalities, of which Umeå and Skellefteå, on the Baltic coast, are the largest. In 2000, the county had a population of 255,640 [160].

Figure 1, The county of Västerbotten, Sweden. Note: From Adolfsson et al., 1981 [15].

23 INTRODUCTION

Healthcare and institutional geriatric care in the county of Västerbotten

Healthcare in the county is organized under the county council with three hospitals, in the cities of Umeå, Skellefteå and Lycksele, forming the backbone of the healthcare system. In addition there are 35 health centers, of which 7 have acute observation wards [161]. The geriatric hospital care comprises four somatic geriatric hospital wards (three in Umeå and one in Lycksele) and two psychogeriatric hospital wards (one in Umeå and one in Skellefteå) [161]. In Sweden, the municipalities now have responsibility for all geriatric care facilities, apart from geriatric and psychogeriatric hospital wards. In 2000, the geriatric care facilities in the county of Västerbotten comprised 68 residential care facilities, 31 nursing homes, 66 group dwellings for people with dementia and 7 rehabilitation or short-stay units [162].

NERVOUS SYSTEM DRUGS

The central nervous system

The central nervous system is by far the most complex organ in the human body. It contains approximately 100 billion neurons and many more supportive cells. Each neuron receives input from between 1 and 100,000 other neurons, forming a complicated network. Its function is to collect information from the sensory organs, to analyze the information and to control the action of the muscles and other bodily functions such as digestion, respiration and heart rate. The human brain also has the ability to enable self-reflection and consciousness, to store memories, to learn things, to reprocess information, to associate, to communicate through language and to thinking formally, so-called cognitive abilities or higher functions. It also integrates moods, feelings and emotions [163].

Prevalence of psychiatric disorders in general populations and among old people

Psychiatric disorders are common. The six-month prevalence of psychiatric disorders, not including dementia, has been estimated at approximately 20% in the adult population. Eight percent will have suffered anxiety disorders, 4 % mood disorders, 5 % substance abuse (alcohol or narcotics), 1% schizophrenia or other psychotic disorders and 2% other psychiatric disorders (including for example eating disorders or severe personality disturbances) [164]. Among old people, the increasing prevalence of dementia is one major difficulty when assessing the prevalence of other psychiatric disorders, as many of them are in some way or another associated with dementia. In one Swedish study, the H70 material, the prevalences of depression, anxiety disorder and psychotic disorders among old people were found to about double with advancing age from 70 to 85 years, using DSM-III-R criteria for diagnosis (which means that depression cannot be diagnosed in people with dementia). Depression increased from 6.1% to 19.8%, anxiety from 6.1% to 10.3% and psychotic disorder from 1.0% to 5.1% [8]. Among people living in geriatric care, the prevalences of psychiatric disorders and symptoms are reported to be higher than in general populations [33, 73].

24 INTRODUCTION

An exposé of the history of psychotropic drugs and analgesics

Opium (Papaver somniferum) has been used since ancient times to treat painful conditions, and it became popular in Europe in the form of “tincture of laudanum” during the 18th and 19th centuries. Laudanum consisted of opium dissolved in sherry (or other alcohol), sometimes flavored with saffron or cinnamon. Morphine was isolated in 1803 by the German pharmacist Friedrish Sertürner (1783-1841), from the juice of the opium poppy. This was the very first time an active ingredient was isolated from a medicinal plant [165]. Morphine and its derivatives have weak antidepressant effects and outstanding analgesic properties, and are still widely used in medicine. The bark of the willow tree (Salix alba), has been used since medieval times in folk medicine to treat pain and lower fever [166]. Later, from the 17th century onwards, cinchona bark (Cinchona spp.) was used for the same purposes [165]. Salicin was isolated from willow tree bark in 1828, and the derivative acetylsalicylic acid was first synthesized in 1853. In pure and stable form, however, the substance was first produced in 1897 [166]. When the supply of cinchona bark became insufficient around 1880, the search for alternatives was intensified. In 1886 a substance derived from coal tar, acetanilide, was serendipitously found to possess antipyretic properties. Due to its unacceptable toxic effects, most importantly cyanosis caused by methemoglobinemia, a number of related substances were tested. The most promising results were found with phenacetin and paracetamol (first synthesized in 1878). Phenacetin and paracetamol were introduced into clinical use in 1887, but paracetamol was soon discarded because it was (falsely) assumed to be more toxic than phenacetin. In 1893 and 1899, paracetamol was found in the urine of individuals who had taken phenacetin and acetanilide respectively, but the discoveries were largely ignored at the time. In 1948, paracetamol was rediscovered to be the primary metabolite of acetanilide and it was shown that the analgesic and antipyretic effects of acetanilide were due to paracetamol, while, more importantly, the side-effect methemoglobinemia was caused by another metabolite. Hence, by using paracetamol instead of acetanilide, the same good analgesic and antipyretic properties were achieved, without the potentially lethal side-effects. From 1955, paracetamol was marketed in the USA, at first under the brand name “Tylenol Children’s Elixir” [138, 167]. From 1899, acetylsalicylic acid had been marketed as an analgesic and antipyretic drug. During the first half of the 20th century, it was the most common over-the-counter analgesic. About the time of the rediscovery of paracetamol, concerns were raised about the gastrointestinal side effects of acetylsalicylic acid, and sales started to fall. However, not until about 1980, did the sales of paracetamol overtake those of acetylsalicylic acid [138, 166]. Apart from acetylsalicylic acid, the first Non-Steroidal Anti-Inflammatory Drugs (NSAID) became available during the 1960s. During the history of human societies, various pharmacological drugs have also been used to alleviate psychiatric symptoms and treat different psychiatric disorders. Probably the first psychotropic drug to be used was alcohol, which has been known for many thousands of years. Opium (morphine, from the herb Papaver somniferum), also known for a very long time, was already used for treatment of melancholy in the days of Hippocrates. Belladonna, or Deadly Nightshade, (Atropa belladonna) is another drug that has been used for more than a thousand years and is still in clinical use [168].

25 INTRODUCTION

Hellebore (Helleborus spp.) was probably the most widely used drug for psychiatric disorders from the days of Hippocrates to the 19th century. The hellebore plant (various species exist) contains alkaloids with emetic, laxative and sedative effects. It is doubtful if there is any psychotropic effect, but medicine at that time focused mainly on expulsion. These drugs are no longer in clinical use [168]. Emil Kraepelin (1856-1926), a German psychiatrist, was the first to make a systematic scientific investigation of the psychotropic effects of different drugs in healthy subjects; he is therefore sometimes referred to as the father of psychopharmacology. He published an investigation of the effects of morphine, tea, alcohol, ether, chloral hydrate and paraldehyde in 1883 [169] (referred to in [170]). Camphor (from Cinnamomum camphora) was the first agent used to induce epileptic seizures as a treatment for psychiatric disorders, at least from the 18th century. Auenbrugger wrote in 1776 that it had to be given in doses that produced convulsions. The camphor convulsive therapy sank into oblivion, and was rediscovered in 1935. Other pharmacological drugs were also later used to induce seizures. Electro-convulsive therapy, ECT, was discovered in 1938 and that treatment has now replaced all other ways of inducing convulsions [168]. ECT is still in clinical use and is regarded as one of the most effective antidepressant treatments [77]. Insulin-coma treatment of schizophrenia was introduced in 1933, and was in use until the discovery of modern antipsychotics in the 1950s [168]. Digitalis (from Common foxglove, Digitalis purpurea) was regarded an effective drug against psychiatric disorders during the 18th and 19th centuries, probably because of observations of the effect on patients with delirium associated with heart failure [168]. The herb Rauwolfia serpentina has long been used in Indian traditional medicine. The active substance, reserpin, was first used in western medicine as anti-hypertensive medication, and its antipsychotic properties were discovered in the 1950s. Reserpin has a somewhat weaker antipsychotic effect than phenothiazine derivatives, but has continued in use as an experimental substance, not least for its ability to induce depression [168, 171]. Reserpin depletes the brain of both serotonin and noradrenaline [153]. Bromide was discovered in 1826, and was used as an anti-epileptic from 1851 (especially in the form of potassium bromide). In time it became widely used as a hypnotic. It was effective as a hypnotic drug in many situations, but tended to accumulate in the body and produce chronic intoxication. It is no longer in clinical use [168]. Chloral hydrate, also a sedative agent, was introduced in 1869 and was used clinically until the 1980s [172]. The first barbituric acid derivatives that were synthesized were barbital in 1903 and phenobarbital in 1912 [168]. The barbiturates were the most widely used hypnotics during the first half of the 20th century, but have now mostly been replaced by the benzodiazepines [153]. Two barbiturates are still in clinical use, thiopental, an intravenous anesthetic agent, and phenobarbital which is used as an anti-epileptic [155]. The anti-manic proprieties of lithium was first described in 1949 [173]. The sedative properties of various antihistamines were discovered during the 1940s, and the drugs were tried for different psychiatric conditions. None of them, however, were more effective than the barbiturates [168]. Some of the sedative

26 INTRODUCTION

antihistamines are still in clinical use as hypnotics or anxiolytics, for example hydroxizin, mainly due to their lack of addictive potential [155]. Phenothiazine was synthesized as early as 1883. The study of the phenothiazine derivatives, many of them strong anti-histamines, during the 1940s led eventually to the synthesis of chlorpromazine in 1950. Chlorpromazine was first used as an induction agent in anesthesia, and was found to have a number of unique and interesting properties. The first report of its antipsychotic effect was published in 1952 by Delay and coworkers. In the following years, many other phenothiazine derivatives were synthesized and numerous articles described their antipsychotic effect [168]. Meprobamat, another anxiolytic drug, was introduced in 1954 [168]. Around 1950, it was noted that one tuberculosis drug, isoniazid, could have some positive effects on the mood of the patients. A related compound iproniazid was described in 1952 as having mood-enhancing properties. It was revealed in 1956 that these compounds blocked the action of the enzyme monoamineoxidase and thereby increased the brain levels of monoamines. The antidepressant effect was established in 1957 [168]. Monoamineoxidase inhibitors is still in clinical use [155]. Imipramin is related to the phenothiazines. It was originally evaluated as an antipsychotic, but was found to have an antidepressant instead of an antipsychotic effect [171]. Imipramin was introduced in 1957 [168]. It was the first tricyclic antidepressant, and was later found to block the re-uptake of brain monoamines [153]. Soon other related drugs, such as amitryptiline, followed [168]. Chlordiazepoxide, the first benzodiazepine, was introduced in 1960, and diazepam a few years later. The benzodiazepines were not derived from any known chemical compound, and the sedative effect of chlordiazepoxide was found during the routine screening process of new compounds at the Hoffman- La Roche laboratory [153, 168]. The benzodiazepines rapidly became the most widely used hypnotics and anxiolytics [168]. They had a number of advantages over the barbiturates, principally less likelihood of developing tolerance, not as easy to over-dose and the lack of enzyme- inducing properties. However, the addictive potential was comparable [153]. Clomethiazole is derived from the thiazole part of vitamin B1. A study of the effects of the compound was published in 1963, describing a number of patients treated for delirium tremens at Beckomberga mental hospital in Sweden [168]. The selective serotonin reuptake inhibitors were introduced during the eighties. The first drug that were introduced was zimelidine [174], followed by fluvoxamine and fluoxetine. Zimelidine was withdrawn in 1983.

The nerve cells, synapses and receptors

The signal transduction between neurons is chemical, via neurotransmitters. The connection between the axon of one nerve cell and the dendrite of another is called a synapse. Many different substances can serve as signal substances and, in addition, each substance can bind to many different receptors. One single nerve cell can have receptors of many different types, and react to stimulation from many different signal substances. One synapse usually uses one single signal substance, but a nerve cell can have many thousands of dendrites and synapses. Nerve-cell receptors can principally be of two different types, ligand gated ion channels, or g-protein coupled receptors, so-called metabotropic receptors. The ion channel receptors directly influence the ion flux over the cell membrane, typically eliciting very fast responses in the form of action

27 INTRODUCTION

potentials. The metabotropic receptors, on the other hand, act more slowly, affecting the sensitivity of the nerve cell to other influences, i.e. stimulation of a metabotropic receptor typically does not elicit an action potential, but affects the nerve cells threshold to fire an action potential, when stimulated by other signal substances.

Transmitter systems

The majority of the excitatory nerve cells of the central nervous system use the transmitter glutamate, and most inhibitory nerve cells the transmitters GABA or glycine. Most glutamate, GABA and glycine receptors are ion channel receptors, as are the receptors of acetylcholine. The main monoaminergic transmitters of the central nervous system are dopamine, noradrenaline, adrenaline, histamine and serotonin. Adrenaline is not as common as the other monoamines and will not be considered further. The monoamine transmitters have some very special roles in the brain, and are involved in processes crucial for the development and treatment of psychiatric disorders. They all share some common features. All are derived from one amino acid, hence the name monoamines. All are produced in rather few neurons grouped in one or a few nuclei in the brain stem or mid-brain, but the neurons project their axonal branches and release their signal substances widely and diffusely over the brain cortex. All monoamines are involved in various aspects of some “regulating” systems, such as mood, motivation, reward, arousal, behaviors et cetera. This perception of the monoamine systems as regulating systems is consistent with the fact that most monoamine receptors are of the metabotropic type [163]. An overview of important transmitter systems is given in Table 1 [163, 175, 176].

Nervous system drug classes

The WHO classification of pharmacological drugs is called the ATC system (Anatomical, Therapeutical, Chemical). This thesis comprises studies of the ATC class N drugs, drugs acting on the nervous system, with the main focus being on psychotropic and analgesic drugs. Included are analgesics (N02), anticonvulsants (N03), Parkinson drugs (N04), antipsychotics (N05A), anxiolytics (N05B), hypnotics and sedatives (N05C), antidepressants (N06A) and anti-dementia drugs (N06D). Anesthetics (N01), psychostimulants (N06B), drugs used when treating substance dependence (N07B) and some additional drugs used in Myasthenia gravis (N07A) or Multiple sclerosis (N07X) are not included, even if they are included under ATC class N. Antipsychotics, anxiolytics, hypnotics, sedatives and antidepressants are sometimes referred to as psychotropic drugs. For an overview of the ATC class N drugs, see Figure 2.

Main effects of different nervous system drugs

An overview of the main classes of nervous system drugs and their effects is given in Table 2 [138, 143, 148, 153, 155]. It is important to notice that all psychiatric disorders are far more complicated than simply signal substance imbalances. Autoregulation of the number of receptors, feedback mechanisms, gene expression, axon sprouting and nerve cell growth or death et cetera in the field of neuropsychopharmacology, and of course psychological and social factors are also of importance for the development of

28 INTRODUCTION

psychiatric disorders. A strong reminder of this is that the effects of antidepressants and antipsychotics, for example, are delayed for some weeks or some days respectively, even if the signal substance levels are affected within less than one hour after oral administration.

N Nervous system drugs

N01 Anesthetics N02 Analgesics N03 Anti-epileptics N04 Parkinson drugs Psychotropic drugs N05 Psycholeptics N05A Antipsychotics N05B Anxiolytics N05C Hypnotics and sedatives N06 Psychoanaleptics N06A Antidepressants N06B Psychostimulants N06D Anti-dementia drugs N07 Other nervous system drugs

Figure 2, Anatomical Therapeutical Chemical (ATC) Classification System. Class N, Nervous system drugs.

The mechanisms of various analgesic drugs have already been described, in the section on the concept of pain. Anticonvulsants are a diverse group of drugs acting through many different mechanisms. Their main effect is to elevate the seizure threshold in people with epilepsy, or to treat ongoing seizures. Parkinson drugs include l-dopa and dopamine agonists. The group actually also includes some anticholinergic agents, which, however, are not included in this thesis. L- dopa is a precursor of dopamine, of which there is a lack in Parkinson’s disease due to the death of dopaminergic neurons, and it increases the levels of dopamine in the brain. The dopamine agonists also enhance the effects of the dopamine system. Antipsychotics, on the other hand, block the dopamine system. In schizophrenia, the dopamine system seems to be over-activated. The atypical antipsychotics also block the effect of serotonin, in addition to dopamine, and thereby have a slightly different profile compared to the so-called conventional antipsychotics. Most anxiolytics and hypnotics, sometimes referred to as minor tranquillizers, produce their effect through enhancing GABA transmission. This is the mechanism for the benzodiazepines. Some drugs in these classes work instead through blocking the effect of histamine. Antidepressants increase the levels of serotonin and also, in varying degrees, the levels of noradrenaline. Tricyclic antidepressants block the reuptake of serotonin and noradrenaline and thereby increase the amount of signal substance in the synaptic cleft. The SSRI selectively block the reuptake of serotonin and does not affect the levels of noradrenaline as much as the tricyclic antidepressants.

29 INTRODUCTION

TABLE 1, OVERVIEW OF IMPORTANT TRANSMITTER SYSTEMS IN THE CENTRAL NERVOUS SYSTEM

Transmitter Derived Produced by neurons Receptor type from… in the brain area … Serotonin (5-HT) the amino acid Raphe nuclei in upper Metabotropic tryptophan brainstem receptors (except 5- HT3 receptor) Noradrenaline the amino acid Locus coeruleus in Metabotropic (NA) tyrosine upper brainstem receptors Dopamine (DA) the amino acid Substantia nigra and Metabotropic tyrosine ventral tegmental area receptors in upper brainstem Histamine (H) the amino acid Tuberomammillary Metabotropic histidine nucleus of receptors hypothalamus Acetylcholine choline + Four cell groups in the Ligand-gated ion (ACh) acetyl CoA basal forebrain channel receptor (nicotinic type), metabotropic receptor (muscarinic type) γ-amino butyric the amino acid no single centre, Ligand-gated ion acid (GABA) glutamate produced by neurons channel receptor all over the brain (some metabotropic receptor subclasses) Glycine the amino acid no single centre, Ligand-gated ion serine produced by neurons channel receptor all over the brain Glutamate the amino acid no single centre, Ligand-gated ion glutamate produced by neurons channel receptor all over the brain (some metabotropic receptor subclasses)

MAO-inhibitors block the effect of the enzyme monoamine oxidase, which degrades serotonin, noradrenaline and dopamine and thereby increases the levels of these transmitters. The tetracyclic antidepressants are thought to block a presynaptic α2- receptor (a noradrenaline receptor) and thereby affect an autoregulatory feedback mechanism which leads to increased levels of the transmitter substance. One tetracyclic antidepressant, maprotiline, is instead a noradrenaline reuptake inhibitor. Anti-dementia drugs currently available comprise acetylcholine-esterase inhibitors and one NMDA receptor agonist. None of the drugs interfere with the underlying pathology of Alzheimer’s disease. The choline esterase inhibitors affect the symptoms produced by a deficit of acetylcholine, by blocking the degrading enzyme, which is located intrasynaptically. The NMDA receptors are one class of glutamate receptors. The theory is that there is too much “noise” in the glutamate transmission in the brain of people with Alzheimer’s disease, and by blocking the NMDA receptor the effect of the pathologically enhanced transmission is diminished [153, 155].

30 INTRODUCTION

Main postsynaptic Involved in … Associated effect psychiatric disorders Excitatory behavior, emotion, mood, circadian Depression, anxiety, rhythm, motor behavior and mental schizophrenia arousal Excitatory sleep and wakefulness, attention, Depression, anxiety feeding behavior Excitatory motor function, motivation, reward and Schizophrenia, reinforcement Parkinson’s disease

Excitatory arousal and attention, sleep-wake cycle, Largely unknown learning, memory, emotions, reactivity of vestibular system Excitatory motor behavior, learning, short-term Alzheimer’s disease memory, arousal, reward, attention

Inhibitory main inhibitory transmitter in the brain

Inhibitory

Excitatory main excitatory transmitter in the brain

Effects and side effects of nervous system drugs among old people

Both pharmacokinetic and pharmacodynamic changes in old age contribute to an increased sensibility to the effects of nervous system drugs in old people compared to younger people [177]. Important pharmacokinetic changes are increased relative fat mass and decreased body water content, reduced protein binding of certain drugs, redused liver function and not at least reduced the drug-eliminating function of the kidneys [178]. Important pharmacodynamic changes are a decrease in the number of receptors in the CNS, e.g. dopamine and choline receptors [177]. These changes are more marked among people suffering from dementia, making them increasingly vulnerable to certain drug effects [179]. Another change is a generally reduced homeostatic function, resulting in an impaired ability of the body to counteract changes in, for example, blood pressure [177].

31 INTRODUCTION

TABLE 2, OVERVIEW OF NERVOUS SYSTEM DRUGS, MAIN MECHANISMS AND EFFECTS

Drug class ATC-code Transmitter Mechanism Main effect system/ target Analgesics N02 Opioid N02A Opioid Receptor agonism Stimulation analgesics receptors of opioid receptors, particularly of µ-type Paracetamol N02B E Endogenous Inhibits reuptake of CB1+ cannabinoid the endogenous system, CB1 cannabinoid receptor (via anandamide via an active TRPV1 metabolite) NSAID M01A Prostaglandin Blockade of cyclo- Prostaglandin synthesis oxygenase levels decrease Anticonvul- N03A Different Different Heightened sants seizure threshold Parkinson drugs N04 L-dopa N04B A DA Precursor in DA DA+ synthesis Other N04B C,D, DA DA receptor DA+ X agonists Antipsychotics N05A Conven- N05A A,B, DA Receptor blockade DA- tional D,F Atypical N05A DA, 5-HT Receptor blockade DA-, 5-HT- E,H,X Lithium N05A N01 Largely unknown Membrane stabilisation Anxiolytics, N05B, C hypnotics and sedatives Anxiolytics, N05B A GABA Receptor binding, GABA benzo- increases the effect transmission+ diazepine type of GABA Hypnotics and N05C sedatives Benzo- N05C D,F GABA Receptor binding, GABA diazepine increases the effect transmission+ type of GABA Clomethia- N05C M02 GABA Receptor binding, GABA zole increases the effect transmission+ of GABA

32 INTRODUCTION

Table 2 continued. Propio- N05C M06 H, (DA,5-HT, Receptor H-, (DA-, 5- mazine NA, ACh) blockade HT-, NA-, ACh-) Antidepres- N06A sants Tricyclics N06A A 5-HT, NA Unselective 5-HT+, NA+ reuptake inhibitor SSRI N06A B 5-HT Selective 5-HT+ reuptake inhibitor MAO- N06A G 5-HT, NA, DA Blockade of 5-HT+, NA+, inhibitor degrading DA+ enzyme (monoamineoxidase) Other N06A X Tetracyclic NA Blockade of NA+ antidepres- autoregulatory sants presynaptic α2- receptors, or noradrenergic reuptake Venla- N06A X16 5- HT, NA Selective 5-HT+, NA+ faxine reuptake inhibitor Anti-dementia N06D drugs Choline- N06D A ACh Blockade of ACh+ esterase intrasynaptic inhibitor degrading enzyme (Acetylcholine- esterase) Memantine N06D X Glutamate NMDA receptor Glutamate- antagonist, modulating effect on transmission

Altogether pharmacokinetic and pharmacodynamic changes lead to the increased effect and increased probability of adverse effects from several nervous system drugs in old people [177, 180]. Of special interest is the increased sensitivity to drugs with anticholinergic properties. Among old people, such drugs might provoke agitation, confusion, impairment of memory and attention and ultimately delirium [177, 179]. Drugs with known anticholinergic properties include tricyclic antidepressants, antihistamines and

33 INTRODUCTION

many antipsychotics [177, 179]. In addition, it has also been shown that many commonly prescribed drugs e.g. prednisolone, theophylline, digoxin, furosemide and nifedipine have some anticholinergic effect [181]. Nervous system drugs often mentioned as inappropriate, or at least more seldom warranted, for old people due to the high risk of adverse effects are drugs with anticholinergic effects, antipsychotics, long-acting benzodiazepines, NSAID and opioid analgesics [137, 177, 182]. The so-called Beers criteria is one example of a list of drugs considered to be inappropriate in old people, its aim being to serve as a tool for the prescribing physician [182]. The use of inappropriate drugs has been linked to an increased risk of hospitalization and even death among old people [183]. Furthermore, many old people use many different drugs concomitantly, due to their multiple medical conditions, which might further increase the risk of developing adverse reactions [184].

Prevalence and time trends in psychotropic drug use among old people

Many articles have reported the prevalence of psychotropic drug use in different populations of old people. Figure 3 illustrates the prevalence of antidepressant use in 22 studies [17, 18, 33, 35, 72, 162, 185-200], in relation to the year the studies were carried out; x stands for geriatric care populations, o for general populations of old people. When comparable data from different years are presented in the same article, the points are aligned. Seven studies provided data from more than one point in time.

Figure 3, Prevalence (%) of antidepressant drug use in 22 studies, 1980 to 2007. Note: When comparable data from different years were presented in the same article, the marks are aligned. x = geriatric care, o = general population of old people.

Note that the different populations are not comparable. Some are from nursing homes only, and some are from all kinds of geriatric care. The various studies also include very different numbers of participants, and the mean age and proportion of people with

34 INTRODUCTION

dementia also differ. The figure must therefore be interpreted with caution. However, a clear trend is found for increased use in recent years, starting around 1990. The reason for this increased use is most probably the introduction of the SSRI. For the years 2000- 2005, the prevalence of antidepressant use among old people in geriatric care seems to be about 35%-45%, and around 10%-15% in a general population of old people. Figure 4 is the corresponding illustration for hypnotic and sedative drugs, including data from 20 studies, of which 4 provided data from more than one point in time [17, 18, 33, 35, 72, 162, 186-189, 191-193, 195, 196, 199-203]. In some studies, the prevalence presented also included anxiolytics. There is no clear time trend, and in addition, there is a large spread between the prevalence in different studies, ranging from 10% to around 55% for geriatric-care populations. Different population characteristics as well as treatment traditions in different countries probably explain this. In general populations the prevalence was around 20%-30%.

Figure 4, Prevalence (%) of sedative drug use in 20 studies, 1980 to 2007. Note: When comparable data from different years were presented in the same article, the marks are aligned. x = geriatric care, o = general population of old people.

Figure 5 refers to antipsychotics. Data from 22 studies are included, and 5 out of these provided data over time [18, 33-35, 72, 162, 186-189, 191-193, 195, 196, 199, 200, 203-207]. As for the hypnotic and sedative drugs, there is no obvious time trend concerning the prevalence of antipsychotic drug use. One trend, however, is that there has been a shift towards atypical antipsychotics, which now constitute at least one half of the antipsychotics prescribed [33, 193, 196, 204, 205, 207]. The prevalence of antipsychotic drug use in geriatric care seems to be around 15%-40% in most studies, and about 2%-10% in most samples from general populations of old people. People suffering from dementia seem to be at increased risk of receiving nervous system drug, especially antipsychotics, compared to people without dementia [33, 191, 203, 208]. Men have been found to receive antipsychotics more often than women, and women to receive antidepressants more often than men [185, 200].

35 INTRODUCTION

Figure 5, Prevalence (%) of antipsychotic drug use in 22 studies, 1980 to 2007. Note: When comparable data from different years were presented in the same article, the marks are aligned. x = geriatric care, o = general population of old people.

36 INTRODUCTION

RATIONALE

Old people who live in geriatric care comprise a group of people with many different concurrent diseases, often including dementia, depression and pain, which are major causes of distress and lower quality of life. Previous research has found that both pain and depression are often under-recognized and poorly treated among old people. At the same time, the use of some nervous system drugs is common among old and very old people, especially among those living in geriatric care facilities. Nervous system drug treatments have become more common in recent years. The drug treatments in themselves constitute a major health problem since old people are, in general, more prone to develop adverse drug effects, especially if they have a dementia disorder. Inappropriate drug use among old people might lead to worsened cognitive function, increased risk of hospitalization and increased mortality. The use of antipsychotics, for example, in people with dementia is common despite low efficacy and serious concerns about their safety. There is a lack of research explaining why this treatment is so often resorted to. Little is also known about whether the current widespread treatment with antidepressants is really appropriate or has improved the mental health of old people. The relation between depression and dementia remains unclear, and evidence supporting the use of antidepressants for people with dementia and depressive symptoms is extremely weak. Thus, there is a current lack of studies describing the prevalence of, and factors associated with, psychotropic and analgesic drug use among old and very old people, with and without dementia.

37 INTRODUCTION

AIM

The overall aim of this thesis was to describe the use of psychotropic drugs and analgesics among old people. The aim not only includes the prevalence of various classes of drugs, but also time trends, prevalence of symptoms that might serve as indications for treatment and comparisons between different groups, e.g. people with or without dementia. There is a special focus on people living in institutional geriatric care, a group of people who often receive nervous system drugs.

SPECIFIC AIMS

I - to compare the answers of the caring staff concerning the resident’s pain treatment with the actual pharmacological pain treatment in a cross-sectional survey of the geriatric care population in the county of Västerbotten.

II - to describe the characteristics of a group of old people with cognitive impairment in geriatric care who were treated with antipsychotics, and to discover whether there were any associations between the use of antipsychotics and BPSD, and other factors linked both to the person and to the geriatric care environment.

III - to compare the occurrence of certain symptoms and behaviors and the prevalence of psychotropic drug use in two cross-sectional surveys from 1982 and 2000, in a population consisting of all those living in geriatric care units, aged 65 years or older, in the county of Västerbotten, in northern Sweden. The results were controlled for demographic changes.

IV - to further explore the relationship between the prevalence of depressive symptoms and the severity of cognitive impairment in relation to the changes in the prevalence of psychotropic drug treatment, in two large, cross-sectional samples from 1982 and 2000.

V - to compare the use of nervous system drugs among people aged 85 years or older, with or without a dementia disorder. People living in their own homes as well as those in institutions were included.

38 METHODS

METHODS

The methods of this thesis are quantitative, epidemiological, cross-sectional, comparative and descriptive in nature. This thesis is based on three data collections, the Äldre vårdade på institution i Västerbottens län år 2000 (“Old people cared for in institutions in the county of Västerbotten in the year 2000”) from May 2000, the Institutionsvård av äldre i AC-län (“Institutional care of the elderly in the county of Västerbotten”) from May 1982 and a part of the GERDA/Umeå 85+-study, collected from 2005 to 2006. These data collections are henceforth referred to as AC2000, AC1982 and GERDA/Umeå 85+. The AC2000 data are used in Papers I, II, III and IV. The AC1982 data are used in Papers III and IV, and the GERDA/Umeå 85+-data in Paper V.

PARTICIPANTS

Some basic characteristics of the participants in the different data collections are presented in Table 3.

AC1982 and AC2000 data collections

The AC1982 and AC 2000 data collections used the same inclusion criteria. All those currently residing in a geriatric care facility in the county of Västerbotten, Sweden in May 1982 and 2000 respectively, were included. Similar data collections were made in the county of Västerbotten in 1975, 1982, 1988 (including only residents in nursing homes), 1994 (including only the municipality of Umeå) and 2000. A new data collection was also made during 2007. The AC1982 data collection was chosen in preference of the collection from 1975 as historical control for the practical reason that the data from 1982 was available in digitalized form. The geriatric care facilities in the county of Västerbotten consisted in May 1982 of 36 homes for the aged, 23 nursing homes, 16 somatic long-stay wards, 9 psychiatric long-stay wards and 9 psycho-geriatric wards. The total population in the county was 245,000, 38,000 (15.5%) were aged 65 years or older. In May 1982, 3,910 people were living in geriatric care (here including psychiatric long-stay wards). The response rate in the AC1982 data collection was 92.3%, rating 3,607 people. For the investigations in Papers III and IV, those living in psychiatric long-stay wards and residents younger than 65 years or those where no age was registered were excluded, giving a final population of 3,195 residents. In May 2000, the total population in the county of Västerbotten was 256,000, of whom 44,211 (17.3%) were aged 65 years or more. The geriatric care facilities comprised 68 residential care facilities (homes for the aged and senior citizen’s apartment), 31 nursing homes, 66 group dwellings for people with dementia, 7 rehabilitation/short-stay units, 2 somatic geriatric and 2 psycho-geriatric hospital clinics. A total of 4,357 people lived in these facilities; the response rate was 87.3% in the AC2000 data collection, thus 3,804 people were rated. Those younger than 65 years were excluded from Paper I which finally included 3,724 people. In Paper II, those younger than 65 years and those with incomplete data concerning age, sex or cognitive impairment were excluded.

39 METHODS

TABLE 3, OVERVIEW OF THE DATA COLLECTIONS, PARTICIPANT CHARACTERISTICS

AC1982 AC2000 GERDA/Umeå 85+ Number of participants included 3195 36691 546 Participation rate 92.3 % 87.3 % 72.4 % Women, n (%) 2014 (63.0) 2479 (67.6) 400 (73.3) Age, mean ± SD 81.7 ± 6.7 83.3 ± 7.0 90.5 ± 4.6 Cognitive impairment/ 1369 (44.2) 2035 (62.1) 247 (45.2) dementia2 n (%) Gottfries’ cognitive score, mean 20.1 ± 8.9 17.3 ± 9.2 - ± SD MMSE, mean ± SD - - 19.3 ± 8.5 MDDAS ADL score (4-24), 17.9 ±6.3 15.8 ± 6.5 - mean ± SD Barthel’s ADL scale (0-20), - - 14.7 ± 6.7 mean ± SD MDDAS psychological 39.8 ± 38.6 35.5 ± 36.9 - symptoms, depressive symptoms score mean ± SD GDS, mean ± SD - - 3.6 ± 2.7 Depression, n (%) - - 209 (38.3) Pain prevalence n/ntotal (%) - 2083/3523 (59.1) 257/471 (54.6) Type of housing Nursing home 888 (27.8) 874 (23.8) 87 (15.9) Group dwelling for people with 0 (0)3 665 (18.1) 52 (9.5) dementia Residential care 1727 (54.1) 1954 (53.3) 81 (14.8) Rehabilitation/ short-stay unit 0 (0)3 44 (1.2) 19 (3.5)4 Psychogeriatric long-stay ward/ 200 (6.3) 41 (1.1) - psychogeriatric clinic Somatic geriatric long-stay 380 (11.9) 91 (2.5) - ward/ somatic geriatric clinic Own house or apartment - - 290 (53.1) Note: 1These numbers corresponds to exclusion criteria used in Paper III and IV. Different exclusion criteria were used in Paper I and II. Paper I included 3,724 people, Paper II 3,338. See Method section for further details. 2 Number of participants with cognitive impairment was assessed with Gottfries scale in the AC1982 and AC2000 data collections and diagnosed according to DSM-IV criteria in the GERDA/Umeå 85+ data collection. 3 This type of housing did not exist 1982. 4 For the Umeå 85+ data collection, this category was labeled “other institutional care”. SD=Standard Deviation, MMSE=Mini Mental State Examination, MDDAS=Multi-Dimensional Dementia Assessment Scale, ADL=Activities of Daily Living, GDS=Geriatric Depression Scale.

Those who had a cognitive score indicating cognitive impairment were selected for further analysis, giving a final study population of 2017 people. In Papers III and IV, those younger than 65 years and those from whom data covering age were missing were excluded (unlike in Paper I), giving a final population of 3,669 people.

40 METHODS

GERDA/Umeå 85+ data collection

The GERDA/Umeå 85+project included half of all those aged 85 years, all of those aged 90 and all those aged 95 or above. The first investigation was carried out in the largely urban municipality of Umeå, Västerbotten, Sweden in 2000-2001 and in five small, predominantly rural municipalities in the inland area of Västerbotten in 2002, namely the municipalities of Vilhelmina, Dorotea, Malå, Storuman and Sorsele. In 2005, the first 5-year follow-up of the Umeå cohort took place, and new people aged 85, 90 and 96 to 99 years were included. At approximately the same time, a similar data collection started in the Finnish municipalities of Vaasa and Mustasaari (Korsholm), as a part of the GERDA/Umeå 85+study, in cooperation with the University of Applied Sciences in Vaasa and Åbo Akademi University in Turku (Åbo), Finland. During 2007, the inland cohort was followed-up, and new people were included, as in Umeå. Paper V uses cross-sectional data from the data collection in Umeå, Vaasa and Mustasaari, which started 2005 and was finished in 2006. Out of 757 eligible people, 546 (72.1%) gave their consent and were also evaluated as to whether or not they had dementia, and were included in the analysis (306 people from Sweden and 240 people from Finland).

PROCEDURES

An overview of the procedures used in the different data collections is presented in Table 4.

AC1982 and AC 2000 data collections, the MDDAS

The assessments in the AC1982 and AC2000 data collections were made using the Multi-Dimensional Dementia Assessment Scale (MDDAS) [17]. The study form was sent to the care settings and the staff were asked to complete the form and return it to the researchers. The staff received written instructions about how to carry out the assessments and were informed that the members of the research team could be contacted by telephone to answer questions or provide additional guidance. The member of staff who knew each resident best was asked to fill in the assessment scales. The staff were informed that their assessment should be based on observations of the resident’s state during the preceding week.

Basic characteristics

Some basic characteristics were registered for each resident - age, sex and how long the resident had been living at the facility. The type of geriatric care facility was also registered. Furthermore, some basic data concerning speech, visual or hearing impairment, paresis and mobility were recorded. Some basic characteristics are included in Papers I-IV.

ADL

An ADL score was calculated based on the resident’s ability to cope with dressing, hygiene, eating and bladder and bowel control.

41 METHODS

TABLE 4, OVERVIEW OF THE DATA COLLECTIONS, PROCEDURES

AC1982 AC2000 GERDA/Umeå 85+ Setting Geriatric care Geriatric care Population Design Cross-sectional Cross-sectional Cross-sectional Participants All ≥65 years All ≥65 years ½ of 85, all 90, all 95+yearolds Method Staff Staff Structured interviews and assessments assessments assessments Collection year 1982 (May) 2000 (May) 2005-2006 Geographical area County of County of Municipalities of Umeå, Västerbotten, Västerbotten, Sweden and Vaasa and Sweden Sweden Mustsaari, Finland Cognitive scale Gottfries’ Gottfries’ MMSE ADL scale MDDAS MDDAS Barthel, (Katz)1 BPSD scale MDDAS MDDAS (OBS)1 Depressive MDDAS MDDAS GDS symptom rating Pain assessment No Yes Yes Registration of Psychotropics Yes Yes current drug use only Data collection III, IV I, II, III, IV V used in Paper Note: 1 Scale not used in any of the papers. MMSE=Mini Mental State Examination, ADL=Activities of Daily Living, MDDAS=Multi-Dimensional Dementia Assessment Scale, BPSD=Behavioral and Psychological Symptoms of Dementia, OBS= Organic Brain Syndrome Scale. GDS=Geriatric Depression Scale

All ADL categories scored 1-5, except that for bladder control, which scored 0-4. Hence the ADL score ranges from 4 to 24, where a higher score indicates greater ADL independence. ADL scores are presented in Papers I-IV, included in the final regression model in Paper II, and divided into three groups representing low, medium or high dependency in ADL, for use in the analyses in Paper III.

Pain

Questions about pain were included in the AC2000 data collection, but not in the AC1982 data collection. Pain was assessed by means of the following questions: Does the patient have pain? If “Yes”: Is the cause of the pain known? Does the patient receive treatment for his/her pain? Does the treatment help? Does the patient experience pain during physical activity? Does the patient experience pain during rest? Try to assess the patient’s experience of pain by entering a cross (X) on the line below: A 100mm Visual Analogous Scale (VAS) without grading, from “No pain” to “Worst thinkable pain”. The length from the left end to the cross was measured and rounded up to next whole centimeter, thus generating a value from 1 to 10. The VAS scale was only filled in when the patient was assessed as having pain. Data on pain were included in Paper I.

42 METHODS

Cognitive function, Gottfries’ cognitive scale

Cognitive function was measured using a scale developed by Gottfries and Gottfries [15, 16]. The scale is presented in Appendix 2. This scale consists of 27 items measuring a person’s cognitive function. A score of less than 24 is considered to indicate cognitive impairment, which correlates with a sensitivity of 90 % and a specificity of 91% to the cut-off 24/30 traditionally used in the Mini Mental State Examination (MMSE) [17]. Cognitive score are presented in Papers I-IV, used as one of the inclusion criteria and included in the final regression model in Paper II and divided into four groups representing no cognitive impairment (score 24 to 27), mild (score 16 to 23), moderate (score 8 to 15) and severe cognitive impairment (score 0 to 7) for use in the analyses in Paper III. The same four groups of cognitive levels were used in the analyses in Paper IV.

Behavioral and psychological symptoms of dementia

The MDDAS contains 25 behavioral items and 14 psychological symptom items. The scales are presented in Appendix 1. Each item is rated on a three-point scale, indicating whether the symptom or behavior occurs at least once a day, once a week or never during the one-week observation period. The MDDAS behavioral and psychological items have good inter- and intra-rater reliability [17]. The variables are dichotomized between at least once a week and less than once a week, when analyzed in Papers II, III and IV.

Workload

The physical and mental workload imposed by a resident is assessed on a five-point scale, from minimal to maximal. There is also a registration of how many staff members are needed to help the resident with morning routines. Workload data are presented and included in the regression model in Paper II.

Additional data

The AC2000 data collection also included questions about ethnicity, falls, food intake, oral status, sleep pattern, non-verbal communication, constipation, accidents, use of physical restraints, pressure ulcers, activities, rehabilitation, social contacts, palliative care, violence and staff attitudes. These data were not used in any of the papers included in this thesis.

Drug data

The MDDAS form includes a registration of current drug prescriptions. A registered nurse always filled in the data concerning prescribed medication, from the resident’s prescription record. In the AC1982 data collection, the registration was restricted to psychotropic medications but in the AC2000 data collection all drugs were registered.

43 METHODS

Terminology notes

The results of the Gottfries’ scale are referred to in Papers I and II as the “orientation score”. Since the scale covers more cognitive domains than orientation, the terminology was changed to “cognitive score” in Papers III and IV. In Paper I, the psychological symptom items of the MDDAS are referred to as “psychiatric symptoms”, as in previous articles from the AC1982 and AC2000 material. This was changed in Papers II-IV, because “psychological” is a term more often used in the literature on the topic, and because we could not defend the use of the term “psychiatric” when no diagnoses were set. In Paper II, the workload items of the MDDAS are referred to as “physical and mental workload”, which better corresponds to the terms fysisk och psykisk arbetsbörda than the previously used term “physical and psychiatric workload”.

GERDA/Umeå 85+ data collection

The participant received one or more home visits from a trained investigator, who was a nurse, a medical doctor, a medical student or a physiotherapist. The data collection comprised structured interviews, assessments and medical record reviews. If necessary relatives and staff were also interviewed. The first interview and assessment usually took about two hours to complete. The GERDA/Umeå 85+ form includes the following parts [209]:

• Background variables about living conditions, family and social network and about growth, school and work history. • Medical history and current health status. Current drug use, both prescription and non-prescription drugs. An experienced geriatrician reviewed the medical diagnoses. Dementia was diagnosed according to the DSM-IV criteria, based on medical history, test results and medical record notes. • Reliable and well-known assessment scales; the Mini Mental State Examination (MMSE) (score 0-30, scores below the cut-off 24/30 indicate cognitive impairment) [13], [14] (referred in [9]), the Mini Nutritional Assessment (MNA) [210], Staircase of ADL (a development of the Katz Index of ADL) [211, 212] and Barthel’s ADL Index (scores 0-20, lower scores indicate more dependence in Activities of Daily Living (ADL)) [213, 214], the Geriatric Depression Scale-15 (GDS-15) (scores 0-15, scores above 4 indicate depression) [215-218], the Montgomery-Åsberg Depression Rating Scale (MADRS) [219, 220], the Philadelphia Geriatric Centre Morale (PGCM) scale (scores 0-17, a higher score indicates higher morale) [221, 222] and the Organic Brain Syndrome (OBS) scale [223-225]. The GDS and PGCM scales could not be administered to people with severe cognitive impairment. • Questions about falls, balance, physical activity, pain, economic situation, perceived health, participation in religious activities, pets, sense of loneliness, safety and recent crises. • Anthropometric measurements, blood pressure, chair-stand test and 2.4 meter walking test.

44 METHODS

Pain was assessed by questioning both the person himself or herself and, if applicable, the caring staff. A person was coded as having pain if they themselves or a staff member said they did.

Drug data coding procedures

The coding procedure for drug data was the same for all three data collections. Information about doses and pro re nata, PRN, (“as needed”) medication was not coded, thus only the figures for ongoing medication were given. In Paper I, PRN medication was considered among those who were assessed as having pain, but were not receiving any regular analgesic medication. Members of the research team grouped the drug data into categories according to the WHO Anatomical Therapeutical Chemical (ATC) classification index. Every person was assigned a dichotomous value for each group. The following groups were included in the papers: Analgesics (N02) in Papers I and V, Antiepileptics (N03) in Paper V, Parkinsson drugs (N04) in Paper V, Anti- psychotics (N05A) in Papers II-V, Anxiolytics, hypnotics and sedatives (N05B and C) in Papers II-V, Antidepressants (N06A) in Papers II-V and Anti-dementia drugs (N06D) in Papers III and V. Some of the groups of drugs were further divided into sub-groups when presented in Papers I-III and V.

Drug data coding and terminology notes

Acetylsalicylic acid, ASA, (ATC class N02B A (Magnecyl®, Treo®, Bamyl® et cetera) and B01A C06 (Trombyl®)) were not included in the category Analgesics (N02), as we could not differentiate between the cases were ASA was used as an analgesic drug and when it was used as a thrombosis profylaxis. However, very few people receive ASA as regular analgesic medication. Alimemazine (Theralen®) was coded as an antipsychotic drug in Papers II, III, IV and V, even though it belongs to ATC class R06A (Anti-histamines for systemic use). However, as a phenothiazine derivative, it has many properties in common with the antipsychotics, not least concerning possible side-effects. Anxiolytics, hypnotics and sedatives, ATC classes N05B and N05C, are referred to as minor tranquillizers and sedatives in Papers III and IV. Clomethiazole (Heminevrin®) was coded as a daytime tranquillizer in Papers III and IV, but as a hypnotic in Paper V. Clomethiazole is a hypnotic drug (N05C) according to the ATC classification, however, in Swedish clinical practice, it has been used most frequently to treat confusion and agitation in patients with dementia, often during the day. In the AC1982 data collection, anxiolytics, hypnotics and sedatives were divided into drugs used in the day and those used at night. The same drug could thus be coded as either or both, dependent on when it was used. Lithium (N05A N01) was included in the category Antipsychotics (N05A) in Paper V, but not in Papers II-IV. Lithium has some unique properties and has little in common with other antipsychotics. NSAID drugs (ATC code M01A) were included in the category Analgesics in Papers I and V. Glucose amine drugs (M01A X05) were not included in this category. Paracetamol (N02B E01) is referred to as acetaminophen in the papers. This is the American generic name for the substance. The name paracetamol, however, is the

45 METHODS

International Nonproprietary Name (INN), recommended by the WHO, and used in the thesis. Propiomazine (Propavan®) was coded as a hypnotic drug (N05C), according to the ATC classification, even if it is a phenothiazine derivative.

ETHICS

In the AC1982 and AC2000 data collections, no consent was received from the residents of the geriatric care facilities. However, no procedure that involved the residents was performed. The data were anonymous, and from the beginning each form was identified only by its code number. It was not possible to link a form to the resident who was assessed. Data were only presented on group level. The AC2000 data collection was approved by the Ethics Committee of the Faculty of Medicine at Umeå University (registration number 00-170). When the AC1982 data collection was conducted the ethics regulations were different, and no such approval was needed. In the GERDA/Umeå 85+ data collection informed consent was received from each participant. If the participant could not make the decision in person, due to cognitive impairment, the next of kin was asked instead. The GERDA/Umeå 85+ data collection was approved by the Ethics Committee of the Faculty of Medicine at Umeå University (registration number 99-326, 05-063M) and the Ethics Committee of Vaasa Central Hospital (registration number 05-87).

STATISTICS

Selection procedures

The AC1982 and AC2000 materials included the total populations of old people living in geriatric care facilities in the county of Västerbotten. Hence no randomization was made. The choice of Västerbotten in preference to other counties in Sweden was not random. The people aged 90 years or 95 years or older, living in the selected municipalities, were all included in the GERDA/Umeå 85+ study. One half of all people aged 85 years old were selected in a semi-randomized procedure - selection of every second person from the Tax Agency’s population record.

Descriptive statistics

Papers I-V all include descriptive statistics. In Paper I the main results were presented as proportions. Pearson’s Chi-square was also used. In Paper II, dichotomous variables were analyzed using the Chi-square test, continuous variables that were normally distributed were analyzed with the independent variable T-test, and non-normally distributed continuous variables were analyzed using the non-parametric Mann-Whitney U-test. In Papers III, IV and V, the Chi-square test and T-test were used. In Paper V Fischer’s exact test was used instead of the Chi-square test when appropriate. Correlation analysis was used in Papers II and V for some additional analyses.

46 METHODS

Regression statistics

In Paper II a multivariate logistic regression analysis, with a backward conditional selection algorithm was used to analyze the use of antipsychotic drugs. Behavioral and psychological symptom factors and type of geriatric care unit, ADL-dependency, cognitive score, age and mental workload (as continuous variables) and sex and whether the person could rise from a chair unaided, were entered into the regression analysis. In Paper III multivariate logistic regression models were used to control for demographic changes between 1982 and 2000. Sex, age, ADL score (divided into three groups) and orientation score (divided into four groups) was included in the regressions, which were conducted for every symptom and the prevalences of different psychotropic drugs. In Paper V, a multivariate regression model was used in one additional analysis to investigate the interaction between the country (Sweden or Finland) and the diagnosis of dementia for the prevalence of certain psychotropic drugs.

Factor analysis

In Paper II, two factor analyses with Varimax rotation were used to reduce the number of factors from the MDDAS behavioral and psychological items. Factors with eigenvalues of above 1.00 were extracted. The results were saved as z-scores (a normalization procedure) for inclusion in the final regression model. The factors were labeled according to previous factor analyses of the MDDAS [162, 226]. A Cronbach α analysis was used to test the factors for internal consistency. The grouping of symptoms into factors was used to select items for the analysis in Paper IV.

Computer programs

The Statistical Package for Social Sciences® SPSS®, version 10.0 for Mac OS 9 (Paper I), and SPSS® version 11.0 for Mac OS X (Papers II-V) were used for data handling and calculations.

48 RESULTS

RESULTS

An overview of some basic characteristics of the participants in the AC1982, AC2000 and GERDA/Umeå 85+ data collections is presented in Table 3 (page 40). An overview of the procedures in the different data collections is presented in Table 4 (page 42). Table 5 summarizes the content and main scope of the various papers.

TABLE 5, OVERVIEW OVER THE PAPERS

Paper I Paper II Paper III Paper IV Paper V Data AC2000 AC2000 AC1982 AC1982 GERDA/ collection AC2000 AC2000 Umeå 85+ Participants 3,724 2,017 6,864 6,864 546 included (cognitively impaired only) Comparison - Anti- People in People of People with between psychotics 1982 vs. different and without groups users/non- 2000 levels of dementia users cognitive impairment and 1982 vs. 2000 Main drug Analgesics Anti- Psycho- Antidepres- All nervous classes studied psychotics tropics sants, system (psycho- drugs tropics) Main Pain BPSD Psycholo- Depressive Dementia, symptoms gical symptoms (Pain) studied symptoms Statistical methods Descriptive X X X X X statistics Regression X X statistics Factor analysis X Note: BPSD= Behavioral and Psychological Symptoms of Dementia.

49 RESULTS

PAPER I

Poor staff awareness of analgesic treatment jeopardises adequate pain control in the care of older people

Paper I included 3,724 people from the AC2000 data collection. Of the studied population, 67.5 % (2,515) were women and the mean age was 83.3±7.0 years. The mean score on the Gottfries’ cognitive scale was 17.0± 9.1 and 55.0% (2,047) met the criteria for cognitive impairment. The mean score for the MDDAS ADL scale was 15.8±6.4. The staff had assessed that 2111 of the residents (56.7 %) suffered from pain. The staff had further answered that the cause of the pain was known in 1744/2111 (82.6 %) cases, that the resident was receiving treatment in 1894/2111(89.7 %) cases, that the treatment helped in 1251/2111 (59.3 %) cases, that the resident experienced pain during physical activity in 1322/2111 (62.6 %) cases and that the resident experienced pain during rest in 812/2111 (38.5 %) of the cases. The VAS-assessment of the residents’ pain was completed for 1969 residents and the mean was 4.8±1.9. The proportion of women judged to be suffering from pain was larger than that for men (59.6% compared to 50.7% p<0.001). The prevalence of pain did not differ significantly between cognitively intact and cognitively impaired residents (58.6% compared to 56.9% p=0.331). In 483 cases (13.0%) the assessor did not know whether or not the resident was in pain and in 151 cases (4.1%) the assessor had not answered the question at all. Hence, in total, 634 cases (17.0 %) were missing data on pain. Those residents did not differ, either regarding the proportion of women or of the cognitively impaired, but they received analgesics less often, were younger and had a lower orientation and ADL-score (data not shown). Those people were regarded as not having pain in the analyses, in order not to overestimate the prevalence of pain. Of the population of 3724 residents, 1999 (53.7 %) were receiving at least one analgesic drug as regular medication. Paracetamol was received by 1853 (49.8 %) of the residents, an opioid drug by 815 (21.9 %) and a NSAID by 217 (5.8 %). The use of nervous system drugs in the different data collections is presented in Table 6. Note that the numbers in Table 6 are calculated on the 3669 people selected for the analyses in Papers III and IV, and the numbers therefore differ slightly from those presented in Paper I. A larger proportion of women than men received analgesic drugs (56.0% compared to 48.8% p<0.001) and a larger proportion of people with cognitive impairment received such drugs than those not cognitively impaired (57.6% compared to 49.7% p<0.001). Of the 2111 residents judged to be suffering from pain, 1521 (72.1%) received analgesic medication on a regular basis (1401 (66.4 %) received paracetamol, 682 (32.3 %) received opioid analgesics and 178 (8.4 %) received a NSAID). Hence 590 (27.9%) of the residents judged to be suffering from pain did not receive any analgesic drug as regular medication. This proportion did not differ between women and men (27.5% compared to 29.2% p=443), but people with cognitive impairment were more often treated with regular analgesic medication when in pain (23.9% compared to 32.7% p<0.001).

50 RESULTS

TABLE 6, NERVOUS SYSTEM DRUG USE IN THE DIFFERENT DATA COLLECTIONS, N (%)

Drug class ATC-code AC1982 AC2000 GERDA/Umeå (n=3195) (n=3669) 85+ (n=546) Analgesics N02 - 1985 (54.1) 210 (38.5) Opioid analgesics N02A - 804 (21.9) 60 (11.0) Paracetamol N02B E - 1837 (50.1) 189 (34.6) NSAID1 M01A - 214 (5.8) 30 (5.5) Anticonvulsants N03A - 205 (5.6) 17 (3.1) Parkinson drugs N04 - 173 (4.7) 13 (2.4) L-dopa N04B A - 139 (3.8) 8 (1.5) Other N04B C,D,X - 73 (2.0) 8 (1.5) Antipsychotics2 N05A 802 (25.1) 760 (20.7) 63 (11.5) Conventional N05A A,B,D,F 802 (25.1) 439 (12.0) 18 (3.3) Atypical N05A E,H,X n/a 349 (9.5) 51 (9.3) Lithium N05A N01 - 21 (0.6) 1 (0.2) Anxiolytics, hypno- N05B, C 421 (13.2) 1440 (39.2) 184 (33.7) tics and sedatives Anxiolytics, N05B A 159 (5.0)3 420 (11.4) 71 (13.0) benzodiazepine type Hypnotics and N05C 291 (9.1)5 1246 (34.0) 164 (30.0) sedatives4 Benzodiazepine N05C D,F - 891 (24.3) 151 (27.7) type Clomethiazole N05C M02 - 146 (4.0) 7 (1.3) Propiomazine N05C M06 - 357 (9.7) 21 (3.8) Antidepressants N06A 200 (6.3) 1465 (39.9) 117 (21.4) Tricyclics N06A A 174 (5.4) 81 (2.2) 6 (1.1) SSRI N06A B 8 (0.3)6 1069 (29.1) 94 (17.2) MAO-inhibitor N06A G n/a 3 (0.1) 1 (0.2) Other7 N06A X 18 (0.6) 354 (9.6) 27 (4.9) Venlafaxine N06A X16 n/a 235 (6.4) 7 (1.2) Any psychotropic N05A,B,C, 1207 (37.8) 2371 (64.6) 260 (47.6) drug N06A Anti-dementia drugs N06D n/a 145 (4.0) 42 (7.7) Choline-esterase N06D A n/a 145 (4.0) 32 (5.9) inhibitor Memantine N06D X n/a n/a 14 (2.6) Note: 1 NSAID included for the sake of completeness 2 Lithium is included in the category Antipsychotics (N05A). 3 In AC1982 the category Anxiolytics, benzodiazepine type (N05B A) includes all N05B and C drugs used in daytime, including clomethiazole. 4 In AC1982 the category Hypnotics and sedatives includes all N05B and C drugs used in nighttime. 5 Clomethiazole is included in the category Hypnotics and sedatives (N05C), except for 1982, see note 3. 6 In 1982 eight people received zimelidine, the very first SSRI, which was then withdrawn in 1983. 7 Tetracyclic antidepressants are included in the category Other. - = No data concerning the drug class were collected, n/a = not available, no drugs in the class were registered at the date of the data collection. NSAID= Non-Steroidal Anti-Inflammatory Drugs, SSRI=Selective Serotonin Reuptake Inhibitor, MAO-inhibitor= Mono-Amine Oxidase inhibitor.

51 RESULTS

The VAS pain assessment for those on regular analgesic treatment was 5.0±1.9 compared to 4.4±1.6 among those without regular analgesic treatment (p<0.001). Out of the 590 people judged to be suffering from pain and not receiving any regular analgesic medication, 220 (another 10.4%) had PRN analgesics, mainly paracetamol. Thus 17.5% of those reported to have pain had neither regular nor PRN analgesics. The staff had noted that 89.7% of the residents received treatment for their pain, when they answered the assessment form. This is an over-estimation compared with the actual prevalence of analgesic treatment. If the resident received regular pain medication, the answer to the question of whether the resident received treatment for their pain was in the affirmative in 95.1%; if the resident received only PRN medication 80.9% of the answers were in the affirmative, and if they received neither regular nor PRN medication 72.7% were still in the affirmative. The figures are presented in Table 7.

TABLE 7, AC2000, THE STAFF’S ANSWER TO THE QUESTION ABOUT PAIN TREATMENT COMPARED TO ACTUAL REGULAR AND PRN ANALGESIC TREATMENT

“Does the patient Regular analgesic Only PRN analgesic No analgesic receive treatment for medication medication medication his/her pain?”1 n=1521 n=220 n=370 “Yes” n (%) 1447 (95.1) 178 (80.9) 269 (72.7) “No” n (%) 19 (1.2) 27 (12.3) 66 (17.8) “Don’t know” n (%) 15 (1.0) 4 (1.8) 9 (2.4) No answer n (%) 40 (2.6) 11 (5.0) 26 (7.0) Note: Ntotal in this analysis was 3,724 people. 1This question was only answered if the patient was judged to suffer pain, n=2111. PRN= pro re nata (“as needed”)

The tendency among the staff to overestimate the residents’ treatment differed among the various types of dwellings (nursing homes 56.7%, group dwelling 66.1% and residential care 78.3%. The difference between the first two and the last mentioned is significant, p<0.001 and p=0.049 respectively). A few other groups of drugs can sometimes be prescribed for pain. Those who were in pain but received no regular analgesic medication did not differ from those who were treated with analgesics, regarding the prevalence of treatment with nitroglycerine, cortisone or tricyclic antidepressants (data not shown), but they received anti-epileptic drugs less often (4.1% compared to 6.8% p=0.019).

52 RESULTS

PAPER II

Relationship between antipsychotic drug use and Behavioral and Psychological Symptoms of Dementia in old people with cognitive impairment living in geriatric care

Paper II included 2017 people with cognitive impairment from the AC2000 data collection. Basic characteristics of these people are presented in Table 8. Those who were prescribed antipsychotic drugs were compared to those who were not.

TABLE 8, AC2000, PEOPLE WITH COGNITIVE IMPAIRMENT, N=2017, COMPARISON BETWEEN PATIENTS WITH AND WITHOUT ANTIPSYCHOTIC DRUG TREATMENT

Antipsychotics Antipsychotics p-value Total non-user user1 Cases n (%) 1486 (73.7) 531 (26.3) 2017 (100.0) Women n (%) 1060 (71.3) 334 (62.9) <0.001 1394 (69.1) Mean age±SD 83.7±6.68 82.7±7.08 0.004 83.5±6.80 ADL score (4-24) 13.1±6.21 12.4±5.66 0.065 12.9±6.07 mean±SD Cognitive score (0-27) 11.4±7.13 10.7±6.48 0.030 11.2±6.97 mean±SD Walks independently n 558 (38.2) 227 (43.6) 0.030 785 (39.6) (%) Can rise from chair 794 (54.2) 328 (62.4) 0.001 1122 (56.4) unaided n (%) Confined to bed n (%) 67 (4.6) 13 (2.5) 0.037 80 (4.1) Impaired vision n (%) 212 (14.7) 93 (17.9) 0.085 305 (15.6) Impaired hearing n (%) 157 (10.9) 60 (11.5) 0.688 217 (11.0) Physical workload (1-5) 3.0±1.44 3.0±1.38 0.970 3.0±1.42 mean±SD Mental workload (1-5) 2.5±1.28 3.2±1.26 <0.001 2.7±1.31 mean±SD Group dwelling n (%) 392 (26.4) 213 (40.1) <0.001 605 (30.0) Nursing home n (%) 452 (30.4) 159 (29.9) 0.838 611 (30.3) Rehabilitation/short-stay 23 (1.5) 6 (1.1) 0.488 29 (1.4) unit n (%) Residential care n (%) 572 (38.5) 141 (26.6) <0.001 713 (35.3) Somatic geriatric clinic 19 (1.3) 4 (0.8) 0.328 23 (1.1) n (%) Psychogeriatric clinic 28 (1.9) 8 (1.5) 0.573 36 (1.8) n (%) Note: SD=Standard Deviation, ADL=Activities of Daily Living 1Patients with ongoing medication with at least one antipsychotic drug (ATC code N05A).

53 RESULTS

Antipsychotic drug users were found in univariate analyses to be more often men, younger, more ADL-dependent and to have on average a lower score of the Gottfries’ cognitive scale. They were also more mobile and imposed a greater mental workload on the staff. They lived more often in a group dwelling for demented people and less often in residential care. Psychotropic drug use among these 2017 people is presented in Table 9. A total of 531 people (26.3%) used antipsychotic drugs, 285 (14.1%) used conventional antipsychotics (ATC code N05A A, B, D, F) and 270 (13.4%) used atypical antipsychotics (N05A E, H, X).

TABLE 9, PSYCHOTROPIC DRUG USE, AC2000, RESIDENTS WITH COGNITIVE IMPAIRMENT, N=2017

Drug class ATC-code n (%) Antipsychotics1 N05A 531 (26.3) Conventional N05A A,B,D,F 285 (14.1) Atypical N05A E,H,X 270 (13.4) Anxiolytics, benzodiazepine type N05B A 273 (13.5) Hypnotics and sedatives2 N05C 640 (31.7) Antidepressants N06A 873 (43.3) Note: 1 Lithium is not included in the category Antipsychotics. 2 Clomethiazole is included in the category Hypnotics and sedatives (N05C).

A factor analysis with Varimax rotation was used to group the behavioral and psychological symptom items of the MDDAS. The factor analyses were performed separately for behaviors and psychological symptoms. The results of the factor analyses were labeled and are presented in Table 10, along with the prevalences of the different behaviors and symptoms. A multivariate regression model was constructed including significant univariate findings and the BPSD factors obtained, saved as a normalized z-score. The regression model is shown in Table 11. Eleven different factors correlated significantly with the use of antipsychotics. Male sex, living in a group dwelling for demented people, and the ability to rise from a chair were associated significantly with the use of antipsychotics. Three different behavior factors (aggressive behavior, verbally disruptive/ attention- seeking behavior and wandering behavior) and two psychological symptom factors (depressive symptoms and hallucinatory symptoms) correlated significantly. Mental workload, ADL-independence and age also associated significantly with the prescribing of antipsychotics. The odds ratio assigned to the behavior and psychological symptom factors is to be interpreted as meaning that one standard deviation change in for example aggressiveness gives a 33% higher probability of being prescribed antipsychotics. The model produced a concordance between observed and predicted values of 76.0%, and a Cox & Snell R square of 0.12.

54 RESULTS

TABLE 10, AC2000, FACTOR ANALYSIS OF BEHAVIORAL AND PSYCHOLOGICAL 1 SYMPTOMS OF THE MULTI-DIMENSIONAL DEMENTIA ASSESSMENT SCALE, N=2017

BPSD factors Prevalence Factor Variance α- Contributing MDDAS items (%) loading explained value (%) Behaviors Aggressive behavior 10.8 0.758 Hits patients/staff 16.9 0.82 Aggressive threats (words or 36.3 0.78 gestures) to patients/staff Resists being dressed and 36.9 0.69 undressed Spits out drugs 22.7 0.57 Shrieks and shouts 21.9 0.51 continuously Wandering behavior 9.9 0.597 Lies in other patient’s beds 5.6 0.63 Piles up chairs, pushes tables, 8.4 0.58 upends furniture Pick things from other patient’s 10.5 0.57 boxes and closets Restless behavior 9.3 0.695 Mixes up food 21.9 0.69 Rolls up tablecloths 21.1 0.62 Eats potted soil, cigarette ends, 2.9 0.60 etc Tears up newspaper, etc 10.4 0.59 Eats other’s food 8.7 0.58 Escape behavior 8.4 0.645 Packs up his/her things, is 13.4 0.71 often on the way home Hides things 23.7 0.70 Often stands at the outer door 15.7 0.56 wanting to go out Verbally disruptive/attention seeking 7.4 0.504 behavior Constantly seeks attention of 54.5 0.76 the staff Does not talk spontaneously 72.4 -0.67 with patients/staff Interrupted night sleep 56.7 0.54 Regressive/inappropriate behavior 5.0 0.406 Smears faeces on clothes, 13.0 0.82 furniture, etc Urinates in wastepaper baskets, 9.5 0.52 wash basins or on the floor Cumulative variance explained: 50.9

55 RESULTS

Psychological symptoms, Table 10 continued. Depressive symptoms 16.1 0.730 Sad 53.2 0.85 Crying 27.0 0.83 Anxious and fearful 43.4 0.59 Hallucinatory symptoms 13.8 0.721 Hallucinates auditorially 16.3 0.90 Hallucinates visually 23.8 0.87 Speaks to her/himself 41.6 0.53 Paranoid symptoms 12.9 0.704 Easily annoyed 42.3 0.84 Suspicious 34.9 0.82 Passivity 12.4 0.616 Does not cooperate 54.7 0.85 Lacks initiative 79.8 0.82 Does not seek help 45.9 0.50 Hyperactive symptoms 11.6 0.579 Overactive/manic 15.2 0.83 Disturbed and restless 57.2 0.68 Cumulative variance explained: 66.8 Note: 1 The factor analysis included 2017 people with cognitive impairment, as in Paper II, please see method section for further details. Items that not contributed more than 0.5 to any of the behavior factors, prevalence in parenthesis: “Unruly in bed, throws bedclothes on floor” (20.6%), “Wanders back and forth alone or with other patients” (29.2%), “Does not want to go to bed” (21.9%) and “Undresses in the dayroom” (7.6%). Items that not contributed more than 0.5 to any of the psychological symptom factors: “Complains” (41.9%).

TABLE 11, AC2000, REGRESSION MODEL OF ANTIPSYCHOTIC DRUG USE AMONG PEOPLE WITH COGNITIVE IMPAIRMENT, N=2017

Odds 95% Confidence p-value ratio interval ADL score 0.97 0.94 - 0.99 0.007 Age 0.98 0.96 - 0.99 0.043 Aggressive behavior 1.31 1.15 - 1.50 <0.001 Can rise from chair 1.68 1.19 - 2.36 0.003 Depressive symptoms 1.15 1.02 - 1.30 0.019 Group dwelling 1.39 1.07 - 1.81 0.006 Hallucinatory symptoms 1.21 1.08 - 1.35 0.001 Male sex 1.40 1.08 - 1.82 0.013 Mental workload 1.26 1.13 - 1.40 <0.001 Verbally disruptive behavior 1.25 1.09 - 1.43 0.002 Wandering behavior 1.19 1.06 - 1.34 0.003 Note: Analysis includes 2017 people with cognitive impairment, see Method section for further details. ADL=Activities of Daily Living, higher score = more independent Model Cox & Snell R square =0.12, concordance between observed and predicted value =0.76.

56 RESULTS

PAPER III

Symptoms of mental health and psychotropic drug use among old people in geriatric care, changes between 1982 and 2000

Paper III included 3195 people from the AC1982 data collection and 3669 people from the AC2000 data collection. Some basic characteristics of the two populations are presented in Table 3 (page 40). Significant changes had occurred in several respects regarding the composition of the population between the first and the second investigations. The geriatric care population in 2000 was older (p<0.001) and included a higher proportion of women (p<0.001). The mean score of the Gottfries’ cognitive scale was lower (p<0.001) and the proportion of people with cognitive impairment was higher (p<0.001). The mean score of the MDDAS ADL scale was also lower (p<0.001), corresponding to an increased ADL dependence on average between 1982 and 2000. The use of psychotropic drugs is presented in Table 6 (page 51). Psychotropic drug use became much more common (an increase from 37.8% to 64.6 % p<0.001), particularly the use of antidepressants (6.3% compared to 39.9% p<0.001) and anxiolytics and hypnotics (13.2% compared to 39.2% p<0.001). The prevalence of antipsychotic drug use decreased (25.1% compared to 20.7% p<0.001). In 2000, 81 people (2.2%) used the long-acting benzodiazepine nitrazepam. The prevalences of the fourteen psychological symptoms of the MDDAS are presented in Table 12. Six signs or symptoms had become more prevalent by 2000: “Complains”, “Hallucinates auditory”, “Hallucinates visually”, “Speaks to her/himself”, “Suspicious” and “Overactive/manic”. Two symptoms, “Sad” and “Crying”, had become less prevalent. Suspecting that many of the symptom or behavior prevalences were affected by the changes in population composition, we carried out a binary logistic regression for each symptom to compensate for sex, age, ADL performance and level of cognitive impairment, generating an odds ratio for the symptom to occur in 2000 as compared to 1982. The results are presented in Table 13. Six symptoms had an Odds Ratio of less than one, which means that the probability of finding the symptom is lower in 2000 than in 1982, in an equally cognitively impaired, equally ADL-dependent person of the same age and sex. Two symptoms had an Odds Ratio greater than one, and six did not differ significantly from one. The Odds Ratio for antidepressant use and for anxiolytics and hypnotics was 10.4 and 3.0 respectively.

57 RESULTS

TABLE 12, AC1982 AND AC2000, PREVALENCE OF PSYCHOLOGICAL SYMPTOMS OF THE

MULTI-DIMENSIONAL DEMENTIA ASSESSMENT SCALE, N/NTOTAL (%)

AC1982 (n=3195) AC2000 (n=3669) p-value Depressive symptoms Sad 1628/3135 (51.9) 1462/3103 (47.1) <0.001 Crying 930/3130 (29.7) 747/3093 (24.2) <0.001 Anxious and fearful 1193/3131 (38.1) 1113/3089 (36.0) 0.091 Complains 1126/3122 (36.1) 1214/3097 (39.2) 0.011 Hallucinatory symptoms Hallucinates auditory 309/3100 (10.0) 375/3080 (12.2) 0.006 Hallucinates visually 348/3110 (11.2) 534/3091 (17.3) <0.001 Speaks to her/himself 826/3124 (26.4) 978/3104 (31.5) <0.001 Paranoid symptoms Easily annoyed 1102/3139 (35.1) 1103/3110 (35.5) 0.766 Suspicious 857/3134 (27.3) 930/3115 (29.9) 0.028 Passivity Does not cooperate 1395/3125 (44.6) 1361/3105 (43.8) 0.521 Lacks initiative 1970/3121 (63.1) 2027/3095 (65.5) 0.051 Seeks help2 1597/3122 (51.2) 1614/3088 (52.3) 0.380 Hyperactive symptoms Overactive/manic 231/3099 (7.5) 364/3103 (11.7) <0.001 Disturbed and restless 1334/3127 (42.7) 1389/3100 (44.8) 0.088 Note: 1 For each item, the number of affirmative answers is given first, then the total number of answers to the specific question, then the percentage 2 This item contributed negatively to the factor.

TABLE 13, AC1982 AND AC2000, ODDS RATIO OF SYMPTOMS AND TREATMENTS IN 2000 COMPARED TO 1982, N=3195+3669

p-value Odds ratio1 95% Confidence interval Sad <0.001 0.724 0.648-0.808 Crying <0.001 0.667 0.589-0.754 Anxious and fearful <0.001 0.728 0.649-0.817 Hallucinates visually 0.003 1.268 1.082-1.486 Disturbed and restless 0.004 0.842 0.749-0.947 Does not cooperate <0.001 0.666 0.587-0.756 Lacking initiative <0.001 0.665 0.583-0.759 Overactive/manic <0.001 1.439 1.194-1.735

Any psychotropic drug <0.001 2.792 2.501-3.117 Anxiolytics, hypnotics <0.001 3.019 2.641-3.451 and sedatives Antidepressants <0.001 10.353 8.734-12.273 Note: 1 Corrected for sex, age, ADL performance (high, medium or low dependency) and cognitive impairment (no cognitive impairment, mild, medium, or severe cognitive impairment). Only significant differences are shown.

58 RESULTS

PAPER IV

On depression in dementia

Paper IV included the same population as Paper III, 3195 people from the AC1982 data collection and 3669 people from the AC2000 data collection. A variable labeled depressive symptoms was constructed as the sum of the MDDAS psychological symptom “Sad” “Crying” and “Anxious and fearful”, according to the factor analysis presented in Table10, where these items grouped together. In Table 14 the mean score for depressive symptoms is presented according to four different levels of cognitive impairment, representing no cognitive impairment (Gottfries’ cognitive score 24-27), mild cognitive impairment (score 16-23), moderate cognitive impairment (score 8-15) and severe cognitive impairment (score 0-7). There had been a significant decrease in depressive symptom scores between 1982 and 2000 in all groups except that with a cognitive score of between eight and fifteen, i.e. moderate cognitive impairment.

1 TABLE 14, AC1982 AND AC2000, MEAN SCORE OF DEPRESSIVE SYMPTOMS IN RELATION 2 TO COGNITIVE IMPAIRMENT

AC1982 AC2000 Depressive symptom score1, mean±SD, (n)3 p-value4 Severe cognitive 43.1±39.4, (n=412) 35.9±37.0, (n=619) 0.003 impairment2 p-value5 = p=0.070 ∧ p<0.001 Moderate cognitive 47.9±38.8, (n=466) 47.7±37.3, (n=601) 0.923 impairment2 p-value5 = p=0.981 ∨ p<0.001 Mild cognitive impairment2 47.9±39.1, (n=429) 39.3±36.7, (n=601) <0.001 p-value5 ∨ p<0.001 ∨ p<0.001 No cognitive impairment2 34.7±37.5, (n=1681) 25.4±33.9, (n=1095) <0.001 All residents 39.8±38.6, (n=2988) 35.5±36.9, (n=2916) <0.001 Note: 1 Depressive symptom score calculated as 100x(“Sad”+”Crying”+”Anxious and fearful”)/3. Each variable could have the value of 0 or 1. 2 Cognitive score ranges from 0 to 27, where a lower score means more cognitive impairment. The cut-off 24/27 indicates cognitive impairment. The scale is subdivided into three groups, 0-7 (severe cognitive impairment), 8-15 (moderate cognitive impairment) and 16-23 (mild cognitive impairment). 3 There are a number of residents with missing values concerning level of cognitive impairment; hence the numbers of residents in the groups are less than the total number of residents assessed for the symptoms. 4 Pair-wise comparison between the two years. 5 Pair-wise comparison between groups of different cognitive impairment. SD=Standard Deviation

Men and women differed regarding depressive symptom score. In 1982, the women had a mean score of 45.5 compared to 29.8 for the men (p<0.001). By 2000, the score was 38.5 for women and 28.8 for men (p<0.001). Hence the prevalence had decreased significantly between 1982 and 2000 among women (p<0.001), but not among men (p=0.497). When the different cognitive impairment groups were analyzed separately,

59 RESULTS

however, there was a significant decrease among the men with no cognitive impairment, but not in any of the other groups of cognitive impairment among men (data not shown). Psychotropic drug use in the different groups of cognitive impairment is presented in Table 15. Antidepressant drug use increased in all groups of cognitive impairment, and the increase was largely due to the SSRI, which constituted 88.8% (1330/1463) of the antidepressant prescriptions in 2000. The use of anxiolytics and hypnotics also increased. Antipsychotic drug use, on the other hand, became less common in all groups, except the group with a cognitive score of 24 or above (no cognitive impairment).

TABLE 15, PSYCHOTROPIC DRUG USE, AC1982 AND AC2000, COMPARISON BETWEEN PEOPLE HAVING DIFFERENT LEVELS OF COGNITIVE IMPAIRMENT

1982 (n=3064) 2000 (n=3210) p-value Antipsychotics, N05A, n (%) Severe cognitive impairment 190 (44.3) 180 (27.3) <0.001 Moderate cognitive impairment 191 (40.6) 195 (30.4) <0.001 Mild cognitive impairment 122 (27.9) 140 (21.0) 0.009 No cognitive impairment 259 (15.0) 178 (14.3) 0.609 All residents 802 (25.1) 752 (20.5) <0.001 Anxiolytics, hypnotics and sedatives, N05B & C, n (%) Severe cognitive impairment 63 (14.7) 226 (34.2) <0.001 Moderate cognitive impairment 64 (13.6) 274 (42.7) <0.001 Mild cognitive impairment 43 (9.8) 255 (38.3) <0.001 No cognitive impairment 241 (14.0) 530 (42.7) <0.001 All residents 421 (13.2) 1440 (39.2) <0.001 Antidepressants, N06A, n (%) Severe cognitive impairment 19 (4.4) 221 (33.5) <0.001 Moderate cognitive impairment 33 (7.0) 329 (51.2) <0.001 Mild cognitive impairment 40 (9.1) 296 (44.4) <0.001 No cognitive impairment 102 (5.9) 447 (36.0) <0.001 All residents 200 (6.3) 1464 (39.9) <0.001 Note: Cognitive scores range from 0 to 27, where a lower score means more cognitive impairment. The cut-off 24/27 indicates cognitive impairment. The scale is subdivided into three groups, 0-7 (severe cognitive impairment), 8-15 (moderate cognitive impairment) and 16-23 (mild cognitive impairment). Sufficient data to calculate cognitive score were obtained in 3064/3195 cases in 1982 and in 3210/3669 cases in 2000.

60 RESULTS

A higher proportion of women than men used antidepressants. This was the case both in 1982 (7.2% compared to 4.6% p=0.004) and 2000 (42.1% compared to 35.3% p<0.001). There were no differences between the sexes concerning the use of anxiolytics and hypnotics, either in 1982 or in 2000 (data not shown). Antipsychotic drug use was equally common among men and women in 1982 (data not shown), but more common among men by 2000 (22.9% compare to 19.3% p=0.011). A person who had at least two out of three of the following symptoms - “Sad”, “Crying” or “Anxious and fearful”, more often used psychotropic drugs than those without such symptoms. This was true of antidepressants (10.9% compared to 3.4% p<0.001 in 1982 and 51.7% compared to 35.0% p<0.001 in 2000), anxiolytics and hypnotics (17.4% compared to 10.6% p<0.001 in 1982 and 49.3% compared to 35.4% p<0.001 in 2000) and antipsychotics (28.7% compared to 22.8% p<0.001 in 1982 and 28.1% compared to 18.6% p<0.001 in 2000).

61 RESULTS

PAPER V

The use of nervous system drugs among very old people with and without dementia

In Paper V, the total number of participants was 546. The prevalence of dementia increased with age, from 31.3% among the 85-year-olds to 48.1% among those who were 90 years old and 58.1 % among those who were aged 95 years or older (p<0.001). Women had a higher prevalence of dementia than men (p<0.001). The characteristics of the participants, with and without a dementia disorder, are presented in Table 16.

TABLE 16, GERDA/UMEÅ 85+, CHARACTERISTICS OF PARTICIPANTS WITH AND WITHOUT DEMENTIA

With Without Total p-value dementia dementia Number of participants 247 (45.2) 299 (54.8) 546 n (%) (100.0) Women n (%) 201 (81.4) 199 (66.6) 400 (73.3) <0.001 Age, mean ± SD 91.6 ± 4.7 89.5 ± 4.2 90.5 ± 4.6 <0.001 MMSE, mean ± SD 12.3 ± 7.7 24.8 ± 3.6 19.3 ± 8.5 <0.001 Barthel’s ADL score, mean 10.1 ± 6.9 18.6 ± 3.0 14.7 ± 6.7 <0.001 ± SD GDS score, mean ± SD 4.2 ± 2.9 3.3 ± 2.5 3.6 ± 2.7 0.006 MNA score, mean ±SD 19.5 ± 4.3 24.5 ± 3.2 22.1 ± 4.5 <0.001 Pain preceding week n/total 104/198 153/273 (56.0) 257/471 0.449 evaluated (%) (52.5) (54.6) PGCM score, mean ± SD 11.0 ± 3.3 12.1 ± 3 .2 11.8 ± 3.3 0.005 Type of housing Living in own house or 66 (26.7) 224 (74.9) 290 (53.1) <0.001 apartment n (%) Residential care n (%) 36 (14.6) 45 (15.1) 81 (14.8) Nursing home n (%) 81 (32.8) 6 (2.0) 87 (15.9) Group dwelling for people 48 (19.4) 4 (1.3)1 52 (9.5) with dementia n (%) Other institutional care 11 (4.5) 8 (2.7) 19 (3.5) n (%) Note: SD= Standard Deviation, MMSE=Mini-Mental State Examination (scores 0-30), GDS= Geriatric Depression Scale (scores 0-15), Barthel’s ADL= Activities of Daily Living (scores 0-20), PGCM= Philadelphia Geriatric Centre Morale scale (scores 0-17), MNA= Mini-Nutritional Assessment (scores 0- 30). 1 Four people lived in a group dwelling for people with dementia even though they did not have a dementia disorder - there were other causes. Data on accommodation type were missing for 17 of the participants.

62 RESULTS

Participants suffering from a dementia disorder had higher scores on the GDS, lower MNA scores (higher risk of malnutrition), lower scores on the MMSE and Barthel’s ADL scale, and more often lived in an institutional care facility. There was no difference in the prevalence of pain between participants with and without dementia. When the MMSE score was 19 or lower, more than 50% of the participants had a dementia diagnosis, and more than 90% when the MMSE was 15 or lower. Of those with a dementia diagnosis, 132 (53.4%) were diagnosed as having Alzheimer’s type dementia, 72 (29.1%) as having vascular dementia and 22 (8.9%) as having other dementia disorders. Dementia type was not specified in 21 cases (8.9%). Among those whose MMSE score was 17 or lower, more than 50% lived in some kind of institutional care facility. Correlation between the MMSE score and prevalence of institutional care was -0.58 (p<0.001). The use of nervous system drugs (ATC class N) is presented in Table 17. A higher proportion of participants with dementia used paracetamol, antipsychotics, clomethiazole, anxiolytics of benzodiazepine type, antidepressants (particularly SSRI), and anti-dementia drugs. There were no differences concerning opioid analgesics, anticonvulsants, Parkinson drugs and hypnotics. Of the participants who had experienced pain the preceding week, either self- or staff-reported, 49.8% were receiving regular analgesic treatment. People with dementia received treatment in 70.2% of cases, compared to 35.9% of those without dementia (p<0.001). Another 25.5% of those without dementia and 11.5% of those with dementia had analgesics “as needed”. Hence 38.6% of those without dementia who had experienced pain during the preceding week did not use any analgesic drug, either regularly or “as needed”, compared to 18.3% (p=0.001) of those with dementia. Regarding drugs with direct counteracting effects, 21 (17.9%) of those receiving an antidepressant drug (both with and without dementia) also received an atypical antipsychotic agent, one person received both L-dopa and an antipsychotic drug, and three people received both drugs with anticholinergic proprieties and choline-esterase inhibitors. There were 6 people (1.1%) using the long-acting benzodiazepine nitrazepam. The drugs clomethiazole and propiomazine were only available in Sweden and the percentages are, therefore, calculated only for the 306 participants from Sweden. The participants from the two countries did not differ in mean age, proportion of women, mean GDS score, mean Barthel ADL score, mean MMSE score or proportion of participants living in institutional geriatric care (data not shown). However, the proportion of people who had a dementia diagnosis was greater in Finland (52.1% compared to 39.9%, p=0.004). The use of antipsychotics was more common in Finland (15.0% compared to 8.8%, p=0.025). Use of anxiolytics of benzodiazepine type was also more common (20.0% compared to 7.5%, p<0.001), as was the use of memantine (Finland, 5.0%, Sweden 0.7%, p=0.001). For all other drugs investigated, there were no significant differences (data not shown). The relative impact of the country and dementia diagnosis respectively for the prevalence of antipsychotics and benzodiazepine anxiolytics was investigated using a logistic regression, including the interaction term. This showed that for antipsychotics, the country was not in fact significantly associated (data not shown), but for anxiolytics, the odds ratio associated with living in Finland was 3.6 (confidence interval 1.5 to 8.6, p=0.005).

63 RESULTS

TABLE 17, NERVOUS SYSTEM DRUG USE, GERDA/UMEÅ 85+, COMPARISON BETWEEN PARTICIPANTS WITH OR WITHOUT DEMENTIA, N (%)

Drug class ATC-code With Without p-value dementia dementia (n=247) (n=299) Analgesics N02 132 (53.4) 78 (26.1) <0.001 Opioid analgesics N02A 29 (11.7) 31 (10.4) 0.610 Paracetamol N02B E 125 (50.6) 64 (21.4) <0.001 NSAID1 M01A 10 (4.0) 20 (6.7) 0.178 Anticonvulsants N03A 7 (2.8) 10 (3.3) 0.732 Parkinson drugs N04 4 (1.6) 9 (3.0) 0.289 L-dopa N04B A 3 (1.2) 5 (1.7) 0.735 FE Other N04B C,D,X 2 (0.8) 6 (2.0) 0.303 FE Antipsychotics2 N05A 55 (22.3) 8 (2.7) <0.001 Conventional N05A A,B,D,F 14 (5.7) 4 (1.3) 0.005 Atypical N05A E,H,X 47 (19.0) 4 (1.3) <0.001 Lithium N05A N01 1 (0.4) 0 (0.0) 0.452 FE Anxiolytics, hypnotics N05B, C 91 (36.8) 93 (31.1) 0.158 and sedatives Anxiolytics, N05B A 47 (19.0) 24 (8.0) <0.001 benzodiazepine type Hypnotics and N05C 79 (32.0) 85 (28.4) 0.367 sedatives3 Benzodiazepine type N05C D,F 70 (28.3) 81 (27.1) 0.745 Clomethiazole N05C M02 7 (2.8) 0 (0.0) 0.004 FE Propiomazine N05C M06 11 (4.5) 10 (3.3) 0.502 Antidepressants N06A 83 (33.6) 34 (11.4) <0.001 Tricyclics N06A A 2 (0.8) 4 (1.3) 0.694 FE SSRI N06A B 67 (27.1) 27 (9.0) <0.001 MAO-inhibitor N06A G 1 (0.4) 0 (0.0) 0.452 FE Other4 N06A X 20 (8.1) 7 (2.3) 0.002

Venlafaxine N06A X16 6 (2.4) 1 (0.3) 0.050 FE Any psychotropic drug N05A,B,C, N06A 148 (59.9) 112 (37.5) <0.001 Anti-dementia drugs N06D 42 (17.0) 0 (0.0) <0.001 Choline-esterase N06D A 32 (13.0) 0 (0.0) <0.001 inhibitor Memantine N06D X 14 (5.7) 0 (0.0) <0.001 Notes: 1 NSAID included for the sake of completeness 2 Lithium is included in the category Antipsychotics (N05A). 3 Clomethiazole is included in the category Sedatives (N05C). 4 Tetra-cyclic antidepressants are included in the category Other. FE Fisher’s exact test, NSAID= Non-Steroidal Anti-Inflammatory Drugs, SSRI=Selective Serotonin Reuptake Inhibitor, MAO-inhibitor= Mono-Amine Oxidase inhibitor. The p-values are calculated with the Chi-square test unless otherwise specified.

64 RESULTS

ADDITIONAL RESULTS

Mini Mental State Examination versus Gottfries’ cognitive scale

The aim of this complementary analysis was to compare the MMSE with Gottfries’ cognitive scale, to support the methods used in Papers I-IV. The Mini Mental State Examination (MMSE) is used worldwide in geriatric practice to screen for cognitive impairment. A score of less than 24/30 is traditionally considered to indicate cognitive impairment. In many clinical or research situations it is desirable not only to differentiate between those with or without cognitive impairment, but also to grade the level of cognitive impairment. The MMSE is also commonly used for this purpose. Those living in geriatric care were selected from the GERDA/Umeå 85+ data collection, they were then matched for age in years with people from the AC1982 or AC2000 data collections. A random procedure was used to select matches, from those people who were of the right age. People from both samples were eligible if they were evaluated with the MMSE or the Gottfries’ cognitive scale respectively, and had a score indicating cognitive impairment. A total of 248 pairs of people were extracted, giving a total of 496 people (mean age 91.9± 4.4 years). The number of women was 399 (80.4 %). The cognitive score frequency distributions of the two samples were then compared. Difference in deviance from ideal distribution (rectangular distribution) and floor effect (proportion of those at zero points) was tested with the non-parametrical Mann-Whitney U-test. The mean deviance from the rectangular distribution was 3.22 ± 2.0 for Gottfries’ cognitive scale and 5.78 ± 6.8 for the MMSE (p=0.048). The number of people receiving a score of zero (the floor effect of the scale) was 15 (6.9%) for Gottfries’ scale and 46 (18.5%) for the MMSE (p<0.001). In conclusion the analysis seems to indicate that the Gottfries’ scale has an advantage over the MMSE when it comes to distributing a sample of people with cognitive impairment living in geriatric care equally over the scale, and that the MMSE seems to have a larger floor effect than Gottfries’ cognitive scale, when used in this kind of population.

Evaluation of the questions about pain included in the AC2000 and GERDA/Umeå 85+ data collections

For a description of the pain assessments, see Method section. In the GERDA/Umeå 85+ data collection, pain was assessed by questioning both the person him- or herself and, if applicable, the caring staff. Answers were received from both the person him- or herself and the caring staff for a total of 86 people. Of these people 71 (82.6%) were women and 69 (80.2%) had a dementia disorder. Mean age was 92.9 ± 4.6 years. The people themselves assessed that they were in pain in 38 cases (44.2%), the staff answered that the resident was in pain in 46 cases (53.5%). The answers were in agreement in 64 cases (74.4%), and overall correlation between the answers was 0.50. For people without dementia (MMSE score 22.6 ± 3.4) the agreement was 16/17 (94.1%) and the correlation was 0.88, for people with dementia (MMSE score 12.0 ± 6.2) the agreement was 48/69 (69.6%) and the correlation 0.41.

65 RESULTS

For the VAS assessment of pain, double assessments were received in 15 cases. Correlation was 0.56, p=0.030, (for 9 people without dementia 0.67, p= 0.048, for 6 people with dementia -0.42 p=0.412). In conclusion, the answers from residents and staff concerning pain showed a fair level of agreement and correlation, among very old people. The answers from residents and staff agreed well in the case of those without dementia, but was poorer among those suffering from dementia.

A calculation of the numbers needed to treat based on data from Paper III

This calculation is based on the data presented in Tables 12 and 13 (page 58). Numbers needed to treat is a measure of how many people have to receive the drug for one person to be relieved from the investigated disease or symptom. The calculation makes use of the fact that very few people received treatment in 1982. The reasoning is based on the assumption that all effects in symptoms, when controlled for demographic changes, can be attributed to the increased use of psychotropic drugs. A raw numbers needed to treat

(pt2000 " pt1982) (NNT) was calculated as NNT = where pt= prevalence of pharmaco- (ps1982 " ps2000 ) logical treatment and ps= prevalence of symptom. A corrected NNT was then calculated as $ $ ' ' ! pt1982 & ORt "& ) ) & % 1# pt1982 ( ) # pt1982 & $ $ pt '' ) & 1982 ) & 1+ & ORt "& )) ) % % % 1# pt1982 (( ( NNTcorr = $ $ ' ' ps1982 & ORs "& ) ) & % 1# ps1982 ( ) ps1982 # & $ $ ps '' ) & 1982 ) & 1+ & ORs "& )) ) % % % 1# ps1982 (( (

where ORt= Odds Ratio of pharmacological treatment in 2000 compared to 1982 and ORs= Odds Ratio of symptom in 2000 compared to 1982. Note: the odds of an event ! equals the probability divided by (1- the probability), i.e. odds=p/(1-p). The relative complexity of the formula above stems from the back-and-forth calculations between odds and probabilities. NNT was calculated for antidepressants for the symptoms sad, crying, lacks initiative and does not cooperate, and for benzodiazepines for the symptoms anxious and fearful and disturbed and restless. The calculation was also performed for the possible side-effects - manic/overactive and hallucinates visually. A remission rate was calculated as 1/NNT. The results are presented in Table 18. The adjusted NNT for the symptom “Sad” was 4.4, for “Crying” 4.6 and for “Lacks initiative” 3.6. This corresponds to remission rates of 23%, 22% and 28% respectively.

66 RESULTS

TABLE 18, AC1982 AND AC2000, CALCULATED NUMBERS NEEDED TO TREAT AND REMISSION RATES FOR DIFFERENT SYMPTOMS, N=3195+3669

NNT NNT - Adjusted Calculated value remission rate (%) Sad 6.96 4.40 22.7 Crying 6.07 4.58 21.8 Anxious and fearful 8.57 2.55 39.2 Hallucinates visually -13.661 -7.321 Does not cooperate 3.65 27.4 Lacks initiative 3.57 28.0 Overactive/manic -11.991 -8.541 Disturbed and restless 4.41 22.7 Note: NNT= Numbers Needed to Treat, see Method section for further details. Remission rate= 1/NNT. The values for the variables sad, crying, lacking initiatives and does not cooperate are all calculated for antidepressants, as well as overactive/manic and hallucinates visually. Disturbed and restless and Anxious and fearful are calculated for benzodiazepines. 1A negative value means that one out of, for example, 11.9 with medication will get the symptom, or for remission rate that 8.54% of treated persons will develop the symptom/adverse effect.

68 DISCUSSION

DISCUSSION

THE MAIN FINDINGS

Old people in general, and especially those affected by dementia disorders, are more sensitive to the side effects of drugs than younger people. This is why the extensive use of nervous system drugs among old people living in geriatric care and very old people in general is a matter of concern. In the investigations contained in this thesis, those people suffering from dementia in particular seemed to be at increased risk of receiving some nervous system drugs, such as antipsychotic drugs. The use of antipsychotic drugs for people with cognitive impairment living in geriatric care was found to be correlated to several behaviors and symptoms that are not proper indications for antipsychotic drug use, and also factors related more to the staff and the caring situation. The prevalence of psychotropic drug use in 1982 was compared with that in 2000. Over the course of eighteen years, from 1982 to 2000, there was a manifold increase in the use of antidepressants, anxiolytics, hypnotics and sedatives in geriatric care, but the use of antipsychotics had decreased slightly. During the same time, the prevalence of several psychological symptoms had decreased significantly, correcting for demographic changes. One analysis of calculated numbers needed to treat however indicated poor remission rates of depressive symptoms, suggesting that even better results might be achievable. Two psychological symptoms were found to have increased in prevalence when controlling for demographic changes - visual hallucinations and overactive/manic symptoms. The depressive symptoms of people with moderate cognitive impairment did not at all improve, despite the fact that about 50% of them were being treated with antidepressants. One possible explanation might be that depressive symptoms have different etiologies in the various stages of a dementia disorder. Roughly a quarter of the people experiencing pain in geriatric care did not receive any regular analgesic treatment. One possible reason might be misconceptions among caring staff about whether or not the people were in fact receiving analgesic treatment. Such misconceptions were found to be common.

PREVALENCE OF PSYCHOTROPIC AND ANALGESIC DRUG USE

Prevalence numbers for different drug classes are presented in all papers. For all three data collections, the term prevalence refers to the point prevalence of nervous system drug use. Concerning the symptoms and behaviors of the MDDAS, the prevalence numbers refer to one-week prevalences. Papers I and V present data on analgesic medication. In geriatric care facilities, a total of 54% of the people received analgesics, and 22% of them received opioid analgesics. In most cases the opioid analgesic drugs were combined with paracetamol. Among the very old people in the GERDA/Umeå 85+ data collection, 39% received analgesics, and 11% opioid-type analgesics. Analgesic use was high among old people living in geriatric care and among very old people in general, and the prevalence numbers presented in the papers are comparable to [102, 106, 109, 227-229], or somewhat higher than those previously presented [116].

69 DISCUSSION

Prevalence numbers for psychotropic drugs are presented in Papers II-V. Of those in geriatric care in 2000, 40% used antidepressants, 21% used antipsychotics and 39% used anxiolytics, hypnotics or sedatives. These number are also in line with those found in other studies in geriatric care, however, the use of anxiolytics, hypnotics and sedatives lies in the upper range [18, 33, 35, 106, 187, 189, 192, 193, 201, 204]. Some previous studies, however, have found higher rates of antipsychotic treatment [18, 189, 193, 200]. Among the very old people included in the GERDA/Umeå 85+ data collection, 21% used antidepressants, 12% used antipsychotics and 34% used anxiolytics, hypnotics or sedatives. Few comparable studies have been published, but the prevalences is at least comparable to the Kungsholmen data [188]. The prevalence of antidepressant use is a little higher in the GERDA/Umeå 85+ data collection, the probable explanation being an increased use in recent years. Compared to the GERDA/Umeå 85+ data collection of 2000, there have been no major changes. In 2000, 19% received antidepressants, 32% received anxiolytics, hypnotics or sedatives and 18% received antipsychotics (including propiomazine) [72].

Time trends in psychotropic drug use

Some rather clear time trends were found when comparing the prevalence of psychotropic drug use between the AC1982 and AC2000 data collections. There was a manifold increase in the use of antidepressants, which is in line with the findings presented in many other studies [185, 188, 196-199]. The main reason is most probably the introduction of the SSRI, enabling wider use in old people. In the county of Västerbotten, the use of anxiolytics, hypnotics and sedatives also seems to have increased in geriatric care during the 18 years separating the two AC data collections. This large increase does not correspond to the findings in other studies, some of which even reported a reduction in benzodiazepine use [188, 202]. The use of antipsychotics declined slightly in geriatric care in Västerbotten between 1982 and 2000. The results from other studies are conflicting [34, 196, 199]. The massive marketing of the new atypical antipsychotics, which account for an increasing share of the antipsychotics [196, 204-206], might have contributed to increased use of antipsychotics in some countries.

APPROPRIATENESS OF NERVOUS SYSTEM DRUG USE

Cross-sectional epidemiological studies cannot determine casual relationships between different variables. Despite this fundamental weakness in epidemiological cross- sectional studies, the analyses in this thesis provide data, which might be discussed in terms of the appropriateness of nervous system drug treatment. It is possible from cross- sectional data to find correlations, which might indicate the nature of the underlying relationships. The discussion below is based on the assumption that the correlations found reflect some of the picture of nervous system drug use in the old population. What, then, constitutes an appropriate drug treatment? A intuitive definition might be that when there is a proper indication for the treatment, the appropriate drug is chosen and given in appropriate doses, adjusted to the person’s individual characteristics, and the treatment is thoroughly evaluated concerning effects and side effects, both in short and the long term, and the treatment is adjusted accordingly.

70 DISCUSSION

Further, when a treatable disorder is present, leading to lower quality of life for the person afflicted or an increased risk of some future adverse events, drug treatment or non-pharmacological treatments are considered and initiated if warranted. Since all three data collections provided data on the various symptoms and characteristics of the people included, in addition to drug data, the appropriateness could be investigated and discussed in a variety of ways.

Appropriateness of nervous system drug use in relation to indications for treatment

The finding in Paper I, that a significant proportion of the residents in geriatric care assessed as suffering from pain were not receiving any pharmacological pain treatment indicates inappropriateness. The finding is a strong indicator of a prevailing under- recognition and under-treatment of pain in geriatric care, consistent with the findings of previous studies [98, 102, 106, 111]. The data on pain and pain treatment from the GERDA/Umeå 85+ data collection presented in Paper V indicate that the problem is at least as prevalent among a general population of very old people, including both those living in their own homes as well as those in geriatric care institutions. The data presented in Paper I further indicated that in many cases misconceptions exist among the staff in the geriatric care settings, which might provide an explanation of some of this under-treatment. When the person was assessed as suffering from pain, but was not receiving any pharmacological pain treatment, in about 70% of cases the member of staff making the assessment still falsely believed that the resident was receiving treatment. This finding has not been reported previously. The estimated prevalence of these misconceptions was higher in residential care facilities than in nursing homes. In nursing homes, the contacts between the various categories of staff are generally closer, and there are more registered nurses. This fact might have contributed to staff in nursing homes having more realistic perceptions of current pharmacological treatment, nevertheless even there more than 50% were wrong about the pain treatment for those with pain, when in fact there was none. Closer contacts between the professional categories are probably needed to bridge this knowledge gap. One positive aspect in pain treatment is that so many of those with dementia and concurrent pain seem to be receiving pain treatment, both in the AC2000 and GERDA/Umeå 85+ data collections. In people with dementia, who might have problems communicating their pain problems, regular analgesic medication should be preferred to “as needed”, to ensure that they receive pain relief. On the other hand, when more people receive drugs, more side effects can also be expected. It is always important to follow up the treatment, concerning effects and side effects, and to discontinue the treatment when it is no longer needed. For many reasons antipsychotic treatment is of special interest when studying nervous system drug use among old people. The treatment has many adverse effects, such as sedation, extra-pyramidal side effects, anti-cholinergic effects and detrimental cardiovascular effects, such as stroke [38-42, 155, 179], and is associated with increased mortality rates [42-48]. Thus it is seldom warranted considering the, at best, modest treatment results [36-38]; yet it is used rather often [18, 33, 35, 187, 189, 193, 199, 200, 204]. Aggression and agitation and, even more so, wandering behavior and shouting, cannot in general be considered a proper indication for antipsychotic treatment,

71 DISCUSSION

considering the effects and side effects. Many of these behaviors and psychological symptoms were found to be common among people with cognitive impairment living in geriatric care. Paranoia of psychotic dimension and hallucinations (not illusions) might be considered proper indications for antipsychotic treatment, together with other psychotic features. The evidence for a dopaminergic excess in people with dementia and psychosis is, however, weak [230]. It should also be considered whether the treatment really would improve the person’s quality of life, and if not, it should not be initiated. There is also very little evidence concerning long-term treatment of the behavioral and psychological symptoms of dementia [231-233], therefore antipsychotic treatments should be regularly evaluated and reconsidered. In Paper II it was found, in a multivariate regression analysis, that the use of antipsychotic drugs among people with cognitive impairment living in geriatric care was related to several different factors. First, there is the relation to the fact that the person was living in a group dwelling for people with dementia, the perceived mental workload for the staff when caring for the resident and the resident’s ability to rise from a chair which indicated a relation to the caring situation rather than to the resident’s own experiences of symptoms. Further, among the behaviors and symptoms that were related, only hallucinatory symptoms might be considered an appropriate indication for treatment. The relation with aggressive behavior, verbally disruptive/attention-seeking behavior and wandering behavior indicates that antipsychotic treatment might be used to treat these conditions in geriatric care facilities. Depressive symptoms could be regarded as a possible adverse reaction and the relation to male sex might be related to both treatment traditions and prejudices, and to the fact that male residents are probably regarded more threatening when aggressive than female residents. Taken together, and considering the overall rather high prevalence of antipsychotic drug use among old and very old people with dementia presented in Papers II-IV, this indicates an inappropriate and too extensive use of these drugs. Anti-dementia drugs were used by about 7% (145/2035) of those with cognitive impairment in the AC2000 data collection and 8% of those with dementia in the GERDA/Umeå 85+ data collection. This deserves some concern, since many more could possibly benefit from such treatment [234]. However, it is possible that the proportion of people receiving anti-dementia drugs is greater today than in 2000, since the drugs were rather new then. The efficacy of the choline-esterase inhibitors is often modest, and their use is still being debated [235, 236]. It is clear that some people benefit more from the treatment than others. If the drug does not have the effect sought, ongoing use is not warranted, but the drugs should in most cases at least be tried.

Appropriateness of nervous system drug use in relation to treatment results

Even if a drug treatment is initiated, a follow-up might often be needed after some time, for example to adjust the doses of antidepressants or analgesics if the effect sought is not achieved, or side-effects are significant. Some of the findings in this thesis points to poor treatment results from certain nervous system drugs among old people, which is inappropriate. In Paper III, a significant reduction in the prevalence of several symptoms of mental health was found between 1982 and 2000, among old people living in geriatric care, when controlling for demographic changes. This is probably at least partly due to the increase in antidepressant treatment, which was found to have increased from 6.3%

72 DISCUSSION

to 39.9% between the years 1982 and 2000. Other possible reasons, such as improvements in the care of people with dementia and better recognition of treatable disorders could not, of course, be excluded. However, the large increase in the use of antidepressants seems important. It is interesting and satisfying to find that the prevalence of depressive symptoms has decreased in geriatric care, as it indicates that these symptoms are treatable even among old people living in geriatric care. However, in an additional analysis the numbers needed to treat was calculated, based on the adjusted odds ratios for the different symptoms. These numbers needed to treat indicated that the overall remission rate for depressive symptoms was low, calculated to be just above 20%. This finding is in line with other epidemiological data [72], but is much below the remission rate of about 80% that is mentioned as being possible to achieve in old people [78]. Assuming that these figures are accurate, they would suggest that the remission rate is too low, probably due in turn to poor follow-up. To achieve higher remission rates for depression or depressive symptoms, diagnosis, treatment and follow-up probably all need improvement. Underlying causes such as obstructive sleep apnea, vitamin B12 deficiency and adverse drug effects must be properly diagnosed and targeted. Antidepressant drug treatment often needs increasing doses, switching drugs or using adjuvant treatments, to achieve full remission. Very good treatment results among old people have been obtained with ECT and it should be considered as an alternative [77]. There is also some evidence to support the finding that better treatment results can be obtained by combining pharmacological treatment with psychological therapy [237]. In addition, two symptoms were found to have increased in prevalence when controlling for demographic changes - visual hallucinations and overactive/manic symptoms. Interestingly, both of these symptoms have been described as possible side effects of SSRI antidepressants [155, 238-240], again illustrating the need for proper follow-up when nervous system drug treatment is initiated. In Paper IV, the changes in prevalences of depressive symptoms are investigated for people with varying degrees of cognitive impairment. The main finding was that the prevalence of depressive symptoms had decreased in all cognitive impairment groups, except that with moderate cognitive impairment. Why was there no improvement in this group, despite their having received antidepressant treatment in more than 50% of the cases? Two main etiologies of depression in dementia have been discussed in previous articles on the topic. The first hypothesis is that depression is a reaction, the suggested cause being awareness of the dementia disorder and functional decline [86]. The second is that there are neuropathological changes, in which depression is thought to correlate to the loss of serotonergic neurons. There is more evidence today to support the latter hypothesis [87, 241]. These two hypotheses seem to be applicable to different stages of dementia. Whereas awareness is a prerequisite for reactive depression, which thus might account for depression in the earlier stages of dementia, neuronal loss and neurotransmitter deficit probably worsen with the disorder, with increasing impact as the disorder progresses. A third possible reason is a chronic stress reaction. Chronic stress has previously been proposed as a reason for depression in the elderly in general [242]. When the dementia disorder is moderate to severe, the person with dementia will have problems interpreting what is happening to him/her and will have increasing communication

73 DISCUSSION

deficits of both impressive and expressive type. The person might become unable to understand the caring situation and, for example, being dressed or showered by people that he/she does not recognize, might be very stressful and lead to both aggressive behavior and possibly to depression. When the dementia reaches its final stages, the person might no longer be concerned about not understanding his or her surroundings. A simplified theoretical model of these etiologies of depression in dementia is outlined in Figure 6.

Figure 6, Theoretical model of etiology of depression in dementia.

Reactive depression, chronic stress reaction and neuronal loss are labeled A, B and C respectively. A modifying factor, D, is added to the figure to account for the staff’s increasing difficulty in interpreting the symptoms of depression in those with the severest dementia. Apart from these four factors numerous others (such as previous depression or genetic predisposition, previous stroke and sleep apnea) certainly contribute to a varying extent, probably not so strongly correlated, however, to the level of cognitive impairment. Some factors, such as malnutrition and an increasing sensitivity to detrimental drug side effects probably increases as shown by curve C. The main finding in Paper IV was that the prevalence of depressive symptoms had not decreased among people with moderate cognitive impairment, despite the 51%

74 DISCUSSION

prevalence of treatment with antidepressants, in contrast to people with both milder and more severe cognitive impairment. According to the suggested model, the interpretation of this could be that SSRI treatment has some effect in reactive depression and on the serotonin deficit that is the result of organic brain injury, but not so much on the stress- induced depressive symptoms in middle-stage dementia. These symptoms might be better off treated with non-pharmacological strategies supporting understanding, perhaps through pedagogical measures [64], and better-educated caring staff. Concerning analgesic drugs, the VAS pain assessment was higher among those receiving regular analgesic treatment than among those who had pain but no regular analgesic treatment. The main reason for this is probably that the former group had worse pain in the first place. Nevertheless, it raises the question of whether the pain treatment was sufficient. Forty-one percent of those receiving regular analgesic treatment were given an opioid drug, the rest had only paracetamol or sometimes NSAID. However, because the questions in the MDDAS form were possibly interpreted differently by the assessors, we could not know if the pain assessment concerned the resident’s pain “before” or “after” the analgesic drugs were given, making the figures difficult to interpret. Only 478 people out of 3724 (12.8%) received an analgesic drug and were not in pain. These people could be regarded as being properly treated, even if some of them could also have been over-treated.

Appropriateness of nervous system drug use in relation to differences between various groups of people

Yet another way of investigating the appropriateness of drug treatment is to compare various groups. If there is a difference, for which no obvious explanation exists, then the difference itself indicates inappropriateness. It is then open to discussion whether it is the first group that is receiving too little or the second that is receiving too much. This thesis contains a few comparisons between men and women and between people with and without dementia, which provides relevant data. Men seem to be at increased risk of receiving antipsychotics (Paper II). People with dementia also seem to be at increased risk of receiving antipsychotics compared to those without dementia (Papers IV and V). People with dementia seem to receive analgesics more often (Paper V), despite the same prevalence of pain as people without dementia (Papers I and V). People with cognitive impairment receive antidepressants more often (Paper IV). Most striking is the large difference between those with and those without dementia in the prevalence of antipsychotic drug treatment. However, certain symptoms are more common among people with dementia, which might explain the differences (Paper II). As has previously been discussed, however, there is little evidence to support this use. In the GERDA/Umeå 85+ data collection, participants from Finland more often received benzodiazepine anxiolytics, but apart from that, there were no major differences between the participants in Sweden and Finland.

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Appropriateness of nervous system drug use in relation to known potentially inappropriate medications

Finally, some drugs have so many side effects that their use is seldom warranted at all in old people. The Beers criteria is one list of such drugs, aimed at helping doctors avoid medications dangerous for their old patients [182]. It should be noted, however, that all these drugs may be warranted in some special situations, and the criteria should be regarded as rules of thumb. Even pure anti-cholinergics may, in fact, be warranted in some situations. Drugs mentioned as being inappropriate for old people in the Beers criteria include tricyclic antidepressants, long-acting benzodiazepines, antihistamines, anticholinergics and full-dose NSAID. Antipsychotics are also seldom warranted, and are regarded in this thesis as potentially inappropriate. Opioid analgesics are somewhat special in that they often produce side effects, but also often have outstanding analgesic properties, so the medication cannot be regarded as generally inappropriate for old people. It is important, however, that their use is properly evaluated, and that potential side effects, such as constipation, are prevented. With these criteria in mind, in interpreting the findings in the papers, the following is found: In geriatric care, the AC2000 data collection, 2.2% of the people received tricyclic antidepressants, 39.2% received anxiolytics, hypnotics or sedatives, mainly benzodiazepines, and 2.2% used the long-acting benzodiazepine nitrazepam, 20.7% received antipsychotics, and 5.8% received NSAID as a regular treatment. Among very old people, in the GERDA/Umeå 85+ data collection, 6 people (1.1%) received tricyclic antidepressants, 33.7% received anxiolytics, hypnotics or sedatives, 1.1% used nitrazepam, 11.5% received antipsychotics and 5.5% received NSAID. Apparently, the use of benzodiazepines is very widespread among old and very old people in Västerbotten. Especially since the effect of benzodiazepines decreases when used as standing medication, and concerning the risk of side effects, they seem to be overused in this population. Intermittent use should be preferred to regular use, and other measures to improve sleep quality should be used together or instead of hypnotics [243]. In geriatric care, it seems important to retain an even diurnal rhythm i.e. no power-naps in the daytime, and a sufficient amount of daylight and activity in the day, as well as hygienic sleep measures such as a dark, silent and pleasantly cool bedroom. Another important aspect concerning benzodiazepine use is the high prevalence of sleep apnea syndrome in this age group, often unnoticed. Many of the people in geriatric care have had a stroke, and many of them have obstructive sleep apnea [89]. Benzodiazepines are hazardous for these people, and their use is absolutely contraindicated [155]. The extensive use of antipsychotics has already been discussed. The prevalence of tricyclic antidepressant use seems fair, and probably constitutes a treatment for neuropathic pain, a proper indication [158]. The low prevalence of tricyclic use indicates that SSRI have now almost totally replaced the tricyclics in the treatment of depression, which is in line with the current treatment guidelines [70, 77, 79]. The use of NSAID was low compared to that in some studies, and may, or may not, be appropriate. Since no information was gathered concerning the doses and indications, this could not be determined from the present studies. In old and very old

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people, NSAID have a less advantageous side-effect profile, and should be used with caution [157, 177].

ETHICAL CONSIDERATIONS

One of the main ethical considerations of the AC1982 and AC2000 data collections is that no informed consent was received from the residents. On the other hand, it was not possible to identify who contributed to each data item, for example, no personal code numbers were stored. Data were only presented at group level. But, the residents were unaware that they were assessed by the staff at the geriatric care settings, a procedure that might be considered somewhat ethically questionable. One defense is that the ends could justify the means in that the residents or other people in the same circumstances could, in the long run, benefit from the results of the research. It is also important to note that there was no intervention or testing that included the residents, and the residents were not harmed, or at risk. The AC2000 data collection was approved by the ethics committee at Umeå University. For the AC1982 data collection no such approval was sought, as the regulations regarding ethics were different at that time. The procedures, however, were the same as in the AC2000 data collection. In the GERDA/Umeå 85+ data collection, informed consent was received from the participants for the interview, assessments and review of medical records. In cases of severe cognitive impairment, when no informed consent could be given, the next of kin were asked instead. Here, the consent of the next of kin was accepted, because it was regarded as important not to exclude people with dementia. This group is otherwise often neglected or excluded in research, which is a problem. The group of people receiving most nervous system drugs, is also the group least investigated [82]. That the GERDA/Umeå 85+ data collection and interview procedure were regarded as safe and harmless, contributed to the decision to include people who could not give their own consent. It was always possible for people to discontinue the interview, if wanted to. The procedures were approved by ethics committees. One ethical problem with the GERDA/Umeå 85+ procedures was that many of the questions included deal with serious aspects of life, such as loneliness, losses, depression and zest for life. Questions about money and social networks might also have evoked sad feelings. Through being asked some of the questions, the participants were possibly made acutely aware of their reduced cognitive and functional abilities, which might have been experienced as demanding. People with mild cognitive impairment are often aware of their problems with some of the MMSE tasks, and might feel they are failures, and for people in denial of their cognitive problems, the assessment might be conceived as insulting. That the interviews were performed by trained investigators, with professional backgrounds in healthcare was one measure used to counteract this problem, together with the possibility for the participants to discontinue the interview at any time. Another very important aspect is that the home visits were not performed under pressure against the clock, and there was often time to round off the visit with social talk and sometimes a coffee after completion of the formal interview.

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METHODOLOGICAL CONSIDERATIONS

Cross-sectional epidemiological studies

It may be questioned whether there really is a need for yet another epidemiological cross-sectional study. What has not already been investigated, and what contribution can a cross-sectional study make to the research field of geriatrics? Is it not so, that cross-sectional studies are inferior to randomized controlled trials in almost every way, and therefore just a waste of money? Epidemiological cross-sectional studies have some weaknesses but also some strengths when it comes to understanding a scientific issue. The most fundamental weakness is the problem of cause and effect, which this study type generally cannot differentiate between. In investigating the effect of a drug, for example, the evidence has a very low value compared to a randomized, double-blinded placebo-controlled trial. The impact of confounding variables, only partly dealt with in cross-sectional studies by means of the multivariate statistical techniques, is also more difficult to evaluate than in a randomized controlled trial, where the randomization process is thought to counteract the problem. However, the randomized controlled trial also has some weaknesses. One of the most important is the apparent risk of selection effects, which might compromise the transferability to general groups of people. In the field of geriatric medicine, the exclusion of very old people, people with dementia or people with many concurrent medical conditions are examples of such selection. The problem is that these people receive the drugs in general practice, even if they have not been evaluated in these particular groups. Another problem is that effect measurements are chosen in advance and are often influenced by the expectations of the investigator, which in the case of various drugs often includes the manufacturer, who wants to prove the advantages of the product. There is always a risk that the researchers will find only what they are looking for. Therefore, there is a need of both non-company financed randomized drug evaluations and cross-sectional studies. The reason cross-sectional epidemiological studies are also needed is that they can answer the question of how the drug is actually used in common clinical practice, outside the controlled and sometimes artificial circumstances of the randomized trial. They can also point to the characteristics of the people receiving these drugs, perhaps indicating the underlying process of prescription. Hence cross-sectional studies bridge the gap between when the drug should be used and when it is actually used. In order to be able to add to the accumulated knowledge, the cross-sectional epidemiological study has to be carried out well and creatively but always carefully interpreted. There is seldom any need for mere prevalences, plenty of which are often already published. One possible exception is very old people, for whom prevalence data is scarcer. Making comparisons between different groups or investigating the relation to certain individual or group characteristics might on the other hand sometimes result in valuable contributions. Another difficulty when interpreting the results of Paper II, for example, is that the relationship between symptoms and treatments is affected by the results of the treatment. If, for example, antipsychotic drug treatment was always initiated if a person experienced hallucinations, and the treatment was 100% effective, no statistical relationship would have been revealed. That many behavioral and psychological

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symptoms were statistically associated with antipsychotic treatment thus also means that the treatments were not so effective. If some symptom were effectively treated, the relationship would have been obscured. This problem is probably larger concerning antidepressant treatment and analgesic treatment. No attempt was made to analyze the relation between depressive symptoms and antidepressants, and analgesics and pain in the cross-sectional materials.

Study population

Three different study populations were included in the papers. The AC1982 and AC2000 data collections both included people living in geriatric care in the county of Västerbotten, Sweden. The populations were fairly comparable, but by 2000 the number of people with cognitive impairment had become much greater. This was accounted for in Paper III by using a logistic regression to correct for the differences, and in Paper IV by dividing the study sample into four groups with different levels of cognitive function. Other changes were minor compared to the changes in the proportion of people with cognitive impairment, and, for example, the lower mean ADL-capacity among those included in the AC2000 data collection compared to the AC1982 data collection, was probably a result of this change. The GERDA/Umeå 85+ data collection differed from the AC data collections in that it comprised both people living in their own homes as well as those living in institutions, and also in that the age of the people selected was different. The GERDA/Umeå 85+ data collection also included people from both Sweden and Finland.

Procedures in data collection

Reliability of the MDDAS

The MDDAS instrument has previously been found to have good, but not excellent, intra- and inter-rater reliability [17]. The reliability also varied between different items in the scale. In general, the large sample size compensates for the weaknesses in the reliability of the instrument. One methodological problem, however, is that the reliability of the MDDAS items over time has not been tested. One possibility is that the staff members who answered the questionnaire in 2000 did not interpret the symptoms exactly as their colleagues did in 1982, in some systematic way. For example, it is possible that the level of education of the staff working in geriatric care was somewhat higher in 2000, which might possibly have some effect. On the other hand, the items in the MDDAS are easy to understand, are formulated in everyday language, and should therefore probably not be so much affected by education level. Another reliability problem of the MDDAS is the inter-rater reliability between people working in different geriatric care facilities. It might be that people working in group dwellings for those with dementia or psychogeriatric hospital wards are more familiar and accustomed to behavioral disturbances among people with dementia, and regard the behaviors as “normal”, having a higher threshold for rating them than the staff in, for example, a residential care facility. This reliability has not been tested, and systematic errors might have affected the results of Paper II especially, which includes comparisons between different types of facilities. This effect might possibly to some

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extent account for the finding that “living in a group dwelling for people with dementia” was a risk factor for receiving antipsychotics. The items “physical and mental workload” in the MDDAS might be similarly affected by the different interpretations of “normal” level in different geriatric care facilities.

Characteristics of Gottfries’ cognitive scale

Gottfries’ cognitive scale is included in the MDDAS instrument [15, 16]. It includes 27 questions, and the cut-off has been validated against the MMSE [17]. The Gottfries’ cognitive scale is presented in Appendix 2. One of the scale’s main advantages is that it can be distributed to and carried out by staff members at geriatric care settings without them receiving any specific training. The scale does not require any testing or involvement of the resident and thus seems to be well suited to large questionnaire surveys like the AC1982 and AC2000 data collections. A completely different methodology would have been required to distribute the MMSE instead of Gottfries’ cognitive scale in these data collections, as the MMSE requires both some basic training of the staff and the cooperation of the resident. One important reason for continuing to use the MDDAS and Gottfries’ cognitive scale in the regularly recurrent AC data collections is also comparability over time. In one additional analysis in this thesis, some characteristics of the MMSE and Gottfries’ cognitive scale were compared in an age-matched selection of people from the three data collections. It is important to note that no direct comparison could be made, as different people were assessed with the two scales. One clinical experience of the MMSE is that relatively few people receive scores of one through ten, and that the floor effect, i.e. the number of people receiving a score of zero is rather large. This implies that the scale is ordered but is not so well suited for use as a nominal scale in statistical analyses. The analysis showed that the Gottfries’ cognitive scale distributed the people more equally over the scale, and that it had less of a floor effect than the MMSE. This could be interpreted to mean that the Gottfries’ cognitive scale is more suited for use in grading cognitive impairment among very old people living in geriatric care, at least for research purposes. These results should be interpreted with caution, and need to be tested formally in one population to be confirmed.

Reliability of the pain questions

The GERDA/Umeå 85+ data collection included the same pain assessment as the AC2000 data collection. In the GERDA/Umeå 85+ form, the same questions were, if applicable, posed to both the persons themselves and to the staff. It was therefore possible to make a reliability analysis, and the results are presented in one additional analysis in this thesis. The results were that among people without dementia there was a very good agreement between the assessments, while among people with dementia the results were much poorer, which was not surprising. It is important to remember that people with dementia do not necessarily give the correct answer; it might also be that the staff can remember more clearly how the resident felt and reacted over a longer period of time, whereas the person suffering from dementia answers according to how he/she feels right now.

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Instruments similar to the pain assessments included in the AC2000 and GERDA/Umeå 85+ data collections, for example the pain questions in the Minimum Data Set (an evaluation tool used in American nursing homes) have been found sufficiently reliable to be used in epidemiological studies [117, 244, 245].

Reliability and validity of drug data

The overall quality of the drug data is regarded as good in all data collections. Data on doses and use of drugs “as needed” were collected, but not coded. One exception is for analgesic drugs among those who were assessed as having pain, for whom “as needed” medication was coded during a second review of the questionnaire forms, to be included in Paper I. In the AC data collections, the prescription record of the resident was copied by hand into the study form. In 1982 the copying procedure was performed by the head nurse or superintendent, in 2000 probably most often by nurses or in some cases by caring staff. However, in 2000, the drug data registration task was merely one of copying, while the researchers performed the coding and grouping of different drugs. Hence in 2000 the registration of the drugs did not require any knowledge of the characteristics of different drugs. In 1982, however, the form requested registration of psychotropic drugs only, thus the task required knowledge of the actions of the drugs, or at least which drugs were included in the category psychotropics. Since drug distribution was more centralized to the nurses or superintendents at that time, the registration was made by someone with medical education. The data are, therefore, assumed to be of good quality anyway, but this procedure is a possible source of error. The researchers subsequently did the grouping and coding of the drug data. Another problem is that some people with no cognitive impairment living in residential care facilities had responsibility for their own medication and the staff did not have access to the prescription records. Regrettably these people could not be separated from those who did not actually have any medication. This is a source of error. It could have affected the results somewhat, leading for example to a somewhat too low estimate of the prevalence of nervous system drugs. Nevertheless, the overall effect of this systematic error is judged to be small and it has probably not affected the main findings. In AC1982, the anxiolytics, hypnotics and sedatives were divided into drugs used in the day and those used at night. Hence, the same drug could possibly have been coded as either one or another, depending on when it was used. These categories do not directly correspond to the division into anxiolytics and hypnotics and sedatives, used in AC2000. However, coding clomethiazole as a daytime tranquillizer in the AC2000 data when used in Papers III and IV makes the data from 1982 and 2000 fairly comparable. Clomethiazole, although a hypnotic according to the ATC-classification, is most often used for agitation in people with dementia. In the GERDA/Umeå 85+ data collection drug data were collected from both the interviews and the medical records, and crosschecked, thus the data is thought to be of good quality.

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Reliability of the scales included in the GERDA/Umeå 85+ data collection

The GERDA/Umeå 85+ data collection comprises several scales assessing various aspects of the people included, for example the MMSE, the GDS, the MNA and the PGCMS. The scales were chosen because they were well known and had already been found to be reliable. In this thesis, the results of these assessments were only presented as a background description of the people included in the study. The results of the OBS scale and the MMSE were included in the data on which the experienced geriatrician based his diagnosis of dementia, together with all the information available from the medical records and the interview forms.

Participation rate and missing values

The numbers of missing values were relatively low in all three data collections. The participation rates were 92%, 87% and 72% in the AC1982, AC2000 and GERDA/Umeå 85+ data collections respectively. Bearing in mind that questionnaire surveys often have a rather large number of missing values, the participation rate of the AC data collections must be regarded as high. The fact that staff members, and not the residents themselves, answered the questionnaires naturally contributed to the high participation rate. Concerning the GERDA/Umeå 85+ data collection, one has to remember that many people in these high ages have serious medical or cognitive disorders. Some people even died after inclusion but before they could be interviewed. Bearing this in mind, the participation rate in this data collection must also be regarded as good, a fact that can probably be explained by the home-interview procedure. A questionnaire survey of people in these ages would probably have had a very high drop-out rate. The numbers of missing values were larger in 2000 than in 1982. This is a problem when comparing the results from the two AC data collections, but it is estimated that the missing values are fairly randomly distributed and should not therefore compromise the main findings. Some questions in the data collections also had a higher rate of missing values. It is also impossible to know whether people with or without dementia declined participation to a greater extent in the GERDA/Umeå 85+data collection and this might, of course, have affected the estimation of the prevalence of dementia, for example.

Statistical considerations

Power issues

For the AC1982 and AC2000 data collections, the sample size is judged to be sufficiently large to detect any clinically relevant differences between groups in the included variables, except if there where very few people in one of the groups of interest. The AC data collections, which were total population surveys of people in geriatric care were, if anything, over-powered. This leads to the situation that some differences, albeit highly significant, might sometimes not be relevant at all. This has to be taken into account when interpreting the data.

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In the GERDA/Umeå 85+ data collection on the other hand, which seems small compared to the AC collections, might sometimes have been under-powered for detecting relevant differences, possibly rendering so-called type II-errors.

Selection procedures

No randomization was performed in the AC1982 and AC2000 procedures. These collections were instead total population samples of the people in geriatric care in Västerbotten, making them representative even without randomization. (In some way, the procedure might thus be regarded as a random selection of 100% of the target population.) In the GERDA/Umeå 85+ data collection people aged 90 and 95 years or more were likewise total population samples. Among people aged 85 years, a semi- randomized procedure was performed in selecting every second person from the Tax Board’s population record. Initially lots were drawn to determine whether the first or second person in the record should be chosen thus minimizing the risk of systematic errors. In the Swedish personal identification number system, the first six digits represent year|month|day of birth, the following three are separation numbers and the last digit is a control digit. The third digit of the separation numbers indicates the sex of the individual, men having odd numbers and women even numbers. If, for example, one uses a selection procedure taking from the record the first person born on every day, this would produce a 55/45% overrepresentation of women. The procedure used in the GERDA/Umeå 85+ data collection did not produce any such error.

Statistical tests

For univariate statistics, Chi-square tests, t-test and the Mann-Whitney tests were used, when appropriate. The use of non-parametrical tests in Paper II was, however, unnecessary but does not make any difference. T-tests would have rendered approximately the same results, as did the Mann-Whitney tests, due to the large sample size. Multivariate statistics was used in Paper II to find factors related to antipsychotic drug use and in Paper III to control for demographic changes. The binary logistic regressions used a backward conditional selection algorithm. The use of a factor analysis to find factors to be entered into the regression model in Paper II, was motivated by the need to reduce the large number of symptoms and behaviors. Entering a large number of factors with high correlations into a regression model is problematic, as it weakens the model. The factors obtained from a rotated factor analysis are per definition un-correlated and hence suitable for entry into a regression model. The drawback is that the factors explain only one part of the total variance in the original variables, and thus some data is “lost”.

Risk of mass significance effects of multiple tests

For all three data collections and for all analyses in the papers, the use of a large number of pair-wise, univariate, comparisons has probably produced a number of type I errors, i.e. random significances. However, even if the 0.05 level was used throughout the thesis, most differences discussed were significant at much higher levels e.g. <0.001, which means a much smaller risk of type I errors.

83 DISCUSSION

In some cases, multivariate regression was used, which controls for confounding. In the interpretation of the findings in all papers, one single significant difference was not that important, instead the general pattern was investigated, and the patterns were usually supported by many different observations.

Risk of type I errors with post-hoc analyses

The hypotheses of this thesis were formulated after the collection of the data materials (post-hoc). This implies an increased risk of type I errors as there is always a risk that many possible hypotheses are tested, formally or informally, against the data set and the ones that do not hold are discarded at an early stage. Thus there is an inflated risk of type I errors associated with post-hoc data. The exact impact of this effect is, however, impossible to estimate, but post-hoc analyses should be clearly stated as such, to allow everyone to use their own judgement when interpreting the results. Extra caution is needed when the post-hoc analyses are sub-group analyses, or deal with just a few out of a large battery of outcome measures. In this thesis, most analyses performed deal with the prevalences of different drugs, behaviors and symptoms. The outcome data are presented for everyone included, which in the case of the AC data collections are whole-population samples, and sub-group analyses are only performed for well-defined and relevant groups, e.g. people with or without cognitive impairment and men and women. It is therefore estimated, that the post-hoc methodology does not interfere with the interpretation of the main findings of this thesis.

Representativeness and transferability of the results

The results from the AC2000 study probably hold true for people living in geriatric care in Sweden, possibly also for comparable western countries such as the other Nordic countries, at least if the basic characteristics, such as the proportion of people with cognitive impairment, are about the same. It is reasonable to believe that the results from the GERDA/Umeå 85+ study are fairly representative of very old people in general, in Sweden and perhaps also other comparable western countries.

84 DISCUSSION

CLINICAL IMPLICATIONS

The main findings in this thesis are that there are indications of an extensive and sometimes probably inappropriate use of nervous system drugs among old people in geriatric care, and very old people in general. People with dementia appeared to be at increased risk of receiving certain drugs, particularly antipsychotics. At the same time, there were indications of poor recognition and treatment of certain health problems, such as pain and depression, which are major causes of poor quality of life among old people. Everyone involved in the care of old people has a responsibility to contribute to the improvement in these areas. The doctors responsible should investigate the people more carefully prior to the initiation of nervous system drug treatment, and continue to follow up the treatment results. Many of the problems, which this thesis has pointed out, might be avoidable if the routines surrounding the initiation and, probably most importantly, the follow-up of drug treatments were improved. Doctors should also take the reports from the drug manufacturers with a pinch of salt, knowing that their primary goal is to make a profit, and not to improve the lives of the consumers of the drug, and they should always draw on the best available evidence when choosing a treatment. Non-pharmacological treatment strategies of, for example, behavioral disturbances in a person with dementia should be tried and evaluated more often, and all treatment should aim at improving the quality of life of the person with dementia, not simply to reduce the caregivers’ burden. The registered nurses and licensed practical nurses should be more sensitive to the symptoms and side effects among the people living in the care facilities and report them to the doctors. It is important that nursing staff are educated concerning the common symptoms of old age, and learn, for example, that depression and pain are not a part of normal aging, and should thus not be neglected. Nursing staff should also be educated and trained to deal with behavioral disturbances non- pharmacologically. For those living in their own homes as well as for people living in institutional geriatric care, recognition of disorders such as pain and depression must be improved. Again, everyone working in healthcare has a responsibility to be vigilant and ask about these conditions, so that they do not go unrecognized.

85 DISCUSSION

IMPLICATIONS FOR FURTHER RESEARCH

Changes in psychotropic drug treatment over time should be followed. For example, is the use of antidepressants stabilizing at a 40-50% level in geriatric care or will the increase continue? How large a proportion of those with dementia will receive anti- dementia drugs? Is the use of antipsychotics continuing to decrease, or will the atypical antipsychotics contribute to an increased use, even in Sweden? The prescription process, involving the people who are receiving drugs, the staff at the geriatric care settings and the prescribing doctors, needs to be elucidated, especially concerning psychotropic drugs and analgesics. Various interventions should be evaluated targeting staff knowledge, communication and evaluation of different conditions and medications, to improve drug use among old people. The area of non-cognitive symptoms among people with dementia needs to be investigated further. There is a need for better differentiation between subgroups of symptoms, and there is a need for evaluation tools that are more sensitive to subtle differences. Pathological changes in the brain of affected people need to be investigated for the different behaviors and symptoms, to better identify those who would benefit from various treatments. The different nervous system drugs need further evaluation in placebo-controlled studies and in direct comparisons between different drugs, within and between drug classes. These trials should preferably be carried out without the involvement of the manufactures of the various drugs, to ensure the credibility of the results. In the case of the behavioral and psychological symptoms of dementia, the drug trials should include a careful differentiation between different symptoms and behaviors, and evaluation of the treatment strategies and results for each one. All drugs commonly used among very old people should preferably be properly evaluated in clinical trials among those people.

86 CONCLUSIONS

CONCLUSIONS

The use of nervous system drugs is common among old people living in geriatric care and very old people in general. People suffering from dementia seem particularly to be at increased risk of receiving some nervous system drugs, such as antipsychotic drugs. The use of antipsychotic drugs for people with cognitive impairment living in geriatric care was found to be correlated to several behaviors and symptoms that are not proper indications for antipsychotic drug use, and also to factors more related to the staff and the caring situation. Considering the doubtful efficacy and known side effects associated with antipsychotics, this treatment needs particular concern. Over the course of eighteen years, from 1982 to 2000, there was a manifold increase in the use of antidepressants and anxiolytics, hypnotics and sedatives in geriatric care, but the use of antipsychotics decreased slightly. During the same period, the prevalence of several psychological symptoms decreased significantly, correcting for demographic changes. One analysis of calculated numbers needed to treat however indicated poor remission rates, suggesting that even better results might be achievable. People with moderate cognitive impairment did not improve at all regarding depressive symptoms, despite the fact that about 50% were being treated with antidepressants. One possible explanation might be that depressive symptoms have different etiologies in different stages of a dementia disorder. About a quarter of those experiencing pain in geriatric care were not receiving any regular analgesic treatment. One possible reason might be misconceptions among caring staff about whether or not the people were having analgesic treatment. Such misconceptions were found to be common. In conclusion, psychotropic and analgesic drug use among old people in geriatric care, and very old people in general, was found to be common and in many cases possibly inappropriate.

87 ACKNOWLEDGEMENTS

ACKNOWLEDGEMENTS

This study was carried out at the Department of Community Medicine and Rehabilitation, Geriatric Medicine, Umeå University, Umeå, Sweden. The study was supported financially by grants from the Umeå University Foundation for Medical Research, the Swedish Foundation for Healthcare Sciences and Allergy Research, the Field Research Centre for the Elderly in Västerbotten, the Swedish Research Council (K2005-27VX-15357-01A), the Swedish Dementia Association (Stiftelsen Demensfonden) and Erik and Anne-Marie Detlof’s Foundation, Umeå University.

I would like to thank everyone that has helped me with this thesis, and in particular:

My supervisor Yngve Gustafson, who has always supported me in my work, read it and commented on it and has always had time to discuss it with me. He has an outstanding ability to provide an encouraging word when it is needed the most and he has taught me a great deal about research and geriatrics.

Stig Karlsson, my co-supervisor, who has also helped me very much during the work on this thesis.

My co-authors, Per-Olof Sandman, Kristina Kallin and Ellinor Bergdahl who have helped me to prepare the manuscripts and given valuable commentaries on the texts. A special thank to Per-Olof Sandman for letting me use and analyze the fantastic AC materials, on which so much of this thesis is based.

My present and former colleagues at the Department of Geriatric Medicine: Håkan Littbrand, Birgitta Olofsson, Mikael Stenvall, Lena Molander, Mia Conradsson, Ellinor Bergdahl, Kristina Kallin, Gustaf Bucht, Tony Pellfolk, Eva Elgh, Nina Lindelöf, Karin Gladh, Maria Lundström, Maine Carlsson, Staffan Eriksson, Martin Gustafson, Petra von Heideken Wågert, Erik Rosendahl, Sture Eriksson and Undis Englund.

My co-workers from the Umeå 85+ inland 2007 Malå and Storuman data collection tour: Kerstin Gustavsson, Johan Mattilas and Robert Linder.

Lisbeth Fagerström, Magdalena Vähäkangas, Anne Hietanen, Ellinor Bergdahl, Maria Lundström and Mia Conradsson for their work with the GERDA/Umeå 85+ data collection.

My co-workers at the Geriatric Centre at Umeå University Hospital: The staff on Wards 1, 2, 3 and 4, all the medical secretaries and all the doctors.

Patricia Schrimpton for careful language revision of manuscripts and the thesis.

88 ACKNOWLEDGEMENTS

My friends from the collectives of the Foggy pig and the TV-mast: Nils Boman, Petter Karlsson, Ola Ling, Pär Parbring, Mikael Holmgren, Gustaf Löfgren, Viveca Luc and Martin Solymar.

Nils Boman, who first came up with the idea that I should study medicine. All other friends in the great county of Västerbotten and the rest of Sweden.

My family, Anders Lövheim, Christina Fahlgren-Lövheim, Ivar Lövheim and Jona Lövheim.

My relatives: grandparents, uncles and aunts, cousins and their spouses and children, and family-in-law to be, and last, but not least my fiancée Eva Maaherra.

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104 APPENDIX

APPENDIX 1, THE MULTI DIMENSIONAL DEMENTIA ASSESSMENT SCALE, BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS

105 APPENDIX

APPENDIX 1, THE MULTI DIMENSIONAL DEMENTIA ASSESSMENT SCALE, BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS, ENGLISH TRANSLATION

BEHAVIORS, PSYCHOLOGICAL SYMPTOMS (Mark with an “X”) Every day Sometimes Never /week

87 Takes things from fellow patients’ drawers    and cupboards 88 Packs up his/her things, is often    on the way home 89 Often stands at the other door and wants out    90 Mixes up food    91 Eats potted soil, cigarette butts etc    92 Undresses in the dayroom    93 Unruly in bed, throws bedclothes on the floor    94 Wanders alone or with other    patients back and forth 95 Piles up chairs, pushes tables,    upends furniture etc 96 Urinates in wastepaper baskets, washbasins    or on the floor 97 Spits out medicine    98 Speaks spontaneously with staff or patients    99 Shrieks and shouts continuously    100 Smears faeces on clothes, furniture etc    101 Constantly seeks attention of the staff    102 Eat other’s food    103 Will not go and sleep    104 Disturbed sleep at night    105 Goes and lies in other patients’ beds    106 Hits patients/staff    107 Aggressive threats (words or gestures)    to patients, staff 108 Tears up newspapers etc    109 Hides things    110 Rolls up table cloth    111 Resists being dressed and undressed    112 Sad    113 Cries    114 Disturbed and restless    115 Easily annoyed    116 Suspicious    117 Hallucinates (visional)    118 Hallucinates (auditory)    119 Fearful   

106 APPENDIX

120 Speaks to him/her self    121 Complaining    122 Takes initiative    123 Cooperates    124 Seeks help    123 Overactive (“manic”)   

Note: From Sandman Per-Olof, Aspects of institutional care of patients with dementia. Umeå University Medical Dissertations, New series No. 181, 1986, Umeå 1986. The translations of some of the items differs slightly from the ones presented in the papers and in the tables.

107 APPENDIX

APPENDIX 2, THE GOTTFRIES’ COGNITIVE SCALE

108 APPENDIX

APPENDIX 2, THE GOTTFRIES’ COGNITIVE SCALE, ENGLISH TRANSLATION

ASSESSMENT OF ORIENTATION ABILITIES (NB! Answer to every question (even if you are unsure about it) Yes No 126 Knows his first name   127 Knows his family name   128 Knows his age   129 Knows his birthday   130 Knows the year of his birth   131 Knows the name of relatives   132 Knows the name of at least some of the staff   133 Knows the name of at least one fellow patient   134 Knows that he/she is in a hospital   135 Knows the name of the hospital   136 Knows in which town the hospital is situated   137 Knows where he/she has lived before   138 Recognizes his relatives   139 Knows something of relatives’ present conditions   140 Knows the season   141 Knows the date   142 Knows the day of the week   143 Knows the month   144 Knows the year   145 Knows where the lavatory of the department is   146 Knows where the kitchen of the department is   147 Knows where his bed is   148 Can distinguish between patients and staff   149 Understands when there are visitors   150 Understands about mails, letters, cards   151 Can distinguish between his own and other people’s things   152 Knows the hours of the meals  

Note: From Sandman Per-Olof, Aspects of institutional care of patients with dementia. Umeå University Medical Dissertations, New series No. 181, 1986, Umeå 1986.

109