Use and safety of psychotropic drugs in elderly patients
Gianluca Trifi rò
Th e work presented in this thesis was conducted both at the Department of Medical
Informatics of the Erasmus Medical Center, Rotterdam, Th e Netherlands and the Depart-
ment of Clinical and Experimental Medicine and Pharmacology of University of Messina,
Th e studies reported in chapter 2.2 and 4.3 were respectively supported by grants from the
Italian Drug Agency and Pfi zer.
Th e contributions of the general practitioners participating in the IPCI, Health Search/
Th ales, and Arianna databases are greatly acknowledged.
Financial support for printing and distribution of this thesis was kindly provided by
IPCI, SIMG/Health Search, Eli Lilly Nederland BV, Boehringer-Ingelheim B.V., Novartis
Pharma B.V. and University of Messina.
Cover design by Emanuela Punzo, Antonio Franco e Gianluca Trifi rò. Th e background
photo in the cover is a landscape from Santa Lucia del Mela (Sicily) and was kindly pro-
vided by Franco Trifi rò. Th e photo of the elderly person is from Antonio Franco Trifi rò.
Layout and print by Optima Grafi sche Communicatie, Rotterdam, Th e Netherlands.
Use and Safety of Psychotropic Drugs in Elderly Patients
Gebruik en veiligheid van psychotropische medicaties
in de oudere patienten
ter verkrijging van de graad van doctor
aan de Erasmus Universiteit Rotterdam
op gezag van de rector magnifi cus
Prof.dr. S.W.J. Lamberts
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden
op vrijdag 26 juni 2009 om 11.00 uur
Gianluca Trifi rò
geboren te Messina (Italy)
Prof.dr. M.C.J.M. Sturkenboom
Prof. A.P. Caputi
Overige leden: Prof.dr. G. Gambassi
Prof.dr. B.H.Ch. Stricker
Dr. D.W.J. Dippel
To my Mother
Rationale for this research
Aim and outline of the Th esis
Antipsychotic drugs in elderly: use and safety
Antipsychotic prescribing pattern among Italian general
practitioners: a population-based study during 1999-2002 years.
Prescribing pattern of antipsychotic drugs in Italian general
population: focus on elderly with dementia during the years
Risk of stroke with typical and atypical anti-psychotics: a
retrospective cohort study including unexposed subjects.
All-cause mortality associated with atypical and typical
antipsychotics in demented outpatients.
Fatal and non fatal community acquired pneumonia associated
with antipsychotic drug use in elderly patients.
Safety of antipsychotics in elderly patients with dementia: atypical
and conventional agents have the same risks?
Antidepressant drugs in elderly: use and safety
Antidepressant drugs: prevalence, incidence and indication of use
in general practice of Southern Italy during the years 2003-2004.
Risk of ischemic stroke associated with antidepressant drug use in
Preventing drug interactions with antidepressants in the elderly.
Anti-Parkinson drugs in elderly: use and safety
Prescribing pattern of Anti-Parkinson drugs in Southern Italy:
cross-sectional analysis in the years 2003-5.
Burden of cardiovascular diseases in elderly with Parkinson’s
disease who start a dopamine agonist agent.
Th e risk of cardiac valve regurgitation with ergot and non-ergot
derived dopamine agonist use in Parkinson’s disease.
5. General discussion
Summary of the thesis
About the author
1.1. RATIONALE FOR THIS RESEARCH
Late life neuropsychiatric disorders
By 2050 we expect two billion persons over 65 years worldwide. As the propor-
tion of the world’s population in the older ages continues to increase, the burden
of Alzheimer’s disease (AD), Parkinson’s disease (PD) and other neuropsychiatric
disorders increase as well. Th e percentage of persons with Alzheimer’s disease
increases from 1 of 60-year-olds to about 30 of 85-year-olds .
Prevalence studies estimated that 24.3 million people have currently dementia
worlwide, with 4.6 million new cases of dementia every year (one new case every
7 seconds). Th e number of people aff ected by dementia will double every 20 years
to 81.1 million by 2040 .Th e prevalence of Parkinson’s disease in persons above
65 years is 1.8 in Europe, with an increase from 0.6 in those aged 65 to 69 years
to 2.6 in those 85 to 89 years .
Alzheimer’s disease is a progressive neurodegenerative disorder manifested by
cognitive and memory deterioration leading to progressive impairment of ac-
tivities in daily living. Behavioral and psychotic symptoms of dementia (BPSD),
including agitation, aggression, and psychoses, frequently occur in patients with
dementia, particularly in advanced stages of the disease .
Parkinson’s disease is primarily considered a motor disease characterized by rest
tremor, rigidity, bradykinesia and postural disturbances. However, neuropsychiat-
ric complications, including mood and anxiety disorders, fatigue, apathy, psycho-
sis, cognitive impairment, dementia, sleep disorders and addictions, frequently
complicate the course of the illness .
Independent of these well defi ned neurodegenerative diseases, a variety of
psychiatric disturbances commonly occur in advanced age, ranging from depres-
sive symptoms to anxiety and psychotic disorders. Th e prevalence of depressive
symptoms is 5–13, but depression in elderly is often under-diagnosed and under-
Anxiety disorders aff ect up to 20 of the community-dwelling elderly .
Th e prevalence of psychotic symptoms (i.e. hallucinations and delusions) in the
geriatric population ranges from 0.2 to 4.8 in an outpatient setting, and are as
high as 10–63 in elderly living in nursing home .
Overall, late life neuropsychiatric disorders are disabling conditions that result
in a lower quality of life of elderly patients and their caregivers, earlier institution-
alization, and excess mortality.
Use of psychotropic drugs in elderly
Appropriate and judicious use of psychotropic drugs may dramatically improve
the quality of life and functional status of many elderly patients with neuropsy-
chiatric disorders [10-12].
However, the decision to prescribe a psychotropic agent in elderly patients is a
complex issue for a number of reasons. First, randomized clinical trials (RCTs) of
psychotropic drugs in geriatric patients with mental illnesses are very scarce. Only
recently a number of RCTs of mostly atypical antipsychotics have been conducted
in demented patients . Second, due to signifi cant diff erences in pharmacoki-
netic and pharmacodynamic profi les, fi ndings from RCTs of psychotropic drugs
in younger persons may not be directly generalized to the geriatric population.
Drug metabolism and clearance can be signifi cantly reduced in older patients, as
a result of impaired liver and renal functionality, which increases the potential for
adverse drug reactions [14-16].
Th ird, the dose response eff ect is diff erent in older patients since not only phar-
macokinetics but also the pharmacodynamics change. Despite all these diffi culties
and the increased susceptibility to adverse drug reactions in elderly, one in fi ve
community-dwelling elderly persons receives currently psychotropic medications
, and this rate is even higher in nursing home and long term facilities setting,
where psychoactive agent overuse and disuse is the leading cause of preventable
adverse drug reactions .
A brief overview of current knowledge and guidelines regarding the use and
recommendations of specifi c psychotropic drugs (antipsychotics, antidepressants
and anti-Parkinson drugs) in elderly is presented below.
Antipsychotic (AP) drugs (comprising conventional and atypical agents) are widely
used in late life psychiatric disorders, such as psychoses, agitation and behavioral
and psychological symptoms of dementia .
During the last two decades, the atypical antipsychotics, such as olanzapine,
risperidone and quetiapine, have started to replace the older conventional anti-
psychotics, like phenothiazine (i.e. thioridazine and chlorpromazine) and buty-
rophenones (i.e. haloperidol) in the pharmacological management of psychotic
Several practice guidelines recommend atypical antipsychotics as the fi rst line
option in the treatment of chronic psychoses .
Reason is the better safety profi le of atypicals as compared to conventional
antipsychotics, especially regarding extrapyramidal adverse events .
However, the increasing use of atypical antipsychotics has resulted in a grow-
ing number of safety alerts, especially regarding off -label use. Based on a pooled
analysis of available randomized placebo-controlled clinical trials (RCTs), the
UK Committee on Safety of Medicines (CSM) has highlighted a 3-fold increased
risk of cerebrovascular events in elderly with dementia, who were treated with
risperidone or olanzapine in March 2004 .
In April 2005, another warning was issued by the Food and Drug Administra-
tion (FDA) to inform health professionals about the results of a pooled analysis
of 17 RCTs reporting a 1.7 times increased risk of all-cause mortality associated
with atypical antipsychotic use in elderly dementia patients . Cerebrovascular
events, pneumonia and arrhythmias were the most frequently reported causes of
death. In June 2008, the FDA extended this warning also to the typical anti-
Th ese safety alerts have ignited a very animated debate in the scientifi c com-
munity. Some authors judged the warnings on atypical antipsychotics as unneces-
sarily alarming and potentially detrimental for elderly patients with dementia, in
light of a possible more widespread use of conventional antipsychotics, as recently
documented by a Canadian study .
Given the extent of use and the safety concerns, epidemiologic evidence on
the use and the risks of antipsychotic drugs in the geriatric population is urgently
Antidepressants (ADs) are frequently prescribed for the treatment of depressive
symptoms and anxiety disorders in elderly. Initially, the tricyclic antidepressants
(TCAs) were mainly used for these indications, despite TCAs have poorly toler-
ated in elderly, mostly due to their anticholinergic eff ects.
Th e introduction of selective serotonin reuptake inhibitors (SSRIs) in the 80s
has markedly changed the management of depression in elderly [28-29]. SSRIs,
including sertraline, fl uoxetine, paroxetine, fl uvoxamine, citalopram, and escit-
alopram, are currently considered as fi rst-line drugs in the treatment of late-life
depression, due to similar effi cacy but more favorable tolerability, compared to
other antidepressants [30-31]. However, concerns about the safety of SSRIs are
growing, due to their anti-platelet activity which may increase the risk of bleeding
SSRIs decrease intracellular contents of serotonin in platelets by blocking sero-
tonin transporter 5-HTT, thus inhibiting platelet function. Of particular interest
is the relationship between antidepressant drug use and risk of both hemorrhagic
and ischemic cerebrovascular events. Th ese associations are diffi cult to study since
depression may be a risk factor and result of (minor) stroke . Some previous
studies failed to demonstrate an association between use of SSRIs and hemorrhagic
stroke [35-37], while epidemiologic evidence on the risk of ischemic stroke in
elderly patients is currently missing. Studying this relationship in an observational
setting is complicated since elderly patients that are treated with antidepressants
often have several cardiovascular risk factors and take many concomitant medica-
Polypharmacy may predispose elderly patients using antidepressants to develop
drug-drug interactions. Older compounds, such as TCAs or Monoamine oxidase
inhibitors (MAOIs), acting on a broad range of receptors and enzymes have a
greater potential to interact pharmacodynamically with other medications aff ect-
ing the same system(s) than newer agents (SSRIs) which have a more specifi c
mechanisms of action . On the other hand, SSRI use in the elderly is associated
with the possibility of clinically relevant pharmacokinetic interactions with other
medications due to their inhibitory eff ect on CYP enzymes. Th e diff erential eff ects
of various SSRIs on CYPs are well characterized in vitro, with the potential to
interact with other drugs being greater for fl uvoxamine, fl uoxetine and paroxetine
and lower for sertraline, citalopram and escitalopram [39-40].
Th erefore, the potential for drug-drug interactions should guide the selection
of an appropriate antidepressant in elderly. Comprehensive reviews of antidepres-
sant drug interactions in the elderly have been published, allowing for a better
Levodopa (L-Dopa) is the most eff ective drug for the treatment of Parkinson’s
disease (PD), although this medication is associated with limiting and poorly
tolerated motor and non-motor side eff ects, particularly, in the advanced stages
of the disease . Other anti-Parkinson drugs (APDs) are commonly used in
clinical practice, either as monotherapy or as adjunctive therapy with L-Dopa,
to delay or reduce its motor and non-motor complications and to maximise drug
eff ectiveness: ergot-derived (i.e. cabergoline, pergolide, and bromocriptine) and
non ergot-derived (i.e. ropinirole and pramipexole) dopamine agonists (DAs),
anticholinergic drugs, amantadine, selegiline and catecol-O-methyltraserase
(COMT) inhibitors .
Dopamine agonists have been increasingly used as monotherapy in early PD to
delay the start of L-Dopa treatment in the last decade . Since 2002, a number
of case reports of fi brosis valvular heart disease associated with pergolide and there-
after also with cabergoline have been published. Th is association was confi rmed by
several prevalence echocardiographic studies in patients with Parkinson’s disease.
15 Download full-text
However, only one study looked at clinically diagnosed cardiac valve fi brosis us-
ing data from an electronic health record database [46-49]. Laboratory studies
indicate that the eff ects of dopamine agonists may be linked to the activation of
the serotonin 5-HT2B receptor .
Since some ergot derived DAs are strong agonists of 5-HT2B receptors, fi brotic
valvular damage is thought to occur through preferential activation of this recep-
tor expressed on heart valves.
As a consequence of the growing evidence about the risk of fi brotic heart valve
disease, pergolide was withdrawn from the US market, and cabergoline as well as
pergolide are now second line treatment for PD in Europe, and their use requires
On the basis of these health policy interventions, a dramatic impact on the
prescribing pattern of anti-Parkinson drugs is expected in the following years.
1.2. AIM AND OUTLINE OF THE THESIS
Th e general objective of the research described in the present thesis was to ob-
tain a better understanding of the use and safety of antipsychotic (chapter 2),
antidepressant (chapter 3), and anti-Parkinson drugs (chapter 4) in community
dwelling elderly patients.
Specifi cally, with respect to antipsychotic drugs, we fi rst analysed the trends
in prescriptions in Italy with a special focus on patients with dementia (chapter
2.1). In the same setting it was measured if the safety warnings that have been
issued by regulatory agencies changed the prescribing pattern of antipsychotics
in elderly demented patients in the recent years (chapter 2.2). Th ese safety alerts,
together with a growing number of observational studies, questioned the actual
tolerability of atypical and typical antipsychotic use in elderly patients. To further
assess the safety risks, we fi rst investigated the risk of stroke associated with the
use of diff erent antipsychotic drugs in Italy by using the electronic health record
database Health-Search/Th ales (HS) (chapter 2.3). Second, we analysed the risk
of all cause mortality (chapter 2.4) and fatal and non-fatal pneumonia (chapter
2.5) in association with atypical either typical antipsychotics in a cohort of elderly
outpatients, using data from the Integrated Primary Care Information (IPCI),
which is a Dutch general practice database. Finally, we conducted a comprehensive
review of the the safety of atypical and typical antipsychotics in elderly demented
patients (chapter 2.6).
Regarding antidepressant drugs, we analysed their prescribing pattern in adults
and elderly persons in Italian general practice (chapter 3.1). Subsequently we as-