human psychopharmacology

Hum Psychopharmacol Clin Exp 2003; 18: 185–190.

Published online 11 December 2002 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hup.467

REVIEW

Use of paroxetine for the treatment of depression and anxiety

disorders in the elderly: A review
Michel Bourin*1,2
1
Neurobiology of Anxiety and Depression, Faculty of Medicine, Nantes, France
2
Neurochemical Research Unit, University of Alberta, Edmonton, Alberta, Canada

Paroxetine is a potent selective serotonin reuptake inhibitor (SSRI) with indications for the treatment of depression, obsessive–
compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post-
traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. There is wide interindividual variation in the
pharmacokinetics of paroxetine in adults as well as in the elderly with higher plasma concentrations and slower elimination
noted in the latter. Elimination is also reduced in severe renal and hepatic impairment, however, serious adverse events are
extremely rare even in overdose. A Pub Med search was used to collect information on the efficacy and tolerability in elderly
patients. There are few studies of depression in the elderly and only one study in the old–old. In anxiety disorders including
general anxiety disorder, panic disorder, obsessive–compulsive disorder and social anxiety, there are no studies at all in the
elderly. However, the safety of the drug allows its prescription in the elderly. In summary, paroxetine is well tolerated in the
treatment of depression in those between the ages of 65 and 75, although few studies have examined its use in those of 75 and
older. Copyright # 2002 John Wiley & Sons, Ltd.

key words — paroxetine; elderly; depression; generalized anxiety disorder; obsessive–compulsive disorder; panic disorder;
social phobia

INTRODUCTION (Marazziti et al., 2001). In elderly patients, plasma

Paroxetine is the most potent inhibitor of 5-HT reup-
take of all the currently available antidepressants. Its
effect on norepinephrine (NE) uptake is much lower
although greater than that of any of the other SSRIs.
Paroxetine’s inhibition of NE uptake may contribute
to its better efficacy at higher doses (Redrobe et al.,
1998). The pharmacological profile of the 5-HT trans-
porter is not modified qualitatively by age, but quan-
titative changes in its affinity occur with paroxetine,
pKi values decrease in elderly subjects of both sexes
* Correspondence to: Dr M. Bourin, Neurobiology of Anxiety and
Depression, Faculty of Medicine, BP 53508, 44035 Nantes, Cedex 1,
France. E-mail: mbourin@sante.univ-nantes.fr
concentrations of paroxetine at steady state are higher
and the terminal elimination half-life is longer than
those reported in younger subjects (Budman et al.,
1995). The large degree of interindividual variability
in the pharmacokinetics of paroxetine previously
described is seen in different age groups (Lundmark
et al., 1989). However, it is advised that elderly
patients start on lower doses of paroxetine. Table 1
shows the pharmacokinetic parameters in the elderly
across a dose range of 15–30 mg (single dose).
Paroxetine is approved for the treatment of depres-
sion world-wide and is one of the SSRIs prescribed
most. It demonstrates a broad spectrum of efficacy
and it has been extensively studied in depression as
well as being approved for the treatment of obsessive–
compulsive disorder (OCD), panic disorder (PD) and

Copyright # 2002 John Wiley & Sons, Ltd. Received 16 July 2002
186
Table 1. Pharmacokinetic parameters of paroxetine in the elderly
after oral administration of single doses of paroxetine over the range
20–30 mg (mean values). Adapted from Bourin et al., 2001
Dose (mg) 15 20
Cmax (ng/ml) 36.3 16.7
Cmin (ng/ml) 15.9 6.9
tmax (h) 4.0 5.3
t½ (h) 25.7 21.2
AUC (ng.h/ml) 103 546
social anxiety (SA) in different countries. It is also
used in the treatment of generalized anxiety disorder
(GAD), post-traumatic stress disorder (PTSD), pre-
menstrual dysphoric disorder, diabetic neuropathy,
vaso-vagal syncope and chronic headache (Bourin
et al., 2001).
Depression and anxiety disorders including GAD
are frequent in elderly people. The prevalence of
depression in that population is around 15%. The dif-
ficulty of treating elderly patients is linked to the high
level of co-morbidity including psychiatric and
somatic illness. Another problem is the lack of clinical
trials in old–old patients, i.e. more than 75 years old.
The target of the present paper is to give a review
using a Pub Med search of the use of paroxetine in
the treatment of depression and anxiety disorders in
elderly patients as defined previously and to make
proposals for the use of the drug in this category of
patients.
CLINICAL STUDIES OF EFFICACY
There are few studies on the efficacy of paroxetine in
treating depression in patients aged 65 to 75 and only
one in old–old patients. In anxiety disorders there are
no studies available in the elderly. Paroxetine is not
alone in this among the other SSRIs.
DEPRESSION
Depression is a disabling illness with a marked impact
on occupational and social functioning given its high
prevalence (Keller et al., 1992). It is associated with
significant morbidity and mortality (Goodwin and
Jamison, 1990). Clinically significant depression
affects some 15% of the elderly population (Menting
et al., 1996). Treatment of depression in the elderly
is often complicated by physical co-morbidity
(Guillibert et al., 1989), multiple concomitant
medications and alterations in drug absorption and
Copyright # 2002 John Wiley & Sons, Ltd.
m. bourin
metabolism with age (Dunner, 1994). Elderly patients
are therefore more susceptible than younger adults to
adverse effects and drug–drug interactions, requiring
30 cautious and rational antidepressant therapy (Kamath
et al., 1996).
47.0
10.8 The main problem with all the studies reviewed is
3.2 that the age of the patients was up to 60 or 65 years but
28.3 it is difficult to know how many patients were up to
348 75, and if this oldest population responds to SSRIs.
Most studies included patients up to 60 years old but
with few patients up to 75 (Muijsers et al., 2002).
More often there are recommendations for safety with
no data on the efficacy in old–old patients (Preskorn,
1993; Cassano et al., 2002). Even a meta-analysis
(Mittmann et al., 1997) was not convincing because
of the age of the patients (60 and more).
Paroxetine has been shown to have equivalent effi-
cacy to amitriptyline in elderly patients with an appar-
ently earlier onset in three studies (Geretsegger et al.,
1995; Mulsant et al., 1999; Hutchinson et al., 1992).
A comparison of paroxetine and fluoxetine in 106
depressed elderly outpatients favoured paroxetine,
although the overall response rates were quite low
(Schöne and Ludwig, 1993). Both drugs improved
cognitive functioning but paroxetine had an earlier
onset of effect (Katona et al., 1998; Schnyder,
1996). On the other hand, there was an accelerating
response of paroxetine in geriatric depression com-
bined with sleep deprivation (Bump et al., 1997).
In a meta-analysis of ten studies in elderly patients,
paroxetine (n ¼ 387) was as effective an antidepres-
sant as active controls (amitriptyline n ¼ 110; clomi-
pramine n ¼ 109; doxepin n ¼ 102; mianserin
n ¼ 28) after 5/6 weeks, but the end point of the stu-
dies is unknown (Dunbar, 1995). In a recent extensive
review of 20 randomized trials comparing the acute
efficacy of tricyclics and SSRIs in more than 1500
older depressed outpatients it was concluded that they
have a similar efficacy, but that SSRIs may be better
tolerated, given that the dropout rates for SSRIs were
one third to one half lower than the drop out rate with
tricyclics (Schneider, 1996).
Elderly patients are vulnerable to a recurrence of
depression and benefit from long term antidepressant
therapy. Physicians increasingly use SSRIs as mainte-
nance therapy, however, there is only one study
(Bump et al., 2001) showing that paroxetine was as
efficacious as nortriptyline in the prevention of relapse
and recurrence over an 18 month period.
A study examined whether paroxetine produces
cognitive toxicity in elderly patients suffering from
a major depressive episode (Nebes et al., 1999).
Measures of attention and cognitive speed showed a
Hum Psychopharmacol Clin Exp 2003; 18: 185–190.
 paroxetine in elderly
significant improvement with treatment, while mem-
ory remained unchanged, the slight increase in serum
anticholinergicity seen in some elderly patients did
not impair cognitive function, even in patients with
a preexisting cognitive impairment.
More recently a randomized double-blind placebo-
controlled 8-week trial compared paroxetine and pla-
cebo in very old nursing home residents with non-
major depression (Burrows et al., 2002). The main
outcome measure was the primary nurse’s clinical
impression of change (CGI-C). Additional outcome
measures were an improvement on the interview-
derived Hamilton depression rating scale (HDRS)
and Cornell scale for depression (CS) scores.
Twenty-four subjects with a mean age of 87.9 were
enrolled and 20 subjects completed the trial. The pla-
cebo response was high, and when all subjects were
considered, there were no differences in improvement
between the paroxetine and placebo groups. Paroxe-
tine was not clearly superior to placebo in this small
study of very old nursing home residents with non-
major depression, and there was a risk of adverse cog-
nitive effects. Because of the high placebo response
and the trend towards improvement in the more
severely ill patients, it is possible that a larger study
would have demonstrated a significant therapeutic
effect for paroxetine compared with placebo. This
study also illustrates the discordance between patient
and caregiver ratings, and the difficulties in studying
very elderly patients with mood disorders.
The relationship of the serotonin transporter gene
promoter region polymorphism (5-HTTLPR) with
antidepressant response was examined in elderly
patients receiving paroxetine or nortriptyline (Pollock
et al., 2000). Patients were treated for up to 12 weeks
and assessed weekly with clinical ratings and measure-
ments of plasma drug concentrations. Twenty-one of
the paroxetine-treated subjects were found have the
ll genotype and 30 had at least one s allele. During
treatment with paroxetine, the mean reductions from
baseline in HRSD were significantly more rapid for
patients with the ll genotype than for those possessing
an s allele, despite equivalent paroxetine concentra-
tions. The onset of response to nortriptyline was not
affected. Allelic variation of 5-HTTLPR may contri-
bute to the variable initial response in patients treated
with an SSRI. This study is in accordance with two
animal studies comparing SSRIs with TCAs (Bourin
et al., 1998; David et al., 2001) in young and old mice
in a behavioral test. In conclusion, among the studies
published in the literature there were none on the effi-
cacy of any SSRI in the treatment of depression in
old–old patients.
Copyright # 2002 John Wiley & Sons, Ltd.
187
ANXIETY DISORDERS
There is evidence to suggest that anxiety disorders are
at times under-diagnosed and under-treated in aged
patients (Sheikh, 1996). Epidemiological studies
show that 25% of patients over 65 years old in old
folks residences are often treated with benzodiaze-
pines. Few quality of life studies concerning aged peo-
ple have been performed, although anxiety symptoms
have been associated with a mortality increase, all
causes disconcerted and notably sudden cardiac
deaths. It is also known that anxious people use the
medical services more than others (Lindesay, 1991).
There are no special studies in old–old patients so it
was necessary to extrapolate from young adult
patients studies.
Generalized anxiety disorder
There is evidence that tricyclic antidepressants are at
least as effective as benzodiazepines in the treatment
of GAD. Furthermore, the positive results obtained
with tricyclics have not been translated into clinical
popularity in the treatment of GAD perhaps due to
the side effect profile and life threatening potential in
overdose. Paroxetine, at a dose of 20 mg/day, was com-
pared with a benzodiazepine in a pilot study of DSM-
IV defined GAD (Rocca et al., 1997). For the first 2
weeks of treatment, the benzodiazepine demonstrated
greater efficacy, but from week 4 (the next protocol
defined assessment time), both paroxetine and the tri-
cyclic were more effective in reducing symptoms.
Paroxetine at a mean dose of 20 mg/day, in another
pilot study, was found to improve the scores of various
items of the temperament and character inventory in
DSM-IV defined GAD patients, specifically harm
avoidance, novelty seeking, self-directedness and
cooperativeness (Allgulander et al., 1998). A more
recent study (Pollack et al., 2001) showed clearly that
paroxetine in doses of 20 to 50 mg once daily was
effective in patients with GAD; improvement of core
symptoms of GAD occured early and was associated
with a significant reduction in disability after only 8
weeks of treatment.
There is no special study of paroxetine in the
elderly presenting with GAD so it seems that 20 mg
daily is sufficient.
Panic disorder
Panic disorder is an incapacitating condition with long
term negative consequences. Lifetime prevalence is
estimated between 1.5% and 3% and may be up to
more than 15%.
Hum Psychopharmacol Clin Exp 2003; 18: 185–190.
188 m. bourin
In patients with panic disorder with or without
agoraphobia, paroxetine, 10–60 mg/day, significantly
reduced the frequency of panic attacks and led to a
greater improvement in generalized anxiety and pho-
bic avoidance compared with placebo (Ballenger
et al., 1998). Response to paroxetine was evident after
3–4 weeks and its efficacy in reducing panic attack
frequency was maintained for up to 48 weeks. Treated
patients continued to show improvement and demon-
strated a lower risk of relapse (Oehrberg et al., 1995).
In the treatment of panic disorders with or without
agoraphobia, it is recommended to start paroxetine at
a dose of 10 mg/day as a single morning dose and to
increase the dose by 10 mg/day increments on a
weekly basis to a maximum of 40 mg/day in elderly,
debilitated or patients with severe renal or hepatic
impairment. In adults, the usual effective dose is
around 40 mg/day and this dose was found to be sig-
nificantly better than placebo in achieving a panic-free
state, while 10 to 20 mg/day was associated with a sta-
tistical trend.
After 6–12 months of treatment, an attempt to taper
and to discontinue the drug is suggested. If the patient
experiences relapse, the treatment should be started
again.
Obsessive–compulsive disorder
Obsessive–compulsive disorder (OCD) is a chronic
and disabling condition. Its lifetime prevalence is esti-
mated to be between 2% and 4%. Paroxetine at a dose
of 20–60 mg/day, significantly reduced the scores on
the Yale-Brown obsessive–compulsive scale com-
pared with placebo (Zohar and Judge, 1996).
Response to paroxetine was apparent after 2 weeks
and more significant after 6 weeks. Its efficacy was
maintained for up to 12 weeks. Paroxetine, 20–
60 mg/day, was at least as efficacious as clomipra-
mine, 50–250 mg/day.
In the treatment of OCD, it is recommended to start
paroxetine as a single morning dose of 10 mg/day and
to increase the dose by 10 mg/day increments on a
weekly basis up to a maximum of 60 mg/day in adults
or up to 40 mg/day in elderly, debilitated or patients
with severe renal or hepatic impairments. In adults
the usual effective dose is around 40 mg/day. Paroxe-
tine appears to be a possible first-line treatment for
OCD given that its efficacy is comparable to that of
clomipramine but it is significantly better tolerated.
The drop-out rate related to adverse events was signif-
icantly lower, 9% for paroxetine versus 17% for clo-
mipramine.
Copyright # 2002 John Wiley & Sons, Ltd.
Social anxiety
Social anxiety, usually starts in adolescence around
15–16 years of age and follows a continuous and
chronic course. It is an anxiety associated with social
and performance situations leading to physical symp-
toms including blushing, sweating, tremor and fre-
quently avoidance behavior and negative cognitive
interpretations abuse and suicide attempts. Lifetime
prevalence is high ranging from 10% to 15%.
In patients with social phobia, as defined by
DSM-IV, paroxetine at a dose of 20–60 mg/day,
improved the clinical severity of symptoms signifi-
cantly better than placebo (Baldwin et al., 1999). The
onset of action occurred after 2 weeks, the improve-
ment with paroxetine was clearly demonstrated from
weeks 3 and 4, to week 12 (end of the trial). The super-
iority of paroxetine was demonstrated also in terms of
number of patients responding (Stein et al., 1996,
1999). All doses of paroxetine were significantly better
than placebo but there was no significant difference
between 20, 40, 50 or 60 mg/day (Mancini and Van
Ameringen, 1996). It is possible to prescribe only
20 mg or less in the elderly.
ADVERSE EFFECTS AND TOLERABILITY
In the treatment of depression and anxiety disorders,
avoiding particular side effects is an important factor
influencing the choice of drug. Some side effects may
pose serious risks for the health of the patient, e.g. car-
diac arrhythmia, while others may interfere with daily
activities, e.g. driving. Side effects impact negatively
on compliance and therefore the response to treat-
ment. One study of tolerance was performed in 16
non-hospitalized depressed patients, aged 72–86 years
(Ghose, 1997). Patients were randomly selected to
receive either 15 or 30 mg daily for 42 days in a
double-blind study. At the dosages used, no changes
in blood pressure, heart rate, salivary volume, visual
choice reaction time, critical flicker fusion threshold
and short term memory were observed in these
patients. There were four drop-outs during the first
week due to a lack of motivation, skin rash and upper
gastrointestinal symptoms (n ¼ 2).
In GAD, patients receiving paroxetine at a dose of
20 mg/day did not show any significant difference in
premature study terminations due to adverse effects
than patients treated with diazepam (Rocca et al.,
1997). Nausea was more frequent with paroxetine
and drowsiness more frequent with the benzodiaze-
pine. In comparison with a tricyclic, paroxetine
patients experienced fewer side effects; constipation,
Hum Psychopharmacol Clin Exp 2003; 18: 185–190.
 paroxetine in elderly
drowsiness and dry mouth were more frequent with
the tricyclic. Side effects tended to diminish after
the first week of treatment. Dry mouth was more fre-
quently reported with paroxetine doses of 40 mg/day
versus doses of 20 mg/day and placebo. This was also
true but to a lesser extent for diarrhoea, sweating,
asthma and tremor depending on the studies. No clini-
cally significant change in vital signs or laboratory
parameters was reported. An upward titration of the
dose of paroxetine at the beginning of treatment
appeared to avoid early treatment-related jitteriness
or anxiety-like symptoms that have been described
with SSRIs. During long term treatment, weight gain
with paroxetine, was greater than with placebo, but
significantly less than with clomipramine.
Treatment with paroxetine is not associated with
the development of DSM-IV criteria for physical or
psychological dependence. However, abrupt disconti-
nuation after 12 weeks treatment in panic disorder
patients with a 10–60 mg daily dose of paroxetine,
resulted in at least one symptom such as dizziness,
sweating, flu-like symptoms, nausea, diarrhoea,
insomnia, tremor, fatigue, headache, agitation, visual
phenomena and confusion being reported in 34.5% of
paroxetine treated patients versus 13% of placebo
treated patients. Most of the adverse events were not
clinically significant. In contrast, tapered discontinua-
tion over 3 weeks in panic disorder patients previously
treated with paroxetine, 20–60 mg/day for up to 48
weeks, was not associated with adverse events.
Knowledge of drug–drug interactions may also be
clinically very important, a summary of reported
and potential drug interactions is provided in Table 2.
Table 2. Reported and potential drug interactions with paroxetine
Increased adverse events
Antidepressants (desipramine, imipramine, nortriptyline, ami-
triptyline, trimipramine)
Antipsychotics (thioridazine, clozapine, molindone, haloperidol,
pimozide)
Anticonvulsants (phenytoin)
Type 1c antiarrhythmics (propafenone, flecaine)
Anticholinergics (benztropine, procyclidine)
Xanthines (theophylline)
5-HT 1B/1D agonists (sumatriptan)
Hypnotics (zolpidem)
Potentiated serotonergic activity
MAOIs including moclobemide
Trazodone, nefazodone
Lithium
Tryptophan
OTC cold preparations
Increased bleeding diathesis
Warfarin
Copyright # 2002 John Wiley & Sons, Ltd.
189
Special problems and risk factors with paroxetine
in the elderly
As with other SSRIs, paroxetine induces hyponatrae-
mia with a higher incidence in the elderly than in the
young adult (6.3/1000 for fluoxetine, 3.5/1000 for par-
oxetine). So approximately 1/200 elderly people trea-
ted per year with fluoxetine or paroxetine developed
complicating hyponatraemia (Wilkinson et al., 1999).
Low body weight was a particular risk factor. Most
cases occurred within 3 weeks of treatment. In sum-
mary, paroxetine offers distinct advantages over the
older antidepressants, particularly the TCAs, in terms
of anticholinergic, sedative and cardiovascular
adverse effects as well as safety in overdose. These
differences are particularly important in special popu-
lations such as the elderly.
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