CliniCal pharmaCology & TherapeuTiCs | VOLUME 85 NUMBER 1 | JANUARY 2009
nature publishing group
There is limited geriatrics-oriented clinical pharmacological
information available to guide pharmacotherapy in late-
life psychiatric disorders. In this paper, we review available
data on interindividual differences in drug exposure and
central nervous system functioning, amplified by drug–drug
interactions in the elderly, that may contribute to variable
responses to treatment and significant adverse drug effects.
The inclusion of greater numbers of elderly persons in clinical
trials and the vigorous application of clinical pharmacologic
methodology (i.e., pharmacoepidemiology, population
pharmacokinetic modeling, and pharmacogenetics) will be
critical for improving safety and personalization of drug and
dose selection for elderly patients.
Late-Life Psychiatric Disturbances
Although the rates of depressive symptomatology are compa-
rable in younger and older adults (5–13%), the elderly face a
chronic disease profile that is often not alleviated by treatment,
is likely to recur/relapse, and frequently involves cognitive
decline.1 Late-life anxiety disorders affect 2–19% of the com-
munity-dwelling elderly, with almost 20% additionally experi-
encing symptomatology that does not meet diagnostic criteria.
Also common in 10–70% of dementia sufferers are behavioral
and psychiatric symptoms of dementia (BPSDs) such as agita-
tion, aggression (physical and verbal), and psychosis.2 Late-
life psychiatric disturbances result in a lower quality of life; an
increase in disability rates; and a risk of dementia, placement
in long-term care, and cognitive decline as well as a risk of
extrapyramidal symptoms and mortality, which may include
unDerrePresentation in cLinicaL triaLs
Antidepressant drug trials in geriatric patients are very sparse
and limited to academic sites, as are studies in those with
chronic psychotic illnesses (e.g., schizophrenia). By contrast,
there have been a number of drug trials in dementia patients
with BPSDs. To date, there have been only two significant trials
of antidepressants in the “old-old.” A randomized, placebo-
controlled trial of citalopram in those aged ≥75 years did not
find a significantly different rate of remission between medica-
tion and placebo groups.7 Reynolds and colleagues determined
that 65% of the depressed elderly who achieved initial response
to paroxetine and psychotherapy remained in remission for
up to 2 years during maintenance treatment.8 In contrast,
in the case of atypical antipsychotic drugs, because there is
a potential for achieving a specific indication for treatment
of psychosis in dementia, there were at least 15 double-blind
placebo-controlled trials (only 6 of which were published)
from 1995 to 2005. Although efficacy was demonstrated in
trials of risperidone and olanzapine, based on the pooled data,
mortality was higher in patients treated with atypical antip-
sychotics as compared with those who received the placebo
(3.5% vs. 2.3%).9
Variable interindividual drug exposure can contribute to
mixed outcomes. For example, it is challenging to adminis-
ter antipsychotics to acutely agitated patients. In the same
patients, the variation in risperidone concentration exposure
was found to be ~125% when they were in the acute in-patient
unit and 70% when they were transferred to the long-term
care setting.10 These variable exposures are potential contribu-
tors to the risk of adverse drug reactions (ADRs) and lack
of response. The Clinical Antipsychotic Trials of Intervention
Effectiveness–Alzheimer’s Disease (CATIE-AD) included
260 dementia patients receiving treatment for BPSDs with
olanzapine, quetiapine, risperidone, or placebo. Between 21
and 32% of the patients experienced improvement in their
symptoms, whereas 5% (placebo) to 24% (olanzapine) of the
patients discontinued treatment on account of intolerable
side effects, thereby demonstrating an unfavorable risk-to-
benefit ratio.11 This relatively low response rate in typical
clinical studies may be secondary to relatively poor adher-
ence to medication schedules in respect of antipsychotic drugs
(<70% of the doses were taken correctly).12 This provides a
significant challenge in interpreting the assignment of treat-
ment, given the inconsistency of drug exposure inherent in
these low adherence rates. The rationale for using risperidone
The Critical Role of Clinical Pharmacology in
BG Pollock1,2,3, CE Forsyth2,3 and RR Bies1,4
1Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 2University of Toronto, Faculty of Medicine, Department of Psychiatry, Institute of Medical
Sciences, Toronto, Ontario, Canada; 3Rotman Research Institute at Baycrest, Toronto, Ontario, Canada; 4Pharmaceutical Sciences and Psychiatry, School of Pharmacy
and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Correspondence: BG Pollock (Bruce_Pollock@camh.net)
Received 2 September 2008; accepted 30 September 2008; advance online publication 26 November 2008. doi:10.1038/clpt.2008.229
90 VOLUME 85 NUMBER 1 | JANUARY 2009 | www.nature.com/cpt
or other dopamine receptor–blocking drugs to treat BPSDs
in patients who have existing dopaminergic deficits associ-
ated with dementia remains open to question.13 Serotonergic
dysfunction in dementia patients has been associated with
BPSDs,14 and further trials of serotonergic medications in the
treatment of agitation are being sponsored by the National
Institute on Aging.
One in five community-dwelling elderly persons is pre-
scribed psychotropic medications.15 Additionally, between
20.9 and 44.3% of long-term-care residents are dispensed
antipsychotics.16,17 Psychotropic drugs are among one of the
leading causes of preventable ADRs in long-term-care facili-
ties.18 Pharmacoepidemiology has revealed safety concerns that
are not apparent from efficacy trials or routine clinical use of
psychotropics. Nursing-home residents have experienced cer-
ebrovascular events and increased mortality consequent to the
use of atypical antipsychotic drugs.19 The risk of falls and fragil-
ity fractures increase in community-dwelling elderly persons
with long-term use of selective serotonin reuptake inhibitors
(SSRIs).20 The elderly are at particular risk for upper gastrointes-
tinal bleeding associated with the use of SSRIs. The bleeding may
result from the direct effects of SSRIs on platelet aggregation21
and can be further compromised with the concomitant use of
nonsteroidal antiinflammatory drugs or low-dose aspirin.22
While the US Food and Drug Administration found, from data
in a pooled analysis from 372 efficacy trials,23 a decreased inci-
dence of suicidal tendencies (thoughts and behaviors) in patients
aged ≥65 years, a study based on prescription data found an
increased risk of actual suicide in the depressed elderly within
the first month of initiating SSRI treatment.24
A significant proportion of ADRs (~70–80%) are related to
concentration. Cholinergic events (e.g., nausea, vomiting, and
diarrhea) can occur with higher doses of cholinesterase inhibi-
tors and can become severe with rapid dosage increases or if
metabolism by the cytochrome (CYP) P450 enzyme 3A4 is
inhibited (e.g., with donepezil or galantamine). Variability in
drug concentrations is often not evaluated, and in regulatory
trials with younger, healthier subjects, medications are often
administered at or close to their highest tolerable dose to ensure
efficacy. In elderly patients, this translates into serious ADRs,
such as are seen after the use of bupropion and clozapine (e.g.,
dose-related seizures) or fluoxetine and risperidone (e.g., dose-
related agitation, akathisia, and extrapyramidal symptoms).
Pharmacokinetic analysis generally calls for the collection of
numerous samples from a small number of volunteers (6 to 12
subjects). Single-dose studies generally fail to provide this type
of analysis for elderly volunteers. Studies evaluating pharma-
cokinetics through multiple dosing reveal nonlinear relation-
ships. Population pharmacokinetics, an alternative to traditional
modeling, uses mixed-effects methods. Only a few samples (e.g.,
one or two) from each subject contributes to individual and pop-
ulation pharmacokinetic parameters, and heterogeneity among
older adults is better accounted for by including covariates such
as medication use, illness, and age. The results are more clinically
relevant because a larger number of patients are included in the
analyses. Population pharmacokinetic modeling has demon-
strated that there is a linear decline in citalopram clearance from
ages 22 to 93 years by 2.3 l/h per decade.25 Recent evidence from
the CATIE found that elderly patients may have greater exposure
to risperidone’s active metabolite, 9-OH risperidone, because
of a 20% decrease in elimination.26 No age-associated changes
in olanzapine or quetiapine pharmacokinetics were found in
this study. Variability in the elimination of olanzapine was best
accounted for by smoking status, with smokers clearing olanza-
pine 55% faster than nonsmokers.27 Quetiapine clearance was
higher when there was concomitant use of bupropion, and body
weight significantly influenced the volume of distribution. In
general, there is a trend toward decreases in clearance in elderly
individuals. Nonetheless, because there is greater interindividual
variability of drug concentrations, which are difficult to pre-
dict in the elderly, dosages comparable to those administered
to younger adults may be required for effective therapy in some
Many antidepressant drugs (e.g., nortriptyline, desipramine,
paroxetine, venlafaxine) and antipsychotic drugs (e.g., per-
phenazine, thioridazine, and risperidone) are hydroxylated by
the CYP2D6 isozyme.28 There does not appear to be an age-
associated decline in the activity of this enzyme in older, unmed-
icated adults, although significant interactions can occur from
common medications, either competitively (e.g., perphenazine)
or noncompetitively (e.g., paroxetine, fluoxetine, bupropion),
inhibiting CYP2D6. Within the Caucasian population, 7% of
individuals are genetically poor CYP2D6 metabolizers. A study
carried out in elderly subjects that used CYP2D6 identification
prospectively found that poor metabolizers experienced more
severe extrapyramidal side effects than extensive metabolizers
CYP2C19 metabolizes diazepam, escitalopram, mephenytoin,
and phenytoin.30 The demethylation of tertiary tricyclic antide-
pressants is partially dependent on this isozyme and is inhib-
ited by fluvoxamine and fluoxetine. Some research shows that
CYP2C19 functioning declines with age.31 Inhibition of CYP2C9
by fluvoxamine and fluoxetine decreases the clearance of war-
farin’s active S-enantiomer. R-warfarin will accumulate with
inhibition of CYP1A2 (fluvoxamine) and 3A4 ( fluvoxamine,
fluoxetine), also affecting S-warfarin clearance.
CYP3A4 drugs such as sertraline, mirtazapine, alpraxolam,
and triazolam can be affected by age and gender (Table 1). This
enzyme is inhibited significantly by fluvoxamine and fluoxet-
ine, via its demethylated metabolite, norfluoxetine. CYP1A2 is
induced in postmenopausal women receiving growth hormone
treatment and is inhibited by estrogen replacement.
The accumulation of an antidepressant drug’s active hydroxy-
lated metabolites (e.g., nortriptyline and bupropion) can have
clinical consequences. Imipramine’s active metabolite, 2-OH
desipramine, is twice as potent in eliciting arrhythmias as imi-
pramine itself,32 and the concentrations of the metabolite have
been associated with prolonged QRS intervals. The accumulation
CliniCal pharmaCology & TherapeuTiCs | VOLUME 85 NUMBER 1 | JANUARY 2009
of venlafaxine’s metabolite can impair cardiac conduction.33
Older patients with decreased renal or hepatic function may
develop unexpected extrapyramidal side effects due to accumu-
lation of 9-OH risperidone. The elderly are typically prescribed
nonsteroidal antiinflammatory drugs and angiotensin-converting
enzyme inhibitors, which potentially reduce lithium clearance.
Older adults are more susceptible to increased pharmacody-
namic effects at lower drug concentrations than younger adults
are. In one of the first pertinent studies, Reidenberg and col-
leagues found that older adults showed greater sedation at
lower diazepam concentrations than younger adults did.34 Even
healthy elderly persons have been noted to have significant cog-
nitive impairment as compared with younger volunteers at the
same intravenous dose of scopolamine (0.5 mg).35
Obesity, poor nutrition, and high triglyceride levels can
increase the risk of cardiovascular events with chronic use of
antipsychotics in the elderly. In elderly patients, risperidone has
a linear concentration side-effect profile, olanzapine demon-
strates a curvilinear dose–response relationship, and quetiapine
is administered across a very wide range of doses.
SSRIs have a much wider therapeutic index than tricyclic anti-
depressants; nonetheless, avoidable ADRs (e.g., cognitive and
psychomotor events) occur when SSRI concentrations become
needlessly high. Bradycardia may intensify with the use of SSRIs
in the elderly.36 Inappropriate antidiuretic hormone secretion
consequent to the intake of SSRIs or venlafaxine is reported
mainly in patients aged ≥65 years. Some degree of hyponatremia
is experienced by up to 12% of older adults taking SSRIs37 and
can occur at 13 days after commencement of treatment (range
3–120 days). Patients with idiopathic Parkinson’s disease have
demonstrated parkinsonism or motor worsening after SSRI use.
This may be a function of reduced dopaminergic transmission
related to serotonin in a population with already compromised
dopamine reserves. Higher concentrations of tricyclic anti-
depressants prolong QTc intervals and pose a greater risk of
arrhythmias. Venlafaxine’s cardiovascular toxicity is increased
by CYP2D6 inhibition, and, in older patients, dropout rates con-
form to an ascending dose–response model.38 The association
between adherence to the medication regimen and response to
the drug in elderly persons with depression may not be strictly
related to the average exposure or the average number of tablets
taken correctly. It may be that gaps in treatment are a significant
contributor to poor treatment response.39
Genetic variability may impact response to SSRIs in older
adults. The number of geriatric studies examining receptor/
transporter sites is limited, and these few have focused on the
serotonin transporter (5HTT). A functional polymorphism
in the promoter region of the 5HTT results in a short (s) or
long (l) allele. The s variant has been associated with poorer
SSRI response.40–42 However, in a Korean population of elderly
patients with depression, those expressing the s/s allele and the
l/l variant of the intron 2 variable number of tandem repeats
polymorphism were found to be more likely to respond to treat-
ment with fluoxetine or sertraline than those with other genetic
combinations.43 Elderly persons who are heterozygous for the s
allele experience greater side effects (gastrointestinal complaints,
table 1 impact of aging on the pharmacokinetics of antidepressant drugs
Class, medicationelderly (n) age range Dose (mg/day) effect of advanced age
Selective serotonin reuptake inhibitors
Fluvoxamine13 63–7750 b.i.d. (28 days) Peak plasma concentration, AUC, t1/2, and steady-state plasma
levels similar to those in younger adults50
Fluoxetine11 65–77 40 q.d.
Sertraline22>6550 → 200 q.d. (21 days) Higher concentrations in older men than in younger men;
concentrations similar to those in younger women52
Paroxetine21 72 (median) 20–30 q.d. (49 days)Steady state increased 20%,
t1/2 increased from 21 to 30 h at 20 mg, and to 38 h at 30 mg53
Plasma level-to-dose ratio increased54;
t1/2 increased by 30%55
Oral clearance decreased with increasing age (average clearance
in young patients 16.5 l/h, 22–65 years of age, vs. 6.34 l/h in older
patients, aged 75–93 years; clearance decreased 2.3 l/h for each
decade of age)25
20 q.d. (14 days)
10 → 30 q.d. (35 days)
Escitalopram 1865–80 10 (21 days) Maximum concentration 34% higher, AUC 50% higher,
t1/2 increased (40.7 h vs. 27.3 h)56
Serotonin norepinephrine reuptake inhibitors
Venlafaxine 1860–8050 t.i.d. (5 days)Steady-state t1/2 increased by 24%; active metabolite: decreased
clearance (0.29 l/h/kg vs. 0.38 l/h/kg), t1/2 longer (13 h vs. 10 h),
steady-state t1/2 increased 14%57
Other second-generation antidepressants
Bupropion6 63–76100 Apparent clearance reduced by 20%58
AUC higher, minimum steady-state plasma level higher59
Mirtazapine 1665–74 20 (7 days)
→, Titrated to; AUC, area under the concentration–time curve; b.i.d., twice daily; q.d., once daily; t1/2, half-life; t.i.d., three times daily.
92 VOLUME 85 NUMBER 1 | JANUARY 2009 | www.nature.com/cpt
fatigue, agitation, sweating, and dizziness) to paroxetine treat-
ment than l allele carriers do.44
Neuronal changes with aging (e.g., decreased dopamine or
acetylcholine) can lead to greater sensitivity to D2 antagonists
and antimuscarinic agents. Age-related reductions in cortical D2
and 5HT2a receptors can also have implications on the effects
of atypical antipsychotics as well as some antidepressants.45,46
Tardive dyskinesia from the use of conventional antipsychotic
drugs has been shown to occur frequently and with rapid onset
in older patients. Recent pharmacokinetic/pharmacodynamic
studies using positron emission tomography have found that,
after controlling for risperidone concentration, older schizo-
phrenic patients will experience extrapyramidal symptoms when
60% of the D2 receptors are bound by risperidone, whereas
younger adults do not have these side effects until binding
occurs up to 80%.47
Anticholinergic effects, such as dry mouth, tachycardia,
blurred vision, urinary retention, and constipation, can mark-
edly impair quality of life in elderly patients. Cognitive mani-
festations may be slight (mild confusion, short-term memory
impairment) or more severe (delirium). These effects are par-
ticularly problematic in patients with dementia, and even agents
with modest anticholinergicity can impact cognition in older
adults. Serum anticholinergic activity (representative of over-
all anticholinergicity from all medications and their metabo-
lites) was found in almost 90% of the samples from a group
of community-based elderly persons, and even low levels of
such serum activity were associated with impairment in cog-
nition.48 Anticholinergic activity was assessed in a study of 107
medications commonly prescribed to the elderly and may help
to guide medication selection and assess anticholinergic bur-
den.49 Medications with noradrenergic properties can lead to
dry mouth and urinary retention in elderly men, tachycardia,
and aggravation of hypertension and tremor.
In the absence of basic clinical pharmacologic information relating
to geriatric patients, more intensive and standardized postmarket-
ing studies are essential. Obtaining minimally invasive drug expo-
sure data and DNA in both clinical trials and in postmarketing
studies will assist in determining unanticipated drug interactions
and ADRs, such as those seen with SSRIs (e.g., fragility fractures,
hyponatremia, and risk for completed suicide after initial treat-
ment). The inclusion of structural and functional imaging with
genetic investigations and the capture of drug-exposure informa-
tion provide opportunities to reduce heterogeneity and improve
the efficacy and safety of psychotropic medications.
This work was supported by the Sandra A. Rotman Program in
confLict of interest
B.G.P. has received grants or research support from the National Institutes
of Health and Janssen Pharmaceuticals. He serves on the advisory board
of Forest Laboratories and Lundbeck Inc., and has consulted for Wyeth,
Takeda Pharmaceuticals, and GlaxoSmithkline, and is a faculty member of
the Lundbeck International Institute. Until 2005 he was a member of the
speakers’ bureau for Forest and Lundbeck. The other authors declared no
conflict of interest.
© 2008 American Society for Clinical Pharmacology and Therapeutics
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