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Publisher: College of Pharmacy
Place of Publication: Gainesville, Fla.
Publication Date: April 2010
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DEPRESSION IN THE ELDERLY:
DRUG INTERACTIONS AND
TOLERABILITY FOR FIRST-LINE
PHARMACOTHERAPY

Erica M. Fernandez, Pharm.D. Candidate


he estimated rate of depression among elderly

is 11% with virtually no difference between
men and women.1 With a growing number of
pharmacotherapeutic options, choosing the right
medication for the right person is increasingly compli-
cated. In a survey by Kaufman et al., 12% of the
study's elderly population took 10 or more medica-
tions, while close to 50% were on at least five medica-
tions.2 Additionally, careful selection of antidepressant
therapy is needed as age-related physiological changes
are responsible for many variations in the pharma-
cokinetic (PK) and pharmacodynamic (PD) properties
of drugs.3 The vulnerability of elderly patients to the
side effects of centrally acting medications adds an-
other challenge to therapy selection. The purpose of
this review is to provide information on potential drug
interactions and differences in tolerability with first
line agents in the treatment of the depressed elderly
patient

AGING EFFECTS ON PK & PD PARAMETERS

Aging limits the ability of the body to continue peak
functioning. The absorption, distribution, metabolism,
and excretion of medications are dependent upon the
function of these regulatory processes within the
body. Changes such as decreased blood flow to the
liver reduces first pass metabolism, thus affecting the
conversion of pro-drugs (e.g. ACE inhibitors) or the


metabolism of active ones (e.g. propranolol).3 Changes
in body composition affect the distribution of polar
and nonpolar medications due to changes in fat con-
tent3 Glomerular filtration rate (GFR) is inversely pro-
portional to age, which may necessitate a change in
dose or frequency or substituting an alternative first-
line treatment3
Although less understood, PD implications of aging
have been studied with several drugs. The results of
these studies vary from drug to drug. With respect to
psychotropic drugs occasionally used as adjuvant
therapy in depression, elderly patients are often more
vulnerable to experiencing delirium, arrhythmias, ex-
trapyramidal side effects and orthostatic hypoten-
sion.4 Increasing age is also associated with increased
sensitivity to the CNS side effects of benzodiazepines.5


FIRST-LINE TREATMENT OPTIONS


Several classes of medications are currently avail-
able for treating elderly patients with depression.
These classes include Selective Serotonin Reuptake
Inhibitors (SSRIs), Serotonin/Norepinephrine Reup-
take Inhibitors (SNRIs), nefazodone, mirtazapine, and
buproprion. These drugs differ in tolerability profiles
as well as degree of possible drug interactions.





INSIDE THIS ISSUE:

DEPRESSION IN THE ELDERLY: DRUG
INTERACTIONS AND TOLERABILITY FOR FIRST-
LINE PHARMACOTHERAPY


mm
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VOLUME 25, ISSUE 7 APRIL 2010
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SELECTIVE SEROTONIN REUPTAKE INHIBITORS

SSRIs are common first-line agents for depression
in elderly patients.5 In 2003, the majority of antide-
pressants (78%) prescribed to treat depression in eld-
erly were SSRIs.6 The mechanism by which SSRIs re-
lieve depression remains unknown; serotonin levels
increase upon first administration, but depression re-
sponse takes several weeks.7 Key differences between
SSRIs include the drug's affinity for certain CYP en-
zymes and their side effect profiles.

Cytochrome P450 (CYP) Metabolism ofSSRIs
Drugs with high affinity for cytochrome P450
isoenzymes have a higher potential for interactions
with other drugs that are substrates for the same
isoenzyme (Table 1). This interaction is more concern-
ing for drugs that have a narrow therapeutic index,
since a slight displacement in metabolism may cause
subtherapeutic or toxic drug levels. Paroxetine has a
high affinity for CYP2D6 and low affinity for CYP3A4.8,
9 Paroxetine and fluoxetine are both potent inhibitors
of CYP2D6 and mild inhibitors of CYP3A4.10 Fluoxetine
is also a moderate inhibitor CYP2C9, and a mild to
moderate inhibitor of CYP2C19. In vitro and in vivo
studies demonstrated fluoxetine's inhibition at
CYP2D6 and CYP2C9 is partially due to its active me-
tabolite (norfluoxetine), which is also responsible for
its increased half life compared to other SSRIs.11 Flu-
voxamine potently inhibits CYP1A2 and 2C19, moder-
ately inhibits CYP2C9 and 3A4, but only mildly inhibits
2D6.10 Sertraline, citalopram, and escitalopram are
often considered the SSRIs with the least interaction
potential. None are potent inhibitors of any cyto-
chrome P450 isoenzymes, however sertraline is a
modestly more potent inhibitor at CYP2D6 than citalo-
pram or escitalopram.10 The effects of sertraline on
CYP2D6 is likely dependent on dose and is smaller
than paroxetine.12 Citalopram is a racemic mixture of R
and S enantiomers.13 The inactive R-enantiomer of ci-
talopram is metabolized by CYP2D6, and believed to
be the contributing factor for mild CYP2D6 inhibi-
tion.13 However, two studies have found significantly
higher serum concentrations of drugs that are known
substrates of CYP2D6 with administration of escitalo-
pram (S-enantiomer).13,14

Studied Drug-Drug Interactions with SSRIs
In vitro studies of isoenzyme potency do not al-
ways predict clinically significant interactions. How-
ever, isoenzyme potency is directly related to the se-
verity of the drug-drug interaction in many cases. In
the case of benzodiazepines, fluoxetine and fluvoxam-
ine have both been found to impair the biotransforma-


tion of diazepam, alprazolam and bromazepam.15-18
Although benzodiazepines have wide therapeutic indi-
ces, the combination of benzodiazepines with other
centrally acting drugs, such as barbiturates, may lead
to severe interactions. Studies show the potent inhibi-
tion of CYP2D6 by fluoxetine and paroxetine increase
plasma concentrations of many first generation antip-
sychotics (e.g. haloperidol).19 The adverse effect pro-
files include extrapyramidal symptoms, which develop
more frequently at higher serum concentrations. The
potent inhibition of CYP1A2 by fluvoxamine can lead
to 3-fold higher clozapine plasma concentrations.20
Tricyclic antidepressant (TCA) toxicity has been seen
in patients soon after concomitant SSRI administra-
tion. Fluoxetine, paroxetine, and sertraline may in-
crease TCA plasma concentrations by 40 to 300 per-
cent 10,19
Fluvoxamine can increase the INR of stable war-
farin therapies by up to 65%.21 This interaction is
likely attributable to the potent inhibition of CYP2C19.
Due to the ability of SSRIs to inhibit the metabolizing
enzymes of 3-blockers, coadministration of these
agents may lead to elevated serum concentrations of 3
-blockers, resulting in decreased heart rate and blood
pressure. For example, paroxetine inhibits CYP2D6 the
major metabolizing enzyme of metoprolol. Likewise,
fluvoxamine inhibits CYP1A2 which metabolizes pro-
pranolol.22-23 Cases of increased edema, nausea, and
flushing have been reported with verapamil and
nifedipine when either was administrated with
fluoxetine.5 Several case reports document possible
drug-drug interactions with fluvoxamine and theo-
phylline or tacrine.19 Multiple case reports associate
paroxetine administration temporally with phenytoin
intoxication.19 SSRIs increase the risk of serotonin syn-
drome, thus monitoring of concomitant drug therapy
affecting serotonin levels is vital. Drugs known to alter
serotonin include MAOIs, meperidine, dextromethor-
phan, tramadol and possibly lithium.19

SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS

SNRIs are newer than SSRI antidepressants, but
current available data suggests there are no differ-
ences in efficacy between the classes.24 Venlafaxine,
desvenlafaxine, and duloxetine are SNRIs but have dif-
ferent CYP enzyme affinity. Venlafaxine is a weaker
inhibitor of CYP2D6 than fluoxetine, fluvoxamine, and
sertraline.10 Studies show minimal effects of venla-
faxine on CYP1A2, 2C9, and 3A4.25 Duloxetine has been
studied less frequently in the general population; how-
ever, it is a moderate inhibitor of 2D6.26 In vitro stud-
ies show an insignificant inhibitory effect on CYP1A2,
and no effects on 2C9, 2C19, and 3A4.27 Patroneva et


Pha rma Note Volume 25, Issue 7 I April 2010


Volume 25, Issue 7 1 April 2010


PharmaNote








Table 1. CYP Inhibition and Common Isoenzyme Substrates

CYTOCHROME P450 ISOENZYME

Drug 3A4 2D6 2C19 2C9 1A2

Fluoxetine
+/++ +++ +/++ ++ +
(Prozac)

Paroxetine
+ +++ + + +
(Paxil)

Fluvoxamine
++ + +++ ++ +++
(Luvox)

Sertraline
+ +/++ + + +
(Zoloft)

Citalopram 0 + 0 0 0
S(Celexa
(Celexa)


Escitalopram
(Lexapro)

Venlafaxine
(Effexor)

Desvenlafaxine
(Pristiq)

Duloxetine
(Cymbalta)

Nefazodone
(Serzone)

Mirtazapine
(Remeron)

Buproprion
(Wellbutrin)


0/+


0/+


alprazolam
amlodipine
atorvastatin
clarithromycin
dextromethorphan
diazepam
diltiazem
lovastatin
salmeterol
simvastatin
tacrolimus
verapamil
zolpidem


amitriptyline
carvedilol
codeine
dextromethorphan
flecainide
haloperidol
lidocaine
metoprolol
nebivolol
ondansetron
oxycodone
propranolol
tamoxifen
tramadol


Carisoprodol
clopidogrel
indomethacin
nelfinavir
PPIs
phenytoin
propranolol
warfarin


* = not a complete list; 0 = none-to-minimal inhibition; + = mild inhibition; ++ = moderate inhibition; +++ = potent inhibition.
PPIs = Proton Pump Inhibitors.
Adapted from various sources.13"'9'35


ri irmaNIlL V/ul 25II II l7


Common
Substrates


celecoxib
glipizide
glyburide
ibuprofen
losartan
S-warfarin
tolbutamide


amitriptyline
naproxen
ondansetron
propranolol
theophylline
verapamil
zileuton
zolmitriptan


I Hniol 201


oume ssue pr


r iai mai cUL







al. found duloxetine significantly elevated serum
plasma levels of desipramine, a CYP2D6 substrate,
while desvenlafaxine (Pristiq), the active metabolite
of venlafaxine, did not28 This finding suggests that the
ability of venlafaxine to cause significant drug interac-
tions with substrates of CYP2D6 is lower than duloxet-
ine.
Studies evaluating the significant drug interactions
with SNRIs in elderly are scarce in comparison with
SSRIs. Despite the lack of evidence in elderly, many
conclusions from interactions studied in healthy indi-
viduals have been extrapolated to this population.
Venlafaxine interacts with CYP2D6 substrates,
imipramine and risperidone, by decreasing their clear-
ance and increasing serum drug concentrations.29,30
Preskorn et. al. found duloxetine, but not escitalopram
or sertraline, significantly increased the AUC of
metoprolol, likely due to its inhibition of CYP2D6.14

OTHER ANTIDEPRESSANTS

Other medications often used for depression in
elderly include nefazodone, mirtazapine, and bupro-
prion. Nefazodone is a 5HT-2 antagonist that inhibits
serotonin and norepinephrine reuptake with weak cl-
adrenergic agonism.31 Nefazodone is a potent inhibitor
of CYP3A4,31 and can increase the risk of QTc interval
with terfenadine, nephrotoxicity with tacrolimus and
cyclosporine, and incidents of rhabdomyolysis with
simvastatin.10 Other documented interactions include
serum increases in benzodiazepines (alprazolam, tria-
zolam, and midazolam), haloperidol, and clozapine.10
Nefazodone also weakly inhibits CYP2D6.
Mirtazapine potently antagonizes the 5HT-2 recep-
tors and histamine-1 (Hi) receptors.31 Mirtazapine is a


substrate of CYP3A4 with minimal effects on the CYP
enzyme system.31
Buproprion produces its actions independent of
serotonin; it blocks the reuptake of dopamine and
norepinephrine, yet like all other antidepressants its
specific mechanism of action is unknown.32 In vitro
studies and in vivo studies differ in conclusions of
CYP2D6 inhibition by the active metabolite, hydroxy-
bupropion. In vitro studies suggest the inhibition is
minimal,33 however an in vivo study showed bupro-
prion as a potent CYP2D6 inhibitor when probed with
dextramethorphan.34 Strengthening the evidence of
buproprion as a CYP2D6 inhibitor are case reports
linking buproprion administration to nortriptyline and
metoprolol toxicity.10 Cytochrome P450 involvement
is an important aspect to consider when choosing a
first-line treatment option for depression in the eld-
erly.

SIDE EFFECT PROFILES

An additional characteristic of antidepressants fac-
toring into the decision of first-line therapy is adverse
effects. Sedation, fatigue, and drowsiness are some of
the most common reasons of discontinuation of anti-
depressants (Table 2). Preskorn et. al. found the high-
est reported frequencies of drowsiness among SSRIs
with paroxetine and fluvoxamine (14.3% and 17.2%
incidence respectively) and fatigue most frequent with
paroxetine (10.3% incidence).36 The affinity of mirta-
zapine for H1 receptors produces sedative effects,
which may be more pronounced in the elderly. Con-
versely, reports of insomnia among SSRIs are highest
with fluoxetine, citalopram and stertraline.5 Specifi-
cally with SSRIs, a common cause of discontinuation is


Table 2. Comparison of Adverse Effects of Antidepressant Agents.

# OF RANDOMIZED
ADVERSE EVENT COMPARISONS MEAN INCREASE
CONTROLLED TRIALS

Weight gain 7 Mirtazapine vs. fluoxetine, paroxetine, tra- 0.8-3.0 kg
Weight gain 7
zodone, venlafaxine (mirtazapine)

MEAN INCIDENCE

l d 5 Paroxetine vs. fluoxetine, fluvoxamine, nefa-
Sexual dysfunction 5 21% vs. 5%
zodone, sertraline
Diarrhea 15 Sertraline vs. buproprion, fluoxetine, mirta- 42% vs. 25%
Diarrhea 15 42% vs. 25%
zapine, paroxetine, venlafaxine

Nausea and vomiting 15 Venlafaxine vs. SSRIs as a class 33% vs. 22%

Adapted from Simon, G.37

nDr r + \/ I 7 An:il 2 1 0


r m iI tI IIULC


oume ssue pr







nausea with a 15-40% occurrence in patients starting
therapy.5 This adverse effect may be due to the anti-
cholinergic properties of some SSRIs, and can poten-
tially dissipate as the sensitization of 5-HT receptors
builds.5 Both citalopram and escitalopram are associ-
ated with less nausea.5 Alpha 1-adronergic blockade
by nefazodone may lead to orthostatic hypotension,
thus increasing the risk for falls among elderly pa-
tients.10 Commonly prescribed BPH medications may
potentiate this adverse effect With respect to SSRIs,
dizziness in patients with late-life depression is re-
ported very often with paroxetine and sertraline.5 Not
all side effects are created equal; some may be thera-
peutic for a side effect of another medication. For ex-
ample, a patient with insomnia caused by levothyrox-
ine may be prescribed mirtazapine in place of a tradi-
tional SSRI to aid in sleep. Additionally, patients suf-
fering from constipation regularly may benefit from an
agent commonly associated with diarrhea (i.e. ser-
traline).


SUMMARY


The number of medications available for first-line
treatment of depression in elderly patients is consid-
erable. Because of the chronic nature of the disease
and the delay in treatment response, starting doses
should be lower and titration schedules less aggres-
sive in this population regardless of the choice of anti-
depressant The key is choosing medications on a case
by case basis. Carefully examine the depressed pa-
tient's current medication regimen for possible drug-
drug interactions. Consider past medical history and
progression of current disease states as predictors of
future medications which may interact with the anti-
depressant When antidepressant treatment is neces-
sary the common adverse effects of the selected anti-
depressant should be opposite of side effects that are
idiopathically present and/or the result of other medi-
cations the depressed patient is taking in an attempt
to neutralize patient discomfort





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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacotherapy and Translational
Research
University of Florida



John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
PharmD


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