Citaloprami

a review of pharmacological and clinical effects

Kalyna Bezchlibnyk-Butler, BScPhm; Ivana Aleksic, BSc; Sidney H. Kennedy, MD

Bezchlibnyk-Butler Department of Pharmacy, and Centre for Addiction and Mental Health (CAMH), Toronto, Ont., and
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta.; Aleksic CAMH; Kennedy
CAMH and Department of Psychiatry, University of Toronto, Toronto, Ont.

Objective: To provide clinicians with a critical evaluation of citalopram, a selective serotonin reuptake
inhibitor (SSRI) that has been available in Canada since March 1999. Data sources: Commercial search-
es (MEDLINE and BiblioTech) and an "in-house" search (InfoDrug) were used to find published English-lan-
guage references for clinical and preclinical publications. There was no restriction of publication dates.
Primary index terms used were: pharmacological properties, receptors, pharmacological selectivity, phar-
macokinetics, age-related pharmacokinetics, sex-related pharmacokinetics, renal dysfunction, hepatic dys-
function, cytochrome activity, drug interactions, adverse reactions, antidepressant switching, precautions,
overdose, drug discontinuation, children, geriatric, depression, combination therapy, placebo control,
refractory depression, anxiety disorders and medical disorders. Study selection: A total of 74 studies
were reviewed. Twenty-one of these studies specifically examined the clinical efficacy and tolerability of
citalopram in depressive disorders as well as other disorders. In depressive disorders, clinical studies were
required to have either placebo or active comparison controls for a minimum of 3 weeks. For other dis-
orders, in the absence of double-blind trials, open-label studies were included. Pharmacological studies
were limited to animal studies focusing on citalopram's selectivity and receptor specificity, and positron
emission tomography studies were incorporated to include human pharmacological data. Pharmacokinetic
studies focused on the metabolism, safety and tolerability of citalopram, specifically with reference to
adverse reactions, drug interactions and overdose in addition to citalopram's effect on vulnerable popula-
tions, such as children, the elderly and patients with metabolic diseases. Data extraction: Data on clini-
cal studies were summarized according to test measures, study duration and outcome of study.
Pharmacokinetic and pharmacodynamic studies were summarized according to properties and interactions.
Adverse reactions were extracted to outline citalopram's safety profile. Data synthesis: Citalopram is an
SSRI antidepressant with a more specific and selective pharmacological profile than other antidepressants
of its class. It is well tolerated, and drug interactions are not a significant concern. It is also reasonably safe
for populations vulnerable to pharmacokinetic effects, such as the elderly and patients with metabolic dis-
eases. In addition to its tolerability, citalopram is effective in the treatment of major depression, other

Correspondence to: Dr. Sidney H. Kennedy, Mood and Anxiety Disorders Program, CAMH, Clarke Site, 250 College St., Toronto ON
MST I R8; sidney [email protected]

Medical subject headings: antidepressive agents; citalopram; drug interactions; pharmacokinetics; pharmacology; serotonin uptake inhibitors
J Psychiatry Neurosci 2000;25(3):241-54.
Submitted Sept. 3, 1999
Revised Dec. 2, 1999; Jan. 21, 2000
Accepted Jan. 25, 2000
2000 Canadian Medical Association

25, iio
Vol. 25, no 3, 2000 Journal of Psychiatt.
journal Psychiatry & Neuroscience
& Neuroscience 0
241
 depressive disorders and panic disorder. It has the potential to effectively treat other anxiety disorders and sub-
stance-use disorders; in addition, it may be useful in several medical conditions. Conclusions: There is evidence
to support the role of citalopram as a well-tolerated and effective SSRI antidepressant. There is a need for fur-
ther evaluation of its role in psychiatric disorders other than major depressive disorder.

Objectif: Fournir aux cliniciens une evaluation critique du citalopram, inhibiteur selectif du recaptage de la sero-
tonine (ISRS), disponible au Canada depuis mars 1999. Sources de donnees: On a effectue des recherches
commerciales (MEDLINE et BiblioTech) et des recherches ((internes)) (InfoDrug) pour trouver des references
cliniques et precliniques publiees en anglais. 11 n'y avait aucune restriction quant aux dates de publication. Les prin-
cipaux termes d'indexation utilises ont et6 les suivants (en anglais): proprietes pharmacologiques, recepteurs, se-
lectivite pharmacologique, pharmacocinetique, pharmacocin6tique liMe a l'age, pharmacocin6tique liMe au sexe,
dysfonction renale, dysfonction hepatique, activite cytochromique, interactions m6dicamenteuses, effets indesira-
bles, changement d'antidepresseur, precautions, surdose, interruption du medicament, enfants, geriatrique,
depression, therapie combin6e, contr6le par placebo, depression rebelle, troubles de l'anxiete et troubles medi-
caux. Selection des etudes: On a passe en revue 74 etudes au total, dont 21 portaient sp6cifiquement sur l'ef-
ficacite clinique et la tolerabilite du citalopram dans des cas de troubles depressifs et autres. Dans les cas de trou-
bles depressifs, les etudes cliniques devaient comporter des contr6les par placebo ou comparaison active pen-
dant au moins trois semaines. Dans le cas d'autres troubles, comme il n'y avait pas d'etude a double insu, on a
inclus des etudes ouvertes. Les etudes pharmacologiques ont ete limitees aux etudes animales portant avant tout
sur la selectivite du citalopram et la specificite des recepteurs, et l'on a incorpore des etudes de tomographie par
emission de positrons afin d'inclure des donnees pharmacologiques portant sur les etres humains. Les 6tudes
pharmacocinetiques ont porte avant tout sur le metabolisme, l'innocuite et la tolerabilite du citalopram, specifi-
quement en ce qui concerne les effets indesirables, les interactions medicamenteuses et les surdoses, outre l'ef-
fet du citalopram sur des populations vulnerables comme les enfants, les personnes ag6es et les patients atteints
de troubles du metabolisme. Extraction des donnees : On a resume les donnees sur les etudes cliniques en
fonction des mesures des 6preuves, de la duree de l'etude et de son resultat. On a resum6 les 6tudes pharmaco-
cinetiques et pharmacodynamiques en fonction des propri6t6s et des interactions. On a extrait les effets indesira-
bles pour tracer le profil d'innocuite du citalopram. Synthese des donnees : Le citalopram est un antid6-
presseur ISRS qui a un profil pharmacologique plus specifique et selectif que celui d'autres antidepresseurs de sa
cat6gorie. 11 est bien tolere et les interactions medicamenteuses ne repr6sentent pas un probleme important. 11
est aussi raisonnablement sOr pour les populations vulnerables aux effets pharmacocin6tiques comme les per-
sonnes agees et les patients atteints de troubles du metabolisme. Outre sa tol6rabilit6, le citalopram est efficace
dans le traitement de depressions majeures, d'autres troubles depressifs et des troubles paniques. 11 peut traiter
efficacement d'autres troubles de l'anxiete ou lies a l'utilisation de substances et il peut aussi etre utile pour traiter
plusieurs problemes m6dicaux. Conclusions: Des donnees probantes appuient le role du citalopram comme
antidepresseur ISRS efficace et bien tol6re. 11 faut evaluer plus a fond son r6le dans le traitement de troubles psy-
chiatriques autres que le trouble depressif majeur.

Introduction weeks of antidepressant therapy in family practice set-

tings had discontinued treatment.4
Despite the availability in Canada of 8 first-choice anti- The availability in Canada of citalopram as an alter-
depressant agents for the treatment of major depres- native antidepressant agent within the selective sero-
sion,' reports of underdetection and undertreatment of tonin reuptake inhibitor (SSRI) class provides the clini-
depression, as well as poor compliance with treatment, cian with an additional choice in the pharmacological
are prevalent. According to reports from epidemiologi- management of depression. The purpose of this review
cal studies in Ontario2 and in 5 European countries,3 is to provide clinicians with the information needed to
only 20% to 25% of identified individuals who were compare citalopram with existing antidepressant
experiencing a depressive episode received any form of agents. Although in Canada citalopram is indicated
antidepressant therapy. In addition, more than 50% of only for the treatment of patients with major depres-
patients with depression who were followed up after 12 sion, evidence of its efficacy in other disorders, includ-
 Citalopram - pharmacological and clinical effects

ing anxiety disorders, disorders of substance use and dopamine uptake minimally.11'7 Its ratio inhibition con-
other medical disorders, will also be summarized. stant (IC,, NA/IC5o 5-HT) for 5-HT uptake is over 3000
times lower than that for norepinephrine uptake; this is
Pharmacodynamic properties significantly higher than the IC,, of other SSRI antidepres-
sant agents such as paroxetine (IC,, = 280), sertraline (IC,,
Effect on receptors = 840), fluvoxamine (IC_, = 160) and fluoxetine (IC,, = 54)211

Because of its selectivity for 5-HT uptake sites, citalopram

Citalopram and its metabolites are racemic compounds has been used in in vitro autoradiographic techniques in
with both S-(+) and R-(-) enantiomers. The S-(+) the rhesus monkey to label 5-HT uptake sites in the frontal,
enantiomer of citalopram is pharmacologically active in parietal and occipital cortices.1"
relation to inhibition of serotonin (5-HT) reuptake, and Citalopram's specificity for 5-HT uptake sites is also
it accounts for 24% to 49% of the total plasma citalo- supported by in vivo studies. [3H] citalopram is the most
pram level,5'6 whereas the R-(-) enantiomer of citalo- selective 5-HT uptake inhibitor available; however, it is
pram appears to be pharmacologically inactive. The less potent than [3H] paroxetine, which is the most potent
S/R ratio varies from 0.32 to 1.25.7 inhibitor of 5-HT uptake sites among the SSRI antide-
There is an acute increase in extracellular 5-HT levels pressant medications.19 Consequently, because of the
in animals following citalopram 10 mg/kg twice daily, greater affinity of [3H] paroxetine for the 5-HT uptake site,
which in turn results in activation of somatodendritic 5- it is considered a preferred radioligand in positron emis-
HTIA autoreceptors." The result of this acute activation is sion tomography (PET) research.'9 Nonetheless, when
a feedback inhibition in the raphe nucleus, with down- citalopram was administered parenterally and McNeil
regulation of autoreceptors and a subsequent increase in 5652 (McN5652) was used as a PET radioligand, results
serotonergic neurotransmission.""" This delay in autore- indicated that 500/o to 80% occupancy was achieved in
ceptor down-regulation coincides with the usual "ther- regions of high 5-HT transporter density.20 This finding
apeutic lag" of 2 to 3 weeks. In vitro studies have also not only confirms that citalopram is an effective inhibitor
confirmed that citalopram has very low affinity and of 5-HT uptake sites but also supports the use of
selectivity for post-synaptic 5-HT receptors (5-HT,A, 5- McN5652 as an effective radioligand in PET research.
HTIB, 5-HT2A and 5-HT2,) and also for adrenergic, hista-
minergic, muscarinic and dopaminergic receptors.6"' 13 Pharmacokinetics
In vitro studies indicate that citalopram has addition-
al selectivity and affinity for 5-HT1, receptors, and may Pharmacokinetic properties
function as an antagonist at this receptor; however,
definitive in vivo evidence is unavailable.'4 Theo- Absorption and distribution
retically, this could hasten the time to antidepressant
clinical response, but there is no clinical evidence to The absorption of citalopram is not affected by food,
substantiate this claim. Additional in vivo studies have and its oral bioavailability is reported to be approxi-
suggested that co-administration of a 5-HTIA receptor mately 80%. Peak plasma levels occur 2 to 4 hours after
antagonist such as (S)-5-fluoro-8-hydroxy-2-(dipropyl- single or multiple doses, and the mean peak plasma
amino)-tetralin [(S)-UH-301] or [(+)-WAY100135] can concentration (Cmax) following dosages of 40 mg per day
augment both acute and chronic effects of citalopram at steady state is 311 nmol/L." Citalopram is 80% pro-
on central serotonergic neurotransmission." 16 It is as yet tein bound, somewhat less than other SSRIs; therefore,
uncertain whether co-administration of 5-HT1A antago- it is less likely to be involved in drug interactions that
nists in clinical populations would hasten citalopram's occur secondary to drug displacement from protein
antidepressant effect. binding. It is widely distributed among peripheral tis-
sues, with the volume of distribution (V,) estimated to
Selectivity of 5-HT uptake sites be between 12 and 16 L/kg.7 (Table 1)
At clinically relevant doses, citalopram displays linear
Citalopram is the most selective inhibitor of 5-HT uptake pharmacokinetics.2' There is a linear correlation between
currently available. In vitro studies have corroborated this dose and steady-state concentration of citalopram and
claim and confirmed that it inhibits norepinephrine and its metabolites.7 However, no clear correlation has been

Vol. 2S,
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Neuroscl'ence 243
established between plasma concentration and clinical Elimination
response. Inter-individual variation in plasma levels is
about 7-fold and appears to be independent of sex or age Citalopram shows biphasic elimination. The distribu-
(up to age 65).725 Intra-individual variability is estimated tion phase lasts about 10 hours. The terminal (or elimi-
at 15%.7 Steady-state plasma levels are reached within 1 nation) half-life (T1,2) has been determined to be 30 to 35
to 2 weeks at each dose level. With 20 to 60 mg per day, hours for citalopram, 50 hours for DCT and 100 hours
steady-state plasma levels, measured at trough, were for DDCT.7 Due to its relatively long half-life, citalo-
reported to be 130 (standard deviation 70) nmol/L at 20 pram can be administered once daily.
mg, to 400 (SD 200) nmol/L at 60 mg.7 Up to 23% of the dose of citalopram is excreted
unchanged in the urine.7 Renal clearance is estimated at
Metabolism 2.8 to 3.3 L per hour, whereas systemic clearance ranges
from 23 to 28 L per hour.21
Citalopram is metabolized in the liver by 2 N-demethy-
lation steps, to demethylcitalopram (DCT) via CYP2C19 Factors influencing variability
and 3A4, and to didemethylcitalopram (DDCT) via
CYP2D6. Oxidation occurs by monoamine oxidases A Age-related pharmacokinetic effects
and B and aldehyde oxidase, to form a propionic acid
derivative and citalopram-N-oxide.7223 Studies using single and multiple doses of citalopram in
At single doses, as well as at steady-state plasma con- subjects over 60 years of age indicate that the area under
centrations, the amount of metabolites, in relation to the the dose concentration curve (AUC) increased between
parent drug citalopram, are 30% to 50% for DCT and 23% and 30% compared with younger subjects. The T112
5% to 10% for DDCT.7 In vitro studies suggest that increased by 30% to 50%, and the steady-state plasma
citalopram is at least 4 times more potent than DCT and level increased 4-fold.7 The ratio of DCT to citalopram
13 times more potent than DDCT in inhibiting the reup- decreased significantly, as compared with that reported
take of 5-HT. Since these metabolites enter the brain less in younger patients, suggesting possible age-related
readily and are present in lower concentrations, they do changes in the activity of CYP2C19.27 This drug-to-
not appear to play a major role in the clinical action of metabolite ratio was higher in patients in whom the
citalopram.26 The N-oxide and propionic acid derivative plasma half-life of citalopram was the longest and clear-
are present in low concentrations in plasma. The impact ance the shortest.7 Because of potential pharmacokinet-
of metabolizer status (poor or extensive) on citalopram ic differences in elderly patients compared with mid-
metabolism is considered to be clinically insignificant. dle-life patients, it is recommended that elderly patients
receive lower initial doses, and that the maintenance
dosage not exceed 40 mg per day.

Ka Sex-related pharmacokinetic effects

-M .: Five studies did not demonstrate sex differences.26
2:2tio4h
Similarly, no differences in steady-state plasma levels or
other parameters were seen between men and women
in clinical studies. Therefore, current recommendations
suggest equivalent dosing for male and female patients.

Renal dysfunction and pharmacokinetic effects

In patients with mild to moderate renal impairment (crea-

tinine clearance greater than 20 mL per minute), oral dear-
ance of citalopram was decreased by 17% and T1,2 was
'i w ii -1i ; . .- -- :----.-
moderately increased; the peak plasma concentration was
W-iet>_il*~~~~~-;u ,. unaffected.2 In these patients, dosage adjustment is not

:tSj 144 Revme 4s~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

00** i Wdiihiiwi"16
1: 7. .Ilx., :..-- 1', IN
 Citalopram - pharmacological and clinical effcts

required. However, since there are no data on the pharma- Interactions with tricyclic antidepressants
cokinetics of citalopram in patients with chronic or severe
renal impairment, caution should be exercised when the The combination of tricyclic antidepressants such as
drug is used in patients with severe renal dysfunction. amitriptyline or maprotiline with citalopram (20 to 60 mg
per day) produced no significant increases in the plasma
Hepatic dysfunction and pharmacokinetic effects level of either drug.-4 In combination with imipramine,
however, 40 mg of citalopram increased the AUC of the
In patients with impaired hepatic function, oral clear- imipramine metabolite desipramine by 50%.35 With
ance of citalopram is reduced by 37% and T112is dou- clomipramine, one study did not show changes in plas-
bled; the peak plasma concentration, however, is unaf- ma levels; however, a second study demonstrated that 25
fected.28 It is recommended that patients with compro- to 150 mg of clomipramine significantly increased the
mised liver function receive lower initial doses and that plasma level of both citalopram (prescribed in dosages of
the maintenance dosage should be carefully monitored. 10 to 80 mg per day) and DCT.21'3
Like the other SSRIs, citalopram may enhance the
Drug interactions serotonergic effects of coprescribed drugs, including
buspirone, lithium and clomipramine, and these combi-
Cytochrome activity nations should be used with caution. Serotonin syn-
drome is characterized by nausea, diarrhea, dizziness,
In vitro data demonstrate that citalopram is a weak confusion, agitation, sweating, shivering, fever, tremor,
inhibitor of CYP 1A2, 2D6 and 2C19 isoenzymes and incoordination, hyper-reflexia and myoclonus; unless
that it does not inhibit CYP3A4; this suggests that citalo- therapy is stopped this may progress to coma and death.
pram would have little inhibitory effect (in vivo) on
drugs that are metabolized by these isoenzymes.29 Interactions with monoamine oxidase inhibitors
CYP3A4 and 2C19 are the primary enzymes involved
in the metabolism of citalopram;24 therefore, potent Citalopram should not be used in combination with
inhibitors of these isoenzymes (e.g., CYP3A4 inhibitors either reversible or irreversible monoamine oxidase
ketoconazole, itraconazole, macrolide antibiotics and inhibitors (MAOIs) because of the risk of serotonin syn-
nefazodone; CYP2C19 inhibitor omeprazole) may drome.6 Myoclonus and death have been reported after
decrease the clearance of citalopram.26'3 There are, how- overdoses of moclobemide and citalopram in combina-
ever, no clinical reports of these interactions to date. tion.3648 Although there is a report on the safe combination
Although CYP2D6 is involved in the conversion of DCT of citalopram (20 mg) with the MAO-B inhibitor selegiline
to DDCT, inhibition of this isoenzyme is not expected to (10 mg),39 caution should be exercised with higher doses
have clinically significant consequences.2431 of selegiline because of the loss of MAO-B selectivity.

Interactions with SSRI antidepressant medications Interactions with antipsychotic medications

The SSRIs are dissimilar in their potential for drug inter- There have been no reports of significant changes in the
actions when administered with other drugs. Based on plasma levels of several antipsychotic agents (haloperi-
in vitro cytochrome P-450 enzyme studies as well as in dol, chlorpromazine, methotrimeprazine, perphenazine,
vivo evidence, both citalopram and sertraline appear to pericyazine, thioridazine and zuclopenthixol) when
have a lower potential for drug interactions than the these drugs are combined with citalopram (40 mg per
other SSRIs when administered in lower therapeutic day) for periods of at least 3 months; the plasma level of
dosage ranges.2 In one of the few reports of citalopram citalopram and DCT also remained stable.23?4 In one
in combination with another SSRI, increasing dosages study, however, methotrimeprazine was shown to
of fluvoxamine over 14 days (50 to 100 mg per day) increase the steady-state concentration of citalopram by
increased the plasma level of citalopram (40 mg per up to 36% and the steady-state concentration of DCT by
day) by more than 200% over 21 days; the ratio of S-(+) 10% to 20%. SSRIs, including citalopram, may aggra-
to R-(-) isomers was also altered, i.e., the pharmacolog- vate antipsychotic-induced extrapyramidal effects (e.g.,
ically more active S-(+) isomer was increased.33 parkinsonism).6

Vol. 25, no
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245

245
Interactions with other medications renal clearance of DCT and DDCT was reduced by 26%
and 36%, respectively.2'
Serum citalopram levels increased when carbamazepine, Summaries of pharmacokinetic and pharmacody-
which had been coprescribed with citalopram, was discon- namic interactions with citalopram and the clinical sig-
tinued in 2 patients; this suggests possible enzyme induc- nificance are listed in Tables 2 and 3.
tion of citalopram metabolism with carbamazepine.41 In
addition, metoprolol plasma levels were reported to dou- Adverse reactions
ble with the co-administration of citalopramY4
Citalopram does not appear to interact with digoxin, Information on citalopram's side-effect profile is avail-
mood stabilizers, alcohol and most benzodiazepines.213' able from controlled and uncontrolled studies as well as
A slight increase in the plasma levels of citalopram and postmarketing surveillance reports. Several meta-
DCT has been reported with alprazolam7' Although a analyses have also been conducted.46
pharmacokinetic interaction has not been seen with In pooled comparative studies, citalopram's tolerabil-
warfarin and citalopram, the prothrombin time was ity profile was similar to that of other SSRIs and superi-
reported to increase by 5%;43 the significance of this is or to that of tricyclic antidepressants.47 A meta-analysis
yet to be determined. demonstrated that the most common side effects report-
Oral clearance of citalopram was shown to decrease ed with citalopram, at therapeutic doses, are nausea and
by 29% when cimetidine (400 mg twice daily) was vomiting (20%), increased sweating (18%), headache
added to a stable regimen of citalopram 40 mg per day. (18%), dry mouth (17%), tremor (16%), sedation(15%)
The 24-hour AUC of DCT was increased by 43% and the and insomnia (15%).46 Citalopram appears to cause stim-

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 Citalopram -pharmacological and clinical effets

ulation only rarely and is relatively well tolerated in young and elderly subjects revealed no changes in cardiac
elderly patients with depression.48 The range of reported conduction.6 No QTc changes have been reported, to date,
side effects across several studies is reported in Table 4. in patients with pre-existing conduction disturbances or
Side effects are usually mild to moderate and occur dur- ischemia.46 Similarly, citalopram did not affect cardiac con-
ing the first few weeks of treatment. Most side effects duction in patients taking other medications that could
decrease over time, except for dyspepsia and sweating.' prolong the QTc interval.46 The only common change in
Various forms of sexual dysfunction have been the ECG of patients taking citalopram is a slight decrease
reported in up to 75% of patients treated with SSRIs.49 in heart rate, which also occurs with other SSRIsY4
The rate of spontaneously reported sexual dysfunction Phasic craving for carbohydrates and accompanying
with citalopram is less than 10%, although this may weight gain was reported in 8 out of 18 patients during
turn out to be higher when direct questioning is short-term treatment with citalopram 20 to 40 mg per
employed.21 Three cases of transient clitoral priapism day.51 This was an unexpected side effect, as enhanced
have also been reported.-' 5-HT transmission is usually associated with decreased
Hepatic, renal or hematological adverse events occur carbohydrate intake and anorexia.51
rarely.2' There is a low potential for seizures or extrapyra- A favourable side-effect profile in the elderly has been
midal effects with therapeutic dosages of citalopram.47 supported by data from a number of meta-analyses. In
Citalopram has not been associated with serious cardio- this population, the most common side effects reported
vascular toxicity, even in elderly patients or in patients include asthenia, insomnia, somnolence, tremor, dry
with pre-existing cardiovascular disease. Electro- mouth, headache and nausea.- Women reported more
cardiograms (ECGs) recorded during clinical trials of both adverse effects than men, but only "headache" reached
a statistically significant difference between sexes.*

Precautions and contraindications

Although studies of citalopram in normal volunteers,
using dosages of 40 mg per day, did not produce
impairment of intellectual function or psychomotor
performance, the same cautions that apply to the use of
psychoactive drugs while driving or operating haz-
ardous machinery apply to citalopram.
$;m ' 4.40''r
Use of antidepressants in patients with bipolar disorder
Pi r i . *
has been associated with an increased risk of mania or
eri>-;§ 't} Hsa?
,..!2..2rp4-
hypomania. Placebo-controlled studies in predominantly
unipolar populations suggest that the risk of inducing
mania with citalopram is low (occurring in 0.2% of 1063
patients);26 the risk of inducing mania in bipolar patients
is likely similar to the reported risk with other SSRIs.
Increased risk of suicide attempts is inherent in
depression and may persist until there is significant
remission of mood symptoms. Patients at high risk for
suicide should be supervised when antidepressant ther-
apy is initiated, and prescriptions for citalopram should
be written for small drug quantities to minimize the risk
5ia *' '. of intentional overdose.
Hyponatremia and the syndrome of inappropriate
antidiuretic hormone secretion have been reported as
-qfp ;- 4 2 rare adverse events in citalopram use.26 Clinical symp-
toms include increased water intake, weight gain,
s
'. 3-s- z1'
li' i i
a weakness, lethargy and confusion.

Ye3^:It;
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 In clinical trials, seizures were reported in 0.25% of Switching antidepressants
patients receiving therapeutic doses of citalopram,26
which is comparable to reported rates with most other From tricyclic antidepressants to citalopram
antidepressants.
At standard therapeutic dosages, the potential for a drug
Overdose interaction between citalopram and most tricycic antide-
pressants is low, although elevated plasma levels of
When taken in overdose, citalopram appears to have a desipramine and imipramine have been reported in com-
relatively wide safety margin.52 In an evaluation of 44 bination with citalopram. Conversely, citalopram levels
cases of overdose involving citalopram alone, Personne were elevated in combination with clomipramine.A53
et al53 reported that ingestion of 600 mg or less resulted When switching to citalopram, we suggest a cautious
in mild symptoms only. The most common symptoms approach that would involve tapering the tricyclic anti-
following mild overdose include tiredness, confusion, depressant by 25 to 50 mg every 2 to 3 days and, mid-
dizziness, stomach pain, sweating, nausea, sinus tachy- way through this period, initiating citalopram therapy at
cardia and tremor.7 10 mg daily, increasing to 20 mg daily after 5 to 7 days.
Convulsions were seen in 6 of 34 patients (18%) who When switching from desipramine, imipramine or
took between 600 and 1900 mg of citalopram, and some clomipramine, citalopram should be initiated at 10 mg
ECG abnormalities were also evident. Ingestion of more daily when the dosage of tricycic drug has been reduced
than 1900 mg resulted in ECG changes as well as seizures to 50 mg per day.
in 47%/o of patients.' Additional rare adverse effects fol-
lowing massive ingested doses, have included amnesia, From SSRI antidepressants to citalopram
hyperventilation, cyanosis, coma, rhabdomyolysis and
ECG changes (including QTc prolongation).164" When switching from sertraline or paroxetine to citalo-
In a review of 6 deaths following citalopram overdose, pram, a simple crossover approach to citalopram at a
additional drugs were detected in 5 of the cases.26 dose of 20 mg can be adopted. In the case of fluoxetine,
Moclobemide was ingested with citalopram in 3 reported since residual norfluoxetine continues to inhibit
deaths, and the plasma levels of both drugs were high.37 CYP3A4, a starting dose of citalopram 10 mg is recom-
Following overdose, gastric evacuation by lavage and mended. Since fluvoxamine has been shown to double
the use of activated charcoal should be considered. the plasma level of citalopram owing to its inhibitory
Symptomatic and supportive treatment is recommend- effect on CYP2C19 and 3A4, it is advisable to taper flu-
ed. Due to the large volume of distribution of citalo- voxamine to 50 mg per day for at least 5 days before
pram, forced diuresis, dialysis, hemoperfusion and starting citalopram at a dosage of 10 mg per day.
exchange transfusion are unlikely to be of benefit.26
From reversible and irreversible
Drug discontinuation effects MAOI antidepressants to citalopram
Short-term clinical trials have not demonstrated evi- Moclobemide should be discontinued for a minimum of
dence of the discontinuation (withdrawal) symptoms 48 hours before starting citalopram 10 mg daily. A min-
that may occur with other SSRIs,47 although, in contrast imum of 14 days must elapse from the discontinuation
to other specific trials designed to examine drug dis- of an irreversible MAOI (e.g., phenelzine, tranyl-
continuation effects across SSRIs,m there have been no cypromine, isocarboxazid) before starting citalopram.
specific evaluations of symptoms following citalopram
discontinuation. There is anecdotal evidence that citalo- Safety in special populations&
pram may be associated with symptoms similar to
those associated with discontinuation of other SSRIs, Pregnant and lactating women
including nausea, vomiting, insomnia, somnolence,
dizziness, agitation, asthenia, headache and impaired In preclinical studies, citalopram was shown to have
concentration.26- As with other SSRIs, gradual tapering adverse effects on embryo/fetal and postnatal develop-
should minimize discontinuation symptoms. ment when given in doses that were toxic to the animal
 ::: :: : X: - ::X:HE DiS: :u:E::: : ):E :*-C,iSta opra*'ii.i-iX;rackgta and e*.cDXts:AV

mother and greater than the human therapeutic dose.26 antidepressant medications. At a dosage of 20 to 40 mg
There are no available controlled studies in pregnant daily, citalopram was comparable in efficacy to 100 to
women; therefore, citalopram should be used in this pop- 200 mg daily of fluvoxamine in the treatment of unipo-
ulation only when the potential benefits justify the risk. lar major depression,6" and 20 mg of citalopram was as
Citalopram is excreted in human breast milk. It was effective as treatment with 20 mg of fluoxetine.62 An
estimated in one study that the infant would receive additional study used a flexible regime of up to 60 mg
1.8% of the weight-adjusted maternal dose of citalo- daily, and noted that citalopram was as effective and
pram.5 There are 2 reports of infants experiencing well tolerated as sertraline.63
excessive sedation, decreased feeding and weight loss
when exposed to citalopram through breastfeeding.26 Placebo-controlled studies in acute and
maintenance treatment of major depression
Children and adolescents
Placebo-controlled trials have demonstrated that citalo-
There have been no double-blind studies and few open pram is effective not only in the acute treatment of
trials of citalopram in children or adolescents. In one depression but also during continuation therapy to pre-
open-label assessment of the safety and efficacy of vent relapse (Table 6). In a meta-analysis of 9 placebo-
citalopram in children with obsessive-compulsive dis- controlled studies, citalopram was superior to placebo
order, 75% of patients' symptoms improved at dosages at both 20 and 40 mg daily dosages.64 Furthermore, in 2
up to 40 mg per day, and side effects were considered placebo-controlled studies conducted by Montgomery
to be minor and transient.57 et al,65TM citalopram was effective in preventing relapse
of depressive symptoms at 20, 40 and 60 mg daily, for
Elderly patients periods of up to 6 months.
A number of double-blind studies have been performed Severe and treatment-resistant depression
in patients older than 60 years of age. No overall differ-
ences in efficacy or safety were documented in these Although there is evidence that 20 mg per day of citalo-
clinical trials.4648 Because of changes observed in the pram is the minimum effective dosage for the treatment
pharmacokinetic parameters of citalopram in elderly of major depression, in at least one study there was evi-
subjects (i.e., AUC, T,,2), use of lower doses is recom- dence of a dose-response relation according to severity
mended in this population.7 of depression. Montgomery et al,23 using a placebo-con-
trolled design, found that patients who were severely
Human clinical trials depressed responded to a dosage of 40 mg of citalo-
pram daily, but not to a lower dosage of 20 mg daily.
Comparisons with other antidepressants Citalopram may also be effective at higher doses or
with augmentation strategies in the treatment of refrac-
Citalopram has demonstrated efficacy in the treatment tory depression. A double-blind, placebo-controlled
of major depression (Table 5). In comparison with tri- trial conducted by Baumann et a167 found that the com-
cyclic antidepressants, citalopram is equally effective, bination of lithium and 20 to 60 mg daily of citalopram
with fewer reported adverse events. When adminis- was superior to placebo and to citalopram alone in
tered in dosages of 10 to 60 mg daily, citalopram was as relieving unipolar resistant depression (Table 7).
effective and better tolerated than 50 to 150 mg daily of
imipramine and 75 to 225 mg daily of amitriptyline.5'59 Other depressive disorders
In a double-blind multicentre clinical study, citalopram
(40 mg daily) was found to be as effective as clomip- There is tentative evidence to support the use of citalo-
ramine (150 mg per day) in the treatment of non- pram in combination with light therapy in the treat-
endogenous depression; however, clomipramine was ment of seasonal affective disorder.T8 Citalopram has
found to be superior to citalopram in the treatment of also proven to be effective in the treatment of depres-
endogenous depression.60 sion related to physical illnesses, including poststroke
Citalopram has also been compared with other SSRI depression69 and depression in dementia (Table 8).70

VoIW
25, *,Xwl
..2
 I mi777777T.
7.17'11 "" ot* .: T

Anxiety disorders nificantly more effective than placebo in the treatment

of panic disorder, with the lower dosage range (20 to 30

Several anxiety disorders have also been treated suc- mg daily) of citalopram being more effective than the

cessfully with citalopram. Citalopram, at dosages of higher range (40 to 60 mg daily).71 This is in contrast to

either 20 to 30 mg daily or 40 to 60 mg daily, was sig- findings in studies of major depression, in which high-

tIo".4 0

iebid 8 wk
I-.:

.24 tw AA
-,
P . .11 l.
I., .. .- T--l

'l, .:
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...
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A
.; "!..

Study Description ~~~~~~~~~~~DuratonPatiena Oscm

CloamV. plcdtPA ..aaltI ot4 to 6 wk 99HmD AMadCIade ly a
flesbie
r fissd.ose 10 solmg daily) cilepram vat supeior te pMeotbsh 0a 40
c ~~~~~~~~~~~6
wk acute 107' I0 pisscnbd 4!fud CS --

2. 20mg% clalopram
Cllxmirlas Cctatnterp 1.86 wk acute I. 391 Ntmsc *WA.4Sq41
PrvnIon Tre wgop:2'.24 wk 2.226i loe r44 am 'v* tr*
dt$pram-1.4mb20'40 or 60mg continuation
I.Opn tothHmO e
2., RdpamtMd*SUd
Placqk 'Oft sme.-dose of cisuloprun as citalopram accordn tLJUW. le

250 Revue & psychiatric itt

Rt*. de et de
**6**
beot64d.b.
de micuroscience
Vol. 25, nO 3, 2000
 Citalopram - pharmacological and clinical effects

er dosages tend to show increased efficacy. In addition, cantly decreased desire and craving for alcohol, in addi-
there is open-label evidence suggesting that citalopram tion to consumption and liking of alcohol (Table 10).
is effective in the treatment of generalized social pho-
bia;72 however, further controlled studies are needed to Other medical conditions
corroborate this finding. There is also preliminary evi-
dence that 40 to 60 mg daily of citalopram may be effec- Citalopram may also be effective in the treatment of cer-
tive in the treatment of obsessive-compulsive disorder tain medical conditions, including diabetic neuropa-
in adults7? as well as in children?.7 A summary of stud- thy76 and poststroke crying (Table 11).7
ies using citalopram in the treatment of anxiety disor-
ders is presented in Table 9. Role in current pharmacotherapy
Addiction disorders or alcohol abuse Citalopram is an antidepressant agent with a mecha-
nism of action similar to that of other SSRI antidepres-
Balldin et a17P demonstrated that citalopram, at 40 mg sant agents, and it is the most selective inhibitor of 5-HT
daily, reduced alcohol intake in male heavy drinkers reuptake currently available. It has minimal potential
who consumed 60 to 100 g of pure alcohol daily. Another for drug interactions, although it is contraindicated in
study conducted by Naranjo et al7l examined the effects combination with MAOI antidepressants. Furthermore,
of 40 mg daily of citalopram on alcohol consumption in citalopram is well tolerated, and side effects are usually
both men and women. In this study, citalopram was mild to moderate. It is suitable for populations such as
administered in a double-blind fashion, and it signifi- the elderly and patients with renal and hepatic dys-

Study Description Duration Patdents Outcome

Citalopram v. placebo in Double-blind, placebo-controlled 6 wk 199 134 completed reat m-D, MADRS and
severe depression23 Treatment groups: CGI scores showed that here was a sica
40 mg cltaopram adantage for 40 mg citalepren compared wih
20 mg citalopram 20 mg citalopram and placebo. There was no
Placebo signfiant difference in efficac between 20 mg
- ~~~~~~A--.
Citalopram ,cmbined wkdh After 4 wks of 40-60m open label treatnent with 2 wk 24 HamD and UKUsores ated t
lithium in treatment- citapa, non-responders received, double-blind: clalopram4lthlum combination was signfficandy
resistant deprssio' lihiunm ( OR more effective and better tolertd than other
c dapa + placebo OR t ments
citalopram f fl m(80 mg)

Study c~~ ~~~~

~~ ~~ ~~ ~~ ~~Duradon
~~~dnts
~~ ~~ ~~ ~~ ~~ ~~ ~~ ~~~~~~~~~~~~~
Citalopram incombiaLtin wth+ ,lac ll 1r 8(lunae) CPRStand ta I d tem th
light th y nTreatment oups: wzs nwre ec
40mg cluleprani +lig+ hettirpy treatment with placebo in relIeDlngSAD
Phw bo +* W' wrap
j 6 A AA

jimO mg pram .#p ta patiens and liation of dep

Otalp. v$ebn e~ely. &;Md, placebo- ~149 W..dhe itu4~
6wk j'mD,flM*S0nt0
nd de_ $-Ealtcores
.- shtdu ialopram s Sgnifrin mo
dementia: Ta p effecdvtw tre_ with pacebo i depession and
l 0-30mng ciaormlpncii4nd.eointucinn
Placebo assoclated .i1 dy t UKU sc showed

'Seasonal aeale disorder

tCompr.hansive Psychopadoic&al Ratin S&le
tMelancholia Scle

Vol. 25, no
no 3, 2000 Journal
journal ofof Psychiatry
Psychiatry && Neuroscience
Neuroscience 251
 Bezchibnykutleret al

function; however, clinicians may need to make dosage disorders, substance use disorders and a few medical

adjustments to meet their special requirements. conditions. Consequently, citalopram can be implement-
Citalopram has proven to be effective in treating major ed as standard antidepressant therapy in the treatmnent of
depression, other depressive disorders and panic disor- major depressive disorder and may be indicated in the
der. It may be effective in the treatment of other anxiety future for treatment of other psychiatric disorders.

pI 1, wk 475

or fli0:1
VO*
24 wvk"

O0 wk

I:.. ii" 1"A' ,-, -

"Itw-,.&.
5). 12 *k
-W -.
W.OWU"-'

s$c

In-im" "we-- ~~~~~~2.I wk for kehol

Shady biiti~~~~~~~~tbn ~~uradonPauOutcome

2.'2 wk

~~ .OSh4#o*o-contro~~~~~lled, 1..3 wk 16 13 ~s

2. Placbo

252 psyth..i etet de

Revue de psychiatric de neuroscience
neuroscience
Vol. 25, no

Vol. 25, nO 3, 2000

3,
 Citalopram- pharmacological and ;clinical effect

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