ADIS DRUG EVALUATION

Citalopram A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Treatment of Depression

Stuart Noble and Paul Benfield Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

eNS Drugs 1997 Nov; 8 (5): 410-431 1172-7047/97/0011-0410/$11.00/0

© Adis International Umited. AU rights reserved.

U.G. Ahlfors, Hesperia Hospital, Helsinki, Finland; G. Andersen, Department of Neurology, Aarhus Kommunehospital, Aarhus, Denmark; P. Baumann, Unite de Biochimie et Psychopharmacologie Clinique, Departement Universitaire de Psychiatrie Adulte, Prilly-Lausanne, Switzerland; P. Bech, Department of Psychiatry, Frederiksborg General Hospital, Hillered, Denmark; K. Bresen, Department of Clinical Pharmacology, Odense University, Odense, Denmark; G.D. Burrows, Department of Psychiatry, University of Melbourne, Heidelberg, Victoria, Australia; E de Jonghe, Psychiatrisch Ziekenhuis, Amsterdam, The Netherlands; R.R. Kydd, Department of Psychiatry and Behavioural Science, School of Medicine, University of Auckland, Auckland, New Zealand; S.A. Montgomery, Department of Psychiatry, St Mary's Hospital Medical School, London, England; W.Z. Potter, Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, Maryland, USA; E. Richelson, Departments of Psychiatry and Pharmacology, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

Contents Summary ................... . 1. Overview of Pharmacodynamic Properties

1.1 Inhibition of Serotonin Uptake . . . . . . 1.2 Effects on Receptors . . . . . . . . . . . 1.3 Behavioural Effects . . . . . . . . . . . . 1.4 Inhibition of Hepatic Cytochrome P450 Systems

2. Pharmacokinetic Properties ......... . 2.1 Absorption and Plasma Concentrations . 2.2 Metabolism . . . . . . . 2.3 Elimination . . . . . . . . 2.4 Special Patient Groups. 2.5 Drug Interactions . . . .

3. Clinical Efficacy ...... . 3.1 Placebo-Controlled and Dose-Finding Studies

3.1.1 General Depression . . 3.1.2 Post-Stroke Depression ......... . 3.1.3 Relapse Prevention . . . . . . . . . . . .

3.2 Comparative Studies. . . . . . . . . . . . . . . 3.2.1 Comparisons with Tricyclic and Tetracyclic Antidepressants 3.2.2 Comparisons with Other SSRls

4. Tolerability ............ . 4.1 General Tolerability Profile . . . . . .

4.1.1 Adverse Events ....... . 4.1.2 Overdose. . . . . . . . . . . .

4.2 Comparisons with Traditional Antidepressants 4.3 Comparisons with Other SSRls . . . . . . . . . .

5. Dosage and Administration. . . . . . . . . . . . . . 6. Place of Citalopram in the Management of Patients with Depression

.411 · 413 .413 .414 .414 .414 .415

415 415 416 416 416 417 417 417 418 419 419 419 422 422

.422 · 422 .424 · 425 .426 · 427 · 427

Cita!opram: A Review

Summary Synopsis

Pharmacodynamic Properties

Pharmacokinetic Properties

Citalopram is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhib­itor (SSRI) which has been evaluated primarily in the treatment of major depres­sion. In well controlled short term studies, citalopram had efficacy similar to that of a number of, but not all, tricyclic or tetracyclic antidepressants and was as effective as fluoxetine and fluvoxamine. There is some evidence of a faster onset of action for citalopram compared with fluoxetine. Initial data suggest that citalopram is effective in the prevention of depressive relapse and in the treatment of post-stroke depression.

The anticholinergic and cardiovascular adverse events often seen with tricy­clic antidepressants generally occur less frequently or are infrequent with citalopram, as with other SSRIs. Citalopram has been well tolerated in the elderly and in patients with existing cardiovascular disease. In vitro and in vivo phar­macodynamic studies suggest that citalopram is a weak inhibitor of cytochrome P450 (CYP) 2D6, and data from several interaction studies in patients and healthy volunteers are consistent with this finding.

411

Thus, citalopram is an effective and well tolerated SSRI which, like the other members of its class, represents a suitable first-line therapy for major depression. Additional efficacy data would be beneficial in clarifying the potential of citalopram in the elderly and in patients with post-stroke depression or pre­existing cardiovascular disorders, for whom anticholinergic or cardiovascular adverse events (caused by tricyclic antidepressants) are a serious concern. The main distinguishing feature of citalopram within its class is its apparent low propensity to cause problematic drug interactions with CYP2D6 substrates; these include a number of commonly prescribed drug classes, such as anti psychotics, tricyclic antidepressants, antiarrhythmics and P-blockers. Thus, citalopram may prove useful in the many patients with depression who require one or more such agents for treatment of additional psychiatric or general disorders.

Citalopram is a potent in vitro inhibitor of serotonin (5-hydroxytryptamine; 5-HT) uptake. Its activity in this respect is more than 3000 times greater than that against noradrenaline (norepinephrine) uptake, making it the most serotonin-selective agent in its class. Citalopram has low affinity in vitro for adrenergic, muscarinic, dopaminergic and serotonergic receptors. Evidence from behavioural studies in animals supports a selective facilitatory effect of citalopram on serotonergic neurotransmission.

Citalopram is a weaker in vitro and in vivo inhibitor of the hepatic cytochrome P450 (CYP) 2D6 isozyme than paroxetine and fluoxetine and therefore has a lower potential for pharmacokinetic interactions with cytochrome CYP2D6 sub­strates such as tricyclic antidepressants and antipsychotic agents.

Peak plasma concentrations of citalopram are observed 2 to 4 hours after single or multiple oral doses and steady-state plasma concentrations are reached after about 1 week of daily administration. The plasma concentration-dose relationship for citalopram is linear for doses of 10 to 60mg.

Citalopram is converted by hepatic CYP isozymes to the metabolites demethyl- and didemethyl-citalopram which are less lipophilic than the parent molecule (and are weaker serotonin reuptake inhibitors).

Preliminary indications suggest that citalopram may cause only moderate pharmacokinetic interactions or have no effect when coadministered with tricy-

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Clinical Efficacy

Tolerability

Noble & Benfield

c1ic antidepressants which are metabolised by CYP2D6, although formal studies of such interactions are limited. Available data suggest that coadministration of citalopram and antipsychotic agents does not cause any significant pharmaco­kinetic interactions.

The elimination half-life of citalopram following oral administration is about 30 hours, with an estimated clearance of 26 to 28 Llh. Approximately 12% of an oral dose of citalopram is excreted unchanged into the urine.

Aging appears to be associated with increased plasma concentrations and de­creased clearance of citalopram. Similar effects are seen in patients with renal or hepatic dysfunction.

In well controlled clinical studies, score reductions for the Hamilton Depression Rating Scale (HDRS) or Montgomery-Asberg Depression Rating Scale (MADRS) ranged from about 43 to 81 % with citalopram and from about 56 to 71 % with tricyclic or tetracyclic antidepressants. In the largest comparative study published to date, reductions in HDRS scores after 6 weeks were similar for citalopram and imipramine in more than 400 patients from general practice. Fur­thermore, the proportions of patients whose HDRS score was reduced by ~50% were similar for citalopram and imipramine. In smaller studies, citalopram had end-point efficacy similar to that of amitriptyline or maprotiline (2 studies each), although comparisons with mianserin have produced somewhat contradictory findings. Citalopram was less effective than clomipramine in a single study. Re­sults from meta-analyses indicate that citalopram is broadly similar to tricyclic agents (amitriptyline, clomipramine, nortriptyline and imipramine) in its antide­pressant efficacy in clinical trials.

Citalopram had overall efficacy similar to that of fluoxetine in general practice patients and in psychiatric inpatients and outpatients. However, analysis of 3 different clinical parameters after 2 weeks indicated that the effects of citalopram were achieved significantly faster than those of fluoxetine in the general practice study; no significant difference between the two treatment groups was apparent at subsequent timepoints. A comparison of citalopram with fluvoxamine in pa­tients with major depression demonstrated equivalent efficacy for the 2 drugs.

Data from clinical trials and meta-analyses suggest that nausea and vomiting (20% incidence in a meta-analysis of746 patients), increased sweating, dry mouth and headache were the most common adverse events experienced by citalopram recipients. The anticholinergic and cardiovascular adverse events often seen with tricyclic antidepressants (dry mouth, constipation, tachycardia, orthostatic hypo­tension) appear to occur less frequently or to be infrequent with citalopram in most large studies. Data from 2 comparative studies suggest that there are no major differences in tolerability between citalopram and fluoxetine, although vomiting during the first week of treatment was significantly more common in citalopram recipients (3.8%) than in fluoxetine recipients (0%) in one study (the citalopram dosage in this trial was twice that recommended for initial treatment). Nausea and diarrhoea were significantly more common in patients receiving fluvoxamine 100 to 200 mg/day than in those receiving citalopram 20 to 40 mg/day in a single study (the starting dosage of fluvoxamine was twice that normally recommended). This difference was apparent at all timepoints for nau­sea, but had disappeared by week 6 for diarrhoea.

Clinical and postmarketing experience with citalopram suggests that it is not associated with serious cardiovascular toxicity, and is well tolerated in patients

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Citaiopram: A Review 413

with existing cardiovascular conditions, in those who are receiving drugs that may cause ECG abnormalities and in the elderly. Like the other SSRIs, citalopram appears to be less toxic than tricyclic antidepressants when taken in overdose during suicide attempts.

Dosage and Administration

The recommended oral treatment regimen for citalopram in depressed patients is 20 to 60mg once daily, titrated to therapeutic effect, with a minimum treatment period of 6 months to prevent relapse. Citalopram 20 to 30mg once daily is currently recommended for elderly patients. Dosage adjustments are not neces­sary in patients with mild or moderate renal impairment; information on the use of citalopram in patients with severe renal dysfunction is lacking. Citalopram 20 to 30mg is recommended as the maximum dose in patients with impaired hepatic function. Citalopram should not be given to patients who are taking monoamine oxidase inhibitors.

Citalopram is an antidepressant agent which selectively inhibits the reuptake of serotonin (5-hydroxytryptamine; 5-HT) into presynaptic nerve terminals, thus potentiating serotonergic neuro­transmission. Reuptake inhibition of neurotrans­mitters such as serotonin or noradrenaline (norepi­nephrine) is associated with clinical antidepressant effects, although the exact mechanisms involved have yet to be established. Citalopram, like other selective serotonin reuptake inhibitors (SSRIs), has been assessed for the treatment of a wide range of psychological and psychiatric disorders. Although citalopram appears to be of value in the treatment of conditions such as panic disorder,[1.31 demen­tia,[41 impulsive aggressive behaviour[51 and post­stroke pathological crying,[61 this review addresses its use in patients with major depressive disorder.

1. Overview of Pharmacodynamic Properties

Citalopram is available as a racemic mixture; however, in vitro and in vivo studies in rodents have shown that the pharmacological activity of the drug resides primarily in the (S)-( +) enantiomer, for both citalopram and its primary metabolite demethyl­citalopramPl

Many aspects of the relationship between the serotonergic and clinical effects of citalopram (and other SSRIs) have yet to be clearly established (see review by Goodwin[81). There is a 2- to 3-week delay in the onset of the clinical effects of citalopram

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and other SSRIs. This has been attributed to the following sequence of events: (i) short term treat­ment causes an increase in extracellular serotonin levels, which activates somatodendritic 5-HT1A auto­receptors; (ii) this results in feedback inhibition of the raphe nucleus; (iii) long term treatment causes down-regulation of the autoreceptors and a sub­sequent increase in serotonergic neurotransmission. The time taken for the autoreceptors to become down-regulated is expressed clinically as a delay in antidepressant efficacy. However, data on the effects of long term administration of citalopram on autoreceptor blockade are inconclusive.l9,101

Data from in vivo studies suggest that coadmin­istration of a 5-HT1A receptor antagonist may re­duce the latency of the clinical effects of citalo­pram, by ameliorating the increase in extracellular serotonin levels in the raphe nuclei and the sub­sequent reduction in the activity of serotonin neu­rons associated with short term administration of the SSRI.lII-131

1.1 Inhibition of Serotonin Uptake

Numerous in vitro studies (reviewed by Milne and Goa[l41) have shown that citalopram inhibits serotonin uptake. These investigations also indi­cate that citalopram is one of the three most potent inhibitors of serotonin uptake available (together with sertraline and paroxetine) and is the most se­lective agent in this respect (table I), with an inhi-

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bition constant (Kj) for serotonin uptake 3077 times lower than that for noradrenaline uptake.[16]

The primary metabolites of citalopram, demethyl­and didemethyl-citalopram, are also highly selec­tive serotonin uptake inhibitors, with in vitro sero­tonin/noradrenaline uptake inhibition ratios of 53 and 64, respectively.[15] The potencies of these me­tabolites as serotonin uptake inhibitors are, how­ever, about 10 times less than that of citalopram,l15]

Ex vivo data on the relative pharmacological activity of citalopram (reviewed by Hyttel[15,17]) confirm that it is one of the most potent and selec­tive serotonin uptake inhibitors available.

1.2 Effects on Receptors

Citalopram has shown very low affinity in vitro (more than 200 times lower than that for the sero­tonin uptake site)[15] for a range of important recep­tor types, including CXI-, CX2-, ~I- and ~2-adrenergic, muscarinic, histamine HI. dopamine 0 1 and 02, benzodiazepine, opioid and y-aminobutyric acid (GAB A) receptors,l14,15,18,19] It also has low affin-ity for a range of serotonin receptors (5-HTIA, 5-HTIB, 5-HT2A, 5-HT2c),114,20]

In contrast to results for several tricyclic anti­depressants, down-regulation of ~-adrenergic re­ceptors has not been reported during long term treatment with citalopram.[21-23] Citalopram, like tricyclic antidepressants, increases the density of cxl-adrenoceptors after repeated treatment,l24] Long term administration of citalopram in rats did not cause any significant adaptive modification of brain

Noble & Benfield

serotonin transporters, 5-HTIB autoreceptors, or 5-HT3 or 5-HT4 receptors.!25] Striatal dopaminergic neurotransmission in humans does not appear to be affected by citalopram,l26]

1 .3 Behavioural Effects

The effects of citalopram in several behavioural models provide indirect evidence for a facilitatory effect on serotonergic neurotransrnission. Citalo­pram, like other serotonin reuptake inhibitors, po­tentiates effects such as tremor, lateral head move­ments and hindlimb rigidity which are caused by administration of serotonin precursors (l-5-hydroxy­tryptophan or tryptophan) or serotonin plus mono­amine oxidase inhibitors to rodents,l14,15,27]

In contrast, citalopram and its metabolites had little or no effect in behavioural models used to as­sess noradrenergic and dopaminergic effects.[14,15,17,27]

Administration of citalopram 10, 20 or 40mg for 8 days had no detrimental effect on psychomotor performance in a placebo-controlled study in healthy volunteers. [28] In fact, citalopram increased thresholds in the critical flicker fusion test in this investigation, indicating improved CNS function.

1.4 Inhibition of Hepatic Cytochrome P450 Systems

Citalopram is metabolised in part by the hepatic cytochrome P450 (CYP) isozyme 206 (section 2.2). Since a variety of other drugs, including tricyclic antidepressants, are eliminated by CYP206,[29] and other SSRIs have been shown to be potent in-

Table I. In vitro inhibition of radiolabelled neurotransmitter uptake by selected antidepressants (data from Hyttel[1S1 and Richelson & Pfenning(161)

Drug Inhibition of uptake (ICsa, nmol/L)

serotonin noradrenaline (5-hydroxytryptamine; 5-HT) (norepinephrine)

Citalopram 1.8 6100

Sertraline 0.19 160

Paroxetine 0.29 81

Fluvoxamine 3.8 620

Fluoxetine 6.8 370

Clomipramine 1.5 21

dopamine

40000

48

5100

42000

5000

4300

Serotonin selectivity (noradrenaline/serotonin uptake inhibition)

ICsa Ki

3400

840 280

160

54 14

3077

71

23

5

Abbreviations: ICso = concentration required to inhibit uptake by 50%; Ki = inhibition constant for blockade of uptake.

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Citaiopram: A Review

hibitors of this system in vitro,[30,31] the potential exists for pharmacokinetic interactions between such drugs when they are coadministered.

In studies using human liver microsomes, cital­opram was a less potent inhibitor of CYP2D6 (Ki = 5.1 Jlmol/U30] and 19 Jlmol/U31]) than paroxet­ine and fluoxetine (Ki values <1 Jlmol/L). The in­hibitory activity of citalopram was about 34[30] and 53[31] times lower than that of the most potent drug (paroxetine) in these analyses.

In vivo results are consistent with in vitro find­ings. Data from a single-dose study in healthy volunteers indicate that, in contrast to fluoxetine and paroxetine (which were both potent inhibi­tors), citalopram and fluvoxamine had only modest activity against CYP2D6P2] Citalopram had no sig­nificant activity against either CYP2Cl9 or CYPIA2 in this study. The result for CYP2Cl9 is unexpected, since this isoform is at least partly involved in the conversion of citalopram to demethyl-citalopram (see section 2.2) and is inhib­ited by citalopram in vitro.

2. Pharmacokinetic Properties

Pharmacokinetic data from healthy volunteers who received multiple-dose oral citalopram are summarised in table II.

Table II. Pharmacokinetic properties of citalopram (CIT) and demethyl-citalopam (DCIT). All data (mean values) are from 12 healthy volunteers who received oral CIT 40 mg/day for 21 days,(331 except for!1,~ (data from 7 healthy volunteers who received CIT 50 mg/day for 18 days )(341

Parameter CIT DCIT

tmax (h) 3.7 5.4

Cmax (nmoI/L) 311 114

AUCO·24h (nmol/L • h) 5607 2380

CUF(Uh) 22.7

CLR (Uh) 3.3a 8.Sa

Excretion (%) 6.0" 16.6a

t1,. (h) 33

a n =9.

Abbreviations: AUCo·24h = area under the plasma concentration­time curve over 24h; Cmax = peak plasma concentration; CLR = renal clearance; CUF = oral clearance; tmax = time to Cmax; \1,. = terminal elimination half-life.

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415

2.1 Absorption and Plasma Concentrations

Citalopram displays high bioavailability (~80%[34,35]) after oral administration to volunteers. Peak plasma concentrations were observed 2 to 4 hours after single or repeated oral doses in volunteers,[33,34,36] with steady-state plasma concentrations (24 to 210 Jlg/L in patients who received 40 mg/day in clinical tri­alS[37-40]) achieved after 1 week in most stud­iesp4,36,41,42]

A linear plasma concentration-dose relationship for citalopram was observed over the dose range 10 to 60mgJ34,36.41-43] Considerable interindivid­ual variability was evident in the ratio of maximum to minimum serum concentration for dose- and weight-related serum citalopram concentration and for serum demethyl-citalopram concentration in 169 psychiatric patients)44]

The plasma concentration of the pharmaco­logically active (S)-(+) enantiomer accounted for between 24 and 49% of the citalopram in the plasma of 29 depressed patients who received 20 to 80 mg/day)45] The mean ratio of the (S)-( +) to (R)-(-) enantiomers for citalopram was 0.65 (n = 5)[46] and 0.56 (n = 29)[45] in patients with depres­sion. For demethyl-citalopram, the ratio was 0.75 [46] and 0.69)45] No clear relationship between plasma concentrations of citalopram and clinical antide­pressant efficacy has been demonstrated)14,35]

The volume of distribution of citalopram has been estimated to be between 12 and 16 LlkgP4]

2.2 Metabolism

Citalopram is a lipophilic molecule which is not readily eliminated by the kidney. Instead, it is me­tabolised by hepatic CYP isozymes to polar meta­bolites which are more easily excreted. Data from an in vivo study in healthy volunteers indicate that the primary metabolite demethyl-citalopram is produced in part via CYP2C 19 and then converted to didemethyl-citalopram, the latter step being partly catalysed by the CYP2D6 isozymeP9] In contrast, results from an in vitro study using human liver microsomes suggest that CYP2C19 plays a relatively minor role in the conversion of citalo-

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pram to demethyl-citalopram [consistent with only minor inhibition of this system by citalopram in vitro[47] (section 1.4)], and that CYP3A4 is the major isoform involvedJ48]

The ratio of parent drug to metabolite is about 2 to 3 for demethyl-citalopram (see table II) and 10 to 15 for didemethyl-citalopramJ35.36,41,43]

2.3 Elimination

When given as a single oral dose to volunteers, citalopram displays an initial distribution phase lasting for about 10 hours, followed by mono­exponential elimination with a half-life (ty~) of about 30 hoursP4,36] Similarly, a ty~ of about 33 hours was recorded when citalopram 50mg was given once daily for 18 days to 7 volunteersp4] Demethyl-citalopram and didemethyl-citalopram are eliminated with a ty~ of about 2 and 4 days, respectivelyJ43]

Estimates for the total clearance of citalopram following oral administration ranged from about 26 to 28 Llh[34,41,49] (2,8 Llh for renal clear­ance[33]). In separate studies involving volunteers (n = 7)[34] or psychiatric patients (n = 15),[50] the proportion of a once-daily citalopram dose which was excreted unchanged into the urine during steady-state treatment was 12[50] and 13%,[34] re­spectively, Almost 70% of the total dose was not detected as parent drug or metabolites, suggesting significant faecal excretion or alternative metabo­lic breakdown.[50]

2.4 Special Patient Groups

Dose- and weight-corrected serum concentra­tions of citalopram and parent drug plus demethyl­citalopram increased linearly with age in a group of 169 psychiatric patients (aged 10 to 89 years).[44] The fraction of demethyl-citalopram decreased significantly with increasing age. Mean clearance decreased and mean tY2 increased in 11 elderly de­pressed patients when compared with values ob­tained for younger healthy volunteers and patients in other studies.[51] Although these results suggest that aging may affect the pharmacokinetics of

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Noble & Benfield

citalopram, direct comparisons between older and younger patients or volunteers are not available.

The steady-state plasma concentration (CSS) of citalopram and demethyl-citalopram [(S)-(+) en­antiomers] ranged from 11.2 to 92.2 ~g/L and 11.0 to 22.0 ~g/L, respectively, in 8 elderly patients with dementia who received citalopram 10 mg/day for 3 days followed by 20 mg/day for 2 weeks.[52] The ratio of (S)-( +) to (R)-( -) enantiomers was 0.65 for citalopram and 1.1 for demethyl-citalopram. Paral­lel comparisons of enantiomer ratios between el­derly and younger individuals are not available.

Renal excretion of citalopram and its metabo­lites is reduced in patients with renal impair­mentP5,43] Similarly, hepatic dysfunction is asso­ciated with reduced clearance (steady-state plasma concentrations increased approximately 2-fold).[35]

2.5 Drug Interactions

Although a number of in vivo drug interaction studies involving citalopram are available, direct comparisons with other SSRIs in this respect are not.

No significant changes in the steady-state con­centrations of haloperidol, chlorpromazine, zuclo­penthixol, levomepromazine, thioridazine or per­phenazine were reported in 90 patients with schizophrenia who continued to take one of these antipsychotic drugs (after at least 3 months' pre­vious treatment) plus citalopram 40 mg/day as part of a placebo-controlled studyJ53] Furthermore, plasma concentrations of citalopram and demethyl­citalopram were stable and within the expected range during the 12-week treatment period.

Similarly, steady-state comedication with cital­opram (median 40mg, range 10 to 80mg) and any one of several antipsychotic agents (perphenazine, thioridazine, periciazine, chlorpromazine, haloper­idol, zuclopenthixol or levomepromazine) pro­duced no significant change in serum citalopram or demethyl-citalopram concentrations in 19 psychi­atric patients compared with those in a group of patients receiving only citalopramJ44]

The addition of citalopram 20 to 60mg once daily to existing treatment with amitriptyline 75

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Citalopram: A Review

to 150 mg/day (n = 3), clomipramine 75 mg/day (n = 1) or maprotiline 150 mg/day (n = 1) produced no significant increase' in the plasma concentra­tions of the tricyclic agents in 5 patients with de­pression.l54] In a second investigation (n = 8 healthy volunteers),[55] citalopram 40mg once daily had no effect on the area under the plasma concen­tration-time curve (AVC) or tY2 of imipramine (sin­gle 100mg dose), but increased the AVC for the primary metabolite desipramine by 50%. In con­trast, steady-state comedication with citalopram (median 40mg, range 10 to 80mg) and clomipram­ine (median 100mg, range 25 to 150mg) signifi­cantly increased the serum concentrations of citalopram and demethyl-citalopram in 12 psychiat­ric patients, compared with those in a group of sim­ilar patients recei ving only citalopram. [44] However, the extent of this increase was not specified.

After 21 days' administration of citalopram 40 mg/day in healthy volunteers, coadministration of cimetidine 400mg twice daily for 8 days reduced the oral clearance of citalopram (by 29%) and in­creased the 24-hour AVC for demethyl-citalopram (by 43%)J33] Elimination of demethyl-citalopram and didemethyl-citalopram was also reduced (re­spective decreases of 26 and 36% for renal clear­ance and 17 and 31 % for urinary excretion). Nev­ertheless, the authors of this study concluded that citalopram dosage reduction is not required when the drug is coadministered with cimetidine, be­cause of the moderate extent of pharmacokinetic interaction, the high degree of interindividual pharmacokinetic variability and the overall toler­ability profiles of the 2 drugs.

The pharmacokinetic interaction between cital­opram and fluvoxamine was studied in 7 patients who had failed to respond to 3 weeks' treatment with citalopram 40 mg/day.l56] Addition offluvox­amine (50 mg/day on days 1 to 7, 100 mg/day on days 14 to 21) to the existing citalopram regimen produced a significant increase in plasma concen­trations of both citalopram enantiomers 019,167 and 207% increase after 7, 14 and 21 days for the pharmacologically active form) [p < 0.02]. Fluvoxamine augmentation also significantly in-

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417

creased the ratio of the (S)-( +) to (R)-( -) citalopram enantiomers (from 0.48 at baseline to 0.84 after 7, 14 and 21 days).

No significant pharmacokinetic interaction was observed between single-dose warfarin and multi­ple-dose citalopram in a crossover study in 12 healthy volunteers.l57]

3. Clinical Efficacy

The antidepressant effects of citalopram have been assessed in numerous comparative studies. Most patients had a Hamilton Depression Rating Scale (HDRS)[58] score ~18 or a Montgomery­Asberg Depression Rating Scale (MADRS)[59] score ~22 at baseline. The principal methods used to measure antidepressive efficacy were the HDRS, MADRS and Clinical Global Impression (CGI) scale.l60] Citalopram was given once daily in all studies.

3,1 Placebo-Controlled and Dose-Finding Studies

3. 1. 1 General Depression Citalopram was generally more effective than

placebo (p < 0.05), as assessed by statistical com­parisons of standard rating scores at study end­points, in a number of randomised, double-blind studies in patients with major depression.l61 -65] However, it should be noted that the absolute extent of the benefit over placebo varied some­what, depending on the parameter being used.

Citalopram 20 to 80 mg/day was significantly more effective than placebo according to both pri­mary (HDRS) and secondary (CGI and Zung self­rating scale) assessments in 180 patients with mod­erate to severe depression (this study has not yet been published in full).l62] The reduction from baseline in total HDRS score (last observation car­ried forward after 4 weeks' treatment) was 39% in the citalopram group compared with 27% in the placebo group. For the CGI severity item, the im­provement from baseline was 21 % with citalopram and 15% with placebo.

Reductions from baseline rating scores of about 45% (HRDS) and 50% (MADRS) were noted with

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citalopram 10 to 30 mg/day compared with reduc­tions of 24% (HDRS) and 38% (MADRS) with placebo (p < 0.05) in 133 elderly patients.£65] The proportion of these patients who showed ~50% improvement from baseline was similar for citalo­pram and placebo using HDRS but greater with citalopram than with placebo for MADRS (53 vs

28%, P < 0.05). Similarly, patients who received citalopram had a higher rate of overall improve­ment in CGI (60%) than those in the placebo group (24%; p < 0.05) after 6 weeks. However, the inci­dence of withdrawal from the study as a result of inadequate efficacy (no effect or deterioration) was similar for the 2 groups (24 vs 22%).

Meta-analysis of 5 placebo-controlled clinical trials involving a total of 396 patients indicated that the proportion of patients with a reduction in HDRS score of ~50% was either 15% (intention­to-treat analysis) or 18% (efficacy analysis) higher with citalopram than with placebo (p < 0.05).£66]

The largest available dose-finding study of citalopram compared the efficacy of 10, 20, 40 and 60 mg/day with that of placebo in 650 patients with moderate to severe depression;[61] however, this trial has not been published in full. Although only citalopram 40 and 60 mg/day were significantly more effective than placebo in reducing the total HDRS score (p < 0.05), all 4 citalopram groups had a significantly greater improvement in the HDRS depressed mood item than placebo recipients (p < 0.05). Furthermore, citalopram 10, 20, 40 and 60 mg/day were all significantly more effective than placebo (p < 0.05) according to analysis of the percentage of patients with a ~50% reduction in MADRS score [=50, 50, 60 and 57.5%, respec­tively, vs 32% (estimated from a graph)]. Citalopram 40 and 60 mg/day generally provided the highest level of clinical improvement in this study.

The results from the large dose-finding study[61] are broadly consistent with those from a meta­analysis[67] of 949 patients who took part in 9 pla­cebo-controlled studies of citalopram. A daily dose of 20mg was the minimum necessary for a clini­cally superior effect relative to placebo, but higher daily doses (40 or 60mg) were optimal for the treat-

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Noble & Benfield

ment of patients with severe or recurrent depres­sion.

No significant differences in CGI, HDRS or MADRS scores were observed between citalopram 20 mg/day and placebo in 106 patients with mod­erate or severe depression.[64] However, citalopram 40 mg/day was significantly more effective than citalopram 20 mg/day and placebo according to the same criteria after 6 weeks (quantitative data on the extent of clinical improvement were not pro­vided).

The effect of adding lithium to treatment with citalopram was assessed in 24 patients with depres­sion who had not responded to 4 weeks' treatment with citalopram 20 to 60 mg/day (44 other patients responded to the initial phase of citalopram ther­apy).£68] After I additional week of combination therapy, complete response (~50% reduction in HDRS score) was more common in patients who received lithium 800 mg/day plus citalopram (6 of 10) than in those who received placebo plus citalopram (2 of 14). The total HDRS and CGI scores in the lithium plus citalopram group were significantly lower than those in the citalopram plus placebo group (p < 0.05). When patients in the latter group were switched to receive lithium plus citalopram for a further week, the number of com­plete responders increased from 2 of 14 to 8 of 14.

3.1.2 Post-Stroke Depression Improvements in HDRS and MADRS scores

were significantly greater for citalopram than for placebo in a 6-week study in patients with post­stroke depression (p < 0.05; mean patient age >65 years).£63] HDRS scores were reduced by 41 % (in­tention-to-treat analysis; n = 33) and 48% (efficacy analysis; n = 27) in patients treated with citalopram 10 to 40 mg/day, compared with 25% (n = 33) and 26% (n = 32), respectively, in patients who re­ceived placebo. For MADRS scores, the reductions were 41 % (intention-to-treat) and 47% (efficacy) for citalopram and 25% (both analyses) for pla­cebo. There was no significant difference between citalopram and placebo in HDRS score reduction in patients who had experienced stroke within 6 weeks of entering the trial. However, in patients

eNS Drugs 1997 Nov; 8 (5)

Citalopram: A Review

who entered the study 7 weeks or more after stroke, reductions in HDRS scores were significantly greater with citalopram (46%) than with placebo (16%; p < 0.005). Furthermore, 12 of 18 patients (67%) in this group responded to treatment with citalopram compared with 3 of 20 patients (15%) for placebo (statistical significance not provided).

3.1.3 Relapse Prevention Prevention of recurrent depressive episodes has

been studied in 2 groups of patients who responded to short term treatment with citalopram.[69,70] De­pressed patients who had a MADRS score of ~12 after 8 weeks of treatment with citalopram re­ceived double-blind continuance treatment with citalopram 20 to 60 mg/day (patients received the dosage which was effective in the short term phase; n = 152) or placebo (n = 74) for 6 months in one studyPO] Relapse (MADRS score ~25) occurred in 13,8% of patients treated with citalopram and 24.3% of patients treated with placebo (p < 0.05). The risk of relapse was highest in the first 2 months of continuance treatment, during which there were no significant differences between treatments. In the final 3 months of treatment, relapse was ap­proximately 3 times more likely to occur in the placebo group than in the citalopram group (statis­tical significance not provided).

Citalopram 20 and 40 mg/day had similar effi­cacy in preventing relapse (MADRS score ;::::22) and were significantly better than placebo in 147 pa­tients who had responded to acute treatment with citalopram for 6 weeks (MADRS score ~12).l69] Relapse rates after 24 weeks of continuation treat­ment were 8 and 12% with citalopram 20 and 40mg, respectively, and 31 % with placebo (p < 0.05 vs both active treatments).

3.2 Comparative Studies

3.2.1 Comparisons with Tricyclic and Tetracyclic Antidepressonts

Clinical Trials Citalopram has been compared with a variety of

tricyclic and tetracyclic antidepressant agents in several well controlled clinical trials (table III). Dosages of both citalopram and comparator agents

© Adis Intemafional Limited. All rights reserved.

419

were titrated to achieve therapeutic efficacy, where appropriate, in most studies.

Reductions in HDRS or MADRS scores ranged from about 43 to 81 % with citalopram and from 56 to 71 % with reference antidepressants in a number of studies lasting up to 6 weeksJ37,38,40,73]

In the largest prospective study to date, cital­opram was compared with the tricyclic agent imip­ramine in more than 400 patients from general practice who had HDRS scores of;::::14 (mean score at baseline was ",22)p3] Reductions in HDRS scores in patients treated with citalopram 10 to 30 mg/day (20 or 30 mg/day in week 3 onwards), citalopram 20 to 60 mg/day (40 or 60 mg/day in week 3 onwards) and imipramine 50 to 150 mg/day (100 or 150 mg/day in week 3 onwards) were sim­ilar after 6 weeks (primary study end-point) and 22 weeks (continuation phase) [fig. 1]. In addition, the number of responders (;::::50% reduction) for HDRS scores at the same timepoints was similar in the citalopram and imipramine groups (63.6,59.5 and 57.6% at 6 weeks; 81.6, 86.6 and 88.9% at 22 weeks). The number of patients classified as being 'much' or 'very much' improved on the CGI was also similar for all 3 treatments after 6 and 22 weeks. Four patients each in the 2 citalopram groups withdrew from the study because of a lack of efficacy (no change or deterioration), compared with 1 patient in the imipramine group.

Citalopram also had similar antidepressant ef­ficacy to the tetracyclic antidepressant agent map­rotiline in 90 depressed patients in a 6-week study[38] (fig. 2). There were no significant differ­ences between the treatments when patients were analysed according to subgroup diagnoses (endog­enous or non-endogenous depression and melan­cholic or non-melancholic patients). Analysis us­ing the CGI produced similar results to those with theMADRS.

In contrast to the studies above, citalopram was less effective than the tricyclic agent clomipram­ine in 102 inpatients with depression.l72] When the total study population (patients with endogenous and non-endogenous depression) was analysed, 60% of patients receiving clomipramine and 30% of

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420 Noble & Benfield

Table III. Comparative efficacy of citalopram (CIT) and tricyclic or tetracyclic antidepressants: summary of data from randomised double-blind studiesa

Reference (type of pts) Study Treatment and No. of Assessment Comparative Comments duration dosage (mg od evaluable methods efficacy (total (wk) PO) ptsb rating scores)C

Comparisons with amitriptyline (AMI)

Gravem et al[39] (inpt + 6 CIT 20-60 19 +4 MADRS CIT=AMle AMI> CIT for reduced sleep outpt)d AMI 75-225 19 + 1 at weeks 1 and 3e

Shaw et al[71] (inpt + outpt) 6 CIT 20-60 24 total HDRS, MADRS CIT=AMI

AMI 75-225 20 total

Comparison with clomipramine (CLO)

Danish University 5 CIT 40 38 + 12 HDRS CLO>CIT CLO > CIT for sleep Antidepressant Groupl72]

CLO 150 37 + 15 disturbance (weeks 1 to 5) (mainly inpt) and depression/guilt (week

3)e

Comparison with imipramine (IMI)

Rosenberg et a1. 173] (gp) 6 CIT 10-30 165 totale HDRS, CGI CIT=IMI CIT = IMI for pts who

CIT 20-60 163 totale continued treatment to 22wk (n = 280)

IM150-150 85 totale

Comparisons with maprotiline (MAP)

Bouchard et al. [38] (NS) 6 CIT 40-60 18+28 CGI, MADRS CIT=MAP

MAP 75-150 17 + 27

Timmerman et al.[74] (inpt)1 4 CIT 40-60 8+6 HDRS CIT=MAP

MAP 75-150 8+5

Comparisons with mianserin (MIA)

Ahlfors et al.[40] (inpt) 4 CIT 40-60 17 + 11 MADRS Endogenous: MIA> CIT for several

MIA 60-90 14 + 14 CIT=MIA; MADRS items (1 in non-endogenous: endogenous group, 7 in MIA>CIT non-endogenous group); MIA

> CIT for global assessment at weeks 1 and 2 in pts with endogenous depression

de Wilde et al.[37] (inpt) 6 CIT 40-80 29 totale CGI, MADRS CIT=MIA MADRS: CIT> MIA for

MIA60-120 29 totale several items during treatment and for total score at weeks 1 and 2; CGI: CIT> MIA for total score at week 2

a Concomitant treatment with sedative or neuroleptic agents (usually benzodiazepines) was permitted where appropriate in most studies.

b Endogenously depressed + non-endogenously depressed according to the Newcastle Scale I.

c At study end-point.

d All pts were severely depressed, with a high frequency of previous depressive episodes and mental disorders among close relatives.

e Efficacy analysis; last observation carried forward to study end-point.

Pts with severe depression.

Abbreviations and symbols: CGI = Clinical Global Impression; gp = general practice; HDRS = Hamilton Depression Rating Scale; inpt = inpatients; MADRS = Montgomery-Asberg Depression Rating Scale; NS = not stated; od = once daily; outpt = outpatients; PO = orally; pts = patients; > indicates significantly better (p < 0.05) efficacy than comparator; = indicates similar efficacy to comparator.

© Adis International Lirnited. All rights reserved. eNS Drugs 1997 Nov: 8 (5)

Citalopram: A Review

100

l 80 Q) c 'ai ~ ~ § 60

812 .::0 c :I: 40 ~ .S:

-g II: 20

C IT 10·30 mglday

o CIT 20·60 mglday

o IMISO· 1S0 mglday

4 6 Week

22

Fig. 1. Comparative efficacy of citalopram (CIT) and imipramine (IMI) in general practice patients with depressionF3J Reductions from baseline in Hamilton Depression Rating Scale (HDRS) scores during once-daily treatment in a randomised, double­blind multicentre study. Treatment regimens: CIT 10 to 30 mg/day = 10 mg/day week 1, 20 mg/day week 2, 20 or 30 mg/day week 3 onwards; CIT 20 to 60 mg/day = 20 mg/day week 1, 40 mg/day week 2, 40 or 60 mg/day week 3 onwards; IMI 50 to 150 mg/day = 50 mg/day week 1, 100 mg/day week 2, 100 or 150 mg/day week 3 onwards. Main study period was 6 weeks, with an optional continuation phase for a further 16 weeks. Num­ber of patients at baseline/after 22 weeks: CIT 10 to 30 mg/day = 165/114; CIT 20 to 60 mg/day = 163/112; IMI50 to 150 mg/day = 85/54.

those recelvmg citalopram had a complete re­sponse (no depression) at the end of the study pe­riod (p < 0.005). In addition, individual HDRS item scores for sleep disturbance (weeks I to 5) and depression/guilt (week 3) were significantly greater with citalopram than with clomipramine (p < 0.05). In the subgroup of patients with endoge­nous depression (n = 75), there was a statistically significant difference in favour of clomipramine in total HDRS scores after 2,3 and 4 weeks (p < 0.05), but not after 5 weeks.

Somewhat variable results regarding relative efficacy have emerged from 2 much smaller, but well controlled, clinical trials.[37,40] Both involved about 60 patients with depression and compared citalopram with the tetracyclic antidepressant mian­serin (table III). One study revealed that citalo­pram was as effective as, or more effective than, mianserin;[37] conversely, mianserin had efficacy

© Adis International Limited. All rights reserved.

421

similar to or greater than that of citalopram in the other triaU40]

Two relatively small studies compared citalo­pram with the tricyclic antidepressant amitripty­line[39.71] (table III); the 2 drugs had similar anti­depressive efficacy in both investigations .

Meta-Analyses Indications of broadly similar efficacy for cit­

alopram and tricyclic antidepressants in prospec­tive clinical trials[39,71,73] are supported by a meta­analysis of 5 published and unpublished studies which compared citalopram with these reference agents [amitriptyline (2 studies), clomipramine, nortriptyline and imipraminej.l66] On the basis of HDRS responses in 327 patients, no differences were detected between citalopram and the tricy­clic drugs when both intention-to-treat and effi­cacy analyses were used. A separate meta-analysis of 125 patients who received citalopram or ami­triptyline in 2 clinical trials suggests that these treatments are similar in efficacy.[66]

A meta-analysis[75] of 270 patients who were treated in 5 clinical trials also failed to detect any statistically significant differences in efficacy be­tween citalopram and reference antidepressants (maprotiline,[38,74] clomipramine[72] or amitripty­line[39.7J]). However, in the 2 trials in which only inpatients were enrolled, a small to moderate effect in favour of the comparator antidepressant (c1omip­ramine[72] or maprotiline[74]) was detected.[75]

Cost Effectiveness The relative cost effectiveness of I-year main­

tenance therapy with citalopram compared with standard episodic treatment with traditional tricy­clic agents (doxepin, amitriptyline and trimipram­ine) has been modelled for a German healthcare setting using decision analysis techniques (costs were obtained from standard German tariffs and clinical data were from published studies and US clinical practice guidelines).l76] Long term mainte­nance treatment with citalopram was predicted to be more effective and less costly than standard episodic treatment with antidepressants, although these efficacy data were not derived from compar­ative clinical studies. In this model, it was assumed

CNS Drugs 1997 Nov; 8 (5)

422

40 D CIT

35 r-f--

D MAP

30

~ 25 a " til

c--f--rJ) 20 a: 0 « :::a 15

~r--

0-r-

10 ,.- r---

5

0 o 2 4 6 Week

Fig. 2. Comparative efficacy of citalopram (CIT) and maprotiline (MAP) in patients with depression.13s1 Mean Montgomery­Asberg Depression Rating Scale (MADRS) scores in patients who received CIT 40 to 60mg (n = 46) or MAP 75 to 150mg (n = 44) once daily for 6 weeks in a randomised double-blind multi­centre trial.

that time without depression was 7.9% higher in patients receiving citalopram maintenance treat­ment than in those receiving standard therapy. Re­sulting total costs (direct and indirect) during the 12-month treatment period were approximately 33% lower for citalopram initial plus maintenance therapy [DM7985 (1993 Deutschmarks)] than for episodic treatment with TCAs (DM II 948).

3.2.2 Comparisons with Other SSRls Two large clinical trials have compared the

efficacy of citalopram with that of fluoxetine, one in patients from general practice,[77) the other in a group of psychiatric inpatients and outpatients[78) (table IV).

In both investigations, there were no significant between-group differences in the reduction in total MADRS score from baseline to week 8 (the pri­mary efficacy end-point). Similarly, the number of patients with a ~50% reduction from baseline in MADRS score or a MADRS score ~12 (complete response) at 8 weeks did not differ significantly between the 2 treatment groups in either study. Equivalent efficacy for citalopram and fluoxetine was also indicated by analysis of results for HDRS, CGI severity of illness ratings and global evalua-

© Adis International Limited. All rights reseNed.

Noble & Benfield

tion of improvement at study end-points. However, citalopram 20 mg/day had a significantly faster on­set of action than fluoxetine 20 mg/day in the gen­eral practice study: after 2 weeks' treatment, more citalopram than fluoxetine recipients had a com­plete response as measured using the MADRS (27 vs 16%; p = 0.034) [fig. 3] or HDRS (quantitative data not provided, p = 0.025), or a ~50% reduction from baseline in MADRS score (35 vs 24%, P = 0.048).[77) A more rapid therapeutic onset for citalopram than for fluoxetine was also evident in the subgroup of patients with severe depression (HDRS score ~25, n = 96) at baseline in the psy­chiatric study. After 2 weeks, 16% of such patients who received citalopram showed a complete re­sponse (HDRS score ~7), compared with none of those who received fluoxetine (p = 0.003).[78)

Cita)opram has also been compared with the SSRI fluvoxamine in a single well controlled study in 217 outpatients with major depression(79) (table IV) [this trial was designed primarily to com­pare tolerability]. Mean HDRS scores at all time­points were similar for patients receiving citalo­pram or fluvoxamine, as was the overall reduction from baseline in HDRS score at week 6 (study end­point) [table IV]. Similarly, the proportion of pa­tients who had a complete response (HDRS score ~7) did not differ significantly between groups (14 vs 9%). Analysis using the CGI and the Zung self­rating depression scale confirmed the similar over­all efficacy of the 2 drugs. The overall level of clin­ical response in this study was relatively low (table IV); this may have been due to the fact that many patients had a prolonged current depressive epi­sode and had proved refractory to other antidepres­sive treatments.

4. Tolerability

4.1 General Tolerability Profile

4. 1. 1 Adverse Events Data from a meta-analysis of 746 depressed pa­

tients who took part in several short term, double­blind studies indicate that the most frequent ad­verse events associated with citalopram are

eNS Drugs 1997 Nov; 8 (5)

Citalopram: A Review 423

Table IV. Comparative efficacy of citalopram (CIT) and other selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors: summary of data from randomised, double-blind, multicentre clinical trials

Reference Study Treatment No. of HDRS MADRS Overall efficacy· (type of pts) duration and dosage pts reduction ptswith reduction ptswith

(wk) (mgod PO) from <:50% from <:50% baseline reduction baseline reduction in total from baseline in total from score (%) (%) score (%) baseline (%)

Comparison with fluvoxamine (FLY) Haffmans et al.[79J 6 CIT20-40b 108e 33 31 CIT",FLV (outpt) FLV 100-200d 10ge 27 28

Comparisons with fluoxetlne (FLX) Bougerol et al.[78J (inpt 8 CIT 40 147" 63 69 CIT",FLX +outpt) FLX20 149" 64 73

Palris et alF7J (gp) 8 CIT 20 153" =60' 70 78 CIT", FLX (CIT> FLX

FLX20 161" =60' 66 76 for onset of action)

a Based on comparison of total rating scores for the primary efficacy assessment (HDRS[79J or MADRs[77·78J) at study end-point.

b 20mg od (in the evening) for 1 wk, 30mg od for 3wk; latter dosage was continued through weeks 4 to 6 or increased to 40mg od if clinical response was insufficient.

c Intention-to-treat analysis.

d 100mg od (in the evening) for 1 wk, 150mg bid (50mg at noon, 150mg in the evening) for 3wk; latter dosage was continued through weeks 4 to 6 or increased to 200mg bid (100mg at noon and in the evening) if clinical response was insufficient.

e Evaluable pts who received at least 14 days' treatment.

Estimated from a graph.

Abbreviations and symbols: bid = twice daily; gp = general practice; HDRS = Hamilton Depression Rating Scale; inpt = inpatients; MADRS = Montgomery-Asberg Depression Rating Scale; od = once daily; outpt = outpatients; PO = orally; pts = patients; > indicates significantly better (p < 0.05) efficacy than comparator; '" indicates similar efficacy to comparator.

nausea/vomiting (20%), increased sweating (18%) and dry mouth and headache (17% ) JSO]

Serious cardiovascular adverse events have not been reported during clinical trials of citalopram, several of which reported no significant changes in ECG measurements for patients receiving the drugPS,40,63,72,74] Furthermore, serious cardiovas-cular events have not been recorded during post­marketing surveillance of depressed patients who received citalopram,l35] Data from 374 patients who either had pre-existing cardiac disease or were also receiving agents likely to cause ECG abnormalities (including tricyclic agents, antipsychotics, cal­cium antagonists, ~-blockers, ~-agonists or digi­talis) indicated no evidence of citalopram-induced QTc (QT interval corrected for heart rate) ECG changes (manufacturer's data on file reported by Baldwin and Johnson[SI]). Citalopram had no sig­nificant effect on ECG patterns and did not induce arrhythmia in 1160 patients (30% of whom were

© Adis Intemaflonal Umlted. All rights reserved.

over 60 years of age) in phase II and III clinical trials.[35]

The incidence and severity of adverse events in elderly patients receiving citalopram appears to be similar to that noted for younger patients,[51,65] although direct comparisons have not been re­ported. The proportions of patients (aged ~65 years) who experienced no adverse events during a 6-week double-blind trial (n = 133) were 63% for citalopram and 75% for placebo.[65] Although global ratings indicated more adverse events with citalopram than with placebo after 2 weeks, this difference was not apparent at weeks 4 and 6. Heart rate showed a significant reduction compared with baseline (6 beats/minute) for citalopram at week 4 (p < 0.05).

Sexual dysfunction (including diminished libido, delayed orgasm or anorgasmia) has been reported in as many as one-third of patients treated with some other SSRls.[S2] Anorgasmia and reduced li-

eNS Drugs 1997 Nov; 8 (5)

424

(\J 80 v Q)

o OJ

~ 60 II: Cl « ::;: OJ 40 §

= .~

t 20 en c: Q)

~ 0.. 0 II I

D elT DFLX

-

I n 2

r---

r--

4

Week

I""""""' t--

6

~

-

8

Fig. 3. Comparative efficacy of citalopram (CIT) and fluoxetine (FLX) in general practice patients with depression.l771 Percent­age of patients who had a complete response [Montgomery­Asberg Depression Rating Scale (MADRS) s12] during 8 weeks of once-daily treatment with CIT 20mg (n = 153) or FLX 20mg (n = 161) in a randomised, double-blind multicentre trial. Sym­bol: * p = 0.034 vs FLX.

bido have each been reported in a single patient treated with citalopram.[83,84J It is not clear whether impaired sexual function was specifically investi­gated as part of the adverse event reporting in most clinical trials. However, the incidence of anorgas­mia in a clinical trial in 475 patients with panic disorder was 1 % with citalopram 10 or 15 mg/day, 9% with 20 or 30 mg/day and 10% with 40 or 60 mg/day, compared with 10% in those treated with clomipramine 60 or 90 mg/day [no significant dif­ferences between treatments; incidence in the citalopram 20 or 30 mg/day and 40 or 60 mg/day groups, and in the clomipramine group, was signif­icantly greater than that with placebo (O%)]JIJ There are 3 case reports of transient clitoral pria­pism during the second week of citalopram therapy (painful in 2 patients, associated with sexual arousal in the third)J85J There was no recurrence of this event in any of the patients, despite continued citalopram treatment.

Phasic craving for carbohydrate and accompa­nying weight gain was reported during short term (up to 4 weeks) treatment with citalopram 20 to 40 mg/day in 8 of 18 patients with anxiety or mood disorders.[861 This effect is unexpected, since en-

© Adis International Umited. All rights reserved .

Noble & Benfield

hancement of serotonergic neurotransmission is gen­erally associated with a reduction in carbohydrate intakeJ86J

4. 1.2 Overdose It is generally accepted that the SSRls are less

toxic than tricyclic antidepressants when taken in overdose during suicide attempts.[87] There have been 4 cases of fatal overdose involving patients who ingested between 840 and 3920mg of citalo­pram (based on amount of drug missing from pack­ages found nearby). Drugs other than citalopram [ethanol, diazepam, demethyldiazepam, zopiclone and/or paracetamol (acetaminophen)] were de­tected at relatively low concentrations in the blood of 3 of the 4 patients.[8RJ Two additional cases of fatal citalopram overdose have been reported, but the probable ingested dose in these individuals was unknown (although one individual was known to have ingested I 960mg of citalopram alone I week prior to death); ethanol or other drugs were also detected at low concentrations in these patients.[88J The postmortem citalopram concentration in the 6 patients ranged from 5.2 to 49 Ilg/g of femoral vein blood (equivalent to 15 to 150 IlmoIlL); this com­pares with a reported postmortem blood concen­tration after standard therapeutic use of 0.3 Ilg/g. Arrhythmia and seizures have been suggested as possible causes of death , but this has not been proved.

Of interest, an additional 58 nonfatal citalo­pram overdoses have been reported in which the amount of drug ingested [400 to 5200mg (n = 5)[89J and 600 to 5200mg (n = 53)[901] was similar to that in the fatal overdoses.[88J Personne et aJ.l90J re­ported that convulsions were seen in 6 of 34 pa­tients who ingested citalopram 600 to 1900mg and in 9 of 19 patients taking 1900 to 5200mg; no clin­ically significant arrhythmia was seen in these pa­tients and there were no deaths.

Three fatal cases of serotonin syndrome have been reported after overdose with citalopram plus the monoamine oxidase inhibitor moclobemide.[9IJ However, the concentrations of moclobemide in the blood at autopsy were considerably higher, and exceeded normal therapeutic concentrations to a

eNS Drugs 1997 Nov; 8 (5)

Citalopram: A Review

greater degree, than those of citalopram in each case.

4.2 Comparisons with Traditional Antidepressants

Accurate assessment of differences in tolerabil­ity between citalopram and traditional antidepres­sants is difficult, since most comparative trials were relatively small (only 2 studies involved more than about 100 patients in total). For this reason, meta-analysis has also been used, in an attempt to assess effects across a greater number of patients.

In a 6-week multi centre study of more than 400 general practice patients with depression,l73J sev­eral adverse events, including anticholinergic and cardiovascular phenomena, occurred significantly less often with citalopram than with imipramine (fig. 4). Dry mouth and nausea were the most com­mon adverse events in citalopram recipients. Ad­verse events were considered 'acceptable' (mini­mal or no influence on daily performance) by 75% of patients receiving citalopram 10 to 30 mg/day (20 or 30 mg/day in weeks 3 to 6), 70% of those receiving citalopram 20 to 60 mg/day (40 or 60 mg/day in weeks 3 to 6) and 59% ofthose receiving imipramine 50 to ISO mg/day (100 or 150 mg/day in weeks 3 to 6) [p < 0.05 for citalopram 10 to 30 mg/day vs imipramine]. Withdrawals due to ad­verse events accounted for 6 or 10% of patients receiving citalopram 10 to 30 mg/day or 20 to 60 mg/day, respectively, compared with 13% of those receiving imipramine 50 to 150 mg/day.

Useful tolerability data are also available from a large study comparing citalopram with clomip­ramine in 475 patients with panic disorder. lll Citalopram produced significantly less dry mouth [12% (10 or 15 mg/day), 12% (20 or 30 mg/day) or 17% (40 or 60 mg/day)] than clomipramine 60 or 90 mg/day (33%) [p value not stated]. In addi­tion, dizziness was significantly more common in clomipramine-treated patients (18%) than in those treated with citalopram 40 or 60 mg/day (7%) [p value not stated]. However, citalopram was asso­ciated with a significantly higher incidence of headache [33% (10 or 15 mg/day) or 29% (40 or

© Adis Internotional Limited. All rights reserved .

Asthenia

Somnolence ~_--'-_...,

• CIT 10-30 mg/day o CIT 20-60 mg/day o IM150-150 mg/day

Nervousness 1---.......

Insomnia

Tremor r----'--...,

Dry mouth f------...L:....-----.,

Nausea ~ __ -I

Constipation f----1-----,

Postural hypotension ~.l.:..-_ .....

Tachycardia ~...L:.... __ ....,

Increased p--a:..., sweating

o 10 20 30 40 Patients (%)

50

425

60

Fig_ 4_ Comparative tolerability of citalopram (CIT) and imipra­mine (IMI) in general practice patients with depression.[731 Ad­verse events occurring with total incidence ~1 0% among all patients (corrected for baseline events) during a 6-week, randomised, double-blind multicentre study. Treatment re­gimens: CIT 10 to 30 mg/day = 10 mg/day week 1, 20 mg/day week 2, 20 or 30 mg/day week 3 onwards (n = 187); CIT 20 to 60 mg/day = 20 mg/day week 1, 40 mg/day week 2, 40 or 60 mg/day week 3 onwards (n = 193); IMI 50 to 150 mg/day = 50 mg/day week 1, 100 mg/day week 2, 100 or 150 mg/day week 3 onwards (n = 92). Symbol: * p < 0.05 vs 1M!.

60 mg/day)] than clomipramine (16%), and also a significantly higher incidence of abdominal pain [5% (20 or 30 mg/day) or 7% (40 or 60 mg/day) vs

0% with clomipramine]. In contrast to results from the studies discussed

above, there were no significant differences in the incidence of individual adverse events between pa­tients receiving citalopram 40 to 60 mg/day and those receiving maprotiline 75 to 150 mg/day in a 6-week clinical trial (n = 90»)38J The incidence of

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cardiovascular events (orthostatic symptoms and tachycardia) was 13% with citalopram and 18% with maprotiline, and no significant difference was seen between groups in heart rate, blood pressure or ECG measurements. Nausea was reported by 5 patients who received citalopram (n = 46) but was absent in maprotiline recipients (n = 44). Two pa­tients receiving maprotiline withdrew because of adverse events (drowsiness and hypotension in 1 patient and tremor, irritability and insomnia in the other) and there were no withdrawals from the citalopram group.

The largest meta-analysis available analysed data from 139 patients treated with citalopram and 144 patients treated with tricyclic antidepres­sants.(80) Anticholinergic effects were significantly less common in citalopram recipients than in pa­tients receiving tricyclic agents (= 17 vs 27% for constipation, =24 vs 42% for dry mouth and = 19 vs 34% for accommodation disturbances; p < 0.05). Confusion and dizziness were also significantly less common with citalopram (p < 0.05). In con­trast, nausea/vomiting and reduced sleep occurred more frequently with citalopram (=28 and 19%, respectively) than with tricyclic agents (=17 and 7%, respectively) [p < 0.05]. The severity of most individual adverse events was lower at the end of the treatment period than at baseline in patients treated with citalopram; however, slight increases in severity were seen in the first few weeks of treat­ment for tremor, nausea and tendency to sweat (statistical analysis not provided). Accommoda­tion disturbance was the only adverse event which increased in severity during treatment with cital­opram. Cardiovascular events were not reported in this study, which dealt with only the 10 most com­monly reported adverse events.

A meta-analysis of 2 clinical trials involving a total of 137 patients indicated that citalopram pro­duced a significantly lower incidence of dry mouth and tremor than the tricyclic agent amitriptyline (3.5 vs 27.1 % and 0 vs 12.5%, respectively; inten­tion-to-treat analysis).[66) Headache, sweating and nausea occurred with similar frequency for both treatments.

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Noble & Benfield

4.3 Comparisons with Other SSRls

Data from 2 large well controlled clinical trials (one in patients from general practice,(77) the other in psychiatric inpatients and outpatients(78)) indi­cate that citalopram and fluoxetine have broadly similar tolerability profiles.[77.78) Most adverse events occurred in fewer than about 5% of citalo­pram recipients, the exceptions being nausea (10[77) or 15%(78)), headache (10%[78)) and abdominal pain (8%[78)). Adverse events occurring in >5% of flu­oxetine recipients were nausea (8[77) or 10%[78)), headache (10%[78)) and weight decrease (8%[77)).

There were no significant differences between treatment groups in the incidence of most adverse events in these 2 studies. Back pain occurred in 4% of citalopram recipients but was absent in flu­oxetine recipients in the general practice trial (p = 0.03);[77) however, this event has not previously been reported in patients receiving citalopram or, indeed, in patients treated with other SSRIs. In the other study, vomiting was significantly more common in citalopram recipients than in fluoxetine recipients (3.8 vs 0%, P = 0.03).[78) However, this difference was apparent only during the first week of treatment. It should be noted that the citalopram dosage in this trial was twice that recommended as the appropriate starting dosage (section 5).

Citalopram 20 to 40 mg/day was associated with significantly less nausea and diarrhoea than flu­voxamine 100 to 200 mg/day (p ::;; 0.026) in a ran­domised comparative trial.(79) However, fluvoxam­ine was started at a dosage twice that normally recommended (50 mg/day). The incidence of both events in citalopram recipients was highest in week 1 (nausea: 25 vs 35% with fluvoxamine; diarrhoea: 9 vs 14%). The difference in the incidence ofnau­sea was apparent at all timepoints, whereas the in­cidence of diarrhoea was similar for citalopram and fluvoxamine recipients after 6 weeks. The higher incidence of nausea (and a trend towards a higher incidence of vomiting) in the fluvoxamine group was reflected in a significantly greater need for an­tiemetic therapy. There were no statistically signif­icant differences between groups for other adverse events; 14% of citalopram recipients and 21 % of

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Citalopram: A Review

fluvoxamine recipients withdrew from the study because of adverse events.

5. Dosage and Administration

An initial oral citalopram dosage of 20mg once daily is recommended for the treatment of de­pressed patients, titrated to a maximum of 60mg daily depending upon patient response.[351 A treat­ment duration of at least 6 months is recommended for the prevention of relapse,£351 Citalopram 20 to 30 mg/day is recommended for elderly patients,£351 Dosage adjustment is not required in patients with mild or moderate renal failure; there is no informa­tion on the use of citalopram in patients with severe renal impairment.[35] The maximum recommended dosage for patients with hepatic dysfunction is 20 to 30 mg/day.[351 Citalopram should not be given to patients who are receiving monoamine oxi­dase inhibitors,£351

6. Place of Citalopram in the Management of Patients with Depression

Depression is a debilitating psychiatric disorder which presents numerous challenges to patients and their families, healthcare professionals and society in general. It is a common condition which is often chronic and recurrent, is associated with high rates of mortality and is associated with sig­nificant socioeconomic costs (table V).

During the last decade, the place of the tricyclic antidepressants as first-line therapy for depression has increasingly been taken by the SSRls, which are now widely accepted as having similar overall efficacy, a better tolerability profile and a lower likelihood of causing death when taken in over­dose. [87,97,981

The efficacy of the SSRls in inpatients with se­vere depression has been controversial, as a result of conflicting results from clinical trials (reviewed by Cohen[971). Nevertheless, the bulk of the avail­able clinical data suggests that the SSRls and tri­cyclic antidepressants have similar overall efficacy in this group.l971

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Table V. Overview of the epidemiological, pathological and socioeconomic characteristics of major depression[87,92.96j

Prevalence 1-year rate = 10%; lifetime rate = 17%

Typical disease course Chronic and recurrent

Mortality

Probability of a second depressive episode is >50%, probability of a third episode is 80 to 90%

Later episodes tend to be more severe and more refractory than initial episodes

Most suicides are associated with suboptimal treatment (or no treatment) of depression

Suicide is the ninth most common cause of death in the US

Socioeconomic impact Estimated total annual cost" of $US44 billion in the US

Major cause of disability, reduced productivity and absence from work

In comparison with unaffected individuals, patients with major depression have a 4.8 times greater risk of experiencing ~1 disability dayb and a 3.2 times greater risk of missing ~1 day of work

a 1990 US dollars; includes direct costs of psychiatric, medical and pharmacological care, mortality costs arising from depression-related suicides and morbidity costs associated with absence from work or reduced productivity during disease episodes while at work.

b A day in which the individual spent all or part of the time in bed, or was prevented from performing their normal activities, because of illness.

Broadly speaking, the different SSRls are con­sidered to have equivalent overall efficacy.l98,991

Although some clinical trials have revealed statis­tically significant differences between drugs (usu­ally apparent in the early stages of treatment but not at study end-points) [reviewed by de Jonghe and Swinkels[99]], the transient nature of these dif­ferences and the lack of unequivocal confirmatory evidence means that the clinical significance of these findings is questionable.

Against this background, the choice of which SSRI to use may be influenced by pharmacody­namic, pharmacokinetic and tolerability issues in relation to the particular medical history, clinical presentation and needs of individual patients.l99-1011 However, as with overall efficacy, there is no de­finitive evidence regarding the clinical signifi-

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cance of apparent differences between the SSRls in these respects.l99]

Citalopram is a potent SSRI which has the high­est selectivity of any of the drugs in this class. However, there is no clear evidence to date that this selectivity translates into any clinical advantage for citalopram compared with the other SSRls. Cital­opram has shown overall efficacy similar to that of a number of, but not all, tricyclic or tetracyclic antidepressants with which it has been compared. It also appears to be as effective as fluoxetine or fluvoxamine, although there is some evidence that the clinical effects of citalopram are achieved more rapidly than those of fluoxetine.

Initial placebo-controlled studies suggest that citalopram is effective in the prevention of relapse in patients who respond to short term treatment with the drug. This is important, since adequate management of depression requires long term main­tenance therapy to prevent recurrence, once the ini­tial disease episode has been brought under control.

Tolerability data from the 2 largest available comparative clinical trials of citalopram and from meta-analyses are consistent with the well estab­lished differences between the SSRls and tricyclic agents with respect to anticholinergic and cardio­vascular events. Importantly, citalopram has not been associated with serious cardiovascular toxic­ity, even in patients with existing cardiovascular disorders. Some differences in gastrointestinal tol­erability between citalopram and fluoxetine (in fa­vour of fluoxetine) or fluvoxamine (in favour of citalopram) have been reported. However, these have each occurred in only a single clinical trial and, in each case, the drug showing poorer toler­ability was started at a dosage higher than that normally recommended. Thus, at present, it is not possible to draw any definitive conclusions about clinically significant differences in tolerability be­tween citalopram and other SSRls.

It is well known that the CYP2D6 isozyme which is involved in the metabolism of citalopram is also responsible for the metabolism of a variety of other drugs, including antiarrhythmics, ~-blockers, anti psychotics and almost all tricyclic antidepres-

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Noble & Benfield

sants.[29] Moreover, a number of SSRls, including paroxetine and fluoxetine, are potent inhibitors of CYP2D6 in vitro[30,31,I02] and, thus, have the poten­tial to cause clinically significant pharmacoki­netic interactions when administered in combina­tion with CYP2D6 substrates. Indeed, clinically significant effects on parameters such as AVC and clearance have been observed in patients who re­ceived tricyclic antidepressants together with SSRIs (reviewed by Br0sen[I03] and van Harten[lOI]).

Citalopram is a less potent in vitro and in vivo

inhibitor of CYP2D6 than other SSRls, including paroxetine (the most potent agent in these investi­gations) and fluoxetine. Data from healthy volun­teers and patients with psychiatric disorders sug­gest that citalopram has a relatively low potential for interaction with other drugs that are metabo­lised by CYP2D6. However, direct comparisons with other SSRls are not available and data on interactions with tricyclic agents are limited. Cital­opram was associated with only moderate interac­tions (compared with those seen for other SSRls[ 1031) or had no effect when coadministered with tricyclic antidepressants in the few studies available to date. The absence of significant inter­actions with antipsychotic agents may prove valu­able, since patients with psychiatric and/or psy­chotic disorders often receive concomitant treatment with a antipsychotic agent and an antidepressant.

Citalopram has been well tolerated in elderly patients and its low propensity for cardiovascular and anticholinergic adverse events, like that of other SSRls, may be of particular value in this group. The potential for fewer drug interactions would make citalopram a particularly suitable op­tion for elderly patients, who are more likely than younger patients to be receiving additional medi­cation. However, the comparative antidepressant efficacy of citalopram in the elderly remains to be determined. Moreover, citalopram was not always superior to placebo in the only available clinical trial in the elderly (section 3.1).

In summary, citalopram is an effective and well tolerated antidepressant which, like the other SSRls, is a suitable first-line option in the treat-

eNS Drugs 1997 Nov; 8 (5)

Citalopram: A Review

ment of major depression and causes fewer cardio­vascular and anticholinergic adverse events than tricyclic antidepressants. Clarification of the effi­cacy of citalopram in patients for whom the latter events are a serious concern (the elderly, or patients with post-stroke depression or existing cardiovas­cular disorders) would help to establish its clinical value. In the meantime, in vitro and in vivo data suggest that citalopram has a relatively low pro­pensity for pharmacokinetic interactions with an­tipsychotic agents, tricyclic antidepressants and other substrates of CYP2D6. This may make citalopram an attractive option for the many pa­tients with depression who require such agents for treatment of coexisting psychiatric conditions or more general disorders.

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Correspondence: Stuart Noble, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auck­land 10, New Zealand E-mail: demail@adis.co.nz

eNS Drugs 1997 Nov; 8 (5)