Citalopram: New SSRI for Treatment of Depression

By William T. Elliott, MD, and James Chan, PharmD, PhD

Anew selective serotonin reuptake inhibitor (SSRI), citalopram, was approved by the FDA in July for the treatment of depression. The drug is to be marketed under the trade name Celexa by Forest Laboratories and Parke-Davis. It is the fifth SSRI to be approved for use in this country, joining fluoxetine, paroxetine, sertraline, and fluvoxamine. Its action appears to be limited to the potentiation of serotonergic activity in the central nervous system, with minimal effect on norepinephrine and dopamine transmitter reuptake.1 It has no or minimal affinity for serotonin, histamine, muscarinic, adrenergic, dopamine, gamma aminobutyric acid, or benzodiazepine receptors.1 Citalopram is well-absorbed and has a long elimination half-life (35 hours) that permits once daily dosing. The drug also appears to have a low potential for drug interactions involving the cytochrome P450 system.

Indications

Citalopram is indicated for the treatment of depression.

Dosing

Citalopram is available as 20 mg and 40 mg tablets. The initial dose is 20 mg once daily. It may be administered in the morning or evening and may be taken without regard to meals. The dose may be increased to 40 mg once daily. Increases should occur in increments of 20 mg at intervals of no less than one week. Certain patients may require a dose of 60 mg/d; however, doses above 40 mg are not ordinarily recommended.1 A dose of 20 mg once daily is the recommended dose for most elderly patients and those with hepatic impairment. Titrate to 40 mg only for nonresponding patients.1

Potential Advantages

Based on limited data, citalopram appears to be a weak inhibitor of cyctochrome P450 isoenzymes 1A2, 2D6, and 2C19 and does not appear to inhibit 3A4.1,2 Fluvoxamine has been reported to inhibit 1A2; fluoxetine, norfluoxetine, sertraline, and paroxetine, 2D6; fluoxetine, sertraline, and fluvoxamine, 2C; and fluvoxamine, nefazodone, fluoxetine, and sertraline, 3A4.1,2

Potential drug interactions involving 2D6 include antipsychotics, antiarrhythmics, and secondary amine tricyclic antidepressants. Those involving 2C include phenytoin and diazepam; 3A4 interactions include carbamazepine and aprazolam, and 1A2 interactions include theophylline and haloperido.l,12

In studies involving normal volunteers, citalopram (40 mg/d) did not impair intellectual function or psychomotor performance. It does not appear to potentiate the cognitive and motor effects of alcohol, although coadministration is not recommended.1

Potential Disadvantages

Side effects reported (compared to placebo) with citalopram include dry mouth (20% vs 14%), nausea (21% vs 14%), somnolence (18% vs 10%), and ejaculation disorder (6% vs 1%). In vitro data indicate that citalopram is metabolized via cytochrome P450 3A4 and 2C19. Potential inhibitors of these isoenzymes may reduce the metabolism of citalopram.1 Citalopram may increase the plasma level of metoprolol. While coadministration had no significant effects on blood pressure or heart rate, the cardioselectivity of metoprolol may be decreased.1

Comments

Citalopram has been available, and has been used extensively, in Europe for many years (e.g., United Kingdom since 1989). It has a good track record in Europe, where it has generally been found to be effective and well tolerated. The majority of published data on the drug are from European studies. Comparative studies with other SSRIs, namely fluoxetine and sertraline, suggest that citalopram is at least as effective and has similar side effects.3,4 In an eight-week study involving 357 patients with unipolar depression, citalopram 20 mg was reported to be similar to 20 mg fluoxetine in improving various depression scores (MADRS, HAM-D, and CGI). Back pain occurred more frequently in the citalopram-treated patients (3.3% vs 0%). The onset of effect may be earlier with citalopram, with a higher percent of patients showing improvement at the two-week assessment period. No significant difference was observed after two weeks.4 Patients not receiving benzodiazepines may respond better to citalopram than those receiving benzodiazepines.9 In a 24-week study (n = 400), sertraline was compared to citalopram (mean dose of 82 mg and 32 mg, respectively) in patients with major depression. No statistical differences were seen in efficacy, incidence of side effects, or medication compliance.3 Comparative trials with tricyclic antidepressants indicated similar efficacy but a lower frequency of adverse events.5,6

Studies have indicated that citalopram is efficacious and well-tolerated by elderly patients with depression with or without dementia disorder.7,8

Clinical Implications

Depression is a common mental disorder seen in clinical practice. It is frequently underdiagnosed and inadequately treated. The point prevalence of this disorder is 2.3-3.2% for men and 4.5-9.3% for women, with a lifetime incidence of 7-12% in men and 20-25% in women. Only one-third to one-half of patients with major depression are diagnosed by primary care and other practitioners.10 With pharmacotherapy, there appears to be high variability in patient response. In general, there is a high rate of discontinuation and switching of antidepressants and variability in medication adherence.11 Citalopram provides clinicians with another effective SSRI that may have the advantage of reduced potential for drug-drug interactions for those patients who are on multiple medications.

The wholesale price of citalopram is about $2.00 per tablet for either the 20 mg or 40 mg strength. Cost is competitive to or slightly less than other SSRIs.

References

1. Celexa Product Information. Forest Pharmaceutical, Inc. July 1998.

2. Baumann P. Clin Pharmacokinet 1996;31:444-465.

3. Ekseliius L, et al. Int Clin Psychopharmacol 1997; 12:323-331.

4. Patris M, et al. Int Clin Psychopharmacol 1996;11: 129-136.

5. Rosenberg C, et al. Int Clin Psychopharmacol 1994;9 (Suppl 1):41-48.

6. Fuglum E, et al. Acta Psychiatr Scand 1996;94:18-25.

7. Gottfries CG, et al. Int Clin Psychopharmacol 1992;6 (Suppl 5):55-64.

8. Nyth AL, et al. Acta Psychiatr Scand 1992;86:138-145.

9. Bougerol T, et al. Clin Drug Invest 1997;14:77-89.

10. AHCPR Clinical Practice Guideline. Depression in Primary Care: Volume 1. 1993.

11. Thompson D, et al. Am J Man Care 1996;2:1239-1246.

12. Nemeroff CB, et al. Am J Psychiatry 1996;153:311-320.