Prog. Neero-Psyehophnrmacol F7 Biol. Psychiat. 1982. Vol. 6. pp. 275-276 0278-58461821030275-02503.00/0 Printed in Greet Britain. All rights reserved. Copyrighl © 1982 Pergamon Press Ltd.

CITALOPRAM

AN INTRODUCTION

During the last decade the search for better antidepressant drugs has been intensified, since established tricyclic antidepressant drugs are ineffective for some patients and, in addition, induce undesirable side-effects. Of these~ the anticholinergic and cardiovascu- lar effects are the most troublesome.

It is desirable that an antidepressant drug should give immediate relief, but unfortuna- tely most existing compounds require several weeks before clear effect is apparent. There- fore, the latest research has been concentrated on drugs without these side effects and with an earlier onset of action.

Since the underlying biochemical events in endogenous depression are still unknown, the- oretical explanations abound. A commonly accepted view is that two mechanisms in depres- sion operate~ one characterized by a decreased noradrenaline (NA) activity and the other by a decreased serotonin (5-HT) activity. In the former the most effective treatment is considered to be inhibition of NA uptake and in the latter, inhibition of 5-HT uptake. The first generation of antidepressants either affect both NA and 5-HT, or NA alone. Most newer antidepressants are compounds which preferentially potentiate 5-HT by inhibition of 5-HT uptake. However, a few newer antidepressants, which do not fit into this pattern (since neither NA- nor 5-HT-uptake is inhibited) are in clinical use.

The new compound citalopram - to which this issue is devoted - is a potent and selective 5-HT uptake inhibitor. Citalopram is a phthalane derivative. The only point of resemblance to the tricyclic drugs is a 3-carbon side chain which contains a tertiary amino group.

Citalopram has no effect on NA and dopamine (DA) uptake and does not inhibit monoamine oxidase. It has no antagonistic activity towards DA, NA, 5-HT, histamine, gamma aminobuty- ric acid (GABA)~ acetylcholine and morphine receptors. Cardiotoxic effects are not seen even when animals are exposed to concentrations far above the therapeutic level.

Citalopram is metabolized by demethylation and N-oxidation. Although the metabolites are less potent than citalopram they retain its specific effect. The kinetics of citalopram in the baboon, dog, rat, and mouse is characterized by efficient hepatic clearance and short half-lives. High drug levels can nevertheless be maintained by repeated administration once daily to dogs, or with the diet to rats and mice. In these species demethylated metabolites are present in addition to the parent compound.

Citalopram is rapidly absorbed and slowly eliminated in man. The kinetics is linear and characterized by a half-life of 1.5 days. A steady state plasma level of 245 nM is seen in patients if a daily dose of 40 mg is given. The metabolite, desmethylcitalopram, is found in concentrations 2 to 3 times lower than citalopram, whereas the levels of didesmethylci- talopram are negligible. In a series of open clinical trials citalopram has shown antide- pressant properties similar to those of known antidepressants. In a trial performed on I0 endogenously depressed in-patients (Gottlieb et al., 1980) there was a pronounced or mode- rate response in seven patients and slight or no response in three. In another trial (Lin- degaard Pedersen et al.~ 1981, 1982) 16 endogenously depressed patients were treated. Nine patients fulfilled the criteria for complete recovery after 4 weeks, three patients were partial or late responders while four patients showed no improvement. Twelve patients were followed in the outpatient clinic for periods of 3 months to 2 years. No patients devel- oped depression during treatment, but eight patients relapsed when withdrawn from citalo- pram. Seven of them recovered when the treatment was reinstated. In both of these clinical trials side effects were few or absent and neither anticholinergic nor cardiovascular ef- fects were observed.

In this issue two other open trials are reported. The patients here are elderly patients with a long history of depression. Many of the patients suffered from chronic somatic diseases and were under long-term treatment with such drugs as diuretics, antihyperten- sives or vasodilators. Gastpar and Gastpar carried out a trial with I0 patients. After 3 weeks of treatment, 6 patients were full responders, two were partial responders while two were non-responders. Most of the clinical effect was already apparent after one week of treatment. In the other trial by ~fsti, 26 severely depressed patients were treated for 4 weeks. Nineteen of the patients entered the trial with scores of more than 25 points on the Hamilton rating scale - 5 of them with a score of more than 35. Six of the patients

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276 J. Hyttel

achieved a final score of less than 8. However, half of the patients had a final score of less than 16, which is satisfactory for such a severely depressed group. In both of these trials side-effects seen were mild and transient. Other~ as yet unreported, open trials have been performed with similar outcome. Several controlled clinical trials where citalo- pram is compared to established antidepressants, are now in progress.

The extreme selectivity of citalopram, with 5-HT-uptake inhibition as the only recogni- zable effect - and its proven antidepressive effect coupled with a lack of anticholinergic and cardiovascular side-effects, together open new perspectives for clinical research on endogenous depression.

This issue will show that citalopram is thoroughly characterized pharmacologically and pharmacokinetically.

However, further clinical work is needed to fully characterize the clinical potential of this new drug.

John Hyttel~ DSc. Topic Editor

References

GOTTLIEB, P., WANDALL~ T. and FREDRICSON OVER@~ K. (1980) Initial, clinical trial of a new~ specific 5-HT reuptake inhibitor, citalopram (Lu 10-171). Acta psychiat, scand. 62:236-244.

LINDEGAARD PEDERSEN~ O.~ BJERRE 9 M.~ KRAGH-S@RENSEN~ P. and BRUUN KRISTENSENp C. (1981) Citalopram -a specific 5-HT uptake inhibitor: Clinical effect in short and longterm treatment. Abstract from III World Congress of Biological Psychiatry. Stockholm, June 28 - July 3~ 1981.

LINDEGAARD PEDERSEN~ 0. I KRAGH-S@RENSEN, P., BJERRE~ M.~ FREDRICSON OVER@, K. and GRAM~ L.F. (1982). Citalopram, a selective serotonin reuptake inhibitor 9 clinical antide- pressive and long term effect - A phase II study. Psychopharmacology. 77: 199-204.

Inquiries and reprint-request should be addressed to:

John Hyttel~ D.Sc. Department of Pharmacology and Toxicology H. Lundbeck & Co. A/S Ottiliavej 7-9~ DK-2500 Copenhagen-Valby Denmark