Research report
Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial

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Abstract

Background: A consistent finding in major depression has been a low plasma and red cell folate which has also been linked to poor response to antidepressants. The present investigation was designed to investigate whether the co-administration of folic acid would enhance the antidepressant action of fluoxetine. Methods: 127 patients were randomly assigned to receive either 500 μg folic acid or an identical looking placebo in addition to 20 mg fluoxetine daily. All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale (17 item version) score for depression of 20 or more. Baseline and 10-week estimations of plasma folate and homocysteine were carried out. Results: Patients receiving folate showed a significant increase in plasma folate.This was less in men than in women. Plasma homocysteine was significantly decreased in women by 20.6%, but there was no significant change in men. Overall there was a significantly greater improvement in the fluoxetine plus folic acid group. This was confined to women where the mean Hamilton Rating Scale score on completion was 6.8 (S.D. 4.1) in the fluoxetine plus folate group, as compared to 11.7 (S.D. 6.7) in the fluoxetine plus placebo group (P<0.001).A percentage of 93.9 of women, who received the folic acid supplement, showed a good response (>50% reduction in score) as compared to 61.1% of women who received placebo supplement (P<0.005). Eight (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus placebo group 19 (29.7%) patients reported such symptoms (P<0.05). Limitations and conclusions: Folic acid is a simple method of greatly improving the antidepressant action of fluoxetine and probably other antidepressants. Folic acid should be given in doses sufficient to decrease plasma homocysteine. Men require a higher dose of folic acid to achieve this than women, but more work is required to ascertain the optimum dose of folic acid.

Introduction

The WHO ranks unipolar major depression as the fourth most important cause of premature mortality and disability (Murray and Lopez, 1997), and yet the treatment of this illness remains unsatisfactory. In terms of efficacy, antidepressants have not improved since their introduction in the 1950s. In a comprehensive study of more than 9000 clinical reports, the US Agency for Health Care Policy and Research found that the response rate, defined as a 50% or greater improvement on a standardised depression scale, had not changed with the introduction of the selective serotonin reuptake inhibitors in the last twenty years. Treatment by the active drug produced a response in 50% of patients as compared to 32% on placebo (Agency for Health Care Policy and Research, 1999).

One of the most robust findings in the biochemistry of major depression is of low plasma and red cell folate in these patients. Patients with low plasma folate responded less well to treatment by antidepressants (Reynolds et al., 1970, Abou-Saleh and Coppen, 1986, Abou-Saleh and Coppen, 1989, Carney et al., 1990, Fava et al., 1997).

These observations prompted us to carry out a randomised placebo-controlled trial to see if the co-administration of folic acid with fluoxetine would enhance its antidepressant effect.

Section snippets

Study details

A randomised, double-blind, parallel group, placebo-controlled trial, completed in a multicentre general practice setting, as outlined in Fig. 1.

Patients

One hundred and twenty seven patients attending 19 general practitioners with a special interest in depression, were enrolled in the study using a randomised schedule stratified for sex. The General Practitioners were known to be interested in depressive illness and attended training sessions in the use of the DSM-III-R (American Psychiatric

Results

There were no significant differences between the two treatment groups in all baseline characteristics.

The mean age of all 62 patients on fluoxetine plus folic acid was 41.9 (S.D. 12.0) and the mean age of all 65 patients on fluoxetine plus placebo was 44.3 (S.D. 14.6). There was no significant difference between the ages of the two treatment groups or between men and women.

Fifty-one patients (33 women and 18 men) on fluoxetine plus folic acid and 58 patients (36 women and 22 men) on fluoxetine

Discussion

It has now been established in many investigations that folic acid will lower plasma homocysteine (Homocysteine Lowering Trialists’ Collaboration, 1998).

This study demonstrates that only in female depressed patients does the co-administration of folic acid substantially and significantly improve the response to fluoxetine. Only 6.1% of the women given fluoxetine and folic acid failed to respond (according to the >50% improvement criterion) as compared to 38.9% given fluoxetine alone. Using a

Acknowledgements

Dr. David Horrobin was an unfailing source of help and encouragement during all stages of the trial.

The study was funded by Scotia Pharmaceuticals. The GP trialists were recruited and trained by Professor G. Beaumont and Dr. M. Gringras. The GPs participating in the study were Doctors:

M. Adler (Harrow n=7), W. Aitchison (Houston n=7), T. Baldwin (Cwmbran n=6), A. Berger (Milton Keynes n=7), G. Bhatia (Nottingham n=7), J. Bochsler (London n=7), P. Brahma (West Yorks n=7, A. Bremner (Rutherglen n

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