A number of placebo-controlled trials and uncontrolled case reports have shown that monoamine oxidase inhibitors (MAOIs) may be effective in the major subtypes of depression as well as in some other psychiatric disorders, including bulimia nervosa (Walsh et al., 1984, 1985; Kennedy et al., 1988; Walsh et al., 1988; Rothschild et al., 1994).
Reversible inhibitors of MAO-A (RIMAs), such as brofaromine and moclobemide, seem to be safer than the older irreversible MAOIs, such as tranylcypromine or phenelzine, since they are less likely to increase blood pressure, do not require dietary restrictions and have fewer drug interactions (Gasic et al., 1983; Bieck and Antonin, 1989).
Moclobemide (Da Prada et al., 1989; Cesura and Pletscher, 1992; Fitton et al., 1992; Freeman, 1993) is an oral, selective and reversible inhibitor of MAO type A, the enzyme mainly involved in serotonin and noradrenaline deamination. It is rapidly absorbed after oral administration, reaching peak blood levels after 30-60 min. Its half-life is approximately 1-2 h, but increases after multiple administration; elimination is mainly by the liver. The adverse effects of moclobemide seem to be minimal, with a hypertension risk that is not different from that of placebo. The short duration of action and reversibility of MAO inhibition presumably minimize the interactions of moclobemide with the tyramine present in foods.
Moclobemide potentiation of the pressor response to oral tyramine is approximately 10 times less marked than after tranylcypromine; in real life situations, the ingestion of less than 100 mg of tyramine is highly unlikely to produce a clinically relevant increase in blood pressure (Korn et al., 1988). At therapeutic doses, moclobemide potentiates the intravenous tyramine pressor effect three times less than the old irreversible MAO inhibitors; at the highest therapeutic dose, the tyramine sensitivity factor for moclobemide is only one-seventh to one-tenth that of tranylcypromine or phenelzine (Zimmer, 1990). The duration of inhibition is closely related to the reversibility of inhibition, ranging from up to 2 days with high doses of moclobemide to 3 weeks with tranylcypromine, and several months for clorgyline and phenelzine (Zimmer, 1990).
Because the new generation of RIMAs are significantly safer, they should be studied in all of the conditions responsive to MAOIs.
Brofaromine has well-established antidepressant properties and some placebo-controlled studies have also demonstrated its efficacy in panic disorder with and without agoraphobia (Bakish et al., 1993), and in bulimia nervosa (Kennedy et al., 1993). Nevertheless, further trials are necessary to confirm these promising results.
There is evidence in favour of the placebo-controlled efficacy of moclobemide in depression (Casacchia et al., 1984; Versiani et al., 1989; Bakish et al., 1992; Ose and Holm, 1992; Lotufo-Neto et al., 1999). A review of three placebo-controlled trials and four three-way comparative trials of moclobemide, placebo and one of the standard tricyclic antidepressants (imipramine, clomipramine or amitriptyline) indicated that approximately twice as many of the patients receiving moclobemide showed a marked improvement in comparison with those receiving placebo; the tolerability of moclobemide was good and better than that of the tricyclic antidepressants (Silverstone, 1993).
Two placebo-controlled studies have also established the efficacy of moclobemide in social phobia (Versiani et al., 1992; International Multicenter Clinical Trial Group on Moclobemide in Social Phobia, 1997). However, a recent study (Schneier et al., 1998) found that its efficacy was not accompanied by significant differences in most primary outcome measures, and the small effect sizes for all of the outcome measures suggested that it did not have a major clinical effect. Some other controlled studies have found negative results: in a dose-response trial (75 mg, 150 mg, 300 mg, 600 mg or 900 mg daily), moclobemide was not efficacious on social phobia after 12 weeks (Noyes et al., 1997), and a placebo-controlled study found that moclobemide with clinical management was not superior to placebo in the treatment of panic disorder with agoraphobia. Furthermore, the combination of moclobemide with cognitive-behavioural therapy did not yield significantly better short-term results than cognitive-behavioural therapy with placebo (Loerch et al., 1999).
No controlled trial has yet examined moclobemide in bulimia nervosa.
Bulimia nervosa was first described as a new syndrome by Russell in 1979, and was included in the Diagnostic and Statistical Manual of Mental Disorders in 1980 (American Psychiatric Association, DSM-III). Three features are required to make a diagnosis of bulimia nervosa: recurrent episodes of binge-eating with a sense of a lack of control, compensatory behaviours (self-induced vomiting, purging, dieting, excessive exercising) and over-concern with weight and shape (weight phobia). The individuals who suffer from bulimia nervosa are of average or above average weight.
Serendipity, psychopathology (the relationship between bulimia nervosa and affective disorders) and neurochemistry (neuromodulator functions) have suggested some pharmacological strategies that can be used to modify bingeing and purging behaviours, and the use of antidepressants has proved to be a profitable approach, with positive results being found in more than 90% of the placebo-controlled investigations. A change in the frequency of the core bulimic symptoms (i.e. a decrease in the number of bingeing episodes) was the main measure of efficacy in all of the studies.
In some placebo-controlled studies, the first generation MAOIs, phenelzine (Walsh et al., 1984, 1985, 1988; Rothschild et al., 1994) and isocarboxazid (Kennedy et al., 1988) had a considerable therapeutic effect that was not limited to patients with clinically significant depression. However, the clinical usefulness of MAOIs was limited by the need to select patients who can adhere to a tyramine-free diet.
A more recent placebo-controlled study carried out by Kennedy et al. (1993) found that brofaromine, a MAO-A-specific reversible inhibitor, significantly decreased the number of vomiting episodes.
For these reasons, moclobemide might be a good candidate to treat patients with bulimia nervosa, which is characterized by binge-eating episodes with the recurrent ingestion of high quantities of tyramine-rich foods (Russell, 1979; Walsh, 1993).
The subjects were women aged 18-40 years who met the DSM-IV (American Psychiatric Association, 1994) criteria for bulimia nervosa. Of 103 potential patients seen in three eating disorder units during 6 consecutive months, 78 were recruited. They provided their written informed consent and ethical approval for the study was given by the Ethics Committees of the involved units. The 25 excluded subjects had a known hypersensitivity to MAOIs, neurological disorders, a history of schizophrenia or bipolar disorder (I or II), a history of suicide attempts, recent substance abuse, a current diagnosis of a major depressive episode, a high suicidal risk, unstable or uncontrolled medical diseases, a clinically significant electrocardiogram (ECG), a body mass index (BMI) > 27 or < 17, or had received psychotropic medication in the preceding 4 weeks. The patients did not receive any concomitant psychotherapy during the study.
The patients were screened by experienced interviewers using four questionnaires: HAMD (Hamilton, 1967), BITE (Henderson and Freeman, 1987), EDI (Garner et al., 1983) and TFEQ (Stunkard and Messick, 1985). A daily diary was provided at trial entry, and the subjects were instructed to record episodes of binge eating and purging or non-purging compensatory behaviours.
After a 1-week, single-blind placebo run-in period, the inclusion criteria were checked again. Anyone who had experienced a more than 50% reduction in binge frequency during this week was removed from the study as a placebo-responder. After randomization to moclobemide or placebo, the remaining patients were seen once a week for the following 6 weeks. A 1-week low-dose period (400 mg) was followed by a full dose (600 mg) period. No further dose increase was allowed. On each occasion, food diaries were collected and questionnaires completed before a brief (10-20 min) examination concentrating on changes in symptoms, effects and compliance.
Weight, ECG and a complete laboratory screening were verified before and after the study; systolic and dyastolic blood pressure were measured weekly.
The between-group differences were assessed using a parametric test for numerical variables and a nonparametric test for categorical variables. The efficacy and safety frequency data were studied using a non-parametric test, and the psychometric data were compared using ANOVA.
Of the 78 patients who entered the trial, 77 met the enrollment criteria after the one-week washout: 38 were randomly allocated to moclobemide and 39 to placebo. No statistically significant differences were found between the two groups at baseline with regard to age, weight, height, BMI, or the mean scores of the HAM-Depression Scale, the BITE Symptom Scale and the BITE Severity Scale (Table 1). The frequencies of bingeing (M: 6.2 versus 6.5) and vomiting episodes (M: 4.8 versus 5.7) were not significantly different.
Twenty-five patients (10 on active treatment and 15 on placebo) dropped out for different reasons and only nine for adverse events: four in the moclobemide group and five in the placebo group. Three of the four moclobemide-treated patients who dropped out because of adverse events had an intercurrent respiratory infectious disease; the fourth experienced a derealization crisis, vertigo and sleepiness (the only possibly trial drug related case).
It is worth noting that no hypertensive crisis or changes in blood pressure were observed in either group. This is particularly relevant because subjects suffering from bulimia nervosa are at very high risk of ingesting large amounts of tyramine-rich foods, and the analysis of the food diaries of our study patients confirmed a large consumption of tyramine-contaning foods (expecially chocolate and cheese), although their precise amounts were difficult to quantify exactly. Table 2 shows the adverse events reported by the patients in the two groups.
Fifty-two patients completed the trial. Table 3 lists the mean ± SE weekly number of bingeing and vomiting episodes, and the mean HAM-D, BITE Symptom and Severity, EDI and TFEQ Restriction, Disinhibition and Hunger scores, at baseline and at the end-point. The mean changes from baseline were not statistically different between the two groups for any of the efficacy measures.
Under the present study conditions, moclobemide was not efficacious in treating bulimia nervosa symptoms in a significantly sized sample.
We used the moclobemide dose usually prescribed to treat depression (600 mg), but perhaps a higher dose may be more effective; further studies are needed to answer this point. In a placebo-controlled study, Kennedy et al. (1993) found that brofaromine (another MAO-A-specific reversible inhibitor) had a significant effect in decreasing the number of vomiting episodes. Brofaromine differs from moclobemide insofar as it also has serotonin reuptake inhibiting properties (Waldmeier et al., 1993) and, given the growing evidence supporting the efficacy of serotonin reuptake inhibitors in the treatment of binge eating (Walsh, 1993), its serotoninergic properties may explain this difference.
Previously, the question has been raised as to whether treatment with moclobemide is associated with a risk for hypertensive events. In 1995, two letters to The Lancet(Boyd, 1995; Coulter and Pillans, 1995) reported a total of 16 patients who developed hypertension in association with the use of moclobemide. The authors suggested that blood pressure should be regularly monitored and that there is a particular need for dietary restrictions. Laux et al. (1996) questioned these remarks and declared that there is no empirical evidence for a higher than usual risk of hypertensive events with moclobemide.
In a recent placebo-controlled trial of moclobemide involving 77 patients suffering from social phobia, no hypertensive reactions or other serious adverse effects were observed (Schneier, Goetz et al., 1998), but all of the patients followed a low-tyramine diet during the study as a precaution.
Our study supports the optimistic point of view: moclobemide was well tolerated by a sample of bulimic subjects without any dietary restriction. In particular, it did not induce any hypertensive crisis regardless of the ingestion of large amounts of tyramine-rich foods.
It must be underlined that the mean age of our sample was markedly lower than that of the patients described in the studies mentioned above, e.g. the median in our sample was 24 years versus the 61 years in Boyd's sample (1995). This could explain the different results. On the other hand, our patients were especially prone to the putative side-effects of the drug because of their eating disorder.
In conclusion, our data raise doubts about the alleged need for diet restriction and strict monitoring when using moclobemide, at least in young patients.
This work was supported in part by a grant from Roche.
American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders,
3rd edn (DSM-III) Washington, DC: American Psychiatric Association.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders,
4th edn (DSM-IV) Washington, DC: American Psychiatric Association.
Bakish D, Bradwejn J, Nair N, et al.
(1992) A comparison of moclobemide
, amitriptyline and placebo in depression: a Canadian multicentre study. Psychopharmacology106:
Bieck PR, Antonin KH (1989) Tyramine
potentiation during treatment with MAO inhibitors: brofaromine and moclobemide
versus irreversible inhibitors. J Neural Transm28:
Boyd IW (1995) Hypertension with moclobemide
Casacchia M, Carolei A, Barba C, et al.
(1984) A placebo-controlled study of the antidepressant activity of moclobemide
, a new MAO-A inhibitor. Pharmacopsychiatry17:
Cesura AM, Pletscher A (1992) The new generation of monoamine oxidase inhibitors. Progr Drug Res28:
Coulter DM, Pillans PI (1995) Hypertension with moclobemide
Da Prada M, Kettler R, Keller HH, Burkard WP, Haefely WE (1989) Preclinical profiles of the novel reversible MAO-A inhibitors, moclobemide
and brofaromine, in comparison with irreversible MAO inhibitors. J Neural Transmiss28:
Fitton A, Faulds D, Goa KI (1992) Moclobemide
: a review of its pharmacological properties and therapeutic use in depressive illness. Drugs43:
Freeman H (1993) Moclobemide
Garner DM, Olmsted MP, Polivy J (1983) Development and validation of a multi-dimensional eating disorder inventory for anorexia nervosa and bulimia. Int J Eat Disord2:
Gasic S, Korn A, Eichler HG, et al.
(1983) Cardiocirculatory effects of moclobemide
(Ro 11-1163), a new reversible, a short-acting MAO-inhibitor with preferential type A inhibition, in healthy volunteers and depressive patients. Eur J Clin Pharmacol25:
Hamilton M (1967) Hamilton Rating Scale for Depression (HRSD) - 17 items. Br J Soc Clin Psychol6:
Henderson M, Freeman CP (1987) A self-rating scale for bulimia: the BITE. Br J Psychiatry150:
International Multicenter Clinical Trial Group on Moclobemide
in Social Phobia. Moclobemide
in social phobia (1997) A double-blind, placebo-controlled clinical study. Eur Arch Psychiatry Clin Neurosci247:
Kennedy SH, Piran N, Warsh TJ, Prendergast P, Mainprize E, Whynot C, Garfinkel PE (1988) A trial of isocarboxazid in the treatment of bulimia nervosa
. J Clin Psycopharmacol8:
Kennedy SH, Goldbloom DS, Ralevski E, Davis C, D'Souza JD, Lofehy J (1993) Is there a role for selective monoamine oxidase inhibitor therapy in Bulimia nervosa
? A placebo controlled trial of brofaromine. J Clin Psycopharmacol13:
Korn A, Da Prada M, Raffesberg W, et al.
Effect of moclobemide
, a new reversible monoamine oxidase inhibitor, on absorption and pressor effect of tyramine
. J Cardiovascul Pharmacol11:
Laux G, Philipp M, Kohnen R (1996) Hypertension with moclobemide
Loerch B, Graf-Morgenstern M, Hautzinger M, et al.
Randomised placebo-controlled trial of moclobemide
, cognitive-behavioural therapy and their combination in panic disorder with agoraphobia. Br J Psychiatry174:
Lotufo-Neto F, Trivedi M, Thase ME (1999) Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide
and brofaromine for the treatment of depression. Neuropsychopharmacology20:
Noyes Jr R, Moroz G, Davidson JR, et al.
in social phobia: a controlled dose-response trial. J Clin Psycopharmacol17:
Ose E, Holm P (1992) Moclobemide
and placebo in mild major depression: a double-blind randomized trial. Psychopharmacology106:
Rothschild R, Quitkin HM, Quitkin FM, et al.
(1994) A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives. Int J Eat Disord15:
Russell GFM (1979) Bulimia nervosa
: an ominous variant of anorexia nervosa. Psychol Med9:
Schneier FR, Goetz D, Campeas R, et al.
(1998) Placebo-controlled trial of moclobemide
in social phobia. Br J Psychiatry172:
Silverstone T (1993) Moclobemide
-placebo-controlled trials. Int Clin Psychopharmacol7:
Stunkard AJ, Messick KS (1985) The Three Factor Eating Questionnaire to measure dietary restrain, disinhibition and hunger. J Psychosomat Res29:
Versiani M, Oggero U, Alterwein P, et al.
(1989) A double-blind comparative trial of moclobemide
versus imipramine and placebo in major depressive episodes. Br J Psychiatry155:
Versiani M, Nardi AE, Mundim FD, et al.
(1992) Pharmacotherapy of social phobia. A controlled study with moclobemide
and phenelzine. Br J Psychiatry161:
Waldmeier PC, Glatt A, Jaekel J (1993) Brofaromine: a monoamine oxidase-A and serotonin uptake inhibitor. Clin Neuropharmacol16(Suppl. 2):
Walsh BT (1993) Binge eating in bulimia nervosa
. In: Binge Eating: Nature, Assessment and Treatment
(CG Fairburn, GT Wilson, eds), New York: Guilford Press, pp. 37-49.
Walsh BT, Stewart JW, Roose SP, et al.
(1984) Treatment of bulimia with phenelzine. A double-blind, placebo-controlled study. Arch Gen Psychiatry41:
Walsh BT, Stewart JW, Roose SP, et al.
(1985) A double-blind trial of phenelzine in bulimia. J Psychiatry Res19:
Walsh BT, Gladis MA, Roose SP, Stewart JW, Stetner F, Glassman AH (1988) Phenelzine versus placebo in 50 patients with bulimia. Arch Gen Psychiatry45:
Zimmer RH (1990) Relationship between tyramine
potentiation and monoamine oxidase (MAO) inhibition: comparison between moclobemide
and other MAO inhibitors. Acta Psychiatr Scand360: