Efficacv of reversible inhbitors of monoamine oxidas&A in various forms of depression Y. Lecrubier', J.
Lecrubier Y, Guelfi JD. Efficacy of reversible inhibitors of monoamine oxidase-A in various forms of depression. Acta Psychiatr Scand 1990: Suppl 360: 18-23.
~
'
The design and the main therapeutic results of 3 controlled double-blind studies comparing moclobemide with tricyclics and/or placebo in depressed patients are presented. Moclobemide, a reversible inhibitor of monoamine oxidase (RIMA), preferentially inhibits MAO-A. It showed good effcacy in major depression (DSM-111), both endogenous and non-endogenous. The 3 studies included a total of 763 patients. The therapeutic results are similar to those observed with tricyclics (2/3 good responders). Tolerability was significantly better. The onset of action was evaluated in 2 studies and was faster in the patients treated with moclobemide. The fact that reversible inhibitors of MAO-A demonstrate good efficacy independently of the diagnostic category of depression is an important new
No therapeutic manual recommends the use of classical irreversible monoamine oxidase inhibitors (MAOIs) for the treatment of endogenous depression. On the one hand, MAOIs are considered to be less effective than tricyclic antidepressants (1, 2). On the other hand, they are known to induce hypertensive episodes when associated with vasopressive amines ( 3 ) as well as rare but severe interactions with tricyclic antidepressants ( 3 ) . Finally, endogenously depressed patients are considered to be poor responders (4). Nevertheless, MAOIs remained classified as antidepressants. Their use was largely confined to a target population on the borderline between depression and anxiety and/or personality disorders, i.e., patients qualified as suffering from neurosis, chronic dysphoric state, atypical depression, dysthymic disorder or anxious depression. MAOIs appeared to be superior to placebo in all of these overlapping categories; however, only some of these heterogeneous populations seemed to respond better to MAOIs than to tricyclic antidepressants (TCAs). Attempts over the years to better define the target population for MAOIs in non-endogenous depression have resulted in some progress. MA01 responders were initially characterized as chronically depressed patients with marked feelings of inadequacy, overreactivity, phobias, and hysterical features (1). This characterization led to the poorly defined term atypical depression. In 1976 Tyrer ( 5 ) proposed a syndrome comprising somatic 18
D. Guelfi'
'Chargl! de Recherche INSERM, Hbpital de la SalpBtriBre, 'H6pital Sainte-Anne, Paris, France
Key words: rnoclobernide; endogenous depression; non-endogenous depression; antidepressant drug; monoamine oxidase inhibitor
1
Y. Lecrubier M.R, Charge de Recherche INSERM, Hbpital de la SalpbtriBre, INSERM U 302, Pavilion Clerarnbault, 47 bld de I'Hbpital, 75013 Paris, France
anxiety, phobia, anergia, irritability, and hypochondriasis. Klein & Davis (6) and Liebowitz & Klein (7) introduced 2 other important concepts for better defining these patients: rejection sensitivity as a significant factor in depression, and the existence of reverse vegetative symptoms (oversleeping, overeating). MAOIs could finally be claimed to have certain advantages over TCAs in 2 patient populations: panic disorders with agoraphobia, and atypical depression. In atypical depression, mood reactivity is combined with a syndrome comprising reverse vegetative symptoms and severe fatigue in patients exhibiting rejection sensitivity as a trait. A number of studies confirmed the possibility of using MAOIs in treating non-endogenous depression and demonstrated that, given adequate dosage (8), very little difference could be found between MAOIs and TCAs (9, 10). In the early 1980s, this observation suggested the possibility of defining specific patient populations for which MAOIs would be effective. Lack of MA01 efficacy in endogenously depressed patients (but not in non-endogenously depressed patients) was proclaimed very early; consequently, few studies have been carried out since the 1960s. Nevertheless, open studies reported the efficacy of tranylcypromine (1 1) and phenelzine (12) in endogenously depressed patients not responsive to TCAs, including bipolar patients. The previous disappointing results of MAOIs in endogenous patients could have been attributable
to the following factors: 0 Most studies were carried out using phenelzine at doses lower than 60 mg/d. The effective dose in these patients is now known to range from 60-90 mg/d. 0 Because of the slow onset of clinical response, the duration of treatment was often inappropriately short. 0 At the clinical level, attempting to separate endogenous from non-endogenous patients, melancholic from non-melancholic patients and situational from non-situational patients gives rise to potential overlaps. When carefully evaluated, the therapeutic responses engendered by MAOIs and TCAs fail to be explained by any of these considerations. A number of factors in the early 1980s favoured reassessment of the therapeutic possibilities of MAOIs in depression: New classifications and operational criteria better defined different types of depressed patients. Reversible inhibitors of MA0 (RIMAs) that preferentially inhibited MAO-A became available. Because their reversibility opened up the possibility of exploring a wider dose range and decreasing interactions with tyramine, these new agents were more suitable instruments for therapeutic research. The possibilities of effective chemotherapy generated considerable optimism in the 1960s. This was followed by the discovery of a large number of new chemotherapeutic compounds in the 1970s. Despite this progress, in the 1980s we were still confronted with “resistant” patients, difficulties in treating chronic mild depression, and lack of a well-tolerated, long-term treatment for endogenously depressed patients. These problems are still with us. Three principal questions had to be answered to determine the potential therapeutic value of the new RIMAs in treating depression: 0 Do RIMAs show superior efficacy against placebo in endogenously depressed and non-endogenously depressed patients? 0 Do RIMAs show equal or superior efficacy against a reference TCA in endogenously depressed patients? 0 Do RIMAs show equal or superior efficacy against a reference TCA in non-endogenously but moderately depressed patients? Moclobemide was used as the representative RIMA in 3 studies specifically designed to answer these questions. These studies were carefully constructed to ensure methodologically satisfactory conditions, i.e., large patient groups treated for a sufficient period of time. Although many other
studies have been performed with moclobemide, only these 3 key studies will be summarized here. Material, methods and results Efficacy of moclobemide vs imipramine and placebo in major
depressive episodes A multicentre, prospective, randomized, doubleblind, placebo-controlled trial was carried out to compare the efficacy of moclobemide versus imipramine and placebo in depressed outpatients presenting a major depressive episode as defined by DSM-I11 (13). Treatment lasted 6 weeks with no run-in period. Assessments were performed on days 0, 3, 7, 14, 21, 28, and 42. Efficacy was evaluated using the 17-item Hamilton Rating Scale for Depression (HRSD) (14) and the Clinical Global Impression (CGI). Tolerance was evaluated based on reports of adverse effects, CGI, vital signs, electrocardiogram (ECG), and the judgement of a laboratory panel. A flexible dosage was allowed, variable within a range of 100%: 300-600 mg/day for moclobemide, 100-200 mg/day with imipramine. The mean dosage after 3 weeks of treatment was 510 mg/day for moclobemide and 160 mg/day for imipramine. Ten centres recruited 490 patients; 164 patients were randomly allocated to the moclobemide group, 164 to the clomipramine group, and 162 to the placebo group. Fifty per cent of these patients were endogenously depressed according to ICD-9 and most were unipolar, thus permitting evaluation of efficacy in both types of patients in the same study. The percentage of dropouts was acceptable for a 6-week treatment period: moclobemide = 11%, imipramine= 12% and placebo=26%. Demographic characteristics, the duration of the episode (approximately 40 weeks) and the number of previously treated patients (approximately 100 per group) were comparable in all groups. The sex ratio was identical in both active drug groups (30% males, 70% females). The main result is presented in Fig. 1. HRSD revealed moclobemide and imipramine to have similar evolutions and to achieve similar results over the 6 weeks of treatment. The Wilcoxon signed-rank test showed a mean improvement of 52% in the moclobemide group and 56% in the imipramine group (NS). Both treatments were significantly better than the 29% improvement with placebo (P10.0001). The final mean HRSD score for the 2 drugs was less than 10, which is within the usual range of efficacy of the reference drug. The same results were observed for CGI. Splitting the sample population into endogenous 19
!"I
----
MOCLOBEMIDE IMIPRAMINE
30
5
I
5 t
,*I
BEFORE 0
I
3
1
7
14
21 28 TREATMENT DAY
42
Fig. 1. Evolution of total HRSD score according to treatment group for patients presenting a major depressive episode (DSM111).
(n= 80 per group) and non-endogenous patients showed the 2 drugs to be equally effective, and in both cases significantly better than placebo. The mean final improvement among endogenously depressed patients was 50.9% in the moclobemide group, 51.7% in the imipramine group, and 29.0% in the placebo group. Efficacy of moclobemide vs clomipramine in endogenously depressed patients
A 6-week prospective, randomized, double-blind trial was carried out in endogenously depressed inpatients (15). All subjects were adults and judged to be endogenously depressed according to both ICD-9 and the 1971 version of the Newcastle scale (1 6). Moreover, all the subjects fulfilled the criteria for a major depressive episode (DSM-111) and had global scores of 2 2 5 on the MADRS (17) after a washout period of 3-7 d. The length of the washout period depended on whether or not individual patients had been previously treated. Assessments took place on days 0, 3, 7, 14, 21, 28, and 42. Efficacy was evaluated against the MADRS global score and the CGI. At the outset, all patients received a minimal dosage of moclobemide 450 mg/d or clomipramine 150 mg/d. They then moved into a flexible dosage period where the individual dosage was determined as a function of efficacy and tolerance. The ranges were 300-600 mg/d for moclobemide and 100-200 mg/d for clomipramine. Clomipramine 100-200 mg/d is the standard treatment for endogenously depressed patients in France. The mean dosages after 3 weeks were 476 mg/d for moclobemide and 154 mg/d for clomipramine. Thirteen participating centres recruited 62 patients for the moclobemide group, of whom 56 were unipolar, and 67 patients for the clomipramine group, of whom 62 were unipolar. The final
result of the study is therefore relevant only for unipolar endogenously depressed patients. The percentage of early terminations in the 2 groups was similar (24% for moclobemide and 16% for clomipramine). The 2 groups of patients did not differ in terms of demographic characteristics, duration of the present episode ( > 3 months: moclobemide group = 56%, clomipramine group = 50%), number of previous episodes (1 episode, 33% in both groups; 2-5 episodes, moclobemide =23%, clomipramine = 25%) or sex ratio. The principal results are presented in Fig. 2. Moclobemide and clomipramine showed similar efficacy after 6 weeks of treatment. The final global MADRS score was less than 10, which is within the usual range of efficacy of the reference drug after 6 weeks. There was no statistical difference in the curves showing the evolution of improvement for the 2 treatments; however, patients on moclobemide tended to improve earlier. The mean onset of action as determined by the investigators was 10 d (SD+5) for moclobemide and 13 d (SD 5 ) for clomipramine (P
Lecrubier Y, Guelfi JD. Efficacy of reversible inhibitors of monoamine oxidase-A in various forms of depression. Acta Psychiatr Scand 1990: Suppl 360: 18-23.
~
'
The design and the main therapeutic results of 3 controlled double-blind studies comparing moclobemide with tricyclics and/or placebo in depressed patients are presented. Moclobemide, a reversible inhibitor of monoamine oxidase (RIMA), preferentially inhibits MAO-A. It showed good effcacy in major depression (DSM-111), both endogenous and non-endogenous. The 3 studies included a total of 763 patients. The therapeutic results are similar to those observed with tricyclics (2/3 good responders). Tolerability was significantly better. The onset of action was evaluated in 2 studies and was faster in the patients treated with moclobemide. The fact that reversible inhibitors of MAO-A demonstrate good efficacy independently of the diagnostic category of depression is an important new
No therapeutic manual recommends the use of classical irreversible monoamine oxidase inhibitors (MAOIs) for the treatment of endogenous depression. On the one hand, MAOIs are considered to be less effective than tricyclic antidepressants (1, 2). On the other hand, they are known to induce hypertensive episodes when associated with vasopressive amines ( 3 ) as well as rare but severe interactions with tricyclic antidepressants ( 3 ) . Finally, endogenously depressed patients are considered to be poor responders (4). Nevertheless, MAOIs remained classified as antidepressants. Their use was largely confined to a target population on the borderline between depression and anxiety and/or personality disorders, i.e., patients qualified as suffering from neurosis, chronic dysphoric state, atypical depression, dysthymic disorder or anxious depression. MAOIs appeared to be superior to placebo in all of these overlapping categories; however, only some of these heterogeneous populations seemed to respond better to MAOIs than to tricyclic antidepressants (TCAs). Attempts over the years to better define the target population for MAOIs in non-endogenous depression have resulted in some progress. MA01 responders were initially characterized as chronically depressed patients with marked feelings of inadequacy, overreactivity, phobias, and hysterical features (1). This characterization led to the poorly defined term atypical depression. In 1976 Tyrer ( 5 ) proposed a syndrome comprising somatic 18
D. Guelfi'
'Chargl! de Recherche INSERM, Hbpital de la SalpBtriBre, 'H6pital Sainte-Anne, Paris, France
Key words: rnoclobernide; endogenous depression; non-endogenous depression; antidepressant drug; monoamine oxidase inhibitor
1
Y. Lecrubier M.R, Charge de Recherche INSERM, Hbpital de la SalpbtriBre, INSERM U 302, Pavilion Clerarnbault, 47 bld de I'Hbpital, 75013 Paris, France
anxiety, phobia, anergia, irritability, and hypochondriasis. Klein & Davis (6) and Liebowitz & Klein (7) introduced 2 other important concepts for better defining these patients: rejection sensitivity as a significant factor in depression, and the existence of reverse vegetative symptoms (oversleeping, overeating). MAOIs could finally be claimed to have certain advantages over TCAs in 2 patient populations: panic disorders with agoraphobia, and atypical depression. In atypical depression, mood reactivity is combined with a syndrome comprising reverse vegetative symptoms and severe fatigue in patients exhibiting rejection sensitivity as a trait. A number of studies confirmed the possibility of using MAOIs in treating non-endogenous depression and demonstrated that, given adequate dosage (8), very little difference could be found between MAOIs and TCAs (9, 10). In the early 1980s, this observation suggested the possibility of defining specific patient populations for which MAOIs would be effective. Lack of MA01 efficacy in endogenously depressed patients (but not in non-endogenously depressed patients) was proclaimed very early; consequently, few studies have been carried out since the 1960s. Nevertheless, open studies reported the efficacy of tranylcypromine (1 1) and phenelzine (12) in endogenously depressed patients not responsive to TCAs, including bipolar patients. The previous disappointing results of MAOIs in endogenous patients could have been attributable
to the following factors: 0 Most studies were carried out using phenelzine at doses lower than 60 mg/d. The effective dose in these patients is now known to range from 60-90 mg/d. 0 Because of the slow onset of clinical response, the duration of treatment was often inappropriately short. 0 At the clinical level, attempting to separate endogenous from non-endogenous patients, melancholic from non-melancholic patients and situational from non-situational patients gives rise to potential overlaps. When carefully evaluated, the therapeutic responses engendered by MAOIs and TCAs fail to be explained by any of these considerations. A number of factors in the early 1980s favoured reassessment of the therapeutic possibilities of MAOIs in depression: New classifications and operational criteria better defined different types of depressed patients. Reversible inhibitors of MA0 (RIMAs) that preferentially inhibited MAO-A became available. Because their reversibility opened up the possibility of exploring a wider dose range and decreasing interactions with tyramine, these new agents were more suitable instruments for therapeutic research. The possibilities of effective chemotherapy generated considerable optimism in the 1960s. This was followed by the discovery of a large number of new chemotherapeutic compounds in the 1970s. Despite this progress, in the 1980s we were still confronted with “resistant” patients, difficulties in treating chronic mild depression, and lack of a well-tolerated, long-term treatment for endogenously depressed patients. These problems are still with us. Three principal questions had to be answered to determine the potential therapeutic value of the new RIMAs in treating depression: 0 Do RIMAs show superior efficacy against placebo in endogenously depressed and non-endogenously depressed patients? 0 Do RIMAs show equal or superior efficacy against a reference TCA in endogenously depressed patients? 0 Do RIMAs show equal or superior efficacy against a reference TCA in non-endogenously but moderately depressed patients? Moclobemide was used as the representative RIMA in 3 studies specifically designed to answer these questions. These studies were carefully constructed to ensure methodologically satisfactory conditions, i.e., large patient groups treated for a sufficient period of time. Although many other
studies have been performed with moclobemide, only these 3 key studies will be summarized here. Material, methods and results Efficacy of moclobemide vs imipramine and placebo in major
depressive episodes A multicentre, prospective, randomized, doubleblind, placebo-controlled trial was carried out to compare the efficacy of moclobemide versus imipramine and placebo in depressed outpatients presenting a major depressive episode as defined by DSM-I11 (13). Treatment lasted 6 weeks with no run-in period. Assessments were performed on days 0, 3, 7, 14, 21, 28, and 42. Efficacy was evaluated using the 17-item Hamilton Rating Scale for Depression (HRSD) (14) and the Clinical Global Impression (CGI). Tolerance was evaluated based on reports of adverse effects, CGI, vital signs, electrocardiogram (ECG), and the judgement of a laboratory panel. A flexible dosage was allowed, variable within a range of 100%: 300-600 mg/day for moclobemide, 100-200 mg/day with imipramine. The mean dosage after 3 weeks of treatment was 510 mg/day for moclobemide and 160 mg/day for imipramine. Ten centres recruited 490 patients; 164 patients were randomly allocated to the moclobemide group, 164 to the clomipramine group, and 162 to the placebo group. Fifty per cent of these patients were endogenously depressed according to ICD-9 and most were unipolar, thus permitting evaluation of efficacy in both types of patients in the same study. The percentage of dropouts was acceptable for a 6-week treatment period: moclobemide = 11%, imipramine= 12% and placebo=26%. Demographic characteristics, the duration of the episode (approximately 40 weeks) and the number of previously treated patients (approximately 100 per group) were comparable in all groups. The sex ratio was identical in both active drug groups (30% males, 70% females). The main result is presented in Fig. 1. HRSD revealed moclobemide and imipramine to have similar evolutions and to achieve similar results over the 6 weeks of treatment. The Wilcoxon signed-rank test showed a mean improvement of 52% in the moclobemide group and 56% in the imipramine group (NS). Both treatments were significantly better than the 29% improvement with placebo (P10.0001). The final mean HRSD score for the 2 drugs was less than 10, which is within the usual range of efficacy of the reference drug. The same results were observed for CGI. Splitting the sample population into endogenous 19
!"I
----
MOCLOBEMIDE IMIPRAMINE
30
5
I
5 t
,*I
BEFORE 0
I
3
1
7
14
21 28 TREATMENT DAY
42
Fig. 1. Evolution of total HRSD score according to treatment group for patients presenting a major depressive episode (DSM111).
(n= 80 per group) and non-endogenous patients showed the 2 drugs to be equally effective, and in both cases significantly better than placebo. The mean final improvement among endogenously depressed patients was 50.9% in the moclobemide group, 51.7% in the imipramine group, and 29.0% in the placebo group. Efficacy of moclobemide vs clomipramine in endogenously depressed patients
A 6-week prospective, randomized, double-blind trial was carried out in endogenously depressed inpatients (15). All subjects were adults and judged to be endogenously depressed according to both ICD-9 and the 1971 version of the Newcastle scale (1 6). Moreover, all the subjects fulfilled the criteria for a major depressive episode (DSM-111) and had global scores of 2 2 5 on the MADRS (17) after a washout period of 3-7 d. The length of the washout period depended on whether or not individual patients had been previously treated. Assessments took place on days 0, 3, 7, 14, 21, 28, and 42. Efficacy was evaluated against the MADRS global score and the CGI. At the outset, all patients received a minimal dosage of moclobemide 450 mg/d or clomipramine 150 mg/d. They then moved into a flexible dosage period where the individual dosage was determined as a function of efficacy and tolerance. The ranges were 300-600 mg/d for moclobemide and 100-200 mg/d for clomipramine. Clomipramine 100-200 mg/d is the standard treatment for endogenously depressed patients in France. The mean dosages after 3 weeks were 476 mg/d for moclobemide and 154 mg/d for clomipramine. Thirteen participating centres recruited 62 patients for the moclobemide group, of whom 56 were unipolar, and 67 patients for the clomipramine group, of whom 62 were unipolar. The final
result of the study is therefore relevant only for unipolar endogenously depressed patients. The percentage of early terminations in the 2 groups was similar (24% for moclobemide and 16% for clomipramine). The 2 groups of patients did not differ in terms of demographic characteristics, duration of the present episode ( > 3 months: moclobemide group = 56%, clomipramine group = 50%), number of previous episodes (1 episode, 33% in both groups; 2-5 episodes, moclobemide =23%, clomipramine = 25%) or sex ratio. The principal results are presented in Fig. 2. Moclobemide and clomipramine showed similar efficacy after 6 weeks of treatment. The final global MADRS score was less than 10, which is within the usual range of efficacy of the reference drug after 6 weeks. There was no statistical difference in the curves showing the evolution of improvement for the 2 treatments; however, patients on moclobemide tended to improve earlier. The mean onset of action as determined by the investigators was 10 d (SD+5) for moclobemide and 13 d (SD 5 ) for clomipramine (P
