British Journal of Psychiatry (1992), 161, 665—670
Clomipramine versus Phenelzine in Obsessive—Compulsive Disorder A Controlled
Clinical Trial
J. VALLEJO, J. OLIVARES, T. MARCOS, A. BULBENA and J. M. MENCHON
A double-blindclinicaltrial of clomipramineversusphenelzinewas carriedout on 30 patients sufferingfrom DSM-lll obsessive—compulsive disorder.The studyperiodwas 12 weeks, and the maximumdoses used (from the fifth week on) were 225 mg/day for clomipramine(14 patients)and 75 mg/day for phenelzine(12 patients);four patientsdroppedout. Obsessive symptoms improved significantly in both drug groups, but there was no significant difference
between groups. Depressivesymptoms improvedbefore obsessiveones.
for OCD. Furthermore, we set out to investigate
Treatment of obsessive—compulsive disorder (OCD) has embraced different therapeutic strategies, from psychoanalysis to psychosurgery, including the whole range of psychotropic drugs. In several controlled
whether the antiobsessive effectiveness of these drugs is determined by the initial level of depression.
studies (Montgomery, 1980; Thoren et al, 1980; Insel
Method
et a!, 1983; Flament et al, 1985; Mavissakalian et al, 1985), antidepressants, and particularly clomipramine,
The final sample comprised 30 out-patients who met
have proved efficacious when compared with pla cebo. Likewise, a specific antiobsessive action of
DSM-III diagnostic criteria for OCD (American Psychiatric Association, 1980), referred to a university psychiatric clinic
clomipramine has been suggested, substantiated by its superiority when compared with amitriptyline
(Ananth et a!, 1979), nortriptyline (Thoren et al,
criteria, entry into the trial required that the duration of the disorder exceeded two years and that the depressive component, if present, appeared at least six months after
1980), imipramine (Volavska eta!, 1985), desipramine
the OCD. This latter requirementexcludedany pathology
(Insel et a!, 1985; Zohar & Insel, 1987), and
secondary to depressive disorders (anankastic
zimeidine
(Mavissakalian
(Rapoport
& Michelson,
eta!,
age, exclusionif pregnant or breast feeding, absence of
1980), imipramine
1983), and mianserin
(Jaskari, 1980) have not confirmed such differences. Marks et a! (1980, 1988)suggest that the antiobsessive efficacy of clomipramine is enhanced by a coexisting depressive state, while other authors dispute this (Ananth et al, 1979; Montgomery, 1980; Thoren et a!, 1980; Insel et a!, 1983; Flament et a!, 1985; Mavissakalian et a!, 1985; Volavska et a!, 1985;
Zohar & Insel, 1987). Since Joel's initial communication
depression).
Other selection criteria were as follows: 18—65 years of
(Insel eta!, 1985), although some studies
with desipramine
by primaryhealthcentres.In additionto DSM-Ill inclusion
organic brain pathology, absence of severe physical disorder, and no history of psychosis or other disorder (sociopathy,
hysteria, drug or alcohol abuse) that was likely
either to confound diagnosis or to interfere with the interpretationof the therapeuticresponse. Becauseof such requirements, 12 of the 42 patients initially referred were not entered in the trial. Reasons for exclusion were as follows: pregnancy (1 patient), age under 18 (1 patient) psychopathy
(1 patient), schizophrenia
(1 patient), hysteria
(2 patients), anankastic depression (3 patients), and refusal
to give signed informed consent (3 patients).
in 1959, mono
amine oxidase inhibitors (MAOIs) have been used to treat OCD. There has been a renewed interest in these
antidepressants and good results with tranylcypromine (Jenike, 1981; Swinson, 1984), nialamide (Rihmer et a!, 1982), and pheneizine (Isberg, 1981; Jenike et a!, 1983) have been reported, both in single case studies and with small samples. None the less, Insel
et a! (1983) found clomipramine to be better than clorgyline in a randomised cross-over double-blind study with 13 patients, although some of the subjects responded to MAOIs. We thought it appropriate to evaluate the clinical efficacy of the MAO! phenelzine in a double-blind comparison with clomipramine, a standard treatment 665
The 30 patients completed a two-week wash-out period,
during which they receivedplacebo. During the last two days of this period,
psychometric
tests and laboratory
screening were carried out. Patients
were then randomly
assigned
to either clomi
pramine or phenelzine. The drugs were administered in the following dosages: first and second weeks, clomipramine 75 mg/day or phenelzine 45 mg/day; third and fourth weeks, clomipramine 150 mg/day or phendzine 60 mg/day;
from the fifth week to the 12th week, clomipramine 225 mg/day or phenelzine75 mg/day (the maximumdoses used). The drugswere administeredin similarcapsules. All patients were given written instructions regarding diet, as
appropriate for prescriptions of MAOIs. One of the authors (JO) checkedpatients twicemonthly so as to administer tests, ensure compliance with medication,
666
VALLEJO
and recommend the treatment regime for the next two weeks. Interviews with family members were carried out to ensure compliance with medication. Thus, at the end of the 12-week trial, all patients had had six check-up visits in addition to the baseline visit. The blindness of the assessors was not checked. In addition to medical history, physical examination, routine laboratory tests, and an electrocardiogram, the following questionnairesand laboratorytests wereadminis tered during the baseline examination. The Lynfield Obsessional-Compulsive Inventory (LOCI), a modified version of Leyton's Obsessional Inventory. Scores on this 20-item scale range from 20 to 100 (Allen & Tune, 1975).
The Obsessive-CompulsiveInterviewChecklist(OCIC), a 66-item modified version of the original scale (Philpott, 1975). It evaluates activities; compulsion is rated on a 0—3-pointscale and total scores range from 0 to 198. The Maudsley Obsessive-Compulsive Inventory (MOCI)
(Rachman & Hodgson's (1980)definitiveversion with 30 items and a maximum score of 30). The Vallejo Obsessional Personality Inventory (VOPI). Designed by one of the authors (JV), this 31-item question naire assesses obsessive personality traits, and has a
maximum score of 31. The Global Evaluation Scale(GES). The patient scores his/her clinical condition from 0 to 10. A score of 0 is assignedwhen the subjectdeclaresthat his/her clinicalstate is at its worst, while 10 corresponds to total recovery.
The HamiltonRatingScalefor Depression(HRSD).This is a 21-item scale with scores ranging from 0 to 65 (Hamilton, 1960). The Hamilton Rating Scale for Anxiety (HRSA). This is a 14-item scale with scores ranging
from 0 to 56
(Hamilton, 1959).
ET AL
weeks (i.e. seven times in all). The LHK, MGS, LES, and baseline and post-dexamethasone cortisol levels were measured only at baseline. Statistical analysis
The study was designed to examine: (a) the global effectiveness of antidepressant treatment in OCD; (b) the individual efficacy of clomipramine and phenelzine; (c) the
relative effectiveness of the two drugs; (d) the relationship between both antiobsessive efficacy of treatment and initial depression, and changes in the depressive component throughout treatment; and (e) the predictive indices of pharmacological response. The homogeneityof both sampleswas evaluatedthrough
x2analysisand Fisher'sexacttest for qualitativevariables and the Mann—WhitneyU test for the quantitative data. For the comparison of global effectiveness of anti depressant medication, Wilcoxon's test was applied. For comparisons between groups, the 1-test was used; non parametric tests (Mann—Whitney in the case of unpaired groups and Wilcoxon in paired groups) were used for variables that were not normally distributed. To measure change, percentage changes (index values minus final values, divided by index values, and multiplied by 100) were used for quantitative variables. The relationships between the antiobsessive efficacy of treatment and initial depression and changes in the depressivecomponentthroughouttreatment,and prediction indices of pharmacological response were analysed with Pearson's
correlation.
Given the number of comparisons carried out in the analysis of the data, Bonferroni's adjustment was applied throughout.
The Eysenck Personality Inventory,Form B (EPI-B).
This assesses dimensions of neuroticism (EPI-N) and extraversion (EPI-E), with scores ranging from 0 to 25 (Eysenck & Eysenck, 1964).
Results Of the 30 subjects, 26 completed the trial (14 on clomi
The Lowenthal-Haven-Kaplan(LHK).Thisis an 11-item pramine, 12 on phenelzine). Of the four subjects who scale assessingsocial network. Only 6 items are scored. dropped out, two were from the clomipramine group, one Scores of 6-12 correspond to high social support, 13-18 to medium social support, and 19-24 to low social support
(Lowenthal & Haven, 1986). The Medalie-Goldbourt Scale (MGS). This is a 4-item scale measuring marital difficulties (Medalie & Goldbourt, 1976). The minimum support
score is 4 and maximum
is high when scores are 4-8,
medium
16. Social when 9—12,
and low when 13—16. The LifeExperienceSurvey(LES).This46-itemquestion naire assesses life events (Sarason,
1978). The present study
rated only presence or absence of life events during the year
before onset of the disorder.
of whom dropped out because of adverse effects - nausea,
vomiting,dizziness,and restlessness- and the otherbecause she showed delusions of referenceten days after beginning the treatment, after the obsessive symptoms had begun to resolve. Her affect was not elevated, expansive, or irritable.
Qomipramine was withdrawnand haloperidol was started. The delusionalcondition improved,but obsessivesymptoms reappeared. The two other patients who dropped out, from
the phenelzinegroup, both did so because of restlessness and general ill-health and dizziness. Characteristics of these four patients did not differ from those of the fmal sample.
Thegeneralcharacteristicsof the samplewereas follows:
of 5@g/dl. The LOCI, VOPI, and EPI were administered at the
mean (s.d.) age was 32 (11) years: there were 12 men and 14women, 10(38%) singleand 16(62°lo) married,19(73%) of middle social class and 7 (27°lo) of low social class. Social support was high in 9 (35%), medium in 11 (42%), and low in 6 (23%) patients. Life events before onset of the disorder were detected in 18 (69%) patients. Mean (s.d.)
beginning and at the end of the study. The OCIC, MOCI,
ageat onsetwas 15(8)years, meanageat first consultation
GES, HRSD,
26 (11) years, mean number of years between onset of
Baseline cortisol and post-dexamethasone cortisol were analysed by radioimmunoassay. Post-dexamethasone cortisol
was determined following the technique of Carroll et a! (1981), which established a cut-off point for non-suppression
and HRSA were administered
every two
667
CLOMIPRAMINE V. PHENELZINE IN OCD Table 1
symptoms and first consultation 9 (11), mean of duration of the disorder 17 (14) years. Five (19%) subjects had
previously been in-patients. Eight (31%) patients met criteria for major depressive disorder,
three of whom had
previouslyattemptedsuicide.Threemorepatients,showing no depressionwhenassessed in the presentepisode,had also attempted suicide in the past. Eleven(42%)patients
had
a family history of obsessivedisorders and 9 (35%) had family histories of other disorders. Only 7 (27%) patients
had no psychiatric family history. Mean baseline cortisol level was 23.8 (8.2) @sg/dland mean post-dexamethasone cortisollevel was 3.7 (3.8)@ig/dl. Six (23%) subjects were non-suppressors.
Response
to clomipramine
Rating Baseline (s.d.)P'Clomipramine scales mean (s.d.)6
and to phenelzine
w w meaneeks(s.d.)12 meaneeks
14)LOCI (n= (13.5)NANA40.8(11.4)NSOCIC 45.2
(30.4)52.3(40.1)39.7(28.9)0.01MOCI 75.2 (3.4)16.6(4.6)12.1(4.7)0.02VOPI 18.9 (2.8)NANA19.1(2.8)NSGES 19.5
(1.7)3.8(2.8)5.4(2.5)0.01HRSD 1.6 (6.3)13.9(6.0)11.5(6.9)0.01HRSA 20.1 (8.7)16.1(6.9)14.1(8.7)0.01EPI-N 24.6
13.6 The onlysignificantdifferencebetweenthe clomipramine (3.7)NANA13.5(4.6)NSEPI-E (3.7)NANA11.6(4.8)NSPhene/zine 10.6 and phenelzinegroups was on the GES score (P
Clomipramine versus Phenelzine in Obsessive—Compulsive Disorder A Controlled
Clinical Trial
J. VALLEJO, J. OLIVARES, T. MARCOS, A. BULBENA and J. M. MENCHON
A double-blindclinicaltrial of clomipramineversusphenelzinewas carriedout on 30 patients sufferingfrom DSM-lll obsessive—compulsive disorder.The studyperiodwas 12 weeks, and the maximumdoses used (from the fifth week on) were 225 mg/day for clomipramine(14 patients)and 75 mg/day for phenelzine(12 patients);four patientsdroppedout. Obsessive symptoms improved significantly in both drug groups, but there was no significant difference
between groups. Depressivesymptoms improvedbefore obsessiveones.
for OCD. Furthermore, we set out to investigate
Treatment of obsessive—compulsive disorder (OCD) has embraced different therapeutic strategies, from psychoanalysis to psychosurgery, including the whole range of psychotropic drugs. In several controlled
whether the antiobsessive effectiveness of these drugs is determined by the initial level of depression.
studies (Montgomery, 1980; Thoren et al, 1980; Insel
Method
et a!, 1983; Flament et al, 1985; Mavissakalian et al, 1985), antidepressants, and particularly clomipramine,
The final sample comprised 30 out-patients who met
have proved efficacious when compared with pla cebo. Likewise, a specific antiobsessive action of
DSM-III diagnostic criteria for OCD (American Psychiatric Association, 1980), referred to a university psychiatric clinic
clomipramine has been suggested, substantiated by its superiority when compared with amitriptyline
(Ananth et a!, 1979), nortriptyline (Thoren et al,
criteria, entry into the trial required that the duration of the disorder exceeded two years and that the depressive component, if present, appeared at least six months after
1980), imipramine (Volavska eta!, 1985), desipramine
the OCD. This latter requirementexcludedany pathology
(Insel et a!, 1985; Zohar & Insel, 1987), and
secondary to depressive disorders (anankastic
zimeidine
(Mavissakalian
(Rapoport
& Michelson,
eta!,
age, exclusionif pregnant or breast feeding, absence of
1980), imipramine
1983), and mianserin
(Jaskari, 1980) have not confirmed such differences. Marks et a! (1980, 1988)suggest that the antiobsessive efficacy of clomipramine is enhanced by a coexisting depressive state, while other authors dispute this (Ananth et al, 1979; Montgomery, 1980; Thoren et a!, 1980; Insel et a!, 1983; Flament et a!, 1985; Mavissakalian et a!, 1985; Volavska et a!, 1985;
Zohar & Insel, 1987). Since Joel's initial communication
depression).
Other selection criteria were as follows: 18—65 years of
(Insel eta!, 1985), although some studies
with desipramine
by primaryhealthcentres.In additionto DSM-Ill inclusion
organic brain pathology, absence of severe physical disorder, and no history of psychosis or other disorder (sociopathy,
hysteria, drug or alcohol abuse) that was likely
either to confound diagnosis or to interfere with the interpretationof the therapeuticresponse. Becauseof such requirements, 12 of the 42 patients initially referred were not entered in the trial. Reasons for exclusion were as follows: pregnancy (1 patient), age under 18 (1 patient) psychopathy
(1 patient), schizophrenia
(1 patient), hysteria
(2 patients), anankastic depression (3 patients), and refusal
to give signed informed consent (3 patients).
in 1959, mono
amine oxidase inhibitors (MAOIs) have been used to treat OCD. There has been a renewed interest in these
antidepressants and good results with tranylcypromine (Jenike, 1981; Swinson, 1984), nialamide (Rihmer et a!, 1982), and pheneizine (Isberg, 1981; Jenike et a!, 1983) have been reported, both in single case studies and with small samples. None the less, Insel
et a! (1983) found clomipramine to be better than clorgyline in a randomised cross-over double-blind study with 13 patients, although some of the subjects responded to MAOIs. We thought it appropriate to evaluate the clinical efficacy of the MAO! phenelzine in a double-blind comparison with clomipramine, a standard treatment 665
The 30 patients completed a two-week wash-out period,
during which they receivedplacebo. During the last two days of this period,
psychometric
tests and laboratory
screening were carried out. Patients
were then randomly
assigned
to either clomi
pramine or phenelzine. The drugs were administered in the following dosages: first and second weeks, clomipramine 75 mg/day or phenelzine 45 mg/day; third and fourth weeks, clomipramine 150 mg/day or phendzine 60 mg/day;
from the fifth week to the 12th week, clomipramine 225 mg/day or phenelzine75 mg/day (the maximumdoses used). The drugswere administeredin similarcapsules. All patients were given written instructions regarding diet, as
appropriate for prescriptions of MAOIs. One of the authors (JO) checkedpatients twicemonthly so as to administer tests, ensure compliance with medication,
666
VALLEJO
and recommend the treatment regime for the next two weeks. Interviews with family members were carried out to ensure compliance with medication. Thus, at the end of the 12-week trial, all patients had had six check-up visits in addition to the baseline visit. The blindness of the assessors was not checked. In addition to medical history, physical examination, routine laboratory tests, and an electrocardiogram, the following questionnairesand laboratorytests wereadminis tered during the baseline examination. The Lynfield Obsessional-Compulsive Inventory (LOCI), a modified version of Leyton's Obsessional Inventory. Scores on this 20-item scale range from 20 to 100 (Allen & Tune, 1975).
The Obsessive-CompulsiveInterviewChecklist(OCIC), a 66-item modified version of the original scale (Philpott, 1975). It evaluates activities; compulsion is rated on a 0—3-pointscale and total scores range from 0 to 198. The Maudsley Obsessive-Compulsive Inventory (MOCI)
(Rachman & Hodgson's (1980)definitiveversion with 30 items and a maximum score of 30). The Vallejo Obsessional Personality Inventory (VOPI). Designed by one of the authors (JV), this 31-item question naire assesses obsessive personality traits, and has a
maximum score of 31. The Global Evaluation Scale(GES). The patient scores his/her clinical condition from 0 to 10. A score of 0 is assignedwhen the subjectdeclaresthat his/her clinicalstate is at its worst, while 10 corresponds to total recovery.
The HamiltonRatingScalefor Depression(HRSD).This is a 21-item scale with scores ranging from 0 to 65 (Hamilton, 1960). The Hamilton Rating Scale for Anxiety (HRSA). This is a 14-item scale with scores ranging
from 0 to 56
(Hamilton, 1959).
ET AL
weeks (i.e. seven times in all). The LHK, MGS, LES, and baseline and post-dexamethasone cortisol levels were measured only at baseline. Statistical analysis
The study was designed to examine: (a) the global effectiveness of antidepressant treatment in OCD; (b) the individual efficacy of clomipramine and phenelzine; (c) the
relative effectiveness of the two drugs; (d) the relationship between both antiobsessive efficacy of treatment and initial depression, and changes in the depressive component throughout treatment; and (e) the predictive indices of pharmacological response. The homogeneityof both sampleswas evaluatedthrough
x2analysisand Fisher'sexacttest for qualitativevariables and the Mann—WhitneyU test for the quantitative data. For the comparison of global effectiveness of anti depressant medication, Wilcoxon's test was applied. For comparisons between groups, the 1-test was used; non parametric tests (Mann—Whitney in the case of unpaired groups and Wilcoxon in paired groups) were used for variables that were not normally distributed. To measure change, percentage changes (index values minus final values, divided by index values, and multiplied by 100) were used for quantitative variables. The relationships between the antiobsessive efficacy of treatment and initial depression and changes in the depressivecomponentthroughouttreatment,and prediction indices of pharmacological response were analysed with Pearson's
correlation.
Given the number of comparisons carried out in the analysis of the data, Bonferroni's adjustment was applied throughout.
The Eysenck Personality Inventory,Form B (EPI-B).
This assesses dimensions of neuroticism (EPI-N) and extraversion (EPI-E), with scores ranging from 0 to 25 (Eysenck & Eysenck, 1964).
Results Of the 30 subjects, 26 completed the trial (14 on clomi
The Lowenthal-Haven-Kaplan(LHK).Thisis an 11-item pramine, 12 on phenelzine). Of the four subjects who scale assessingsocial network. Only 6 items are scored. dropped out, two were from the clomipramine group, one Scores of 6-12 correspond to high social support, 13-18 to medium social support, and 19-24 to low social support
(Lowenthal & Haven, 1986). The Medalie-Goldbourt Scale (MGS). This is a 4-item scale measuring marital difficulties (Medalie & Goldbourt, 1976). The minimum support
score is 4 and maximum
is high when scores are 4-8,
medium
16. Social when 9—12,
and low when 13—16. The LifeExperienceSurvey(LES).This46-itemquestion naire assesses life events (Sarason,
1978). The present study
rated only presence or absence of life events during the year
before onset of the disorder.
of whom dropped out because of adverse effects - nausea,
vomiting,dizziness,and restlessness- and the otherbecause she showed delusions of referenceten days after beginning the treatment, after the obsessive symptoms had begun to resolve. Her affect was not elevated, expansive, or irritable.
Qomipramine was withdrawnand haloperidol was started. The delusionalcondition improved,but obsessivesymptoms reappeared. The two other patients who dropped out, from
the phenelzinegroup, both did so because of restlessness and general ill-health and dizziness. Characteristics of these four patients did not differ from those of the fmal sample.
Thegeneralcharacteristicsof the samplewereas follows:
of 5@g/dl. The LOCI, VOPI, and EPI were administered at the
mean (s.d.) age was 32 (11) years: there were 12 men and 14women, 10(38%) singleand 16(62°lo) married,19(73%) of middle social class and 7 (27°lo) of low social class. Social support was high in 9 (35%), medium in 11 (42%), and low in 6 (23%) patients. Life events before onset of the disorder were detected in 18 (69%) patients. Mean (s.d.)
beginning and at the end of the study. The OCIC, MOCI,
ageat onsetwas 15(8)years, meanageat first consultation
GES, HRSD,
26 (11) years, mean number of years between onset of
Baseline cortisol and post-dexamethasone cortisol were analysed by radioimmunoassay. Post-dexamethasone cortisol
was determined following the technique of Carroll et a! (1981), which established a cut-off point for non-suppression
and HRSA were administered
every two
667
CLOMIPRAMINE V. PHENELZINE IN OCD Table 1
symptoms and first consultation 9 (11), mean of duration of the disorder 17 (14) years. Five (19%) subjects had
previously been in-patients. Eight (31%) patients met criteria for major depressive disorder,
three of whom had
previouslyattemptedsuicide.Threemorepatients,showing no depressionwhenassessed in the presentepisode,had also attempted suicide in the past. Eleven(42%)patients
had
a family history of obsessivedisorders and 9 (35%) had family histories of other disorders. Only 7 (27%) patients
had no psychiatric family history. Mean baseline cortisol level was 23.8 (8.2) @sg/dland mean post-dexamethasone cortisollevel was 3.7 (3.8)@ig/dl. Six (23%) subjects were non-suppressors.
Response
to clomipramine
Rating Baseline (s.d.)P'Clomipramine scales mean (s.d.)6
and to phenelzine
w w meaneeks(s.d.)12 meaneeks
14)LOCI (n= (13.5)NANA40.8(11.4)NSOCIC 45.2
(30.4)52.3(40.1)39.7(28.9)0.01MOCI 75.2 (3.4)16.6(4.6)12.1(4.7)0.02VOPI 18.9 (2.8)NANA19.1(2.8)NSGES 19.5
(1.7)3.8(2.8)5.4(2.5)0.01HRSD 1.6 (6.3)13.9(6.0)11.5(6.9)0.01HRSA 20.1 (8.7)16.1(6.9)14.1(8.7)0.01EPI-N 24.6
13.6 The onlysignificantdifferencebetweenthe clomipramine (3.7)NANA13.5(4.6)NSEPI-E (3.7)NANA11.6(4.8)NSPhene/zine 10.6 and phenelzinegroups was on the GES score (P
