Clinical
Pharmacology
of Phenelzine
Donald S. Robinson, MD; Alexander Nies, MD; C. Lewis Ravaris, PhD, MD; John O. Ives, MD; Diantha Bartlett, MS
\s=b\ There is renewed interest in the clinical pharmacology of phenelzine sulfate and other monoamine oxidase (MAO) inhibitors. Newer clinical and analytic techniques recently have been applied to investigations of this class of drugs in man. The results show that drugs such as phenelzine are effective in nonendogenous depression and phobic disorders. Clinical response to phenelzine is related to platelet MAO inhibition and dosage per unit body weight. High percent MAO inhibition in platelets at two weeks is associated with greater improvement
after a six-week course of treatment. Our data show that a safe, effective phenelzine dose is 1 mg/kg body weight per day. These results have delineated the pharmacologic and therapeutic effects of phenelzine and support a continuing role for MAO inhibitors in psychopharmacology. (Arch Gen Psychiatry 35:629-635, 1978)
monoamine oxidase inhibitors (MAOI) have clinical use since the 1950s,13 acceptable scientific proof of their therapeutic efficacy was lacking until the present decade. Response to MAOIs generally has been considered to be unpredictable. They were gradually replaced by the tricyclic antidepressant drugs because of risk of hypertensive crises due to ingestion of tyramine containing foods or interacting drugs such as decongestants and amphetamines.4 Nevertheless, MAOIs continued to be used by some clinicians even in the absence of conclusive proof of efficacy and despite their toxic potential. A number of descriptive studies and anecdotal reports in the early 1960s5"1" suggested that a subgroup of patients labeled "atypical depression" responded to iproniazid and other MAOIs. This preferential therapeutic role for MAOIs was believed by many to be distinct from that of the more widely used tricyclic antidepressants (TCA).
Although
11 been in
From the Departments of Medicine and Pharmacology (Dr Robinson), Psychiatry (Drs Nies, Ravaris, Ives), and Epidemiology (Ms Bartlett), University of Vermont College of Medicine, Burlington. Reprint requests to Clinical Pharmacology Unit, University of Vermont College of Medicine, Burlington, VT 05401 (Dr Robinson).
RECENT EFFICACY STUDIES OF PHENELZINE The first
adequate efficacy trial of an MAOI (phenel¬ double-blind comparison of imipramine, phen¬
zine) elzine, and placebo in 250 depressed inpatients in the was a
Medical Research Council trial." This well-designed double-blind clinical experiment employed what is now known to be an adequate dose and duration of phenelzine treatment, 60 mg/day for one month. Unfortunately, the patient sample was presumably inappropriate for assess¬ ing MAOI effectiveness since the sample comprised hospi¬ talized psychiatric patients. The published description of the patient sample indicates that it consisted almost entirely of patients with the more severe endogenous depressions and possibly some with other psychotic disor¬ ders with depressive symptomatology. Such a sample has a lower probability of MAOI response since more recent efficacy studies in ambulatory patients, as well as the earlier anecdotal reports, point towards this class of drugs having their greatest benefit in nonendogenous (atypical)
depressions. The discovery that platelets are a rich source of MAO activity and the development of a convenient blood platelet MAO assay in man1- led to our interest in studying MAOIs more systematically, using the blood assay as a monitoring technique analagous to measuring actual drug concentra¬ tion itself. Assay of phenelzine blood levels directly has not been feasible up to now presumably because of its low plasma concentration and the fact that the drug binds irreversibly to intracellular enzymes. Our initial phenelzine trial" was begun in 1969 after an extensive planning period necessary to develop a satisfac¬ tory experimental protocol and valid rating techniques suitable for the assessment of drug effects in a clinically diverse sample of depressed patients. A structured inter¬ view schedule was constructed to permit accurate and reliable classification and stratification of
a
heterogeneous
sample of patients with depressive syndromes, as well as to detect change over time due to drug effects.14 Clinical
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were obtained as objectively as possible using the Standardized Depression Interview (SDI) adminis¬ tered by a single trained interviewer who was not a psychiatrist. The SDI includes 21 items contained in the Hamilton Depression Scale13 and 23 additional items or variables thought to be useful in distinguishing between endogenous and nonendogenous types of depression.14·16 A numerical index, the diagnostic index (DI), similar to those reported by other investigators17·'" can be calculated from the weighted item scores of the SDI, thus providing an overall measure of the mixture of endogenous and nonen¬ dogenous symptoms in the illness of an individual patient. A patient can thus be placed along a continuum from a high (predominantly endogenous) to a low (predominantly nonendogenous) index. Examples of the most heavily weighted endogenous and nonendogenous items of the SDI are given in Table 1. Such classical endogenous items as "loss of interest" and "early morning awakening" are used in computation of the DI but do not appear in Table 1 because of their lower weightings. When the SDI was constructed, we elected to assign DI item weights on the basis of the rank of item loadings in published factor analytic studies.11'"-'1 In a double-blind, placebo-controlled experiment outpa¬ tients were assigned six weeks treatment with phenelzine sulfate (Nardil) 60 mg/day, or phenelzine-placebo in a manner that matched the two groups for clinical variables (age, sex, DI, and severity).13 The patients, largely referred from private practices of family physicians, suffered persistent and significantly disabling depressive symp¬ tomatology, and many had received a trial of a benzodiazepine or tricyclic antidepressant, most often in low dosage, before referral. Sixty patients completed the six-week treatment, with the phenelzine-treated patient group ex¬ hibiting significantly greater clinical improvement on all rating measures. The SDI subscales, hypochondriasisagitation, irritability, and psychomotor change, showed an especially marked improvement with phenelzine treatment compared with placebo. This was perhaps the first adequately controlled clinical trial of phenelzine that provided satisfactory proof of efficacy. Since patients with the lower DI scores tended to show more marked improve¬ ment with phenelzine, this trial also was consistent with the clinical lore that MAOIs are more effective in nonen¬
rating data
dogenous depressions.14
About the same time two other groups of investigators reported evidence of phenelzine efficacy, one for treat¬ ment of phobic anxiety- ' and the other for neurotic depres¬ sion.24 The latter study observed significant improvement only in slow acetylators of phenelzine compared to placebotreated patients, but the treatment period was brief (three weeks), with but two weeks at full dosage. Negative results of two double-blind phenelzine trials were also reported at about the same time.-3-6 One of these was a comparative study of amitriptyline 75 to 150 mg/day or phenelzine 22.5 to 45 mg/day in a predominantly outpatient sample.-3 Although amitriptyline was found to be superior to phen¬ elzine on several measures, this may be counterbalanced by the significantly larger number of amitriptyline dropouts. Even more importantly, the doses of phenelzine employed were ineffective or at best marginally effective. In their -
Table 1— Examples of the More Heavily Weighted Items of the Standard Depression Interview That Contribute to the Diagnostic Index
Endogenous Items Suicidal ideation Weight loss
Depressed mood Agitation Retardation
Guilt Hallucinations Nihilistic delusions Loss of insight
Depersonalization
Relative
Weight 16 + 14 + 12 + 12 12 +
Nonendogenous
Relative
Items
Weight
Psychic anxiety Somatic anxiety
-16 -12
Initial insomnia General somatic Suicidal attempts
+ 12
(communicative) Weight gain
+ 10
Actual loss
-10
+
8
Longstanding phobia Self pity Hysterical personality
-10 -8
-6
large double-blind, placebo-controlled cooperative trial, Raskin et al26 studied 325 newly admitted depressed patients who were randomly assigned to diazepam, phenel¬ zine, or placebo. Since the patient sample was derived from nine cooperating psychiatric hospitals, there was presum¬ ably a predominance of patients with endogenous depres¬ sions as well as some schizophrenics with associated depressions. Thus, the patient sample was probably inap¬ propriate for assessing MAOI efficacy. Again, the phenel¬ zine dose employed was low (45 mg/day). After our first phenelzine trial" we elected to carry out a second phenelzine-placebo study of similar design in order to replicate the first study and to examine further dose response relationships. This study14 " again demonstrated phenelzine efficacy in an independent sample of depressed outpatients. Furthermore, dose was found to be an impor¬ tant variable since patients treated with phenelzine 60 mg/day improved significantly more than the placebo group, while treatment with phenelzine 30 mg/day did not differ significantly from placebo. Also, analysis of the combined high-dose phenelzine groups from the two studies showed positive associations between dose, platelet MAO inhibition, and clinical improvement. These results discussed further in a later section of this paper. Concurrent with this second trial another double-blind study was reported by Mountjoy and Roth2" in which a combination of phenelzine and diazepam was compared with placebo and diazepam in depressed outpatients clas¬ sified as depressive neuroses. These investigators did not observe significant differences between the two treat¬ ments but their results may have been confounded by the somewhat lower doses employed as well as reduced adher¬ ence to the research protocol because primary responsi¬ bility for care was retained by the patient's own clinician. Also, the concurrent use of two benzodiazepines, diazepam 15 mg/day, and nitrazepam 10 mg at bedtime, contributes to the difficulties in assessment of outcome. are
PHENELZINE STUDIES IN PROGRESS
number of trials of phenelzine for the of treatment depressive and phobic disorders under way by There
are a
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SCL-90 SCORES •-·
Table 2.—Comparison of Treatment Response In Low and High Monoamine Oxidase (MAO) Inhibition Groups Treated With Phenelzine, 60 mg/day*
PHEN 60 mg/day (n=55)
Percent Relative Improvement
_A_
too
-
Standardized
Low
Depression Interview
Inhibition ;
Subscale Score_(N Total depression_47
=
±
Hypochondriasis_23 Psychomotor change depression
Hamilton
BO
DEPRESSION
±
"
36)_Pt 10_67 ± 5_< .05
13)
(N
=
57 50
± ±
6
23_54 14_54
±
6_
80%), with tryptamine as substrate.
100-,
-i 60mg " "-·
6Gmg
dropouts
—T.—-J 30mg
Fig 4.—Mean platelet monoamine oxidase (MAO) inhibition ± SD depressed patients (N 55) from current phenelzine-amitriptyline trial after two, four, and six weeks of treatment with phenelzine 60 mg/day with benzylamine and tryptamine as substrates. Mean inhibition (substrate tryptamine) is shown for patients who dropped out after at least two weeks of treatment (N 13). of
=
=
analysis, correlations between improve¬ degree of platelet MAO inhibition were positive for all SDI symptom items with tryptamine as substrate, whereas this does not consistently occur for MAO inhibi¬ tion at two weeks with benzylamine. estingly
in this
ment and
2
4
WEEKS
6
Fig 3.—Mean platelet monoamine oxidase (MAO) inhibition ± SEM (with benzylamine substrate) of depressed patients in placebo-controlled clinical trials1327 treated with either phenelzine 60mg(N 47) or phenelzine 30 mg (N 16) daily for six weeks. Mean inhibition for dropouts from the high dose treatment groups =
is also shown
=
(N
=
9).
phenelzine-treated patients (Table 2). Analysis using either relative improvement or absolute change scores gives similar findings, that is there is a significant associa¬ tion between high inhibition and clinical improvement with the phenelzine 60 mg/day dose. Perhaps of more interest and greater potential use is the question whether monitoring MAO inhibition in an individual patient early in the course of treatment relates to and can predict ultimate clinical response. In the current study we assay platelet MAO activity every two weeks with both benzyl¬ amine (as in previous studies) and tryptamine as substrates. Response to a course of phenelzine treatment and MAO inhibition measured at 14 days of treatment using tryptamine as substrate is shown in Fig 2. Treat¬ ment outcomes at 6 weeks are significantly different for the high and low inhibition groups at two weeks based on the Hamilton depression (P < .05), total anxiety (P < .05), and somatic anxiety (P < .025) improvement scores. Inter-
TIME COURSE OF MAO INHIBITION DURING PHENELZINE THERAPY
Fig 3, the time interval from start of plateau percent inhibition was found to be dose dependent in the placebo-controlled phenelzine trials. Mean platelet MAO inhibition had reached plateau by two weeks of treatment in the low-dose phenelzine groups and remained relatively stable throughout the course of treat¬ ment. However, in the high-dose phenelzine group, mean inhibition at two weeks was 79%, reaching a plateau of 92% As shown in
treatment to
at four weeks and 91% at six weeks of treatment. In the current trial as well, the phenelzine treatment group does not reach plateau until between two and four weeks of treatment (Fig 4) with both substrates, benzylamine and
tryptamine.
This finding suggests that phenelzine metab¬ olism is dose dependent and that phenelzine might be inhibiting its own biotransformation at higher doses (zero order kinetics). Drugs that exhibit zero order kinetics have longer elimination half-lives with increasing dose, a pharmacokinetic property that can produce substantial changes in pharmacologie and clinical effects (both therapeutic and toxic) in response to small dosage increments. The discrepant results from the various reported phenelzine studies may in part be explained by this nonlinear relation¬ ship between dose and drug level (effect) since dose
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SCL-90 SCORE
Table 3.—Occurrence of Side Effects in Double-Blind Phenelzine-Amitriptyline Clinical Trial*
100-,
Phenelzine,
1-0
mg/Kg
Orthostatic
Dry mouth
27/50 (49)
hypotension_ Sedation_27/55 (49)_28/50 (56) "Proportion (%) of patients who experienced during six-week treatment period is given.
0-8
Amitriptyline,
60 mg/day_150 mg/day 26/55 (47)_19/50 (38) 42/50
(84)
drug-induced side effect
mg/Kg
platelet MAO inhibition as a function of phenelzine dose (mg/kg) also shows significant positive correlations at two, four, and six weeks of
treatment
(r
=
.29, .56, and .42
respectively). Thus, phenelzine dose (mg/kg) correlates both with the drug's pharmacologie and therapeutic
WEEKS OF TREATMENT
Fig 5.—Mean improvement (± SEM) in Symptom Check List (SCL-90) total score of depressed patients treated in double-blind controlled trial with fixed dose of phenelzine 60 mg/day for six weeks (N 55) stratified by high (> 1.0 mg/kg) and low (< 0.8 =
mg/kg) phenelzine
dose.
selection then would critically influence clinical outcome. This will require further investigation but suggests that a practical test of percent inhibition has clinical potential. DOSAGE
(mg/kg) AND RESPONSE
TO PHENELZINE
Dropouts receiving the 60 mg/day dosage achieve
lower
percent inhibition
at both two and four weeks on the average, although this difference is not significant perhaps due to small sample sizes (Fig 3 and 4). Possible explana¬ tions for this finding are that dropouts may be rapid
metabolizers of
phenelzine or merely
are
physically larger
(greater apparent volumes of distribution) and receive a dosage based on mg/kg body weight. This makes it pertinent to examine the relationship of dosage (mg/kg) to
lower
therapeutic outcome within treatment groups. Our previous phenelzine trials conclusively demonstrated that dosage is an important treatment variable.27 We examined individual patient response in relation to phen¬ elzine dose (mg) per unit body weight (kg) for all phenelzine-treated patients from our two previous and the current clinical trials. Dose (mg/kg) was correlated with improvement within the patient group treated with the fixed phenelzine dose (60 mg/day). This analysis showed that phenelzine dosage on a mg/kg basis correlates signif¬ icantly with improvement on certain symptom measures although the correlation coefficients are low presumably because of the large variance term for symptom improve¬ ment. When the phenelzine treatment group from the current trial is stratified according to low (< 0.8 mg/kg) and high (> 1.0 mg/kg) dose, there is a significant differ¬ ence in improvement in SCL-90 total score (Fig 5) at six weeks (P < .05). Thus, within a patient group receiving a fixed phenelzine dosage schedule of 60 mg/day, lighter patients who get the greater relative dose tend to improve more than the heavier patients. Analysis of percent
effects. In establishing the optimal therapeutic dose, one must also consider the relation of side effects to dosage in order to maximize the therapeutic ratio (benefit/risk). When we analyzed side effects using a standard rating instrument in our current phenelzine-amitriptyline trial, significant differences in occurrence of side effects between the two drugs were not detected except for the incidence of dry mouth (Table 3). Within the phenelzine treatment group the relationship of dose (mg/kg) and side effects was examined by 2 analysis of patient subgroups stratified by dose. Phenelzine side effects do not correlate with high or low mg/kg dosage. It remains to be established whether monitoring MAO inhibition or plasma drug levels in indi¬ vidual patients will be useful in minimizing side effects while optimizing therapeutic effect. ACETYLTRANSFERASE PHENOTYPE AND PHENELZINE TREATMENT A number of drugs of the hydrazine class, which includes phenelzine, undergo acetylation as a major biotransforma¬ tion pathway, as has been shown for isoniazid, hydralazine, and various sulfa drugs. On the basis of studies that have categorized patients by their rate of acetylation of isoni¬ azid or one of the sulfas, it has been suggested that the clinical effects of phenelzine treatment differ in so-called slow and fast acetylators. In a study of 47 depressed patients, Price Evans et al31 reported a retrospective analysis showing that "severe" side effects of phenelzine were more common among slow acetylators of isoniazid. More recently, Johnstone and Marsh have reported differ¬ ential therapeutic response to phenelzine in two separate outpatient studies of patients with "neurotic" depres¬ sion.2432 Slow acetylators of sulfadimidine show signifi¬ cantly greater improvement than fast acetylators in these two studies. Acetylator status did not relate to side effects, however. In the second study,32 MAO inhibition, assessed indirectly by urinary tryptamine excretion, was not signif¬ icantly different in slow and fast acetylators, although the slow acetylators tended to excrete greater amounts of tryptamine. We are in the process of determining acetylator status using sulfapyridine in phenelzine-treated patients from our three series. Preliminary results show 21 patients to be slow and eight patients to be fast acetylators of sulfapyr-
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¡dine. No significant differences in improvement on SDÌ subscale scores, global response, side effects, or percent MAO inhibition exist between the slow and fast acetyla¬ tors. However, it is of interest that when one relates the ratio of acetylated/free sulfapyridine in urine to improve¬ ment, most SDI symptom items show a negative (although low) correlation of relative improvement to acetylation ratio, indicating a trend for patients with a lower rate of
acetylation
acebo I Phenelzine 60
improve more. Hypochondriasis (r —.25, .05), psychomotor change (r —.24, < .05) and Hamilton Depression Score (r < .1) showed —.16, significant negative correlations. Our experience, thus far, has shown that categorical discrimination between fast and slow acetylators is imprecise because the distribution is not clearly bimodal and a substantial number of patients to
=
Pharmacology
of Phenelzine
Donald S. Robinson, MD; Alexander Nies, MD; C. Lewis Ravaris, PhD, MD; John O. Ives, MD; Diantha Bartlett, MS
\s=b\ There is renewed interest in the clinical pharmacology of phenelzine sulfate and other monoamine oxidase (MAO) inhibitors. Newer clinical and analytic techniques recently have been applied to investigations of this class of drugs in man. The results show that drugs such as phenelzine are effective in nonendogenous depression and phobic disorders. Clinical response to phenelzine is related to platelet MAO inhibition and dosage per unit body weight. High percent MAO inhibition in platelets at two weeks is associated with greater improvement
after a six-week course of treatment. Our data show that a safe, effective phenelzine dose is 1 mg/kg body weight per day. These results have delineated the pharmacologic and therapeutic effects of phenelzine and support a continuing role for MAO inhibitors in psychopharmacology. (Arch Gen Psychiatry 35:629-635, 1978)
monoamine oxidase inhibitors (MAOI) have clinical use since the 1950s,13 acceptable scientific proof of their therapeutic efficacy was lacking until the present decade. Response to MAOIs generally has been considered to be unpredictable. They were gradually replaced by the tricyclic antidepressant drugs because of risk of hypertensive crises due to ingestion of tyramine containing foods or interacting drugs such as decongestants and amphetamines.4 Nevertheless, MAOIs continued to be used by some clinicians even in the absence of conclusive proof of efficacy and despite their toxic potential. A number of descriptive studies and anecdotal reports in the early 1960s5"1" suggested that a subgroup of patients labeled "atypical depression" responded to iproniazid and other MAOIs. This preferential therapeutic role for MAOIs was believed by many to be distinct from that of the more widely used tricyclic antidepressants (TCA).
Although
11 been in
From the Departments of Medicine and Pharmacology (Dr Robinson), Psychiatry (Drs Nies, Ravaris, Ives), and Epidemiology (Ms Bartlett), University of Vermont College of Medicine, Burlington. Reprint requests to Clinical Pharmacology Unit, University of Vermont College of Medicine, Burlington, VT 05401 (Dr Robinson).
RECENT EFFICACY STUDIES OF PHENELZINE The first
adequate efficacy trial of an MAOI (phenel¬ double-blind comparison of imipramine, phen¬
zine) elzine, and placebo in 250 depressed inpatients in the was a
Medical Research Council trial." This well-designed double-blind clinical experiment employed what is now known to be an adequate dose and duration of phenelzine treatment, 60 mg/day for one month. Unfortunately, the patient sample was presumably inappropriate for assess¬ ing MAOI effectiveness since the sample comprised hospi¬ talized psychiatric patients. The published description of the patient sample indicates that it consisted almost entirely of patients with the more severe endogenous depressions and possibly some with other psychotic disor¬ ders with depressive symptomatology. Such a sample has a lower probability of MAOI response since more recent efficacy studies in ambulatory patients, as well as the earlier anecdotal reports, point towards this class of drugs having their greatest benefit in nonendogenous (atypical)
depressions. The discovery that platelets are a rich source of MAO activity and the development of a convenient blood platelet MAO assay in man1- led to our interest in studying MAOIs more systematically, using the blood assay as a monitoring technique analagous to measuring actual drug concentra¬ tion itself. Assay of phenelzine blood levels directly has not been feasible up to now presumably because of its low plasma concentration and the fact that the drug binds irreversibly to intracellular enzymes. Our initial phenelzine trial" was begun in 1969 after an extensive planning period necessary to develop a satisfac¬ tory experimental protocol and valid rating techniques suitable for the assessment of drug effects in a clinically diverse sample of depressed patients. A structured inter¬ view schedule was constructed to permit accurate and reliable classification and stratification of
a
heterogeneous
sample of patients with depressive syndromes, as well as to detect change over time due to drug effects.14 Clinical
Downloaded From: http://archpsyc.jamanetwork.com/ by a New York University User on 03/15/2016
were obtained as objectively as possible using the Standardized Depression Interview (SDI) adminis¬ tered by a single trained interviewer who was not a psychiatrist. The SDI includes 21 items contained in the Hamilton Depression Scale13 and 23 additional items or variables thought to be useful in distinguishing between endogenous and nonendogenous types of depression.14·16 A numerical index, the diagnostic index (DI), similar to those reported by other investigators17·'" can be calculated from the weighted item scores of the SDI, thus providing an overall measure of the mixture of endogenous and nonen¬ dogenous symptoms in the illness of an individual patient. A patient can thus be placed along a continuum from a high (predominantly endogenous) to a low (predominantly nonendogenous) index. Examples of the most heavily weighted endogenous and nonendogenous items of the SDI are given in Table 1. Such classical endogenous items as "loss of interest" and "early morning awakening" are used in computation of the DI but do not appear in Table 1 because of their lower weightings. When the SDI was constructed, we elected to assign DI item weights on the basis of the rank of item loadings in published factor analytic studies.11'"-'1 In a double-blind, placebo-controlled experiment outpa¬ tients were assigned six weeks treatment with phenelzine sulfate (Nardil) 60 mg/day, or phenelzine-placebo in a manner that matched the two groups for clinical variables (age, sex, DI, and severity).13 The patients, largely referred from private practices of family physicians, suffered persistent and significantly disabling depressive symp¬ tomatology, and many had received a trial of a benzodiazepine or tricyclic antidepressant, most often in low dosage, before referral. Sixty patients completed the six-week treatment, with the phenelzine-treated patient group ex¬ hibiting significantly greater clinical improvement on all rating measures. The SDI subscales, hypochondriasisagitation, irritability, and psychomotor change, showed an especially marked improvement with phenelzine treatment compared with placebo. This was perhaps the first adequately controlled clinical trial of phenelzine that provided satisfactory proof of efficacy. Since patients with the lower DI scores tended to show more marked improve¬ ment with phenelzine, this trial also was consistent with the clinical lore that MAOIs are more effective in nonen¬
rating data
dogenous depressions.14
About the same time two other groups of investigators reported evidence of phenelzine efficacy, one for treat¬ ment of phobic anxiety- ' and the other for neurotic depres¬ sion.24 The latter study observed significant improvement only in slow acetylators of phenelzine compared to placebotreated patients, but the treatment period was brief (three weeks), with but two weeks at full dosage. Negative results of two double-blind phenelzine trials were also reported at about the same time.-3-6 One of these was a comparative study of amitriptyline 75 to 150 mg/day or phenelzine 22.5 to 45 mg/day in a predominantly outpatient sample.-3 Although amitriptyline was found to be superior to phen¬ elzine on several measures, this may be counterbalanced by the significantly larger number of amitriptyline dropouts. Even more importantly, the doses of phenelzine employed were ineffective or at best marginally effective. In their -
Table 1— Examples of the More Heavily Weighted Items of the Standard Depression Interview That Contribute to the Diagnostic Index
Endogenous Items Suicidal ideation Weight loss
Depressed mood Agitation Retardation
Guilt Hallucinations Nihilistic delusions Loss of insight
Depersonalization
Relative
Weight 16 + 14 + 12 + 12 12 +
Nonendogenous
Relative
Items
Weight
Psychic anxiety Somatic anxiety
-16 -12
Initial insomnia General somatic Suicidal attempts
+ 12
(communicative) Weight gain
+ 10
Actual loss
-10
+
8
Longstanding phobia Self pity Hysterical personality
-10 -8
-6
large double-blind, placebo-controlled cooperative trial, Raskin et al26 studied 325 newly admitted depressed patients who were randomly assigned to diazepam, phenel¬ zine, or placebo. Since the patient sample was derived from nine cooperating psychiatric hospitals, there was presum¬ ably a predominance of patients with endogenous depres¬ sions as well as some schizophrenics with associated depressions. Thus, the patient sample was probably inap¬ propriate for assessing MAOI efficacy. Again, the phenel¬ zine dose employed was low (45 mg/day). After our first phenelzine trial" we elected to carry out a second phenelzine-placebo study of similar design in order to replicate the first study and to examine further dose response relationships. This study14 " again demonstrated phenelzine efficacy in an independent sample of depressed outpatients. Furthermore, dose was found to be an impor¬ tant variable since patients treated with phenelzine 60 mg/day improved significantly more than the placebo group, while treatment with phenelzine 30 mg/day did not differ significantly from placebo. Also, analysis of the combined high-dose phenelzine groups from the two studies showed positive associations between dose, platelet MAO inhibition, and clinical improvement. These results discussed further in a later section of this paper. Concurrent with this second trial another double-blind study was reported by Mountjoy and Roth2" in which a combination of phenelzine and diazepam was compared with placebo and diazepam in depressed outpatients clas¬ sified as depressive neuroses. These investigators did not observe significant differences between the two treat¬ ments but their results may have been confounded by the somewhat lower doses employed as well as reduced adher¬ ence to the research protocol because primary responsi¬ bility for care was retained by the patient's own clinician. Also, the concurrent use of two benzodiazepines, diazepam 15 mg/day, and nitrazepam 10 mg at bedtime, contributes to the difficulties in assessment of outcome. are
PHENELZINE STUDIES IN PROGRESS
number of trials of phenelzine for the of treatment depressive and phobic disorders under way by There
are a
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SCL-90 SCORES •-·
Table 2.—Comparison of Treatment Response In Low and High Monoamine Oxidase (MAO) Inhibition Groups Treated With Phenelzine, 60 mg/day*
PHEN 60 mg/day (n=55)
Percent Relative Improvement
_A_
too
-
Standardized
Low
Depression Interview
Inhibition ;
Subscale Score_(N Total depression_47
=
±
Hypochondriasis_23 Psychomotor change depression
Hamilton
BO
DEPRESSION
±
"
36)_Pt 10_67 ± 5_< .05
13)
(N
=
57 50
± ±
6
23_54 14_54
±
6_
80%), with tryptamine as substrate.
100-,
-i 60mg " "-·
6Gmg
dropouts
—T.—-J 30mg
Fig 4.—Mean platelet monoamine oxidase (MAO) inhibition ± SD depressed patients (N 55) from current phenelzine-amitriptyline trial after two, four, and six weeks of treatment with phenelzine 60 mg/day with benzylamine and tryptamine as substrates. Mean inhibition (substrate tryptamine) is shown for patients who dropped out after at least two weeks of treatment (N 13). of
=
=
analysis, correlations between improve¬ degree of platelet MAO inhibition were positive for all SDI symptom items with tryptamine as substrate, whereas this does not consistently occur for MAO inhibi¬ tion at two weeks with benzylamine. estingly
in this
ment and
2
4
WEEKS
6
Fig 3.—Mean platelet monoamine oxidase (MAO) inhibition ± SEM (with benzylamine substrate) of depressed patients in placebo-controlled clinical trials1327 treated with either phenelzine 60mg(N 47) or phenelzine 30 mg (N 16) daily for six weeks. Mean inhibition for dropouts from the high dose treatment groups =
is also shown
=
(N
=
9).
phenelzine-treated patients (Table 2). Analysis using either relative improvement or absolute change scores gives similar findings, that is there is a significant associa¬ tion between high inhibition and clinical improvement with the phenelzine 60 mg/day dose. Perhaps of more interest and greater potential use is the question whether monitoring MAO inhibition in an individual patient early in the course of treatment relates to and can predict ultimate clinical response. In the current study we assay platelet MAO activity every two weeks with both benzyl¬ amine (as in previous studies) and tryptamine as substrates. Response to a course of phenelzine treatment and MAO inhibition measured at 14 days of treatment using tryptamine as substrate is shown in Fig 2. Treat¬ ment outcomes at 6 weeks are significantly different for the high and low inhibition groups at two weeks based on the Hamilton depression (P < .05), total anxiety (P < .05), and somatic anxiety (P < .025) improvement scores. Inter-
TIME COURSE OF MAO INHIBITION DURING PHENELZINE THERAPY
Fig 3, the time interval from start of plateau percent inhibition was found to be dose dependent in the placebo-controlled phenelzine trials. Mean platelet MAO inhibition had reached plateau by two weeks of treatment in the low-dose phenelzine groups and remained relatively stable throughout the course of treat¬ ment. However, in the high-dose phenelzine group, mean inhibition at two weeks was 79%, reaching a plateau of 92% As shown in
treatment to
at four weeks and 91% at six weeks of treatment. In the current trial as well, the phenelzine treatment group does not reach plateau until between two and four weeks of treatment (Fig 4) with both substrates, benzylamine and
tryptamine.
This finding suggests that phenelzine metab¬ olism is dose dependent and that phenelzine might be inhibiting its own biotransformation at higher doses (zero order kinetics). Drugs that exhibit zero order kinetics have longer elimination half-lives with increasing dose, a pharmacokinetic property that can produce substantial changes in pharmacologie and clinical effects (both therapeutic and toxic) in response to small dosage increments. The discrepant results from the various reported phenelzine studies may in part be explained by this nonlinear relation¬ ship between dose and drug level (effect) since dose
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SCL-90 SCORE
Table 3.—Occurrence of Side Effects in Double-Blind Phenelzine-Amitriptyline Clinical Trial*
100-,
Phenelzine,
1-0
mg/Kg
Orthostatic
Dry mouth
27/50 (49)
hypotension_ Sedation_27/55 (49)_28/50 (56) "Proportion (%) of patients who experienced during six-week treatment period is given.
0-8
Amitriptyline,
60 mg/day_150 mg/day 26/55 (47)_19/50 (38) 42/50
(84)
drug-induced side effect
mg/Kg
platelet MAO inhibition as a function of phenelzine dose (mg/kg) also shows significant positive correlations at two, four, and six weeks of
treatment
(r
=
.29, .56, and .42
respectively). Thus, phenelzine dose (mg/kg) correlates both with the drug's pharmacologie and therapeutic
WEEKS OF TREATMENT
Fig 5.—Mean improvement (± SEM) in Symptom Check List (SCL-90) total score of depressed patients treated in double-blind controlled trial with fixed dose of phenelzine 60 mg/day for six weeks (N 55) stratified by high (> 1.0 mg/kg) and low (< 0.8 =
mg/kg) phenelzine
dose.
selection then would critically influence clinical outcome. This will require further investigation but suggests that a practical test of percent inhibition has clinical potential. DOSAGE
(mg/kg) AND RESPONSE
TO PHENELZINE
Dropouts receiving the 60 mg/day dosage achieve
lower
percent inhibition
at both two and four weeks on the average, although this difference is not significant perhaps due to small sample sizes (Fig 3 and 4). Possible explana¬ tions for this finding are that dropouts may be rapid
metabolizers of
phenelzine or merely
are
physically larger
(greater apparent volumes of distribution) and receive a dosage based on mg/kg body weight. This makes it pertinent to examine the relationship of dosage (mg/kg) to
lower
therapeutic outcome within treatment groups. Our previous phenelzine trials conclusively demonstrated that dosage is an important treatment variable.27 We examined individual patient response in relation to phen¬ elzine dose (mg) per unit body weight (kg) for all phenelzine-treated patients from our two previous and the current clinical trials. Dose (mg/kg) was correlated with improvement within the patient group treated with the fixed phenelzine dose (60 mg/day). This analysis showed that phenelzine dosage on a mg/kg basis correlates signif¬ icantly with improvement on certain symptom measures although the correlation coefficients are low presumably because of the large variance term for symptom improve¬ ment. When the phenelzine treatment group from the current trial is stratified according to low (< 0.8 mg/kg) and high (> 1.0 mg/kg) dose, there is a significant differ¬ ence in improvement in SCL-90 total score (Fig 5) at six weeks (P < .05). Thus, within a patient group receiving a fixed phenelzine dosage schedule of 60 mg/day, lighter patients who get the greater relative dose tend to improve more than the heavier patients. Analysis of percent
effects. In establishing the optimal therapeutic dose, one must also consider the relation of side effects to dosage in order to maximize the therapeutic ratio (benefit/risk). When we analyzed side effects using a standard rating instrument in our current phenelzine-amitriptyline trial, significant differences in occurrence of side effects between the two drugs were not detected except for the incidence of dry mouth (Table 3). Within the phenelzine treatment group the relationship of dose (mg/kg) and side effects was examined by 2 analysis of patient subgroups stratified by dose. Phenelzine side effects do not correlate with high or low mg/kg dosage. It remains to be established whether monitoring MAO inhibition or plasma drug levels in indi¬ vidual patients will be useful in minimizing side effects while optimizing therapeutic effect. ACETYLTRANSFERASE PHENOTYPE AND PHENELZINE TREATMENT A number of drugs of the hydrazine class, which includes phenelzine, undergo acetylation as a major biotransforma¬ tion pathway, as has been shown for isoniazid, hydralazine, and various sulfa drugs. On the basis of studies that have categorized patients by their rate of acetylation of isoni¬ azid or one of the sulfas, it has been suggested that the clinical effects of phenelzine treatment differ in so-called slow and fast acetylators. In a study of 47 depressed patients, Price Evans et al31 reported a retrospective analysis showing that "severe" side effects of phenelzine were more common among slow acetylators of isoniazid. More recently, Johnstone and Marsh have reported differ¬ ential therapeutic response to phenelzine in two separate outpatient studies of patients with "neurotic" depres¬ sion.2432 Slow acetylators of sulfadimidine show signifi¬ cantly greater improvement than fast acetylators in these two studies. Acetylator status did not relate to side effects, however. In the second study,32 MAO inhibition, assessed indirectly by urinary tryptamine excretion, was not signif¬ icantly different in slow and fast acetylators, although the slow acetylators tended to excrete greater amounts of tryptamine. We are in the process of determining acetylator status using sulfapyridine in phenelzine-treated patients from our three series. Preliminary results show 21 patients to be slow and eight patients to be fast acetylators of sulfapyr-
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¡dine. No significant differences in improvement on SDÌ subscale scores, global response, side effects, or percent MAO inhibition exist between the slow and fast acetyla¬ tors. However, it is of interest that when one relates the ratio of acetylated/free sulfapyridine in urine to improve¬ ment, most SDI symptom items show a negative (although low) correlation of relative improvement to acetylation ratio, indicating a trend for patients with a lower rate of
acetylation
acebo I Phenelzine 60
improve more. Hypochondriasis (r —.25, .05), psychomotor change (r —.24, < .05) and Hamilton Depression Score (r < .1) showed —.16, significant negative correlations. Our experience, thus far, has shown that categorical discrimination between fast and slow acetylators is imprecise because the distribution is not clearly bimodal and a substantial number of patients to
=
