Genetics and Psychopharmacology. Mod. Probl. Pharmacopsych., vol. 10, pp. 30-37, ed. J. Mendlewícz, Brussels (Karger, Basel 1975)
Relationship between Acetylator Status and Response to Phenelzine Eve C. Johnstone
In clinical practice it is an everyday observation that the response of patients to standard dosages of drugs is extremely variable. When a drug is administered in controlled conditions to large numbers of patients and a graph drawn of their response, a unimodal curve representing continuous variation may be found, but in some instances the curve will be bimodal or even trimodal, representing discontinuous variation. It has, in the past, tended to be assumed that the variability of drug metabolism and response is of the unimodal continuous type (viz., in the individual patient, therapeutic or side-effects known to result from a given drug could be produced given adequate dosage) but there are examples of discontinuous variability which are of clinical relevance. Bimodal or trimodal distribution of response may represent two or three genetically determined phenotypes. The term `polymorphism' is used when several phenotypes exist within the same population and are maintained from one generation to the next by genetic mechanisms. It is now known that there is a polymorphism for the acetylation of certain drugs. Acetylation polymorphism was first studied with reference to the antituberculous drug isoniazid, which was shown to be effective in the treatment of tuberculosis in 1952 (1). Shortly afterwards it was found that patients differed greatly in the way in which they metabolised isoniazid (2). Hughes et al. showed that isoniazid was excreted as unchanged drug, as acetylated derivative and as other metabolites and that while the percentage of acetylated derivative varied among different subjects from 14 to 70 %, the pattern of excretion for the individual was constant. This and other studies suggested that the variability in the inactivation of isoniazid is of the discontinuous kind, i.e. that the population is divided into two classes, rapid and slow inactivators. Twin studies and racial studies (3, 4) suggested that there was a genetic basis for this polymorphism and the detailed study of 484 subjects by Evans et al. (5) offered definite evidence
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Department of Psychological Medicine, University of Glasgow, Glasgow
31
that this was the case. Intestinal absorption, protein binding, renal glomerular clearance and renal tubular absorption were found to be irrelevant to the polymorphism (6) and it seemed likely that the difference between the rapid and slow inactivators was metabolic. The fact that the proportion of free unchanged drug excreted varied inversely with the proportion of acetylated drug (2) tended to suggest that the difference lay in speed of acetylation. This idea was confirmed by Evans and White (7) who showed that the livers of rapid inactivators of isoniazid have greater acetylating powers than those of slow inactivators, and by Peters et al. (8) who showed that acetylation was the primary metabolic reaction determining inactivator status for isoniazid. Satisfactory evidence was then available to show that the metabolism of isoniazid was determined by a genetic polymorphism controlling acetylation. The practical relevance of this was shown by studies indicating that slow mactivators of isoniazid had a greater liability than fast to develop isoniazid-induced peripheral neuropathy (10, 11). Clearly, it was likely that any drug metabolised by acetylation would be subject to this polymorphism and therefore the effects of such a drug in a random population would vary as a result. In fact, acetylation polymorphism accounts for little of the widespread variability in the response of human subjects to the vast range of drugs which they ingest, as few drugs are metabolised by this mechanism. Sulphadimidine is polymorphically acetylated (9) and there is evidence to suggest that hydrallazine (7, 12). and the hydrazine drug, phthivazíd (13), are substrates for polymorphic acetylation. It is probable that derivatives of hydrazine would be metabolised in a similar way. The anti-depressant drug, phenelzine, is a substituted hydrazine. This drug is a monoamine oxidase inhibitor (ΜΑΟΙ). Drugs of this group prevent the intraneuronal deamination of monoamines and increase their concentration in the brain in both animals (14) and man (15). The fact that these drugs are effective in relieving depression is one of the pieces of evidence for the theory that monoamines have a central role in the aetiology of depressive illness. The poor response of some depressed patients (16) to these drugs has been disappointing from the point of view of management of the individual and from the point of view of the theory. Pare et al. (17) studied the response of depressed patients to anti-depressants of the ΜΑΟΙ group and of the tricyclic group to examine the responses of individual patients in succeeding illnesses and to compare the responses of first-degree relatives to these drugs. Patients tended to respond in a consistent way in succeeding illnesses and the responses of first-degree relatives were also consistent, suggesting that genetic factors might be of relevance. Being a hydrazine derivative, phenelzine is likely to be subject to polymorphic acetylation. If this were so it would account for the variable results produced by the drug and for the apparent genetic tendency of the response. The possibility that the response of depressed patients to phenelzine might be related to acetylator status was studied in 1965 by Evans et al. (18). They
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Johnstone
32
Johnstone Table L. Details of patients studied at outset of project of Evans et al. (18) Clinical classification
Neurotic depression
Rapid acetylators
Slow acetylators
num- age (years) weight (kg) ber and and mean ± SEM mean ± SEM
num- age (years) weight (kg) ber and and mean ± SEM mean ± SEM
9
35.11 ± 4.20
133.00 9.95
16
38.44 ± 2.84
142.33 ± 6.53
Endogenous 8 depression
38.38 ± 3.47
145.50 11.19
17
48.59 ± 2.87
155.59 7.14
Total
36.65 ± 2.70
138.88 ± 7.38
33
43.36 ± 2.36
149.37 ± 5.04
17
Ni significant differences in weight between slow and rapid acetylators. Slow acetylators with endogenous depression have a higher mean age than the other three phenotypic and disease categories (p < 0.001). Reproduced by kind permission of Prof. D.A. Price Evans, Liverpool.
Table 17. Clinical responses observed (mean ± SEM of the ratios of each parameter before and after phenelzine therapy) in study of Evans et al. (18) Number of patients
Hildreth score Depression rating Anxiety rating (after (before before + 10) log,a 1 + 10) log,u 1 + 10) after 01 before after
log,
rapid slow rapid
slow
rapid
slow
rapid
slow
Neurotic depression
9
15
1.0663 ± 1.0784 ± 1.1292 ± 1.1432 ± 1.1044 ± 1.1501 ± 0.0068 0.0082 0.0330 0.0274 0.0260 0.0280
Endogenous depression
8
15
1.0576 ± 1.0837 ± 1.0701 ± 1.1311 ± 1.0758 ± 1.0968 0.0040 0.0113 0.0127 0.0403 0.0150 0.0157
All patients 17
30
1.0622 ± 1.0811 ± 1.1014 ± 1.1371 ± 1.0909 ± 1.1234 0.0039 0.0068 0.0200 0.0240 0.0153 0.0165 t = 1.970 p < 0.10
t = 1.015 p > 0.10
t = 1.309 p > 0.10
Reproduced by kind permission of Prof. D.A. Price Evans, Liverpool.
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Clinical classification
33
Relationship between Acetylator Status and Response to Phenelzíne
Table III. Incidence of adverse effects in phenelzine therapy (trial of Evans et al., 18) Acetylator phenotype
Rapid Slow Total
Total
Adverse effects nil
slight
severe
12 16 28
5 6 11
0 9 9
17 31 48
studied the response of 47 depressed patients to a 4-week course of phenelzine, given in a dose of 15 mg t.i.d. The acetylator phenotype was determined by an ísoniazid loading method prior to treatment being begun and ratings of depression and anxiety were carried out before and after treatment. The group consisted of 17 fast acetylators and 30 slow. 23 of the patients were classed as having endogenous depression and 24 as having neurotic depression. Full details of the patients and their response to phenelzine are contained in tables I—I11. Assessment of the psychiatric state was made by means of the Hamilton anxiety and depression scales and by means of the Hildreth self-rating feeling attitude scale (19-21). Side-effects were recorded only if they were spontaneously reported. No significant differences were found in clinical improvement between the two phenotypes but severe side-effects were reported only by slow acetylators although slight side-effects occurred in both groups. This distribution of side-effects supported the idea that phenelzine was subject to polymorphic acetylation in human populations but this study gave no evidence to suggest that acetylator phenotype was related to the anti-depressant effect of the drug. The findings of the Medical Research Council (MRC) study in 1965 suggested that phenelzine would not benefit endogenously depressed patients (16) who comprised half of the population of this study. Johnstone and Marsh (22) in 1973 carried out a 6-week double-blind cross-over trial of phenelzine versus placebo in 72 patients with neurotic depression and related the response of these patients to their acetylator phenotype. Each patient had 1 week on phenelzine 15 mg t.i.d. followed by 2 weeks on phenelzine 30 mg t.i.d. either before or after 3 weeks of placebo. The sample consisted of 39 slow acetylators and 33 fast. The mental state was assessed by means of a modification of the standardised psychiatric interview devised by Goldberg et al. (23) (table IV). These two groups did not differ in age or placebo response but they did differ in response to phenelzine. A trend whereby phenelzine was more effective as an antidepressant in slow acetylators than in fast was shown throughout the study and at times this achieved statistical significance. The trial showed that for fast
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Reproduced by kind permission of Prof. D.A. Price Evans, Liverpool.
Johnstone
34
Table IV. Modified Goldberg score Symptom areas
depression anxiety phobias obsessions and compulsions
Manifest abnormalities
depressed anxious
Overall severity =
symptom score + (manifest abnormality score X 2)
Table V. Comparison between response of fast and slow acetylators to placebo and Phenelzine (trial of Johnstone and Marsh, 22) Drug
Fast acetylators
Slow acetylators
p`
Week 3 scores: Placebo Phenelzine
5.83 ± 4.43 (n = 23) 5.80±4.55 (n = 10)
8.39 ± 5.79 (n = 23) 2.18±2.48(n=16)
NS
Relationship between Acetylator Status and Response to Phenelzine Eve C. Johnstone
In clinical practice it is an everyday observation that the response of patients to standard dosages of drugs is extremely variable. When a drug is administered in controlled conditions to large numbers of patients and a graph drawn of their response, a unimodal curve representing continuous variation may be found, but in some instances the curve will be bimodal or even trimodal, representing discontinuous variation. It has, in the past, tended to be assumed that the variability of drug metabolism and response is of the unimodal continuous type (viz., in the individual patient, therapeutic or side-effects known to result from a given drug could be produced given adequate dosage) but there are examples of discontinuous variability which are of clinical relevance. Bimodal or trimodal distribution of response may represent two or three genetically determined phenotypes. The term `polymorphism' is used when several phenotypes exist within the same population and are maintained from one generation to the next by genetic mechanisms. It is now known that there is a polymorphism for the acetylation of certain drugs. Acetylation polymorphism was first studied with reference to the antituberculous drug isoniazid, which was shown to be effective in the treatment of tuberculosis in 1952 (1). Shortly afterwards it was found that patients differed greatly in the way in which they metabolised isoniazid (2). Hughes et al. showed that isoniazid was excreted as unchanged drug, as acetylated derivative and as other metabolites and that while the percentage of acetylated derivative varied among different subjects from 14 to 70 %, the pattern of excretion for the individual was constant. This and other studies suggested that the variability in the inactivation of isoniazid is of the discontinuous kind, i.e. that the population is divided into two classes, rapid and slow inactivators. Twin studies and racial studies (3, 4) suggested that there was a genetic basis for this polymorphism and the detailed study of 484 subjects by Evans et al. (5) offered definite evidence
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Department of Psychological Medicine, University of Glasgow, Glasgow
31
that this was the case. Intestinal absorption, protein binding, renal glomerular clearance and renal tubular absorption were found to be irrelevant to the polymorphism (6) and it seemed likely that the difference between the rapid and slow inactivators was metabolic. The fact that the proportion of free unchanged drug excreted varied inversely with the proportion of acetylated drug (2) tended to suggest that the difference lay in speed of acetylation. This idea was confirmed by Evans and White (7) who showed that the livers of rapid inactivators of isoniazid have greater acetylating powers than those of slow inactivators, and by Peters et al. (8) who showed that acetylation was the primary metabolic reaction determining inactivator status for isoniazid. Satisfactory evidence was then available to show that the metabolism of isoniazid was determined by a genetic polymorphism controlling acetylation. The practical relevance of this was shown by studies indicating that slow mactivators of isoniazid had a greater liability than fast to develop isoniazid-induced peripheral neuropathy (10, 11). Clearly, it was likely that any drug metabolised by acetylation would be subject to this polymorphism and therefore the effects of such a drug in a random population would vary as a result. In fact, acetylation polymorphism accounts for little of the widespread variability in the response of human subjects to the vast range of drugs which they ingest, as few drugs are metabolised by this mechanism. Sulphadimidine is polymorphically acetylated (9) and there is evidence to suggest that hydrallazine (7, 12). and the hydrazine drug, phthivazíd (13), are substrates for polymorphic acetylation. It is probable that derivatives of hydrazine would be metabolised in a similar way. The anti-depressant drug, phenelzine, is a substituted hydrazine. This drug is a monoamine oxidase inhibitor (ΜΑΟΙ). Drugs of this group prevent the intraneuronal deamination of monoamines and increase their concentration in the brain in both animals (14) and man (15). The fact that these drugs are effective in relieving depression is one of the pieces of evidence for the theory that monoamines have a central role in the aetiology of depressive illness. The poor response of some depressed patients (16) to these drugs has been disappointing from the point of view of management of the individual and from the point of view of the theory. Pare et al. (17) studied the response of depressed patients to anti-depressants of the ΜΑΟΙ group and of the tricyclic group to examine the responses of individual patients in succeeding illnesses and to compare the responses of first-degree relatives to these drugs. Patients tended to respond in a consistent way in succeeding illnesses and the responses of first-degree relatives were also consistent, suggesting that genetic factors might be of relevance. Being a hydrazine derivative, phenelzine is likely to be subject to polymorphic acetylation. If this were so it would account for the variable results produced by the drug and for the apparent genetic tendency of the response. The possibility that the response of depressed patients to phenelzine might be related to acetylator status was studied in 1965 by Evans et al. (18). They
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Johnstone
32
Johnstone Table L. Details of patients studied at outset of project of Evans et al. (18) Clinical classification
Neurotic depression
Rapid acetylators
Slow acetylators
num- age (years) weight (kg) ber and and mean ± SEM mean ± SEM
num- age (years) weight (kg) ber and and mean ± SEM mean ± SEM
9
35.11 ± 4.20
133.00 9.95
16
38.44 ± 2.84
142.33 ± 6.53
Endogenous 8 depression
38.38 ± 3.47
145.50 11.19
17
48.59 ± 2.87
155.59 7.14
Total
36.65 ± 2.70
138.88 ± 7.38
33
43.36 ± 2.36
149.37 ± 5.04
17
Ni significant differences in weight between slow and rapid acetylators. Slow acetylators with endogenous depression have a higher mean age than the other three phenotypic and disease categories (p < 0.001). Reproduced by kind permission of Prof. D.A. Price Evans, Liverpool.
Table 17. Clinical responses observed (mean ± SEM of the ratios of each parameter before and after phenelzine therapy) in study of Evans et al. (18) Number of patients
Hildreth score Depression rating Anxiety rating (after (before before + 10) log,a 1 + 10) log,u 1 + 10) after 01 before after
log,
rapid slow rapid
slow
rapid
slow
rapid
slow
Neurotic depression
9
15
1.0663 ± 1.0784 ± 1.1292 ± 1.1432 ± 1.1044 ± 1.1501 ± 0.0068 0.0082 0.0330 0.0274 0.0260 0.0280
Endogenous depression
8
15
1.0576 ± 1.0837 ± 1.0701 ± 1.1311 ± 1.0758 ± 1.0968 0.0040 0.0113 0.0127 0.0403 0.0150 0.0157
All patients 17
30
1.0622 ± 1.0811 ± 1.1014 ± 1.1371 ± 1.0909 ± 1.1234 0.0039 0.0068 0.0200 0.0240 0.0153 0.0165 t = 1.970 p < 0.10
t = 1.015 p > 0.10
t = 1.309 p > 0.10
Reproduced by kind permission of Prof. D.A. Price Evans, Liverpool.
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Clinical classification
33
Relationship between Acetylator Status and Response to Phenelzíne
Table III. Incidence of adverse effects in phenelzine therapy (trial of Evans et al., 18) Acetylator phenotype
Rapid Slow Total
Total
Adverse effects nil
slight
severe
12 16 28
5 6 11
0 9 9
17 31 48
studied the response of 47 depressed patients to a 4-week course of phenelzine, given in a dose of 15 mg t.i.d. The acetylator phenotype was determined by an ísoniazid loading method prior to treatment being begun and ratings of depression and anxiety were carried out before and after treatment. The group consisted of 17 fast acetylators and 30 slow. 23 of the patients were classed as having endogenous depression and 24 as having neurotic depression. Full details of the patients and their response to phenelzine are contained in tables I—I11. Assessment of the psychiatric state was made by means of the Hamilton anxiety and depression scales and by means of the Hildreth self-rating feeling attitude scale (19-21). Side-effects were recorded only if they were spontaneously reported. No significant differences were found in clinical improvement between the two phenotypes but severe side-effects were reported only by slow acetylators although slight side-effects occurred in both groups. This distribution of side-effects supported the idea that phenelzine was subject to polymorphic acetylation in human populations but this study gave no evidence to suggest that acetylator phenotype was related to the anti-depressant effect of the drug. The findings of the Medical Research Council (MRC) study in 1965 suggested that phenelzine would not benefit endogenously depressed patients (16) who comprised half of the population of this study. Johnstone and Marsh (22) in 1973 carried out a 6-week double-blind cross-over trial of phenelzine versus placebo in 72 patients with neurotic depression and related the response of these patients to their acetylator phenotype. Each patient had 1 week on phenelzine 15 mg t.i.d. followed by 2 weeks on phenelzine 30 mg t.i.d. either before or after 3 weeks of placebo. The sample consisted of 39 slow acetylators and 33 fast. The mental state was assessed by means of a modification of the standardised psychiatric interview devised by Goldberg et al. (23) (table IV). These two groups did not differ in age or placebo response but they did differ in response to phenelzine. A trend whereby phenelzine was more effective as an antidepressant in slow acetylators than in fast was shown throughout the study and at times this achieved statistical significance. The trial showed that for fast
Downloaded by: Université de Paris 193.51.85.197 - 2/11/2020 6:38:47 PM
Reproduced by kind permission of Prof. D.A. Price Evans, Liverpool.
Johnstone
34
Table IV. Modified Goldberg score Symptom areas
depression anxiety phobias obsessions and compulsions
Manifest abnormalities
depressed anxious
Overall severity =
symptom score + (manifest abnormality score X 2)
Table V. Comparison between response of fast and slow acetylators to placebo and Phenelzine (trial of Johnstone and Marsh, 22) Drug
Fast acetylators
Slow acetylators
p`
Week 3 scores: Placebo Phenelzine
5.83 ± 4.43 (n = 23) 5.80±4.55 (n = 10)
8.39 ± 5.79 (n = 23) 2.18±2.48(n=16)
NS
