European Journal of Clinical Pharmacology © by Springer-Verlag 1978
Europ. J. clin. Pharmacol. 14, 185-190 (1978)
Clinical Response and Plasma Concentration of Amitriptyline and its Metabolite Nortriptyline S. Vandel, B. Vandel, M. Sandoz, G. Allers, P. Bechtel, and R. Volmat Laboratoire de PharmacologieClinique et Clinique de Neurologieet Psychiatric, Centre Hospitalier Universitaire de Besan~on, France
Summary. Plasma levels of amitriptyline and nortriptyline were measured twice weekly in 62 patients treated for three weeks with i.m. amitriptyline 120 rag/day. In half the patients the ratio of amitriptyline to nortriptyline was under 1 and in the other half it was greater than 1. 30 of these 62 patients were clinically monitored with the Hamilton Rating Scale and the side effects of the drug were recorded. There was no correlation between plasma level of the drug and its side effects, but there was a statistically significant curvilinear correlation between the plasma levels of amitriptyline plus nortriptyline and nortriptyline alone, and the clinical effect. The practical value of this type of investigation was demonstrated by showing that patients whose drug plasma level was not in the therapeutic range, were clinically improved after adjustment of the dose. The plasma level of amitriptyline plus nortriptyline must lie between 60 to 220 ng/ml, and that of nortriptyline between 60 to 140 ng/ml, to obtain the best clinical effect. Associated treatments, age, weight and sex of patients, and the type of depression did not appear significantly to affect the plasma level of the drug. Key words: amitriptyline, nortriptyline, depression, therapeutic plasma level, Hamilton rating scale
It is well known that 20 to 30% of depressed patients are not improved by tricyclic antidepressant therapy. Some authors (Alexanderson et al., 1969; Asberg, 1976; Hammer et al., 1967; Sj6qvist, 1971; Tillement, 1973) have reported that there is no correlation between the dose of these drugs and the plasma level produced. Attempts to explain the reason for the therapeutic failures have looked for a relation-
ship between the plasma level of the drug and its clinical effect. Even today however, there are still discrepancies in the literature, probably in part due to the different methodologies used. The present investigation was concerned with the relationship between the plasma level of amitriptyline and its metabolite nortriptyline, and the therapeutic response. In a group of 62 depressed patients, the drug plasma concentration was first determined during treatment for three weeks with amitriptyline. Clinical improvement in 30 of these patients was monitored with the Hamilton Rating Scale. A relationship between the plasma concentration of the drug and its clinical effect was found, so the attempt was made to determine if the active compound were amitriptyline or nortriptyline or both. After dividing the patients into two groups, the correlation with endogenous or exogenous depressive illness was finally studied.
Patients and Methods Patients
62 patients with exogenous or endogenous depressive illnesses (without delusional pathology) were treated for at least three weeks by daily i. m. administration of amitriptyline 120 mg. In addition, all patients received benzodiazepine and 47 of them were also given a phenothiazine (Table 1). Clinical Examination
Of the 62 patients, 13 with an exogenous depressive illness and 17 with endogenous depression (Gurney et al., 1972) were clinically monitored once a week by the same psychiatrist, who used the Hamilton Rat0031-6970/78/0014/0185/$01.20
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S. Vandel et al.: Amitriptyline Metabolism and Clinical Response
Blood Samples and Drug Assay
Table 1. Drug associations
Drug associations
Number of patients
Dose
Levomepromazine Chlorpromazine Propericiazine Cyamepromazine Diazepam Lorazepam Meprobamate Clorazepate
35 5 6 1 28 4 1 5
30 to 300 mg 100 to 400 mg 20 to 70 mg 200 mg 20 to 30 mg 7,5 to 15 mg 1600 mg 15 to 150mg
(17) (1) (14) (2) (I)
In brackets: number of patients clinically monitored with Hamilton Rating Scale
Table 2. Factors affecting the plasma level of amitriptyline plus
The plasma level of amitriptyline and nortriptyline in each patient was analysed twice a week using a gas chromatographic method (Volmat et al., 1977). One determination was done on the day of the Hamilton Rating Scale and the second three days after to check on the patient's compliance with treatment. The blood samples were taken in the morning before administration of the drug.
Statistical Analysis Covariance analysis (Philippe, 1967) was used to determine the correlation between the plasma level of the drug and the clinical effect.
nortriptyline Factors
Mean SE AMT + NT plasma levels at steady state
Student's t test
1. Plasma Levels
± 60
significant
The plasma level of amitriptyline and nortriptyline reached a steady state about the 9th day of treatment. In the 62 patients, the mean plasma concentration during the steady state varied between 120 and 140 ng/ml. The ratio of amitriptyline and nortriptyline in the group of 62 patients did not show any particular distribution of the plasma level of the metabolite in relation to the level of amitriptyline; half the patients had a ratio below 1 and the other half had a ratio above 1. In 2/3 of the patients there was no alteration in the ratio of amitriptyline and nortriptyline concentration during treatment; and in the other patients, q~ showed an increase in the ratio, 1/3 a decrease and in 1/3 the figure remained about 1. No statistical relationship was found between the plasma level of the drug and age, sex and weight of patients, diagnosis or associated treatment (Table 2).
p=0.10
2. Correlation between Clinical Effect and Plasma Level
male
128 ng/ml
non
female
146 ng/ml 4-68 0.87 significant
20-30years 31--40 years 41-50 years 51-60 years 60 and more
130ng/ml 132ng/ml 103ng/ml 115ng/ml 165ng/ml
+49 4- 63 4- 29 +49 ±94
0.04 1.61 0.75 0.77
122ng/ml 51-60kg 109ng/ml 61-70kg 148ng/ml 71-80kg 137ng/ml 80 and more 96ng/mi
-39 ±36 -2_65 ±77 ±25
0.73 1.15 0.50 1.37
Sex Age
Weight 40-50kg
Drug with assophenothiazine 141 ng/ml ciations without phenothiazine 121 ng/ml Diagnosis
endogenous depres~on exogenous depression
± 62
non Ngnificant
non significant
non 0.79
± 71
118ng/ml
±90
160 ng/ml
±50
Results
1.50
ing Scale (Knesevich et al., 1977), and a side effects rating scale (Asberg, 1974). •These 30 patients presented a severe depressive state. In 27 cases the Hamilton Rating scores were between 30 and 35, and in the other 3 cases they were 20 at the beginning of the investigation.
In the 30 patients clinically monitored with the Hamilton Rating Scale, a statistically significant (P ----0.05) curvilinear correlation was found between the plasma level of amitriptyline plus nortriptyline at steady state and the clinical effect. The therapeutic plasma level was within the range of 60 to 220 ng/ml (Fig. 1). Clinical improvement occurred between the 9th and 15th days of treatment, when the plasma concentration of the drug was at the therapeutic level. A similar correlation (P = 0.001) was observed if only the plasma concentration of nortriptyline was considered. The therapeutic range of the plasma con-
S. Vandel et al.: AmitriptylineMetabolism and Clinical Response
187
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Fig. 1. Correlation between the plasma level of amitriptyline plus nortriptyline at steady state and the Hamilton Rating scores in 30 patients given amitriptyline 120 mg daily. (n = number ol determinations of plasma concentration of the drug)
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Fig. 2. Correlation between the plasma level of amitriptyline and nortriptyliue [ ] at steady state and the Hamilton rating score.
(n = number of determinations of plasma concentration of the drug) @4 II
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Fig. 3. Correlation between the plasma level of amitriptyline plus endogenous
20
depressive
illnesses.
(n = number of determinations of plasma concentration of the
I01 LEVEL
140
141 180
181 2 2 0
221
+
(ng/ml)
Fig. 4. Correlation between the plasma level of nortriptyline at steady state and the Hamilton rating scores in endogenous [ ] and exogenous [ ] depressive illnesses. (n = number of determinations of plasma concentration of the drug)
drug)
centration of this metabolite was between 60 to 140 ng/ml (Fig. 2). No statistically significant correlation was found between the plasma level of amitriptyline and the clinical response (Fig. 2). The plasma level of amitriptyline plus nortriptyline, or of nortriptyline alone, gave a better correlation with the clinical effect in the group of endogenous depression (P = 0.3), than in the exogenous depressions (P = 0.5; Figs. 3 and 4),
but due to the reduced number of cases, these correlations must be accepted with caution. In the first group (endogenous depressive illnesses) the therapeutic range of plasma levels was: 60 ng/ml < amitriptyline + nortriptyline < 180 ng/ml 60 ng/ml < nortriptyline < 140 ng/ml In the second group (exogenous depressive illnesses), the therapeutic range was:
S. Vandel et al.: Amitriptyline Metabolism and Clinical Response
188 {o E ¢M
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b) 3 patients with - plasma level of amitriptyline + nortriptyline > 220 ng/ml - plasma level of nortriptyline > 140 ng/ml c) 3 patients with - plasma level of amitriptyline + nortriptyline in the therapeutic range - plasma level of nortriptyline < 60 ng/ml The 5 patients of Groups A and B showed improvement after dosage adjustment, when the plasma level of amitriptyline plus nortriptyline, and of nortriptyline alone, had reached the therapeutic range. In Group C, 2 patients improved when nortriptyline was added to the treatment with amitriptyline: the plasma level of nortriptyline rose above 60 ng/ml. The third patient in this group improved when nortriptyline was added to the treatment with amitriptyline, and the plasma level of nortriptyline increased from 26 to 52 ng/ml.
L E V E L (ng/rnl)
Fig. 5. Correlation between the plasma level of amitriptyline plus nortriptyline [~]], amitriptyline [ ] and nortriptyline [ ] at steady state and the side effects of the drug. (n = number of determinations of plasma concentration of the drug)
Discussion
1. Factors Influencing Plasma Level of the Antidepressant Table 3. Amitriptyline and nortriptyline ratios in eight patients who improved clinically despite a low drug plasma level Plasma level of AMT + NT
Plasma level of NT
Ratio Hamilton AMT/NT score
78 67 79 54 95 97 55 76
30 10 31 44 50 52 31 40
> 1 > 1 >1 < 1 < 1 < 1 <1 < 1
6 9 5 4 6 6 5 10
60 ng/ml < amitriptyline + nortriptyline < 220 ng/ml 60 ng/ml < nortriptyline < 140 ng/ml There was a curvilinear correlation between the plasma level of nortriptyline and side effects of the drug (P = 0.1), but not with amitriptyline alone, or with amitriptyline + nortriptyline (Fig. 5) At the end of a three week treatment with amitriptyline 120mg per day, 8 of the 30 patients showed no improvement. There were three groups: a) 2 patients with - plasma level of amitriptyline + nortriptyline < 60 ng/ml - plasma level of nortriptyline < 60 ng/ml
As others have found, there was no relationship in this group of patients, between drug dosage and its plasma concentration when measured at steady state. This lack of relationship, in the case of tricyclic antidepressants, is due to differences in the metabolic rate under the control of hereditary factors (Alexanderson et al., 1969), and possibly to interaction with other drugs. In the present study (Table 2), however, no statistically significant variation of plasma levels in the 47 patients who had received a neuroleptic drug was found. Here, the results disagree with those of certain other authors, who have described an increase in the plasma level of antidepressant drugs in patients receiving a neuroleptic agent (OlivierMartin et al., 1975). Asberg found a relationship between the type of depression and the plasma level of the antidepressant drug, but in the present patients, the relationship was not statistically significant (Table 2).
2. Plasma Level of the Drug and Clinical Response Several authors have looked for a correlation between the plasma level of an antidepressant and the clinical response (Angst and Rothweiler, 1974; Burrows et al., 1972, 1974; Gram et al., 1975; Hammer et al, 1967; Kupfer et al., 1977; Montgomery, 1975; Moody et al., 1967; Whyte et al., 1976). In this study there was a 95% chance of improvement of the depression when the plasma level of amitriptyline
S. Vandel et al.: Amitriptyline Metabolism and Clinical Response
plus nortriptyline was adjusted to between 60 and 220 ng/ml. The likelihood reached 99% when the plasma level of nortriptyline lay between 60 and 140ng/ml. In our trial, 4 patients showed no improvement despite a plasma level of nortriptyline above 140 ng/ml, but they did recover when, after adjustment of the dose, the plasma level of nortriptyline reached the therapeutic range. This data agrees with that of Asberg and Kragh-S6rensen (Asberg, 1971, 1974, 1976; Kragh-S6rensen et al., 1973, 1976). Ziegler et al. (1976) did not find a curvilinear relationship between the plasma level of the drug and the clinical response. But, in their study the only patient with a plasma level above 250 ng/ml had a Hamilton score of 10 and, after dosage adjustment, the plasma level decreased to 125 ng/ml and the Hamilton score fell to 2. In a study of 15 patients Braithwaite et al. (1972) found 2 instances of a plasma level above 250 ng/ml and clinical improvement. Coppen (1976) reported a linear response, but his paper does not contain details of the maximum plasma level in the three patients with the highest values. During and at the end of the three weeks of treatment, 5 patients with a plasma level of drug above 250ng/ml and no clinical improvement showed recovery after drug adjustment and a decrease in its plasma level. This suggests that there may a curvilinear correlation between plasma level and clinical response. From the present results, the antidepressive effect of amitriptyline is questionable, because the only relationship observed were those between the plasma level of amitriptyline plus nortriptyline, and nortriptyline (as an amitriptyline metabolite), and the clinical effect. If nortriptyline alone were the antidepressant agent, it is important to know the metabolic "profile" of the patient. If the biotransformation rate of amitriptyline to nortriptyline were low, it would appear necessary to increase the dosage of amitriptyline to obtain a therapeutic plasma level of nortriptyline, or to prescribe nortriptyline. But it is not possible to give a definite answer to this question, because of the 8 patients who showed clinically improvement with a plasma level of amitriptyline plus nortriptyline of about 60 ng/ml, only 5 had an amitriptyline/nortriptyline ratio less than 1 (Table 3). This does not agree with Ziegler et al. (1976), who found a correlation between the plasma level of amitriptyline plus nortriptyline, and amitriptyline alone and the clinical effect, but not between the latter and nortriptyline alone. Acknowledgements. Our thanks are due to Mrs. H. Faucheux for the determinations of drug concen-
189
tration. We owe particular gratitude to Mrs. C. Gaudemard and Mr. Philippe for their assistance with the statistical calculations.
References Alexanderson, B., Evans, D. A., Sj6qvist, F.: Steady State plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br. med. J. 1969/IV, 764-768 Angst, J., Rothweiler, R.: Blood levels and clinical effects of maprotiline (Ludiomil®). In classification and prediction of outcome of depression. Symposia Medica Hoechst 8, 237-244 (1974) Asberg, M.: Plasma nortriptyline levels. Relationship to clinical effects. Clin. Pharmacoi. Ther. 16, 215-229 (1974) Asberg, M.: Treatment of Depression with Tricyclic Drugs. Pharmacokinetic and Pharmacodynamic Aspects. Pharmakopsychiatrie. Neuropsychopharmacologie 9, 18-26 (1976) Asberg, M., Cronholm, B., Sj6qvist, F., Tuck, D.: Relationship between plasma level and therapeutic effect of nortriptyline. Br. med. J. 1971/!!I, 331-334 Braithwaite, R. A., Goulding, R., Theand, G., Bailey, J., Coppen, A.: Plasma concentration of amitriptyline and clinical response. Lancet 1972/1, 1297-1300 Burrows, G.D.: Clinical and Pharmacological Studies in depressive illness. M. D. Thesis, University of Melbourne, 1973 Burrows, G. D., Davies, B., Scoggins, B. A.: Plasma concentration of nortriptyline and clinical response in depressive illness. Lancet 1972/11, 619-623 Burrows, G.D., Scoggins, B.A., Turecek, L.R., Davies, B.: Plasma nortriptyline and clinical response. Clin. Pharmacol. Ther. 16, 639-644 (1974) Coppen, A.: The effective dosage of antidepressants. Postgrad. med. J. 52, (Suppl. 3), 72-74 (1976) Gram, L., Reisby, N., Ibsen, I., Nagy, A., Dencker, S., Bech, P., Petersen, G.: Christiansen, J.: Plasma levels and antidepressive effect of imipramine. Clin. Pharmacol. Ther. 19, 318-324 (1975) Gurney, C., Roth, M., Garside, R.F., Kerr, T. A., Schapira, K.: Studies in the classification of affective disorders. Br. J. Psychiat. 121, 162-166 (1972) Hammer, W., Idestr6m, C.M., Sj6qvist, F.: Chemical control of antidepressant drug therapy, in Antidepressant Drugs, (ed. S. Garattini and M.N.G. Dukes) p. 301-310. Amsterdam: Excerpta Medica 1967 Hammer, W., Martens, S., Sj6qvist, F.: A comparative study of the metabolism of desmethylimipramine, nortriptyline, and oxyphenylbutazone in man. Clin. Pharmacol. Ther. 10, 44-49 (1969) Hammer, W., Sj6qvist, F.: Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci. 6, 1895-1903 (1967) Knesevich, J. W., Biggs, J. T., Clayton, J., Ziegler, V. E.: Validity of the Hamilton Rating Scale for depression. Br. J. Psychiat. 131, 49-52 (1977) Kragh-Sfrensen, P., Asberg, M., Eggert-Hansen, C.: Plasma nortriptyline levels in endogenous depression. Lancet 1973/I, 113-115 Kragh-S6rensen, P., Eggert-Hansen, C., Baastrup, P., Hvidberg, E.F." Self inhibiting action of nortriptylin's antidepressive effect at high plasma levels. Psychopharmacologia, 45, 305-312 (1976) Kupfer, D. J., Hanin, I., Spiker, D. G., Grau, T., Coble, P.: Amitriptyline plasma levels and clinical response in primary depression. Clin. Pharmacol. Ther. 22, 904-911 (1977)
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Montgomery, S.: The relationship between plasma concentrations of amitriptyline and therapeutic response. Paper read to the British Academy of Psychopharmacology, London, July 1, 1975 Moody, J. P., Tait, A. C., Todrick, A.: Plasma levels of imipramine and desmethyl-imipramine during therapy. Br. J. Psychiat., 113, 183-193 (1967) Olivier-Martin, R., Marzon, D., Buchsensehutz, E., Pichot, P., Boissier, J.: Concentrations plasmatiques de l'imipramine et de la desmethylimipramine et effet antid6presseur au cours d'un traitement contr616. Psychopharmacologia, 41, 187-195 (1975) Philippe, J.: Les m6thodes statistiques en pharmacie et en chimie, p. 152-181. Paris: Masson 1967 Sj6qvist, F.: A pharmacokinetie approach to the treatment of depression. Int. Pharmacopsychiat., 6, 147-169 (1971) Tillement, J.P.: Pharmacocin6tique des antid6presseurs. Th6rapie, 28, 249-268 (1973) Volmat, R., Bechtel, P., Allers, G., Vandel, B., Vandel, S.: Mesure de la concentration plasmatique et effet antid~presseur de l'amitriptyline. Thfrapie, 32, 309-319 (1977)
Whyte, S., MacDonald, A., Naylor, G., Moody, J.: Plasma concentrations of protriptyline and clinical effects in depressed Women. Br. J. Psychiat., 128, 384-390 (1976) Ziegler, V., Co., B., Taylor, J., Clayton, P., Biggs, J.: Amitriptyline plasma levels and therapeutic response. Clin. Pharmacol. Ther., 19, 795-801 (1976) Ziegler, V., Clayton, P., Taylor, J., Co, B., Biggs, J.: Nortriptyline plasma levels and therapeutic response. Clin. Pharmacol. Ther., 20, 458-462 (1976)
Note added in proof
lism of amitriptyline is avoided and non-enzymatic factors such as hepatic blood-flow will be important for rate of metabolism and possibly the ratios of various metabolites (Alvan et al., 1977). There is a tendency towards smaller interindividual variability in plasma concentrations of amitriptyline and nortriptyline at steady state in our work compared to that of others.
In the light of the correspondence (Potter, Goodwin, Coppen) in the Lancet (1978/I, 1049-1050), regarding the exact relationship between plasma levels of amitriptyline and its metabolite nortriptyline and clinical outcome, we would like to add the following comments. Our patients have been treated with intramuscular amitriptyline while studies discussed in the correspondence have employed oral treatment. After i.m. administration, the first pass metabo-
Received." April 17, 1978, accepted in revised form: June27, 1978
Dr. S. Vandel Laboratoire de Pharmacologic Clinique Centre Hospitalier Universitaire 2 Place St. Jacques F - 2 5 0 3 0 Besanqon C6dex, France
Alvan, G., Borg~, O., Lind, M., Palmer, L., Siwers, B.: First pass hydroxylation of nortriptyline: concentrations of parent drug and major metabolites in plasma. Europ. J. Clin. Pharmacol. 11, 219-224 (1977)
