EVALUATION OF PSYCHOTROPIC DRUGS

Br. J. clin. Pharmac. (1976), Supplement, 29-34 THE SIGNIFICANCE OF DRUG INTERACTIONS IN THE EVALUATION OF PSYCHOTROPIC DRUGS R.A. BRAITHWAITE National Poisons Information Centre and Poisons Unit, Guy's Hospital, London SE1 In recent years the subject of drug interactions has attracted much attention and numerous lists of possible adverse interactions have been widely publicized. However, a large number of interactions have been postulated purely on the basis of animal experiments, in vitro microsomal studies and single clinical cases. Thus, it has become difficult for the practising clinician to distinguish clearly between those interactions which are important and supported by good clinical evidence, and those which are of doubtful or even mythical occurrence. It is impossible to validate suspected drug interactions on the basis of single-dose studies in two or three volunteer subjects. In order to substantiate fully an interaction between two drugs, studies should be carried out under experimental conditions which are as close to the therapeutic situation as possible. Usually, this is at 'steady-state' and where the drugs in question have been administered over a period of several weeks, often throughout the illness. Drug interactions, particularly in the field of psychiatric medicine, should be recognized as being one of several factors which can modify clinical response. As their overall importance has yet to be fully established, one cannot be complacent about the situation, since the practice of polypharmacy is probably at its zenith in psychiatric medicine. When two or more drugs are prescribed together, the resultant pharmacological effect may be the same, greater or less than that predicted from the pharmacological actions of the individual drugs concerned. Two concurrently administered drugs may interact for one or several reasons, but some of the principal mechanisms involved in precipitating a drug interaction are shown in Table 1. Some interactions concerning psychotropic preparations are clinically important and fortunately are now well recognized by clinicians. These are the interaction between monoamine oxidase (MAO) inhibitor drugs and sympathomimetic amines (Sjoqvist, 1965; Granville-Grossman, 1971), and that between guanidine hypotensive agents and tricyclic antidepressant drugs (Skinner, Coull & Johnson, 1969; Mitchell, Arias & Oates, 1967; Meyer, McAllister & Goldberg, 1970; Mitchell et al., 1970). Concerning the reported adverse reaction between MAO inhibitors and tricyclic antidepressants, the subject is still very much open to debate (Stockley, 1974), with much clinical evidence in support of the therapeutic benefits of such combinations, principally that from the work of Sargant (1971). Problems associated with interactions or interference at the site of drug absorption have come much more into focus in recent years. In particular, the low bioavailability of oral chlorpromazine preparations which results from metabolism of the drug as it passes through the intestinal wall has obviously had an influence on the dosage form of phenothiazine preparations (Curry, D'Mello & Mould, 1971; Hollister & Curry, 1971). It is now well known that many hypnotic and sedative drugs, particularly the barbiturates, are potent inducers of hepatic microsomal enzymes in man and can lead to an enhanced rate of drug metabolism (Conney, 1967; Prescott, 1971; Breckenridge & Orme, 1971; McDonald et al., 1969; Stephenson et al., 1972). The influence of concurrent barbiturate administration on steady-state tricyclic antidepressant plasma concentrations has been recently documented by Swedish workers (Hammer, Idestrom & Sjoqvist, 1967; Alexanderson, Prince- Evans & Sjoqvist, 1969). In a study of our own, shortly to be published, we have found that steadystate plasma nortriptyline concentrations in maximally induced epileptic patients are less by about 60% than those found in other non-induced, depressed patients Table 1 Principle mechanisms of drug interactions 1. Interference with drug absorption 2. Plasma-protein binding (a) displacement (b) increased binding 3. Drug distribution and tissue uptake 4. Competition or interference at receptor site(s) 5. Hepatic drug metabolism (a) induction (b) inhibition 6. Renal drug excretion (a) increased (b) decreased 7. Miscellaneous (a) inhibition of monoamine oxidase

30 R.A. BRAITHWAITE Nortriptyline (100 mg/day) Nitrazepam (10 mg/day) Chlordiazepoxide (40 mg/day) Chlordiazepoxide (40 mg/day) Diazepam (20 mg/day) 0)~~~~~~~~~~~~~~~~~7 C i, 0-5 150 oc 1o50 I I I Il I I II II Diazepam (40 mg/day) IE U,1 en 0 10 20 30 40 50 60 90 100 Time (days) Figure 1 Plasma nortriptyline concentrations in a patient during chronic antidepressant medication with nortriptyline, also concurrent medication with nitrazepam, diazepam and chlordiazepoxide. receiving equivalent doses of nortriptyline (Braithwaite & Richens, 1974). Concerning the inhibition of drug metabolism, the situation is still unclear and very few clinical studies concerning psychotropic drugs have been published. Moody and his associates reported a large increase in one patient's plasma imipramine and desipramine levels when chlorpromazine was combined with the imipramine medication (Moody, Tait & Todrick, 1967). More recently Gram and Fredericson-Overo (1972) demonstrated that the drugs perphenazine, haloperidol and chlorpromazine were able to inhibit significantly the metabolism of imipramine and nortriptyline. However, this latter study was carried out by administering single doses of "4C-labelled antidepressant, before, during and after brief treatment with the various neuroleptics; therefore, the clinical significance of this study is uncertain. The central stimulant drug methylphenidate (Ritalin) has been shown to be a potent inhibitor of imipramine metabolism, causing dramatic increases in plasma imipramine and desipramine concentrations in patients (Wharton et al., 1971). However, the effect of methylphenidate administration on plasma anticonvulsant levels is controversial. In one study methylphenidate inhibited the metabolism of anticonvulsant levels and produced toxicity in one patient (Garrettson, Perel & Dayton, 1969). More recently Kupferberg and associates (Kupferberg, Jeffery & Hunninghake, 1972) reported that methylphenidate administration to 11 epileptic patients for a 6-week period, did not alter plasma anticonvulsant concentrations from control values. In contrast to the above compounds, the benzodiazepine group of drugs seem free of any clinically significant potential with regard to both the inhibition or induction of hepatic drug metabolism (Orme, Breckenridge & Brooks, 1972; Silverman & Braithwaite, 1973). That the benzodiazepines do not have any significant influence upon steady-state plasma concentrations of tricyclic antidepressants may be seen in Figures 1 and 2. Despite many such studies, we are still no nearer an assessment of the overall significance of drug interactions in clinical psychiatric practice. In the treatment of depression in general practice and in hospital outpatient clinics, poly-pharmacy seems to be the rule rather than the exception. In a random survey of 13 patients who were ostensibly receiving antidepressant medication with nortriptyline, most were also receiving concurrent medication with various other psychotropic preparations (Table 2), of whom six were receiving various 'enzyme inducing' hypnotics. The plasma nortriptyline levels recorded in this same group of patients ranged from 20 to 246 ng/ml, a 12-fold variation (Table 2). Thus, at first sight, drug interactions may have produced some of the variation in plasma nortriptyline concentrations observed in this group of patients. Several recent studies have demonstrated a relationship between plasma concentrations of a number of tricyclic antidepressant drugs and clinical response. Moreover, therapeutic failure in a number of patients may be due to either very low or even too high plasma antidepressant concentrations (Walter, 1971; Asberg et al., 1971; Braithwaite et al., 1972; Kragh-Sorensen, Asberg & Eggert-Hansen, 1973). These studies in the main have been carefully conducted, using selected patients, quantitative rating

SIGNIFICANCE OF DRUG INTERACTIONS 31 Amitriptyline (80 mg/day) Oxazepam 45 mg/day i 60 G) (D 40 20 1 1 40 50 60 70 80 Time (days) Figure 2 Plasma amitriptyline (U) and nortriptyline (0) concentrations in a patient during chronic antidepressant medication with amitriptyline, also concurrent medication with oxazepam. scales and the repeated estimation of plasma antidepressant concentrations. The concurrent administration of other psychotropic preparations was reduced to a minimum. In marked contrast to the above studies, a multi-centre trial was carried out to investigate the relationship between plasma nortriptyline concentrations and clinical response in a large group of depressed outpatients treated with various doses of nortriptyline (Collaborative Study, 1974). In this study no relationship whatsoever was observed between plasma nortriptyline concentrations and either a satisfactory or unsatisfactory clinical response (Figure 3). However, of the 45 patients investigated, two-thirds were also receiving concurrent medication with other psychotropic compounds, namely: 19 patients were receiving benzodiazepines, six receiving phenothiazines, three receiving lithium and five receiving various hypnotic or sedative drugs. The problem of the interpretation of drug-plasma concentration data in such studies is obvious. This may be illustrated by the cases of two patients included in the study. The first patient was reported as having a satisfactory clinical response to nortriptyline and had a plasma level of 161 ng/ml; however, this patient was also receiving chlorpromazine, chlordiazepoxide and nitrazepam. The second patient was reported as having an unsatisfactory clinical response and had a plasma nortriptyline level of only 20 ng/ml; this patient was also receiving glutethimide, nitrazepam and phenobarbitone. The last had not been prescribed and was only detected by analysis of the patient's urine. Table 2 Plasma nortriptyline levels in randomly selected patients receiving nortriptyline Patient Daily dose of Plasmanortriptyline No. Sex nortriptyline level Concomitant medication (mg) (ng/ml) 1 M 150 246 2 F 150 125 Promazine, dichloralphenazone 3 F 150 97 4 F 150 132 Promazine, dichloralphenazone 5 F 150 180 Amylobarbitone, quinalbarbitone 6-150 128 Promazine 7 F 75 50 Nitrazepam 8-75 148 Chlorpromazine 9 F 75 139 Diazepam 10 F 75 223 11 F 75 20 Amylobarbitone 12 F 75 20 Amylobarbitone 13 F (dose unknown) 100 Diazepam, phenytoin, promazine methaqualone, diphenhydramine

32 R.A. BRAITHWAITE :...:..:., '.,..P,latma,rYotW 1 leve (ng/ml) ' ' 1,''*,:::' -, 0. r.~ 10,. 2;.,5-0.~ ~ AGO...*. atactory Us patients. Figure 3 The relationship between plasma nortriptyline concentrations and 'satisfactory' and unsatisfactory clinical response in a group of 45 depressed outpatients treated with nortriptyline. Each box represents one patient. (Figure taken from Collaborative Study, 1974.) Thus, it can be seen that in the clinical assessment of a particular antidepressant medication, the concurrent administration of other psychotropic preparations is an obvious complicating factor, but the 500 7 400 0) 300 co cx E 200 co 100 Patients Figure 4 Mean steady-state plasma nortriptyline levels in patients receiving nortriptyline (50-200 mg/ day). (R.A. Braithwaite, unpublished material.) overall clinical significance of these 'interactions' in the practical treatment of such a diverse and complex illness as depression is difficult, perhaps impossible to assess. But other equally important factors influencing clinical response and possible drug interactions have also to be considered. First, there are large individual differences in the rates of tricyclic antidepressant metabolism which are largely genetically determined. Patients receiving similar 'therapeutic' doses of drug may have very different steady-state plasma concentrations (Figures 4 and 5). Second, a large proportion of patients may not take their medication as prescribed. Willcox, Gillan & Hare (1965) reported that 40% of a group of psychiatric outpatients being treated for depression with imipramine were not taking their medication as prescribed and, more recently, a study by Johnson (1973) of depressed patients treated in general practice, showed that of the patients given 'therapeutic' doses of antidepressant, about 50% had stopped taking their drugs 3 weeks after they were first prescribed. Finally, those drugs which are potent inducers of hepatic microsomal enzymes may give rise in the long term to complications due to enhanced rates of endogenous vitamin and steroid metabolism (Greenwood, Prunty & Silver, 1973). In conclusion, it

SIGNIFICANCE OF DRUG INTERACTIONS 33 200 150- CD 100 E CD 50 50 Patients Figure 5 Mean steady-state plasma amitriptyline (-) and nortriptyline (0) levels in patients receiving amitriptyline (50-1 50 mg/day) (R.A. Braithwaite, unpublished material.) seems desirable that those patients who require chronic psychotropic medication should receive those preparations which are not potent inducers of metabolism. Further, many of the complications of those interactions influencing rates of drug metabolism could in fact be easily avoided by the judicious adjustment of drug dosages and by monitoring drug plasma concentrations during therapy. References ALEXANDERSON, B., PRICE-EVANS, D.A. & SJOQVIST, F. (1969). Steady-state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy. Br. Med. J., 4, 764-768. ASBERG, M. et al. (1971). Relationship between plasma level and therapeutic effect of nortriptyline, Br. Med. J., 3, 331-334. BRAITHWAITE, R.A. et al. (1972). Plasma concentration of amitriptyline and clinical response, Lancet i, 1297-1300. BRAITHWAITE, R.A. & RICHENS, A. (1974). To be published. BRECKENRIDGE, A. & ORME, M. (1971). Clinical implications of enzyme induction. Ann. N.Y. A cad. Sci., 179, 421-43 1. COLLABORATIVE STUDY (1974). Post. Grad. Med. J. To be published. CONNEY, A.H. (1967). Pharmacological implications of microsomal enzyme induction. Pharmac. Rev., 19, 3 17-366. CURRY, S.H., D'MELLO, A. & MOULD, G.P. (1971). Destruction of chlorpromazine during absorption in the rat in vivo and in vitro. Br. J. Pharmac., 42, 403-411. GARRETTSON, L.K., PEREL, J.M. & DAYTON, P.G. (1969). Methylphenidate interaction with both anticonvulsants and ethyl biscoumacetate. J. Amer. med. Assoc., 207, 2053-2061. GRAM, L.F. & FREDRICSON-OVERO, K. (1972). Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man. Br. Med. J., 1, 463-465. 3 GRANVILLE-GROSSMAN, K. (1971). In: Recent Advances in Clinical Psychiatry, p.43. London: J. & A. Churchill. GREENWOOD, R.H., PRUNTY, F.T.G. & SILVER, J. (1973). Osteomalacia after prolonged glutethimide administration. Br. Med. J., 1, 643-645. HAMMER, W., IDESTROM, C.M. & SJOQVIST, F. (1967). Chemical control of antidepressant drug therapy. In Garattini, S. and Dukes, M.N.G. (eds) Proc. 1st Int. symp. on antidepressant drugs, Milan 1966. Excerpta Medica Int. Congr. Ser., 122, 301-310. HOLLISTER, L.E. & CURRY, S.H. (1971). Urinary excretion of chlorpromazine metabolites following single doses and in steady state conditions. Res. Comm. Chem. Path. Pharmac., 2, 330-338. JOHNSON, D.A.W. (1973). Treatment of depression in general practice. Br. Med. J., 2, 18-20. KRAGH-SORENSEN, P., ASBERG, M. & EGGERT-HANSEN, C. (1973). Plasma nortriptyline levels in endogenous depression. Lancet, i, 113-115. KUPFERBERG, H.J., JEFFERY, W. & HUNNINGHAKE, D.B. (1972). Effect of methyl phenidate on plasma anticonvulsant levels. Clin. Pharmac. Ther., 13, 201-204. McDONALD, M.G. et al. (1969). The effects of phenobarbital, chloral betaine, and glutethimide administration on warfarin plasma levels and hypoprothrombinemic responses in man. Clin. pharmac. Ther., 10, 80-84. MEYER, J.F., McALLISTER, C.K. & GOLDBERG, L.I. (1970). Insidious and prolonged antagonism of guanethidine by amitriptyline. J. Amer. med. Assoc., 213, 1487-1488.

34 R.A. BRAITHWAITE MITCHELL, J.R. et al.. (1970). Guanethidine and related agents III: antagonism by drugs which inhibit the norepinephrine pump in man. J. Clin. Invest., 49, 1596-1604. MITCHELL, J.R., ARIAS, L. & OATES, J.A. (1967). Antagonism of the antihypertensive action of guanethidine sulphate by desipramine hydrochloride. J. Am. med. Ass., 202, 973-976. MOODY, J.P., TAIT, A. C. & TODRICK, A. (1967). Plasma levels of imipramine and desmethylimipramine during therapy. Br. J. Psychiat., 113, 183-193. ORME, M., BRECKENRIDGE, A. & BROOKS, R.V. (1972). Interactions of benzodiazepines with warfarin. Br. Med. J.,3,611-614. PRESCOTT, L.F. (1971). Drug metabolism and therapeutics. Scott. med. J., 16, 121-129. SARGANT, W. (1971). Safety of combined anti-depressant drugs. Br. med. J., 1, 555-556. SILVERMAN, G. & BRAITHWAITE, R.A. (1973). Benzodiazepines and tricyclic antidepressant plasma levels. Br. Med. J., 3, 18-20. SJOQVIST, F. (1965). Psychotropic drugs (2) interaction between monoamine oxidase (MAO) inhibitors and other substances. Proc. roy. Soc. Med., 58, 967-978. SKINNER, C., COULL, D.C. & JOHNSON, A.W. (1969). Antagonism of the hypotensive action of bethanidine and debrisoquine by tricyclic antidepressants. Lancet, ii, 564-567. STEPHENSON, I.H. et al. (1972). Changes in human drug metabolism after long-term exposure to hypnotics. Br. Med. J., 4, 322-324. STOCKLEY, I. (1974). In Drug Interactions, p. 15. London: The Pharmaceutical Society Press. WALTER, C.J.S. (1971). Drug plasma levels and clinical effect. Proc. roy. Soc. Med., 64, 282-285. WILLCOX, D.R.C., GILLAN, R. & HARE, E.H. (1965). Do psychiatric outpatients take their drugs? Br. Med. J., 2, 790-792. WHARTON, R.N. et al. (1971). A potential clinical use for methylphenidate with tricyclic antidepressants. Amer. J. Psychiat. 127, 1619-1625.