782
tainers (to which macrophages are likely to adhere) and freezing and thawing cycles (which are likely to diminish the viability of any remaining cells) ? Furthermore, to what degree is the variability in the composition of donated and pooled human milk important in feeding low birthweight infants ? How much concern should we give to pharmacological and environmental contaminants ? Australia antigen may be present in human milk13 and is unlikely to be destroyed by pasteurisation. Though neonatal infection by this route has not been recorded, is it satisfactory to regard the chance of such infection as remote and not screen mothers or milk for Australia antigen, as suggested by McEnery and Chattopadhyay ? Or would such screening make the system too complicated and expensive-and destroy the very simplicity which is the great attraction of the Whipps Cross Hospital bank? The history of neonatal care is littered with examples of catastrophes which have arisen from the uncritical adoption of theoretical advances.14 The workers from Whipps Cross and King's College Hospital claim that the babies in their nurseries fed on raw banked human milk have done well. Before human milk banks are accepted uncritically, however, it needs to be shown, preferably by controlled trials, that feeding banked human milk compared with standard formula feeds actually reduces the incidence of necrotising enterocolitis and other infections. It also needs to be shown that low-birthweight babies grow as well on banked human milk as on formula feeds and are at least at no disadvantage in terms of their subsequent growth and neurological development during infancy. Fresh milk from a baby's own mother offers obvious nutritional and antimicrobial advantages. Nevertheless, by the very nature of the babies in a special-care baby unit many of the mothers cannot provide fresh milk for every feed, and if human milk is to be used some system of milk banking is essential. For the time being those who are persuaded of the case for using banked human milk must take special care of it, including attention to the details of the technique and sterility of its collection (King's College Hospital has produced an excellent booklet on this aspect); the time and method of storage of the milk in the home; the speed of transportation of the milk to the hospital; the handling and heat treatment of the milk in the hospital; and its bacteriological screening, storage, thawing, and delivery to the infant. Only through attention to every detail in this pathway will it be possible to ensure that the product is safe and yet not subjected to any step which will spoil the very components which justify its use. The human milk industry needs to establish standards of practice. It has a long way to go before it can rival the systems established over many years in the bovine dairy industry. Lonnerdal, B, Forsum, E, and Hambraeus, L, Nutrition Reports International, 1976, 13, 125. 2 Rassin, D K, Sturman, J A, and Gaul, G E, Early Human Development, 1978, 2, 1. 3Bullen, J J, Rogers, J H, and Leigh, L, British Medical3Journal, 1972, 1, 69. 4Lodinova, R, and Jouia, V, Acta Paediatrica Scandinavica, 1977, 66, 705. 5 Pitt, J, Barlow, B, and Heird, W C, Pediatric Research, 1977, 11, 906. 6 Lancet, 1977, 1, 459. 7 Committee on Mothers' Milk of American Academy of Pediatrics, Journal of Pediatrics, 1943, 23, 112. 8 Dynski-Klein, M, British Medical Journal, 1946, 2, 258. 9 Davy, S T, Nursing Times, 1975, 71, 758. 10 Williamson, S, et al, British Medical_Journal, 1978, 1, 393. 1 Ford, J E, et al, J'ournal of Pediatrics, 1977, 90, 29. 12 Gibbs, J H, et al, Early Human Development, 1977, 1, 227. 13 Linnemann, C C, and Goldberg, S, Lancet, 1974, 2, 155. 4 Baum, J D, Macfarlane, J A, and Tizard, J P M, in Benefits and Hazards of the New Obstetrics, eds T Chard and M Richards, p 126 (Clinics in Developmental Medicine No 64). London, Heinemann, 1977.
BRITISH MEDICAL JOURNAL
16 SEPTEMBER 1978
Intensive iron-chelation in thalassaemia Children with homozygous beta-thalassaemia can be kept in good health for the first decade of life with regular blood transfusions. Iron, however, steadily accumulates from the transfusions (and in some cases from increased gastrointestinal absorption1), leading to cardiac, endocrine, and hepatic damage and death in early adult life, usually from heart failure or arrhythmias.2 In the absence of an effective oral chelating agent for iron parenteral desferrioxamine has been used since the mid-1960s in an attempt to treat this fatal iron loading. Daily intramuscular injections of 05-1-0 g of desferrioxamine slow up liver fibrosis in thalassaemic children,3 but they produce insufficient urinary iron excretion to keep pace with iron loading from transfusions so that by the age of 6 about 10 g of excess iron has usually accumulated.4 Indeed, liver biopsy specimens have shown tissue damage from excess iron even in early infancy,5 and the effect on survival of treatment with intramuscular desferrioxamine has proved unconvincing. A new approach to the use of desferrioxamine came from the observation that iron excretion is greater with prolonged intravenous infusion.46 7 At equal doses both intravenous and subcutaneous infusions are much more effective than are intramuscular injections.8-10 Correcting the deficiency of ascorbic acid associated with iron overload increases excretion still further. 9-12 Furthermore, much larger doses are possible with infusions, yielding 24-hour urinary iron excretions in the most heavily iron-loaded patients of up to 200 mg4 7 10 (equivalent to one unit of blood) or more2 -and measurements of urinary iron are an underestimate, for one-third of the total excretion occurs in the stools.'3 14 Studies of the kinetics of iron removal with different routes and doses of desferrioxamine suggest that in many cases 12-hour overnight subcutaneous infusions (given with a small syringe pump into the anterior abdominal wall) may be nearly as effective as 24hour continuous infusions and interfere less with daily routine.10 An important recent finding is that 12-hour subcutaneous infusions at doses as low as 0-5 g can produce a negative iron balance even in very young children with previous transfusion iron loads of less than 10 g, so that iron toxicity may prove to be preventable.'5 Regular subcutaneous infusions for over two years in children aged 3 years and over have produced no evidence of decreasing response.9 10 Intramuscular desferrioxamine has been used safely for over a decade, but long-term infusions will call for careful monitoring for cataracts, known to occur in dogs at high doses.'6 These results are exciting, but can they be translated into a practical and tolerable treatment for more than a handful of patients, and produce matching clinical benefits-and can the damage, particularly to the heart, be reversed? A long-term trial of intensive prophylactic treatment with regular subcutaneous infusions in young children may be needed to discover if the potential benefits outweigh the social inconvenience and high financial cost of this approach. In the meantime individual treatment should be tailored not only to the response to desferrioxamine'0 but also to social circumstances. One compromise may be to use daily intramuscular injections with 24-48 hour intravenous infusions of larger doses at the time of blood transfusions.12 17 We need to persuade the drug companies to take up the challenge of finding a better way (possibly a depot preparation) for getting
BRITISH MEDICAL JOURNAL
16 SEPTEMBER 1978
a slow release of desferrioxamine into the body. There would be a potentially large world market. Heinrich, H C, et al, Zeitschrift fur Kinderheilkunde, 1973, 115, 1. Engle, M A, Annals of the New York Academy of Sciences, 1964, 119, 694. Barry, M, et al, British Medical Journal, 1974, 2, 16. 4Modell, C B, and Beck, J, Annals of the New York Academy of Sciences, 1974, 232, 201. Iancu, T C, Neustein, H B, and Landing, B H, in Iron Metabolism. Ciba Foundation Symposium 51 (New Series), p 293. Amsterdam, Elsevier/ North Holland, 1977. 6 Thompson, R B, Owen, D M, and Bell, W N, American J3ournal of the Medical Sciences, 1967, 253, 453. 7Propper, R D, Shurin, S B, and Nathan, D G, New England Journal of Medicine, 1976, 294, 1421. 8 Hussain, M A M, et al, Lancet, 1976, 2, 1278. 9 Propper, R D, et al, New England Journal of Medicine, 1977, 297, 418. 10 Pippard, M J, Callender, S T, and Weatherall, D J, Clinical Science and Molecular Medicine, 1978, 54, 99. 11 Hussain, M A M, et al, Lancet, 1977, 1, 977. 12 Cohen, A, and Schwartz, E, Journal of Pediatrics, 1978, 92, 643. 13 Cumming, R L C, et al, British of Haematology, 1969, 17, 257. 14 Pippard, M J, and Callender, S T, Paper presented at the meeting of the European Iron Club, Noordwijkerhout, Netherlands, May 1978. 15 Pippard, M J, et al, Lancet, 1978, 1, 1178. 16 Ciba Pharmaceutical Company, Clinical Pharmacology and Therapeutics, 1969, 10, 595. ' Modell, B, Archives of Disease in Childhood, 1977, 52, 489. 2
3
J7ournal
Tricyclic antidepressant concentrations and clinical response At least one in every four depressed patients responds inadequately to tricyclic antidepressants. One explanation is the wide variation in the individual plasma concentrations of these drugs. The unanswered question is whether the failure rate could be reduced by monitoring pharmacokinetic factors such as "steady-state" plasma concentrations. Most studies have concerned nortriptyline, simply because techniques for measuring it were developed early and because interpreting the results is not complicated by the presence of active metabolites. In the initial limited Scandinavian study' both low concentrations ( 150 tg/ 1) of nortriptyline after two weeks' treatment seemed to be associated with a poor clinical response. This was confirmed in a trial of 30 patients, in whom seven of 11 non-responders had concentrations over 170 tg/l; within a week of reducing dosage five of the seven were well,2 a finding later repeated.3 Similarly, in an American study4 with 18 outpatients the nine with plasma nortriptyline concentrations between 50 and 139 pg/l showed more improvement after six weeks than those with concentrations above this range; and an English study5 of 36 depressed inpatients again supported this. By contrast, two Australian studies6 7 and an earlier English one" found no relation between nortriptyline concentrations and clinical response, and the results in yet another Scandinavian evaluation9 were unconvincing. None of these clinical studies included comprehensive pharmacokinetic estimations. The recently published data of Montgomery and his associates, however, provide strong evidence that high plasma nortriptyline concentrations-in this instance over 200 tgjl-are significantly less effective than intermediate ones. After receiving only a placebo for several days 18 depressed inpatients were given nortriptyline, 100 mg at night for four weeks. Plasma concentrations at the end ranged from 120 to 681 tg /1. For the first two weeks the
783
clinical response was unrelated to concentration, but those with concentrations below 200 ,ug/l continued to respond over the third and fourth weeks, whereas those with high concentrations improved no further. One patient with high concentrations became confused, but otherwise side effects were not related to drug concentrations. High plasma concentrations cannot, apparently, be guessed at on clinical grounds alone. In the pharmacokinetic study'1 nortriptyline concentrations were measured for 48 hours after a single 100-mg dosebefore the course'of treatment. The mean plasma clearance of the drug in the patients was unexpectedly only about half that of normal people (26-1 v 52-6 1/h), which accounted for the high plasma concentrations found later with continuous treatment. Montgomery et al suggest that this finding may reflect preselection of patients: those who respond are treated successfully by general practitioners, while those who do not, who have a slow clearance and high antidepressant concentrations, are referred to hospital. The results of the pharmacokinetic study imply that a single estimation of plasma nortriptyline 48 hours after a test dose will accurately predict eventual steady-state concentrations, and hence could be used to adjust clinical dosage. What about amitriptyline, which in Britain we use much more than nortriptyline ? Amitriptyline is extensively metabolised to nortriptyline by N-desmethylation, so that after taking amitriptyline for a few weeks the concentration of nortriptyline is similar to that of amitriptyline. The earliest report12 claimed a strong correlation between plasma tricyclic concentrations and clinical response, and similar results were reported by workers in St Louis'314 and Pittsburg:"5 the higher the concentration of tricyclics, the better the response. There was no apparent curvilinear relation to concentration, as with nortriptyline. An attempt to replicate the earlier results in a multicentre WHO collaborative study on 54 patients was unsuccessful'6; this study has been criticised'7 as untypical, however, because the clinical response of the patients was so dismal. Studies with other antidepressants have been too few to permit conclusions. The lack of consistency in these studies may be due to technical problems with estimating drug concentrations; different ways of evaluating clinical response and types of patient; and further pharmacokinetic factors, such as differences in plasma binding. Other pharmacological problems include extrapolation from plasma concentrations to those at the presumed site of action and differences in the sensitivity of effector systems; attempts have been made to correlate clinical response with pharmacodynamic responses such as inhibition of the tyramine pressor response. Nevertheless, we now have good evidence that the clinical response to nortriptyline is related to concentrations below about 200 Fg/l and above 50 Ftg/l. Why the higher concentrations should be ineffective is unknown. The new rapid and cheap immunoassay techniques for estimating tricyclic antidepressives should hasten the translation of these research findings into routine clinical practice. We could increase the efficacy of nortriptyline at least by monitoring plasma concentrations to predict the correct dosage. I 2
Medical,Journal,
Asberg, M, et al, British 1971, 3, 331. Kragh-S0rensen, P, Asberg, M, and Eggert-Hansen, C, Lancet, 1973, 1, 113. 3Kragh-Sorensen, P, et al, Psychopharmacologia, 1976, 45, 305. 4Ziegler, V E, et al, Clinical Pharmacology and Therapeutics, 1976, 20, 458. Montgomery, S, Braithwaite, R A, and Crammer, J L, British Medical J3ournal, 1977, 2, 166. 6 Burrows, G D, Davies, B, and Scoggins, B A, Lancet, 1972, 2, 619. 7 Burrows, G D, et al, Clinical Pharmacology and Therapeutics, 1974, 16, 639. 8 Lyle, W H, et al, Postgraduate Medical Journal, 1974, 50, 282.
tainers (to which macrophages are likely to adhere) and freezing and thawing cycles (which are likely to diminish the viability of any remaining cells) ? Furthermore, to what degree is the variability in the composition of donated and pooled human milk important in feeding low birthweight infants ? How much concern should we give to pharmacological and environmental contaminants ? Australia antigen may be present in human milk13 and is unlikely to be destroyed by pasteurisation. Though neonatal infection by this route has not been recorded, is it satisfactory to regard the chance of such infection as remote and not screen mothers or milk for Australia antigen, as suggested by McEnery and Chattopadhyay ? Or would such screening make the system too complicated and expensive-and destroy the very simplicity which is the great attraction of the Whipps Cross Hospital bank? The history of neonatal care is littered with examples of catastrophes which have arisen from the uncritical adoption of theoretical advances.14 The workers from Whipps Cross and King's College Hospital claim that the babies in their nurseries fed on raw banked human milk have done well. Before human milk banks are accepted uncritically, however, it needs to be shown, preferably by controlled trials, that feeding banked human milk compared with standard formula feeds actually reduces the incidence of necrotising enterocolitis and other infections. It also needs to be shown that low-birthweight babies grow as well on banked human milk as on formula feeds and are at least at no disadvantage in terms of their subsequent growth and neurological development during infancy. Fresh milk from a baby's own mother offers obvious nutritional and antimicrobial advantages. Nevertheless, by the very nature of the babies in a special-care baby unit many of the mothers cannot provide fresh milk for every feed, and if human milk is to be used some system of milk banking is essential. For the time being those who are persuaded of the case for using banked human milk must take special care of it, including attention to the details of the technique and sterility of its collection (King's College Hospital has produced an excellent booklet on this aspect); the time and method of storage of the milk in the home; the speed of transportation of the milk to the hospital; the handling and heat treatment of the milk in the hospital; and its bacteriological screening, storage, thawing, and delivery to the infant. Only through attention to every detail in this pathway will it be possible to ensure that the product is safe and yet not subjected to any step which will spoil the very components which justify its use. The human milk industry needs to establish standards of practice. It has a long way to go before it can rival the systems established over many years in the bovine dairy industry. Lonnerdal, B, Forsum, E, and Hambraeus, L, Nutrition Reports International, 1976, 13, 125. 2 Rassin, D K, Sturman, J A, and Gaul, G E, Early Human Development, 1978, 2, 1. 3Bullen, J J, Rogers, J H, and Leigh, L, British Medical3Journal, 1972, 1, 69. 4Lodinova, R, and Jouia, V, Acta Paediatrica Scandinavica, 1977, 66, 705. 5 Pitt, J, Barlow, B, and Heird, W C, Pediatric Research, 1977, 11, 906. 6 Lancet, 1977, 1, 459. 7 Committee on Mothers' Milk of American Academy of Pediatrics, Journal of Pediatrics, 1943, 23, 112. 8 Dynski-Klein, M, British Medical Journal, 1946, 2, 258. 9 Davy, S T, Nursing Times, 1975, 71, 758. 10 Williamson, S, et al, British Medical_Journal, 1978, 1, 393. 1 Ford, J E, et al, J'ournal of Pediatrics, 1977, 90, 29. 12 Gibbs, J H, et al, Early Human Development, 1977, 1, 227. 13 Linnemann, C C, and Goldberg, S, Lancet, 1974, 2, 155. 4 Baum, J D, Macfarlane, J A, and Tizard, J P M, in Benefits and Hazards of the New Obstetrics, eds T Chard and M Richards, p 126 (Clinics in Developmental Medicine No 64). London, Heinemann, 1977.
BRITISH MEDICAL JOURNAL
16 SEPTEMBER 1978
Intensive iron-chelation in thalassaemia Children with homozygous beta-thalassaemia can be kept in good health for the first decade of life with regular blood transfusions. Iron, however, steadily accumulates from the transfusions (and in some cases from increased gastrointestinal absorption1), leading to cardiac, endocrine, and hepatic damage and death in early adult life, usually from heart failure or arrhythmias.2 In the absence of an effective oral chelating agent for iron parenteral desferrioxamine has been used since the mid-1960s in an attempt to treat this fatal iron loading. Daily intramuscular injections of 05-1-0 g of desferrioxamine slow up liver fibrosis in thalassaemic children,3 but they produce insufficient urinary iron excretion to keep pace with iron loading from transfusions so that by the age of 6 about 10 g of excess iron has usually accumulated.4 Indeed, liver biopsy specimens have shown tissue damage from excess iron even in early infancy,5 and the effect on survival of treatment with intramuscular desferrioxamine has proved unconvincing. A new approach to the use of desferrioxamine came from the observation that iron excretion is greater with prolonged intravenous infusion.46 7 At equal doses both intravenous and subcutaneous infusions are much more effective than are intramuscular injections.8-10 Correcting the deficiency of ascorbic acid associated with iron overload increases excretion still further. 9-12 Furthermore, much larger doses are possible with infusions, yielding 24-hour urinary iron excretions in the most heavily iron-loaded patients of up to 200 mg4 7 10 (equivalent to one unit of blood) or more2 -and measurements of urinary iron are an underestimate, for one-third of the total excretion occurs in the stools.'3 14 Studies of the kinetics of iron removal with different routes and doses of desferrioxamine suggest that in many cases 12-hour overnight subcutaneous infusions (given with a small syringe pump into the anterior abdominal wall) may be nearly as effective as 24hour continuous infusions and interfere less with daily routine.10 An important recent finding is that 12-hour subcutaneous infusions at doses as low as 0-5 g can produce a negative iron balance even in very young children with previous transfusion iron loads of less than 10 g, so that iron toxicity may prove to be preventable.'5 Regular subcutaneous infusions for over two years in children aged 3 years and over have produced no evidence of decreasing response.9 10 Intramuscular desferrioxamine has been used safely for over a decade, but long-term infusions will call for careful monitoring for cataracts, known to occur in dogs at high doses.'6 These results are exciting, but can they be translated into a practical and tolerable treatment for more than a handful of patients, and produce matching clinical benefits-and can the damage, particularly to the heart, be reversed? A long-term trial of intensive prophylactic treatment with regular subcutaneous infusions in young children may be needed to discover if the potential benefits outweigh the social inconvenience and high financial cost of this approach. In the meantime individual treatment should be tailored not only to the response to desferrioxamine'0 but also to social circumstances. One compromise may be to use daily intramuscular injections with 24-48 hour intravenous infusions of larger doses at the time of blood transfusions.12 17 We need to persuade the drug companies to take up the challenge of finding a better way (possibly a depot preparation) for getting
BRITISH MEDICAL JOURNAL
16 SEPTEMBER 1978
a slow release of desferrioxamine into the body. There would be a potentially large world market. Heinrich, H C, et al, Zeitschrift fur Kinderheilkunde, 1973, 115, 1. Engle, M A, Annals of the New York Academy of Sciences, 1964, 119, 694. Barry, M, et al, British Medical Journal, 1974, 2, 16. 4Modell, C B, and Beck, J, Annals of the New York Academy of Sciences, 1974, 232, 201. Iancu, T C, Neustein, H B, and Landing, B H, in Iron Metabolism. Ciba Foundation Symposium 51 (New Series), p 293. Amsterdam, Elsevier/ North Holland, 1977. 6 Thompson, R B, Owen, D M, and Bell, W N, American J3ournal of the Medical Sciences, 1967, 253, 453. 7Propper, R D, Shurin, S B, and Nathan, D G, New England Journal of Medicine, 1976, 294, 1421. 8 Hussain, M A M, et al, Lancet, 1976, 2, 1278. 9 Propper, R D, et al, New England Journal of Medicine, 1977, 297, 418. 10 Pippard, M J, Callender, S T, and Weatherall, D J, Clinical Science and Molecular Medicine, 1978, 54, 99. 11 Hussain, M A M, et al, Lancet, 1977, 1, 977. 12 Cohen, A, and Schwartz, E, Journal of Pediatrics, 1978, 92, 643. 13 Cumming, R L C, et al, British of Haematology, 1969, 17, 257. 14 Pippard, M J, and Callender, S T, Paper presented at the meeting of the European Iron Club, Noordwijkerhout, Netherlands, May 1978. 15 Pippard, M J, et al, Lancet, 1978, 1, 1178. 16 Ciba Pharmaceutical Company, Clinical Pharmacology and Therapeutics, 1969, 10, 595. ' Modell, B, Archives of Disease in Childhood, 1977, 52, 489. 2
3
J7ournal
Tricyclic antidepressant concentrations and clinical response At least one in every four depressed patients responds inadequately to tricyclic antidepressants. One explanation is the wide variation in the individual plasma concentrations of these drugs. The unanswered question is whether the failure rate could be reduced by monitoring pharmacokinetic factors such as "steady-state" plasma concentrations. Most studies have concerned nortriptyline, simply because techniques for measuring it were developed early and because interpreting the results is not complicated by the presence of active metabolites. In the initial limited Scandinavian study' both low concentrations ( 150 tg/ 1) of nortriptyline after two weeks' treatment seemed to be associated with a poor clinical response. This was confirmed in a trial of 30 patients, in whom seven of 11 non-responders had concentrations over 170 tg/l; within a week of reducing dosage five of the seven were well,2 a finding later repeated.3 Similarly, in an American study4 with 18 outpatients the nine with plasma nortriptyline concentrations between 50 and 139 pg/l showed more improvement after six weeks than those with concentrations above this range; and an English study5 of 36 depressed inpatients again supported this. By contrast, two Australian studies6 7 and an earlier English one" found no relation between nortriptyline concentrations and clinical response, and the results in yet another Scandinavian evaluation9 were unconvincing. None of these clinical studies included comprehensive pharmacokinetic estimations. The recently published data of Montgomery and his associates, however, provide strong evidence that high plasma nortriptyline concentrations-in this instance over 200 tgjl-are significantly less effective than intermediate ones. After receiving only a placebo for several days 18 depressed inpatients were given nortriptyline, 100 mg at night for four weeks. Plasma concentrations at the end ranged from 120 to 681 tg /1. For the first two weeks the
783
clinical response was unrelated to concentration, but those with concentrations below 200 ,ug/l continued to respond over the third and fourth weeks, whereas those with high concentrations improved no further. One patient with high concentrations became confused, but otherwise side effects were not related to drug concentrations. High plasma concentrations cannot, apparently, be guessed at on clinical grounds alone. In the pharmacokinetic study'1 nortriptyline concentrations were measured for 48 hours after a single 100-mg dosebefore the course'of treatment. The mean plasma clearance of the drug in the patients was unexpectedly only about half that of normal people (26-1 v 52-6 1/h), which accounted for the high plasma concentrations found later with continuous treatment. Montgomery et al suggest that this finding may reflect preselection of patients: those who respond are treated successfully by general practitioners, while those who do not, who have a slow clearance and high antidepressant concentrations, are referred to hospital. The results of the pharmacokinetic study imply that a single estimation of plasma nortriptyline 48 hours after a test dose will accurately predict eventual steady-state concentrations, and hence could be used to adjust clinical dosage. What about amitriptyline, which in Britain we use much more than nortriptyline ? Amitriptyline is extensively metabolised to nortriptyline by N-desmethylation, so that after taking amitriptyline for a few weeks the concentration of nortriptyline is similar to that of amitriptyline. The earliest report12 claimed a strong correlation between plasma tricyclic concentrations and clinical response, and similar results were reported by workers in St Louis'314 and Pittsburg:"5 the higher the concentration of tricyclics, the better the response. There was no apparent curvilinear relation to concentration, as with nortriptyline. An attempt to replicate the earlier results in a multicentre WHO collaborative study on 54 patients was unsuccessful'6; this study has been criticised'7 as untypical, however, because the clinical response of the patients was so dismal. Studies with other antidepressants have been too few to permit conclusions. The lack of consistency in these studies may be due to technical problems with estimating drug concentrations; different ways of evaluating clinical response and types of patient; and further pharmacokinetic factors, such as differences in plasma binding. Other pharmacological problems include extrapolation from plasma concentrations to those at the presumed site of action and differences in the sensitivity of effector systems; attempts have been made to correlate clinical response with pharmacodynamic responses such as inhibition of the tyramine pressor response. Nevertheless, we now have good evidence that the clinical response to nortriptyline is related to concentrations below about 200 Fg/l and above 50 Ftg/l. Why the higher concentrations should be ineffective is unknown. The new rapid and cheap immunoassay techniques for estimating tricyclic antidepressives should hasten the translation of these research findings into routine clinical practice. We could increase the efficacy of nortriptyline at least by monitoring plasma concentrations to predict the correct dosage. I 2
Medical,Journal,
Asberg, M, et al, British 1971, 3, 331. Kragh-S0rensen, P, Asberg, M, and Eggert-Hansen, C, Lancet, 1973, 1, 113. 3Kragh-Sorensen, P, et al, Psychopharmacologia, 1976, 45, 305. 4Ziegler, V E, et al, Clinical Pharmacology and Therapeutics, 1976, 20, 458. Montgomery, S, Braithwaite, R A, and Crammer, J L, British Medical J3ournal, 1977, 2, 166. 6 Burrows, G D, Davies, B, and Scoggins, B A, Lancet, 1972, 2, 619. 7 Burrows, G D, et al, Clinical Pharmacology and Therapeutics, 1974, 16, 639. 8 Lyle, W H, et al, Postgraduate Medical Journal, 1974, 50, 282.
