The Journal of the Royal Medlco-Chlrurglcal Society 01 Glasgow, the Medlco-Chlrurglcal Soelety of Edinburgh, and the Scottish Society for Experimental Medicine ISSN: 0036·9330
Volume 22 OCTOBER 1977 Number 4
Scottish Medical Journal
TRYPTOPHAN AND AFFECTIVE DISORDERS
the metabolism of another neurotransmitter. A group of 'mixed depressives' had ventricular CSF levels of tryptophan significantly As a result of several recent human studies below a 'control' group of neurological made possible by technical and clinical patients. It was concluded that there was an innovations the role of L-tryptophan, the association between mood and concentration aminoacid precursor of 5 hydroxytryptamine of tryptophan (and tyrosine) in the brain. (5 HT) in the pathogenesis and treatment However, when the 'group of depressives' of affective disorders is becoming clearer. was looked at in more detail an interesting For instance, Stein et al. (1976) have studied dichotomy emerged. Thus, patients who the relationship between mood and free and presented clinically with severe retardation total plasma tryptophan in 18 women during had low concentrations of ventricular tryptothe postpartum period - a time frequently phan whilst those with high levels of agitation/ associated with emotional lability and 'deanxiety, or in which the psychiatric diagnosis pression'. The patients rated themselves on a was non depressive agitation/anxiety had number of 'target' symptoms for depression higher levels. These observations are conand a total 'affective score' was also calsistent with at least one study which found culated. Those with 'depressed' mood had low levels of tryptophan in the lumbar CSF low free plasma tryptophan levels which of depressives (Coppen et al., 1972) but not were similar to those found in a 'control' with another (Ashcroft et al., 1973). group consisting of women with endogenous Although not directly comparable (but depression. Patients 'less' depressed and a certainly more relevant) Bridges data for group of 'normal' controls had higher ventricular CSF accord well with that of tryptophan levels. A second study by Handley et al. (1977) the majority of workers who have found investigated the relationship between mood reduced levels of 5HIAA in the lumbar CSF changes and plasma tryptophan and cortisol of depressives (reviewed by Post et al., levels in postpartum women studied daily 1973). Bridges recommends that information on during the second to fifth days. Over this period plasma free tryptophan concentra- brain 5HT metabolism obtained by studying tions tended to rise whilst plasma cortisol the CSF of psychiatric patients might be declined. There was a significant positive considered in relation to specific symptoms correlation between plasma free tryptophan (of depression) such as agitation and retardaconcentrations and mood state - this has tion and the mechanism by which tryptophan also been shown by Coppen et al. (1973) in a alleviates the illness. study of depressives. In the field of clinical psychiatry the uses A recent biochemical and clinical investiga- and limitations of tryptophan in the treatment tion on psychiatric patients has taken the of depression are becoming clearer. Thus, story a little further. Bridges et al. (1976) a multicentre study carried out in Scandhave measured levels of tryptophan and the inavia using a common protocol commain metabolite of 5 HT, 5 HIAA in the pared L-tryptophan (more active than the ventricular CSF of depressives and other D-form) with imipramine. Improvement psychiatric patients. For comparison the in both groups of patients which was equivadopamine precursor tyrosine and the major lent was highly statistically significant. Side dopamine metabolite homovanillic acid effects in the tryptophan group were less (HVA) were also determined as indices of frequent than in the imipramine group 245
Comments
(Jensen et aI., 1975). Similar findings have been reported by Rao and Broadhurst (1976). Several other investigations using combinations of L-tryptophan and monoamineoxidase inhibitor and chlormipramine have confirmed both the intrinsic anti-depressant action of the former as well as an additive effect when used with other appropriate drugs (Coppen et al., 1963; Pare 1963; Glassman & Platman, 1969; Wallinder et al., 1975). Another study carried out under the auspices of the Clinical Trials Sub-Committee of the Medical Research Council has compared L-tryptophan and amitriptyline in depressive illness (Herrington et al., 1976). Depressed patients, who were considered suitable for drug treatment were allocated randomly for 4 weeks either amitriptyline (up to 150 mg. daily) or L-tryptophan (up to 8 g. daily). The trial utilising a double dummy procedure was double blind and comprehensive ratings were made at the start and weekly during the subsequent 4 weeks. The patients were then observed for a further 6 months. Both groups improved steadily over the course of 4 weeks and there were no marked differences between the treatment groups. However the tryptophan treated patients showed a reduced tendency to relapse over the 6 months follow-up period. It was also observed that within the tryptophan group anxious patients improved least; this is entirely consistent with Bridges biochemical findings (Bridges et aI., 1976). Although some early claims comparing tryptophan favourably with ECT have not stood the test of replication (Herrington et al., 1974; Carroll et al., 1970), the recent biochemical and clinical work suggests that the aminoacid may play an important role in the pathogenesis and treatment of depression. It is probable that functional deficiency of 5HT in certain parts of the brain underlie (some types) of affective disorder and further research might confirm a specific relationship to retardation and other manifestations of 'biological hypoactivity' . 5HT depleted depressives might be expected to respond favourably to oral L-tryptophan since it is 246
known that the rate of brain 5HT synthesis depends upon the level of free plasma tryptophan. Unfortuntely not all depressives have depleted cerebral 5HT and not all depressives respond to L-tryptophan. Furthermore, it is likely that other neurotransmitters such as dopamine, tryptamine etc. may also be concerned in depression and that as well as absolute concentrations the ratio of one to the other may also be critical; also 'receptor sensitivity' might be altered. More clinical and biochemical research, in tandem is required to conclude the story. ALLAN J. COOPER, Consultant Psychiatrist Department of Psychiatry, St. Mary's Medical School, London. REFERENCES
Ashcroft, G. W., Blackburn, I. M., Eccleston, D., Glen, A. I. M., Hartley, W., Kinloch, N. K, Lonergan, M., Murray, L. G., Pullar, I. A. (1973). Changes on recovery in the concentrations of tryptophan and the biogenic amine metabolites in the cerebrospinal fluid of patients with affective illness. Psychological Medicine, 3, 319 Bridges, P. K., Bartlett, J. R., Sepping, P., Kantamaneni, B. D., Curzon, G. (1976). Precursors and metabolites of 5-hydroxtryptamine and dopamine in the ventricular cerebrospinal fluid of psychiatric patients. Psychological Medicine, 6, 399 Carroll, B. J., Mowbray, R. M., Davies, B. (1970). Sequential comparison of L-tryptophan with ECT in severe depression. Lancet, 1, 967 Coppen, A., Shaw, D. M. (1963). Potentiation of the antidepressive effect of a monoamine-oxidase inhibitor by tryptophan. Lancet, 1, 79 Coppen, A., Brooksbank, B. W. L., Peet, M. (1972). Tryptophan concentration in the cerebrospinal fluid of depressive patients. Lancet, 1, 1393 Coppen, A., Eccleston, E. G., Peet, M. (1973). Total and free tryptophan concentration in the plasma of depressive patients. Lancet, 2, 60 Glassman, A. H., Platman, S. R. (1969). Potentiation of a monoamine oxidase inhibitor by tryptophan. Journal of Psychiatric Research, 7, 83 Handley, S. L., Dunn, T. L., Baker, J. M., Cockshott, C., Gould, S. (1977). Mood changes in puerperium, and plasma tryptophan and cortisol concentrations. British Medical Journal, 2, 18 Herrington, R. N., Bruce, A., Johnstone, E. C. (1974). Comparative trial of L-tryptophan and ECT in severe depressive illness. Lancet, 2, 731 Herrington, R. N., Bruce, A., Johnstone, E. C., Lader, M. H. (1976). Comparative trial of Ltryptophan and amitriptyline in depressive illness. Psychological Medicine, 6, 673
Comments
Jensen, K., Fruensgaard, K., Ahlfors, U. G., Pihkanen, T. A., Tuomikoski, S., Ose, E., Deneker, S. J., Lindberg, D., Nagy, A. (1975). Tryptophan/ Imipramine in depression. Lancet, 2, 920 Pare, C. M. B. (1963). Potentiation of monoamineoxidase inhibitors by tryptophan. Lancet, 2, 527 Post, R. M., Kotin, J., Goodwin, F. K., Gordon, E. K. (1973). Psychomotor activity and cerebrospinal fluid amine metabolites in affective illness. American Journal of Psychiatry, 130, 67
Rao Bapuji, Broadhurst, A. D. (1976). Tryptophan and depression. British MedicalJournal, 1,460 Stein, G., Milton, F., Bebbington, P., Wood, K., Coppen, A. (1976). Relationship between mood disturbances and free and total plasma tryptophan in postpartum women. British Medical Journal, 2,457 Walinder, J., Skott, An., Nagy, A., Carlsson, A., Roos, Bjoru-Erik (1975). Potentiation of antidepressant action of clomipramine by tryptophan. Lancet, 1, 984
247
Volume 22 OCTOBER 1977 Number 4
Scottish Medical Journal
TRYPTOPHAN AND AFFECTIVE DISORDERS
the metabolism of another neurotransmitter. A group of 'mixed depressives' had ventricular CSF levels of tryptophan significantly As a result of several recent human studies below a 'control' group of neurological made possible by technical and clinical patients. It was concluded that there was an innovations the role of L-tryptophan, the association between mood and concentration aminoacid precursor of 5 hydroxytryptamine of tryptophan (and tyrosine) in the brain. (5 HT) in the pathogenesis and treatment However, when the 'group of depressives' of affective disorders is becoming clearer. was looked at in more detail an interesting For instance, Stein et al. (1976) have studied dichotomy emerged. Thus, patients who the relationship between mood and free and presented clinically with severe retardation total plasma tryptophan in 18 women during had low concentrations of ventricular tryptothe postpartum period - a time frequently phan whilst those with high levels of agitation/ associated with emotional lability and 'deanxiety, or in which the psychiatric diagnosis pression'. The patients rated themselves on a was non depressive agitation/anxiety had number of 'target' symptoms for depression higher levels. These observations are conand a total 'affective score' was also calsistent with at least one study which found culated. Those with 'depressed' mood had low levels of tryptophan in the lumbar CSF low free plasma tryptophan levels which of depressives (Coppen et al., 1972) but not were similar to those found in a 'control' with another (Ashcroft et al., 1973). group consisting of women with endogenous Although not directly comparable (but depression. Patients 'less' depressed and a certainly more relevant) Bridges data for group of 'normal' controls had higher ventricular CSF accord well with that of tryptophan levels. A second study by Handley et al. (1977) the majority of workers who have found investigated the relationship between mood reduced levels of 5HIAA in the lumbar CSF changes and plasma tryptophan and cortisol of depressives (reviewed by Post et al., levels in postpartum women studied daily 1973). Bridges recommends that information on during the second to fifth days. Over this period plasma free tryptophan concentra- brain 5HT metabolism obtained by studying tions tended to rise whilst plasma cortisol the CSF of psychiatric patients might be declined. There was a significant positive considered in relation to specific symptoms correlation between plasma free tryptophan (of depression) such as agitation and retardaconcentrations and mood state - this has tion and the mechanism by which tryptophan also been shown by Coppen et al. (1973) in a alleviates the illness. study of depressives. In the field of clinical psychiatry the uses A recent biochemical and clinical investiga- and limitations of tryptophan in the treatment tion on psychiatric patients has taken the of depression are becoming clearer. Thus, story a little further. Bridges et al. (1976) a multicentre study carried out in Scandhave measured levels of tryptophan and the inavia using a common protocol commain metabolite of 5 HT, 5 HIAA in the pared L-tryptophan (more active than the ventricular CSF of depressives and other D-form) with imipramine. Improvement psychiatric patients. For comparison the in both groups of patients which was equivadopamine precursor tyrosine and the major lent was highly statistically significant. Side dopamine metabolite homovanillic acid effects in the tryptophan group were less (HVA) were also determined as indices of frequent than in the imipramine group 245
Comments
(Jensen et aI., 1975). Similar findings have been reported by Rao and Broadhurst (1976). Several other investigations using combinations of L-tryptophan and monoamineoxidase inhibitor and chlormipramine have confirmed both the intrinsic anti-depressant action of the former as well as an additive effect when used with other appropriate drugs (Coppen et al., 1963; Pare 1963; Glassman & Platman, 1969; Wallinder et al., 1975). Another study carried out under the auspices of the Clinical Trials Sub-Committee of the Medical Research Council has compared L-tryptophan and amitriptyline in depressive illness (Herrington et al., 1976). Depressed patients, who were considered suitable for drug treatment were allocated randomly for 4 weeks either amitriptyline (up to 150 mg. daily) or L-tryptophan (up to 8 g. daily). The trial utilising a double dummy procedure was double blind and comprehensive ratings were made at the start and weekly during the subsequent 4 weeks. The patients were then observed for a further 6 months. Both groups improved steadily over the course of 4 weeks and there were no marked differences between the treatment groups. However the tryptophan treated patients showed a reduced tendency to relapse over the 6 months follow-up period. It was also observed that within the tryptophan group anxious patients improved least; this is entirely consistent with Bridges biochemical findings (Bridges et aI., 1976). Although some early claims comparing tryptophan favourably with ECT have not stood the test of replication (Herrington et al., 1974; Carroll et al., 1970), the recent biochemical and clinical work suggests that the aminoacid may play an important role in the pathogenesis and treatment of depression. It is probable that functional deficiency of 5HT in certain parts of the brain underlie (some types) of affective disorder and further research might confirm a specific relationship to retardation and other manifestations of 'biological hypoactivity' . 5HT depleted depressives might be expected to respond favourably to oral L-tryptophan since it is 246
known that the rate of brain 5HT synthesis depends upon the level of free plasma tryptophan. Unfortuntely not all depressives have depleted cerebral 5HT and not all depressives respond to L-tryptophan. Furthermore, it is likely that other neurotransmitters such as dopamine, tryptamine etc. may also be concerned in depression and that as well as absolute concentrations the ratio of one to the other may also be critical; also 'receptor sensitivity' might be altered. More clinical and biochemical research, in tandem is required to conclude the story. ALLAN J. COOPER, Consultant Psychiatrist Department of Psychiatry, St. Mary's Medical School, London. REFERENCES
Ashcroft, G. W., Blackburn, I. M., Eccleston, D., Glen, A. I. M., Hartley, W., Kinloch, N. K, Lonergan, M., Murray, L. G., Pullar, I. A. (1973). Changes on recovery in the concentrations of tryptophan and the biogenic amine metabolites in the cerebrospinal fluid of patients with affective illness. Psychological Medicine, 3, 319 Bridges, P. K., Bartlett, J. R., Sepping, P., Kantamaneni, B. D., Curzon, G. (1976). Precursors and metabolites of 5-hydroxtryptamine and dopamine in the ventricular cerebrospinal fluid of psychiatric patients. Psychological Medicine, 6, 399 Carroll, B. J., Mowbray, R. M., Davies, B. (1970). Sequential comparison of L-tryptophan with ECT in severe depression. Lancet, 1, 967 Coppen, A., Shaw, D. M. (1963). Potentiation of the antidepressive effect of a monoamine-oxidase inhibitor by tryptophan. Lancet, 1, 79 Coppen, A., Brooksbank, B. W. L., Peet, M. (1972). Tryptophan concentration in the cerebrospinal fluid of depressive patients. Lancet, 1, 1393 Coppen, A., Eccleston, E. G., Peet, M. (1973). Total and free tryptophan concentration in the plasma of depressive patients. Lancet, 2, 60 Glassman, A. H., Platman, S. R. (1969). Potentiation of a monoamine oxidase inhibitor by tryptophan. Journal of Psychiatric Research, 7, 83 Handley, S. L., Dunn, T. L., Baker, J. M., Cockshott, C., Gould, S. (1977). Mood changes in puerperium, and plasma tryptophan and cortisol concentrations. British Medical Journal, 2, 18 Herrington, R. N., Bruce, A., Johnstone, E. C. (1974). Comparative trial of L-tryptophan and ECT in severe depressive illness. Lancet, 2, 731 Herrington, R. N., Bruce, A., Johnstone, E. C., Lader, M. H. (1976). Comparative trial of Ltryptophan and amitriptyline in depressive illness. Psychological Medicine, 6, 673
Comments
Jensen, K., Fruensgaard, K., Ahlfors, U. G., Pihkanen, T. A., Tuomikoski, S., Ose, E., Deneker, S. J., Lindberg, D., Nagy, A. (1975). Tryptophan/ Imipramine in depression. Lancet, 2, 920 Pare, C. M. B. (1963). Potentiation of monoamineoxidase inhibitors by tryptophan. Lancet, 2, 527 Post, R. M., Kotin, J., Goodwin, F. K., Gordon, E. K. (1973). Psychomotor activity and cerebrospinal fluid amine metabolites in affective illness. American Journal of Psychiatry, 130, 67
Rao Bapuji, Broadhurst, A. D. (1976). Tryptophan and depression. British MedicalJournal, 1,460 Stein, G., Milton, F., Bebbington, P., Wood, K., Coppen, A. (1976). Relationship between mood disturbances and free and total plasma tryptophan in postpartum women. British Medical Journal, 2,457 Walinder, J., Skott, An., Nagy, A., Carlsson, A., Roos, Bjoru-Erik (1975). Potentiation of antidepressant action of clomipramine by tryptophan. Lancet, 1, 984
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