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THYROTROPIN-RELEASING HORMONE IN CHRONIC SCHIZOPHRENIA
869 TRYPTOPHAN PLUS A PYRROLASE INHIBITOR FOR DEPRESSION
antidepressant action of administration of a be enhanced joint by L-tryptophan may tryptophan-pyrrolase inhibitor such as allopurinol’ or nicotinamide2 has been discussed.3 We expressed doubt about the usefulness of nicotinamide because its inhibition of tryptophanpyrrolase activity has been demonstrated only after acute (and not chronic) administration, and in adrenalectomised or hypophysectomised but not intact rats. Our allopurinol suggestion was supported by the finding4 that its acute administration (but not that of nicotinamide) enhances the rise in rat-brain tryptophan following a loading dose of the aminoacid. Since SiR,—The suggestion that
the
then, we have found that chronic nicotinamide administration
(in drinking-water) inhibits the pyrrolase activity. Effective inhibition of the apoenzyme activity occurs as early as 1 day after administration of a dose as little as 1 mg/kg body-weight (in the form of a 10 mg/1 solution in drinkingwater). This dose is equivalent to a 70 mg dose given to a 70 kg patient per day. In view of this finding, and of the recently reported’ success of a tryptophan-nicotinamide therapy of unipolar depression, the following findings concerning the effects to rats
of allopurinol, nicotinamide, and also glucose (which also inhibits tryptophan-pyrrolase activity6) on rat-brain tryptophan concentration may be of interest (see accompanying table).
lase-inhibiting dose of it is 5 g/kg/day in the rat, which is equivalent to 350 g/70 kg patient/day. We thank the Medical Research Council for support, and Mr A.
Dacey, Miss Jill C. Davis, and Mr C. J. Morgan for assistance. University Hospital of Wales, Addiction Unit Research Laboratory, Whitchurch Hospital, Cardiff CF4 7XB.
A. A.-B. BADAWY M. EVANS
THYROTROPIN-RELEASING HORMONE IN CHRONIC SCHIZOPHRENIA
SIR,-Intravenous administration of synthetic thyrotropin-releasing hormone (T.R.H.) has been reported as leading to a prompt amelioration of schizophrenic symptoms in a pilot study involving four female patients.1 The only additional published report regarding T.R.H. in other than affective psychotic illness is that of Draysonwho gave T.R.H. to three patients with cyclical psychoses and failed to observe any clinical change. We have given T.R.H. to three treatment-resistant chronic schizophrenic males in an inpatient research setting in which all subjects were drug-free for at least a month prior to study. Synthetic T.R.H. 600 pg (Abbott,38579 ’) or matching placebo administered by slow intravenous injection at 8 A.M. for 5 days followed by a 2-day holiday and then crossover to the treatment not given. Order of treatment was random; neither the person giving the injection nor any of the clinical staff was aware of the nature of the substance being given. The patient’s clinical status was estimated by a 28-item nurses’ rating-scale completed for each shiftas well as by clinical observation by the resident psychiatrist. Particular attention was paid to each patient on the first day of each series of injections because of the reported rapid onset of clinical change.’ Statistical comparison of active T.R.H. vs. placebo was by t test of the means for appropriate questions for the five days of each treatment period. The results are summarised in the accompanying table. was
EFFECTS OF ALLOPURINOL, NICOTINAMIDE, OR GLUCOSE ON RAT-BRAIN TRYPTOPHAN CONCENTRATION I
Male Wistar rats (140-160 g body-weight) were maintained cube diet M.R.C. no. 41B and water ad libitum. Allopurinol was given in a single intraperitoneal injection of 20 mg/kg 3,5 h before death. Nicotinamide or glucose was administered in drinking-water for 3 and 2 days, respectively. The doses were 100 mg/1 and 100g/1, respectively. Each individually housed rat was killed by decapitation between 10 and 11 h. Braintryptophan concentration was determined8at 1 h after an intra-peritoneal injection of 0-9% Nad or tryptophan (50 mg/kg in 0.9 NaCl). The results show that, at 1 h after 0-9% NaCI, brain-tryptophan concentration was increased (p=0.0050.001) by 38, 41, and 52% by allopurinol, nicotinamide, and
EFFECTS OF SYNTHETIC-T.R.H. ADMINISTRATION ON THE SYMPTOMS OF SCHIZOPHRENIA IN THREE CHRONIC SCHIZOPHRENIC PATIENTS
on
The increase in brain-tryptophan con1 h after a tryptophan load was also enhanced (P=0-01-0-001) by the same treatments by 48, 53, and 27%, respectively. The above results therefore provide a biochemical basis for the usefulness of either allopurinol or nicotinamide as a tryptophan-pyrrolase inhibitor if given with L-tryptophan for the treatment of depression, or individually for prophylactic purposes. We, however, recommend that nicotinamide should be given in doses smaller than 1 g/day, in order to avoid any excessive disturbance in the equilibrium of the liver nicotinamide/adenine-dinucleotide systems. Our results also suggest that glucose may be useful. We found that the smallest pyrro-
glucose, respectively. centration observed
at
1. Badawy, A. A.-B., Evans, M. Biochem. J. 1973, 133, 585. 2 Young, S. N., Sourkes, T. L. Lancet. 1974, ii, 897. 3 Badawy, A. A.-B., Evans, M. ibid. p. 1209. 4 Fernando, J. C., Joseph, M. H., Curzon, G. ibid, 1975, i, 171. 5. MacSweeney, D. A. ibid. Sept. 13, 1975, p. 510. 6 Yuwiler, A., Wetterberg, L., Geller, E. Biochim. biophys. Acta. 428 7 Bloxam, D. L., Warren, W. H. Anal. Biochem. 1974, 60, 621 8 Denckla, W. D., Dewey, H. K. J. Lab. clin. Med. 1967, 69, 160.
The table shows that the clinical condition of two of the three patients-particularly that of patient 3worsened somewhat. The depression score for these two patients was significantly greater during the week on T.R.H. than in the week on placebo-a finding which stands in contrast to earlier reports suggesting that T.R.H. has anti-
depressant activity.4 Although bearing the same diagnosis, the patients reported here are in many ways significantly different from those in Wilson’s1 earlier report of beneficial effects of T.R.H. in schizophrenia. His patients were " recently readmitted to the hospital, and their prognoses for
1970, 208,
1. Wilson, I. C., Lara, P. P., Prange, A. J., Jr. Lancet, 1973, ii, 43. 2. Drayson, A. M. ibid. 1974, i, 312. 3. Wyatt, R. J., Kupfer, D. J. Psychol. Rep. 1968, 23, 1331. 4. Prange, A. J., Wilson, I. C., Lara, P. P., Alltop, L. B., Breese, G. R. Lancet, 1972, ii, 999.
870 additional social remission were good ".1 The patients we are reporting had a mean age of 31 years, average duration of illness of 13 years, and mean hospital stay of 8 years. All were men and were diagnosed as chronic undifferentiated schizophrenia. Off medication they were bizarre, autistic, and hallucinated. On medication they were under considerably better social control but showed the usual hallmarks of having severe chronic process schizophrenic illness. Our patients must be regarded as significantly more ill than those in the other report. Our clinical results do not give any encouragement for further study of a similar population of chronic schizophrenics, but it does remain possible that there might be some individuals carrying this diagnosis who would be particularly responsive to exogenous T.R.H. In this vein it has been shown in a number of studies that T.R.H. is ineffective in depressed patients as a group.6-8 The positive and reproducible result found by van der VisMelsonin a case of depression with possible organic features as well as the case-report of tranquillisation in a 15-year-old boy with cerebral gigantism and explosive behaviour 10 should stimulate further work on a possible role of T.R.H. in maintaining behavioural homceostasis.
There are many letters from those who anticipate the worst when SI units are introduced, but a dearth of letters from those with first-hand experience of the change. As consultants in a laboratory which adopted SI units over seven months ago, we feel that the problems have been exaggerated. Admittedly the unfamiliar figures have involved more work, and it will take many more months before we are totally conversant with the system, especially for the less common tests; but the costs have been negligible, there have been no serious problems or complaints, and the clinical staff have been most cooperative. It would be unrealistic to claim many benefits of the change, though eventually these should come with greater uniformity, Here and now there are some advantages. For example, acidbase disorders are easier to comprehend in term of hydrogenion concentration than in the inverse logarithmic pH system; in hyperosmolar coma moles are much easier to comprehend than mass. Many laboratories like our own have been stimulated into trying to make reports more informative-for instance, by including preprinted reference values. Hopefully the inconvenience of unfamiliar values might lead to greater discrimination in requesting laboratory work, and more thought about the meaning of the results.
Addendum. Davis et al. (Davis, K. E., Hollister, L. E., Berger, P. A. Am. y. Psychiat. 1975, 132, 951), have just reported that seven of nine male chronic schizophrenic patients deteriorated while receiving oral T.R.H. The other two patients improved somewhat, but these changes were not ascribed to the medication.
A. M. BOLD P. WILDING
Laboratory of Clinical LLEWELLYN B. BIGELOW Psychopharmacology, National Institute of Mental Health? J. CHRISTIAN GILLIN Saint Elizabeth’s Hospital, CHARLES SEMAL Wm. A. White Building, Washington, D.C. 20032, U.S.A RICHARD J. WYATT SI UNITS
Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15 2TH.
RELIEF OF MYOCLONUS BY L-TRYPTOPHAN
SIR,-Last year Van Woert and Sethyand Chadwick
reported relief of post-anoxic myoclonus3 by L-5-hydroxytryptophan (L-5-H.T.P.), the immediate preWe observed in 2 cases a cursor of serotonin (5-H.T.).
et
al.
similar beneficial effect with L-5-H.T.P. In addition both patients were improved by L-tryptophan, the parent compound in the biosynthesis of 5-H.T. man was examined 9 months after a his chest which restricted his respiratory movements for 10 minutes. He emerged from the initial state of coma and convulsions with persistent completely disabling action myoclonus and mild cerebellar signs. There were involuntary jerks of trunk and limbs activated by willed movements. Case 2.-A 72-year-old woman had had a respiratory arrest following intoxication with barbiturates. Her neurological condition 27 months after the anoxic incident resembled that in case 1.
Case l.-A
crush
SIR,-Professor Alberti (Oct. 25, p. 820) writes of "the joy that SI has brought to the clinical biochemist". Perhaps such a serious topic needs the injection of a little humour and irony. Unfortunately some of the published letters on SI units are
downright misleading. Whether the introduction of SI units in their present form into clinical medicine is on balance a good idea is a matter of opinion. The amount of consultation that took place before a decision to introduce these was made is a matter of fact. Clark and Sheldon (Oct. 11, p. 700), in a statement typical of many, assert that the recommendations on SI units were drawn up "without consultation, discussion, approval, or consent" (i.e., by clinicians). We were not members of the working-party on SI units, but we are led to believe this is not true and that after the working-party representing scientific bodies had drafted their recommendations, the D.H.S.S. consulted user organisations, including the clinical Royal Colleges. Only after approval had been given and comments noted was it decided to recommend the introduction of SI units. Detailed proposals were published over a year ago in the Journal of Clinical Pathology and articles on SI units have since appeared in many other journals. Initial apathy about SI units, presumably in the hope that they would go away, is followed by a late waking up to the implications. It is fashionable to blame the D.H.S.S. for everything we don’t like; in this instance it would be more appropriate for any dissatisfied clinicians to direct their fire at their representatives. 5. Mountjoy, C. Q., Price, J. S., Weller, M., Hunter, P., Hall, R., Dewar, J. H. ibid. 1974, i, 958. 6. Coppen, A., Peet, M., Montgomery, S., Bailey, J., Marks, V., Woods, P. ibid. 1974, ii, 433. 7. Hollister, L. E., Berger, P., Floradell, L. O., Arnold, R. C., Johnson, A. Archs gen. Psychiat. 1974, 31, 468. 8. Benkert, O., Martschke, D., Gordon, A. Lancet, 1974, ii, 1146. 9. van der Vis-Melson, M. J. E., Wiener, J. D. ibid. 1972, ii, 1415. 10. Tiwary, C. M., Frias, J. L., Rosenbloom, A. L. ibid. p. 1086.
injury
In each
suspension of methylcellulose and water L-tryptophan per 15 ml. was prepared administered orally at the level of 10 g. daily in five
containing and
64-year-old
to
case a
1 g. of
divided doses. The beneficial effect was moderate and was reversed by substitution of placebo. In contrast to L-5-H.T.P., administration of L-tryptophan represents a more specific means of increasing brainserotonin levels selectively in the serotonergic neurons. This is so because the enzyme which transforms L-tryptophan to serotonin, the rate-limiting L-tryptophan hydroxylase, is localised specifically in serotonin neurons in the brain. Thus, it has been demonstrated that, following parenteral administration of L-tryptophan in laboratory animals, (a) there is a several-fold increase in brain-serotonin levels,4 (b) the pattern of the increased serotonin levels parallels the normal pattern of serotonin distribution,’ and (c) the concentrations of brain tyrosine, dopamine, and homovanillic acid are not significantly different from normal values.6 In the light of these data, the beneficial effect of oral L-tryptophan 10 g. daily, as observed in our 2 cases, can be 1. Van Woert, M. H., Sethy, V. H. Lancet 1974, i, 1285. 2. Chadwick, D., Reynolds, E. H., Marsden, C. D. ibid. 1974, ii, 111, 3. Lance, J. W., Adams, R. D. Brain 1963, 86, III. 4. Moir, A. T. B., Eccleston, D. J. Neurochemistry, 1968, 15, 1093. 5. Moir, A. T. B. Br. J. Pharmac. 1971, 43, 715. 6. Moir, A. T. B. ibid. p. 724.
antidepressant action of administration of a be enhanced joint by L-tryptophan may tryptophan-pyrrolase inhibitor such as allopurinol’ or nicotinamide2 has been discussed.3 We expressed doubt about the usefulness of nicotinamide because its inhibition of tryptophanpyrrolase activity has been demonstrated only after acute (and not chronic) administration, and in adrenalectomised or hypophysectomised but not intact rats. Our allopurinol suggestion was supported by the finding4 that its acute administration (but not that of nicotinamide) enhances the rise in rat-brain tryptophan following a loading dose of the aminoacid. Since SiR,—The suggestion that
the
then, we have found that chronic nicotinamide administration
(in drinking-water) inhibits the pyrrolase activity. Effective inhibition of the apoenzyme activity occurs as early as 1 day after administration of a dose as little as 1 mg/kg body-weight (in the form of a 10 mg/1 solution in drinkingwater). This dose is equivalent to a 70 mg dose given to a 70 kg patient per day. In view of this finding, and of the recently reported’ success of a tryptophan-nicotinamide therapy of unipolar depression, the following findings concerning the effects to rats
of allopurinol, nicotinamide, and also glucose (which also inhibits tryptophan-pyrrolase activity6) on rat-brain tryptophan concentration may be of interest (see accompanying table).
lase-inhibiting dose of it is 5 g/kg/day in the rat, which is equivalent to 350 g/70 kg patient/day. We thank the Medical Research Council for support, and Mr A.
Dacey, Miss Jill C. Davis, and Mr C. J. Morgan for assistance. University Hospital of Wales, Addiction Unit Research Laboratory, Whitchurch Hospital, Cardiff CF4 7XB.
A. A.-B. BADAWY M. EVANS
THYROTROPIN-RELEASING HORMONE IN CHRONIC SCHIZOPHRENIA
SIR,-Intravenous administration of synthetic thyrotropin-releasing hormone (T.R.H.) has been reported as leading to a prompt amelioration of schizophrenic symptoms in a pilot study involving four female patients.1 The only additional published report regarding T.R.H. in other than affective psychotic illness is that of Draysonwho gave T.R.H. to three patients with cyclical psychoses and failed to observe any clinical change. We have given T.R.H. to three treatment-resistant chronic schizophrenic males in an inpatient research setting in which all subjects were drug-free for at least a month prior to study. Synthetic T.R.H. 600 pg (Abbott,38579 ’) or matching placebo administered by slow intravenous injection at 8 A.M. for 5 days followed by a 2-day holiday and then crossover to the treatment not given. Order of treatment was random; neither the person giving the injection nor any of the clinical staff was aware of the nature of the substance being given. The patient’s clinical status was estimated by a 28-item nurses’ rating-scale completed for each shiftas well as by clinical observation by the resident psychiatrist. Particular attention was paid to each patient on the first day of each series of injections because of the reported rapid onset of clinical change.’ Statistical comparison of active T.R.H. vs. placebo was by t test of the means for appropriate questions for the five days of each treatment period. The results are summarised in the accompanying table. was
EFFECTS OF ALLOPURINOL, NICOTINAMIDE, OR GLUCOSE ON RAT-BRAIN TRYPTOPHAN CONCENTRATION I
Male Wistar rats (140-160 g body-weight) were maintained cube diet M.R.C. no. 41B and water ad libitum. Allopurinol was given in a single intraperitoneal injection of 20 mg/kg 3,5 h before death. Nicotinamide or glucose was administered in drinking-water for 3 and 2 days, respectively. The doses were 100 mg/1 and 100g/1, respectively. Each individually housed rat was killed by decapitation between 10 and 11 h. Braintryptophan concentration was determined8at 1 h after an intra-peritoneal injection of 0-9% Nad or tryptophan (50 mg/kg in 0.9 NaCl). The results show that, at 1 h after 0-9% NaCI, brain-tryptophan concentration was increased (p=0.0050.001) by 38, 41, and 52% by allopurinol, nicotinamide, and
EFFECTS OF SYNTHETIC-T.R.H. ADMINISTRATION ON THE SYMPTOMS OF SCHIZOPHRENIA IN THREE CHRONIC SCHIZOPHRENIC PATIENTS
on
The increase in brain-tryptophan con1 h after a tryptophan load was also enhanced (P=0-01-0-001) by the same treatments by 48, 53, and 27%, respectively. The above results therefore provide a biochemical basis for the usefulness of either allopurinol or nicotinamide as a tryptophan-pyrrolase inhibitor if given with L-tryptophan for the treatment of depression, or individually for prophylactic purposes. We, however, recommend that nicotinamide should be given in doses smaller than 1 g/day, in order to avoid any excessive disturbance in the equilibrium of the liver nicotinamide/adenine-dinucleotide systems. Our results also suggest that glucose may be useful. We found that the smallest pyrro-
glucose, respectively. centration observed
at
1. Badawy, A. A.-B., Evans, M. Biochem. J. 1973, 133, 585. 2 Young, S. N., Sourkes, T. L. Lancet. 1974, ii, 897. 3 Badawy, A. A.-B., Evans, M. ibid. p. 1209. 4 Fernando, J. C., Joseph, M. H., Curzon, G. ibid, 1975, i, 171. 5. MacSweeney, D. A. ibid. Sept. 13, 1975, p. 510. 6 Yuwiler, A., Wetterberg, L., Geller, E. Biochim. biophys. Acta. 428 7 Bloxam, D. L., Warren, W. H. Anal. Biochem. 1974, 60, 621 8 Denckla, W. D., Dewey, H. K. J. Lab. clin. Med. 1967, 69, 160.
The table shows that the clinical condition of two of the three patients-particularly that of patient 3worsened somewhat. The depression score for these two patients was significantly greater during the week on T.R.H. than in the week on placebo-a finding which stands in contrast to earlier reports suggesting that T.R.H. has anti-
depressant activity.4 Although bearing the same diagnosis, the patients reported here are in many ways significantly different from those in Wilson’s1 earlier report of beneficial effects of T.R.H. in schizophrenia. His patients were " recently readmitted to the hospital, and their prognoses for
1970, 208,
1. Wilson, I. C., Lara, P. P., Prange, A. J., Jr. Lancet, 1973, ii, 43. 2. Drayson, A. M. ibid. 1974, i, 312. 3. Wyatt, R. J., Kupfer, D. J. Psychol. Rep. 1968, 23, 1331. 4. Prange, A. J., Wilson, I. C., Lara, P. P., Alltop, L. B., Breese, G. R. Lancet, 1972, ii, 999.
870 additional social remission were good ".1 The patients we are reporting had a mean age of 31 years, average duration of illness of 13 years, and mean hospital stay of 8 years. All were men and were diagnosed as chronic undifferentiated schizophrenia. Off medication they were bizarre, autistic, and hallucinated. On medication they were under considerably better social control but showed the usual hallmarks of having severe chronic process schizophrenic illness. Our patients must be regarded as significantly more ill than those in the other report. Our clinical results do not give any encouragement for further study of a similar population of chronic schizophrenics, but it does remain possible that there might be some individuals carrying this diagnosis who would be particularly responsive to exogenous T.R.H. In this vein it has been shown in a number of studies that T.R.H. is ineffective in depressed patients as a group.6-8 The positive and reproducible result found by van der VisMelsonin a case of depression with possible organic features as well as the case-report of tranquillisation in a 15-year-old boy with cerebral gigantism and explosive behaviour 10 should stimulate further work on a possible role of T.R.H. in maintaining behavioural homceostasis.
There are many letters from those who anticipate the worst when SI units are introduced, but a dearth of letters from those with first-hand experience of the change. As consultants in a laboratory which adopted SI units over seven months ago, we feel that the problems have been exaggerated. Admittedly the unfamiliar figures have involved more work, and it will take many more months before we are totally conversant with the system, especially for the less common tests; but the costs have been negligible, there have been no serious problems or complaints, and the clinical staff have been most cooperative. It would be unrealistic to claim many benefits of the change, though eventually these should come with greater uniformity, Here and now there are some advantages. For example, acidbase disorders are easier to comprehend in term of hydrogenion concentration than in the inverse logarithmic pH system; in hyperosmolar coma moles are much easier to comprehend than mass. Many laboratories like our own have been stimulated into trying to make reports more informative-for instance, by including preprinted reference values. Hopefully the inconvenience of unfamiliar values might lead to greater discrimination in requesting laboratory work, and more thought about the meaning of the results.
Addendum. Davis et al. (Davis, K. E., Hollister, L. E., Berger, P. A. Am. y. Psychiat. 1975, 132, 951), have just reported that seven of nine male chronic schizophrenic patients deteriorated while receiving oral T.R.H. The other two patients improved somewhat, but these changes were not ascribed to the medication.
A. M. BOLD P. WILDING
Laboratory of Clinical LLEWELLYN B. BIGELOW Psychopharmacology, National Institute of Mental Health? J. CHRISTIAN GILLIN Saint Elizabeth’s Hospital, CHARLES SEMAL Wm. A. White Building, Washington, D.C. 20032, U.S.A RICHARD J. WYATT SI UNITS
Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15 2TH.
RELIEF OF MYOCLONUS BY L-TRYPTOPHAN
SIR,-Last year Van Woert and Sethyand Chadwick
reported relief of post-anoxic myoclonus3 by L-5-hydroxytryptophan (L-5-H.T.P.), the immediate preWe observed in 2 cases a cursor of serotonin (5-H.T.).
et
al.
similar beneficial effect with L-5-H.T.P. In addition both patients were improved by L-tryptophan, the parent compound in the biosynthesis of 5-H.T. man was examined 9 months after a his chest which restricted his respiratory movements for 10 minutes. He emerged from the initial state of coma and convulsions with persistent completely disabling action myoclonus and mild cerebellar signs. There were involuntary jerks of trunk and limbs activated by willed movements. Case 2.-A 72-year-old woman had had a respiratory arrest following intoxication with barbiturates. Her neurological condition 27 months after the anoxic incident resembled that in case 1.
Case l.-A
crush
SIR,-Professor Alberti (Oct. 25, p. 820) writes of "the joy that SI has brought to the clinical biochemist". Perhaps such a serious topic needs the injection of a little humour and irony. Unfortunately some of the published letters on SI units are
downright misleading. Whether the introduction of SI units in their present form into clinical medicine is on balance a good idea is a matter of opinion. The amount of consultation that took place before a decision to introduce these was made is a matter of fact. Clark and Sheldon (Oct. 11, p. 700), in a statement typical of many, assert that the recommendations on SI units were drawn up "without consultation, discussion, approval, or consent" (i.e., by clinicians). We were not members of the working-party on SI units, but we are led to believe this is not true and that after the working-party representing scientific bodies had drafted their recommendations, the D.H.S.S. consulted user organisations, including the clinical Royal Colleges. Only after approval had been given and comments noted was it decided to recommend the introduction of SI units. Detailed proposals were published over a year ago in the Journal of Clinical Pathology and articles on SI units have since appeared in many other journals. Initial apathy about SI units, presumably in the hope that they would go away, is followed by a late waking up to the implications. It is fashionable to blame the D.H.S.S. for everything we don’t like; in this instance it would be more appropriate for any dissatisfied clinicians to direct their fire at their representatives. 5. Mountjoy, C. Q., Price, J. S., Weller, M., Hunter, P., Hall, R., Dewar, J. H. ibid. 1974, i, 958. 6. Coppen, A., Peet, M., Montgomery, S., Bailey, J., Marks, V., Woods, P. ibid. 1974, ii, 433. 7. Hollister, L. E., Berger, P., Floradell, L. O., Arnold, R. C., Johnson, A. Archs gen. Psychiat. 1974, 31, 468. 8. Benkert, O., Martschke, D., Gordon, A. Lancet, 1974, ii, 1146. 9. van der Vis-Melson, M. J. E., Wiener, J. D. ibid. 1972, ii, 1415. 10. Tiwary, C. M., Frias, J. L., Rosenbloom, A. L. ibid. p. 1086.
injury
In each
suspension of methylcellulose and water L-tryptophan per 15 ml. was prepared administered orally at the level of 10 g. daily in five
containing and
64-year-old
to
case a
1 g. of
divided doses. The beneficial effect was moderate and was reversed by substitution of placebo. In contrast to L-5-H.T.P., administration of L-tryptophan represents a more specific means of increasing brainserotonin levels selectively in the serotonergic neurons. This is so because the enzyme which transforms L-tryptophan to serotonin, the rate-limiting L-tryptophan hydroxylase, is localised specifically in serotonin neurons in the brain. Thus, it has been demonstrated that, following parenteral administration of L-tryptophan in laboratory animals, (a) there is a several-fold increase in brain-serotonin levels,4 (b) the pattern of the increased serotonin levels parallels the normal pattern of serotonin distribution,’ and (c) the concentrations of brain tyrosine, dopamine, and homovanillic acid are not significantly different from normal values.6 In the light of these data, the beneficial effect of oral L-tryptophan 10 g. daily, as observed in our 2 cases, can be 1. Van Woert, M. H., Sethy, V. H. Lancet 1974, i, 1285. 2. Chadwick, D., Reynolds, E. H., Marsden, C. D. ibid. 1974, ii, 111, 3. Lance, J. W., Adams, R. D. Brain 1963, 86, III. 4. Moir, A. T. B., Eccleston, D. J. Neurochemistry, 1968, 15, 1093. 5. Moir, A. T. B. Br. J. Pharmac. 1971, 43, 715. 6. Moir, A. T. B. ibid. p. 724.