LETTERS TO THE EDITORS
Br. J. clin. Pharmac. (1978), 6
541
DOPAMINE AGONISTS FOR NEGATIVE SYMPTOMS IN SCHIZOPHRENIA A number of authors have suggested that the primary disturbance in schizophrenia may be hypersensitivity of the dopamine receptor (Bowers, 1974; Crow, Deakin, Johnstone & Longden, 1976; Kapit, 1977) and supportive evidence for this from spiroperidolbinding studies in post-mortem brain has recently been reported by Owen, Crow, Poulter, Cross, Longden & Riley (1978). Chouinard & Jones (1978) have proposed that such a dopamine-receptor hypersensitivity results from a central dopamine deficiency and have argued that levodopa would be a useful adjunct to neuroleptics in the treatment of negative symptoms and in preventing both psychotic and hyperkinetic positive symptoms due to further hypersensitivity. They also suggested that patients with only negative symptoms should respond to treatment with levodopa alone. Following a similar line of reasoning (but thinking of the negative symptoms as resulting from receptor hyposensitivity or 'resistance' after years of dopamine excess) and encouraged by an earlier report of beneficial results in a six week trial of levodopa in chronic schizophrenics (Buchanan, Parton, Warren & Baker, 1975), I have treated two residual schizophrenics with the dopamine agonist bromocriptine, in an open pilot study. The patients were both male and aged 44 and 37 years respectively. Both were extremely inert, emotionally blunted and socially withdrawn. Patient A had been in hospital for 29 years, was virtually mute and known not to have replied verbally to questions for many years although he occasionally muttered incoherently to himself. Patient B had been ill for 16 years and in hospital for the past 6 years. He replied monosyllabically and smoked cigarettes until they burned his fingers. Neither had shown any significant improvement on a range of neuroleptic drugs given orally or by depot injection. Before the trial patient A had had no medication for 1 week, and patient B none for 5 months. They were both given bromocriptine 2.5 mg three times a day and the dose doubled each week for 3 weeks until they were taking 60 mg daily in three divided doses, which was then continued for 4 weeks. There was no evidence from interview or nurses' ratings of ward behaviour of any lessening in negative symptoms during this time or after discontinuation of the treatment. Both patients were described as being more 'alert', motor activity was increased and in patient A the base-line daily pedometer reading rose from 1.5 to 5.0 miles. However, there was no corresponding improvement in social contacts, speech or affective response. The restless overactivity in patient A was finally associated with a re-emergence of sudden aggressive outbursts suggesting an exacerbation of otherwise unexpressed positive
symptoms. He had also become incontinent of faeces at times. Tongue protruding movements and repetitive hand slapping were also observed in patient A on 30 mg bromocriptine daily. These did not occur on 60 mg daily but gave way to a continual plucking at his clothes. Because of the deterioration in patient A and the lack of any beneficial response in patient B, bromocriptine was stopped. At the end of the study the scores for 'social withdrawal' on the Wing (1961) scale were 8 (patient A) and 7 (patient B). This brief trial, therefore, does not support the idea that negative symptoms could be reversed or positive (psychotic or dyskinetic) symptoms prevented by a dopamine agonist, which, like levodopa, should supplement a putative dopamine deficit and/or reverse a dopamine-receptor denervation hypersensitivity. The development of dyskinetic symptoms in one patient is also noteworthy since these generally appear to have occurred with bromocriptine only when used after or in combination with levodopa (Debono, Marsden, Asselman & Parkes, 1976; Caine, Plotkin, Williams, Nutt, Neophytides & Teychenne, 1978; Pearce and Pearce, 1978; and Shaw, Lees & Stem, 1978). However, two questions remain, (i) does bromocriptine reach mesolimbic dopamine-receptor sites? and (ii) the negativefeatures occurring early in a schizophrenic illness may be quite different from the negative symptoms of the 'defect state', as pointed out by Johnstone, Crow, Frith, Carney & Price (1978). D.J. KING
Department of Therapeutics & Pharmacology, The Queen's University of Belfast, and Holywell Hospital, Antrim Received August 24, 1978
References BOWERS, M.B. (1974). Central dopamine turnover in schizophrenic syndromes. Arch. Gen. Psychiat., 31, 50-54. BUCHANAN, F.H., PARTON, R.V., WARREN, J.W. & BAKER, E.P. (1975). Double blind trial of L-dopa in chronic schizophrenia. Aust. N.Z. J. Psychiat., 9, 269-271. CALNE, D.B., PLOTKIN, C., WILLIAMS, A.C., NUTT, J.G., NEOPHYTIDES, A. & TEYCHENNE, P.F. (1978). Longterm treatment of Parkinsonism with bromocriptine. Lancet, i, 735-737.
542
LETTERS TO THE EDITORS
Br. J. clin. Pharmac. (1978), 6
CHOUINARD, G. & JONES, B.D. (1978). Schizophrenia as dopamine-deficiency disease. Lancet, ii, 99-100.
is schizophrenia also a 'denervation hypersensitivity'? Medical Hypotheses, 3, 207-2 10.
CROW, T.J., DEAKIN, J.F.W., JOHNSTONE, E.C. &
OWEN, F., CROW, T.J., POULTER, M., CROSS, A.J.,
LONGDEN, A. (1976). Dopamine and schizophrenia. Lancet, ii, 563-566.
LONGDEN, A. & RILEY, G.J. (1978). Increased dopamine-receptor sensitivity in schizophrenia. Lancet, ii, 223-225. PEARCE, I. & PEARCE, J.M.S. (1978). Bromocriptine in Parkinsonism. Br. med. J., 1, 1402-1404. SHAW, K.M., LEES, AJ. & STERN, G.M. (1978). Bromocriptine in Parkinson's disease. Lancet, i, 1255. WING, J.K. (1961). A simple and reliable subclassification of chronic schizophrenia. J. mental Sci., 107, 862-875.
DEBONO, A.G., MARSDEN, C.D., ASSELMAN, P. &
PARKES, J.D. (1976). Bromocriptine and dopamine receptor stimulation. Br. J. clin. Pharnac., 3, 977-982. JOHNSTONE, E.C., CROW, T.J., FRITH, C.D., CARNEY,
M.W.P. & PRICE, J.S. (1978). Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet, i, 848-851. KAPIT, R.M. (1977). Schizophrenia and tardive dyskinesia:
DEPRENYL IS METABOLIZED TO METHAMPHETAMINE AND AMPHETAMINE IN MAN (-)-Deprenyl (Figure 1) is a monoamine oxidase (MAO) inhibitor with selective action against the B form of the enzyme (Knoll, 1976). Its administration prevents the degradation of dopamine in human brain, where this is a substrate for MAO B (Glover, Sandier, Owen & Riley, 1977); however, it leaves the peripheral mechanisms normally preventing a hypertensive response following tyramine administration intact (Elsworth, Glover, Reynolds, Sandler, Lees, Phuapradit, Shaw, Stern & Kumar, 1978), although this amine interacts adversely with all other irreversible MAO inhibitors so far described. Because of this freedom from what has come to be called the 'cheese effect', deprenyl, in combination with L-dopa, provides both a rational and safe therapy for the treatment of Parkinson's disease (Birkmayer, Riederer Ambrozi & Youdim, 1977; Lees, Shaw, Kohout, Stem, Elsworth, Sandler & Youdim, 1977). Little is known of the metabolism of deprenyl either in man or animals. However, by analogy with that of the not dissimilar MAO inhibitor, pargyline (N-methylN-propynylbenzylamine), which is metabolized in mammals to benzylamine (Edwards & Blau, 1973; Durden, Philips & Boulton, 1976), it seemed possible that deprenyl might be degraded to amphetamine. Indeed, a preliminary in vitro study (unpublished) showed that rat liver homogenates convert some of the drug to amphetamine and methamphetamine. We therefore sought to identify these compounds in human urine after the administration of therapeutically-active doses of (-)-deprenyl. Urine samples (24 h) were collected from six normal male volunteers on the third day each of test and placebo administration during the course of a doubleblind crossover study of the effects of (-)-deprenyl hydrochloride on sleep. The volunteers, who received either 5 or 10 mg of this drug (Table 1) in a single dose
CH3
daily, were free from other medication whilst the experiment lasted. Urine was stored at -200C and thawed immediately before assay. Amphetamines in 0.5 ml urine were quantified after adding an internal standard, p-methylphenylethylamine. Samples were then subjected to acid hydrolysis (pH 1) at 100°C for 1 h to release any conjugates present. Quantification was achieved by extraction of the amines from alkaline urine into hexane, back-extraction into acid, derivatization with pentafluorobenzoyl chloride and a
CH
CH2CHN /|~~~~ \H2C=C H ~ C H3
b
oCH3
C H2CHNH
C
CH2CHNH2
O
CH3
Figure 1 The structural formulae of a) deprenyl, b) methamphetamine and c) amphetamine.
Br. J. clin. Pharmac. (1978), 6
541
DOPAMINE AGONISTS FOR NEGATIVE SYMPTOMS IN SCHIZOPHRENIA A number of authors have suggested that the primary disturbance in schizophrenia may be hypersensitivity of the dopamine receptor (Bowers, 1974; Crow, Deakin, Johnstone & Longden, 1976; Kapit, 1977) and supportive evidence for this from spiroperidolbinding studies in post-mortem brain has recently been reported by Owen, Crow, Poulter, Cross, Longden & Riley (1978). Chouinard & Jones (1978) have proposed that such a dopamine-receptor hypersensitivity results from a central dopamine deficiency and have argued that levodopa would be a useful adjunct to neuroleptics in the treatment of negative symptoms and in preventing both psychotic and hyperkinetic positive symptoms due to further hypersensitivity. They also suggested that patients with only negative symptoms should respond to treatment with levodopa alone. Following a similar line of reasoning (but thinking of the negative symptoms as resulting from receptor hyposensitivity or 'resistance' after years of dopamine excess) and encouraged by an earlier report of beneficial results in a six week trial of levodopa in chronic schizophrenics (Buchanan, Parton, Warren & Baker, 1975), I have treated two residual schizophrenics with the dopamine agonist bromocriptine, in an open pilot study. The patients were both male and aged 44 and 37 years respectively. Both were extremely inert, emotionally blunted and socially withdrawn. Patient A had been in hospital for 29 years, was virtually mute and known not to have replied verbally to questions for many years although he occasionally muttered incoherently to himself. Patient B had been ill for 16 years and in hospital for the past 6 years. He replied monosyllabically and smoked cigarettes until they burned his fingers. Neither had shown any significant improvement on a range of neuroleptic drugs given orally or by depot injection. Before the trial patient A had had no medication for 1 week, and patient B none for 5 months. They were both given bromocriptine 2.5 mg three times a day and the dose doubled each week for 3 weeks until they were taking 60 mg daily in three divided doses, which was then continued for 4 weeks. There was no evidence from interview or nurses' ratings of ward behaviour of any lessening in negative symptoms during this time or after discontinuation of the treatment. Both patients were described as being more 'alert', motor activity was increased and in patient A the base-line daily pedometer reading rose from 1.5 to 5.0 miles. However, there was no corresponding improvement in social contacts, speech or affective response. The restless overactivity in patient A was finally associated with a re-emergence of sudden aggressive outbursts suggesting an exacerbation of otherwise unexpressed positive
symptoms. He had also become incontinent of faeces at times. Tongue protruding movements and repetitive hand slapping were also observed in patient A on 30 mg bromocriptine daily. These did not occur on 60 mg daily but gave way to a continual plucking at his clothes. Because of the deterioration in patient A and the lack of any beneficial response in patient B, bromocriptine was stopped. At the end of the study the scores for 'social withdrawal' on the Wing (1961) scale were 8 (patient A) and 7 (patient B). This brief trial, therefore, does not support the idea that negative symptoms could be reversed or positive (psychotic or dyskinetic) symptoms prevented by a dopamine agonist, which, like levodopa, should supplement a putative dopamine deficit and/or reverse a dopamine-receptor denervation hypersensitivity. The development of dyskinetic symptoms in one patient is also noteworthy since these generally appear to have occurred with bromocriptine only when used after or in combination with levodopa (Debono, Marsden, Asselman & Parkes, 1976; Caine, Plotkin, Williams, Nutt, Neophytides & Teychenne, 1978; Pearce and Pearce, 1978; and Shaw, Lees & Stem, 1978). However, two questions remain, (i) does bromocriptine reach mesolimbic dopamine-receptor sites? and (ii) the negativefeatures occurring early in a schizophrenic illness may be quite different from the negative symptoms of the 'defect state', as pointed out by Johnstone, Crow, Frith, Carney & Price (1978). D.J. KING
Department of Therapeutics & Pharmacology, The Queen's University of Belfast, and Holywell Hospital, Antrim Received August 24, 1978
References BOWERS, M.B. (1974). Central dopamine turnover in schizophrenic syndromes. Arch. Gen. Psychiat., 31, 50-54. BUCHANAN, F.H., PARTON, R.V., WARREN, J.W. & BAKER, E.P. (1975). Double blind trial of L-dopa in chronic schizophrenia. Aust. N.Z. J. Psychiat., 9, 269-271. CALNE, D.B., PLOTKIN, C., WILLIAMS, A.C., NUTT, J.G., NEOPHYTIDES, A. & TEYCHENNE, P.F. (1978). Longterm treatment of Parkinsonism with bromocriptine. Lancet, i, 735-737.
542
LETTERS TO THE EDITORS
Br. J. clin. Pharmac. (1978), 6
CHOUINARD, G. & JONES, B.D. (1978). Schizophrenia as dopamine-deficiency disease. Lancet, ii, 99-100.
is schizophrenia also a 'denervation hypersensitivity'? Medical Hypotheses, 3, 207-2 10.
CROW, T.J., DEAKIN, J.F.W., JOHNSTONE, E.C. &
OWEN, F., CROW, T.J., POULTER, M., CROSS, A.J.,
LONGDEN, A. (1976). Dopamine and schizophrenia. Lancet, ii, 563-566.
LONGDEN, A. & RILEY, G.J. (1978). Increased dopamine-receptor sensitivity in schizophrenia. Lancet, ii, 223-225. PEARCE, I. & PEARCE, J.M.S. (1978). Bromocriptine in Parkinsonism. Br. med. J., 1, 1402-1404. SHAW, K.M., LEES, AJ. & STERN, G.M. (1978). Bromocriptine in Parkinson's disease. Lancet, i, 1255. WING, J.K. (1961). A simple and reliable subclassification of chronic schizophrenia. J. mental Sci., 107, 862-875.
DEBONO, A.G., MARSDEN, C.D., ASSELMAN, P. &
PARKES, J.D. (1976). Bromocriptine and dopamine receptor stimulation. Br. J. clin. Pharnac., 3, 977-982. JOHNSTONE, E.C., CROW, T.J., FRITH, C.D., CARNEY,
M.W.P. & PRICE, J.S. (1978). Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet, i, 848-851. KAPIT, R.M. (1977). Schizophrenia and tardive dyskinesia:
DEPRENYL IS METABOLIZED TO METHAMPHETAMINE AND AMPHETAMINE IN MAN (-)-Deprenyl (Figure 1) is a monoamine oxidase (MAO) inhibitor with selective action against the B form of the enzyme (Knoll, 1976). Its administration prevents the degradation of dopamine in human brain, where this is a substrate for MAO B (Glover, Sandier, Owen & Riley, 1977); however, it leaves the peripheral mechanisms normally preventing a hypertensive response following tyramine administration intact (Elsworth, Glover, Reynolds, Sandler, Lees, Phuapradit, Shaw, Stern & Kumar, 1978), although this amine interacts adversely with all other irreversible MAO inhibitors so far described. Because of this freedom from what has come to be called the 'cheese effect', deprenyl, in combination with L-dopa, provides both a rational and safe therapy for the treatment of Parkinson's disease (Birkmayer, Riederer Ambrozi & Youdim, 1977; Lees, Shaw, Kohout, Stem, Elsworth, Sandler & Youdim, 1977). Little is known of the metabolism of deprenyl either in man or animals. However, by analogy with that of the not dissimilar MAO inhibitor, pargyline (N-methylN-propynylbenzylamine), which is metabolized in mammals to benzylamine (Edwards & Blau, 1973; Durden, Philips & Boulton, 1976), it seemed possible that deprenyl might be degraded to amphetamine. Indeed, a preliminary in vitro study (unpublished) showed that rat liver homogenates convert some of the drug to amphetamine and methamphetamine. We therefore sought to identify these compounds in human urine after the administration of therapeutically-active doses of (-)-deprenyl. Urine samples (24 h) were collected from six normal male volunteers on the third day each of test and placebo administration during the course of a doubleblind crossover study of the effects of (-)-deprenyl hydrochloride on sleep. The volunteers, who received either 5 or 10 mg of this drug (Table 1) in a single dose
CH3
daily, were free from other medication whilst the experiment lasted. Urine was stored at -200C and thawed immediately before assay. Amphetamines in 0.5 ml urine were quantified after adding an internal standard, p-methylphenylethylamine. Samples were then subjected to acid hydrolysis (pH 1) at 100°C for 1 h to release any conjugates present. Quantification was achieved by extraction of the amines from alkaline urine into hexane, back-extraction into acid, derivatization with pentafluorobenzoyl chloride and a
CH
CH2CHN /|~~~~ \H2C=C H ~ C H3
b
oCH3
C H2CHNH
C
CH2CHNH2
O
CH3
Figure 1 The structural formulae of a) deprenyl, b) methamphetamine and c) amphetamine.
