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Examining the dopamine hypotheses of schizophrenia and of mania using the prolactin response to antipsychotic drugs
?Jrurophrrr,llucci/o~~ Vol. 22, No. 4. pp. 539-541. Printed in Great Britain
1983
~~8-3908~83~~40539-03~3.~~0 Pergamon Press Ltd
EXAMINING THE DOPAMINE HYPOTHESES OF SCHIZOPHRENIA AND OF MANIA USING THE PROLACTIN RESPONSE TO ANTIPSYCHOTIC DRUGS T. Academic
Unit of
SILVERSTONE
and J.
C~OKSON
Human Psychopharmacology, Medical Colleges of St Bartholomew’s and the London Hospitals, London, England
According to the dopamine (DA) hypothesis of schizophrenia (Carlsson, 1977), symptoms result from overactivity in central DA pathways in the brain. In keeping with this view is the finding that antipsychotic drugs which are effective in the management of schizophrenia are all potent DA receptor blockers (Creese, Burt and Synder, 1976). As such they cause a rise in plasma prolactin (PRL) levels by blocking DA receptors in the anterior pituitary (Rubin and Hays, 1980). However, the time courses of these two responses are not the same following treatment with antipsychotic drugs: the level of plasma prolactin rises steeply within the first week and then plateaus whereas the clinical response is usually delayed, with maximal improvement occurring in the second and third weeks (Meltzer and Fang, 1976; Wiles, Kolakowska, McNeilly, Mandelbrote and Gelder, 1976; Cotes, Crow, Johnstone, Bartlett and Bourne, 1978). Mania is another psychiatric syndrome in which overactivity in central DA pathways has been implicated in pathogenesis (Silverstone. 1979; Post, Jimmerson, Bunney and Goodwin, 1980). Consistent with this hypothesis is the good clinical response which follows treatment with pimozide, a relatively specific dopamine receptor blocking compound (Cookson, Silverstone and Wells, 1981). In contrast to what was observed in schizophrenic patients, the rise in prolactin during treatment with pimozide was closely paralleled in time with improvement in mental state (Cookson, Silverstone and Rees, 1982); this was also true of haloperidol (HP) (Cookson, Moult, Wiles and Besser, unpublished). The present paper presents a comparison of the inter-relationship between clinical response and rise in prolactin levels in the two conditions, schizophrenia and mania, using two drugs, pimozide (PMZ) and haloperidol (HP). METHODS
Eleven patients fulfilling the Research Diagnostic Criteria (RDC) for schizophrenia (Spitzer, Endicott and Robins, 1978) and 21 patients fulfilling the criteria for mania were studied. All patients were drugfree and in good physical health. Treatment with
pimozide was started at a daily dose of 10-40 mg and was adjusted as necessary during the I4 day observation period; there were 6 schizophrenic and 11 manic patients treated with pimozide. The daily starting dose of haloperidol was 20 mg in the 5 schizophrenic patients and from 12.5 to 60 mg in the IO manic patients. Some of the manic patients received an intravenous loading dose of haloperidol ranging from 2.5 to 10mg. Six of the 11 manic patients on pimozide and 9 of the 10 on haloperidol required treatment with an antiparkinsonian drug (usually procyclidine), All the schizophrenics treated with pimozide and 3 of those on haloperidol required procyclidine. Clinical assessments in the schizophrenic patients were made with the Montgomery rating scale (Montgomery, Taylor and Montgomery, 197X), and in the manic group with the Petterson rating scale (Petterson, Fyro and Sedvall, 1973). Ratings were done before treatment was started and subsequently on days 1, 3, 7 and 14 of treatment. Blood was drawn following each clinical rating for prolactin estimations using a radio-immunoassay.
RESULTS
As can be seen in Figures 1 and 2 the pattern of rise of prolactin was similar in both clinical groups following treatment with haloperidol, and in the manic patients treated with pimozide. The much greater variance observed in the schizophrenic patients who received pimozide tended to obscure the overall pattern of response. The time course of clinical response to both haloperidol and pimozide among the schizophrenic patients (Fig. 1) did not conform to the rise in prolactin levels nearly as closely as it did among the manic patients (Fig. 2). Not only was there a greater delay in clinical response within the schizophrenic group, much of the improvement seen occurred during the second week. Among the manic patients, on the other hand, improvement began within 24 hr of treatment starting with the greatest change in clinical status occurring during the first 7 days. 539
540
T. SILVERST~NE and J. COOKSON SCHIZOPHRENIA
- HALOPERIDOL
SCHIZOPHRENIA
Prolectin
J15 7
3
0
I. Mean
MANIA
01
14
7
3 DAYS
plasma levels of prolactin (+o) and mean Montgomery scores following treatment with haloperidol and pimozide in schizophrenia.
-
-1
-I
14
DAYS
Fig.
(n=6l
$_
In=51
0 01
- PIMOZIOE
HALOPERIDOL
MANIA
h=lO)
-
PIMOZIDE
(*SE)
(O---O)
In=111 Clinical
1
CllfllC.4
rating -- I ___---___--/ L
5 01
3
7
14
plasma
01
3
7
14
DAYS
DAYS
Fig. 2. Mean
C
prolactin levels (M) and mean Petterson scores (w---O) treatment with haloperidol and pimozide in mania.
DISCUSSION
The finding that the time course of clinical improvement following treatment with both haloperidol and pimozide more closely corresponded to the rise in prolactin levels in the manic patients than in the schizophrenic patients, treated with either of the two drugs, suggests that the response to treatment with antipsychotic drugs is more closely linked to DA receptor blockade in mania than in schizophrenia. As far as schizophrenia is concerned these results are similar to those of Meltzer and Fang (1976), Wiles et al. (1976) and Cotes et al. (1978); and consistent with the results of a study in which prolactin in the cerebrospinal fluid (CSF) was measured and compared to the clinical status following treatment with melperone (Htirnryd, Bjerkenstedt and Gullberg, 1982). The view that the clinical response to both haloperidol and pimozide is only loosely coupled to DA receptor blockade is in keeping with the recent observation that the response to acute administration of amphetamine in schizophrenic patients bore little relationship to the clinical response to pimozide (Van
(*SE)
following
Kammen, Docherty, Marder, Schulz, Dalton and Bunney, 1982). This finding, like the results presented here, runs counter to the straightforward DA hypothesis of schizophrenia. With regard to mania, the findings are in contrast to a recent report of two patients with hypomania in which the rise in prolactin, following treatment with haloperidol, preceded any clinical response (Shur and Checkley, 1982). The present results, in possibly more severely ill manic patients, clearly showed clinical improvement to occur at the same time as the rise in prolactin. Such an association is consistent with a DA hypothesis of mania which attributes a key role to (Silverstone, 1979; DA pathways in its pathogenesis Post et al., 1980).
REFERENCES Carlsson, A. (1977). Does dopamine play a role in schizophrenia? Psychol. Med. 7: 583-597. Cookson, J., Silverstone, T. and Wells, B. (1981). Doubie-
blind comparative trial of pimozide and chlorpromazine in mania. Acta psychiat. stand. 64: 381-397.
Dopamine
hypothesis
of schizophrenia
Cookson, J., Silverstone, T. and Rees, L. (1982). Plasma prolactin and growth hormone levels in manic patients treated with pimozide. Br. .I. Psychiut. 140: 274279. Cotes, P. M., Crow. T. J., Johnstone. E. C.. Bartlett, W. and Bourne, R. C. (1978). Neuroendocrine changes in acute schizophrenia as a function of clinical state and neuroleptic medication. Psychol. Med. 8: 657-665. Creese. I.. Burt, D. R. and Snyder. S. H. (1976). Dopamine receptor binding predicts clinical and p~rmacologic~ potencies of antipsychotic drugs. Scierrce 192: 481-483. Harnryd, C., Bjerkenstedt, L. and Gullberg, B. (1982). Therapeutic outcome, monoamine metabolism and prolactin levels in schizophrenic women treated with melperone or placebo. Ahstructs of Proc. 13th CINP Conyre% Jurtrstt/am p. 3 IO. Meltzer, H. Y. and Fang, V. S. (1976). The effect of neuroleptics on serum prolactin in schizophrenic patients. Arc/s grn. Ps~l~~~juf. 33: 279-286. Montgomery, S. A.. Taylor, P. and Montgomery, D. (1978). Development of a schizophrenia scale sensitive to change. Nelrropharrtfucolo~~ 17: 1061-1062. Petterson. U.. Fyro. B. and Sedvall, G. (1973). A new scale for the longitudinal rating of manic states. Actu psychiat. sctrt~d. 49: 248-256.
and mania
541
Post, R. M., Jimmerson. D. C., Bunney, W. E. and Coodwin, F. K. (1980). Dopamine and mania: behavioural and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmucoloyy 67: 297-305. Rubin, R. T. and Hays, S. E. (1980). The prolactin secretory response to neuroleptic drugs: mechanisms, applications and limitations. Psyehonruroe~~tdocrin~~~~~~ 5: I 2 i - i 37. Shur, E. and Checkley, S. (1982). Prolactin response to neuroleptic challenge. Br. J. Psqx+riat. 140: 43 l-2. Siiverstone, T. (1979). Psychopharmacology of manicdepressive illness. in: Cztrret~t Thrmrs iu Psychiorr) (Gaind, R. N. and Hudson. B. L., Eds), Vol. 2, pp. 271-282. MacMillan, London. Spitzer, R. L., Endicott, J. and Robins. E. (1978). Research diagnostic criteria. Archs gem Psychiar. 35: 773p782. Van Kammen, D. P., Docherty, J., Marder, S., Schulz. S. C., Dalton. L. and Bunney, W. E. (1982). Antipsychotic effects of pimozide in schizophrenia. Anhs prt. Ps_yc/kt. 39: 261-266. Wiles, D. H.. Kolakowska, T., McNeilly, A. S.. Mandelbrote, B. M. and Gelder, M. C. (1976). Clinical significance of plasma chlorpromazine levels: I. Plasma levels of the drug, some of its metabolites and prolactin during acute treatment. Psycho/. Med. 6: 407-415.
1983
~~8-3908~83~~40539-03~3.~~0 Pergamon Press Ltd
EXAMINING THE DOPAMINE HYPOTHESES OF SCHIZOPHRENIA AND OF MANIA USING THE PROLACTIN RESPONSE TO ANTIPSYCHOTIC DRUGS T. Academic
Unit of
SILVERSTONE
and J.
C~OKSON
Human Psychopharmacology, Medical Colleges of St Bartholomew’s and the London Hospitals, London, England
According to the dopamine (DA) hypothesis of schizophrenia (Carlsson, 1977), symptoms result from overactivity in central DA pathways in the brain. In keeping with this view is the finding that antipsychotic drugs which are effective in the management of schizophrenia are all potent DA receptor blockers (Creese, Burt and Synder, 1976). As such they cause a rise in plasma prolactin (PRL) levels by blocking DA receptors in the anterior pituitary (Rubin and Hays, 1980). However, the time courses of these two responses are not the same following treatment with antipsychotic drugs: the level of plasma prolactin rises steeply within the first week and then plateaus whereas the clinical response is usually delayed, with maximal improvement occurring in the second and third weeks (Meltzer and Fang, 1976; Wiles, Kolakowska, McNeilly, Mandelbrote and Gelder, 1976; Cotes, Crow, Johnstone, Bartlett and Bourne, 1978). Mania is another psychiatric syndrome in which overactivity in central DA pathways has been implicated in pathogenesis (Silverstone. 1979; Post, Jimmerson, Bunney and Goodwin, 1980). Consistent with this hypothesis is the good clinical response which follows treatment with pimozide, a relatively specific dopamine receptor blocking compound (Cookson, Silverstone and Wells, 1981). In contrast to what was observed in schizophrenic patients, the rise in prolactin during treatment with pimozide was closely paralleled in time with improvement in mental state (Cookson, Silverstone and Rees, 1982); this was also true of haloperidol (HP) (Cookson, Moult, Wiles and Besser, unpublished). The present paper presents a comparison of the inter-relationship between clinical response and rise in prolactin levels in the two conditions, schizophrenia and mania, using two drugs, pimozide (PMZ) and haloperidol (HP). METHODS
Eleven patients fulfilling the Research Diagnostic Criteria (RDC) for schizophrenia (Spitzer, Endicott and Robins, 1978) and 21 patients fulfilling the criteria for mania were studied. All patients were drugfree and in good physical health. Treatment with
pimozide was started at a daily dose of 10-40 mg and was adjusted as necessary during the I4 day observation period; there were 6 schizophrenic and 11 manic patients treated with pimozide. The daily starting dose of haloperidol was 20 mg in the 5 schizophrenic patients and from 12.5 to 60 mg in the IO manic patients. Some of the manic patients received an intravenous loading dose of haloperidol ranging from 2.5 to 10mg. Six of the 11 manic patients on pimozide and 9 of the 10 on haloperidol required treatment with an antiparkinsonian drug (usually procyclidine), All the schizophrenics treated with pimozide and 3 of those on haloperidol required procyclidine. Clinical assessments in the schizophrenic patients were made with the Montgomery rating scale (Montgomery, Taylor and Montgomery, 197X), and in the manic group with the Petterson rating scale (Petterson, Fyro and Sedvall, 1973). Ratings were done before treatment was started and subsequently on days 1, 3, 7 and 14 of treatment. Blood was drawn following each clinical rating for prolactin estimations using a radio-immunoassay.
RESULTS
As can be seen in Figures 1 and 2 the pattern of rise of prolactin was similar in both clinical groups following treatment with haloperidol, and in the manic patients treated with pimozide. The much greater variance observed in the schizophrenic patients who received pimozide tended to obscure the overall pattern of response. The time course of clinical response to both haloperidol and pimozide among the schizophrenic patients (Fig. 1) did not conform to the rise in prolactin levels nearly as closely as it did among the manic patients (Fig. 2). Not only was there a greater delay in clinical response within the schizophrenic group, much of the improvement seen occurred during the second week. Among the manic patients, on the other hand, improvement began within 24 hr of treatment starting with the greatest change in clinical status occurring during the first 7 days. 539
540
T. SILVERST~NE and J. COOKSON SCHIZOPHRENIA
- HALOPERIDOL
SCHIZOPHRENIA
Prolectin
J15 7
3
0
I. Mean
MANIA
01
14
7
3 DAYS
plasma levels of prolactin (+o) and mean Montgomery scores following treatment with haloperidol and pimozide in schizophrenia.
-
-1
-I
14
DAYS
Fig.
(n=6l
$_
In=51
0 01
- PIMOZIOE
HALOPERIDOL
MANIA
h=lO)
-
PIMOZIDE
(*SE)
(O---O)
In=111 Clinical
1
CllfllC.4
rating -- I ___---___--/ L
5 01
3
7
14
plasma
01
3
7
14
DAYS
DAYS
Fig. 2. Mean
C
prolactin levels (M) and mean Petterson scores (w---O) treatment with haloperidol and pimozide in mania.
DISCUSSION
The finding that the time course of clinical improvement following treatment with both haloperidol and pimozide more closely corresponded to the rise in prolactin levels in the manic patients than in the schizophrenic patients, treated with either of the two drugs, suggests that the response to treatment with antipsychotic drugs is more closely linked to DA receptor blockade in mania than in schizophrenia. As far as schizophrenia is concerned these results are similar to those of Meltzer and Fang (1976), Wiles et al. (1976) and Cotes et al. (1978); and consistent with the results of a study in which prolactin in the cerebrospinal fluid (CSF) was measured and compared to the clinical status following treatment with melperone (Htirnryd, Bjerkenstedt and Gullberg, 1982). The view that the clinical response to both haloperidol and pimozide is only loosely coupled to DA receptor blockade is in keeping with the recent observation that the response to acute administration of amphetamine in schizophrenic patients bore little relationship to the clinical response to pimozide (Van
(*SE)
following
Kammen, Docherty, Marder, Schulz, Dalton and Bunney, 1982). This finding, like the results presented here, runs counter to the straightforward DA hypothesis of schizophrenia. With regard to mania, the findings are in contrast to a recent report of two patients with hypomania in which the rise in prolactin, following treatment with haloperidol, preceded any clinical response (Shur and Checkley, 1982). The present results, in possibly more severely ill manic patients, clearly showed clinical improvement to occur at the same time as the rise in prolactin. Such an association is consistent with a DA hypothesis of mania which attributes a key role to (Silverstone, 1979; DA pathways in its pathogenesis Post et al., 1980).
REFERENCES Carlsson, A. (1977). Does dopamine play a role in schizophrenia? Psychol. Med. 7: 583-597. Cookson, J., Silverstone, T. and Wells, B. (1981). Doubie-
blind comparative trial of pimozide and chlorpromazine in mania. Acta psychiat. stand. 64: 381-397.
Dopamine
hypothesis
of schizophrenia
Cookson, J., Silverstone, T. and Rees, L. (1982). Plasma prolactin and growth hormone levels in manic patients treated with pimozide. Br. .I. Psychiut. 140: 274279. Cotes, P. M., Crow. T. J., Johnstone. E. C.. Bartlett, W. and Bourne, R. C. (1978). Neuroendocrine changes in acute schizophrenia as a function of clinical state and neuroleptic medication. Psychol. Med. 8: 657-665. Creese. I.. Burt, D. R. and Snyder. S. H. (1976). Dopamine receptor binding predicts clinical and p~rmacologic~ potencies of antipsychotic drugs. Scierrce 192: 481-483. Harnryd, C., Bjerkenstedt, L. and Gullberg, B. (1982). Therapeutic outcome, monoamine metabolism and prolactin levels in schizophrenic women treated with melperone or placebo. Ahstructs of Proc. 13th CINP Conyre% Jurtrstt/am p. 3 IO. Meltzer, H. Y. and Fang, V. S. (1976). The effect of neuroleptics on serum prolactin in schizophrenic patients. Arc/s grn. Ps~l~~~juf. 33: 279-286. Montgomery, S. A.. Taylor, P. and Montgomery, D. (1978). Development of a schizophrenia scale sensitive to change. Nelrropharrtfucolo~~ 17: 1061-1062. Petterson. U.. Fyro. B. and Sedvall, G. (1973). A new scale for the longitudinal rating of manic states. Actu psychiat. sctrt~d. 49: 248-256.
and mania
541
Post, R. M., Jimmerson. D. C., Bunney, W. E. and Coodwin, F. K. (1980). Dopamine and mania: behavioural and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmucoloyy 67: 297-305. Rubin, R. T. and Hays, S. E. (1980). The prolactin secretory response to neuroleptic drugs: mechanisms, applications and limitations. Psyehonruroe~~tdocrin~~~~~~ 5: I 2 i - i 37. Shur, E. and Checkley, S. (1982). Prolactin response to neuroleptic challenge. Br. J. Psqx+riat. 140: 43 l-2. Siiverstone, T. (1979). Psychopharmacology of manicdepressive illness. in: Cztrret~t Thrmrs iu Psychiorr) (Gaind, R. N. and Hudson. B. L., Eds), Vol. 2, pp. 271-282. MacMillan, London. Spitzer, R. L., Endicott, J. and Robins. E. (1978). Research diagnostic criteria. Archs gem Psychiar. 35: 773p782. Van Kammen, D. P., Docherty, J., Marder, S., Schulz. S. C., Dalton. L. and Bunney, W. E. (1982). Antipsychotic effects of pimozide in schizophrenia. Anhs prt. Ps_yc/kt. 39: 261-266. Wiles, D. H.. Kolakowska, T., McNeilly, A. S.. Mandelbrote, B. M. and Gelder, M. C. (1976). Clinical significance of plasma chlorpromazine levels: I. Plasma levels of the drug, some of its metabolites and prolactin during acute treatment. Psycho/. Med. 6: 407-415.