- Email: [email protected]
Dopamine and mania
Journal of Affective Disorders, 5 (1983) 91-96
91
Elsevier Science Publishers
Dopamine and Mania The Effects of Trans- and Cis-Clopenthixol in a Double-Blind Pilot Study Willem A. Nolen Department of BiologicalPsychiatry, ChristelijkPsychiatrischCentrum Bloemendaal, The Hague (The Netherlands) (Received 23 April, 1982) (Revised, received 2 August, 1982) (Accepted 10 August, 1982)
Summary Sordinol ~ is composed of the mixture of cis-clopenthixol and trans-clopenthixol. The two isomers do not differ in several pharmacological properties, for instance anti-noradrenergic effect. However, cis-clopenthixol possesses anti-dopaminergic effects, while trans-clopenthixol does not. Sordinol-depot ® contains the almost pure cis-clopenthixol and appears to be less sedating than the oral and short-lasting intramuscular administration forms. In a double-blind pilot study with 10 manic patients, trans-clopenthixol was compared with cis-clopenthixol. Although not reaching statistical significance, cisclopenthixol showed anti-manic effects, while trans-clopenthixol remained ineffective. It is concluded that the anti-dopaminergic effect of cis-clopenthixol is essential for its anti-manic effect, which is in agreement with the hypothesis of involvement of the dopaminergic system in the pathogenesis of mania.
Introduction Neuroleptics show several effects such as antipsychotic, extrapyramidal and sedative effects. Clinically the antipsychotic effect is the most important. Probably it is related to the blockade of receptors at the dopaminergic neurones in the nucleus Reprint requests: Willem A. Nolen, M.D., Department of Biological Psychiatry, Christelijk Psychiatrisch Centrum Bloemendaal, Monsterseweg93, 2553 RJ 's-Gravenhage,The Netherlands. 0165-0327/83/0000-0000/$03.00 © 1983 Elsevier Science Publishers
92
accumbens (Crow et al. 1977). The antipsychotic effect often coincides with extrapyramidal side effects, related to the blockade of dopamine receptors in the striatum. The third important effect of many (but not all) neuroleptics is the sedative one, probably related to their anti-noradrenergic and anti-histaminergic effects. Many neuroleptics can produce drowsiness and sleepiness. Sometimes this effect is required by the treating psychiatrist, but at other times it is an unwanted side effect. Clopenthixol (Sordinol ®) is considered a sedative neuroleptic, i.e. besides antipsychotic effects it also possesses sedative effects. Both the oral and the shortlasting intramuscular administration forms are often used in our hospital for the treatment of manic or otherwise restless patients with good results. After the introduction of the depot form of Sordinol ® (clopenthixol-decanoate) we were surprised by the impression that this form of administration appeared to be less sedating. Similar observations were made by several other colleagues. The most reasonable explanation for this difference between the two forms of administration is their different chemical composition (Petersen et al., 1977) (Table 1). The oral and the shortlasting intramuscular forms of Sordinol ® consist of a mixture of the two stereo-isomers cisand trans-clopenthixol (33% and 67%, respectively). Sordinol-depot ~' contains almost pure cis-clopenthixol (98%). Although not differing in many pharmacological properties, cis- and trans-clopenthixol differ in one important aspect. The cis-form blocks the dopamine receptor, whereas the trans-form does not. The effects on several other receptors are equal, as for instance on the (beta-l-) noradrenaline receptor. Both isomers are equally potent in antagonising the stimulation of noradrenaline-sensitive adenylate cyclase in rat brain homogenates. In this aspect they are comparable with for instance chiorpromazine and haloperidol (Horn and Phillipson 1976). Gravem et al. (1978) have compared the oral racemate Sordinol e (33% cis, 67% trans) with the pure oral form of cis-clopenthixol. In a double-blind study 57 mostly chronic schizophrenic patients were treated for 2 months with the pure cis-form (29 patients) or with the mixture (28 patients). The antipsychotic effect of the cis-form was found to be equal to that of the mixture, whereas on a mg to mg basis the cis-form was twice as active as the mixture. Sedation was observed more frequently in the patients treated with the mixture (5 out of 28) than in the patients treated with the cis-form (1 out of 29). Although not explicitly mentioned by Gravem et al., it appeared that the mixture showed more sedative effects resulting from the adding of trans-clopenthixol to cis-clopenthixol. In two earlier pilot studies we gave 25 mg of the almost pure (98%) trans-clopenthixol to healthy volunteers (Nolen 1981). Six volunteers were given trans-clopenthixol in a double-blind cross-over design in TABLE 1 CHEMICAL
COMPOSITION
Sordinol ® oral form Sordinol ® intramuscular form Sordinol-depot ®
OF THE DIFFERENT
ADMINISTRATION
FORMS OF SORDINOL x
Cis-clopenthixol
Trans-clopenthixol
33% 33% 98%
67% 67% 2%
93 comparison with placebo. All 6 could discriminate the day of the active drug. On that day they all were sedated and drowsy. The other three took 25 mg transclopenthixol in an open design, and they experienced the same effect. Measuring of plasma levels of both trans- and cis-clopenthixol showed that this effect coincided with the plasma level of trans-clopenthixol. From Gravem's and our study we concluded that trans-clopenthixol, although apparently not an anti-dopaminergic drug, might have sedative or other non-specific properties. In order to evaluate its efficacy we decided to test the drug in manic patients.
Study Design Ten patients were studied, all suffering from a manic episode according to RDC and DSM-III criteria. Patients with a (too) severe mania which might lead to exhaustion, and patients with psychotic features were excluded. Before entering the study any neuroleptic used so far, was discontinued. If lithium was used, it was continued (with plasma levels between 0.8 and 1.2 mequiv./I). After a wash-out period of at least 2 days, cis- or trans-clopenthixol was given for 5 or 6 days, at a dose of initially 50 mg twice daily, with a maximum of 150 mg twice daily. The effect was rated on the Bech-Rafaelsen Mania Scale, a rating-scale ranging from 0 to 44 points (Rafaelsen, personal communication). All patients gave their informed consent.
Results The results are presented in Table 2 and Fig. I. Five patients were given transciopenthixol. In patient D this drug had to be discontinued after 3 days because of an increase of agressive behaviour. The other 4 patients showed no improvement. Patient Hi was given extra haloperidol on 3 nights because of severe restlessness. The other 5 patients received cis-ciopenthixol. Patient Be dropped out after 2 days because of aggravation of his mental state. Patient K became very sedated and refused further treatment despite apparent improvement. Two patients (Ho and V) responded well on cis-clopenthixol and were switched to Sordinoi ~ after the study period. The 5th patient (Br) showed no improvement. Because of the small number of patients and the large range of data obtained statistical comparisons of both groups showed no significant differences. However, a trend exists towards a better result with cis-clopenthixol (3 out of 5 patients improved) compared with trans-clopenthixol (none out of 5). The patients treated with trans-clopenthixol received more medication (maximal mean 270 mg daily) than the patients treated with the cis-form (170 mg daily), which also indicates less efficacy of trans-clopenthixol. The degree of mania, as scored on the rating-scale, was comparable as regards the mean; the rang'e, however, was larger in the patients treated with the cis-form. The treatment results also showed a large range, with again
94 TABLE 2 EFFECTS OF CIS- AND TRANS-CLOPENTHIXOL IN 10 P A T I E N T S , S C O R E D BECH-RAFAELSEN MANIA SCALE AND AS GLOBAL CLINICAL EFFECT
ON
Patient
Treatment
Maximal dose
N u m b e r of treatment days
Amelioration o n B.R.M.S.
Global clinical effect a
Be Ho K Br V Mean
cis cis cis cis cis
150 200 100 300 100 170
mg mg mg mg mg mg
2 6 2 5 6 4.2
- 2 (36 - , 38) I I (26 ~ 15) 16 (22 ---, 6) 0 (7~ 7) 9 (22 - , 13) 6.8 (22.6 15.8)
+ + + 0 + +
Hi S 0 D Ha Mean
trans trans trans trans trans
300 300 300 300 150 270
mg mg mg mg mg mg
5 6 6 3 5 5
6 (29 ---, 23) - 10 (15 ~ 25) 1 (22 --, 21) 3 (25 ---, 22) 1 (19 --, 18) 0.2 (22 ---, 21.8)
0 0 0 0
- = worsened, 0 = unchanged, completely recovered.
+ = slightly
improved,
+ + = markedly
improved,
THE
+ + + =
BMRS
BRMS 4O A
Be= / B e 35
35
30
30 Ho
Hi
D~
25
-
S Hi
©
0 .20
20
15
:o
15
H elk I
~
/
i'~'~
~ Ha
10
1C
(~r~ ~
K
days idays e Fig. 1. Effects o f cis-clopenthixol ( A ) a n d trans-clopenthixol ( B ) as s c o r e d o n the Bech R a f a e l s e n M a n i a Scale in 10 p a t i e n t s .
95 a trend towards a better effect of cis-clopenthixol: from - 2 to + 16 in the patients treated with the cis-form, from - 1 0 to + 6 in the patients treated with the trans-form. The side effects were mild. Three of the 5 patients treated with the cis-form and none of the 5 patients treated with the trans-form showed a slight parkinsonism. Only 1 patient, treated with the cis-form, became clearly sedated. In the other patients sedative effects were not observed.
General Discussion
Our study is a pilot study with a small number of patients. Despite this limitation, which did not allow us to reach statistically significant results, a tentative conclusion may be drawn. Trans-clopenthixol does not have anti-manic effects, while cisclophenthixol has. This indicates that the anti-dopaminergic property of cisclopenthixol is essential for its effect. Searching the literature we found two reports showing that pimozide, a rather selective anti-dopaminergic but not sedative drug is an effective anti-manic drug. Cookson et al. (1981) studied the anti-manic effects of pimozide in comparison with chlorpromazine. Pimozide was found to be equally effective: it produced more parkinsonism and was less sedating. Post et al. (1980) treated 8 manic patients with pimozide in a double-blind placebo-controlled design. They also observed a good anti-manic effect. From both studies it can be concluded that pimozide shows anti-manic effects without being sedative. This indicates that the anti-manic effects of neuroleptics probably are the result of dopaminergic blockade, which is in agreement with the hypothesis of the involvement of the dopaminergic system in the pathogenesis of mania. This hypothesis is supported by several other findings: hypomanic and manic states can be evoked by L-dopa (the precursor of dopamine), amphetamine (a dopamine releaser) or piribedil (a specific dopamine receptor agonist). AMPT (a-methyl-p-tyrosine), which inhibits tyrosine-hydroxylase resulting in a lower production of L-dopa from tyrosine, is reported to possess some anti-manic effectivity, while inhibition of DBH (dopamine-fl-hydroxylase) which results in a lower production of noradrenaline from dopamine, has no effect (Post 1978; Post et al. 1980; Silverstone 1979). Besides anti-dopaminergic effects many neuroleptics also have anti-noradrenergic effects. In animals, blockade of the noradrenaline receptor results in palpebral ptosis, while dopaminergic blockade results in catalepsy. The ratio of sedative effects of neuroleptics to anti-psychotic effects in man correlates with the ratio in which they produce palpebral ptosis to catalepsy in animals. Sedative neuroleptics, as for instance chlorpromazine, show a higher ratio than less sedative drugs such as pimozide (Janssen en Van Bever 1978). The sedative properties of many neuroleptics seem to be merely side effects, not essential for their anti-manic effect, and probably resulting from anti-noradrenergic or anti-histaminergic effects.
96
Acknowledgements I w o u l d like to t h a n k L u n d b e c k a n d Co., C o p e n h a g e n , D e n m a r k , for p r o v i d i n g t h e d r u g s . I also t h a n k Ben M u l l e r , L u n d b e c k N e d e r l a n d BV, A m s t e r d a m , for his s u p p o r t a n d M a r r i e k e V a n V e e l e n for h e r t e c h n i c a l a s s i s t a n c e .
References Cookson, J.C., Silverstone, T. and Wells, B., A double-blind comparative trial of pimozide and chlorpromazine in mania - - A test of the dopamine hypotheses, Acta Psychiat. Scand., 64 (1981) 381-397. Crow, T.J., Deakin, J.W.F. and Longden, A.., The nucleus accumbens, possible site of antipsychotic action of neuroleptic drugs? Psychol. Med., 7 (1977) 213-221. DSM-III, Diagnostic and Statistical Manual of Mental Disorders, 3rd edition. American Psychiatric Association, 1980. Gravem, A., Engstrand, E. and Guleng, R.J., cis (Z)-clopenthixol and clopenthixol (Sordinol~) in chronic psychotic patients, Acta Psychiat, Scand., 58 (1978) 384-388. Horn, A.S. and Phillipson, O.T., A noradrenalin sensitive adenylate cyclaze in the rat limbic forebrain -Preparation, properties and the effects of agonists, adrenolytics and neuroleptic drugs, Europ. J. Pharmacol., 37 (1976) 1 11. Janssen, P.A.J. and Van Bever, W.F.M., Structure-activity relationships of the butyrophenones and diphenylbutylpiperidines. In: L.L. lversen, S.D. Iversen and S.H. Snyder (Eds.), Handbook of Psychopharmacology, Vol. 10, Plenum Press, New York, NY, 1978, pp. 1-35. Nolen, W.A., Evaringen met transclopenthixol, Cobo-Bulletin 81-2 (1981) 49-54. Petersem P.V., Moller Nielsen, I., Pedersen, V., Jorgensen, A. and Lassen, N., Thioxanthenes. In: E. Usdin and I.S. Forest (Eds.), Psychotherapeutic Drugs, Part 2 (Applications) (Psychopharmacology Series, No. 2), Plenum, New York, NY, 1977, pp. 827-867. Post, R.M., Frontiers in affective disorder research - - New pharmacological agents and new methodologies. In: M.A. Lipton, A. DiMascio and K.F. Killam (Eds.), Psychopharmacology, A Generation of Progress, Raven Press, New York, NY, 1978, pp. 1323 1335. Post, R.M., Jimerson, D.C., Bunney, W.E. and Goodwin, F.K., Dopamine and mania - - Behavioral and biochemical effects of the dopamine receptor blocker pimozide, Psychopharmacology, 67 (1980) 297-305. Silverstone, T., Psychopharmacology of manic-depressive illness. In: R.L. Gaind and B.L. Hudson (Eds.), Current Themes in Psychiatry, Vol. 3, Macmillan, London, 1979. RDC R.L. Spitzer and J.E. Endicott (Research Diagnostic Criteria for a Selected Group of Functional Disorders), New York State Psychiatric Institute, New York, NY, 1977.
91
Elsevier Science Publishers
Dopamine and Mania The Effects of Trans- and Cis-Clopenthixol in a Double-Blind Pilot Study Willem A. Nolen Department of BiologicalPsychiatry, ChristelijkPsychiatrischCentrum Bloemendaal, The Hague (The Netherlands) (Received 23 April, 1982) (Revised, received 2 August, 1982) (Accepted 10 August, 1982)
Summary Sordinol ~ is composed of the mixture of cis-clopenthixol and trans-clopenthixol. The two isomers do not differ in several pharmacological properties, for instance anti-noradrenergic effect. However, cis-clopenthixol possesses anti-dopaminergic effects, while trans-clopenthixol does not. Sordinol-depot ® contains the almost pure cis-clopenthixol and appears to be less sedating than the oral and short-lasting intramuscular administration forms. In a double-blind pilot study with 10 manic patients, trans-clopenthixol was compared with cis-clopenthixol. Although not reaching statistical significance, cisclopenthixol showed anti-manic effects, while trans-clopenthixol remained ineffective. It is concluded that the anti-dopaminergic effect of cis-clopenthixol is essential for its anti-manic effect, which is in agreement with the hypothesis of involvement of the dopaminergic system in the pathogenesis of mania.
Introduction Neuroleptics show several effects such as antipsychotic, extrapyramidal and sedative effects. Clinically the antipsychotic effect is the most important. Probably it is related to the blockade of receptors at the dopaminergic neurones in the nucleus Reprint requests: Willem A. Nolen, M.D., Department of Biological Psychiatry, Christelijk Psychiatrisch Centrum Bloemendaal, Monsterseweg93, 2553 RJ 's-Gravenhage,The Netherlands. 0165-0327/83/0000-0000/$03.00 © 1983 Elsevier Science Publishers
92
accumbens (Crow et al. 1977). The antipsychotic effect often coincides with extrapyramidal side effects, related to the blockade of dopamine receptors in the striatum. The third important effect of many (but not all) neuroleptics is the sedative one, probably related to their anti-noradrenergic and anti-histaminergic effects. Many neuroleptics can produce drowsiness and sleepiness. Sometimes this effect is required by the treating psychiatrist, but at other times it is an unwanted side effect. Clopenthixol (Sordinol ®) is considered a sedative neuroleptic, i.e. besides antipsychotic effects it also possesses sedative effects. Both the oral and the shortlasting intramuscular administration forms are often used in our hospital for the treatment of manic or otherwise restless patients with good results. After the introduction of the depot form of Sordinol ® (clopenthixol-decanoate) we were surprised by the impression that this form of administration appeared to be less sedating. Similar observations were made by several other colleagues. The most reasonable explanation for this difference between the two forms of administration is their different chemical composition (Petersen et al., 1977) (Table 1). The oral and the shortlasting intramuscular forms of Sordinol ® consist of a mixture of the two stereo-isomers cisand trans-clopenthixol (33% and 67%, respectively). Sordinol-depot ~' contains almost pure cis-clopenthixol (98%). Although not differing in many pharmacological properties, cis- and trans-clopenthixol differ in one important aspect. The cis-form blocks the dopamine receptor, whereas the trans-form does not. The effects on several other receptors are equal, as for instance on the (beta-l-) noradrenaline receptor. Both isomers are equally potent in antagonising the stimulation of noradrenaline-sensitive adenylate cyclase in rat brain homogenates. In this aspect they are comparable with for instance chiorpromazine and haloperidol (Horn and Phillipson 1976). Gravem et al. (1978) have compared the oral racemate Sordinol e (33% cis, 67% trans) with the pure oral form of cis-clopenthixol. In a double-blind study 57 mostly chronic schizophrenic patients were treated for 2 months with the pure cis-form (29 patients) or with the mixture (28 patients). The antipsychotic effect of the cis-form was found to be equal to that of the mixture, whereas on a mg to mg basis the cis-form was twice as active as the mixture. Sedation was observed more frequently in the patients treated with the mixture (5 out of 28) than in the patients treated with the cis-form (1 out of 29). Although not explicitly mentioned by Gravem et al., it appeared that the mixture showed more sedative effects resulting from the adding of trans-clopenthixol to cis-clopenthixol. In two earlier pilot studies we gave 25 mg of the almost pure (98%) trans-clopenthixol to healthy volunteers (Nolen 1981). Six volunteers were given trans-clopenthixol in a double-blind cross-over design in TABLE 1 CHEMICAL
COMPOSITION
Sordinol ® oral form Sordinol ® intramuscular form Sordinol-depot ®
OF THE DIFFERENT
ADMINISTRATION
FORMS OF SORDINOL x
Cis-clopenthixol
Trans-clopenthixol
33% 33% 98%
67% 67% 2%
93 comparison with placebo. All 6 could discriminate the day of the active drug. On that day they all were sedated and drowsy. The other three took 25 mg transclopenthixol in an open design, and they experienced the same effect. Measuring of plasma levels of both trans- and cis-clopenthixol showed that this effect coincided with the plasma level of trans-clopenthixol. From Gravem's and our study we concluded that trans-clopenthixol, although apparently not an anti-dopaminergic drug, might have sedative or other non-specific properties. In order to evaluate its efficacy we decided to test the drug in manic patients.
Study Design Ten patients were studied, all suffering from a manic episode according to RDC and DSM-III criteria. Patients with a (too) severe mania which might lead to exhaustion, and patients with psychotic features were excluded. Before entering the study any neuroleptic used so far, was discontinued. If lithium was used, it was continued (with plasma levels between 0.8 and 1.2 mequiv./I). After a wash-out period of at least 2 days, cis- or trans-clopenthixol was given for 5 or 6 days, at a dose of initially 50 mg twice daily, with a maximum of 150 mg twice daily. The effect was rated on the Bech-Rafaelsen Mania Scale, a rating-scale ranging from 0 to 44 points (Rafaelsen, personal communication). All patients gave their informed consent.
Results The results are presented in Table 2 and Fig. I. Five patients were given transciopenthixol. In patient D this drug had to be discontinued after 3 days because of an increase of agressive behaviour. The other 4 patients showed no improvement. Patient Hi was given extra haloperidol on 3 nights because of severe restlessness. The other 5 patients received cis-ciopenthixol. Patient Be dropped out after 2 days because of aggravation of his mental state. Patient K became very sedated and refused further treatment despite apparent improvement. Two patients (Ho and V) responded well on cis-clopenthixol and were switched to Sordinoi ~ after the study period. The 5th patient (Br) showed no improvement. Because of the small number of patients and the large range of data obtained statistical comparisons of both groups showed no significant differences. However, a trend exists towards a better result with cis-clopenthixol (3 out of 5 patients improved) compared with trans-clopenthixol (none out of 5). The patients treated with trans-clopenthixol received more medication (maximal mean 270 mg daily) than the patients treated with the cis-form (170 mg daily), which also indicates less efficacy of trans-clopenthixol. The degree of mania, as scored on the rating-scale, was comparable as regards the mean; the rang'e, however, was larger in the patients treated with the cis-form. The treatment results also showed a large range, with again
94 TABLE 2 EFFECTS OF CIS- AND TRANS-CLOPENTHIXOL IN 10 P A T I E N T S , S C O R E D BECH-RAFAELSEN MANIA SCALE AND AS GLOBAL CLINICAL EFFECT
ON
Patient
Treatment
Maximal dose
N u m b e r of treatment days
Amelioration o n B.R.M.S.
Global clinical effect a
Be Ho K Br V Mean
cis cis cis cis cis
150 200 100 300 100 170
mg mg mg mg mg mg
2 6 2 5 6 4.2
- 2 (36 - , 38) I I (26 ~ 15) 16 (22 ---, 6) 0 (7~ 7) 9 (22 - , 13) 6.8 (22.6 15.8)
+ + + 0 + +
Hi S 0 D Ha Mean
trans trans trans trans trans
300 300 300 300 150 270
mg mg mg mg mg mg
5 6 6 3 5 5
6 (29 ---, 23) - 10 (15 ~ 25) 1 (22 --, 21) 3 (25 ---, 22) 1 (19 --, 18) 0.2 (22 ---, 21.8)
0 0 0 0
- = worsened, 0 = unchanged, completely recovered.
+ = slightly
improved,
+ + = markedly
improved,
THE
+ + + =
BMRS
BRMS 4O A
Be= / B e 35
35
30
30 Ho
Hi
D~
25
-
S Hi
©
0 .20
20
15
:o
15
H elk I
~
/
i'~'~
~ Ha
10
1C
(~r~ ~
K
days idays e Fig. 1. Effects o f cis-clopenthixol ( A ) a n d trans-clopenthixol ( B ) as s c o r e d o n the Bech R a f a e l s e n M a n i a Scale in 10 p a t i e n t s .
95 a trend towards a better effect of cis-clopenthixol: from - 2 to + 16 in the patients treated with the cis-form, from - 1 0 to + 6 in the patients treated with the trans-form. The side effects were mild. Three of the 5 patients treated with the cis-form and none of the 5 patients treated with the trans-form showed a slight parkinsonism. Only 1 patient, treated with the cis-form, became clearly sedated. In the other patients sedative effects were not observed.
General Discussion
Our study is a pilot study with a small number of patients. Despite this limitation, which did not allow us to reach statistically significant results, a tentative conclusion may be drawn. Trans-clopenthixol does not have anti-manic effects, while cisclophenthixol has. This indicates that the anti-dopaminergic property of cisclopenthixol is essential for its effect. Searching the literature we found two reports showing that pimozide, a rather selective anti-dopaminergic but not sedative drug is an effective anti-manic drug. Cookson et al. (1981) studied the anti-manic effects of pimozide in comparison with chlorpromazine. Pimozide was found to be equally effective: it produced more parkinsonism and was less sedating. Post et al. (1980) treated 8 manic patients with pimozide in a double-blind placebo-controlled design. They also observed a good anti-manic effect. From both studies it can be concluded that pimozide shows anti-manic effects without being sedative. This indicates that the anti-manic effects of neuroleptics probably are the result of dopaminergic blockade, which is in agreement with the hypothesis of the involvement of the dopaminergic system in the pathogenesis of mania. This hypothesis is supported by several other findings: hypomanic and manic states can be evoked by L-dopa (the precursor of dopamine), amphetamine (a dopamine releaser) or piribedil (a specific dopamine receptor agonist). AMPT (a-methyl-p-tyrosine), which inhibits tyrosine-hydroxylase resulting in a lower production of L-dopa from tyrosine, is reported to possess some anti-manic effectivity, while inhibition of DBH (dopamine-fl-hydroxylase) which results in a lower production of noradrenaline from dopamine, has no effect (Post 1978; Post et al. 1980; Silverstone 1979). Besides anti-dopaminergic effects many neuroleptics also have anti-noradrenergic effects. In animals, blockade of the noradrenaline receptor results in palpebral ptosis, while dopaminergic blockade results in catalepsy. The ratio of sedative effects of neuroleptics to anti-psychotic effects in man correlates with the ratio in which they produce palpebral ptosis to catalepsy in animals. Sedative neuroleptics, as for instance chlorpromazine, show a higher ratio than less sedative drugs such as pimozide (Janssen en Van Bever 1978). The sedative properties of many neuroleptics seem to be merely side effects, not essential for their anti-manic effect, and probably resulting from anti-noradrenergic or anti-histaminergic effects.
96
Acknowledgements I w o u l d like to t h a n k L u n d b e c k a n d Co., C o p e n h a g e n , D e n m a r k , for p r o v i d i n g t h e d r u g s . I also t h a n k Ben M u l l e r , L u n d b e c k N e d e r l a n d BV, A m s t e r d a m , for his s u p p o r t a n d M a r r i e k e V a n V e e l e n for h e r t e c h n i c a l a s s i s t a n c e .
References Cookson, J.C., Silverstone, T. and Wells, B., A double-blind comparative trial of pimozide and chlorpromazine in mania - - A test of the dopamine hypotheses, Acta Psychiat. Scand., 64 (1981) 381-397. Crow, T.J., Deakin, J.W.F. and Longden, A.., The nucleus accumbens, possible site of antipsychotic action of neuroleptic drugs? Psychol. Med., 7 (1977) 213-221. DSM-III, Diagnostic and Statistical Manual of Mental Disorders, 3rd edition. American Psychiatric Association, 1980. Gravem, A., Engstrand, E. and Guleng, R.J., cis (Z)-clopenthixol and clopenthixol (Sordinol~) in chronic psychotic patients, Acta Psychiat, Scand., 58 (1978) 384-388. Horn, A.S. and Phillipson, O.T., A noradrenalin sensitive adenylate cyclaze in the rat limbic forebrain -Preparation, properties and the effects of agonists, adrenolytics and neuroleptic drugs, Europ. J. Pharmacol., 37 (1976) 1 11. Janssen, P.A.J. and Van Bever, W.F.M., Structure-activity relationships of the butyrophenones and diphenylbutylpiperidines. In: L.L. lversen, S.D. Iversen and S.H. Snyder (Eds.), Handbook of Psychopharmacology, Vol. 10, Plenum Press, New York, NY, 1978, pp. 1-35. Nolen, W.A., Evaringen met transclopenthixol, Cobo-Bulletin 81-2 (1981) 49-54. Petersem P.V., Moller Nielsen, I., Pedersen, V., Jorgensen, A. and Lassen, N., Thioxanthenes. In: E. Usdin and I.S. Forest (Eds.), Psychotherapeutic Drugs, Part 2 (Applications) (Psychopharmacology Series, No. 2), Plenum, New York, NY, 1977, pp. 827-867. Post, R.M., Frontiers in affective disorder research - - New pharmacological agents and new methodologies. In: M.A. Lipton, A. DiMascio and K.F. Killam (Eds.), Psychopharmacology, A Generation of Progress, Raven Press, New York, NY, 1978, pp. 1323 1335. Post, R.M., Jimerson, D.C., Bunney, W.E. and Goodwin, F.K., Dopamine and mania - - Behavioral and biochemical effects of the dopamine receptor blocker pimozide, Psychopharmacology, 67 (1980) 297-305. Silverstone, T., Psychopharmacology of manic-depressive illness. In: R.L. Gaind and B.L. Hudson (Eds.), Current Themes in Psychiatry, Vol. 3, Macmillan, London, 1979. RDC R.L. Spitzer and J.E. Endicott (Research Diagnostic Criteria for a Selected Group of Functional Disorders), New York State Psychiatric Institute, New York, NY, 1977.