Central D1- and D2-receptor occupancy during antipsychotic drug treatment

Pmg. Neuro-Fsychophormoco1. & Biof. Psychiot. 1990, Vol. 14, p&x?6S-767 Printed in Great Britain. Ail rights reserved

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FRITS-AXEI,WIESELl, LARS FARDE, ANNA-LENA NORDSTRt)E(t and GbRAW SRDVALL Department of Psychiatry and Fsychology, Karolinska Institute, Rarolinska Hospital, Stockholm, Sweden (Final form, October 19891

Abstract Introduction Eiiethods Patients 2.2: PET Determination of 02' and Dl-Dopamine Receptor Occupanoy 3. Results and Discussion * 3.1. D.pecsptor Occupancy 3.2. D -Receptor Occupancy 4. &Elusions Acknowledgements References 1.

kl

759 760 760 760 761

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Abstract

Wiesel, Frits-Axel, Lam Fdrdel Anna-Lena Nordstrttmand G&an Sedvall: Central D - and D -Receptor Occupancy During Antipsychotic Drug Treatment. Prog, ~eu~~-Psy~h~phar~~ol* & 3iol. Psychiat. 1990, 14:759-767 1.

2.

It has been unequivocally shown that antipsychotic compounds reduce dopaminergic transmission.A relationship in vitro between the potency for the antipsychotic effect and the blockade of D2-dopamine receptors has been shown. No such relationships have been demonstrated for any other central receptor population. Positron emission tomography (PET) has made it possible to investigate interactions of psychotropic drugs with central receptors in the living human brain. Using the selective D2 rece tor antagonist raclopride fabelled with positron emitting isotope flC, it has been shown that chemically distinct classical neuroleptics in conventional doses occupy a high degree (6%89%) of the D -receptors in the human brain. The results substantiate the opinio it that the antipsychotic effects is mediated by a blockade of D2-dapamine receptors.ll

3.

4,

C-lab&led D -antaThe degree of binding to D -receptors using the gonist from Schering fSCH $33903 as the ligand was also determined. The D -receptor occupancy seemed to be dependent on the type of the antip.& ychotic compound studied. The atypical neuroleptic compound clozapine demonstrated a different binding profile than the cfassicaf neurolepties. Thus, elozapi-ne in conventional doses occupied D2-receptors to a smaller extent (40%, 408, 65%) than classical neuroleptics. The occupation of D -receptors was higher (so%, 42%) than that of classical compounds rOz36%1, _______~l_________c____I

1 Present address: Department of Psychiatry, Uppsala University, Ullerdker, Uppsala, Sweden, 359

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760

5.

The unique clinical profile of clozapine may be related to its potency on both D - and D -receptors. The distribution of D -receptors varies from that'of D -r&eptors in the human brain which Aay be one reason for the importance of blocking both Dl- and D2-receptors for a full antipsychotic response.

Keywordsr D -dopamine receptors, D2-dopamine receptors, neuroleptics, positron em 4ssion tomography, receptor occupancy, schizophrenia. Abbreviations: positron emission tomoqraphy (PET). 1. Introduction It is widely accepted, that the therapeutic effect of neuroleptic drugs is related to their ability to antagonize the action of the neurotransmitter dopamine by their blockade of central dopamine receptors. There are two major subtypes of dopamine receptors, D1-receptors that stimulate a dopamine sensitive adenylate cyclaee and D2 -receptors that inhibit or do not stimulate the dopamine sensitive adenylate cyclase (Kebabian and Calne 1979). The blockade of D2-dopamine receptors has been suggested to mediate the antipsychotic effect, a hypothesis supported by the demonstration of a linear correlation between drug affinity for central D2-dopamine receptors in animals and antipsychotic potency in humans (Seeman et al 1976). Such a correlation has not been demonstrated for the D1-dopamine receptor or for any other central receptor type (Peroutka and Snyder 1980). Until recently it was not possible to demonstrate in vivo, that neuroleptics block dopamine receptors in man: however, the development of positron emission tomography

(PET) has enabled direct visualization of the bind-

ing of psychoactive drugs in the living human brain (Sedvall et al 1986). Radiolabelled neuroleptics have been shown to bind specifically in the human striatum (Wagner et al 1983; Farde et al 1985). With PET and radioligand binding techniques it is possible to study to which extent neuroleptics block D2-receptors or interact with Dl -receptors in drug treated patients. The present paper deals with D1- and D2 -receptor occupancy of neuroleptics in patients treated with conventional clinical doses. 2. Methods 2.1. Patients The patients satisfied DSM-III criteria (3rd ed 1982) for a schizophrenic disorder, the age range at the time of investigation was 19-51 years. The patients had all been under treatment with conventional doses of an antipsychotic drug for at least one month and had responded well to the treatment. Extrapyramidal side effects were registered immediately after the PET investigation. It should be emphasized, that only one antipsychotic drug had been given during the month preceding the experiment. The patients were not

761

~p~~~n~receptor occupancy

treated with any other psychotropic drug at the time of the i~~~~thPt~~~~ Receptor occupancy was determined in a ANT-experiment six hours after the morning (last) dose or in case of depot neuraIeptics at the end of the injection interval.The studies were approved by the Ethics Commitee of the Xarolinska hospital, St~~kh~~rn,Sweden, and all patients had given their informed consent. 2.2. PET ~e~errn~nat~~~of D2- and fll-DopamineReceptor

Occupancy

Zn order to quantitate the lnteractian of neuroIeptics with receptor binding one has to develop a model for receptor quantification.Farde and coworkers fl986) have developed the saturation technique to determine D2dopamine receptor numbers in viva in the human brain with PET. In the studies of D2-xecepkors the highfy selective DZ-antagonfst racloprfde, a substituted benzamide, has been used as l&and, Raclopride Is labelled with 21C which is a positron emitting isotope with a half life af 20 minutes, The radiolabelled ligand Is administered as a bafus intravenously and the accumulation of the radioactivity is measured by the positron camera in sections of the brain (Farde et al 19SS). For the quantitatibn af DZ-receptors a tracer dose (high specific activity) and a saturating dose 4x0~ specific activity) have been given to healthy controls and to drug-naive sehisaphrenic patients, These patients have then been used as a reference material to calculate the receptor occupancy in drug treated patients Garde et al 19881, Tn the drug treated patients the tracer llC-racfopride (100 HEqCl)tg) was injected intravenously and the radioactivity In seven sectians of the brain was followed with tke pGSitXGn camera ~S~a~~~tr~nixPC38Q-78) by sequential scans during 51 minutes. The faurtb section was used to optimally image the caudate and the putamen. This section level had been identified prior to the ~ST-~nves~~gat~~nby computerized tomography and defined as 3 mm above the foramen of Nbnroe (Farde et al.2988). Regional radioactivity was measured for each sequential scan* corrected for =%-decay and plotted versus time. Specific D 2-receptor binding was defined as the difference between radioactivity in the ~utarne~and the cerebellum, a region with a negligible density of DZ-dbpamine receptors O?arde et al 198%). Radioactivity fn cerebellum was used as an estimate of the free radioligand concentration in the brain, Receptor occupancy in the drug treated patients was defined as the reduction of specific ISC-raelopride binding in relation to the expected binding in the absence of previous drug treatment {Farde et a_?_ 19881, En the study of D1-dopamLne receptor accupancy the Dl-antagonist SCH-23390 labelled with "CT was used as l&and (Farde et al 198fI. The procedure was otherwise identical to that for determination of D2-receptor occupancy. The expected binding was based cn experiments in seven healthy subjects (Parde et al 1987).

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3. Results and Discussion 3.1. D2-Receptor Occupancy Patients treated with chemically distinct neurofeptic drugs demonstrated similar receptor occupancy levels. The receptor occupancy varied between 40-88%. The data substantiate the view that the antipsychotic effect is mediated by D2 receptor blockade, Phenothiazines in moderate aoaes resulted in a receptor occupancy between 75-80% {Table 1). Perphenazinc in a high dose, 60 mg per day, resulted in a receptor

occupancy of 88% and also parkinsonism. The thioxanthenes flu-

penthixol and zuclopenthixol gave similar occupancy values as the phenothiazines. Haloperidol in a wide dose range, 4 to 12 mg daily, resulted in occupancy values between 81-86% (Table 2). In several cases receptor occupancy above 80% was associated with extrapyramidal symptoms like akathisia, dystonia and parkiasonism. Pimozide in a moderate dose resulted in a receptor occupancy of 77% and also akathisia. The benzamides,sulpiride, remoxipride and raclopride, al.1 resulted in a substantial D2-receptor occupancy (Table 3). In average slightly lower occupancy values were obtained and in no case extrapyramidal side effects were registered. The dibenzodiazepine clozapine differed from the other neuroleptic compounds with lower receptor occupancy values between 40 to 65% (Table 4). Table 1 D2-Dopamine Receptor Occupancy in Patients with Schizophrenia Treated with Antipsychotic Drugs Daily Dose [mg)

Drugs

Receptor Occupancy

PHENOTHIAZINES chlorpromazine thioridazine trifluperazine perphenazine perphenazine

200 300 10 8 60

80 75 80 79 88 parkinsonism

THIOXANTHENES flupenthixol flupenthixol dec suclopenthixol dec

10 40 weekly 200 every 2nd week

74

1) The PET

(%)

;;1,

investigation was made one week after the drug injection.

Except for clozapine, each of the antipsychotic drugs induced a greater than 65% occupancy of D2-dopamine receptors in the putamen. This kind of affinity is the basis for the dopamine hypothesis of the mechanism of action for the antipsychotic drugs. All the patients had responded well to the treatment, but with receptor occupancy around 80% extrapyramidal side effects were seen more frequently. This could indicate, that a lower receptor occupancy is required for the antipsychotic effect than the occupancy

Dopamine receptor occupancy

763

Table 2 D2-Dopamine Receptor Occupancy in Patients with Schizophrenia Treated with Antipsychotic Drugs Drugs

Daily Dose (mg)

BUTYROPHENONES haloperidol haloperidol haloperidol haloperidol haloperidol melperone melperone

12 8 6 6 4 300 250

DIPHENYLBUTYLS pimozide

8

Receptor Occupancy (%)

86 84 85 89 81 74 11

akathisia dystonia parkinsonism akathisia

77 akathisia

Table 3 D2-Dopamine Receptor Occupancy in Patients with Schizophrenia Treated with Antipsychotic Drugs

Drugs

Daily Dose (mg)

BENZAMIDES sulpiride sulpiride sulpiride remoxipride raclopride raclopride

800 800 800 400 8 6

Receptor Occupancy (%)

82 73 68 74 72 65

Table 4 D2-Dopamine Receptor Occupancy in Patients with Schizophrenia Treated with Antipsychotic Drugs

Drugs DIBENZODIAZEPINES clozapine clozapine clozapine

Daily Dose (mg)

600 500 300

Receptor Occupancy ($1

65 42 40

resulting in extrapyramidal side effects. TO examine the time courses of receptor occupancy in the brain and drug concentrations in the plasma two patients were studied. One patient had been treated with sulpiride 600 mg b.i.d. for seven weeks. He was withdrawn from

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treatment and PET-experiments were made 3, 6 and 27 hours after the last dose intake. Despite a several fold reduction in serum concentrations of sulpiride the dopamine receptor occupancy remained above 65% during 27 hours (Farde et al 1988). In another experiment a patient treated with haloperidol 6 mg b.i.d. for three months was investigated with PET 6, 30 and 53 hours after the last dose was given. Also in this patient only a reduction of a few % in the D2-dopamine receptor occupancy was found despite of a several fold reduction of the haloperidol plasma concentration values. This nonlinear relationship between plasma drug levels and receptor occupancy may be due to a slower dissociation rate of the drug from the receptor than the rate by which the concentration of the free drug is reduced or there may be a hyperbolic relationship between specific binding and free drug concentration in brain (Farde et al 1988). An experiment with successive dose reductions of sulpiride was undertaken to examine the two hypotheses. In a patient

treated with sulpiride, the

dose was reduced stepwise from 1600 mg to 0 mg daily. More than one week elapsed between each dose reduction (400 mg) to obtain steady state levels at each dose and a PET-investigation was made at the end of the dose reduction interval. The reduction in D2-dopamine receptor occupancy in relation to the dose followed a curve with a hyperbolic shape while the reduction of sulpiride in serum had a linear shape (Farde et al 1988). This experimental finding, supports the view that receptor occupancy follows a hyperbolic function in relation to drug concentration or dose. The reported findings have an immediate clinical relevance since the receptor occupancy with conventional doses of neuroleptics is in the more flat part of the curve which implies, that large dose changes will result only in smaller changes in receptor occupancy. This is probably a contributing factor to the negative results in finding a dose effect relationship in the neuroleptic treatment of schizophrenic patients (Baldessarini and Davis 1980; Dahl 1986). The results suggest the existence of a threshold for the occupancy giving rise to extrapyramidal side effects. If there is a threshold also for the antipsychotic effect it will probably be at a lower level than the threshold for side effects. 3.2. I&-Receptor Occupancy There is a new interest of the significance of Dl-receptor blockade in the treatment of schizophrenic patients. Behavioural experiments in the rat have demonstrated, that Dl- and D2 -receptor types cooperate. To obtain a full behavioural dopaminergic response both receptor types must be activated (Longini et al 1987). The effect of neuroleptic treatment on D1-receptors in the living human brain has not been possible to study until the development of PET. A limited number of neuroleptic compounds has been investigated so far. It seemed as if the chemical structure of the neuroleptic compound

Dopamine receptor occupancy

765

determined to which degree the receptors were occupied (Table 5). Perphenazine and sulpiride did not seem to interact with Dl-receptors, whereas thioridazine and flupenthixol seemed to interact with the Dl-receptors but to a much lower degree than with the D2-receptors. Clozapine showed the highest degree of Dl-receptor occupancy, 40% and 42%. In some patients we have been able to investigate receptor occupancy of both Dl- and D2dopamine receptors. It seemed as if clozapine differed from the other compounds by having a similar receptor occupancy with both receptor types (Table 6). It may be speculated, that the special clinical characteristics Table 5 Dl-Dopamine Receptor Occupancy in Patients with Schizophrenia Treated with Antipsychotic Drugs

Drugs

Daily Dose (mg)

Receptor Occupancy

PHENOTHIAZINES perphenazine thioridazine

16 200

0 29

THIOXANTHENES flupenthixol dec zuclopenthixol dec

40 weekly 200 every 2nd week

36 11

BENZAMIDES sulpiride

800

-7

DIBENZODIAZEPINES clozapine clozapine

500 300

40 42

(%)

Table 6 D 1- and D 2-Dopamine Receptor Occupancy in Patients with Schizophrenia Treated with Antipsychotic Drugs

Drugs

Daily Dose (mgf

Receptor Occupancy D1

(%)

D2

flupenthixol dec zuclopenthixol dec

40 weekly 200 every 2nd week

:!

sulpiride

800

-7

82

clozapine clozapine

500 300

40 42

42 40

1) One week after the drug injection

for clozapine i.e. no extrapyramidal side effects, no risk for tardive dyskinesia and more effective in the treatment of schizophrenic patients (30% of patients not responding to classical neuroleptics respond to clozapine treatment),

(Povlsen et al 1985; Kuha and Miettinen 1986; Kane et

al 1988) is due to a similar effect of clozapine on both Dl- and D2-

F.-A. Wiesel etal.

766

receptors. A full antipsychotic effect may require a substantial and similar blockade of both Dl- and D2-receptors. 4. Conclusions Neuroleptic drug treatment caused a substantial blockade of central D2dopamine receptors. A curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The degree of Dl-dopamine receptor occupancy was dependent on the type of neuroleptic drug. It is proposed, that the unique clinical profile of clozapine is related to a combined and a moderate blockade of both Dl- and D2-dopamine receptors. Acknowledgements The assistance of the the members of the Stockholm PET group is gratefully acknowledged. This study was supported by The Swedish Medical Recearch Council (07027, 08318), The National Institute of Mental Health US, The Bank of Sweden Tercentenary Fund and The Karolinska Institute. References BALDESSARINI, J. and DAVIS, J.M. (1980) What is the best maintenance dose of neuroleptics in schizophrenia? Psychiatry Res. 2: 115-122. DAHL, S.G. (1986) Plasma level monitoring of antipsychotic drugs. Clinical utility. Clin. Pharmacokinetics 11: 36-61. FARDE, L., EHRIN, E., ERIKSSON, L., GREITZ, H., HEDSTRDM, C-G., LITTON, J-E. and SEDVALL, G. (1985) Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc. Natl. Acad. Sci. USA -82: 3863-3867. FARDE, L., HALL, H., EKRIN, E., and SEDVALL, G. (1986) Quantitative analysis of dopamine D2 receptor binding in the living human brain by positron emission tomography. Science 231: 258-261. FARDE, L., HALLDIN, C., STONE-ELANDER, S., and SEDVALLllG. (1987) PET C-SCH 23390 and "Canalysis of human dopamine receptor subtypes using raclopride. Psychopharmacol. -92: 278-284. L., WIESEL, F-A., HALLDIN, C., and SEDVALL, G. (1988) Central D2receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch. Gen. Psychiatry -45: 71-76.

FARDB,

dopamine

KANE, J., HONIGFELD, G., SINGER, J., and MELTZER, H. (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry -45: 789-796. KEBABIAN, J-W., and CALNE, D.B. (1979) Multiple receptors for dopamine. Nature 277: 93-96.

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KUHA, S., and MIETTINEN, E. (1986) Long-term effect of clozapine in schizophrenia. Nord. Psykiatr. Tidskr. -40: 225-230. LONGONI, R., SPINA, L., and DI CHIARA, G. (1987) Permissive role of D-l receptor stimulation for the expression of D-2 mediated behavioral responses: A quantiative phenomenological study in rats. Life Sci. -41: 2135-2145. PEROUTKA, S.J., and SNYDER, S.H. (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, alfa-adrenergic, and histamine receptors to clinical potency. Am. J. Psychiatry 137: 1518-1522. POVLSEN, U.J., NORING, U., FOG, R., and GERLACH, J. (1985) Tolerability and therapeutic effect of clozapine. Acta Psychiatr. Stand. -71: 176-185. SEDVALL, G., FARDE; L., PERSSON, A., and WIESEL, F-A. (1986) Imaging of neurotransmitter receptors in the living human brain.Arch. Gen. Psychiatry -43: 995-1005. SEEMAN, P., LEE, T., and CHAU-WONG, M. (1976) Antipsychotic drug doses and neurolepticldopamine receptors. Nature 261: 717-719. WAGNER, H.N., BURNS, H.D., DANNALS, R.F., WONG, D.S., LANGSTROM, B., DUELFER, T., FROST, J.J., RAVERT, H.T., LINKS, J.M., ROSENBLOOM, S.B., LUKAS, S.E., KRAMER, A.V:, and KUHAR, M.J. (1983) Imaging dopamine receptors in the human brain by positron tomography. Sience 221: 1264-1266. Inquiries and reprint requests should be addressed to: Professor Frits-Axe1 Wiesel Department of Psychiatry Uppsala University Ulleraker S-750 17 UPPSALA Sweden