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Electric convulsive therapy (ECT) increases plasma and red blood cell haloperidol neuroleptic activities
Life Sciences, Vol. 33, pp. 1797-1803 Printed in the U.S.A.
Pergamon Press
ELECTRIC CONVULSIVE THERAPY (ECT) INCREASES PLASMA AND RED BLOOD CELL HALOPERIDOL NEUROLEPTIC ACTIVITIES Anri Aobal , Yasuhide2Kakita1, Noboru Eamaguchi', Masahiko Stido', Makiko Shibata , Kenichi Kitani , and Kazuo Hasegawa 1 Department of Neuropsychiatry 2St. Marianna University School of Medicine Tokyo Metropolitan Institute of Gerontology 35-2, Sakae-cho, Itabashi-ku, Tokyo, JAPAN (Received in final form August 15, 1983) Summary In nine schizophrenic patients (five males and four females) on haloperidol treatment, plasma and red blood cell (RBC) haloperidol neuroleptic activities were measured before and after ECT by radioreceptor assay. Five patients randomly selected from these patients also served as controls on another occasion and neuroleptic activities in plasma and RBC were examined before and after the premeditation only. All patients given ECT showed a considerable increase in plasma and RBC haloperidol neuroleptic activities after ECT (% increase in plasma neuroleptic activity, 28-4092; mean + SD, 136 + 155X, P(O.005, Wilcoxon test; % increase in RBC neuroleptic activity, ll-121%; mean + SD, 59 f. 40%, P
It has been well established that ECT is effective for the treatment of affective disorders (1). Some studies suggest that ECT is also effective in treating Schizophrenia (1,2). However the mechanisms of the action of ECT are known only in part. On the other hand, it is known that antipsychotic agents such as haloperidol have a beneficial effect on schizophrenia, presumably by blocking the dopamine receptor (3, 4). Recent studies have reported that the plasma haloperidol level measured by a radioreceptor assay is well correlated with clinical improvement in psychotic patients (5-7). This suggests that the radioreceptor assay can selectively detect the dopamine antagonistic potency (neuroleptic activity). There are several studies which compared the efficacy of a combination of ECT and an antipsychotic agent with that of ECT therapy alone (1, 2, 8-10). Smith et al. (9) found greater short term (1 and 3 week) improvement scores for patients treated with ECT and chlorpromazine than for those treated with ECT alone. However, the efficacy of combination therapy is still subject of debate. Furthermore, we have no information whether these two different therapies interact with each other or whether they work only additively. *To whom all correspondence should be addressed. 0024-3205183 $3.00 + .OO Copyright (c) 1983 Pergamon Press Ltd.
1798
Haloperidol Neuroleptic Activity After ECT
Vol. 33, No. 18, 1983
During the course of our pharmacodynamic study on haloperidol therapy, we have incidentally found that ECT increases the plasma and RBC haloperidol neuroleptic activities in patients on haloperidol therapy. To our knowledge no study has documented the effect of ECT on plasma haloperidol neuroleptic activity. Subjects and method Five male and four female patients diagnosed as schizophrenic according to Feighner's Criteria (11) were studied. Clinical data on these patients are summarized in TABLE I. Their age ranged from 20 to 35 years. Haloperidol was given orally three times a day (12 to 40 mg as a daily dose at W-l, 12&i, and 6PM). ECT was done after the specified oral dose was given for at least three weeks. A haloperidol study was done when the first ECT was given. After obtaining a baseline blood sample, five hundred ug of atropine and 0.5g of thiamylal sodium were given i.v. as premeditation about 3 to 5 minutes before each session. ECT was given to all patients at 11 AM. The convulsions were induced by a lOO-volt, alternating current electric stimulation of five seconds through bilateral temporal electrodes. No muscle paralyzing agent such as succinylcholine was given. The length of each convulsion was recorded. TABLE I Clinical Data on Subjects Studied for Haloperidol Neuroleptic Activity before and after ECT Case Number
Sex
1
M
Age (years) 20 23 22 33 35 21 28 27 27
Body weight (kg) 55 54 60 61 54 53 55 70 47
Daily dose (mg) 18 12 30 30 40 24 20 20 20
(mg/kg) 0.33 0.22 0.50 0.50 0.74 0.45 0.36 0.29 0.43
The length of convulsion (seconds) 40 48 40 39 23 31 31 37 45
All blood samples for haloperidol neuroleptic activity determination were drawn into vacuum tubes containing solid heparin before and 10 to 15 min after ECT. Serial blood samples were drawn thereafter at appropriate times in two selected cases. Blood samples were centrifuged at room temperature to separate plasma from RBC. Plasma and RBC samples were then transferred to polypropylene tubes and stored at -20°C until analyzed by radioreceptor assay. Two depressed patients without any medication were also given ECT, and neuroleptic activities were similarly measured before and after ECT. Blood samples were also drawn from five patients on haloperidol therapy before and after only the premeditation was given. These patients were randomly selected from the patients given ECT and were examined on different days than the ECT study. The radioreceptor assay was performed by the technique previously published by Cohen et al. (12) with a slight modification. Caudates were dissected from calf brain at a local slaughterhouse and immediately placed in an ice-cold 50 mM Tris-HCl buffer, pH 7.7. Tissue was homogenized within 1 hour in 20 volumes of buffer in a glass homogenizer with a teflon piston 10 strokes up and down at 400 rpm. The homogenate was centrifuged at 20,000 g for 15 minutes. The resulting pellet was washed with 20 volumes of buffer
Vol. 33, No. 18, 1983
Haloperidol Nueroleptic Activity After ECT
1799
and resuspended in 10 volumes of 50 mM Tris-HCl, pH 7.7 with 5 mM Na2 EDTA and 1.1 mM L-ascorbic acid. Aliquots (2.5 ml) of this suspension (crude homogenate) were stored at -80°C until used for radioreceptor assay. A 2.5 ml aliquot of crude homogenate was thawed, diluted with 10 ml of 50 mM Tris-HCl, pH 7.7 to which 5 mM Na EDTA and 1.1 ml4 L-ascorbic acid were added. The assay system containe3 300 ul of this homogenate in 0.9 ml total volume. Other constituents were 150 ul of + butaclamol (final concentration 100 nM) or buffer, 150 ul 9f an unknown plasma sample to be analyzed or control plasma, and 300 ul of H-spiroperidol (New England Nuclear, 50.7 Ci/mmol) at a final concentration of 300 pM. Incubation was at 37°C for 15 minutes with subsequent rapid filtration on a manifold with Whatman GF/B filters. The filters were washed three times with 5 ml of buffer at room temperature. Then they were dried at 8O'C for 30 minutes and put into glass scintillation vials to which 8 ml of toluene were added, The vials were counted with an Aloka liquid scintillation spectsometer (LSC-653). The specific binding was determined as the difference in H-spiroperidol bound in the presence and absence of butaclamol. For the calculation of plasma and RBC haloperidol neuroleptic activity in the unknown samples, a standard curve was plotted on semi-logarithmic table and the haloperidol neuroleptic activity in the unknown sample was directly determined from the percent inhibition of the sample. All the samples were determined in duplicate and the results reported were the means of the duplicate determinations. Using this procedure, the interassay coefficient of variation was 15% on 10 different occasions and the intraassay variation was 7% for 12 aliquots. Results Table I summarizes the clinical information of the subjects studied. FIG. 1 shows the relation between plasma haloperidol neuroleptic activity immediately before (left panel) and after (right panel) the ECT and its daily dose (mg/kg). A significant positive correlation was found between the dose and plasma neuroleptic activity for both measurements before and after ECT. However, after ECT, the correlation coefficient became lower.
(nM),
> 52004
Y=232X-43
9150-
I=0.88
‘i
Y=320X-31’
7
t !!I & ;100z 2 b -
50-
8 0.2
0.4
0.0
0.8
HALOPERIDOL DOSE(mglkg)
FIG. 1 Correlation between haloperidol daily dose (mg/kg) and plasma haloperidol neuroleptic activity before (left panel) and after (right panel) ECT.
1800
Haloperidol Neuroleptic Activity After ECT
>
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Vol. 33, No. 18, 1983
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5
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CASENUMBER
CASENUMBER
FIG. 2
FIG.3
FIG.2 (left) Plasma haloperidol neuroleptic activity in patients ECT. White columns indicate values before ECT and black columns after ECT. FIG.3 (right) Plasma neuroleptic activity in patients given only medication. White columns indicate values before anesthesia and columns values during anesthesia.
(nM)
I
given values preblack
(nM)
kaoo i= 2
$oB 6 5100g
CASE NUMBER
FIG.4
i-l
CASE NUMBER
FIG.5
FIG.4 (left) RBC haloperidol neuroleptic activity in patients with ECT. White columns indicate values before ECT and black columns values after ECT. FIG.5 (right) RBC haloperidol neuroleptic activity in patients given only premeditation. White columns indicate values before anesthesia and black columns values during anesthesia.
Vol. 33, No. 18, 1983
Haloperidol Neuroleptic Activity After ECT
1801
200c*se3 150-
loo-
k
50-
I -10 0
b case4
60
-10
TIME AFTER ECT
0
60
(mm)
FIG. 6 One hour follow up study for haloperidol neuroleptic activity after ECT in two selected cases. Open circles indicate RBC haloperidol neuroleptic activity and closed circles plasma haloperidol neuroleptic activity. FIG. 2 shows plasma haloperidol activities measured before and after ECT for each patient. In all patients neuroleptic activity increased after ECT. The increase of activity ranged from 16 to 163 nM, the average of net increase of activity being 49f45 nM (mean +- S.D., PLO.005, Wilcoxon test). When the increase was expressed as the percent increase, it ranged from 28 to 409% (136 + 155X, mean f. S.D.). On the other hand, in patients who were not given ECT but only given premeditation, no significant increase in plasma neuroleptic activity was observed (FIG. 3). Eight patients given ECT also showed an increase in RBC haloperidol neuroleptic activity ranging from 11 to 121% (59 + 40%, mean + S.D., P(O.005, Wilcoxon test) (FIG. 4). In four control studies without ECT, a decrease rather than an increase in RBC neuroleptic activity was observed (FIG. 5). Due to the inadequate storage condition, RBC neuroleptic activities for the patient No.9 were unable to measure. The percent of increase in plasma neuroleptic activity after ECT did not show any significant correlation with sex, age, body weight, daily dose, or the length of convulsion. Furthermore, plasma neuroleptic activities were not detectable by the radioreceptor assay in two depressed patients without any medication either before or after ECT therapy. FIG. 6 shows the time course study for plasma and RBC haloperidol neuroleptic acivities in two patients. Both plasma and RBC neuroleptic activities rose immediately after the ECT and returned nearly to the baseline level one hour after ECT. Discussion Radioreceptor assay is based on the dopamine antagonistic potency of the drug in plasma and RBC. Therefore, it is possible that the increased neuroreptic activity observed after ECT was due to some endogeneous
1802
Haloperidol Neuroleptic Activity After ECT
Vol. 33, No. 18, 1983
substance(s) having a dopamine antagonistic potency. However in two depressed patients without haloperidol therapy, the plasma neuroleptic activity after ECT was not detectable by radioreceptor assay. Thus, it appears most likely that the observed increase in neuroleptic activity after ECT in patients on haloperidol treatment is due to increased haloperidol in plasma and RBC and not due to endogenous substance(s) having neuroleptic activity. The mechanism for an ECT induced increase in haloperidol neuroleptic activity in plasma remains unknown. The rate of increase did not show any correlation with sex, age, body weight, daily dose, or the length of convulsion. It is most probable that ECT made a redistribution of haloperidol in the body increasing the plasma level. Since haloperidol activity in red blood cells also rose after ECT, it seems that ECT made a haloperidol release from other tissues. There are several possibilities that account for the results seen in the present study. One possibility is the redistribution of the drug from non-specific and specific sites in the brain due to an ECT-induced change in the blood brain barrier. This possibility is not unlikely as haloperidol brain levels are normally 20 times blood levels (13). It is well known that ECT can change the permeability of the blood brain barrier resulting in the change in brain concentration of a given substance (14). The second possibility is the redistribution of haloperidol from fat tissues. This is also likely as the majority of haloperidol is distributed in fat tissues. The third is the redistribution from specific binding sites in brain. This seems less likely as such sites account for a small proportion of the drug. Thus, there is probably too little drug to cause the effect seen. The fourth possibility is the transient increase in absorption of the drug from the gut. This seems less likely, although there may still be some amount of drug in the gut 5 hours after dosing when ECT is given. We are at present unable to determine which of the above possibilities is the cause for our observation. Furthermore, although we think the first two possibilities are more likely than the other two, they may have an opposite effect concerning the brain haloperidol concentration. And in either case, the change may be transient. Thus, the implication of the observation made in the present study to the efficacy of combined therapy of ECT and haloperidol is not clear. Nevertheless the redistribution of haloperidol neuroleptic activity induced by ECT suggests these two therapeutic procedures are actually interacting with each other. It would be worthwhile to pursue the problem whether this interaction of the two therapies really affects their therapeutic efficacies on schizophrenic patients. Finally, although the mechanism for our observation remains unknown, the observation that the haloperidol plasma level rose after ECT suggests that such a change may occur with other lipophilic drugs and may not be specific to haloperidol. Acknowledgements This work was partly supported by a research grant "Pharmacodynamics in the elderly" of Tokyo Metropolitan Institute of Gerontology. The authors wish to thank Mr. M. Dennin who kindly reviewed the manuscript and Mrs. T. Ohara who typed the manuscript. Reference 1. 2. 3. 4.
M. FINK, Convulsive Therapy: Theory and Practice. Raven Press (1979). C. SALZMAN, Am. J. Psychiatry, 137:9, 1032-1041, (1980). P. SEEMAN, T. LEE, M. CHAU-WONG and K. WONG, Nature 261, 717-718, (1976) S. H. SNYDER, D. C. U'PRICHARD and D. A. GREENBERG, 1n:Psychopharmacology (ed. M. A. LIPTON, A. DIMASCIO and K. F. KILLAM), 361-370, Raven Press (1978).
Vol. 33, No. 18, 1983
Haloperidol Neuroleptic Activity After ECT
1803
5. J. E. ROSENBLATT, R. J. PARY, L. B. BIGELOW, L. E. DELISI, R. L. WAGNER, J. E. KLEINMAN, D. R. WEINBERGER, S. G. POTKIN, D. SHILING, D. V. JESTE, P. L. ALEXANDER and R. J. WYATT, In: Neuroreceptors (ed. E. USDIN, W. E. BUNNEY JR and J. M. DAVIS), 165-188, JOHN WILEY & SONS, ChichesteriNew York/ Brisbane/Toronto, (1981) 6. B. M. COHEN and J. F. LIPINSKI, In: Neuroreceptors, (ed. E. USDIN, W. E. BUNNEY JR and J. M. DAVIS), 199-214, JOHN WILEY & SONS, Chichester/New York/Brisbane/Tronto, (1981). 7. R. C. SMITH, G. VROULIS, C. H. MISRA, J. SCHOOLAR, C. DEJOHN, P. KORIVI, D. E. LEELAVANTHI and D. ARZU, Commun. Psychopharm, 4_, 451-465, (1980) 8. R. T. CHILDERS, Am. J. Psychiatry, 120, 1010-1011, (1964). 9. K. SMITH, W. R. P. SURPHLIS, M. D. GYNTHER and A. M. SHIMKUNAS, J. Nerv. Ment. Dis. 144, 284-292, (1967). 10. R. E. MINTER and M. R. MANDEL, J. Nerv. Ment. Dis. 167, 726-733, (1979). 11. P. FEIGHNER, E. ROBINS, S. B. GUZE, R. A. WOODRUFF, G. WINOKUR and R. MUNOZ, Arch. Gen. Psychiatry, 6, 57-63, (1972). 12. M. B. COHEN, M, HERSCHEL and A. AOBA, Psychiatry Res. l_, 199-208, (1979). 13. B. M. COHEN, M. HERSCHEL, E. MILLER, H. MAYBERG and R. J. BALDESSARINI, Neuropharmacology, 19, 663-668, (1980) 14. P. K. AWASTHI, K. SHANKER, A. GULATI, K. N. DHAWAN and P. BHARGAVA, Pharmacol. Res. Commun. 3, 983-992, (1982).
Pergamon Press
ELECTRIC CONVULSIVE THERAPY (ECT) INCREASES PLASMA AND RED BLOOD CELL HALOPERIDOL NEUROLEPTIC ACTIVITIES Anri Aobal , Yasuhide2Kakita1, Noboru Eamaguchi', Masahiko Stido', Makiko Shibata , Kenichi Kitani , and Kazuo Hasegawa 1 Department of Neuropsychiatry 2St. Marianna University School of Medicine Tokyo Metropolitan Institute of Gerontology 35-2, Sakae-cho, Itabashi-ku, Tokyo, JAPAN (Received in final form August 15, 1983) Summary In nine schizophrenic patients (five males and four females) on haloperidol treatment, plasma and red blood cell (RBC) haloperidol neuroleptic activities were measured before and after ECT by radioreceptor assay. Five patients randomly selected from these patients also served as controls on another occasion and neuroleptic activities in plasma and RBC were examined before and after the premeditation only. All patients given ECT showed a considerable increase in plasma and RBC haloperidol neuroleptic activities after ECT (% increase in plasma neuroleptic activity, 28-4092; mean + SD, 136 + 155X, P(O.005, Wilcoxon test; % increase in RBC neuroleptic activity, ll-121%; mean + SD, 59 f. 40%, P
It has been well established that ECT is effective for the treatment of affective disorders (1). Some studies suggest that ECT is also effective in treating Schizophrenia (1,2). However the mechanisms of the action of ECT are known only in part. On the other hand, it is known that antipsychotic agents such as haloperidol have a beneficial effect on schizophrenia, presumably by blocking the dopamine receptor (3, 4). Recent studies have reported that the plasma haloperidol level measured by a radioreceptor assay is well correlated with clinical improvement in psychotic patients (5-7). This suggests that the radioreceptor assay can selectively detect the dopamine antagonistic potency (neuroleptic activity). There are several studies which compared the efficacy of a combination of ECT and an antipsychotic agent with that of ECT therapy alone (1, 2, 8-10). Smith et al. (9) found greater short term (1 and 3 week) improvement scores for patients treated with ECT and chlorpromazine than for those treated with ECT alone. However, the efficacy of combination therapy is still subject of debate. Furthermore, we have no information whether these two different therapies interact with each other or whether they work only additively. *To whom all correspondence should be addressed. 0024-3205183 $3.00 + .OO Copyright (c) 1983 Pergamon Press Ltd.
1798
Haloperidol Neuroleptic Activity After ECT
Vol. 33, No. 18, 1983
During the course of our pharmacodynamic study on haloperidol therapy, we have incidentally found that ECT increases the plasma and RBC haloperidol neuroleptic activities in patients on haloperidol therapy. To our knowledge no study has documented the effect of ECT on plasma haloperidol neuroleptic activity. Subjects and method Five male and four female patients diagnosed as schizophrenic according to Feighner's Criteria (11) were studied. Clinical data on these patients are summarized in TABLE I. Their age ranged from 20 to 35 years. Haloperidol was given orally three times a day (12 to 40 mg as a daily dose at W-l, 12&i, and 6PM). ECT was done after the specified oral dose was given for at least three weeks. A haloperidol study was done when the first ECT was given. After obtaining a baseline blood sample, five hundred ug of atropine and 0.5g of thiamylal sodium were given i.v. as premeditation about 3 to 5 minutes before each session. ECT was given to all patients at 11 AM. The convulsions were induced by a lOO-volt, alternating current electric stimulation of five seconds through bilateral temporal electrodes. No muscle paralyzing agent such as succinylcholine was given. The length of each convulsion was recorded. TABLE I Clinical Data on Subjects Studied for Haloperidol Neuroleptic Activity before and after ECT Case Number
Sex
1
M
Age (years) 20 23 22 33 35 21 28 27 27
Body weight (kg) 55 54 60 61 54 53 55 70 47
Daily dose (mg) 18 12 30 30 40 24 20 20 20
(mg/kg) 0.33 0.22 0.50 0.50 0.74 0.45 0.36 0.29 0.43
The length of convulsion (seconds) 40 48 40 39 23 31 31 37 45
All blood samples for haloperidol neuroleptic activity determination were drawn into vacuum tubes containing solid heparin before and 10 to 15 min after ECT. Serial blood samples were drawn thereafter at appropriate times in two selected cases. Blood samples were centrifuged at room temperature to separate plasma from RBC. Plasma and RBC samples were then transferred to polypropylene tubes and stored at -20°C until analyzed by radioreceptor assay. Two depressed patients without any medication were also given ECT, and neuroleptic activities were similarly measured before and after ECT. Blood samples were also drawn from five patients on haloperidol therapy before and after only the premeditation was given. These patients were randomly selected from the patients given ECT and were examined on different days than the ECT study. The radioreceptor assay was performed by the technique previously published by Cohen et al. (12) with a slight modification. Caudates were dissected from calf brain at a local slaughterhouse and immediately placed in an ice-cold 50 mM Tris-HCl buffer, pH 7.7. Tissue was homogenized within 1 hour in 20 volumes of buffer in a glass homogenizer with a teflon piston 10 strokes up and down at 400 rpm. The homogenate was centrifuged at 20,000 g for 15 minutes. The resulting pellet was washed with 20 volumes of buffer
Vol. 33, No. 18, 1983
Haloperidol Nueroleptic Activity After ECT
1799
and resuspended in 10 volumes of 50 mM Tris-HCl, pH 7.7 with 5 mM Na2 EDTA and 1.1 mM L-ascorbic acid. Aliquots (2.5 ml) of this suspension (crude homogenate) were stored at -80°C until used for radioreceptor assay. A 2.5 ml aliquot of crude homogenate was thawed, diluted with 10 ml of 50 mM Tris-HCl, pH 7.7 to which 5 mM Na EDTA and 1.1 ml4 L-ascorbic acid were added. The assay system containe3 300 ul of this homogenate in 0.9 ml total volume. Other constituents were 150 ul of + butaclamol (final concentration 100 nM) or buffer, 150 ul 9f an unknown plasma sample to be analyzed or control plasma, and 300 ul of H-spiroperidol (New England Nuclear, 50.7 Ci/mmol) at a final concentration of 300 pM. Incubation was at 37°C for 15 minutes with subsequent rapid filtration on a manifold with Whatman GF/B filters. The filters were washed three times with 5 ml of buffer at room temperature. Then they were dried at 8O'C for 30 minutes and put into glass scintillation vials to which 8 ml of toluene were added, The vials were counted with an Aloka liquid scintillation spectsometer (LSC-653). The specific binding was determined as the difference in H-spiroperidol bound in the presence and absence of butaclamol. For the calculation of plasma and RBC haloperidol neuroleptic activity in the unknown samples, a standard curve was plotted on semi-logarithmic table and the haloperidol neuroleptic activity in the unknown sample was directly determined from the percent inhibition of the sample. All the samples were determined in duplicate and the results reported were the means of the duplicate determinations. Using this procedure, the interassay coefficient of variation was 15% on 10 different occasions and the intraassay variation was 7% for 12 aliquots. Results Table I summarizes the clinical information of the subjects studied. FIG. 1 shows the relation between plasma haloperidol neuroleptic activity immediately before (left panel) and after (right panel) the ECT and its daily dose (mg/kg). A significant positive correlation was found between the dose and plasma neuroleptic activity for both measurements before and after ECT. However, after ECT, the correlation coefficient became lower.
(nM),
> 52004
Y=232X-43
9150-
I=0.88
‘i
Y=320X-31’
7
t !!I & ;100z 2 b -
50-
8 0.2
0.4
0.0
0.8
HALOPERIDOL DOSE(mglkg)
FIG. 1 Correlation between haloperidol daily dose (mg/kg) and plasma haloperidol neuroleptic activity before (left panel) and after (right panel) ECT.
1800
Haloperidol Neuroleptic Activity After ECT
>
f200-
f200
5
F s
g150-
9150ii !!i 0
k d
Vol. 33, No. 18, 1983
-
$ooz
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d i
123456789
1
4
5
6
9
CASENUMBER
CASENUMBER
FIG. 2
FIG.3
FIG.2 (left) Plasma haloperidol neuroleptic activity in patients ECT. White columns indicate values before ECT and black columns after ECT. FIG.3 (right) Plasma neuroleptic activity in patients given only medication. White columns indicate values before anesthesia and columns values during anesthesia.
(nM)
I
given values preblack
(nM)
kaoo i= 2
$oB 6 5100g
CASE NUMBER
FIG.4
i-l
CASE NUMBER
FIG.5
FIG.4 (left) RBC haloperidol neuroleptic activity in patients with ECT. White columns indicate values before ECT and black columns values after ECT. FIG.5 (right) RBC haloperidol neuroleptic activity in patients given only premeditation. White columns indicate values before anesthesia and black columns values during anesthesia.
Vol. 33, No. 18, 1983
Haloperidol Neuroleptic Activity After ECT
1801
200c*se3 150-
loo-
k
50-
I -10 0
b case4
60
-10
TIME AFTER ECT
0
60
(mm)
FIG. 6 One hour follow up study for haloperidol neuroleptic activity after ECT in two selected cases. Open circles indicate RBC haloperidol neuroleptic activity and closed circles plasma haloperidol neuroleptic activity. FIG. 2 shows plasma haloperidol activities measured before and after ECT for each patient. In all patients neuroleptic activity increased after ECT. The increase of activity ranged from 16 to 163 nM, the average of net increase of activity being 49f45 nM (mean +- S.D., PLO.005, Wilcoxon test). When the increase was expressed as the percent increase, it ranged from 28 to 409% (136 + 155X, mean f. S.D.). On the other hand, in patients who were not given ECT but only given premeditation, no significant increase in plasma neuroleptic activity was observed (FIG. 3). Eight patients given ECT also showed an increase in RBC haloperidol neuroleptic activity ranging from 11 to 121% (59 + 40%, mean + S.D., P(O.005, Wilcoxon test) (FIG. 4). In four control studies without ECT, a decrease rather than an increase in RBC neuroleptic activity was observed (FIG. 5). Due to the inadequate storage condition, RBC neuroleptic activities for the patient No.9 were unable to measure. The percent of increase in plasma neuroleptic activity after ECT did not show any significant correlation with sex, age, body weight, daily dose, or the length of convulsion. Furthermore, plasma neuroleptic activities were not detectable by the radioreceptor assay in two depressed patients without any medication either before or after ECT therapy. FIG. 6 shows the time course study for plasma and RBC haloperidol neuroleptic acivities in two patients. Both plasma and RBC neuroleptic activities rose immediately after the ECT and returned nearly to the baseline level one hour after ECT. Discussion Radioreceptor assay is based on the dopamine antagonistic potency of the drug in plasma and RBC. Therefore, it is possible that the increased neuroreptic activity observed after ECT was due to some endogeneous
1802
Haloperidol Neuroleptic Activity After ECT
Vol. 33, No. 18, 1983
substance(s) having a dopamine antagonistic potency. However in two depressed patients without haloperidol therapy, the plasma neuroleptic activity after ECT was not detectable by radioreceptor assay. Thus, it appears most likely that the observed increase in neuroleptic activity after ECT in patients on haloperidol treatment is due to increased haloperidol in plasma and RBC and not due to endogenous substance(s) having neuroleptic activity. The mechanism for an ECT induced increase in haloperidol neuroleptic activity in plasma remains unknown. The rate of increase did not show any correlation with sex, age, body weight, daily dose, or the length of convulsion. It is most probable that ECT made a redistribution of haloperidol in the body increasing the plasma level. Since haloperidol activity in red blood cells also rose after ECT, it seems that ECT made a haloperidol release from other tissues. There are several possibilities that account for the results seen in the present study. One possibility is the redistribution of the drug from non-specific and specific sites in the brain due to an ECT-induced change in the blood brain barrier. This possibility is not unlikely as haloperidol brain levels are normally 20 times blood levels (13). It is well known that ECT can change the permeability of the blood brain barrier resulting in the change in brain concentration of a given substance (14). The second possibility is the redistribution of haloperidol from fat tissues. This is also likely as the majority of haloperidol is distributed in fat tissues. The third is the redistribution from specific binding sites in brain. This seems less likely as such sites account for a small proportion of the drug. Thus, there is probably too little drug to cause the effect seen. The fourth possibility is the transient increase in absorption of the drug from the gut. This seems less likely, although there may still be some amount of drug in the gut 5 hours after dosing when ECT is given. We are at present unable to determine which of the above possibilities is the cause for our observation. Furthermore, although we think the first two possibilities are more likely than the other two, they may have an opposite effect concerning the brain haloperidol concentration. And in either case, the change may be transient. Thus, the implication of the observation made in the present study to the efficacy of combined therapy of ECT and haloperidol is not clear. Nevertheless the redistribution of haloperidol neuroleptic activity induced by ECT suggests these two therapeutic procedures are actually interacting with each other. It would be worthwhile to pursue the problem whether this interaction of the two therapies really affects their therapeutic efficacies on schizophrenic patients. Finally, although the mechanism for our observation remains unknown, the observation that the haloperidol plasma level rose after ECT suggests that such a change may occur with other lipophilic drugs and may not be specific to haloperidol. Acknowledgements This work was partly supported by a research grant "Pharmacodynamics in the elderly" of Tokyo Metropolitan Institute of Gerontology. The authors wish to thank Mr. M. Dennin who kindly reviewed the manuscript and Mrs. T. Ohara who typed the manuscript. Reference 1. 2. 3. 4.
M. FINK, Convulsive Therapy: Theory and Practice. Raven Press (1979). C. SALZMAN, Am. J. Psychiatry, 137:9, 1032-1041, (1980). P. SEEMAN, T. LEE, M. CHAU-WONG and K. WONG, Nature 261, 717-718, (1976) S. H. SNYDER, D. C. U'PRICHARD and D. A. GREENBERG, 1n:Psychopharmacology (ed. M. A. LIPTON, A. DIMASCIO and K. F. KILLAM), 361-370, Raven Press (1978).
Vol. 33, No. 18, 1983
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