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Tolerance to phenothiazines in schizophrenic patients
Gen. Pharmac., 1976, Vol. 7, pp. 377 to 379. Pergamon Press. Printed in Great Britain
MINIREVIEW TOLERANCE TO PHENOTHIAZINES IN SCHIZOPHRENIC PATIENTS PARVIZ MALEK-AHMADI AND JAMES L. CHAPEL
University of Missouri-Columbia, Department of Psychiatry, Columbia, Missouri 65201, U.S.A. (Received 27 July 1976)
SINCE the introduction of chlorpromazine into psychiatry, it has been learned from clinical observations and experimental investigations that some schizophrenic patients have a higher tolerance to phenothiazines than do normal subjects. This paper briefly reviews some of the clinical and experimental observations in relation to this tolerance.
N E U R O P H Y S I O L O G I C A L ASPECTS OF P H E N O T H I A Z I N E TOLERANCE
In 1948, Drohocki (1948) designed a simple and reliable electronic device which made possible largescale longitudinal studies of the amounts and quantitative variations of the spontaneous electrical energy of the brain. Data from Drohocki's integrator (which can measure continuously and automatically the energy CLINICAL ASPECTS OF content of the EEG) have revealed that phenothiaP H E N O T H I A Z I N E S TOLERANCE zines and other antipsychotic agents, such as butyroIn normal subjects, chlorpromazine results in a phenones, produce varying degrees of increased EEG considerable degree of sedation when given for the variability (Sugerman, 1964). Drugs, such as amphetafirst time in single doses of 100-200mg. Larger mines and LSD cause a decrease in EEG variability amounts can lead to central nervous system depres- in normal subjects (Murphee, et al., 1962). Using sion to the point of somnolence or coma. Clinical quantitative electroencephalographic procedures, observations suggest that schizophrenic patients not Goldstein et al. (1963), suggested there was a differonly develop tolerance to the hypotensive effects of ence between the spontaneous cortical activity of norchlorpromazine but they also exhibit a tolerance to mal subjects and chronic schizophrenic patients. They the behavioral effects of the drug during short- and referred to this difference as a reduced EEG variabilong-term administration. As Hollister (1970) has lity in the patients, and based on the fact that LSD stated, the ability to tolerate antipsychotic drugs di- was capable of reducing EEG variability in normal rectly correlates with the severity of psychosis. subjects, they concluded that psychotic symptoms, Tolerance to phenothiazines may be explained by whether in schizophrenic patients or induced by LSD, the variations in the rate of absorption and metabo- are accompanied by reduced EEG variability. Reduclism of the phenothiazines. However, these variations tion of EEG variability, as they pointed out, repredo not account for the fact that some schizophrenics sented a state of overstimulation in the central nerare able to tolerate megadoses of injectable pheno- vous system. thiazines (Rifkin et al., 1971). Previous to Goldstein's studies, Davis (1942) had Tolerance to phenothiazines does not seem to be concluded that 61% of schizophrenic patients in her attributed to the psychomotor agitation since it is study had 'choppy' activity in qualitative eleetroencealso present in withdrawn schizophrenic patients. The phalographic procedure. She regarded 'choppy' actifact that some schizophrenic patients show minimal vity as indicating, primarily, overstimulation of responses to the behavioral effects of chlorpromazine, schizophrenic patients. Whatmore & Ellis (1964) conas compared with those of normal subjects, suggests cluded that this overstimulation is accompanied by that a central mechanism might be responsible. increased motor activity in schizophrenic patients. It has been demonstrated that antianxiety agents They coined the term 'hyperponesis' which refers to such as benzodiazepine derivatives are not effective a neurophysiologic state consisting of hyperactivity in the treatment of schizophrenia. Thus, one can con- in pathways extending from motor and premotor corclude that a high level of anxiety is not responsible tical neurons through pyramidal and extrapyramidal for the tolerance of schizophrenic patients to tracts to the peripheral musculature, which results in phenothiazines. myographically measurable muscular activity. 377 G.P. 7/6 a
378
PARVIZ MALEK-AHMADIAND JAMESL. CHAPEL
According to Whatmore & Ellis (1964), this exaggerated activity in the central nervous system of schizophrenic patients may be localized to a portion of motor system or generalized to include the whole motor system. These variations may explain some of the differences in terms of psychomotor activity in schizophrenic patients. For instance, in catatonic schizophrenia when this overstimulation extends through the pyramidal tracts, the patient exhibits psychomotor agitation (excited type); otherwise, the patient remains inactive (withdrawn type). Interestingly enough, Venables & Wing (1962) have indicated that the most withdrawn schizophrenic patients are the most overstimulated. Central nervous system overstimulation in schizophrenic patients does not respond to barbiturates, benzodiazepine derivatives, or alcohol. It is only diminished by adequate doses of phenothiazines (especially chlorpromazine, which presumably has more sedative effect) or other antipsychotic agents. Reduction of the central nervous system overstimulation by whatever means corresponds with increased EEG variability and improvement in the clinical picture. BIOCHEMICAL ASPECTS OF PHENOTH1AZINE TOLERANCE Goldstein et al. (1963) were of the opinion that overstimulation could result from 'information input overload', i.e. an exaggerated input to the brain from the periphery accompanied by a decrease in the ability of the brain to handle such supramaximal charges. However, they made brief reference to the presence of an abnormal stimulating metabolite responsible for the overstimulation of the central nervous system. Carlsson & Lindqvist (1963) first suggested that phenothiazines block dopamine receptors in the central nervous system. By blocking the dopamine receptors, these agents produce a functional deficiency of dopamine. One might speculate that the therapeutic effect of phenothiazines and other antipsychotic agents may be related to the dopamine receptor sites in the cerebral cortex. This speculation is compatible with the neurochemical model of schizophrenia proposed by Wise & Stein (1973), whose studies demonstrated that dopamine-beta-hydroxylase (DBH) activity was significantly reduced in the brain of schizophrenic patients (see Fig. 1). This enzyme converts dopamine to norepinephrine; therefore, its deficiency results in accumulation of dopamine and its psychotoxic derivatives in the central nervous system. Chlorpromazine molecule exerts its antischizophrenic activity by superimposing on dopamine molecule (Snyder et al., 1974). If DAs and DA, are the number of dopamine molecules in the brain of a schizophrenic patient and nonschizophrenic subject, respectively, it can be concluded that : DA~ > DA..
Dopamine-beta-hydroxylase deficiency hypothesis Tyrosine Tyrosine hydroxylase Dihydroxyphenylalanine (DOPA) DOPA decarboxylase Dopamine ,6-Hydroxydopamine , j, Dopamine-beta-hydroxylase Norepinephrine Fig. 1. Therefore, when all dopamine molecules are to be superimposed in the certain area of the brain, more chlorpromazine molecules are required for this purpose in schizophrenic patient as compared to nonschizophrenic subject. On the other hand, the amount of chlorpromazine necessary for a beneficial effect in schizophrenia can be reduced if dopamine synthesis is blocked by alpha-methylparatyrosine. It has also been demonstrated that administration of 1-Dopa to schizophrenic patients exacerbates the schizophrenic symptomatology (Yaryura-Tobias & Merlis, 1970). 1-Dopa, the immediate metabolic precursor of dopamine, is presumed to increase the concentration of dopamine in the brain. Based on the above observations, it would be reasonable to speculate that central nervous system overstimulation associated with the tolerance to antipsychotic agents is due to accumulation of dopamine or its psychotoxic derivatives (6-hydroxydopamine), and only phenothiazines or other antipsychotic agents are capable of reducing overstimulation by blocking the dopamine receptors.
SUMMARY
Clinical observations suggest that some schizophrenic patients exhibit an abnormal tolerance to antipsychotic agents. This tolerance is associated with decreased EEG variability which represents overstimulation of the central nervous system. This overstimulation may be due to accumulation of dopamine or a dopamine derivative substance in the central nervous system. Antipsychotic agents block the action of dopamine and therefore exert therapeutic effect in schizophrenia. The absence of tolerance to antipsychotic drugs may indicate the presence of a 'schizophreniform' psychosis rather than a 'typical' schizophrenic process.
REFERENCES
CARLSSONA. & LINDQVIST,M. (1963) Effects of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta pharmac. tox. 20, 140-144. DAVIS P. A. (1942) Comparative study of the EEGs of schizophrenic and manic depressive patients. Am. J. Psychiat. 114, 882 889.
Tolerance to phenothiazines in schizophrenic patients DROHOCKI L. (1948) L'int6grateur de l'61ectroproduction c6r6brale pour r61ectroencephalographic quantitative. Rev. Neurol. 80, 619-624. GOLDSTEINL., MURPHEEH. B., SUGERMANA. A., PFEIFFER C. C. t~ JENNEYE. H. (1963) Quantitative electroencephalographic analysis of naturally occurring (schizophrenic) and drug-induced psychotic states in human males. Clin. Pharmac. Ther. 4, 10-21. HOLLISTERL. E. (1970) Choice of antipsychotic drugs. Am. J. Psychiat. 127, 186--190. MtlRPHEE H. B., JENNEY E. G. • PFEIFFER C. C. (1962) Quantitative electroencephalographic analysis of the effects of lysergic acid diethylamide (LSD-25) and D-amphetamine in man. Fedn Proc. Fedn Am. Socs exp. Biol. 21, 337. RIFKIN A., QUITKIN F., CARILLOC. & KLEIN D. F. (1971) Very high dosage fluphenazine for nonchronic treatment-refractory patients. Archs gen. Psychiat. 25, 398-403.
379
SNYDERS. H., SHAILESHP. B., YAMAMURAH. I. & GREENBERG D. (1974) Drugs, neurotransmitters, and schizophrenia. Science 184, 1243-1253. SUGERMAN A. A. (1964) A pilot study of floropipamide (dipiperon) Dis. nerv. Syst. 25, 355-358. SUGERMANA. A., GOLDSTEINL., MURPHEEH. B., PFEIFFER C. C. t~ JENNEY E. H. (1964) EEG and behavioral changes in schizophrenia. Archs yen. Psychiat. 10, 340-344. VENAaLES P. H. & Wlr~G J. K. (1962) Level of arousal and subclassification of schizophrenia. Archs #en. Psychiat. 7, 114-119. WHmMORE G. B. & ELLIS,R. M. (1964) Some neurophysiologic aspects of schizophrenia: an electromyographic study. Am. J. Psychiat. 120, 1116-1169. WISE C. G. & STEIN L. (1973) Dopamine-beta-hydroxylase deficits in the brain of schizophrenic patients. Science 181, 344-347. YARYURA-TOmASJ. A. & MERLIS S. (1970) Levodopa and schizophrenia. J. Am. med. Ass. 21L 1857.
MINIREVIEW TOLERANCE TO PHENOTHIAZINES IN SCHIZOPHRENIC PATIENTS PARVIZ MALEK-AHMADI AND JAMES L. CHAPEL
University of Missouri-Columbia, Department of Psychiatry, Columbia, Missouri 65201, U.S.A. (Received 27 July 1976)
SINCE the introduction of chlorpromazine into psychiatry, it has been learned from clinical observations and experimental investigations that some schizophrenic patients have a higher tolerance to phenothiazines than do normal subjects. This paper briefly reviews some of the clinical and experimental observations in relation to this tolerance.
N E U R O P H Y S I O L O G I C A L ASPECTS OF P H E N O T H I A Z I N E TOLERANCE
In 1948, Drohocki (1948) designed a simple and reliable electronic device which made possible largescale longitudinal studies of the amounts and quantitative variations of the spontaneous electrical energy of the brain. Data from Drohocki's integrator (which can measure continuously and automatically the energy CLINICAL ASPECTS OF content of the EEG) have revealed that phenothiaP H E N O T H I A Z I N E S TOLERANCE zines and other antipsychotic agents, such as butyroIn normal subjects, chlorpromazine results in a phenones, produce varying degrees of increased EEG considerable degree of sedation when given for the variability (Sugerman, 1964). Drugs, such as amphetafirst time in single doses of 100-200mg. Larger mines and LSD cause a decrease in EEG variability amounts can lead to central nervous system depres- in normal subjects (Murphee, et al., 1962). Using sion to the point of somnolence or coma. Clinical quantitative electroencephalographic procedures, observations suggest that schizophrenic patients not Goldstein et al. (1963), suggested there was a differonly develop tolerance to the hypotensive effects of ence between the spontaneous cortical activity of norchlorpromazine but they also exhibit a tolerance to mal subjects and chronic schizophrenic patients. They the behavioral effects of the drug during short- and referred to this difference as a reduced EEG variabilong-term administration. As Hollister (1970) has lity in the patients, and based on the fact that LSD stated, the ability to tolerate antipsychotic drugs di- was capable of reducing EEG variability in normal rectly correlates with the severity of psychosis. subjects, they concluded that psychotic symptoms, Tolerance to phenothiazines may be explained by whether in schizophrenic patients or induced by LSD, the variations in the rate of absorption and metabo- are accompanied by reduced EEG variability. Reduclism of the phenothiazines. However, these variations tion of EEG variability, as they pointed out, repredo not account for the fact that some schizophrenics sented a state of overstimulation in the central nerare able to tolerate megadoses of injectable pheno- vous system. thiazines (Rifkin et al., 1971). Previous to Goldstein's studies, Davis (1942) had Tolerance to phenothiazines does not seem to be concluded that 61% of schizophrenic patients in her attributed to the psychomotor agitation since it is study had 'choppy' activity in qualitative eleetroencealso present in withdrawn schizophrenic patients. The phalographic procedure. She regarded 'choppy' actifact that some schizophrenic patients show minimal vity as indicating, primarily, overstimulation of responses to the behavioral effects of chlorpromazine, schizophrenic patients. Whatmore & Ellis (1964) conas compared with those of normal subjects, suggests cluded that this overstimulation is accompanied by that a central mechanism might be responsible. increased motor activity in schizophrenic patients. It has been demonstrated that antianxiety agents They coined the term 'hyperponesis' which refers to such as benzodiazepine derivatives are not effective a neurophysiologic state consisting of hyperactivity in the treatment of schizophrenia. Thus, one can con- in pathways extending from motor and premotor corclude that a high level of anxiety is not responsible tical neurons through pyramidal and extrapyramidal for the tolerance of schizophrenic patients to tracts to the peripheral musculature, which results in phenothiazines. myographically measurable muscular activity. 377 G.P. 7/6 a
378
PARVIZ MALEK-AHMADIAND JAMESL. CHAPEL
According to Whatmore & Ellis (1964), this exaggerated activity in the central nervous system of schizophrenic patients may be localized to a portion of motor system or generalized to include the whole motor system. These variations may explain some of the differences in terms of psychomotor activity in schizophrenic patients. For instance, in catatonic schizophrenia when this overstimulation extends through the pyramidal tracts, the patient exhibits psychomotor agitation (excited type); otherwise, the patient remains inactive (withdrawn type). Interestingly enough, Venables & Wing (1962) have indicated that the most withdrawn schizophrenic patients are the most overstimulated. Central nervous system overstimulation in schizophrenic patients does not respond to barbiturates, benzodiazepine derivatives, or alcohol. It is only diminished by adequate doses of phenothiazines (especially chlorpromazine, which presumably has more sedative effect) or other antipsychotic agents. Reduction of the central nervous system overstimulation by whatever means corresponds with increased EEG variability and improvement in the clinical picture. BIOCHEMICAL ASPECTS OF PHENOTH1AZINE TOLERANCE Goldstein et al. (1963) were of the opinion that overstimulation could result from 'information input overload', i.e. an exaggerated input to the brain from the periphery accompanied by a decrease in the ability of the brain to handle such supramaximal charges. However, they made brief reference to the presence of an abnormal stimulating metabolite responsible for the overstimulation of the central nervous system. Carlsson & Lindqvist (1963) first suggested that phenothiazines block dopamine receptors in the central nervous system. By blocking the dopamine receptors, these agents produce a functional deficiency of dopamine. One might speculate that the therapeutic effect of phenothiazines and other antipsychotic agents may be related to the dopamine receptor sites in the cerebral cortex. This speculation is compatible with the neurochemical model of schizophrenia proposed by Wise & Stein (1973), whose studies demonstrated that dopamine-beta-hydroxylase (DBH) activity was significantly reduced in the brain of schizophrenic patients (see Fig. 1). This enzyme converts dopamine to norepinephrine; therefore, its deficiency results in accumulation of dopamine and its psychotoxic derivatives in the central nervous system. Chlorpromazine molecule exerts its antischizophrenic activity by superimposing on dopamine molecule (Snyder et al., 1974). If DAs and DA, are the number of dopamine molecules in the brain of a schizophrenic patient and nonschizophrenic subject, respectively, it can be concluded that : DA~ > DA..
Dopamine-beta-hydroxylase deficiency hypothesis Tyrosine Tyrosine hydroxylase Dihydroxyphenylalanine (DOPA) DOPA decarboxylase Dopamine ,6-Hydroxydopamine , j, Dopamine-beta-hydroxylase Norepinephrine Fig. 1. Therefore, when all dopamine molecules are to be superimposed in the certain area of the brain, more chlorpromazine molecules are required for this purpose in schizophrenic patient as compared to nonschizophrenic subject. On the other hand, the amount of chlorpromazine necessary for a beneficial effect in schizophrenia can be reduced if dopamine synthesis is blocked by alpha-methylparatyrosine. It has also been demonstrated that administration of 1-Dopa to schizophrenic patients exacerbates the schizophrenic symptomatology (Yaryura-Tobias & Merlis, 1970). 1-Dopa, the immediate metabolic precursor of dopamine, is presumed to increase the concentration of dopamine in the brain. Based on the above observations, it would be reasonable to speculate that central nervous system overstimulation associated with the tolerance to antipsychotic agents is due to accumulation of dopamine or its psychotoxic derivatives (6-hydroxydopamine), and only phenothiazines or other antipsychotic agents are capable of reducing overstimulation by blocking the dopamine receptors.
SUMMARY
Clinical observations suggest that some schizophrenic patients exhibit an abnormal tolerance to antipsychotic agents. This tolerance is associated with decreased EEG variability which represents overstimulation of the central nervous system. This overstimulation may be due to accumulation of dopamine or a dopamine derivative substance in the central nervous system. Antipsychotic agents block the action of dopamine and therefore exert therapeutic effect in schizophrenia. The absence of tolerance to antipsychotic drugs may indicate the presence of a 'schizophreniform' psychosis rather than a 'typical' schizophrenic process.
REFERENCES
CARLSSONA. & LINDQVIST,M. (1963) Effects of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta pharmac. tox. 20, 140-144. DAVIS P. A. (1942) Comparative study of the EEGs of schizophrenic and manic depressive patients. Am. J. Psychiat. 114, 882 889.
Tolerance to phenothiazines in schizophrenic patients DROHOCKI L. (1948) L'int6grateur de l'61ectroproduction c6r6brale pour r61ectroencephalographic quantitative. Rev. Neurol. 80, 619-624. GOLDSTEINL., MURPHEEH. B., SUGERMANA. A., PFEIFFER C. C. t~ JENNEYE. H. (1963) Quantitative electroencephalographic analysis of naturally occurring (schizophrenic) and drug-induced psychotic states in human males. Clin. Pharmac. Ther. 4, 10-21. HOLLISTERL. E. (1970) Choice of antipsychotic drugs. Am. J. Psychiat. 127, 186--190. MtlRPHEE H. B., JENNEY E. G. • PFEIFFER C. C. (1962) Quantitative electroencephalographic analysis of the effects of lysergic acid diethylamide (LSD-25) and D-amphetamine in man. Fedn Proc. Fedn Am. Socs exp. Biol. 21, 337. RIFKIN A., QUITKIN F., CARILLOC. & KLEIN D. F. (1971) Very high dosage fluphenazine for nonchronic treatment-refractory patients. Archs gen. Psychiat. 25, 398-403.
379
SNYDERS. H., SHAILESHP. B., YAMAMURAH. I. & GREENBERG D. (1974) Drugs, neurotransmitters, and schizophrenia. Science 184, 1243-1253. SUGERMAN A. A. (1964) A pilot study of floropipamide (dipiperon) Dis. nerv. Syst. 25, 355-358. SUGERMANA. A., GOLDSTEINL., MURPHEEH. B., PFEIFFER C. C. t~ JENNEY E. H. (1964) EEG and behavioral changes in schizophrenia. Archs yen. Psychiat. 10, 340-344. VENAaLES P. H. & Wlr~G J. K. (1962) Level of arousal and subclassification of schizophrenia. Archs #en. Psychiat. 7, 114-119. WHmMORE G. B. & ELLIS,R. M. (1964) Some neurophysiologic aspects of schizophrenia: an electromyographic study. Am. J. Psychiat. 120, 1116-1169. WISE C. G. & STEIN L. (1973) Dopamine-beta-hydroxylase deficits in the brain of schizophrenic patients. Science 181, 344-347. YARYURA-TOmASJ. A. & MERLIS S. (1970) Levodopa and schizophrenia. J. Am. med. Ass. 21L 1857.