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Neuroleptics, extrapyramidal symptoms, and serum-calcium levels
Comprehensive Psychiatry (Official Journal of the American Psychopathological
VOL. 25, NO. 6
Association)
NOVEMBER/DECEMBER
1984
Neuroleptics, Extrapyramidal Symptoms, and SerumCalcium Levels Mohamed H. El-Defrawi and Thomas J. Craig A prospective study of 34 new admissions to a psychiatric center revealed an 80% incidence of extrapyramidal symptoms among patients receiving only neuroleptic drugs (N = 24) during the first 2 weeks of hospitalization. The occurence of acute dystonic reactions and parkinsonian symptoms (but not akathisia) in this group was significantly associated with a decrease in serumcalcium levels. The findings suggest the need for (1) prophylactic use of antiparkinsonian drugs during the initial stages of neuroleptic treatment and (2) further research into the possible role of calcium metabolism in the production of extrapyramidal side effects.
T
HE three major neuroleptic-induced
extrapyramidal movement disorders (EPS) (acute dystonia, akathisia and Parkinsonism-like symptoms) usually occur within days to weeks after the start of neuroleptic treatment and are controlled by adjusting neuroleptic dosage, changing the neuroleptic (NL), or adding an antiparkinsonian drug CAP). The etiology of these syndromes is thought to be a druginduced dopamine-acetylcholine imbalance in the nigrostriatal region of the brain. The incidence of these movements has been linked to a number of factors including biological sensitivity, neuroleptic molecular structure, dosage and duration of neuroleptic treatment, and age and sex. ’ Reported incidence rates have varied from less than 20%* to as high as 95%,’ depending on the methodology and population demographics of particular studies. A careful calculation of the expected incidence of these EPS under specified clinical conditions is of crucial importance in view of the current controversy regarding the role of AP drugs in the use of neuroleptic medication. Conventional wisdom has advised against the routine use of AP medication with neuroleptics unless patients develop EPS 4*5to spare patients the risk of AP-induced side effects.@ Other authors have recommended routine prophylactic use of AP drugs with neuroleptics, especially to prevent the emergence of akinesia.9-‘1 In addition, several clinical and psychopharmacological studies have suggested a role for calcium in the etiology of the side effects either on the basis of underlying metabolic calcium changes or due to functional calcium changes secondary to neuroleptic administration. Alexander, Van Kammen, and Bunneyl* reported lower From Mohomed H. El-Defrowi. M.D.. Division of Children’s Psychiatry, Columbia University, New York State Psychiatric Institute, New York, NY; and Thomas J. Craig, M.D., M.P.H., Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY and the Deportment of Psychiatry and Behavioral Science, State University of New York ot Stony Brook, Stony Brook, N. YI Address reprint requests to Thomas J. Craig, M.D., M.P.H.. 40 Woodbine Rood, New City, NY 10956. @I984 by Grune & Strorton, Inc. WIO-440X/84/2506-ooo1$03.00/0 Comprehensive Psychiatry, Vol. 25, No. 6, (November/December)
1984
539
540
EL-DEFRAWI
AND CRAIG
serum calcium levels during neuroleptic administration as compared to drug-free periods with an additional decrease in serum calcium coincident with the emergence of EPS. Furthermore, one report described several patients with untreated hypoparathyroidism and hypocalcemia who suffered acute dystonia within hours of the administration of small doses of phenothiazine. I3 Recent psychopharmacological studies have indicated that antipsychotic drugs show selective binding to the calcium-dependent activator (calmodulin) of several enzyme systems.‘“” Phenothiazines are known to be effective chelators of calcium,‘* a mechanism that might relate to their biochemical and pharmacologic actions.19-21 Seeman** reported that free calcium can displace membrane-absorbed chlorpromazine (CPZ) in the same way that free CPZ displaces membrane-bound calcium ions. Calcium has been suggested to be an important intracellular messenger that regulates a variety of enzyme systems in the synthesis and release of neurotransmitters.23s24 Although the effects of calcium at the cellular level cannot be directly inferred from alterations in serum calcium, physiological studies have shown an association between decreased extracellular calcium levels and increased behavioral and neuronal excitability.25 In view of these findings, the present study has addressed two clinical questions: (1) What is the incidence of EPS in a sample of admissions to a state hospital during the first 2 weeks of treatment?, and (2) are neuroleptic-induced EPS associated with alterations in serum-calcium levels? MATERIALS
AND METHODS
Consecutive patients admitted to a large state hospital were entered into the present study if they met the following criteria: male, admitted between Monday and Friday morning, consented to an examination and serum-calcium determination on at least two occasions. The final study sample was also limited to those patients who remained hospitalized for 2 weeks to permit the second study assessment. After giving consent, all study patients were examined for EPS within 72 hours of admission by one of the authors (MED) using the Simpson-Angus Neurological Rating Scale (NRS).26 After this rating, information was obtained from the patient, treating physician, and available records regarding DSM III diagnosis and history of neuroleptic use prior to admission. Independently, within 24 hours of admission, a serum-calcium level was determined as part of the routine admission SMAC-20. Two weeks after the initial evaluation, a second assessment was carried out using the same rating scale and serum-calcium determination. In addition, ward staff were asked to immediately report to the investigators if any study patient developed EPS during the 2-week period. One investigator (MED) routinely canvassed the wards on a daily basis for evidence of this reaction. Those patients who developed EPS prior to the second formal evaluation received an additional evaluation of EPS and serum-calcium level at the time of the reaction.
RESULTS A total of 45 patients meeting the criteria were consecutively admitted during the study period. Of these, eight were discharged before the final evaluation and three withdrew from the study, representing 24.4% of the initial eligible population. Thus, the study sample consisted of 34 patients, 27 of whom received neuroleptics during the study period and 7 of whom received no neuroleptics. Two of the neuroleptic-treated patients were discharged after stays of 9 and 11 days but were kept in the study sample because they had received a complete set of evaluations. All patients were physically well. Half of the subjects were under age 35, with an age range of 21 to 73. Twenty-three (67.7%) received the diagnosis of schizophrenia,
NEUROLEPTICS.
EXTRAPYRAMIDAL
541
SYMPTOMS
Table 1. ExtrapyramIdal Symptoms (EFS) Over First 2 Weeks of Treatment by Neurolsptk Treatment ParklnsonwnLike Symptoms Acute
None Neuroleptlc
Dystonia
Akathlsia
on
Rating
Total
(NL)
Treatment’
N
%
N
5
(20.6)
3
(100.0)
-
No NL
6
(65.7)
-
Total
14
(41.2)
NL + AP
‘NL Only versus Other
5
5
%
N
(20.6)
6
-
-
-
-
(14.7)
Y No EPS versus All EPS: Chl square
% (25.0)
N
%
6
(33.3)
_ 6
= 13.94, P <
(17.7)
-
N ,
*4
%
(100.0)
3
(100.0)
1
(14.3)
7
UOO.0)
9
(26 5)
34
(100.0)
01
the other diagnostic categories being alcoholism (4), affective disorder (4), and one each of dementia, atypical psychosis, and borderline personality. Table 1 summarizes the results bearing on the first study question. Only 20.1% of those patients treated with only NL drugs failed to show EPS during the 2week study period as compared to virtually all of those receiving either NL plus AP drugs or no NL drugs, a finding that was highly statistically significant (Chi square = 13.94, P < .Ol). The one patient with EPS by rating in the no NL drugs group was a 59-year-old man with a prior 30-year history of psychiatric hospitalization who had evidence of EPS on admission that did not change substantially during the 2-week study period and may represent idiopathic parkinsonian symptoms or a persistent sequel of neuroleptic treatment in the past. The actual picture was more complex than that suggested by Table 1 because ten patients who received only NL drugs had been receiving these drugs during the 2 weeks prior to admission, four of these (40%) experienced no EPS during the study period. When this group is removed from the group given only NL drugs in Table 1, 13 (92.9%) of the 14 patients who had not received NL drugs during the 2 weeks prior to admission developed EPS during the study period, including 4 of the 5 patients experiencing acute dystonic reactions and 5 of the 6 patients developing akathisia. All serum-calcium levels determined during the study period were within normal limits. Significantly more patients experiencing EPS showed a decrease in their serum-calcium levels during the study period, exclusively among patients experiencing acute dystonia (of whom 80% showed a decrease) and those showing parkinsonism-like symptoms (44.4% showing a decrease). In contrast, none of the patients developing akathisia and only one (7.1%) of 14 patients with no EPS showed a serum-calcium decrease. The comparisons of serum-calcium changes for those patients with no EPS as compared to those with acute dystonia and with acute dystonia and/or EPS (other than akathisia) were both highly statistically significant (Chi square = 10.09, P < .Ol and Chi square = 8.02, P < .Ol, respectively). However, there was no systematic difference in the initial serumcalcium levels between those developing and not developing EPS and the magnitude of the average serum-calcium changes was generally modest. A total of 7 specific neuroleptics were used by the 27 patients receiving them during the study period. Because of the small numbers receiving any given neuroleptic, no meaningful conclusions could be drawn as to a differential propensity for causing EPS across neuroleptics. However, the dosages used were generally
542
EL-DEFRAWI
AND CRAIG
modest and not substantially different between those developing EPS and those not developing EPS. The time of onset of EPS varied according to category. Acute dystonic reactions occurred earliest, with average onset 1.8 days after admission (range 1 to 4 days) while akathisia had an average onset of 5.5 days after admission (range 1 to 11 days). The exact onset for Parkinsonism-like symptoms on rating only could not be determined because in only one case did the ward staff note its presence prior to the second study rating. DISCUSSION
The present findings are limited by the naturalistic nature of the study and the relatively small sample size. Both limitations were considered acceptable in its context as a pilot study, however, future replications should include a more systematic experimental design including, if practicable, random allocation of patients to, at a minimum, the NL drugs only and NL-plus-AP drug conditions and a placebo control at least for the AP drugs. However, despite these limitations, the magnitude of the observed findings is provocative. In addition, the present study expands the current literature in being, to our knowledge, the first prospective study of the association between neuroleptic-induced EPS and serum-calcium levels. The two major findings of the present study are (1) that the vast majority of patients receiving NL drugs in the absence of AP drugs showed evidence of EPS during the first 2 weeks of such treatment, and that (2) there is a significant association between the emergence of acute dystonic or parkinsonian symptoms and a decrease in serum-calcium levels. The fact that 80% of those patients treated with only neuroleptics showed evidence of extrapyramidal movements during the first 2 weeks of treatment is consistent with earlier reports. For example, Biner and Levyz7 report a 95% incidence of extrapyramidal reactions in Asians and a 67.5% incidence in non-Asians during the first 2 weeks of haloperidol therapy. Likewise, Angus and Simpson** cited the incidence of EPS to range from 44% to 88%. However, other studies have suggested a lower incidence.2 Undoubtedly, factors such as patient age and sex, and the type and dosage of the neuroleptic will influence this incidence rate.29 Nevertheless, the magnitude of the present findings suggests that the current practice of withholding AP drugs until the development of EPS may need to be reassessed. This conclusion is further supported by the fact that eight of the nine cases of parkinsonism-like symptoms went unrecognized and untreated by the clinical staff and were only discovered at the second study examination. This finding supports the suggestion by Manos, Gkiozepas, and Logothetis30 that structured-assessment instruments such as the Simpson-Angus scale be used routinely to identify these symptoms. In addition, the 20% incidence of acute dystonic reactions is similar to that cited by Angus and Simpson** and, in view of the potentially lethal nature of such effects,3*p32 further supports the advisability of routine prophylactic use of antiparkinsonian medication, at least during the initial few weeks of neuroleptic treatment. Clearly, as noted earlier, controlled replication studies are needed to definitively address this issue because the few studies to examine the efficacy of initial anticholinergic found a significant reduction prophylaxis have found conflicting results, some 29*33,34
NEUROLEPTICS,
EXTRAPYRAMIDAL
543
SYMPTOMS
in EPS with such prophylaxis while others35*36 reported no difference between prophylactic and control patient populations in EPS incidence. Of importance in evaluating these studies, however, is the fact that the former studies, like the present one, were generally prospective in design while the latter (finding no difference) were retrospective. The finding of a decrease in serum-calcium levels among significantly more patients developing dystonic or parkinsonism-like symptoms is consistent with literature cited earlier suggesting a role for calcium metabolism in the emergence of EPS. While the complexities of calcium metabolism cannot be directly inferred from the total serum-calcium determination, the present findings suggest that the initial serum-calcium levels are not systematically different among those developing EPS as compared to those not developing such symptoms. Thus, at least from this small sample, initial serum-calcium levels did not predict development of subsequent EPS, unlike the findings of Alexander et al.i2 in a retrospective study. In addition, the administration of neuroleptics did not routinely lower serum-calcium levels in all patients. Also, at least as regards serum-calcium determinations, hypocalcemia does not appear to play a role in the development of EPS. Finally, although the numbers are small, the findings suggest that if calcium metabolism is involved in the development of some EPS, akathisia may differ qualitatively from acute dystonia and parkinsonism-like symptoms because none of the akathisia patients showed a decrease in serum calcium. The present findings suggest the need for more systematic prospective study of the interaction of neuroleptic use, serum calcium, and EPS in a larger sample. Such a study should include restriction to one or perhaps two neuroleptics of different chemical classes (e.g., phenothiazine and a butyrophenone) with purportedly different effects on the calcium-calmodulin system, controlling for dose and serum level of the neuroleptic. In addition, more systematic measurement of serum-calcium levels, especially as regards ionized versus unionized calcium fractions is indicated. ACKNOWLEDGMENTS The authors
acknowledge
the assistance
of Charlotte
E. Oliver, R.N., Director,
Rockland
Psychiatric
Center (RPC). and Joseph Barsa, M.D., Unit Chief of the RPC admission unit, and their staff during the conduct of this study, and of Frances Simpson for manuscript preparation.
REFERENCES Donlan PT, Stenson RL: Neuroleptic-induced extrapyramidal symptoms. Dis Nerv Syst 37:629-635, 1976 2. Klett CJ, Point P, Caffey E Jr: Evaluating the long term need for antiparkinsonian drugs by chronic schizophrenics. Arch Gen Psychiatr 26:374-379, 1972 3. Donlan PT, Axelrod AD, Tupin JP, Chien C: Comparison of depot fluphenazines: duration of action and incidence of side effects. Compr Psychiatry 17:369-376, 1976 4. Crane GE: Pseudoparkinsonism and tardive dyskinesia. Arch Neurol 27:426-430, 1972 5. Crane GE, Naranjo ER: Motor disorders induced by neuroleptics: a proposed new classification. Arch Gen Psychiatr 24:179-184, 1971 6. Parks JO: Adverse effects of antiparkinsonian drugs. Drugs 21:341-353, 1981 7. Klawans HL, Weiner WJ: The pharmacology of choreatic movement disorders. Prog Neurobiol 6:49-80, 1976 1.
544
EL-DEFRAWI
AND CRAIG
8. Mindham RHS: Antiparkinsonian drugs and depot neuroleptics. Br J Psychiatr 141:21 l212, 1982 (letter to editor) 9. Rifkin A, Quitkin F, Klein D: Akinesia. A poorly recognized drug-induced extrapyramidal behavior disorder. Arch Gen Psychiatr 32:672-674, 1975 10. Van Putten T: The many faces of akathisia. Compr Psychiatry 16:4347, 1975 11. Huttenbach DE: A middle ground in prophylactic antiparkinsonian medication. Am J Psychiatr 134:82&821, 1977 (letter to editor) 12. Alexander PE, van Kammen DB, Bunney WE Jr: Serum calcium and magnesium levels in schizophrenia. II. Possible relationship to extrapyramidal symptoms. Arch Gen Psychiatr 36: 1372-l 377, 1979 13. Schaff M, Payne CA: Dystonic reactions to prochlorperazine in hypoparathyroidism. New Engl J Med 18991-995, 1966 14. Levin RM, Weiss B: Selective binding of antipsychotics and other psychoactive agents to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. J Pharmacol Exp Ther 208454-459, 1979 15. Levin RM, Weiss B: Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. Mol Pharmacol 13:69&697, 1977 16. Wolff DJ, Brostrom CO: Calcium-dependent cyclic nucleotide phosphodiesterase from brain. Identification of phospholipids as calcium-independent activators. Arch Biochem Biophys 173:720-731, 1976 17. Mori T, Taki V, Minakucci R, Yu B, Mishizuka Y: Inhibitory action of chlorpromazine, dibucaine, and other phospholipid-interacting drugs on calcium-activated, phospholipiddependent protein kinase. J Biol Chem 255:8378-8380, 1980 18. Weiss B, Levin RM: Mechanism for selectively inhibiting the activation of cyclic nucleotide phosphodiesterase and adenylate cyclase by antipsychotic agents, in George WJ, Ignarra LJ (eds): Advances in Cyclic Nucleotide Research (vol 9). New York, Raven Press 1978, pp 285-303 19. Osborn M, Weber K: Damage of cellular functions by trifluoperazine, a calmodulinspecific drug. Exp Cell Res 130:484-488, 1980 20. Levin RM, Weiss B: Selective inhibition of an activable ATPase by trifluoperazine. Pharmacologist 20~195, 1978 (abstr) 21. Raess BU, Vincenzi FF: Calmodulin activation of red blood cell (Ca + Mg)-ATPase and its antagonism by phenothiazines. Mol Pharmacol 18:253-258, 1980 22. Seeman P: The membrane actions of anesthetics and tranquilizers. Pharmacol Rev 24:583-655, 1972 23. Dodge FA Jr, Rahamimoff R: Cooperative action of calcium ions in transmitter release at the neuromuscular junction. J Physiol 193:419-432, 1967 24. Means AR, Dedman JR: Calmodulin-an intracellular calcium receptor. Nature 285:73-77, 1980 25. Curtis DR, Perrin DD, Watkins JC: The excitation of spinal neurons by the iontophoretic application of agents which chelate calcium. J Neurochem 6:1-20, 1960 26. Simpson GM, Angus JWS: Drug-induced extrapyramidal disorders. Acta Psychiatr Stand (Suppl) 212:11-19, 1970 27. Binder RL, Levy R: Extrapyramidal reactions in Asians. Am J Psychiatr 138:12431244, 1981 28. Angus JWS, Simpson GM: Hysteria and drug-induced dystonia. Acta Psychiatr Stand (Suppl) 212:52-58, 1970 29. Keepers GA, Clappison VJ, Casey DE: Initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatr 40: 1113-l 117, 1983 30. Manos N, Gkiozepas J, Logothetis J: The need for continuous use of antiparkinsonian medication with chronic schizophrenic patients receiving long-term neuroleptic therapy. Am J Psychiatr 138:184-188, 1981 3 1. Moss HB, Green A: Neuroleptic-associated dysphagia confirmed by esophageal manometry. Am J Psychiatr 139:515-516, 1982 32. McDonal CE Jr: Haloperidol and laryngeal-pharyngeal dystonia. Am J Psychiatr 138:1262-1263, 1981 (letter to editor)
NEUROLEPTICS,
EXTRAPYRAMIDAL
SYMPTOMS
545
33. Hanlon TE, Schoenrich C, Freinek E, et al: Perphenazine benztropine mesylate treatment of newly admitted psychiatric patients. Psychopharmacology 9:328-339, 1966 34. Stem T, Anderson W: Benztropine prophylaxis of dystonic reactions. Psychopharmacology 61:261-262, 1979 35. Di Mascio A, Demergian E: Antiparkinson drug overuse. Psychosomatics 11:596601, 1970 36. Swett C Jr, Cole JO, Shapiro S, et al: Extrapyramidal side effects in chlorpromazine recipients: Emergence according to benztropine prophylaxis. Arch Gen Psychiatr 34:942943, 1977
VOL. 25, NO. 6
Association)
NOVEMBER/DECEMBER
1984
Neuroleptics, Extrapyramidal Symptoms, and SerumCalcium Levels Mohamed H. El-Defrawi and Thomas J. Craig A prospective study of 34 new admissions to a psychiatric center revealed an 80% incidence of extrapyramidal symptoms among patients receiving only neuroleptic drugs (N = 24) during the first 2 weeks of hospitalization. The occurence of acute dystonic reactions and parkinsonian symptoms (but not akathisia) in this group was significantly associated with a decrease in serumcalcium levels. The findings suggest the need for (1) prophylactic use of antiparkinsonian drugs during the initial stages of neuroleptic treatment and (2) further research into the possible role of calcium metabolism in the production of extrapyramidal side effects.
T
HE three major neuroleptic-induced
extrapyramidal movement disorders (EPS) (acute dystonia, akathisia and Parkinsonism-like symptoms) usually occur within days to weeks after the start of neuroleptic treatment and are controlled by adjusting neuroleptic dosage, changing the neuroleptic (NL), or adding an antiparkinsonian drug CAP). The etiology of these syndromes is thought to be a druginduced dopamine-acetylcholine imbalance in the nigrostriatal region of the brain. The incidence of these movements has been linked to a number of factors including biological sensitivity, neuroleptic molecular structure, dosage and duration of neuroleptic treatment, and age and sex. ’ Reported incidence rates have varied from less than 20%* to as high as 95%,’ depending on the methodology and population demographics of particular studies. A careful calculation of the expected incidence of these EPS under specified clinical conditions is of crucial importance in view of the current controversy regarding the role of AP drugs in the use of neuroleptic medication. Conventional wisdom has advised against the routine use of AP medication with neuroleptics unless patients develop EPS 4*5to spare patients the risk of AP-induced side effects.@ Other authors have recommended routine prophylactic use of AP drugs with neuroleptics, especially to prevent the emergence of akinesia.9-‘1 In addition, several clinical and psychopharmacological studies have suggested a role for calcium in the etiology of the side effects either on the basis of underlying metabolic calcium changes or due to functional calcium changes secondary to neuroleptic administration. Alexander, Van Kammen, and Bunneyl* reported lower From Mohomed H. El-Defrowi. M.D.. Division of Children’s Psychiatry, Columbia University, New York State Psychiatric Institute, New York, NY; and Thomas J. Craig, M.D., M.P.H., Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY and the Deportment of Psychiatry and Behavioral Science, State University of New York ot Stony Brook, Stony Brook, N. YI Address reprint requests to Thomas J. Craig, M.D., M.P.H.. 40 Woodbine Rood, New City, NY 10956. @I984 by Grune & Strorton, Inc. WIO-440X/84/2506-ooo1$03.00/0 Comprehensive Psychiatry, Vol. 25, No. 6, (November/December)
1984
539
540
EL-DEFRAWI
AND CRAIG
serum calcium levels during neuroleptic administration as compared to drug-free periods with an additional decrease in serum calcium coincident with the emergence of EPS. Furthermore, one report described several patients with untreated hypoparathyroidism and hypocalcemia who suffered acute dystonia within hours of the administration of small doses of phenothiazine. I3 Recent psychopharmacological studies have indicated that antipsychotic drugs show selective binding to the calcium-dependent activator (calmodulin) of several enzyme systems.‘“” Phenothiazines are known to be effective chelators of calcium,‘* a mechanism that might relate to their biochemical and pharmacologic actions.19-21 Seeman** reported that free calcium can displace membrane-absorbed chlorpromazine (CPZ) in the same way that free CPZ displaces membrane-bound calcium ions. Calcium has been suggested to be an important intracellular messenger that regulates a variety of enzyme systems in the synthesis and release of neurotransmitters.23s24 Although the effects of calcium at the cellular level cannot be directly inferred from alterations in serum calcium, physiological studies have shown an association between decreased extracellular calcium levels and increased behavioral and neuronal excitability.25 In view of these findings, the present study has addressed two clinical questions: (1) What is the incidence of EPS in a sample of admissions to a state hospital during the first 2 weeks of treatment?, and (2) are neuroleptic-induced EPS associated with alterations in serum-calcium levels? MATERIALS
AND METHODS
Consecutive patients admitted to a large state hospital were entered into the present study if they met the following criteria: male, admitted between Monday and Friday morning, consented to an examination and serum-calcium determination on at least two occasions. The final study sample was also limited to those patients who remained hospitalized for 2 weeks to permit the second study assessment. After giving consent, all study patients were examined for EPS within 72 hours of admission by one of the authors (MED) using the Simpson-Angus Neurological Rating Scale (NRS).26 After this rating, information was obtained from the patient, treating physician, and available records regarding DSM III diagnosis and history of neuroleptic use prior to admission. Independently, within 24 hours of admission, a serum-calcium level was determined as part of the routine admission SMAC-20. Two weeks after the initial evaluation, a second assessment was carried out using the same rating scale and serum-calcium determination. In addition, ward staff were asked to immediately report to the investigators if any study patient developed EPS during the 2-week period. One investigator (MED) routinely canvassed the wards on a daily basis for evidence of this reaction. Those patients who developed EPS prior to the second formal evaluation received an additional evaluation of EPS and serum-calcium level at the time of the reaction.
RESULTS A total of 45 patients meeting the criteria were consecutively admitted during the study period. Of these, eight were discharged before the final evaluation and three withdrew from the study, representing 24.4% of the initial eligible population. Thus, the study sample consisted of 34 patients, 27 of whom received neuroleptics during the study period and 7 of whom received no neuroleptics. Two of the neuroleptic-treated patients were discharged after stays of 9 and 11 days but were kept in the study sample because they had received a complete set of evaluations. All patients were physically well. Half of the subjects were under age 35, with an age range of 21 to 73. Twenty-three (67.7%) received the diagnosis of schizophrenia,
NEUROLEPTICS.
EXTRAPYRAMIDAL
541
SYMPTOMS
Table 1. ExtrapyramIdal Symptoms (EFS) Over First 2 Weeks of Treatment by Neurolsptk Treatment ParklnsonwnLike Symptoms Acute
None Neuroleptlc
Dystonia
Akathlsia
on
Rating
Total
(NL)
Treatment’
N
%
N
5
(20.6)
3
(100.0)
-
No NL
6
(65.7)
-
Total
14
(41.2)
NL + AP
‘NL Only versus Other
5
5
%
N
(20.6)
6
-
-
-
-
(14.7)
Y No EPS versus All EPS: Chl square
% (25.0)
N
%
6
(33.3)
_ 6
= 13.94, P <
(17.7)
-
N ,
*4
%
(100.0)
3
(100.0)
1
(14.3)
7
UOO.0)
9
(26 5)
34
(100.0)
01
the other diagnostic categories being alcoholism (4), affective disorder (4), and one each of dementia, atypical psychosis, and borderline personality. Table 1 summarizes the results bearing on the first study question. Only 20.1% of those patients treated with only NL drugs failed to show EPS during the 2week study period as compared to virtually all of those receiving either NL plus AP drugs or no NL drugs, a finding that was highly statistically significant (Chi square = 13.94, P < .Ol). The one patient with EPS by rating in the no NL drugs group was a 59-year-old man with a prior 30-year history of psychiatric hospitalization who had evidence of EPS on admission that did not change substantially during the 2-week study period and may represent idiopathic parkinsonian symptoms or a persistent sequel of neuroleptic treatment in the past. The actual picture was more complex than that suggested by Table 1 because ten patients who received only NL drugs had been receiving these drugs during the 2 weeks prior to admission, four of these (40%) experienced no EPS during the study period. When this group is removed from the group given only NL drugs in Table 1, 13 (92.9%) of the 14 patients who had not received NL drugs during the 2 weeks prior to admission developed EPS during the study period, including 4 of the 5 patients experiencing acute dystonic reactions and 5 of the 6 patients developing akathisia. All serum-calcium levels determined during the study period were within normal limits. Significantly more patients experiencing EPS showed a decrease in their serum-calcium levels during the study period, exclusively among patients experiencing acute dystonia (of whom 80% showed a decrease) and those showing parkinsonism-like symptoms (44.4% showing a decrease). In contrast, none of the patients developing akathisia and only one (7.1%) of 14 patients with no EPS showed a serum-calcium decrease. The comparisons of serum-calcium changes for those patients with no EPS as compared to those with acute dystonia and with acute dystonia and/or EPS (other than akathisia) were both highly statistically significant (Chi square = 10.09, P < .Ol and Chi square = 8.02, P < .Ol, respectively). However, there was no systematic difference in the initial serumcalcium levels between those developing and not developing EPS and the magnitude of the average serum-calcium changes was generally modest. A total of 7 specific neuroleptics were used by the 27 patients receiving them during the study period. Because of the small numbers receiving any given neuroleptic, no meaningful conclusions could be drawn as to a differential propensity for causing EPS across neuroleptics. However, the dosages used were generally
542
EL-DEFRAWI
AND CRAIG
modest and not substantially different between those developing EPS and those not developing EPS. The time of onset of EPS varied according to category. Acute dystonic reactions occurred earliest, with average onset 1.8 days after admission (range 1 to 4 days) while akathisia had an average onset of 5.5 days after admission (range 1 to 11 days). The exact onset for Parkinsonism-like symptoms on rating only could not be determined because in only one case did the ward staff note its presence prior to the second study rating. DISCUSSION
The present findings are limited by the naturalistic nature of the study and the relatively small sample size. Both limitations were considered acceptable in its context as a pilot study, however, future replications should include a more systematic experimental design including, if practicable, random allocation of patients to, at a minimum, the NL drugs only and NL-plus-AP drug conditions and a placebo control at least for the AP drugs. However, despite these limitations, the magnitude of the observed findings is provocative. In addition, the present study expands the current literature in being, to our knowledge, the first prospective study of the association between neuroleptic-induced EPS and serum-calcium levels. The two major findings of the present study are (1) that the vast majority of patients receiving NL drugs in the absence of AP drugs showed evidence of EPS during the first 2 weeks of such treatment, and that (2) there is a significant association between the emergence of acute dystonic or parkinsonian symptoms and a decrease in serum-calcium levels. The fact that 80% of those patients treated with only neuroleptics showed evidence of extrapyramidal movements during the first 2 weeks of treatment is consistent with earlier reports. For example, Biner and Levyz7 report a 95% incidence of extrapyramidal reactions in Asians and a 67.5% incidence in non-Asians during the first 2 weeks of haloperidol therapy. Likewise, Angus and Simpson** cited the incidence of EPS to range from 44% to 88%. However, other studies have suggested a lower incidence.2 Undoubtedly, factors such as patient age and sex, and the type and dosage of the neuroleptic will influence this incidence rate.29 Nevertheless, the magnitude of the present findings suggests that the current practice of withholding AP drugs until the development of EPS may need to be reassessed. This conclusion is further supported by the fact that eight of the nine cases of parkinsonism-like symptoms went unrecognized and untreated by the clinical staff and were only discovered at the second study examination. This finding supports the suggestion by Manos, Gkiozepas, and Logothetis30 that structured-assessment instruments such as the Simpson-Angus scale be used routinely to identify these symptoms. In addition, the 20% incidence of acute dystonic reactions is similar to that cited by Angus and Simpson** and, in view of the potentially lethal nature of such effects,3*p32 further supports the advisability of routine prophylactic use of antiparkinsonian medication, at least during the initial few weeks of neuroleptic treatment. Clearly, as noted earlier, controlled replication studies are needed to definitively address this issue because the few studies to examine the efficacy of initial anticholinergic found a significant reduction prophylaxis have found conflicting results, some 29*33,34
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SYMPTOMS
in EPS with such prophylaxis while others35*36 reported no difference between prophylactic and control patient populations in EPS incidence. Of importance in evaluating these studies, however, is the fact that the former studies, like the present one, were generally prospective in design while the latter (finding no difference) were retrospective. The finding of a decrease in serum-calcium levels among significantly more patients developing dystonic or parkinsonism-like symptoms is consistent with literature cited earlier suggesting a role for calcium metabolism in the emergence of EPS. While the complexities of calcium metabolism cannot be directly inferred from the total serum-calcium determination, the present findings suggest that the initial serum-calcium levels are not systematically different among those developing EPS as compared to those not developing such symptoms. Thus, at least from this small sample, initial serum-calcium levels did not predict development of subsequent EPS, unlike the findings of Alexander et al.i2 in a retrospective study. In addition, the administration of neuroleptics did not routinely lower serum-calcium levels in all patients. Also, at least as regards serum-calcium determinations, hypocalcemia does not appear to play a role in the development of EPS. Finally, although the numbers are small, the findings suggest that if calcium metabolism is involved in the development of some EPS, akathisia may differ qualitatively from acute dystonia and parkinsonism-like symptoms because none of the akathisia patients showed a decrease in serum calcium. The present findings suggest the need for more systematic prospective study of the interaction of neuroleptic use, serum calcium, and EPS in a larger sample. Such a study should include restriction to one or perhaps two neuroleptics of different chemical classes (e.g., phenothiazine and a butyrophenone) with purportedly different effects on the calcium-calmodulin system, controlling for dose and serum level of the neuroleptic. In addition, more systematic measurement of serum-calcium levels, especially as regards ionized versus unionized calcium fractions is indicated. ACKNOWLEDGMENTS The authors
acknowledge
the assistance
of Charlotte
E. Oliver, R.N., Director,
Rockland
Psychiatric
Center (RPC). and Joseph Barsa, M.D., Unit Chief of the RPC admission unit, and their staff during the conduct of this study, and of Frances Simpson for manuscript preparation.
REFERENCES Donlan PT, Stenson RL: Neuroleptic-induced extrapyramidal symptoms. Dis Nerv Syst 37:629-635, 1976 2. Klett CJ, Point P, Caffey E Jr: Evaluating the long term need for antiparkinsonian drugs by chronic schizophrenics. Arch Gen Psychiatr 26:374-379, 1972 3. Donlan PT, Axelrod AD, Tupin JP, Chien C: Comparison of depot fluphenazines: duration of action and incidence of side effects. Compr Psychiatry 17:369-376, 1976 4. Crane GE: Pseudoparkinsonism and tardive dyskinesia. Arch Neurol 27:426-430, 1972 5. Crane GE, Naranjo ER: Motor disorders induced by neuroleptics: a proposed new classification. Arch Gen Psychiatr 24:179-184, 1971 6. Parks JO: Adverse effects of antiparkinsonian drugs. Drugs 21:341-353, 1981 7. Klawans HL, Weiner WJ: The pharmacology of choreatic movement disorders. Prog Neurobiol 6:49-80, 1976 1.
544
EL-DEFRAWI
AND CRAIG
8. Mindham RHS: Antiparkinsonian drugs and depot neuroleptics. Br J Psychiatr 141:21 l212, 1982 (letter to editor) 9. Rifkin A, Quitkin F, Klein D: Akinesia. A poorly recognized drug-induced extrapyramidal behavior disorder. Arch Gen Psychiatr 32:672-674, 1975 10. Van Putten T: The many faces of akathisia. Compr Psychiatry 16:4347, 1975 11. Huttenbach DE: A middle ground in prophylactic antiparkinsonian medication. Am J Psychiatr 134:82&821, 1977 (letter to editor) 12. Alexander PE, van Kammen DB, Bunney WE Jr: Serum calcium and magnesium levels in schizophrenia. II. Possible relationship to extrapyramidal symptoms. Arch Gen Psychiatr 36: 1372-l 377, 1979 13. Schaff M, Payne CA: Dystonic reactions to prochlorperazine in hypoparathyroidism. New Engl J Med 18991-995, 1966 14. Levin RM, Weiss B: Selective binding of antipsychotics and other psychoactive agents to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. J Pharmacol Exp Ther 208454-459, 1979 15. Levin RM, Weiss B: Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. Mol Pharmacol 13:69&697, 1977 16. Wolff DJ, Brostrom CO: Calcium-dependent cyclic nucleotide phosphodiesterase from brain. Identification of phospholipids as calcium-independent activators. Arch Biochem Biophys 173:720-731, 1976 17. Mori T, Taki V, Minakucci R, Yu B, Mishizuka Y: Inhibitory action of chlorpromazine, dibucaine, and other phospholipid-interacting drugs on calcium-activated, phospholipiddependent protein kinase. J Biol Chem 255:8378-8380, 1980 18. Weiss B, Levin RM: Mechanism for selectively inhibiting the activation of cyclic nucleotide phosphodiesterase and adenylate cyclase by antipsychotic agents, in George WJ, Ignarra LJ (eds): Advances in Cyclic Nucleotide Research (vol 9). New York, Raven Press 1978, pp 285-303 19. Osborn M, Weber K: Damage of cellular functions by trifluoperazine, a calmodulinspecific drug. Exp Cell Res 130:484-488, 1980 20. Levin RM, Weiss B: Selective inhibition of an activable ATPase by trifluoperazine. Pharmacologist 20~195, 1978 (abstr) 21. Raess BU, Vincenzi FF: Calmodulin activation of red blood cell (Ca + Mg)-ATPase and its antagonism by phenothiazines. Mol Pharmacol 18:253-258, 1980 22. Seeman P: The membrane actions of anesthetics and tranquilizers. Pharmacol Rev 24:583-655, 1972 23. Dodge FA Jr, Rahamimoff R: Cooperative action of calcium ions in transmitter release at the neuromuscular junction. J Physiol 193:419-432, 1967 24. Means AR, Dedman JR: Calmodulin-an intracellular calcium receptor. Nature 285:73-77, 1980 25. Curtis DR, Perrin DD, Watkins JC: The excitation of spinal neurons by the iontophoretic application of agents which chelate calcium. J Neurochem 6:1-20, 1960 26. Simpson GM, Angus JWS: Drug-induced extrapyramidal disorders. Acta Psychiatr Stand (Suppl) 212:11-19, 1970 27. Binder RL, Levy R: Extrapyramidal reactions in Asians. Am J Psychiatr 138:12431244, 1981 28. Angus JWS, Simpson GM: Hysteria and drug-induced dystonia. Acta Psychiatr Stand (Suppl) 212:52-58, 1970 29. Keepers GA, Clappison VJ, Casey DE: Initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatr 40: 1113-l 117, 1983 30. Manos N, Gkiozepas J, Logothetis J: The need for continuous use of antiparkinsonian medication with chronic schizophrenic patients receiving long-term neuroleptic therapy. Am J Psychiatr 138:184-188, 1981 3 1. Moss HB, Green A: Neuroleptic-associated dysphagia confirmed by esophageal manometry. Am J Psychiatr 139:515-516, 1982 32. McDonal CE Jr: Haloperidol and laryngeal-pharyngeal dystonia. Am J Psychiatr 138:1262-1263, 1981 (letter to editor)
NEUROLEPTICS,
EXTRAPYRAMIDAL
SYMPTOMS
545
33. Hanlon TE, Schoenrich C, Freinek E, et al: Perphenazine benztropine mesylate treatment of newly admitted psychiatric patients. Psychopharmacology 9:328-339, 1966 34. Stem T, Anderson W: Benztropine prophylaxis of dystonic reactions. Psychopharmacology 61:261-262, 1979 35. Di Mascio A, Demergian E: Antiparkinson drug overuse. Psychosomatics 11:596601, 1970 36. Swett C Jr, Cole JO, Shapiro S, et al: Extrapyramidal side effects in chlorpromazine recipients: Emergence according to benztropine prophylaxis. Arch Gen Psychiatr 34:942943, 1977