Prophylactic Antiparkinson Drug Use: I. Initial Prophylaxis and Prevention of Extrapyramidal Side Effects Michael
The use troversial.
effects remain
of prophylactic
R. Lavin,
antiparkinson
MD,
and
medications
Arthur
Rifkin,
during
neuroleptic
MD
treatment
is con-
Although the eflhcacy of these agents in the treatment of extrapyramidal side is well established, the questions of when to initiate therapy and for how long unanswered. There are only a few double-blind, placebo-controlled studies on the
value
of concurrent antiparkinson drug use at the beginning of neuroleptic treatment. reviewed all studies on initial prophylaxis, and found most to be met hodologically deficient. There is evidence to support the use of these agents to prevent acute dystonic reactions. Further work needs to focus on other types of extrapyramidal symptoms. In light of the inability to predict who will experience these side effects, the authors conclude that initial prophylaxis is beneficial for most patients who are starting neuroleptic medications.
The authors
T
he use of prophylactic antiparkinson medication during neuroleptic treatment is controversial. Although the efficacy of these agents in the treatment of drug-induced extrapyramidal side effects (EPS) is well established, the questions of when to initiate therapy and for how long remain unanswered. “Initial prophylaxis” involves the administration of the antiparkinson agents at the beginning of neuroleptic treatment. The issue of prophylaxis has assumed more importance currently in light of the recognition that antipsychotic medications-including the highpotency agents with an increased risk of associated EPS-are being used at greater doses than in the past.1 Many studies have been conducted to determine the effectiveness of prophylactic therapy. The results are often confusing and contradictory. The effectiveness of concurrent administration of antiparkinson and antipsychotic agents at the start of treatment has been the subject of only a few doubleblind, placebo-controlled studies. We have, therefore, decided to review all the available literature on the value of initial prophylaxis in preventing EPS (Table I). of Psychiatry (Dr. Lavin), Hillside Hospital, New Hyde Park, New York, and the Department of Psychiatry (Dr. Rifkin), Queens Hospital Center Affiliation, Long Island Jewish Medical Center, Jamaica, New York. Address for reprints: Arthur Rifkin, MD, Department of Psychiatry, Queens Hospital Center Affiliation, Long Island Jewish Medical Center, 82-68 164th St., Jamaica, NY 11432. From
the Department
i CIIn Pharmacol
1991;31:763-768
REVIEW Ia.
OF
STUDIES
Retrospective
Studies
of Initial
Prophylaxis
Study design and results. Swett et al.2 completed a study of 654 inpatients who were receiving chlorpromazine. Diagnosis of psychopathology was not provided. A total of 86 patients (13%) received benztropine prophylaxis at an average of 2 mg/day. The authors defined prophylaxis as the “concurrent administration of the benztropine and chlorpromazine for at least 24 hours prior to the appearance of EPS.” The remaining 568 patients did not receive any anticholinergic
medication.
The
duration
of study
was
not noted. Nurse monitors followed medication responses, and a research psychopharmacologist evaluated all suspected side reactions. The authors indicate that 8 of 86 (9.3%) of the patients in the prophylaxis group experienced EPS compared with 60 of 568 (10.6%)
patients
in the placebo
and dose of chlorpromazine fect the results.” The authors no indication for prophylaxis
group.
Age,
sex,
did not “materially afconclude that there is of EPS.
Critique. There are many limitations in this study. The lack of clearly defined rating scales for EPS and unspecified study duration make interpretation difficult. The antiparkinson drug was used at submaximal therapeutic doses. Moreover, there were no statistical analysis of the data.
763
AND
LAVIN
RIFKIN
TABLE Studies Study
Design
of Initial
Prophylaxis
Duration
Patients
654 82 98 215 23 202 83 122 36
EPS Sought
Unspecified
Unknown
Dystonia
None
et aI. et al. Moleman et al. Keepers et al. Boyer et al. Stramek et al. Goldstein et al. Hanlon et al. Johnstone et al.
Retrospective Retrospective
Unknown Unknown
Retrospective Retrospective Retrospective Prospective Double blind, placebo Double blind, placebo Double blind, placebo
cont. cont.
Unknown 3 weeks Unknown 1 week 4 weeks 6 weeks 4 weeks
Manos
Double
cont.
4 weeks
42
Aki.,
cont.
15 days
39
Dys.
Swett Stern
et al.
Winslow DYS
=
et al. dystonia,
blind,
placebo
Double blind, placebo PA RK
=
Parkinsonism, AKA
=
cont.
Akathisia, AP
Antiparkin son agent, A K!
Study design and results. Stern and Anderson3 conducted a retrospective study of 82 consecutively admitted inpatients who had received oral high-potency antipsychotics in doses that were equivalent to chlorpromazine 200 mg or more per day. The patients were diagnosed with “acute psychosis,” paranoid schizophrenia, or affective psychosis. Four different neuroleptics were used at varying doses. A patient was considered to have received prophylaxis if there was concurrent administration of 2 mg/day of benztropine alone, with the antipsychotic. Follow-up phone calls were made to all patients at 3 months, on average, after hospital discharge (in some cases as long as 6 months). Forty patients (49%) were contacted and asked in a “standardized interview format to recall stiffness of the muscle in the face, neck, or tongue. A patient was judged to have experienced dystonia if there was a complaint of tightened cervical muscles and if anticholinergic treatment was begun.” Of the 40 responders, 13 had experienced “dystonic reactions” (33%)-12 of these had not received prophylaxis. Although the two study groups did not differ in dose of the antipsychotic, the patients with acute dystonias received an average 585 mg of chlorpromazine equivalents whereas those with dystonia received 344 mg. The authors recommend prophylaxis for preventing acute dystonic reactions. .
.
.
Critique. This nonblind, unrandomized study has several methodologic problems. Lack of a formal assessment of dystonia, unclear duration of study, and the use of low doses of benztropine make the results difficult to accept.
764
5
.1 Clin Pharmacol
199131:763-768
Dys.,
Aka.,
% EPS AP)
(-1+
Scale
tremor,
rigid
Review
10.6/9.3 30/2 sheets
Dys., Aka., Park. Dystonia Dystonia Dys., Aka., Park. Aka., Aki., Park.
None None None
Park.
Rating scale
=
Aka.,
Park.,
40/37
70/23 94/0 2 1/13 32/2 27/10 Unable to calculate
Unknown Unknown
Dys.
Simpson-Angus None
85/27 47/0
Akinesia.
Study design and results. Moleman et a!4 evaluated 98 in patients with nine different ICD-9 diagnoses, most commonly affective psychosis (23%), schizophrenia (20%), and nonorganic psychosis (22%). Most patients received haloperidol ied from 3 to 60 mg/day. Apparently
and trihexyphenidyl agents at varying means
of
review
and
were used as doses. EPS were sheets
that
were
the dose orphenadrine
var-
antiparkinson evaluated completed
by by
a
psychiatric resident. They recorded the incidence but not severity of side effects. Symptoms of EPS were not differentiated but consisted mainly of akathisia, rigidity, tremor, or dystonia. Some patients were receiving concurrent medications like antidepressants, lithium, and benzodiazepines. Overall, 55 of 98 (56%) patients had some form of EPS develop. Sixteen of 43 patients (37%) who were receiving prophylaxis experienced parkinsonism compared with 22 of 55 (40%) patients who were receiving placebo. Age was found to be the only significant factor in the probability of parkinsonism developing (P < .003). The probability increased with youth. However, no comparison between study groups was made. The authors did not specify the groups to which the patients belonged when reporting dystonic reactions and akathisia. The authors conclude that the use of prophylactic antiparkinson agents reduces the occurrence of parkinsonism only in younger patients. They suggest that these agents only be used when symptoms have already developed. Critique.
lacked
any
This
nonblind,
randomization
retrospective
of patients
or placebo
study
con-
INITIAL
trol. The manner of EPS detection, lack akinesia, use of concurrent medications ent anticholinergic activity (i.e., tricyclic sants)
in some
EPS raises
patients
questions
and
about
AND
PROPHYLAXIS
of search for with inherantidepres-
incomplete
the
EXTRAPYRAMIDAL
reporting
validity
of the
of
results.
Study design and results. Keepers et al5 performed a retrospective review of 215 inpatients with diagnoses of schizophrenia, schizophreniform, or schizoaffective disorder. Seven different neuroleptics and four different anticholinergics were used at varying doses. Duration of study was the first 3 weeks of neuroleptic treatment. The charts were reviewed for any notes that concerned dystonic reactions, akathisia, and parkinsonism. Eighty patients (37%) received prophylactic antiparkinson medication, whereas 135 (63%) patients did not. There were no statistically significant differences between the two groups with respect to patient age, sex, length of hospitalization, or dose of neuroleptic. About 70% of those without prophylaxis experienced EPS compared with 23% of those in the prophylaxis group (P
The use troversial.
effects remain
of prophylactic
R. Lavin,
antiparkinson
MD,
and
medications
Arthur
Rifkin,
during
neuroleptic
MD
treatment
is con-
Although the eflhcacy of these agents in the treatment of extrapyramidal side is well established, the questions of when to initiate therapy and for how long unanswered. There are only a few double-blind, placebo-controlled studies on the
value
of concurrent antiparkinson drug use at the beginning of neuroleptic treatment. reviewed all studies on initial prophylaxis, and found most to be met hodologically deficient. There is evidence to support the use of these agents to prevent acute dystonic reactions. Further work needs to focus on other types of extrapyramidal symptoms. In light of the inability to predict who will experience these side effects, the authors conclude that initial prophylaxis is beneficial for most patients who are starting neuroleptic medications.
The authors
T
he use of prophylactic antiparkinson medication during neuroleptic treatment is controversial. Although the efficacy of these agents in the treatment of drug-induced extrapyramidal side effects (EPS) is well established, the questions of when to initiate therapy and for how long remain unanswered. “Initial prophylaxis” involves the administration of the antiparkinson agents at the beginning of neuroleptic treatment. The issue of prophylaxis has assumed more importance currently in light of the recognition that antipsychotic medications-including the highpotency agents with an increased risk of associated EPS-are being used at greater doses than in the past.1 Many studies have been conducted to determine the effectiveness of prophylactic therapy. The results are often confusing and contradictory. The effectiveness of concurrent administration of antiparkinson and antipsychotic agents at the start of treatment has been the subject of only a few doubleblind, placebo-controlled studies. We have, therefore, decided to review all the available literature on the value of initial prophylaxis in preventing EPS (Table I). of Psychiatry (Dr. Lavin), Hillside Hospital, New Hyde Park, New York, and the Department of Psychiatry (Dr. Rifkin), Queens Hospital Center Affiliation, Long Island Jewish Medical Center, Jamaica, New York. Address for reprints: Arthur Rifkin, MD, Department of Psychiatry, Queens Hospital Center Affiliation, Long Island Jewish Medical Center, 82-68 164th St., Jamaica, NY 11432. From
the Department
i CIIn Pharmacol
1991;31:763-768
REVIEW Ia.
OF
STUDIES
Retrospective
Studies
of Initial
Prophylaxis
Study design and results. Swett et al.2 completed a study of 654 inpatients who were receiving chlorpromazine. Diagnosis of psychopathology was not provided. A total of 86 patients (13%) received benztropine prophylaxis at an average of 2 mg/day. The authors defined prophylaxis as the “concurrent administration of the benztropine and chlorpromazine for at least 24 hours prior to the appearance of EPS.” The remaining 568 patients did not receive any anticholinergic
medication.
The
duration
of study
was
not noted. Nurse monitors followed medication responses, and a research psychopharmacologist evaluated all suspected side reactions. The authors indicate that 8 of 86 (9.3%) of the patients in the prophylaxis group experienced EPS compared with 60 of 568 (10.6%)
patients
in the placebo
and dose of chlorpromazine fect the results.” The authors no indication for prophylaxis
group.
Age,
sex,
did not “materially afconclude that there is of EPS.
Critique. There are many limitations in this study. The lack of clearly defined rating scales for EPS and unspecified study duration make interpretation difficult. The antiparkinson drug was used at submaximal therapeutic doses. Moreover, there were no statistical analysis of the data.
763
AND
LAVIN
RIFKIN
TABLE Studies Study
Design
of Initial
Prophylaxis
Duration
Patients
654 82 98 215 23 202 83 122 36
EPS Sought
Unspecified
Unknown
Dystonia
None
et aI. et al. Moleman et al. Keepers et al. Boyer et al. Stramek et al. Goldstein et al. Hanlon et al. Johnstone et al.
Retrospective Retrospective
Unknown Unknown
Retrospective Retrospective Retrospective Prospective Double blind, placebo Double blind, placebo Double blind, placebo
cont. cont.
Unknown 3 weeks Unknown 1 week 4 weeks 6 weeks 4 weeks
Manos
Double
cont.
4 weeks
42
Aki.,
cont.
15 days
39
Dys.
Swett Stern
et al.
Winslow DYS
=
et al. dystonia,
blind,
placebo
Double blind, placebo PA RK
=
Parkinsonism, AKA
=
cont.
Akathisia, AP
Antiparkin son agent, A K!
Study design and results. Stern and Anderson3 conducted a retrospective study of 82 consecutively admitted inpatients who had received oral high-potency antipsychotics in doses that were equivalent to chlorpromazine 200 mg or more per day. The patients were diagnosed with “acute psychosis,” paranoid schizophrenia, or affective psychosis. Four different neuroleptics were used at varying doses. A patient was considered to have received prophylaxis if there was concurrent administration of 2 mg/day of benztropine alone, with the antipsychotic. Follow-up phone calls were made to all patients at 3 months, on average, after hospital discharge (in some cases as long as 6 months). Forty patients (49%) were contacted and asked in a “standardized interview format to recall stiffness of the muscle in the face, neck, or tongue. A patient was judged to have experienced dystonia if there was a complaint of tightened cervical muscles and if anticholinergic treatment was begun.” Of the 40 responders, 13 had experienced “dystonic reactions” (33%)-12 of these had not received prophylaxis. Although the two study groups did not differ in dose of the antipsychotic, the patients with acute dystonias received an average 585 mg of chlorpromazine equivalents whereas those with dystonia received 344 mg. The authors recommend prophylaxis for preventing acute dystonic reactions. .
.
.
Critique. This nonblind, unrandomized study has several methodologic problems. Lack of a formal assessment of dystonia, unclear duration of study, and the use of low doses of benztropine make the results difficult to accept.
764
5
.1 Clin Pharmacol
199131:763-768
Dys.,
Aka.,
% EPS AP)
(-1+
Scale
tremor,
rigid
Review
10.6/9.3 30/2 sheets
Dys., Aka., Park. Dystonia Dystonia Dys., Aka., Park. Aka., Aki., Park.
None None None
Park.
Rating scale
=
Aka.,
Park.,
40/37
70/23 94/0 2 1/13 32/2 27/10 Unable to calculate
Unknown Unknown
Dys.
Simpson-Angus None
85/27 47/0
Akinesia.
Study design and results. Moleman et a!4 evaluated 98 in patients with nine different ICD-9 diagnoses, most commonly affective psychosis (23%), schizophrenia (20%), and nonorganic psychosis (22%). Most patients received haloperidol ied from 3 to 60 mg/day. Apparently
and trihexyphenidyl agents at varying means
of
review
and
were used as doses. EPS were sheets
that
were
the dose orphenadrine
var-
antiparkinson evaluated completed
by by
a
psychiatric resident. They recorded the incidence but not severity of side effects. Symptoms of EPS were not differentiated but consisted mainly of akathisia, rigidity, tremor, or dystonia. Some patients were receiving concurrent medications like antidepressants, lithium, and benzodiazepines. Overall, 55 of 98 (56%) patients had some form of EPS develop. Sixteen of 43 patients (37%) who were receiving prophylaxis experienced parkinsonism compared with 22 of 55 (40%) patients who were receiving placebo. Age was found to be the only significant factor in the probability of parkinsonism developing (P < .003). The probability increased with youth. However, no comparison between study groups was made. The authors did not specify the groups to which the patients belonged when reporting dystonic reactions and akathisia. The authors conclude that the use of prophylactic antiparkinson agents reduces the occurrence of parkinsonism only in younger patients. They suggest that these agents only be used when symptoms have already developed. Critique.
lacked
any
This
nonblind,
randomization
retrospective
of patients
or placebo
study
con-
INITIAL
trol. The manner of EPS detection, lack akinesia, use of concurrent medications ent anticholinergic activity (i.e., tricyclic sants)
in some
EPS raises
patients
questions
and
about
AND
PROPHYLAXIS
of search for with inherantidepres-
incomplete
the
EXTRAPYRAMIDAL
reporting
validity
of the
of
results.
Study design and results. Keepers et al5 performed a retrospective review of 215 inpatients with diagnoses of schizophrenia, schizophreniform, or schizoaffective disorder. Seven different neuroleptics and four different anticholinergics were used at varying doses. Duration of study was the first 3 weeks of neuroleptic treatment. The charts were reviewed for any notes that concerned dystonic reactions, akathisia, and parkinsonism. Eighty patients (37%) received prophylactic antiparkinson medication, whereas 135 (63%) patients did not. There were no statistically significant differences between the two groups with respect to patient age, sex, length of hospitalization, or dose of neuroleptic. About 70% of those without prophylaxis experienced EPS compared with 23% of those in the prophylaxis group (P
