Department of Psychiatry and Psychotherapy; University of Lübeck, Germany
Department of Neurology; University of Lübeck, Germany
Department of Psychiatry and Psychotherapy; University of Lübeck, Germany
Department of Neurology, University of Lübeck, Germany
Correspondence: Dr Reb Rebekka ekka Lencer, Klinik für Psychiatrie und Psychotherapie, Universitä zu Lübeck, Ratzeburger Allee 160, 23538 Lü, Germany. Tel: +49 451 500 2444; fax: +49 451 500 4957; e-mail: lencer.r{at}psychiatry.uni-luebeck.de
Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To identify predictor variables for neuroleptic-induced extrapyramidal symptoms, particularly considering family history of primary movement disorders.
Method We investigated 100 in-patients receiving a stable neuroleptic medication with regard to occurrence of extrapyramidal symptoms, drug history and detailed family history of primary movement disorders.
Results Step-wise logistic regression analysis revealed that a positive family history was a significant predictor for lifetime prevalence of extrapyramidal symptoms, including reported and currently observed symptoms. The duration of exposure to neuroleptic medication and age were further predictors.
Conclusions Our findings underline the notion of genetic susceptibility for secondary extrapyramidal symptoms and suggest possible shared genetic factors in primary and secondary movement disorders as well as psychotic disorders.
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INTRODUCTION |
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METHOD |
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Operational psychiatric lifetime diagnoses according to DSMIV (American Psychiatric Association, 1994) were established using the German version of the Mini-International Neuropsychiatric Interview (MINI; Sheehan et al, 1998) and the Structured Clinical Interview for Personality Disorders (SCIDII; Spitzer & Williams, 1987). Diagnoses were divided into four categories: organic psychiatric disorders, including all forms of alcohol and drug dependence; psychotic disorders; affective disorders; and other Axis I or Axis II disorders. Psychopathological symptom severity was rated on the Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962). Each participant underwent a complete neurological examination with particular emphasis on specific signs of acute dystonic reaction, parkinsonism, akathisia and tardive dyskinesia. The following rating scales were used to assess the severity of extrapyramidal symptoms (van Harten et al, 1997): the Abnormal Involuntary Movement Scale (AIMS; National Institute of Mental Health, 1975); the Tsui Rating Scale for Cervical Dystonia (Tsui et al, 1986) and the Burke Rating Scale for Primary Torsion Dystonias (Burke et al, 1985); Part III of the Unified Parkinson's Disease Rating Scale (UPDRS; Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease, 2003); the global score on the Hillside Scale (Fleischhacker et al, 1991) and the Barnes Akathisia Scale (Barnes, 1989). History of extrapyramidal symptoms on previous neuroleptic treatment was explored in a structured interview developed by our group, covering the typical symptoms of acute dystonic reaction, parkinsonism, akathisia and tardive dyskinesia. To check the reliability of their answers, participants were asked about the consequences of the development of their movement disorder (for example, change in medication or administration of biperiden). In addition, clinical records covering former treatment phases were reviewed to complete the information. Family history of movement disorders was obtained by means of a structured interview developed in our department, specifically covering symptoms of Parkinson's disease (stiffness of movement, gait problems, tremor, change in facial expression, lateralisation of symptoms), dystonia and psychiatric disorders in first-degree to third-degree relatives. This structured interview had previously been shown to provide reliable data in a large epidemiological study (Klein et al, 1999). A diagnosis of a primary movement disorder was only made if the criteria for the disorder were clearly fulfilled by the symptom description given by the patient. Relatives were asked to also undergo the structured interview whenever possible.
Statistical procedure
Pearson's chi-squared tests for independence were performed to investigate
the relationship between categorical outcome variables (lifetime occurrence of
extrapyramidal symptoms, including reported and currently observed symptoms;
reported extrapyramidal symptoms during previous treatment phases; currently
observed extrapyramidal symptoms; extrapyramidal symptoms on typical
neuroleptic medication; extrapyramidal symptoms on atypical neuroleptic
medication; lifetime occurrence and currently observed acute dystonic
reaction, parkinsonism, akathisia and tardive dyskinesia) and possible
categorical predictor variables (gender; age; psychiatric diagnostic category;
dosage range; duration of exposure to any neuroleptic medication; duration of
exposure to typical neuroleptic medication; duration of exposure to atypical
neuroleptic medication; positive family history of primary movement disorder).
To achieve the required expected cell frequency of more than 5 in
2-tests, we defined three different age groups: 1840
years, 4160 years and >60 years. For the same reason, duration of
exposure to neuroleptic medication was categorised as <6 months, 6 months
to 5 years, and >5 years. For easier comparison, drug dosages were defined
as low, medium or high, based on current clinical practice. Chi-squared values
are reported with two-tailed probabilities. Relationships between possible
predictor and outcome variables with P<0.5 revealed by
2-tests were entered in a step-wise logistic regression
analysis to identify predicted probabilities for extrapyramidal symptoms
(probability to enter at 0.05). By use of a logistic regression analysis, all
predictor variables are considered within one testing procedure, including
intercorrelations, which reduces the probability of type I errors. All
statistical procedures were performed using the Statistical Package for the
Social Sciences (version 11.0).
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RESULTS |
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Lifetime prevalence of extrapyramidal symptoms
Lifetime prevalence of extrapyramidal symptoms, including both reported and
currently observed symptoms, was 65% (Table
2). Acute dystonic reactions occurred most commonly (41%),
followed by parkinsonism (37%), akathisia (19%) and tardive dyskinesia (4%).
It should be noted that several patients suffered from more than one type of
extrapyramidal symptom. Of those who had experienced such symptoms, more
patients had been exposed to typical than to atypical medication. Details of
mean age and distribution of gender are given in
Table 2.
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Currently observed extrapyramidal symptoms
At the time of examination, most patients were taking an atypical
neuroleptic medication (Table
3). Extrapyramidal symptoms were diagnosed in 34% of patients. The
most commonly observed symptom was parkinsonism (19%), followed by acute
dystonic reaction (15%), akathisia (5%) and tardive dyskinesia (3%). Again,
some patients were diagnosed with more than one type of extrapyramidal
symptom. Table 3 gives further
clinical characteristics and details concerning dosages of neuroleptic
medication.
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Reported symptoms and family history of primary movement disorders
Fifty-three patients (29 men and 24 women, mean age 36.3 years, s.d.=13.2)
reported that they had experienced extrapyramidal symptoms during previous
treatment phases. Information about the family history of primary movement
disorders was available for 98 participants and could be assessed for a total
of 1316 relatives, 438 of whom were first-degree relatives. Thirty-two of
these 98 patients (20 men and 12 women) reported a positive family history,
resulting in a total of 47 affected relatives, or a prevalence of a primary
movement disorder of 3.5% among all relatives. Specifically, the prevalences
were 1.1% (n=14) for Parkinson's disease, 1.6% (n=21) for
tremor and 0.9% (n=2) for dystonia. Among relatives of patients with
lifetime extrapyramidal symptoms (n=848), the prevalences were 1.4%
(n=12) for Parkinson's disease, 2.4% (n=20) for tremor and
1.1% (n=9) for dystonia, whereas among the relatives of patients
without lifetime extrapyramidal symptoms (n=468), the prevalences
were 0.4% (n=2) for Parkinson's disease, 0.2% (n=1) for
tremor and 0.6% (n=3) for dystonia. A subgroup analysis was performed
using data from 27 (2.1%) first-degree relatives of 21 patients who were seen
personally by one of the investigators. In all of them, the presence or
absence of a primary movement disorder was confirmed as established by the
family history interview (25 relatives without a primary movement disorder, 1
with dystonia and 1 with tremor). In order to avoid multiple inclusion of
patients with more than one affected relative in further statistical analyses,
we considered only the closest relative of those patients. This resulted in 12
patients with a relative with Parkinson's disease (5 first-degree relatives
and 7 second-degree relatives), 11 patients with a relative with tremor (6
first-degree relatives and 5 second-degree relatives) and 9 patients with a
relative with dystonia (7 first-degree relatives and 2 second-degree
relatives).
Relationship between possible predictor and outcome variables
Family history of primary movement disorder
The family history of primary movement disorders was related to lifetime
prevalence of extrapyramidal symptoms (EPS) (2=8.35, d.f.=1,
P<0.01), currently observed EPS (
2=8.05, d.f.=1,
P<0.01), prevalence of reported EPS (
2=6.75,
d.f.=1, P<0.01) and lifetime prevalence of acute dystonic reaction
(
2=4.69, d.f.=1, P=0.03).
Table 4 shows that the
prevalence of these four related outcome variables was higher in participants
with a positive family history than in patients with a negative history.
Furthermore, lifetime prevalence of acute dystonic reaction was related to the
subtype of primary movement disorders occurring in relatives
(
2=8.27, d.f.=3, P=0.04). Lifetime acute dystonic
reaction occurred in 7 of 9 (78%) patients with a family history of dystonia,
but only in 7 of 12 (58%) patients with a family history of Parkinson's
disease, 4 of 11 (36%) patients with a family history of tremor and 22 of 44
(50%) patients with a negative family history.
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Age
We further observed a strong relation between age and lifetime prevalence
of EPS (2=15.13, d.f.=2, P<0.01), reported EPS
(
2=15.70, d.f.=2, P<0.01) and lifetime prevalence of acute
dystonic reaction (
2=9.82, d.f.=2, P<0.01). The prevalence
of the three related outcome variables was higher in the youngest age group
than in either of the other age groups
(Table 4).
Duration of exposure to neuroleptic medication
The duration of exposure to any neuroleptic medication was related to the
lifetime prevalence of EPS (2=17.86, d.f.=2,
P<0.01), the prevalence of reported EPS (
2=34.96,
d.f.=2, P<0.01) as well as the lifetime occurrence of parkinsonism
(
2=6.67, d.f.=2, P=0.04) and akathisia
(
2=8.41, d.f.=2, P=0.02). More specifically, the
duration of exposure to typical neuroleptics was associated with the lifetime
prevalence of EPS (
2=18.71, d.f.=3, P<0.01), the
prevalence of reported EPS (
2=27.78, d.f.=3,
P<0.01), occurrence of EPS on typical neuroleptics
(
2=7.83, d.f.=2, P=0.02), lifetime prevalence of
acute dystonia (
2=10.68, d.f.=3, P=0.01),
parkinsonism (
2=12.75, d.f.=3, P<0.01) and
akathisia (
2=8.59, d.f.=2, P=0.04). The duration of
the exposure to atypical neuroleptics was related to the prevalence of
reported EPS (
2=14.91, d.f.=3, P=0.01). As summarised
in Table 4, we found the
prevalence of all statistically related outcome variables to increase with
longer duration of neuroleptic medication.
For all other relationships between possible predictor variables (gender,
psychiatric diagnostic category or dosage range) and outcome variables
considered in 2 tests, P>0.05. Thus, only the
following possible predictor variables were entered in a logistic regression
analysis: family history of primary movement disorders; age; duration of
exposure to any neuroleptic medication; duration of exposure to typical
neuroleptics; and duration of exposure to atypical neuroleptic medication.
Occurrence of tardive dyskinesias was excluded from outcome variables because
of the small number of cases identified.
Predictors revealed by logistic regression analysis
We found that lifetime occurrence of EPS (yes or no) could be correctly
predicted in 74% of all cases by knowing the duration of treatment with
typical neuroleptics, and family history of primary movement disorders.
Lifetime occurrence of acute dystonic reaction (yes or no) could be predicted
in 65% of cases taking into account the exposure to typical neuroleptic
medication and age. Both lifetime occurrence of parkinsonism (yes or no) and
of akathisia (yes or no) were predicted correctly in 72% and 82%,
respectively, by the duration of typical neuroleptic medication. Reported EPS
(yes or no), regardless of the subtype, were correctly predicted in 82% of
cases by the duration of exposure to typical neuroleptic medication, age and
family history of primary movement disorders. Currently observed EPS (yes or
no) were predicted in 68% of all cases by the family history of primary
movement disorders. Extrapyramidal symptoms on typical neuroleptic medication
(yes or no) could be predicted in 73% when considering the duration of
exposure. As can be seen from the regression coefficients B in
Table 5, the probability for
the occurrence of symptoms always increased with the duration of exposure to
neuroleptic medication, younger age and positive family history.
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DISCUSSION |
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Prevalence rates for extrapyramidal symptoms and primary movement disorders
Based on a sample that represents a typical cohort of in-patients with
acute psychotic symptoms, we observed a lifetime prevalence of extrapyramidal
symptoms of 65% and a point prevalence of 34%, comparable to rates reported in
large epidemiological studies (Ayd,
1961; Swett, 1975;
Owens & Johnstone, 1982).
Compared with these studies, the mean age of our patients was low, and the
rate of patients ever having been treated with atypical neuroleptics was high
(87%). The percentage of patients who had been exposed to neuroleptics for
less than 6 months was high (38%). The overall prevalence of about 3% for
primary movement disorders in all relatives seems plausible. Higher prevalence
rates of Parkinson's disease, tremor and dystonia among relatives of patients
with lifetime extrapyramidal symptoms than among relatives of patients without
such symptoms are comparable with results reported by others, although our
study was not designed as a population-based casecontrol study
(Marder et al, 1996;
Louis et al, 2003).
The relatives' diagnoses could be confirmed in a small subgroup.
Predictors of extrapyramidal symptoms
In our sample, logistic regression analysis revealed that a positive family
history had significant predictive value for the occurrence of extrapyramidal
symptoms. The probability of observed symptoms at the time of examination, for
which it was the only predictor, as well as of lifetime prevalence of symptoms
and reported symptoms, was increased in patients who had a relative with a
primary movement disorder. The strongest predictive value was found for the
duration of treatment with typical neuroleptics (lifetime occurrence of EPS,
acute dystonic reaction, parkinsonism, akathisia, and EPS on typical
neuroleptics) as well as with any neuroleptic medication (reported EPS). The
probability of extrapyramidal symptoms increased with longer duration of
exposure. Furthermore, younger age was also a significant predictor for the
occurrence of symptoms, especially for acute dystonic reaction.
Positive family history of primary movement disorders
The finding that a positive family history of primary movement disorders
had a significant impact on the occurrence of extrapyramidal symptoms has two
main implications. First, our results suggest that primary and secondary
movement disorders may share common genetic factors. Second, the association
with primary movement disorders observed in patients suffering from psychotic
symptoms and developing extrapyramidal symptoms may represent a dysfunction
within a common pathway of the dopaminergic system. This system is involved
not only in primary and secondary movement disorders but also in psychotic
disorders. Earlier hypotheses suggest that such symptoms might represent
exacerbated involuntary movements that are directly related to cerebral
dysfunctions underlying psychotic diseases i.e. a dysfunction within
the dopaminergic system (Ayd,
1961; Owen & Johnstone, 1982). Indeed, both Kraepelin
(1971) and Bleuler
(1950) described
spasmodic phenomena in the musculature and extraordinary
movements of the tongue and lips in patients with psychosis long before
the introduction of neuroleptic drugs. Other studies have confirmed this
observation by the finding that prevalence and distribution of extrapyramidal
symptoms were the same in treated and never-treated patients and depended only
on the age at onset of the psychotic illness (Owen & Johnstone, 1982;
Srinivasan et al,
2001). Further studies should address the question whether the
occurrence of such symptoms represents an endophenotype for schizophrenia, as
has been shown for other neurological dysfunctions in neuroleptic-naïve
patients with psychosis (Gottesman &
Gould, 2003). Genetic association studies of candidate genes, such
as dopamine receptor genes, will be the natural extension of our study to
elucidate the hypothesised common underlying mechanism at the molecular
level.
Duration of neuroleptic medication
We observed a strong effect of duration of exposure to neuroleptic
medication, especially of typical neuroleptics, on the occurrence of
extrapyramidal symptoms, including the subtypes acute dystonic reaction,
parkinsonism and akathisia. Although many authors have proposed such an
effect, retrospective studies rarely confirmed this notion
(Marsalek, 2000). From our
results, however, it can be assumed that the longer the exposure to
neuroleptic drugs, the higher the prevalence of these symptoms. This finding
may support the hypothesis of an accumulating toxic effect of neuroleptic
drugs that is suggested to be higher in the typical drugs than in the
atypicals, with the exception of clozapine
(Gil-ad et al, 2001).
An effect of dosage on occurrence of extrapyramidal symptoms at the time of
examination could not be confirmed.
None of the predictor variables entered in the logistic regression analysis
was found to predict the occurrence of extrapyramidal symptoms in patients
taking atypical neuroleptics. The significant relation observed in the
2 test between reported symptoms and the duration of
medication with atypical neuroleptics may be interpreted as a trend. However,
the long-term effect of atypical neuroleptics on extrapyramidal symptoms may
yet not have been verified, since only a small proportion of patients had been
exposed to these drugs for more than 5 years (10%), and this aspect remains a
matter of debate (Tarsy et al,
2002).
Other possible predictors: age, gender and psychiatric diagnosis
We were able to validate young age as a predictor for the occurrence of
extrapyramidal symptoms, especially of acute dystonia
(Ayd, 1961; Swett, 1975). This finding
gives further support to the genetic influence on occurrence of these
symptoms. In contrast, there is no evidence from our data for either
diagnostic specificity or gender as a predictor for the occurrence of
symptoms.
Methodological limitations
Our study design must be regarded as somewhat explorative, since for most
of the relatives the diagnosis of a primary movement disorder could only be
established through the family history interview. This procedure might have
reduced the validity and reliability of the data, although special efforts
were made to rate a family history as positive only if the criteria were
unambiguously fulfilled. In a clinical setting, this is also the most
practical way to gather information and decide whether a patient is at risk of
developing extrapyramidal symptoms because of a positive family history.
We are aware that the way in which we categorised neuroleptic dosages may appear arbitrary. By definition, atypical neuroleptic dosages cannot be converted to chlorpromazine equivalents. We therefore decided to use a categorisation based on clinical experience. The distribution of dosage ranges in our sample appears reasonable (22% on low, 52% on medium and 26% on high medication dosages). Exact dosages could only be assessed for the time of examination.
Genetic considerations
Our data imply two hypotheses. First, our findings underline the notion of
genetic susceptibility for secondary extrapyramidal symptoms, and second, they
suggest possible shared genetic factors in primary and secondary movement as
well as in psychotic disorders.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication February 4, 2004. Revision received August 10, 2004. Accepted for publication August 11, 2004.
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