| | Evolution of neuroleptic-induced extrapyramidal syndromes under long-term neuroleptic treatmentReceived 30 July 2007; received in revised form 17 October 2007; accepted 25 October 2007. published online 06 December 2007. Abstract BackgroundThe long-term evolution of neuroleptic-induced extrapyramidal syndromes (EPS) of Parkinsonism, akathisia and tardive dyskinesia (TD) is still a controversial issue worth exploring. MethodA total of 200 inpatients on regular typical neuroleptics (NL) and/or clozapine were assessed in 1995 with regard to the prevalence of EPS. Altogether, 83 patients could be reassessed in 2003/04 (63 had died) using the same methods. Strict definitions of EPS were used. The complete account of NL therapy the patients were prescribed between 1995 and 2003/04 (including atypical NL other than clozapine) was considered. ResultsThe prevalences found in 1995 and 2003/04 were 17% and 29% for Parkinsonism, 14% and 14% for akathisia, and 24% and 13% for TD. There were considerable intra-individual fluctuations in EPS occurrence even when the overall prevalence rate remained the same. In intra-individual comparisons of EPS ratings on both assessments, there was a tendency for worsening of Parkinsonism to be associated with a current (2003/04) therapy with typical NL; worsening of akathisia was associated with a current therapy with atypical NL other than clozapine, amelioration of akathisia with a current therapy with clozapne; and, basically, there were no significant associations found between the changes in TD ratings and the long-term therapy with typical NL, clozapine, and other atypical NL, considering cumulative doses of all these drugs. In a multivariate analysis, there was a tendency for the long-term evolution of TD to depend on illness duration as the only variable. ConclusionsThere are intra-individual fluctuations in all EPS over longer time periods. The choice of current NL therapy has an impact on Parkinsonism and akathisia. The long-term evolution of TD appears independent of NL prescriptions. 1. Introduction  Neuroleptic drugs (NL) are indispensable in treating psychotic disorders, yet all of them are fraught with potentially serious side effects. The occurrence of extrapyramidal syndroms (EPS) in terms of Parkinsonism, akathisia, and tardive dyskinesia (TD) respresents one of the most serious complications of therapy with NL. In individual samples of patients treated wit typical NL and clozapine prevalences of these EPS were 36%, 9%, and 40% (Van Harten et al., 1996), 20%, 11%, and 22% (Modestin et al., 2000) and 23%, 31% and 32% (Janno et al., 2004) for Parkinsonism, akathisia, and TD, respectively. Regarding TD, considered to be the most frequent and significant complication encountered with NL treatment (Llorca et al., 2002), the overall mean prevalence among chronically treated patients was estimated to be about 24% (Jeste and Caligiuri, 1993). Atypical NL are said to carry a substantially lower risk of EPS, including TD, than typical agents (Toffelson et al., 1997, Correll et al., 2004); atypical NL caused fewer EPS even when lower doses of typical NL were used in the individual trials (Geddes et al., 2000). On the other hand, the risk of EPS is not negligible even with atypical NL (Schatzberg et al., 2002), optimal doses of low-potency conventional NL might not induce more EPS than atypical NL (Leucht et al., 2003) and also, second-generation antipsychotics do not represent a homogneous group. Some atypical NL such as risperidone and amisulpride cause dose-related EPS (Davis et al., 2003). Furthermore, in some patients, weight gain and its complications caused by atypical NL may pose a greater long-term risk for the patient than EPS (Schatzberg et al., 2002), and recent effectiveness studies failed to demonstrate a significant difference between typical and atypical NL with regard to the ratings of Parkinsonism, akathisia, and dyskinesia (Lieberman et al., 2005, Jones et al., 2006). In 1995 we studied the prevalence of neuroleptic-induced extrapyramidal syndromes in a sample of patients, treated with typical NL and/or clozapine (Modestin et al., 2000). Eight to nine years later, the same patients were re-assessed in order to study the longer-term evolution of these EPS and its relationship to the NL medication taken by the patients between both assessments. During this time period, other atypical NL were introduced on the broad-scale basis. Also, the influence of NL-induced EPS on quality of life and depressive symptoms was assessed. 2. Methods In August 1995, in a cross-sectional study, 200 inpatients, all of them treated with typical neuroleptics and/or clozapine on a regular basis, were assessed with regard to the point prevalence of Parkinson syndrome, akathisia, and TD (Modestin et al., 2000). A re-assessment of the same sample in an identical way was carried out in 2003/2004. Additionally, quality of life and depression measures were applied at the second assessment to test their possible influence on the EPS ratings. 2.1. Study subjects Out of 200 (100%) patients, 117 could not be reached: 63 (31.5%) of them had died, 37 (18.5%) were unwilling to participate, and 17 (8.5%) patients could not be traced. A total of 83 patients (41.5% of the original sample) were studied between December 2003 and August 2004. This sample comprised 55 (66%) men and 28 (34%) women; their average age in 2004 was 49.4 years (SD 12,5), and their average illness duration 24.5 years (SD 12.0). At the time of the study, 21 (25%) were living at home and 17 (20%) were in psychiatric or other hospitals; the majority, 43 (52%) were in various institutions. The diagnoses of these patients are indicated in Table 1. The majority of patients in the category “other disorders” suffered from substance use disorders and personality disorders. The proportion of patients who participated in the individual parts of the study (neurological assessment, medication survey, and self-rating scales) differed to some extent. It should be noted that only about a half of the patients filled in the questionnaires. 2.2. Instruments In the study patients, a systematic neurological examination was carried out in exactly the same way as in the original study. Also, the same instruments were used: 2.2.1. Unified Parkinson's Disease Rating Scale UPDRS UPDRS (Fahn et al., 1987), enabling to assess the extent of Parkinson syndrome, is a widely used, reliable and valid scale (Martinez-Martin et al., 1994). The section “Motor examination” of the Scale was used, consisting of 14 items. As in the first study, the definition by Van Harten et al. (1996) was used to define the Parkinson syndrome as a case (RC+). 2.2.2. Barnes Akathisia Scale BAS BAS is a scale of a high inter-rater reliability, composed of three parts: objective akathisia, subjective akathisia, and ensuing distress (Barnes, 1989). An adjusted operationalized global score was used. It was calculated considering the ratings of objective akathisia, subjective akathisia and distress (0–3), and the categories of no akathisia, pseudoakathisia, questionable akathisia, mild akathisia, and moderate akathisia. No case of severe akathisia was encountered. For the case definition (at least mild akathisia), both objective and subjective and/or distress manifestations were required. 2.2.3. Abnormal Involuntary Movements Scale AIMS AIMS (Guy, 1976) a scale of high validity and inter-rater reliability (Lane et al., 1985) was used for the rating of tardive dyskinesia (TD). The 5-grade scale contains 12 items, 7 of them having been considered. For the case definition the research criteria for TD (Schooler and Kane, 1982) were used (RC+). 2.2.4. Short form of the WHO Quality of Life Questionnaire (WHOQOL-BREF) in its German version WHOQOL-BREF is a widely used instrument with good reliability and very good overall construct validity (Angermeyer et al., 2000). The questionnaire encompasses 4 domains (physical, psychological, social relationships and environment) and global score. Higher ratings indicate a better quality of life. To test the reliability of the ratings, Cronbach's alpha were calculated and found to be 0.92 for the whole scale and 0.73–0.83 for the four individual subscales. 2.2.5. Beck Depression Inventory (BDI) in its German version BDI (Hautzinger et al., 1995) is a reliable self-report inventory to assess the grade of a depressive mood. In this study, Cronbach's alpha was 0.85. In addition, demographic and clinical data including a complete account of the NL treatment the patients received between both assessments was obtained from the clinical charts. 2.3. Procedure The study design was approved by the local ethic committee. All patients were contacted and included in the study provided they gave their written informed consent. According to their wish, the examination took place either in the psychiatric hospital attended by the patients or in their home. The systematic neurological examination of the patients at the first assessment in 1995 was carried out by one of the authors of the previous paper (Modestin et al., 2000) and of this paper (P.L.S.), trained for this task for over 20 h. The neurological examination in 2003/04 was performed by another author (M.V.W.), who had been trained for this task in the same way as was the examiner in the first study. In order to guarantee the ratings to be identical as far as possible, the first 17 patients and further 10 patients chosen at random in the course of the study were rated independently by both these two investigators. The kappa coefficients were 0.85 for Parkinsonism, 0.84 for akathisia, and 0.66 for TD (p <0.001 for all kappas). In the case of disagreement, the best estimate diagnosis was chosen in the case of joint ratings. Furthermore, the patients were asked to fill in the WHOQOL-BREF and BDI. A total of 73 patients (out of 83) gave informed written consent to study their past and present medication. All their inpatient and outpatient charts were thoroughly scrutinized and the NL medication the patients had actually received according to the prescriptions in the charts was registered. In order to compare the NL dose and to calculate the cumulative dose of NL they had received between 1995 and 2003/04, all NL doses were transformed in mg equivalent chlorpromazine (CPZ) according to the ratios used at the first assessment and indicated by Clark and Del Guidice (1970) and Dietmaier and Laux (1992). Regarding NLs not available at the time of the first study, the new edition of Dietmaier and Laux (1998), publication by Woods (2003) and the average doses recommended by the individual producers (Morant, 2004) were considered. The 1:1 mg equivalent ratio of clozapine to CPZ was determined. Calculating the cumulative doses, the periods off medication were included with 0 mg. As Parkinsonism and akathisia represent temporary conditions depending on the type of NL currently given, changes in these EPS (comparing ratings at the first and second assessment) were related to the NL medication at the time of the second assessment. In contrast, TD develops slowly and in dependence on the amount of NL the patient had received. Therefore, changes in TD prevalence were primarily related to the prescribed cumulative NL dose the patients received between 1995 and 2003/04. For the most part, only unequivocal cases of EPS were considered: for Parkinsonism and TD, research criteria (RC) defined by Van Harten et al. (1996) and Schooler and Kane (1982), respectively, had to be fulfilled, in the case of akathisia at least a mild form with both objective and subjective and/or distress manifestations was required. Nevertheless, studying the changes in all these three EPS over time, a more detailed classification was used, including categories of uncertain Parkinsonism (presence of symptoms, but RC not fulfilled), pseudoakathisia (only objective signs present) and questionable akathisia (only subjective and distress symptoms present), and uncertain TD (presence of symptoms, but RC not fulfilled). Regarding all EPS, lower ratings in 2003/04 indicated an improvement, higher ratings a worsening of the individual EPS. Improvement of a syndrome was indicated by a shift in the direction from “presence of the syndrome, RC fulfilled” to “presence of the syndrome, RC not fulfilled” to “absence of the syndrome”. 2.4. Statistical evaluation Evaluating the data, X2 test, Fisher exact test and McNemar test were used for categorical variables and Wilcoxon test (Z test statistics) and Kruskal–Wallis test (X2 approximations) for continuous variables. With regard to the many comparisons shown in Table 4, Table 5, the results were considered introducing Bonferroni correction for multiple comparisons. In addition, binary logistic regression analysis (backward procedure) was carried out studying risk factors for TD changes. For a variable to be retained in the model, a p range of 0.05–0.1 was chosen. 3. Results In Table 1, 83 study participants are compared with 117 drop-outs with regard to the 1995 data. As can be seen, men were over-represented among the study participants. Incidentally, in the whole original sample, the majority (57%) were men. Also, the participants were significantly younger, this mainly due to the higher average age (64 years, SD=20) of the deceased patients. There was a tendency for the organic disorders to be over-represented among the drop-outs in general and the deceased drop-outs in particular. Out of a total of 63 deceased patients, 15 (24%) were diagnosed with an organic disorder, and out of 16 drop-outs with organic disorder, 15 died. There were no significant differences between the study subjects and drop-outs with regard to the Parkinson syndrome ratings, akathisia occurrence and TD ratings, nor were there any significant differences in the proportion of patients having been prescribed typical neuroleptics (NL) and clozapine, and in the dosages of these NL. Table 2 compares NL medication on the index day in 1995, the index day in 2003/04 and throughout the 9-year period, indicating the average daily dose on the index days and the average cumulative dose for the whole period. The whole range of atypical NL were prescribed. On the index-day 2003/04 16 patients received olanzapine, 11 patients risperidone, 4 patients amisulpride, 2 patients quetiapine, and 1 patient sertindole. Antiparkinsonian drugs were also assessed. In 1995, 27 out of 83 followed-up patients (33%) received antiparkinsonian medication (average dose was 5.4±2.5 mg equivalent biperiden/die); in 2003/04 16 out of 79 patients (20%) were treated with these drugs (average dose was 5.0±2.3 mg equivalent biperiden/die). In 12 of these 16 patients, Parkinson syndrome was diagnosed. In Table 3 the prevalences of Parkinson syndrome, akathisia, and TD in 1995 and in 2003/04 are given. In 2003/04, Parkinson syndrome was identified in 29%, akathisia in 14%, and dyskinesia in 13%. A significantly higher proportion of patients suffered from Parkinsonism in 2003/04 than in 1995 (29% vs 17%, corresponding to an increase of 77%). The proportion of patients with akathisia was the same (14%) in both assessments. Finally, the prevalence of TD significantly decreased in 2003/04 (from 24% to 13%, a decrease of 47%). The proportion of patients presenting an individual extrapyramidal syndrome in the long term was relatively small: 8 patients had Parkinsonism, 3 patients akathisia and 7 patients TD on both occasions. Regarding Parkinsonism, the syndrome disappeared in 5 patients and it re-appeared in 15 patients; akathisia was no longer present in 8 patients, it appeared for the first time in 8 other patients; finally, TD was newly diagnosed in 3 patients and it could no longer be identified in 12 patients. In Table 4 the proportions of patients showing improvement, remaining the same and getting worse with respect to the individual EPS (in intra-individual comparisons of 2003/04 ratings with those from 1995) are indicated in relation to the type and average dose of the NL medication taken in 2003/04 (in the case of Parkinsonism and akathisia) and the cumulative dose of the NL taken between 1995 and 2003/04 (in the case of TD), respectively. In this comparison, patients who were effectively treated with an NL of the corresponding class, alone or in combination, were considered. There is a tendency for a worsening of the Parkinson syndrome to be associated with the current therapy with typical NL. Worsening of akathisia is associated with current atypical NL whereas clozapine seems to exert a beneficial effect on akathisia. After correction for multiple comparisons (p<.007), these associations are no longer significant. Finally, no significant associations were found between changes in TD ratings and long-term therapy with typical NL, clozapine, and other atypical NL in univariate comparisons. Altogether, higher AIMS scores, indicating worsening of TD, were found in 11 out of 79 patients, lower AIMS scores, indicating less dyskinesia, were found in 22 patients. In 28 of these 33 patients (8 with worsening, 20 with improvement of TD), complete data sets were available. In a binary logistic regression analysis considering these 28 patients, the role of sex, age, diagnosis (functional psychosis vs. other disorders), illness duration and cumulative dose of typical NL, clozapine, and atypical NL was studied, the improvement or worsening of TD serving as a dependent variable. Illness duration was found to be the only variable predicting, to some degree, the TD outcome (Wald statistics 3.61, p (1)=.058) — illness duration in patients with worsening of TD was almost twice as long (23.3 years vs. 12.8 years). The Nagelkerkes R2 was .22; thus, it can be said that the model explains about 20% of the variance. Without considering possible predictors, 71% cases (20/28) would have been correctly classified. Considering illness duration, the proportion of correct classified cases increased to 86% (24/28). A total of 54 patients filled in the WHOQOL-BREF (4 of them did not complete all domains) and 41 patients the BDI. In Table 5 the patients' average ratings are given along with the WHOQOL-BREF ratings obtained for the general population and a population of psychiatric patients by Angermeyer et al. (2000), and BDI ratings obtained for healthy probands and depressed patients by Hautzinger et al. (1995). Note that higher ratings indicate a higher quality of life. In our sample, there were no significant differences in the ratings between men and women except for a tendency for men to score higher in the psychic domain of WHOQOL-BREF: 64 (SD 17) vs. 54 (SD 25); Z=1.70, p=0.09. In the physical domain of WHOQOL-BREF the patients with Parkinson syndrome scored significantly lower and the patients with dyskinesia tended to score lower; otherwise, there were no significant differences between the ratings of patients with and without EPS. After correction for multiple comparisons (p<.008), even these associations are no longer significant. Also, there were no significant differences in any of the scores in relation to the NL class and NL dose at the time of the investigation. Correlating BDI and WHOQOL-BREF scores with each other, significant negative correlations were found for all individual WHOQOL-BREF domains (r between −0.46 for the environment and −0.75 for the physical domain, p<0.005 for all correlations). 4. Discussion Out of a total of 200 patients in the original sample, only 83 could be included in this follow-up study. This was mainly due to the high mortality rate; the majority (54%) of the drop-outs had died. Among the study participants there was a higher proportion of men (66%) than in the original sample (57%). This may be explained by the fact that in the original sample the women were older than the men (53 years vs. 45 years, z=2.61, p=0.009), and age significantly predicted the drop-out due to death. It should particularly be noted that there were no significant differences between the study participants and drop-outs with regard to the frequency and intensity of EPS and NL treatment (see Table 1). In 1995 only typical NL and clozapine were available; up to 2003/04 the majority of patients had also received atypical NL other than clozapine. In the course of the 8–9 years of this naturalistic study, the majority of the patients were treated with different combinations of NL for different periods of time. Only a minority of 21 out of 73 patients (29%) were treated with NL of one class (in terms of typical NL, clozapine and other atypical NL) during the time span between 1995 and 2003/04. Also, comparing NL therapy at both assessments, the tendency for concurrent combining of NL of different classes increased from 15% to 31%. Generally, combining different NL, both concurrently and consecutively, resulted in higher NL doses. It is important to note, however, that even in 1995 and the preceding years the concurrent and consecutive prescription of both typical NL and clozapine was the rule; all but one of 200 patients received typical NL, 121 of them were also treated with clozapine; only 1 patient was prescribed clozapine exclusively. Compared with other studies, prevalence rates of EPS found in this study in 2003/04 – 29% for Parkinsonism, 14% for akathisia, and 13% for TD – seem to be somewhat lower than those indicated by other authors, especially as far as TD is concerned: rates of 23%, 31% and 32% (Janno et al., 2004) and 35%, 15% and 43% (Halliday et al., 2002) have been reported. Diagnostic heterogeneity of our sample (only half were diagnosed with schizophrenia) was suspected to account for the difference; however, it hardly plays a role: as demonstrated, only illness duration contributed to the TD prognosis and there was no significant difference between patients with schizophrenic and other disorders regarding this variable. Strict definitions of EPS were used and, of course, the EPS prevalences vary to some degree in dependence on the individual sample; this also explains the differences between the whole original sample of 200 patients and the present subsample of 83 patients, both calculations based on the same 1995 assessment: 20%, 11%, and 22% versus 17%, 14%, and 24% respectively. Furthermore, regarding TD, comparable (14%, Eberhard et al., 2006) or even lower (9%, Kasper et al., 2005) prevalences were found in recent studies. As only 1 out of 8 patients with the diagnosis “other” disorder was not on NL in 2003/04, the inclusion of the patients of this diagnostic category will hardly have influenced the results. Regarding EPS, there were fluctuations between both assessments; EPS receded in some and appeared for the first time in other patients, in spite of the continuation of the NL therapy in the vast majority (90%) of them. These fluctuations concerned all EPS: Parkinson syndrome, the prevalence of which increased significantly from 17% to 29% between both assessments, but also akathisia, the prevalence of which remained the same (14%) and, last but not least TD, the prevalence of which significantly decreased from 24% in 1995 to 13% in 2003/04. Considering the category of uncertain dyskinesia (presence of symptoms, but RC not fulfilled), worsening of the syndrome was observed in 11 patients and improvement in 22 patients. Thus, TD is not always persistent or irreversible. A very similar result has been recently reported by Eberhard et al. (2006): In a 5-year longitudinal study on TD, the number of patients who became free of TD was higher than the number of those who developed TD. The decrease in the TD prevalence is not easy to explain. It occurred in spite of the higher age of the patients (they were 8–9 years older at the second assessment); higher age has been considered a risk factor for TD (Dose, 2004). At the first assessment, all patients were hospitalized and as such intensively treated; the number of masked TD could have therefore been even higher than later on. The second assessment was frequently carried out in the patients' home environment; their possibly more relaxed condition could have exerted a beneficial effect on their TD. Eight patients were no longer taking NL. Nevertheless, whereas in 7 of them no change in the TD rating occurred, in one a worsening was noted. Eberhard et al. (2006) argued that this finding is due to the exposure of patients to atypical antipsychotics; nevertheless, 85% of our patients were still receiving typical NL, alone or in combination with atypical ones. Finally, we consider the reliability of the ratings to have been good enough so as not to be responsible for the finding. Multivariate evaluation revealed the illness duration – independent of age – as the only variable being significantly associated with TD worsening. In any case, TD can fluctuate. Findings by Casey et al. (1986) are in agreement with our results: treating a small group of patients with stable doses of typical NL over 11 years resulted in a decrease of TD ratings by 24% — and in an increase of Parkinsonism ratings by 31%. The increase of the Parkinsonism prevalence in our sample could be related to the increase in age; in higher age, cases of idiopathic Parkinsonism may join the cases of NL-induced Parkinsonism. The inverse development of TD (decreased frequency) and Parkinsonism (increased frequency) could be related to the reduced amount of available dopamine at the receptors relevant for both syndromes (Casey et al., 1986). Newer theories dealing with the different frequency of EPS prescribing different NL, refer to the different rate of D2 receptor occupancy (Farde et al., 1992, Kapur et al., 2000), the rapidity of dopamine dissociation from the D2 receptors (Kapur and Seeman, 2001) and the differences in affinity of various NL to bind on D2 and 5-HT-2A receptors, respectively (Meltzer et al., 1989, Gardner et al., 2005). It is difficult, however, to relate these theories to our results, the more so, as for the most part the changes in the prevalence rates of EPS could not be correlated with NL therapy in this study. It was one of the principal aims of this study to explore the long-term evolution of EPS in relation to NL therapy. Relating the changes in Parkinson syndrome between 1995 and 2003/04 with NL medication in terms of the NL class and the NL dose the patients received in 2003/04, no significant results were obtained. Nevertheless, regarding akathisia, patients on clozapine improved significantly, whereas patients on other atypical NL became significantly worse, disregarding possible combinations with NL of another class. These findings must be interpreted with caution considering the number of comparisons that were carried out. Nevertheless, the latter finding confirms the assumption that atypical antipsychotics continue to carry notable risks for EPS, particularly akathisia (Shirzadi and Ghaemi, 2006). This is not unimportant as akathisia predicts more severe psychopathology (Nair et al., 1999). Beneficial effects of clozapine on akathisia (and other extrapyramdial syndromes) have been reported (Spivak et al., 1997, Levin et al., 1992). In the case of TD, cumulative NL doses from 1995 to 2003/04 were considered. Basically, the evolution of TD was not correlated with any NL type nor with the doses; the significant difference in patients treated with typical NL must not be overvalued since both patients with higher and lower ratings obtained higher cumulative doses than patients with the same ratings. It would be too speculative to assume that in patients with lower ratings/improvement of TD the NL dose had recently been increased and the TD masked. Thus, we replicated our previous finding (Modestin et al., 2000); we failed to demonstrate a beneficial effect of clozapine on the prevalence of TD in the past and we also failed to demonstrate such an effect of clozapine and other atypical NL in the present study. In contrast to our results, Halliday et al. (2002) found a significant increase of TD prevalence over the previous 20 years in a sample of schizophrenic patients; however, they also found no significant relationship between TD (and Parkinsonism) and any of the NL categories including oral standard and atypical antipsychotics. In short-term comparison, older patients with borderline TD treated with typical NL were approximately twice as likely to develop definitive TD compared with those prescribed atypical NL (Dolder and Jeste, 2003). In patients with preexisting TD atypical NL may even show antidyskinetic properties (Caroff et al., 2002). Our results do not endorse the assumption of atypical NL having a reduced risk of causing TD and an ability to suppress pre-existing TD (Pierre, 2005). Correspondingly, among patients with a diagnosis of TD, the same incidence of use of atypical NL as conventional NL was found, even after adjusting for age, gender, race, diagnosis, and anti-Parkinsonian drugs (Marshall et al., 2002). Only a subgroup of our patients filled in the WHOQOL and BDI questionnaires. Our probands, previous in-patients, scored higher in the WHOQOL than other psychiatric patients, but lower than the general population sample, the corresponding data having been reported by Angermeyer et al. (2000). A similar pattern was found with regard to BDI scores: again, scores of our probands were higher than scores obtained in healthy probands, but lower than scores obtained in depressed patients by Hautzinger et al. (1995). With the exceptions of a worse physical quality of life in patients with Parkinson syndrome and, perhaps, with dyskinesia which, in spite of their face validity, could have come about by chance due to multiple comparisons, no differences were found with regard to all WHOQOL and BDI ratings between patients suffering and not suffering from the individual extrapyramidal syndromes. As the scales were completed reliably by our patients, we conclude that other factors must be more decisive for the quality of life in these patients than EPS. The negative correlations between BDI and all WHOQOL domains point to the importance of depressive feelings for the quality of life. Some authors found that second generation antipsychotics did not improve quality of life more so that the first generation ones (Kilian et al., 2004), other authors found atypical NL to be superior to typical NL regarding quality of life (Ritsner et al., 2004, Mortimer and Al-Abib, 2007). Even if the latter findings were valid, EPS must not necessarily be involved. Limitations regarding our study should be mentioned. Less than half of the original sample could be followed-up; nevertheless, there were no substantial differences between the participants and drop-outs and especially, there were no significant differences with regard to the extrapyramidal syndromes and NL therapy at the first assessment. Our study was a naturalistic study and the treatment was prescribed without any restrictions by the physicians treating individual patients. Combining of NL of different types (typical, atypical, clozapine), concurrently and/or consecutively, was frequent. Unfortunately, we were not able to consider the influence of the individual combinations — the groups would have become too small for reliable and clinically useful comparisons. The effects of the individual NL classes were studied disregarding eventual NL combinations and we cannot exclude the possibility that interactions between NL could have influenced the results. Among our probands, there were no cases of manifest non-compliance. However, as far as we know, tests such as measurements of NL plasma concentrations were not carried out, so that non-compliance in individual patients cannot be excluded completely. In spite of these limitations, the results of the study allow the following conclusions: NL of different classes (typical and atypical) are relatively frequently combined. In the case of such a combination there is a tendency towards higher total dosages. Prevalences of the individual NL-induced EPS (Parkinsonism, akathisia and TD) fluctuate in the course of time; in some patients these syndromes disappear, in others they appear for the first time. These fluctuations take place even when the overall prevalence of the individual extrapyramidal syndrome remains the same and they also concern TD, which is thus neither persistent nor irreversible in many patients. In this study, the overall prevalence of TD decreased, the overall prevalence of Parkinsonism increased, the latter possibly due to the higher age of the patients at the second assessment. We were not able to demonstrate any influence of the current NL therapy (in terms of the NL class and dose) on the change in the ratings of Parkinson syndrome; in contrast, improvement of akathisia was associated with current clozapine therapy, worsening of akathisia with current therapy with other atypical NL. Most importantly, there was no association between the development of TD and therapy with NL of any class including clozapine and other atypicals. Thus, the purported TD suppressing and TD preventive effect of atypical NL could not be endorsed. In general it may be said that the occurrence of extrapyramidal syndromes had no impact on the patients' ratings of quality of life nor on their depression ratings. Role of funding source There was no funding for this study. Contributors Jiri Modestin designed the study; Marianne Vogt Wehrli and Jiri Modestin wrote the study protocol; Marianne Vogt Wehrli and Patrik Lukas Stephan examined the patients; Marianne Vogt Wehrli collected the treatment data; Puspa Agarwalla undertook the statistical analyses; and Jiri Modestin wrote the manuscript draft. All authors have contributed to and have approved the final manuscript. Conflict of interest All authors declare that they have no conflicts of interest. Acknowledgements We gratefully acknowledge the patients who participated in the study. References Angermeyer et al., 2000. 1.Angermeyer MC, Kilian R, Matschinger H. WHOQOL-100 AND WHAOQOL-BREF. Göttingen: Hogrefe; 2000;. Barnes, 1989. 2.Barnes TRE. A rating scale for drug-induced akathisia. Br. J. Psychiatry. 1989;154:672–676. MEDLINE |
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Dietmaier and Laux, 1992. 8.Dietmaier O, Laux G. Übersichtstabellen. In: Riederer P, Laux G, Pöldinger W editor. Neuro-Psychopharmaka, Bd.4. Wien: Springer; 1992;p. 197–213. Dietmaier and Laux, 1998. 9.Dietmaier O, Laux G. Übersichtstabellen. In: Riederer P, Laux G, Pöldinger W editor. Neuro-Psychopharmaka. Ein Therapie-Handbuch, Bd.4, 2.Auflage. Wien: Springer; 1998;p. 505–525. Dolder and Jeste, 2003. 10.Dolder CR, Jeste DV. Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients. Biol. Psychiatry. 2003;53:1142–1145. Abstract | Full Text |
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University of Zurich, Department of Psychiatry (Burghölzli Hospital), Lenggstrasse 31, CH-8032 Zurich, Switzerland  Corresponding author. Tel.: +41 44 384 26 70; fax: +41 44 384 27 19.
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