International Journal of Psychiatry in Clinical Practice, 2007; 11(2): 112
122

ORIGINAL ARTICLE

Quetiapine demonstrates good tolerability and is associated with improvements in extrapyramidal symptoms in patients with schizophrenia switched from other antipsychotics: results of a naturalistic study

JONATHAN S. E. HELLEWELL Trafford General Hospital, Manchester, UK

Abstract Objectives. Compared with conventional agents, atypical antipsychotics such as quetiapine (Seroquel† ; AstraZeneca) show improved tolerability and a lower liability to cause extrapyramidal symptoms (EPS). In the routine treatment of schizophrenia, it is usual practice to consider a change of medication when the current treatment is ineffective or poorly tolerated, although few studies are available to guide clinicians. This paper reports the results from the Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication (SPECTRUM) trial, a 12-week, open-label, noncomparative study that evaluated clinical benefit and tolerability of switching patients with schizophrenia from their existing antipsychotic to quetiapine. Method. Patients were switched because of intolerance to, or lack of efficacy with, their previous antipsychotic. Quetiapine was titrated to 400 mg/day over 7 days, then dosed flexibly up to 750 mg/day over the remaining weeks (mean modal dose 505 mg/day). Results. In the overall population of 506 evaluable patients, quetiapine was well tolerated, with a low incidence of adverse events and minimal requirement for anticholinergic medication. Significant improvements in EPS, including parkinsonism and akathisia, were observed, irrespective of reason for switching, although greatest improvements were observed in patients switching because of EPS. Conclusions. This study provides further evidence for the utility and tolerability of quetiapine, in patients with schizophrenia who had been switched from a previous antipsychotic, following problems with efficacy or tolerability.

Key Words: Quetiapine, schizophrenia, tolerability, extrapyramidal symptoms

Introduction Traditionally, the primary goal when treating schizophrenia has been the control of positive symptoms. However, clinicians are now increasingly interested in improving patients’ satisfaction with, and the subjective tolerability of, antipsychotic medicines [1,2]. Extrapyramidal symptoms (EPS), including parkinsonism, akathisia, dystonia and tardive dyskinesia, are among the most common and distressing problems experienced by patients taking conventional antipsychotics [3]. As such, they have a strong potential to affect adherence to treatment, leading to reduced clinical effectiveness and consequent relapse [4]. Over the last decade, the addition of various atypical agents to the antipsychotic armamentarium has presented the psychiatrist with a welcome expansion in therapeutic options, and these newer agents are now well-established treatment options for patients with schizophrenia. Compared with

conventional agents, atypical agents offer broader efficacy profiles, and may be more effective in improving the negative and cognitive deficits in schizophrenia, in addition to the classic positive psychotic symptoms [5]. With particular regard to both early and late EPS, the newer agents appear to be better tolerated than the older agents [4]. There is evidence that this improved tolerability has a positive influence upon patients’ initial subjective experiences of treatment and thus leads in turn, to improved adherence and thereby to better outcomes [6,7]. Nonetheless, the atypical antipsychotics differ from one another in terms of their propensity for EPS (including akathisia), weight gain, neuroendocrine abnormalities and cardiac effects [3]. The introduction of these atypical agents has presented clinicians with new challenges, especially in relation to determining new treatment strategies. Altamura and colleagues [8], when considering the challenges facing clinicians in the treatment of

Correspondence: Dr Jonathan Hellewell, Consultant Psychiatrist, Moorside Unit, Trafford General Hospital, Manchester M41 5SL, UK. Tel: /44 161 746 2680. Fax: /44 161 746 2672. E-mail: [email protected]

(Received 27 September 2005; accepted 25 June 2006) ISSN 1365-1501 print/ISSN 1471-1788 online # 2007 Taylor & Francis DOI: 10.1080/13651500600885549

Quetiapine improves EPS in schizophrenia patients 113 schizophrenia, concluded that the new generation atypical agents should be deployed in a rational and evidence-based manner, and that all patients with schizophrenia should be considered for treatment, rather than just those with refractory illness or troublesome side effects. The guidelines suggested that the newer agents should be administered at optimal doses, thereby achieving maximal benefit with minimal adverse effects, and that, where possible, combination therapy should be avoided, as this may limit tolerability. Although atypical agents are associated with a lower burden of EPS, clinicians need to remain aware of other side effects, which, in the absence of EPS, may assume a greater prominence [9]. In the routine treatment of schizophrenia, clinicians are commonly required to consider changes in medication. Reasons for switching include the perception of a lack of efficacy, adverse events such as EPS, or other tolerability problems; switching is undertaken either to optimise efficacy or to take advantage of a different tolerability profile that might better meet the needs of the patient. However, a major difficulty in clinical practice has been the lack of reliable studies that clinicians might draw upon when making treatment decisions, specifically in weighing up the relative merits of different medication regimens. On reviewing the utility and place in treatment of the newer agents, Hellewell and Gerlach concluded that atypical antipsychotics are deployed with best effect when there is ongoing consultation between clinician and patient about symptoms, adverse events, and expectations of treatment [9]. As the newer agents offer differing tolerability profiles, their widespread use has enabled more attention to be focused on the patient’s overall well being and quality of life, rather than solely on psychotic symptoms [2,7,10]. Clinical trials have demonstrated that the atypical antipsychotic quetiapine (Seroquel† ; AstraZeneca) has broad efficacy in schizophrenia, with improvements seen in the four domains of positive, negative, cognitive and affective symptomatology [11,12]. Quetiapine has also been found to be at least as effective as the conventional antipsychotic agent haloperidol and the atypical antipsychotic agent, risperidone, in the treatment of schizophrenia [11,13
15]. In patients with schizophrenia who have a history of partial response to conventional antipsychotics, a clinical picture commonly encountered in routine psychiatric practice, quetiapine demonstrated both significantly greater efficacy and fewer treatment-related adverse events, than seen with haloperidol [16]. EPS and elevated serum prolactin levels occur commonly with conventional and with some of the atypical antipsychotic agents [9]. In contrast, quetiapine shows a minimal tendency to induce EPS (including akathisia) or ele-

vated prolactin levels, with rates being no greater than placebo, across the entire therapeutic dose range [13
15,17]. Although double-blind, placebo-controlled trials are necessary for the registration of a new drug, there are often many important differences between standard clinical trials and routine clinical practice. Therefore, it is often not easy for the clinician to make the necessary inferences as to how the agent may function when used in routine clinical practice. For example, there are often differences in the types of patients recruited, and clinical trials tend to have rigid criteria for inclusion and exclusion, together with strict and often arbitrary rules on dosing. Moreover, trials tend to be of short duration, whereas patients with schizophrenia require longterm treatment. Surveys of patients’ experience on antipsychotics, although not without limitations, allow clinicians greater understanding of how best to use these antipsychotics, and although patients’ subjective experiences have often been overlooked, this has now become an expanding research area [2,18]. Recently, there has been an awareness of the broader concept of clinical effectiveness, rather than the more narrow traditional focus on efficacy. Standard clinical trials address questions of efficacy and investigate whether new agents appear efficacious within certain, narrowly defined parameters, whereas naturalistic studies, involving patients more representative of those routinely seen in clinical practice, are needed to study effectiveness. The concept of effectiveness encompasses changes within the overlapping domains of symptom control, tolerability, quality of life and subjective experience/ acceptability of treatment. Thus, naturalistic studies of clinical effectiveness address the important question of whether new treatments are likely to benefit patients, when deployed in routine clinical practice. The Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication (SPECTRUM) trial is an example of a pragmatic, ‘real-life’ study, providing information on the outcomes of quetiapine use in a large population of patients with schizophrenia who had been switched to quetiapine because of problems with previous medications. In essence, patients had to be judged by their clinicians to be experiencing suboptimal outcomes on their existing treatment regimens, with problems in the areas of tolerability, or of symptom control, or both. The adoption of a naturalistic design supplements earlier comparative studies and thus provides valuable information on the use of quetiapine in the real world. Efficacy and tolerability data from this study, as well as a post-hoc analysis in patients switching from haloperidol, olanzapine or risperidone have been previously published [19,20]. This paper further expands on the tolerability findings, with particular focus on EPS.

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Methods Patients In order to maximise the degree to which study results could be generalised to routine clinical practice, inclusion criteria were intentionally set very widely and exclusion criteria kept to the minimum. Patients could be recruited to the study if they were aged between 18 and 65 years and met DSM-IV diagnostic criteria for schizophrenia. In addition, it was a requirement that patients were considered by their clinicians as suitable for a change in treatment, for reasons of either ongoing side effects with, or inadequate response to, their previous antipsychotic medication. With regard to inadequate response, there were no restrictions upon whether this was in the areas of positive, negative or general symptomatology, cognitive impairment, or behavioural disturbance, such as aggression or hostility. Written, informed consent was obtained from all patients. By intention, exclusion criteria were kept to the minimum. However, patients were excluded if they were suffering from significant severe or chronic physical illness, had previously been intolerant of quetiapine, were already taking quetiapine, or had been treated in the previous month with clozapine. Patients previously treated with depot antipsychotics were allowed, although it was a requirement that this had been discontinued at least one dosing interval prior to recruitment. Study design and treatment This was a 12-week study, using an open, noncomparative design. Patients were recruited by clinicians at 85 centres, in 13 countries. Previous antipsychotic medication was maintained at the original doses on Days 1
3, reduced by 50% on Days 4
7, and discontinued on Day 8. Concomitantly, patients were administered 50 mg of quetiapine on Day 1 and 100 mg on Day 2, followed by 200 mg on Day 3, and 300 mg on Day 4. Between Days 5 and 8, the daily dose was increased to 400 mg. From Day 9 onwards, dosing was at the discretion of the investigator, with patients receiving up to 750 mg/day, in two doses. As in wider clinical practice, clinicians were free to use quetiapine as they thought best, in the light of changes in the patient’s condition. Patients already established for 4 weeks or more on antidepressant medication, were allowed to continue with this treatment, although no subsequent dose alterations were permitted. In keeping with the naturalistic approach, patients could remain in the study if they and their clinician regarded this as clinically appropriate. Subjects could be withdrawn following the emergence of an adverse event, if there was an observable lack of efficacy or clinical deterioration, or for a number of

administrative reasons such as protocol deviation, loss to follow-up, nonadherence to treatment, or the withdrawal of informed consent. Efficacy assessments The primary endpoint of the study was the change in the Index of Clinical Benefit (ICB), from baseline to Week 12. The ICB, a novel instrument designed to assess the clinical effectiveness of new treatment, shares similarities with the Clinical Global Impression (CGI) efficacy index [21], but is a global measure, incorporating assessments of both efficacy and side effects. Secondary endpoints included changes from baseline to Week 12 in scores on the Positive and Negative Syndrome Scale (PANSS) [22], the CGI Severity of Illness and Global Improvement scales and the Calgary Depression Scale for Schizophrenia (CDSS) [23]. Assessments were made on Day 1 and at Weeks 6 and 12. Tolerability assessments Tolerability was assessed using the Simpson
Angus Scale (SAS), as a measure of parkinsonism, and the Barnes Akathisia Scale (BAS). Patients were regarded as having clinically significant akathisia if their BAS score was two or above. To determine the effect of quetiapine treatment on weight gain, the body mass index (BMI) was calculated, with patients assigned to one of the following categories, as described by Brecher et al. [24]: underweight (BMI B/18.5 kg/m2); normal weight (BMI 18.5 to B/25 kg/m2); overweight (BMI 25 to B/30 kg/m2); obese (BMI 30 to B/35 kg/m2); severely obese (BMI ]/35 kg/m2). For the SAS, BAS and BMI, changes were assessed from baseline to Week 12. The use of anticholinergic medication, as a symptomatic treatment for EPS, was also used as an index of tolerability. The study protocol required prior anticholinergic medication to be withdrawn by Week 6; this facilitates the use of anticholinergic medication as a functional measure of the level of EPS associated with quetiapine treatment. Adverse events, as reported by the patient or observed by the investigator, were recorded both during the study and, thereafter, over a 7-day follow-up period. Statistical analysis The intention was to recruit 500 patients to the study. Analysis of efficacy endpoints was conducted on the intention-to-treat population (ITT), comprising all patients with data for one or more postbaseline visits. Analyses were carried out using the last value carried forward (LVCF) approach; in addition, for some variables, analyses were also performed on an observed case basis, at Weeks 6 and 12. Analysis of covariance, for the least square

Quetiapine improves EPS in schizophrenia patients 115 mean (LSM) change from baseline, was employed to determine statistical significance. Data from all patients who received one or more doses of quetiapine were included in the analyses of tolerability and safety endpoints. SAS and BAS scores were analysed by an LVCF approach, with statistical significance determined using covariance analysis of the LSM change from baseline.

Results Patients In total, 509 patients, with a mean age (range) of 35 (17
68) years, were recruited to the study (Table I [19]). Of these, 354 (69.5%) patients had been switched to quetiapine because of an inadequate response to their previous antipsychotic, while 151 (29.7%) had been switched following intolerance of their previous antipsychotic. In four (0.8%) patients, the reason for switching was not recorded. Of those patients entering the study because of intolerance of previous medication, 75 had been switched because of EPS, 40 following weight gain, nine due to sexual dysfunction and eight due to anticholinergic side effects, while a variety of other reasons were recorded for the remaining 19 patients. Of the 509 patients entering the study, 365 (71.7%) completed the 12-week treatment period. Table I. Patient demographics (n/509) (reproduced with kind permission [19]). Male:female, n Mean age, years (range) Mean time since first diagnosis, years (SD) Mean weight, kg (SD) Mean BMI, kg/m2 (SD)

290:219 35 (17
68)a 8.7 (9.1) 72.4 (17.7) 25.87 (5.86)

Reason for switching, n (%) Inadequate response Intolerance Not recorded

354 (69.5) 151 (29.7) 4 (0.8)

Previous antipsychotic medication, n (%) Olanzapine monotherapy Risperidone monotherapy Any typical monotherapy Any combination of antipsychotics Haloperidol (5/10 mg/day)b Other

66 55 186 142 43 60

(13.0) (10.8) (36.5) (27.9) (8.4) (11.8)

Dose of previous monotherapy antipsychotic, mg/day, mean (range) Olanzapine 18.1 (2.5
200) Risperidone 4.4 (1
12) Haloperidol 6.2 (1
10) Response to previous antipsychotic, n (%) Complete Partial Treatment resistant Not recorded

42 399 59 9

(8.3) (78.4) (11.6) (1.8)

A total of 144 patients discontinued the study early, 30 (5.9% of the total population) due to adverse events, 26 (5.1%) following withdrawal of consent, 25 (4.9%) with a report of lack of efficacy or deterioration in their condition, 24 (4.7%) after non-adherence to the protocol, 22 (4.3%) being lost to follow-up, while 17 (3.3%) discontinued for other reasons. In the subset of 75 patients entering the study because of EPS, 52 (69%) completed treatment: patients were withdrawn due to withdrawal of informed consent (seven); adverse events (seven); lack of efficacy/condition deteriorated (five), and protocol nonadherence (four). Treatment In order to establish the most commonly administered dose of quetiapine, the mean modal dose was calculated, since this most closely reflects the doses used by patients following the initial titration period. The mean modal dose of quetiapine was 505 mg/day (range 472
539 mg/day); there were no apparent differences between subpopulations of patients, as defined by previous antipsychotic medication. Efficacy A full report on efficacy data has been published previously [19]. In summary, for patients switching to quetiapine, over two-thirds (69%) met a priori criteria for clinical benefit, on the basis of positive changes on the ICB scale. As the ICB is a composite measure, integrating both efficacy and tolerability, these improvements in ICB score may represent either improvements in therapeutic benefit, the reduction in side effects, or both. Switching to quetiapine also resulted in significant reductions in PANSS total, positive subscale, negative subscale and general psychopathology scores (all P B/0.001, baseline to Week 12 [LVCF]). Similar improvements in PANSS total scores were observed in all subgroups, as defined by reason for switching or previous medication. These improvements in symptom rating and ICB scores were mirrored by improvements in the CGI-Severity of Illness; switching to quetiapine resulted in a significant decrease in mean CGI-Severity of Illness score by Week 12 (P B/0.001, LVCF) [19]. Using a threshold of 6 or more on the CDSS scale, a group of patients with clinically significant depressive symptoms was identified. In this group, there was an almost complete improvement in depressive symptomatology. Adverse events

a

Two patients outside the eligible age range were recruited to the study and included in the safety and ITT populations. b The haloperidol group of patients are a subset of those previously receiving any typical monotherapy.

There were 506 patients who received at least one dose of quetiapine and were therefore evaluable for tolerability analyses. In total, 252 patients were

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recorded as experiencing an adverse event. However, in only 30 of these patients (5.9% of the total sample) did this result in withdrawal from the study. The most frequent treatment-emergent adverse event was somnolence, experienced by 84 patients (Table II [19]), although the number of patients reporting somnolence appeared to diminish over time. New reports of EPS were uncommon, irrespective of prior medication, with only 24 (4.7%) of the 506 patients reported as developing an EPS-related adverse event (Table IIIa,b [19,25]). Of these, 17 completed the study, while seven withdrew. In total, 151 patients entered the study because of tolerability problems on their previous medication. Of the 75 patients who had entered the study due to EPS on previous medication, only six (8%) were reported to develop EPS after switching to quetiapine. Similarly, of the 76 patients who had switched due to other tolerability problems, only two (3%) were reported as developing EPS after entry to the study. By the end of the study, the mean weight for the overall population had shown a slight increase (by 0.69 kg at Week 12 [LVCF]). However, patients who had switched to quetiapine following weight gain with their previous antipsychotic therapy tended to show a reduction, with a mean decrease in weight of /1.4 kg at the end of the study. It was also found that in 361 (80%) of the 452 evaluable patients there had been no change in BMI category. Of the remaining 91 patients, 55 (12.2%) shifted to a higher BMI category and 36 (7.9%) shifted to a lower BMI category. Thus, for the overwhelming majority of patients, quetiapine had no clinically important adverse effects on weight. Rating scale assessments of EPS With regard to EPS, quetiapine was well tolerated, both in terms of new developments of EPS and in the improvement of pre-existing motor side effects. Symptoms of parkinsonism and akathisia, as measured by the Simpson
Angus and Barnes Akathisia Scales, improved in the group as a whole, from baseline to Week 12 of treatment; LSM (SE) change Table II. Treatment-emergent adverse events as reported by ]/4% of patients (reproduced with kind permission [19]). No. (%) patients Treatment-emergent adverse events Somnolence Asthenia Dizziness Insomnia Constipation Dry mouth Weight gaina Headache a

Defined as a complaint of weight gain.

84 27 24 24 23 22 22 21

(16.6) (5.3) (4.7) (4.7) (4.5) (4.3) (4.3) (4.2)

Table III. (a) Number (%) of patients with EPS-related adverse events in the total population and (b) split by prior therapy (reproduced with kind permission [19,25]). Total no. (%) patients reporting ]/1 EPS-related event (a) EPS-related events Total (n /506) Akathisia Dystonia Extrapyramidal symptoms Hypertonia Tremor (b) Prior therapy Total (n /506)a Olanzapine monotherapy (n/66) Risperidone monotherapy (n/55) Any typical monotherapy (n/186) Any combination therapy (n/142) Haloperidol 5/10 mg/day (n/43)b

24 8 1 9 2 6

(4.7) (1.6) (0.2) (1.8) (0.4) (1.2)

5 (7.6) 1 (1.8) 8 (4.3) 9 (6.3) 2 (4.7)

a Fifty-seven patients switched from another therapy type and were not included in the final analysis. b The haloperidol group of patients are a subset of those previously receiving any typical monotherapy.

was /2.84 (0.09; P B/0.001; baseline 13.8), and /0.5 (0.02; P B/0.001; baseline 0.6) for SAS and BAS scores, respectively (Figures 1a,b [26]). In total, 59.7% of patients showed an improvement in their SAS score and 29.9% on the BAS score (Figures 2a,b). Of the 449 patients for whom BAS scores were measured, 361 patients did not have akathisia when they entered the trial; at Week 12, only two (0.5%) of these met the criterion for akathisia. Of the 88 patients entering the trial with akathisia, 77 patients (87.5%) did not have clinically significant akathisia after Week 12 of treatment with quetiapine, as indicated by a BAS score of one or less. Improvements in ratings of EPS were observed in all groups, irrespective of the reason for switching (Figures 1a,b [26]), but the change appeared to be greatest in those patients for whom EPS had been cited as the reason for switching. In terms of the numbers of patients showing improvements in either their SAS or BAS scores, these were also found to be greatest in those patients who had entered the study due to EPS, with over 86% showing improvement in SAS score and 47% in BAS score (Figure 2a,b). Of the 68 patients switching because of EPS on their previous antipsychotic, 27 met criteria for akathisia at baseline. However, at Week 12, all but one of these patients had shown an improvement, with one remaining unchanged rather than deteriorating. In order to explore the impact of prior treatments on EPS, improvements in parkinsonism and akathisia were examined in all pre-treatment groups

Quetiapine improves EPS in schizophrenia patients 117

Figure 1. Improvements in (a) SAS and (b) BAS total scores at Week 12, overall and according to reason for switching (reproduced with kind permission [26]).

(Figure 3a [25]). The greatest mean improvement in SAS score was observed in patients that had been switched from haloperidol ( B/10 mg/day), who tended to have somewhat higher mean SAS scores at baseline. Data for patients receiving haloperidol at doses /10 mg/day were not analysed. In terms of the proportion of patients showing an improvement in their SAS score, this appeared to be greatest in the subgroup of patients who had switched from combination antipsychotics (71% of patients) compared with olanzapine monotherapy (52.5%), risperidone monotherapy (58%), typical monotherapy (60.6%), and haloperidol (B/10 mg/ day) (60.5%). For BAS score, the greatest mean improvement was in the group who had been switched from haloperidol (B/10 mg/day) (Figure 3b [25]). These patients tended to have higher mean BAS scores at baseline. In terms of the proportion of patients who experienced an improve-

ment in their BAS score, this was also greatest in the haloperidol subgroup (36.8% of patients) compared with olanzapine monotherapy (23.3%), risperidone monotherapy (32%), typical monotherapy (33.1%), and combination antipsychotics (31.3%). Anticholinergic use It was a requirement of the study protocol that anticholinergic use was to be discontinued by Week 6. Prior to baseline and during Weeks 1 and 2 (the cross-titration period), around 30% of patients received anticholinergics. However, once patients entered the flexible quetiapine dosing period, a marked reduction in anticholinergic use was observed, with a low rate, of around 10%, maintained thereafter (Figure 4 [26]). This was true irrespective of prior treatment and was consistent with a near complete improvement in EPS.

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Figure 2. Changes in (a) SAS and (b) BAS total scores, overall and according to reason for switching.

Discussion This study demonstrates that, for the majority of patients, quetiapine is a well-tolerated antipsychotic. Switching to quetiapine was associated, for many patients, with a substantial improvement in parkinsonism; many also showed improvements in akathisia. The greatest improvements were observed in those patients who had encountered tolerability problems with their previous medication. Uniquely for a first-line atypical antipsychotic, the incidence of EPS with quetiapine is not significantly different to placebo, across the entire dose range [13]. In contrast, dose-related EPS have been reported with risperidone, olanzapine, ziprasidone and amisulpride [27,28], while in a 4-month com-

parative study, a significantly greater proportion of risperidone-treated patients had moderate or substantial EPS than had patients receiving quetiapine [14]. In the SPECTRUM study, quetiapine was well tolerated, with a low reported rate of EPS (4.7%), and, in particular, of akathisia (1.6%). These figures compare favourably with those observed by Casey et al. in a study involving patients who were switched, using three different switching strategies, from their current antipsychotic to aripiprazole [29]. Akathisia was observed in 15% of those patients switching to aripiprazole after an abrupt discontinuation of their previous antipsychotic. In those in whom the previous antipsychotic was discontinued over 2 weeks, akathisia was seen in 11%. However, in those

Quetiapine improves EPS in schizophrenia patients 119

Figure 3. Improvements in (a) SAS and (b) BAS total scores at Week 12 according to previous antipsychotic therapy (reproduced with kind permission [25]).

Figure 4. Patients receiving anticholinergic medication throughout the study (reproduced with kind permission [26]).

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patients for whom aripiprazole was introduced while the previous antipsychotic was withdrawn, akathisia was observed in 21%. In the present study, significant improvements in EPS were observed, irrespective of whether patients were switched for reasons of efficacy or tolerability. In general, patients who had experienced EPS with their previous antipsychotic treatment or who had been switched to quetiapine because of tolerability problems tended to show the greatest improvements in SAS and BAS scores. This study is not unique in demonstrating improvements following switching to quetiapine after an inadequate response or intolerance to previous antipsychotic medication. Indeed, the Seroquel Clinical Use in Real-life Environment (SECURE) study found that 60% of patients who switched to quetiapine showed a response on the ICB, and that quetiapine appeared to be better tolerated than did olanzapine, risperidone, and haloperidol [30]. In the Seroquel Outcomes Study (SOS), patients switched to quetiapine following antipsychotic-induced EPS tended to show significant improvements in SAS scores over 6 months of treatment [31]. Finally, in the study in partially responsive schizophrenia, reported by Emsley et al., patients randomised to quetiapine showed greater improvement than those randomised to haloperidol [16]. There have been a number of other studies involving a switch to new generation antipsychotics that have shown encouraging results. For example, a longitudinal study examining the clinical and resource utilisation of switching stable outpatients from a conventional to an atypical antipsychotic (clozapine, risperidone and olanzapine) indicated that switching to an atypical can result in lasting improvements in clinical response and quality of life, together with reduced need for hospitalisation and community support [32]. However, there are important tolerability differences between atypical agents. For example, although improvements in psychiatric symptoms and EPS were reported after switching to olanzapine, significant weight gain was also seen to occur with this agent [33]. In the present study, quetiapine was well tolerated, as demonstrated by the low use of anticholinergic medication and the low withdrawal rate (only 5.9% of patients), following adverse events. Somnolence was the most commonly reported adverse event. However, this is likely to have often been of only modest severity, since withdrawal for this reason was uncommon. Somnolence with quetiapine is often transient; indeed the number of patients reporting this diminished over time. Somnolence is, of course, not confined solely to treatment with quetiapine and is commonly reported with other atypical antipsychotics [3]. The weight gain associated with some atypical antipsychotics is often regarded as unwelcome and may prove a major limitation to adherence. In

addition, there is an increased risk of morbidity and mortality, from a range of conditions, including hypertension and coronary heart disease [24]. Although mean weight of the population as a whole increased slightly, 80% of patients showed no change in their BMI category, suggesting that, for the majority of patients, quetiapine is not associated with significant weight gain. The importance of good tolerability should not be underestimated. Although first-line atypical agents in general are similarly efficacious, a patient will not obtain full benefit from treatment if the side effects are such that they are unwilling to take the medication, no matter how effective this may be. A survey questioning patients’ attitudes towards antipsychotics found that the single most commonly reported reason for nonadherence, reported by over 50% of more than 300 nonadherent patients, was the experience of side effects [34]. In a later study, patients listed EPS as among the most intolerable and disabling of these treatment-related adverse events [4]. It is clear, therefore, that the tolerability of an antipsychotic, particularly the propensity for EPS, is likely to impact considerably upon treatment outcome. Although the open-label design and lack of a control group are clearly limitations of this study, the substantial sample, broad recruitment criteria and freedom from restrictions on dosing mean that the results might readily be generalised to wider clinical practice. In comparison with standard, double-blind clinical trials, this study more closely reflects the real world. The finding of good tolerability, combined with favourable efficacy results, suggests that switching a patient to quetiapine might result in increased adherence and ultimately a more promising clinical outcome for the patient. Conclusions The SPECTRUM study provides further evidence of quetiapine’s clinical effectiveness across a broad spectrum of patients with schizophrenia. The majority of patients derived considerable benefit by switching to quetiapine from treatments that had offered them either only a partially efficacious response or had produced potentially distressing side effects. Patients tend to cite side effects, particularly EPS, as their main reason for not adhering to antipsychotic treatment. Importantly in this study, many patients derived significant improvements in EPS, with the greatest improvement seen in those patients who had switched from previous antipsychotics due to EPS. As such, the data presented here provide compelling evidence of the significant clinical advantage that may be obtained with quetiapine, not only for patients switching from a conventional medication, but for those changing from other atypical treatments with different tolerability profiles.

Quetiapine improves EPS in schizophrenia patients 121 Key points

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3 November 2002. [19] De Nayer A, Windhager E, Irmansyah, et al. Efficacy and tolerability of quetiapine in patients with schizophrenia switched from other antipsychotics. Int J Psychiatry Clin Pract 2003;7:59
66. [20] Larmo I, de Nayer A, Windhager E, et al. Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone. Hum Psychopharmacol Clin Exp 2005;20:573
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. Patients with schizophrenia who are treated with conventional antipsychotics commonly experience extrapyramidal symptoms (EPS) . In this trial, which involved patients switching to the atypical antipsychotic quetiapine because of intolerance to or lack of efficacy with their previous antipsychotic, quetiapine was generally well tolerated, with a low incidence of adverse events and a minimal requirement for anticholinergic medication . Many patients experienced significant improvements in EPS, including both parkinsonism and akathisia . The greatest improvements in EPS were seen in those patients who had been switched to quetiapine because of EPS with their previous antipsychotic . This study highlights the significant clinical benefits that might follow switching to quetiapine, from either conventional or other atypical medications Statement of interest/Acknowledgements This research was supported by AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA. I thank Dr A Gordon, from Complete Medical Communications Ltd, who provided editorial assistance on behalf of AstraZeneca. The SPECTRUM study investigators were: L Adler; R Aguiar; D Baettig; L Baudewijns; G Beckers; J Boucek; H Calil; J Campos; C Cetti; W Chefarzt; D Chetty; B Daeng; E De Bleeker; A De Nayer; P de Sousa; A Diefenbacher; M Driessen; S Elsner; F Faltus; M Ferla; L Ferreira; M Ferro; C Gagiano; A Gamito; B Gro¨ssl; A Guimara˜es; J Hallak; K Ha¨nninen; G Hart; H-J Haug; M Haushofer; H Helleybuyck; M Herrera; J Horacek; E Iacoponi; Irmansyah; J Ja¨a¨skela¨inen; H Jacobs; P Ko¨nig; H Koponen; I Larmo; M Lourenc¸o; M Louza; N Lumingkewas; E Maura; O-P Mehtonen; F Mesotten; K Meyer; V Muchl; M Mu¨ller; D Nina; M Ortiz; A Palha; A da Silva; W Pitchot; T Platz; P Ramjee; S Rataemane; I de Oliveria; M Renz; E Revez; H Rittmannsberger; C Robotti; L Roelens; A de la B Sa´nchez; D Sahagun; H Schubert; D Seabra; RG Sepulveda; I Shirakawa; Ph Snauwaert; Z Stankova; M Steyn; C Stuppa¨ck; A Tronco; M Versiani; K Vukovic; E Windhager; J Wirtz; D Wynchank; M Xavier; R Zenner.

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