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Efficacy and tolerability of quetiapine in poorly responsive, chronic schizophrenia
Schizophrenia Research 66 (2004) 143 – 150 www.elsevier.com/locate/schres
Efficacy and tolerability of quetiapine in poorly responsive, chronic schizophrenia Peter F. Buckley a,*, Jeffrey M. Goldstein b, Robin A. Emsley c a
Department of Psychiatry and Health Behavior, Medical College of Georgia, 1515 Pope Avenue, Augusta, GA 30912, USA b Clinical Medical Group, AstraZeneca Pharmaceuticals, Wilmington, DE, USA c Department of Psychiatry, Faculty of Medicine, University of Stellenbosch, Tygerberg, Cape Town, South Africa Received 12 August 2002; received in revised form 19 June 2003; accepted 25 June 2003
Abstract With the notable exception of clozapine, there is at present insufficient information on the efficacy of atypical antipsychotic medications in patients with poorly responsive schizophrenia. The present study reports on the efficacy and tolerability of quetiapine and haloperidol in patients with schizophrenia who showed no response to treatment with fluphenazine. This study is a post hoc subanalysis of an 8-week, double-blind study of patients receiving quetiapine 600 mg/day or haloperidol 20 mg/day. The proportion of patients classified as ‘‘Clinical Global Impression responders’’ (defined as Clinical Global Impression Severity of Illness score of V 3 at study end) was greater in the quetiapine group compared with the haloperidol group (51% vs. 25%; P = 0.023). Overall, quetiapine was well tolerated with less extrapyramidal side-effects and reduction in prolactin when compared to haloperidol. Weight gain was modest but more apparent in quetiapine-treated patients. Quetiapine is an appropriate treatment choice in patients who do not respond to prior antipsychotic treatment. D 2003 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Antipsychotic; Quetiapine; Haloperidol
1. Introduction Patients with schizophrenia exhibit a wide range of symptomatic response to antipsychotic therapies (Emsley and Oosthuisen, 2003). A minority of patients show complete resolution of symptoms. The majority of patients have a partial response to treatment, which can range from mild and/or intermittently persistent
* Corresponding author. Tel.: +1-706-721-6719; fax: +1-706868-0762. E-mail address: [email protected] (P.F. Buckley). 0920-9964/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2003.06.001
symptoms to severe, persistent, and disabling symptoms. The ‘boundary’ of partial responder and treatment refractory is still unclear, and definitions of treatment response schizophrenia continue to evolve over time, while the more severe and refractory schizophrenia was originally conceptualized as patients with severe illness and most aptly defined and recognized as those patients who remained long term in state hospitals (Barnes et al., 2003); the advent of clozapine and the consequent substantial regress of such patients into community living (Essock et al., 2002) has prompted a reconceptualization of refractory schizophrenia and what can (and cannot) be reasonably
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expected from current-day pharmacotherapy with typical and atypical antipsychotics. The refractory schizophrenia patient group is now defined partially from a failure of typical antipsychotics (Kane et al., 1988) and from such conventional measures as a lack of improvement by 20% on symptomatic rating scales (Kane et al., 1988; Bondolfi et al., 1998). Recent definitions of response schizophrenia also emphasize impairment of psychosocial functioning (Kane et al., 1988; Conley and Buchanan, 1997), sustained cognitive impairment (Green, 1996), and some incorporate patient tolerability and subjective response to treatment (Voruganti et al., 2000). This broader, multidimensional approach is in keeping with raised expectations from treatment and with evolving data that atypical antipsychotics may exert effects that reach beyond reduction in psychosis alone (Buckley, 2001). While the evidence for clozapine’s efficacy in more treatment-refractory (TR) schizophrenia is substantial and compelling (Wahlbeck et al., 1999; Chakos et al., 2001), there is less information on the use of each of the new antipsychotics in this patient subgroup. In an elegant, single-site study that mirrored in design the pivotal clozapine trial by Kane et al. (1988), olanzapine and chlorpromazine were shown to be effective in only 7% and 0% of well-characterized TR patients, respectively (Conley et al., 1998). A recent study (Volavka et al., 2002) comparing clozapine, olanzapine, risperidone, and haloperidol confirmed the superiority of atypical agents (especially clozapine and olanzapine) to a group of patients who were characterised as having had a previous ‘‘suboptimal treatment response.’’ The authors make this distinction from treatment refractory because the entry criteria for this study were less stringent than in other previous clozapine trials. In another study (Wirshing et al., 1999), which was of sound methodology and had good characterization of the patient sample, 32% (n = 9) of risperidone patients showed a >20% improvement at 8 weeks, compared with 14% (n = 4) of haloperidol patients. The difference observed between the treatment groups was not statistically significant (Wirshing et al., 1999). Other studies that employ less stringent criteria for the evaluation and definition of TR schizophrenia generally report higher response rates (20 –30%) for olanzapine (Martin et al., 1997; Tollefson et al., 2001) or risperidone (Klieser et al.,
1995; Bondolfi et al., 1998). A recent study of clozapine (Kane et al., 2001) in ambulatory (suboptimal responder) patients showed substantial advantage for clozapine over haloperidol. A similar study comparing clozapine with risperidone showed superior response but more attenuated differences between clozapine and risperidone (Schooler et al., 2003). A recent report of a 6-week comparative trial of ziprasidone and haloperidol in Chinese patients with treatment-refractory schizophrenia showed similar efficacy between both agents. There is recent information on the efficacy of aripiprazole in treatment-refractory patients. Which comes from doubleblind comparative study between aripiprazole and perphenazine (Kane, 2003) response was observed in both groups. In summary, although definitions of the extent of poor response differ substantially across available studies of atypical antipsychotics, there is some evidence of superior efficacy of atypical antipsychotic in TR populations. Moreover, there is more information available for clozapine, risperidone, and olanzapine in this patient population information for quetiapine, ziprasidone, and for the newest agent aripiprazole. With respect to quetiapine, sporadic case reports suggest beneficial effects and also highlight the advantages of quetiapine’s favorable side-effect profile in patient population (Chinchilla et al., 1997; Koziupa, 1999). This side-effect profile involves negligible rates of extrapyramidal symptoms (EPS) (Kasper and Muller-Spahn, 2000), lack of sustained elevation of prolactin (Arvanitis and Miller, 1997; Kasper and Muller-Spahn, 2000), and low propensity for weight gain (Brecher et al., 2000). This profile may be particularly advantageous in this TR population who require high doses of medication for efficacy and who have been exposed to the side-effect risk of multiple previous medications. In a recent clinical trial (Emsley et al., 2000), quetiapine demonstrated a better response rate and superior tolerability compared with haloperidol in patients with schizophrenia who had a history of partial response to conventional antipsychotic therapy. An important feature of this study was that inadequate prior response to antipsychotic was also confirmed during the initial 4 weeks’ run-in phase with fluphenazine 20 mg/day. The objective of the current post hoc subanalysis is to report on those patients contained
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within the original study who showed no change or a worsening of symptoms during the run-in treatment phase with fluphenazine.
2. Methods The original study, reported in detail elsewhere (Emsley et al., 2000), was a multicenter, double-blind, randomized, comparator-controlled, parallel-group trial in patients with schizophrenia who had a history of persistent positive symptoms while previously taking antipsychotics. The majority of patients had shown inadequate response to treatment with conventional antipsychotic medications. Ten patients had previously been treated with risperidone. One patient had previously been treated with olanzapine. Four patients had been previously treated with clozapine. However, these patients were intolerant to—rather than refractory to— clozapine therapy. Patients who were resistant to clozapine, who had a history of agranulocytosis, or who had an acute exacerbation of schizophrenia within the prior 3 months were not considered for this study. None of the study patients had previously been treated with quetiapine. Patients eligible for the current study had the following characteristics: male or female aged 18 years or over; schizophrenia diagnosed using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV, 1994) criteria for either catatonic, disorganized, paranoid, or undifferentiated; persistent positive symptoms whilst previously taking antipsychotics; a Positive and Negative Syndrome Scale (PANSS) positive subscale score z 15; and a Clinical Global Impression (CGI) Severity of Illness score z 3. All patients provided written informed consent and were required to withdraw from psychotropic medication before entry into the fluphenazine run-in phase, with the exception of long-term use of benzodiazepine treatment. All eligible patients initially received fluphenazine 20 mg/day in a 4-week, open-label phase. In the original study (Emsley et al., 2000), 365 entered the fluphenazine 4-week treatment phase. Thereafter, 288 patients were randomized to receive either quetiapine or haloperidol. The present study concerns a subgroup of the original study which focuses on those patients who did not respond or even worsened during the 4-week trial of fluphenazine. This sub-
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group comprised 95 patients since after 4 weeks, a total of 95 patients were found to have a failed response to fluphenazine (defined as no change or an increase in the PANSS total score between baseline and following fluphenazine treatment). This subgroup of patients had consequently been randomized to receive either a fixed dose of quetiapine 600 mg/day or haloperidol 20 mg/day, in a double-blind fashion, for an additional 8 weeks. The use of benzodiazepines and anticholinergic medication was permitted during the trial. The primary measure of efficacy was response to treatment over 8 weeks. The three main criteria for defining patients who had responded to treatment were a decrease in PANSS total score of z 20% from baseline (at the end of the fluphenazine trial) to week 8 (termed ‘‘PANSS responders’’); a CGI Severity of Illness score of V 3 at week 8 (termed ‘‘CGI responders’’); and a decrease in PANSS total score of z 20% from baseline plus a CGI Severity of Illness score of V 3 at week 8 (termed ‘‘combined responders’’). The definition of a response to treatment being a decrease in PANSS total score of z 20% was based on trials involving refractory patients from the current literature (Kane et al., 1988; Bondolfi et al., 1998; Conley et al., 1998; Flynn et al., 1998). Other efficacy measures of the study included changes from baseline to week 8 in the following: PANSS total and subscale (positive, negative, and general psychopathology) scores; derived Brief Psychiatric Rating Scale (BPRS) total, positive, and mood cluster (depressive mood, anxiety, guilt feelings, tension) scores; and CGI Severity of Illness score. Tolerability endpoints were assessed between baseline and week 8 of the study. These included the proportion of patients requiring anticholinergic therapy for the treatment of EPS; incidence of EPS-related adverse events; changes in Simpson Angus Scale score; and changes in serum prolactin concentrations. Development of clinically significant EPS was defined as an increase in the Simpson Angus Scale total score of z 14. All adverse events were recorded, and routine clinical laboratory tests, measurements of vital signs, and electrocardiograms (ECGs) were performed throughout the trial. Logistic regression analysis was used to compare the proportion of responders for each criterion between treatment groups and to compare the proportion
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Table 1 Patient demographics and baseline (week 4) parameters
3. Results
Demographic parameter
Quetiapine group
Haloperidol group
Number of patients exposed Age (years) Mean (S.D.) Range Sex: number (%) of patients Male Female Mean baseline PANSS total score PANSS positive PANSS negative PANSS general Simpson Angus score Time since first diagnosis (years)
54
41
39.0 (11.1) 19 – 72
40.6 (12.0) 19 – 62
38 (70.4) 16 (29.6) 92.8 22.7 25.9 44.2 16.8 13.2
24 (58.5) 17 (41.5) 94.0 23.8 24.1 46.2 16.6 11.5
Of 95 patients who had exhibited a failed response to fluphenazine, 54 patients were randomized to receive quetiapine, and 41 patients received haloperidol for 8 weeks. In this post hoc subanalysis, the treatment groups were well matched demographically and with respect to baseline PANSS total scores, which were 92.8 for the quetiapine group and 94.0 for the haloperidol group (Table 1). Post-baseline efficacy measures were actually recorded for 93 of 95 randomized patients: 53 patients in the quetiapine group and 40 patients in the haloperidol group. The mean dose of quetiapine was 530 mg/day (range 163– 580). The mean dose of haloperidol was 18 mg/day (range 7– 19). A statistically significant difference in the proportion of CGI responders in the ITT population was reported for the quetiapine group over the haloperidol group (51% vs. 25%; P = 0.023) (Fig. 1). A total of 59% of quetiapine-treated patients were defined as PANSS responders compared with 38% of haloperidol-treated patients ( P = 0.071) (Fig. 1). The percentage of combined responders was also numerically (but not statistically) greater for the quetiapine group than the haloperidol group (41% vs. 22%; P = 0.083) (Fig. 1). Excluding patients who had already attained CGI score of 3 at baseline did not materially alter these results. However, when an alternative definition of CGI ‘responder’ (based on CGI improvement at week 12— rather than CGI severity), was employed, this yielded
S.D. = standard deviation, PANSS = Positive and Negative Syndrome Scale.
of patients developing clinically significant EPS. Mean change from baseline to week 8 (last observation carried forward [LOCF]) and from baseline to each week (observed cases; data not presented) was assessed using analysis of covariance (ANCOVA), with baseline score as the covariate. The current study’s subanalysis, which included patients who met all protocol specifications, was used to test whether the statistics of the original study’s main analysis were robust. The intent-to-treat (ITT) population was analyzed. A P-value of < 0.05 was considered statistically significant. All statistical tests were two-sided.
Fig. 1. Percentage of treatment responders (defined as z 20% reduction in Positive and Negative Syndrome Scale [PANSS] or Clinical Global Impression [CGI] Severity of Illness score of V 3, or both) (intent-to-treat population) at study end (week 8) for patients treated with quetiapine 600 mg/day or haloperidol 20 mg/day. Patients had previously displayed no response to conventional antipsychotic treatment.
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overall higher and comparable response rates in both groups (74.3% quetiapine, 62.1% haloperidol, odds ratio 1.77, P = 0.294). At study end (week 8), the quetiapine-treated group showed numerically greater (but nonsignificant) improvements in the PANSS total ( 14.5 vs. 11.0; P=.04) and positive ( P = 0.52), negative ( P = 0.29), and general psychopathology ( P = 0.53) subscale scores compared with the haloperidol group (Fig. 2). Similarly, changes in derived BPRS total score from baseline to study end numerically revealed greater (but statistically nonsignificant) reductions in total ( 8.9 vs. 6.6, P = 0.37), positive subscale ( P = 0.16), and mood cluster (defined as the sum of items for anxiety, guilt feelings, depression, and tension) ( P = 0.69) in the quetiapine-treated group compared with the haloperidol-treated group. The mean change in CGI Severity of Illness score after 8 weeks’ treatment was also greater for quetiapine ( 0.71) compared with haloperidol ( 0.26) ( P = 0.056). The Simpson Angus Scale total score showed significant decreases from baseline to study end for patients receiving quetiapine compared with those given haloperidol (mean changes 3.3 vs. 1.8; least squares mean changes 3.09 vs. 1.60, P = 0.047) (Fig. 3). The incidence of EPS-related adverse events from baseline to the end of study was slightly lower in the quetiapine group (19%) than in the haloperidol group (23%). Only 12% of patients in the quetiapine group developed clinically significant EPS (defined as an increase in Simpson Angus Scale total score >14)
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Fig. 3. Percentage of patients at study end showing change in Simpson Scale score after treatment with quetiapine 600 mg/day or haloperidol 20 mg/day for 8 weeks. Patients had previously displayed no response to conventional antipsychotic treatment.*P = 0.005 vs. haloperidol.
compared with 23% of patients in the haloperidol group ( P = 0.172). No fluphenazine washout period was incorporated in the design of this study; therefore, this may have some impact on EPS data. Anticholinergic medication was not required by 56% of quetiapine patients compared with 25% of haloperidol patients during the randomized phase of the trial. However, before randomization, when patients were receiving fluphenazine, 38% of the quetiapine group and 60% of the haloperidol group had started a treatment regimen with anticholinergic medication. ANCOVA revealed that serum prolactin concentrations, which were increased throughout the flu-
Fig. 2. Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general psychopathology scores (intent-to-treat population) for patients treated with quetiapine 600 mg/day or haloperidol 20 mg/day for 8 weeks. Patients had previously displayed no response to conventional antipsychotic treatment.
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Fig. 4. Change in serum prolactin concentrations after 8 weeks’ treatment with quetiapine 600 mg/day or haloperidol 20 mg/day in patients following 4 weeks’ fluphenazine 20 mg/day treatment. *P < 0.001 vs. haloperidol.
phenazine run-in period, were significantly reduced after 8 weeks’ treatment with quetiapine compared with haloperidol ( 729.5 mU/l vs. 23.5 mU/l; P < 0.001) (Fig. 4). No statistically significant changes in vital signs or ECGs were observed from baseline to end of study for either the quetiapine or haloperidol treatment groups. Mean change in weight from baseline to study end was statistically significant (1.96 F 5.16 kg; P = 0.013) for quetiapine but not (0.05 F 4.48 kg; P = 0.95) for haloperidol. About 17% of quetiapine-treated patients and 6% of haloperidol-treated patients had a 7% or greater increase in weight ( P = 0.179).
4. Discussion The present ‘‘post hoc’’ analysis of the original study (Emsley et al., 2000) complements the available literature on atypical antipsychotics in patients with more recalcitrant forms of schizophrenia. The rates of response observed in the present study are comparable with those of the larger and more inclusive study of partial responders (Emsley et al., 2000). This suggests that quetiapine’s efficacy is not confined to just those with persistent symptoms, and this atypical agent is also effective in patients with more severe and recalcitrant symptoms. In a meta-analysis of clinical trials of atypical antipsychotics in TR schizophrenia, Chakos et al. (2001) concluded that (with the notable exception of
clozapine) there was insufficient information on efficacy of atypicals in severely ill patients. While this lack of information can, in part, be attributable to the relatively rapid pace of new drug development and to consequent lack of ‘‘real-time’’ information on efficacy in distinct patient populations, there is also a tendency not to focus efforts on the TR group where expectations of new therapies may be low (Buckley et al., 2001; Barnes et al., 2003). Moreover, there is a wide divergence of definitions of TR reflected in the existing literature, and this obfuscates a clear appreciation of the impact of treatment with atypicals in this patient group. This point is well exemplified in a recent study of treatment response in 84 patients with TR schizophrenia who were treated with clozapine (Reese et al., 2001). When definitions of TR and (correspondingly) response criteria from other published studies (least stringent: Bondolfi et al., 1998; intermediate: Conley and Buchanan, 1997; most stringent: Conley et al., 1998) were applied to this patient group, the percentage of responders ranged from 48% to 16%. These issues are also of relevance to the present study, which is a subanalysis of a larger study by Emsley et al. (2000) of patients with inadequate response to fluphenazine (which ranged from partial response to worsening of symptoms) during a 4-week trial. The present study focused on the subset of patients who showed no response or worsening of symptoms. While this is a clinically representative group of patients with severe and persistent illness, definition of treatment responsiveness in the present study should be considered in the context of other defined refractory groups reported previously for olanzapine and risperidone therapy (Conley et al., 1998; Wirshing et al., 1999; Azorin et al., 2001). This point warrants further elaboration since the response rates in these groups are relatively high in light of the patients’ previous unsatisfactory response to antipsychotics, including the fluphenazine phase. The response was most notable on the CGI measure using both categorical and dimensional estimates of response. It is also plausible that the longer duration of time available for treatment response contributed to this outcome. Additionally, as already well emphasized, this is a patient population with persistent symptoms in spite of prior pharmacotherapy and they had failed a 4-week trial of fluphenazine at an appropriate dose. The fluphenazine phase was sin-
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gle-blinded, and it is possible that this could have led to the expectation of minimal change during this treatment phase. The lack of demonstrated superior and differential efficacy of each atypical in TR schizophrenia means that other factors such as tolerability are important in deciding between drugs for this patient group. In this regard, the superior tolerability reported here for quetiapine over haloperidol is consistent with other recent reports on this atypical antipsychotic (Arvanitis and Miller, 1997; Copolov et al., 2000; Emsley et al., 2000; Kasper and Muller-Spahn, 2000). In particular, the change in Simpson Angus Scale total score from baseline was markedly lower at study end for patients receiving quetiapine compared with those given haloperidol, and the proportion of quetiapine-treated patients that developed clinically significant EPS during treatment was almost half that of the haloperidol-treated group. However, the study design did not include a fluphenazine washout period; this may have influenced the incidence of EPS-related adverse events during switching to either quetiapine or haloperidol. Additionally, serum prolactin levels were high in all patients following the 4-week fluphenazine run-in period; however, at study end, these levels were significantly reduced in the quetiapine group compared with the haloperidol group, indicating that quetiapine appears not to result in sustained elevation of plasma prolactin levels. This is of considerable importance for patients with more severe schizophrenia who may require doses substantially above that for acute maintenance treatment. On the other hand, weight gain (mean of just under 2 kg) was observed in quetiapine-treated patients compared with the haloperidol-treated group whose weight was essentially unchanged during the study. The proportion of patients with a 7% increase in weight did not differ significantly between the two treatment groups. Additional studies are clearly warranted to evaluate quetiapine’s efficacy in more well-defined TR populations. Comparing quetiapine’s efficacy and tolerability with that of other atypicals (rather than with conventional medications) would also be valuable in such refractory populations. These data are needed in order to determine reliably the relative merits of each atypical agent in patients with TR schizophrenia and to guide clinicians in decisions regarding the most appropriate treatment choices. Available data suggest
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that patients who fail on one atypical antipsychotic may respond well to another agent (Conley et al., 1999). On the other hand, at the present time, there is no definitive evidence that (aside from clozapine) one atypical is superior over another in patients with TR schizophrenia. It is likely that differentiation between agents will occur as more information emerges in the coming years from clinical trials which focus on patients with treatment-refractory schizophrenia.
References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association, American Psychiatric Press, Washington, DC. Arvanitis, L.A., Miller, B.G., 1997. Multiple fixed doses of ‘‘Seroquel’’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol. Psychiatry 42 (4), 233 – 246. Azorin, J.M., Spiegel, R., et al., 2001. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am. J. Psychiatry 158 (8), 1305 – 1313. Barnes, T.R.E, Schulz, S., Buckley, P., 2003. Treatment refractory schizophrenia. In: Hirsch, S., Weinberger, D. (Eds.), Schizophrenia. Blackwell, New York, NY, pp. 489 – 516. Bondolfi, G., Dufour, H., et al., 1998. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am. J. Psychiatry 155 (4), 499 – 504. Brecher, M., Rak, I.W., et al., 2000. The long-term effect of quetiapine (‘Seroquel’) monotherapy on weight in patients with schizophrenia. Int. J. Psychiatry Clin. Pract. 4, 287 – 291. Buckley, P.F., 2001. Broader therapeutic uses for atypical antipsychotic medications. Biol. Psychiatry, 912 – 924. Buckley, P., Miller, A., et al., 2001. When symptoms persist: clozapine augmentation strategies. Schizophr. Bull. 27 (4), 615 – 628. Chakos, M., Lieberman, J., et al., 2001. Effectiveness of secondgeneration antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am. J. Psychiatry 158 (4), 518 – 526. Chinchilla, A., Vega, M., et al., 1997. A long-term treatment with ‘Seroquel’ (quetiapine) in a severe schizophrenia patient. Eur. Neuropsychopharmacol. 7 (Suppl. 2), S198 – S199. Conley, R.R., Buchanan, R.W., 1997. Evaluation of treatment-resistant schizophrenia. Schizophr. Bull. 23 (4), 663 – 774. Conley, R.R., Tamminga, C.A., et al., 1998. Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. Am. J. Psychiatry 155 (7), 914 – 920. Conley, R.R., Tamminga, C.A., et al., 1999. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol. Psychiatry 46 (1), 73 – 77. Copolov, D.L., Link, C.G., et al., 2000. A multicentre, double-
150
P.F. Buckley et al. / Schizophrenia Research 66 (2004) 143–150
blind, randomized comparison of quetiapine (ICI 204,636, ‘Seroquel’) and haloperidol in schizophrenia. Psychol. Med. 30 (1), 95 – 105. Emsley, R.A., Oosthuisen, P., 2003. The new and evolving pharmacotherapy of schizophrenia. Psychiatr. Clin. North Am. 26 (1), 141 – 163. Emsley, R.A., Raniwalla, J., et al., 2000. A comparison of the effects of quetiapine (‘seroquel’) and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group. Int. Clin. Psychopharmacol. 15 (3), 121 – 131. Essock, S.M., Frisman, L.K., et al., 2002. Parmacoeconomics of schizophrenia. In: Davis, K. (Ed.), Neuropsychopharmacology: A Fifth Generation of Progress. Raven Press, New York. Flynn, S.W., MacEwan, G.W., et al., 1998. An open comparison of clozapine and risperidone in treatment-resistant schizophrenia. Pharmacopsychiatry 31 (1), 25 – 29. Green, M.F., 1996. What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry 153 (3), 321 – 330. Kane, J.M., 2003. Aripiprazole for treatment-refractory schizophrenia. Presentation at the Annual meeting of the American Psychiatric Association, San Fransico, May. Kane, J., Honigfeld, G., et al., 1988. Clozapine for the treatmentresistant schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45 (9), 789 – 796. Kane, J.M., Marder, S.R., Schooler, N.R., Wirshing, W.C., Umbricht, D., Baker, R.W., Wirshing, D.A., Safferman, A., Ganguli, R., McMenuman, M., Borenstein, M., 2001. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison. Arch. Gen. Psychiatry 58 (10), 965 – 972. Kasper, S., Muller-Spahn, F., 2000. Review of quetiapine and its clinical applications in schizophrenia. Expert. Opin. Pharmacother. 1 (4), 783 – 801. Klieser, E., Lehmann, E., et al., 1995. Randomized, double-
blind, controlled trial of risperidone versus clozapine in patients with chronic schizophrenia. J. Clin. Psychopharmacol. 15 (1, Suppl. 1), 45S – 51S. Koziupa, D., 1999. The efficacy of quetiapine in relieving persistent symptoms in a patient with poor response to both conventional and atypical antipsychotic therapy. J. Clin. Psychol. 60 (Suppl. 23), 13. Martin, J., Gomez, J.C., et al., 1997. Olanzapine in treatment-refractory schizophrenia: results of an open label study. The Spanish Group for the Study of Olanzapine in Treatment-Refractory Schizophrenia. J. Clin. Psychiatry 58 (11), 479 – 483. Reese, S., Flynn, S., et al., 2001. Varying definitions of treatment refractoriness and treatment response influence assessment of clinical value of clozapine. Schizophr. Res. 49, 242 – 243. Schooler, N.R., Marder, S.R., Kane, J.M., et al., 2003. Clozapine and risperidone in moderately refractory schizophrenia: a six month double-blind comparison. Schizophr. Res. 60 (1), 302. Tollefson, G.D., Birkett, M.A., et al., 2001. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol. Psychiatry 49 (1), 52 – 63. Volavka, J., Czobor, P., et al., 2002. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am. J. Psychiatry 159 (2), 255 – 262. Voruganti, L., Cortese, L., et al., 2000. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side-effect profile and impact on quality of life. Schizophr. Res. 43 (2 – 3), 135 – 145. Wahlbeck, K., Cheine, M., et al., 1999. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and metaanalysis of randomized trials. Am. J. Psychiatry 156 (7), 990 – 999. Wirshing, D.A., Marshall Jr., B.D., et al., 1999. Risperidone in treatment-refractory schizophrenia. Am. J. Psychiatry 156 (9), 1374 – 1379.
Efficacy and tolerability of quetiapine in poorly responsive, chronic schizophrenia Peter F. Buckley a,*, Jeffrey M. Goldstein b, Robin A. Emsley c a
Department of Psychiatry and Health Behavior, Medical College of Georgia, 1515 Pope Avenue, Augusta, GA 30912, USA b Clinical Medical Group, AstraZeneca Pharmaceuticals, Wilmington, DE, USA c Department of Psychiatry, Faculty of Medicine, University of Stellenbosch, Tygerberg, Cape Town, South Africa Received 12 August 2002; received in revised form 19 June 2003; accepted 25 June 2003
Abstract With the notable exception of clozapine, there is at present insufficient information on the efficacy of atypical antipsychotic medications in patients with poorly responsive schizophrenia. The present study reports on the efficacy and tolerability of quetiapine and haloperidol in patients with schizophrenia who showed no response to treatment with fluphenazine. This study is a post hoc subanalysis of an 8-week, double-blind study of patients receiving quetiapine 600 mg/day or haloperidol 20 mg/day. The proportion of patients classified as ‘‘Clinical Global Impression responders’’ (defined as Clinical Global Impression Severity of Illness score of V 3 at study end) was greater in the quetiapine group compared with the haloperidol group (51% vs. 25%; P = 0.023). Overall, quetiapine was well tolerated with less extrapyramidal side-effects and reduction in prolactin when compared to haloperidol. Weight gain was modest but more apparent in quetiapine-treated patients. Quetiapine is an appropriate treatment choice in patients who do not respond to prior antipsychotic treatment. D 2003 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Antipsychotic; Quetiapine; Haloperidol
1. Introduction Patients with schizophrenia exhibit a wide range of symptomatic response to antipsychotic therapies (Emsley and Oosthuisen, 2003). A minority of patients show complete resolution of symptoms. The majority of patients have a partial response to treatment, which can range from mild and/or intermittently persistent
* Corresponding author. Tel.: +1-706-721-6719; fax: +1-706868-0762. E-mail address: [email protected] (P.F. Buckley). 0920-9964/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2003.06.001
symptoms to severe, persistent, and disabling symptoms. The ‘boundary’ of partial responder and treatment refractory is still unclear, and definitions of treatment response schizophrenia continue to evolve over time, while the more severe and refractory schizophrenia was originally conceptualized as patients with severe illness and most aptly defined and recognized as those patients who remained long term in state hospitals (Barnes et al., 2003); the advent of clozapine and the consequent substantial regress of such patients into community living (Essock et al., 2002) has prompted a reconceptualization of refractory schizophrenia and what can (and cannot) be reasonably
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expected from current-day pharmacotherapy with typical and atypical antipsychotics. The refractory schizophrenia patient group is now defined partially from a failure of typical antipsychotics (Kane et al., 1988) and from such conventional measures as a lack of improvement by 20% on symptomatic rating scales (Kane et al., 1988; Bondolfi et al., 1998). Recent definitions of response schizophrenia also emphasize impairment of psychosocial functioning (Kane et al., 1988; Conley and Buchanan, 1997), sustained cognitive impairment (Green, 1996), and some incorporate patient tolerability and subjective response to treatment (Voruganti et al., 2000). This broader, multidimensional approach is in keeping with raised expectations from treatment and with evolving data that atypical antipsychotics may exert effects that reach beyond reduction in psychosis alone (Buckley, 2001). While the evidence for clozapine’s efficacy in more treatment-refractory (TR) schizophrenia is substantial and compelling (Wahlbeck et al., 1999; Chakos et al., 2001), there is less information on the use of each of the new antipsychotics in this patient subgroup. In an elegant, single-site study that mirrored in design the pivotal clozapine trial by Kane et al. (1988), olanzapine and chlorpromazine were shown to be effective in only 7% and 0% of well-characterized TR patients, respectively (Conley et al., 1998). A recent study (Volavka et al., 2002) comparing clozapine, olanzapine, risperidone, and haloperidol confirmed the superiority of atypical agents (especially clozapine and olanzapine) to a group of patients who were characterised as having had a previous ‘‘suboptimal treatment response.’’ The authors make this distinction from treatment refractory because the entry criteria for this study were less stringent than in other previous clozapine trials. In another study (Wirshing et al., 1999), which was of sound methodology and had good characterization of the patient sample, 32% (n = 9) of risperidone patients showed a >20% improvement at 8 weeks, compared with 14% (n = 4) of haloperidol patients. The difference observed between the treatment groups was not statistically significant (Wirshing et al., 1999). Other studies that employ less stringent criteria for the evaluation and definition of TR schizophrenia generally report higher response rates (20 –30%) for olanzapine (Martin et al., 1997; Tollefson et al., 2001) or risperidone (Klieser et al.,
1995; Bondolfi et al., 1998). A recent study of clozapine (Kane et al., 2001) in ambulatory (suboptimal responder) patients showed substantial advantage for clozapine over haloperidol. A similar study comparing clozapine with risperidone showed superior response but more attenuated differences between clozapine and risperidone (Schooler et al., 2003). A recent report of a 6-week comparative trial of ziprasidone and haloperidol in Chinese patients with treatment-refractory schizophrenia showed similar efficacy between both agents. There is recent information on the efficacy of aripiprazole in treatment-refractory patients. Which comes from doubleblind comparative study between aripiprazole and perphenazine (Kane, 2003) response was observed in both groups. In summary, although definitions of the extent of poor response differ substantially across available studies of atypical antipsychotics, there is some evidence of superior efficacy of atypical antipsychotic in TR populations. Moreover, there is more information available for clozapine, risperidone, and olanzapine in this patient population information for quetiapine, ziprasidone, and for the newest agent aripiprazole. With respect to quetiapine, sporadic case reports suggest beneficial effects and also highlight the advantages of quetiapine’s favorable side-effect profile in patient population (Chinchilla et al., 1997; Koziupa, 1999). This side-effect profile involves negligible rates of extrapyramidal symptoms (EPS) (Kasper and Muller-Spahn, 2000), lack of sustained elevation of prolactin (Arvanitis and Miller, 1997; Kasper and Muller-Spahn, 2000), and low propensity for weight gain (Brecher et al., 2000). This profile may be particularly advantageous in this TR population who require high doses of medication for efficacy and who have been exposed to the side-effect risk of multiple previous medications. In a recent clinical trial (Emsley et al., 2000), quetiapine demonstrated a better response rate and superior tolerability compared with haloperidol in patients with schizophrenia who had a history of partial response to conventional antipsychotic therapy. An important feature of this study was that inadequate prior response to antipsychotic was also confirmed during the initial 4 weeks’ run-in phase with fluphenazine 20 mg/day. The objective of the current post hoc subanalysis is to report on those patients contained
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within the original study who showed no change or a worsening of symptoms during the run-in treatment phase with fluphenazine.
2. Methods The original study, reported in detail elsewhere (Emsley et al., 2000), was a multicenter, double-blind, randomized, comparator-controlled, parallel-group trial in patients with schizophrenia who had a history of persistent positive symptoms while previously taking antipsychotics. The majority of patients had shown inadequate response to treatment with conventional antipsychotic medications. Ten patients had previously been treated with risperidone. One patient had previously been treated with olanzapine. Four patients had been previously treated with clozapine. However, these patients were intolerant to—rather than refractory to— clozapine therapy. Patients who were resistant to clozapine, who had a history of agranulocytosis, or who had an acute exacerbation of schizophrenia within the prior 3 months were not considered for this study. None of the study patients had previously been treated with quetiapine. Patients eligible for the current study had the following characteristics: male or female aged 18 years or over; schizophrenia diagnosed using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV, 1994) criteria for either catatonic, disorganized, paranoid, or undifferentiated; persistent positive symptoms whilst previously taking antipsychotics; a Positive and Negative Syndrome Scale (PANSS) positive subscale score z 15; and a Clinical Global Impression (CGI) Severity of Illness score z 3. All patients provided written informed consent and were required to withdraw from psychotropic medication before entry into the fluphenazine run-in phase, with the exception of long-term use of benzodiazepine treatment. All eligible patients initially received fluphenazine 20 mg/day in a 4-week, open-label phase. In the original study (Emsley et al., 2000), 365 entered the fluphenazine 4-week treatment phase. Thereafter, 288 patients were randomized to receive either quetiapine or haloperidol. The present study concerns a subgroup of the original study which focuses on those patients who did not respond or even worsened during the 4-week trial of fluphenazine. This sub-
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group comprised 95 patients since after 4 weeks, a total of 95 patients were found to have a failed response to fluphenazine (defined as no change or an increase in the PANSS total score between baseline and following fluphenazine treatment). This subgroup of patients had consequently been randomized to receive either a fixed dose of quetiapine 600 mg/day or haloperidol 20 mg/day, in a double-blind fashion, for an additional 8 weeks. The use of benzodiazepines and anticholinergic medication was permitted during the trial. The primary measure of efficacy was response to treatment over 8 weeks. The three main criteria for defining patients who had responded to treatment were a decrease in PANSS total score of z 20% from baseline (at the end of the fluphenazine trial) to week 8 (termed ‘‘PANSS responders’’); a CGI Severity of Illness score of V 3 at week 8 (termed ‘‘CGI responders’’); and a decrease in PANSS total score of z 20% from baseline plus a CGI Severity of Illness score of V 3 at week 8 (termed ‘‘combined responders’’). The definition of a response to treatment being a decrease in PANSS total score of z 20% was based on trials involving refractory patients from the current literature (Kane et al., 1988; Bondolfi et al., 1998; Conley et al., 1998; Flynn et al., 1998). Other efficacy measures of the study included changes from baseline to week 8 in the following: PANSS total and subscale (positive, negative, and general psychopathology) scores; derived Brief Psychiatric Rating Scale (BPRS) total, positive, and mood cluster (depressive mood, anxiety, guilt feelings, tension) scores; and CGI Severity of Illness score. Tolerability endpoints were assessed between baseline and week 8 of the study. These included the proportion of patients requiring anticholinergic therapy for the treatment of EPS; incidence of EPS-related adverse events; changes in Simpson Angus Scale score; and changes in serum prolactin concentrations. Development of clinically significant EPS was defined as an increase in the Simpson Angus Scale total score of z 14. All adverse events were recorded, and routine clinical laboratory tests, measurements of vital signs, and electrocardiograms (ECGs) were performed throughout the trial. Logistic regression analysis was used to compare the proportion of responders for each criterion between treatment groups and to compare the proportion
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Table 1 Patient demographics and baseline (week 4) parameters
3. Results
Demographic parameter
Quetiapine group
Haloperidol group
Number of patients exposed Age (years) Mean (S.D.) Range Sex: number (%) of patients Male Female Mean baseline PANSS total score PANSS positive PANSS negative PANSS general Simpson Angus score Time since first diagnosis (years)
54
41
39.0 (11.1) 19 – 72
40.6 (12.0) 19 – 62
38 (70.4) 16 (29.6) 92.8 22.7 25.9 44.2 16.8 13.2
24 (58.5) 17 (41.5) 94.0 23.8 24.1 46.2 16.6 11.5
Of 95 patients who had exhibited a failed response to fluphenazine, 54 patients were randomized to receive quetiapine, and 41 patients received haloperidol for 8 weeks. In this post hoc subanalysis, the treatment groups were well matched demographically and with respect to baseline PANSS total scores, which were 92.8 for the quetiapine group and 94.0 for the haloperidol group (Table 1). Post-baseline efficacy measures were actually recorded for 93 of 95 randomized patients: 53 patients in the quetiapine group and 40 patients in the haloperidol group. The mean dose of quetiapine was 530 mg/day (range 163– 580). The mean dose of haloperidol was 18 mg/day (range 7– 19). A statistically significant difference in the proportion of CGI responders in the ITT population was reported for the quetiapine group over the haloperidol group (51% vs. 25%; P = 0.023) (Fig. 1). A total of 59% of quetiapine-treated patients were defined as PANSS responders compared with 38% of haloperidol-treated patients ( P = 0.071) (Fig. 1). The percentage of combined responders was also numerically (but not statistically) greater for the quetiapine group than the haloperidol group (41% vs. 22%; P = 0.083) (Fig. 1). Excluding patients who had already attained CGI score of 3 at baseline did not materially alter these results. However, when an alternative definition of CGI ‘responder’ (based on CGI improvement at week 12— rather than CGI severity), was employed, this yielded
S.D. = standard deviation, PANSS = Positive and Negative Syndrome Scale.
of patients developing clinically significant EPS. Mean change from baseline to week 8 (last observation carried forward [LOCF]) and from baseline to each week (observed cases; data not presented) was assessed using analysis of covariance (ANCOVA), with baseline score as the covariate. The current study’s subanalysis, which included patients who met all protocol specifications, was used to test whether the statistics of the original study’s main analysis were robust. The intent-to-treat (ITT) population was analyzed. A P-value of < 0.05 was considered statistically significant. All statistical tests were two-sided.
Fig. 1. Percentage of treatment responders (defined as z 20% reduction in Positive and Negative Syndrome Scale [PANSS] or Clinical Global Impression [CGI] Severity of Illness score of V 3, or both) (intent-to-treat population) at study end (week 8) for patients treated with quetiapine 600 mg/day or haloperidol 20 mg/day. Patients had previously displayed no response to conventional antipsychotic treatment.
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overall higher and comparable response rates in both groups (74.3% quetiapine, 62.1% haloperidol, odds ratio 1.77, P = 0.294). At study end (week 8), the quetiapine-treated group showed numerically greater (but nonsignificant) improvements in the PANSS total ( 14.5 vs. 11.0; P=.04) and positive ( P = 0.52), negative ( P = 0.29), and general psychopathology ( P = 0.53) subscale scores compared with the haloperidol group (Fig. 2). Similarly, changes in derived BPRS total score from baseline to study end numerically revealed greater (but statistically nonsignificant) reductions in total ( 8.9 vs. 6.6, P = 0.37), positive subscale ( P = 0.16), and mood cluster (defined as the sum of items for anxiety, guilt feelings, depression, and tension) ( P = 0.69) in the quetiapine-treated group compared with the haloperidol-treated group. The mean change in CGI Severity of Illness score after 8 weeks’ treatment was also greater for quetiapine ( 0.71) compared with haloperidol ( 0.26) ( P = 0.056). The Simpson Angus Scale total score showed significant decreases from baseline to study end for patients receiving quetiapine compared with those given haloperidol (mean changes 3.3 vs. 1.8; least squares mean changes 3.09 vs. 1.60, P = 0.047) (Fig. 3). The incidence of EPS-related adverse events from baseline to the end of study was slightly lower in the quetiapine group (19%) than in the haloperidol group (23%). Only 12% of patients in the quetiapine group developed clinically significant EPS (defined as an increase in Simpson Angus Scale total score >14)
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Fig. 3. Percentage of patients at study end showing change in Simpson Scale score after treatment with quetiapine 600 mg/day or haloperidol 20 mg/day for 8 weeks. Patients had previously displayed no response to conventional antipsychotic treatment.*P = 0.005 vs. haloperidol.
compared with 23% of patients in the haloperidol group ( P = 0.172). No fluphenazine washout period was incorporated in the design of this study; therefore, this may have some impact on EPS data. Anticholinergic medication was not required by 56% of quetiapine patients compared with 25% of haloperidol patients during the randomized phase of the trial. However, before randomization, when patients were receiving fluphenazine, 38% of the quetiapine group and 60% of the haloperidol group had started a treatment regimen with anticholinergic medication. ANCOVA revealed that serum prolactin concentrations, which were increased throughout the flu-
Fig. 2. Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general psychopathology scores (intent-to-treat population) for patients treated with quetiapine 600 mg/day or haloperidol 20 mg/day for 8 weeks. Patients had previously displayed no response to conventional antipsychotic treatment.
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Fig. 4. Change in serum prolactin concentrations after 8 weeks’ treatment with quetiapine 600 mg/day or haloperidol 20 mg/day in patients following 4 weeks’ fluphenazine 20 mg/day treatment. *P < 0.001 vs. haloperidol.
phenazine run-in period, were significantly reduced after 8 weeks’ treatment with quetiapine compared with haloperidol ( 729.5 mU/l vs. 23.5 mU/l; P < 0.001) (Fig. 4). No statistically significant changes in vital signs or ECGs were observed from baseline to end of study for either the quetiapine or haloperidol treatment groups. Mean change in weight from baseline to study end was statistically significant (1.96 F 5.16 kg; P = 0.013) for quetiapine but not (0.05 F 4.48 kg; P = 0.95) for haloperidol. About 17% of quetiapine-treated patients and 6% of haloperidol-treated patients had a 7% or greater increase in weight ( P = 0.179).
4. Discussion The present ‘‘post hoc’’ analysis of the original study (Emsley et al., 2000) complements the available literature on atypical antipsychotics in patients with more recalcitrant forms of schizophrenia. The rates of response observed in the present study are comparable with those of the larger and more inclusive study of partial responders (Emsley et al., 2000). This suggests that quetiapine’s efficacy is not confined to just those with persistent symptoms, and this atypical agent is also effective in patients with more severe and recalcitrant symptoms. In a meta-analysis of clinical trials of atypical antipsychotics in TR schizophrenia, Chakos et al. (2001) concluded that (with the notable exception of
clozapine) there was insufficient information on efficacy of atypicals in severely ill patients. While this lack of information can, in part, be attributable to the relatively rapid pace of new drug development and to consequent lack of ‘‘real-time’’ information on efficacy in distinct patient populations, there is also a tendency not to focus efforts on the TR group where expectations of new therapies may be low (Buckley et al., 2001; Barnes et al., 2003). Moreover, there is a wide divergence of definitions of TR reflected in the existing literature, and this obfuscates a clear appreciation of the impact of treatment with atypicals in this patient group. This point is well exemplified in a recent study of treatment response in 84 patients with TR schizophrenia who were treated with clozapine (Reese et al., 2001). When definitions of TR and (correspondingly) response criteria from other published studies (least stringent: Bondolfi et al., 1998; intermediate: Conley and Buchanan, 1997; most stringent: Conley et al., 1998) were applied to this patient group, the percentage of responders ranged from 48% to 16%. These issues are also of relevance to the present study, which is a subanalysis of a larger study by Emsley et al. (2000) of patients with inadequate response to fluphenazine (which ranged from partial response to worsening of symptoms) during a 4-week trial. The present study focused on the subset of patients who showed no response or worsening of symptoms. While this is a clinically representative group of patients with severe and persistent illness, definition of treatment responsiveness in the present study should be considered in the context of other defined refractory groups reported previously for olanzapine and risperidone therapy (Conley et al., 1998; Wirshing et al., 1999; Azorin et al., 2001). This point warrants further elaboration since the response rates in these groups are relatively high in light of the patients’ previous unsatisfactory response to antipsychotics, including the fluphenazine phase. The response was most notable on the CGI measure using both categorical and dimensional estimates of response. It is also plausible that the longer duration of time available for treatment response contributed to this outcome. Additionally, as already well emphasized, this is a patient population with persistent symptoms in spite of prior pharmacotherapy and they had failed a 4-week trial of fluphenazine at an appropriate dose. The fluphenazine phase was sin-
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gle-blinded, and it is possible that this could have led to the expectation of minimal change during this treatment phase. The lack of demonstrated superior and differential efficacy of each atypical in TR schizophrenia means that other factors such as tolerability are important in deciding between drugs for this patient group. In this regard, the superior tolerability reported here for quetiapine over haloperidol is consistent with other recent reports on this atypical antipsychotic (Arvanitis and Miller, 1997; Copolov et al., 2000; Emsley et al., 2000; Kasper and Muller-Spahn, 2000). In particular, the change in Simpson Angus Scale total score from baseline was markedly lower at study end for patients receiving quetiapine compared with those given haloperidol, and the proportion of quetiapine-treated patients that developed clinically significant EPS during treatment was almost half that of the haloperidol-treated group. However, the study design did not include a fluphenazine washout period; this may have influenced the incidence of EPS-related adverse events during switching to either quetiapine or haloperidol. Additionally, serum prolactin levels were high in all patients following the 4-week fluphenazine run-in period; however, at study end, these levels were significantly reduced in the quetiapine group compared with the haloperidol group, indicating that quetiapine appears not to result in sustained elevation of plasma prolactin levels. This is of considerable importance for patients with more severe schizophrenia who may require doses substantially above that for acute maintenance treatment. On the other hand, weight gain (mean of just under 2 kg) was observed in quetiapine-treated patients compared with the haloperidol-treated group whose weight was essentially unchanged during the study. The proportion of patients with a 7% increase in weight did not differ significantly between the two treatment groups. Additional studies are clearly warranted to evaluate quetiapine’s efficacy in more well-defined TR populations. Comparing quetiapine’s efficacy and tolerability with that of other atypicals (rather than with conventional medications) would also be valuable in such refractory populations. These data are needed in order to determine reliably the relative merits of each atypical agent in patients with TR schizophrenia and to guide clinicians in decisions regarding the most appropriate treatment choices. Available data suggest
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that patients who fail on one atypical antipsychotic may respond well to another agent (Conley et al., 1999). On the other hand, at the present time, there is no definitive evidence that (aside from clozapine) one atypical is superior over another in patients with TR schizophrenia. It is likely that differentiation between agents will occur as more information emerges in the coming years from clinical trials which focus on patients with treatment-refractory schizophrenia.
References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association, American Psychiatric Press, Washington, DC. Arvanitis, L.A., Miller, B.G., 1997. Multiple fixed doses of ‘‘Seroquel’’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol. Psychiatry 42 (4), 233 – 246. Azorin, J.M., Spiegel, R., et al., 2001. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am. J. Psychiatry 158 (8), 1305 – 1313. Barnes, T.R.E, Schulz, S., Buckley, P., 2003. Treatment refractory schizophrenia. In: Hirsch, S., Weinberger, D. (Eds.), Schizophrenia. Blackwell, New York, NY, pp. 489 – 516. Bondolfi, G., Dufour, H., et al., 1998. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am. J. Psychiatry 155 (4), 499 – 504. Brecher, M., Rak, I.W., et al., 2000. The long-term effect of quetiapine (‘Seroquel’) monotherapy on weight in patients with schizophrenia. Int. J. Psychiatry Clin. Pract. 4, 287 – 291. Buckley, P.F., 2001. Broader therapeutic uses for atypical antipsychotic medications. Biol. Psychiatry, 912 – 924. Buckley, P., Miller, A., et al., 2001. When symptoms persist: clozapine augmentation strategies. Schizophr. Bull. 27 (4), 615 – 628. Chakos, M., Lieberman, J., et al., 2001. Effectiveness of secondgeneration antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am. J. Psychiatry 158 (4), 518 – 526. Chinchilla, A., Vega, M., et al., 1997. A long-term treatment with ‘Seroquel’ (quetiapine) in a severe schizophrenia patient. Eur. Neuropsychopharmacol. 7 (Suppl. 2), S198 – S199. Conley, R.R., Buchanan, R.W., 1997. Evaluation of treatment-resistant schizophrenia. Schizophr. Bull. 23 (4), 663 – 774. Conley, R.R., Tamminga, C.A., et al., 1998. Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. Am. J. Psychiatry 155 (7), 914 – 920. Conley, R.R., Tamminga, C.A., et al., 1999. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol. Psychiatry 46 (1), 73 – 77. Copolov, D.L., Link, C.G., et al., 2000. A multicentre, double-
150
P.F. Buckley et al. / Schizophrenia Research 66 (2004) 143–150
blind, randomized comparison of quetiapine (ICI 204,636, ‘Seroquel’) and haloperidol in schizophrenia. Psychol. Med. 30 (1), 95 – 105. Emsley, R.A., Oosthuisen, P., 2003. The new and evolving pharmacotherapy of schizophrenia. Psychiatr. Clin. North Am. 26 (1), 141 – 163. Emsley, R.A., Raniwalla, J., et al., 2000. A comparison of the effects of quetiapine (‘seroquel’) and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group. Int. Clin. Psychopharmacol. 15 (3), 121 – 131. Essock, S.M., Frisman, L.K., et al., 2002. Parmacoeconomics of schizophrenia. In: Davis, K. (Ed.), Neuropsychopharmacology: A Fifth Generation of Progress. Raven Press, New York. Flynn, S.W., MacEwan, G.W., et al., 1998. An open comparison of clozapine and risperidone in treatment-resistant schizophrenia. Pharmacopsychiatry 31 (1), 25 – 29. Green, M.F., 1996. What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry 153 (3), 321 – 330. Kane, J.M., 2003. Aripiprazole for treatment-refractory schizophrenia. Presentation at the Annual meeting of the American Psychiatric Association, San Fransico, May. Kane, J., Honigfeld, G., et al., 1988. Clozapine for the treatmentresistant schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45 (9), 789 – 796. Kane, J.M., Marder, S.R., Schooler, N.R., Wirshing, W.C., Umbricht, D., Baker, R.W., Wirshing, D.A., Safferman, A., Ganguli, R., McMenuman, M., Borenstein, M., 2001. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison. Arch. Gen. Psychiatry 58 (10), 965 – 972. Kasper, S., Muller-Spahn, F., 2000. Review of quetiapine and its clinical applications in schizophrenia. Expert. Opin. Pharmacother. 1 (4), 783 – 801. Klieser, E., Lehmann, E., et al., 1995. Randomized, double-
blind, controlled trial of risperidone versus clozapine in patients with chronic schizophrenia. J. Clin. Psychopharmacol. 15 (1, Suppl. 1), 45S – 51S. Koziupa, D., 1999. The efficacy of quetiapine in relieving persistent symptoms in a patient with poor response to both conventional and atypical antipsychotic therapy. J. Clin. Psychol. 60 (Suppl. 23), 13. Martin, J., Gomez, J.C., et al., 1997. Olanzapine in treatment-refractory schizophrenia: results of an open label study. The Spanish Group for the Study of Olanzapine in Treatment-Refractory Schizophrenia. J. Clin. Psychiatry 58 (11), 479 – 483. Reese, S., Flynn, S., et al., 2001. Varying definitions of treatment refractoriness and treatment response influence assessment of clinical value of clozapine. Schizophr. Res. 49, 242 – 243. Schooler, N.R., Marder, S.R., Kane, J.M., et al., 2003. Clozapine and risperidone in moderately refractory schizophrenia: a six month double-blind comparison. Schizophr. Res. 60 (1), 302. Tollefson, G.D., Birkett, M.A., et al., 2001. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol. Psychiatry 49 (1), 52 – 63. Volavka, J., Czobor, P., et al., 2002. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am. J. Psychiatry 159 (2), 255 – 262. Voruganti, L., Cortese, L., et al., 2000. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side-effect profile and impact on quality of life. Schizophr. Res. 43 (2 – 3), 135 – 145. Wahlbeck, K., Cheine, M., et al., 1999. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and metaanalysis of randomized trials. Am. J. Psychiatry 156 (7), 990 – 999. Wirshing, D.A., Marshall Jr., B.D., et al., 1999. Risperidone in treatment-refractory schizophrenia. Am. J. Psychiatry 156 (9), 1374 – 1379.