| | A randomized, flexible-dose, quasi-naturalistic comparison of quetiapine, risperidone, and olanzapine in the short-term treatment of schizophrenia: The QUERISOLA trialReceived 6 June 2007; received in revised form 10 September 2007; accepted 12 September 2007. published online 16 October 2007. Abstract This was a randomized, flexible-dose, rater-blind, parallel-group, quasi-naturalistic trial comparing the efficacy, safety, and tolerability of quetiapine, risperidone, and olanzapine in patients with schizophrenia hospitalized for severe psychotic symptoms. Seventy-five patients were randomized to quetiapine (n =25), risperidone (n=25), or olanzapine (n=25). Mean doses at Week 8 were: 590.0 mg/day quetiapine; 5.1 mg/day risperidone; 15.1 mg/day olanzapine. Four quetiapine, five risperidone, and five olanzapine patients discontinued prior to Week 8. There were no significant differences between groups in the primary efficacy measures of improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 8 in the per protocol (PP) population and the number of completers who experienced ≥ 40% improvement on the same scale. PP and intent-to-treat analyses showed significant improvement from baseline in each component of a PANSS-derived battery, without significant differences between treatments. No quetiapine patients, one risperidone, and four olanzapine patients reported an adverse event (AE) of moderate intensity; no severe AEs were reported. A linear mixed model for repeated measures showed an effect of treatment on body weight, with significant differences favoring quetiapine over risperidone and olanzapine. Simpson–Angus Scale scores were significantly worse with risperidone compared with both olanzapine and quetiapine at Week 3 and compared with quetiapine thereafter. Use of concomitant medications for anxiety or tension was significantly less frequent with quetiapine. In conclusion, quetiapine, risperidone, and olanzapine have similar efficacy in schizophrenia, but there are drug-specific differences for some AEs and in the use of concomitant medication that differentiate these agents. 1. Introduction  Meta-analyses and systematic reviews largely agree that, with some drug-specific differences, atypical antipsychotics offer benefits with respect to efficacy and tolerability over the conventional antipsychotics for the short-term treatment of patients with schizophrenia (Bagnall et al., 2000, Davis et al., 2003, Duggan et al., 2005, El Sayeh and Morganti, 2006, Emsley and Oosthuizen, 2004, Gardner et al., 2005, Hunter et al., 2003, Leucht et al., 2003, Lieberman et al., 2005b, Srisurapanont et al., 2004). Atypical antipsychotics may therefore be regarded as appropriate first-line options. The identification of first-line drugs is the first step in the decision-making process to select the best possible pharmacological strategy, because for optimized interventions, first-choice rather than first-line drugs are needed. To reach evidence-based conclusions on first-choice treatments, head-to-head comparisons between different first-line options are required. However, only a few trials of atypical antipsychotics involve direct comparisons (Addington et al., 2004, Breier et al., 2005, Davis et al., 2003, Duggan et al., 2005, El Sayeh and Morganti, 2006, Emsley and Oosthuizen, 2004, Gilbody et al., 2000, Jayaram et al., 2005, Kasper et al., 2001, Kraus et al., 2005, Lieberman et al., 2005b, Srisurapanont et al., 2004, Tandon and Fleischhacker, 2005, Tandon and Jibson, 2005, Tandon and Jibson, 2003, Zhong et al., 2006, Lieberman et al., 2005a). Furthermore, a substantial gap exists between these trials and real-life practice, since in almost all of these studies patient inclusion criteria were highly stringent, wash-out periods were required after previous medications, concomitant treatments were usually not allowed, and fixed doses of study medication were used. The present study compared the atypical antipsychotics quetiapine, risperidone, and olanzapine for the short-term treatment of patients with severe schizophrenia, using a study design based, in an analogy to the real world, on flexible doses, less stringent recruitment criteria, and the possible use of concomitant, non-antipsychotic medication if needed. 2. Methods 2.1. General study design The QUERISOLA trial is a flexible-dose, randomized, parallel-group, rater-blinded, quasi-naturalistic study of quetiapine, risperidone, and olanzapine for the treatment of patients with schizophrenia who were hospitalized for severe psychotic symptoms (study number was 5077IT/SACC). The study is quasi-naturalistic because a randomized design with rater-blinded evaluators was coupled with clinical management similar to that used in clinical practice. For example, the physician was not blinded and had the discretion to choose from different options regarding switching, the suspension of non-allowed medications, and study drug titration. Furthermore, based on clinical judgment, the physician could use flexible dosing and prescribe some co-therapies. The study design was approved by the Brescia Spedali Civili Ethical Committee and the trial was conducted in accordance with the Declaration of Helsinki (South Africa revision, 1996). 2.2. Protocol amendments In the original protocol, patients were to be randomized to quetiapine, risperidone, or olanzapine in a 2:1:1 ratio with an 8-week acute treatment phase plus an 8-week follow-up phase in which patients were to be maintained on their original antipsychotic or switched to alternative treatments. However, enrolment difficulties relating to study exclusion criteria restricted the sample to 75 patients. Consequently, randomization based on an equal ratio was conducted. Recruitment of fewer patients than planned, and problems with one center being unable to maintain continuity of care following acute treatment, resulted in the number of patients entering the follow-up phase being too small for statistical evaluation. Therefore, only the results of the 8-week acute treatment phase were analyzed and are reported herein. 2.3. Patients Patients were recruited from three mental health departments in Lombardy, Italy (Brescia University and Spedali Civili, Milano Ospedale Fatebenefratelli, and Cremona Istituti Ospitalieri). Patients who were consecutively and voluntarily admitted to one of the three sites were enrolled provided they gave written informed consent and fulfilled the study inclusion and exclusion criteria. Inclusion criteria were: age between 18 and 65 years; a DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) diagnosis of schizophrenia (American Psychiatric Association, 2000); a total score of ≥ 70 on the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987); and no exposure to depot antipsychotics in the previous 6 weeks. In addition, patients needed to have a level of understanding and cooperativeness sufficient to participate in the study and communicate with the study investigators. Exclusion criteria included: current DSM-IV-TR axis I comorbid disorders; a history of substance-abuse related disorders in the preceding 6 months; concomitant severe, unstable physical illnesses; contraindications to treatment with risperidone, olanzapine, or quetiapine; and a physician's opinion that it would be inappropriate to discontinue non-allowed drugs within 4 days. 2.4. Treatments Patients were allocated to quetiapine, risperidone, or olanzapine treatment according to a randomization list generated using a random-number table. If a patient had a history of use of one of the three study medications, only the two others were included in the randomization, irrespective of the effects of the previous treatment. Pre-existing or de novo treatment with benzodiazepines for anxiety or tension, anticholinergic drugs and/or benzodiazepines for movement disorders, and flurazepam, flunitrazepam or zolpidem for insomnia was allowed. However, supplementary use of other antipsychotics, mood stabilizers, or antidepressants was not permitted, except during the 4-day tapering period. The maximum allowed total daily doses were 8 mg for risperidone, 20 mg for olanzapine, and 800 mg for quetiapine, based on manufacturers dosing guidelines, and the suggestions of an expert consensus guideline (Kane et al., 2003). As per the manufacturers guidelines, quetiapine and risperidone were administered twice daily as divided doses; olanzapine was administered once daily. At the screening visit, patients received a concise motivational intervention talk focused on a valid pharmacological adherence, relevant for successful treatment. The treating physician also discussed the possibility of switching, following informed consent, to alternative treatments due to a lack of efficacy, distressing adverse events (AEs), or physical problems related to their medication. 2.5. Assessments PANSS, Simpson–Angus Scale for extrapyramidal symptoms (SAS) (Simpson and Angus, 1970), Barnes Akathisia Rating Scale (BARS) (Barnes, 1989), and Abnormal Involuntary Movement Scale (AIMS) (Psychopharmacology Research Branch, 1976) scores, and vital signs and body weight were all assessed at the screening visit and 7, 14, 21, 28, 35, 42, and 56 days thereafter. Physical examination, complete blood chemistry, and hematology were carried out at the screening visit and at Week 8. All assessments were repeated whenever a patient discontinued prematurely. Patients continued as in- or out-patients based on the physician's judgment with regard to ongoing hospitalization. Spontaneously reported emergent AEs of moderate-to-severe intensity and reasons for early discontinuation were all recorded in detail. All assessments and completion of case report forms were carried out by a psychiatrist who had experience of the protocol study procedures and demonstrated valid inter-reliability in the DSM-IV-TR diagnosis of schizophrenia and use of the selected rating scales. The evaluators were completely unaware of the treatment received by the patients. 2.6. Evaluation of efficacy, safety, and tolerability Efficacy was evaluated using a PANSS-derived battery, which comprised the total scale; the positive, negative, and general subscales; the Lindenmayer's domains of psychopathology (Lindenmayer et al., 1994); Brief Psychiatric Rating Scale (BPRS) hostility cluster (anxiety, tension, hostility, suspiciousness, uncooperativeness, excitement; derived from PANSS); and BPRS factor V (hostility, suspiciousness, uncooperativeness; derived from PANSS). The predefined primary efficacy measures were the change from baseline in PANSS total score after 8 weeks in the per protocol (PP) population and the number and proportion of completers who experienced at least 40% improvement on the same scale. All other changes from baseline at any scheduled visit for each component of the PANSS-derived battery in either the PP or intent-to-treat (ITT) populations were secondary efficacy measures, as were the proportions of completers who achieved at least a 20% or 30% improvement in PANSS total score. Safety and tolerability were evaluated by: spontaneously reported emergent moderate-to-severe AEs; any clinically relevant abnormalities in the physical examination, vital signs, blood chemistry, and hematology; and changes from baseline in body weight and SAS, BARS, and AIMS scores. Supplementary use of allowed medications was also recorded. 2.7. Statistical analyses Data were expressed as mean (standard deviation [SD]), median (inter-quartile range [IQR]), and/or percentage values. Significance was set at p=0.05. Baseline key demographic, psychopathological, and physical characteristics of the three treatment groups were compared by one-way analysis of variance (ANOVA) or Kruskal–Wallis test with post hoc comparisons if continuous and χ2 test if categorical. For each drug, the endpoint doses of completers and those of patients who discontinued treatment early were compared by Student's t-test. The discontinuation rates in the different arms were compared by the χ2 test and analyzed using a logistic regression model that also included sex, age, and baseline PANSS total score as predictive variables. For each component of the PANSS-derived battery, the PP and ITT last observation carried forward (LOCF) endpoint changes from baseline were tested by analysis of covariance (ANCOVA), adjusting for initial values and using the treatments as covariates. For a change in the 8-week PANSS total score, an F-test for equivalence (Welleck, 2003) was also applied; the test assumed a priori that the score changes had a normal distribution and were equivalent in the different arms if they did not exceed a 10% difference. The rates of quetiapine, risperidone, and olanzapine completers reaching a 40%, 30%, or 20% improvement from baseline in PANSS total score were compared by the χ2 test. For each component of the PANSS-derived battery, a linear mixed model for repeated measures was also applied to the score changes from baseline that occurred at any visit. No adjustments for multiple testing were performed. Safety and tolerability data were evaluated using the same statistical approaches as were used for the efficacy analyses, and were assessed according to the ITT population. The use of concomitant medications in the three arms was compared using the χ2 test and ANCOVA, adjusting for the individual time spent in the trial. 3. Results 3.1. Patient characteristics and disposition Baseline key demographic, psychopathological, and physical characteristics were comparable across the treatment groups (Table 1). Baseline mean PANSS total scores were 101.3 in the quetiapine group, 98.5 in the olanzapine group and 96.0 in the risperidone group. No cases of first-episode schizophrenia occurred in any of the three treatment arms. | | |  | | Risperidone (n=25) | Olanzapine (n=25) | Quetiapine (n=25) | |
|---|
| Age (years); mean±SD | 43±13 | 35±11 | 39±9 | | | Sex; n (%) | | | Females | 15 (60) | 7 (28) | 11 (44) | | | Males | 10 (40) | 18 (72) | 14 (56) | | | PANSS score; mean±SD | | | Total | 96.0±20.5 | 98.5±20.0 | 101.3±20.0 | | | Positive subscale | 25.0±7.3 | 24.7±7.8 | 26.3±6.9 | | | Negative subscale | 23.2±8.2 | 25.3±9.2 | 26.1±9.9 | | | General subscale | 47.8±11.0 | 48.5±9.3 | 49.0±9.4 | | | SAS score; lower quartile, median, upper quartile | 0, 1, 3 | 0, 1, 6 | 0, 0, 5 | | | BARS score; lower quartile, median, upper quartile | 0, 0, 0 | 0, 0, 0 | 0, 0, 2 | | | AIMS score; lower quartile, median, upper quartile | 0, 0, 1 | 0, 0, 1 | 0, 0, 2 | | | Weight (kg); mean±SD | 70±14 | 68±15 | 79±16 | | | Illness duration (years); lower quartile, median, upper quartile | 2, 10, 20 | 1, 7, 15 | 5, 13, 19 | | | Heart rate (bpm); mean±SD | 86±12 | 80±7 | 84±12 | | | Systolic blood pressure (mm Hg); mean±SD | 117±17 | 126±10 | 121±18 | | | Diastolic blood pressure (mm Hg); mean±SD | 74±11 | 78±7 | 75±8 | | | | |
Fourteen patients (18.7%) discontinued the assigned treatment prior to Week 8, with no statistically significant difference between groups: four (16%) patients were on quetiapine, five (20%) on risperidone, and five (20%) on olanzapine (Table 2). Logistic regression analysis showed that early discontinuation was not influenced by type of treatment, sex, age, duration of the disorder, or baseline PANSS total score. | | | | Reason | Number of patients who discontinued treatment early | |
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| Risperidone | Olanzapine | Quetiapine | |
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| Withdrawal of consent | 3 | 2 | 2 | | | Lost to follow-up | – | 1 | 1 | | | Poor response | 1 | 1 | 1 | | | Protocol violation | 1 | – | – | | | Adverse event | – | 1 | – | | | Total | 5 | 5 | 4 | | | | |
The ITT population comprised all 75 patients enrolled. The PP population comprised the 61 patients who completed the 8-week treatment period. 3.2. Treatments At the 8-week endpoint, the mean (± SD) doses were 590.0±175 mg/day, 5.1±1.5, and 15.1±5.8 for quetiapine, risperidone, and olanzapine, respectively. In each treatment arm, the final doses in completers did not significantly differ from those in patients who discontinued early. Thirty-nine patients (52%) at some point received one or more concomitant medications for anxiety, insomnia, and/or movement disorders (Table 3). Thirty-four patients received supplementation with benzodiazepines (Table 3). A small minority of patients received zolpidem or flurazepam for insomnia (quetiapine, five; risperidone, eight; olanzapine, three), or anticholinergics or benzodiazepines for movement disorders (quetiapine, two; risperidone, five; olanzapine, two). 3.3. Efficacy 3.3.1. Primary efficacy measures In the PP population at Week 8, mean reductions in PANSS total scores were 37.0, 32.1, 34.4 points from mean baseline values of 100.3, 95.4, and 96.9 in the quetiapine, risperidone, and olanzapine groups, respectively (Fig. 1a). These improvements were statistically significant in all treatment arms, with no significant difference between arms. The lack of significant difference between treatment arms was confirmed by the results of a test for equivalence (p=0.025). There was also no significant difference between the three arms in the numbers of completers with a ≥ 40% reduction from baseline in PANSS total score at Week 8 (quetiapine, 10/21 [48%]; risperidone, 8/20 [40%]; olanzapine, 8/20 [40%]). 3.3.2. Secondary efficacy measures Improvements from baseline in all other components of the PANSS-derived battery at Week 8 in the PP population were statistically significant in all treatment arms, with no significant difference between arms (Fig. 1). There was also no significant difference between the three arms in the numbers of completers with a ≥ 30% reduction (quetiapine, 15/21 [71%]); risperidone, 9/20 [45%]; olanzapine, 13/20 [65%]) or ≥ 20% reduction (quetiapine, 17/21 [81%]; risperidone, 14/20 [70%]; olanzapine, 18/20 [90%]) from baseline in PANSS total score at Week 8. Linear mixed models for repeated measures in the ITT population showed that the quetiapine, risperidone, and olanzapine groups had similar improvements over time for each component of the PANSS-derived battery and that for each component the first significant improvement over baseline scores occurred at Week 1. Fig. 2, Fig. 3, Fig. 4 show the improvements over time in mean PANSS total, positive subscale, and negative subscale scores. 3.4. Safety and tolerability Only five patients (6.7%) spontaneously reported an AE of moderate intensity during the trial: quetiapine group, no events; risperidone group, one event (parkinsonian symptoms); olanzapine group, four events (weight gain, anxiety, pneumonia, scrotal eczema). No severe AEs were spontaneously reported. No clinically relevant physical abnormalities or pathological changes in vital signs, routine blood chemistry, or hematology were recorded during the trial period. SAS scores were significantly worse in the risperidone group compared with both the olanzapine and quetiapine groups at Week 3, and compared with the quetiapine group at each subsequent visit (Table 4). Median changes in BARS and AIMS scores did not show significant treatment effects within groups, although BARS and AIMS scores numerically worsened in patients receiving risperidone. | | | | | SAS scores (lower quartile, median, upper quartile) | Kruskal–Wallis test(p-value) | |
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| | RIS | OLA | QUE | QUE vs. RIS | QUE vs. OLA | RIS vs. OLA | |
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| Baseline | 0.0, 1.0, 3.0 | 0.0, 1.0, 6.0 | 0.0, 0.0, 5.0 | | | | | | Week 1 | 0.0, 1.0, 9.0 | 0.0, 1.0, 4.0 | 0.0, 1.0, 3.0 | ns | ns | ns | | | Week 2 | 1.0, 2.0, 7.0 | 0.0, 1.0, 4.0 | 0.0, 0.0, 2.5 | ns | ns | ns | | | Week 3 | 1.0, 4.0, 9.0 | 0.0, 0.0, 4.0 | 0.0, 0.0, 3.5 | 0.009 | ns | 0.039 | | | Week 4 | 1.00, 3.00, 10.25 | 0.0, 0.0, 4.0 | 0.0, 0.0, 3.0 | 0.025 | ns | ns | | | Week 5 | 1.25, 2.50, 9.25 | 0.0, 0.0, 5.0 | 0.0, 0.0, 1.0 | 0.006 | ns | ns | | | Week 6 | 2.0, 3.0, 10.0 | 0.0, 0.0, 4.0 | 0.0, 0.0, 1.0 | 0.005 | ns | ns | | | Week 8 | 1.00, 3.00, 10.25 | 0.00, 0.50, 4.25 | 0.0, 0.0, 1.0 | 0.005 | ns | ns | | | | |
At the final visit, a ≥ 7% increase in baseline body weight occurred in 8%, 8%, and 29% of quetiapine, risperidone, and olanzapine patients, respectively; the difference between the olanzapine group compared with the risperidone and quetiapine groups was close to significance (χ2 2df: p=0.057). A linear mixed model for repeated measures showed an effect of treatment (p<0.05) on body weight, with significant differences favoring quetiapine compared with risperidone (p=0.025) and olanzapine (p=0.008). 4. Discussion To our knowledge, this is the first short-term trial in severe schizophrenia that compares three atypical antipsychotics head-to-head. The results of this trial demonstrate that quetiapine, risperidone, and olanzapine are similarly effective, with 40–48% of completers in each treatment group experiencing a ≥ 40% reduction from baseline in PANSS total score at Week 8. In addition, the three comparators showed similar safety and tolerability profiles, but had drug-specific differences in their potential to induce certain AEs and in the rate of use of concomitant medications. Our efficacy results are largely similar to those of other short-term, randomized, head-to-head trials in patients with schizophrenia that used PANSS to compare the efficacy of two of the three atypical antipsychotics evaluated in this study (Tandon and Jibson, 2005, Zhong et al., 2006). As in our study, these trials found that quetiapine, risperidone, and olanzapine had broadly comparable efficacy in improving overall psychotic symptoms and the positive and negative symptoms of schizophrenia. This finding is supported further by studies which have shown that, although the affinities of the atypical antipsychotics for the D2 receptor vary, all reach the 70% occupancy rate considered necessary to elicit antipsychotic effects (Seeman, 2002). The similar advantage of olanzapine and quetiapine over risperidone regarding induction of parkinsonian symptoms, and the differing risk of weight gain (quetiapine<risperidone<<olanzapine) were not unexpected considering the current literature on these issues (Haro and Salvador-Carulla, 2006, Newcomer, 2005). Nevertheless, only one patient receiving risperidone and one patient receiving olanzapine spontaneously reported parkinsonian symptoms and weight gain, respectively, as moderate AEs. In our current study, 8% of patients receiving quetiapine experienced a clinically significant (≥ 7%) increase in baseline weight at Week 8 compared with 8% and 29% of patients receiving risperidone and olanzapine, respectively. A recent retrospective analysis of weight gain associated with quetiapine treatment found that after 12 weeks of treatment 17.94% of patients experienced a ≥ 7% gain in baseline body weight (Brecher et al., 2007). A previous double-blind, 8-week study comparing risperidone and olanzapine in 377 patients with schizophrenia or schizoaffective disorder found that 12% of risperidone-treated and 27% of olanzapine-treated patients had a ≥ 7% increase in body weight (Conley and Mahmoud, 2001). The smaller number of patients receiving concomitant benzodiazepines for anxiety or tension in the quetiapine group may indicate the particular value of quetiapine when treating patients with schizophrenia who present with severe levels of these symptoms. The fact that over 50% of patients received supplementary medications at some time may be evidence that the stringent procedures commonly employed in clinical trials are a long way from those typical of natural and quasi-natural settings, and thus may generate evidence that is misleading for routine purposes. Definite conclusions on these issues must await results from further studies. A number of indicators support the idea that this quasi-naturalistic study reflects ‘real-world’ patient management. First, the low rates of early discontinuation were nearer to the rates typically found in routine practice than those generally observed in short-term trials in patients with severe schizophrenia. Secondly, the small number of spontaneously reported moderate-to-severe AEs is also more in keeping with normal practice than a clinical trial. Finally, the mean doses of the three atypical antipsychotics at Week 8 were close to the mean doses that have been routinely used in patients with severe schizophrenia admitted during the last 2 years to the Brescia University and Spedali Civili Psychiatric Unit (quetiapine, 630.7±114.2 mg/day; risperidone, 5.6±1.2 mg/day; olanzapine, 18.6±1.4 mg/day). This suggests that the treating physicians maintained their usual prescribing practices in this study. The mean doses of quetiapine used at Week 8 in this trial, and in daily practice in our unit, were similar to that used for patients with schizophrenia in hospitals operated by the New York State Office of Mental Health in 2004 (611±332 mg/day) (Citrome et al., 2005). The pivotal Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (Lieberman et al., 2005b) also aimed to reflect ‘real-world’ practice. Our study differed from CATIE in a number of key ways. In the CATIE study antipsychotics were initially given under double-blind conditions; recruitment included patients with chronic schizophrenia irrespective of the severity of the disorder; patients with a history of treatment-resistant schizophrenia were excluded; the endpoint was all-cause discontinuation; the doses in a sizeable proportion of olanzapine-treated patients exceeded those indicated on the insert package; and the dose equivalence was questionable, as the ratio between the modal dose used and the maximum dose indicated by the manufacturers differentiated olanzapine from perphenazine, risperidone, quetiapine, and ziprasidone. Furthermore, in our study there was no exclusion of those individuals with a history of treatment-resistant schizophrenia and more equitable dose ranges were used across the treatment groups. The fact that the final mean daily doses of quetiapine, risperidone and olanzapine were within the ranges recommended by the manufacturers and were approximately 75% of the maximum doses used in the most recent clinical trials of these medications, adds to the value of this study. Furthermore, the mean doses of the study medications in the current trial were 25% (for olanzapine and quetiapine) and 36% (for risperidone) less than the maximum doses permitted in the study protocol. Other strengths of our study that protect against the risk of subtle bias include the a priori definition of the limits valid for treatment equivalence and the decision to present both PP and ITT analyses (Heres et al., 2006). Limitations of this study were the lack of double-blind evaluations and of a placebo arm, which were precluded by the choice of a naturalistic treatment strategy. However, the use of independent blind raters minimized the possibility of biased results. Bias with regard to randomization was unlikely, as the treatment groups were comparable in their baseline demographic, psychopathological, and physical characteristics. However, separation between specific and aspecific treatment effects was not possible because of the absence of a placebo group. Because of the short tapering period there may be a concern that clinical improvements in the first week of treatment may not be completely attributable to the study drugs. Whilst this is a possibility, placebo-controlled trials have demonstrated the superior efficacy of quetiapine, risperidone, and olanzapine compared with placebo after 1 week of treatment. In addition, ineffectiveness of previous medication was the most common reason for entering into the current study. The short treatment duration may have resulted in fewer patients experiencing a meaningful improvement. Nevertheless, it is likely that many patients may experience only marginal improvement even after a prolonged treatment with antipsychotic medication. Therefore, the development of new antipsychotic drugs with improved efficacy and safety profiles remains a vitally important goal. In conclusion, the similar efficacy of quetiapine, risperidone, and olanzapine suggests that these drugs are effective treatments for patients with severe schizophrenia. Differences between these agents in the risk of weight gain, the risk of developing parkinsonian symptoms, and the rate of use of concomitant medication may guide clinicians towards treatment choice. However, for a true individualization of first-choice therapy, drug-specific differences in efficacy, tolerability, and acceptability should all be considered, possibly together with non-phenomenological outcome predictors. Role of funding source Funding for this study was provided by an AstraZeneca grant; AstraZeneca evaluated and approved the study design; had no role in the collection, analysis and interpretation of data and in the writing of the report; AstraZeneca gave support to the author in adjusting the English translation of the manuscript and choosing the journal for submission. Contributors Author Sacchetti designed the study, wrote the protocol, interpreted data and wrote the first draft of the manuscript. Author Valsecchi managed the literature searches and analyses, supervised data collection and contributed to data interpretation. Author Parinello undertook the statistical analysis. All authors contributed to and have approved the final manuscript. Conflict of interest In the past 5 years, Professor Sacchetti has received funding for research, advisory board membership, and sponsored lectures from Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, InnovaFarma, Janssen-Cilag, Lundbeck, Pfizer, Sanofi-Aventis, and Wyeth. He is not a shareholder in any of these corporations. In the past 5 years, Dr. Valsecchi has received funding for research and sponsored lectures from Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Pfizer, and Wyeth. He is not a shareholder in any of these corporations. In the past 5 years, Dr. Parrinello has received funding for research and sponsored lectures from AstraZeneca, Eli Lilly, Laboratori Guidotti, Roche, Servier, and Stroeder Farmaceutici. Acknowledgments This study (no. 5077IT/SACC) was supported by AstraZeneca. 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a Department of Psychiatry, Brescia University School of Medicine, Brescia, Italy b University Psychiatric Unit, Brescia University School of Medicine and Brescia Spedali Civili, Brescia, Italy c Department of Mental Health, Brescia Spedali Civili, Brescia, Italy d Centre of Behavioural and Neurodegenerative Disorders, Brescia University and EULO, Brescia, Italy e Department of Biomedical Sciences and Biotechnologies, Section of Medical Statistics and Biometry, Brescia University School of Medicine, Brescia, Italy  Corresponding author. University Psychiatric Unit, Brescia Spedali Civili, Piazza Spedali Civili, 1, 25123 Brescia, Italy. Tel.: +39 030 3995233/381749; fax: +39 030 3384089.
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