Introduction

Balancing risks and benefits of antipsychotic agents and subsequently, guaranteeing a good adherence to treatment is the real challenge in the treatment of first-episode psychosis individuals (Crespo-Facorro et al. 2008). Discontinuation of antipsychotic treatment during early phases after a first episode of psychosis has proven to increase the risk of poor adherence in the long run (Abdel-Baki et al. 2012). Second generation antipsychotics (SGAs) are the first-line drug treatment for individuals suffering from a first-episode schizophrenia (Lieberman 1996). SGAs have shown higher treatment effectiveness compared to first generation antipsychotics (FGAs) (findings primarily driven by haloperidol) in first-episode patients (Crespo-Facorro et al. 2011, 2012; Green et al. 2006; Kahn et al. 2008). The clinical effects and profile of side effects differ between SGAs (Tandon et al. 2008). Less evident seems to be the notion that some of the SGAs might be more effective (in terms of treatment discontinuation) than others (Johnsen and Jorgensen 2008; Leucht et al. 2009). Most of the medium term randomized studies have shown similar rates of all-cause treatment discontinuation in first-episode patients treated with different SGAs (Crespo-Facorro et al. 2011; Kahn et al. 2008; McEvoy et al. 2007). Differences among SGAs in terms of effectiveness have turned out to be a topic of increasing clinical interest, although direct comparisons between the different SGAs are limited in real world clinical practice.

We aimed to evaluate clinical effectiveness at medium term (1 year) of three SGAs (aripiprazole, ziprasidone and quetiapine) widely used to treat individuals with a first episode of non-affective psychosis. We hypothesize that likely disparity in efficacy and side effect profiles may mediate differences in effectiveness. Previous studies from our group investigating the effectiveness of these three SGAs at short term in the same sample have revealed a higher risk of treatment discontinuation in patients initially treated with quetiapine (Crespo-Facorro et al. 2013a, b). Specific short- and mid-term distinctions in clinical efficacy and safety profiles of individual antipsychotics may determine changes in SGAs’ effectiveness across time.

Experimental procedures

Study setting and financial support

Data for the present investigation were obtained from an ongoing epidemiological and 3-year longitudinal intervention program of first-episode psychosis (PAFIP) conducted at the outpatient clinic and the inpatient unit at the University Hospital Marques de Valdecilla, Spain (Pelayo-Teran et al. 2008). Conforming to international standards for research ethics, this program was approved by the local institutional review board. Patients meeting inclusion criteria and their families provided written informed consent to be included in the PAFIP.

Subjects

From October 2005 to January 2011, all referrals to PAFIP were screened for patients who met the following criteria: (1) 15–60 years; (2) living in the catchment area; (3) experiencing their first episode of psychosis; (4) no prior treatment with antipsychotic medication or, if previously treated, a total lifetime of adequate antipsychotic treatment of less than 6 weeks; (5) DSM-IV criteria for brief psychotic disorder, schizophreniform disorder, schizophrenia, or schizoaffective disorder. Patients were excluded for any of the following reasons: (1) meeting DSM-IV criteria for drug dependence, (2) meeting DSM-IV criteria for mental retardation, (3) having a history of neurological disease or head injury. The diagnoses were confirmed using the Structured Clinical Interview for DSM-IV (SCID–I) (First et al. 2001) carried out by an experienced psychiatrist 6 months on from the baseline visit. Our operational definition for a “first episode of psychosis” included individuals with a non-affective psychosis (meeting the inclusion criteria defined above) who have not received previous antipsychotic treatment regardless of the duration of psychosis.

Study design

This is a prospective, randomized, flexible dose, open-label study. We used a simple randomization procedure. A computer-generated randomization list was drawn up by a statistician. At study intake, all patients but eight were antipsychotic naïve. Dose ranges were 5–30 mg/day of aripiprazole, 40–160 mg/day of ziprasidone and 100–600 mg/day of quetiapine. Rapid titration schedule (5 days), until optimal dose was reached, was as a rule used unless severe side effects occur. At the treating physician’s discretion, the dose and type of antipsychotic medication could be changed based on clinical efficacy and the profile of side effects during the follow-up period. Antimuscarinic medication, lormetazepam and clonazepam, were permitted for clinical reasons. No antimuscarinic agents were administered prophylactically. Antidepressants and mood stabilizers were permitted if clinically needed.

The severity scale of the Clinical Global Impression (CGI) scale (Guy 1976) the Brief Psychiatric Rating Scale (BPRS) (expanded version of 24 items) (Overall and Gorham 1962), the Scale for the Assessment of Positive symptoms (SAPS) (Andreasen 1984), the Scale for the Assessment of Negative symptoms (SANS) (Andreasen 1983), the Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al. 1993) and the Young Mania Rating Scale (YMRS) (Young et al. 1978) were used to evaluate clinical symptomatology. To assess general adverse event experiences, the scale of the Udvalg for Kliniske Undersogelser (UKU) (Committee of Clinical Trials) (Lingjaerde et al. 1987), the Simpson-Angus Rating Scale (SARS) (Simpson and Angus 1970) and the Barnes Akathisia Scale (BAS) (Barnes 1989) were used to assess side effects. The same trained psychiatrist (BC-F) completed all clinical assessments.

Outcome measures

Primary outcome measures: effectiveness

The main outcome of effectiveness was the percentage of discontinuation of the initially assigned treatment (patients who completed the 1 year follow-up assessment and changed initial antipsychotic) and the mean time to all-cause medication discontinuation (two accepted indexes of medication effectiveness). Four reasons for the discontinuation were recorded: (1) insufficient efficacy; (2) marked side effects; (3) patient reported non-adherence and (4) other causes. If more than one reason for discontinuation was present, the most important reason according to the above ranking was selected. Insufficient efficacy was established at the treating physician’s judgment only after at least 3 weeks of treatment.

Secondary outcome measures: efficacy and safety

The efficacy outcomes were the mean change from baseline to 1 year in BPRS, SAPS and SANS total scores. Additional analyses included changes from baseline to 1 year in CGI, YMRS and CDSS total scores. The patients were defined as responders to the optimum dose of antipsychotic at 1 year if a ≥40 % reduction of the BPRS total scores at intake and had a CGI severity score of ≤4. In addition, we also explored the rate of responders if a cutoff of ≥50 % reduction of the BPRS total scores at intake was used.

The adverse events were evaluated using the UKU side effect rating scale. Those treatment–emergent adverse events that occurred at a rate of at least 5 % in either treatment group are considered. Only those adverse effects rated as moderate or severe and with a possible causal relationship to medication of possible or probable were recorded. Treatment–emergent akathisia (BAS) and extrapyramidal symptoms (SARS) were assessed by both baseline-to-end changes and newly emergent categorical changes. Clinical assessments and measurements of side effects were completed at baseline, 6 weeks, 3 months and 1 year.

Statistical analyses

To ensure group comparability, baseline sociodemographic and clinical characteristics were tested by 1-way analysis of variance (ANOVA) or χ 2 test for categorical variables. The proportion of patients who were compliant (good adherence), the frequency of patients who used hypnotics, mood stabilizers, antimuscarinic drugs, benzodiazepines or antidepressants, and the BAS and SARS were categorically analyzed between groups by chi-square test.

The primary aim of this study was to test the hypothesis that the three antipsychotic treatments would result in different effectiveness. Kaplan–Meier survival curves and a log-rank test were used to assess time to all-cause medication discontinuation. Percentages of discontinuation rates between groups were examined by means of chi-square tests. For secondary efficacy and safety measures, analysis was by intention-to-treat. In addition, per protocol analyses were performed as well and are available upon request. Differences between groups in the degree of change in clinical scores from baseline were evaluated with analysis of covariance after baseline scores were controlled. All patients included in the analysis had at least the baseline and 1-year assessments. Within-group comparisons were also explored by using the t test to analyse baseline to end point differences. By using Fisher’s exact and chi-square tests evaluated categorical data were evaluated. All hypotheses were tested by using a two-sided significant level of 0.05.

The Statistical Package for Social Science, version 19.0, was used for statistical analyses. All hypotheses were tested by using a two-sided significant level of 0.05. No adjustments were made for multiple comparisons.

Results

Description of study cohort

Figure 1 shows the trial profile. Of 224 individuals who were initially randomized to treatments, 22 were finally removed from the data set because it was verified they did not fully meet inclusion criteria or they did not give or remove proper written consent during the first week. Thus, 202 patients who gave written consent to their participation in the study and fulfilled inclusion criteria at 6 months were included in our analyses. The sample size (175) resulted in a sufficient statistical power (95 %) to detect statistically significant differences between groups considering a potential effect size of 0.30 (results based on GPower v 3.1.5). At the baseline, only eight (4.0 %) of patients reported some prior antipsychotic treatment. The mean self-reported duration of prior treatment was 1.5 weeks (SD = 1.3; range = 0.4–4.0). Before starting on the assigned drug, these subjects underwent a 2–4-day washout period. The overall dropout rate at 1 year was small (N = 27; 13.37 %) (16 patients were lost during follow-up (four aripiprazole, three ziprasidone and nine quetiapine); six patients did not show up at 1-year assessment (four aripiprazole and two ziprasidone); four persons committed suicide during 1-year follow-up (one aripiprazole, one ziprasidone and two quetiapine); one sudden death (aripiprazole). All, but ten individuals, were white Caucasian. Demographic and clinical characteristics of patients are shown in Table 1.

Fig. 1
figure 1

Flow diagram of subject through the phases of the randomized trial

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Table 1 Demographic and clinical characteristics of 202 drug-naïve patients with a first episode of psychosis randomly assigned to treatment with aripiprazole, ziprasidone or quetiapine
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In those patients who continued on initially prescribed drug the mean (SD) and median antipsychotic doses at 1 year were: aripiprazole = 11.6 (5.8) mg/day and 10.0 mg/day; ziprasidone = 61.0 (24.1) mg/day and 60.0 mg/day; and quetiapine = 311.4 (177.3) mg/day and 300.0 mg/day.

Primary outcome measures

Treatment discontinuation rate and time to discontinuation

The treatment discontinuation rate for any cause differed significantly between treatment groups (χ 2 = 22.545; p < 0.001) (Table 2). Patients on quetiapine showed a higher rate (82.3 %) of treatment discontinuation than aripiprazole (43.6 %) and ziprasidone (66.1 %) individuals. Insufficient efficacy in the group of quetiapine is the main reason for discontinuation rate differences (χ 2 = 19.436; p < 0.001). The mean time (days) to all-cause discontinuation was 106.71 (95 % CI, 75.19–138.22) for aripiprazole, 129.88 (95 % CI, 95.50–164.25) for ziprasidone and 77.24 (95 % CI, 52.88–101.59) for quetiapine. There was a significant difference between groups in time to discontinuation (Log Rank = 30.732; p < 0.001) (see Fig. 2). Discontinuation rates because of side effects differed significantly between treatment groups (quetiapine 11.3%, ziprasidone 29 % and aripiprazole 10.3 %; χ 2 = 10.576; p = 0.005).

Table 2 Treatment doses and treatment discontinuation by allocated treatment
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Fig. 2
figure 2

Kaplan–Meier survival curves for time to treatment discontinuation because any cause

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Secondary outcome measures

Clinical efficacy

There were no statistically significant differences in the severity of symptoms at baseline and at 1 year between treatment groups (Table 3). The univariate ANOVA analysis showed no differences between treatments in reducing symptoms. The rate of responders (≥40 % BPRS and ≤4 CGI) did not differ between groups (aripiprazole, 84.8 %; ziprasidone, 88.9 %; quetiapine, 76.0 %; F = 3.271; p = 0.195). This difference in the rate of responders between groups was not statistically significant either when the criteria of at least 50 % decrease in total BPRS at baseline was used as cutoff (aripiprazole, 84.8 %; ziprasidone, 87.0 %; quetiapine, 76.0 %; F = 2.513; p = 0.285). Per-protocol analysis showed, after controlling by SAPS total score at baseline, differences between treatments in reducing positive symptoms (F = 5.000; p = 0.009). The post hoc pairwise tests revealed a lower effect of quetiapine compared to aripiprazole and ziprasidone (quetiapine vs. ziprasidone, p = 0.018; quetiapine vs. aripiprazole, p = 0.011; ziprasidone vs. aripiprazole, p = 1.000).

Table 3 Intention-to-treat sample: psychopathological characteristics at baseline, at 1 year and clinical changes during the follow-up period
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Safety

Extrapyramidal symptoms

Intention-to-treat analyses have shown no significant differences in the increment of extrapyramidal signs at 1 year (SARS total score) between treatments (F = 0.677; p = 0.510). The percentage of patients with treatment–emergent parkinsonism (a total score higher than 3 on the SARS at 6-week, 3-month or/and 1-year assessments, given a total score of 3 or less at baseline) was not statistically different between treatment arms (aripiprazole = 17.7 %; ziprasidone = 19.6 % and quetiapine 14.3 %; χ 2 = 0.461; p = 0.794).

There was not a significant difference between treatments in the severity of akathisia (BAS total score) at 12-month assessment (F = 1.705; p = 0.185). Although the difference did not reach a significant level, a higher number of individuals in the aripiprazole- (30.6 %) and ziprasidone-treated groups (26.0 %) experienced treatment–emergent akathisia (BAS global score of 2 or more at 6-week, 3-month or/and 1-year evaluations, given a global score of less that 2 at baseline visit) compared to quetiapine-treated subjects (14.0 %) (χ 2 = 3.910; p = 0.142). Per-protocol analysis showed rather similar results (data available upon request).

Adverse events

Intention-to-treat analyses of moderate and severe side events that occurred at a rate of at least 5 % in either treatment group are displayed in Table 4. No significant differences between treatments were found. When all adverse events (including also mild events) are considered, no significant differences between treatments were either found (see Table S1).

Table 4 Intention-to-treat sample: moderate or severe treatment–emergent adverse events that occurred at a rate of at least 5 % in either treatment group
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Concomitant medication use

Intention-to-treat analyses showed that patients on ziprasidone were taking significantly more antidepressants at 1-year assessment compared to those patients on aripiprazole and quetiapine (18.0 % quetiapine; 30.9 % ziprasidone and 11.3 % aripiprazole; χ 2 = 7.214; p = 0.027). No significant differences were found between groups in the rate of antimuscarinic agents, benzodiazepines, mood stabilizers and hypnotics use at 1 year (see Table S2).

Discussion

Aripiprazole and ziprasidone have demonstrated significantly higher effectiveness (lower discontinuation rate) than quetiapine in the treatment of first-episode patients at 1 year. Insufficient efficacy in the group of quetiapine is the main reason for discontinuation rate differences between antipsychotics. Intention-to-treat analysis revealed no treatment advantages in reducing the severity of symptomatology between the three SGAs. The profile of motor side effects varies between treatments.

Effectiveness

Treatment discontinuation rate during the acute treatment of first-episode patients was significantly greater in patients given quetiapine (82.3 %) mainly due to insufficient efficacy. Higher risk of treatment discontinuation in quetiapine-treated patients has already been described during early phases of treatment (Abdel-Baki et al. 2012). It is of interest that most of the discontinuations in the group of quetiapine were due to inefficacy and occurred at early stages of the treatment (see Fig. 2). The mean time to discontinuation in the quetiapine group was significantly shorter (77.2 days) than in the other two treatment groups (106.71 days in the aripiprazole group and 129.88 days in the ziprasidone group). Effectiveness studies using standard dosage ranges pointed out that quetiapine may be somewhat less effective than some other widely used SGAs (Sparshatt et al. 2011). Our results are consistent with the notion that most of the patients who start quetiapine stop taking it within a few weeks (Komossa et al. 2010). Inadequate and transiently dopamine −2 receptor occupancy with quetiapine may lead to insufficient antipsychotic efficacy (Tauscher-Wisniewski et al. 2002). Nevertheless, previous medium-term randomized studies in first episode showed similar rates of all-cause treatment discontinuation in first-episode patients treated with quetiapine compared to other SGAs (Kahn et al. 2008; McEvoy et al. 2007). Kahn and colleagues (2008) described no difference between quetiapine and ziprasidone in the rate of treatment discontinuation for any cause, although discontinuation because of insufficient efficacy was to some extent higher in quetiapine (40 %) compared with ziprasidone (26 %) at 1 year. Similarly, we found that discontinuation because of insufficient efficacy was higher in quetiapine (41.9 %) compared with ziprasidone (17.7 %) at 1 year. It is of note that Ziprasidone discontinuation seems to occur later on during treatment likely due to the emergence of side effects (29 %). In a sponsored investigation, McEvoy and colleagues (2007) neither observed significant differences between olanzapine, risperidone and quetiapine in clinical efficacy and rate of treatment discontinuation after 1 year.

No differences in depressive symptoms improvement between treatments were observed. Open-label trials had pointed out that quetiapine may be a useful agent in the management of depressive symptoms in individuals with psychosis (Lee et al. 2009; Sajatovic et al. 2002). In previous first-episode studies there were no significant differences between SGAs (including quetiapine) in reducing depressive symptoms after 1 year of treatment (Kahn et al. 2008; McEvoy et al. 2007). No notable changes on negative symptoms were found with any of the three antipsychotics.

Side effects and concomitant medications

The differences in the percentage of patients with treatment–emergent parkinsonism (aripiprazole = 17.7 %; ziprasidone = 19.6 % and quetiapine 14.3 %) and akathisia (aripiprazole: 30.6 %, ziprasidone: 26.0 % and quetiapine: 14.0 %) may be of clinical interest. A higher percentage of extrapiramidal side effects and akathisia in aripiprazole- and ziprasidone-treated individuals during the acute treatment of a first episode has been described (Crespo-Facorro et al. 2013b). A higher incidence of akathisia early after aripiprazole treatment was initiated has been previously reported (Kerwin et al. 2007). Grootens and colleagues (2011) described that significantly more patients on ziprasidone needed antimuscarinic to relieve extrapyramidal symptoms compare to olanzapine-treated patients with recent onset schizophrenia.

No significant differences were found in the frequency of body weight increase between treatments. Intention-to-treat analysis revealed that 20 % of the individuals on quetiapine, 21.9 % on aripiprazole and 18.2 % on ziprasidone showed a rapid body weight gain (Table 4). Komossa and colleagues (2010) described that quetiapine led to more weight increases than ziprasidone. The host of metabolic consequences associated with the use of SGAs is now a major issue in the pharmacological treatment of psychosis. A thorough description and analysis of the effect of the three SGAs on metabolic variables in this sample will be discussed in upcoming articles from our group. In a recent review article, quetiapine showed significantly less use of concomitant antimuscarinic medication than olanzapine, risperidone and ziprasidone (Rummel-Kluge et al. 2012). Interestingly, discontinuation rate due to severe or intolerable side effects in our study was relatively low (16.3 %). We may conclude that, although differences in side effect profile exist, aripiprazole, ziprasidone and quetiapine are devoid of severe adverse side effects that may hazard medication compliance or treatment continuation.

Limitations and strengths

Several limitations should be taken into account when interpreting our results. First, as a practical clinical trial, patients and observers (BC-F, IM, RP-I) were not blinded to treatments in our study. The fact that the observers knew the medications prescribed may have involuntarily biased the outcomes. As a non-industry-funded study, the risk for systematic biased measuring study outcomes favouring any of the three SGAs is limited. Second, the mean doses of quetiapine used could be understood as somewhat low to treat first-episode individuals. However, controlled investigations have clearly confirmed that standard dosage range is appropriate in everyday clinical practice with no advantages of high dosage (Johnsen and Jorgensen 2008). Optimal doses of antipsychotics within licensed range were chosen based on clinical efficacy and the presence of adverse effects, and were adjusted according to the clinical situation of each individual.

Conclusions

Patients on quetiapine were more likely to discontinue treatment after a first episode of non-affective psychosis at medium term due to insufficient efficacy compared to aripiprazole and ziprasidone patients. Establishing differences between SGAs may help clinicians on prescribing decision for treatment of individuals presenting with first-episode schizophrenia. Properly balancing risks and benefits of antipsychotic agents and consequently, guaranteeing a good adherence to antipsychotic treatment is the real challenge in the treatment of first-episode psychosis individuals.