Antipsychotic Treatment Effectiveness in First Episode of Psychosis: PAFIP 3-Year Follow-Up Randomized Clinical Trials Comparing Haloperidol, Olanzapine, Risperidone, Aripiprazole, Quetiapine, and Ziprasidone

Received: September 1, 2019; Revised: December 25, 2019; Accepted: January 22, 2020 217 Copyedited by: © The Author(s) 2020. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Regular Research Article Antipsychotic Treatment Effectiveness in First Episode of Psychosis: PAFIP 3-Year Follow-Up Randomized Clinical Trials Comparing Haloperidol, Olanzapine, Risperidone, Aripiprazole, Quetiapine, and Ziprasidone Marcos Gómez-Revuelta, JoséMaría Pelayo-Terán, María Juncal-Ruiz, Javier Vázquez-Bourgon, Paula Suárez-Pinilla, Rodrigo Romero-Jiménez, EstherSetién Suero, Rosa Ayesa-Arriola, Benedicto Crespo-Facorro University Hospital Marqués de Valdecilla, IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain (Drs Gómez-Revuelta, Pelayo-Terán, Vázquez-Bourgon, Suárez-Pinilla, Romero- Jiménez, Suero, and Ayesa-Arriola); CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain (Drs Gómez-Revuelta, Pelayo-Terán, Juncal-Ruiz, Vázquez-Bourgon, Suárez-Pinilla, Romero-Jiménez, Suero, Ayesa-Arriola, Crespo-Facorro); Servicio de Psiquiatría y Salud Mental. Hospital El Bierzo. Servicio de Salud de Castilla y León (SACYL), Ponferrada (León), Spain (Dr Pelayo-Terán); Hospital Universitario Virgen del Rocío, Department of Psychiatry, Universidad de Sevilla, Sevilla, Spain. Instituto de Investigacion Sanitaria de Sevilla, IBiS(Dr Crespo-Facorro); Sierrallana Hospital, Department of Psychiatry, IDIVAL, School of Medicine, University of Cantabria, Torrelavega, Spain (Dr Juncal-Ruiz). Correspondence: José María Pelayo Terán, MD, PhD, University Hospital Marqués de Valdecilla-IDIVAL CIBERSAM, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain, Avda. Valdecilla, s/n. | 39008 SANTANDER, Cantabria (pelay[email protected]). Abstract Background: Different effectiveness profiles among antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to impact on long-term outcome. The aim of this study is to compare the clinical effectiveness of olanzapine, risperidone, haloperidol, aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up. Method: From February 2001 to January 2011, 2 phases of a prospective, randomized, open-label study were undertaken. Atotal of 376 first-episode drug-naïve patients were randomly assigned to olanzapine (n = 55), risperidone (n = 63), haloperidol (n = 56), aripiprazole (n = 78), ziprasidone (n = 62), or quetiapine (n = 62) and followed up for 3years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy. Results: The overall dropout rate at 3years reached 20.75%. Treatment discontinuation rates were significantly different among treatment groups (olanzapine = 69.09, risperidone = 71.43, aripiprazole = 73.08%, ziprasidone = 79.03%, haloperidol = 89.28%, applyparastyle "fig//caption/p[1]" parastyle "FigCapt" applyparastyle "fig" parastyle "Figure" International Journal of Neuropsychopharmacology (2020) 23(4): 217–229 doi:10.1093/ijnp/pyaa004 Advance Access Publication: 24 January 2020 Regular Research Article International Journal of Neuropsychopharmacology (2020) 23(4): 217–229 doi:10.1093/ijnp/pyaa004 Advance Access Publication: , 2020 Regular Research Article Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 218 | International Journal of Neuropsychopharmacology, 2020 and quetiapine = 95.53%) (χ2 = 79.86; P = .000). Statistically significant differences in terms of lack of efficacy, adherence, and tolerability were observed among treatment groups along the 3-year follow-up, determining significant differences in time to all-cause discontinuation (log-rank = 92.240; P = .000). Significant differences between treatments were found in the categories of sleepiness/sedation, increased sleep duration, akinesia, weight gain, ejaculatory dysfunction, extrapyramidal-symptoms, and amenorrhea. Conclusions: Olanzapine, risperidone, and aripiprazole presented advantages for the first-line treatment of first episode of psychosis in terms of effectiveness. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis.ClinicalTrials.gov Identifier: NCT02526030 https://clinicaltrials.gov/show/ NCT02526030 Keywords: schizophrenia, antipsychotics, first-episode-psychosis Introduction Implementing the most suitable treatment strategies and making appropriate clinical decisions about individuals with a first episode of psychosis (FEP) is a complex and crucial task with relevant impact in illness outcome (Crespo-Facorro etal., 2016). Antipsychotics have demonstrated over the last 4 decades that they work both to treat acute psychotic episodes and to reduce relapse rates over the short to medium term (Correll etal., 2018). Prevention of recurrent episodes is likely to be critical to prevent disease progression (Emsley etal., 2013; Pelayo-Terán etal., 2017). Relapses involve an increased risk for a poorer and delayed response in the subsequent episode with higher treatment doses, potential side-effects emergence, and longer duration of active psychosis determining neurotoxicity (Pelayo-Terán etal., 2018; Samara et al., 2015; Takeuchi etal., 2019). Nonadherence to medication seems to represent the highest risk for relapse after a FEP. Lack of efficacy, poor tolerability, and acceptability are the other main causes that increase the risk for discontinuation during early phases after a FEP. Hence, higher treatment discontinuation rates are linked to higher relapse rates and a worsened prognosis (Leucht etal., 2013). That is why FEP first-line antipsychotic choice is so critical. Arecent meta-analysis focused on long-term patients with schizophrenia suggested that, although there are some significant differences in effectiveness, efficacy, and tolerability among second-generation antipsychotics (SGAs) in the long-term treatment of schizophrenia due to the limited number of head-to-head clinical trials available so far, the comparative effectiveness of some SGAs is unclear (Kishimoto etal., 2019). Therefore, knowledge about the comparative clinical characteristics of antipsychotics in the long-term treatment (in which the magnitude of benefits and risks of medications may be different from acute phase treatment) of schizophrenia is important albeit insufficient so far (Correll and Hert,2013). Thus, with this pool analysis, comparing head-to-head 6 antipsychotics widely used in routine clinical settings, we aim to add detailed information on effectiveness, efficacy, and tolerability outcomes to contribute to further guide the evidence-based long-term treatment of patients with schizophrenia (Crespo- Facorro etal., 2012; Gómez-Revuelta etal., 2018). This may lead to identify predictors of beneficial outcomes with specific antipsychotics, which would further enhance the ability to personalize treatments. We hypothesize that differences regarding the efficacy, tolerability, and adherence would result in differential effectiveness to lead such a critical election as first antipsychotic choice may be for the outcome of FEP patients. Experimental Procedures Study Setting Data for the present investigation were obtained from an ongoing 3-year longitudinal intervention program of first-episode psychosis called PAFIP (Programa de Atención a las Fases Iniciales de Psicosis) conducted at the outpatient clinic and the inpatient unit of the University Hospital Marqués de Valdecilla, Spain (Pelayo-Terán 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 prior to their inclusion to the program. Participants From February 2001 to January 2011, all referrals to PAFIP were screened for patients who met the following criteria: (1) 15–60years old; (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, psychotic disorder not otherwise Significance Statement Despite the fact that antipsychotics are recommended for the maintenance treatment in schizophrenia, comparative long-term effectiveness among antipsychotics is unclear, as long-term head-to-head comparisons among SGAs are limited in clinical practice and, especially, in first-episode-psychosis. The present paper supplies evidence on the differences in terms of long-term effectiveness among 6 widely used SGAs (olanzapine, risperidone, haloperidol, aripiprazole, quetiapine, and ziprasidone). Results showed remarkable effectiveness, efficacy, and safety differences between the 6 antipsychotics included in the study. We distinguished 2 treatment groups according to their effectiveness performance: olanzapine, risperidone, and aripiprazole presented clear advantages for the first-line treatment of FEP. Multiple tolerability profiles and different efficacy measures were identified and may lead to fit the best antipsychotic choice after FEP. Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 Copyedited by: Gómez-Revuelta etal. | 219 specified, 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 (First etal., 2002) 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 nonaffective psychosis (meeting the inclusion criteria defined above) regardless of the duration of untreated psychosis. StudyDesign Patients included in this study were assigned in 2 different albeit consecutive phases of the PAFIP (2001–2004 and 2005–2011), encompassing 2 randomized, flexible-dose, and open-label clinical trials. During the first phase, from February 2001 to September 2005, patients were randomly assigned to treatment with olanzapine, risperidone, or haloperidol. Consecutively, between October 2005 and January 2011, patients were randomly assigned to treatment with aripiprazole, ziprasidone, or quetiapine. We used a simple randomization procedure. An automated randomization list was drawn up. At study intake, all patients but 11 (2.92%) were antipsychotic naïve (mean duration of prior treatment = 2.75 weeks, SD = 1.8, range = 0.4–4.0). Before starting on the assigned drug, these participants underwent a 2- to 4-day washout period. Mean antipsychotic doses expressed as chlorpromazine equivalents (CPZeq; mg/d) (Woods, 2003) were as follows: olanzapine 5–20mg/d (100–400 CPZeq), risperidone 3–6mg/d (150– 300 CPZeq), haloperidol 3–9 mg/d (150–450 CPZeq), quetiapine 100–600mg/d (133.33–800 CPZeq), ziprasidone 40–160mg/d (66.67– 266.67 CPZeq), and aripiprazole 5–30 mg/d (66,67–400 CPZeq). Rapid titration schedule (5days), until optimal dose was reached, was used as a rule unless severe side effects occurred. At the treating psychiatrist´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. Anticholinergic medication, lormetazepam, and clonazepam were permitted for clinical reasons. No anticholinergic 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, 1989), 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. The scale of the Udvalg for Kliniske Undersogelser (UKU) (Committee of Clinical Trials) (Lingjærde 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. Clinical assessments and measurements were completed at baseline, 3 weeks, 6 weeks, 3months, 6months, 12months, 18months, 24months, 30months, and 36months. All patients included in the analysis had at least the baseline and 3-year assessments, and they were considered for drop-out in those cases in which they did not attend 2 consecutive check-point assessments. The same trained psychiatrist (B.C.-F.) completed all clinical assessments. Outcome Measures Primary Outcome Measures: Effectiveness The main outcome of effectiveness was the all-cause treatment discontinuation rate, which is the percentage of all-cause discontinuation of the initially assigned treatment (patients who completed the 3-year follow-up assessment and their initial antipsychotic treatment were switched during follow-up) and the mean time to all-cause medication discontinuation. Four reasons for the discontinuation were recorded: (1) nonsufficient or insufficient efficacy, (2) significant side effects, (3) nonadherence, and (4) other causes. Insufficient efficacy was established at the treating physician’s judgment only after at least 3 weeks of treatment. Adherence to antipsychotic drugs was assessed by the information obtained from patients, close relatives, and staff (nurse, social worker, and psychiatrists) involved in the follow-up. According to previous definition (Gómez- Revuelta etal., 2018), patients were consensually dichotomized into having a good (defined as patients regularly taking at least 90% of prescribed medication) and a poor adherence (medium or poor compliance). If more than 1 reason for discontinuation was present, the most important reason according to the above ranking was selected. Secondary Outcome Measures: Efficacy andSafety The efficacy outcomes were the mean change from baseline to 3years in BPRS, SAPS, and SANS total scores. Additional analyses included changes from baseline to 3years in CGI, YMRS, and CDSS total scores. Patients were defined as responders to the optimum dose of antipsychotic if they had a ≥50% reduction of BPRS total score and a CGI severity-score ≤4 after 6months since the beginning of the treatment. Side effects were evaluated using the UKU side effects rating scale. Only side effects rated as moderate or severe and with a possible causal relationship to medication were recorded. Treatment-emergent akathisia and extrapyramidal symptoms were assessed using BAS and SARS scales. Statistical Analyses All data were tested for normality (using Kolmogorov-Smirnov test) and equality of variances (using Levene test). To ensure group comparability, baseline sociodemographic and clinical characteristics were tested by 1-way ANOVA or Kruskal-Wallis tests for continuous variables or by chi-squared tests for qualitative variables. Kaplan-Meier survival curves and log-rank tests were used to assess time to all-cause medication discontinuation. Concerning these 2 analyses, patients were followed-up from the inclusion in the study until discontinuation of the initial treatment or censoring. Survival time could be censored by the end of the observation period or by lost to follow-up. For efficacy and safety measures, we performed both intention-to-treat analyses and per-protocol analyses. Differences between groups in the degree of change in clinical scores from baseline were evaluated with ANCOVA after baseline scores were controlled. Finally, comparisons of the discontinuation rates and the prevalence of side effects as well as the use of concomitant treatment between the 6 antipsychotics were carried out, performing chi-squared tests with Bonferroni correction for multiple comparisons when necessary. STATA 15.1 was used for statistical analysis. Statistical tests were 2-tailed with a 95% confidence interval. Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 220 | International Journal of Neuropsychopharmacology, 2020 Results Of 406 individuals who were initially randomized to treatments, 30 were finally removed from the dataset after verifying they did not fully meet inclusion criteria or removed proper written consent during the first week. Thus, the final sample consisted of 376 participants who were randomly assigned to 6 different antipsychotic treatments: 55 patients were randomly assigned to the olanzapine group, 63 to the risperidone group, 56 to the haloperidol group, 78 patients to the aripiprazole group, 62 were assigned to the quetiapine group, and 62 to the ziprasidone group (Figure1). The overall dropout rate at 3years was small (n = 78; 20.74%); 46 patients dropped out prior to treatment discontinuation and were censored for the survival analysis (5-haloperidol, 9-olanzapine, 10-risperidone, 9-aripiprazole, 8-quetiapine, and 5- ziprasidone). Our study gave the option to patients who were stable (symptom free for at least 12months) and functionally recovered (at least 6months under sustained recovery) to discontinue use of antipsychotic treatment while continuing to be followed-up by study clinicians (Mayoral-van Son etal., 2016). Seventeen patients entered this antipsychotic discontinuation program and were carefully monitored during the following 18months after discontinuation. Sixteen of these 17 patients completed the 3-year assessment but were censored for the primary outcome analysis. Five patients committed suicide during the 3-year follow-up (1 olanzapine, 1 aripiprazole, 1 ziprasidone, and 2 quetiapine) and there was 1 sudden death (aripiprazole; heart attack). All but 11 individuals in the study were white Caucasian (no significant differences were found between treatment groups after Bonferroni correction). Instead, we found significant differences between treatment groups concerning some demographic variables (living with parents, single status, age at admission, age at FEP onset, and duration of illness), which were adjusted by Bonferroni correction later. Demographic and clinical characteristics of patients are shown in Table1. Primary Outcome Measures Treatment Discontinuation Rate and Time to Discontinuation An impressive 79.25 % of the initial sample completed follow-up. Overall treatment discontinuation rate (the cumulative percentage of discontinuation considering the 6 arms of the study) also reached 79.25% by 3 years, which is in line with other medium and long-term (52 weeks or more) follow-up studies (Lieberman etal., 2005; Kahn et al., 2008a). It differed significantly between treatment groups (χ 2 = 79.860; P = .000) (Table2). Patients on quetiapine showed a higher (95.16 %) treatment discontinuation rate than those on olanzapine (69.09%), risperidone (71.43%), aripiprazole (73.08 %), ziprasidone (79.03 %), or haloperidol (89.28%). The mean time (days) until discontinuation was 855days for olanzapine, 786days for risperidone, 452days for aripiprazole, 295days for haloperidol, 251days for ziprasidone, and 60days for quetiapine. There was a significant difference between groups (log rank = 90.240; P = .000) (see Figure2). Log-rank pairwise comparisons showed no statistical differences between Figure 1. Consort flow chart. Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 Copyedited by: Gómez-Revuelta etal. | 221 Table 1. Demographic and clinical characteristics of 376 drug-naïve patients with a FEP randomly assigned to treatment with olanzapine, risperidone, haloperidol, aripiprazole, ziprasidone, or quetiapine Aripiprazole (n = 78) Risperidone (n = 63) Olanzapine (n = 55) Quetiapine (n = 62) Ziprasidone (n = 62) Haloperidole (n = 56) Total (n = 376) Characteristic Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Statistics P Age at admission (y) 32.1 11.1 26.3 11.6 27.5 6.9 31.0 9.2 32.1 10.5 28.3 8.7 29.55 2.61 F = 5.19 .00 Age at psychosis onset (y) 30.9 9.9 25.2 7.2 26.5 6.8 30.3 9.2 31.1 10.6 36.8 7.5 28.47 2.36 F = 5.61 .00 Duration of illnessa (mo) 31.1 56.4 29.5 39.6 21.2 33.2 22.1 42.8 16.4 29.4 32.3 39.7 25.43 5.86 z = 13.85 .017 Duration of psychosis (mo) 2.25 17.1 13.4 21.8 12.1 19.1 3.0 11.0 2.25 9.0 17.8 37.2 8.46 6.21 z = 5.33 .377 n % n % n % n % n % n % n % χ2P Schizophrenia diagnosis 39 50.0 36 57.14 29 52.73 38 61.29 36 58.06 42 75.0 220 58.51 9.608 .087 Gender (male) 38 48.72 39 61.90 33 60.0 41 66.13 29 46.77 36 64.29 216 57.45 8.9622 .111 Race (Caucasian) 76 97.44 63 100.0 55 100.0 58 93.55 58 93.55 56 100.0 366 97.34 11.6443 .040 Education level (elementary) 31 39.74 34 53.97 27 49.09 38 61.29 27 43.55 28 50.0 185 49.20 7.7968 .168 Socioeconomic status of parents (not/less qualified) 34 44.16 36 60.0 32 58.18 30 48.39 28 45.16 36 64.29 196 52.69 9.0923 .105 Urban area (yes) 55 71.43 50 79.37 41 74.55 48 77.42 46 74.19 41 73.21 281 74.93 1.4769 .916 Living with parents (yes) 31 40.26 45 71.43 31 56.36 33 53.23 29 46.77 34 60.71 203 54.13 16.018 .007 Student (yes) 16 20.8 11 17.5 10 18.0 8 12.9 15 24.2 14 25.0 74 19.68 3,340 0,007 Single (yes) 50 64.94 56 88.89 43 78.18 41 66.13 44 70.97 47 83.93 281 74.93 16.429 .006 Unemployed (yes) 35 45.45 32 50.79 23 41.82 32 51.61 23 37.1 24 42.86 169 45.07 3.848 .571 Family psychiatric history (yes) 17 21.8 7 11.1 15 27.3 14 22.6 17 27.4 13 23.2 83 22.07 1,866 0,100 Hospital status inpatient (yes) 26 33.33 30 47.62 20 36.36 21 33.87 21 33.87 15 26.79 133 35.37 6.227 0 Tobacco use (yes) 47 60.26 38 60.32 32 58.18 39 62.90 33 53.23 31 55.36 220 58.51 1.620 .899 Cannabis use (yes) 30 38.46 31 49.21 26 47.27 29 46.77 20 32.26 25 44.64 161 42.82 5.3967 .369 Alcohol use (yes) 40 51.28 37 58.73 25 46.3 39 62.9 29 46.77 34 60.71 204 54.4 6.3721 .272 Other drugs (yes) 15 19.5 17 27.0 17 30.9 18 29.0 6 9.7 13 23.2 86 22.87 0,699 .624 Abbreviation: FEP, first episode of psychosis. Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 222 | International Journal of Neuropsychopharmacology, 2020 olanzapine, risperidone, and aripiprazole. However, results differed significantly favoring any antipsychotic when compared with quetiapine: aripiprazole (χ 2 = 28.95; P < .001), ziprasidone (χ 2 = 14.29; P < .001), olanzapine (χ 2 = 45.56; P = .156), haloperidol (χ 2 = 18.84; P < .001), and risperidone (χ 2 = 46.52; P < .001). Results also highlighted higher effectiveness of risperidone (χ 2 = 9.44; P = .002) and aripiprazole (χ 2 = 7.657; P = .022) over haloperidol. Olanzapine also took significant advantage over haloperidol (χ 2 = 11.23; P = .001) and ziprasidone (χ 2 = 8.81; P = .003). We only found a trend towards nondiscontinuation favoring aripiprazole and risperidone over ziprasidone and no differences were found between ziprasidone and haloperidol. Non- or insufficient efficacy in the group of quetiapine was the main reason for discontinuation rate differences (χ 2=87.43; P = .000). Patients under quetiapine treatment were significantly more likely to discontinue due to non- or insufficient efficacy compared with aripiprazole (χ 2 = 32.15; P = .000), ziprasidone (χ 2 = 19.35; P = .000), olanzapine (χ 2 = 39.91; P = .000), risperidone (χ 2 = 41.17; P = .000), or haloperidol patients (χ 2 = 27.83; P = .000). No significant differences were found between the remaining treatment groups. Mean (SD) doses (adjusted by chlorpromazine equivalents) prior to discontinuation due to non- or insufficient efficacy were aripiprazole-520 CPZeq (SD = 131.7), ziprasidone-386.5 CPZeq (SD = 149.5), haloperidol-351.8 CPZeq (SD = 164.9), olanzapine-510 CPZeq (SD = 292.4), risperidone-550 CPZeq (SD = 229.1), and quetiapine-586.2 CPZeq (SD = 251.1). Analysis of treatment discontinuation due to side effects revealed significant differences between groups (quetiapine 12.9%, ziprasidone 37.1%, risperidone 31.7%, olanzapine 14.5%, haloperidol 31.1%, and aripiprazole 12.82 %; χ 2 = 19.800; P = .001). Patients on ziprasidone discontinued treatment due to side effects significantly more frequently than those on aripiprazole (χ² = 11.490; P = .001), olanzapine (χ² = 12.400; P = .000), or quetiapine (χ² = 9.677; P = .006). We did not find significant differences in the direct comparisons between the remaining groups. Finally, there was a remarkable difference in terms of treatment adherence as individuals in the risperidone group showed better adherence than those individuals in the aripiprazole (χ² = 12.13; P = .001), quetiapine (χ² = 19.43; P = .000), and haloperidol groups (χ² = 10.59; P = .001); aripiprazole patients also demonstrated worse adherence than those under treatment with ziprasidone (χ² = 8.45; P = .003). Mean chlorpromazine equivalent daily doses at 3 years were: aripiprazole 16.3 mg = 216.8 (SD = 164.1) CPZeq; ziprasidone 121.3 mg = 202.2 (SD = 136.5) CPZeq; quetiapine 195.9 mg = 261.1 (SD = 136.5) CPZeq; risperidone 2.9 mg = 145 (95) (SD = 136.5) CPZeq; olanzapine 8.74 mg = 174.8 (SD = 92) CPZeq; and haloperidol 3.2 mg = 160 (SD = 60) CPZeq. No significant differences were observed (P = .279). Secondary Outcome Measures Clinical Efficacy ANCOVA analyses showed multiple differences (Table3) in the changes of the total scores of the clinical scales between treatments after controlling by baseline measurements except for the SANS score (P = .265) and the negative dimension score (P = .314). Thereby, significant differences on clinical scales showed CGI improvement: significantly larger for aripiprazole vs haloperidol and ziprasidone vs haloperidol, and olanzapine; SAPS score: olanzapine improvement significantly lower compared with aripiprazole and ziprasidone; positive dimension: aripiprazole and ziprasidone scores were significantly lower than those proceeding from haloperidol and olanzapine patients; disorganized dimension: patients on aripiprazole, quetiapine, and ziprasidone got significant larger improvements than olanzapine patients; CDSS score: ziprasidone and quetiapine patients got significant improvements in depressive symptoms compared with haloperidol patients; YMRS score: significant improvement for aripiprazole compared with olanzapine. Per protocol analyses solely unveiled significant differences concerning CGI (P = .008) and YMRS (P = .001) baseline scores. Bonferroni posthoc analyses showed significantly higher baseline scores for aripiprazole compared with olanzapine and risperidone for both clinical scales (data available upon request). Safety AdverseEvents Intention-to-treat analyses of moderate and severe side effects that were frequent (in at least 5% of patients in any of the treatment groups) are displayed in Table4. Significant differences between treatments were found in the categories of sleepiness/sedation, increased sleep duration, akinesia, weight gain, ejaculatory dysfunction, and amenorrhea. After adjustment by Bonferroni correction, aripiprazole was shown to cause less increased sleep duration than quetiapine (P = .015) and ziprasidone (P = .05) and risperidone was also less likely to do so than olanzapine, quetiapine, haloperidol, and ziprasidone Figure 2. Kaplan-Meyer survival graph: any cause discontinuation. Table 2. Any-Cause Discontinuation Rate and Discontinuation Rates by AllocatedCauses Aripiprazole (n = 78) Risperidone (n = 63) Olanzapine (n = 55) Quetiapine (n = 62) Ziprasidone (n = 62) Haloperidol (n = 56) Total (n = 376) Total % Total % Total % Total % Total % Total % Total % χ²P Any cause discontinuation 57 73.08 45 71.43 38 69.09 59 95.53 49 79.03 50 89.28 298 79.25 79.86 .000 No efficacy 12 15.38 9 14.28 6 10.91 31 50,0 13 20.97 11 19.64 82 21.81 87.43 .000 No adherence 26 33.3 6 9.53 15 27.27 12 19.3 8 12.9 16 28.57 83 22.07 25.87 .000 Side effects 10 12.83 20 31.75 8 14.55 8 12.9 23 37.1 18 32.14 87 23.14 19.80 .001 Dropout 9 11.54 10 15.87 9 16.36 8 13.33 5 8.06 5 8.93 46 12.23 15.13 .010 Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 Copyedited by: Gómez-Revuelta etal. | 223 Table 3. Intention-to-Treat Sample: Psychopathological Characteristics at Baseline and 3 Years and Clinical Changes During Follow-UpPeriod Aripiprazole (n = 66) Risperidone (n = 45) Olanzapine (n = 43) Quetiapine (n = 45) Ziprasidone (n = 52) Haloperidole (n = 47) Total (n = 298) Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Statistic Value P CGI - Baseline 6.6 0.6 6.1 0.7 6.0 0.8 6.5 0.6 6.3 0.6 6.2 0.6 6.3 0.7 F 6.553 .000 CGI - 3Y 2.5 1.7 3.1 1.6 3.1 1.6 2.5 1.8 2.1 1.4 3.4 1.6 2.7 1.7 F 4.440 .001 CGI - 3Y-Baseline −4.2 1.8 −3.0 1.8 −2.9 1.7 −4.1 1.9 −4.2 1.5 −2.8 1.8 −3.6 1.8 F 7.757 .000 (Covariated) CGI - 3Y-Baseline −3.9 0.2 −3.2 0.2 −3.2 0.3 −3.9 0.2 −4.2 0.2 −2.9 0.2 F 4.602 .000 CDSS - Baseline 2.8 3.6 1.3 2.3 2.6 3.4 2.7 3.3 2.0 3.5 2.0 2.6 2.3 3.2 F 1.514 .185 CDSS - 3Y 0.7 1.8 0.8 1.7 0.7 1.6 0.1 0.3 0.3 0.9 1.5 2.8 0.7 1.7 F-w 6.822 .000 CDSS - 3Y-Baseline −2.1 4.1 −0.6 2.7 −1.9 3.7 −2.6 3.3 −1.8 3.5 −0.5 3.7 −1.6 3.6 F 2.713 .021 (Covariated) CDSS - 3Y-Baseline −1.6 0.2 −1.5 0.3 −1.6 0.3 −2.2 0.2 −2.0 0.2 −0.7 0.2 F 4.240 .001 Total BPRS - Baseline 67.7 12.6 57.4 10.3 59.4 11.9 63.9 12.0 61.7 12.6 61.8 11.2 62.4 12.2 F 4.951 .000 Total BPRS - 3Y 29.6 10.0 33.3 12.2 35.6 14.4 30.6 9.8 29.1 7.3 35.7 13.7 32.1 11.5 F-w 3.242 .009 Total BPRS - 3Y-Baseline −38.0 15.1 −24.1 16.9 −23.8 20.3 −33.3 13.7 −32.6 12.0 −26.0 18.4 −30.3 16.9 F-w 6.382 .000 (Covariated) Total BPRS - 3Y-Baseline −32.9 1.4 −28.9 1.7 −26.7 1.7 −31.9 1.7 −33.3 1.6 −26.6 1.6 F 3.476 .005 Total SAPS - Baseline 14.6 4.4 13.3 4.2 12.2 4.5 13.9 4.1 13.9 4.3 13.4 3.5 13.6 4.2 F 1.780 .117 Total SAPS - 3Y 1.0 2.8 2.6 4.2 3.5 5.5 1.4 3.0 1.1 2.7 2.6 3.9 1.9 3.8 F-w 3.166 .010 Total SAPS - 3Y-Baseline −13.6 4.7 −10.7 5.6 −8.7 6.3 −12.5 5.3 −12.8 4.6 −10.7 4.9 −11.7 5.4 F 5.791 .000 (Covariated) Total SAPS - 3Y-Baseline −12.7 0.5 −11.0 0.5 −10.0 0.6 −12.2 0.5 −12.6 0.5 −11.0 0.5 F 4.351 .001 Total SANS - Baseline 7.5 6.8 7.4 6.5 7.4 6.0 6.3 6.0 6.1 5.4 7.0 6.2 6.9 6.2 F 0.497 .778 Total SANS - 3Y 3.9 5.7 4.0 4.9 3.9 5.4 3.8 5.8 3.1 4.8 5.7 5.3 4.2 5.4 F 1.379 .232 Total SANS - 3Y-Baseline −3.6 8.3 −3.3 8.3 −2.6 7.5 −2.5 5.7 −3.0 7.5 −1.3 7.5 −2.8 7.5 F 0.577 .717 (Covariated) Total SANS - 3Y-Baseline −3.1 0.7 −3.0 0.8 −2.1 0.8 −3.1 0.8 −3.8 0.7 −1.3 0.8 F 1.298 .265 Positive dim - Baseline 7.6 2.6 7.4 2.5 7.1 2.4 7.6 2.4 7.3 2.3 7.8 2.1 7.5 2.4 F 0.445 .816 Positive dim - 3Y 0.5 1.8 1.5 2.2 1.8 2.6 1.0 1.9 0.5 1.3 1.9 3.1 1.1 2.2 F-w 4.064 .002 Positive dim - 3Y-Baseline −7.0 2.8 −6.0 3.0 −5.3 3.5 −6.6 3.0 −6.8 2.6 −5.9 3.4 −6.3 3.1 F 2.317 .044 (Covariated) Positive dim - 3Y-Baseline −7.0 0.3 −6.0 0.3 −5.6 0.3 −6.5 0.3 −6.9 0.3 −5.6 0.3 F 4.112 .001 Disorganized dim - Baseline 7.0 3.2 5.9 3.4 5.1 3.6 6.3 3.2 6.6 3.5 5.6 2.8 6.2 3.4 F 2.205 .054 Disorganized dim - 3Y 0.5 1.5 1.2 2.5 1.7 3.4 0.4 1.4 0.6 1.8 0.7 1.3 0.8 2.1 F-w 1.650 .151 Disorganized dim - 3Y-Baseline −6.5 3.6 −4.7 4.1 −3.4 4.0 −5.9 3.6 −6.0 3.6 −4.9 3.0 −5.4 3.8 F 4.691 .000 (Covariated) Disorganized dim - 3Y-Bas −5.8 0.3 −5.0 0.3 −4.4 0.3 −5.8 0.3 −5.6 0.3 −5.4 0.3 F 3.282 .007 Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 224 | International Journal of Neuropsychopharmacology, 2020 (all P < .05). Quetiapine was associated with increased somnolence compared with aripiprazole (P = .034), but amenorrhea was significantly less likely to emerge in this group compared with haloperidol (P = .037) and risperidone (P = .022). Risperidone produced an greater frequency of ejaculatory dysfunction than aripiprazole (P = .034). Aripiprazole patients were more likely to suffer akinesia compared with olanzapine (P = .004) and ziprasidone patients (P = .033). Finally, olanzapine caused a significantly higher weight gain rate than ziprasidone (P = .001). Perprotocol analysis showed rather similar results (data available in supplementary Material). In this sense, there were only 3 sideeffect categories that showed statistically significant differences (weight gain, sialorrhea, and ejaculatory dysfunction). None of them resulted in statistical significance after post-hoc analyses. Extrapyramidal Symptoms Significant differences in the SARS total score changes at 3years between treatments were found (F = 13.441; P = .020). The percentage of patients with treatment-emergent extrapyramidal symptoms (EPS) was statistically different between treatments (aripiprazole = 23.8%, ziprasidone = 23.5%, quetiapine 20%, risperidone 40%, olanzapine 30%, haloperidol 48.8%; χ 2 = 13.441; P = .020). Haloperidol supplied a significant burden of extrapyramidal side effects compared with aripiprazole, quetiapine, and ziprasidone (all P´s < .05) and so did risperidone compared with quetiapine (P = .043). There was no significant difference between treatments in the severity of akathisia (BAS total score) (F = 0.939; P = .456). Although the difference did not reach significance, more individuals in the aripiprazole (22.6 %), haloperidol (27.7%), and ziprasidone groups (32.7 %) experienced treatment emergent akathisia compared with the other groups (quetiapine 17.8 %, olanzapine 4.7%, and risperidone 17.8%). These differences were significant for the UKU scale akathisia item (χ² = 11.932; P = .036), but after Bonferroni correction only the differences between ziprasidone and olanzapine groups remained significant (P = .001). Per protocol analyses showed no statistically significant differences. Concomitant MedicationUse Significant differences were found between treatment groups regarding the use of benzodiazepines (χ² = 21.52, P = .001), hypnotics (χ² = 47.76, P = .004), and anticholinergics (χ² = 43.76, P = .004). After adjustment by Bonferroni correction, we found that the benzodiazepine use in the aripiprazole group was significantly higher than in the quetiapine, haloperidol, olanzapine, and risperidone groups (all P < .05); similarly, aripiprazole, quetiapine, and ziprasidone patients needed hypnotics more frequently than olanzapine, risperidone, and haloperidol patients (all P < .05 except for the comparison between quetiapine and haloperidol). Almost one-half of the sample required treatment with anticholinergics at any time of the follow-up. Olanzapine (27.27%) stood out for being the treatment group that least frequently needed this sort of treatment (Table5). Discussion Our aim with this research was to supply information from our experience to guide the choice of the first-line treatment for an FEP. Results show remarkable effectiveness, efficacy, and safety differences between the 6 antipsychotics included in the study. We distinguished 2 treatment groups according to their effectiveness performance, multiple tolerability profiles, and different efficacy measures. Aripiprazole (n = 66) Risperidone (n = 45) Olanzapine (n = 43) Quetiapine (n = 45) Ziprasidone (n = 52) Haloperidole (n = 47) Total (n = 298) Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Statistic Value P Negative dim - Baseline 5.0 6.0 6.1 6.0 6.2 5.8 4.3 5.4 3.9 4.7 5.7 5.7 5.2 5.6 F 1.332 .251 Negative dim - 3Y 3.5 5.1 3.3 4.2 4.3 5.3 3.3 5.1 2.8 4.4 5.1 4.9 3.7 4.9 F 1.448 .207 Negative dim - 3Y-Baseline −1.6 7.2 −2.8 6.9 −1.9 7.1 −1.0 5.0 −1.2 6.5 −0.6 6.8 −1.5 6.6 F 0.650 .662 (Covariated) Negative dim - 3Y-Baseline −1.7 0.6 −2.0 0.7 −1.1 0.7 −1.7 0.7 −2.2 0.7 −0.1 0.7 F 1.189 .314 YMRS - Baseline 11.8 5.0 9.0 4.1 8.8 4.3 12.3 5.5 1.7 4.6 9.2 4.6 10.6 4.9 F 5.693 .000 YMRS - 3Y 1.0 2.2 2.1 4.2 3.1 5.0 1.9 3.6 1.5 4.1 2.2 3.3 1.9 3.8 F 1.844 0.104 YMRS - 3Y-Baseline −10.8 5.0 −6.9 5.6 −5.7 6.3 −10.4 6.8 −10.1 4.7 −7.0 5.7 −8.7 5.9 F 7.506 .000 (Covariated) YMRS - 3Y-Baseline −9.7 0.5 −8.3 0.6 −7.3 0.6 −8.8 0.6 −9.2 0.5 −8.2 0.6 F 2.408 .037 Abbreviations: BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Rating Scale for Schizophrenia; CGI, Clinical Global Impression; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; YMRS, Young Mania Rating Scale. Table 3. Continued Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023 Copyedited by: Gómez-Revuelta etal. | 225 Table 4. Intention-to-Treat Sample: Moderate or Severe Treatment-Emergent Adverse Effects That Occurred at a Rate of at Least 5% in Either TreatmentGroup Aripiprazole (n = 66) Risperidone (n = 45) Olanzapine (n = 43) Quetiapine (n = 45) Ziprasidone (n = 52) Haloperidole (n = 47) Total (n = 298) 6wk to 3 y n % n % n % n % n % n % n % Statistic value P Concentration difficulties 13 19.7 5 11.1 8 18.6 6 13.3 10 19.2 12 25.5 54 18.1 χ 24.086 .537 Asthenia/increased fatigability 26 39.4 15 33.3 19 44.2 24 53.3 24 46.2 26 55.3 134 45.0 χ 26.638 .249 Sleepiness/sedation 26 39.4 19 42.2 25 58.1 31 68.9 29 55.8 25 53.2 155 52.0 χ 212.040 .034 Memory impairment 3 4.5 0 0.0 0 0.0 1 2.2 3 5.8 1 2.1 8 2.7 F5.289 .461 Depression 3 4.5 0 0.0 1 2.3 1 2.2 3 5.8 0 0.0 8 2.7 F5.365 .402 Restlessness 3 4.5 2 4.4 1 2.3 1 2.2 3 5.8 4 8.5 14 4.7 F2.826 .774 Increased sleep duration 14 21.2 7 15.6 14 32.6 19 42.2 19 36.5 18 38.3 91 30.5 χ 212.664 .027 Decreased sleep duration 2 3.0 2 4.4 4 9.3 0 0.0 0 0.0 3 6.4 11 3.7 F8..637 .087 Rigidity 2 3.0 1 2.2 0 0.0 1 2.2 6 11.5 2 4.3 12 4.0 F10.331 .116 Akinesia 23 34.8 5 11.1 2 4.7 8 17.8 15 28.8 12 25.5 65 21.8 χ 219.343 .002 Tremor 9 13.6 5 11.1 2 4.7 2 4.4 3 5.8 5 10.6 26 8.7 F5.039 .448 Akathisia 15 22.7 8 17.8 2 4.7 8 17.8 16 30.8 13 27.7 62 20.8 χ 211.932 .036 Increased salivation 11 16.7 13 28.9 2 4.7 9 20.0 9 17.3 11 23.4 55 18.5 χ 29.721 .084 Decreased salivation 5 7.6 6 13.3 9 20.9 8 17.8 9 17.3 9 19.1 46 15.4 χ 25.096 .404 Constipation 7 10.6 4 8.9 5 11.6 7 15.6 5 9.6 3 6.4 31 10.4 F2.314 .820 Miction impairment 4 6.1 1 2.2 0 0.0 1 2.2 1 1.9 1 2.1 8 2.7 F4.310 .665 Vertigo 3 4.5 2 4.4 0 0.0 0 0.0 4 7.7 0 0.0 9 3.0 F8.916 .098 Weight gain 33 50.0 26 57.8 31 72.1 20 44.4 16 30.8 22 46.8 148 49.7 χ 217.911 .003 Diminished sexual desire 6 9.1 7 15.6 4 9.3 6 13.3 4 7.7 5 10.6 32 10.7 F2.189 .829 Orgasmic dysfunction 1 1.5 3 6.7 2 4.7 2 4.4 3 5.8 1 2.1 12 4.0 F2.800 .707 Headache 1 1.5 1 2.2 3 7.0 0 0.0 1 1.9 0 0.0 6 2.0 F7.355 .223 Male Erectile dysfunction 2 6.5 9 34.6 4 14.8 7 24.1 5 22.7 7 22.6 34 20.5 χ 27.858 .164 Ejaculatory dysfunction 2 6.5 10 38.5 2 7.4 6 20.7 5 22.7 4 12.9 29 17.5 F13.531 .025 Female Amenorrhea 5 14.3 9 47.4 2 12.5 0 0.0 7 23.3 8 50.0 31 23.5 F19.925 .001 Galactorrhea 0 0.0 2 10.5 1 6.3 0 0.0 2 6.7 1 6.3 6 4.5 F4.520 .319 Downloaded from https://academic.oup.com/ijnp/article/23/4/217/5715030 by Universidad de Sevilla user on 21 June 2023