Aripiprazole and Risperidone Present Comparable Long-Term Metabolic Profiles: Data From a Pragmatic Randomized Controlled Trial in Drug-Naïve First-Episode Psychosis

Received: November 8, 2021; Revised: April 29, 2022; Accepted: May 26, 2022 795 © The Author(s) 2022. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https:// 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 Aripiprazole and Risperidone Present Comparable Long-Term Metabolic Profiles: Data From a Pragmatic Randomized Controlled Trial in Drug-Naïve First- Episode Psychosis JavierVázquez-Bourgon, MD, PhD , VíctorOrtiz-GarcíadelaFoz, BSc, MarcosGómez-Revuelta, MD, PhD , JacquelineMayoral-vanSon, MD, PhD , MaríaJuncal-Ruiz, MD, PhD, NathaliaGarrido-Torres, MD, BenedictoCrespo-Facorro, MD, PhD Department of Psychiatry, University Hospital Marqués de Valdecilla - Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain (Dr Vázquez-Bourgon, Mr Ortiz-García de la Foz, and Dr Gómez-Revuelta); Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Sevilla, Spain (Drs Vázquez-Bourgon, Mayoral-van Son, Garrido-Torres, and Crespo-Facorro); Department of Medicine and Psychiatry, School of Medicine, Universidad de Cantabria, Santander, Spain (Drs Vázquez-Bourgon, Gómez-Revuelta, and Juncal- Ruiz). Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocío-IBiS, Sevilla, Spain (Drs Mayoral-van Son, Garrido-Torres, and Crespo-Facorro); Department of Psychiatry, Sierrallana Hospital - Instituto de Investigación Marqués de Valdecilla (IDIVAL), Torrelavega, Spain (Dr Juncal-Ruiz). Correspondence: Javier Vázquez-Bourgon, MD, PhD, Department of Psychiatry, University Hospital Marqués de Valdecilla, Avda. Valdecilla s/n, Santander, 39008, Spain (javier[email protected]). Abstract Objective: Aripiprazole and risperidone are 2 of the most used second-generation antipsychotics (SGAs) worldwide. Previous evidence shows a similar effect of these SGAs on weight and metabolic changes in the short term. However, a longer period is necessary for a better assessment of the SGA´s metabolic profile. We aimed to compare the long-term (1-year) metabolic profile of these 2 antipsychotics on a sample of drug-naïve first episode-psychosis (FEP) patients. Methods: A total 188 drug-naïve patients, suffering from a first episode of non-affective psychosis (FEP), were randomly assigned to treatment with either aripiprazole or risperidone. Weight and glycemic/lipid parameters were recorded at baseline and after 1-year follow-up. Results: We observed significant weight increments in both groups (9.2kg for aripiprazole and 10.5kg for risperidone) after 1year of treatment. Despite this, weight and body mass index changes did not significantly differ between treatment groups (P > .05). Similarly, both treatment groups presented similar metabolic clinical impact with a comparable increase in the proportion of participants meeting criteria for metabolic disorders such as obesity or hypercholesterolemia, but not for metabolic syndrome (Δ9.2% vs Δ4.3%) or hypertriglyceridemia (Δ21.9% vs Δ8.0%), where aripiprazole showed worse outcomes than risperidone. International Journal of Neuropsychopharmacology (2022) 25(10): 795–806 https://doi.org/10.1093/ijnp/pyac033 Advance Access Publication: May 31, 2022 Regular Research Article International Journal of Neuropsychopharmacology (2022) 25(10): 795–806 https://doi.org/10.1093/ijnp/pyac033 Advance Access Publication: , 2022 Regular Research Article Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 796 | International Journal of Neuropsychopharmacology, 2022 Conclusion: This study shows that aripiprazole and risperidone share a similar long-term metabolic profile. After 1year of antipsychotic treatment, drug-naïve FEP patients in both treatment groups presented a significant increase in weight and metabolic changes, leading to a greater prevalence of metabolic disorders. Keywords: Metabolism, weight gain, treatment-naïve, second-generation antipsychotic, schizophrenia Introduction Schizophrenia is a neuropsychiatric disorder characterized by a chronic progression and lifetime prevalence of approximately 1% (Kahn etal., 2015). The primary treatment for schizophrenia is second-generation antipsychotics (SGAs) (Goff, 2021). After symptoms have been controlled in individuals with their first episode of psychosis (FEP), it is strongly advised to reduce SGA treatment to the lowest effective dose as soon as possible. This praxis not only ensures symptomatic stability but also reduces the likelihood of emergent adverse events, which would result in poor treatment acceptability and compliance (Goff etal., 2017; Correll etal., 2018). In this regard, SGAs have been widely linked to weight gain, which, along with other lifestyle risk factors, contributes to an increased risk of dyslipidemia, glucose intolerance, diabetes mellitus, metabolic syndrome (MetS), and, ultimately, cardiovascular disease (Henderson et al., 2015; Nielsen et al., 2021). These physical conditions are underlying causes of up to 70% of the excess mortality seen in schizophrenia, resulting in a life expectancy reduction of up to 20years (Owen et al., 2016; Kurdyak et al., 2021). Recent evidence, however, indicates that there are differences in the side effects profile of antipsychotics in terms of weight gain (Leucht etal., 2013; Huhn et al., 2019). A recent meta-analysis described gradual but marked differences between a wide range of antipsychotic treatments regarding weight gain (Huhn etal., 2019). Aripiprazole (a D2 and 5-HT1A receptor partial agonist and 5-HT2A receptor antagonist) and risperidone (a D2, 5-HT2, and NE alpha-2 receptor antagonist) are 2 of the most widely used SGAs (Toto et al., 2019; Taipale et al., 2020). As a result, head-to-head comparisons of tolerability, particularly in terms of metabolic profiles, are timely but currently scarce (Kishimoto etal., 2019). Moreover, literature on this topic showed contradictory results when comparing aripiprazole and risperidone metabolic profiles. A recent meta-analysis of patients with chronic schizophrenia found significant differences in weight gain between aripiprazole and risperidone, with the former being more effective (Huhn etal., 2019). Previous research on FEP patients found that aripiprazole (Vazquez-Bourgon et al., 2018) and risperidone (Perez-Iglesias etal., 2009) had metabolic profiles similar to other SGAs such as olanzapine or quetiapine. Similarly, a recent pooled analysis in FEP patients that included 6 different SGAs (haloperidol, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) and focused on treatment effectiveness found that aripiprazole and risperidone demonstrated clear advantages in effectiveness without demonstrating significant differences in weight gain after long-term follow-up (Gomez-Revuelta et al., 2020). Another recent study carrying head-to-head comparison of aripiprazole and risperidone in the acute-phase treatment of FEP patients (6 weeks after FEP diagnosis) showed no significant differences in weight gain between treatment groups (Gomez-Revuelta et al., 2021). Furthermore, Josiassen etal. (2010) demonstrated that after 8 weeks of treatment, FEP patients receiving aripiprazole gained similar weight to those receiving risperidone (7% vs 7.3% from baseline body weight). Nonetheless, a longer timeframe may be required to properly observe clinically relevant changes in weight and metabolic parameters. Long-term studies on FEP patients show that the majority of this weight gain occurs within the first year of FEP diagnosis, indicating that this is the critical period for these side effects (Bioque etal., 2018; Vázquez-Bourgon etal., 2021). As a result, the first aim of this study was to elucidate whether aripiprazole and risperidone may have distinct tolerability profiles in medication-naïve FEP patients in the first year of treatment. Our main hypothesis was that based on the previous research, aripiprazole and risperidone would present with similar metabolic profiles. Second, we hypothesized that after the first year of antipsychotic treatment, FEP drug-naive patients would have a significant increase in weight and metabolic measures. MATERIALS ANDMETHODS The study was carried out in an early-psychosis intervention program in northern Spain (Programa Asistencial de las Fases Iniciales de Psicosis [PAFIP] program); this is a clinical and research program aimed at providing intensive and specialized treatment to people in Cantabria who have experienced their first episode of non-affective psychosis (Pelayo-Terán et al,. 2008). Furthermore, the study formed part of a pragmatic clinical trial to compare the effectiveness of aripiprazole and risperidone in a sample of drug-naive FEP patients (NCT02532491) (Son etal., 2021). The PAFIP program involves clinical and research activity at the outpatient and inpatient psychiatric units of the University Hospital Marqués de Valdecilla (Santander, Spain). Significance Statement We studied, in a cohort of patients with a first episode of non-affective psychosis, the changes in body weight and glucose/lipid metabolisms observed during the first year after the diagnoses of psychosis and the initiation of antipsychotic treatment. At study entry, patients were randomized to either aripiprazole or risperidone, so we were able to run head-to-head comparisons between antipsychotic treatments. The results showed a significant increase in mean body weight in the whole cohort. Despite this, aripiprazole and risperidone showed a similar metabolic profile and produced comparable weight gain at long term in individuals with a first episode of psychosis. Secondary analyses showed that women had a statistically significant greater increase in body mass index than men. We did not observe sex–treatment interactions in weight gain or metabolic changes. Early preventive measures to avoid weight gain should be put in place when treating individuals for a first episode of psychosis. Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 Aripiprazole vs Risperidone Metabolic Profile | 797 The hospital serves as a reference center for a 580 000-person catchment area and houses the province’s only psychiatric acute inpatient unit as well as a 24-hour emergency care service. Regular meetings with all community mental health teams in Cantabria were maintained in an attempt to reach all persons suffering from FEP in Cantabria to provide them with adequate specialized treatment. Participants The sample for the present study was recruited between February 2011 and October 2018. These patients were referred to the PAFIP program when presenting a FEP and were admitted if they fulfilled the following criteria: (1) aged 15–60 years; (2) met the DSM-IV criteria (according to the Structured Clinical Interview for DSM-IV) 6 months after inclusion for a principal diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, brief reactive psychosis, or psychosis non-otherwise specified; (3) habitually living in the catchment area; (4) no prior treatment with antipsychotic medication; and (5) current psychotic symptoms of at least moderate severity, as assessed by 1 of the 5 items of the Scale for the Assessment of Positive Symptoms (SAPS). Patients were not admitted to the program if they had any of the following conditions: (1) intellectual disability, (2) a neurological disorder, or (3) a drug dependence (DSM-IV criteria). Prior to their inclusion in the study, all participants provided written informed consent, which was approved by the regional ethics committee (Clinical Research Ethics Committee of Cantabria). StudyDesign Patients entering the clinical trial (NCT02532491) were randomly assigned to treatment with aripiprazole (D2 and 5-HT1A receptor partial agonist, and 5-HT2A receptor antagonist) or risperidone (D2, 5-HT2, and NE alpha-2 receptor antagonist). A statistician created a computer-generated randomization list. The treatment dose ranges for aripiprazole were 5–30mg/d and 1–6mg/d for risperidone. Doses could be adjusted within the prescribed range as clinically indicated to target the lowest effective dose. Certain concomitant medications, such as lormetazepam and clonazepam (benzodiazepine receptor agonists, non-selective GABA-A receptor–positive allosteric modulators), were permitted for the management of agitation, general behavior disturbances, and/or insomnia. Only if clinically significant extrapyramidal symptoms occurred was anticholinergic medication (biperiden, at a dose of up to 8mg/d) permitted. If clinically necessary, antidepressants (sertraline, a SERT reuptake inhibitor) and mood stabilizers (lithium; enzyme interactions) were also permitted. Those patients who did not respond after 6 weeks of treatment [<30% total improvement measured by SAPS (Andreasen, 1984) and the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1983) scales] or who experienced significant side effects, measured by the Udvalg für Kliniske Undersogelser (UKU) scale (Lingjaerde etal., 1987), were switched to a different antipsychotic. Patients were clinically evaluated by a senior psychiatrist at baseline and at the following time-points after initiating the treatment: 6 weeks, 12 weeks, and 1year. The NCT02532491 is a clinical trial aimed to evaluate and compare the effectiveness of aripiprazole and risperidone in FEP patients at long term (1year). The clinical trial outcomes were discontinuation rates, changes in psychopathological (e.g., Brief Psychiatric Rating Scale, SAPS, and SANS) and side effects (e.g., UKU, Barnes Akathisia Scale) scales, and relapse and remission rates. Taking advantage of the clinical trial implementation and the systematic measure of anthropometric and metabolic parameters carried out in the patients included in the PAFIP program, we were able to set the following outcomes for the present exploratory analyses associated with the clinical trial. The primary outcome measures for the current study were changes in weight and body mass index (BMI), and the secondary outcomes were changes in metabolic (lipid and glycemic) parameters from baseline to 1year after starting antipsychotic treatment. Laboratory Analysis All determinations were performed in our hospital, including both biochemical and endocrinology analysis. All measurements were obtained after an overnight fast. Patients and family members reported on their fasting state as well as treatment adherence. Glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using automated methods on a TechniconDax (Technicon Instruments Corp, Tarrytown, NY, USA), with reagents provided by Boehringer- Mannheim (Mannheim, Germany). Low-density lipoprotein cholesterol was determined by the Friedewald etal. calculation (Friedewald etal., 1972): Low-density lipoprotein = total cholesterol − (HDL + [triglycerides/5]) Insulin levels were determined using an immunoradiometric assay (Immunotech, Beckman Coulter Company, Prague, Czech Republic) with a 3.3% average interassay coefficient of variation and a 2.8% intraassay coefficient of variation. The sensitivity of the method was 0.5μU/mL. Values for normal-weight participants were 2–17μU/mL. This assay does not show any crossreactivity with human proinsulin and C-peptide. Homeostasis model assessment (HOMA) was used to assess insulin resistance (IR). The HOMA index was calculated using a previously described formula (Matthews etal., 1985): HOMA = [fasting insulin (μU/mL) × fasting glucose (mmol/L)]/22.5. Furthermore, as proposed by McLaughlin and colleagues (McLaughlin etal., 2005), we calculated the triglyceride to HDL cholesterol ratio as a predictor of IR using the optimal cutpoint of 3.5. Statistical Analysis We investigated the relationship between antipsychotic treatment and changes in metabolic parameters. For comparison between groups, an analysis of variance for continuous variables and a chi-square test for categorical variables were used first. Apaired t test was used to determine if there were any statistically significant changes in glycemic and lipid parameters after 1year of antipsychotic treatment. When exploring differences in longitudinal changes between antipsychotic groups, we compared mean differences resulting from 1-year data minus baselinedata. General linear model ANCOVA analyses were performed to explore longitudinal differences in weight and metabolic parameters between antipsychotic treatment groups. Measurements of each parameter at baseline, 3months, and 1year were entered as the dependent variable; the type of medication (treatment group) as the independent variable; and BMI at baseline, gender, and age as covariates. This analysis was carried out following an Intention-to-treat (ITT) approach (per protocol analysis was also performed). We additionally calculated the percentage of participants with pathologic values in weight and glucose and lipid Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 798 | International Journal of Neuropsychopharmacology, 2022 parameters (according to the reference values of our laboratory) at baseline and 1year. To evaluate significant changes in these percentages, we used the McNemar test for repeated measures. Finally, we conducted post-hoc analysis to explore a possible differentiated effect of antipsychotic treatment regarding gender. We used ANCOVA analyses to accomplishthis. For statistical analyses, the Statistical Package for Social Science version 23.0 (IBM Corp, Armonk, NY, USA) was used. All statistical tests were 2-tailed, and significance was set at .05. RESULTS Enrollment and Characteristics of Study Population A total of 299 patients were screened and offered to enter the clinical/research program between February 2011 and October 2018. Atotal of 28 of these individuals were excluded because they did not meet the inclusion criteria or refused to be treated in the program. Another 41 patients were excluded from the statistical analyses for the current study solely because they were not drug free (having been on antipsychotic treatment for >2 days before entering the program). A total of 230 patients were included in the study; they had been randomized to receive (Fig. 1) aripiprazole (n = 114; 49.6%) or risperidone (n = 116; 50.4%). We had a 17.9% dropout rate at 1year (41 patients were lost to follow-up or refused to be evaluated: 23 on the aripiprazole arm and 18 on the risperidone one). As a result, 189 patients entered the current study to assess the long-term changes in the main metabolic values. To avoid data distortion, 9 participants with outlier values for at least 1 of the glycemic/ lipid parameters at baseline (value >3 SDs) were excluded from the analysis (4 of these patients were on aripiprazole and 5 on 299 Screened and informed 230 RandomizedDrug-naïve Patients with First Episode Psychosis 28 Excluded from PAFIP program: -Not meeting inclusion criteria or refusing to be included in the program. 114 Aripiprazole 116Risperidone After 1 year Follow-Up 23 lost follow-up 18 lost follow-up Treatment Allocation 91 Aripiprazole 98 Risperidone 93 Risperidonearm: -31continued on Risperidone -62changed protocol 4excluded for baseline outlier values 5excluded for baseline outlier values Included in the analyses (exclusion of patients with outlier values) 87 Aripiprazole arm: -52continued on Aripiprazole -35changed protocol 41 Excluded from the present study: -For not being drug-naïve. Informed Consentsigned Figure 1. Participant flow in the randomized clinical trial. Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 Aripiprazole vs Risperidone Metabolic Profile | 799 risperidone). Post-hoc statistical analyses that included the outlier participants revealed that their exclusion did not affect the reported results. The clinical and socio-demographic characteristics of the sample are shown in Table 1. The 2 treatment groups were comparable on a wide range of baseline data, including age, ethnicity, substance use, and clinical severity. At the end of follow-up, 46.1% (n = 83) of the 180 patients evaluated continued with the same antipsychotic treatment assigned at baseline (59.8% of aripiprazole group vs 33.3% of risperidone group). After 1 year of treatment, 97 patients did not complete the treatment protocol (supplementary Material, Tables 1, 2, 3A, 3B). The reasons for the treatment switch included side effects (41.2%), inefficacy (38.1%), non-adherence (16.5%), and others (4.1%). Despite the high rate of treatment switches due to side effects, neither weight gain nor metabolic disorders were among the reasons for antipsychotic change. Detailed data on the reasons for the antipsychotic switch in both treatment groups, as well as data on which treatments were prescribed to those patients who discontinued the initial treatment protocol, are available (supplementary Table 1). Mean daily baseline doses (after initial titration) were 9.1mg (SD = 2.5) for aripiprazole and 2.0mg (SD = .4) for risperidone. At the 1-year follow-up (per protocol), mean daily doses were 8.3mg (SD = 3.9) for aripiprazole and 2.3mg (SD = 1.3) for risperidone. Mean antipsychotic doses using chlorpromazine equivalents (Gardner etal., 2010) (where 600mg chlorpromazine is equivalent to 30 mg aripiprazole or 6 mg risperidone) at baseline were 181.6mg (SD = 49.5) aripiprazole and 203.2mg (SD = 40.2) risperidone (P < .001); at 1-year follow-up (intention-to-treat [ITT]), doses were 243.4mg (SD=133.0) in the aripiprazole group and 287.3mg (SD = 200.9) in the risperidone group (P > .05). Table 1. Socio-Demographic and Clinical Characteristics of Study Population Patients’ characteristics Aripiprazole (n = 87) Risperidone (n = 93) Total (n = 180) Mean SD Mean SD Mean SD Age at inclusion, y 32.01 10.69 32.50 10.21 32.26 10.42 DUP, mo 10.60 25.70 15.01 42.93 12.91 35.74 Weight at inclusion, kg 65.24 14.13 63.72 15.66 64.46 14.91 BMI at inclusion, kg/m222.43 3.76 22.47 4.44 22.45 4.12 SAPS at inclusion 15.03 5.00 15.85 5.23 15.46 5.12 SANS at inclusion 5.81 6.23 4.78 5.46 5.28 5.85 n % n % n % Sex, male 49 56.32 49 52.69 98 54.44 Student 23 27.06 19 20.65 42 23.73 Education level, secondary or lower 43 51.19 39 42.39 82 46.59 Family socioeconomic status, low 42 50.60 55 61.11 97 56.07 Living with family 67 79.76 66 71.74 133 75.57 Single 63 74.12 59 64.13 122 68.93 Unemployed 33 39.29 35 38.46 68 38.86 Obesity at inclusion 3 3.45 7 7.61 10 5.59 Diagnosis, schizophrenia 41 47.13 36 38.71 77 42.78 Hospitalization at inclusion 68 78.16 74 79.57 142 78.89 Drug consumption Tobacco 38 45.78 46 51.69 84 48.84 Cannabis 34 39.08 36 38.71 70 38.89 Alcohol 27 31.76 32 35.96 59 33.91 Concomitant treatments Anticholinergics 3 mo 26 32.10 26 28.57 52 30.23 Anticholinergics 6 mo 13 16.46 14 16.09 27 16.27 Anticholinergics 1 y 9 11.11 12 13.48 21 12.35 Antidepressants 3 mo 10 12.35 19 20.88 29 16.86 Antidepressants 6 mo 19 24.05 28 31.82 47 28.14 Antidepressants 1 y 21 25.30 26 29.21 47 27.33 Benzodiazepines 3 mo 19 23.46 29 31.87 48 27.91 Benzodiazepines 6 mo 14 17.72 23 26.14 37 22.16 Benzodiazepines 1 y 15 18.07 19 21.35 34 19.77 Mood stabilizers 3 mo 3 3.70 4 4.40 7 4.07 Mood stabilizers 6 mo 2 2.53 5 5.68 7 4.19 Mood stabilizers 1 y 2 2.41 4 4.49 6 3.49 Hypnotics 3 mo 20 24.69 20 21.98 40 23.26 Hypnotics 6 mo 14 17.72 8 9.09 22 13.17 Hypnotics 1 y 12 14.46 14 15.73 26 15.12 Abbreviations: BMI, body mass index (obesity defined as BMI ≥ 30kg/m2); DUP, duration of untreated psychosis; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms. Statistical analyses: Un-adjusted ANOVA for continuous variables and chi-square test for categorical variables. Non-significant group differences, all P > .05. Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 800 | International Journal of Neuropsychopharmacology, 2022 Weight and Metabolic Changes After the First Year of AntipsychoticTherapy Results from paired t tests in the whole FEP sample showed significant changes in weight as well as glycemic and lipid parameters after 1year of antipsychotic treatment (Table 2). Thus, FEP patients had a significant increase in weight and BMI (t = 16.49, P < .001 and t = 16.62, P < .001, respectively), with a mean increase of 9.9kg in the first year after starting antipsychotic treatment, reflected in a 3.5-point increase inBMI. These changes were also observed when we separately examined both treatment groups and also maintained statistical significance in most of the parameters (Table 2). For example, in the first year of treatment, patients in the aripiprazole and risperidone groups gained 9.2kg and 10.5kg, respectively (t = 11.19, P < .001 and t = 12.12, P < .001, respectively), increasing their mean BMI by 3.2 and 3.7 points. Comparison Between Treatment Groups on Weight and Metabolic Longitudinal Changes During the First Year of AntipsychoticTherapy Through general linear model ANCOVA tests, we explored whether there were significant differences between treatment groups in longitudinal changes in weight and metabolic parameters. These tests revealed no significant differences (all P > .05) in any of the weight and metabolic measures compared between treatment groups (aripiprazole vs risperidone) (Table 3). Following per protocol analysis approach, no significant differences were observed between treatment groups (supplementary Material 2; supplementary Table 2). Both treatment groups followed comparable trajectories of weight and BMI gain throughout the first year of antipsychotic treatment (Fig. 2). Clinical Impact of Weight and MetabolicChanges Similarly, after the first year of antipsychotic treatment, McNemar tests revealed a significant increase in the percentage of FEP patients meeting clinical criteria for obesity and metabolic disorders (Table 4). For example, after comparing the rate of patients with pathological levels before and 1year after initiating antipsychotic treatment, we found a significant increase in the percentage of patients with MetS (2.8% vs 9.4%, P = .010), obesity (BMI ≥ 30kg/m2) (5.6% vs 15.3%; P < .001), hypercholesterolemia (cholesterol > 200mg/dL) (14.5% vs 35.3%; P < .001), and hypertriglyceridemia (triglycerides > 150mg/dL) (3.4% vs 18.2%; Table 2. Changes in Weight and in Glycemic and Lipid Parameters After 1 Year of Antipsychotic Treatment in a Population of Drug-Naïve Patients Weight and metabolic parameters 1-Year follow-up Baseline Mean SD Mean SD Change n t P Anthropometric parameters Weight, kg 74.22 16.49 64.35 14.95 9.873 177 16.487 <.001 Aripiprazole 74.38 14.83 65.17 14.20 9.208 86 11.193 <.001 Risperidone 74.07 18.00 63.57 15.68 10.502 91 12.118 <.001 BMI, kg/m225.90 4.67 22.44 4.14 3.463 177 16.618 <.001 Aripiprazole 25.60 4.02 22.42 3.78 3.189 86 11.378 <.001 Risperidone 26.18 5.22 22.46 4.47 3.721 91 12.170 <.001 Glycemic parameters (fasting) Glucose, mg/dL 89.17 11.66 84.11 9.27 5.057 175 5.347 <.001 Aripiprazole 88.21 11.97 85.27 8.84 2.941 85 2.182 .032 Risperidone 90.08 11.36 83.02 9.59 7.056 90 5.430 <.001 Insulin, µU/mL 11.40 9.15 9.35 9.28 2.049 174 2.362 .019 Aripiprazole 10.30 4.94 9.06 7.06 1.236 85 1.551 .125 Risperidone 12.45 11.80 9.63 11.02 2.825 89 1.863 .066 HOMA index 2.61 2.71 2.02 2.16 0.590 173 2.509 .013 Aripiprazole 2.24 1.13 1.96 1.62 0.277 85 1.480 .143 Risperidone 2.96 3.61 2.06 2.58 0.892 88 2.102 .038 Triglyceride/HDL index 2.46 1.98 1.68 0.94 0.780 143 5.269 <.001 Aripiprazole 2.53 1.84 1.79 0.99 0.740 71 4.067 <.001 Risperidone 2.39 2.11 1.57 0.88 0.821 72 3.501 .001 Lipid parameters (fasting) Cholesterol, mg/dL 190.51 41.57 170.10 33.53 20.410 173 7.341 <.001 Aripiprazole 190.81 46.16 167.44 30.86 23.376 85 5.253 <.001 Risperidone 190.23 36.86 172.68 35.92 17.545 88 5.200 <.001 LDL-cholesterol, mg/dL 116.51 35.78 101.06 28.70 15.443 140 6.254 <.001 Aripiprazole 117.71 40.26 100.41 28.80 17.300 70 4.409 <.001 Risperidone 115.30 30.89 101.71 28.79 13.586 70 4.512 <.001 HDL-cholesterol, mg/dL 51.89 13.32 52.33 13.27 −0.441 143 -0.394 .694 Aripiprazole 51.38 13.86 50.92 12.83 0.465 71 0.338 .736 Risperidone 52.39 12.85 53.72 13.64 −1.333 72 -0.758 .451 Triglycerides, mg/dL 111.91 72.20 79.51 32.03 32.399 148 5.976 <.001 Aripiprazole 114.34 66.74 82.34 31.35 32.000 73 4.456 <.001 Risperidone 109.53 77.51 76.75 32.64 32.787 75 4.024 <.001 Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein. Statistical analyses: paired t test comparison. Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 Aripiprazole vs Risperidone Metabolic Profile | 801 Table 3. Comparison of Longitudinal Changes in Weight and Metabolic Parameters Between Treatment Groups Weight and metabolic parameters Aripiprazole Risperidone Total Baseline 3M 1Y Baseline 3M 1Y Baseline 3M 1Y n Mean SD Mean SD Mean SD n Mean SD Mean SD Mean SD n Mean SD Mean SD Mean SD F P Anthropometric changes Weight, kg 81 64.9 14.1 69.6 14.9 74.2 15.1 87 63.5 15.9 69.1 15.4 74.1 17.9 168 64.2 15.0 69.3 15.1 74.2 16.5 0.050 .824 BMI, kg/m281 22.5 3.8 24.0 4.0 25.7 4.1 87 22.4 4.5 24.4 4.3 26.2 5.2 168 22.4 4.2 24.2 4.1 25.9 4.7 0.315 .576 Lipid parameters Cholesterol, mg/dL 80 168.5 30.7 187.3 35.0 191.6 47.1 81 171.7 34.4 191.0 35.5 191.7 37.5 161 170.1 32.5 189.2 35.2 191.6 42.4 0.196 .658 Triglycerides, mg/dL 69 83.4 31.8 99.4 41.6 116.3 67.7 70 77.2 33.0 94.5 43.3 111.7 79.7 139 80.3 32.4 97.0 42.4 114.0 73.7 0.294 .588 HDL cholesterol, mg/dL 67 51.0 13.1 52.4 13.1 51.7 14.1 67 53.1 13.1 56.1 15.4 52.6 13.2 134 52.0 13.1 54.3 14.4 52.1 13.6 0.406 .525 LDL cholesterol, mg/dL 66 100.9 29.0 114.3 31.8 118.4 41.3 65 102.1 28.9 114.6 32.5 116.5 31.3 131 101.5 28.8 114.5 32.0 117.5 36.6 0.014 .905 Glycemic parameters Glucose, mg/dL 80 85.3 8.9 86.0 8.7 88.4 12.3 83 82.9 9.9 85.3 8.2 89.8 11.5 163 84.1 9.4 85.6 8.4 89.1 11.8 0.326 .569 HOMA index 79 2.0 1.7 2.2 1.2 2.3 1.2 79 2.1 2.7 2.1 1.3 2.9 3.8 158 2.0 2.2 2.1 1.2 2.6 2.8 1.142 .287 HOMA index men 42 1.9 1.7 2.4 1.4 2.5 1.4 40 2.4 3.4 2.3 1.3 3.1 3.7 82 2.2 2.7 2.4 1.4 2.7 2.8 1.121 .293 HOMA index women 37 2.0 1.7 2.0 0.9 2.0 0.9 39 1.8 1.6 1.8 1.2 2.8 3.9 76 1.9 1.6 1.9 1.1 2.4 2.8 0.170 .681 Triglyceride/HDL index 67 1.8 1.0 2.1 1.2 2.6 1.9 67 1.6 0.9 1.9 1.2 2.4 2.2 134 1.7 1.0 2.0 1.2 2.5 2.0 0.192 .662 Insulin total,μU/mL 79 9.0 7.3 10.4 5.1 10.3 5.1 80 9.9 11.6 9.8 5.9 12.4 12.2 159 9.4 9.6 10.1 5.5 11.4 9.4 0.967 .327 Insulin men 42 9.0 8.1 11.1 6.0 11.0 5.9 41 11.4 14.8 10.9 6.4 12.9 11.0 83 10.2 11.9 11.0 6.2 12.0 8.8 1.247 .268 Insulin women 37 9.1 6.3 9.7 3.9 9.5 3.8 39 8.3 6.6 8.7 5.1 11.9 13.5 76 8.7 6.4 9.1 4.5 10.7 10.0 0.029 .865 Hormonal levels Leptin total, ng/mL 77 10.4 12.5 12.8 14.4 14.5 11.6 80 8.9 11.6 13.7 13.6 16.3 14.3 157 9.6 12.0 13.3 14.0 15.4 13.0 0.023 .880 Leptin men 41 7.6 10.3 8.0 8.8 9.5 8.2 41 5.7 6.2 9.1 7.9 12.8 11.4 82 6.6 8.5 8.5 8.3 11.1 10.0 0.447 .506 Leptin women 36 13.6 14.1 18.3 17.5 20.3 12.3 39 12.3 14.7 18.6 16.5 20.0 16.1 75 12.9 14.3 18.5 16.9 20.1 14.3 0.073 .787 Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein. Statistical analyses: GLM ANCOVA model, where measures of each parameters at baseline, 3months, and 1year were the dependent variable; treatment group the independent variable; and baseline BMI, sex, and age were the covariates. Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 802 | International Journal of Neuropsychopharmacology, 2022 P < .001). Except the triglyceride to HDL IR index (6.3% vs 21%, P < .001), we did not find a significant increase in the percentage of patients with pathological criteria for glycemic metabolism measures. When looking at each treatment group separately, we observed similar results in both groups, with increments after 1year in the proportion of the participant reaching the criteria for obesity and other metabolic disorders. However, although the increase in the percentage of patients meeting MetS criteria (from 1.1% to 10.3%, P = .027) and hypertriglyceridemia (from 1.4% to 23.3%, P < .001) was statistically significant in the aripiprazole group, it was not statistically significant in the risperidone group (MetS: from 4.3% to 8.6%, P = .289; hypertriglyceridemia: from 5.3% to 13.3%, P = .149). Post-Hoc Analyses Exploring Sex–Treatment Interaction on Metabolic and WeightChanges Secondary analysis carried out dividing the sample according to sex did not find sex–treatment interaction in weight/BMI or metabolic changes after 1year of treatment. Complete data are available as supplementary material (supplementary material 3; supplementary Tables 3A and 3B). Discussion We discovered that aripiprazole and risperidone have a similar long-term metabolic profile in FEP patients, resulting in a comparable increase in weight gain and an analogous incidence of metabolic alterations after a long-term follow-up. Figure 2. Differences in weight and body mass index (BMI) changes between treatment groups. Downloaded from https://academic.oup.com/ijnp/article/25/10/795/6596170 by Universidad de Sevilla user on 12 June 2023 Aripiprazole vs Risperidone Metabolic Profile | 803 Head-to-Head Comparison Regarding Weight and MetabolicChanges When we explored the possible differential effect of treatments on weight gain and related metabolic side effects, both through intention-to-treat and per-protocol analysis, we observed no significant differences between aripiprazole and risperidone treatment groups (Tables 2 and 3; supplementary Material 2). The analogous trajectories of weight and BMI gain throughout the first year of treatment demonstrate this similarity in the metabolic impact of both antipsychotic treatments (Fig. 2). The lack of significant differences between aripiprazole and risperidone metabolic profiles is contrary to previous evidence in multi-episode schizophrenia patients. Arecent meta-analysis found significant differences in weight gain between aripiprazole and risperidone, where the latter was associated with a greater weight gain (Huhn etal., 2019). In this regard, risperidone has been widely described as one of the antipsychotics linked to increased weight gain and metabolic changes, whereas aripiprazole has traditionally been associated with a lower weight gain. Actually, it was even proposed that aripiprazole may be a weight gain–neutral drug (Kane etal., 2002; McEvoy et al., 2007). Furthermore, several studies have shown that switching from certain antipsychotic treatments to aripiprazole improves weight and metabolic parameters (Siskind etal., 2021). In contrast, studies on FEP patients that excluded confounding factors such as chronicity and antipsychotic polypharmacy found similar results to those found in our study. The current study’s significant increase in weight and BMI matches previous long-term studies from other FEP samples (Perez-Iglesias etal., 2009; Vazquez-Bourgon etal., 2018). In those studies, FEP patients presented significant increments in body weight and Table 4. Comparison of Proportion of Participants With Pathologic Parameters in Weight, Fasting Glucose, and Lipid Levels at Baseline and at 1-Year Follow-up in Each Treatment Group Metabolic conditions 1-Year follow-up Baseline % (n) % (n) % Difference n Pa BMI ≥30kg/m2 Aripiprazole group 10.5 (9) 3.5 (3) 10.0 86 .041 Risperidone group 19.8 (18) 7.7 (7) 12.1 91 .003 Total 15.3 (27) 5.6 (10) 9.6 177 <.001 Metabolic syndrome Aripiprazole group 10.3(9) 1.1(1) 9.2 87 .027 Risperidone group 8.6(8) 4.3(4) 4.3 93 .289 Total 9.4(17) 2.8(5) 6.7 180 .010 Glucose>110 mg/dL Aripiprazole group 2.4 (2) 0 2.3 85 .480 Risperidone group 3.3 (3) 0 3.3 90 .248 Total 2.9 (5) 0 2.9 175 .074 Insulin, µU/mL; men>15.7, women>17.3 Aripiprazole group 9.4(8) 7.1(6) 2.4 85 .773 Risperidone group 14.6(13) 7.9(7) 6.7 89 .211 Total 12.1(21) 7.5(13) 4.6 174 .186 HOMA; men>3.5, women>3.9 Aripiprazole group 7.1(6) 5.9(5) 1.2 85 1.000 Risperidone group 12.5(11) 8.0(7) 4.5 88 .423 Total 9.8(17) 6.9(12) 2.9 173 .424 Triglyceride/HDL index>3.5 Aripiprazole group 22.5 (16) 7.0 (5) 15.5 7 .010 Risperidone group 19.4 (14) 5.6 (4) 13.9 72 .009 Total 21.0 (30) 6.3 (9) 14.7 143 <.001 Cholesterol >200mg/dL Aripiprazole group 36.5 (31) 11.8 (10) 24.7 85 <.001 Risperidone group 34.1 (30) 17.0 (15) 17.1 88 .002 Total 35.3 (61) 14.5 (25) 20.8 173 <.001 LDL cholesterol >130mg/dL Aripiprazole group 34.3 (24) 14.3 (10) 20.0 70 .002 Risperidone group 28.6 (20) 12.9 (9) 15.7 70 .010 Total 31.4 (44) 13.6 (19) 17.9 140 <.001 HDL cholesterol <40mg/dL Aripiprazole group 19.7 (14) 18.3 (13) 1.4 71 1.000 Risperidone group 12.5 (9) 12.5 (9) 0 72 1.000 Total 16.1 (23) 15.4 (22) 0.7 143 1.000 Triglycerides >150mg/dL Aripiprazole group 23.3 (17) 1.4 (1) 21.9 73 <.001 Risperidone group 13.3 (10) 5.3 (4) 8.0 75 .149 Total 18.2 (27) 3.4 (5) 14.9 148 <.001 Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein. aMcNemar test for repeated measures. 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