European Psychiatry Pattern of long-term weight and metabolic www.cambridge.org/epa changes after a first episode of psychosis: Results from a 10-year prospective follow-up of the PAFIP program for early intervention in Research Article psychosis cohort Cite this article: Vázquez-Bourgon J, Gómez- Revuelta M, Mayoral-van Son J, Labad J, Ortiz- García de la Foz V, Setién-Suero E, Ayesa- J. Vázquez-Bourgon1,2,3* , M. Gómez-Revuelta1,3 , J. Mayoral-van Son2,4 , Arriola R, Tordesillas-Gutiérrez D, Juncal- Ruiz M, Crespo-Facorro B (2022). Pattern of J. Labad2,5,6 , V. Ortiz-García de la Foz1 , E. Setién-Suero1 , R. Ayesa-Arriola1,2 , long-term weight and metabolic changes after a first episode of psychosis: Results from a D. Tordesillas-Gutiérrez1,2 , M. Juncal-Ruiz7 and B. Crespo-Facorro2,4 10-year prospective follow-up of the PAFIP 1 Department of Psychiatry, University Hospital Marqués de Valdecilla—Instituto de Investigación Marqués de Valdecilla program for early intervention in psychosis (IDIVAL), Santander, Spain; 2Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Seville, Spain; cohort. European Psychiatry, 65(1), e48, 1–10 3 https://doi.org/10.1192/j.eurpsy.2022.2308 Departamento de Medicina y Psiquiatría, Universidad de Cantabria, Santander, Spain; 4Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocio-IBiS, Seville, Spain; 5Department of Psychiatry, Hospital de Mataró, Received: 23 March 2022 Consorci Sanitari del Maresme, Mataró, Spain; 6Translational Neuroscience Research Unit I3PT-INc-UAB, Institut de Revised: 18 July 2022 Innovació i Investigació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Accepted: 23 July 2022 Spain and 7Department of Psychiatry, Sierrallana Hospital—Instituto de Investigación Marqués de Valdecilla (IDIVAL), Torrelavega, Spain Keywords: Cholesterol; glucose; medication-naïve; second-generation antipsychotic; triglycerides; Abstract weight gain Background. People with psychosis are at higher risk of cardiovascular events, partly explained Author for correspondence: by a higher predisposition to gain weight. This has been observed in studies on individuals with a *Javier Vázquez-Bourgon, first-episode psychosis (FEP) at short and long term (mainly up to 1 year) and transversally at E-mail: javier.vazquez@scsalud.es longer term in people with chronic schizophrenia. However, there is scarcity of data regarding longer-term (above 3-year follow-up) weight progression in FEP from longitudinal studies. The aim of this study is to evaluate the longer-term (10 years) progression of weight changes and related metabolic disturbances in people with FEP. Methods. Two hundred and nine people with FEP and 57 healthy participants (controls) were evaluated at study entry and prospectively at 10-year follow-up. Anthropometric, clinical, and sociodemographic data were collected. Results. People with FEP presented a significant and rapid increase in mean body weight during the first year of treatment, followed by less pronounced but sustained weight gain over the study period (Δ15.2 kg; SD 12.3 kg). This early increment in weight predicted longer-term changes, which were significantly greater than in healthy controls (Δ2.9 kg; SD 7.3 kg). Weight gain correlated with alterations in lipid and glycemic variables, leading to clinical repercussion such as increments in the rates of obesity and metabolic disturbances. Sex differences were observed, with women presenting higher increments in body mass index than men. Conclusions. This study confirms that the first year after initiating antipsychotic treatment is the critical one for weight gain in psychosis. Besides, it provides evidence that weight gain keep progressing even in the longer term (10 years), causing relevant metabolic disturbances. Introduction People with a schizophrenia spectrum disorder present an excess morbidity and mortality when compared with the general population, leading to a reduced life expectancy [1–3]. It has been described that cardiometabolic disorders are among the main natural causes of this excess © The Author(s), 2022. Published by Cambridge mortality [4, 5]. Weight increments and related metabolic changes explaining the latter University Press on behalf of the European cardiometabolic events appear early in the course of the psychotic disorder [6]. In this sense, Psychiatric Association. This is an Open Access article, distributed under the terms of the the first year of the first-episode psychosis (FEP) appears as the critical period for the Creative Commons Attribution licence (http:// development of the metabolic disturbances. For instance, up to 80% of the weight increase creativecommons.org/licenses/by/4.0), which observed at long term (3 years) occurred in this critical period; despite of this, FEP participants permits unrestricted re-use, distribution and continued gaining weight even after this critical period, although at a slower pace [7]. This reproduction, provided the original article is properly cited. observation is also supported by other studies showing that people with psychosis present weight gain and metabolic disturbances during the first 3–4 years of initiating the antipsychotic treatment [8, 9]. Studies, based on individuals with stablished schizophrenia, following cross- sectional and retrospective methodologies, also showed the presence of weight increments even at longer periods [10–13]. Together with this increase in body weight, and mainly as a consequence of it [7, 14], a wide range of lipid and glycemic metabolism alterations appear 2 J. Vázquez-Bourgon et al. progressively in people with psychosis in parallel with the pro- records on each time point. Clinical data were collected at four gression of the mental disorder. For instance, Gardner-Sood et al. different points throughout the 10-year period; baseline, 1-, 3- and [11] reported in a group of 450 participants with chronic psych- 10-year follow-up. Clinical symptoms of psychosis were assessed by osis that half of them were obese, and 57% met criteria for the Scale for the Assessment of Negative Symptoms (SANS) [19] metabolic syndrome, while a fifth met the criteria for type 2 dia- and the Scale for the Assessment of Positive Symptoms (SAPS) [20], betes mellitus. Similarly, Henderson et al. [13] reported an and general psychopathology with the Brief Psychiatric Rating increase in body mass index (BMI), cholesterol, triglycerides, Scale (BPRS) [21]. Participants’ weight and waist circumference and the risk for diabetes, in people with schizophrenia, after were obtained at all time points, while height was measured at the 10 years of having initiated treatment with clozapine. Although time of enrollment. there is mounting evidence regarding a differential effect of anti- Participants from the healthy control group were evaluated at psychotic treatments on weight gain [15], there is scarcity of baseline and 10 years after, where sociodemographic and biometric evidence from prospective longitudinal studies analyzing the pro- data were collected. gression of weight and metabolic changes at long term (10 years) in people with FEP; most of the scientific evidence comes from Laboratory analyses short-term and cross-sectional studies or from retrospective reviews of medical records. All laboratory determinations were performed at the same site, in Taking into account the above evidences, we hypothesize that our hospital, after an overnight fast, at baseline, 1-, 3-, and 10-year people with FEP will present, at 10-year follow-up, a significant follow-ups. Fasting state, as well as treatment compliance (good increase in weight and metabolic disturbances that will be signifi- compliance: taking ≥ 90% of the prescribed treatment), was cantly greater than that observed in healthy participants. This study reported by patients and their family members. Glucose, total aims to explore prospectively the pattern of weight changes and the cholesterol, high density lipoprotein (HDL) cholesterol, and occurrence of metabolic disturbances in a cohort of individuals triglycerides were measured by automated methods on a Techni- with a FEP followed during the first 10 years after the breakout of conDax (Technicon Instruments Corp, Tarrytown, NY), using the their FEP. And secondly, to compare them with a group of healthy reagents supplied by Boehringer-Mannheim (Mannheim, (without psychiatric disorders) participants. Germany). Low density lipoprotein (LDL) cholesterol was deter- mined by the Friedewald et al. [23] calculation. Insulin levels were measured by an immunoradiometric assay (Immunotech, Beck- Methods man Coulter Company, Prague, Czech Republic), where values for normal weight subjects are 2–17 μU/ml. Insulin resistance was Study setting calculated using the homeostasis model assessment (HOMA) The study was part of a prospective longitudinal project on FEP, the index, by means of a previously described formula [22], and “First Episode Psychosis Clinical Program 10” (PAFIP10) study through the triglyceride/HDL cholesterol (TG/HDL) ratio, as [16]. PAFIP-10 is a follow-up at approximately 10 years (range proposed by McLaughlin et al. [24], and with the cut-off point between 8 and 12) of a cohort of individuals with a first episode of of 3.5. nonaffective psychosis initially included in the Cantabria Program for Early Intervention in Psychosis (PAFIP) [17]. Statistical analyses The study was approved by the local ethics committee for clinical research (CEIm Cantabria) in accordance with international stand- To evaluate the changes over time of weight, BMI, lipid, and ards for research ethics (trial number NCT02200588). Participants glycemic measurements in FEP, we used repeated-measures ana- included in the study provided written informed consent for entry lyses of variance (ANOVA) followed by post-hoc Bonferroni tests. initially into PAFIP and for PAFIP-10 reassessment. For these analyses, we included baseline, 1-, 3-, and 10-year measurements. Next, we explored if there were significant differences in the Baseline inclusion criteria longitudinal changes between people with FEP and controls. For All referrals to PAFIP between February 2001 and July 2008 were this, we carried out ANCOVA models where mean variable screened against the following inclusion criteria: age 15–60 years; change (10-year minus baseline measures) was used as the living in the catchment area; experiencing a FEP; no prior treatment dependent variable, subject group (FEP vs. control) as the fixed with antipsychotic medication or, if previously treated, a total factor, and baseline BMI, baseline measurement data, age, and sex lifetime of adequate antipsychotic treatment of less than 6 weeks. as covariates. DSM-IV criteria for drug or alcohol dependence, intellectual dis- To evaluate the clinical impact of the metabolic changes ability, and having a history of neurological disease or head injury observed in the FEP group, we additionally calculated the percent- were exclusion criteria. The diagnoses were confirmed through the age of participants with pathologic values in BMI and glucose and Structured Clinical Interview for DSM-IV (SCID–I) [18]. A group lipid variables (according to the reference values of our laboratory) of subjects without psychiatric illness was recruited as control at baseline and at 10-year follow-up. To evaluate significant changes group through public advertisements, from the same catchment in these percentages, we used the McNemar test for repeated area. Individuals in the control group were matched to FEP cases for measures. age, sex, and ethnicity. Finally, we studied the association between weight gain and metabolic changes. For this, we performed a partial correlation analysis controlling by sex, age, and baseline BMI. And subse- Participants’ clinical assessment quently, we compared the changes in glycemic and lipid meas- Sociodemographic and clinical information was recorded from urements in three different FEP groups regarding the increase in interviews with participants, their relatives, and from medical BMI from baseline (7, 15 [25]): less than 7% increase, between European Psychiatry 3 7 and 20%, and greater than 20%. The three groups were com- Weight and metabolic differences after 10 years of psychosis pared using covariance analysis. breakout Secondary analyses were carried out to explore sex effect on the Individuals with FEP presented a significant increase in their mean long-term weight and metabolic changes in the FEP cohort through weight and BMI, 10 years after their psychosis diagnosis. The mean ANCOVA test. And finally, prediction factors of weight gain were weight gain in this period was 15.2 kg (SD = 12.6) (Table 2). The explored using a cumulative odds ordinal logistic regression with majority (80.8%) of patients experienced a clinically significant proportional odds to determine the effect of sex, age, duration of weight gain (>7% from baseline), with 32.5% of patients having untreated psychosis (DUP), treatment discontinuation, weight increased between 20 and 40% of their basal body weight, and gained at 1 year, HOMA index, leptin, triglycerides, LDL choles- 18.7% even above 40% of their basal weight. terol, and HDL cholesterol at baseline on critical weight gain (≥20% These increments in body weight had a relevant clinical effect; from baseline) at 10 years. the percentage of obese (BMI ≥ 30 kg/m2) among the individuals The Statistical Package for Social Science (SPSS) version 22.0 with psychosis rose from 7 to 36.8% at the end of the 10-year follow- (IBM, Armonk, NY) was used for the statistical analyses. All up. The percentage of those meeting criteria for overweight statistical tests were two-tailed, and the significance was determined (BMI ≥ 25, <30 kg/m2) also increased, from 23.9 to 36.3%, in the at the 0.05 level. same period, leaving just a mere 26.5% of individuals with normal weight at 10-year follow-up (from 69.9% at baseline). The maximum increase in weight occurred in the first year of Results treatment; 58.4% of the total increment in mean weight and 55.6% Characteristics of the cohort of the total increment in mean BMI (see Table 2) occurred in the first year. From year 1 to year 3, the weight gain decreased (trend A total of 209 patients and 57 healthy controls were evaluated toward statistical significance), reaching again statistical signifi- after 10 years of having initiated treatment (Figure 1). FEP cance in the last 7 years of study period. These data showed a patients and healthy controls had similar baseline sociodemo- sustained increase in mean weight and BMI following the first year graphic characteristics (Table 1). At program admission FEP of treatment, with an average increase of 0.7 kg each year (0.35 kg/ patients had a mean age of 29.3 years (SD = 8.8), most of them m2 per year). Leptin plasma levels, as an indicator of adipose mass, were men (54.5%), white (98.6%), from low-middle socioeco- followed a similar trajectory to weight change. nomic status (54.6%), and 71.8% lived with family. Mean DUP Similarly, all lipid and glucose parameters showed a significant was 13.6 months (SD = 29.7), and at presentation the mean SAPS, increase during the 10-year follow-up. Only HDL cholesterol levels SANS, and BPRS were 13.3 (SD = 4.6), 7.8 (SD = 6.4), and 62.0 showed a statistical tendency (p = 0.087) to decrease from baseline (SD = 13.2), respectively. At baseline, 56.5% reported consuming to the end of the study period (Table 2). tobacco, 51.7% alcohol, and 37.8% cannabis. At 6-month follow- up, 61.2% had a confirmed diagnosis of schizophrenia, 1.4% Longitudinal differences in weight and metabolism changes schizoaffective, 23.4% schizophreniform, 7.2% brief psychotic between people with psychosis and healthy controls episode, and 6.7% unspecified psychotic disorder. At the 10-year follow-up, we evaluated 57 individuals from the control Healthy control individuals also present significant increments in group. mean body weight at 10-year evaluation (Supplementary Table S2). Baseline evaluation (February 2001–July 2008) 307 FEP patients 93 healthy controls 98 Excluded: 36 Excluded: - Exitus during follow-up - Refused to participate (n=10) (n=16) - Refused to participate - Non-eligible (n=1) (n=34) - Unreachable (n=7) - Non-eligible (n=18) - Moved away (n=12) - Unreachable n=(22) - Moved away (n=14) 209 FEP patients evaluated at 57 healthy controls evaluated at 10-years follow-up 10-years follow-up 10 years follow-up evaluation Figure 1. Participants’ flow in the study. 4 J. Vázquez-Bourgon et al. Table 1. Sociodemographic and clinical characteristics of study population. FEP patients Healthy controls Total N = 209 N = 57 N = 266 Statistics Mean SD Mean SD Mean SD Stat. Value p Age at admission, years 29.3 8.8 28.6 8.3 29.2 8.7 t 0.563 0.574 Education, years 10.8 3.4 10.8 2.5 10.8 3.2 t 0.117 0.907 N % N % N % Sex, male 114 54.5 33 57.9 147 55.3 X2 0.203 0.652 Ethnicity, white 206 98.6 53 100.0 259 98.9 Fisher 0.770 1.000 Education level, secondary or lower 92 44.0 17 32.1 109 41.6 X2 2.482 0.115 2 Family socioeconomic status, not/low qualified 113 54.6 20 38.5 133 51.4 X 4.327 0.038 2 Single 158 75.6 13 50.0 171 72.8 X 7.646 0.006 Employed/Studying, yes 115 55.0 23 88.5 138 58.7 X2 10.666 0.001 2 Tobacco smoking, yes 118 56.5 31 55.4 149 56.2 X 0.022 0.883 2 Cannabis use, yes 79 37.8 16 28.6 95 35.8 X 1.635 0.201 Alcohol drinking, yes 108 51.7 33 62.3 141 53.8 X2 1.908 0.167 Abbreviation: FEP, first-episode psychosis. The majority of patients (95.2%, n = 199) in this sample were antipsychotic-naïve at study entry. The other 10 patients (4.8%) had been treated with antipsychotics prior to their inclusion in the study, although during a short period of time (median = 5 days). According to the patients and their families’ reports on treatment compliance, 76.9% of patients were good compliers at 1 year, 79.1% at 3 years, and 92.7% at 10 years. Some of the patients were on other concomitant psychopharmacological treatments that potentially contribute to weight gain. Thus, 38 patients (18.2%) were on antidepressant treatment at 1-year follow up, 30 (14.3%) at 3 years, and 36 (17.2%) at 10 years. Besides, six patients (2.9%) were on treatment with mood stabilizers at 1-year follow-up, 13 (6.2%) at 3 years, and 29 (13.9%) at 10 years. Patients presented a high rate of antipsychotic treatment switch during the study period (Supplementary Table S3). Table 2. Descriptive data and ANOVA repeated measures analyses of body weight and metabolic changes during the first 10 years of antipsychotic treatment in a population of individuals with a first-episode psychosis. Baseline mean 1 year mean 3 years mean 10 years mean F repeated Partial eta (SD) n (SD) n (SD) n (SD) n measuresa df p squared Anthropometric changes Weight (kg) 67.0 (13.4) 206 76.0 (15.5) 197 77.4 (16.3) 187 82.4 (18.3) 206 103.9 3; 176 <0.001 0.643 2 BMI (kg/m ) 23.6 (3.7) 204 26.6 (4.3) 195 27.3 (4.7) 186 29.0 (5.8) 204 105.4 3; 176 <0.001 0.646 Lipid parameters Cholesterol (mg/dl) 174.6 (36.9) 207 193.9 (38.6) 199 195.7 (40.1) 193 197.3 (38.6) 199 26.2 3; 178 <0.001 0.310 LDL cholesterol (mg/dl) 108.5 (32.7) 183 123.5 (33.1) 196 120.7 (33.1) 188 122.5 (32.2) 191 17.3 3; 148 <0.001 0.263 HDL cholesterol (mg/dl) 50.4 (13.9) 182 49.8 (12.4) 196 51.0 (14.7) 191 28.9 (13.1) 194 2.2 3; 151 0.087 0.043 Triglycerides (mg/dl) 84.4 (39.9) 181 114.6 (87.2) 195 120.6 (115.8) 192 129.7 (80.4) 195 20.7 3; 151 <0.001 0.295 Glycemic parameters Glucose (mg/dl) 88.0 (21.0) 205 88.7 (13.7) 199 89.9 (13.7) 193 92.3 (14.1) 200 2.9 3; 177 0.037 0.048 HOMA index 1.9 (2.2) 157 2.2 (2.2) 170 2.6 (2.2) 184 3.0 (2.3) 177 6.7 3; 97 <0.001 0.177 HOMA index, men 1.7 (1.5) 85 2.3 (2.6) 94 2.8 (2.6) 99 3.3 (2.7) 97 5.1 3; 51 0.004 0.237 HOMA index, women 2.2 (2.7) 72 2.1 (1.7) 76 2.3 (1.7) 85 2.8 (1.7) 80 3.5 3; 45 0.023 0.201 Triglyceride/HDLc index 1.8 (1.1) 177 2.6 (2.6) 195 2.7 (2.7) 191 3.0 (2.3) 194 17.6 3; 146 <0.001 0.269 Insulin total (μU/ml) 9.1 (9.3) 159 9.9 (8.6) 170 11.2 (7.7) 185 12.8 (8.2) 177 5.2 3; 100 0.002 0.139 Insulin men 8.2 (7.0) 85 9.9 (9.6) 94 11.8 (8.7) 100 13.4 (9.5) 97 4.5 3; 53 0.007 0.213 Insulin women 10.1 (11.4) 74 9.9 (7.2) 76 10.5 (6.4) 85 12.1 (6.2) 80 3.3 3; 47 0.030 0.183 Hormonal levels Leptin total (ng/ml) 8.4 (8.3) 153 13.2 (10.5) 184 13.3 (11.8) 184 21.5 (18.5) 174 35.5 3; 106 <0.001 0.508 Leptin men 4.8 (5.0) 84 8.2 (6.6) 104 8.6 (8.4) 98 13.2 (11.4) 94 17.8 3; 58 <0.001 0.492 Leptin women 12.7 (9.3) 69 19.8 (11.1) 80 18.6 (12.9) 86 31.3 (20.5) 80 21.9 3; 48 <0.001 0.595 Abbreviations: BMI, body mass index; HDL, high density lipoprotein; HOMA, homeostasis model assessment; LDL, low density lipoprotein. a Pillai’s trace statistic F value. European Psychiatry 5 Table 3. Differences in longitudinal changes in anthropometric and metabolic measurements between individuals with psychosis and healthy controls after 10 years of follow-up. People with FEP Healthy controls Statsa Mean diff. (SD) Mean diff. (SD) df F p Anthropometric measures Weight (kg) 15.21 (12.63) 2.89 (7.35) 1; 254 45.61 <0.001 2 BMI (kg/m ) 5.41 (4.55) 1.03 (2.74) 1; 254 43.40 <0.001 Waist circumference (cm) 13.63 (11.74) 4.68 (7.14) 1; 86 16.51 <0.001 Lipid parameters Cholesterol (mg/dl) 21.64 (33.95) 8.79 (36.52) 1; 217 1.42 0.235 HDL (mg/dl) 1.56 (12.49) 2.75 (6.86) 1; 189 6.51 0.012 LDL (mg/dl) 13.80 (28.16) 6.54 (31.45) 1; 186 0.54 0.464 Triglycerides (mg/dl) 44.45 (72.75) 2.75 (52.79) 1; 189 9.53 0.002 Glycemic parameters Glucose (mg/dl) 4.15 (21.68) 4.42 (16.85) 1; 216 4.48 0.036 HOMA index 1.07 (3.19) 0.16 (0.87) 1; 152 13.12 <0.001 HOMA index, men 1.54 (2.79) 0.19 (0.93) 1; 80 6.54 0.013 HOMA index, women 0.54 (3.53) 0.51 (0.67) 1; 72 7.907 0.006 Triglycerides-HDL index 1.13 (2.06) 0.07 (0.97) 1; 185 8.49 0.004 Insulin (μU/ml) 3.64 (12.29) 0.19 (3.59) 1; 155 15.609 <0.001 Insulin, men 5.15 (10.20) 0.78 (3.72) 1; 81 8.36 0.005 Insulin, women 1.99 (14.14) 1.25 (3.27) 1; 74 8.64 0.004 Hormonal levels Leptin (ng/ml) 12.42 (14.55) 4.66 (4.52) 1; 150 9.92 0.002 Leptin, men 7.78 (10.51) 3.85 (4.65) 1; 78 3.49 0.066 Leptin, women 17.45 (16.59) 5.54 (4.39) 1; 72 8.90 0.004 Abbreviations: BMI, body mass index; BP, blood pressure, HDL, high density lipoprotein; HOMA, homeostasis model assessment; LDL, low density lipoprotein. a Statistics: ANCOVA model: parameter change was used as the dependent variable, participants group (psychosis vs. controls) was the fixed factor and baseline BMI, baseline parameter data, age, and sex were used as covariates. However, when comparing people with psychosis and healthy and insulin, and both HOMA index and TG/HDL ratio, indicating controls, we observed that over the 10-year follow-up period, the a greater risk for the development of glucose metabolism alterations individuals with psychosis presented a significantly worse progres- such as glucose intolerance. sion in weight and metabolic measurements (Table 3). For instance, the psychosis group showed a greater increase in mean weight Correlation between long-term weight gain and metabolic (15.21 vs. 2.89 kg, F = 44.58, p < 0.001) and BMI (5.41 vs. 1.03, changes in FEP F = 42.89, p < 0.001) than the control one. Weight gain was positively correlated with insulin increase (r = 0.48, p < 0.001) and with the insulin resistance indexes, HOMA Incidence of clinically relevant abnormal metabolic (r = 0.48, p < 0.001) and triglycerides/HDL (r = 0.51, p < 0.001). A measurements after 10 years of psychosis breakout trend toward significance was observed between weight and glucose The percentage of individuals with psychosis meeting criteria for changes (r = 0.18, p = 0.055). There was also a positive correlation hypertriglyceridemia (>150 mg/dl) and hypercholesterolemia (total between weight gain and triglycerides increase (r = 0.46, p < 0.001), cholesterol > 200 mg/dl) increased significantly, from 7.1 to 24.4% and a negative correlation between weight gain and HDL changes (p < 0.001) and from 23.4 to 41.6% (p < 0.001), respectively, during (r = 0.32, p = 0.001). These associations were significant after the 10-year study period (Table 4). In the same line, the proportion controlling for sex, age, and baseline BMI. of FEP patients with clinically elevated LDL cholesterol (>130 mg/ A relationship between weight increase and changes in meta- dl) rose from 24.2 to 35.2% (p = 0.006). However, no significant bolic variables was detected when we compared three groups of changes were observed in the percentage of FEP patients with low individuals with psychosis according to the increase in their BMI HDL cholesterol (Table 4). (Table 5), where significant differences were observed for insulin, Significant increments were also observed in the percentage of HOMA index and TG/HDL ratio, and triglycerides increments, as people with psychosis meeting clinically elevated levels of glucose well as for HDL cholesterol reductions, between groups. 6 J. Vázquez-Bourgon et al. Table 4. Comparison of proportion of FEP participants with pathologic parameters in weight, glycemic, and lipid parameters at baseline and at 10-year follow-up. 10 years follow-up Baseline % (n) % (n) % difference N pa Anthropometric changes Obesity, BMI ≥ 30 kg/m2 36.8 (74) 7.0 (14) 29.8 201 <0.001 Overweight, BMI ≥ 25,<30 kg/m 2 36.3 (73) 23.9 (48) 12.4 201 0.011 Glycemic parameters Glucose > 110 mg/dl 7.1 (14) 1.5 (3) 5.6 196 0.007 Insulin total (μU/ml) 31.3 (41) 9.2 (12) 22.1 131 <0.001 Levels in men > 15.7 36.2 (25) 7.2 (5) 29.0 69 <0.001 Levels in women > 17.3 25.8 (16) 11.3 (7) 14.5 62 0.078 HOMA index 30.2 (39) 7.0 (9) 23.2 129 <0.001 Levels in men > 3.5 37.7 (26) 2.9 (2) 34.8 69 <0.001 Levels in women > 3.9 21.7 (13) 11.7 (7) 10.0 60 0.238 Triglyceride/HDL index > 3.5 23.8 (39) 11.0 (18) 12.8 164 <0.001 Lipid parameters Cholesterol > 200 mg/dl 41.6 (82) 23.4 (46) 18.2 197 <0.001 LDL cholesterol > 130 mg/dl 35.2 (58) 24.2 (40) 10.8 165 0.006 HDL cholesterol < 40 mg/dl 26.2 (44) 21.4 (36) 4.8 168 0.280 Triglycerides > 150 mg/dl 24.4 (41) 7.1 (12) 17.3 168 <0.001 Abbreviations: BMI, body mass index; HDL, high density lipoprotein; HOMA, homeostasis model assessment; LDL, low density lipoprotein. a McNemar test for repeated measures. Table 5. Changes in glycemic and lipid parameters after 10 years of antipsychotic treatment: comparison of groups with different percentage of weight gain. BMI changes (% from baseline) during the 10 year follow- up period <7% BMI 7–19.9% BMI ≥20% BMI increase from increase from increase from baseline baseline baseline Mean (IC95%) Mean (IC95%) Mean (IC95%) pb A: N = 39 B: N = 60 C: N = 104 df Fa p A versus B A versus C B versus C Change in glucose parameters Glucose (mg/dl) 1.2 ( 6.1, 8.5) 3.9 ( 1.8, 9.6) 5.3 (0.9, 9.8) 2; 190 0.46 0.633 1.000 1.000 1.000 Insulin total (μU/ml) 0.3 ( 4.2, 4.8) 1.6 ( 5.3, 2.1) 8.4 (1.5, 11.3) 2; 129 9.94 <0.001 1.000 0.012 <0.001 HOMA index 0.1 ( 1.2, 1.1) 0.2 ( 1.1, 0.7) 2.3 (1.6, 3.1) 2; 127 10.43 <0.001 1.000 0.003 <0.001 Triglyceride/HDL index 0.4 ( 0.3, 1.1) 0.2 ( 0.4, 0.7) 2.0 (1.6, 2.4) 2; 159 16.10 <0.001 1.000 <0.001 <0.001 Change in lipid parameters Cholesterol (mg/dl) 12.4 (1.1, 23.7) 23.3 (14.3, 32.3) 24.2 (17.3, 31.2) 2; 191 1.62 0.200 0.408 0.251 1.000 LDL cholesterol (mg/dl) 6.8 ( 3.7, 17.3) 14.0 (5.9, 22.2) 16.2 (9.9, 22.5) 2; 160 1.11 0.330 0.850 0.415 1.000 HDL cholesterol (mg/dl) 1.1 ( 3.3, 5.4) 3.6 (0.2, 7.0) 5.4 ( 8.0, 2.8) 2; 163 9.20 <0.001 1.000 0.040 <0.001 Triglycerides (mg/dl) 17.5 ( 6.7, 41.7) 14.7 ( 4.9, 34.3) 72.3 (57.3, 87.3) 2; 163 13.16 <0.001 1.000 0.001 <0.001 Abbreviations: BMI, body mass index; HDL, high density lipoprotein; HOMA, homeostasis model assessment; LDL, low density lipoprotein. a ANCOVA model: parameter change was used as the dependent variable, weight gain group was the fixed factor, and baseline BMI, age, and sex were used as covariates. b Pairwise comparisons based on estimated marginal means; Bonferroni adjustment for multiple comparisons. Secondary analyses: sex differences in weight and metabolic changes in individuals with FEP at longer term (10 years) vs. 7.78, F = 23.29, p < 0.001) than men (Supplementary Table S1). On the contrary, men presented a worse evolution in glucose (5.65 Women with psychosis presented a significantly greater increment vs. 2.32, F = 8.00, p = 0.005) and HDL measurements ( 1.77 in BMI (6 vs. 4.9, F = 4.18, p = 0.042) and leptin levels (17.45 vs. 1.32, F = 4.01, p = 0.045) than women. No other significant European Psychiatry 7 differences were observed in long-term metabolic variables changes 18.0%) [28]. In contrast, the rate of obesity among the FEP group regarding sex. at 10-year follow-up was 36.8%, clearly above that observed in the control group and in the Spanish general population. Secondary analyses: prediction factors of weight increase at 10-year follow-up Clinical impact of developing obesity A cumulative odds ordinal logistic regression with proportional Developing obesity is in itself of clinical relevance. Obese individ- odds was run to determine the effect of sex, age, DUP, treatment uals present a higher all-cause excess mortality, compared with discontinuation, weight gained at 1 year, HOMA index, leptin, people with normal weight [29]. Moreover, presenting obesity, even triglycerides, LDL cholesterol, and HDL cholesterol at baseline on without other metabolic disorders, increases the odds for a negative weight gain at 10 years. prognosis; metabolically healthy obese individuals are at higher risk According to the logistic regression results, the assumption of of developing metabolic risk factors and events than nonobese proportional odds was met, as assessed by a full likelihood ratio test persons [30]. In relation with these and previous studies [6, 7, comparing the fit of the proportional odds model to a model with 14], we observed that gaining weight correlated with undesirable varying location parameters, χ2(8) = 10.079, p = 0.344. The Pearson changes in lipid and glycemic measurements in FEP patients. At goodness-of-fit test indicated that the model was a good fit to the long term, the progressive worsening in the biochemical levels had a observed data (χ2(226) = 247,756, p = 1.096). clinical manifestation in the significant increase in the percentage of Among the variables within the model, DUP had a statistically participants meeting criteria for obesity and metabolic disorders. significant effect on the prediction of whether there is a weight Our results showed a significant increment, in the 10-year increase greater than 20% (Wald χ2(1) = 4.928, p = 0.026). In the follow-up, in the proportion of FEP patients presenting abnormal same direction, the first year weight increase percentage had glucose metabolism measurements, including insulin resistance a statistically significant effect on the prediction of whether indexes, glucose, and insulin levels. Moreover, the mean increments there is a weight increase greater than 20% at 10 years (Wald after 10 years in HOMA index, TG/HDL ratio, and insulin level χ2(1) = 16.189, p < 0.001). And the odds ratio of being in a higher were significantly greater among FEP patients than in healthy category of the dependent variable (weight increase ≥ 20%) for controls. This poorer outcome in glucose metabolism among men versus women was 3.178 (95% CI, 1.137–8.85), a statistically patients with psychosis could be in part explained by the anti- significant effect (χ2(1) =4.858, p = 0.028). On the contrary, the psychotic exposure and other risk factors usually present in this odds of people with psychosis, having discontinued antipsychotic vulnerable population. However, previous studies have suggested treatment, to have a weight increase greater than 20% at 10 years was that individuals with psychosis may be at greater risk of presenting 0.266 (95% CI, 0.096–0.737) times that those that continued taking abnormal glucose metabolism even before the onset of psychosis antipsychotics, a statistically significant effect (χ2(1) = 6.473, [31, 32]. This probable inherent risk could be due to genetic p = 0.011). differences; thus, it has been described an association between insulin resistance and polygenic risk score in antipsychotic naive patients [33] and other biomarkers [34], and insulin resistance in Discussion unaffected siblings of psychosis patients [35]. Despite of this and the results regarding abnormal glucose Long-term weight differences metabolism in our sample, only five individuals had a recorded This study provides evidence, through a prospective methodology, diagnosis of type II diabetes mellitus at the 10-year follow-up and of a significant increment in body weight and BMI at longer term were prescribed oral anti-diabetic drugs. Similarly, only six persons (10 years) in people with FEP. Thus, the participants with FEP in among the psychosis group had a diagnosis of dyslipidemia and this study presented, after their first 10 years of follow-up, an were on pharmacological treatment. average increment of 15 kg in body weight. These results are in line with previous prospective studies on FEPs patients [6, 7, 14, 26] Importance of rapid developing weight gain in psychosis reporting continuous increments in mean body weight and BMI at long term (1 and 3 years). Based mainly on indirect data from The study shows that, according to previous reports [7, 36], the first transversal and retrospective studies on patients with chronic year after initiating the antipsychotic treatment is the critical one, in psychosis [8, 10–13], we can determine that this weight increment which most of the weight gain occurs; up to 60% of the total weight is also present after longer periods of antipsychotic exposure gain observed at 10 years, occurred in the first year. People with (10 years). Besides, a unique prospective study on the weight psychosis in our study presented a rapid increase in body weight progression at longer periods [27], describing the 20-year BMI during the first year of treatment, which was followed by a slower progression of 146 patients after their first hospital admission but constant increase of body weight throughout the 10-year due to psychosis, reported a high prevalence of obesity among follow-up. This initial and rapid increase in body weight during patients with schizophrenia at longer term, reaching 50% at 10 years the first year predicted a critical weight gain (greater than 20% from and 62.1% at the 20-year follow-up. baseline) after 10 years of follow-up. This association is in line with Interestingly, we observed significant differences in the weight previous studies; Vandenberghe et al. [37, 38] reported that early change presented at 10-year follow-up between FEP patients and antipsychotic-induced weight changes predict long-term weight healthy controls; participants in the control group also presented gain, both in adults and adolescents with psychiatric conditions. significant increments in body weight (Δ3.4 kg) and BMI (Δ1 kg/ Besides, both rapid weight gain and steady increase trajectories, m2), but these were significantly smaller than that observed in the such as the pattern described in our study, have been associated psychosis group. Moreover, the rate of obesity among the control with higher risk of mortality. Thus, weight stability has been group at 10-year follow-up (15.8%) was comparable to the preva- associated with a lower mortality [39, 40], while steady weight lence in the Spanish general population (ranging from 14.5 to gainers presented a higher mortality [39, 40]. Besides, obese 8 J. Vázquez-Bourgon et al. patients with trajectories of weight increments were at higher risk of such as glucose intolerance, type 2 diabetes, or dyslipidemia, was excess mortality [42]. These evidences highlight the relevancy of not rigorously explored in our study since the diagnosis of these BMI trajectories versus status. conditions requires at least two separate abnormal measurements [57, 58]. Finally, instead of stratifying patients by weight gain over Sex differences in weight changes time, future works should use cardiometabolic risk calculations, as the proposed by Perry et al. [59] for FEP. We identified sex differences, where women presented a signifi- The main strength of this study is its design; a prospective cantly greater increase in BMI and leptin levels than men, after longitudinal study with an uncommon long-term follow-up 10-year follow-up. Sex differences in the metabolic effect of anti- (10 years), on a cohort of well-characterized individuals with psychotics have been previously described [43, 44], usually indi- FEP, and its comparison with a prospective group of healthy cating a greater risk of weight gain for women. Several studies subjects. Besides, studying a cohort of drug-naïve (at baseline) carried out transversally in patients with chronic schizophrenia patients with a FEP facilitates avoiding the confounding effect of and long-term exposure to antipsychotic medication showed that chronicity and previous exposure to medications with a probable women presented greater weight and BMI and higher rates of effect on metabolism. obesity [43, 45–46], as well as worse measures of abdominal obesity In summary, people with a FEP experienced, at long term (i.e., waist circumference and waist-hip ratio) [46], than men. (10 years), a significantly greater increase in BMI than healthy However, these sex differences in antipsychotic-induced weight controls. Significant differences were also observed in mean gain have not been consistently reported in people with FEP, with changes in metabolic measurements, leading to significant incre- contrary results at long term [14, 27, 36]. It has been suggested that ments in the proportion of FEP participants with obesity and these contrary results may be due to specificity to antipsychotic metabolic disturbances. Participants gained most of the weight in treatments [14, 48]. the first year after their FEP, although they continued gaining Besides, our results showed that men were at higher risk than weight steadily throughout the 10-year follow-up. women of presenting high increase of body weight (≥20% from baseline) at 10-year follow-up. Other variables predicting this high Data Availability Statement. Raw data of this study are accessible and have increase in body weight were a higher weight gain during the first been deposited in a publicly available repository (Mendeley Data: http://doi.org/ 10.17632/b2h5gr9m3c.1). year after the FEP and antipsychotic treatment continuation, in line with previous studies by our group [7, 49]. However, a longer DUP Supplementary Materials. To view supplementary material for this article, also predicted a greater weight increase at long term. DUP has been please visit http://doi.org/10.1192/j.eurpsy.2022.2308. widely associated with a greater severity of psychotic symptoms at presentation [50] and to poorer outcomes of psychosis [51], and Acknowledgment. The authors wish to thank all “Programa Asistencial de las long DUP correlates with long duration of prodromal symptoms Fases Iniciales de Psicosis” (PAFIP) research team and all patients and family and with poorer social support and functioning [52]. In this sense, a members who participated in the study. long DUP could indirectly determine difficulties in self-care and in the access to professional care, which could ultimately lead to Author Contributions. Conceptualization: J.V-B., B.C-F.; Formal analysis: J. V-B., V.O-G., D.T-G.; Funding acquisition: J.V-B., B.C-F.; Investigation: M.G- poorer physical health conditions, such as metabolic syndrome R., J.M-vS., E.S-S., R.A-A., D.T-G., M.J-R., B.C-F.; Methodology: J.V-B., J.M-vS., [53] or glucose intolerance [31], described at baseline in drug-naïve V.O-G., R.A-A., D.T-G., B.C-F.; Project administration: V.O-G.; Resources: J.V- FEP patients. However, this increased risk of metabolic alterations B., M.G-R., V.O-G., B.C-F.; Supervision: B.C-F.; Writing—original draft: J.V-B.; in drug-naïve FEP patients could not be attributed to the DUP Writing—review and editing: J.V-B., M.G-R., J.M-vS., V.O-G., E.S-S., R.A-A., D. [54]. On the other hand, no previous studies have explored the T-G., M.J-R., J.L, B.C-F. effect of DUP on weight changes in FEP, limiting the possibility of comparing our results to previous literature. Financial Support. This study was supported by the Instituto de Investigación The study presents several limitations. The results may be Sanitaria Valdecilla (J.V-B., grant numbers INT/A21/10, INT/A20/04, NEXT- VAL17/24; and Instituto de Salud Carlos III (B.C-F., grant numbers PI020499, affected by sample selection bias considering recruitment was PI050427, PI060507). limited to individuals agreeing to participate after having been re-contacted for a 10-year follow-up. A small group of participants Conflicts of Interest. The authors declare none. (patients n = 5, 2.4%; controls n = 3, 5.3%) were under 18 at study entry, and they had probably grown and got taller during the first 3 years of the study. Unfortunately, we do not have a second measure of height within the first 3 years of study, and therefore References we have used their baseline height for the 1-year and 3-year follow- [1] Hjorthoj C, Sturup AE, McGrath JJ, Nordentoft M. Years of potential life ups BMI calculation (Table 2). Although these individuals present lost and life expectancy in schizophrenia: a systematic review and meta- small mean height increment after 10 years (from baseline 170.8 cm analysis. Lancet Psychiat.2017;4(4):295–301. (SD 7.6) to 10 year 172.9 cm (SD 7.1)), this could have partially [2] Tiihonen J, Lonnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, affected the results of BMI change (Table 2). Patients were not et al. 11-year follow-up of mortality in patients with schizophrenia: a evaluated for research purposes between year 3 and year 10, thus population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620–7. leading to a widely spaced follow-up interval with a lack of clinical, [3] DEH M, Correll CU, Bobes J, Cetkovich-Bakmas M, Cohen D, Asai I, et al. Physical illness in patients with severe mental disorders. I. Prevalence, biometric and social information, which precluded proper analyses impact of medications and disparities in health care. World Psychiatry. of weight trajectories. Data were not available on some relevant 2011;10(1):52–77. variables that affect weight (e.g., diet and physical activity) [55, [4] Melle I, Olav Johannesen J, Haahr UH, Ten Velden Hegelstad W, Joa I, 56]. Dietary and healthy lifestyle counseling was delivered as clin- Langeveld J, et al. Causes and predictors of premature death in ical routine following clinicians’ discretion but was not recorded for first-episode schizophrenia spectrum disorders. World Psychiatry. 2017; research purposes. The clinical repercussion related to weight gain, 16(2):217–8. European Psychiatry 9 [5] Foley DL, Morley KI. Systematic review of early cardiometabolic outcomes [23] Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of the first treated episode of psychosis. Arch Gen Psychiatry. 2011;68(6): of low-density lipoprotein cholesterol in plasma, without use of the 609–16. preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502. [6] Perez-Iglesias R, Mata I, Pelayo-Teran JM, Amado JA, Garcia-Unzueta [24] McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D, et al. MT, Berja A, et al. Glucose and lipid disturbances after 1 year of anti- Is there a simple way to identify insulin-resistant individuals at increased psychotic treatment in a drug-naive population. Schizophr Res. 2009; risk of cardiovascular disease? Am J Cardiol. 2005;96(3):399–404. 107(2–3):115–21. [25] Sachs GS, Guille C. Weight gain associated with use of psychotropic [7] Perez-Iglesias R, Martinez-Garcia O, Pardo-Garcia G, Amado JA, Garcia- medications. J Clin Psychiatry. 1999;60(Suppl 21):16–9. Unzueta MT, Tabares-Seisdedos R, et al. Course of weight gain and [26] Fleischhacker WW, Siu CO, Boden R, Pappadopulos E, Karayal ON, Kahn metabolic abnormalities in first treated episode of psychosis: the first year RS. Metabolic risk factors in first-episode schizophrenia: baseline preva- is a critical period for development of cardiovascular risk factors. Int J lence and course analysed from the European first-episode schizophrenia Neuropsychopharmacol. 2014;17(1):41–51. trial. Int J Neuropsychopharmacol. 2013;16(5):987–95. [8] Mackin P, Waton T, Watkinson HM, Gallagher P. A four-year naturalistic [27] Strassnig M, Kotov R, Cornaccio D, Fochtmann L, Harvey PD, Bromet EJ. prospective study of cardiometabolic disease in antipsychotic-treated Twenty-year progression of body mass index in a county-wide cohort of patients. Eur Psychiatry. 2012;27(1):50–5. people with schizophrenia and bipolar disorder identified at their first [9] Saloojee S, Burns JK, Motala AA. Metabolic syndrome in South African episode of psychosis. Bipolar Disord. 2017;19(5):336–43. patients with severe mental illness: prevalence and associated risk factors. [28] Encuesta Nacional de Salud 2017 [Internet]. Ministerio de Sanidad, Con- PLoS One. 2016;11(2):e0149209. sumo y Bienestar Social, Gobierno de España, http://www.ine.es/jaxi/ [10] Seow LS, Chong SA, Wang P, Shafie S, Ong HL, Subramaniam M. Tabla.htm?path=/t00/mujeres_hombres/tablas_1/l0/&file=d06001.px& Metabolic syndrome and cardiovascular risk among institutionalized L=0; 2017 [accessed 07 December 2021]. patients with schizophrenia receiving long term tertiary care. Compr [29] Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mor- Psychiatry. 2017;74:196–203. tality with overweight and obesity using standard body mass index categories: [11] Gardner-Sood P, Lally J, Smith S, Atakan Z, Ismail K, Greenwood KE, et al. a systematic review and meta-analysis. JAMA. 2013;309(1):71–82. Cardiovascular risk factors and metabolic syndrome in people with estab- [30] Johnson W, Bell JA, Robson E, Norris T, Kivimaki M, Hamer M. Do worse lished psychotic illnesses: baseline data from the IMPaCT randomized baseline risk factors explain the association of healthy obesity with controlled trial. Psychol Med. 2015;45(12):2619–29. increased mortality risk? Whitehall II study. Int J Obes. 2019;43(8): 1578–89. [12] Bobes J, Arango C, Aranda P, Carmena R, Garcia-Garcia M, Rejas J. [31] Pillinger T, Beck K, Gobjila C, Donocik JG, Jauhar S, Howes OD. Impaired Cardiovascular and metabolic risk in outpatients with schizoaffective glucose homeostasis in first-episode schizophrenia: a systematic review disorder treated with antipsychotics: results from the CLAMORS study. and meta-analysis. JAMA Psychiat. 2017;74(3):261–9. Eur Psychiatry. 2012;27(4):267–74. [32] Greenhalgh AM, Gonzalez-Blanco L, Garcia-Rizo C, Fernandez-Egea E, [13] Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie Miller B, Arroyo MB, et al. Meta-analysis of glucose tolerance, insulin, and PM, et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular insulin resistance in antipsychotic-naive patients with nonaffective psych- risks and mortality: results of a 10-year naturalistic study. J Clin osis. Schizophr Res. 2017;179:57–63. Psychiatry. 2005;66(9):1116–21. [33] Tomasik J, Lago SG, Vazquez-Bourgon J, Papiol S, Suarez-Pinilla P, [14] Vazquez-Bourgon J, Perez-Iglesias R, Ortiz-Garcia de la Foz V, Suarez Crespo-Facorro B, et al. Association of insulin resistance with schizophre- Pinilla P, Diaz Martinez A, Crespo-Facorro B. Long-term metabolic effects nia polygenic risk score and response to antipsychotic treatment. JAMA of aripiprazole, ziprasidone and quetiapine: a pragmatic clinical trial in Psychiat. 2019;76(8):864–7. drug-naive patients with a first-episode of non-affective psychosis. Psy- [34] Lago SG, Tomasik J, van Rees GF, Rubey M, Gonzalez-Vioque E, Ramsey chopharmacology. 2018;235(1):245–55. JM, et al. Exploring cellular markers of metabolic syndrome in peripheral [15] Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley blood mononuclear cells across the neuropsychiatric spectrum. Brain G, et al. Comparative effects of 18 antipsychotics on metabolic function in Behav Immun. 2021;91:673–82. patients with schizophrenia, predictors of metabolic dysregulation, and [35] Chouinard VA, Henderson DC, Dalla Man C, Valeri L, Gray BE, Ryan KP, association with psychopathology: a systematic review and network meta- et al. Impaired insulin signaling in unaffected siblings and patients with analysis. Lancet Psychiat. 2020;7(1):64–77. first-episode psychosis. Mol Psychiatry. 2019;24(10):1513–22. [16] Ayesa-Arriola R, Ortiz-Garcia de la Foz V, Martinez-Garcia O, Setien- [36] Bioque M, Garcia-Portilla MAP, Garcia-Rizo C, Cabrera B, Lobo A, Suero E, Ramirez ML, Suarez-Pinilla P, et al. Dissecting the functional Gonzalez-Pinto A, et al. Evolution of metabolic risk factors over a two- outcomes of first episode schizophrenia spectrum disorders: a 10-year year period in a cohort of first episodes of psychosis. Schizophr Res. 2018; follow-up study in the PAFIP cohort - CORRIGENDUM. Psychol Med. 193:188–96. 2021;51:264–77. [37] Vandenberghe F, Gholam-Rezaee M, Saigi-Morgui N, Delacretaz A, [17] Pelayo-Teran JM, Perez-Iglesias R, Ramirez-Bonilla M, Gonzalez-Blanch Choong E, Solida-Tozzi A, et al. Importance of early weight changes to C, Martinez-Garcia O, Pardo-Garcia G, et al. Epidemiological factors predict long-term weight gain during psychotropic drug treatment. J Clin associated with treated incidence of first-episode non-affective psychosis Psychiatry. 2015;76(11):e1417–23. in Cantabria: insights from the clinical programme on early phases of [38] Vandenberghe F, Najar-Giroud A, Holzer L, Conus P, Eap CB, Ambresin AE. psychosis. Early Interv Psychiatry. 2008;2(3):178–87. Second-generation antipsychotics in adolescent psychiatric patients: meta- [18] First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical bolic effects and impact of an early weight change to predict longer term interview for DSM-IV Axis I disorders. In: Clinician version (SCID- weight gain. J Child Adolesc Psychopharmacol. 2018;28(4):258–65. CV), Washington, D.C.: American Psychiatric Press; 1996. [39] Peter RS, Keller F, Klenk J, Concin H, Nagel G. Body mass trajectories, [19] Andreasen N. Scale for the assessment of negative symptoms (SANS). diabetes mellitus, and mortality in a large cohort of Austrian adults. Iowa: University of Iowa; 1983. Medicine (Baltimore). 2016;95(49):e5608. [20] Andreasen NC. Scale for the assessment of positive symptoms (SAPS). [40] Klenk J, Rapp K, Ulmer H, Concin H, Nagel G. Changes of body mass Iowa: Iowa University; 1984, p. 173–80. index in relation to mortality: results of a cohort of 42,099 adults. PLoS [21] Flemenbaum A, Zimmermann RL. Inter- and intra-rater reliability of the One. 2014;9(1):e84817. brief psychiatric rating scale. Psychol Rep. 1973;32(3):783–92. [41] Wang M, Yi Y, Roebothan B, Colbourne J, Maddalena V, Sun G, et al. [22] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner Trajectories of body mass index among Canadian seniors and associated RC. 1985. Homeostasis model assessment: insulin resistance and betacell mortality risk. BMC Public Health. 2017;17(1):929. function from fasting plasma glucose and insulin concentrations in ma. [42] Zheng H, Tumin D, Qian Z. Obesity and mortality risk: new findings from Diabetologia 28 (7), 412–419. PMID: 3899825 DOI: 10.1007/BF00280883 body mass index trajectories. Am J Epidemiol. 2013;178(11):1591–9. 10 J. Vázquez-Bourgon et al. [43] Li Q, Chen D, Liu T, Walss-Bass C, de Quevedo JL, Soares JC, et al. cohorts of first-episode patients: a systematic review. Arch Gen Sex differences in body mass index and obesity in Chinese patients Psychiatry. 2005;62(9):975–83. with chronic schizophrenia. J Clin Psychopharmacol. 2016;36(6):643–8. [52] Kalla O, Aaltonen J, Wahlstrom J, Lehtinen V, Garcia Cabeza I, Gonzalez [44] Lee SY, Park MH, Patkar AA, Pae CU. A retrospective comparison of BMI de Chavez M. Duration of untreated psychosis and its correlates in first- changes and the potential risk factors among schizophrenic inpatients episode psychosis in Finland and Spain. Acta Psychiatr Scand. 2002; treated with aripiprazole, olanzapine, quetiapine or risperidone. Prog 106(4):265–75. Neuro-Psychopharmacol Biol Psychiatry. 2011;35(2):490–6. [53] Garrido-Torres N, Rocha-Gonzalez I, Alameda L, Rodriguez-Gangoso A, [45] Yang F, Wang K, Du X, Deng H, Wu HE, Yin G, et al. Sex difference in the Vilches A, Canal-Rivero M, et al. Metabolic syndrome in antipsychotic- association of body mass index and BDNF levels in Chinese patients with naive patients with first-episode psychosis: a systematic review and meta- chronic schizophrenia. Psychopharmacology. 2019;236(2):753–62. PMID: analysis. Psychol Med. 2021;51(14):2307–20. 30456540 DOI: 10.1007/s00213-018-5107-1 [54] Kirkpatrick B, Miller BJ, Garcia-Rizo C, Fernandez-Egea E, Bernardo M. Is [46] Kraal AZ, Ward KM, Ellingrod VL. Sex differences in antipsychotic related abnormal glucose tolerance in antipsychotic-naive patients with nonaffec- metabolic functioning in schizophrenia spectrum disorders. Psychophar- tive psychosis confounded by poor health habits? Schizophr Bull. 2012; macol Bull. 2017;47(2):8–21. 38(2):280–4. [47] Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, [55] Vancampfort D, Firth J, Schuch FB, Rosenbaum S, Mugisha J, Hallgren M, Remschmidt H, Krieg JC, et al. Antipsychotic-induced body weight gain: et al. Sedentary behavior and physical activity levels in people with predictors and a systematic categorization of the long-term weight course. schizophrenia, bipolar disorder and major depressive disorder: a global J Psychiatr Res. 2009;43(6):620–6. PMID: 19110264 DOI: 10.1016/j.jpsy- systematic review and meta-analysis. World Psychiatry. 2017;16(3): chires.2008.11.001. 308–15. [48] Alberich S, Fernandez-Sevillano J, Gonzalez-Ortega I, Usall J, Saenz M, [56] Firth J, Stubbs B, Teasdale SB, Ward PB, Veronese N, Shivappa N, et al. Gonzalez-Fraile E, et al. A systematic review of sex-based differences in Diet as a hot topic in psychiatry: a population-scale study of nutritional effectiveness and adverse effects of clozapine. Psychiatry Res. 2019;280: intake and inflammatory potential in severe mental illness. World Psych- 112506. iatry. 2018;17(3):365–7. [49] Vazquez-Bourgon J, Mayoral-van Son J, Gomez-Revuelta M, Juncal-Ruiz [57] Siu AL. Screening for high blood pressure in adults: U.S. preventive M, Ortiz-Garcia de la Foz V, Tordesillas-Gutierrez D, et al. Treatment services task force recommendation statement. Ann Intern Med. 2015; discontinuation impact on long-term (10-year) weight gain and lipid 163(10):778–86. metabolism in first-episode psychosis: results from the PAFIP-10 cohort. [58] American_Diabetes_Association. 2. Classification and diagnosis of dia- Int J Neuropsychopharmacol. 2021;24(1):1–7. betes: standards of medical Care in Diabetes-2019. Diabetes Care. 2019; [50] Melle I, Larsen TK, Haahr U, Friis S, Johannessen JO, Opjordsmoen S, 42(Suppl 1):S13–28. et al. Reducing the duration of untreated first-episode psychosis: effects on [59] Perry BI, Osimo EF, Upthegrove R, Mallikarjun PK, Yorke J, Stochl J, et al. clinical presentation. Arch Gen Psychiatry. 2004;61(2):143–50. Development and external validation of the psychosis metabolic risk [51] Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T. calculator (PsyMetRiC): a cardiometabolic risk prediction algorithm for Association between duration of untreated psychosis and outcome in young people with psychosis. Lancet Psychiat. 2021;8(7):589–98.