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Clozapine is seldom prescribed in treatment-resistant schizophrenia (TRS) patients during early phases of the illness. We aimed to examine the pathway and patterns and the impact of clozapine use in patients with TRS who were followed up for 10 years after the first outbreak of the illness. Data were obtained retrospectively from an epidemiological cohort of first episode schizophrenia patients (n = 218) who had been treated in a specialized intervention program (PAFIP). Out of 218, 35 (16%) individuals were on clozapine at 10-year assessment, while 183 (84%) were taking other antipsychotics. Among those 183 psychosis subjects who were not on clozapine, 13 (7.1%) met criteria for TRS. In the clozapine group, ten (28.6%) met criteria for early-TR and twenty-five (71.4%) met criteria for late-TR. Before clozapine treatment was initiated, the median number of days under other antipsychotic treatment was 1551 days (IQR = 1715) and the median time that subjects remained on clozapine was 6.3 years (IC95%: 5.49-7.20). At 10 years, we found that those individuals taking clozapine had higher CGI total scores (F = 12.0, p = 0.001) and SANS total scores (F = 9.27, p = 0.003) than subjects taking other antipsychotics after correcting for baseline values. Interestingly, when performing these analyses at 10 years between subjects taking clozapine (n = 35) and subjects who despite meeting TRS criteria were not taking clozapine (n = 13), we found that subjects taking clozapine had significantly lower total scores on all clinical scales compared with subjects who met TRS criteria and were not taking clozapine (p values, This study has been funded by Instituto de Salud Carlos III through the projects PI14/00639, PI14/00918 and PI17/01056 (Co-funded by European Regional Development Fund/European Social Fund “Investing in your future”) and Fundación Instituto de Investigación Marqués de Valdecilla (NCT0235832 and NCT02534363).

Background Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes. Aims To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories. Method We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases. Results Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F-statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data. Conclusions Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.

Objective To evaluate the ten-year stability of schizophrenia diagnosis in a cohort of first-episode psychosis (FEP) patients and the factors associated with it. Methods Changes in diagnosis of 209 FEP patients were described during ten years of follow-up. Related factors with maintenance or change of schizophrenia diagnosis were evaluated in prospective and retrospective approaches through Binary Logistic Regressions, ROC and survival curves. Results Out of the 209 patients, 126 were diagnosed of schizophrenia six months after their inclusion in the clinical program. Prospective analyses showed that eight of those 126 schizophrenia patients had changed to a different diagnosis after ten years, and predictors of change were better childhood premorbid adjustment, less severity of clinical global impression at baseline, and diagnosis of comorbid personality disorder during follow-up. Retrospectively, out of the 154 patients with schizophrenia in the ten-year assessment, 36 had a different diagnosis at baseline, and those factors related with a different prior diagnosis than schizophrenia were better socioeconomic status and shorter duration of untreated psychosis (DUP). A survival analysis on the timing of schizophrenia diagnosis showed that male gender and longer DUP were predictors of earlier definite diagnosis. Conclusions Diagnostic stability of schizophrenia in our FEP sample is high, especially prospective stability, and the group of patients with diagnostic change corresponded to a milder psychopathological profile before and at the onset of disease. Moreover, we observed a cautious attitude in the diagnosis of schizophrenia in patients with shorter DUP who had schizophrenia diagnosis after ten years.

Schizophrenia is a severe brain disorder with an excess morbidity and mortality partly due to a higher incidence of metabolic disturbances and cardio-vascular events. The exposure to antipsychotic treatment has been observed linked to these metabolic abnormalities. This study explores the metabolic effects of aripiprazol, quetiapine and ziprasidone in drug-naïve patients with a first-episode of psychosis, at long-term. Two-hundred and two patients with first-episode of psychosis were included in the study. Patients were randomly assigned to receive quetiapine, ziprasidone, or aripiprazole. Clinical, sociodemographic and anthropometric measures, as well as lipid and glyceamic parameters, were recorded at baseline and after three years of initiating antipsychotic treatment. Body weight and BMI increased significantly after 3 years of follow-up (F = 35.0, p, The present study was carried out at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Instituto de Salud Carlos III PI020499, PI050427, PI060507; Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004; SENY Fundació Research Grant CI 2005–0308007; and Fundación Marqués de Valdecilla API07/011.

Special Issue: The ENIGMA Consortium: the first 10 years., Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia., Center for Integrated Healthcare, U.S. Department of Veterans Affairs, Grant/Award Number: I01 CX000497; Commonwealth Health Research Board, Grant/Award Number: HRA_POR/2011/100; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Numbers: 478466/2009, 480370/2009; Department of Energy, Labor and Economic Growth, Grant/Award Number: DE-FG02-99ER62764; Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Grant/Award Numbers: K2009-62X-15077-06-3, K2012-61X-15077-09-3, 523-2014-3467, 2009-7053, 2013-2838; Fundação Amazônia Paraense de Amparo à Pesquisa, Grant/Award Numbers: 2009/14891-9, 2010/18672-7, 2012/23796-2, 2013/039; Instituto de Salud Carlos III, Grant/Award Numbers: FIS 00/3095, 01/3129, PI020499, PI060507, PI10/001; National Health and Medical Research Council, Grant/Award Numbers: 1009064, 496682; National Institutes of Health, Grant/Award Numbers: 1RC1MH089257, MH 60722, MH019112, MH064045, MH085096, MH098130, MO1 RR025758, P41RR14075, P50 MH071616, R01 DA053028, R01 EB020062, R01 HD050735, R01 MH056584, R01 MH084803, R01 MH116147, R01 MH117601, R01EB005846, R01EB015611, R01MH074797, R21 MH097196, R21MH097196, R37MH43375, S10 OD023696, T32 AG058507, T32 MH073526, TR000153, U01 MH097435, U24 RR021382A, U24 RR021992, U24 RR025736, U24 RR21992, U24RR021992, U54 EB020403, U54EB020403, UL1 TR000153; National Science Foundation, Grant/Award Numbers: 1636893, 1734853; Norges Forskningsråd, Grant/Award Numbers: 213837, 217776, 223273; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359; Wellcome Trust, Grant/Award Number: 072894/2/03/Z.

Selecting the first antipsychotic agent for the acute phase of a first episode of psychosis (FEP) is a critical task that may impact on the long-term outcome. Despite that, there is a lack of research comparing head-to-head different second-generation antipsychotics at this stage. The aim of this study was to compare the effectiveness of aripiprazole and risperidone in the treatment of the acute phase after a FEP. For that purpose, from February 2011 to October 2018, a prospective, randomized, open-label study was undertaken. Two hundred-sixty-six first-episode, drug-naïve patients were randomly assigned to aripiprazole (n = 136), or risperidone (n = 130) and followed-up for 6-weeks. The primary effectiveness measure was all-cause treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted to assess clinical efficacy. The overall dropout rate at 6-week reached 19.5%. Effectiveness measures were similar between both treatment groups as treatment discontinuation rates (χ2 = 1.863; p = 0.172) and mean time until all-cause discontinuation (log rank = 1.421; p = 0.233) showed no statistically significant differences. In terms of clinical efficacy, risperidone proved a statistically significant better performance according to BPRS mean change between baseline and 6-week total score (t = 3.187; p = 0.002). Patients under risperidone treatment were significantly more likely to suffer sex-related adverse events. In conclusion, no differences regarding effectiveness were found between aripiprazole and risperidone for the acute-phase treatment of FEP. Despite the importance of efficacy during this phase of treatment, selecting the most effective treatment for the long-term outcome, requires addressing safety and patient´s preferences., This study was conducted as part of a the PAFIP-3 clinical trial “Effectiveness of Second Generation Antipsychotics in First Episode Psychosis Patients: 1-year Follow-up (PAFIP3_1Y)”. ClinicalTrials.gov Identifier: (NCT02532491). The authors wish to thank all “Programa Asistencial de las Fases Iniciales de Psicosis”(PAFIP) research team and all patients and family members who participated in the study.

PAFIP Group Study., [Background] The domains of functioning affected by first episode of psychosis (FEP) could be analysed as forming a network of interacting or even reinforcing elements. The reasons why longer duration of untreated psychosis (DUP) might be related to higher disability are not still clear. The aim of the present study is to evaluate how different areas of functioning are inter-related according to the length of DUP in patients with FEP, with a particular focus on studying the relative influence of each other according to lengthy delays in initial treatment., [Method] 441 participants in an epidemiological and intervention program of first episode psychosis (PAFIP) were included in our study. Functioning problems at baseline were assessed with the WHO Disability Assessment Schedule (DAS). Three networks of functioning domains have been estimated according to the length of DUP., [Results] All the DAS items took part in the different networks. We have not found differences across the edge weights in the short, medium and long DUP groups. The domains “social withdrawal”, “participation in the household activities”, “general interest and information”, and “low level of activity” seem to act as bridge items with other areas of functioning in people with longer DUP., [Conclusions] Our results could have clinical implications for patients with longer DUP, in which case, social withdrawal, household activities, level of activity and general interest in the world around them, could be high-priority target areas of treatment, since they seem to be mediating the relation between others areas of functioning., This work was supported by Instituto de Salud Carlos III and Instituto de Investigación Sanitaria Valdecilla (NCT0235832 and NCT02534363). In addition, it was supported by: SAF 2016-76046-R and SAF 2013-46292-R (MINECO) to B.C-F. A-I-Z's work is supported by the PFIS predoctoral program (FI17/00138) from the Instituto de Salud Carlos III (Spain) and co-funded by the European Union (ERDFERDF/ESF, “A way to make Europe”/“Investing in your future”).

While sex differences in schizophrenia have long been reported and discussed, long-term sex differences in outcomes among first episode of psychosis (FEP) patients in terms of the efficacy of Early Intervention Services (EIS) has been an under-explored area. A total of 209 FEP patients (95 females and 114 males) were reassessed after a time window ranging from 8 to 16 years after their first contact with an EIS program (PAFIP) that we will call the 10-year PAFIP cohort. Multiple clinical, cognitive, functioning, premorbid, and sociodemographic variables were explored at 1-year, 3-year and 10-year follow-ups. At first contact, females were older at illness onset, had higher premorbid adjustment and IQ, and were more frequently employed, living independently, and accompanied by a partner and/or children. Existence of a schizophrenia diagnosis, and cannabis and alcohol consumption were more probable among men. During the first 3 years, women showed a significantly better response to minimal antipsychotic dosages and higher rates of recovery than men (50% vs. 30.8%). Ten years later, more females continued living independently and had partners, while schizophrenia diagnoses and cannabis consumption continued to be more frequent among men. Females also presented a lower severity of negative symptoms; however, functionality and recovery differences did not show significant differences (46.7% vs. 34.4%). Between the 3- and 10-year follow-up sessions, an increase in dosage of antipsychotics was observed. These results suggest that the better outcomes seen among women during the first 3 years (while they were treated in an EIS) were in the presence of more favourable premorbid and baseline characteristics. After an average period of 10 years, with the only difference being in negative symptoms course, outcomes for women approximated those of men, drawing particular attention to the increase in dosage of antipsychotic medication once FEP patients were discharged from the EIS program towards community-based services. These findings help to pose the question of whether it is advisable to target sexes and lengthen EIS interventions., This work was supported by the Instituto de Salud Carlos III (PI14/00639 andPI14/00918). No pharmaceutical company has financially supported the study. Dr. Ayesa-Arriola is funded by a Miguel Servet contract from the Carlos III Health Institute (CP18/00003), carried out on Fundación Instituto de Investigación Marqués de Valdecilla.

© The Author(s) 2020., [Background and Objective]: Schizophrenia is a low-prevalence mental disorder with a global age-standardized prevalence of 21 million people (2016). Second-generation antipsychotics (lurasidone and quetiapine XR) are recommended as the first-line treatment for schizophrenia. It is interesting to investigate how the results of clinical studies translate into direct medical costs. The objective of this analysis was to assess the direct medical costs related to pharmaceutical treatments and the management of relapses in patients affected with schizophrenia treated with lurasidone (74 mg) vs quetiapine XR (300 mg) assuming the Italian and Spanish National Health Service perspective. [Methods]: A health economic model was developed based on a previously published model. The analysis considered direct medical costs related to the pharmacological therapies and inpatient or outpatient management of relapses (direct medical costs referred to 2019). The probability of relapses and related costs were derived from two systematic reviews. A deterministic sensitivity analysis was implemented to test the robustness of the results. [Results]: The use of lurasidone (74 mg) compared with quetiapine XR (300 mg) would lead to a reduction in direct medical costs in Italy and Spain, with a lower cost per patient of − 163.7 € (− 9.0%) and − 327.2 € (− 22.7%), respectively. In detail, it would lead to an increase in the cost of therapy of + 53.8% and of + 30.5% in Italy and Spain, respectively, to a decrease in the cost of relapses with hospitalization of − 135.7%, and to an increase in the cost of relapses without hospitalization of + 24.5%. [Conclusions]: The use of lurasidone (74 mg) for the treatment of patients affected with schizophrenia, compared with quetiapine XR (300 mg), would be a cost-saving strategy in the two contexts investigated assuming the National Health Service point of view., This analysis was funded by an unconditional grant from Angelini SpA.

BackgroundThe aim of the current study was to examine the heterogeneity of functional outcomes in first episode psychosis (FEP) patients and related clinical, neurocognitive and sociodemographic factors using a cluster analytic approach.MethodA large sample of FEP patients (N = 209) was functionally reassessed 10 years after the first contact with an early intervention service. Multiple baseline, 3-year and 10-year follow-up variables were explored.ResultsThe cluster analysis emphasized the existence of six independent clusters of functioning: one cluster was normal overall (42.16%), two clusters showed moderate interpersonal (9.63%) or instrumental (12.65%) deficits, two clusters showed more severe interpersonal (12.05%) or interpersonal and instrumental (13.85%) deficits and there was a significantly overall impaired cluster (9.63%). Cluster comparisons showed that several baseline and follow-up factors were differentially involved in functional outcomes.ConclusionsThe current study demonstrated that distinct clusters of functioning in FEP patients can be identified. The fact that a variety of profiles was observed contributes to a better understanding of the nature of the heterogeneity characterizing FEP patients and has clinical implications for developing individualized treatment plans.

Resumen Introduccion La hiperprolactinemia iatrogenica (HPRLi) se ha descrito con mas frecuencia con algunos antipsicoticos, dependiendo de su capacidad de bloqueo de los receptores de dopamina D2. Existe gran heterogeneidad de la practica clinica y posiblemente falta de concienciacion sobre este problema entre los medicos. Dada la elevada frecuencia con la que los pacientes con enfermedad mental grave reciben antipsicoticos de forma prolongada, se precisa vigilar posibles riesgos en su salud fisica. La HPRLi y sus sintomas pueden pasar desapercibidos si no se investigan rutinariamente. Metodologia Se realiza una revision profunda de la literatura para elaborar un consenso multidisciplinario con psiquiatras junto a otros especialistas (de Endocrinologia, Medicina Interna y Oncologia) con el fin de consensuar los riesgos clinicos y los metodos de deteccion mas adecuados de la HPRLi de acuerdo con los distintos niveles de evidencia cientifica ( I - IV) . Resultados Los sintomas a corto plazo incluyen amenorrea, galactorrea y disfuncion sexual (descenso del deseo y disfuncion erectil por hipogonadismo secundario). A medio-largo plazo y relacionado con la disminucion de estrogenos, se pueden inducir baja masa osea (osteopenia y osteoporosis), hipogonadismo, menopausia precoz, incremento del riesgo de algunos tipos de cancer (mama y endometrio), aumento del riesgo cardiovascular, alteraciones en la inmunidad, dislipidemia y disfuncion cognitiva, entre otros. La peticion de niveles de PRL deberia realizarse al inicio del tratamiento en todos los pacientes que reciben antipsicoticos, aunque no se observen sintomas precoces (amenorrea, galactorrea) por el riesgo de subestimar otros sintomas que pueden aparecen a medio plazo. Se aconseja determinar tambien niveles de FSL, LH, testosterona y vitamina D. Se recomienda explorar rutinariamente la funcion sexual, ya que puede ser un sintoma mal tolerado que podria conducir al abandono del tratamiento. Se propone un especial cuidado en ninos y adolescentes, asi como en pacientes con PRL > 50 ng/ml (intensidad moderada), revisando periodicamente si existe hipogonadismo o disfuncion sexual. En los pacientes con PRL > 150 ng/ml debe descartarse siempre un prolactinoma radiologicamente y se debe prestar especial atencion a posibles antecedentes de cancer de mama o endometrio. Se aconseja realizar densitometrias en varones >50 anos y en mujeres con amenorrea > 6 meses o menopausia precoz para detectar osteoporosis y evitar riesgo de fracturas por fragilidad.

Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-na&iuml, ve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1&ndash, 9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1&ndash, 9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-&alpha, ) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.

Aim Early intervention psychiatric services for patients with psychosis aim to limit the most damaging outcomes and reduce the patient's risk of social drift, decreasing illness severity and thus containing healthcare costs. There is a scarcity of studies that focus on first-episode psychosis (FEP), and those few that have been published only looked at direct health costs, but not at indirect costs, which make up the bulk of the budget. Our study aims to explore the short-term (1-year follow-up) economic cost of a FEP Program, including both direct and indirect costs. Methods Data were collected retrospectively from the clinical records of 157 patients included in the Programa Atencion Fases Iniciales de Psicosis, from Marques de Valdecilla University Hospital, Santander. Our data collection sheet collated data from direct and indirect costs associated with the illness. Data were also extracted from the Cantabria Health Service Records. STATA 15.0 was used for statistical analysis. Results On average, the total costs during the first year were €48 353.51 per patient, with direct healthcare costs being €13 729.47 (28.39%), direct non-medical costs €108.6 (0.22%), and indirect costs €34 515.44 (71.39%). We found that hospitalization costs were higher in males (p = 0.081) and in cannabis users (p = 0.032). The number of relapses increased both, hospitalization and treatment costs (r = 0.40 p = 0.000; r = 0.24 p = 0.067, respectively). Conclusions Intensive Early Intervention in Psychosis Services may result in cost savings by decreasing hospitalization, premature mortality, disability, unemployment, and legal problems; however, the first year after diagnosis would represent the one with the highest costs.

Structural and functional imaging of the brain language structures, regions, and circuits has revealed the association between brain anomalies and hallucinations in psychosis (see Chaps. 9, 10, and 11). Similarly genetic investigations have demonstrated the effect of gene variations on the severity of hallucination (see Chap. 7).

Implementing the most suitable treatment strategies and making appropriate clinical decisions about individuals with a first episode of psychosis (FEP) is a complex and crucial task, with relevant impact in illness outcome. Treatment approaches in the early stages should go beyond choosing the right antipsychotic drug and should also address tractable factors influencing the risk of relapse. Effectiveness and likely metabolic and endocrine disturbances differ among second-generation antipsychotics (SGAs) and should guide the choice of the first-line treatment. Clinicians should be aware of the high risk of cardiovascular morbidity and mortality in schizophrenia patients, and therefore monitoring weight and metabolic changes across time is mandatory. Behavioral and counseling interventions might be partly effective in reducing weight gain and metabolic disturbances. Ziprasidone and aripiprazole have been described to be least commonly associated with weight gain or metabolic changes. In addition, some of the SGAs (risperidone, amisulpride, and paliperidone) have been associated with a significant increase of plasma prolactin levels. Overall, in cases of FEP, there should be a clear recommendation of using lower doses of the antipsychotic medication. If no or minimal clinical improvement is found after 2 weeks of treatment, such patients may benefit from a change or augmentation of treatment. Clinicians should provide accurate information to patients and relatives about the high risk of relapse if antipsychotics are discontinued, even if patients have been symptom free and functionally recovered on antipsychotic treatment for a lengthy period of time. This review was carried out at the Hospital Marque´s de Valdecilla, University of Cantabria, Santander, Spain, with the following Grant support: Instituto de Salud Carlos III PI020499, PI050427, PI060507, Plan Nacional de Drugs Research Grant 2005-Orden sco/3246/2004, SENY Fundacio´ Research Grant CI 2005-0308007, Fundacio´n Marque´s de Valdecilla API07/011 and CIBERSAM.

[Objective]: The timing of antipsychotic discontinuation in patients who have fully recovered from their initial episode of psychosis is still open to discussion. We aimed to evaluate the risk of symptom recurrence during the 3 years after antipsychotic discontinuation in a sample of functionally recovered first-episode nonaffective psychosis (FEP) patients (DSM-IV criteria) with schizophrenia spectrum disorder. [Method]: Participants in this open-label, nonrandomized, prospective study were drawn from an ongoing longitudinal intervention program of FEP from a university hospital setting in Spain. From July 2004 to February 2011, functionally recovered FEP individuals were eligible if they met the inclusion criteria of (1) a minimum of 18 months on antipsychotic treatment, (2) clinical remission for at least 12 months, (3) functional recovery for at least 6 months, and (4) stabilization at the lowest effective doses for at least 3 months. Forty-six individuals who were willing to discontinue medication were included in the discontinuation group (target group). Twenty-two individuals opted to stay on the prescribed antipsychotic medication and therefore were included in the maintenance group (control group). Primary outcome measures were relapse rate at 18 and 36 months and time to relapse. [Results]: The rates of relapse over the 3-year period were 67.4% (31 of 46) in the discontinuation group and 31.8% (7 of 22) in the maintenance group. The mean time to relapse was 209 (median = 122) days and 608 (median = 607) days, respectively (log rank = 10.106, P = .001). The resumption of antipsychotic medication after the relapse occurred was associated with clinical stability and lack of further relapses. When the overall group of relapsed individuals from the 2 conditions (N = 38) was compared to those who remained asymptomatic after 3 years (N = 30), there were significant differences (P < .05) in total scores on the Scale for the Assessment of Negative Symptoms, the Clinical Global Impressions scale, and the Disability Assessment Schedule. [Conclusions]: Antipsychotic treatment discontinuation in individuals who had accomplished a functional recovery after a single psychotic episode was associated with a high risk of symptom recurrence. Relapsed individuals had a greater severity of symptoms and lower functional status after 3 years.