First-episode psychosis (FEP) represents one of the main challenges for mental health.1 Its symptoms are grouped as positive, negative, cognitive and affective. FEP can occur at any age, but most people develop it when they are young (80% of first episodes of psychoses occur between 16 and 30 years of age), disrupting their achievement of crucial educational, occupational, and social milestones.2 Without an appropriate differential diagnosis and early intervention, clinical development after a FEP can lead to a chronic condition of varied signs and symptoms.3 For that reason, the early stages of psychosis are often considered to be a “critical period”.4 It has been shown that a late intervention for this population can greatly reduce the quality of life of patients and their families, as well as involve a high cost for society,5,6 representing 11.2% of the global burden of brain disorders in Europe.7

Around 3% of the general population suffers a psychotic episode during their lifetime.8 Psychosis is seen in several psychiatric disorders, including schizophrenia spectrum disorders (i.e., schizophrenia, schizoaffective disorder, delusional disorder, schizophreniform disorder, and brief psychotic disorder), bipolar disorder, and major depression with psychotic features. The lifetime prevalence was around 2% for non-affective psychotic disorders and 0.59% for affective psychotic disorders.8

The clinical evolution after a first episode of schizophrenia (FES) tends to be chronic and variable. Complete remission only occurs in one third of the patients.9 Relapse rates are higher in this critical period after the onset of the illness than in other periods, ranging from 30% to 60% at two years10,11 and up to 80% during the first five years after onset of the illness.12–14 Relapse, characterised by acute psychotic exacerbation, may have devastating repercussions, such as the progressive worsening of personal relationships, education or employment status.15 Additionally, it is associated with a higher risk of chronic or persistent symptoms, progressive functional deterioration and declining or resistance treatment response.16,17 Given the potential harm to the patient and family, second episodes should be an important focus of prevention. They threaten to disrupt psychosocial recovery and also increase the economic costs.18 The FES population represents a unique opportunity to study the clinical variables and the functional outcomes of psychotic disorders and to prevent potential relapses.

Several studies have focused on determining prognostic factors after a FEP. Being male, having greater clinical severity at onset, more negative symptoms at onset, worse premorbid adjustment, worse cognitive performance, lower cognitive reserve, longer duration of untreated psychosis (DUP), alcohol and drug use and poor insight have been related to worse outcome.19–31 More specifically, numerous studies have focused on analyzing risk factors for relapse in FEP. A systematic review and meta-analysis reported that clinical variables and general demographic variables including age of onset, gender, marital status, and employment have little impact on relapse rates. Conversely, non-adhesion with medication – using the reported level of adherence and/or the saliva/plasmatic levels of antipsychotic–, persistent substance use disorder, careers’ criticism and poorer premorbid adjustment significantly increase the risk of relapse in FEP.32 It was found that the most common risk factor by far was antipsychotic medication discontinuation.14,33,34 Thus, adherence and other factors that predispose individuals to relapse should be a major focus of attention in managing schizophrenia.35

Bearing in mind what is stated above and the fact that the first step in preventing negative consequences of a psychotic disorder is to characterize the population, the “Genotype–phenotype and environment interaction. Application of a predictive model in first-episode psychosis” project (also called the PEPs Project) arose the years ago, funded by the Healthcare Research Fund (Spanish acronym, FIS; PI08/0208). It was conducted in the context of the Centre for Biomedical Research in Mental Health Network (Spanish acronym, CIBERSAM) – which promotes collaborative and translational biomedical research of high quality-, and based on the previous experience of the Network of Research in Mental Disorders (Spanish acronym, REM-TAP).36 The main goal for the PEPs Project was to identify genetic and environmental factors of risk and their interaction in the appearance of a FEP, with the purpose of developing more effective strategies of differential diagnosis and treatment. The complete protocol of assessment is extensively described in Bernardo et al. (2013).37

Numerous results derived from the PEPs Project have been as yet published (and the project is still currently producing relevant data) in different high-impact national and international journals (see Fig. 1). The publications derived from the PEPs Project have achieved a total impact of more than 330 with over 300 citations in total. A review of the main results and publications of the PEPs Project can be found in Bernardo et al. (2019).6

Figure 1.

Number of publications derived from the PEPs Project. Numerous results derived from the PEPs Project have been published. The publications derived from the PEPs have achieved a total impact of more than 330 and total citations of more than 300. The most cited topics are: pharmacogenetics, genetic predictors of biological markers, general cognition in first episode psychosis, negative symptomatology, functional outcomes and cognitive reserve.

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In this context, and following similar methods, the “Clinical and neurobiological determinants of second schizophrenia episodes. Longitudinal study on first-episode psychosis” (2EPs Project) was developed. It was funded by the Healthcare Research Fund (PI11/00325).

The purpose of the present article is to describe the rationale for the measurement approach adopted for the 2EPs Project, providing an overview of the selected clinical and functional measures used.

The 2EPs is a multicenter, coordinated, longitudinal follow-up study of three years’ duration with a Spanish sample of patients in remission after a FES. It was designed and conducted between 2011 and 2016, with the main purpose of identifying useful predictive and therapeutic strategies to guide clinical practice and to prevent a worsening in the long-term course.

Specifically, the 2EPs Project has the following objectives: (a) to elaborate a predictive model of second-episode appearance based on clinical characteristics and global functioning; (b) to study neuropsychological profiles related to clinical, diagnostic, global functioning and genetic variables in this cohort of patients who have remitted from a FES, characterizing the profiles of those who relapse and those who do not; (c) to describe genotypic profiles in dopaminergic, serotoninergic and noradrenergic neurotransmission of interest for their roles in the prevention of or propensity to relapse due to psychotic exacerbations, stratifying the sample according to course of illness and sociodemographic and clinical characteristics; (d) to determine the relationship between the genetic polymorphisms involved in the pharmacokinetic and pharmacodynamic phases of the response, as well as the adverse effects of antipsychotic treatment after a FES; (e) to analyze the role of the treatment and the appearance of a new episode; (f) to identify genetic, neuropsychological and clinical variables that predict brain volumes and structural changes during the first three years of follow-up after the appearance of a FES, and (g) to identify the psychosocial interventions that are carried out during the first years of follow-up after the appearance of a FES and assess its relationship with the presence of psychotic relapses and other clinical outcome variables. Fifteen centers participated, coordinated from the Hospital Clínic from Barcelona.

Patients were followed up for 3 years (± 3 months of flexibility) or until relapse (± 3 months of flexibility), whichever happened first, with visits every 3 months (4 visits per year) since the period established between these visits was considered sufficient to detect a relapse. A protocol of telephone calls between visits – or in case patients did not attend the follow-up visit – was implemented in order to detect the highest possible number of relapses and so as not to lose information during the follow-up.

The project includes multiple sub-studies, distributed in a structure of 6 modules. Some sites participated in all the modules and other sites in part of them. The General and basic module assesses the presence or absence of relapses and includes the clinical assessments, evaluation of global functioning, genetic risk and the pharmacogenetics of efficacy and side effects. A second, the Neuroimaging module encompasses the analysis of brain structures for cases at the time of relapse or at end-visit (3-years) using magnetic resonance imaging. The Neurocognition module determines cognitive profiles related to a greater likelihood of having a relapse. A fourth, the Adherence module, aims to establish antipsychotic drug levels in saliva as a method of monitoring drug compliance and assessing the potential benefits of psychoeducational and psychological treatments; the fifth module, the Biological, searches for biomarkers potentially involved in relapses, as anti-inflammatory processes, epigenetics and neurotrophins. The last module is dedicated to Physical health; it was designed to assess whether there is a subgroup of patients with schizophrenia with the comorbid diagnosis of anxiety, which is associated with the same physical disorders frequently associated with schizophrenia. This fact would help to explain part of the increase in morbidity and mortality in schizophrenia. Another purpose of this module is to determine the relationship of the genetic polymorphisms involved in the pharmacokinetic and pharmacodynamic phases of the response, as well as the adverse effects on physical health of antipsychotic treatment after a FES: extrapyramidal, cardiological, metabolic and hormonal. Another goal is to study the relationship between the appearance of side effects, the abandonment of treatment and the appearance of a new episode, and to identify the psychosocial interventions that are carried out during the first years of follow-up and assess their relationship with the presence of psychotic relapses and physical health.

The analysis of all this data promises to help to define early interventions centered on preventing second episodes of schizophrenia (see Fig. 2).

Figure 2.

2EPs Project organization. 15 regional centers recruited patients: Hospital Clínic from Barcelona (main 2EPs coordinator and General/Clinical and Physical Health module coordinator); omplejo Hospitalario de Navarra (Neurocognition module coordinator); Hospital Gregorio Marañón (Neuroimaging module coordinator); Hospital Santiago Apóstol (Adherence module coordinator); Hospital Clínico y Universitario de Zaragoza; Hospital Ramón y Cajal; Universidad del Pais Vasco; Hospital de Sant Pau; Hospital Benito-Menni; Hospital Doce de Octubre; Hospital Sant Joan de Déu; Universidad de Oviedo; Hospital Clínico de Valencia; Hospital de Bellvitge, and Hospital del Mar. An additional group, Universidad de Cádiz, participated as a basic group and was the Biological module coordinator.

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The main purpose of the present article is to report the rationale, the design, the developmental processes and the assessment adopted in the 2EPs Project. This project has the principal objective of evaluating the clinical course and functional outcomes – with neuropsychological assessments, biological, neuroanatomical, genetic adherence and physical health monitoring – over three years of a sample of persons with a FES in remission in order to compare two subgroups of patients; those who present a second episode and those who do not experience relapse.

In first-episode populations, there is ample evidence that an early intervention is efficient. In this way, the design, development and validation of active relapse prevention programs are the first step to ensure a complete and correct approach, guaranteeing individualized and personalized treatments.6,81 Thus, a comprehensive recovery-oriented, evidence-based intervention to promote quality of life, participation in work and school, clinical remission and functional recovery needs to be developed.82,83 Given this need, numerous programs have emerged with the main objective of preventing second episodes and subsequent relapses. One of them was the project “Preventing Relapse Oral Antipsychotics Compared to Injectables eValuating Efficacy” (PROACTIVE), a 30-month relapse prevention study to compare relapses among patients receiving either long-acting injectable or oral second-generation antipsychotics.84 Another big project has been the “European First Episode Schizophrenia Trial” (EUFEST), which was designed to study and to compare the clinical effectiveness of first and second generation antipsychotics in first-episode patients.85 Last but not least, the “Recovery After an Initial Schizophrenia Episode-Early Treatment Program” (RAISE-ETP), which aimed to develop, test, and implement person-centered, integrated treatment approaches for FEP to promote symptomatic and functional recovery.82

After a thorough characterization of first episodes of schizophrenia in the framework of the PEPs Project,37 the 2EPs Project arose to characterize patients at remission from a first episodes in an exhaustive, novel and multimodal way to contribute toward the development of a predictive model of relapse. The only means of preventing relapses is to undertake longitudinal studies in early phases like the PEPs and 2EPs Projects.

Similar to the PEPs Project, in this naturalistic study, the selection of the sample tried to be as close as possible to the “real-world” patients with a FES in remission. For example, this naturalistic approach justifies the inclusion of infantile-juvenile patients (age at onset under 18 years) have been included which will allow the pattern of early onset to be studied in addition to its relationship with this pathology's risk factors when the appearance of the first-episode is very early. Another example is the inclusion of patients with substance use disorders. Due to the fact that people with first-episode schizophrenia frequently have comorbid substance use, usually involving alcohol and cannabis, which put a population particularly at risk of prolonged psychosis and psychotic relapses,86 it was of special interest to include those patients with consumption of substances. The naturalistic design was thus a key factor to assess the applicability of the results to daily clinical practice. The fact that the sample recruited in this project includes FES patients allows us to study the onset of the disease at early stages and limiting confounding variables, such as a long evolution or the long-term effects of antipsychotic medication. It is in the early stages of the disease when the most useful strategies for helping patients including adherence to treatment to understand the benefits of the medication and, especially, to administer them at the appropriate doses, should be implemented.

In our sample, 44% of patients with a FES in clinical remission presented a relapse during the three years of follow-up after the baseline visit. This percentage is in accordance with the well demonstrated data that relapse rates are higher in the critical period after the onset of the illness (until two years) than in other periods, ranging from 30% to 60%.10

It has been well demonstrated that adherence to treatment is a major determinant of treatment success while the lack of it is a global health problem of alarming magnitude, particularly in long-term treatments for chronic conditions.87-88 In developed countries, adherence in patients44 with chronic diseases averages only 50%.76,82,84,85 Poor adherence attenuates optimum clinical benefits and therefore reduces the overall effectiveness of health systems.

In this line, the 2EPs Project may also provide the identification of genetic, neuroimaging, biological and clinical variables and their role in treatment adherence, together with the application of various techniques to determine antipsychotic levels, which allow the validity of new biochemical methods that can help to identify therapeutic compliance to be tested. In the same way, the implementation of new non-invasive strategies for antipsychotic analysis, such as detection in saliva, will reduce the burden associated with transferring to health services to monitor adherence. Furthermore, these new techniques will permit the personalization of patients’ clinical therapies by adjusting the dose.

The proper coordination between centers allowed for the integration of information from the different modules in order to interrelate the hypotheses of the different sub-studies (e.g. at the clinical and neuroimaging, clinical and physical health, clinical and neurocognition levels, adherence to the treatment). This global perspective aimed at developing an evidence-based strategy that provides clinicians with useful resources for intervention in a first-episode with a view to consequent prevention of the second episode as an essential added value to the proposal of clinical intervention guides.

Notwithstanding, some limitations could be considered. One of the difficulties common to all longitudinal studies is the loss of subjects included in the study. To reduce this loss personal contact was established with patients and their families when arranging visits and outpatient follow-up was conducted by the psychiatrists participating in the study. Similarly, compliance in all visits may be lower than expected since the frequency (every three months) and the follow-up period (three years) are high. Again, attempts were made to reduce this loss through personal contact with patients and their caregivers. Moreover, an inherent limitation of clinical and neuropsychological evaluation procedures lies in the inter-observer differences, for which the usual procedures are applied to reduce this type of possible bias. First, semi-structured clinical interviews were included, and second, regular meetings were held to reduce the differences between the neuropsychological evaluators of the different research groups. Lastly, due to the naturalistic design, drug treatment was not controlled. The study participants maintained their usual treatment. Although this may limit the evaluation of some variables, this method eases the recruitment and it also gives a global picture of the usual treatment and outcome in these patients.

Nevertheless, besides these limitations, one strong point of the 2EPs Project (as well as of the PEPs Project) is the broad neuropsychological battery used. Compared to previous first-episode of psychosis projects such as EUFEST, PROACTIVE or RAISE-ETP, which used brief assessment battery or did not have any cognitive data collected,76,82,84,85 the neuropsychological battery employed in this study was extensive and covered the areas proposed by the NIMH MATRICS consensus.63 Moreover, it is worth highlighting that, in line with and as a continuation of the PEPs Project, this is the largest collaborative project ever undertaken in our country, which increases the chances of finding relevant and applicable results for the daily management of psychotic patients.

Thus, a special need in FES populations is to demonstrate the evidence for efficiency in the prevention of relapses, and to ensure that high-quality care is provided in research settings as well as in routine practice. Pragmatic research is being adopted to enhance the generalization of findings to clinical practice and to aid in the recruitment of patient samples that are more broadly representative of community mental health practices.82,84,89,90 The extent to which each informs the other offers the potential for future gains in the delivery of care for people with FES.

In conclusion, after the effective characterization of FES (goals achieved thanks to the PEPs Project) and the study of the variables that can predict the appearance of a relapse (clinical, biological, neuroanatomical, genetic, treatment compilation and physical health monitoring), which was the main purpose of the 2EPs Project, the validation of these interventions in this population taking into account all these variables would validate the clinical guidelines, based on evidence, to define good clinical practice.

This study is coordinated by Dr. Bernardo and is part of the coordinated-multicentre project, funded by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III – Fondo Europeo de Desarrollo Regional, Unión Europea. Una manera de hacer Europa; Centro de Investigación Biomédica en Red de salud Mental, CIBERSAM, by the CERCA Program/Generalitat de Catalunya And Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (2017SGR1355). Departament de Salut de la Generalitat de Catalunya, en la convocatoria corresponent a l’any 2017 de concessió de subvencions del Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016-2020, modalitat Projectes de recerca orientats a l’atenció primària, amb el codi d’expedient SLT006/17/00345. Dr. Bernardo is also grateful for the support of the Institut de Neurociències, Universitat de Barcelona.

Dr. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Lundbeck, Otsuka, Rovi, Menarini and Takeda.

The rest of the authors report no biomedical financial interests or potential conflicts of interest.