Manuel J Cuesta

• Psychiatrist, MD, PhD
• Head of Department at Hospital Universitario de Navarra

Background Suicidal thoughts and behaviors (STBs) are a major concern in people with psychotic disorders. There is a need to examine their prevalence over long-term follow-up after first-episode psychosis (FEP) and determine their early predictors. Methods Of 510 participants with FEP evaluated on 26 risk factors for later outcomes, 260 were reasse...

Background and Hypothesis Relapsing after a first episode of schizophrenia (FES) is a main predictor of clinical and functional prognosis. Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and plasticity, and its signaling may be altered by successive relapses. Design We assessed the impact of first relapse in...

Background Few studies have examined the long-term outcomes of first-episode psychosis (FEP) among patients beyond symptomatic and functional remission. This study aimed to broaden the scope of outcome indicators by examining the relationships between 12 outcomes of FEP patients at 20.9 years after their initial diagnosis. Methods At follow-up, 22...

The application of personalized medicine in patients with first-episode psychosis (FEP) requires tools for classifying patients according to their response to treatment, considering both treatment efficacy and toxicity. However, several limitations have hindered its translation into clinical practice. Here, we describe the rationale, aims and metho...

Purpose Little is known about the relationship between social exclusion and cognitive impairment in psychosis. We conducted a long-term cohort study of first-episode psychosis to examine the association between comprehensive measures of cognitive impairment and social exclusion assessed at follow-up. Methods A total of 173 subjects with first-epis...

Background Evidence suggests a possible relationship between exposure to childhood adversity (CA) and functional impairment in psychosis. However, the impact of CA on long-term outcomes of psychotic disorders remains poorly understood. Methods Two hundred and forty-three patients were assessed at their first episode of psychosis for CA and re-asse...

Purpose People with psychotic disorders have high levels of social exclusion; however, little is known about its early predictors. We present a long-term observational cohort study aimed at examining early risk factors for later social exclusion. Methods A total of 243 subjects were assessed at their first psychotic episode for early risk factors...

Background First-episode psychotic disorders comprise a heterogeneous phenotype with a complex etiology involving numerous common small-effect genetic variations and a wide range of environmental exposures. We examined whether a family of schizophrenia spectrum disorder (FH-Sz) interacts with an environmental risk score (ERS-Sz) regarding the outco...

Introduction Previous research has shown that lower lactate dehydrogenase (LDH) concentrations in cerebrospinal fluid (CSF) are associated with longer prodromal symptoms in first-episode psychosis (FEP). We aimed to study whether there is a relationship between the duration of untreated psychosis (DUP) and LDH and other CSF biomarkers in FEP and wh...

Genome-wide association studies (GWAS) have revealed the polygenic nature of treatment-resistant schizophrenia TRS. Gene expression imputation allowed the translation of GWAS results into regulatory mechanisms and the construction of gene expression (GReX) risk scores (GReX-RS). In the present study we computed GReX-RS from the largest GWAS of TRS...

Background Polygenic risk scores for educational attainment (PRS EA ), cognitive reserve (CR), and clinical symptoms are associated with functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction are yet to be explored. This study assessed the mediating role of CR and clinical symptoms, both nega...

Background Patients with a first episode of psychosis (FEP) display clinical, cognitive, and structural brain abnormalities at illness onset. Ventricular enlargement has been identified in schizophrenia since the initial development of neuroimaging techniques. Obstetric abnormalities have been associated with an increased risk of developing psychos...

Background Although diagnostic instability in first-episode psychosis (FEP) is of major concern, little is known about its determinants. This very long-term follow-up study aimed to examine the diagnostic stability of FEP diagnoses, the baseline predictors of diagnostic change and the timing of diagnostic change. Methods This was a longitudinal an...

Background: The self-report Psychiatric Diagnostic Screening Questionnaire PDSQ is designed to screen Axis I psychiatric disorders. We aim to determine its psychometric properties in Spanish outpatients and assess its relationship with two interviews (for psychopathology and for personality disorders) and clinical/demographic variables. Methodolo...

Background There is strong evidence supporting the association between environmental factors and increased risk of non-affective psychotic disorders. However, the use of sound statistical methods to account for spatial variations associated with environmental risk factors, such as urbanicity, migration, or deprivation, is scarce in the literature....

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia re...

[This corrects the article DOI: 10.3389/fpsyt.2022.982583.].

Aim To determine whether thyroid hormone levels are associated with a specific clinical phenotype in patients with first-episode psychosis (FEP). Methods Ninety-eight inpatients experiencing FEP and with less than 6 weeks of antipsychotic treatment were included in the study and were followed up for one year. Baseline psychiatric evaluation includ...

Treatment-resistant schizophrenia (TRS) is a complex phenotype with important implications in the clinical course of a disease that is both underdiagnosed and poorly treated. The identification of predictors and biomarkers for the early detection and treatment of TRS is a critical step. Large genome-wide association studies (GWAS) have revealed the...

Cannabis use is highly prevalent in first-episode psychosis (FEP) and plays a critical role in its onset and prognosis, but the genetic underpinnings promoting both conditions are poorly understood. Current treatment strategies for cannabis cessation in FEP are clearly inefficacious. Here, we aimed to characterize the association between cannabis-r...

To assess the role of age (early onset psychosis-EOP < 18 years vs. adult onset psychosis-AOP) and diagnosis (schizophrenia spectrum disorders-SSD vs. bipolar disorders-BD) on the duration of untreated psychosis (DUP) and prodromal symptoms in a sample of patients with a first episode of psychosis. 331 patients with a first episode of psychosis (7-...

Background: Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they...

Background: Consistent evidence supports the involvement of genetic and environmental factors, and their interactions, in the etiology of psychosis. First-episode psychosis (FEP) comprises a group of disorders that show great clinical and long-term outcome heterogeneity, and the extent to which genetic, familial and environmental factors account f...

Objective: Psychotic disorders exhibit a complex etiology that combines genetic and environment factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how obstetric complications relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical p...

Background Traumatic life events (TLEs) are one of the most robust environmental risk factors for the onset of first-episode psychosis (FEP). Aims To explore TLEs in FEP patients and healthy controls (HC), to analyze gender differences and to examine whether TLEs were associated with sociodemographic, clinical and psychofunctional variables in all...

Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition...

Background: People with schizophrenia and predominant negative symptoms (PNS) present a different clinical and functional profile from those without such symptomatology. Few studies have examined the risk factors and the incidence of PNS in first-episode schizophrenia patients (FES) and differentiating by sex. This study aims to assess prevalence,...

We examined the empirical validity of a staging model of psychotic disorders primarily based on their long-term course. The model distinguished 6 consecutive stages (2A, 2B, 3A, 3B, 4A, 4B) based on symptom recurrence, persistence and progression, such as functional decline. We analyzed data from 243 participants with first-admission psychosis who...

The validation of nosological diagnoses in psychiatry remains a conundrum. Leonhard's (1979) nosology seems to be one of the few acceptable alternative categorical models to current DSM/ICD systems. We aimed to empirically validate Leonhard's four classes of psychoses: systematic schizophrenia (SSch), unsystematic (USch), cycloid psychosis (Cyclo),...

First-episode psychosis is a critical period for early interventions to reduce the risk of poor outcomes and relapse as much as possible. However, uncertainties about the long-term outcomes of symptomatology remain to be ascertained. The aim of the present study was to use network analysis to investigate first-episode and long-term stages of psycho...

Common mental disorders (CMDs) in mental health settings show high rates of comorbidities. While semi-structured interviews are the gold standard to establish a diagnosis, there are self-report instruments such as the Psychiatric Diagnostic Screening Questionnaire (PDSQ) that aids clinicians in improving the diagnostic process in a time-efficient m...

First-episode psychosis (FEP) patients show structural brain abnormalities at the first episode. Whether the cortical changes that follow a FEP are progressive and whether age at onset modulates these changes remains unclear. This is a multicenter MRI study in a deeply phenotyped sample of 74 FEP patients with a wide age range at onset (15–35 years...

Background Deficits in psychosocial functioning are present in the early stages of psychosis. Several factors, such as premorbid adjustment, neurocognitive performance, and cognitive reserve (CR), potentially influence functionality. Sex differences are observed in individuals with psychosis in multiple domains. Nonetheless, few studies have explor...

Background The prevention of relapse may be a key factor to diminish the cognitive impairment of first-episode schizophrenia (FES) patients. We aimed to ascertain the effects of relapse, and dopaminergic and anticholinergic treatment burdens on cognitive functioning in the follow-up. Methods Ninety-nine FES patients participated in this study. Cog...

Little is known about long-term outcomes of the first episode of psychosis (FEP) other than in the symptomatic domain. We hypothesised that cognitive impairment is associated with poorer multi-domain outcomes at a long-term follow-up of FEP patients. We followed-up 172 FEP patients for a mean of 20.3 years. Ten outcome dimensions were assessed (sym...

Introduction First-episode psychosis is a critical period for early interventions to reduce the risk of poor outcomes and relapse as much as possible. There are now many studies revealing the patterns of course in the short and medium terms, but uncertainties about the long-term outcomes of symptomatology remain to be ascertained. Objectives First...

To explore the influence of cardiovascular risk factors (CVRFs) on cognitive symptoms, functional impairment, and systemic inflammatory markers in first-episode psychosis (FEP) patients at baseline and 2-year follow-up. Method: In a sample of 70 FEP patients and 85 age- and sex-matched healthy controls, we assessed nine modifiable CVRFs. All partic...

Background and Hypothesis A pro-inflammatory phenotype has been related to psychotic disorders. The neutrophil-lymphocyte ratio (NLR) is an accessible biomarker that could be helpful to characterize this systemic inflammation state. Study Design This study evaluated the NLR in a cohort of 310 subjects with a first episode of psychosis (FEP) and a...

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its...

Background: This study compares the effectiveness of a new early intervention service for firstepisode psychosis (FEP) in patients under conventional treatment. Six primary and 10 secondary outcome measures are used to better characterize the comparative effectiveness between two FEP groups. Methods: This study plans to enrol 250 patients aged 15-5...

The main objective of the present study was to investigate the association between several epigenetic clocks, covering different aspects of aging, with schizophrenia relapse evaluated over a 3-year follow-up period in a cohort of ninety-one first-episode schizophrenia patients. Genome-wide DNA methylation was profiled and four epigenetic clocks, in...

Background Clinical intervention in early stages of psychotic disorders is crucial for the prevention of severe symptomatology trajectories and poor outcomes. Genetic variability is studied as a promising modulator of prognosis, thus novel approaches considering the polygenic nature of these complex phenotypes are required to unravel the mechanisms...

Network analysis is an important conceptual and analytical approach in mental health research. However, few studies have used network analysis to examine the structure of cognitive performance in psychotic disorders. We examined the network structure of the cognitive scores of a sample of 207 first-episode psychosis (FEP) patients and 188 healthy c...

Objective Metabolic syndrome is a health-threatening condition suffered by approximately one third of schizophrenia patients and largely attributed to antipsychotic medication. Previous evidence reports a common genetic background of psychotic and metabolic disorders. In this study, we aimed to assess the role of polygenic risk scores (PRSs) on the...

Background The long-term stability of neuromotor domains assessed at the first episode of psychosis (FEP) and their ability for predicting a number of outcomes remains largely unknown, and this study addressed these issues. Methods This was a longitudinal study of 243 participants with FEP who were assessed at baseline for background variables and...

Relapses are frequent in the first years following a first episode of schizophrenia (FES), being associated with a higher risk of developing a chronic psychotic disorder, and poor clinical and functional outcomes. The identification and intervention over factors associated with relapses in these early phases are timely and relevant. In this study,...

Introduction: Sex differences in first episode of psychosis (FEP) have been widely studied. However, the existence of controversial results may be attributable to not considering relevant factors such as substance use. Cannabis use is associated with an earlier age of onset of psychosis and rates of cannabis use are consistently higher among men. T...

Phenotype validation of endogenous psychosis is a problem that remains to be solved. This study investigated the neuropsychological performance of endogenous psychosis subtypes according to Wernicke–Kleist–Leonhard’s classification system (WKL). The participants included consecutive admissions of patients with schizophrenia spectrum disorder or moo...

Neurotrophins have been proposed to be involved in biological mechanisms which might underlie different clinical outcomes in schizophrenia. The aims of the present study were to examine the BDNF/NGF plasma levels in a cohort of first-episode schizophrenia (FES) patients in remission as potential biological predictors of relapse; to study the associ...

Self-reported and interview-based measures can be considered coprimary measures of cognitive performance. We aimed to ascertain to what extent cognitive impairment in psychotic disorders, as assessed with a neuropsychological battery, is associated with subjective cognitive complaints compared to difficulties in daily activities caused by cognitive...

A better understanding of schizophrenia subtypes is necessary to stratify the patients according to clinical attributes. To explore the genomic architecture of schizophrenia symptomatology, we analyzed blood co-expression modules and their association with clinical data from patients in remission after a first episode of schizophrenia. In total, 91...

Objective Neurological correlates of impaired insight in non-affective psychosis remain unclear. This study aimed to review and meta-analyze the studies assessing the grey matter volumetric correlates of impaired insight in non-affective psychosis. Methods This study consisted of a systematic review of 23 studies, and a meta-analysis with SDM-PSI...

Current classification systems use the terms “catatonia” and “psychomotor phenomena” as mere a-theoretical descriptors, forgetting about their theoretical embedment. This was the source of misunderstandings among clinicians and researchers of the European collaboration on movement and sensorimotor/psychomotor functioning in schizophrenia and other...

Background Cognitive reserve (CR) is a protective factor against cognitive and functional impairment in first-episode psychosis (FEP). The aim of this study was to evaluate the differences in clinical presentation according to the use of cannabis (cannabis users vs non-users) among patients presenting a FEP (non-affective vs affective psychosis), t...

This study was aimed at characterizing long-term outcomes of first-admission psychosis and examining their baseline predictors. Participants were assessed at baseline for 38 candidate predictors and re-assessed after a median follow-up of 21 years for symptomatic, functional, and personal recovery. Associations between the predictors and the outcom...

Background Adverse childhood experiences (ACE) have a great impact on mental health outcomes of adults. However, little is known whether ACE may act as modulators of the mental health of health professionals caring for patients with COVID-19. Methods Data were collected through an online cross-sectional survey administered to health professionals...

Negative symptoms are a core dimension of schizophrenia and other psychoses that account for a large degree of the poor functional outcomes related to these disorders. Newer assessment scales for negative symptoms, such as the Clinical Assessment Interview for Negative Symptoms (CAINS), provide evidence for separate dimensions of motivational and p...

Little is known about the pathophysiological mechanisms of relapse in first-episode schizophrenia, which limits the study of potential biomarkers. To explore relapse mechanisms and identify potential biomarkers for relapse prediction, we analyzed gene expression in peripheral blood in a cohort of first-episode schizophrenia patients with less than...

Impairments in a broad range of cognitive domains have been consistently reported in some individuals with first-episode psychosis (FEP). Cognitive deficits can be observed during the prodromal stage. However, the course of cognitive deficits is still unclear. The aim of this study was to identify cognitive subgroups over time and to compare their...

Background Psychopathological symptoms and cognitive impairment are core features of patients with psychotic disorders. Executive dysfunctions are commonly observed and typically assessed using tests like the Wisconsin Card Sorting Test (WCST). However, the structure of executive deficits remains unclear, and the underlying processes may be differe...

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed wi...

Objective There is high prevalence of cigarette smoking in individuals with first-episode psychosis (FEP) prior to psychosis onset. The purpose of the study was to determine the impact of previous tobacco use with or without cannabis on first psychotic experiences in FEP and the impact of this use on age of onset of symptoms, including prodromes....

Objective: To study the differences in early-life characteristics between patients with an early onset of psychotic disorders (EOP, aged < 18 years) versus adult onset of psychotic disorders (AOP, aged ≥ 18 years) and to identify predictors of earlier onset. Methods: 278 patients with a first episode of psychosis between the ages of 7 and 35 years...