Covadonga M. Díaz-Caneja

Predictors of outcome in early-onset psychosis: a systematic review

Given the global burden of psychotic disorders, the identification of patients with early-onset psychosis (EOP; that is, onset before the age of 18) at higher risk of adverse outcome should be a priority. A systematic search of Pubmed, Embase, and PsycInfo (1980 through August 2014) was performed to identify longitudinal observational studies assessing correlates and/or predictors of clinical, functional, cognitive, and biological outcomes in EOP. Seventy-five studies were included in the review. Using multivariate models, the most replicated predictors of worse clinical, functional, cognitive, and biological outcomes in EOP were premorbid difficulties and symptom severity (especially of negative symptoms) at baseline. Longer duration of untreated psychosis (DUP) predicted worse clinical, functional, and cognitive outcomes. Higher risk of attempting suicide was predicted by greater severity of psychotic illness and of depressive symptoms at the first episode of psychosis. Age at onset and sex were not found to be relevant predictors of outcome in most multivariate models, whereas studies using bivariate analyses yielded inconsistent results. Lower intelligence quotient at baseline predicted lower insight at follow-up, worse functional outcomes, and a diagnostic outcome of schizophrenia. Biological predictors of outcome in EOP have been little studied and have not been replicated. Lower levels of antioxidants at baseline predicted greater brain volume changes and worse cognitive functioning at follow-up, whereas neuroimaging markers such as regional cortical thickness and gray matter volume at baseline predicted remission and better insight at follow-up, respectively. EOP patients with poorer premorbid adjustment and prominent negative symptoms at initial presentation are at risk of poor outcome. They should therefore be the target of careful monitoring and more intensive interventions to address whether the disease course can be modified in this especially severely affected group. Early intervention strategies to reduce DUP may also improve outcome in EOP.

Early interventions in risk groups for schizophrenia: what are we waiting for?

Intervention strategies in adolescents at ultra high-risk (UHR) for psychosis are promising for reducing conversion to overt illness, but have only limited impact on functional outcome. Recent studies suggest that cognition does not further decline during the UHR stage. As social and cognitive impairments typically develop before the first psychotic episode and even years before the UHR stage, prevention should also start much earlier in the groups at risk for schizophrenia and other psychiatric disorders. Early intervention strategies could aim to improve stress resilience, optimize brain maturation, and prevent or alleviate adverse environmental circumstances. These strategies should urgently be tested for efficacy: the prevalence of ~1% implies that yearly ~22 in every 100,000 people develop overt symptoms of this illness, despite the fact that for many of them—e.g., children with an affected first-degree family member or carriers of specific genetic variants—increased risk was already identifiable early in life. Our current ability to recognize several risk groups at an early age not only provides an opportunity, but also implies a clinical imperative to act. Time is pressing to investigate preventive interventions in high-risk children to mitigate or prevent the development of schizophrenia and related psychiatric disorders.

A longitudinal study on the relationship between duration of untreated psychosis and executive function in early-onset first-episode psychosis

BACKGROUND The relationship between duration of untreated psychosis (DUP) and executive function (EF) in patients with first-episode psychosis (FEP) is controversial. We aim to assess the influence of DUP on changes in EF over a 2-year period in subjects with early-onset FEP (first psychotic symptom before age 18) and less than 6 months of positive symptoms. METHODS A total of 66 subjects were included in the study (19 females [28.8%], mean age 16.2 ± 1.6 years). The influence of DUP on changes in EF over the 2-year follow-up (expressed as a composite score of 5 cognitive abilities: attention, working memory, cognitive flexibility, response inhibition, and problem solving) was estimated using a multivariate linear regression model after removing the effect of intelligence quotient and controlling for age, gender, diagnosis, premorbid adjustment, severity of positive and negative symptoms at baseline, global functioning at baseline, and mean daily antipsychotic dosage during follow-up. RESULTS Mean DUP was 65.0 ± 6.9 days (95% confidence interval [CI], 51.2, 78.8). Median DUP was 47.5 days (range 2-180 days). Negative symptoms at baseline was the only variable significantly associated with EF at baseline (10.9% of explained variance [e.v. 10.9%], p=0.007). Only shorter DUP (e.v. 8.7%, p=0.013) and greater severity of baseline negative symptoms (e.v. 10.0%, p=0.008) were significantly associated with greater improvement in EF. CONCLUSIONS In early-onset FEP, shorter DUP was associated with greater improvement in EF over a 2-year follow-up period.

Services for people at high risk improve outcomes in patients with first episode psychosis

About one‐third of patients referred to services for people at high risk for psychosis may have already developed a first episode of psychosis (FEP). We compared clinical outcomes in FEP patients who presented to either high risk or conventional mental health services.

Empirical redefinition of delusional disorder and its phenomenology: the DELIREMP study

AIMS Since Kraepelin, the controversy has persisted surrounding the nature of delusional disorder (DD) as a separate nosological entity or its clinical subtypes. Nevertheless, there has been no systematic study of its psychopathological structure based on patient interviews. Our goal was to empirically explore syndromic subentities in DD. METHODS A cross-sectional study was conducted in 86 outpatients with DSM-IV-confirmed DD using SCID-I. Psychopathological factors were identified by factor analysis of PANSS scores. The association between these factors and clinical variables (as per standardized instruments) was analyzed using uni- and multivariate techniques. RESULTS PANSS symptoms were consistent with four factors (Paranoid, Cognitive, Schizoid, and Affective dimensions), accounting for 59.4% of the total variance. The Paranoid Dimension was associated with premorbid paranoid personality disorder, more adverse childhood experiences, chronic course, legal problems, worse global functioning, and poorer treatment adherence and response. The Cognitive Dimension was associated with poorer cognitive functioning, premorbid substance abuse, comorbid somatic diseases, mainly non-prominent visual hallucinations, fewer comorbid depressive disorders, and poorer global functioning. The Schizoid Dimension was associated with being single, a family history of schizophrenia, premorbid personality disorders (largely schizoid and schizotypal), non-prominent auditory hallucinations, and dysthymia. Finally, the Affective Dimension was associated with a family history of depression, premorbid obsessive personality, somatic delusions, absence of reference delusions, tactile and olfactory hallucinations, depressive and anxiety disorders, risk of suicide, and higher perceived stress. CONCLUSION The identification and clinical validation of four separate psychopathological dimensions in DD provide evidence toward a more accurate conceptualization of DD and its types.

Mental disorders of known aetiology and precision medicine in psychiatry: a promising but neglected alliance

Personalized or precision medicine is predicated on the assumption that the average response to treatment is not necessarily representative of the response of each individual. A commitment to personalized medicine demands an effort to bring evidence-based medicine and personalized medicine closer together. The use of relatively homogeneous groups, defined using a priori criteria, may constitute a promising initial step for developing more accurate risk-prediction models with which to advance the development of personalized evidence-based medicine approaches to heterogeneous syndromes such as schizophrenia. However, this can lead to a paradoxical situation in the field of psychiatry. Since there has been a tendency to loosely define psychiatric disorders as ones without a known aetiology, the discovery of an aetiology for psychiatric syndromes (e.g. 22q11.2 deletion syndrome in some cases of schizophrenia), while offering a path toward more precise treatments, may also lead to their reclassification away from psychiatry. We contend that psychiatric disorders with a known aetiology should not be removed from the field of psychiatry. This knowledge should be used instead to guide treatment, inasmuch as psychotherapies, pharmacotherapies and other treatments can all be valid approaches to mental disorders. The translation of the personalized clinical approach inherent to psychiatry into evidence-based precision medicine can lead to the development of novel treatment options for mental disorders and improve outcomes.

Oxidative Stress and Inflammation in Early Onset First Episode Psychosis: A Systematic Review and Meta-Analysis

Abstract Background: People with schizophrenia and other psychosis show increased proinflammatory and prooxidative status. However, the few studies that have specifically assessed oxidative and inflammatory markers in early onset psychosis (onset before age 18) have shown contradictory results. Methods: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews and meta-analyses were used to conduct a systematic literature search to detect studies comparing inflammatory and oxidative markers in early onset psychosis patients and healthy controls. Results: Seven studies met criteria for the qualitative analysis. Four studies met criteria for meta-analysis, comprising an overall sample of 261 early onset psychosis patients and 246 healthy controls. Six independent meta-analyses were performed for catalase, glutathione, glutathione peroxidase, superoxide dismutase, total antioxidant status, and cell/DNA oxidative damage. No significant differences were found between early onset psychosis patients and controls in any of the parameters assessed. Heterogeneity among studies was high. Qualitative analysis of individual studies showed an association of inflammatory and oxidative markers with clinical, cognitive, and neurobiological outcomes, especially in longitudinal assessments. Conclusions: Despite the lack of significant differences between early onset psychosis patients and controls in the oxidative markers assessed in the meta-analyses, results based on individual studies suggest that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first episodes of early onset psychosis.

Polypharmacy with antidepressants in children and adolescents

The aim of this study was to review current epidemiological data on the use of antidepressants in co-prescription with other psychotropic drugs in children and adolescents, as well as available efficacy and safety information. A Medline search from inception until February 2012 was performed to identify epidemiological and clinical studies, reviews and reports containing potentially relevant information on polypharmacy with antidepressants in young people. There has been an increase in polypharmacy in children and adolescents involving antidepressants in recent years. Antidepressants have become one of the drug classes most frequently prescribed in combination and are commonly co-prescribed with stimulants and antipsychotics. Most information regarding efficacy and safety of polypharmacy patterns was provided by case series and open-label studies. Efficacy studies gave some support for the use of a combination of antidepressants and antipsychotics in the management of refractory obsessive-compulsive disorder and some residual symptoms in major depressive disorder. Even less empirical support was found for a combination of stimulants and antidepressants in co-morbid attention deficit hyperactivity disorder and mood or anxiety disorders. Adverse events were similar to those found with individual medication groups, with severe adverse events mostly reported by individual case reports. The use of polypharmacy with antidepressants has become a regular practice in clinical settings. Although there is still little efficacy and safety information, preliminary evidence points to the potential clinical usefulness of some polypharmacy patterns. Further research on patients with co-morbidities or more severe conditions is needed, in order to improve knowledge of this issue.

A Pharmacovigilance Study in First Episode of Psychosis: Psychopharmacological Interventions and Safety Profiles in the PEPs Project

Background: The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. Methods: Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. Results: The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). Conclusions: These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines.

Clinical, Cognitive, and Neuroimaging Evidence of a Neurodevelopmental Continuum in Offspring of Probands With Schizophrenia and Bipolar Disorder

Background Studies in child and adolescent offspring of patients with schizophrenia or bipolar disorders may help understand the influence of neurodevelopmental factors on the premorbid phenotype of these disorders. Aims To assess whether a combination of neurodevelopmental factors discriminates between young offspring of patients with schizophrenia (SzO) or bipolar disorder (BpO) and community controls (CcO). To assess the association between these factors and rates of psychiatric diagnoses in high risk (HR) youth. Methods One hundred thirty-three HR offspring (47 SzO and 86 BpO) and 84 CcO, aged 6-17, underwent cross-sectional clinical, neurocognitive, and structural neuroimaging assessment. Information on perinatal events and early childhood development was also obtained. General linear mixed models were performed to assess group discrimination and association with lifetime axis I psychiatric disorders. Results Multivariate analyses revealed that greater neurological soft signs (NSS), less total grey matter volume (GMV) and a higher frequency of obstetric complications discriminated HR offspring from CcO. When comparing each group individually, greater NSS and a higher frequency of obstetric complications discriminated SzO from CcO, and BpO from CcO, while lower intelligence also discriminated SzO from CcO and from BpO. Within HR offspring, lower intelligence and less total GMV were associated with lifetime incidence of psychiatric disorders. Conclusions Both SzO and BpO showed evidence of neurodevelopmental insult, although this may have a greater impact in SzO. Lower intelligence and less total GMV hold potential as biomarkers of risk for psychiatric disorders in HR youth.