Early Intervention In Schizophrenia Research Articles

Prospects for Neurotrophic Factor-Based Early Intervention in Schizophrenia: Lessons Learned from the Effects of Antipsychotic Drugs on Cognition, Neurogenesis, and Neurotrophic Factors.

Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcomes. However, the most commonly prescribed antipsychotic drugs (APDs) show only marginal beneficial effects on cognition in patients with schizophrenia. The neural mechanisms underlying cognitive disturbances in schizophrenia remain unknown that making drug development efforts very challenging. Since neurotrophic factors are the primary architects of neurogenesis, synaptic plasticity, learning, and memory, the findings from preclinical and clinical studies that assess changes in neurogenesis and neurotrophic factors and their relationship to cognitive performance in schizophrenia, and how these mechanisms might be impacted by APD treatment, may provide valuable clues in developing therapies to combat cognitive deficit in schizophrenia. Numerous evidence produced over the years suggests a deficit in a wide spectrum of neurotrophic factors in schizophrenia. Since schizophrenia is considered a neurodevelopmental disorder, early intervention with neurotrophic factors may be more effective in ameliorating the cognitive deficits and psychopathological symptoms associated with this pathology. In this context, results from initial clinical trials with neurotrophic factors and their future potential to improve cognition and psychosocial functioning in schizophrenia are discussed.

P.0768 Early intervention in schizophrenia: highlight of a specific time-window for the rescue of PVI maturation impairments through MMP9/RAGE pathway inhibition

P.0768 Early intervention in schizophrenia: highlight of a specific time-window for the rescue of PVI maturation impairments through MMP9/RAGE pathway inhibition

Subtyping based on premorbid profile: A strategy to personalize treatment in first‐episode affective psychosis

Premorbid history may have a major influence on the way patients cope with the onset of psychosis. This issue has been widely studied in the context of early intervention in schizophrenia but considerably less is known regarding affective psychosis. Our first goal was to investigate if subgroups could be identified among affective psychosis patients based on premorbid factors. Our second goal was to compare these subtypes according to the evolution of mood symptoms and outcomes at the end of the program. We conducted a 3-year prospective study on a sample of 74 adults aged 18-35 with a first episode of affective psychosis. Latent class analysis (LCA) was used to reveal distinct exploratory subgroups within affective psychosis patients. Three distinct subgroups could be distinguished. One with later onset of psychosis mainly including women with more severe depressive symptoms in the first 6 months contrasting with two other subgroups with more severe manic symptoms all along the follow-up and earlier onset of psychosis, with or without many serious antecedents. The subgroup with many serious antecedents was more likely to require several hospitalizations, less likely to achieve recovery, especially regarding professional integration and return to premorbid general functioning. This study provides further evidence of poor functional recovery in the early phase of affective psychosis and shows that premorbid characteristics allow the identification of subgroups with distinct outcome which may require specification of treatment.

Schizophrenia and education in Chinese metropolises: a population-based study.

Schizophrenia is a public concern in metropolises. Increases in city size may strengthen the correlation between prevalence of schizophrenia and indices of socioeconomic status, such as education. This study used population-based data of adults to investigate the association between education and schizophrenia in Chinese metropolises and its differences between inner city areas and outer suburbs. Data was obtained from the Second China National Sample Survey on Disability in 2006, and analysis was restricted to 189,143 participants aged 18years or older in all counties (districts) of Beijing, Shanghai, and Tianjin. Schizophrenia diagnoses were ascertained according to the International Statistical Classification of Diseases, 10th Revision. Logistic regression models were fitted to examine the association between education and schizophrenia. An inverse U-shaped pattern between education and schizophrenia was found in inner city areas of Chinese metropolises. Compared with the primary school or below group, the odds ratios of junior high school group and senior high school or above group was 2.79 (95% CI 1.96, 3.96) and 1.45(95% CI 0.99, 2.13), respectively. In outer suburbs, junior high school (OR = 0.87, 95% CI 0.63, 1.19) and senior high school or above groups (0.58, 95% CI 0.38, 0.87) were less likely to develop schizophrenia than the primary school or below group. This study showed an association between education and schizophrenia in Chinese metropolises. In inner city areas, the association was an inverse U-shaped pattern between education and schizophrenia, whereas in suburban areas, the association was anegative linearpattern. Our findings can help identify high-risk populations of schizophrenia in Chinese metropolises. Programs for prevention and early intervention of schizophrenia will need to consider the socioeconomic disparities between inner city and outer suburban areas. Public policies can help improve mental health by developing social security for migrants in inner city areas and promoting regional equality.

UNDERSTANDING SCHIZOPHRENIA, UNIFYING THE PHENOMENOLOGICAL AND COGNITIVE SCIENCES APPROACHES

Both philosophy and cognitive science have made valuable contributions towards accounting for the aetiology of Schizophrenia, an illness that possesses a disparate assortment of symptoms. However, there is no firm agreement on what causes such experiences to arise. A theory is proposed which simplifies the signs and symptoms of Schizophrenia and is something which does not appear to exist in the field to date. The model proposed is a hybrid theory, combining the phenomenological approach of Sass and Parnas with elements from Frith and Hemsley’s cognitive science perspective. An argument is that if a hybrid theory was used it would assist in the early intervention of Schizophrenia by providing a focus for treatment during developmental stages. Keywords: psychiatric practice, cognitive science, early intervention in Schizophrenia, prodromal symptoms in Schizophrenia, unification of symptom clusters in Schizophrenia.

Shortening Duration of Treatment Resistance: The Next Step in the Treatment of Schizophrenia

Abstract The early psychosis movement was fuelled by the concept that early recognition and treatment of patients with psychosis could prevent long-term chronic impairment. Indeed, duration of untreated psychosis (DUP) predicts treatment response and early intervention services have since shown added value. However, considerable chronic impairment remains, with about 20%–30% of the patients with schizophrenia not responding to 2 different conventional antipsychotics in adequate doses and duration. In contrast to the research on DUP and early intervention in schizophrenia in general, far less research has systemically assessed the benefits of shortening the time between treatment onset and adequate treatment response. Yet timely recognition of treatment-resistant schizophrenia (TRS) could be vital since studies have indicated that a critical time window in which clozapine is most effective for TRS patients could exist. We believe that introducing the concept of Duration of Treatment Resistance (DTR) may help to investigate whether shortening of DTR by optimizing medication schedules can further prevent or mitigate long-term disability in patients with schizophrenia. In this editorial, we propose a definition of DTR and encourage the field to investigate the potential merits of this concept in future studies.

Recent Advances in the Early Intervention in Schizophrenia: Future Direction from Preclinical Findings.

In the past decade, there has been increasing interest in the potential benefit of early intervention in schizophrenia. Patients with schizophrenia show cognitive impairment for several years preceding the onset of psychosis. The author discusses the recent topics on prevention of schizophrenia. Preclinical findings suggest that maternal immune activation (MIA) produces cognitive deficits as a prodromal symptom in juvenile offspring in rodents. Treatment with anti-inflammatory compounds, such as D-serine, 7,8-dihydroxyflavone (a TrkB agonist), sulforaphane (or its precursor glucoraphanin), and TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea: a soluble epoxide hydrolase inhibitor), during adolescence might prevent the onset of behavioral abnormalities and parvalbumin immunoreactivity in the medial prefrontal cortex of adult offspring after MIA. Based on the role of inflammation and cognitive impairment in the prodromal state, early intervention using anti-inflammatory compounds (i.e., D-serine, sodium benzoate, TrkB agonist, Nrf2 agonist, soluble epoxide hydrolase inhibitor) may reduce the risk of subsequent transition to schizophrenia.

The effect of a mindfulness-based intervention in cognitive functions and psychological well-being applied as an early intervention in schizophrenia and high-risk mental state in a Chilean sample: study protocol for a randomized controlled trial

BackgroundAccording to the projections of the World Health Organization, 15% of all disabilities will be associated with mental illnesses by 2020. One of the mental disorders with the largest social impacts due to high personal and family costs is psychosis. Among the most effective psychological approaches to treat schizophrenia and other psychotic disorders at the world level is cognitive behavioral therapy. Recently, cognitive behavioral therapy has introduced several tools and strategies that promote psychological processes based on acceptance and mindfulness. A large number of studies support the effectiveness of mindfulness in dealing with various mental health problems, including psychosis. This study is aimed at determining the efficiency of a mindfulness-based program in increasing cognitive function and psychological well-being in patients with a first episode of schizophrenia and a high risk mental state (those at risk of developing an episode of psychosis).Methods and designThis is an experimentally designed, multi-center randomized controlled trial, with a 3-month follow-up period. The study participants will be 48 patients diagnosed with schizophrenia (first episode) and 48 with a high-risk mental state, from Santiago, Chile, aged between 15 and 35 years. Participants will be submitted to a mindfulness-based intervention (MBI), which will involve taking part in eight mindfulness workshops adapted for people with psychosis. Workshops will last approximately 1.5 hours and take place once a week, over 8 weeks. The primary outcome will be the cognitive function through Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the secondary outcome will be psychological well-being measured by self-reporting questionnaires.DiscussionThe outcomes of this trial will add empirical evidence to the benefits and feasibility of MBIs for the psychotherapeutic treatment of patients with schizophrenia and high-risk mental states in reducing cognitive impairment in attention, working memory, and social cognition, as well as increasing the psychological well-being by empowering the patients’ personal resources in the management of their own symptoms and psychotic experiences.Trial registrationISRCTN registration number ISRCTN24327446. Registered on 12 September 2016.

The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring

To date, diagnosis of schizophrenia is still based on clinical interviews and careful observations, which is subjective and variable, and can lead to misdiagnosis and/or delay in diagnosis. As early intervention in schizophrenia is important in improving outcomes, objective tests that can be used for schizophrenia diagnosis or treatment monitoring are thus in great need. MicroRNAs (miRNAs) negatively regulate target gene expression and their biogenesis is tightly controlled by various factors including transcription factors (TFs). Dysregulation of miRNAs in brain tissue and peripheral blood mononuclear cells (PBMNCs) from patients with schizophrenia has been well documented, but analysis of the sensitivity and specificity for potential diagnostic utility of these alternations is limited. In this study, we explored the TF-miRNA-30-target gene axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. Using bioinformatics analysis, we retrieved all TFs that control the biogenesis of miRNA 30 members as well as all target genes that are regulated by miRNA-30 members. Further, reverse transcription-quantitative PCR analysis revealed that the early growth response protein 1 (EGR1) and miR-30a-5p were remarkably downregulated, whereas neurogenic differentiation factor 1 (NEUROD1) was significantly upregulated in PBMNCs from patients in acute psychotic state. Antipsychotics treatment resulted in the elevation of EGR1 and miR-30a-5p but the reduction of NEUROD1. Receiver operating characteristic analysis showed that the EGR1-miR-30a-5p-NEUROD1 axis possessed significantly greater diagnostic value than miR-30a-5p alone. Our data suggest the EGR1-miR-30a-5p-NEUROD1 axis might serve as a promising biomarker for diagnosis and treatment monitoring for those patients in acute psychotic state.

The Harms of Antipsychotic Drugs: Evidence from Key Studies.

This safety assessment provides a detailed analysis of key studies and focuses on the six most widely used antipsychotic drugs. Lines of evidence include mechanisms of action, short-term treatment of psychosis, relapse prevention, early intervention in schizophrenia, long-term comparisons between first- and second-generation agents, and flexible treatment algorithms. Despite the diversity of study settings, several common features were seen. All the agents obstruct normal signaling through widely dispersed dopamine D2 receptors. Treatment failure or psychosis relapse was the most frequent outcome in most key studies, ranging from 38 to 93%. High discontinuation rates caused most trials to fail to demonstrate a substantial treatment benefit, or difference from an active comparator. Assessment of harm to the extrapyramidal motor system was confounded because of extensive neurological impairment from previous antipsychotic drug treatment measured at baseline, abrupt discontinuation effects, and high rates of concomitant medications to manage drug adverse effects. Claims that second-generation antipsychotic drugs have safety advantages over classical neuroleptic drugs and prevent relapse were not supported in these key studies. The extent of injury to and impairment of multiple body systems caused by antipsychotic drugs shows the need for a scientific, clinical, and regulatory reappraisal of the appropriate use of these agents.

New Targets for Prevention of Schizophrenia: Is It Time for Interventions in the Premorbid Phase?

A number of influences have converged that make this Special Theme Issue timely: "A New Direction: Considering Developmentally Sensitive Targets for Very Early Intervention in Schizophrenia". These factors include: 1. the substantial knowledge about premorbid developmental vulnerabilities to psychosis, especially regarding schizophrenia; 2. the promising results emerging from interventions during the clinical high-risk (CHR) phase of psychosis and; 3. the recognition that the CHR period is a relatively late phase of developmental derailment. These factors have together led to a perspective that even earlier intervention is warranted. This paper briefly summarizes the articles comprising the Special Theme including new data on early neurocognitive development, proposed potential targets for psychosocial and psychopharmacological interventions during the premorbid period as early as pregnancy, and ethical challenges. These thought experiments must be empirically tested, and the ethical challenges overcome as posed by the various interventions, which range from relatively low risk, supportive, psychosocial to higher risk, experimental, pharmacological interventions. All of the interventions proposed require careful study of ethics, safety, potential stigma, feasibility, efficacy and tolerability, and the meaning to the people involved.

Development of liability syndromes for schizophrenia: Where did they come from and where are they going?

Three decades after Paul Meehl proposed the term "schizotaxia" to describe a conceptual framework for understanding the liability to schizophrenia, Ming Tsuang et al. at Harvard University reformulated the concept as a clinical syndrome with provisional research criteria. The reformulated view relied heavily on more recent data showing that many non-psychotic, un-medicated biological relatives of individuals with schizophrenia showed difficulties in cognitive and other clinical functions that resembled those seen in their ill relatives. The reformulation raised questions about both whether and when liability could be assessed validly in the absence of psychosis, and about the extent to which symptoms of liability are reversible. Both questions bear on the larger issue of early intervention in schizophrenia. This article reviews the efforts of Tsuang et al. to conceptualize and validate schizotaxia as one such syndrome of liability. Towards this end, liability is considered first more generally as an outcome of interactive genetic and environmental factors. Liability is then considered in the context of endophenotypes as a concept that is both broader and is potentially more specific (and predictive) than many DSM or ICD diagnostic symptoms. Liability syndromes are then considered in the context of their proximity to illness, first by reviewing prodromal syndromes (which are more proximal), and then by considering schizotaxia, which, as it is currently formulated, is pre-prodromal and, therefore, less proximal. Finally, challenges to validation and future directions for research are considered.

Cognitive remediation in schizophrenia: efficacy and effectiveness in patients with early versus long‐term course of illness

We examined the efficacy and effectiveness (transfer to functional competence and everyday functioning) of cognitive remediation in early-course (within 5 years of first episode) and long-term (more than 15 years of illness) schizophrenia. Treatment lasted 12 weeks and included computerized exercises, strategic monitoring and methods to transfer cognition to behaviour. Assessments included a standard battery of neurocognition, performance-based measures of social and adaptive competence, and case manager ratings of real-world functional behaviour. Changes from baseline to post-treatment were examined with repeated measures analysis of variance and estimated premorbid intelligence and total months in hospital as covariates. The early-course group had larger improvements in measures of processing speed and executive functions, as well as larger improvements in adaptive competence and real-world work skills. Duration of illness was inversely associated with improvement in neurocognition and real-world work skills. Treatment of cognitive impairments is feasible in both early-course and chronic schizophrenia, but the clinical meaningfulness and generalization to functioning appear to be more substantial when delivered early. Cognitive remediation should be considered a tool for early intervention in schizophrenia.

Prophylactic valproic acid treatment prevents schizophrenia-related behaviour in Disc1-L100P mutant mice.

BackgroundSchizophrenia is a neurodevelopmental disorder with onset early in adulthood. Disrupted-In-Schizophrenia-1 (DISC1) is a susceptibility gene for schizophrenia and other psychiatric disorders. Disc1-L100P mutant mice show behaviors relevant to schizophrenia at 12 weeks, but not at 8 weeks of age, and may be useful for investigating the onset of schizophrenia in early adulthood.MethodsWe investigated whether early valproic acid treatment would prevent behavioral, cellular and gene expression abnormalities in Disc1-L100P mutants.ResultsValproic acid prevented hyperactivity and deficits in prepulse inhibition and latent inhibition in Disc1-L100P mice. Genome-wide transcription profiling identified Lcn2 (lipocalin2) transcripts as being elevated by the Disc1 mutation and corrected by valproate. Disc1-L100P mice also had increased glial cell numbers in the subventricular zone, which was normalized by valproate. Genetic deletion of Lcn2 normalized glial cell numbers and behavior in Disc1-L100P mutants.ConclusionsPharmacological treatments are a feasible way of preventing abnormal behaviour in a genetic model of schizophrenia. Lcn2 is a potential novel drug target for early intervention in schizophrenia.

RAISE: Early Intervention in Schizophrenia Put to the Test

RAISE: Early Intervention in Schizophrenia Put to the Test

Early intervention in schizophrenia in developing countries: Focus on duration of untreated psychosis and remission as a treatment goal

Early intervention services are based on the premise that untreated psychosis may have a deleterious effect on outcome, particularly in the early years of illness. The majority of the studies on duration of untreated psychosis have been conducted in developed countries; therefore this review focuses on publications from developing countries. We also review studies from developing countries that have been published following the Remission in Schizophrenia Working Group criteria.The duration of untreated psychosis is longer in developing countries, and is also associated with poor outcome, whereas remission rates following treatment of first-episode schizophrenia in developing countries appear to be higher than in developed countries. These two findings strongly argue for the establishment of early intervention services for schizophrenia in developing countries.

Process of implementation and development of early psychosis clinical services in Italy: a survey

To carry out an in-depth survey into the method of providing early intervention in schizophrenia in Italy and to evaluate the process of development of early psychosis clinical services following the pilot programme 'Programma 2000' and the publishing of Italian National Guidelines. Topic-specific national and international clinical and research programmes, alongside national guidelines, were taken into consideration in order to create an ad hoc questionnaire. A telephone survey using this questionnaire was carried out. A randomized sample of 152 mental health centres (MHCs) were involved, equal to 21.5% of all Italian MHCs. The process of nationwide diffusion of early psychosis clinical services in Italy is frustratingly slow. Italian MHCs, including a specialized service for early interventions in schizophrenia, are estimated at being between 20% and 30%. Most services adopt a generalist approach and more frequently follow guidelines drawn up within the centres than Italian National Guidelines, involve few patients and provide a high variability of treatment options. The distribution of these services in Italy is not homogenous and influenced by demographic factors. Our data are consistent with worldwide literature showing a slow and variable implementation of early psychosis services in all nations. The main efforts to make these services diffused should be addressed to favour the process of localized adaptation to the guidelines, to demand possible and realistic implementation of the standard method, to stimulate policy endorsement and resources' allocation, and to particularly support the rural and the poorer zones.

Effect of an Education Program on Improving Help-Seeking among Parents of Junior and Senior High School Students in Japan

Early intervention in schizophrenia is important for patient prognosis and quality of life. At the time of the first episode, quality of life is influenced by identification of symptoms and by medical help-seeking behavior. In this prospective cohort study, we investigated help-seeking among 2690 parents of junior and senior high school students before and after the parents viewed a newly developed web-based education program aimed at improving knowledge of schizophrenia. Our web-based education program aimed to improve understanding of schizophrenia, including promotion of help-seeking. Many parents (33.1%-50.0%) consulted a physician in a department of psychosomatic medicine when their child experienced symptoms. Characteristics that predicted a decision not to seek psychiatric medical help were having child with all symptoms, younger parent age, and lower family income (p<0.05). After the education program, the rate of parents who sought medical help within 1 week was significantly higher for all symptom categories except sleeplessness (p=0.001). These findings suggest that the present web-based education program was useful in promoting medical help-seeking behavior among parents of junior and senior high school students in Japan.

Early Intervention for Psychosis

Background Proponents of early intervention have argued that outcome might be improved if more therapeutic effort were focused on the early stages of schizophrenia. Early intervention in schizophrenia has two elements that are distinct from standard care: early detection and phase-specific treatment. Both elements may be offered in addition to standard care, or may be provided by a specialised early intervention team. Early intervention is now well established as a therapeutic approach in America, Europe and Australasia, but it is unclear how far early detection, phase-specific treatments, and the use of early intervention teams are underpinned by evidence of effectiveness. Objectives This review aims to evaluate the effects of: i. early detection and treatment of people with prodromal symptoms; ii. the use of early intervention teams for people in their first episode of psychosis; and iii. phase-specific treatments for people in their first episode of psychosis. Search strategy We searched CINAHL (1982-2002), The Cochrane Controlled Trials Register (November 2001), The Cochrane Schizophrenia Group Register (July 2003), EMBASE (1980-2002), MEDLINE (1966-2002), PsycINFO (1967-2002), reference lists and contacted the European First Episode Network (2003). Selection criteria Randomised controlled trials designed to prevent progression to psychosis in people showing prodromal symptoms, or improve outcome for people with first episode psychosis. Eligible interventions, alone and in combination, included early detection, phase-specific treatments, and care from specialised early intervention teams. Non-randomised trials would only have been included if they had been studies of the effects of early detection strategies in reducing the duration of untreated psychosis (since this issue cannot be addressed by simple randomisation). Data collection and analysis Data were extracted independently by two reviewers and cross-checked. Relative risks (RR) and 95% confidence intervals (CI) were calculated for dichotomous data. Weighted mean differences (WMD) were calculated for continuous data. Main results In theory, seventeen different comparisons are possible, but the review only identified three studies that met inclusion criteria. One small trial (n=59) was concerned with a phase-specific intervention (low dose risperidone and cognitive behavioural therapy) for people with prodromal symptoms. This group were significantly less likely to develop psychosis at 6 month follow up than people who only received care from a specialised team which did not involve phase-specific treatment (n=59, 1 RCT, RR 0.27 CI 0.08 to 0.89, NNT 4 CI 2 to 20). This effect was not significant at 12 month follow up (n=59, 1 RCT, RR 0.54 CI 0.23 to 1.30). Another trial found that people in their first episode receiving a phase-specific intervention (family therapy) plus out patient care did have reduced admission rates care compared with those who received only outpatient care (n=83, 1 RCT, RR 0.28 CI 0.13 to 0.62, NNT 3 CI 2 to 6). The applicability of this finding was, however, questionable.Finally, one last study (n=76), comparing phase-specific intervention (family therapy) plus specialised team with specialised team for people in their first episode of schizophrenia found no difference between intervention and control groups at 12 months for the outcome of relapse but confidence intervals were wide (n=76, RR 1.06 CI 0.31 to 3.65). Reviewers' conclusions We identified insufficient trials to draw any definitive conclusions, although five ongoing trials should report shortly. The substantial international interest in early intervention offers an opportunity to make major positive changes in psychiatric practice, but this opportunity may be missed without a concerted international programme of research to address key unanswered questions.

Early Intervention for Schizophrenia: The Risk-Benefit Ratio of Antipsychotic Treatment in the Prodromal Phase

Early Intervention for Schizophrenia: The Risk-Benefit Ratio of Antipsychotic Treatment in the Prodromal Phase