Early-onset Schizophrenia Spectrum Disorders Research Articles

The NIMH-CATIE Schizophrenia Study: What Did We Learn?

It has been over 10 years since the initiation of the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and 5 years since the first publication of its primary results (1). In this period, the initial report has been cited in the literature over 1,600 times (2) while more than 80 articles from the study’s extensive database (Table 1), as well as a book serving as an archive of the study’s results and implications (3), have been published. In the meantime, several more randomized trials comparing the effectiveness of antipsychotics have been completed (4–6), meta-analyses that bear on the findings of the CATIE study have been performed (7, 8), and commentaries on CATIE’s findings and critiques of its methodology have been published (9–11). All of these help us to view the CATIE study in a broader context and enable us to determine what we really learned from it. When the CATIE study was designed in 1999– 2000, the prevailing opinion of researchers and clinicians alike was that the newer (second-generation) antipsychotic drugs were vastly superior to the older (first-generation) antipsychotic drugs in efficacy and safety. This largely reflected the results of studies sponsored by the manufacturers of the new drugs (12, 13), marketing messages of pharmaceutical companies and the hopes of many who wanted better treatments. Indeed, the hypothesis and expectation of the CATIE study investigators was that the firstgeneration antipsychotic perphenazine would be inferior to the newer agents. Consequently, the finding that perphenazine was similar in effectiveness to most other medications had a profound effect that extended beyond the scientific and psychiatric communities to the lay public and various stakeholder groups. Somewhat sensational news reports decried the preferential use and greater cost of the newer medications and the marketing practices that led to them. For example, the September 21, 2005, editorial page of The New York Times opined, “A government-financed study has provided the strongest evidence yet that the system for approving and promoting drugs is badly out of whack. The study compared five drugs used to treat schizophrenia and found that most of the newest, most heavily prescribed drugs were no better than an older drug that is far cheaper. The nation is wasting billions of dollars on heavily marketed drugs that have never proved themselves in head-to-head competition against cheaper competitors” (14). But what did we really learn from the CATIE study? In this commentary, we summarize its major implications and their relevance to clinical practice. We will also address some of the study’s most relevant critiques.

Prefrontal hyperactivation during a working memory task in early-onset schizophrenia spectrum disorders: An fMRI study

Working memory (WM) dysfunction is increasingly recognized as a core feature of schizophrenia, but few studies have investigated prefrontal activation during WM tasks in early-onset schizophrenia spectrum disorder (EOS). Our aim was to explore prefrontal activation during a WM-task in EOS patients compared to healthy controls using functional magnetic resonance imaging (fMRI). Fifteen patients with EOS and 15 matched healthy controls performed a 0-back and a 2-back task while fMRI data were acquired. Results indicated that even though performance between patients and controls was comparable on both tasks, there was a hyperactivation in patients' ventrolateral prefrontal cortex (VLPFC) during the 2-back task compared to healthy controls. This pattern of activation suggests that, in patients with EOS, the VLPFC compensated in order to match performance of the controls. The activations in the EOS group may reflect the use of a compensatory, cognitive strategy while solving WM-tasks.

Increased familiarity of intellectual deficits in early-onset schizophrenia spectrum disorders

Objectives. Early-onset schizophrenia is considered to be neurobiologically similar to adult-onset forms, although it represents a more severe expression of the disorder. In the present study, we explored putative larger familial vulnerability of intellectual impairments in early-onset schizophrenia spectrum disorders (EOS) when compared to adult-onset (AOS) families. Methods. A sample of 340 subjects including schizophrenia spectrum disorder patients, their first degree relatives and age-matched healthy controls was assessed on intelligence quotient (IQ). We used linear regression analysis and intraclass correlation coefficients (ICC) to explore familial aggregation of IQ across age at onset groups. Results. The relationship between IQ level of patients and their first-degree relatives showed positive linear association (β = 0.43, P < 0.01). High significant familial aggregation was found for intelligence quotient in EOS families (ICC = 0.618, P < 0.01), while AOS families responded to lower estimates (ICC = 0.204, P = 0.26; between ICC comparison z = 1.993, P < 0.05). Conclusions. High aggregation of intellectual performance in the EOS group suggests larger familial vulnerability in early-onset forms of the disease when cognitive functions are considered. Within a continuum of psychopathology in schizophrenia spectrum disorders, specific genetic effects are discussed for distinct onset forms that might be in line with a neurodevelopmental model of the disease.

Outcome in early-onset schizophrenia revisited: Findings from the Early Psychosis Prevention and Intervention Centre long-term follow-up study

Objective To compare the long-term outcome in individuals with early-onset (before age 18) and adult-onset schizophrenia spectrum disorder who were initially diagnosed and treated in the same clinical center. Method A prospective follow-up study of 723 consecutive first-episode psychosis patients (age range 14 to 30 years) on average 7.4 years after initial presentation to an early psychosis service, the Early Psychosis Prevention and Intervention Centre in Melbourne, Australia. The outcome measures included the Brief Psychiatric Rating Scale, the Schedule for the Assessment of Negative Symptoms, the Beck Depression Inventory, the Global Assessment of Functioning Scale, the Social and Occupational Functioning Assessment Scale, and the Quality of Life Scale. Results Follow-up interviews were conducted on 66.9% (484/723) individuals, of whom 75.6% (366/484) received a schizophrenia spectrum disorder diagnosis at baseline. Early-onset schizophrenia spectrum disorder was observed in 11.2% (41/366). At follow-up, individuals with early-onset reported significantly fewer positive symptoms and were characterised by significantly superior functioning on measures assessing global functioning, social-occupational functioning, and community functioning than individuals with adult-onset. The early-onset group also achieved significantly better vocational outcomes and had a more favourable course of illness with fewer psychotic episodes over the last two years prior to follow-up. Finally, when investigated as a continuous variable, younger age at onset significantly correlated with better symptomatic and functional outcomes. Conclusions These results question the assumption that early-onset schizophrenia typically has a poor outcome. Early detection and specialised treatment for the first psychotic episode appear to be more effective at improving long-term functional outcomes in people with early-onset schizophrenia as in those with adult-onset schizophrenia. This possibility and the reasons for it need further investigation.

Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders

BackgroundOver the last few decades, research regarding the age of onset of schizophrenia and its relationship with other clinical variables has been incorporated into clinical practices. However, reports of potential differences in demographic and clinical characteristics between early- and adult-onset schizophrenia spectrum disorders have been controversial. Thus, this study aims to assess differences in demographic and clinical characteristics correlated with age of illness onset in schizophrenia spectrum disorders.MethodsData were collected from 104 patients with schizophrenia and schizoaffective disorder. Diagnosis was made via structured clinical interviews. Assessments of psychiatric symptoms and social and global functioning were completed. The effect of age of onset on demographic and clinical variables was examined using correlation analyses and binary logistic regression models. We chose 17 years of age as the cut-off for early-onset schizophrenia spectrum disorders based on a recent clinical consensus. We further investigated differences in the severity of psychopathology and other clinical variables between the early- and adult-onset groups.ResultsThe binary logistic regression analysis showed that age of onset was significantly related to the cognitive component of the Positive and Negative Syndrome Scale (PANSS) (odds ratio, OR = 0.58; 95% confidence interval, CI = 0.872-0.985; p < 0.001) and Barratt Impulsiveness Scale (BIS) score (OR = 0.94; 95% CI = 0.447-0.744; p = 0.015). Patients with early onset of schizophrenia spectrum disorders had significantly greater levels of cognitive impairment and higher impulsivity. There were significant differences between several demographic and clinical variables, including the negative symptom component of the PANSS (p < 0.001), cognitive component of the PANSS (p < 0.001), BIS score (p = 0.05), and psychological domain of quality of life (QOL) (p = 0.05), between patients with early- and adult-onset schizophrenia spectrum disorders, having controlled for the effect of the current age and duration of illness.ConclusionsOur findings support the hypothesis of an influence of age of onset on illness course in patients with schizophrenia spectrum disorders. This finding may in fact be part of a separate domain worthy of investigation for the development of interventions for early symptoms of schizophrenia.

Brain volumes in psychotic youth with schizophrenia and mood disorders

We sought to test the hypothesis that deficits in grey matter volume are characteristic of psychotic youth with early-onset schizophrenia-spectrum disorders (EOSS) but not of psychotic youth with early-onset mood disorders (EOMD). We used magnetic resonance imaging to examine brain volume in 24 psychotic youth (13 male, 11 female) with EOSS (n = 12) or EOMD (n = 12) and 17 healthy controls (10 male, 7 female). We measured the volume of grey and white matter using an automated segmentation program. After adjustment for age and intracranial volume, whole brain volume was lower in the EOSS patients than in the healthy controls (p = 0.001) and EOMD patients (p = 0.002). The EOSS patients had a deficit in grey matter volume (p = 0.005), especially in the frontal (p = 0.003) and parietal (p = 0.006) lobes, with no significant differences in white matter volume. The main limitations of our study were its small sample size and the inclusion of patients with depression and mania in the affective group. Adolescents with EOSS have grey matter deficits compared with healthy controls and psychotic adolescents with EOMD. Our results suggest that grey matter deficits are not generally associated with psychosis but may be specifically associated with schizophrenia. Larger studies with consistent methods are needed to reconcile the contradictory findings among imaging studies involving psychotic youth.

In This Issue/Abstract Thinking: Persistence of Symptoms in Child Psychiatry

This month's Journal highlights the richness and diversity of the issues, symptoms, and treatment approaches encompassed in the practice of child and adolescent psychiatry. This issue is international, including studies that took place in Singapore, the Netherlands, and Sierra Leone. Diverse diagnoses are considered, including autism, posttraumatic stress disorder and associated symptoms, substance abuse, attention-deficit/hyperactivity disorder (ADHD), and early-onset schizophrenia spectrum disorders.

Double-Blind Maintenance Safety and Effectiveness Findings From the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) Study

To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks. Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.

Neurocognition in Early-Onset Schizophrenia and Schizoaffective Disorders

We examined the neuropsychological functioning of youth enrolled in the NIMH funded trial, Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). We compared the baseline neuropsychological functioning of youth with schizophrenia (SZ, n = 79) to those with schizoaffective disorder (SA, n = 40), and examined the relationship of different variables of illness severity and adaptive behavior to neuropsychological functioning. Participants ranged in age from 8 to 19 years. Diagnostic status was confirmed via structured interview over multiple time points. Domains of neuropsychological functioning included fine-motor, attention, working memory, problem-solving efficiency, inhibitory control, and social cognition. Other variables included intelligence (IQ), academic achievement skills, adaptive behavior, and different measures of illness severity. The two groups did not differ on IQ or on any of the neuropsychological domains. The SZ group performed significantly lower in spelling. A high proportion of individuals in both groups reflected significant intellectual and academic achievement skill deficits. Significant correlations were found between the neurocognitive domains and both illness severity and adaptive behavior variables. There were few differences between the SZ and SA groups on IQ, achievement, or neuropsychological functioning; however, both groups showed significantly high rates of deficits in IQ and basic academic skills. Correlations of the neurocognitive functions with illness severity and adaptive behavior were small to moderate in magnitude. These findings continue to implicate the importance of neurocognitive functioning as a key area of vulnerability in the study of youth with schizophrenia spectrum disorders.

Aripiprazole in the treatment of early-onset schizophrenia spectrum disorder: A case series in Korean children and adolescents

Objective: The aim of this case series was to assess the effectiveness and tol-erability of aripiprazole in Korean children and adolescents with early-onset schizophrenia spectrum (EOSS) disorder. Methods: The medical records of aripiprazole-treated patients with EOSS were retrospectively reviewed. Changes in illness severity were measured using the Clinical Global Impression-Severity of Illness (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Results: Data from 22 children and adolescents were included (12 girls, 10 boys; mean [SD] age, 14.0 [2.4] years). The mean (SD) dosage of aripiprazole was 19.8 (9.4) mg/d (median, 18.7 mg/d; mode, 15, 30 mg/d), and the range of treatment duration was 21 to 838 days. Mean (SD) CGI-S score improved significantly from baseline to end point (from 5.7 [0.7] to 4.3 [1.4]; P < 0.001). Based on changes in chart-extracted CGI-I scores, significantly greater improvement was associated with negative symptoms compared with positive symptoms ( U = 25.5; P = 0.028; r = −0.47). Aripiprazole was discontinued due to insufficient effect in 5 patients (22.7%) and treatment-emergent adverse events in 3 patients (13.6%). Conclusion: The results from this small study suggest that aripiprazole was moderately effective in reducing psychotic symptoms in these Korean children and adolescents with EOSS.

Neuropsychological Profile in Early-Onset Schizophrenia-Spectrum Disorders: Measured With the MATRICS Battery

Neurocognitive impairments have been documented in adolescents with early-onset schizophrenia (EOS). There is still inconsistency regarding an average profile, which could be due to the fact that each study uses different tests. The purpose of this study was to examine whether the "Measurement and Treatment Research to Improve Cognition in Schizophrenia" (MATRICS) battery is useful in detecting differences between the patient group and the healthy controls, and to describe the neuropsychological pattern in the EOS group. Neuropsychological functioning was examined in 31 adolescents with schizophrenia spectrum disorders and 67 healthy controls, using the MATRICS battery. There were significant differences between the patients and the controls on every domain except for social cognition. Patients showed a generalized neurocognitive deficit of 0.8-1.8 SDs compared with controls, with verbal learning, working memory, and visual learning being the most affected areas. The MATRICS battery is sensitive in detecting differences between patients and controls in the adolescent population. However, we question the use of Mayer-Salovey-Caruso Emotional Intelligence Test in this age group. Results document a significant generalized deficit in adolescents with EOS.

Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Rationale, Design, and Methods

Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Rationale, Design, and Methods

Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Demographic and Clinical Characteristics

Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Demographic and Clinical Characteristics

Double-Blind Comparison of First- and Second-Generation Antipsychotics in Early-Onset Schizophrenia and Schizo-affective Disorder: Findings From the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) Study

Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder. This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and >or=20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.

372 – Neuropsychological functioning in adolescents with early-onset schizophrenia-spectrum disorders: Measured with the matrics battery

372 – Neuropsychological functioning in adolescents with early-onset schizophrenia-spectrum disorders: Measured with the matrics battery

A Prospective 12-Week Study of Quetiapine in Adolescents with Schizophrenia Spectrum Disorders

The aim of this study was to investigate the effectiveness, tolerability, and safety of quetiapine in adolescents with schizophrenia, schizophreniform, and schizoaffective disorders in a prospective open-label study. A total of 56 subjects (all-subjects-treated, AST), ages 12-17, received 200-800 mg of quetiapine per day (forced titration to 400 mg within week 1; median study dose 600 mg/day at week 6) in Germany, 2002 through 2004. Primary outcome measure was the change of Positive and Negative Syndrome Scale (PANSS) total score (based on the intent-to-treat (ITT) population, n = 52), secondary outcome measures were changes of PANSS subscales, severity of illness, subjective wellbeing, and safety/tolerability (the latter based on the AST population). Correlates of PANSS response (=50% reduction in PANSS total score) and discontinuation due to lack of effectiveness were analyzed by Cox regression analyses. Twenty-seven subjects (48%) completed the study; 17 subjects (30%) were discontinued due to lack of effectiveness. A significant reduction of PANSS total score (last observation carried forward, LOCF; p < 0.0001; effect size = 0.92) and of secondary effectiveness outcomes were detected. In all, 34.6% fulfilled the PANSS response criterion, correlated with the degree of PANSS total change within week 1. Somnolence (21.4%) and fatigue (17.9%) were the most frequent adverse events. A significant mean weight gain (6.2 kg) and mean decrease in total serum thyroxine (2.5 ng/dl) were detected. In this sample of mostly drug-naïve patients with early-onset schizophrenia spectrum disorders, significant reductions in PANSS total and positive scores were detected. Controlled studies are needed to confirm these findings. The significant weight gain with its potentially severe medical consequences must be weighed against quetiapine's effectiveness.

Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia.

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D2 receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and “high-dose” olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

When Schizophrenia Develops Early, Impairment Often More Severe

When Schizophrenia Develops Early, Impairment Often More Severe

Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Rationale, Design, and Methods

The Treatment of Early Onset Schizophrenia Spectrum Disorders Study is a publicly funded clinical trial designed to compare the therapeutic benefits, safety, and tolerability of risperidone, olanzapine, and molindone in youths with early-onset schizophrenia spectrum disorders. The rationale, design, and methods of the Treatment of Early Onset Schizophrenia Spectrum Disorders Study are described. Using a randomized, double-blind, parallel-group design at four sites, youths with EOSS (ages 8-19 years) were assigned to an 8-week acute trial of risperidone (0.5-6.0 mg/day), olanzapine (2.5-20 mg/day), or molindone (10-140 mg/day). Responders continued double-blind treatment for 44 weeks. The primary outcome measure was responder status at 8 weeks, defined by a 20% reduction in baseline Positive and Negative Symptom Scale scores plus ratings of significant improvement on the Clinical Global Impressions. Secondary outcome measures included assessments of psychopathology, functional impairment, quality of life, and medication safety. An intent-to-treat analytic plan was used. From February 2002 to May 2006, 476 youths were screened, 173 were further evaluated, and 119 were randomized. Several significant study modifications were required to address safety, the use of adjunctive medications, and the termination of the olanzapine treatment arm due to weight gain. The Treatment of Early Onset Schizophrenia Spectrum Disorders Study will inform clinical practice regarding the use of antipsychotic medications for youths with early-onset schizophrenia spectrum disorders. Important safety concerns emerged during the study, including higher than anticipated rates of suicidality and problems tapering thymoleptic agents before randomization.

Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Demographic and Clinical Characteristics

We examined baseline demographic and clinical profiles of youths enrolled from 2001 to 2006 in the publicly funded multicenter, randomized controlled trial Treatment of Early-Onset Schizophrenia Spectrum Disorders. Youths (8-19 years) with schizophrenia (SZ) and schizoaffective disorder were recruited at four academic sites. Diagnosis was made via structured and clinical interviews. Assessments of psychiatric symptoms and social and global functioning were included. A total of 119 youths were enrolled. The mean age at illness onset was 11.1 +/- 3.5 years. Patients with SZ and schizoaffective disorder had similar ratings on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale for Children, and Clinical Global Impression-Severity Scale. The overall level of functioning was similar in the two groups. A comparison to published reports of adults with SZ indicates that these youths may have more severe symptoms based on results of the Positive and Negative Symptom Scale. This is one of the largest samples of youths with SZ spectrum disorders studied to date and the largest assessment of youths with schizoaffective disorder. High rates of symptoms and general psychopathology were noted. There was a substantial degree of social and functional impairment. The symptom profiles are consistent with, but more severe than, those reported in the adult literature.