Treatment histories of patients with a syndrome putatively prodromal to schizophrenia

Recent reports suggest that a symptomatic state that is often prodromal to schizophrenia can be identified prospectively. We examined treatment-seeking histories and psychiatric services received among patients with a syndrome similar to a prodromal state. The records of 47 patients who met the criteria for a prodromal state were reviewed. Most patients had previously sought and received psychiatric services (90 percent), including medications (64 percent), and 51 percent had previously received a psychiatric diagnosis. These data suggest that patients who present with a syndrome putatively prodromal to schizophrenia constitute a clinical population. Research into treatment interventions is indicated.     

Childhood-onset schizophrenia and schizophrenia spectrum disorder

The concept, diagnosis and clinical picture of childhood-onset schizophrenia were presented. The cases with childhood-onset schizophrenia were classified into 4 groups according to their process of growth and development. Furthermore, it has been suggested that the progression of childhood-onset schizophrenia developed on the basis of neuro-developmenal hypothesis might contribute to the understanding of adult onset schizophrenia and early diagnosis and intervention of schizophrenia.     

Childhood-onset schizophrenia: research update.

This review is a research update of recent literature related to childhood-onset schizophrenia (onset of psychotic symptoms by age 12 years). This subgroup of patients has attracted considerable research interest because patients with a childhood onset may represent a more homogeneous patient population in which to search for risk or etiologic factors. We examine data indicating that childhood-onset schizophrenia (COS) shares the same clinical and neurobiologic features as later-onset forms of the disorder. Compared with adults with schizophrenia, however, this subgroup of patients appears to have more severe premorbid neuro-developmental abnormalities, more cytogenetic anomalies, and potentially greater family histories of schizophrenia and associated spectrum disorders. While preliminary, these data indicate that a greater genetic vulnerability may be one of the underpinnings of COS. Future studies of this subgroup may provide important clues as to the genetic basis for schizophrenia and how gene products influence certain features of the disease, such as age of onset and mode of inheritance.     

Childhood-onset schizophrenia: A follow-up study

This paper presents results from the UCLA Follow-Up Study of Childhood-Onset Schizophrenia Spectrum Disorders. Eighteen children with schizophrenia (SZ) were assessed 1 to 7 years following initial project intake. Results demonstrated significant continuity between SZ spectrum disorders in childhood and adolescence. Although not all children who presented initially with SZ continued to meet criteria for SZ spectrum disorder as they progressed through the follow-up period, rates of SZ spectrum disorders ranged from 78-89 % across the first three follow-up years. Rates of continuing SZ ranged from 67 % to 78 % across the three follow-up years and rates of schizoaffective disorder ranged from 11 % to 13 % across the three follow-up years. Variability in levels of functioning were observed with 45 % of the sample showing deteriorating course or minimal improvement and 55 % of the sample showing moderate improvement or good outcomes. This variability in outcome is comparable to that seen in adults with SZ, suggesting that with current treatments childhood-onset does not ensure a more severe disorder.     

Nonresponse to clozapine and premorbid functioning in treatment refractory schizophrenia

Introduction

It is recognized that early treatment can improve outcomes and generally improve recovery potential for those with schizophrenia. Data suggest that poor premorbid functioning has been found to be related to more severe symptoms and poor antipsychotic response; however, little is known about premorbid functioning in patients who have no response to clozapine treatment.

Methods

This study compares the premorbid functioning among patients who responded to clozapine treatment (20% decrease in total Brief Psychiatric Rating Scale [BPRS] score; n = 35) and those who did not respond (n = 50) to 8 weeks of clozapine treatment. Premorbid functioning was assessed using the Cannon-Spoor Premorbid Adjustment Scale.

Results

Patients who did not respond to clozapine had significantly lower total BPRS scores (P = .01) at baseline, driven primarily by lower ratings in hostility (P = .007) and activation (P = .02), compared with those who responded to clozapine. Responders and nonresponders did not differ in their age, race, level of education, marital status, age of onset, characterization of the deficit syndrome, and positive or negative symptoms. Nonresponders to clozapine did not improve in any area of symptoms or global functioning, whereas there were significant improvements in BPRS total scores (analysis of covariance) and all symptom domains in the responder groups (P < .0001). Level of functioning scores in those who responded to clozapine was significantly higher at end point (P = .02). As for premorbid functioning, there were no differences in scores between responders and nonresponders at the time of early and late adolescence; however, there was a trend toward lower premorbid functioning in the clozapine nonresponders on most childhood measures (before the age of 11 years). Clozapine nonresponders tended to be less social and more withdrawn as compared with those who responded to clozapine (P = .08), as well as tended to have poorer adaptation to school (P = .06) and fewer peer relationships (P = .08). These results did not reach significance. Work and/or school performance changed more insidiously in the nonresponders group before illness onset (P = .045).

Discussion

Clozapine is beneficial to many patients with treatment-resistant symptoms; however, nonresponse to this medication may represent a subtype of patients who may present differently with symptoms. These findings should encourage further examination of early childhood indicators and opportunities for appropriate and effective intervention.     

Antipsychotic drug treatment in the prodromal phase of schizophrenia

OBJECTIVE: The safety and tolerability of short-term treatment with a low dose of risperidone was evaluated in adolescents with prodromal symptoms and a family history of schizophrenia. METHOD: Four prodromal high-risk adolescents and six first-episode patients with schizophrenia were treated with average doses of 1.0 and 1.8 mg/day of risperidone, respectively, in an 8- to 12-week open-label trial. RESULTS: No significant treatment-related adverse events were noted. Severity of thought and behavior disturbance ratings declined by about 30%; performance on a test of verbal learning improved by about 100% during treatment in both prodromal and first-episode patients, changes that achieved statistical significance despite the small group sizes. CONCLUSIONS: These findings are preliminary and should not be used to guide health care decisions at this time. Randomized controlled trials are needed to determine whether antipsychotic drug treatment of prodromal patients can delay or prevent onset or attenuate the clinical course of schizophrenia.     

Childhood-onset schizophrenia: rare but worth studying.

Childhood-onset schizophrenia (defined by an onset of psychosis by age 12) is a rare and severe form of the disorder that is clinically and neurobiologically continuous with the adult-onset disorder. There is growing evidence for more salient risk or etiologic factors, particularly familial, in this possibly more homogeneous patient population. For the 49 patients with very early onset schizophrenia studied to date at the National Institute of Mental Health, there were more severe premorbid neuro-developmental abnormalities, a higher rate of cytogenetic anomalies, and a seemingly higher rate of familial schizophrenia and spectrum disorders than later onset cases. There was no evidence for increased obstetric complications or environmental stress. These data, while preliminary, suggest that a very early age of onset of schizophrenia may be secondary to greater familial vulnerability. Consequently, genetic studies of these patients may be particularly informative and may provide important etiologic information.     

Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment. OBJECTIVE: To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious. DESIGN: Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up. SETTING: National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge. PATIENTS: Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics. INTERVENTIONS: After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n = 12) or olanzapine (n = 13). MAIN OUTCOME MEASURES: The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms. RESULTS: Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P = .04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n = 6) and seizures (n = 1). CONCLUSIONS: While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events.     

Childhood-onset schizophrenia: progressive brain changes during adolescence.

BACKGROUND: Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus. METHODS: Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences. RESULTS: Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group. CONCLUSIONS: These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development in schizophrenia.     

Childhood-onset schizophrenia and obstetric complications: a case--control study.

Obstetric complications (OCs) may be a risk factor for developing schizophrenia. In a recent study of a meta-analysis, the odds ratio for the development of the disorder in adulthood associated with OCs has been reported to be about 2.0 (i.e., a two-fold increase in risk). However, little attention has been paid to the involvement of OCs in risk of the development of childhood-onset schizophrenia. Therefore, the authors examined the relationship between OCs and childhood-onset schizophrenia. Thirty-three children, aged 8-13 years (average 12.4 years), meeting the DSM-III-R criteria for schizophrenia, were compared with controls (children with anxiety disorder) matched for sex and age. Childhood-onset schizophrenics showed significantly greater scores in all of the three measures of OCs according to Parnas et al.'s scale compared with controls. Moreover, those individuals exposed to OCs were 3.5 times as likely to develop schizophrenia as were those without OCs. The risk association between OCs and the disorder was far greater for male than for female schizophrenics. Our results, together with those in previous studies showing the association between OCs and adult-onset schizophrenia, suggest that childhood- and adult-onset schizophrenia may, at least in part, share a common neuropathogenesis.     

Childhood-onset schizophrenia: smooth pursuit eye-tracking dysfunction in family members

BACKGROUND: Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. AIMS: To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). METHOD: Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups. RESULTS: COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. CONCLUSIONS: Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. DECLARATION OF INTEREST: The study was done at the National Institutes of Health.     

Estimating premorbid IQ in the prodromal phase of a neurodegenerative disease

Estimates of premorbid intellect are often used in neuropsychological assessment to make inferences about cognitive decline. To optimize the method of controlling for premorbid intellect in assessments of prodromal neurodegenerative disease, we examined performance on the American National Adult Reading Test (ANART; administered during Years 1 and 3) and the two-subtest version of the Wechsler Abbreviated Scale of Intelligence (WASI; administered in Years 2 and 4) in an ongoing prospective longitudinal study of 371 participants with prodromal Huntington disease and 51 participants with normal CAG repeats. Although both measures performed similarly, the ANART demonstrated slightly lower variability in performance over a 2-year period and had slightly higher test-retest reliability than the WASI.     

The treatment of schizophrenia: from premorbid manifestations to the first episode of psychosis

To achieve the best therapeutic results in schizophrenia--like most other disorders--primary prevention is preferable to early and prompt treatment, which, in turn, is preferable to treatment of chronically established illness. Unfortunately, there currently exist no accurate markers that can provide information regarding the future course of illness and guide treatment in asymptomatic or mildly symptomatic individuals. Therefore, most treatment efforts are currently focused on patients who have already experienced their first psychotic episode. This paper reviews the efforts to identify accurate markers heralding psychotic illness, as well as treatment considerations in the early phase of the disease.     

Childhood-onset schizotypal disorder: a follow-up study and comparison with childhood-onset schizophrenia

OBJECTIVE: This paper presents results from the UCLA Follow-Up Study of Childhood-Onset Schizophrenia (SZ) Spectrum Disorders. METHOD: We assessed 12 children with schizotypal personality disorder (SPD) and 18 children with schizophrenia 1-7 years following initial project intake. RESULTS: There was significant continuity between SZ spectrum disorders in childhood and adolescence. Although not all children who presented initially with SZ spectrum disorders continued to meet criteria for SZ spectrum disorder as they progressed through the follow-up period, rates of SZ spectrum disorders ranged from 75% to 92% across the 3 follow-up years for children initially presenting with SPD, and from 78% to 89% for children initially presenting with SZ. CONCLUSION: The most common clinical outcome for children with SPD was continuing SPD, supporting the hypothesis of continuity between childhood and later SPD. However, 25% of the SPD sample developed more severe SZ spectrum disorders (schizophrenia or schizoaffective disorder), also supporting the hypothesis that SPD represents a risk or precursor state for more severe SZ spectrum disorders.     

Evaluating and treating the prodromal stage of schizophrenia

Identification of a person in the prodromal stage of schizophrenia, before the onset of the first episode of psychosis, provides an opportunity for early, potentially preventative, interventions. Recent attempts to develop at risk or prodromal syndrome diagnostic criteria have proved to be successful at identifying individuals at high risk for psychosis. Preliminary investigations find that pharmacologic and psychotherapeutic interventions may reduce the risk of psychosis in at risk individuals, but until more is known, current treatment guidelines recommend close monitoring, therapeutic interventions that address identified problems, including supportive or cognitive therapies to reduce the functional consequences of the presenting symptoms, family interventions to reduce family distress and improve coping, and intervention with schools to decrease likelihood of school failure. Pharmacologic intervention targeting the prodromal symptoms is not recommended, given the uncertain risk to benefit ratio.     

Diagnosing schizophrenia in the initial prodromal phase

BACKGROUND: In schizophrenia research, early detection in the initial prodrome before first psychotic episodes is a major topic. Therefore, the prognostic accuracy of initial prodromal symptoms was examined prospectively. METHODS: The study sample was composed of patients referred to outpatient departments of German psychiatric university departments, because of diagnostic problems, between 1987 and 1991. They were examined with the Bonn Scale for the Assessment of Basic Symptoms and the Ninth Version of the Present State Examination to detect an incipient schizophrenic disorder. Of 385 patients showing no schizophrenia-characteristic symptoms, between 1995 and 1998, 110 with and 50 without initial prodromal symptoms were followed up and reexamined with the same instruments for a transition to schizophrenia. RESULTS: During a mean follow-up period of 9.6 years, 79 (49.4%) of the 160 patients had transited to schizophrenia. The absence of prodromal symptoms excluded a subsequent schizophrenia with a probability of 96% (sensitivity: 0.98; false-negative predictions: 1.3%), whereas their presence predicted schizophrenia with a probability of 70% (specificity: 0.59; false-positive predictions: 20%). Certain disturbances, such as thought interference, disturbances of receptive language, or visual distortions, predicted schizophrenia, even with a probability up to 91% (specificity: 0.85-0.91; false-positive predictions: 1.9%-7.5%). CONCLUSIONS: The Bonn Scale for the Assessment of Basic Symptoms operationalization of prodromal symptoms performed well in the early detection of schizophrenia. It therefore might be useful for the prediction of the disorder, especially if it is further refined to select those items with particularly high prognostic accuracy.     

Evaluating and treating the prodromal stage of schizophrenia

Identification of a person in the prodromal stage of schizophrenia, before the onset of the first episode of psychosis, provides an opportunity for early, potentially preventative, interventions. Recent attempts to develop “at risk#x201D; or #x201C;prodromal syndrome#x201D; diagnostic criteria have proved to be successful at identifying individuals at high risk for psychosis. Preliminary investigations find that pharmacologic and psychotherapeutic interventions may reduce the risk of psychosis in #x201C;at risk#x201D; individuals, but until more is known, current treatment guidelines recommend close monitoring, therapeutic interventions that address identified problems, including supportive or cognitive therapies to reduce the functional consequences of the presenting symptoms, family interventions to reduce family distress and improve coping, and intervention with schools to decrease likelihood of school failure. Pharmacologic intervention targeting the prodromal symptoms is not recommended, given the uncertain riskbenefit ratio.