Brain maturational processes and delayed onset in schizophrenia.

The central feature of schizophrenia is its onset in adolescence. Although this clinical observation is consistent with the view that schizophrenia may be a neurodevelopmental disorder, debate has focused on when the proposed brain maturational deviations may begin and what might be the nature of such defective development. Conflicting models of this illness (e.g., the early and late neurodevelopmental models) have been proposed. In this paper, we will first review concepts from basic developmental neurobiology pertinent to these issues; we then summarize aspects of the neurobiology of schizophrenia that have a particular bearing on the adolescent onset of this illness. We propose that the schizophrenic syndrome may result from early brain adversity and late maturational processes of brain development interacting with adverse humoral, biochemical, and psychosocial factors during adolescence and early adulthood. The onset of schizophrenia in adolescence may be related to the "plasticity switch" secondary to the peripubertal brain maturational changes, perhaps involving an alteration in glutamate receptor function. This loss of plasticity could result in social and nonsocial cognitive deficits that are central to the pathophysiology of schizophrenia; the vulnerable person may therefore utilize prepubertal processing styles that are insufficient to the adaptive and "gistful" abstraction requirements of adult cognition. Schizophrenia onset might occur in the context of psychosocial developmental challenges to a delayed social cognitive capacity among neurodevelopmentally compromised individuals. We review therapeutic implications as well as testable predictions generated by this model, and discuss research strategies that might further our understanding of the brain maturational abnormalities in schizophrenia.

Developmental theory for a cognitive enhancement therapy of schizophrenia.

Recent findings on psychosocial and neurodevelopmental anomalies in schizophrenia patients indicate that deficits related to social cognition-the ability to act wisely in social interactions-may be important constraints on complete social and vocational recovery. Social cognition is acquired over many decades and appears to be partially independent of formal IQ and neuropsychological problems. It invites a more developmental approach to the rehabilitation of schizophrenia, one that we call Cognitive Enhancement Therapy (CET). CET draws on an emerging literature that implicates both pre- and postonset neurodevelopmental difficulties, as well as a complementary literature on diffuse neuropsychological impairments that supports the notion of a neurodevelopmental insult. We analyzed evidence for an associated developmental basis to social cognitive impairment in the context of a model that addressed both the acquisition of interpersonal wisdom and the adaptive process that might follow developmental failures. A contemporary model of human cognition is then used to identify the metacognitive functions that characterize the developmental acquisition of normal cognition and, by inference, the associated difficulties of many patients with schizophrenia. A rehabilitation strategy for schizophrenia, designed to facilitate the metacognitive transition from prepubertal to young adult social cognition, would thus emphasize developmental learning experiences during the remediation of social cognitive deficits. A "gistful" appraisal of interpersonal behavior and novel social contexts best reflects the theoretical intent of this new intervention.

Practice principles of cognitive enhancement therapy for schizophrenia.

Cognitive Enhancement Therapy (CET) is a developmental approach to the rehabilitation of schizophrenia patients that attempts to facilitate an abstracting and "gistful" social cognition as a compensatory alternative to the more demanding and controlled cognitive strategies that often characterize schizophrenia as well as much of its treatment. Selected cognitive processes that developmentally underlie the capacity to acquire adult social cognition have been operationalized in the form of relevant interactive software and social group exercises. Treatment methods address the impairments, disabilities, and social handicaps associated with cognitive styles that appear to underlie the positive, negative, and disorganized symptom domains of schizophrenia. Style-related failures in secondary rather than primary socialization, particularly social cognitive deficits in context appraisal and perspective taking, are targeted goals. Illustrative examples of the techniques used to address social and nonsocial cognitive deficits are provided, together with encouraging preliminary observations regarding the efficacy of CET.

The limitations of antipsychotic medication on schizophrenia relapse and adjustment and the contributions of psychosocial treatment.

Whether psychosocial treatment adds substantially to the prophylactic efficacy of maintenance antipsychotic monotherapy requires a more accurate estimate of relapse risks than those contained in recent reviews. A reappraisal of the literature suggests a 1-year, post-hospital, relapse rate of 40% on medication, and a substantially higher rate among patients who live in stressful environments, rather than earlier estimates of 16%. Relapse rates of 65% at 1 year and over 80% by 2 years among drug discontinued or placebo substituted outpatients are also more accurate than the 53% relapse rate previously estimated. When psychosocial treatment is added to maintenance chemotherapy, there is compelling evidence that relapse rates are reduced by as much as 50% compared with relapse associated with medication and standard care. However, psychosocial treatment without medication is as ineffective as placebo. The additive effects appear greater for recent, theoretically based psychosocial approaches than earlier atheoretical, altruistic forms of caring. However, effects vary according to the patient's clinical state, the nature and timing of the intervention, and the presence of environmental stressors. Regarding adjustment, very little definitive information regarding psychosocial treatment effects has existed until recently. A novel, disorder-relevant approach has now been shown to have broad and significant effects on social adjustment compared with medication and support. However, the magnitude of effects is not fully realized until a third year of treatment: a distinct challenge in the era of managed care. Atypical antipsychotics and more definitive psychosocial strategies that target social cognitive deficits hold promise for enhanced outcomes in the next generation of studies.

Three-year trials of personal therapy among schizophrenic patients living with or independent of family, I: Description of study and effects on relapse rates.

OBJECTIVE: The study of individual psychotherapeutic approaches to the treatment of schizophrenia has yielded equivocal findings, partly because of methodologic problems. Further, the ability of psychosocial treatments to prevent psychotic relapse appears to lessen over time. The authors' goal was to develop and test a demonstrably effective individual therapy for schizophrenia. METHOD: Using a study design that addressed previous methodologic issues, the authors evaluated personal therapy specifically designed to forestall late relapse in patients with schizophrenia. They evaluated the effectiveness of personal therapy over a period of 3 years after hospital discharge among 151 patients with schizophrenia or schizoaffective disorder diagnosed according to Research Diagnostic Criteria. The patients were randomly assigned to receive either personal therapy or contrasting therapies in one of two concurrent trials. One trial studied patients who were living with family (N = 97); the other studied patients who were living independent of family (N = 54). RESULTS: All of the patients had extensive psychiatric histories, but only 44 (29%) experienced recurrent psychotic episodes over the 3-year study period, and only 27 (18%) prematurely terminated the study; most of those who left the study were in the no-personal-therapy conditions. Among patients living with family, personal therapy was more effective than family and supportive therapies in preventing psychotic and affective relapse as well as noncompliance. However, among patients living independent of family, those who received personal therapy had significantly more psychotic decompensations than did those who received supportive therapy. CONCLUSIONS: Personal therapy had a positive effect on adverse outcomes among patients who lived with family. However, personal therapy increased the rate of psychotic relapse for patients living independent of family. The application of personal therapy might best be delayed until patients have achieved symptom and residential stability.

Three-year trials of personal therapy among schizophrenic patients living with or independent of family, II: Effects on adjustment of patients.

OBJECTIVE: Previous analyses of the personal and social adjustment of outpatients with schizophrenia have either relied on the assessment of unrepresentative patients who survived without relapse or used analyses that included relapse assessments, a potential confound when different rates of relapse existed among treatment conditions. The authors' goal was to conduct a study of the effects of personal therapy on outcome that was designed to take into consideration the effects of relapse. METHOD: They evaluated the effectiveness of personal therapy over 3 years after hospital discharge among 151 patients with schizophrenia or schizoaffective disorder. The patients were randomly assigned to receive personal therapy or contrasting therapies in one of two concurrent trials. One trial included patients who were living with family (N = 97); the other included patients who were living independent of family (N = 54). Patients were assessed at 6-month intervals over 3 years of treatment on measures of personal and social adjustment; patients who relapsed and restabilized and those who did not relapse were included. RESULTS: Personal therapy had positive effects on broad components of social adjustment (role performance) but had few differential effects on symptoms, and patients receiving personal therapy remained more anxious than patients who received family or supportive therapy. For patients who were living with family, personal therapy led to better outcomes in overall performance than did the other treatments. Although family therapy had only one positive effect on patients' social adjustment, the personal adjustment (residual symptoms) of patients who received family therapy appeared to improve more than that of patients receiving personal or supportive therapy. For patients not living with family, personal therapy was more successful than supportive therapy in improving work performance and relationships out of the home. Longitudinal effects of personal therapy on symptoms were similar to those of family and supportive therapies, particularly in the first 2 years, but personal therapy effect sizes increased over time on measures of social adjustment. CONCLUSIONS: Personal therapy has pervasive effects on the social adjustment of patients with schizophrenia that are independent of relapse prevention. Supportive therapy, with or without family intervention, produces adjustment effects that peak at 12 months after discharge and plateau thereafter. However, personal therapy, a definitive psychosocial intervention, continues to improve the social adjustment of patients in the second and third years after discharge. Brief treatment would appear to be less effective than a long-term, disorder-relevant intervention for schizophrenia.

Pharmacotherapy of impaired affect in recovering schizophrenic patients.

BACKGROUND: Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken. METHODS: In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks. RESULTS: For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression. CONCLUSION: Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature.

Personal therapy: a disorder-relevant psychotherapy for schizophrenia.

While the long-term care of ambulatory schizophrenia patients requires highly effective interpersonal treatment skills among clinicians, there is little evidence to support an empirically validated individual psychotherapy of schizophrenia. Personal therapy (PT) attempts to address the apparent limitations of traditional psychotherapy by modifying the "model of the person" to accommodate an underlying pathophysiology, minimizing potential iatrogenic effects of maintenance antipsychotic medication, controlling sources of environmental provocation, and extending therapy to a time when crisis management has lessened and stabilization is better ensured. By means of graduated, internal coping strategies, PT attempts to provide a growing awareness of personal vulnerability, including the "internal cues" of affect dysregulation. The goals are to increase foresight through the accurate appraisal of emotional states, their appropriate expression, and assessment of the reciprocal response of others. The strategies are supplemented by phase-specific psychoeducation and behavior therapy techniques. Practical issues in the application of this new intervention are discussed. Preliminary observations from two samples of patients, one living with and the other living independent of family, suggest differential improvement over time among PT recipients.

Prevention of relapse in chronic schizophrenic patients.

New treatments offer hope for a reduction in the rate of relapse among chronic schizophrenic patients. The control of factors such as drug noncompliance, the dose of neuroleptic drug, the level of stimulation in the patient's therapeutic and home environments, extrapyramidal side effects, attention and arousal deficits, and the stresses of everyday life events can reduce the rate of relapse in most patients. A relapse rate of 65% to 70% in the first year following hospital discharge can be reduced to 40% with the use of antipsychotic medication and can be further reduced to less than 20% with the addition of psychosocial therapy. Low doses of antipsychotic drugs combined with psychosocial treatment can have an added positive impact on the quality of life as well.

Cognitive remediation in schizophrenia: proceed ... with caution!

The apparent neglect of neuropsychologic deficits in schizophrenia as the basis for therapeutic intervention, together with only isolated attempts at remediating them, probably reflect the nature of impairments, the functional significance of which is uncertain. A critique of the limitations inherent in the appealing cognitive remediation of the closed-head injured is followed by positive suggestions for the restructuring of cognitive schema that appear to underlie schizophrenic disability in social and vocational functioning.

Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose.

After individual determination of neuroleptic threshold (NT) doses of haloperidol, 106 patients with schizophrenia or schizoaffective disorder (Research Diagnostic Criteria) were treated openly at such doses (mean, 3.7 +/- 2.3 mg/d) for 2 weeks. Ten responding patients were discharged and unavailable for follow-up or refused subsequent randomization, and one non-responding patient refused randomization. The remaining 95 responding or nonresponding patients were then randomly assigned, double-blind, to a dosage of haloperidol two to 10 times higher (mean, 11.6 +/- 4.7 mg/d) or to a continuing NT dosage (mean, 3.4 +/- 2.3 mg/d) for another 2 weeks. Of the 58 patients exposed only to NT dosages of haloperidol, 72% clinically recovered within the 5-week trial. Higher dosages given to 47 patients did not lead to greater improvement in measures of psychosis, but did produce slightly greater declines in measures of hostility. Higher dosages did regularly lead to significant increases in distressing extrapyramidal side effects.

Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia. II. Two-year effects of a controlled study on relapse and adjustment. Environmental-Personal Indicators in the Course of Schizophrenia (EPICS) Research Group.

We demonstrated earlier that a novel family psychoeducational approach and an individual social skills training approach designed for patients living in high-expressed emotion households each reduced schizophrenic relapse by one-half when compared with medication controls in the 1st year after hospital discharge. The combination of treatments resulted in no relapse. Results have now been obtained after 2 years of continuous treatment. By 24 months, a persistent and significant effect of family intervention on forestalling relapse was observed, but the effect of social skills training was lost late in the 2nd year. There was no additive effect on relapse that accrued to the combination of treatments. Beyond 2 years, however, the effect of family intervention was likely compromised as well. Treatment effects on the adjustment of survivors were circumscribed, due, in part, to study design characteristics. Effects generally favored the social skills-alone condition at 1 year and the family condition or combined family/social skills condition at 2 years.

Dose of fluphenazine, familial expressed emotion, and outcome in schizophrenia. Results of a two-year controlled study.

Issues regarding the side effects of antipsychotic medication and the possible contribution of the environment to dose requirements led to a two-year controlled dosage study of maintenance antipsychotic medication and familial environment among recently discharged schizophrenic patients. Seventy stable patients, living in high- or low-expressed emotion (EE) households, were randomized, double blind, to receive a standard dose of fluphenazine decanoate (average, 25 mg every two weeks) or a minimal dose representing 20% of the dose prescribed (average, 3.8 mg every two weeks). No differences in relapse were observed among dose, EE, or dose and EE. Patients in the minimal dose/high-EE condition experienced more minor but aborted episodes in year 2. Side effects were fewer on the minimal dose after one year, and low-EE patients were better adjusted than high-EE patients. Over time, minimal-dose recipients were significantly more improved in their instrumental and interpersonal role performance than were standard-dose recipients.

Information processing and communication deviance in schizophrenic patients and their mothers.

Tests of attention/information processing, the continuous performance test (CPT) and the span of apprehension task (SAT), were given to 25 schizophrenic patients and their mothers. Measures of communication deviance also were obtained from the mothers. Comparison of these assessments in the mothers revealed different transactional profiles for good attenders and poor attenders on the CPT and on the SAT. The relationships between generations (patient and mother) differ from the within-individual relationships. CPT performance by the patient is not significantly correlated with scores from the mother. However, SAT performance by the patient could be related to SAT performance by the mother and specific communication deviance factor scores.

Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia. I. One-year effects of a controlled study on relapse and expressed emotion.

Relapse rates averaging 41% in the first year after discharge among schizophrenic patients receiving maintenance neuroleptic treatment led to the development of two disorder-relevant treatments: a patient-centered behavioral treatment and a psychoeducational family treatment. Following hospital admission, 103 patients residing in high expressed emotion (EE) households who met Research Diagnostic Criteria for schizophrenia or schizoaffective disorder were randomly assigned to a two-year aftercare study of family treatment and medication, social skills training and medication, their combination, or a drug-treated condition. First-year relapse rates among those exposed to treatment demonstrate a main effect for family treatment (19%), a main effect for social skills training (20%), and an additive effect for the combined conditions (0%) relative to controls (41%). Effects are explained, in part, by the absence of relapse in any household that changed from high to low EE. Only the combination of treatment sustains a remission in households that remain high in EE. Continuing study, however, suggests a delay of relapse rather than prevention.