A randomized controlled trial of cognitive remediation and long-acting injectable risperidone after a first episode of schizophrenia: improving cognition and work/school functioning.

BACKGROUND: Cognitive deficits at the first episode of schizophrenia are predictive of functional outcome. Interventions that improve cognitive functioning early in schizophrenia are critical if we hope to prevent or limit long-term disability in this disorder. METHODS: We completed a 12-month randomized controlled trial of cognitive remediation and of long-acting injectable (LAI) risperidone with 60 patients with a recent first episode of schizophrenia. Cognitive remediation involved programs focused on basic cognitive processes as well as more complex, life-like situations. Healthy behavior training of equal treatment time was the comparison group for cognitive remediation, while oral risperidone was the comparator for LAI risperidone in a 2 × 2 design. All patients were provided supported employment/education to encourage return to work or school. RESULTS: Both antipsychotic medication adherence and cognitive remediation contributed to cognitive improvement. Cognitive remediation was superior to healthy behavior training in the LAI medication condition but not the oral medication condition. Cognitive remediation was also superior when medication adherence and protocol completion were covaried. Both LAI antipsychotic medication and cognitive remediation led to significantly greater improvement in work/school functioning. Effect sizes were larger than in most prior studies of first-episode patients. In addition, cognitive improvement was significantly correlated with work/school functional improvement. CONCLUSIONS: These results indicate that consistent antipsychotic medication adherence and cognitive remediation can significantly improve core cognitive deficits in the initial period of schizophrenia. When combined with supported employment/education, cognitive remediation and LAI antipsychotic medication show separate significant impact on improving work/school functioning.

Enhancing return to work or school after a first episode of schizophrenia: the UCLA RCT of Individual Placement and Support and Workplace Fundamentals Module training.

BACKGROUND: This study evaluated in a rigorous 18-month randomized controlled trial the efficacy of an enhanced vocational intervention for helping individuals with a recent first schizophrenia episode to return to and remain in competitive work or regular schooling. METHODS: Individual Placement and Support (IPS) was adapted to meet the goals of individuals whose goals might involve either employment or schooling. IPS was combined with a Workplace Fundamentals Module (WFM) for an enhanced, outpatient, vocational intervention. Random assignment to the enhanced integrated rehabilitation program (N = 46) was contrasted with equally intensive clinical treatment at UCLA, including social skills training groups, and conventional vocational rehabilitation by state agencies (N = 23). All patients were provided case management and psychiatric services by the same clinical team and received oral atypical antipsychotic medication. RESULTS: The IPS-WFM combination led to 83% of patients participating in competitive employment or school in the first 6 months of intensive treatment, compared with 41% in the comparison group (p < 0.005). During the subsequent year, IPS-WFM continued to yield higher rates of schooling/employment (92% v. 60%, p < 0.03). Cumulative number of weeks of schooling and/or employment was also substantially greater with the IPS-WFM intervention (45 v. 26 weeks, p < 0.004). CONCLUSIONS: The results clearly support the efficacy of an enhanced intervention focused on recovery of participation in normative work and school settings in the initial phase of schizophrenia, suggesting potential for prevention of disability.

Cognitive remediation can improve negative symptoms and social functioning in first-episode schizophrenia: A randomized controlled trial.

BACKGROUND: Meta-analyses have reported that the effects of cognitive remediation might go beyond improvement in cognition to include unexpected benefits for schizophrenia patients such as negative symptom reduction and improvements in functioning. In addition, some evidence indicated that these potentially beneficial effects are also present in the initial course of schizophrenia, but work in this area is still developing. METHOD: A RCT compared Cognitive Remediation (CR) to Healthy Behaviors Training (HBT) in 80 patients (78% male) with a mean age of 21.9years and mean education of 12.3years who had a first psychotic episode within two years of study entry. Participants were trained using CR programs or received HBT involving 50 sessions over 6months and then booster sessions over the next 6months. The SANS and BPRS were used to assess symptoms. The UCLA Social Attainment Survey assessed social functioning. RESULTS: Using GLMM, improvements over 12months were found favoring CR for SANS Expressive Symptoms (p<0.01), which was composed of Affective Flattening (p<0.01) and Alogia (p=0.04), and for SANS Experiential Symptoms, composed of Avolition/Apathy (p=0.04) and Anhedonia/Asociality (p<0.01). CR was associated with improvements in social functioning (p=0.05) as compared to HBT. CONCLUSIONS: We confirmed that the beneficial effects of CR appear to extend beyond cognition to improvements in negative symptoms and social functioning in early course schizophrenia patients. These results suggest that cognitive remediation might have an impact when the reduction of risk factors for chronicity is most critical for promoting recovery.

Enhancing Cognitive Training Through Aerobic Exercise After a First Schizophrenia Episode: Theoretical Conception and Pilot Study.

Cognitive training (CT) and aerobic exercise have separately shown promise for improving cognitive deficits in schizophrenia. Aerobic exercise releases brain-derived neurotrophic factor, which promotes synaptic plasticity and neurogenesis. Thus, aerobic exercise provides a neurotrophic platform for neuroplasticity-based CT. The combination of aerobic exercise and CT may yield more robust effects than CT alone, particularly in the initial course of schizophrenia. In a pilot study, 7 patients with a recent onset of schizophrenia were assigned to Cognitive Training & Exercise (CT&E) and 9 to CT alone for a 10-week period. Posit Science programs were used for CT. Neurocognitive training focused on tuning neural circuits related to perceptual processing and verbal learning and memory. Social cognitive training used the same learning principles with social and affective stimuli. Both groups participated in these training sessions 2d/wk, 2h/d. The CT&E group also participated in an aerobic conditioning program for 30 minutes at our clinic 2d/wk and at home 2d/wk. The effect size for improvement in the MATRICS Consensus Cognitive Battery Overall Composite score for CT&E patients relative to CT patients was large. Functional outcome, particularly independent living skills, also tended to improve more in the CT&E than in the CT group. Muscular endurance, cardiovascular fitness, and diastolic blood pressure also showed relative improvement in the CT&E compared to the CT group. These encouraging pilot study findings support the promise of combining CT and aerobic exercise to improve the early course of schizophrenia.

Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial.

IMPORTANCE: Long-acting, injectable, second-generation antipsychotic medication has tremendous potential to bring clinical stability to persons with schizophrenia. However, long-acting medications are rarely used following a first episode of schizophrenia. OBJECTIVE: To compare the clinical efficacy of the long-acting injectable formulation of risperidone with the oral formulation in the early course of schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial performed at a university-based research clinic, between 2005 and 2012. Eighty-six patients with recent onset of schizophrenia were randomized to receive long-acting injectable risperidone or oral risperidone. Half of each group was simultaneously randomized to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being. An intent-to-treat analysis was performed between October 4, 2012, and November 12, 2014. INTERVENTIONS: A 12-month trial comparing the long-acting injectable vs oral risperidone and cognitive remediation vs healthy-behaviors training. MAIN OUTCOMES AND MEASURES: Psychotic relapse and control of breakthrough psychotic symptoms. RESULTS: Of the 86 patients randomized, 3 refused treatment in the long-acting injectable risperidone group. The psychotic exacerbation and/or relapse rate was lower for the long-acting risperidone group compared with the oral group (5% vs 33%; χ21 = 11.1; P < .001; relative risk reduction, 84.7%). Long-acting injectable risperidone better controlled mean levels of hallucinations and delusions throughout follow-up (ß = -0.30; t68 = -2.6, P = .01). The cognitive remediation and healthy-behaviors training groups did not differ significantly regarding psychotic relapse, psychotic symptom control, or hospitalization rates, and there were no significant interactions between the 2 medications and the 2 psychosocial treatments. Discontinuations owing to inadequate clinical response were more common in the oral group than in the long-acting risperidone group (χ21 = 6.1; P = .01). Adherence to oral risperidone did not appear to differ before randomization but was better for the long-acting risperidone group compared with the oral group (t80 = 5.3; P < .001). Medication adherence was associated with prevention of exacerbation and/or relapse (χ21 =11.1; P = .003) and control of breakthrough psychotic symptoms (ß = 0.2; t79 = 2.1; P = .04). CONCLUSIONS AND RELEVANCE: The use of long-acting injectable risperidone after a first episode of schizophrenia has notable advantages for clinical outcomes. The key clinical advantages are apparently owing to the more consistent administration of the long-acting injectable. Such formulations should be offered earlier in the course of illness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00333177.

Negative symptoms and functioning during the first year after a recent onset of schizophrenia and 8 years later.

BACKGROUND: Understanding the longitudinal course of negative symptoms, especially in relationship to functioning, in the early phase of schizophrenia is crucial to developing intervention approaches. The course of negative symptoms and daily functioning was examined over a 1-year period following a recent onset of schizophrenia and at an 8-year follow-up point. METHODS: The study included 149 recent-onset schizophrenia patients who had a mean age of 23.7 (SD=4.4)years and mean education of 12.9 (SD=2.2)years. Negative symptom (BPRS and SANS) and functional outcome (SCORS) assessments were conducted frequently by trained raters. RESULTS: After antipsychotic medication stabilization, negative symptoms during the first outpatient year were moderately stable (BPRS ICC=0.64 and SANS ICC=0.66). Despite this overall moderate stability, 24% of patients experienced at least one period of negative symptoms exacerbation. Furthermore, entry level of negative symptoms was significantly associated with poor social functioning (r=-.34, p<.01) and work/school functioning (r=-.25, p<.05) at 12months, and with negative symptoms at the 8-year follow-up (r=.29, p<.05). DISCUSSION: Early negative symptoms are fairly stable during the first outpatient year, are predictors of daily functioning at 12months, and predict negative symptoms 8years later. Despite the high levels of stability, negative symptoms did fluctuate in a subsample of patients. These findings suggest that negative symptoms may be an important early course target for intervention aimed at promoting recovery.

The impact of second-generation antipsychotic adherence on positive and negative symptoms in recent-onset schizophrenia.

OBJECTIVE: The aim of the study was to explore the extent to which initial severity of positive or negative symptoms in patients with recent-onset schizophrenia is related to medication nonadherence during the first outpatient year. METHODS: The study involved 64 first-episode schizophrenia patients treated with the second-generation oral antipsychotic medication, risperidone, for 12 months. Symptoms were evaluated using the SANS and SAPS completed every 3 months. Pearson correlations between medication adherence and symptoms were examined over each 3-month interval during 12 months of follow-through treatment. Possible causality was inferred from cross-lagged panel analyses. RESULTS: As expected, higher levels of adherence with antipsychotic medication were generally associated with lower levels of concurrent reality distortion (mean of SAPS delusions and hallucinations). Greater adherence during the 3-month baseline interval was generally associated with lower levels of avolition-apathy as well as alogia throughout the first outpatient year. However, medication adherence was not significantly associated with decreases in avolition-apathy or alogia over time. Cross-lagged panel analyses based on correlation coefficients are consistent with a causal relationship between initial medication adherence and lower levels of alogia. A test of mediation confirmed that an indirect path through reality distortion mediated the relationship between medication nonadherence and alogia. CONCLUSIONS: The associations between greater medication adherence and lower levels of negative symptoms appeared to be accounted for by the relationship of both variables to positive psychotic symptoms. The findings suggest that the impact of second-generation antipsychotic medication on suppression of negative symptoms might be mediated via a reduction in positive symptoms.

The relationship of attitudinal beliefs to negative symptoms, neurocognition, and daily functioning in recent-onset schizophrenia.

BACKGROUND: In the early course of schizophrenia, premorbid functioning, negative symptoms, and neurocognition have been robustly associated with several domains of daily functioning. Research with chronic schizophrenia patients suggests that attitudinal beliefs may influence daily functioning. However, these relationships have not been examined in recent-onset schizophrenia patients. METHODS: The sample consisted of recent-onset schizophrenia outpatients (n = 71) who were on average 21.7 (SD = 3.3) years old, had 12.5 (SD = 1.8) years of education, and 5.9 (SD = 6.3) months since psychosis onset. Patients were assessed for premorbid adjustment, positive and negative symptoms, neurocognition, attitudinal beliefs, and daily functioning. Normal controls (n = 20) were screened for psychopathology and demographically matched to the patients. RESULTS: Comparisons indicated that recent-onset patients had higher levels of dysfunctional attitudes and lower self-efficacy compared to healthy controls (t = 3.35, P < .01; t = -4.1, P < .01, respectively). Dysfunctional attitudes (r = -.34) and self-efficacy (r = .36) were significantly correlated with daily functioning. Negative symptoms were found to mediate the relationship between self-efficacy and daily functioning (Sobel test, P < .01), as well as between dysfunctional attitudes and daily functioning (Sobel test, P < .05). Neurocognition was a significant mediator of the relationship between self-efficacy and daily functioning (Sobel test, P < .05). DISCUSSION: Early course schizophrenia patients have significantly more dysfunctional attitudes and lower self-efficacy than healthy subjects. Both self-efficacy and dysfunctional attitudes partially contribute to negative symptoms, which in turn influence daily functioning. In addition, self-efficacy partially contributes to neurocognition, which in turn influences daily functioning.

The puzzle of schizophrenia: tracking the core role of cognitive deficits.

Cognitive deficits in schizophrenia are increasingly accepted as core features of this disorder that play a role as vulnerability indicators, as enduring abnormalities during clinical remission, and as critical rate-limiting factors in functional recovery. This article demonstrates the lasting influence of Norman Garmezy through his impact on one graduate student and then through his later collaborative research with colleagues. The promise of core cognitive deficits as vulnerability indicators or endophenotypes was demonstrated in research with children born to a parent with schizophrenia as well as with biological parents and siblings of individuals with schizophrenia. In studies of patients with a recent onset of schizophrenia, cognitive deficits were found to endure across psychotic and clinically remitted periods and to have a strong predictive influence on likelihood of returning successfully to work or school. Converging lines of evidence for the enduring core role of cognitive deficit in schizophrenia have led in recent years to a burgeoning interest in developing new interventions that target cognition as a means of improving functional recovery in this disorder.

Cardiorespiratory endurance, muscular flexibility and strength in first-episode schizophrenia patients: use of a standardized fitness assessment.

AIM: This study determined the fitness status and examined potential correlates of fitness in first-episode schizophrenia patients using a standardized fitness test protocol. METHODS: A certified fitness instructor administered the Young Men's Christian Association (YMCA) fitness test to 70 recent-onset schizophrenia participants within 3 months of entry into the study. RESULTS: Percentile ranks of scores on muscular strength and endurance, muscular flexibility and cardiorespiratory fitness in our sample were all below the 50th percentile when compared with national norms in the United States. As expected, patients with a higher body mass index and those who smoked had poorer cardiorespiratory fitness. A non-significant trend indicated that patients with a longer duration of illness had worse cardiorespiratory fitness. Exposure to antipsychotic medication was unrelated to cardiorespiratory fitness. CONCLUSION: Results suggest that physical fitness is impaired and might decline over time in first-episode schizophrenia patients, but this needs to be confirmed in a longitudinal study.

Neurocognitive predictors of work outcome in recent-onset schizophrenia.

While the role of neurocognitive impairment in predicting functional outcome in chronic schizophrenia is now widely accepted, the results that have examined this relationship in the early phase of psychosis are surprisingly rather mixed. The predictive role of cognitive impairment early in the illness is of particular interest because interventions during this initial period may help to prevent the development of chronic disability. In a University of California, Los Angeles (UCLA) longitudinal study, we assessed schizophrenia patients with a recent first episode of psychosis using a neurocognitive battery at an initial clinically stabilized outpatient point and then followed them during continuous treatment over the next 9 months. Three orthogonal cognitive factors were derived through principal components analysis: working memory, attention and early perceptual processing, and verbal memory and processing speed. All patients were provided a combination of maintenance antipsychotic medication, case management, group skills training, and family education in a UCLA research clinic. A modified version of the Social Adjustment Scale was used to assess work outcome. Multiple regression analyses indicate that the combination of the 3 neurocognitive factors predicts 52% of the variance in return to work or school by 9 months after outpatient clinical stabilization. These data strongly support the critical role of neurocognitive factors in recovery of work functioning after an onset of schizophrenia. Cognitive remediation and other interventions targeting these early cognitive deficits are of major importance to attempts to prevent chronic disability.

Development and evaluation of a health promotion group for individuals with severe psychiatric disabilities.

OBJECTIVE: A six-step program development and evaluation method integrating recovery principles of empowerment and choice in healthcare decisions with theory driven research from the fields of health promotion and psychiatric rehabilitation is presented. METHODS: A pilot wellness program that taught basic nutrition, exercise, and stress management skills to individuals diagnosed with schizophrenia demonstrates how to complete each step. Pre-post pilot data are analyzed using paired-sample t tests. RESULTS: Nine people diagnosed with schizophrenia participated in the pilot program. Despite a small sample size and limited statistical power, a paired-sample t test suggested that the program appeared to increase participants' self-efficacy for health practices (p<.05), specifically in the domains of psychological well-being (p<.01) and health responsibility (p<.05), while decreasing their perceptions of the overall amount of stress in their life (p<.01). CONCLUSIONS: Treatment providers are encouraged to use the six-step method to create programs that successfully blend empirical research methodology with consumer-centered participation.

Stability of visual masking performance in recent-onset schizophrenia: an 18-month longitudinal study.

Visual masking deficit in schizophrenia has been suggested to be a potential vulnerability marker for schizophrenia. An important characteristic of a vulnerability marker is stability over time, but relatively little is known about the longitudinal course of masking performance of schizophrenia patients. In this study, we examined the stability of visual masking performance in recent-onset schizophrenia patients over an 18-month period. We administered both forward and backward masking trials with multiple stimulus onset asynchronies for four masking conditions at three time points (baseline, 6-month, and 18-month). Recent-onset schizophrenia patients showed stable masking performance for both forward and backward conditions over a period of 18 months. Furthermore, the stable performance was observed across all four masking conditions. The findings of this study provide further support for the view that visual masking deficits reflect a possible vulnerability marker for schizophrenia.