Alexander L. Miller

The functional significance of symptomatology and cognitive function in schizophrenia

The relationships between positive and negative symptomatology, cognitive function, and the ability to perform basic activities of daily living in patients with schizophrenia were examined in two studies. In study 1, 112 medicated patients were assessed utilizing the Brief Psychiatric Rating Scale (positive symptoms), the Negative Symptom Assessment (negative symptoms and cognitive function), and the Functional Needs Assessment (activities of daily living). Study 2 (n = 41), utilized the same measures of symptomatology and added a comprehensive neuropsychological test battery. Regression analyses in both studies determined that symptomatology predicts a relatively small amount of the variance in the ability to perform basic activities of daily living. Cognitive function, whether assessed with the Cognition subscale of the Negative Symptom Assessment or a comprehensive neuropsychological test battery, predicted over 40% of the variance in scores on the Functional Needs Assessment. A path model in which cognition predicted both concurrent symptomatology and activities of daily living and where symptomatology had little direct impact upon activities of daily living fit the data. The importance of addressing cognitive deficits in psychosocial intervention programs is discussed.

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

Do specific neurocognitive deficits predict specific domains of community function in schizophrenia

We examined whether specific neurocognitive deficits predicted specific domains of community outcome in 40 schizophrenic patients. Neuropsychological assessments were conducted before hospital discharge, and measures of functional outcome were obtained 1 to 3.5 years later. A priori hypotheses were generated based upon a recent review by Green (Green MF [1996] What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry, 153(3):321-330). As hypothesized, verbal memory predicted all measures of community outcome, vigilance predicted social outcomes, and executive functioning predicted work and activities of daily living (ADLs). However, in addition to the predicted relationships, many other associations were found between neuropsychological test scores and adaptive function. Furthermore, both cognitive and functional measures were intercorrelated. If deficits in adaptive functioning are neurocognitively multi-determined, utilizing compensatory strategies to bypass multiple areas of cognitive impairment may be more efficient than cognitive remediation in improving community outcomes.

Does cognitive function improve with quetiapine in comparison to haloperidol

Recent evidence suggests that schizophrenia patients taking atypical antipsychotic medications may perform better on some tests of cognitive function than those treated with older antipsychotics. The current study compared the effects of quetiapine and haloperidol on measures of executive function, memory and attention. Subjects were 58 stable outpatients with schizophrenia (DSM III-R) who received a battery of cognitive tests as part of a randomized, double-blind, multi-site clinical efficacy study conducted by AstraZeneca Pharmaceuticals. Cognitive assessments were conducted prior to randomization when patients were receiving < or =30 mg haloperidol or equivalent (mean: 9.2mg/day haloperidol equivalents), and again after 24 weeks of fixed-dose treatment with either quetiapine 600 or 300 mg/day or haloperidol 12 mg/day. Analyses of covariance with planned comparisons were used to compare scores on cognitive measures at the end of 24 weeks by treatment group with baseline cognitive function scores used as covariates. Patients receiving quetiapine 600 mg/day improved to a greater extent than patients receiving haloperidol on overall cognitive function (p<0.02). Specific differences were found for executive function (Verbal Fluency Test, p<0.04), attention (Stroop Color Word Test, p<.03) and verbal memory (Paragraph Recall Test, p<0.02). Treatment group differences were not solely due to benztropine use, medication side effects, or changes in symptomatology. Treatment with quetiapine at higher doses (600 mg/day) relative to haloperidol appears to have a positive impact on important domains of cognitive performance that have been found to predict role function and community outcomes in patients with schizophrenia.

Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-Year Outcomes From the NIMH RAISE Early Treatment Program

OBJECTIVE The primary aim of this study was to compare the impact of NAVIGATE, a comprehensive, multidisciplinary, team-based treatment approach for first-episode psychosis designed for implementation in the U.S. health care system, with community care on quality of life. METHOD Thirty-four clinics in 21 states were randomly assigned to NAVIGATE or community care. Diagnosis, duration of untreated psychosis, and clinical outcomes were assessed via live, two-way video by remote, centralized raters masked to study design and treatment. Participants (mean age, 23) with schizophrenia and related disorders and ≤6 months of antipsychotic treatment (N=404) were enrolled and followed for ≥2 years. The primary outcome was the total score of the Heinrichs-Carpenter Quality of Life Scale, a measure that includes sense of purpose, motivation, emotional and social interactions, role functioning, and engagement in regular activities. RESULTS The 223 recipients of NAVIGATE remained in treatment longer, experienced greater improvement in quality of life and psychopathology, and experienced greater involvement in work and school compared with 181 participants in community care. The median duration of untreated psychosis was 74 weeks. NAVIGATE participants with duration of untreated psychosis of <74 weeks had greater improvement in quality of life and psychopathology compared with those with longer duration of untreated psychosis and those in community care. Rates of hospitalization were relatively low compared with other first-episode psychosis clinical trials and did not differ between groups. CONCLUSIONS Comprehensive care for first-episode psychosis can be implemented in U.S. community clinics and improves functional and clinical outcomes. Effects are more pronounced for those with shorter duration of untreated psychosis.

Executive-frontal lobe cognitive dysfunction in schizophrenia: A symptom subtype analysis

Impairment of executive-frontal lobe functioning, affecting the planning, initiation and regulation of goal-directed behavior, is a common cognitive deficit in schizophrenia. However, it is unclear if deficits in these frontal-lobe-mediated abilities are differentially expressed across clinical subgroups. We analyzed executive-frontal abilities in relation to symptom expression in 53 hospitalized schizophrenic patients. Patients were assigned to one of three subgroups based on rank order analysis of Brief Psychiatric Rating Scale factors: Withdrawal-Retardation, Reality Distortion and Conceptual Disorganization. Executive-frontal tests included Visual Search, Verbal Fluency, Verbal Series Attention, Trail Making - Part B, Symbol Digit, Hopkins Verbal Learning, Digit Span, Wisconsin Card Sorting, Stroop Color-Word and Attentional Capacity. The schizophrenia group showed significant deficits relative to healthy control subjects (n = 20) on all tests. Exploratory factor analysis of test scores revealed three factors: (i) Verbal Processing/Memory; (ii) Cognitive Flexibility/Attention; and (iii) Psychomotor Speed/Visual Scanning. The three symptom subgroups were differentially impaired on executive-frontal abilities: Withdrawal-Retardation on psychomotor speed, verbal fluency, working memory, visual search and cognitive flexibility; Conceptual Disorganization on attention; Reality Distortion on verbal memory. The results have implications for syndrome definition, pharmacological intervention and prediction of outcome in schizophrenia.

A Placebo-Controlled Add-On Trial of the Ampakine, CX516, for Cognitive Deficits in Schizophrenia

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was −0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

Predicting quality of life from symptomatology in schizophrenia at exacerbation and stabilization

There has been little research investigating how symptoms of schizophrenia and changes in symptomatology across the course of the illness relate to measures of quality of life in patients. We examined this issue in 45 patients assessed at hospital admission for illness exacerbation, at stabilization (prior to discharge) and at follow-up (5-9 months post-discharge). Symptom ratings at each time period consisted of the Brief Psychiatric Rating Scale (BPRS) and the Negative Symptom Assessment (NSA). The Heinrichs-Carpenter Quality of Life Scale (QLS) was administered upon admission to the hospital (assessing the 3 months prior to admission) and again at follow-up. Correlational analyses revealed relationships of both positive and negative symptoms with quality of life. These relationships are particularly strong at stabilization. Stepwise regression analyses revealed changes in the NSA motivation component to be most important in predicting quality of life for the patients at follow-up. BPRS psychosis and paranoia components are important predictors of quality of life at stabilization (but not during acute exacerbation). These results are important in terms of understanding the impact of changes in symptomatology on the quality of life for patients with schizophrenia as well as in targeting specific symptom clusters for treatment to maximize quality of life post-hospitalization.

Effectiveness of Switching From Antipsychotic Polypharmacy to Monotherapy

OBJECTIVE This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. METHOD Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. RESULTS Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. CONCLUSIONS Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

Results of Phase 3 of the CATIE Schizophrenia Trial

OBJECTIVE The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes. METHOD Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments. RESULTS Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33-41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall). CONCLUSIONS Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study.