Clinical Antipsychotic Trials Of Intervention Effectiveness Research Articles

Extent of attaining and maintaining symptom remission by antipsychotic medication in the treatment of chronic schizophrenia: Evidence from the CATIE study

BackgroundData on attaining and maintaining symptom remission associated with specific antipsychotic medications are rare and variant. AimsTo examine remission rates and their variation by antipsychotic medication in chronic schizophrenia in the National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) given it has an 18-month duration and representative antipsychotic medications. MethodsSymptom remission was examined using the Remission in Schizophrenia Working Group remission criteria of attaining and maintaining for 6months with mild ratings on 8 specific Positive and Negative Syndrome Scale (PANSS) items. Remission rates were assessed (a) up to 18months across CATIE's switching phases (n=1332); and (b) in phase 1 (that involved double-blind randomization to one of five antipsychotic medications) to compare antipsychotic medication differences in attaining and maintaining remission among patients not in remission at baseline (n=941). ResultsAt baseline 16.2% of patients were in symptomatic remission. Across the medication phases of CATIE only 11.7% attained and then maintained at least 6months of symptomatic remission, and 55.5% (n=623) experienced no symptom remission at any visit. During the first medication randomization phase, attaining and maintaining remission for 6months was highest for the olanzapine (12.4%) medication group followed by the quetiapine (8.2%), perphenazine (6.8%), ziprasidone (6.5%), and risperidone (6.3%) groups. ConclusionsAs currently defined, remission appears to be a very difficult therapeutic target to attain and maintain in chronic schizophrenia and may differ by antipsychotic medication. Pragmatically, remission gradients may be effectively studied by applying modified duration and symptom criteria.

Predicting Psychiatric Hospital Admission Among Adults With Schizophrenia

The authors identified patient characteristics that increased risk of hospital admission among adults with schizophrenia. A total of 1,460 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) clinical trial were followed from the time they began a randomized trial of medication to first schizophrenia-related hospital admission. In 869 person-years of follow-up, 203 patients were hospitalized. Increased risk of hospital admission was associated with early age (≤ 17 years) of first antipsychotic treatment (adjusted hazard ratio [AHR]=2.16, 95% confidence interval [CI]=1.49-3.11), psychiatric hospitalization in past year (AHR=2.99, CI=2.23-4.00), having had DSM-IV alcohol (AHR=1.56, CI=1.16-2.10) or drug (AHR=1.50, CI=1.13-2.00) use disorders in the past five years, and baseline severe symptoms according to the Clinical Global Impressions Scale (AHR=1.54, CI=1.04-2.27), presence of tardive dyskinesia (AHR=1.55, CI=1.07-2.23), a high score on the positive symptoms subscale of the Positive and Negative Syndrome Scale (AHR=1.52, CI=1.07-2.15), and low social function (AHR=1.45, CI=1.03-2.04). As compared with olanzapine, the drugs quetiapine (AHR=2.14, CI=1.39-3.31), perphenazine (AHR=1.80, CI=1.11-2.94), and ziprasidone (AHR=2.70, CI=1.64-4.44) were associated with increased hospitalization risk. Risperidone was associated with a lower hospitalization risk than quetiapine (AHR=1.50, CI=1.01-2.22) and ziprasidone (AHR=1.89, CI=1.19-3.01). Efforts to lower hospital admission risk among individuals with schizophrenia should focus on history of early onset, recent inpatient admission, severe positive symptoms, poor social function, high global illness severity, and comorbid substance use disorders and on selection of an appropriate antipsychotic medication.

Switching Antipsychotic Medications: Not Enough, Too Often, or Just Right?

Switching Antipsychotic Medications: Not Enough, Too Often, or Just Right?

Analysis of efficacy and side effects in CATIE demonstrates drug response subgroups and potential for personalized medicine

ObjectiveThis study aims to improve understanding of antipsychotic non/response and assess the potential for personalized schizophrenia treatment. MethodsWe used data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) and neurocognitive functioning. Side effect measures included weight, lipids, glucose, heart rate and QT prolongation. Latent class analysis was conducted for each of the five drugs on the individual treatment effects to study whether there were subgroups of drug responders. The posterior probabilities of belonging to a particular response group were correlated across drugs to examine if patients not responding to one drug are likely to respond to a different drug and whether response to one drug may help to predict response to another drug. ResultsWe identified four qualitatively distinct response groups: Optimal Responders, Average Responders, Global Responders and Non-Responders. Different patterns of correlations with demographics and clinical variables across classes provided further support for the validity of these groups. The low correlations between posterior probabilities of the same response groups across drugs implied that patients generally belonged to different response groups for different drugs. ConclusionsOur results demonstrate the existence of subgroups of patients characterized by distinct patterns of drug response. Further, findings suggest that patients who experience a poor response to one drug may be an optimal responder to another antipsychotic. Taken together these findings demonstrate the potential to personalize schizophrenia treatment and highlight the importance of identifying better predictors of drug response.

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

Tardive dyskinesia (TD) is a severe adverse effect of chronic antipsychotic drug treatment. In addition to clinical risk factors, TD susceptibility is influenced by genetic predisposition. Recently, Syu et al. (2010) reported a genome-wide association screening of TD in Japanese schizophrenia patients. The best result was association of single-nucleotide polymorphism (SNP) rs2445142 in the HSPG2 (heparan sulfate proteoglycan 2) gene with TD. In the present study, we report a replication study of the five top Japanese TD-associated SNPs in two Caucasian TD samples. Applying logistic regression and controlling for relevant clinical risk factors, we were able to replicate the association of HSPG2 SNP rs2445142 with TD in a prospective study sample of 179 Americans of European origin by performing a secondary analysis of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genome-wide association study data set, and using a perfect proxy surrogate marker (rs878949; P = 0.039). An association of the 'G' risk allele of HSPG2 SNP rs2445142 with TD was also shown in a sample of Jewish Israeli schizophrenia patients (retrospective, cross-sectional design; P = 0.03). Although the associations were only nominally significant, the findings provide further support for the possible involvement of HSPG2 in susceptibility to TD.

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.

Who Is Paying the Price? Loss of Health Insurance Coverage Early in Psychosis

Who Is Paying the Price? Loss of Health Insurance Coverage Early in Psychosis

Longitudinal consent-related abilities among research participants with schizophrenia: Results from the CATIE study

ObjectiveResearch participants must have adequate consent-related abilities to provide informed consent at the time of study enrollment. We sought to determine if research participants with schizophrenia maintain adequate consent-related abilities during a longitudinal study. If participants lose abilities during a trial they may not be able to judge and protect their interests. If reduced abilities are common or can be predicted, special protections can be targeted appropriately. MethodWe examined longitudinal consent-related abilities of participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study using the MacArthur Competence Assessment Tool-Clinical Research (MacCAT-CR) at protocol-specified times over 18months. ResultsOf 1158 research participants in this analysis, most (n=650, 56%) had a stable pattern of MacCAT-CR Understanding scores, 235 (20%) improved substantially with no evidence of decline, 273 (24%) had at least one assessment with substantial worsening. During the course of the trial, 43 (4%) fell below the initial threshold for adequate capacity, which was predicted by lower Understanding scores, more severe positive symptoms, and poorer neurocognitive functioning at baseline, and by increases in negative symptoms and deteriorating global status. ConclusionsMost participants in this long-term study had stable or improved consent-related abilities, but almost one-fourth experienced substantial worsening and 4% of participants fell below the study's capacity threshold for enrollment. Clinical investigators should monitor with special care individuals with marginal capacity or higher levels of psychotic symptoms at study entry and those who exhibit clinical worsening during a study.

Time to All-Cause Treatment Discontinuation as the Primary Outcome in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Study

Time until all-cause treatment discontinuation was the primary outcome of the CATIE trial. We discuss the advantages and disadvantages of this outcome, and evaluate its association with clinical correlates through graphical response profiles. We investigate the characteristics of patients who discontinued for patient decision, including a reclassification of patient decision into other reasons. All-cause discontinuation is compared to a related outcome, time until treatment failure. Patients who discontinued had lower quality of life scores than other patients. Patients discontinuing for lack of efficacy had worsened efficacy scores compared with an improvement for other patients. Those who discontinued for patient decision had lower compliance. Blinded reclassification of discontinuation for patient decision identified 5% of cases as lack of efficacy and 21% as intolerable side effects. Reclassified patients participated in the next study phase at a higher rate than those remaining as patient decision (67% vs. 10%). Treatment group differences for time to discontinuation due to patient decision were attenuated after censoring the reclassified patients, but were still suggestive. Treatment comparisons for time to treatment failure were consistent with all-cause discontinuation, although somewhat smaller. All-cause discontinuation is recommended as a simple and comprehensive outcome for pharmaceutical Phase II-IV clinical trials.

Evidence for a SULT4A1 Haplotype Correlating with Baseline Psychopathology and Atypical Antipsychotic Response

This study evaluated the impact of SULT4A1 gene variation on psychopathology and antipsychotic drug response in Caucasian subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and a replication sample. SULT4A1 haplotypes were determined using SNP data. The relationship to baseline psychopathology was evaluated using linear regression of Positive and Negative Syndrome Scale (PANSS) total score. Drug response was evaluated using Mixed Model Repeat Measures (MMRM) for change in PANSS. For the CATIE sample, patients carrying a haplotype designated SULT4A1-1(+) displayed higher baseline PANSS (p = 0.03) and, when treated with olanzapine, demonstrated a significant interaction with time (p = 0.009) in the MMRM. SULT4A1-1(+) patients treated with olanzapine displayed improved response compared with SULT4A1-1(-) patients treated with olanzapine (p = 0.008) or to SULT4A1-1(+) patients treated with risperidone (p = 0.006). In the replication sample, SULT4A1-1(+) patients treated with olanzapine demonstrated greater improvement than SULT4A1-1(-) patients treated with olanzapine (p = 0.05) or than SULT4A1-1(+) patients treated with risperidone (p = 0.05). If validated, determination of SULT4A1-1 haplotype status might be useful for identifying patients who show an enhanced response to long-term olanzapine treatment. Original submitted 6 October 2010; Revision submitted 9 December 2010.

Serological evidence of exposure to Herpes Simplex Virus type 1 is associated with cognitive deficits in the CATIE schizophrenia sample

Cognitive impairment is a core feature of schizophrenia. Previous studies have indicated that exposure to neurotropic infectious agents such as Herpes Simplex Virus type 1 may contribute to cognitive deficits and neuroanatomical abnormalities in individuals with schizophrenia. We examined the association between exposure to neurotropic infectious agents and cognitive function in 1308 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. This sample included all of the individuals in the CATIE trial for whom baseline blood samples were available. Cognition was evaluated at baseline by a test battery which yielded composite scores in the domains of processing speed, verbal memory, vigilance, reasoning, and working memory as well as a summary neurocognitive score. Solid phase immunoassay techniques were used to measure IgG class antibodies to Herpes Simplex Virus type 1 (HSV-1), Herpes Simplex Virus type 2 (HSV-2), Cytomegalovirus (CMV), and to Toxoplasma gondii ( T gondii) in the sera of the study individuals. We found a significant association between the neurocognitive summary score and antibodies to HSV-1 but not to HSV-2, CMV, or T. gondii. There was also a significant association between HSV-1 exposure and the Verbal Memory, Vigilance, and Processing Speed composite scores. HSV-1 may modulate the neurocognitive function of individuals with schizophrenia through its ability to establish latency in the central nervous system and undergo periodic reactivation. A better understanding of the role of HSV-1 may lead to better methods of treatment for the cognitive impairments associated with schizophrenia.

A Concise Display of Multiple End Points for Benefit–Risk Assessment

The assessment and representation of benefit-risk "balance" in pharmaceutical development have become increasingly important. Although the methodologies may vary considerably in complexity, most approaches to benefit-risk assessment require the simultaneous consideration of information pertaining to multiple end points for multiple treatments. However, the lengthy data tables and displays that are frequently used make this assessment difficult. Using an example from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, this note presents a conceptually simple visualization that facilitates understanding of information on multiple points.

Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia

Tardive dyskinesia (TD) occurs in approximately 20% of patients exposed to long-term antipsychotic treatment and may be influenced by genetic predisposition, in addition to clinical risk factors. In this study, we implemented a two-step approach to identify susceptibility genes for TD. First, we performed a secondary analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) genome-wide association study (GWAS) dataset to identify candidate genes for TD severity. A total of 327 schizophrenia patients treated with antipsychotics who participated in the CATIE trial were included in a TD severity GWAS (approximately 495,000 SNPs). Cases were defined as demonstrating involuntary movements of a mild degree in two or more body regions or of a moderate to severe degree in at least one body region on at least two separate evaluations, whereas controls were completely free of abnormal involuntary movement on all evaluations. Using logistic regression and controlling for population stratification and relevant clinical risk factors, none of the associated SNPs reached GWAS significance; however, several promising SNPs were identified for follow-up investigation. In the second step, we performed an association study of the top 25 SNPs in an independent sample of 170 Jewish, Israeli, schizophrenia patients (retrospective, cross-sectional design). Association of the SNP rs3943552 T allele in the GLI2 gene with TD was observed in a subsample of Ashkenazi Jewish patients (N = 96, P = 0.018; P = 6.2 × 10⁻⁵ in the CATIE sample). The GLI2 gene encodes a transcription factor that participates in the development of the dopaminergic system during embryogenesis. Taken together, our findings support a possible contribution of GLI2 to TD susceptibility.

Caregiver Burden in Alzheimer Disease: Cross-Sectional and Longitudinal Patient Correlates

Alzheimer disease (AD) imposes a severe burden on patients and their caregivers. Although there is substantial evidence of the adverse impact of burden, considerably less is known about its specific correlates and potential causes. The authors use data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-AD study to examine the relationship of burden and depression among AD caregivers to patient and caregiver sociodemographic characteristics, patients' cognitive status, psychiatric and behavioral symptoms, functional abilities, quality of life, and intensity of care provided by caregivers. CATIE-AD included outpatients in usual care settings and assessed treatment outcomes during 9 months. Data were examined from 421 ambulatory outpatients with a diagnosis of dementia of the Alzheimer type or probable AD with agitation or psychosis. The Burden Interview, the Beck Depression Inventory, and the Caregiver Distress Scale were used to evaluate caregiver burden. More severe psychiatric and behavioral problems and decreased patient quality of life, as well as lower functional capability were significantly associated with higher levels of burden and depression among caregivers at baseline. Six-month changes showed that decreased symptoms and improved quality of life were associated with decreased burden and accounted for most of the explained variance in change in burden measures. Severity of psychiatric symptoms, behavioral disturbances, and patients' quality of life are the main correlates of caregivers' experience burden. Psychosocial and pharmacologic interventions targeting these two aspects of the disorder are likely to not only alleviate patient suffering but also promote caregiver well-being.

Antipsychotic‐associated all‐cause and cardiac mortality: what should we worry about and how should the risk be assessed?

Antipsychotic‐associated all‐cause and cardiac mortality: what should we worry about and how should the risk be assessed?

Linkage of Cognitive Impairments With Metabolic Disorders in Schizophrenia

Linkage of Cognitive Impairments With Metabolic Disorders in Schizophrenia

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.

Schizophrenia in a worldwide perspective: explaining similarities and differences

Schizophrenia in a worldwide perspective: explaining similarities and differences

Antipsychotics and Schizophrenia: From Efficacy and Effectiveness to Clinical Decision-Making

To comprehensively review the 2 recent and large antipsychotic effectiveness trials for treatment of schizophrenia: the United Kingdom's Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), and the National Institute of Mental Health-initiated Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. We present a review of the rationale, methodology, and findings to date from the CUtLASS and CATIE schizophrenia trials, including all primary and secondary outcomes. The primary findings from both trials, CUtLASS and CATIE, suggest that first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) are equally effective in the treatment of schizophrenia. The exception is in treatment-resistant populations where clozapine exhibits superiority, compared with other SGAs. In the CATIE trial, there is a suggestion that olanzapine is superior in effectiveness, compared with other nonclozapine SGAs, although this seems to be mediated by past history of olanzapine use, and carries with it increased weight gain and metabolic adverse events. From a cost-effectiveness perspective, there is no evidence that SGAs are superior to FGAs, with findings suggesting the possibility that FGAs may be superior. Past efficacy trials have strongly supported the position that SGAs are superior to FGAs in the treatment of schizophrenia and in side effect profile. Two large independent effectiveness trials, CUtLASS and CATIE, have offered a strong challenge to these claims. Both suggest that SGAs, except clozapine in the treatment-resistant population, offer little, if any, clinical benefits, and, moreover, harbour their own significant side effects.

Practicing evidence-based psychiatry: 1. Applying a study's findings: The threats to validity approach

One critical skill in the practice of evidence-based medicine is the ability to correctly interpret and apply findings of a study relevant to the clinical question needing to be answered. In this paper, we outline an approach to asking the clinical question in a form answerable by a research study and then finding the most relevant study. We next define the two steps in the process of applying a study's findings towards making a treatment decision and discuss the threats to validity approach. We summarize concepts of statistical conclusion validity, internal validity, construct validity, and external validity. We illustrate the method utilizing a clinical vignette that requires choice of an antipsychotic agent. We discuss the results of Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) in schizophrenia and consider the threats to the different forms of validity in CATIE.