Vicki G. Davis

Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: Prospective data from phase 1

BACKGROUND The metabolic syndrome (MS) is associated with increased risk for diabetes mellitus and coronary heart disease, and is highly prevalent among schizophrenia patients. Given concerns over antipsychotic metabolic effects, this analysis explored MS status and outcomes in phase 1 of the CATIE Schizophrenia Trial. METHODS The change in proportion of subjects with MS and individual criteria was compared between antipsychotic treatment groups, along with mean changes for individual criteria. Primary analyses examined subjects with fasting laboratory assessments at baseline and 3 months. Other analyses examined 3-month changes in MS status, waist circumference (WC), HDL cholesterol and blood pressure in all subjects, metabolic changes at the end of phase 1 participation (EOP), and repeated measures changes in HDL, blood pressure (BP) and WC over phase 1. RESULTS At 3 months, there were no significant between-drug differences for the change in proportion of subjects meeting MS status or individual MS criteria in the smaller fasting cohort (n = 281) or for those meeting criteria for parameters not dependent on fasting status (BP, HDL, WC) among all subjects (n=660). Among all subjects whose MS status could be determined at 3 months (n=660), MS prevalence increased for olanzapine (from 34.8% to 43.9%), but decreased for ziprasidone (from 37.7% to 29.9%) (p=.001). Although effect sizes varied across subgroups, at 3 months olanzapine and quetiapine had the largest mean increase in waist circumference (0.7 in. for both) followed by risperidone (0.4 in.), compared to no change for ziprasidone (0.0 in.) and a decrease in waist circumference for perphenazine (-0.4 in.). Olanzapine also demonstrated significantly different changes in fasting triglycerides at 3 months (+21.5 mg/dl) compared to ziprasidone (-32.1 mg/dl). EOP exposure data was obtained, on average, nine months from baseline for all metabolic variables. Results from EOP and repeated measures analyses were consistent with those at 3 months for mean changes in WC and fasting triglycerides, but between group differences emerged for HDL and SBP. CONCLUSIONS This large non-industry sponsored study confirms the differential metabolic effects between antipsychotics. Clinicians are advised to monitor all metabolic parameters, including WC, HDL and serum triglycerides, during antipsychotic treatment.

Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study.

OBJECTIVE Persons with schizophrenia die earlier than the general population, in large part due to cardiovascular disease. The study objective was to examine effects of different antipsychotic treatments on estimates of 10-year coronary heart disease (CHD) risk calculated by the Framingham Heart Study formula. METHOD Change in 10-year risk for CHD was compared between treatment groups in 1125 patients followed for 18 months or until treatment discontinuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. RESULTS The covariate-adjusted mean change in 10-year CHD risk differed significantly between treatments. Olanzapine was associated with a 0.5% (SE 0.3) increase and quetiapine, a 0.3% (SE 0.3) increase; whereas risk decreased in patients treated with perphenazine, -0.5% (SE 0.3), risperidone, -0.6% (SE 0.3), and ziprasidone -0.6% (SE 0.4). The difference in 10-year CHD risk between olanzapine and risperidone was statistically significant (p=0.004). Differences in estimated 10-year CHD risk between drugs were most marked in the tertile of subjects with a baseline CHD risk of at least 10%. Among individual CHD risk factors used in the Framingham formula, only total and HDL cholesterol levels differed between treatments. CONCLUSIONS These results indicate that the impact on 10-year CHD risk differs significantly between antipsychotic agents, with olanzapine producing the largest elevation in CHD risk of the agents studied in CATIE.

Inflammatory markers in schizophrenia: comparing antipsychotic effects in phase 1 of the clinical antipsychotic trials of intervention effectiveness study.

BACKGROUND C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are systemic inflammatory markers (IM) that positively correlate with cardiovascular (CV) risk. Despite the known CV effects of atypical antipsychotics, there is limited prospective data on IM changes during treatment. METHODS The IM outcomes were compared between antipsychotic treatment groups in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial phase 1 with subjects with laboratory assessments at baseline and 3 months (n = 789). RESULTS There were significant treatment differences in CRP, E-selectin, and ICAM-1 at 3 months, with a differential impact of baseline values on the CRP and ICAM-1 results. In overall comparisons, quetiapine and olanzapine had the highest median levels for CRP, and olanzapine for E-selectin and ICAM-1. Olanzapine was significantly different after baseline adjustment than perphenazine (p = .001) for E-selectin, and in those with low baseline CRP (<1 mg/L), olanzapine was significantly different than perphenazine (p < .001), risperidone (p < .001), and ziprasidone (p = .002) for CRP. Perphenazine had the lowest 3-month ICAM-1 levels in subjects with baseline ICAM-1 above the median, but the differences were not statistically significant versus olanzapine (p = .010), quetiapine (p = .010), and risperidone (p = .006) after controlling for multiple comparisons. The 18-month repeated measures CRP analysis confirmed the significantly higher values for olanzapine in those with low baseline CRP. CONCLUSIONS This analysis provides further evidence for differential antipsychotic metabolic liabilities as measured by changes in systemic inflammation. C-reactive protein might emerge as a useful target for CV risk outcomes in schizophrenia patients.

Impact of antipsychotic treatment on nonfasting triglycerides in the CATIE Schizophrenia Trial phase 1.

BACKGROUND Recent literature documents a stronger association between nonfasting triglycerides (TG) and cardiovascular risk compared to fasting TG. Given concerns over antipsychotic effects on serum TG, this analysis explored changes in nonfasting TG in phase 1 of the CATIE Schizophrenia Trial. METHODS Change in nonfasting TG, adjusted for baseline value, was compared between antipsychotic treatment groups using subjects with nonfasting laboratory assessments at baseline and 3 months. RESULTS Among the 246 subjects there were significant treatment differences in 3-month change from baseline (p=0.009). The greatest increases in median and adjusted mean nonfasting TG levels were seen among those randomized to quetiapine (mean+54.7 mg/dl, median+26 mg/dl) and olanzapine (mean+23.4 mg/dl, median+26.5 mg/dl), while ziprasidone was neutral (mean+0.0 mg/dl, median+8 mg/dl), and decreases were seen with risperidone (mean -18.4 mg/dl, median -6.5 mg/dl) and perphenazine (mean -1.3 mg/dl, median -22 mg/dl). Pairwise comparisons indicated a significant between-group difference for perphenazine vs. olanzapine (p=0.002) and a trend for perphenazine vs. quetiapine (p=0.006). CONCLUSIONS This analysis provides further evidence for differential antipsychotic metabolic liabilities, and confirms signals for the effects of olanzapine and quetiapine on serum TG seen in earlier CATIE analyses. Future consensus recommendations will clarify the role of nonfasting TG monitoring in routine clinical practice.

The association between weight change and symptom reduction in the CATIE schizophrenia trial

BACKGROUND Weight gain and changes in metabolic indicators associated with some antipsychotics may be related to symptom improvement and thus an unavoidable correlate of clinical benefit. METHODS Data from the CATIE schizophrenia trial comparing the effectiveness of perphenazine, olanzapine, risperidone, quetiapine and ziprasidone in a randomized, double-blind, trial over 18 months were used to evaluate the relationship between percent change in body mass index (BMI) and change in total serum cholesterol and triglycerides with the Positive and Negative Syndrome Scale (PANSS) score. Analysis of covariance for observations at 3 months and a mixed effects model for all observations up to 18 months adjusted for potentially confounding variables were used to examine these associations. RESULTS In both models, there was a significant association (p = 0.001) between change in PANSS total score and percent change in BMI, equating to a 0.28 and 0.21 point decrease in PANSS total score (range 30-210) per 1% increase in BMI respectively. Change in BMI accounted for 3% or less of variance for change in PANSS scores. There was no evidence that the association of symptoms and weight gain differed across medications in spite of substantial differences in weight gain and other metabolic measures. Neither total serum cholesterol nor triglyceride levels displayed a significant association with change in PANSS. CONCLUSION The magnitude of the relationship between change in BMI and PANSS was too small to be clinically important, indicating that switching medications to one with less metabolic risk is unlikely to result in meaningful loss of clinical benefit.

Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia

OBJECTIVE We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. METHOD This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. RESULTS Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. CONCLUSIONS Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00014001.

Reliability, Validity and Treatment Sensitivity of the Schizophrenia Cognition Rating Scale

Cognitive functioning can be assessed with performance-based assessments such as neuropsychological tests and with interview-based assessments. Both assessment methods have the potential to assess whether treatments for schizophrenia improve clinically relevant aspects of cognitive impairment. However, little is known about the reliability, validity and treatment responsiveness of interview-based measures, especially in the context of clinical trials. Data from two studies were utilized to assess these features of the Schizophrenia Cognition Rating Scale (SCoRS). One of the studies was a validation study involving 79 patients with schizophrenia assessed at 3 academic research centers in the US. The other study was a 32-site clinical trial conducted in the US and Europe comparing the effects of encenicline, an alpha-7 nicotine agonist, to placebo in 319 patients with schizophrenia. The SCoRS interviewer ratings demonstrated excellent test-retest reliability in several different circumstances, including those that did not involve treatment (ICC> 0.90), and during treatment (ICC>0.80). SCoRS interviewer ratings were related to cognitive performance as measured by the MCCB (r=-0.35), and demonstrated significant sensitivity to treatment with encenicline compared to placebo (P<.001). These data suggest that the SCoRS has potential as a clinically relevant measure in clinical trials aiming to improve cognition in schizophrenia, and may be useful for clinical practice. The weaknesses of the SCoRS include its reliance on informant information, which is not available for some patients, and reduced validity when patients self-report is the sole information source.

The Brief Assessment of Cognition In Affective Disorders (BAC-A):performance of patients with bipolar depression and healthy controls.

BACKGROUND Cognitive deficits in bipolar disorder are significant enough to impact everyday functioning. A key question for treatments aimed at cognition is which cognitive domains are most affected by bipolar disorder and which cognitive tests have the best psychometric characteristics for this population. METHOD 432 patients assessed at study entry in a treatment study of bipolar depression were assessed with a version of a new cognitive measure - the Brief Assessment of Cognition in Affective Disorder (BAC-A), which assesses traditional cognitive constructs with six subtests measuring memory, processing speed, working memory, and reasoning and problem solving, and a new measure of affective processing. From the cohort of 432 patients, 309 were selected based upon their demographic similarities to a previously collected healthy control sample of 309 subjects. Patients and controls completed the traditional cognitive tests and the Affective Processing Test. Results. Patients with bipolar depression and healthy controls differed significantly on all cognitive measures (P<0.001). The two alternate forms of the Affective Processing Test were very similar in both groups. The most robust discriminator of the groups was a composite score that combined the six core cognitive subtests of the Brief Assessment of Cognition (BAC) with two of the measures from the Affective Processing Test. LIMITATIONS Test-retest reliabilities of the individual Affective Processing Test measures were low. CONCLUSION The BAC-A is sensitive to the cognitive impairments in bipolar disorder patients in traditional neuropsychological domains and in cognitive processes believed to be specifically impaired in affective disorders.

Virtual Reality Functional Capacity Assessment In Schizophrenia: Preliminary Data Regarding Feasibility and Correlations with Cognitive and Functional Capacity Performance.

INTRODUCTION Assessment of functional capacity is an intrinsic part of determining the functional relevance of response to treatment of cognitive impairment in schizophrenia. Existing methods are highly and consistently correlated with performance on neuropsychological tests, but most current assessments of functional capacity are still paper and pencil simulations. We developed a computerized virtual reality assessment that contains all of the components of a shopping trip. METHODS We administered the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) to 54 healthy controls and to 51 people with schizophrenia to test its feasibility. Dependent variables for the VRFCAT included time to completion and errors on 12 objectives and the number of times that an individual failed to complete an objective. The MATRICS Consensus Cognitive Battery (MCCB) and a standard functional capacity measure, the UCSD Performance-Based Skills Assessment-Brief (UPSA-B) were administered to the patients with schizophrenia. RESULTS Patients with schizophrenia performed more poorly than healthy controls on 10/11 of the time variables, as well as 2/12 error scores and 2/12 failed objectives. Pearson correlations for 7 of 15 VRFCAT variables with MCCB composite scores were statistically significant. CONCLUSION These results provide support for the possibility of computerized functional capacity assessment, but more substantial studies are required.

Can a nonequivalent choice of dosing regimen bias the results of flexible dose double blind trials? The CATIE schizophrenia trial

BACKGROUND One of the major challenges in the design of double-blind flexible-dosing clinical trials comparing active drugs is the selection of dosing regimens that are equivalent across drugs. This study uses data from the CATIE schizophrenia trial to evaluate the hypothesis that drugs that were dosed somewhat higher in the trial than in typical practice would show greater efficacy and more side effects, especially at high capsule levels, than drugs that were dosed at lower relative strengths. METHODS CATIE was a large (N=1460) randomized trial comparing 5 antipsychotics in patients with chronic schizophrenia. The blind was maintained in CATIE by prescribing identical-looking capsules of each medication. Dosing was flexible, such that PIs could prescribe from one to four capsules per day, and could modify the dose based on a patients symptoms and side effects. Capsule strengths for olanzapine (7.5 mg) and quetiapine (200 mg) were relatively higher than for risperidone (1.5 mg), perphenazine (8 mg) or ziprasidone (40 mg). Proportional hazards models of time to all cause discontinuation and mixed regression models for continuous measures of symptoms, quality of life and side effects were used to test for interactions between randomly assigned drug and number of capsules prescribed per visit. We hypothesized that if a dosing bias was present, the flex-dosing design would result in a significant interaction such that drugs with higher relative dosing per capsule would be more effective and have more side effects than drugs with lower relative dosing and that this effect would be greatest at the largest prescribed dosing regimen (4 capsules). RESULTS There were no significant interactions between drug assignment and number of capsules in the proportional hazards analyses of time to all cause discontinuation (p=.77, excluding ziprasidone and .74 in the ziprasidone cohort) or in the mixed model analysis of PANSS symptoms (p=.49), quality of life (p=.45); or measures of tardive dyskinesia (AIMS, p=.47). However a significant interaction was observed on the Barnes akathisia scale (p=.0005), on the Simpson Angus EPS scale (p=.10) and on the analysis of weight (p=0.014). Paired comparisons did not show the hypothesized pattern of relationships for akathisia or EPS, but such a pattern was suggested for olanzapine in the analysis of weight although it emerged at 2, 3 and 4 capsules indicating a general drug effect rather than a relative dosing difference. CONCLUSION Dosing biases do not seem to have affected the results of the CATIE trial.