Sonia M. Davis

Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III.

UNLABELLED One important risk factor for cardiovascular disease is the metabolic syndrome (MS), yet limited data exist on its prevalence in US patients with schizophrenia. METHODS Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assessment of MS prevalence was performed based on National Cholesterol Education Program (NCEP) criteria, and also using a fasting glucose threshold of 100 mg/dl (AHA). Subjects with sufficient anthropometric data, data on use of antihypertensives, hypoglycemic medications or insulin, and fasting glucose and lipid values >8 h from last meal were included in the analysis. Comparative analyses were performed using a randomly selected sample from NHANES III matched 1:1 on the basis of age, gender and race/ethnicity. RESULTS Of 1460 CATIE baseline subjects, 689 met analysis criteria. MS prevalence was 40.9% and 42.7%, respectively using the NCEP and AHA derived criteria. In females it was 51.6% and 54.2% using the NCEP and AHA criteria, compared to 36.0% (p = .0002) and 36.6% (p = .0003), respectively for males. 73.4% of all females (including nonfasting subjects) met the waist circumference criterion compared to 36.6% of males. In a logistic regression model with age, race and ethnicity as covariates, CATIE males were 138% more likely to have MS than the NHANES matched sample, and CATIE females 251% more likely than their NHANES counterparts. Even when controlling for differences in body mass index, CATIE males were still 85% more likely to have MS than the NHANES male sample, and CATIE females 137% more likely to have MS than females in NHANES. CONCLUSIONS The metabolic syndrome is highly prevalent in US schizophrenia patients and represents an enormous source of cardiovascular risk, especially for women. Clinical attention must be given to monitoring for this syndrome, and minimizing metabolic risks associated with antipsychotic treatment.

Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: Data from the CATIE schizophrenia trial sample at baseline

UNLABELLED Persons diagnosed with schizophrenia have higher morbidity and mortality rates from cardiovascular disease, yet often have limited access to appropriate primary care screening or treatment. Metabolic disorders such as diabetes, hyperlipidemia and hypertension are highly prevalent in populations with schizophrenia, exceeding 50% in some studies; however, there have been few published studies on treatment rates among schizophrenia patients screened for these disorders. METHODS Using the baseline data from subjects (N=1460) recruited into the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, we examined the point prevalence of diabetes, hyperlipidemia and hypertension treatment at the time of enrollment for the entire cohort and those with fasting laboratory values obtained 8 or more hours since last meal. RESULTS Rates of non-treatment ranged from 30.2% for diabetes, to 62.4% for hypertension, and 88.0% for dyslipidemia. Nonwhite men were more likely to be treated for DM and dyslipidemia than nonwhite women. CONCLUSIONS These data indicate the high likelihood that metabolic disorders are untreated in patients with schizophrenia, with particularly high rates of non-treatment for hypertension and dyslipidemia. Nonwhite women may be especially vulnerable to undertreatment of dyslipidemia and diabetes compared to nonwhite men. The findings here support the need for increased attention to basic monitoring and treatment of cardiovascular risk factors in this vulnerable and often underserved psychiatric population.

Baseline neurocognitive deficits in the CATIE schizophrenia trial

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An ‘all-comer’ approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13–0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an ‘all-comer’ clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial

BACKGROUND Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Gender differences in chronic major and double depression.

BACKGROUND While the sex difference in prevalence rates of unipolar depression is well established, few studies have examined gender differences in clinical features of depression. Even less is known about gender differences in chronic forms of depression. METHODS 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were administered an extensive battery of clinician-rated and self-report measures. RESULTS Women were less likely to be married and had a younger age at onset and greater family history of affective disorder compared to men. Symptom profile was similar in men and women, with the exception of more sleep changes, psychomotor retardation and anxiety/somatization in women. Women reported greater severity of illness and were more likely to have received previous treatment for depression with medications and/or psychotherapy. Greater functional impairment was noted by women in the area of marital adjustment, while men showed more work impairment. LIMITATIONS Since our population consisted of patients enrolling in a clinical trial, study exclusion criteria may have affected gender-related differences found. CONCLUSIONS Chronicity of depression appears to affect women more seriously than men, as manifested by an earlier age of onset, greater family history of affective disorders, greater symptom reporting, poorer social adjustment and poorer quality of life. These findings represent the largest study to date of gender differences in a population with chronic depressive conditions.

Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: A naturalistic study

BACKGROUND The need for effective, long-term treatment for recurrent or chronic, treatment-resistant depression is well established. METHODS This naturalistic follow-up describes outpatients with nonpsychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham vagus nerve stimulation (VNS) (n = 95). The initial active group received another 9 months, while the initial sham group received 12 months of VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted. RESULTS The primary analysis (repeated measures linear regression) revealed a significant reduction in 24-item Hamilton Rating Scale for Depression (HRSD(24)) scores (average improvement, .45 points [SE = .05] per month (p < .001). At exit, HRSD(24) response rate was 27.2% (55/202); remission rate (HRSD(24) < or = 9) was 15.8% (32/202). Montgomery Asberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0% [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events. CONCLUSIONS These 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in treatment-resistant depression, albeit in the context of changes in depression treatments. Comparative long-term data are needed to determine whether these benefits can be attributed to VNS.

A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression

BACKGROUND Previous reports have described the effects of vagus nerve stimulation plus treatment as usual (VNS+TAU) during open trials of patients with treatment-resistant depression (TRD). To better understand these effects on long-term outcome, we compared 12-month VNS+TAU outcomes with those of a comparable TRD group. METHODS Admission criteria were similar for those receiving VNS+TAU (n = 205) or only TAU (n = 124). In the primary analysis, repeated-measures linear regression was used to compare the VNS+TAU group (monthly data) with the TAU group (quarterly data) according to scores of the 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR(30)). RESULTS The two groups had similar baseline demographic data, psychiatric and treatment histories, and degrees of treatment resistance, except that more TAU participants had at least 10 prior major depressive episodes, and the VNS+TAU group had more electroconvulsive therapy before study entry. Vagus nerve stimulation plus treatment as usual was associated with greater improvement per month in IDS-SR(30) than TAU across 12 months (p < .001). Response rates according to the 24-item Hamilton Rating Scale for Depression (last observation carried forward) at 12 months were 27% for VNS+TAU and 13% for TAU (p < .011). Both groups received similar TAU (drugs and electroconvulsive therapy) during follow-up. CONCLUSIONS This comparison of two similar but nonrandomized TRD groups showed that VNS+TAU was associated with a greater antidepressant benefit over 12 months.

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.

Clinical Symptom Responses to Atypical Antipsychotic Medications in Alzheimer’s Disease: Phase 1 Outcomes from the CATIE-AD Effectiveness Trial

OBJECTIVE The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimers disease and psychosis or agitated behavior. METHOD The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimers Disease (CATIE-AD) Alzheimers disease effectiveness study included 421 outpatients with Alzheimers disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinicians discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals. RESULTS In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo. CONCLUSION In this descriptive analysis of outpatients with Alzheimers disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.

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.