Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) screening and recruitment: methods and results.

The Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study is a systematic investigation of sustained 25% calorie restriction (CR) in non-obese humans. CALERIE is a multicenter (3 clinical sites, one coordinating center), parallel group, randomized controlled trial. Participants were recruited, screened, and randomized to the CR or control group with a 2:1 allocation. Inclusion criteria included ages 21-50 years for men and 21-47 years for women, and a body mass index (BMI) of 22.0 ≤ BMI < 28.0 kg/m(2). Exclusion criteria included abnormal laboratory markers, significant medical conditions, psychiatric/behavioral problems, and an inability to adhere to the rigors of the evaluation/intervention schedule. A multi-stage screening process (telephone screen and 3 in-clinic visits) was applied to identify eligible participants. Recruitment was effective and enrollment targets were met on time. 10,856 individuals contacted the clinical sites, of whom 9787 (90%) failed one or more eligibility criteria. Of the 1069 volunteers who started the in-clinic screening, 831 (78%) were either ineligible or dropped. 238 volunteers were enrolled (i.e., initiated the baseline evaluations), 220 were randomized, and 218 started the assigned intervention (2% from the first screening step). This study offered lessons for future multi-center trials engaging non-disease populations. Recruitment strategies must be tailored to specific sites. A multi-disciplinary screening process should be applied to address medical, physical, and psychological/behavioral suitability of participants. Finally, a multi-step screening process with simple criteria first, followed by more elaborate procedures has the potential to reduce the use of study resources.

Personality profiles among normal aged individuals as measured by the NEO-PI-R.

The revised Neuroticism (N), Extraversion (E), Openness (O) to experience Personality Inventory (NEO-PI-R) is a multidimensional measure of normal personality traits that is intended to assess five major personality dimensions or domains-N, E, O, Agreeableness (A), and Conscientiousness (C). Although several studies have been conducted examining N, E, and O factors in people 65 through to 85 years old, there has been little research examining all five-core domains of personality in individuals 85 and older. We compared the NEO-PI-R domains and facet traits in the middle-aged/young-old versus old-old normal subjects. Thirty-eight community-dwelling subjects (22 women, 16 men) free from major neuropsychiatric disorders were given the NEO-PI-R, a self-administered 240-item personality inventory, assessing 30 facet traits within the five domains. We compared the scores of 21 middle-aged and young-old (age 50-84) individuals, to those of 17 old-old (age 85-100) subjects. The personality profiles of the two groups were similar except that the old-old group had lower scores on Extraversion, and four of the 30 facet traits (warmth, positive emotions, impulsiveness, and order) compared to the middle-aged/young-old group. These results were limited by the cross-sectional design and small sample size. Nonetheless, the findings suggest that the middle-aged/young-old and the old-old normal subjects have fairly similar personality traits.

Cross-sectional study of older outpatients with schizophrenia and healthy comparison subjects: no differences in age-related cognitive decline.

OBJECTIVE: Little is known about the progression of cognitive deficits in older, community-dwelling patients with schizophrenia, especially in comparison to healthy subjects. METHOD: The authors examined the relationship of age to performance on the Mattis Dementia Rating Scale in 116 outpatients with schizophrenia and 122 normal comparison subjects. Subjects ranged in age from 40 to 85 years. RESULTS: Dementia Rating Scale scores were lower in the schizophrenia group but correlated negatively with age in both groups, with no significant differences seen between the schizophrenia and normal comparison groups in slopes that depicted age-related variation. CONCLUSIONS: This cross-sectional study suggests a relatively stable long-term course of cognitive impairment in individuals with schizophrenia, with no evidence of faster cognitive decline in outpatients with schizophrenia than in normal comparison subjects.

Depressive symptoms in schizophrenia.

OBJECTIVE: The authors assessed the presence and severity of depressive symptoms, as well as their associations with other clinical measures, in a group of mid- to late-life patients with schizophrenia who were not in a major depressive episode or diagnosed with schizoaffective disorder. METHOD: Sixty outpatients with schizophrenia between the ages of 45 and 79 years and 60 normal comparison subjects without major neuropsychiatric disorders, proportionally matched for age and gender, were studied. Depressive symptoms were rated primarily with the Hamilton Depression Rating Scale. Standardized instruments were also used to measure global psychopathology, positive and negative symptoms, abnormalities of movement, and global cognitive status. RESULTS: Depressive symptoms were more frequent and more severe in schizophrenic patients than in normal comparison subjects; 20% of the women with schizophrenia had a Hamilton depression scale score of 17 or more. Severity of depressive symptoms correlated with that of positive symptoms but not with age, gender, negative symptoms, extrapyramidal symptoms, or neuroleptic dose. CONCLUSIONS: Depressive symptoms are common in older patients with schizophrenia. They may be an independent, core component of the disorder or, alternatively, may be a by-product of severe psychotic symptoms.

Gender-related clinical differences in older patients with schizophrenia.

BACKGROUND: Gender differences in the clinical presentation of young patients with schizophrenia have been well-documented, yet few studies have investigated gender-related clinical differences in older patients. Furthermore, the symptoms of late-onset schizophrenia have been described, but the interaction between gender and age at onset has not been examined. METHOD: In an older (46-85 years of age) outpatient sample, we assessed clinical characteristics of women and men with early-onset schizophrenia (N = 90) and late-onset schizophrenia (N = 34). Subjects did not differ with respect to age, education, ethnicity, severity of depression, daily neuroleptic dosage, subtype of schizophrenia, total score on the Mini-Mental State Examination, or severity of overall psychopathology. Diagnosis was made using the Structured Clinical Interview for the DSM-III-R or DSM-IV. RESULTS: A significantly greater proportion of women had late-onset schizophrenia (41% vs. 20%), and women overall had more severe positive psychotic symptoms. Although there was no overall gender difference in severity of negative psychotic symptoms, women with late onset had significantly less severe negative symptoms than men with early onset, men with late onset, and women with early onset. Furthermore, age at onset of schizophrenia was inversely correlated with severity of negative symptoms for women, but not for men. These results indicate that women overall may develop more severe positive symptoms than men, and that when women develop schizophrenia after age 45, they may suffer less severe negative symptoms than men or than women with earlier onset. Our results suggest that some of the clinical differences between late-onset and early-onset schizophrenia may relate to gender effects, and that there may be inherent differences in the clinical presentation of schizophrenia that are related to gender and gender by age at onset interactions. CONCLUSION: These differences may reflect the influence of sex hormones and menopause on the clinical presentation of schizophrenia or the possible existence of an "estrogen-related" form of schizophrenia in women with late-onset schizophrenia.

Sacrosidase therapy for congenital sucrase-isomaltase deficiency.

BACKGROUND: The purpose of this study was to determine if sacrosidase, a liquid produced from Saccharomyces cerevisiae containing 6000 IU of sucrase activity per mg protein, prevented symptoms of diarrhea, abdominal cramps, gas, and bloating in patients with congenital sucrase-isomaltase deficiency (CSID) consuming a normal sucrose and carbohydrate-containing diet. METHODS: Twenty-eight children (aged 5 months to 11 years) underwent a randomized, double-blind trial consisting of two phases: 1) three sucrose breath H2 tests with three single-dose treatments (placebo, sacrosidase, and sacrosidase plus milk), and 2) a dose-response phase consisting of four multidose treatments, each for 10 days of full-strength sacrosidase, 1:10 dilution, 1:100 dilution, and 1:1000 dilution. Patients who weighed less than or equal to 15 kg received a dose of sacrosidase and those who weighed more than 15 kg received 2 ml. For the dose-response phase each patient consumed a normal diet. The number of stools and severity of symptoms were recorded daily for each concentration of sacrosidase administered and compared to a baseline period during which the patient took no sacrosidase and consumed a sucrose/starch-free diet. Data were analyzed using an ANOVA model and the nonparameter Wilcoxon signed-rank test. RESULTS: Breath H2 excretion decreased significantly when patients received sacrosidase or sacrosidase plus milk compared to placebo during sucrose breath tests. During the dose-response phase significant treatment differences were observed between the two higher concentrations and the two lower concentrations of sacrosidase for both total stools (p < 0.001) and total symptom score (p = 0.003). Higher concentrations of sacrosidase were associated with fewer stools and a greater number of formed or hard stools compared to lower concentrations and compared to the baseline period. Higher concentrations were also associated with fewer symptoms of gas, abdominal cramps, or bloating, but no differences in vomiting. The only significant adverse event was wheezing in one child with a history of asthma. CONCLUSIONS: Sacrosidase is a safe, effective, well-accepted treatment to prevent gastrointestinal symptoms in patients with CSID consuming a normal diet.

Schizoaffective disorder: a form of schizophrenia or affective disorder?

BACKGROUND: The diagnostic status of schizoaffective disorder continues to be controversial. Researchers have proposed that schizoaffective disorder represents a variant of schizophrenia or affective disorder, a combination of the 2, or an intermediate condition along a continuum between schizophrenia and affective disorder. METHOD: We compared outpatients aged 45 to 77 years with DSM-III-R diagnosis of schizoaffective disorder (N = 29), schizophrenia (N = 154), or nonpsychotic mood disorder (N = 27) on standardized rating scales of psychopathology and a comprehensive neuropsychological test battery. A discriminant function analysis was used to classify the schizoaffective patients based on their neuropsychological profiles as being similar either to schizophrenia patients or to those with nonpsychotic mood disorder. RESULTS: The schizoaffective and schizophrenia patients had more severe dyskinesia, had a weaker family history of mood disorder, had been hospitalized for psychiatric reasons more frequently, were more likely to be prescribed neuroleptic and anticholinergic medication, and had somewhat less severe depressive symptoms than the mood disorder patients. The schizophrenia patients had more severe positive symptoms than the schizoaffective and mood disorder patients. The neuropsychological performances of the 2 psychosis groups were more impaired than those of the nonpsychotic mood disorder patients. Finally, on the basis of a discriminant function analysis, the schizoaffective patients were more likely to be classified as having schizophrenia than a mood disorder. CONCLUSION: These findings suggest that schizoaffective disorder may represent a variant of schizophrenia in clinical symptom profiles and cognitive impairment.

Relationship of neuropsychological and MRI measures to age of onset of schizophrenia.

Age of onset of schizophrenia (AOS) may be largely determined by neurobiological factors. We examined in a diverse sample of schizophrenia out-patients the relationships of AOS with neuropsychological abilities and structural brain abnormalities as measured on cerebral magnetic resonance imaging (MRI). A total of 82 out-patients meeting DSM-III-R criteria for schizophrenia were evaluated with a comprehensive neuropsychological battery and semi-automated quantitatively analysed cerebral MRI. Earlier AOS correlated with poorer performance in learning and abstraction/cognitive flexibility, and with larger volumes of caudate and lenticular nuclei, and smaller volume of thalamus on MRI. A model for predicting AOS consisting of abstraction and thalamic and caudate volumes remained significant after controlling for duration of illness, current age and daily neuroleptic dose. In conclusion, AOS may be related to specific rather than general measures of cognitive performance and structural brain abnormalities.

Minor physical anomalies in older patients with late-onset schizophrenia, early-onset schizophrenia, depression, and Alzheimer's disease.

The authors assessed five groups of older subjects (age > 45) for evidence of minor physical anomalies. The groups were patients with early-onset schizophrenia (onset at age < 45; n = 15), late-onset schizophrenia (onset at age > 45; n = 8), Alzheimer's disease (AD; n = 11), and unipolar depression (n = 11), and normal comparison (NC) subjects (n = 15). Patients with late- and early-onset schizophrenia, and unipolar depression were found to have significantly more anomalies than NC subjects. Patients with AD did not have significantly more anomalies than NC subjects, although the patients with AD were significantly older than the NC subjects. The authors discuss implications of these findings on the pathophysiology of schizophrenia.

Incidence and risk factors for severe tardive dyskinesia in older patients.

BACKGROUND: Severe tardive dyskinesia (TD) represents a serious and potentially disabling movement disorder, yet relatively little is known about the incidence of and risk factors for severe TD. METHOD: We report the results of a longitudinal prospective incidence study of severe TD in 378 middle-aged and elderly neuropsychiatric patients. Psychiatric, neuropsychological, pharmacological and motor variables were obtained at intake and at regular intervals for 36 months. RESULTS: The cumulative incidence of severe TD was 2.5% after one year, 12.1% after two years, and 22.9% after three years. Individual univariable Cox regression analyses were conducted to identify demographic, psychiatric, motor and pharmacological predictors of severe TD. Results indicated that higher daily doses of neuroleptics at study entry, greater cumulative amounts of prescribed neuroleptic, and greater severity of worsening negative symptoms were predictive of severe TD. CONCLUSIONS: These findings suggest that conventional neuroleptics may be prescribed to older patients only when necessary and at the lowest effective dosage. Additional caution is recommended in patients exhibiting negative symptoms.

Validity of specific subscales of the positive and negative symptom scales in older schizophrenia outpatients.

We investigated the construct validity of subscales of the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) along with other measures of psychopathology in 109 schizophrenia outpatients aged 45-84 years. Scores on subscales of the SAPS, SANS and Brief Psychiatric Rating Scale (BPRS) and on the Hamilton Depression Scale (HAM-D) were subjected to a principal components analysis and orthogonal rotation followed by an extension analysis. In both analyses, three of four SAPS subscales had their highest loading on the positive symptom factor and four of five SANS subscales had their highest factor loading on the negative symptom factor. The SAPS bizarre behavior subscale, however, had a much higher loading on the depressive symptom factor than on the positive symptom factor, and the SANS avolition-apathy subscale had moderate loadings on both the negative symptom factor and the depressive symptom factor. The use of SAPS and SANS subscales to represent two constructs was largely (but not entirely) validated among middle-aged and elderly schizophrenia outpatients. The SAPS bizarre behavior subscale and, to a lesser extent, the SANS avolition-apathy subscale appear to represent in this older population a separate construct which may be related to depressive symptoms.

Validating specific psychopathology scales in older outpatients with schizophrenia.

To our knowledge, there have been no published studies validating commonly used psychopathology rating scales in older outpatients with schizophrenia. We studied specific psychopathology rating scales (three subscales of the Brief Psychiatric Rating Scale: positive symptoms, negative symptoms, and depression subscales; the Scale for Assessment of Positive Symptoms; the Scale for the Assessment of Positive Symptoms; the Scale for the Assessment of Negative Symptoms; and the Hamilton Depression Rating Scale) in 101 (age > 45 years) DSM-III-R-diagnosed schizophrenia outpatients. We found high interrater reliability (intra-class correlated coefficient > or = .77) on these scales. Using principal components analysis, we demonstrated satisfactory construct validity, suggesting three factors-positive symptoms, negative symptoms, and depressive symptoms.

Risk factors for orofacial and limbtruncal tardive dyskinesia in older patients: a prospective longitudinal study.

Although there is a consensus that orofacial and limbtruncal subtypes of tardive dyskinesia (TD) exist and may represent distinct pathophysiologic entities, few studies have examined the incidence of and risk factors associated with the development of these TD subtypes. Two hundred and sixty-six middle-aged and elderly outpatients with a median duration of 21 days of total lifetime neuroleptic exposure at study entry were evaluated at 1- to 3-month intervals. Using "mild" dyskinesia in any part of the body for diagnosis of TD, the cumulative incidence of orofacial TD was 38.5 and 65.7% after 1 and 2 years, respectively, whereas that of limbtruncal TD was 18.6 and 32.6% after 1 and 2 years. Preclinical dyskinesia was predictive of both orofacial and limbtruncal TD. History of alcohol abuse or dependence was a significant predictor of orofacial TD only whereas tremor was a significant predictor of limbtruncal TD only. Findings support suggestions that orofacial and limbtruncal TD may represent specific subsyndromes with different risk factors.

Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients.

BACKGROUND: Neuroleptic-induced tardive dyskinesia (TD) is a major iatrogenic disorder that is more prevalent among older patients. The objective of this study was to determine the incidence of and risk factors for TD in neuroleptic-treated patients over age 45 years. METHODS: We studied 266 middle-aged and elderly outpatients with a median duration of 21 days of total lifetime neuroleptic exposure at study entry. Most patients were treated throughout the study with either a high-potency or a low-potency neuroleptic and maintained on relatively low doses. The patients were followed up at 1- to 3-month intervals with "blind" assessment of psychopathologic condition, clinically as well as instrumentally (ie, using electromechanical sensors with computerized data reduction, including spectral analysis) evaluated movement disorder, and global cognitive function. RESULTS: Cumulative incidence of TD was 26%, 52%, and 60% after 1, 2, and 3 years, respectively. The principal risk factors for TD were duration of prior neuroleptic use at baseline, cumulative amount of high-potency neuroleptics, history of alcohol abuse/dependence, borderline or minimal dyskinesia, and tremor on instrumental assessment. CONCLUSION: Use of higher amounts of neuroleptics, particularly high-potency ones, should be avoided in older patients, patients with alcohol abuse/dependence, or patients with a subtle movement disorder at baseline; these patients are at a higher risk of developing TD.

Clinical and neuropsychological characteristics of patients with late-onset schizophrenia.

OBJECTIVE: The goal was to compare clinical and neuropsychological characteristics of patients with late-onset schizophrenia, a poorly studied and controversial entity, with those of patients with early-onset schizophrenia and normal subjects. METHOD: The authors evaluated 25 patients who met DSM-III-R criteria as well as their own research criteria for late-onset schizophrenia (i.e., schizophrenia with onset after age 45) and compared them with 39 patients with early-onset schizophrenia and 35 normal subjects in this nonepidemiologic study. RESULTS: Patients with late-onset schizophrenia were similar to patients with early-onset schizophrenia and different from normal subjects on most clinical and neuropsychological variables assessed, such as psychopathology, family history, childhood social adjustment, and overall pattern of neuropsychological impairment. Compared with the early-onset group, the group with late-onset schizophrenia had a higher percentage of patients who were ever married, a better work history, and a greater frequency of paranoid subtype. CONCLUSIONS: These results support the diagnostic validity of schizophrenia with onset after the age of 45 years.

Group self-identification and adolescent cigarette smoking: a 1-year prospective study.

As an extension of previous work, we analyzed the longitudinal relations between group self-identification and adolescent cigarette smoking. The predictive precedence of cigarette smoking and identification with 6 different types of peer groups was examined. Results indicated that 7th-grade group self-identification predicted 8th-grade cigarette smoking, whereas 7th-grade cigarette smoking did not predict 8th-grade group self-identification. Group self-identification also was compared with 7 other psychosocial variables as predictors of smoking 1 year later. The pattern of results suggests that group self-identification is about as good a predictor of smoking as other psychosocial variables, and that group self-identification is more than a mere proxy of other psychosocial variables.

Neuroleptic treatment of HIV-associated psychosis. HNRC group.

The aim of this rater-blinded randomized study was to evaluate the efficacy and side effects of haloperidol and thioridazine in the treatment of new-onset psychosis in HIV-positive individuals. Participants were 13 men who had no history of psychosis prior to infection with HIV, and whose psychosis was not attributable to delirium or to non-HIV-related organic factors. Participants were evaluated at baseline after at least one month without neuroleptic treatment and then weekly for six weeks of the experimental treatment using several rating scales. The mean daily dose in chlorpromazine equivalents was 124 mg. Both neuroleptics produced modest but significant reduction in overall level of psychosis and in positive symptoms, but not in negative symptoms. All the haloperidol-treated patients developed extrapyramidal side effects and required treatment with anticholinergic medication, whereas three of the five thioridazine-treated patients had noticeable side effects. We make recommendations for the treatment of HIV-associated psychosis with neuroleptics.