Biomedical subjects

Robert P McMahon

Publications and source records attributed to Robert P McMahon.

At least 19 recordsLinked to original sources

PubMed2006

Diet and sex hormones in boys: findings from the dietary intervention study in children.

CONTEXT: Diet reportedly alters serum sex hormone concentrations in adults, but little is known about the influence of diet during puberty on these hormones. OBJECTIVE: We aimed to determine whether an intervention to lower fat intake during adolescence alters serum sex hormone concentrations and progression through puberty. DESIGN: In 1990-1997, we conducted an ancillary study to the Dietary Intervention Study in Children, a multicenter, randomized, controlled clinical trial to test the safety and efficacy of a cholesterol-lowering dietary intervention in children. PARTICIPANTS: Healthy, prepubertal, 8 to 10 yr olds with elevated low-density lipoprotein cholesterol were randomized to usual care or a behavioral intervention. Of 362 randomized Dietary Intervention Study in Children boys, 354 participated in the ancillary study. Eighty-four percent of boys attended last visits when their median time on trial was 7.1 yr. INTERVENTION: The behavioral intervention continued throughout the duration of the trial and promoted a diet with 28% energy from total fat, less than 8% from saturated fat, 9% or less from polyunsaturated fat, and less than 75 mg cholesterol per 1000 kcal. OUTCOME MEASURES: The main outcome measure for boys formulated before study initiation was non-SHBG bound testosterone concentration. Secondary outcomes included serum total testosterone, dihydrotestosterone, androstenedione, estradiol, estrone, SHBG, and Tanner stage. RESULTS: There were no significant treatment group differences in boys' serum hormone levels, SHBG, or Tanner stages at any individual visit or over the course of the trial when evaluated by longitudinal models. CONCLUSION: Modest reductions in total fat, saturated fat, and possibly energy intake do not alter progression through puberty or serum sex hormone concentrations in adolescent boys.

Androstenedione↗

PubMed2006

Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction.

Research suggests that first-degree relatives and individuals with schizophrenia spectrum personality disorders (SSPD) may represent nonpenetrant carriers of the genetic diathesis for schizophrenia. This study examined visuospatial working memory (SWM) as a cognitive endophenotype of schizophrenia by expanding the concept of risk for pathophysiological dysfunction beyond overt psychosis. Risk was thus defined by familial status and the presence or absence of SSPD. SWM was assessed in the following groups, in order of decreasing likelihood of genetic vulnerability: 23 patients with schizophrenia, 17 SSPD relatives of patients with schizophrenia, 23 non-SSPD relatives of patients with schizophrenia, 14 SSPD community members with no family history of psychosis, and 36 non-SSPD community members. SWM performance during a computer task was quantified by A-Prime. Relative risk ratios for SWM deficits were compared among the groups. Compared with community non-SSPD volunteers, relative risk (RR) of SWM deficits was significantly elevated in patients with schizophrenia (RR = 3.76, p = .002) and SSPD family members (RR = 2.97, p = .027), but not in the family non-SSPD (RR = 1.88, p = .241) or community SSPD (RR = 1.03, p = .971) groups. The pattern of SWM performance deficits reflected the proposed model of latent genetic liability, upholding SWM as a viable cognitive endophenotype. The results underscore the importance of including both familial liability and the schizophrenia spectrum when considering risk for schizophrenia and schizophrenia-related traits. This is particularly relevant for research efforts to identify pathophysiological components of the disease.

Adult↗

PubMed2006

Familial aggregation of eye-tracking endophenotypes in families of schizophrenic patients.

BACKGROUND: Abnormal smooth pursuit eye movements (SPEMs) are some of the most reproducible biological changes associated with the susceptibility for schizophrenia. Recent studies have suggested that deficit in predictive pursuit, a specific component of the SPEMs, marks schizophrenia susceptibility. OBJECTIVE: To test whether predictive pursuit contains less extraneous noise and may be under more direct genetic control than the traditional measure of overall pursuit performance using maintenance pursuit gain. DESIGN: Familial aggregation estimation of the predictive pursuit measure and the traditional maintenance pursuit measure in sibling pairs from families of schizophrenic patients. SETTING: Outpatient clinics. PARTICIPANTS: Patients with schizophrenia and their full siblings were recruited, provided that at least 1 sibling pair could be formed per family. Ninety-two siblings were recruited into the study. They formed 70 sibling pairs. Ninety healthy control subjects were also recruited using targeted local community advertisements based on patients' county of residence, aiming to capture the basic demographics of the regions from which the patients were recruited. MAIN OUTCOME MEASURES: Familial correlations and heritability estimates of 2 SPEM measures: maintenance pursuit gain and predictive pursuit gain. RESULTS: The sibling intraclass correlation coefficient of the predictive pursuit gain (r = 0.45-0.48) was significantly higher than that of maintenance pursuit gain (r = 0.02-0.20) (P = .005-.007). Variance component analysis suggested a high genetic loading for predictive pursuit (heritability = 0.90, SE = 0.22; P<.001) but relatively low heritability in the traditional maintenance pursuit measure (heritability = 0.27, SE = 0.21; P = .08). CONCLUSION: These results suggest that predictive pursuit may index stronger genetic effect and may be better suited for genetic studies than the traditional SPEM measure of maintenance pursuit gain.

Adult↗

PubMed2006

Adjunct divalproex or lithium to clozapine in treatment-resistant schizophrenia.

This retrospective study examined adjunct divalproex (N = 15) or lithium (N = 9) in treatment-resistant schizophrenia patients added to clozapine and compared to clozapine monotherapy (N = 25). Six month total BPRS scores were similarly improved in all treatment groups, however significantly greater improvements occurred in the first month for those on divalproex (-9) or lithium (-8) vs. clozapine alone (-4.5) (F = 3.32, df = 10.43, p = 0.0003). Rates of sedation, tachycardia, orthostasis, GI disturbances, confusion and dizziness were similar among groups. Mean weight gain was 8.7 pounds for clozapine monotherapy, 3.0 pounds in the adjunct divalproex group and 13.3 pounds in the adjunct lithium group (P = NS). A trend was noted for greater increases in blood glucose levels for those treated with adjunct lithium (F = 2.62, df = 2.28, p = 0.09). The addition of divalproex was significantly more effective in reducing global symptoms (driven by hostility and anxiety) in the first month of adjunct treatment as compared to clozapine monotherapy and to previous clozapine treatment.

Adult↗

PubMed2006

Impaired control of visual attention in schizophrenia.

To investigate attentional impairment in schizophrenia, the authors examined the performance of 22 patients with schizophrenia and 16 healthy control subjects in 4 visual search tasks that varied in perceptual requirements and in the need for precise attentional control. The rate of search was slowed in the patients in all tasks. However, the degree of slowing was largest in tasks requiring precise attentional control and smallest in tasks that were perceptually difficult but required less attentional control. This pattern of results indicates that the primary impairment of attention in schizophrenia lies in the control of attention and not in the selection processes that operate once attention has been directed to an object.

Adult↗

PubMed2006

Intact attentional control of working memory encoding in schizophrenia.

This study reports evidence that individuals with schizophrenia (SC) demonstrate intact attentional selection for visual working memory (WM) storage. A group of 62 participants with SC and 55 control participants without SC were studied in a series of 5 experiments that examined the ability to use top-down and bottom-up cues to guide WM encoding, as well as the ability to spontaneously select a subset of representations for storage. Participants with SC exhibited a consistent and robust ability to use selective attention in the control of WM in all 5 experiments, demonstrating a remarkable island of preserved functioning given the broad spectrum of impairments of attention and WM that have been widely reported in those with SC. These findings indicate that attention is not globally impaired in SC and make it possible to delineate more precisely the nature of the specific impairment of attention in this disorder.

Attention↗

PubMed2006

Self-perceived barriers to activity participation among sedentary adolescent girls.

PURPOSE: Potential barriers to activity participation were surveyed among adolescent girls and corroborated with other reported information. METHODS: Among 2379 black and white girls enrolled in the NHLBI Growth and Health Study since ages 9 or 10 yr, those reporting weekly activity frequency as "sometimes" or "rarely" were surveyed for three consecutive years from ages 16 or 17 yr. Barriers to activity were assessed using a 10-item questionnaire. Responses were cross-examined with other reported information. Race-specific longitudinal regression examined the impact of barrier scores on activity levels and also potential factors having an impact on barrier scores. RESULTS: Approximately half of the cohort was screened as "sedentary" with a trend toward an increasing proportion with age. Lack of time was cited by 60% of sedentary girls as the leading barrier to activity participation for all 3 yr. Other frequently cited barriers to activity included "I'm too tired" and "They don't interest me." No differences were seen in hours at work or in household chores between those who cited lack of time and those who did not. Barrier score was a significant predictor of habitual activity scores. For both races, body mass index and "would rather do other things than exercise" were significant predictors of barriers, but work, parental education, TV watching, and childbirth were not significant. CONCLUSION: Self-reported barriers to activity participation among sedentary girls were shown to be primarily internal and uncorrelated with other corresponding external factors.

Adolescent↗

PubMed2005

Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia.

A previous study has shown an association between the *2236T > C allele polymorphism of the dihydropyrimidinase-related protein 2 (DRP-2) gene and schizophrenia in a Japanese sample [Nakata et al. (2003); Biological Psychiatry 53:571-576]. DRP-2 is an important molecule in guiding neuronal development and its gene is located in 8p21, a chromosomal region that was previously shown to have significant linkage to schizophrenia and to several deficit symptoms of schizophrenia. We compared the frequency of the DRP-2 *2236T > C polymorphism between subjects with (n = 117) and without (n = 72) schizophrenia, and then further evaluated whether the association was specific for the deficit (n = 24) and nondeficit (n = 93) forms of schizophrenia. In both Caucasians and African-Americans, the C allele occurred more frequently in schizophrenia cases than controls, with this difference achieving statistical significance in Caucasians (C allele frequency: 42.0% in cases vs. 25.0% in controls, P = 0.014) but not African Americans (52.6% in cases vs. 50.0% in controls, P = 0.93). In Caucasians, the frequency of the C allele was significantly higher in both the deficit (allele frequency 53.3%, P = 0.009) and nondeficit (39.2%, P =0.050) forms of schizophrenia compared to controls (allele frequency 25.0%). We conclude that the DRP-2 *2236 C allele may mark another polymorphism in DRP-2, or in a nearby gene, that may influence susceptibility to schizophrenia.

Adult↗

PubMed2005

Depressive symptoms and heart rate variability in postmenopausal women.

BACKGROUND: Depressive symptoms have been associated with increased cardiac morbidity and mortality rates, but the pathophysiologic mechanism linking depressive symptoms to cardiovascular outcome has yet to be fully understood. Lower heart rate variability has also been associated with increased risk of cardiac events in healthy individuals and in patients with coronary artery disease. Findings regarding a relationship between depressive symptoms and heart rate variability that could explain increased cardiovascular risk have been inconsistent across studies. METHODS: As an ancillary study to the Women's Health Initiative Observational Study, 3372 postmenopausal women aged 50 to 83 years were enrolled for further evaluation using 24-hour ambulatory electrocardiographic monitoring. A shortened version of the Center for Epidemiological Studies Depression Scale and the Diagnostic Interview Schedule were administered. Women with adequate electrocardiographic data and depressive symptom information and without coronary artery disease were analyzed (n = 2627). RESULTS: Two hundred sixty-nine women (10.2%) had depressive symptoms as measured using the 2 instruments. Women with depressive symptoms had a higher mean +/- SD heart rate (77.4 +/- 9.6 vs 75.5 +/- 8.5 beats/min) and lower heart rate variability than women without depressive symptoms. All differences remained significant after adjusting for age (P<.01). CONCLUSIONS: Women with depressive symptoms had significant reductions in heart rate variability and higher heart rates, suggestive of increased sympathetic tone. These findings may contribute to the increased cardiac morbidity and mortality rates associated with depression in other studies.

Age Factors↗

PubMed2005

More powerful two-sample tests for differences in repeated measures of adverse effects in psychiatric trials when only some patients may be at risk.

Common adverse effect measures in psychiatric trials are typically analysed with repeated measures ANOVA, despite having distributions which violate key assumptions of that method; moreover, some adverse effects may be concentrated in vulnerable subgroups of participants. For testing treatment differences in adverse effects, we propose use of Kendall's taub as a summary measure of within-participant trends in adverse events, in conjunction with a weighted modification of a rank test proposed by Conover and Salsburg. Data on extrapyramidal side effects from a controlled clinical trial conducted in persons with treatment resistant schizophrenia was used to compare the proposed analysis to repeated measures ANOVA using mixed models and alternate tests for treatment differences in taub trend scores.

Antipsychotic Agents↗

PubMed2005

Working memory consolidation is abnormally slow in schizophrenia.

This study reports evidence that patients with schizophrenia demonstrate a slowing of working memory (WM) consolidation, which is the process of transforming transient perceptual representations into durable WM representations. Sixteen schizophrenia patients and 16 healthy control participants performed a task measuring the visual WM consolidation rate in a change-detection paradigm. A target display containing 3 colored squares was followed by a variable delay of 17-483 ms, a pattern mask, and then a test stimulus. This pattern mask does not interfere with perception but disrupts WM consolidation. Control participants reached no-mask performance by 250 ms, indicating completed WM consolidation, whereas patients failed to reach no-mask performance by 483 ms. Slowed consolidation may play an important and largely unrecognized role in schizophrenia.

Humans↗

PubMed2005

No, it is not possible to be schizophrenic yet neuropsychologically normal.

Cognitive impairment is well documented in schizophrenia, though some reports have been interpreted to suggest that it is possible to have schizophrenia without neuropsychological impairment. The authors tested this by comparing the neuropsychological profiles of closely matched patients with schizophrenia and healthy comparison participants. Sixty-four patients with schizophrenia and 64 healthy comparison cases, matched to within 3 Full-Scale IQ points, were tested using the Wechsler Adult Intelligence Scale (3rd ed.; D. Wechsler, 1997b) and the Wechsler Memory Scale (3rd ed.; D. Wechsler, 1997c). Neuropsychological profiles for these groups were markedly different, with the group of patients with schizophrenia exhibiting performance deficits in memory and speeded visual processing but superior verbal comprehension and perceptual organization relative to the group of healthy comparison participants matched on Full-Scale IQ. Thus, scoring in the normal range does not preclude neuropsychological abnormality in schizophrenia, confirming that neuropsychological impairment is a core feature of the illness.

Adult↗

PubMed2005

Olanzapine treatment of residual positive and negative symptoms.

OBJECTIVE: Olanzapine has been hypothesized to have superior efficacy in patients with treatment-resistant schizophrenia. The authors examined the comparative efficacy and safety of olanzapine and haloperidol in outpatients with partially responsive schizophrenia. METHOD: Sixty-three outpatients with schizophrenia who met retrospective and prospective criteria for either residual positive or residual negative symptoms entered a 16-week double-blind, parallel-groups comparison of olanzapine and haloperidol. RESULTS: There were no significant differences between the two drugs in their effect on positive or negative symptoms. There were no significant differences between the two treatment groups on measures of social and functional outcome. Olanzapine-treated patients had a significant reduction in extrapyramidal symptoms and subjective measures of stiffness and dry mouth, but the increases in systolic blood pressure and weight in olanzapine-treated patients were significantly greater than they were in haloperidol-treated patients. CONCLUSIONS: Olanzapine has limited differential benefit for either positive or negative symptoms in patients with treatment-resistant schizophrenia. Although olanzapine is associated with fewer extrapyramidal symptoms, other side effects may offset this benefit.

Adult↗

PubMed2005

Reliability of a portable head-mounted eye tracking instrument for schizophrenia research.

Smooth pursuit eye movement (SPEM) abnormalities are some of the most consistently observed neurophysiological deficits associated with genetic risk for schizophrenia. SPEM has been traditionally assessed by infrared or video oculography using laboratory-based fixed-display systems. With growing interest in using SPEM measures to define phenotypes in large-scale genetic studies, there is a need for measurement instruments that can be used in the field. Here we test the reliability of a portable, head-mounted display (HMD) eye movement recording system and compare it with a fixed-display system. We observed comparable, modest calibration changes across trials between the two systems. The between-methods reliability for the most often used measure of pursuit performance, maintenance pursuit gain, was high (ICC = 0.96). This result suggests that the portable device is comparable with a lab-based system, which makes possible the collection of eye movement data in community-based and multicenter familial studies of schizophrenia.

Data Display↗

PubMed2004

Cerebellar Purkinje cell loss in aging Hu-Bcl-2 transgenic mice.

The number of cerebellar Purkinje cells is increased by over 40% in young transgenic mice that overexpress a human Bcl-2 transgene (Hu-Bcl-2). To determine whether the Bcl-2-mediated rescue of Purkinje cells persists through life, the numbers of Purkinje cells were estimated in 6-, 12-, 18-, and 24-month-old Hu-Bcl-2 transgenic mice and age-matched controls. In addition, the expression of four markers for Purkinje cell differentiation, calbindin (CaBP), the 67-kDa isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid transaminase (GABA-T), and the NMDA-R1 receptor subtype (NMDA-NR1) was analyzed in 6-month-old Hu-Bcl-2 transgenics and controls to determine whether overexpression of Bcl-2 and rescue from naturally occurring cell death affects the normal differentiation of Purkinje cells. The estimates of Purkinje cell numbers showed that the number of Purkinje cells in the Hu-Bcl-2 transgenics declines after 6 months to approach wild-type values by 18 months. Although the exogenous human BCL-2 is still expressed in Purkinje cells at 24 months, the expression levels of human BCL-2 appear to decline significantly after 6 months, suggesting that survival of the supernumary Purkinje cells depends on the sustained overexpression of Bcl-2. All the Purkinje cells in the Hu-Bcl-2 transgenic mice appeared to express normal levels of the differentiation markers analyzed so there was no evidence for a class of Purkinje cells that do not differentiate normally when rescued from naturally occurring cell death.

4-Aminobutyrate Transaminase↗

PubMed2004

Parametric study of accuracy and response time in schizophrenic persons making visual or auditory discriminations.

The inability to modulate processing time in conjunction with varying difficulty levels may be a core component of schizophrenia's cognitive deficit. In this study we used a parametric design to demonstrate this group's inability to increase and decrease response times in association with varying levels of task demand during auditory and visual recognition tasks. Unlike participants with schizophrenia, healthy volunteers responded to increasing levels of difficulty and high error by robustly increasing their average response times. In the group with schizophrenia, the greater the correlation between a subject's Response-Time and error rate the better was the subject in his/her overall discrimination accuracy. The higher their correlations the better they performed across all levels of difficulty in both modalities. The schizophrenia group's tendency to process high and low error conditions with similar behavioral resources may reflect a relatively static, non-dynamic cognitive repertoire.

Adult↗

PubMed2004

Gamma/beta oscillation and sensory gating deficit in schizophrenia.

Sensory gating can be measured by the suppression of auditory evoked potentials in a paired-click paradigm. The normal gating of the P50 response to the second stimulus (S2) is impaired in many schizophrenic patients. Various in vitro and in vivo evoked potential paradigms have shown that a stimulus evokes early gamma frequency oscillation, which is followed by beta frequency oscillation. The gamma-to-beta shift in response to the first stimulus (SI) in the paired-click paradigm may contain critical electrophysiological signals that modulate the S2 suppression. The results of the present study showed that post-SI beta frequency response was inversely correlated to the S2 P50 response in patients with schizophrenia.

Acoustic Stimulation↗

PubMed2004

Effects of acute and chronic clozapine on D-amphetamine-induced disruption of auditory gating in the rat.

RATIONALE: Auditory gating deficits observed in patients with schizophrenia have been modeled in animals administered the indirect-acting monoaminergic agonist, D-amphetamine (AMPH). The atypical antipsychotic drug clozapine (CLOZ) reverses the disruption of auditory gating in schizophrenic patients. However, its effects on psychostimulant-induced deficits in animals have yet to be assessed. OBJECTIVES: In the present series of experiments, an auditory evoked potential paradigm was used to: (a) confirm the ability of AMPH to alter auditory gating in the anesthetized rat, (b) specify the nature of the accompanying change(s) in evoked potential waveforms and (c) determine the effects of CLOZ administration on AMPH-induced alterations in auditory gating. METHODS: We compared the effects of acute (5 mg/kg, i.p.) and chronic (28 days, 0.5 mg/ml in drinking water) CLOZ on AMPH-induced (1.8 mg/kg, i.p.) alterations in evoked potentials recorded in the hippocampus of anesthetized rats during presentation of a pair of identical tones. Gating was assessed by comparing the amplitude of conditioning and test responses in CLOZ and AMPH-treated rats. RESULTS: The ratio of test to conditioning response amplitude (T/C ratio) was not altered by vehicle or CLOZ alone. However, T/C ratio was significantly increased following AMPH due to suppression of the conditioning response. Acute but not chronic CLOZ attenuated but did not prevent the increase in T/C ratio. CONCLUSIONS: Qualitative differences between the idiopathic gating deficits observed in schizophrenic patients and AMPH-induced increases in T/C ratio in animals limit this models utility as a means of evaluating the ability of atypical antipsychotic drugs to restore normal sensory gating.

Amphetamine↗