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Biomedical subjects

Bruce G Pollock

Publications and source records attributed to Bruce G Pollock.

At least 73 records · Page 4Linked to original sources
PubMed2003

Paroxetine-induced hyponatremia in the elderly due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

This study investigated the development of hyponatremia and its underlying mechanism in elderly patients prescribed paroxetine. Patients were 15 men and women (mean age, 75.7 +/- 5.3 years) who were participants in a treatment study of late-life depression and who were without medical illness or other medications known to cause hyponatremia or alter antidiuretic hormone (ADH) secretion. Blood samples for measurement of plasma sodium, ADH, blood urea nitrogen (BUN), creatinine, glucose, and osmolality were determined prior to initiation of paroxetine (week 0) and at 2, 4, 6, and 12 weeks of treatment with paroxetine. Hyponatremia (serum sodium < 135 mEq/L) was identified in 6 of 15 patients after 2 weeks of treatment with paroxetine. Despite low plasma osmolality, ADH levels were not suppressed appropriately. Data suggest hyponatremia is a common adverse event in elderly patients prescribed paroxetine and implicates inappropriate secretion of ADH as the potential mechanism.

Aged↗
PubMed2003

alpha1-acid glycoprotein in late-life depression: relationship to medical burden and genetics.

Serum alphal-acid glycoprotein (AAG) concentrations were examined in relationship to age, medical burden, depression, and mental status in elderly control (n = 19, mean age = 72.1 +/- 6.8 years) and depressed (n = 58, mean age = 71.9 +/- 7.1 years) subjects. DNA was analyzed for allelic variants of the AGP1 (ORM1) gene in both groups. Depressed subjects' AAG serum levels were measured at baseline and after 6 weeks of antidepressant treatment. Before treatment, depressed subjects had significantly higher serum AAG concentrations than nondepressed controls (t49.2 = -3.48, P = .0011). Pretreatment AAG levels also correlated with degree of medical burden, measured by the Cumulative Illness Rating Scale-Geriatrics (r = 0.28, P = .0303), but not with age, depression severity, or cognitive scores. There was no significant difference between responders and nonresponders on changes in AAG levels from baseline to week 6. Frequency differences in ORM1 allelic variants apparently did not influence increased AAG concentrations in depressed patients.

Aged↗
PubMed2003

Serotonin transporter promoter polymorphism in African Americans : allele frequencies and implications for treatment.

BACKGROUND: Americans of African ancestry are less likely to receive a selective serotonin reuptake inhibitor (SSRI) for treatment of major depressive disorder than Americans of European ancestry. A functional insertion/deletion polymorphism in the promoter of the serotonin transporter (5-HTT) gene SLC6A4 has been shown to modulate SLC6A4 transcription, affecting response to SSRIs. Several studies in populations of predominantly European ancestry have consistently found that the SLC6A4 promoter polymorphism (referred to as the 5-HTT-linked polymorphic region; 5-HTTLPR) long (L) allele is associated with better response to SSRI treatment than the short (S) allele. OBJECTIVE: The frequency of SLC6A4 (5-HTTLPR) alleles in 865 black Americans and Afro-Caribbeans was examined to assess possible implications for treatment. STUDY DESIGN AND METHODS: SLC6A4 (5-HTTLPR) genotypes were determined in individuals with self-identified African ancestry from South Carolina (n = 489), western Pennsylvania (n = 207), and Tobago (n = 169). Frequencies were compared using chi-square analyses. RESULTS: It was verified that the L allele is highly prevalent in Americans of African ancestry, ranging from 77% in western Pennsylvania to 87% in South Carolina. The frequency of the SLC6A4-(L) allele is significantly higher in African-Americans than has been reported for European-Americans (typically 56-60%). There are both statistically significant geographic differences and slight deviations from Hardy-Weinberg equilibrium. CONCLUSIONS: Given the potential influence on treatment response, these findings have implications for the use of SSRIs in this population. The results suggest that additional studies to examine the impact of these alleles on treatment response in African-Americans are warranted.

Black or African American↗
PubMed2003

Gender differences in the pharmacokinetics and pharmacodynamics of antidepressants.

The paucity of research on gender-specific differences related to antidepressants is a significant public health deficiency and represents an understudied and necessary research area. The current data suggest that the pharmacokinetics of antidepressant drugs can be substantially different between men and women as a result of differences in both the metabolizing enzymes and the expression of P-glycoprotein MDR1. The data suggest that different pharmacodynamic responses are observed between premenopausal women and men. Women are more likely to respond better to an MAOI antidepressant compared to men. In addition, men respond better to TCAs than women in this age group, but differences diminish after menopause. Given the evidence of distinct gender-specific differences, it is critical that these differences be addressed more widely in research evaluating the administration of antidepressants in women.

Antidepressive Agents↗
PubMed2003

An intent-to-treat method for enhancing analysis of clinical trials with rescue medication: a mixed-model approach.

An intent-to-treat (IT) analysis includes all observed data, even those obtained after the primary treatment assignment is changed or rescue treatment is substituted. The so-called "pragmatic" approach accounts for this type of treatment change or rescue treatment. The advantage of the pragmatic approach to IT analysis is that the timing and duration of the rescue treatment can be included in the analysis with mixed-effect modeling, which estimates the difference between the randomized treatment arms while adjusting for the use (timing and duration) of the subsequent treatment. We illustrate the inclusion of information on rescue treatment timing and duration in the analysis of a two-arm randomized clinical trial comparing antidepressant medications in an elderly depressed population. In this study, the randomized treatments are found to be similar. This enhanced analysis, where information about rescue treatment is implicitly added in the model, corroborates our previous two-piece spline analysis, where information about rescue treatment was not included. In addition, a significant drug by rescue interaction indicates a differential effect of the timing of rescue treatment between the two treatments. This analytic approach illustrates the importance of collecting and incorporating data after rescue, including the timing of rescue.

Data Interpretation, Statistical↗
PubMed2002

A randomized, placebo-controlled trial of paroxetine in nursing home residents with non-major depression.

Depression is common across a broad spectrum of severity among nursing home residents. Previous research has demonstrated the effectiveness of antidepressants in nursing home residents with major depression, but it is not known whether antidepressants are helpful in residents with less severe forms of depression. We conducted a randomized double-blind placebo-controlled 8-week trial comparing paroxetine and placebo in very old nursing home residents with non-major depression. The main outcome measure was the primary nurse's Clinical Impression of Change (CGI-C). Additional outcome measures were improvement on the interview-derived Hamilton Depression Rating Scale (HDRS) and Cornell Scale for Depression (CS) scores. Twenty-four subjects with a mean age of 87.9 were enrolled and twenty subjects completed the trial. Placebo response was high, and when all subjects were considered, there were no differences in improvement between the paroxetine and placebo groups. Two subjects that received paroxetine developed delirium, and subjects that received paroxetine were more likely to experience a decrease in Mini Mental State Exam scores (P =.03). There were no differences in serum anticholinergic activity between groups. In a subgroup analysis of 15 subjects with higher baseline HDRS and CS scores, there was a trend toward greater improvement in the paroxetine group in an outcome measure that combined the CGI-C and interview-based measures (P =.06). Paroxetine is not clearly superior to placebo in this small study of very old nursing home residents with non-major depression, and there is a risk of adverse cognitive effects. Because of the high placebo response and the trend towards improvement in the more severely ill patients, it is possible that a larger study would have demonstrated a significant therapeutic effect for paroxetine as compared with placebo. The study also illustrates the discordance between patient and caregiver ratings, and the difficulties in studying very elderly patients with mood disorders.

Aged↗
PubMed2002

Serotonin modulation of cerebral glucose metabolism measured with positron emission tomography (PET) in human subjects.

To develop a method to measure the dynamic response of the serotonin system in vivo, the effects of intravenously administered citalopram (the most selective of the serotonin reuptake inhibitors) on cerebral glucose metabolism were evaluated. Cerebral glucose metabolism was measured with positron emission tomography (PET) in 14 normal subjects scanned after administration of saline placebo and citalopram administered on 2 separate days. Citalopram administration resulted in a decrease in metabolism in the right anterior cingulate gyrus (BA 24/32), right superior (BA 9) and right middle frontal gyrus (BA 6), right parietal cortex (precuneus), right superior occipital gyrus, left thalamus, and right cerebellum. Increased metabolism was observed in the left superior temporal gyrus and left occipital cortex. Alterations in metabolism by acute citalopram administration involved the heteromodal association cortices that also show metabolic alterations in patients with geriatric depression and overlap with the regions affected by antidepressant treatment. Future studies will evaluate how the acute metabolic response to citalopram relates to the metabolic response after chronic treatment in patients with geriatric depression.

Adult↗
PubMed2002

Course and rate of antidepressant response in the very old.

OBJECTIVE: The authors examined elderly patients with major depression to determine the relationship of current age to treatment response course and success rate. METHODS: Three studies of elderly depressed patients provided data on antidepressant treatment response in 323 subjects, treated in protocols using either nortriptyline or paroxetine. We grouped the subjects by current age: 'young-old' (59-69, N=163), 'middle-old' (70-75, N=80), and 'older-old' (76-99, N=80). We employed mixed-effect random regression analyses to examine Hamilton Rating Scale for Depression scores over 12 weeks of acute treatment. RESULTS: Older-old patients responded as quickly and successfully as the young- and middle-old. CONCLUSIONS: Major depression in the very old can be treated as successfully as in early old age.

Age Factors↗
PubMed2002

Effect of nortriptyline and paroxetine on CYP2D6 activity in depressed elderly patients.

This study was performed in elderly patients (1) to assess the degree to which CYP2D6 mediated metabolism of debrisoquine at baseline determines plasma concentration to dose quotients for nortriptyline or paroxetine after 4 weeks of treatment, and (2) to compare the effects of nortriptyline and paroxetine on debrisoquine metabolism after 6 weeks of treatment. CYP2D6 activity was estimated in 66 subjects (71.4 +/- 7.2 years) before initiating treatment and again after 6 weeks of treatment with either nortriptyline or paroxetine under randomized, double-blind conditions according to a standard protocol. CYP2D6 activity was estimated by the debrisoquine recovery ratio in a 6- to 8-hour urine sample collected after oral administration of 10 mg debrisoquine sulfate. Nortriptyline and paroxetine plasma concentrations were obtained weekly. Baseline debrisoquine recovery ratio values were significantly correlated with the plasma concentration to dose quotient at 4 weeks for both nortriptyline ( = -0.75, = 0.0001, N = 29) and paroxetine ( = -0.50, = 0.003, N = 33). Treatment with either nortriptyline or paroxetine was associated with a significant decrease in the median debrisoquine recovery ratio, reflecting inhibition of CYP2D6 metabolism. The percent decrease associated with nortriptyline was significantly smaller than that with paroxetine ( < 0.0001). None of the patients treated with nortriptyline but 19 of the 32 extensive metabolizers treated with paroxetine were converted to phenotypic poor metabolic status. Our observations of CYP2D6 inhibition are consistent with data and results obtained in younger healthy volunteers. The significant correlations between baseline debrisoquine recovery ratio and the plasma concentrations to dose quotients at 4 weeks for both nortriptyline and paroxetine are consistent with CYP2D6 playing a major role in the metabolism of both drugs. CYP2D6 inhibition by paroxetine, which effectively converted 59% of patients to phenotypic PMs, may be especially relevant for elderly patients given their generally higher concentration of paroxetine.

Adrenergic Agents↗
PubMed2002

Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients.

OBJECTIVE: Until recently, conventional antipsychotics were the standard pharmacotherapy for psychosis and behavioral disturbances associated with dementia. This double-blind, placebo-controlled study compared the acute efficacy of the selective serotonin reuptake inhibitor citalopram and the neuroleptic perphenazine with placebo for the treatment of psychosis and behavioral disturbances in nondepressed patients with dementia. METHOD: Eighty-five hospitalized patients with at least one moderate to severe target symptom (aggression, agitation, hostility, suspiciousness, hallucinations, or delusions) were randomly assigned to receive either citalopram, perphenazine, or placebo under double-blind conditions for up to 17 days. RESULTS: Patients treated with citalopram or perphenazine showed statistically significant improvement on several Neurobehavioral Rating Scale factor scores. Compared to those receiving placebo, only patients treated with citalopram showed significantly greater improvement in their total Neurobehavioral Rating Scale score as well as in the scores for the agitation/aggression and lability/tension factors. Side effect scores were similar among the three treatment groups. CONCLUSIONS: Citalopram was found to be more efficacious than placebo in the short-term hospital treatment of psychotic symptoms and behavioral disturbances in nondepressed, demented patients.

Aged↗
PubMed2002

Interrater reliability in clinical trials of depressive disorders.

OBJECTIVE: The goal of this study was to review the reported methods of rater training, assessment of interrater reliability, and rater drift in clinical trials of treatments for depressive disorders. METHOD: Two psychiatrists independently identified all original reports of clinical trials relevant to depressive disorders published between 1996 and 2000 in the American Journal of Psychiatry and the Archives of General Psychiatry. Reported methods of rater training, assessment of interrater reliability, and rater drift were systematically summarized. RESULTS: Sixty-three original papers met criteria for inclusion. Only 11 (17%) of the studies reported the number of raters. Only two (9%) of the 22 multicenter and four (10%) of the 41 single-center trials documented rater training. Only nine (22%) of the single-center trials and three (14%) of the multicenter trials reported interrater reliability, despite a median number of five raters (range=2-20). Only three (5%) of the 63 articles reported rater drift. CONCLUSIONS: Few published reports of clinical trials of treatments for depressive disorders document adequately the number of raters, rater training, assessment of interrater reliability, and rater drift.

Depressive Disorder↗
PubMed2002

Risperidone and 9-hydroxyrisperidone concentrations are not dependent on age or creatinine clearance among elderly subjects.

Risperidone is extensively metabolized to an active metabolite, 9-hydroxyrisperidone (9-OH), which is dependent on renal clearance. Risperidone and 9-OH clearances are reduced in the elderly when compared to young subjects. The objective of this study was to determine whether among elderly subjects, risperidone and 9-OH clearance would further decline with increasing age and decreasing creatinine clearance (CrCl). Twenty geriatric inpatients were evaluated in a naturalistic setting with regard to total daily risperidone dose and dosing interval. Creatinine clearance was determined using an 8-hour urine collection. Risperidone and 9-OH concentrations were determined by radioimmunoassay. Spearman's correlation coefficients were used to examine the impact of age and CrCl on concentrations of risperidone, 9-OH, their sum, and the quotient of 9-OH/risperidone. Mean age was 76.4 +/- 9 years (range 56-91). Mean CrCl was 55.4 +/- 32.8 mL/min/1.73 m2 (range 17-142 mL/min/1.73 m2). Mean risperidone daily dose was 1.3 +/- 0.7 mg. Steady-state risperidone and 9-OH concentrations were 4.1 +/- 5.3 ng/mL and 9.1 +/- 6.2 ng/mL, respectively. Mean 9-OH/risperidone was 6.2 +/- 6.1. Concentrations of risperidone, 9-OH, their sum, and 9-OH/risperidone were not significantly correlated with age or CrCl. These results were unchanged when concentrations were corrected for total daily risperidone dose. Among elderly subjects, risperidone and 9-OH clearance do not decline with increasing age or declining CrCl.

Age Factors↗
PubMed2002

Risk factors for falls during treatment of late-life depression.

BACKGROUND: Prior studies have found that antidepressant medications are associated with an increased risk of falling in elderly persons. However, little is known about the prevention of falls during treatment for depression in elderly persons. This study evaluated the time course and potential risk factors for falls in a treatment protocol for late-life depression to identify specific at-risk periods and risk factors for falls in this population. METHOD: One hundred four subjects aged 69 years and over were treated in a protocolized manner using paroxetine and interpersonal psychotherapy. Those who did not respond received augmentation therapy with bupropion, nortriptyline, or lithium. Subjects were assessed at baseline and weekly during treatment; demographic and clinical characteristics of those who experienced a fall during treatment were compared with those who did not fall. Cox proportional hazards models were used to define risk factors for falls in univariate and multivariate models. RESULTS: During a mean of 21 weeks of treatment, 40 subjects (38%) fell. About half (53%) of the subjects fell during the first 6 weeks of treatment. In the multivariate model, memory impairment and orthostatic changes in blood pressure during treatment were risk factors for falling. Additionally, augmentation with bupropion appeared to be a risk factor for falls in univariate analysis, but this result is preliminary due to the small number of subjects who took bupropion. CONCLUSION: Increased monitoring for falls is warranted during the acute treatment of late-life depression. When treating such patients, clinicians should be especially watchful of those with memory impairments or those who develop orthostatic blood pressure changes; orthostatic blood pressure should be measured throughout acute treatment. Additionally, augmenting paroxetine with bupropion may also increase the risk of falls, and this medication combination should be used with caution in elderly patients.

Accidental Falls↗
PubMed2002

A critical appraisal of the utility of the serum anticholinergic activity assay in research and clinical practice.

The serum anticholinergic activity (SAA) assay was originally designed to quantify the anticholinergic burden of drug exposure. The same assay has been used to measure the anticholinergic activity of standard drug solutions. There are limitations to the use of the assay in research and in applying these findings to clinical practice. Assays of standard drug solutions do not account for pharmacokinetic differences among drugs, which limits the interpretation of such measurements. In addition, emerging evidence has suggested that anticholinergic medications may not be the only cause of elevated SAA. Despite these limitations, elevated SAA has been consistently associated with cognitive impairment and delirium in a number of research settings. Such findings have prompted investigators to consider the potential application of the SAA assay in research and in clinical practice. Therefore, the objectives of this review are to summarize the current literature involving the SAA assay, describe the relative merits and shortfalls of the SAA assay as a research tool, and discuss the potential for use of the SAA assay as a clinical tool.

Animals↗
PubMed2002

The relationship of an anticholinergic rating scale with serum anticholinergic activity in elderly nursing home residents.

ndings support the validity of the CR-ACh-mod. However, unexplained variance in SAA suggests that the CR-ACh-mod could benefit from improvements. Future research will evaluate the effect of including factors such as dose and the relative anticholinergic burden from drugs at each of the rating levels. An alternative explanation for the variance which is supported by recent research is that nondrug factors contribute to SAA.

Aged↗
PubMedDate not supplied

Intent-to-treat analysis for clinical trials: use of data collected after termination of treatment protocol.

Following patients for a period of time after termination of treatment protocols is a common practice in clinical trials of drug treatments. After termination of the protocol treatment, patients are usually provided with medical care as deemed appropriate, e.g. different doses of the same drug, augmentation with other drugs, or different drugs. Data collected on patients when they are not in the treatment protocol are termed "off-treatment" data to be differentiated from "on-treatment" data that are collected while patients are in the treatment protocol. The purpose of the present paper is to describe some recent statistical methodological advances in the use of "off-treatment" data for intent-to-treat (IT) analysis using mixture models [Biometrics 52 (1996) 1002]. Two-piece spline models conditional on the protocol treatment dropout time are developed first. The two pieces of the spline model represent the on-treatment and off-treatment segments of data and are joined at the dropout time. The weighted average of the two-piece conditional models across realizations of the dropout times provides the mixture model for the pragmatic IT analysis. The weights are the estimates of the probabilities of the dropout times. The mixture model is amenable to an explanatory analysis which assumes that the patients remain on their assigned treatments. The model allows the parameters of the splines to depend on the dropout time. Statistical inference is based on bootstrap sampling procedures. We have illustrated this methodology using data from a drug trial comparing nortriptyline and paroxetine in the treatment of major depression in older patients.

Clinical Trials as Topic↗
PubMedDate not supplied

Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine.

Cognitive dysfunction is common in older persons suffering from a major depression. However, the degree to which this dysfunction is reversible with successful treatment of the depression remains uncertain. The present study examined the effects that treatment (randomized double-blind design) with either an SSRI (paroxetine) or a tricyclic antidepressant (nortriptyline) had on cognition in older depressed patients. The patients' performance was compared to that of a group of normal controls of similar age and education. Patients and controls were administered measures of working memory, information-processing speed, episodic memory and attention five times over the course of a 12 week trial. At baseline, the patients performed more poorly than the elderly controls on all cognitive measures. While the patients' performance did improve over the course of their treatment, the magnitude of this improvement did not exceed that produced in the elderly controls by practice alone. The same pattern of results was evident in both intent-to-treat and responder analyses. Thus, there was no evidence that the depressed patients' cognitive performance normalized after response to antidepressant therapy. Neither the patients' age at onset nor their baseline level of cognitive functioning influenced the amount by which their performance improved over the 12 week trial. There was no difference between paroxetine and nortriptyline in the amount of cognitive change associated with treatment. The present results suggest that cognitive dysfunction persists in older depressed patients even after their mood disorder has responded to antidepressant medications.

Aged↗