Depressed geriatric patients show substantial intersubject variability in cognitive performance, ... more Depressed geriatric patients show substantial intersubject variability in cognitive performance, which complicates attempts to evaluate the cognitive effects of depression and of antidepressant therapy. This variability may reflect the multiple medications older patients take, many of which have anticholinergic effects. This study examined whether serum anticholinergicity (SA) explained some of the variability in depressed geriatric patients' memory performance. Before starting antidepressant treatment, 36 elderly depressed subjects were given a verbal learning test. At the same time, a blood sample was taken and analyzed by radioreceptor binding assay to determine their SA level. Nineteen of the subjects had detectable levels (mean = 0.28 pmole atropine equivalent). Subjects with an SA of zero showed significantly better delayed recall than did those with a positive SA level. Thus, even very low SA may produce subtle decrements in memory performance, an area of cognition known to be highly sensitive to anticholinergic effects.
The metabolic ratios (MRs) between debrisoquine (DBQ) and 4-hydroxydebrisoquine in urine after a ... more The metabolic ratios (MRs) between debrisoquine (DBQ) and 4-hydroxydebrisoquine in urine after a single dose of 10 mg DBQ was determined in 175 unmedicated, healthy subjects older than age 59 (mean of 75 years). Creatinine clearance was determined on the same 8-hour urine collection. Test procedures were well tolerated in all cases. Although age was significantly correlated with creatinine clearance (r = -.38), there was no relationship between age and MR. Analysis by kernel density estimation revealed a bimodal distribution of MRs with an antimode of 11.6. Six subjects (3.4%) were categorically slow DBQ metabolizers (MR greater than 11.6). The proportion of elderly slow metabolizers approaches the lower range determined in a younger population. Our findings, that DBQ oxidative metabolism does not necessarily change with aging, alone, and that (genetic) slow DBQ metabolizers endure into old age, remaining at risk for treatment with many commonly used psychotropics, suggests the need to study the relevance of metabolic phenotyping in elderly psychiatric patients.
Journal of pediatric gastroenterology and nutrition
Determine whether infliximab use and other potential predictors are associated with decreased pre... more Determine whether infliximab use and other potential predictors are associated with decreased prevalence and severity of depression in pediatric patients with Crohn's disease (CD). Five hundred and fifty (n = 550) youth aged 9-17 with biopsy-confirmed CD were consecutively recruited as part of a multicenter randomized-controlled trial. 499 patients met study criteria and were included in the analysis. At recruitment, each subject and a parent completed the Children's Depression Inventory (CDI). A child or parent CDI ≥ 12 was used to denote clinically significant depressive symptoms (CSDS). Child and parent CDI scores were summed to form total CDI (CDIT). Infliximab use, demographic information, steroid use, laboratory values, and Pediatric Crohn's Disease Activity Index (PCDAI) were collected as potential predictors of depression. Univariate regression models were constructed to determine relationships between predictors, CSDS, and CDIT. Stepwise multivariate regression ...
Background: Pediatric patients with inflammatory bowel disease (IBD) have high rates of abdominal... more Background: Pediatric patients with inflammatory bowel disease (IBD) have high rates of abdominal pain. The study aims were to (1) evaluate biological and psychological correlates of abdominal pain in depressed youth with IBD and (2) determine predictors of abdominal pain in Crohn's disease (CD) and ulcerative colitis (UC). Methods: Seven hundred sixty-five patients aged 9 to 17 years with IBD seen over 3 years at 2 sites were screened for depression. Depressed youth completed comprehensive assessments for abdominal pain, psychological (depression and anxiety), and biological (IBD-related, through disease activity indices and laboratory values) realms. Results: Two hundred seventeen patients with IBD (161 CD, 56 UC) were depressed. One hundred sixty-three (120 CD, 43 UC) patients had complete abdominal pain index scores. In CD, abdominal pain was associated with depression (r = 0.33; P < 0.001), diarrhea (r = 0.34; P = 0.001), erythrocyte sedimentation rate (r = 0.22; P = 0.0...
Clinical evidence and expert opinion support using a combination of an antipsychotic and an antid... more Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods. The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration. Population pharmacokinetic analysis comprised 336 samples from 175 ind...
The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients ra... more The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients randomly assigned to double-blind treatment with paroxetine (N=31) or nortriptyline (N=30). Both antidepressants were titrated in a standardized manner, and plasma was sampled weekly for measurement of paroxetine and nortriptyline and its hydroxy metabolite concentrations. Serum anticholinergicity was measured at baseline and after 1, 4, and 6 weeks of treatment. Side effects were assessed by using a validated scale. After correcting for pretreatment anticholinergicity, the authors found that mean serum anticholinergicity for the nortriptyline-treated patients was significantly greater than that for the paroxetine group at all weeks assessed. Serum anticholinergicity was significantly correlated with nortriptyline but not with paroxetine plasma levels. Complaints of dry mouth and tachycardia were significantly more frequent and severe in the nortriptyline group. These findings suggest that...
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 1997
Citalopram, in European studies, has shown some early promise for treatment of poststroke depress... more Citalopram, in European studies, has shown some early promise for treatment of poststroke depression and behavioral complications of dementia. An open pilot study of citalopram was conducted in 16 patients with dementia and behavioral disturbances. Citalopram was well tolerated by 13 of the patients, and 9 had a clinically impressive response. A significant overall mean reduction in disruptive vocalizations was observed by means of a novel technique of computer-assisted real-time observation. The mean citalopram plasma level-to-dose ratio was found to be twice that previously reported in younger patients. These pilot findings should encourage future placebo concentration-controlled trials.
To examine whether a drug-metabolizing enzyme changes with normal aging, the S:R index of S-mephe... more To examine whether a drug-metabolizing enzyme changes with normal aging, the S:R index of S-mephenytoin 4-hydroxylation was determined in 150, unmedicated elderly Americans (mean age 75.4). Ten (6.7%) were identified as categorically slow metabolizers (S:R ratios greater than or equal to .95). This increased incidence of slow metabolizers was accounted for by a significant and previously unreported, increased proportion of slow metabolizers among the black (18.5%) as compared to the white subjects (4.1%) (P = .017). There was no relationship found between S:R ratios and age or creatinine clearance.
To investigate whether variable antidepressant response may be influenced by an interaction betwe... more To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used. There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. The results demonstrate a concentration-response relation for paroxetine in late-life depr...
Depressed geriatric patients show substantial intersubject variability in cognitive performance, ... more Depressed geriatric patients show substantial intersubject variability in cognitive performance, which complicates attempts to evaluate the cognitive effects of depression and of antidepressant therapy. This variability may reflect the multiple medications older patients take, many of which have anticholinergic effects. This study examined whether serum anticholinergicity (SA) explained some of the variability in depressed geriatric patients&amp;amp;#39; memory performance. Before starting antidepressant treatment, 36 elderly depressed subjects were given a verbal learning test. At the same time, a blood sample was taken and analyzed by radioreceptor binding assay to determine their SA level. Nineteen of the subjects had detectable levels (mean = 0.28 pmole atropine equivalent). Subjects with an SA of zero showed significantly better delayed recall than did those with a positive SA level. Thus, even very low SA may produce subtle decrements in memory performance, an area of cognition known to be highly sensitive to anticholinergic effects.
The metabolic ratios (MRs) between debrisoquine (DBQ) and 4-hydroxydebrisoquine in urine after a ... more The metabolic ratios (MRs) between debrisoquine (DBQ) and 4-hydroxydebrisoquine in urine after a single dose of 10 mg DBQ was determined in 175 unmedicated, healthy subjects older than age 59 (mean of 75 years). Creatinine clearance was determined on the same 8-hour urine collection. Test procedures were well tolerated in all cases. Although age was significantly correlated with creatinine clearance (r = -.38), there was no relationship between age and MR. Analysis by kernel density estimation revealed a bimodal distribution of MRs with an antimode of 11.6. Six subjects (3.4%) were categorically slow DBQ metabolizers (MR greater than 11.6). The proportion of elderly slow metabolizers approaches the lower range determined in a younger population. Our findings, that DBQ oxidative metabolism does not necessarily change with aging, alone, and that (genetic) slow DBQ metabolizers endure into old age, remaining at risk for treatment with many commonly used psychotropics, suggests the need to study the relevance of metabolic phenotyping in elderly psychiatric patients.
Journal of pediatric gastroenterology and nutrition
Determine whether infliximab use and other potential predictors are associated with decreased pre... more Determine whether infliximab use and other potential predictors are associated with decreased prevalence and severity of depression in pediatric patients with Crohn's disease (CD). Five hundred and fifty (n = 550) youth aged 9-17 with biopsy-confirmed CD were consecutively recruited as part of a multicenter randomized-controlled trial. 499 patients met study criteria and were included in the analysis. At recruitment, each subject and a parent completed the Children's Depression Inventory (CDI). A child or parent CDI ≥ 12 was used to denote clinically significant depressive symptoms (CSDS). Child and parent CDI scores were summed to form total CDI (CDIT). Infliximab use, demographic information, steroid use, laboratory values, and Pediatric Crohn's Disease Activity Index (PCDAI) were collected as potential predictors of depression. Univariate regression models were constructed to determine relationships between predictors, CSDS, and CDIT. Stepwise multivariate regression ...
Background: Pediatric patients with inflammatory bowel disease (IBD) have high rates of abdominal... more Background: Pediatric patients with inflammatory bowel disease (IBD) have high rates of abdominal pain. The study aims were to (1) evaluate biological and psychological correlates of abdominal pain in depressed youth with IBD and (2) determine predictors of abdominal pain in Crohn's disease (CD) and ulcerative colitis (UC). Methods: Seven hundred sixty-five patients aged 9 to 17 years with IBD seen over 3 years at 2 sites were screened for depression. Depressed youth completed comprehensive assessments for abdominal pain, psychological (depression and anxiety), and biological (IBD-related, through disease activity indices and laboratory values) realms. Results: Two hundred seventeen patients with IBD (161 CD, 56 UC) were depressed. One hundred sixty-three (120 CD, 43 UC) patients had complete abdominal pain index scores. In CD, abdominal pain was associated with depression (r = 0.33; P < 0.001), diarrhea (r = 0.34; P = 0.001), erythrocyte sedimentation rate (r = 0.22; P = 0.0...
Clinical evidence and expert opinion support using a combination of an antipsychotic and an antid... more Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods. The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration. Population pharmacokinetic analysis comprised 336 samples from 175 ind...
The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients ra... more The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients randomly assigned to double-blind treatment with paroxetine (N=31) or nortriptyline (N=30). Both antidepressants were titrated in a standardized manner, and plasma was sampled weekly for measurement of paroxetine and nortriptyline and its hydroxy metabolite concentrations. Serum anticholinergicity was measured at baseline and after 1, 4, and 6 weeks of treatment. Side effects were assessed by using a validated scale. After correcting for pretreatment anticholinergicity, the authors found that mean serum anticholinergicity for the nortriptyline-treated patients was significantly greater than that for the paroxetine group at all weeks assessed. Serum anticholinergicity was significantly correlated with nortriptyline but not with paroxetine plasma levels. Complaints of dry mouth and tachycardia were significantly more frequent and severe in the nortriptyline group. These findings suggest that...
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 1997
Citalopram, in European studies, has shown some early promise for treatment of poststroke depress... more Citalopram, in European studies, has shown some early promise for treatment of poststroke depression and behavioral complications of dementia. An open pilot study of citalopram was conducted in 16 patients with dementia and behavioral disturbances. Citalopram was well tolerated by 13 of the patients, and 9 had a clinically impressive response. A significant overall mean reduction in disruptive vocalizations was observed by means of a novel technique of computer-assisted real-time observation. The mean citalopram plasma level-to-dose ratio was found to be twice that previously reported in younger patients. These pilot findings should encourage future placebo concentration-controlled trials.
To examine whether a drug-metabolizing enzyme changes with normal aging, the S:R index of S-mephe... more To examine whether a drug-metabolizing enzyme changes with normal aging, the S:R index of S-mephenytoin 4-hydroxylation was determined in 150, unmedicated elderly Americans (mean age 75.4). Ten (6.7%) were identified as categorically slow metabolizers (S:R ratios greater than or equal to .95). This increased incidence of slow metabolizers was accounted for by a significant and previously unreported, increased proportion of slow metabolizers among the black (18.5%) as compared to the white subjects (4.1%) (P = .017). There was no relationship found between S:R ratios and age or creatinine clearance.
To investigate whether variable antidepressant response may be influenced by an interaction betwe... more To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used. There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. The results demonstrate a concentration-response relation for paroxetine in late-life depr...
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Papers by Margaret Kirshner