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Biomedical subjects

Nathan Herrmann

Publications and source records attributed to Nathan Herrmann.

At least 37 records · Page 2Linked to original sources
PubMed2005

Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study.

OBJECTIVE: To compare the incidence of admissions to hospital for stroke among older adults with dementia receiving atypical or typical antipsychotics. DESIGN: Population based retrospective cohort study. SETTING: Ontario, Canada. Patients 32,710 older adults (< or = 65 years) with dementia (17,845 dispensed an atypical antipsychotic and 14,865 dispensed a typical antipsychotic). MAIN OUTCOME MEASURES: Admission to hospital with the most responsible diagnosis (single most important condition responsible for the patient's admission) of ischaemic stroke. Observation of patients until they were either admitted to hospital with ischaemic stroke, stopped taking antipsychotics, died, or the study ended. RESULTS: After adjustment for potential confounders, participants receiving atypical antipsychotics showed no significant increase in risk of ischaemic stroke compared with those receiving typical antipsychotics (adjusted hazard ratio 1.01, 95% confidence interval 0.81 to 1.26). This finding was consistent in a series of subgroup analyses, including ones of individual atypical antipsychotic drugs (risperidone, olanzapine, and quetiapine) and selected subpopulations of the main cohorts. CONCLUSION: Older adults with dementia who take atypical antipsychotics have a similar risk of ischaemic stroke to those taking typical antipsychotics.

Aged↗
PubMed2005

Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe.

CONTEXT: The pathophysiology of major depressive disorder (MDD) includes disturbances in several neuroanatomical substrates and neurotransmitter systems. The challenge is to elucidate the brain mechanisms of MDD behavioral symptoms, chiefly those of anhedonia. OBJECTIVES: To visualize the neuroanatomical substrates implicated in altered reward processing in MDD, using functional magnetic resonance imaging in combination with a dopaminergic probe (a 30-mg dose of oral dextroamphetamine sulfate) to stimulate the brain reward system; and to test the hypothesis that a hypersensitive response to dextroamphetamine in MDD involves the prefrontal cortex and the striatum. DESIGN AND INTERVENTIONS: Among subjects with MDD and healthy control subjects, functional magnetic resonance imaging data were collected before and after single-blind administration of dextroamphetamine. SETTING: Subjects were recruited through local newspaper advertisements and by word of mouth. PARTICIPANTS: Twelve depressed subjects (mean age, 34.83 years; male-female ratio, 6:6) met criteria for MDD according to the DSM-IV, were not taking antidepressants, and had no comorbid Axis I disorders. Twelve control subjects (mean age, 29.33 years; male-female ratio, 5:7) were healthy volunteers without a history of Axis I disorders. MAIN OUTCOME MEASURES: Functional magnetic resonance imaging blood oxygen level-dependent activation was measured during a controlled task, and dextroamphetamine-induced subjective effects were assessed using the Addiction Research Center Inventory. RESULTS: Subjects with MDD had a hypersensitive response to the rewarding effects of dextroamphetamine (2-fold increase; t(21) = 2.74, P = .01), with altered brain activation in the ventrolateral prefrontal cortex and the orbitofrontal cortex and the caudate and putamen (F(1,44) = 11.93, P = .001). CONCLUSION: Dopamine-related neuroanatomical substrates are involved in altered reward processing in MDD, shedding light on the neurobiology of the anhedonic symptoms in MDD and suggesting these substrates as future therapeutic targets.

Adult↗
PubMed2005

Antipsychotic use in the elderly: shifting trends and increasing costs.

OBJECTIVE: The purpose of this study was to assess trends in utilization and costs of antipsychotic drugs among a population of older adults over time, with respect to the prevalence of users, shifts in prescribing patterns, and related financial implications. DESIGN: Cross-sectional time series of quarterly and annual antipsychotic utilization and cost were obtained from administrative databases for calendar years 1993 through 2002. SETTING AND PARTICIPANTS: A population-based study of more than 1.4 million residents of the province of Ontario aged 65 years or older. MEASUREMENTS: Data sources used included the Ontario Drug Benefits (ODB) database and Statistics Canada census data. RESULTS: The prevalence of antipsychotic users increased by 34.8% over the study period from 2.2% at the beginning of 1993 to 3.0% of the elderly at the end of 2002 (p < 0.01). This was associated with a 749% increase in total cost (from $3.7 million in 1993 to $31.4 million in 2002; p < 0.01). The atypical antipsychotics, which were not available in 1993, made up 82.5% of the antipsychotics dispensed and 95.2% of costs in 2002. CONCLUSIONS: The modest increase in antipsychotic prevalence in the elderly over the last ten years has been associated with a substantial increase in cost, with a significant shift towards use of the atypical antipsychotics. As the atypical antipsychotics are increasingly used for patients with dementia, which is becoming more prevalent in the aging population, an understanding of the benefits of these medications must be balanced with a detailed understanding of the material and financial implications.

Aged↗
PubMed2005

Antidepressants, warfarin, and the risk of hemorrhage.

BACKGROUND: Case reports suggest that some selective serotonin reuptake inhibitors can interact with warfarin to increase the likelihood of bleeding. We speculated that, among patients receiving warfarin, initiation of selective serotonin reuptake inhibitor treatment would be associated with an increased risk of hospitalization for upper gastrointestinal tract bleeding (UGIB). METHODS: We conducted a population-based, nested, case-control study involving Ontario residents 66 years or older continuously treated with warfarin for at least 1 year. Cases admitted with UGIB were compared with matched controls (1:10) to explore the odds ratio for initiation of various antidepressants within 42, 90, and 180 days before the index admission. RESULTS: From January 1994 to December 2002, we identified 98,784 elderly patients continuously receiving warfarin for at least 1 year; of whom 1538 (0.6%) were admitted to hospital for UGIB. The adjusted odds ratio for fluoxetine/fluvoxamine exposure in 90 days before UGIB hospitalization is 1.2 (95% confidence interval, 0.8-1.7), and the adjusted odds ratio for other selective serotonin reuptake inhibitors in the same period was 1.1 (95% confidence interval, 0.9-1.4). The odds ratios for exposure to antidepressants in 180 days before UGIB hospitalization were similar. CONCLUSION: The initiation of selective serotonin reuptake inhibitor treatment in patients receiving warfarin was not associated with a significant increase in the risk of hospitalization for UGIB.

Aged↗
PubMed2005

A population-based assessment of the potential interaction between serotonin-specific reuptake inhibitors and digoxin.

AIM: In vitro evidence suggests that some serotonin-specific reuptake inhibitors (SSRIs) inhibit P-glycoprotein, a multidrug efflux pump responsible for the elimination of several drugs including digoxin. We sought to determine if some SSRIs cause digoxin toxicity in the clinical setting. METHODS: Population-based nested case-control study set in Ontario, Canada from 1994 to 2001. We studied all patients 66 years or older treated with digoxin. Prescription and hospital admission records were analysed to determine the relationship between the initiation of SSRI therapy and hospital admission for digoxin toxicity in the subsequent 30 days. RESULTS: Among 245 305 older patients treated with digoxin, we identified 3144 cases of digoxin toxicity. After adjusting for potential confounders, we observed an increased risk of digoxin toxicity following initiation of paroxetine [odds ratio (OR) 2.8; 95% confidence interval (CI) 1.6, 4.7], fluoxetine (OR 2.9; 95% CI 1.5, 5.4), sertraline (OR 3.0; 95% CI 1.9, 4.7), and fluvoxamine (OR 3.0; 95% CI 1.5, 5.7). However, an elevated risk was also seen with tricyclic antidepressants (OR 1.5; 95% CI 1.0, 2.4) and benzodiazepines (OR 2.1; 95% CI 1.7, 2.5), drugs classes having no known pharmacokinetic interaction with digoxin. There was no statistical difference in the risk of digoxin toxicity among any of the agents tested. CONCLUSIONS: We found no major discrepancy in the risk of digoxin toxicity after initiation of various SSRI antidepressants, suggesting that the inhibition of P-glycoprotein by sertraline and paroxetine observed in vitro is unlikely to be of major clinical significance.

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PubMed2005

Mental health-related drug utilization among older adults: prevalence, trends, and costs.

OBJECTIVE: Authors assessed temporal changes in mental health-related drug utilization and costs in an older population. METHODS: This was a population-based, cross-sectional time-series analysis of more than 1.4 million residents of Ontario, Canada, age 65 years or older. The study examined mental health-related drug utilization and costs, as derived from administrative databases from 1993 through 2002. They assessed use of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and acetylcholinesterase inhibitors (AChEIs), assessing trends over time. RESULTS: The prevalence of mental health-related drug use increased from 21.3% of the older population in the beginning of 1993 to 23.8% by the end of 2002. The proportion of benzodiazepine prescriptions was the highest of all such drugs, but declined from approximately 67% of prescriptions, in 1993, to 38%, in 2002. Significant temporal increases were observed for use of antidepressants (5.6%, in 1993, to 10.9%, in 2002), antipsychotics (1.9% in 1993; 2.9% in 2002), and AChEIs (0.1% in 1999; 1.5% in 2002). These increases were associated with a 210% increase in total standardized expenditures on mental health-related drugs, from approximately $32 per older resident ($40 million total) in 1993 to $99 per older resident ($149 million total) in 2002. AChEIs accounted for fewer than 6% of prescriptions, but 25% of the costs. CONCLUSIONS: Significant shifts in prescription of mental health-related drugs and their costs have occurred over the past decade among older individuals with the introduction of newer, more expensive agents. Future research should address the appropriate balancing of increased costs versus their benefits in this population.

Aged↗
PubMed2005

Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials.

OBJECTIVE: The authors explored the effect of galantamine on behavioral symptoms in Alzheimer disease (AD). METHODS: Data were pooled from 2,033 subjects with mild-to-moderate AD who had participated in one of three randomized, double-blind, placebo-controlled trials of 3-, 5-, and 6-month durations. Subjects included in this post hoc analysis had received treatment with either placebo (N=686) or galantamine (N=1347) in total daily doses of 16 mg, 24 mg, or 32 mg. Behavioral symptoms were measured on the 10-item Neuropsychiatric Inventory (NPI). Four symptom clusters were defined a priori: 1) delusions, hallucinations; 2) agitation, depression, anxiety, apathy, irritability; 3) disinhibition, elation, aberrant motor behavior; 4) hallucinations, anxiety, apathy, aberrant motor behavior. RESULTS: At endpoint, mean changes from baseline in NPI scores were significantly different between galantamine-treated subjects and placebo-treated subjects, favoring galantamine for several measures: total NPI, individual domains of agitation/aggression, anxiety, disinhibition, and aberrant motor behavior, and Clusters 1, 3, and 4. The magnitude of the effect sizes was small. CONCLUSIONS: In this pooled sample of more than 2,000 subjects with mild-to-moderate AD, those who received galantamine therapy experienced modestly better, but statistically significant, outcomes in their behavioral symptoms than placebo-treated subjects. The cluster of hallucinations, anxiety, apathy and aberrant motor behaviors may represent a specific group of cholinergic-responsive behavioral symptoms.

Aged↗
PubMed2005

Do atypical antipsychotics cause stroke?

Post hoc analyses of pooled results from 11 randomised controlled trials of risperidone and olanzapine in elderly dementia subjects revealed an increased incidence of cerebrovascular adverse events compared with placebo. Reanalysis of the risperidone trials suggests that some of the increased incidence may be accounted for by nonspecific events that were not strokes. Large observational administrative health database studies appear to confirm that risperidone and olanzapine are not associated with an increased risk of stroke in elderly patients compared with typical antipsychotics or untreated dementia patients. A larger number of subjects with vascular and mixed dementias were included in the risperidone studies compared with the olanzapine studies, which likely accounts for the increased incidence of cerebrovascular adverse events in the risperidone trials compared with the olanzapine studies. Potential mechanisms proposed to explain an association between atypical antipsychotics and cerebrovascular adverse events include thromboembolic effects, cardiovascular effects (e.g. orthostatic hypotension, arrhythmias), excessive sedation resulting in dehydration and haemoconcentration, and hyperprolactinaemia. However, there is little evidence to support these hypothesised mechanisms at present. The association between atypical antipsychotics and cerebrovascular adverse events requires further clarification. At the present time, this association is another factor that clinicians should consider when weighing the risks and benefits of treating behavioural and psychological disturbances in elderly dementia patients.

Antipsychotic Agents↗
PubMed2004

Medical illness and the risk of suicide in the elderly.

BACKGROUND: Suicide is a leading cause of death, and rates are especially high among the elderly. Medical illnesses may predispose to suicide, but few controlled studies have examined the association between specific diseases and suicide. We explored the relationship between treatment for several illnesses and the risk of suicide in elderly patients using a population-based approach. METHODS: All Ontario residents 66 years or older who committed suicide between January 1, 1992, and December 31, 2000, were identified from provincial coroners' records. Their prescription records during the preceding 6 months were compared with those of living matched controls (1:4) to determine the presence or absence of 17 illnesses potentially associated with suicide. RESULTS: During the 9-year study period, we identified 1354 elderly patients who died of suicide. The most common mechanisms involved firearms (28%), hanging (24%), and self-poisoning (21%). Specific illnesses associated with suicide included congestive heart failure (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.33-2.24), chronic obstructive lung disease (OR, 1.62; 95% CI, 1.37-1.92), seizure disorder (OR, 2.95; 95% CI, 1.89-4.61), urinary incontinence (OR, 2.02; 95% CI, 1.29-3.17), anxiety disorders (OR, 4.65; 95% CI, 4.07-5.32), depression (OR, 6.44; 95% CI, 5.45-7.61), psychotic disorders (OR, 5.09; 95% CI, 3.94-6.59), bipolar disorder (OR, 9.20, 95% CI, 4.38-19.33), moderate pain (OR, 1.91; 95% CI, 1.66-2.20), and severe pain (OR, 7.52; 95% CI, 4.93-11.46). Treatment for multiple illnesses was strongly related to a higher risk of suicide. Almost half the patients who committed suicide had visited a physician in the preceding week. CONCLUSIONS: Many common illnesses are independently associated with an increased risk of suicide in the elderly. The risk is greatly increased among patients with multiple illnesses. These data may help clinicians to identify elderly patients at risk of suicide and open avenues for prevention.

Aged↗
PubMed2004

Medial temporal hypoperfusion and aggression in Alzheimer disease.

BACKGROUND: It is not understood why some patients with Alzheimer disease (AD) display aggression and others do not. OBJECTIVE: To examine the relation between regional brain perfusion and aggression in AD. DESIGN: Single-photon emission computed tomographic scans were coregistered to a standardized template in Talairach space, generating mean ratios of uptake referenced to the cerebellum. PARTICIPANTS: Forty-nine outpatients (25 men and 24 women; mean +/- SD age, 74 +/- 11 years) with probable AD (Mini-Mental State Examination score, 17.7 +/- 5.0; 30 aggressive and 19 nonaggressive), comparable in age, sex, and severity of cognitive impairment. MAIN OUTCOME MEASURES: Regional perfusion ratios were determined for 5 bilateral regions of interest: orbitofrontal, middle medial temporal, inferior medial temporal, hypothalamus/thalamus, and anterior cingulate. RESULTS: Compared with nonaggressive patients, aggressive ones displayed hypoperfusion in the right and left middle medial temporal regions of interest (P = .02 for both), but not the others (all (t tests, unpaired, 2-tailed). On regression analyses, right middle temporal hypoperfusion (P = .001), younger age (P = .002), greater activity disturbances (P = .004), and higher Mini-Mental State Examination scores (P = .04) independently predicted aggression, accounting for 44% of the total variance (F = 8.7; P<.001). Statistical parametric mapping analyses supported right middle medial temporal hypoperfusion in the aggressive group (P = .008). CONCLUSION: In this sample of patients with AD, the right middle medial temporal region emerged as an important neural correlate of aggression.

Aged↗
PubMed2004

Growth hormone response to clonidine predicts aggression in Alzheimer's disease.

OBJECTIVE: The neurobiology of aggression in Alzheimer's Disease (AD) remains unknown. The objective of this study was to determine if altered central noradrenergic (NE) responsiveness is related to aggression in AD. METHODS: Fifteen institutionalized, non-depressed elderly (11 males, four females, mean age 81.5 +/- 5.5) with probable AD, severe cognitive impairment (MMSE mean 3.3 +/- 4.6) and significant behavioral disturbances (Neuropsychiatric Inventory (NPI) score > or = 8) were studied. Growth Hormone (GH) response to clonidine challenge (5 microg/kg) was used as an index of central alpha(2)-adrenergic function. RESULTS: When patients were divided into those with preserved GH response (GH maximum change from baseline > 0, n = 6) and those with blunted GH response (GH maximum change from baseline < or = 0, n = 9) there were significant differences in levels of aggression as measured by the Cohen-Mansfield Agitation Inventory (CAMI) physical aggression subscale (p = .026). Patients with blunted GH response also had significantly higher levels of aggression against others on the retrospective Overt Aggression Scale (p = 0.027). CONCLUSIONS: Certain types of physically aggressive behaviors are associated with a blunted GH response to clonidine challenge. This finding is consistent with compensatory down-regulation of post-synaptic alpha(2)-adrenergic receptors in response to enhanced NE outflow in aggressive AD patients.

Adrenergic alpha-Agonists↗
PubMed2004

Atypical antipsychotics and risk of cerebrovascular accidents.

OBJECTIVE: Randomized controlled trials have suggested that at least one atypical antipsychotic may be associated with an increased risk of stroke in older people with dementia. This study examined the association between atypical antipsychotic use and stroke in the elderly. METHOD: The authors conducted a retrospective population-based cohort study of patients over the age of 66 by linking administrative health care databases. Three cohorts-users of typical antipsychotics, risperidone, and olanzapine-were identified and compared. RESULTS: Subjects treated with typical antipsychotics (N=1,015) were compared with those given risperidone (N=6,964) and olanzapine (N=3,421). Model-based estimates adjusted for covariates hypothesized to be associated with stroke risk revealed relative risk estimates of 1.1 (95% CI=0.5-2.3) for olanzapine and 1.4 (95% CI=0.7-2.8) for risperidone. CONCLUSIONS: Olanzapine and risperidone use were not associated with a statistically significant increased risk of stroke compared with typical antipsychotic use.

Aged↗
PubMed2004

The role of norepinephrine in the behavioral and psychological symptoms of dementia.

The behavioral and psychological symptoms of dementia (BPSD) are common serious problems that are a major contributor to caregiver burden. Despite their significance, the underlying neurobiology of these disturbances is still unclear. This review examines the role of norepinephrine (NE) on BPSD, including depression, aggression, agitation and psychosis. A number of lines of evidence suggest that NE dysfunction leading to BPSD may result from increased NE activity and/or hypersensitive adrenoreceptors compensating for loss of NE neurons with progression of Alzheimer's disease (AD). With greater appreciation of the underlying neurobiology of behavioral and psychological symptoms of dementia (BPSD) more effective, rational, targeted pharmacotherapy will hopefully emerge.

Animals↗
PubMed2004

Noradrenergic activity is associated with response to pindolol in aggressive Alzheimer's disease patients.

Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer's disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 +/- 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 +/- 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 microg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = -2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.

Administration, Oral↗