Biomedical subjects

Benoit H Mulsant

Publications and source records attributed to Benoit H Mulsant.

At least 73 records · Page 4Linked to original sources

PubMed2003

Occurrence and course of suicidality during short-term treatment of late-life depression.

BACKGROUND: Elderly persons (> or =65 years) have the highest rate of suicide; still, little is known about the occurrence, course, and responsivity of suicidal ideation during treatment of depression in late life and how suicidality affects treatment response. METHODS: This study was undertaken to determine (1) how suicidal ideation changes during short-term depression treatment and (2) whether treatment response differs among 3 groups of patients based on their levels of suicidality at baseline and during treatment (those with a recent suicide attempt or current suicidal ideation [high-risk group; n = 46], those with recurrent thoughts of death [moderate-risk group; n = 143], or those with no suicide attempt, suicidal ideation, or thoughts of death [low-risk group; n = 206]). This is a secondary analysis of pooled data from 3 treatment studies of late-life major depression. Participants were 395 elderly persons with a current major depressive episode, treated as inpatients or outpatients under protocolized conditions with paroxetine hydrochloride or nortriptyline hydrochloride, with or without interpersonal psychotherapy. Changes in suicidal ideation over time, rate of responses, and time to response in each group were compared. RESULTS: Suicidal ideation decreased rapidly early in the course of treatment, with more gradual change thereafter. At the beginning of treatment, 77.5% of the patients reported suicidal ideation, thoughts of death, or feelings that life is empty. After 12 weeks of treatment, suicidal ideation had resolved in all treated patients; 4.6% still reported thoughts of death. However, 6-week (P =.001) and 12-week (P =.02) rates of response were significantly lower in high-risk patients than in low- and moderate-risk patients. High- and moderate-risk patients needed a significantly (P<.001) longer time to respond than low-risk patients (median time to response, 6 and 5 vs 3 weeks). CONCLUSIONS: While suicidal ideation resolves rapidly, the resolution of thoughts about death is more gradual. Suicidal elderly persons with depression require special attention during depression treatment because they have a lower response rate and need a longer time to respond.

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PubMed2003

Depression and Bipolar Support Alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life.

OBJECTIVES: To review progress made during the past decade in late-life mood disorders and to identify areas of unmet need in health care delivery and research. PARTICIPANTS: The Consensus Development Panel consisted of experts in late-life mood disorders, geriatrics, primary care, mental health and aging policy research, and advocacy. EVIDENCE: (1) Literature reviews addressing risk factors, prevention, diagnosis, treatment, and delivery of services and (2) opinions and experiences of primary care and mental health care providers, policy analysts, and advocates. CONSENSUS PROCESS: The Consensus Development Panel listened to presentations and participated in discussions. Workgroups considered the evidence and prepared preliminary statements. Workgroup leaders presented drafts for discussion by the Consensus Development Panel. The final document was reviewed and edited to incorporate input from the entire Consensus Development Panel. CONCLUSIONS: Despite the availability of safe and efficacious treatments, mood disorders remain a significant health care issue for the elderly and are associated with disability, functional decline, diminished quality of life, mortality from comorbid medical conditions or suicide, demands on caregivers, and increased service utilization. Discriminatory coverage and reimbursement policies for mental health care are a challenge for the elderly, especially those with modest incomes, and for clinicians. Minorities are particularly underserved. Access to mental health care services for most elderly individuals is inadequate, and coordination of services is lacking. There is an immediate need for collaboration among patients, families, researchers, clinicians, governmental agencies, and third-party payers to improve diagnosis, treatment, and delivery of services for elderly persons with mood disorders.

Age Factors↗

PubMed2003

APOE is associated with age-of-onset, but not cognitive functioning, in late-life depression.

OBJECTIVE: There is a recognized but poorly understood relationship between late-life depression (LLD) and progressive dementia. Both cognitive impairment co-occurring with LLD and a late age-of-onset of first lifetime depressive episode appear to be associated with subsequent progressive dementia. A history of major depression, especially when the first onset occurs in late-life, has been identified as a risk factor for Alzheimer's disease (AD). The major genetic risk factor for sporadic AD is carrying one or more apolipoprotein E4 (APOE4) alleles. We hypothesized that the association between LLD and dementia risk would be mediated by APOE4, specifically that APOE4 allele frequency would be associated with cognitive impairment and later age-of-depression-onset. We also predicted that APOE4 allele frequency would be increased among subjects with LLD. METHODS: We compared the distribution of APOE2, APOE3, and APOE4 alleles in groups of LLD (n=160), AD (n=568) and elderly control (EC; n=156) subjects. RESULTS: The allele distribution of the cognitively impaired LLD subgroup was not different from either the cognitively normal subgroup or the EC group but was different from the AD group. However, mean age-of-onset of depression in APOE4 carriers (51.4+/-20.7) was significantly lower than non-carriers (58.8+/-16.8). The allele distribution in LLD overall was significantly different from the AD but not the EC group. CONCLUSIONS: The finding that neither LLD, accompanying cognitive impairment, nor late age-of-onset was associated with an increased APOE4 allele frequency suggests that LLD acts as a risk factor for developing AD as well as non-AD dementia through mechanisms independent of APOE4. The unexpected finding that age-of-onset of LLD was significantly reduced in APOE4 carriers is similar to the association between APOE4 and age-of-onset in AD. Replication of the association of APOE4 with earlier age-of-depression-onset is indicated.

Age of Onset↗

PubMed2003

Good treatment outcomes in late-life depression with comorbid anxiety.

BACKGROUND: Late-life depression studies have found that comorbid anxiety, as a symptom or comorbid disorder, is associated with poorer treatment response and increased likelihood of dropout. This study evaluated the impact of comorbid anxiety on response, dropouts, and side effects, in elderly subjects treated for depression. METHODS: We analyzed data from a 12-week trial comparing nortriptyline and paroxetine in 116 patients aged 60 and older with depression. Subjects classified as having anxious depression were compared to those with nonanxious depression in terms of treatment response rate, time to response, dropout rate, and early side effects. The analysis was replicated with another study, in which 125 subjects aged 69 and older were treated openly with paroxetine and interpersonal psychotherapy. RESULTS: Anxious and nonanxious groups did not differ in terms of response rates, time to response, dropout rates, or time to dropout. Side effects declined more quickly and more significantly in the anxious group than in the nonanxious group. LIMITATIONS: Subjects were treated in a specialty mental health setting, and the findings may not apply in other settings. CONCLUSIONS: We found no association between comorbid anxiety and a poorer prognosis during acute treatment of late-life depression. For elderly patients with anxious depression, standardized treatment in the mental health sector is associated with a good response.

Age of Onset↗

PubMed2003

Treatment considerations for anxiety in the elderly.

Anxiety is common in the elderly and can present as a primary anxiety disorder or as a symptom of another disorder. Generalized anxiety disorder, in particular, is a common syndrome in late life. Anxiety symptoms are also common features of late-life depression and dementia. Treatment of anxiety in elderly persons has typically involved the use of benzodiazepines, which are often effective but problematic because they are associated with increased risk of cognitive impairment, falls, and fractures. Based on their safety and efficacy, antidepressants, particularly serotonergic medications, are considered first-line treatment for most anxiety disorders as well as anxiety symptoms of major depressive disorder. Psychotherapy, particularly cognitive-behavioral therapy, may be effective in these disorders as well; research is underway to adapt this therapy to the needs of elderly persons. Anxiety symptoms in dementia are poorly understood but may respond to atypical antipsychotics, serotonergic antidepressants, or mood stabilizers. Overall, the research in late-life anxiety has not caught up to the literature in late-life depression and, for the most part, treatment recommendations must be extrapolated from studies in young adults.

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PubMed2003

Achieving long-term optimal outcomes in geriatric depression and anxiety.

Depression and anxiety disorders are very common in the elderly. Data accumulated over the past 2 decades have shown that most older patients can tolerate and respond to acute treatment with serotonergic antidepressants, other psychotropic agents, or manual-based psychotherapy. However, outcomes under usual-care conditions remain poor. This review proposes that clinicians may significantly improve the long-term outcomes of their older patients with depression and anxiety by focusing on four key factors: (1) identification and treatment of comorbid conditions; (2) full remission of acute symptoms; (3) education of patients, families, and professional colleagues about the need for long-term treatment; and (4) prevention and management of medication side-effects.

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PubMed2003

Apathy and executive function in depressed elderly.

Apathy and executive cognitive dysfunction (ECD) are important though conceptually different aspects of late-life depression. The primary objective of this study was to evaluate the relationship of apathy to ECD. The authors also evaluated the relationship of apathy and ECD to global cognitive impairment and word generation. Fifty-two elderly subjects with major depression and MMSE scores of 15 or greater were evaluated with apathy-related items from the Hamilton rating scale for depression (ApHRSD), the Executive Interview (EXIT), the Dementia Rating Scale (DRS), and the Controlled Oral Word Association test (COWA). ApHRSD scores were not significantly correlated with any of these variables. EXIT scores were correlated significantly with DRS and COWA. The results suggest that apathy and ECD may be independent of each other in some samples of elderly with late-life depression. Correlations may have been reduced by low variance for the variables of interest and by psychometric limitations of the ApHRSD.

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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.

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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.

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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

Assessment of late life depression.

This article focuses on diagnostic and nosologic challenges intrinsic to geriatric depression, including characteristics interfering with symptom and syndrome ascertainment, the impact of medical and cognitive disorders, the usefulness of screening instruments, and barriers imposed by treatment settings. The article also identifies gaps in existing knowledge and outlines a research agenda. Nosologic characterization of depressives syndromes contributed by specific medical disorders may lead to effective strategies for prevention and treatment of depression. Studies need to examine whether treatment of depression can improve the outcome of medical illnesses requiring active patient involvement in treatment. Considering disability a distinct aspect of health status may add an important dimension to the assessment of depression and result in complementary interventions aimed at depression and disability concurrently. The provisional criteria for depression of Alzheimer's disease, if validated, may facilitate treatment research. Studies need to characterize cognitive dysfunctions associated with later development of dementia or poor treatment response in patients with depression. Care managers working together with primary care physicians can improve the recognition and treatment of depressed elderly patients by obtaining the training in using validated instruments and treatment algorithms.

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PubMed2002

Post stroke depression: epidemiology, pathophysiology, and biological treatment.

Depression is a common occurrence after stroke and is associated with excess disability, cognitive impairment, and mortality. The authors undertook a systematic review of the English language literature to review several aspects of this illness, including the prevalence of this disorder, the debate on its etiology, and the current understanding of the biological treatment of poststroke depression. Methodological problems encountered in the study of poststroke depression are highlighted throughout the manuscript. The authors conclude that the available evidence supports poststroke depression as being multifactorial in origin and consistent with the biopsychosocial model of mental illness.

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PubMed2002

Rates and predictors of mortality in an aging, rural, community-based cohort: the role of depression.

CONTEXT: Depression, functional disability, cognitive impairment, and self-rated health all predict mortality in the elderly population. There is no consensus on their relative contributions when examined together. OBJECTIVES: To measure rates and identify predictors of mortality in an aging community-based cohort. DESIGN: Ten-year prospective epidemiological study. Predictor variables examined in Cox proportional hazards models were self-rated health, ability to perform instrumental activities of daily living (IADLs), depressive symptoms, and cognitive functioning, controlling for age, sex, education, and number of prescription drugs. SETTING: A largely blue-collar rural community in southwestern Pennsylvania. PARTICIPANTS: A population-based cohort of 1064 adults, 67 years or older at the beginning of follow-up. MAIN OUTCOME MEASURES: Mortality at 3, 5, and 10 years (133, 218, and 482 deaths, respectively). RESULTS: Mortality rates were similar to those of the 1990 US population. Older age, male sex, IADL disability, and number of prescription drugs measured at baseline were significant predictors of mortality at all 3 follow-up end points. Depression at baseline predicted earlier (3- and 5-year) mortality but not later (10-year) mortality. The interaction between self-rated health and depression independently and strongly predicted mortality at all end points. Cognitive functioning predicted mortality only when IADL disability was excluded from the model. CONCLUSIONS: Age, sex, depression, and functional disability are strong and consistent independent predictors of mortality in older adults in the community, in addition to objective medical burden (prescription drugs). Depression alone predicts mortality in the shorter rather than longer term, but in combination with poor self-rating of health, it strongly predicts mortality at all end points.

Activities of Daily Living↗

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.

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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↗