National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology.

The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.

Impact of maintenance ECT on concentration and memory.

INTRODUCTION: With the increased administration of outpatient electroconvulsive therapy (ECT), it is important to develop methods for monitoring patients for adverse effects of treatment. This pilot study was designed to evaluate the utility of using telephone assessments to determine whether patents receiving maintenance ECT (MECT) experience cognitive deficits related to individual treatments. METHOD: Patients were recruited from an existing population of outpatients receiving MECT. The consenting patients were called on three occasions and given a battery of telephone cognitive assessments including Orientation-Memory-Concentration, Buschke Selective Reminding, Verbal Fluency, "World" Backwards, Serial Sevens, and Wechsler Logical Memory. The occasions for the telephone interviews were the day before ECT, the day after a treatment, and a week later. RESULTS: Sixteen patients completed the study. The correlation between baseline and time 3 ranged from 1.00 for spelling "world" backward to 0.509 for Verbal Fluency Category, indicating considerable variability in test-retest reliability. One test, Verbal Fluency Category, showed group level effects, with decrements in performance the day after a treatment. One of the 16 patients showed global cognitive deficits the day after a treatment. DISCUSSION: The pilot results suggest that telephone assessment may be a useful approach for monitoring patients receiving outpatient ECT. Monitoring may serve to guide clinicians in advising individuals and their caregivers about the return to activities after an individual treatment. Overall these findings support the tolerability of MECT.

Chronic depression in the elderly: approaches for prevention.

Depression in old age frequently follows a chronic and/or relapsing course, related to medical comorbidity, cognitive impairment and depletion of psychosocial resources. As endorsed by the US National Institutes of Health (NIH) Consensus Development Conference on the Diagnosis and Treatment of Late Life Depression, a major goal of treatment is to prevent relapse, recurrence and chronicity. We believe that most, if not all, elderly patients with major depressive episodes are appropriate candidates for maintenance therapy, because of the vulnerability to relapse and recurrence and because of the favourable benefit to risk ratio of available treatments. Antidepressant pharmacotherapy is the mainstay of this therapeutic goal, but psychosocial approaches (especially interpersonal psychotherapy) have also been shown to contribute significantly to prevention of a chronic depressive illness and to prevention of the disability that attends depression. Studies published to date have established the long term or maintenance efficacy of the tricyclic antidepressant nortriptyline. Current, ongoing studies are addressing the maintenance efficacy of paroxetine and citalopram to prolong recovery in depression associated with old age. These studies are focusing particularly on patients aged 70 years and above, who are at high risk of recurrence, and on patients in primary care settings, where under-recognition and under-treatment of depression in the elderly have been costly from a public health perspective in terms of increased medical utilisation, burden to patients and families, and high rates of suicide. Depression in old age is a major contributor to the global burden of illness-related disability, but it is extremely treatable if appropriate pharmacotherapy is prescribed and accepted by patients and their caregivers.

Pharmacological treatment of depression in older primary care patients: the PROSPECT algorithm.

PROSPECT (Prevention of Suicide in Primary care Elderly-Collaborative Trial) is testing whether a trained clinician (the 'health specialist') can work in close collaboration with a primary care physician to implement a comprehensive depression management program and improve outcomes in older depressed patients. An algorithm guiding the selection and use of antidepressant medications has been developed to assist PROSPECT health specialists. This algorithm is presented and the rationale underlying the proposed treatment sequence is discussed. The PROSPECT algorithm builds upon existing guidelines after updating them and adapting them to the special circumstances of older primary care patients. Special attention has been paid to the tolerability and the target doses of the recommended antidepressant agents and to the duration of antidepressant trials. Patients who are unable to tolerate or do not respond to an antidepressant can be switched to another agent or be treated with interpersonal psychotherapy. Agents that produce only a partial response can be combined with other antidepressants or with interpersonal psychotherapy. Treatments for which empirical evidence exists are favored. However, treatments that are often poorly tolerated by elderly patients are given lower priority than treatments more likely to be tolerated. Similarly, trials that are simpler to implement in primary care are favored.

Survival of hospitalized elderly patients with delirium: a prospective study.

The authors tested the relationship between clinically diagnosed delirium during hospitalization and increased mortality after accounting for pre-hospital measures of global cognition, physical functioning, and medical comorbidity. Patients (N=102), 53 of which were hospitalized during the course of a year, received the Mini-Mental State Exam, Physical Self-Maintenance Scale, Cumulative Illness Rating Scale, and 15-item Geriatric Depression Scale. Mortality rates were determined at discharge and after 3 years. Patients who developed delirium did not differ on pre-hospitalization levels of depression, global cognitive performance, physical functioning, or medical comorbidity. Three-year mortality in the hospitalized subjects was 75% for delirium patients vs. 51% for control patients (risk ratio=2.24). Delirium occurring during hospitalization places elderly subjects at long-term risk of mortality. This effect is not accounted for by earlier measures of cognitive, functional, or health status.

Validating the diagnosis of delirium and evaluating its association with deterioration over a one-year period.

The authors probed the associations between clinical diagnoses and independent research measures of cognitive, behavioral, and electroencephalographic (EEG) changes in hospitalized older patients and investigated the contribution of medical illness to deterioration. Patients (N=96; 47 of whom were hospitalized during the course of 1 year; 12 diagnosed with delirium) received tests of cognitive and physical functioning and the Cumulative Illness Rating Scale, specific neuropsychological tests, and a two-channel EEG. Delirium was associated with independent measures of cognitive decline and EEG slowing. Hospitalization was associated with deterioration in functional status during the year, whether or not patients showed delirium. Results suggest that medical illness leading to hospitalization can contribute significantly to deterioration in self-care, and, when it is associated with delirium, to deterioration in cognitive performance and cerebral activity over a period of 1 year.

Pharmacotherapy of depression in older patients: a summary of the expert consensus guidelines.

Depression in older adults increases disability, medical morbidity, mortality, suicide risk, and healthcare utilization. Most studies of antidepressants are conducted in younger adults, and clinicians often have to extrapolate from findings in populations that do not present the same problems as older patients. Older patients often have serious coexisting medical conditions that may contribute to or complicate treatment of depression; they tend to take multiple medications, some of which may contribute to depression or interact with antidepressants; and they metabolize medications slowly and are more sensitive to side effects than younger patients. To address clinical questions not definitively answered in the research literature, the authors surveyed 50 experts on the pharmacotherapy of depressive disorders in older patients. The survey contained 64 questions with 857 options: 618 of the options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions; for the other 239 options, the experts were asked to write in answers or check a box. The experts reached consensus on 89% of the options rated on the 9-point scale. Categorical rankings (first line/preferred, second line/alternate, third line/usually inappropriate) were assigned to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for common and important clinical scenarios. The authors summarize the expert consensus methodology and the experts' recommendations and discuss how they relate to research findings. The experts recommend including both antidepressant medication and psychotherapy in treatment plans for nonpsychotic unipolar major depressive disorder of any severity, as well as for dysthymic disorder or persistent minor depressive disorder. They would also consider using either medication or psychotherapy alone for milder depression. For unipolar psychotic major depression, the treatment of choice is an antidepressant plus one of the newer atypical antipsychotics, with electroconvulsive therapy another first-line option. If the patient has a comorbid medical condition that is contributing to the depression, the experts recommend treating both the depression and the medical condition from the outset. The SSRIs were the top-rated antidepressants for all types of depression, with highest ratings for efficacy and tolerability given to citalopram and sertraline. Paroxetine was another first-line option, and fluoxetine was rated high second line. The preferred psychotherapy techniques for treating depression in older patients are cognitive-behavioral therapy, supportive psychotherapy, problem-solving psychotherapy, and interpersonal psychotherapy. The experts also recommended use of psychosocial interventions (e.g., psychoeducation, family counseling, visiting nurse services) in addition to pharmacotherapy and psychotherapy. Within limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction concerning common clinical dilemmas in older patients. They cannot address the complexities of each individual patient's care and can be most helpful in the hands of experienced clinicians.

The expert consensus guideline series. Pharmacotherapy of depressive disorders in older patients.

OBJECTIVES: Depression in older patients contributes to personal suffering and family disruption and increases disability, medical morbidity, mortality, suicide risk, and healthcare utilization. The majority of clinical trials of antidepressant treatments are conducted in younger patients. For this reason, clinicians often have to extrapolate from studies in populations that do not present the same problems as older patients. For example, older patients often have serious coexisting medical conditions that may contribute to the depression and complicate the choice of treatment. Older patients as a rule need to be on many medications, some of which may contribute to depression and/or interact with antidepressants. Finally, older adults metabolize medications slowly and are more sensitive to side effects than younger patients. Because of these complexities, we conducted a consensus survey of expert opinion on the pharmacotherapy of depressive disorders in older patients to address clinical questions not definitively answered in the research literature. METHOD: After reviewing the literature and convening a work group of experts, we prepared a written survey with 64 questions that asked about 857 options. 618 of the options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions. For the other options, the experts were asked to write in answers (e.g., average doses) or to check a box to indicate their preferred answer. We sent the survey to 50 national experts on geriatric depression, all of whom completed it. Consensus on each option was defined as a nonrandom distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. RESULTS: The expert panel reached consensus on 89% of the options rated on the 9-point scale. The experts stress the importance of identifying coexisting medical conditions that may be contributing to the depression or complicate treatment. For unipolar nonpsychotic major depression, the preferred strategy is an antidepressant (selective serotonin reuptake inhibitor [SSRI] or venlafaxine XR preferred) plus psychotherapy. For unipolar psychotic major depression, the treatment of choice is an antidepressant (SSRI or venlafaxine XR) plus one of the newer atypical antipsychotics. Electroconvulsive therapy is also first line. For dysthymic disorder or persistent milder depression, the experts recommend combining an antidepressant (SSRIs preferred) and psychotherapy. If the patient has a comorbid medical condition (e.g., hypothyroidism) that is contributing to the depression, the experts recommend treating both the depression and the medical condition from the outset. The SSRIs were the top-rated antidepressants for all types of depression. Among them, the experts gave the highest ratings for efficacy and tolerability to citalopram and sertraline. Paroxetine was another first-line option, and fluoxetine was rated high second line. The preferred psychotherapy techniques for treating depression in older patients are cognitive-behavioral therapy, supportive psychotherapy, problem-solving psychotherapy, and interpersonal psychotherapy. The experts also give strong support to including appropriate psychosocial interventions (e.g., psychoeducation, family counseling, visiting nurse services) in the treatment program. The majority of experts would continue treatment with antidepressant medication for at least 1 year if a patient has had a single episode of severe unipolar major depression, for 1-3 years for a patient who has had 2 such episodes, and for longer than 3 years if there is a history of 3 or more episodes. CONCLUSIONS: The experts reached a high level of consensus on the appropriateness of including both antidepressant medication, specifically SSRIs, and nonpharmacological modalities in treatment plans for severe depression. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction for addressing common clinical dilemmas in older individuals. They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions. Nonetheless, the guidelines cannot address the complexities involved in the care of each individual patient and can be most helpful in the hands of experienced clinicians.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.

OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities. DESIGN: Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial. SETTING: Twenty-seven nursing homes across the United States. PARTICIPANTS: Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7. MEASUREMENTS: The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs). RESULTS: Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed. CONCLUSION: Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.

Clinical laboratory measures in relation to depression, disability, and cognitive impairment in elderly patients.

To characterize the dimensions of physiological abnormalities that commonly occur in older individuals in a residential care setting and to evaluate their association with clinical measures, the authors conducted an exploratory factor analysis on clinical laboratory measures from a sample of 231 elderly residents (mean age: 86) living in a nursing home and congregate apartment facility. An eight-factor solution accounted for 70.2% of the variance in these measures; factors identified were interpreted as indices of renal function, protein/calorie/nutritional status, serum electrolytes/osmolarity, liver function, acute-phase processes, plasma lipids, acid/base status, and renal-tubular function. The nutritional factor was significantly associated with measures of disability and the presence of depression. The acute-phase processes factor was significantly associated with cognitive impairment.

Effects of alcohol consumption on the treatment of depression among elderly patients.

The authors examined the effects of alcohol use on the short-term and 3-4-month treatment outcomes of patients with late-life depression. Patients (N=2,666) were assessed for symptoms of depression, alcohol use, and disability during an initial inpatient hospitalization and then 3-4 months postdischarge. Contrary to our hypothesis that alcohol consumption imparted a significant additive detriment to treatment outcome in patients already suffering from major depression, the results suggest that treatment was effective even in those with concomitant use of alcohol. Moreover, there appeared to be an added benefit when even modest alcohol consumption was decreased among elderly patients suffering from depression.

Change in disability follows inpatient treatment for late life depression.

OBJECTIVES: The objective of this study was to examine the relationship between functional disability and improvement in late life depression after acute inpatient treatment. DESIGN: The study was a longitudinal assessment of depression and disability. Patients were assessed during an initial inpatient hospitalization and then 3 months postdischarge. SETTING: All patients were evaluated initially after admission to one of 71 inpatient psychiatric treatment facilities. PARTICIPANTS: The study comprised of 2572 patients older than age 60 who were relatively cognitively intact and experiencing significant depressive symptoms. MEASUREMENTS: Depressive symptoms were measured using the Geriatric Depression Scale. Disability was measured using the Instrumental Activities of Daily Living Scale and the Medical Outcomes SF-36. RESULTS: Depressive symptoms improved in the majority of patients. Moreover, improvement in depressive symptomatology was significantly related to improvement in instrumental activities of daily living (IADLs) and to health-related quality of life as measured by the SF-36. This relationship was strongest among those who initially presented with some disability in IADLs. CONCLUSIONS: This work underscores further the disabling nature of depression. Moreover, findings from this study suggest that treatment focused on depression can lead to significant improvements in both depressive symptoms and functional abilities. However, the results also suggest that the relationship between depression and disability is complex and that the effect of treating depression is not the only factor in the reversal of disability.

Heuristic comparison of sertraline with nortriptyline for the treatment of depression in frail elderly patients.

Studies have demonstrated that the selective serotonin reuptake inhibitor antidepressants have similar efficacy to other agents, such as tricyclic antidepressants. However, data are limited for direct comparisons with other antidepressants. The authors conducted a contemporaneous comparison of nursing home residents treated with open-label sertraline in doses up to 100 mg/day with nursing home residents treated in a double-blind randomized study of low vs. regular doses of nortriptyline. There were 97 patients enrolled in the study (28 treated with sertraline), with an average treatment duration of 55 days. There were no differences in the tolerability of sertraline vs. nortriptyline. However, in this group of frail older adults, sertraline was not as effective as nortriptyline for the treatment of depression.

Drug treatment of depression in frail elderly nursing home residents.

The authors conducted a randomized, double-blind, 10-week clinical trial of two doses of nortriptyline in eight nursing homes. Sixty-nine patients, average age 79.5 years, were randomized to receive regular doses (60 mg-80 mg/day) vs. low doses (10 mg-13 mg/day) of nortriptyline. Among the more cognitively intact patients, there was a significant quadratic relationship defining a "therapeutic window" for nortriptyline plasma levels and clinical improvement. There were also significant differences in plasma level-response relationships between depressed patients who were cognitively impaired and those who were more cognitively intact. Depression remains a syndrome that responds to specific treatment, even in frail nursing home patients, and those depressions that occur in patients with significant dementia may represent a treatment-relevant condition with a different plasma level-response relationship than in depression alone.