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Antidepressant medication and interpersonal psychotherapy (IPT) are both recommended interventions in depression treatment guidelines based on literature reviews and meta-analyses. However, ‘conventional’ meta-analyses comparing their efficacy are limited by their reliance on reported study-level information and a narrow focus on depression outcome measures assessed at treatment completion. Individual participant data (IPD) meta-analysis, considered the gold standard in evidence synthesis, can improve the quality of the analyses when compared with conventional meta-analysis.
We describe the protocol for a systematic review and IPD meta-analysis comparing the efficacy of antidepressants and IPT for adult acute-phase depression across a range of outcome measures, including depressive symptom severity as well as functioning and well-being, at both post-treatment and follow-up (PROSPERO: CRD42020219891).
We will conduct a systematic literature search in PubMed, PsycINFO, Embase and the Cochrane Library to identify randomised clinical trials comparing antidepressants and IPT in the acute-phase treatment of adults with depression. We will invite the authors of these studies to share the participant-level data of their trials. One-stage IPD meta-analyses will be conducted using mixed-effects models to assess treatment effects at post-treatment and follow-up for all outcome measures that are assessed in at least two studies.
This will be the first IPD meta-analysis examining antidepressants versus IPT efficacy. This study has the potential to enhance our knowledge of depression treatment by comparing the short- and long-term effects of two widely used interventions across a range of outcome measures using state-of-the-art statistical techniques.
Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD).
In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.
Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.
We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
Given the rather modest clinical effects of cholinesterase inhibitors, an important question is: For how long should they be prescribed? The clinical trials that supported marketing of the drugs were only 3–6 months in duration. A couple of 12-month, placebo-controlled donepezil trials showed some advantage for Mini-Mental State Examination (MMSE) scores and maintaining a level of activities of daily living (ADL) function during that interval (Mohs et al., 2001; Winblad et al., 2001). The controversial AD2000 trial in the UK tended to show MMSE and ADL efficacy over at least two years (Courtney et al., 2004), but the authors questioned whether treatment was worthwhile or cost-effective.
Background: The purpose of this study is to identify factors that predict nursing home placement among community-dwelling Alzheimer's disease (AD) patients with psychosis and/or agitation in a randomized clinical trial (ClinicalTrials.gov number, NCT00015548).
Methods: 418 participants with AD enrolled in the Clinical Antipsychotic Trial of Intervention Effectiveness – AD (CATIE-AD) trial of anti-psychotic medications and having no evidence of nursing home use at baseline were followed at 9 months post-random assignment using data provided by caregiver proxy. χ2 tests, t-tests and Cox proportional hazard modeling were used to examine the baseline correlates of nursing home use.
Results: Of outpatients with no prior nursing home use, 15% were placed in a nursing home in the 9 months following baseline, with the average time to placement being 122 days. Bivariate analyses indicate that those with prior outpatient mental health use at study entry were more likely to be admitted; so too were those with worse physical functioning – i.e. lower scores on the AD Cooperative Study Activities of Daily Living Scale (ADCS-ADL), lower utility scores on the Health Utility Index (HUI)-III, and worse cognition on the Mini-mental State Examination. Controlling for other factors, non-Hispanic white race (hazard ratio [HR] = 2.16) and prior mental health use (HR = 1.87) increased the likelihood of admission. Those with higher ADCS-ADL scores were less likely to be placed (HR = 0.97).
Conclusions: Factors leading to nursing home entry among psychotic/agitated AD patients are similar to the general population, though high incidence of nursing home entry highlights the importance of accounting for such utilization in health economic studies of AD outcomes. It also highlights the importance of using information on ADLs and other characteristics to develop profiles identifying those at greater or lesser risk of nursing home entry and, in so doing, inform population planning associated with AD and identification of those patients and caregivers who might benefit most from interventions to prevent eventual placement.
Whether we need another meta-analysis of clinical trials of antipsychotic treatment of patients with behavioral and psychological symptoms of dementia (BPSD) depends on how we define meta analysis and our expectations for the results of such an analysis.
The antidepressant literature for depression in late life tends to be interpreted as saying that certain antidepressant medications—e.g., nortriptyline, doxepin, fluoxetine—have fewer and milder side effects than others, whereas overall efficacy is equivalent (Plotkin et al., 1987; Rush, 1993; Salzman et al., 1995; Schneider, 1994). Further examination of this literature, however, suggests that both efficacy and side effect rates for any particular medication vary among trials, and often depend on the medications being compared, the use of placebe, the dose, and the design of the trial.
In this report we review selected clinical trials, and summarize and discuss a previously published meta-analysis. Treatment recommendations from the 1991 NIH Consensus Development Conference on the Diagnosis and Treatment of Depression in Late Life and from the Agency for Health Care Policy Research are discussed. Directions for fume research are suggested.
Both antidepressant medications and brief structured psychotherapies have efficacy in the acute treatment of elderly depressed outpatients with major unipolar, nondelusional depression. Effective treatment for depression involves consideration of the type and severity of illness, adequate prescribing, patient education, and regular patient monitoring for compliance, symptom change, side effects, and intercurrent medical disorders, which may complicate antidepressant therapy.
This article reviews the history of Clinical Global Impressions of Change (CGIC) instruments, their use and limitations in clinical trials of Alzheimer's disease, and the development of the National Institute on Aging's Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC). Originally, CGICs were simple and unstructured instruments that asked a clinician to rate change over the duration of a clinical trial. The method, however, failed to consistently detect treatment effects, leading to the development of more structured and subsequently validated approaches, such as the Clinician Interview-Based Impression Scale (CIBI) and the ADCS-CGIC. Both are currently used in clinical trials. The implications and importance of choosing an appropriate global rating are discussed.
Both pharmacologic and nonpharmacologic methods can be used to treat behavioral disturbances of dementia. Many drugs and drug classes have been advocated as having putative efficacy in treating nonspecific behavioral symptoms; the list includes neuroleptics, anxiolytics, antidepressants (e.g., trazodone), anticonvulsants (e.g., carbamazepine and valproic acid), lithium, β-adrenergic blockers, selegiline, and buspirone. Neuroleptics are among the most commonly prescribed psychotropic drugs for behavioral symptoms and have been described as being “modestly effective” in controlling agitation, both in patients with dementia and in elderly patients in general. To examine the relative efficacy of neuroleptics in treating behavioral disturbances of dementia, the author and colleagues performed a meta-analysis of clinical trials published in the literature from 1954 to 1989.
Personality traits in euthymic elderly subjects with and without past histories of major depressive episodes were assessed using the Structured Clinical Interview for DSM-III-R and the Social Adjustment Scale-SR. Recovered depressed subjects were characterized by significantly more personality traits from DSM-III-R Clusters B and C than controls, and they exhibited differences in social adjustment, as well. Subjects who have recovered from depressive episodes may show significant diferences in personality and social adjustment that might represent residua of past depression, a trait characteristic, or a risk factor for recurrence.
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