Jacqueline A. Stack

Maintenance Treatment of Depression in Old Age: A Randomized, Double-blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Donepezil Combined With Antidepressant Pharmacotherapy

CONTEXT Cognitive impairment in late-life depression is a core feature of the illness. OBJECTIVE To test whether donepezil hydrochloride and antidepressant therapy is superior to placebo and antidepressant therapy in improving cognitive performance and instrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment. DESIGN Randomized, double-blind, placebo-controlled maintenance trial. SETTING University clinic. PARTICIPANTS One hundred thirty older adults aged 65 years and older with recently remitted major depression. INTERVENTIONS Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo. MAIN OUTCOME MEASURES Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression. RESULTS Donepezil and antidepressant therapy temporarily improved global cognition (treatment × time interaction, F₂,₂₁₆ = 3.78; P = .03), but effect sizes were small (Cohen d = 0.27, group difference at 1 year). A marginal benefit to cognitive instrumental activities of daily living was also observed (treatment × time interaction, F₂,₁₃₇ = 2.94; P = .06). The donepezil group was more likely than the placebo group to experience recurrent major depression (35% [95% confidence interval {CI}, 24%-46%] vs 19% [95% CI, 9%-29%], respectively; log-rank χ² = 3.97; P = .05; hazard ratio = 2.09 [95% CI, 1.00-4.41]). Post hoc subgroup analyses showed that of 57 participants with mild cognitive impairment, 3 of 30 participants (10% [95% CI, 0%-21%]) receiving donepezil and 9 of 27 participants (33% [95% CI, 16%-51%]) receiving placebo had a conversion to dementia over 2 years (Fisher exact test, P = .05). The mild cognitive impairment subgroup had recurrence rates of major depression of 44% with donepezil vs 12% with placebo (likelihood ratio = 4.91; P = .03). The subgroup with normal cognition (n = 73) showed no benefit with donepezil and no increase in recurrence of major depression. CONCLUSIONS Whether a cholinesterase inhibitor should be used as augmentation in the maintenance treatment of late-life depression depends on a careful weighing of risks and benefits in those with mild cognitive impairment. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00177671.

Inhibition of Caffeine Metabolism by Estrogen Replacement Therapy in Postmenopausal Women

This study was conducted to investigate the effect of therapeutic estrogen on cytochrome P450 1A2‐mediated metabolism in postmenopausal women using caffeine as a model substrate. Twelve healthy postmenopausal women underwent estrogen replacement therapy in the form of estradiol (Estrace). Estradiol was initiated at a dose of 0.5 mg a day and titrated to achieve a steady‐state plasma concentration of 50 to 150 pg/ml. Caffeine metabolic ratios (CMR; paraxanthine/ caffeine) were assessed both before and after 8 weeks of estrogen replacement. For the 12 subjects, there was a mean reduction in CMR of −29.2 25.0 (p = 0.0019). Consistent with previous results found in younger women, these results indicate that exogenous estrogen in older women may inhibit CYP1A2‐mediated caffeine metabolism.

Two-Year Follow-Up of Elderly Patients With Mixed Depression and Dementia: Clinical and Electroencephalographic Sleep Findings

In a two‐year follow‐up of 16 patients with mixed symptoms of depression and dementia, eight showed clinical improvement and eight showed deterioration. Improvement at two‐year follow‐up was associated with several baseline measures: a Folstein Mini‐Mental State score of 21 or greater, a Hamilton Depression score of 21 or greater, and a sleep efficiency of less than 75%. These findings suggest that in the elderly with mixed symptoms of depression and dementia, a more favorable outcome is associated with initially greater depressive symptomatology, higher cognitive function, and moderate sleep continuity disturbance (“early morning awakening”).

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

BACKGROUND Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. METHODS We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. FINDINGS From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. INTERPRETATION In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. FUNDING National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Body pain and treatment response in late-life depression.

OBJECTIVE The authors investigated the influence of body pain on 1) time to treatment response and 2) suicidal ideation, in late-life depression. They hypothesized that higher levels of body pain would predict a longer time to and lower likelihood of response, and increased levels of suicidal ideation. METHODS Subjects (N=187) were older adult outpatients (age > or =69 years), with current episodes of major depression, who were openly treated with paroxetine up to 40 mg daily and weekly interpersonal psychotherapy. Response was defined as 3 consecutive weeks of Hamilton Rating Scale for Depression at < or =10. Body pain was measured with the Bodily Pain Index of the SF-36 quality-of-life assessment. Authors used survival-analysis models on the responder sample to test the effect of body pain on response, after controlling for severity of depression. RESULTS Overall response rate was 75.4%. Nonresponders reported more severe pain at baseline. After covarying for severity of baseline depression, no effect was found for physical pain on time-to-response or degree of suicidality. Bodily pain remained stable during acute treatment for responders, independent of depression response to combination psychotherapy and antidepressant treatment. CONCLUSIONS Older adult patients with higher levels of physical pain can still respond to antidepressant treatment; however, reported bodily pain may be associated with a more difficult-to-treat depression.

Longitudinal Analysis of Nortriptyline Side Effects in Elderly Depressed Patients

Forty-five depressed elderly patients were closely monitored in a research setting during treatment with nortriptyline and interpersonal psychotherapy for 7 consecutive months of acute and continuation treatment. Overall, nortriptyline was efficacious and well tolerated in this group. The frequency of somatic complaints measured by the Rating Scale for Side Effects declined by 50% during the acute phase of treatment, suggesting that many somatic complaints that may be attributed to side effects of nortriptyline are actually somatic symptoms of depression. The authors discuss the implications of these findings and offer practical advice for the treating clinician. (J Geriatr Psychiatry Neurol 1991;4:226-230).

Recruitment Methods for Intervention Research in Bereavement-Related Depression: Five Years' Experience

The authors compared various strategies for recruiting elderly subjects with bereavement-related depression into a randomized clinical trial. Over 5 years, they empaneled 65 patients from a total of 441 subjects screened (14.7%). Response to media advertisements was the single most effective strategy (54% of subjects). Another effective, but labor-intensive, strategy was using letters to bereaved spouses found through newspaper obituaries (14%); another 14% were referred by friends who had seen study advertisements. Information letters to healthcare providers yielded no study participants. Pathways to study participation did not differ as a function of race or gender and did not influence study retention or remission rates. Our experience suggests that successful intake depends on a personal mode of recruitment.

Treating Depression to Remission in Older Adults: A Controlled Evaluation of Combined Escitalopram with Interpersonal Psychotherapy versus Escitalopram with Depression Care Management

More than half of the older adults respond only partially to first‐line antidepressant pharmacotherapy. Our objective was to test the hypothesis that a depression‐specific psychotherapy, Interpersonal Psychotherapy (IPT), when used adjunctively with escitalopram, would lead to a higher rate of remission and faster resolution of symptoms in partial responders than escitalopram with depression care management (DCM).

Accelerating symptom-reduction in late-life depression: a double-blind, randomized, placebo-controlled trial of sleep deprivation.

OBJECTIVE Authors tested the hypothesis that one night of total sleep deprivation (TSD) would accelerate antidepressant response to paroxetine, as compared with TSD+placebo (PBO) and paroxetine-alone, in late-life major depression. METHODS Eighty elderly outpatients with current episodes of non-psychotic, non-bipolar major depression were randomly assigned to one of three treatment conditions: TSD+paroxetine (N = 27), TSD + PBO (N = 27), and paroxetine-only (N = 26). Primary outcome was percentage of subjects in each condition who demonstrated early response (Hamilton Rating Scale for Depression scores [Ham-D: 17-item] of < or = 10) or remission (score of < or = 7) on Day 14. RESULTS Response rates after 14 days were 22% in subjects randomly assigned to the TSD + paroxetine condition, 41% in TSD + PBO, and 46% in paroxetine alone. Remission rates after 14 days were 11% in TSD+paroxetine, 22% in TSD + PBO, and 38% in paroxetine. After adjusting for baseline depression severity, there were no statistically significant differences in response or remission rates. CONCLUSION Contrary to the study hypothesis, one night of total sleep deprivation did not accelerate onset of antidepressant response to paroxetine pharmacotherapy of late-life depression. The data suggest, rather, that the two interventions might have counteracted each other.

A comparison of the frequencies of risk factors for depression in older black and white participants in a study of indicated prevention

BACKGROUND To compare the frequencies of risk factors, we describe risks for depression as a function of race among consecutively admitted participants in a randomized clinical trial of indicated depression prevention in later life. METHODS Seventy-two black and 143 white participants were screened for risk factors for depression. RESULTS Black participants were more likely to have fewer years of education and lower household income. They were more likely to be obese, live alone, experience functional disability, have a history of alcohol and drug abuse, and have lower scores on the Mini-mental State Examination and the Executive Interview (EXIT). White participants were not found to have greater prevalence or higher mean score on any risk factor. On average, black participants experienced approximately one more risk factor than white participants (t(213) = 3.32, p = 0.0011). CONCLUSIONS In our sample, black participants had higher frequencies of eight risk factors for depression and a greater mean number of risk factors compared to white participants.