Sati Mazumdar

Allelic Variation in the Serotonin Transporter Promoter Affects Onset of Paroxetine Treatment Response in Late-Life Depression

The relationship of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) to antidepressant response was examined in 95 elderly patients receiving a protocolized treatment for depression with paroxetine or nortriptyline. Patients were treated for up to 12 weeks and assessed weekly with clinical ratings and measurements of plasma drug concentrations. Twenty-one of the paroxetine-treated subjects were found to have the ll genotype and 30 had at least one s allele. There were no baseline differences between these groups in pretreatment Hamilton Rating Scale for Depression (HRSD) scores or anxiety symptoms. During acute treatment with paroxetine, mean reductions from baseline in HRSD were significantly more rapid for patients with the ll genotype than for those possessing an s allele, despite equivalent paroxetine concentrations. Onset of response to nortriptyline was not affected. Allelic variation of 5-HTTLPR may contribute to the variable initial response of patients treated with a selective serotonin reuptake inhibitor.

Efficacy of Brief Behavioral Treatment for Chronic Insomnia in Older Adults

BACKGROUND Chronic insomnia is a common health problem with substantial consequences in older adults. Cognitive behavioral treatments are efficacious but not widely available. The aim of this study was to test the efficacy of brief behavioral treatment for insomnia (BBTI) vs an information control (IC) condition. METHODS A total of 79 older adults (mean age, 71.7 years; 54 women [70%]) with chronic insomnia and common comorbidities were recruited from the community and 1 primary care clinic. Participants were randomly assigned to either BBTI, consisting of individualized behavioral instructions delivered in 2 intervention sessions and 2 telephone calls, or IC, consisting of printed educational material. Both interventions were delivered by a nurse clinician. The primary outcome was categorically defined treatment response at 4 weeks, based on sleep questionnaires and diaries. Secondary outcomes included self-report symptom and health measures, sleep diaries, actigraphy, and polysomnography. RESULTS Categorically defined response (67% [n = 26] vs 25% [n = 10]; χ(2) = 13.8) (P < .001) and the proportion of participants without insomnia (55% [n = 21] vs 13% [n = 5]; χ(2) = 15.5) (P < .001) were significantly higher for BBTI than for IC. The number needed to treat was 2.4 for each outcome. No differential effects were found for subgroups according to hypnotic or antidepressant use, sleep apnea, or recruitment source. The BBTI produced significantly better outcomes in self-reported sleep and health (group × time interaction, F(5,73) = 5.99, P < .001), sleep diary (F(8,70) = 4.32, P < .001), and actigraphy (F(4,74) = 17.72, P < .001), but not polysomnography. Improvements were maintained at 6 months. CONCLUSION We found that BBTI is a simple, efficacious, and durable intervention for chronic insomnia in older adults that has potential for dissemination across medical settings. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00177203.

Serotonin 1A receptor binding and treatment response in late-life depression.

Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT1A) receptor as a regulator of treatment response, particularly the 5-HT1A autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT1A receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4±5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0±6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP=2.31±0.90) relative to control (BP=3.69±1.56) subjects (p=0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r=0.60, p=0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r=0.52, p=0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT1A autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Age-associated alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.

A Twelve-Week, Double-Blind, Randomized Comparison of Nortriptyline and Paroxetine in Older Depressed Inpatients and Outpatients

Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind randomized comparison in 116 psychiatric inpatients and outpatients (mean age: 72+/-8 years) who presented with a major depressive episode or melancholic depression. Discontinuation and response rates were compared in patients who began or who completed treatment. The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine (33% vs. 16%). There were no significant differences between the rates of response in the Intent-to-Treat analysis (nortriptyline: 57% vs. paroxetine: 55% ), or the Completer analysis (nortriptyline: 78% vs. paroxetine: 84%). Although paroxetine appears to be better tolerated than nortriptyline, the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients, including hospitalized patients and those with melancholic features.

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.

Sleep after spousal bereavement: A study of recovery from stress ☆

AIM In this study, we compared repeated measures of electroencephalographic (EEG) sleep and subjective sleep quality in nondepressed, spousally bereaved elders and a healthy control group, in order to search for possible psychobiological correlates of bereavement not confounded by concurrent major depression. METHOD Laboratory-based EEG sleep studies and measures of subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]) were repeated at 3, 6, 11, 18, and 23 months after spousal bereavement in a study group of 27 elderly volunteers. Data were compared with similar measures from a control group of 27 nonbereaved subjects recorded on three occasions 1 year apart. Repeated-measures analysis of variance (ANOVA), using age as a covariate, examined effects due to time on selected variables in the bereaved group, as well as effects due to group, time, and group-by-time interactions in the experimental and control subjects. RESULTS Bereaved and control groups showed consistent differences over time in the phasic measures of rapid eye movement (REM) sleep (higher in bereaved subjects during the first and third REM sleep periods), but were similar on all other EEG sleep measures over the 2 years of observation. The bereaved showed a small decline in the percentage of slow-wave sleep over 2 years, but measures of sleep efficiency, REM latency, and delta sleep ratio were stable and did not differ from values seen in control subjects. Bereaved and control subjects were also similar on subjective sleep quality. CONCLUSION During successful adaptation to the loss of a spouse, and in the absence of major depression, spousal bereavement is associated with elevation in the phasic measures of REM sleep but does not appear to be associated with other physiologic sleep changes typical of major depression when studied at 3 to 23 months after the event. Although this observation does not preclude the possibility of significant sleep disturbance nearer the time of the event, it suggests that preservation of normal sleep following a major negative life event may be an important correlate of the resilience seen in successful aging. The elevation in REM density may provide a psychobiological correlate of bereavement not confounded by concurrent major depression.

Comparisons of methods for multiple hypothesis testing in neuropsychological research.

Hypothesis testing with multiple outcomes requires adjustments to control Type I error inflation, which reduces power to detect significant differences. Maintaining the prechosen Type I error level is challenging when outcomes are correlated. This problem concerns many research areas, including neuropsychological research in which multiple, interrelated assessment measures are common. Standard p value adjustment methods include Bonferroni-, Sidak-, and resampling-class methods. In this report, the authors aimed to develop a multiple hypothesis testing strategy to maximize power while controlling Type I error. The authors conducted a sensitivity analysis, using a neuropsychological dataset, to offer a relative comparison of the methods and a simulation study to compare the robustness of the methods with respect to varying patterns and magnitudes of correlation between outcomes. The results lead them to recommend the Hochberg and Hommel methods (step-up modifications of the Bonferroni method) for mildly correlated outcomes and the step-down minP method (a resampling-based method) for highly correlated outcomes. The authors note caveats regarding the implementation of these methods using available software.

Cognitive performance in suicidal depressed elderly: preliminary report.

OBJECTIVE Deficits in executive functions may play an important role in late-life suicide; however the association is understudied. This study examined cognitive function in general and executive functioning specifically in depressed elderly with and without suicidal ideation and attempts. DESIGN Case-control study. SETTING University-affiliated psychiatric hospital. PARTICIPANTS We compared 32 suicidal depressed participants aged 60 and older with 32 non-suicidal depressed participants equated for age, education, and gender. MEASUREMENTS We assessed global cognitive function and executive function with the Dementia Rating Scale (DRS) and the Executive Interview (EXIT25), respectively. RESULTS Suicidal and non-suicidal depressed groups were comparable in terms of severity of depression and burden of physical illness. Suicidal participants performed worse on the EXIT25, and on the DRS total scale, as well as on Memory and Attention subscales. The differences were not explained by the presence of dementia, substance use, medication exposure, or brain injury from suicide attempts. CONCLUSIONS Poor performance on tests of executive function, attention, and memory is associated with suicidal behavior in late-life depression.

Social rhythm stability following late-life spousal bereavement : associations with depression and sleep impairment

The aim of this study was to investigate changes in social rhythm stability and sleep in spousally bereaved subjects (n = 94) and in nonbereaved elderly control subjects (n = 45). Social rhythm stability and activity level were measured with a diary-like instrument, the Social Rhythm Metric (SRM). We observed that spousal bereavement, per se, was not associated with a lower social rhythm stability or activity level except in the presence of a major depressive episode. We also observed an inverse correlation between severity of depression and social rhythm stability, and a positive correlation between depression and both subjective and objective measures of sleep impairment. Higher social rhythm stability was correlated with better sleep in subjects with high activity levels, but not in subjects with low activity levels. Longitudinal data, including pre-bereavement assessment of social rhythm stability, are necessary to ascertain directional effects, i.e., whether loss of spouse occasions disruption of social rhythms or whether such disruption precedes sleep impairment and depression.