Plasma biosignature and brain pathology related to persistent cognitive impairment in late-life depression.

Cognitive impairment is highly prevalent among individuals with late-life depression (LLD) and tends to persist even after successful treatment. The biological mechanisms underlying cognitive impairment in LLD are complex and likely involve abnormalities in multiple pathways, or 'cascades,' reflected in specific biomarkers. Our aim was to evaluate peripheral (blood-based) evidence for biological pathways associated with cognitive impairment in older adults with LLD. To this end, we used a data-driven comprehensive proteomic analysis (multiplex immunoassay including 242 proteins), along with measures of structural brain abnormalities (gray matter atrophy and white matter hyperintensity volume via magnetic resonance imaging), and brain amyloid-ß (Aß) deposition (PiB-positron emission tomography). We analyzed data from 80 older adults with remitted major depression (36 with mild cognitive impairment (LLD+MCI) and 44 with normal cognitive (LLD+NC)) function. LLD+MCI was associated with differential expression of 24 proteins (P<0.05 and q-value <0.30) related mainly to the regulation of immune-inflammatory activity, intracellular signaling, cell survival and protein and lipid homeostasis. Individuals with LLD+MCI also showed greater white matter hyperintensity burden compared with LLD+NC (P=0.015). We observed no differences in gray matter volume or brain Aß deposition between groups. Machine learning analysis showed that a group of three proteins (Apo AI, IL-12 and stem cell factor) yielded accuracy of 81.3%, sensitivity of 75% and specificity of 86.4% in discriminating participants with MCI from those with NC function (with an averaged cross-validation accuracy of 76.3%, sensitivity of 69.4% and specificity of 81.8% with nested cross-validation considering the model selection bias). Cognitive impairment in LLD seems to be related to greater cerebrovascular disease along with abnormalities in immune-inflammatory control, cell survival, intracellular signaling, protein and lipid homeostasis, and clotting processes. These results suggest that individuals with LLD and cognitive impairment may be more vulnerable to accelerated brain aging and shed light on possible mediators of their elevated risk for progression to dementia.

Complicated grief and bereavement-related depression as distinct disorders: preliminary empirical validation in elderly bereaved spouses.

OBJECTIVE: This study sought to determine whether a set of symptoms interpreted as complicated grief could be identified and distinguished from bereavement-related depression and whether the presence of complicated grief would predict enduring functional impairments. METHOD: Data were derived from a study group of 82 recently widowed elderly individuals recruited for an investigation of physiological changes in bereaved persons. Baseline data were collected 3-6 months after the deaths of the subjects' spouses, and follow-up data were collected from 56 of the subjects 18 months after the baseline assessments. Candidate items for assessing complicated grief came from a variety of scales used to evaluate emotional functioning (e.g., the Hamilton Depression Rating Scale, the Brief Symptom Inventory). The outcome variables measured were global functioning, medical illness burden, sleep, mood, self-esteem, and anxiety. RESULTS: A principal-components analysis conducted on intake data (N = 82) revealed a complicated grief factor and a bereavement-depression factor. Seven symptoms constituted complicated grief: searching, yearning, preoccupation with thoughts of the deceased, crying, disbelief regarding the death, feeling stunned by the death, and lack of acceptance of the death. Baseline complicated grief scores were significantly associated with impairments in global functioning, mood, sleep, and self-esteem in the 56 subjects available for follow-up. CONCLUSIONS: The symptoms of complicated grief may be distinct from depressive symptoms and appear to be associated with enduring functional impairments. The symptoms of complicated grief, therefore, appear to define a unique disorder deserving of specialized treatment.

Treatment of consecutive episodes of major depression in the elderly.

OBJECTIVE: The purpose of this study was to determine treatment outcome in elderly patients with consecutively treated episodes of recurrent unipolar major depression. METHOD: Subjects were 32 "young" elderly patients with recurrent unipolar depression (mean age = 66.8 years, SD = 5.1) and with two consecutively treated episodes of major depression. Both index and subsequent episodes of major depression were treated in open trial with combined nortriptyline and interpersonal psychotherapy. Rates of remission in index and subsequent episodes were compared by using nonparametric statistics and survival analysis with proportional hazards modeling. RESULTS: Of 30 patients who completed treatment of the subsequent episode, 27 (90%) achieved stable remission of symptoms in both consecutively treated episodes, whereas three patients (10%) did not. Twenty-two (81%) of 27 patients who responded to treatment had a shorter time to remission in treatment of the subsequent episode than in the index episode. Survival analysis with proportional hazards modeling detected a significant difference in time to remission of the index and subsequent episodes (32 paired observations). CONCLUSIONS: In this research study group, recurrent episodes of unipolar major depression in the young elderly were successfully treated to remission in over 80% of patients by using combined pharmacotherapy and psychotherapy similar to that employed in treatment of the index episode. Remission rate and time to remission in consecutively treated episodes were comparable to those in a group of midlife patients with recurrent depression reported by Kupfer et al. in 1989. Thus, recurrent depressive disorder appears to be as treatable in the young elderly as it is in midlife patients.

Hopelessness in suicide attempters after acute treatment of major depression in late life.

The relation between hopelessness and suicide attempts in the elderly was examined by studying the course of hopelessness in depressed patients. Sixty-three elderly patients with recurrent major depression were treated with nortriptyline and interpersonal psychotherapy and underwent serial ratings of hopelessness and depression during the acute and continuation phases of treatment. Patients who had made a suicide attempt in the past had significantly higher hopelessness scores than nonattempters during both phases of treatment. They were also more likely to drop out of treatment. A high degree of hopelessness persisting after remission of depression in elderly patients appears to be associated with a history of suicidal behavior. It may also increase the likelihood of premature discontinuation of treatment and lead to future suicide attempts or suicide.

Life events and the research diagnostic criteria endogenous subtype. A confirmation of the distinction using the Bedford College methods.

BACKGROUND: Despite the advances in biological and psychosocial assessment methods, reliable distinction between depressed patients with endogenous presentations or melancholic symptom features and those with nonendogenous presentations has remained elusive. METHODS: Ninety patients with histories of frequent unipolar episodes classified as endogenous or nonendogenous by the Research Diagnostic Criteria were interviewed with the Bedford College Life Events and Difficulties Schedule regarding the 6 months before onset of their most recent episode of depression. RESULTS: Patients meeting the Research Diagnostic Criteria for definite endogenous subtype differed significantly from patients with nonendogenous features in terms of the proportion experiencing severe life stress in the 6 months before onset of their depressive episode (P < = .04). Furthermore, survival analysis revealed a closer temporal association between severe event and depression onset among patients with nonendogenous features (P < .02). CONCLUSION: Even among patients with a history of multiple recurrences of depression, psychological stress plays an important role in the timing of onset of episodes characterized by nonendogenous features.

Sleep in bereavement-related depression during and after pharmacotherapy with nortriptyline.

Our objective was to assess the effects of nortriptyline on electroencephalographic sleep and subjective sleep quality in spousally bereaved, depressed elders. Ten elderly volunteers with bereavement-related major depression had electroencephalographic sleep studies while depressed, after remission of depressive symptoms while still taking nortriptyline, and after nortriptyline discontinuation. Changes in sleep measures over time were compared both within bereaved subjects and with age- and sex-matched healthy controls. Remission of depressive symptoms while still on nortriptyline was associated with improvements in sleep quality (P < .002), rapid eye movement (REM) percent (P < .02), REM latency (P < .05), REM density (P < .05), and delta sleep ratio (P < .05). After discontinuation of nortriptyline, REM percent, REM latency, and delta ratio reverted to pretreatment levels, while sleep efficiency and sleep quality continued to show improvement coincident with sustained clinical remission. These data suggest that nortriptyline may be clinically useful in treating the sleep disturbance of elders with bereavement-related depression and that a double-blind, placebo-controlled, randomized clinical trial is warranted.

Stressful life events, social rhythms, and depressive symptoms among the elderly: an examination of hypothesized causal linkages.

This study sought to determine possible causal linkages among stressful life events, social rhythms, and levels of depressive symptomatology for 81 elderly subjects (51 recently widowed, 30 healthy controls). We examined the associations among stressful life events (i.e., bereavement status at baseline or a severely threatening event occurring between baseline and followup), social rhythm stability, and the level of depressive symptoms. Results indicated that while stressful life events were not associated with significant changes in social rhythm stability, social rhythm stability was a significant negative correlate of both baseline and followup levels of depressive symptomatology; that is, lower levels of social rhythm stability at baseline were associated with high levels of depressive symptoms at baseline (rho = -0.33, n = 81, p < 0.001) and at followup (rho = -0.23, n = 81, p < 0.05). Bereavement was also a significant positive correlate of depressive symptomatology both at baseline (rho = 0.79, n = 81), p < 0.0001) and at followup (rho = 0.55, n = 81, p < 0.0001). It is likely that future research will benefit from social rhythm assessment obtained temporally closer to major life events and from the use of structured interviews to ascertain the presence of syndromal major depression at followup as well as the inclusion of subjects with a wider range of functional impairments. Nevertheless, these results represent a first step in disentangling possible causal connections among stressful life events, social rhythms, and depressive symptomatology.

The Pittsburgh Sleep Diary.

Increasingly, there is a need in both research and clinical practice to document and quantify sleep and waking behaviors in a comprehensive manner. The Pittsburgh Sleep Diary (PghSD) is an instrument with separate components to be completed at bedtime and waketime. Bedtime components relate to the events of the day preceding the sleep, waketime components to the sleep period just completed. Two-week PghSD data is presented from 234 different subjects, comprising 96 healthy young middle-aged controls, 37 older men, 44 older women, 29 young adult controls and 28 sleep disorders patients in order to demonstrate the usefulness, validity and reliability of various measures from the instrument. Comparisons are made with polysomnographic and actigraphic sleep measures, as well as personality and circadian type questionnaires. The instrument was shown to have sensitivity in detecting differences due to weekends, age, gender, personality and circadian type, and validity in agreeing with actigraphic estimates of sleep timing and quality. Over a 12-31 month delay, PghSD measures of both sleep timing and sleep quality showed correlations between 0.56 and 0.81 (n = 39, P < 0.001).

Correlation of nocturnal penile tumescence and daytime affect intensity in depressed men.

Although depressed patients have been shown to have diminished nocturnal penile tumescence (NPT), there remains considerable variability of NPT in depression. We hypothesized that affective experience during the day accounts for some of this variability. Forty-five depressed men had assessments of affect intensity and affect balance, NPT, and daytime sexual function, both before and after treatment with Beck's cognitive behavior therapy (CBT). Forty-three normal control subjects were studied for comparison. Daytime affect intensity in depressed men, but not in control subjects, correlated significantly and positively with measures of NPT duration and rigidity both before and after treatment, regardless of the adequacy of daytime sexual function. When the effect of daytime affect on REM activity was controlled, the observed correlations became nonsignificant at pretreatment, but remained significant at posttreatment. Neuropharmacologically mediated changes in arousal responsivity associated with depression may underlie the observed relation between daytime affect intensity, rapid eye movement activity, and NPT.

Peripheral thermal responsivity to facial cooling during sleep.

A recently developed technique for examining thermal sensitivity during sleep was used to assess whether skin and core temperature responses to thermal stimulation were altered by sleep state. The technique was designed to probe thermal responsivity without altering core body temperature or inducing awakening. Twenty-seven young men and women were studied during a sleep deprivation night and a sleep night three nights later. Cold water stimulation of the face alternated with an equal period of rewarming across a 40-min cycle throughout the night. Skin temperature from the finger and rectal temperature were continuously assessed. Sleep continuity and architecture were largely uninfluenced by the thermal stimulation. Finger skin temperature decreased during cold facial stimulation in both sleep and waking states. Skin temperature changes during sleep were approximately one-fifth the magnitude of those during waking. Core temperature was minimally influenced. REM sleep was associated with a greater amplitude decrease in finger temperature than was non-REM (NREM) sleep. The results support the utility of the technique as a probe of thermal responsivity during sleep and suggest a reduction of thermal responsivity during sleep and, more tentatively, an altered responsivity during REM versus NREM sleep.

Combined pharmacotherapy and psychotherapy in the acute and continuation treatment of elderly patients with recurrent major depression: a preliminary report.

OBJECTIVE: The authors examined the rate of response to the combination of nortriptyline and interpersonal psychotherapy for acute and continuation treatment of elderly patients with recurrent major depression. METHOD: The subjects were 73 elderly patients, 61 of whom completed treatment. Nortriptyline steady-state blood levels were maintained at 80-120 ng/ml, and interpersonal psychotherapy was administered weekly for 9.1 weeks (medium) of acute therapy and was decreased from biweekly to triweekly during 16 weeks of continuation therapy. During acute treatment nonresponding patients also received brief adjunctive pharmacotherapy with lithium or perphenazine. RESULTS: Of the 61 subjects given adequate trials of nortriptyline and interpersonal psychotherapy, 48 (78.7%) achieved full remission (Hamilton depression rating of 10 or lower over 16 weeks of continuation therapy), 10 patients (16.4%) did not respond (Hamilton rating never below 15), and three achieved only partial remission (Hamilton rating of 11-14). Early versus late onset was not associated with a difference in response rate. During the placebo-controlled, double-blind transition to maintenance therapy, 19 (76.0%) of the 25 patients randomly assigned to placebo maintenance conditions showed continued recovery and six relapsed. None of the 24 patients assigned to nortriptyline conditions relapsed. CONCLUSIONS: Use of nortriptyline plus interpersonal psychotherapy for 9.1 weeks (median) of acute and 16 weeks of continuation therapy appears to be associated with good response and relatively low attrition but about a 25% chance of relapse during double-blind discontinuation of nortriptyline. These data require confirmation in a controlled clinical trial of acute and continuation therapy.

Treatment of depression in special populations.

The purpose of this review is to set forth guidelines for the treatment of depression in several special populations: (1) the elderly (both ambulatory and institutionalized); (2) patients with concurrent neurologic disorders (Alzheimer's disease, Parkinson's disease, and stroke) and depression; and (3) patients with bereavement-related depression. This is a selective review of studies published in the past 10 years that have utilized structured psychiatric interviewing, randomized clinical trials, and/or monitoring of plasma antidepressant levels. Published data support specific efficacy and safety claims for both pharmacotherapeutic and psychotherapeutic approaches to the treatment of major depression in elderly ambulatory and institutionalized patients. In the case of depression associated with Alzheimer's, Parkinson's, and stroke, there is also evidence of efficacy for antidepressant medication. Finally, bereavement-related syndromal depression appears to respond to antidepressant medication, but further controlled evaluation is desirable. As emphasized by the 1991 National Institutes of Health Consensus Development Conference on the Diagnosis and Treatment of Depression in Late Life, depression in the elderly should be recognized as treatable and should be treated vigorously. Rather than being dismissed as a normal reaction to the multiple medical and psychosocial burdens of late life, it should be treated appropriately to reduce an important source of excess disability.

Sleep in spousally bereaved elders with subsyndromal depressive symptoms.

Spousal bereavement in late life frequently leads to major depression. However, many people suffer from "minor" depressive symptoms that entail considerable suffering even in the absence of syndromal major depression. We describe longitudinal electroencephalographic (EEG) sleep and clinical evaluations in 14 elderly, recently spousally bereaved subjects who were experiencing subsyndromal depressive symptoms. While subjects did not meet diagnostic criteria for syndromal major depression, they did have mildly elevated scores on the Hamilton Rating Scale for Depression (mean = 10.6, range = 8-16) at the time of initial sleep studies (T1), which were carried out, on average, 5.5 months after loss of the spouse. Entry into the study was limited to volunteers who did not have a personal history of major depression or psychiatric disorder. Twelve subjects underwent followup clinical and EEG sleep evaluations (T2), 9.9 months after spousal loss. Fifty percent continued to show depressive symptoms at 6-month followup. Test-retest comparisons of sleep and clinical measures were made with a group of sex- and age-matched control subjects who were neither bereaved nor depressed. EEG sleep measures did not significantly correlate with time from loss of spouse, severity of depressive symptoms, or subjective sleep quality. Analysis of variance with repeated measures detected a significant group X time interaction effect for delta sleep ratio (decreasing in controls but increasing in the bereaved).

Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale.

Reliable quantitative ratings of chronic medical illness burden have proved to be difficult in geropsychiatric practice and research. Thus, the purpose of the study was to demonstrate the feasibility and reliability of a modified version of the Cumulative Illness Rating Scale (CIRS; Linn et al., 1968) in providing quantitative ratings of chronic illness burden. The modified CIRS was operationalized with a manual of guidelines geared toward the geriatric patient and for clarity was designated the CIRS(G). A total of 141 elderly outpatient subjects (two medical clinic groups of 20 each, 45 recurrent depressed subjects, 21 spousally bereaved subjects, and 35 healthy controls) received comprehensive physical examinations, reviews of symptoms, and laboratory testing. These data were then used by nurse practitioners, physician's assistants, and geriatric psychiatrists to compute CIRS(G) ratings of chronic illness burden. As hypothesized, analysis of variance demonstrated significant differences among groups with respect to total medical illness burden, which was highest among medical clinic patients and lowest in control subjects. Good interrater reliability (i.e., intraclass correlations of 0.78 and 0.88 in a subsample of 10 outpatients and a separate group of 10 inpatients, respectively) was achieved for CIRS(G) total scores. Among medical clinic patients, a significant correlation was found, as expected, between CIRS(G) chronic illness burden and capability as quantified by the Older Americans Activities of Daily Living Scale; and between CIRS(G) scores and physicians' global estimates of medical burden. Finally, with repeated measures of illness burden approximately 1 year from symptom baseline, significant rises were detected, as expected. The current data suggest that the CIRS(G) can be successfully applied in medically and psychiatrically impaired elderly subjects, with good interrater reliability and face validity (credibility).

Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology.

The metabolic ratios (MRs) between debrisoquine (DBQ) and 4-hydroxydebrisoquine in urine after a single dose of 10 mg DBQ was determined in 175 unmedicated, healthy subjects older than age 59 (mean of 75 years). Creatinine clearance was determined on the same 8-hour urine collection. Test procedures were well tolerated in all cases. Although age was significantly correlated with creatinine clearance (r = -.38), there was no relationship between age and MR. Analysis by kernel density estimation revealed a bimodal distribution of MRs with an antimode of 11.6. Six subjects (3.4%) were categorically slow DBQ metabolizers (MR greater than 11.6). The proportion of elderly slow metabolizers approaches the lower range determined in a younger population. Our findings, that DBQ oxidative metabolism does not necessarily change with aging, alone, and that (genetic) slow DBQ metabolizers endure into old age, remaining at risk for treatment with many commonly used psychotropics, suggests the need to study the relevance of metabolic phenotyping in elderly psychiatric patients.

The balance of positive and negative affects in major depression: a further test of the States of Mind model.

The States of Mind (SOM) model provided a framework for assessing the balance between self-reported positive and negative affects in a sample of 39 outpatients with major depression and 43 healthy control subjects. The SOM model proposes that healthy functioning is characterized by an optimal balance of positive (P) and negative (N) cognitions or affects (P/(P + N) approximately 0.63), and that psychopathology is marked by deviations from the optimal balance. Research thus far has focused on the functional significance of cognitive rather than affective balance. Within this framework, we hypothesized that patients in untreated episodes of major depression would balance their positive and negative affects at the same level where depressed patients in other studies have balanced their positive and negative cognitions--namely, at P/(P + N) approximately 0.37. Points and confidence interval (CI) estimation procedures yielded results (mean = 0.35, 95% CI = 0.30 - 0.40) consistent with this hypothesis in a sample of 39 depressed male outpatients. Correlational analysis indicated that affect balance is inversely related to symptom severity as measured by self-report (Beck) and clinician-rating (Hamilton) scales.

Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test.

OBJECTIVE: This study characterized objectively the hypersomnia frequently seen in the depressed phase of bipolar affective disorder. On the basis of previous work in sleep and affective disorders, it has been hypothesized that the hypersomnia is related to greater REM sleep. This hypothesis was tested by using a multiple sleep latency test to compare bipolar affective disorder with narcolepsy, a well-defined primary sleep disorder associated with known REM sleep dysfunction. METHOD: Twenty-five bipolar depressed patients were selected on the basis of complaints of hypersomnia. They underwent 2 nights of polysomnography followed by a multiple sleep latency test. Data on their nocturnal sleep and daytime naps were compared with similar data on 23 nondepressed narcoleptic patients referred for sleep evaluation. RESULTS: Despite their complaints of hypersomnia, no abnormalities were noted for the bipolar group in the results from the multiple sleep latency test. Contrary to the working hypothesis, REM sleep was notably absent during daytime naps in the depressed patients, in marked contrast to the findings for the narcoleptic group. CONCLUSIONS: The complaint of sleepiness in the hypersomnic bipolar depressed patient appears to be related to the lack of interest, withdrawal, decreased energy, or psychomotor retardation inherent in the anergic depressed condition, rather than an increase in true sleep propensity or REM sleep propensity.