Pretreatment REM sleep and subjective sleep quality distinguish depressed psychotherapy remitters and nonremitters.

BACKGROUND: We compared pretreatment subjective and electroencephalographic sleep measures among depressed patients who remitted with psychotherapy alone and those who did not remit. METHODS: Patients were 111 midlife women with recurrent major depressive disorder. Baseline psychiatric ratings and sleep studies were conducted prior to treatment with weekly interpersonal psychotherapy. Remission was defined as a score of < or = 7 for 3 consecutive weeks on the Hamilton Depression Rating Scale. Clinical and sleep measures were compared between remitters (n = 62) and nonremitters (n = 49) using t tests and random regression. Linear discriminant function analyses were used to categorize remitters and nonremitters on the basis of sleep measures. RESULTS: Treatment nonremitters had significantly worse subjective sleep quality and significantly elevated phasic REM sleep as measured by multivariate and univariate analyses. The linear accumulation of REM activity during sleep occurred at a significantly higher rate in nonremitters than in remitters. Linear discriminant function analyses based on subjective sleep quality and REM activity correctly identified 68.3% of nonremitters and 68.5% of remitters. CONCLUSIONS: These findings highlight the role of subjective and REM sleep measures as correlates of short-term psychotherapy treatment response in major depressive disorder. Disturbed sleep may be a physiological indicator of increased limbic and brain stem arousal.

Maintenance nortriptyline effects on electroencephalographic sleep in elderly patients with recurrent major depression: double-blind, placebo- and plasma-level-controlled evaluation.

Our aim was to contrast the effects of maintenance nortriptyline and placebo on electroencephalographic sleep measures in elderly recurrent depressives who survived 1-year without recurrence of depression. Patients on nortriptyline took longer to fall asleep and did not maintain sleep better than patients on placebo; however, maintenance nortriptyline was associated with more delta-wave production and higher delta-wave density in the first non-REM (NREM) period relative to the second. Nortriptyline levels were positively but weakly related to all-night delta-wave production during maintenance (accounting for 6.6% of the variance in delta-wave counts). Total phasic REM activity increased 100% under chronic nortriptyline relative to placebo, with a robust increase in the rate of REM activity generation across the night. Effective long-term pharmacotherapy of recurrent major depression is associated with enhancement in the rate of delta-wave production in the first NREM period (i.e., delta sleep ratio) and of REM activity throughout the night.

Comorbid anxiety disorders in depressed elderly patients.

OBJECTIVE: Anxiety disorders are common in adults with depressive disorders, but several studies have suggested a relatively low prevalence of anxiety disorders in older individuals with depression. This cross-sectional study measured current and lifetime rates and associated clinical features of anxiety disorders in depressed elderly patients. METHOD: History of anxiety disorders was assessed by using a structured diagnostic instrument in 182 depressed subjects aged 60 and older seen in primary care and psychiatric settings. Associations between comorbid anxiety disorders and baseline characteristics were measured. The modified structured instrument allowed detection of symptoms that met inclusion criteria for generalized anxiety disorder in a depressive episode. RESULTS: Thirty-five percent of older subjects with depressive disorders had at least one lifetime anxiety disorder diagnosis, and 23% had a current diagnosis. The most common current comorbid anxiety disorders were panic disorder (9.3%), specific phobias (8.8%), and social phobia (6.6%). Symptoms that met inclusion criteria for generalized anxiety disorder, measured separately, were present in 27.5% of depressed subjects. Presence of a comorbid anxiety disorder was associated with poorer social function and a higher level of somatic symptoms. Symptoms of generalized anxiety disorder were associated with a higher level of suicidality. CONCLUSIONS: Contrary to previous reports, the present study found a relatively high rate of current and lifetime anxiety disorders in elderly depressed individuals. Comorbid anxiety disorders and symptoms of generalized anxiety disorder were associated with a more severe presentation of depressive illness in elderly subjects.

Serum anticholinergicity in elderly depressed patients treated with paroxetine or nortriptyline.

OBJECTIVE: The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients randomly assigned to double-blind treatment with paroxetine (N=31) or nortriptyline (N=30). METHOD: Both antidepressants were titrated in a standardized manner, and plasma was sampled weekly for measurement of paroxetine and nortriptyline and its hydroxy metabolite concentrations. Serum anticholinergicity was measured at baseline and after 1, 4, and 6 weeks of treatment. Side effects were assessed by using a validated scale. RESULTS: After correcting for pretreatment anticholinergicity, the authors found that mean serum anticholinergicity for the nortriptyline-treated patients was significantly greater than that for the paroxetine group at all weeks assessed. Serum anticholinergicity was significantly correlated with nortriptyline but not with paroxetine plasma levels. Complaints of dry mouth and tachycardia were significantly more frequent and severe in the nortriptyline group. CONCLUSIONS: These findings suggest that, at therapeutic plasma concentrations, paroxetine has approximately one-fifth the anticholinergic potential of nortriptyline in older patients.

Effects of age at onset of first lifetime episode of recurrent major depression on treatment response and illness course in elderly patients.

OBJECTIVE: The goal of this study was to examine treatment outcome differences in relation to age at onset of first lifetime episode of recurrent major depression in elderly patients. METHOD: Patients were grouped as having early-onset (N = 129) or late-onset (N = 58) depression. Early onset was defined as having a first lifetime episode of major depression at age 59 or earlier; late onset was defined as age 60 or later. The two groups of patients were compared with respect to demographic and clinical characteristics, types of treatment given (nortriptyline and interpersonal psychotherapy), and treatment outcomes. RESULTS: The groups did not differ in the percentage of patients who remitted, recovered, or relapsed during continuation treatment or in the percentage who experienced a recurrence of major depression during the first year of maintenance treatment. However, early-onset patients took 5-6 weeks longer to achieve remission than did late-onset patients, and a higher proportion had a history of suicide attempts. CONCLUSIONS: These data suggest that age at lifetime onset of recurrent major depression does not influence short- or long-term treatment response in elderly patients treated with combined interpersonal psychotherapy and nortriptyline, with the exception of slowing the speed of remission in early-onset cases. Difference in remission speed may reflect the greater number of previous episodes in the early-onset patients. Nevertheless, the likelihood of a longer time to remission, together with a higher rate of past suicide attempts, suggests that elderly depressed patients with a history of early-onset illness need particularly careful management.

How common is resistance to treatment in recurrent, nonpsychotic geriatric depression?

OBJECTIVE: Effective treatments are available for major depressive disorder in later life. The purpose of this study was to elucidate the frequency of treatment resistance among the elderly. METHOD: Treatment resistance, defined as lack of recovery despite combined pharmacotherapy and psychotherapy, was prospectively examined in 180 elderly patients in an episode of recurrent, nonpsychotic major depression who were referred to a university medical center for treatment. They received open acute and continuation treatment with nortriptyline and interpersonal psychotherapy. RESULTS: Among the 159 patients who completed acute treatment, 19 (11.9%) did not experience a remission of depression. In addition, nine patients who had achieved remission relapsed during continuation therapy and did not recover despite vigorous treatment. Hence, excluding dropouts, 18.4% of the patients met the criteria for treatment resistance by their lack of response to acute treatment or by relapsing during continuation therapy and not recovering subsequently despite further vigorous treatment. CONCLUSIONS: The study suggests a relatively low rate of resistance to treatment among depressed geriatric patients referred to a university tertiary care setting.

Acute efficacy of ECT in the treatment of major depression in the old-old.

OBJECTIVE: There are few data addressing the outcome of ECT for persons over 75 years of age. In a prospective, multisite study, the authors compared characteristics and treatment outcomes of adult (59 and younger), young-old (60 to 74 years), and old-old (75 and older) patients treated with ECT for major depression. METHOD: At four hospitals, 268 patients with primary unipolar major depression and scores of at least 20 on the 24-item Hamilton Depression Rating Scale were treated with suprathreshold right unilateral or bilateral ECT in a standardized manner. Demographic variables, clinical characteristics, and short-term outcomes of the three groups were compared. RESULTS: The demographic and clinical characteristics of the old-old patients were similar to those of the young-old patients, whereas both groups differed from the adult patients on these variables. Both older groups had significantly greater burdens from physical illness and global cognitive impairment at baseline than the adult subjects. Both older groups had shorter index depressive episodes and were less likely to have had inadequate responses to adequate medication trials before ECT. The older groups had higher seizure thresholds, but the three groups received similar courses of treatment. The adult patients experienced a significantly lower rate of ECT response (54%) than the young-old patients (73%), while the old-old patients had an intermediate rate of response (67%). CONCLUSIONS: Despite a higher level of physical illness and cognitive impairment, even the oldest patients with severe major depression tolerate ECT in a manner similar to that for younger patients and demonstrate similar or better acute response.

Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy?

BACKGROUND: This analysis sought to determine whether lorazepam influences time to response or rate of response in elderly depressed patients receiving nortriptyline and psychotherapy and to examine clinical and polysomnographic correlates of lorazepam treatment. METHOD: Patients with recurrent major depressive disorder (N = 119; mean +/- SD age = 68.0 +/- 6.1 years; diagnosis defined by Research Diagnostic Criteria) received acute treatment with nortriptyline and interpersonal psychotherapy. Thirty-five patients received open-label adjunctive lorazepam for anxiety or insomnia symptoms (LZ+) and 84 did not. Statistical analyses were conducted between the LZ+ group and a group of 35 patients who received no lorazepam (LZ-) and were matched for anxiety level. Patients had polysomnographic studies prior to treatment and after remission of depressive symptoms. RESULTS: The LZ+ group reported more anxiety on the Brief Symptom Inventory (p = .04) compared with the remaining 84 patients. The LZ+ group had a greater proportion of endogenous depression subtype than the anxiety-matched LZ- group, in addition to more abnormal EEG sleep (higher percentage of REM sleep, shorter REM latency, lower delta sleep ratio). Mean time to initial antidepressant response was no different between groups. However, a significantly greater proportion of LZ+ than LZ- patients responded to acute treatment (91.4% vs. 71.4%; p < .03). CONCLUSION: Adjunctive lorazepam does not slow the antidepressant response to combined antidepressant/psychotherapy treatment in elderly depressed patients, and it is associated with a greater likelihood of antidepressant response. A greater percentage of patients treated with lorazepam have endogenous depression subtype and abnormal sleep findings (EEG) than those who are not treated with lorazepam. Adjunctive lorazepam is useful for treating anxiety in elderly depressed patients.

A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life.

OBJECTIVE: To conduct the first randomized study comparing the efficacy of an antidepressant alone versus an antidepressant plus a neuroleptic in the treatment of late-life psychotic depression. METHOD: The efficacy of nortriptyline plus placebo versus nortriptyline plus perphenazine was compared in 36 patients aged 50 years or older presenting with a major depressive episode with psychotic features (DSM-III-R criteria). Patients were started openly on nortriptyline treatment titrated to therapeutic levels. They were then randomly assigned under double-blind conditions to addition of perphenazine or placebo. Outcomes were compared in the 2 treatment groups using measures including the Hamilton Rating Scale for Depression (HAM-D) and the Brief Psychiatric Rating Scale (BPRS); side effects were assessed with the Geriatric Movement Disorder Assessment. RESULTS: Both treatments were well tolerated. Of the 36 randomly assigned patients, 2 (1 in each group) dropped out due to treatment-related adverse effects. Four additional patients dropped out for administrative reasons. Thirty patients received nortriptyline for at least 4 weeks combined with either perphenazine (N = 14) or placebo (N = 16) for at least 2 weeks (median = 9 weeks). There was no significant difference between the completers in the 2 treatment groups when comparing their scores on the HAM-D, the BPRS, its psychoticism subscale, or any side effects measure. Rates of response (defined as resolution of both depression and psychosis) did not differ significantly in the 2 groups (nortriptyline-plus-perphenazine group, 50% vs. nortriptyline-plus-placebo group, 44%). CONCLUSION: When treating older patients with psychotic depression, the addition of a moderate dose of a traditional neuroleptic to a tricyclic antidepressant was well tolerated but did not improve efficacy. This finding supports existing data suggesting that the pathophysiology (and thus the required treatment) of psychotic depression may be different early and late in life.

High levels of hopelessness persist in geriatric patients with remitted depression and a history of attempted suicide.

OBJECTIVE: To determine whether a high level of hopelessness after treatment of a depressive episode is an indicator of a history of lifetime suicide attempts in older people. DESIGN: Groups of suicide attempters, suicidal ideators, and nonsuicidal patients were compared via analysis of variance with respect to levels of hopelessness, depression, anxiety, and global functioning before and after treatment of depression. SETTING: An outpatient research clinic providing two treatment protocols of late-life mood disorders. PARTICIPANTS: A total of 107 consecutive outpatients (mean age 67) with major depression who responded to treatment. MEASUREMENTS: Levels of hopelessness, severity of depression, anxiety, and global functioning were compared across the three groups at the beginning of treatment and at remission. RESULTS: After remission there were no differences between the three groups in depression severity, anxiety, and global functioning. Hopelessness remained significantly higher in the attempter group than among ideators or nonsuicidal patients. CONCLUSIONS: Suicide attempts, the most important risk factor for subsequent suicide, are associated with persistent, high levels of hopelessness following remission of depression in late-life patients. These findings suggest that treatments designed specifically to lower hopelessness (such as cognitive, behavioral or interpersonal therapy) may be effective in reducing suicide risk.

Protecting sleep quality in later life: a pilot study of bed restriction and sleep hygiene.

We tested two interventions for improving sleep consolidation and depth in normal elderly participants: a modification of sleep-restriction therapy and sleep-hygiene education. Twenty-one elderly participants without sleep disorders were randomized to sleep hygiene plus bed restriction (i.e., restricting time in bed by 30 minutes nightly for one year) or to sleep hygiene alone. Participants in the bed-restriction group showed a median increase in sleep efficiency of 6.1% versus 1.8% in participants receiving sleep hygiene instruction, and an increase in allnight delta EEG power. Self-reported mood on awakening in the morning showed greater improvement over the first eight weeks in the sleep-hygiene condition. The use of sleep hygiene was associated with initial improvement in daytime well-being, whereas bed restriction led to sustained improvements in sleep continuity and sleep depth.

Residual analysis in random regressions using SAS and S-PLUS.

A program package RRAP: Random Regression Residual Analysis Program using SAS [1] and S-PLUS [2] is available for performing random regression residual analysis. The PROCEDURE MIXED from SAS is used for statistical inference. Both elementary-level and individual-level residuals are used. The S-PLUS programs provide: (1) a transformation to orthogonalize the elementary-level correlated residuals for standard regression residual analyses; and (2) several statistics and plots for checking model assumptions, assessing model fitting and detecting outlying individuals. RRRAP starts with a SAS Macro RRRAPMAC on the data followed by a S-PLUS Program DoRRRAP on a UNIX system.

Effect of nortriptyline and paroxetine on extrapyramidal signs and symptoms: A prospective double-blind study in depressed elderly patients.

Selective serotonin-reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) have been reported to induce extrapyramidal signs and symptoms (EPS). The authors examined the change from baseline EPS, measured by an objective rating scale, in a group of elderly depressed patients participating in an ongoing randomized, double-blind comparison of nortriptyline and paroxetine. Mild baseline EPS were present in both groups. After 6 weeks of antidepressant treatment, patients in the nortriptyline group showed a significant decrease in total EPS scores. Patients in the paroxetine group showed a similar decrease in EPS from baseline, which did not reach statistical significance. There was no significant difference between nortriptyline and paroxetine in the change in EPS.

Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly.

Elderly depressed patients are vulnerable to recurrence of depression and benefit from long-term antidepressant therapy. Physicians increasingly use selective serotonin re-uptake inhibitors (SSRIs) as maintenance therapy, although in the absence of data showing that SSRIs are as efficacious as tricyclic antidepressants (TCAs) in the prevention of depression relapse and recurrence. Our objective was to evaluate, in an open trial, the efficacy of paroxetine versus nortriptyline for preventing recurrence of depression in the elderly. Elderly patients with major depression were randomly assigned in a double-blinded fashion to receive either paroxetine or nortriptyline for the acute treatment of depression. Patients who did not respond or tolerate their assigned medications were crossed over openly to the comparator agent. Patients whose depression remitted continued antidepressant medication (paroxetine n = 38; nortriptyline n = 21) during an open 18-month follow-up study. We examined the rates of and times to relapse and to termination of treatment for any reason. Paroxetine (PX) and nortriptyline (NT) patients had similar rates of relapse (16% vs. 10%, respectively) and time to relapse (60.3 weeks vs. 58.8 weeks, respectively) over 18 months. A lower burden of residual depressive symptoms and side effects during continuation and maintenance treatment was evident in nortriptyline-treated patients. Paroxetine and nortriptyline demonstrated similar efficacy in relapse and recurrence prevention in elderly depressed patients over an 18-month period.

Circadian rhythms in human performance and mood under constant conditions.

UNLABELLED: This study explored the relationship between circadian performance rhythms and rhythms in rectal temperature, plasma cortisol, plasma melatonin, subjective alertness and well-being. Seventeen healthy young adults were studied under 36 h of 'unmasking' conditions (constant wakeful bedrest, temporal isolation, homogenized 'meals') during which rectal temperatures were measured every minute, and plasma cortisol and plasma melatonin measured every 20 min. Hourly subjective ratings of global vigour (alertness) and affect (well-being) were obtained followed by one of two performance batteries. On odd-numbered hours performance (speed and accuracy) of serial search, verbal reasoning and manual dexterity tasks was assessed. On even-numbered hours, performance (% hits, response speed) was measured at a 25-30 min visual vigilance task. Performance of all tasks (except search accuracy) showed a significant time of day variation usually with a nocturnal trough close to the trough in rectal temperature. Performance rhythms appeared not to reliably differ with working memory load. Within subjects, predominantly positive correlations emerged between good performance and higher temperatures and better subjective alertness; predominantly negative correlations between good performance and higher plasma levels of cortisol and melatonin. Temperature and cortisol rhythms correlated with slightly more performance measures (5/7) than did melatonin rhythms (4/7). Global vigour correlated about as well with performance (5/7) as did temperature, and considerably better than global affect (1/7). IN CONCLUSION: (1) between-task heterogeneity in circadian performance rhythms appeared to be absent when the sleep/wake cycle was suspended; (2) temperature (positively), cortisol and melatonin (negatively) appeared equally good as circadian correlates of performance, and (3) subjective alertness correlated with performance rhythms as well as (but not better than) body temperature, suggesting that performance rhythms were not directly mediated by rhythms in subjective alertness.

Subjective health measures and acute treatment outcomes in geriatric depression.

BACKGROUND: Prior research suggests that elderly patients are less likely to respond to antidepressant treatment if they have low self-rated health. However, successful treatment for depression has been associated with improvement in self-rated health and other health measures. OBJECTIVES: To examine measures of self-rated health, physical disability, and social function as predictors of treatment response in late-life depression, and to assess these same health measures as treatment outcomes. We hypothesized that greater impairment in these measures would predict poorer treatment response, and that these measures would show significant improvements with recovery from depression. METHOD: Subjects were enrolled in a depression intervention study for people aged 60 and older with recurrent unipolar major depression; they were assessed with measures of self-rated health, physical disability, and social functioning at baseline and at the end of treatment. Baseline measures were compared between the 88 remitters, 11 non-remitters, and seven dropouts. Additionally, changes in the measures were examined in subjects who recovered from the index depressive episode. RESULTS: Subjects with poorer self-rated health at baseline were more likely both to drop out of treatment and to not respond to adequate treatment. This relationship was independent of demographic measures, severity of depression, physical and social functioning, medical illness, personality, hopelessness, overall medication use, and side effects or non-compliance with treatment. CONCLUSION: Although this finding is preliminary because of the small number of dropouts and non-remitters, it suggests that lower self-rated health may independently predict premature discontinuation of treatment for depression. Additionally, subjects who recovered from depression showed significant improvements in self-rated health, physical disability, and social functioning.

Age at onset in geriatric bipolar disorder. Effects on clinical presentation and treatment outcomes in an inpatient sample.

The authors report on 62 inpatients over age 60 who met DSM-III-R criteria for bipolar disorder, divided into early- and late-onset groups by their median age at lifetime onset, 49 years, in order to examine differences in demographic and clinical characteristics, treatment parameters, and outcome in the two groups during a short-term hospitalization. The late-onset group was more likely to have psychotic features and to demonstrate cerebrovascular risk/burden. However, both groups had similar and highly significant improvements in the Brief Psychiatric Rating Scale, Global Assessment Scale, and the Mini-Mental State Exam, and 87% were able to be discharged to settings no more restrictive than those at admission.

Which elderly depressed patients remain well on maintenance interpersonal psychotherapy alone?: report from the Pittsburgh study of maintenance therapies in late-life depression.

The aim of this study was to identify elderly depressed patients who can remain well on maintenance Interpersonal Psychotherapy (IPT) alone, after discontinuation of antidepressant medication. Using Cox proportional hazards models, increased severity of depression at pretreatment was associated with increased recurrence rates, to an extent greater in patients maintained on monthly IPT than in those maintained on nortriptyline. The long-term response to maintenance IPT was correctly identified in 20/25 cases by a pretreatment Hamilton score of > or = 20. Fourteen of sixteen patients with pretreatment scores of > or = 20 experienced recurrence of major depression on maintenance IPT, while 6/9 patients with pretreatment scores of less than 20 did not. (Fisher exact P = .01). The same pattern of recurrence in relation to severity was not evident in maintenance placebo, nortriptyline, or combination treatment. In addition, Hamilton scores during continuation treatment were lower (< or = 7) among those who remained well on maintenance IPT than among those who had recurrences. Elderly patients whose depressions are milder at baseline and who show excellent symptomatic remission during acute and continuation therapy may be good candidates for monthly maintenance IPT after initial successful treatment with antidepressant medication and psychotherapy.

Effect of continuation treatment on residual symptoms in late-life depression: how well is "well"?

UNLABELLED: The objectives of this report were (1) to describe residual depressive symptoms in elderly patients during continuation therapy with combined nortriptyline and interpersonal psychotherapy; (2) to determine which symptoms were persistent; (3) to determine the clinical correlates of residual depressive symptoms; and (4) to document distinct response pattern clusters during combined continuation therapy. METHOD: Box plot analyses of Hamilton depression scores and Global Assessment Scale scores, repeated twice monthly over 4 months, were conducted using data from 105 elderly depressives. Temporal trends in the data were examined via random regression analysis. Individual trajectories for each of the 105 patients were examined for patterns of response during continuation therapy. RESULTS: We observed a low mean Hamilton rating of 7 (SD = 2.3) at the start of continuation therapy and 5 (SD = 3.0) at the end. Both Hamilton and GAS scores showed modest but significant improvement over time. Hamilton variability was most apparent in symptoms of mood lowering, apathy, anxiety (psychological and somatic), feelings of guilt, anergia, insomnia, and loss of libido; other symptoms (retardation, agitation, hypochondriasis, loss of appetite, loss of weight, suicidal ideation, and loss of insight) showed clear resolution. A diagnosis of RDC situational depression was associated with higher levels of residual symptoms, while level of chronic medical burden, personality dysfunction, and social support were not. Examination of response patterns showed that a quarter of patients experienced one or more brief symptomatic exacerbations. CONCLUSION: On average, an excellent level of symptom resolution was achieved for most patients with Hamilton scores comparable to those seen in healthy elderly controls. These data support a position of therapeutic optimism in late-life depression and underscore full remission as an achievable therapeutic goal.