The time course of nonchronic major depressive disorder. Uniformity across episodes and samples. National Institute of Mental Health Collaborative Program on the Psychobiology of Depression--Clinical Studies.

BACKGROUND: Most natural history studies of affective disorders have emphasized the prediction of eventual recovery. Little is known of changes over time in the immediate probability of recovery. METHODS: To identify regularities in the timing of recovery from nonbipolar major depressive disorders, we considered only episodes that began during follow-up to increase the accuracy with which onsets were timed and to limit the study sample to individuals who had a demonstrably episodic course. Five participating centers conducted baseline assessments and followed probands (N = 605) and nonclinical subjects (relatives, controls, and spouses, N = 826) up for 6 years. During that time, 359 probands had at least one prospectively observed episode, and 181 had two episodes; corresponding numbers for the nonclinical subjects were 216 and 78, respectively. Our analyses considered the distribution of episode lengths across ascertainment source (probands vs nonclinical subjects), center, and episode number (first vs second prospectively observed episode). RESULTS: Distribution was remarkably uniform. Regardless of ascertainment source, center, or episode number, recovery occurred within 3 months in 40% of episodes, within 6 months in 60%, and within 1 year in 80%; 20% had more protracted courses. CONCLUSIONS: Once triggered, the immediate likelihood of recovery changes over time in a predictable fashion. This has practical implications for the study of antidepressant efficacy and theoretical implications for factors involved in affective dysregulation.

Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects.

The course of illness of 431 subjects with major depression participating in the National Institute of Mental Health Collaborative Depression Study was prospectively observed for 5 years. Twelve percent of the subjects still had not recovered by 5 years. There were decreasing rates of recovery over time. For example, 50% of the subjects recovered within the first 6 months, and then the rate of recovery declined markedly. Instantaneous probabilities of recovery reflect that the longer a patient was ill, the lower his or her chances were of recovering. For patients still depressed, the likelihood of recovery within the next month declined from 15% during the first 3 months of follow-up to 1% to 2% per month during years 3, 4, and 5 of this follow-up. The severity of current psychopathology predicted the probability of subsequent recovery. Subjects with moderately severe depressive symptoms, minor depression, or dysthymia had an 18-fold greater likelihood of beginning recovery within the next week than did subjects who were at full criteria for major depressive disorder. Many subjects who did not recover continued in an episode that looked more like dysthymia than major depressive disorder.

Recovery after 5 years of unremitting major depressive disorder.

BACKGROUND: The long-term course of depression in patients who present for treatment carries prognostic and therapeutic implications. This study presents prospective data on the time to recovery from an episode of major depressive disorder of 5 years' duration among patients followed up since 1978 in the National Institutes of Mental Health Collaborative Program on the Psychobiology of Depression. METHODS: Survival analysis was used to examine the 10-year course of the 431 probands with major depressive disorder with a specific focus on the 35 probands who were observed to be continuously ill for the first 5 years. Univariate analytic techniques were used to describe the demographic and clinical variables in the group that recovered and the group that did not. By study design, somatic treatment was assessed but not controlled by the investigators. RESULTS: By year 10, 93% (Kaplan-Meier estimate) of probands had recovered from their intake episode of major depressive disorder. In those ill for the first 5 years, 38% had recovered within the next 5 years. Shorter duration of illness prior to intake and being married were associated with the group that recovered. Pharmacological treatment dosages averaged 100 mg of imipramine hydrochloride equivalent in the chronically ill group. CONCLUSIONS: Despite lengthy periods of illness, people continued to recover from major depressive disorder for up to 10 years of prospective follow-up. Few demographic and clinical variables distinguished those who recovered from those who did not. Treatment, as observed in this naturalistic study, was at a low level despite lengthy illness.

Recovery from major depression. A 10-year prospective follow-up across multiple episodes.

BACKGROUND: Major depressive disorder is often marked by repeated episodes of depression. We describe recovery from major depression across multiple mood episodes in patients with unipolar major depression at intake and examine the association of sociodemographic and clinical variables with duration of illness. METHODS: A cohort of 258 subjects treated for unipolar major depressive disorder was followed up prospectively for 10 years as part of the Collaborative Depression Study, a multicenter naturalistic study of the mood disorders. Diagnoses were made according to the Research Diagnostic Criteria, and the course of illness was assessed with the Longitudinal Interval Follow-up Evaluation. Survival analyses were used to calculate the duration of illness for the first 5 recurrent mood episodes after recovery from the index episode. RESULTS: Diagnosis remained unipolar major depressive disorder for 235 subjects (91%). The median duration of illness was 22 weeks for the first recurrent mood episode, 20 weeks for the second, 21 weeks for the third, and 19 weeks for the fourth and fifth recurrent mood episodes; the 95% confidence intervals were highly consistent. From one episode to the next, the proportion of subjects who recovered by any one time point was similar. For subjects with 2 or more recoveries, the consistency of duration of illness from one recovery to the next was low to moderate. None of the sociodemographic or clinical variables consistently predicted duration of illness. CONCLUSION: In this sample of patients treated at tertiary care centers for major depressive disorder, the duration of recurrent mood episodes was relatively uniform and averaged approximately 20 weeks.

Psychosocial disability during the long-term course of unipolar major depressive disorder.

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders.

BACKGROUND: Investigations of unipolar major depressive disorder (MDD) have focused primarily on major depressive episode remission/recovery and relapse/recurrence. This is the first prospective, naturalistic, long-term study of the weekly symptomatic course of MDD. METHODS: The weekly depressive symptoms of 431 patients with MDD seeking treatment at 5 academic centers were divided into 4 levels of severity: (1) depressive symptoms at the threshold for MDD; (2) depressive symptoms at the threshold for minor depressive or dysthymic disorder (MinD); (3) subsyndromal or subthreshold depressive symptoms (SSDs), below the thresholds for MinD and MDD; and (4) no depressive symptoms. The percentage of weeks at each level, number of changes in symptom level, and medication status were analyzed overall and for 3 subgroups defined by mood disorder history. RESULTS: Patients were symptomatically ill in 59% of weeks. Symptom levels changed frequently (1.8/y), and 9 of 10 patients spent weeks at 3 or 4 different levels during follow-up. The MinD (27%) and SSD (17%) symptom levels were more common than the MDD (15%) symptom level. Patients with double depression and recurrent depression had more chronic symptoms than patients with their first lifetime major depressive episode (72% and 65%, respectively, vs 46% of follow-up weeks). CONCLUSION: The long-term weekly course of unipolar MDD is dominated by prolonged symptomatic chronicity. Combined MinD and SSD level symptoms were about 3 times more common (43%) than MDD level symptoms (15%). The symptomatic course is dynamic and changeable, and MDD, MinD, and SSD symptom levels commonly alternate over time in the same patients as a symptomatic continuum of illness activity of a single clinical disease.

Does major depression result in lasting personality change?

OBJECTIVE: Individuals with a history of depression are characterized by high levels of certain personality traits, particularly neuroticism, introversion, and interpersonal dependency. The authors examined the "scar hypothesis," i.e., the possibility that episodes of major depression result in lasting personality changes that persist beyond recovery from the depression. METHOD: A large sample of first-degree relatives, spouses, and comparison subjects ascertained in connection with the proband sample from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression were assessed at two points in time separated by an interval of 6 years. Subjects with a prospectively observed first episode of major depression during the interval were compared with subjects remaining well in terms of change from time 1 to time 2 in self-reported personality traits. All subjects studied were well (had no mental disorders) at the time of both assessments. RESULTS: There was no evidence of negative change from premorbid to postmorbid assessment in any of the personality traits for subjects with a prospectively observed first episode of major depression during the interval. The results suggested a possible association of number and length of episodes with increased levels of emotional reliance and introversion, respectively. CONCLUSIONS: The findings suggest that self-reported personality traits do not change after a typical episode of major depression. Future studies are needed to determine whether such change occurs following more severe, chronic, or recurrent episodes of depression.

Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects.

OBJECTIVE: There has been speculation in the literature about a link between fluoxetine use and suicidal behavior. The authors of this study hypothesized that there is no elevation in risk of suicidal behavior associated with use of fluoxetine. METHOD: The data come from the National Institute of Mental Health Collaborative Depression Study, a prospective, naturalistic follow-up of persons who presented for treatment of affective disorders. The analyses included data on 643 subjects who were followed up after fluoxetine was approved by the Food and Drug Administration in December 1987 for the treatment of depression. RESULTS: Nearly 30% (N = 185) of the study group was treated with fluoxetine at some point during the follow-up period. Relative to the other subjects, those who were subsequently treated with fluoxetine had onset of affective illness at a younger age and, after intake into the study and before 1988, had elevated rates of suicide attempts before fluoxetine treatment. A mixed-effects survival analysis that incorporated treatment exposure time, multiple treatment trials, and multiple suicide attempts per subject showed that relative to no treatment, use of fluoxetine and use of other somatic antidepressants were associated with nonsignificant reductions in the likelihood of suicide attempts or completions. Severity of psychopathology was strongly associated with elevated risk, and each suicide attempt after intake into the Collaborative Depression Study was associated with a marginally significant increase in risk of suicidal behavior. CONCLUSIONS: The results do not support the speculation that fluoxetine increases the risk of suicide. Rather, there was a nonsignificant reduction in risk of suicidal behavior among patients treated with fluoxetine, even though those subjects were more severely ill before treatment with fluoxetine.

Recurrence after recovery from major depressive disorder during 15 years of observational follow-up.

OBJECTIVE: The recurrence of an affective disorder in people who initially recover from major depressive disorder was characterized by using the unique longitudinal prospective follow-up data from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression-Clinical Studies. METHOD: Up to 15 years of prospective follow-up data on the course of major depressive disorder were available for 380 subjects who recovered from an index episode of major depressive disorder and for 105 subjects who subsequently remained well for at least 5 years after recovery. Baseline demographic and clinical characteristics were examined as predictors of recurrence of an affective disorder. The authors also examined naturalistically applied antidepressant therapy. RESULTS: A cumulative proportion of 85% (Kaplan-Meier estimate) of the 380 recovered subjects experienced a recurrence, as did 58% (Kaplan-Meier estimate) of those who remained well for at least 5 years. Female sex, a longer depressive episode before intake, more prior episodes, and never marrying were significant predictors of a recurrence. None of these or any other characteristic persisted as a predictor of recurrence in subjects who recovered and were subsequently well for at least 5 years. Subjects reported receiving low levels of antidepressant treatment during the index episode, which further decreased in amount and extent during the well interval. CONCLUSIONS: Few baseline demographic or clinical characteristics predict who will or will not experience a recurrence of an affective disorder after recovery from an index episode of major depressive disorder, even in persons with lengthy well intervals. Naturalistically applied levels of antidepressant treatment are well below those shown effective in maintenance pharmacotherapy studies.

Prognostic effect of the variable course of alcoholism on the 10-year course of depression.

OBJECTIVE: The purpose of this study was to examine the predictive effect of the clinical activity of patients' alcohol use on the course of major depressive disorder. METHOD: One hundred seventy-six probands with Research Diagnostic Criteria (RDC) diagnoses of both major depressive disorder and alcoholism were compared to 412 probands with major depressive disorder only by using 10 years of short-interval, prospective follow-up data collected as part of the National Institute of Mental Health Collaborative Depression Study. The course of depression was examined by using intensity analysis to represent transitions between states of major depressive disorder. The effect of patients' RDC alcoholism status on the long-term course of major depressive disorder was examined by stratifying the analyses by three levels of alcoholism--never alcoholic, not meeting criteria for current alcoholism, and current alcoholism. RESULTS: Depressed probands who were either never alcoholic or currently nonactive alcoholic had twice the likelihood of recovery from major depressive disorder than did actively alcoholic depressed probands. The three levels of alcoholism did not differentially predict recurrence of major depressive disorder. CONCLUSIONS: These findings provide long-term, empirically derived evidence for the deleterious effect of current alcoholism on recovery from depression. The lack of a differential effect of the three levels of alcoholism on recurrence of major depressive disorder suggests that other factors may have greater predictive value.

Multiple recurrences of major depressive disorder.

OBJECTIVE: The authors of this study examined multiple recurrences of unipolar major depressive disorder. METHOD: A total of 318 subjects with unipolar major depressive disorder were prospectively followed for 10 years within a multicenter naturalistic study. Survival analytic techniques were used to examine the probability of recurrence after recovery from the index episode. RESULTS: The mean number of episodes of major depression per year of follow-up was 0. 21, and nearly two-thirds of the subjects suffered at least one recurrence. The number of lifetime episodes of major depression was significantly associated with the probability of recurrence, such that the risk of recurrence increased by 16% with each successive recurrence. The risk of recurrence progressively decreased as the duration of recovery increased. Within subjects, there was very little consistency in the time to recurrence. CONCLUSIONS: Major depressive disorder is a highly recurrent illness. The risk of the recurrence of major depressive disorder progressively increases with each successive episode and decreases as the duration of recovery increases.

Benzodiazepine use in anxiety disordered patients with and without a history of alcoholism.

BACKGROUND: People with a history of alcohol use disorders are thought to be at risk for misusing prescribed benzodiazepines. We examine the use of prescribed benzodiazepines in anxiety disordered subjects with and without a history of alcohol dependence or abuse. METHOD: A group of 343 subjects in the Harvard/Brown Anxiety Disorders Research Program (HARP) who were taking benzodiazepines at the time of entry into a prospective study of anxiety disorders serve as the study group. Subjects with (N=99) and without (N=244) a history of alcohol use or dependence (DSM- III-R) are examined for their reported total daily dose, p.r.n. use, or continued use of benzodiazepines. RESULTS: There is no significant difference in maximum daily dose or continued use of benzodiazepines over 12 months of follow- up. There is a clinically small but statistically significant difference in median daily dose during the second but not the first 6 months of follow-up for the alcohol history positive versus alcohol history negative groups. Additionally, there was significantly less reported use of p.r.n. benzodiazepines in the alcohol history positive versus alcohol history negative subjects during the second 6 months, but not the first 6 months, of follow-up. CONCLUSION: The presence or absence of a history of alcohol use disorders is not a strong predictor of the use of benzodiazepines in subjects with anxiety disorders over 12 months of prospective follow-up.

Secular trends in lifetime onset of MDD stratified by selected sociodemographic risk factors.

We used multivariate proportional hazards (Cox) models to investigate the effects of cohort of birth on age of first onset of major depression measured independently at two occasions, about six years apart, in the first degree relatives of probands with major affective illnesses. We estimated the cohort trends in strata defined by sociodemographic and other measures, to see if the cohort trends are the same across strata. Graphical summaries of the trends reveal a generally consistent pattern of increasing rates and earlier age of onset with successive birth cohorts, across all strata examined. The relatives with a divorced parent had a somewhat delayed secular increase, suggesting either a ceiling effect or an interaction of the two risk factors (recent cohort of birth and divorced parents) such that the combined effect is less than the sum of the individual effects. Otherwise, the cohort effect is persistent and ubiquitous in this sample.

Cognitive-behavioral treatment for depression in alcoholism.

Alcoholics with depressive symptoms score > or = 10 on the Beck Depression Inventory (A.T. Beck, C. H. Ward, M. Mendelson, J. Mock, & J. Erbaugh, 1961) received 8 individual sessions of cognitive-behavioral treatment for depression (CBT-D, n = 19) or a relaxation training control (RTC; n = 16) plus standard alcohol treatment. CBT-D patients had greater reductions in somatic depressive symptoms and depressed and anxious mood than RTC patients during treatment. Patients receiving CBT-D had a greater percentage of days abstinent but not greater overall abstinence or fewer drinks per day during the first 3-month follow-up. However, between the 3- and 6-month follow-ups, CBT-D patients had significantly better alcohol use outcomes on total abstinence (47% vs. 13%), percent days abstinent (90.5% vs. 68.3%), and drinks per day (0.46 vs. 5.71). Theoretical and clinical implications of using CBT-D in alcohol treatment are discussed.

Recovery, chronicity, and levels of psychopathology in major depression.

Major depression is a chronic and recurrent disorder for many people who are afflicted by it. There is a wealth of literature addressing the course of this disorder with follow-up times varying from several months to several decades, which gives a remarkably consistent picture in treated and untreated populations. Fortunately, most people who develop major depression recover from their initial episode; unfortunately, a significant minority do not recover fully and a near majority develop additional episodes. This article examines a selected group of studies that have examined the course of depression, with a focus on a large naturalistic longitudinal prospective study of affective disorders--the NIMH Collaborative Depression Study.

Five-year course of major depression: effects of comorbid alcoholism.

Some patients enter psychiatric treatment with clear cases of both major depression and alcoholism. While assumptions are often made about the relationships of these two conditions, little empirical evidence exists on the effects of sustained remissions in alcoholism on sustained remissions in depression. 127 patients with both disorders at treatment entry were studied over a 5-year period. Survival analyses with time-dependent covariates indicating alcoholism status were used to investigate remissions and relapses in major depression. Remission in alcoholism strongly and significantly increased the chances of remission in depression and were also related to reduced chances of depression relapse, although at a weaker level.

Personality traits in subjects with bipolar I disorder in remission.

This study compared the personality traits of subjects with bipolar I disorder in remission to the personality traits of subjects with no history of any mental illness. Subjects were assessed as part of a prospective, multicenter, naturalistic study of mood disorders. Diagnoses were rendered according to Research Diagnostic Criteria, through use of the Schedule for Affective Disorders and Schizophrenia - Lifetime Version. A total of 30 euthymic bipolar I subjects were compared to 974 never-ill subjects on 17 personality scales selected for their relevance to mood disorders. The subjects with bipolar I disorder in remission had more aberrant scores on 6 of the 17 personality measures, including Emotional Stability, Objectivity, Neuroticism, Ego Resiliency, Ego Control, and Hysterical Factor. These findings indicate that patients with bipolar I disorder in remission have personality traits that differ from those of normal controls.

Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.

BACKGROUND: The study tested whether level of recovery from major depressive episodes (MDEs) predicts duration of recovery in unipolar major depressive disorder (MDD) patients. METHODS: MDD patients seeking treatment at five academic centers were followed naturalistically for 10 years or longer. Patients were divided on the basis of intake MDE recovery into residual depressive symptoms (SSD; N=82) and asymptomatic (N=155) recovery groups. They were compared on time to first episode relapse/recurrence, antidepressant medication, and comorbid mental disorders. Recovery level was also compared to prior history of recurrent MDEs ( > 4 lifetime episodes) as a predictor of relapse/recurrence. RESULTS: Residual SSD compared to asymptomatic recovery patients relapsed to their next MDE > 3 times faster (median=68 vs. 23 weeks) and to any depressive episode > 5 times faster (median=33 vs. 184 weeks). Residual SSD recovery status was significantly associated with early episode relapse (OR=3.65) and was stronger than history of recurrent MDEs (OR=1.64). Rapid relapse in the SSD group could not be attributed to higher comorbidity or lower antidepressant treatment. LIMITATIONS: Although inter-rater agreement on weekly depressive symptom ratings was very high (ICC > 0.88), some error may exist in assigning recovery levels. Antidepressant treatments were recorded, but were not controlled. CONCLUSIONS: MDE recovery is a powerful predictor of time to episode relapse/recurrence. Residual SSD recovery is associated with very rapid episode relapse which supports the idea that SSD is an active state of illness. Asymptomatic recovery is associated with prolonged delay in episode recurrence. These findings of this present study have important implications for the goals of treatment of MDD and for defining true MDE recovery.