A Brief Clinical Tool to Estimate Individual Patients' Risk of Depressive Relapse Following Remission: Proof of Concept.

OBJECTIVE: The authors sought to determine whether symptoms experienced by formerly depressed patients after at least 8 weeks of remission can be used to identify their risk for relapse during the next 6 months. METHOD: The study included 188 patients with major depressive disorder from the National Institute of Mental Health Collaborative Depression Study who had at least one Symptom Checklist-90 (SCL-90) assessment after at least 8 weeks of full remission from a depressive episode (defined as a value of 1 on the weekly psychiatric rating scale for all depressive conditions, recorded on Longitudinal Follow-Up Evaluation interviews). Mixed logistic regression was used to identify a set of SCL-90 items that were most predictive of relapse compared with nonrelapse within the next 6 months. RESULTS: Of 514 SCL-90 assessments completed after remission, 73 (14.2%) were followed by depressive relapse within 6 months. Seventeen SCL-90 items (including symptoms of depression, anxiety, and psychological vulnerability) significantly distinguished relapse from nonrelapse. Of these, a set of 12 symptoms maximally separated relapse from nonrelapse. Experiencing one or more of these symptoms had a sensitivity of 80.8% and a specificity of 51.2% for identifying a period in which a relapse occurred, with a positive predictive value of 21.5% and a negative predictive value of 94.2%. The relapse rate was 5.8% when none of the 12 symptoms were present, 16.4% when one to five symptoms were present, 34.1% when six to nine symptoms were present, and 72.7% when 10 or more symptoms were present. CONCLUSIONS: A brief symptom scale can be used to identify patients who, despite full remission from a depressive episode, are at substantial risk of relapse within the next 6 months, and this can be used to provide a basis for personalizing the intensity of follow-up visits.

A New Empirical Definition of Major Depressive Episode Recovery and Its Positive Impact on Future Course of Illness.

OBJECTIVE: To provide the first head-to-head test of the predictive validity of 2 resolution levels included in the current consensus definition of major depressive episode (MDE) recovery and provide an empirically based, clinically useful definition of the end of an MDE. METHOD: 322 participants entering the National Institute of Mental Health Collaborative Depression Study with MDE (diagnosed by Research Diagnostic Criteria) in 1978-1981, and followed thereafter for up to 31 years, were divided into those with 8 consecutive weeks of asymptomatic MDE recovery or residual subsyndromal depressive symptom (SSD) resolution of their index MDE. These 2 levels of recovery were defined based on weekly symptom status on all depressive conditions, assessed by Longitudinal Interval Follow-Up Evaluation (LIFE) interviews conducted every 6 months. Primary measures of validity of these 2 alternative definitions were first well interval duration and long-term depressive illness burden. Groups were also compared on clinical variables, antidepressant treatment, and psychosocial function. RESULTS: 61.2% of subjects recovered asymptomatically from their index MDE. By survival analysis, they remained free of a depressive episode relapse or recurrence 4.2 times longer than those with SSD resolution (median = 135 vs 32 weeks; χ² = 70.65; P < .0001). This was not attributable to a difference in intensity of antidepressant medication. Compared to asymptomatic recovery, SSD resolution was associated with significantly longer and more severe index MDEs, with more miscellaneous psychopathology as well as increased long-term psychosocial dysfunction and a greater depressive illness burden during the ensuing 10 or 20 years. Asymptomatic MDE resolution was a stronger predictor of time well than any of 18 other predictors, singly or combined. Eight consecutive weeks of asymptomatic recovery had 93% overlap with a 4-week definition and conferred little benefit over 4 weeks. CONCLUSIONS: Four consecutive weeks of asymptomatic recovery defines the end of an MDE and the beginning of a stable well state with improved psychosocial function. Residual symptom resolution is a continuation of an active state of the episode, not the end of an MDE.

Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects.

Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as ways to prevent and treat these disturbances. An illustrative case vignette is presented describing a patient's experience of cycles of manic-like behavior and depression while on high-dosage prednisone, with long-term cognitive disorganization, vulnerability to stress, and personality changes. Severe neuropsychiatric consequences (including suicide, suicide attempt, psychosis, mania, depression, panic disorder, and delirium, confusion, or disorientation) have been reported to occur in 15.7 per 100 person-years at risk for all glucocorticoid courses, and 22.2 per 100 person-years at risk for first courses. The majority of patients experience less severe but distressing and possibly persistent changes in mood, cognition, memory, or behavior during glucocorticoid treatment or withdrawal. Although prediction of such effects is difficult, risks vary with age, gender, dosage, prior psychiatric history, and several biological markers. Key mechanisms thought to underlie these risk factors are briefly described. Recommendations are given for identifying individual risk factors and for monitoring and managing adverse neuropsychiatric effects of glucocorticoids.

The prevalence and severity of depressive symptoms along the spectrum of unipolar depressive disorders: a post hoc analysis.

OBJECTIVE: To explore which symptoms are common in patients who experience a range of symptom severity that spans minor depression and major depressive disorder (MDD). METHOD: A post hoc analysis of subjects entering outpatient, pharmacologic treatment studies for minor depression or MDD who provided baseline data on the Inventory for Depressive Symptomatology-Clinician Rated (IDS-C) was performed in November 2000. The minor depression sample included 161 patients diagnosed according to the National Institute of Mental Health Diagnostic Interview Schedule, while the MDD subjects included 969 subjects diagnosed according to the Structured Clinical Interview for DSM-III-R. Descriptive statistics were calculated for the total IDS-C score and for each item-rating score for both groups. The percentages of patients within the low, medium, and high severity groups of minor depression and MDD endorsing each IDS-C item were calculated and used to identify specific patterns of prevalence across the 6 groups: symptoms with high prevalence in all groups (core symptoms), those with increasing prevalence across groups (continuum symptoms), and those that become prominent only at a certain threshold of illness severity. RESULTS: The mean (SD) IDS-C score was 21.18 (5.37) for minor depression patients, while it was 37.14 (7.27) for the MDD patients (P = .0001). Ten items pertaining mostly to mood state and cognition were identified as "core" symptoms of depression based on their high prevalence in all groups. Fourteen items consisting mostly of neurovegetative and somatic symptoms were identified as "continuum" symptoms based on their general pattern of increasing prevalence across the 6 severity groups. Four "threshold" symptoms, including suicidal ideation, psychomotor slowing, gastrointestinal symptoms, and panic/phobic symptoms, were prevalent in only the most severely depressed groups. CONCLUSIONS: The presence of core, continuum, and threshold depressive symptoms indicates central features of both minor depression and MDD as well as symptoms that increase or emerge with depressive illness severity. Some of the core symptoms of minor depression and MDD are not included in DSM depressive criteria or traditional assessment rating scales.

The challenge of connecting the dots in the B.R.A.I.N.

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress.

Overt irritability/anger in unipolar major depressive episodes: past and current characteristics and implications for long-term course.

IMPORTANCE: Although symptoms of irritability or anger are not central to the diagnosis of unipolar major depressive episodes (MDEs), these symptoms have been found, in cross-sectional studies, to be highly prevalent and associated with increased comorbidity and depressive illness burden. OBJECTIVE: To determine the prevalence of overtly expressed irritability/anger and its effect on intake presentation and the long-term course of illness. DESIGN: A prospective, naturalistic investigation of patients with unipolar MDEs, studied systematically at intake and during up to 31 years of follow-up. SETTING: Five US academic medical centers. PARTICIPANTS: Patients entered the National Institute of Mental Health Collaborative Depression Study during an MDE in 1978, 1979, 1980, or 1981. Patients with unipolar MDE at intake (n = 536) were divided into those with and those without current comorbid overtly expressed irritability/anger. EXPOSURE: In this observational, longitudinal study, patients received treatment that was recorded but not controlled. MAIN OUTCOMES AND MEASURES: Groups were compared on illness severity and chronicity, psychosocial impairment, quality of life, suicidal behavior, lifetime comorbid diagnoses, impulse control, and measures associated with bipolarity. RESULTS: Overt irritability/anger was present in 292 of 536 participants with a unipolar MDE at study intake (54.5%). It was associated with significantly increased depressive severity, longer duration of the index MDE, poorer impulse control, a more chronic and severe long-term course of illness, higher rates of lifetime comorbid substance abuse and anxiety disorder, more antisocial personality disorders, greater psychosocial impairment before intake and during follow-up, reduced life satisfaction, and a higher rate of bipolar II disorder in relatives. No association was found with increased suicidal ideation or behavior. Results were not explained by comorbidity or other manic spectrum symptoms. CONCLUSIONS AND RELEVANCE: This study extends results of cross-sectional investigations and indicates that irritability/anger during MDEs is a highly prevalent clinical marker of a more severe, chronic, and complex depressive illness. Findings have important implications for assessment and treatment.

Fluoxetine increases suicide ideation less than placebo during treatment of adults with minor depressive disorder.

OBJECTIVE: Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with minor depressive disorder. METHODS: Research subjects were adult outpatients with minor depressive disorder (N = 162), who received fluoxetine or placebo in a prospective, 12-week, double-blind randomized trial. The research participants were evaluated weekly with standard rating scales that included four suicide-related items: item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 points on any of these items. RESULTS: Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine-treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p = 0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p = 0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. CONCLUSIONS: Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with minor depressive disorder during 12 weeks of treatment.

Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes.

BACKGROUND: There is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of 'depressive mixed state.' This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined. METHODS: Bipolar (type I or II) patients with an MDE at intake (N=142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation. RESULTS: Subsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms. LIMITATIONS: The findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment. CONCLUSIONS: The presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality.

Subthreshold depression and successful aging in older women.

OBJECTIVES: Subthreshold depression (StD) is common in older adults and is associated with poor self-rated health. However, the impact of StD on broader indicators of successful aging, such as positive psychological constructs, cognitive functioning, or quality of well-being, has not been assessed. The authors compared persons with scores above and below a predetermined threshold on the Center for Epidemiological Studies Scale for Depression (CES-D) with nondepressed (ND) persons on measures of multiple domains associated with successful aging. DESIGN: Cross-sectional survey-based psychological assessments. PARTICIPANTS: A total of 1,979 community-dwelling older women participating in the Women's Health Initiative study. MEASUREMENTS: ND was defined as a CES-D score below 8, StD as a score between 8 and 15, and CES-D Depression (CD) as a score of 16 or above. The study questionnaire consisted of multiple self-reported measures of positive psychological functioning (e.g., optimism and resilience), cognitive functioning and complaints, and quality of well-being. The authors also obtained a history of diagnosis, treatment, and hospitalization related to mental health problems. RESULTS: Overall 20.2% of women met CES-D criteria for StD and 7% for CD. Women with StD had worse self-rated successful aging, worse physical and emotional functioning, lower optimism, more negative attitudes toward aging, lower personal mastery and self-efficacy, and greater anxiety and hostility than ND women but scored better on all these measures than women with CD. Subjects with StD also had higher self-reported rates of previous diagnosis, treatment, and hospitalization for mental health problems than the ND group. Subjects with StD with depressed mood and/or anhedonia were largely similar to those without these symptoms. CONCLUSIONS: Mild-moderate levels of depressive symptoms that likely fall under a general category of StD were common and were associated with worse functioning on virtually every component of successful aging that the authors examined. StD represents a clinical entity that may affect the longitudinal course of successful aging for large numbers of persons and is a potential target for clinical intervention.

Conference summary and conclusions. A comprehensive approach to predicting and managing mood effects of glucocorticoids.

The discovery of glucocorticoids and their enormous therapeutic benefits led to the use of these compounds as valuable medications for a wide variety of diseases. In 1950 this effort was ushered in by a landmark event-the awarding of the 1950 Nobel Prize in Physiology and Medicine to Drs. Phillip Hench, Edward Kendall, and Tadeus Reichstein. It was Hench who described and researched the successful use of the glucocorticoid, cortisone, and pituitary adrenocorticotrophic hormones to treat rheumatoid arthritis. Significant scientific discovery preceded Hench and colleagues' efforts, but the revolutionary accumulation of discovery in glucocorticoids since then is one of the unique scientific stories in the history of medicine. The scientific conference upon which this volume is based represents an attempt to convene a state-of-the-science meeting on the current understanding and scientific status of this fascinating, far-reaching, and fast-moving field. This last chapter will summarize the exciting presentations of this 2-day conference.

Anxiety and outcome in bipolar disorder.

OBJECTIVE: Important differences exist between bipolar disorder with and without comorbid anxiety, but little is known about the long-term prognostic significance of coexisting anxiety in bipolar disorder. The authors sought to identify the anxiety features most predictive of subsequent affective morbidity and to evaluate the persistence of the prognostic relationship. METHOD: Probands with bipolar I or II disorder from the National Institute of Mental Health Collaborative Depression Study were followed prospectively for a mean of 17.4 years (SD=8.4) and were characterized according to various manifestations of anxiety present at baseline. A series of general linear model analyses examined the relationship between these measures and the proportion of follow-up weeks in episodes of major depression and in episodes of mania or hypomania. RESULTS: Patients whose episode at intake included a depressive phase spent nearly three times as many weeks in depressive episodes than did those whose intake episode was purely manic. Psychic and somatic anxiety ratings, but not the presence of panic attacks or of any lifetime anxiety disorder, added to the predictive model. Combined ratings of psychic and somatic anxiety were associated in a stepwise fashion with a greater proportion of weeks in depressive episodes, and this relationship persisted over the follow-up period. CONCLUSIONS: The presence of higher levels of anxiety during bipolar mood episodes appears to mark an illness of substantially greater long-term depressive morbidity.

Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence.

CONTEXT: Both bipolar disorder type I and type II are characterized by frequent affective episode relapse and/or recurrence. An increasingly important goal of therapy is reducing chronicity by preventing or delaying additional episodes. OBJECTIVES: To determine whether the continued presence of subsyndromal residual symptoms during recovery from major affective episodes in bipolar disorder is associated with significantly faster episode recurrence than asymptomatic recovery and whether this is the strongest correlate of early episode recurrence among 13 variables examined. DESIGN: An ongoing prospective, naturalistic, and systematic 20-year follow-up investigation of mood disorders: the National Institute of Mental Health Collaborative Depression Study. SETTING: Five academic tertiary care centers. PARTICIPANTS: Two hundred twenty-three participants with bipolar disorder (type I or II) were followed up prospectively for a median of 17 years (mean, 14.1 [SD, 6.2] years). MAIN OUTCOME MEASURE: Participants defined as recovered by Research Diagnostic Criteria from their index major depressive episode and/or mania were divided into residual vs asymptomatic recovery groups and were compared according to the time to their next major affective episodes. RESULTS: Participants recovering with residual affective symptoms experienced subsequent major affective episodes more than 3 times faster than asymptomatic recoverers (hazard ratio, 3.36; 95% confidence interval, 2.25-4.98; P < .001). Recovery status was the strongest correlate of time to episode recurrence (P < .001), followed by a history of 3 or more affective episodes before intake (P = .007). No other variable examined was significantly associated with time to recurrence. CONCLUSIONS: In bipolar disorder, residual symptoms after resolution of a major affective episode indicate that the individual is at significant risk for a rapid relapse and/or recurrence, suggesting that the illness is still active. Stable recovery in bipolar disorder is achieved only when asymptomatic status is achieved.

Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders.

OBJECTIVE: The research literature on psychosocial disability and work in mood disorders has either focused on relatively short-term course, or did not consider direct comparisons of these domains across all three of the affective subtypes of bipolar I (BP-I), bipolar II (BP-II), and unipolar major depressive disorders (UP-MDD). METHODS: Mean composite measures of psychosocial impairment and months at specific levels of overall and work impairment were compared for 158 BP-I, 133 BP-II, and 358 UP-MDD patients based on semi-structured interviews conducted during 15 years of follow-up in the NIMH Collaborative Depression Study (CDS). These are contrasted with a single month of psychosocial impairment ratings for a sample of 1787 subjects with no current psychiatric disorder. RESULTS: Patients with mood disorders experienced some degree of disability during the majority of long-term follow-up (54 to 59% of months), including 19 to 23% of months with moderate and 7 to 9% of months with severe overall impairment. Severe disability occurred a substantial percentage of time only in the specific area of work role function. BP-I patients were completely unable to carry out work role functions during 30% of assessed months, which was significantly more than for UP-MDD and BP-II patients (21% and 20%, respectively). CONCLUSIONS: These findings have public health, economic, and clinical importance, and underscore the need to reduce the chronicity and impairment associated with these three prevalent affective disorder subtypes. Interventional research is just beginning to address these challenges.

Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study.

CONTEXT: Evidence of psychosocial disability in bipolar disorder is based primarily on bipolar I disorder (BP-I) and does not relate disability to affective symptom severity and polarity or to bipolar II disorder (BP-II). OBJECTIVE: To provide detailed data on psychosocial disability in relation to symptom status during the long-term course of BP-I and BP-II. DESIGN: A naturalistic study with 20 years of prospective, systematic follow-up. SETTING: Inpatient and outpatient treatment facilities at 5 US academic centers. Patients One hundred fifty-eight patients with BP-I and 133 patients with BP-II who were followed up for a mean (SD) of 15 (4.8) years in the National Institute of Mental Health Collaborative Depression Study. MAIN OUTCOME MEASURES: The relationship, by random regression, between Range of Impaired Functioning Tool psychosocial impairment scores and affective symptom status in 1-month periods during the long-term course of illness from 6-month and yearly Longitudinal Interval Follow-up Evaluation interviews. RESULTS: Psychosocial impairment increases significantly with each increment in depressive symptom severity for BP-I and BP-II and with most increments in manic symptom severity for BP-I. Subsyndromal hypomanic symptoms are not disabling in BP-II, and they may even enhance functioning. Depressive symptoms are at least as disabling as manic or hypomanic symptoms at corresponding severity levels and, in some cases, significantly more so. At each level of depressive symptom severity, BP-I and BP-II are equally impairing. When asymptomatic, patients with bipolar disorder have good psychosocial functioning, although it is not as good as that of well controls. CONCLUSIONS: Psychosocial disability fluctuates in parallel with changes in affective symptom severity in BP-I and BP-II. Important findings for clinical management are the following: (1) depressive episodes and symptoms, which dominate the course of BP-I and BP-II, are equal to or more disabling than corresponding levels of manic or hypomanic symptoms; (2) subsyndromal depressive symptoms, but not subsyndromal manic or hypomanic symptoms, are associated with significant impairment; and (3) subsyndromal hypomanic symptoms appear to enhance functioning in BP-II.

Tachyphylaxis in unipolar major depressive disorder.

BACKGROUND: Major depressive disorder is usually a recurring illness, and maintenance treatment is used to forestall or prevent recurrent episodes of depression. This study describes recurrence of major depression despite maintenance pharmacotherapy, termed tachyphylaxis. METHOD: The study sample consisted of 103 subjects who participated in the NIMH Collaborative Depression Study, a multicenter longitudinal observational study of the mood disorders. Subjects diagnosed with unipolar major depressive disorder according to Research Diagnostic Criteria were enrolled from 1978-1981 and prospectively followed for up to 20 years. As an observational study, treatment was recorded but not controlled by anyone connected with the study. Subjects were selected for the present study if at some point during follow-up they received antidepressant medication for treatment of an episode of major depressive disorder, recovered from this episode, and subsequently received maintenance pharmacotherapy. Some subjects were successfully treated for multiple episodes of major depressive disorder and then received maintenance medication after each of these episodes, resulting in multiple maintenance treatment intervals. Data were collected using the Longitudinal Interval Follow-Up Evaluation, and mixed-effects logistic regression was used to test the association of sociodemographic and clinical variables with tachyphylaxis. RESULTS: For the 103 subjects, there were 171 maintenance treatment intervals in which a subject received maintenance pharmacotherapy after having recovered from an episode of major depressive disorder. The median duration of maintenance treatment was 20 weeks. Tachyphylaxis occurred during 43 (25%) of these 171 maintenance treatment intervals. The subtype of melancholic (endogenous) major depressive disorder significantly elevated the risk of tachyphylaxis during the subsequent maintenance treatment interval. CONCLUSIONS: Despite the use of maintenance pharmacotherapy, major depression recurs in a considerable number of patients. Improved prophylaxis for these patients requires other treatment strategies based upon a greater understanding of recurrence.

Randomized, placebo-controlled trial of fluoxetine for acute treatment of minor depressive disorder.

OBJECTIVE: Minor depressive disorder is both common and associated with significant psychosocial impairment. This study examined antidepressant treatment efficacy in a large group of patients with minor depressive disorder. METHOD: One hundred sixty-two patients with minor depressive disorder were randomly assigned to receive fluoxetine or placebo in a 12-week, double-blind study; 73% (59 of 81) of the patients in each treatment group completed the study. Patients were evaluated weekly with standard depression rating instruments and measures of psychosocial impairment. Hypotheses were tested by last-observation-carried-forward analysis of variance (ANOVA) and confirmed by mixed (random-effects) regression analysis. RESULTS: At baseline, minor depressive disorder patients were mildly to moderately depressed, with a corresponding degree of functional impairment. Over 12 weeks of treatment, both ANOVA and mixed regression showed fluoxetine to be superior to placebo as indicated by significantly greater improvement of fluoxetine-treated patients in scores on the 30-item clinician-rated Inventory of Depressive Symptomatology, the 17-item and 21-item Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Clinical Global Impression severity scale. Improvement in Global Assessment of Functioning Scale score was significantly greater for the fluoxetine group in mixed regression analysis only. Patients in both treatment groups reported a similar number and severity of adverse events during the 12-week treatment period. CONCLUSIONS: Clinicians frequently encounter minor depressive disorder either as a prodromal or residual phase of illness in major depressive disorder or as de novo minor depressive disorder episodes. Fluoxetine is significantly superior to placebo in reducing minor depressive disorder symptoms within a 12-week period. Improvement in psychosocial function with fluoxetine may take longer than 12 weeks.