Version July 2025
INTRODUCTION —
Major depressive disorder (unipolar major depression) and persistent depressive disorder (dysthymia) represent depressive syndromes that are distinguished by the type and number of symptoms that occur as well as their duration. Depressive symptoms can include depressed mood, loss of interest or pleasure in most or all activities, insomnia or hypersomnia, change in appetite or weight, psychomotor retardation or agitation, low energy, poor concentration, thoughts of worthlessness or guilt, and recurrent thoughts about death or suicide [1]. The World Health Organization estimated that major depressive disorder was the 11th greatest cause of disability and mortality in the world among 291 diseases and causes of injuries [2].
Preliminary studies suggest that course of illness may be associated with functional and structural brain changes. As an example, functional magnetic resonance imaging (MRI) studies of individuals with depression detect increased activity in limbic regions and decreased activity in the frontal cortex [3]. Similarly, in a one-year prospective study of patients with treatment-resistant major depression (n = 26) who received pharmacotherapy, remission was associated with subtle increases in hippocampal volume and cortical thickness, whereas nonremission was associated with decreased volume and thickness on MRI [4].
This topic reviews the course of illness in adults with major depressive disorder and persistent depressive disorder. The course of illness in psychotic depression and minor depression is discussed separately, as are the epidemiology, clinical features, diagnosis, and treatment of depression:
●(See "Major depression in adults: Epidemiology".)
●(See "Approach to the adult patient with suspected depression".)
●(See "Major depressive disorder in adults: Approach to initial management".)
●(See "Unipolar depression in adults: Choosing treatment for resistant depression".)
●(See "Diagnosis and management of late-life depression".)
DEFINITIONS —
Major depressive disorder (unipolar major depression) and persistent depressive disorder (dysthymia) are defined in the American Psychiatric Association's Diagnostic and Statistical Manual, Fifth Edition, Text Revision [1]:
●Major depressive disorder is diagnosed in patients who have suffered at least one major depressive episode (table 1). An episode is a period lasting at least two weeks, with five or more of the following nine symptoms: depressed mood, loss of interest or pleasure in most or all activities, insomnia or hypersomnia, change in appetite or weight, psychomotor retardation or agitation, low energy, poor concentration, thoughts of worthlessness or guilt, and recurrent thoughts about death or suicide.
●Persistent depressive disorder (dysthymia) is diagnosed in patients with depressed mood for at least two years that is accompanied by at least two of the following symptoms: decreased or increased appetite, insomnia or hypersomnia, low energy, poor self-esteem, poor concentration, and hopelessness (table 2).
Additional information about the clinical presentation and diagnosis of major depressive disorder and persistent depressive disorder (dysthymia) is discussed separately. (See "Approach to the adult patient with suspected depression".)
The term recovery is used to indicate the resolution of a depressive episode [5]. Although different definitions of recovery exist, many long-term observational studies require at least two consecutive months with no more than one or two mild symptoms of depression and no impairment of psychosocial functioning.
STUDY SETTING —
The setting of a study can affect the observed course of illness for depressed patients. Individuals who are identified in the community surveys may have a more benign course than patients at tertiary care facilities; in either case, the individuals or patients may not be receiving treatment [6,7]. In addition, patients seen in routine clinical practice often differ from patients who are followed after they complete randomized trials. Patients who participate in trials are usually recruited through advertisements, are willing to risk assignment to placebo, and meet extensive exclusion criteria that are typically used in industry-sponsored trials; thus, these patients may have less suicidality, psychosis, comorbidity, and functional impairment [8-10].
MAJOR DEPRESSIVE DISORDER —
The course of illness for major depressive disorder is heterogeneous, which may reflect that the disorder represents a variety of illnesses that differ in their pathogenesis, clinical presentation, and treatment response [11-13]. Patients may experience a single major depressive episode, follow a highly recurrent course with full resolution of symptoms between episodes, or spend much of their lives struggling with persistent, fluctuating symptoms. Depressive episodes can range in intensity from states that produce limited impairment and are little noticed by others, to catatonic or psychotic conditions that render the patient incapable of self-care.
Although the large majority of major depressive episodes eventually end [6,14-16], some patients are ill for much of their lives due to recurrences and/or lengthy episodes. A 12-year, prospective observational study of 431 patients with major depressive disorder, who sought treatment at study intake, found that they were depressed for 59 percent (mean average) of the follow-up time [7]. In a six-year, prospective observational study of 903 patients with major depressive disorder, most of whom were treated in primary care settings, symptoms were present for 50 to 100 percent of the follow-up time in 36 percent of the patients [17].
Recovery — The median time to recovery from a major depressive episode in prospective observational studies is approximately 20 weeks [14,15]. This finding is consistent across multiple recurrent episodes in both individuals who have not sought treatment and treated patients.
Prospective studies have found that the probability of recovery from major depression progressively decreases as the duration of the episode increases (figure 1 and figure 2) [14,15].
Major depressive episodes may remit quickly. Prospective observational studies have found that episodes (some of which were untreated) often remitted soon after onset (eg, ≤8 weeks), in a reproducible manner across different patient populations (figure 2 and figure 1) [14,15]. In addition, remission of depressive episodes that occurs during treatment that is started soon after onset of the episode often appears to be the result of a placebo effect [18]. (See "Major depressive disorder in adults: Approach to initial management", section on 'Mild major depression'.)
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project, a large study of outpatients with major depressive disorder who underwent sequenced trials of antidepressant treatment, found an overall remission rate of 67 percent [19]. However, a reanalysis of these data did not assume that participants who dropped out of the study had outcomes similar to those who remained and reported a remission rate of 88 percent [20].
Risk factors for a longer time to recovery from major depression that are not confined to a particular age or diagnostic subgroup include:
●Longer episode duration at baseline [21-23]
●Greater baseline symptom severity [24-26]
●Psychotic features (ie, delusions and/or hallucinations) [27-29]
●Higher levels of anxiety [24,30,31]
●Pre-existing comorbid disorders [23,26], including personality disorders [21,24,32-34]
●High levels of neuroticism [34-37]
●Poorer psychosocial functioning [24,31,38-42]
●Childhood maltreatment [31,41,43,44]
Recurrence — Major depressive disorder is highly recurrent [6,45-47]:
●In a prospective study of individuals in the Dutch general population who had recovered from an episode of major depression (n = 687), the cumulative rate of recurrence at [48]:
•5 years was 13 percent
•10 years was 23 percent
•20 years was 42 percent
●In a prospective study of 318 patients who recovered from a major depressive episode and were assessed semiannually or annually for up to 10 years, 64 percent suffered at least one subsequent episode [49]. The median time to recurrence for the first the recurrent episode was approximately 3 years and for subsequent episodes was 1 to 1.5 years.
The risk of recurrence appears to be greatest in the first few months after recovery from a major depressive episode. Thereafter, the probability of recurrence progressively decreases as the duration of recovery (wellness) increases. As an example, a prospective study found that among 318 patients who recovered from a major depressive episode, approximately [49]:
●20 percent suffered a recurrence in months 1 through 6 after recovery
●19 percent in months 7 through 12 after recovery
●15 percent in months 13 through 18
●13 percent in months 19 through 24
●11 percent in months 25 through 30
●9 percent in months 31 through 36
Clinical factors that may be associated with recurrence of major depression include:
●Prior history of recurrence – This is the most consistently identified risk factor [32,48-56]. As an example, a prospective study of 318 patients found that each recurrence increased the risk of a subsequent recurrence by 16 percent [49].
●Residual depressive symptoms – This is another potent risk factor [50,53,54,56-59]. As an example, a prospective study of 322 patients found that the median time to recurrence was four times shorter for patients with one or two mild symptoms during the recovery period than for patients with no symptoms (32 versus 135 weeks) [60].
●Childhood maltreatment – A meta-analysis of seven epidemiologic studies found that individuals with a history of childhood maltreatment (ie, physical or sexual abuse, neglect, or family conflict or violence) had twice the odds of recurrent depressive episodes, compared with individuals without childhood maltreatment [43]. In patients with treatment-resistant depression, the number of adverse childhood events is associated in step-wise fashion with symptom severity and the likelihood of suicide attempts and inpatient admission [61]. Time to recurrence of depressive symptoms also appears shorter among those with negative youth experiences [48].
●Other factors such as:
•Greater severity (intensity) of the preceding depressive episode [21,48,50,62,63]
•Younger age at time of assessment [48,50,62]
•Younger age of onset of major depressive disorder [64]
•Comorbid personality disorder [32,34,65]
•Poorer psychosocial functioning [42,48]
•Feeling that life circumstances are beyond one's control (ie, low mastery) [55]
•Emotional dysregulation and repeated exposure to adversity [56,66]
Treatment-resistant depression — Relapse appears to be greater in patients with major depression who require more than one course of treatment to remit, compared with patients who remit after the initial course of treatment [67]. In the STAR*D study, which prospectively administered up to four sequential trials of pharmacotherapy to patients who presented with major depression, more than 1500 patients remitted and were followed for up to one year [19]. The rate of relapse after each treatment step was as follows:
●Remission occurred with initial treatment – 34 percent relapsed
●Remission occurred with step two – 47 percent
●Remission occurred with step three – 43 percent
●Remission occurred with step four – 50 percent
The difference in relapse following remission after initial treatment and after step two was statistically significant.
It is not clear if all-cause mortality or suicide is greater in treatment-resistant depression, compared with the general population of patients with depression [67,68]. Mortality in depression is discussed elsewhere in this topic. (See 'Mortality' below.)
Long-term course of illness — For any individual patient who suffers more than one episode of major depression, time to recovery and time to recurrence are inconsistent across multiple episodes [15,49,69]. However, long-term prospective studies of patients with major depression, receiving various levels of treatment or none at all, have found that course of illness remains the same for the cohort over time, including [14,15,70,71]:
●Mean time to recovery from an episode of major depression
●Probability of recurrence
●Amount of time ill with major depression
As an example, a study prospectively followed 220 patients with major depressive disorder for 20 years, and examined the proportion of weeks ill with major depression [72]. The 20 years of follow-up were grouped into five-year periods to determine whether the proportion of weeks ill with depression changed over time, and patients were divided into three groups according to their age at study intake (mean age 25, 36, and 55 years). The amount of time ill with depression did not change as patients moved from their third decade of life to their fifth decade, from their fourth to their sixth decade, or their sixth to their eighth decade of life (figure 3).
Clinical features that are present during the initial episode of major depressive disorder may be associated with a greater lifetime burden of depressive symptoms. As an example, a retrospective, multinational, community-based study of individuals (n>8000) found that early age of onset, suicidal ideation and behavior, severe dysphoria, and anxiety during the first lifetime episode of major depression were associated with a greater persistence and severity of subsequent depressive symptoms [73].
Clinicians may conclude that the course of illness tends to worsen in major depression (eg, episodes appear to progressively become longer or more frequent) when in fact it does not, because patients who experience more symptoms are more likely to continue visiting clinicians than patients who remain euthymic for long periods [74].
Functioning — Although psychosocial functioning typically improves in patients who recover from a major depressive episode, functional recovery often takes longer than syndromal recovery [75]. As an example, a prospective study of patients with recurrent major depression (n>1000) found that on average, functional recovery lagged behind syndromal recovery by approximately one year [76]. The delay in functional recovery was attributed primarily to subsyndromal symptoms, and the persistence of these symptoms speaks to the need for continuation treatment.
Additional information about functional impairment in major depression is discussed separately. (See "Depression in adults: Clinical features and diagnosis", section on 'Impact on function'.)
Quality of life — Depression is associated with impaired quality of life, which refers to subjective satisfaction with one's physical, psychologic, and social functioning. Quality of life may remain impaired despite resolution of the depressive syndrome. As an example, the STAR*D study prospectively administered citalopram to patients with major depression who were followed for up to 12 months [77]. Quality of life was impaired in nearly all patients at study intake. Among patients who remitted (n>800), quality of life remained impaired in more than 30 percent, and was severely impaired in 9 percent.
PERSISTENT DEPRESSIVE DISORDER —
Diagnostic and Statistical Manual, Fifth Edition, Text Revision (DSM-5-TR) consolidates dysthymic disorder and chronic major depression into persistent depressive disorder because there was little difference between dysthymic disorder and chronic major depression with regard to demographics, symptom patterns, treatment response, and family history [78-81]. The diagnostic criteria for persistent depressive disorder in the DSM-5-TR [1] are nearly identical to the criteria for dysthymic disorder [82]. The primary difference is that persistent depressive disorder also includes patients who were previously labelled as chronic major depression.
Much of the literature regarding depression recurrence and recovery is based upon the diagnostic categories used prior to DSM-5 (ie, dysthymic disorder and chronic major depression).
Additional information about the clinical features and diagnosis of depressive disorders is discussed separately. (See 'Definitions' above and "Depression in adults: Clinical features and diagnosis" and "Approach to the adult patient with suspected depression".)
With dysthymic syndrome — In follow-up studies of dysthymia, most episodes resolved, but recurrence was common:
●A prospective study of 82 patients with dysthymia followed for up to 10 years found that approximately 74 percent recovered; the median time from study entry to recovery was approximately four years [83].
●A prospective study of 53 patients who recovered from dysthymia and were followed for a median of eight years found that 55 percent suffered a recurrence [83].
Also, patients with dysthymic disorder recovered more slowly than patients with nonchronic major depression. In an observational study of 49 patients followed prospectively for six months, recovery occurred in fewer patients with dysthymia compared with major depression (25 versus 63 percent) [84].
Observational studies of dysthymia found that patients usually had exacerbations that met criteria for a major depressive episode, a phenomenon labelled "double depression" [85]. As an example, two studies of dysthymia (190 and 87 patients) found that most patients also met criteria for major depression (62 and 59 percent of patients) [83]. Underlying dysthymia also seemed to worsen the course of major depression; studies found that among patients who recovered from major depressive episodes superimposed upon dysthymia, time to relapse of another major depressive episode was shorter than that experienced by patients who recovered from major depression not superimposed upon dysthymia [85,86]. (In DSM-5-TR, the formal diagnosis for double depression is persistent depressive disorder with intermittent major depressive episodes [1].)
In studies of dysthymic disorder, predictors of poor outcome included:
●Family history of dysthymic disorder or chronic major depression [83,87]
●High neuroticism scores [87]
●Comorbid anxiety disorder [88,89]
With persistent major depressive episode — In DSM-5-TR, patients who meet full criteria for an episode of major depression continuously for two years are given the diagnosis persistent depressive disorder with persistent major depressive episode [1].
Prospective observational studies found that the probability of recovery from a persistent depressive episode was less than the rate of recovery from shorter episodes [90]. Nevertheless, some or most patients with a persistent depressive episode recovered [90,91]:
●A prospective observational study, at a tertiary medical center, of 35 patients with major depression who were continuously ill for five years found that during the following five years, recovery occurred in 38 percent [92].
●A nationally representative community survey in the United States identified individuals with a persistent depressive episode (n = 504) and found that after three years of follow-up, only 12 percent continued to meet criteria for major depression [44].
Clinical factors at baseline that were associated with a shorter time to recovery from a persistent depressive episode in prospective studies included a high level of psychosocial functioning, less severe depressive symptoms, absence of psychiatric comorbidity, and absence of psychosis [90].
MINOR DEPRESSION —
Course of illness in minor depression is discussed separately. (See "Minor depression in adults: Epidemiology, clinical presentation, and diagnosis", section on 'Course of illness'.)
MORBIDITY —
Major depression adversely affects overall health, causing disability, diminishing functioning and quality of life, and worsening the prognosis of general medical illnesses [93].
●Disability – According to the World Health Organization, depression is the single largest cause of disability worldwide, and most of this burden occurs in low- and middle-income nations [94]. In the United States, major depression was the ninth most common cause of disability [95]. Most individuals with major depression experience reduced quality of life, ie, the subjective satisfaction with one's physical, psychologic, and social functioning [96].
●Impact on health outcomes – Depression is associated with an increased risk of multiple general medical conditions and may adversely affect their outcomes [97-103]. The relationship between depression and comorbid medical conditions is discussed separately. (See "Depression in adults: Clinical features and diagnosis", section on 'Medical illnesses'.)
MORTALITY
All-cause — All-cause mortality is approximately 50 to 100 percent greater in individuals with depression, compared with those without depression [104-109]. As an example, in a meta-analysis of 293 studies from 35 countries, the adjusted risk of mortality was higher in those with versus those without depression (relative risk [RR] 1.52, 95% CI 1.45-1.59) [110]. A subsequent meta-analysis found similar results [111]. Study heterogeneity was high in both meta-analyses. In a large cohort study, excess mortality rates associated with depression were comparable to those with smoking [112].
Large cohort studies also suggest that depression shortens life expectancy. As an example, in a population-based Danish cohort, individuals with depression had an estimated life expectancy that was approximately 11 years shorter than that of the general population [113]. Similarly, in a cohort of over 4.5 million United States military veterans, those with depression died an average of five years earlier (71 versus 76 years for those without depression) [114]. Both mild and severe levels of depression are associated with excess mortality. (See "Minor depression in adults: Epidemiology, clinical presentation, and diagnosis", section on 'All-cause mortality'.)
Excess mortality in those with depression is greater for males than females [115,116]. In a meta-analysis of 13 prospective studies of adults with depression, excess mortality was two times greater in males than in females (RR 2.0, 95% CI 1.6-2.4) [117].
Comorbid medical illness does not fully explain the excess mortality among those with depression [118-120]. A community-based survey of 61,349 participants found that excess mortality rates associated with depression were only partly explained by somatic symptoms or illnesses [112]. In addition, depressive symptoms are associated with higher risks of death in patients with cancer and diabetes [121,122].
Suicide — Major depression greatly increases the risk of suicide and is the leading cause of suicide death worldwide [123-125]. In a prospective study that followed 186 patients with major depressive disorder for up to 38 years, the incidence of suicide was 27 times greater than that for the general population [105]. Among those with depression, risk factors for suicide include prior history of suicide attempt, male sex, family history of a psychiatric disorder, severe depressive symptoms, comorbid anxiety, and misuse of alcohol or drugs [126]. Additional information about suicide is discussed separately. (See "Suicidal ideation and behavior in adults".)
Homicide — Individuals with depressive disorders appear at higher risk of mortality due to homicide. In a Swedish national registry study, individuals with depression had increased rates of homicidal death, compared with those without any mental disorder, even after adjustment for sociodemographic factors (hazard ratio [HR] 2.6, 95% CI 1.7-3.8) [127].
Accidental death — Individuals with depression may be at increased risk of dying from accidents (eg, motor vehicle accidents, falls, or accidental poisoning) [128]. In a Swedish national registry study, those with depression experienced higher rates of accidental deaths, even after adjusting for sociodemographic factors and substance use disorders (HR 2.5 and 2.2 for males and females, respectively) [129].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)
SUMMARY AND RECOMMENDATIONS
●Major depressive disorder
•Recovery – The median time to recovery from a major depressive episode is approximately 20 weeks. However, some episodes remit quickly. Possible risk factors for a longer time to recovery include longer episode duration at baseline, greater baseline symptom severity, psychotic features, higher levels of anxiety, pre-existing comorbid disorders, high levels of neuroticism, poorer psychosocial functioning, and a history of childhood maltreatment. (See 'Recovery' above.)
•Recurrence – Among patients with major depressive disorder, recurrent episodes occur in approximately 50 percent. The risk of recurrence appears to be greatest in the first few months after recovery from a major depressive episode and then progressively decreases as the duration of recovery (wellness) increases. Factors that may be associated with recurrence include prior history of recurrence, residual depressive symptoms, childhood maltreatment, symptom severity of the preceding depressive episode, younger age at time of assessment, younger age of onset of major depressive disorder, and comorbid personality disorder. (See 'Recurrence' above.)
•Long-term course of illness – For any individual patient who suffers more than one episode of major depression, time to recovery and time to recurrence are inconsistent across multiple episodes. However, for groups of patients, course of illness remains the same for the cohort over time, including mean time to recovery from an episode of major depression, probability of recurrence, and amount of time ill with major depression. (See 'Long-term course of illness' above.)
•Stability of diagnosis – Patients who are initially and correctly diagnosed with major depressive disorder may eventually change diagnosis to bipolar disorder or schizophrenia. (See "Depression in adults: Clinical features and diagnosis", section on 'Reliability and stability of diagnosis'.)
●Persistent depressive disorder – Although most episodes of persistent depressive disorder resolve, recurrences are common. Most patients with persistent depressive disorder have exacerbations that meet criteria for a major depressive episode. (See 'Persistent depressive disorder' above.)
●Morbidity and mortality – Depression adversely affects patients' overall health and is associated with:
•Poor psychosocial and physical functioning (see 'Functioning' above)
•Increased risks and worse outcomes of general medical illness, such as coronary heart disease, diabetes mellitus, and stroke (see 'Morbidity' above and "Depression in adults: Clinical features and diagnosis", section on 'Medical illnesses')
•Increased all-cause mortality, completed suicide, homicidal death, and accidental death (see 'Mortality' above)
