Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Unipolar depression in adults: Course of illness

Author: William Coryell, MD
Section Editor: Peter P Roy-Byrne, MD
Deputy Editor: David Solomon, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2020. | This topic last updated: Apr 26, 2020.

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 structural brain
changes. As an example, a one-year prospective magnetic imaging study followed patients
with treatment resistant unipolar major depression (n = 26) who were treated with
pharmacotherapy, and found that remission was associated with subtle increases in
hippocampal volume and cortical thickness, whereas nonremission was associated with
decreased volume and thickness [3].
:
This topic reviews the course of illness in patients with major depressive disorder and
persistent depressive disorder (dysthymia). The course of illness in psychotic depression
and minor depression is discussed separately, as is the epidemiology, clinical features,
diagnosis, and treatment of depression:

● (See "Unipolar major depression with psychotic features: Maintenance treatment and
course of illness", section on 'Course of illness'.)
● (See "Unipolar minor depression in adults: Epidemiology, clinical presentation, and
diagnosis", section on 'Course of illness'.)
● (See "Unipolar depression in adults: Epidemiology, pathogenesis, and neurobiology".)
● (See "Unipolar depression in adults: Assessment and diagnosis".)
● (See "Unipolar major depression in adults: Choosing initial treatment".)
● (See "Unipolar depression in adults: Choosing treatment for resistant depression".)
● (See "Diagnosis and management of late-life unipolar 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 (DSM-5) [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
"Unipolar depression in adults: Assessment and diagnosis".)

The term recovery is used to indicate the resolution of a depressive episode [4]. 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 [5,6]. 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 [7-9].

MAJOR DEPRESSIVE DISORDER

The course of illness for major depressive disorder (unipolar major depression) is
heterogeneous, which may reflect that the disorder represents a number of different
illnesses that differ in their pathogenesis, clinical presentation, and treatment response [10-
12]. 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 [5,13-15], some
patients are ill for much of their lives due to recurrences and/or lengthy episodes. A
prospective observational study of 431 patients with major depressive disorder who sought
treatment at study intake and were then followed for up to 12 years found that they were
depressed for 59 percent (mean average) of the follow-up time [6].

Diagnostic stability — Patients who are initially and correctly diagnosed with major
depressive disorder may eventually change diagnosis.

Patients with bipolar disorder often suffer one or more episodes of major depression and
initially receive a diagnosis of major depressive disorder, prior to their first manic or
hypomanic syndrome. As an example, a meta-analysis identified five longitudinal studies
with adults and adolescents (total n >3000) who were diagnosed with major depressive
disorder; the mean length of follow-up across the studies ranged from 12 to 18 years [16].
Bipolar disorder was eventually diagnosed in 23 percent. The probability of switching
diagnoses was greatest in the first five years of follow-up, and was higher in patients with
the following characteristics:

● Younger age of onset of their first lifetime major depressive episode

● Family history of bipolar disorder

● During major depressive episodes:

• Psychosis (eg, delusions and/or hallucinations)

• Subthreshold hypomanic symptoms such as decreased need for sleep, unusually

high energy, or increased goal directed activity

In addition, treatment resistance in patients with major depressive disorder and the presence
of comorbid attention deficit hyperactivity disorder or substance use disorders are
associated with diagnostic conversion to bipolar disorder [17,18].

Additional information about distinguishing unipolar depression and bipolar depression,

which differ in treatment, is discussed separately. (See "Bipolar disorder in adults:
Assessment and diagnosis", section on 'Unipolar major depression'.)
:
At least 5 to 15 percent of patients initially diagnosed with major depressive disorder
eventually change diagnosis to a schizophrenia-spectrum disorder [19-23]. In a 10-year
follow-up study of 77 patients diagnosed with psychotic major depression at baseline, the
diagnosis changed to schizophrenia in 30 percent; predictors included negative symptoms
(eg, flat affect, apathy, poverty of speech, and abulia) and psychosocial impairment [24].
Repeated diagnostic examinations find that the change from major depressive disorder to
schizophrenia occurs more frequently than the reverse [20,23,24]. (See "Depression in
schizophrenia".)

Recovery — The median time to recovery from a major depressive episode in prospective
observational studies is approximately 20 weeks [13,14]. This finding is consistent in treated
patients with multiple recurrent episodes (up to five), and for individuals in the community
who have not sought treatment.

Prospective observational studies have found that the probability of recovery from major
depression progressively decreases as the duration of the episode increases [13,14]. This
decreasing rate of recovery is graphically illustrated (figure 1 and figure 2).

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)
[13,14]. 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
[25,26]. Thus, for mild to moderate depression with recent onset and no suicidality or
psychosis, reassurance and watchful waiting with short-term follow-up (eg, two weeks) may
be a reasonable alternative to antidepressant treatment. (See "Unipolar depression in adults
and initial treatment: General principles and prognosis", section on 'Reluctance to start
treatment'.)

There are several risk factors for a longer time to recovery from major depression, which
have been identified in at least two separate prospective observational studies that included
at least two years of follow-up and were not confined to a particular age or diagnostic
subgroup:
:
 ● Longer episode duration at baseline [27-29]
● Greater baseline symptom severity [30-33]
● Psychotic features (ie, delusions and/or hallucinations) [34-36]
● Higher levels of anxiety [30,37-40]
● Pre-existing comorbid disorders [29,31,33], including personality disorders [27,30,41-
43]
● High levels of neuroticism [43-47]
● Poorer psychosocial functioning [30,40,48-52]
● Childhood maltreatment [40,51,53,54]

Recurrence — Major depressive disorder is highly recurrent [5,55-57]:

● 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
[58]:

• 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 semi-annually or annually for up to 10 years, 64 percent suffered at
least one subsequent episode [59]. 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
[59]:

● 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 [41,58-
69]. As an example, a prospective study of 318 patients found that each recurrence
increased the risk of a subsequent recurrence by 16 percent [59].

● Residual depressive symptoms – This is another potent risk factor [61,64,66,67,69-73].

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) [74,75].

● Childhood maltreatment – A meta-analysis of seven epidemiologic studies (10,191

depressed individuals) found that recurrent depressive episodes were twice as likely
among individuals who were mistreated during childhood (physical or sexual abuse,
neglect, or family conflict or violence) compared with individuals who were not [53]. A
subsequent study of 687 euthymic individuals with a lifetime history of unipolar major
depression found that time to recurrence was shorter among individuals with negative
youth experiences [58].

● Other factors such as:

• Greater severity (intensity) of the preceding depressive episode [18,27,58,61,76]

• Younger age at time of assessment [58,61,76,77]

• Younger age of onset of major depressive disorder [62,78]

• Comorbid personality disorder [41,43,79]

• Poorer psychosocial functioning [52,58]

:
 • Feeling that life circumstances are beyond one’s control (ie, low mastery) [68]

• Emotional dysregulation and repeated exposure to adversity [69,80]

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 [81]. In the Sequenced Treatment Alternatives
to Relieve Depression (STAR*D) study, which prospectively administered up to four
sequential trials of pharmacotherapy to patients who presented with unipolar major
depression, more than 1500 patients remitted and were followed for up to one year [82]. 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 [81,83]. 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 [14,59,84]. 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 [13,14,85,86]:

● 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 [87]. The 20
years of follow-up were grouped into 5-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 unipolar major depression 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 unipolar major depression were associated with a greater persistence
and severity of subsequent depressive symptoms [88].

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 [89].

Functioning — Although psychosocial functioning typically improves in patients who

recover from a major depressive episode [90], functional recovery often takes longer than
syndromal recovery [91]. As an example, a prospective study of patients with recurrent
unipolar depression (n >1000) found that on average, functional recovery lagged behind
syndromal recovery by approximately one year [92]. 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 unipolar depression is discussed

separately. (See "Unipolar depression in adults: Clinical features", section on 'Functional
impairment'.)

Quality of life — Depression is associated with impaired quality of life, which refers to
subjective satisfaction with one’s physical, psychological, and social functioning. Quality of
:
life may remain impaired despite resolution of the depressive syndrome. As an example, the
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study prospectively
administered citalopram to patients with unipolar major depression who were followed for up
to 12 months [93]. 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 (DYSTHYMIA)

The diagnostic criteria for persistent depressive disorder (dysthymia) in the Diagnostic and
Statistical Manual, Fifth Edition (DSM-5) [1] are nearly identical to the criteria for dysthymic
disorder in DSM-IV-TR [94]. The primary difference is that persistent depressive disorder
also subsumes patients who were labelled as chronic unipolar major depression in DSM-IV-
TR (which categorized chronic major depression as a subset of unipolar major depression).
DSM-5 consolidated dysthymic disorder and chronic major depression into persistent
depressive disorder (dysthymia) because there was little difference between dysthymic
disorder and chronic major depression with regard to demographics, symptom patterns,
treatment response, and family history [95-98]. However, much of the literature is based
upon the diagnoses used prior to DSM-5.

Additional information about the clinical features and diagnosis of depressive disorders is
discussed separately. (See 'Definitions' above and "Unipolar depression in adults:
Assessment and diagnosis".)

Dysthymic disorder — In follow-up studies of dysthymic disorder, most episodes resolved

but recurrence was common [99]:

● A prospective study of 82 patients with dysthymic disorder followed for up to 10 years

found that approximately 74 percent recovered; the median time from study entry to
recovery was approximately four years [100].

● A prospective study of 53 patients who recovered from dysthymic disorder and were
followed for a median of eight years found that 55 percent suffered a recurrence [100].
:
Also, patients with dysthymic disorder recovered more slowly than patients with non-chronic
major depression [99]. In an observational study of 49 patients followed prospectively for six
months, recovery occurred in fewer patients with dysthymic disorder compared with unipolar
major depression (25 versus 63 percent) [101].

Observational studies of dysthymic disorder found that patients usually had exacerbations
that met criteria for a major depressive episode, a phenomenon labelled “double depression”
[102]. As an example, two studies of dysthymic disorder (190 and 87 patients) found that
most patients also met criteria for major depression (62 and 59 percent of patients)
[100,103]. Underlying dysthymia also seemed to worsen the course of major depression;
studies found that among patients who recovered from major depressive episodes
superimposed upon dysthymic disorder, time to relapse of another major depressive episode
was shorter than that experienced by patients who recovered from major depression not
superimposed upon dysthymic disorder [102,104]. (In DSM-5, 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 [100,105]

● High neuroticism scores [105]
● Comorbid anxiety disorder [106,107]

Chronic major depression — In DSM-IV-TR, patients who met full criteria for an episode of
major depression continuously for two years were diagnosed with chronic major depression
[94]. In DSM-5, these patients are given the diagnosis persistent depressive disorder with
persistent major depressive episode [1].

Prospective observational studies found that the probability of recovery from an episode of
chronic major depression was less than the rate of recovery from shorter episodes [108].
Nevertheless, patients with chronic major depression recovered [108,109]:

● 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 [110].

● A nationally representative community survey in the United States identified individuals

with chronic major depression (n = 504) and found that after three years of follow-up,
only 12 percent continued to meet criteria for major depression [54].

Thus, clinicians should encourage patients to continue treatment and efforts to manage their
illness despite persistent symptoms [111].

Clinical factors at baseline that were associated with a shorter time to recovery from chronic
major depression in prospective studies included a high level of psychosocial functioning,
less severe depressive symptoms, absence of psychiatric comorbidity, and absence of
psychosis [108].

MINOR DEPRESSION

Course of illness in minor depression is discussed separately. (See "Unipolar minor

depression in adults: Epidemiology, clinical presentation, and diagnosis", section on 'Course
of illness'.)

MORBIDITY

Depression may adversely affect the overall health of patients [112]. Depression is
associated with coronary heart disease, diabetes mellitus, Parkinson disease, stroke, and
with worse outcomes in comorbid general medical illnesses [113-119]. In addition,
depression in later life may be an independent risk for subsequent cognitive decline [120-
122] and possibly dementia [123]. (See "Mild cognitive impairment: Epidemiology, pathology,
and clinical assessment", section on 'Neuropsychiatric symptoms'.)

MORTALITY

All cause — All cause mortality is approximately 50 to 100 percent greater in depressed
:
individuals, compared with nondepressed individuals [124-129]. As an example:

● A meta-analysis of 293 studies from 35 countries (n >100,000 depressed individuals

and >1,600,000 nondepressed individuals) found that the risk of mortality was 52
percent greater in depressed individuals; heterogeneity across studies was high [130]

● A subsequent meta-analysis of 43 studies (sample size not provided) found that the risk
of mortality was 71 percent greater in depressed individuals; heterogeneity across
studies was high [131]

● A subsequent national registry study identified more than 900,000 individuals who died,
including more than 78,000 with a lifetime diagnosis of unipolar depression [132]. All-
cause mortality was two times greater in people with depression, compared with the
general population. Assuming onset of depression at age 30, life expectancy in
depressed individuals was roughly 11 years shorter.

In addition, a retrospective study of military veterans with a history of depression (n

>700,000) or without depression (n >4,000,000) found that the mean age of death was 71
versus 76 years [133]. Major depression and less severe (minor) depression are each
associated with excess mortality. (See "Unipolar minor depression in adults: Epidemiology,
clinical presentation, and diagnosis", section on 'All-cause mortality'.)

The excess mortality that is observed in depression is greater for men than women. A meta-
analysis of 13 prospective observational studies (n >5500 depressed men and women)
found that the risk of death was twice as great in depressed men than in depressed women
[134]. In two community registry studies, life expectancy for depressed males was 11 and 15
years shorter compared to the general population, and for depressed females was 7 and 13
years shorter [135,136].

For some patients with depression plus a general medical disease, it appears that the
mortality risk of depression is not fully explained by the comorbid medical illness [137-139]:

● A community survey and mortality database of 61,349 individuals found that depressive
disorders were associated with an increased mortality that was only partly explained by
somatic symptoms or illnesses (hazard ratio 1.5, 95% CI 1.4-1.7) [140].
:
 ● A meta-analysis of 25 observational studies (9417 patients) showed that mortality rates
were 25 percent higher in cancer patients with depressive symptoms compared with
nondepressed cancer patients (risk ratio 1.25, 95% CI 1.12-1.40), and 39 percent
higher in cancer patients diagnosed with major or minor depression (risk ratio 1.39, 95%
CI 1.10-1.89) [141].

● In a prospective study of 4873 women, mortality was higher for women with depression
plus diabetes mellitus (relative risk 3.1, 95% CI 2.7-3.6) than diabetes alone (relative
risk 1.7, 95% CI 1.5-1.9) [142].

Continuity of care with the same psychiatrist for major depression is associated with
decreased all-cause mortality [143].

One aspect that is typically not addressed in studies of depression and mortality is whether
the increased risk for death varies according to lifetime extent of depressive morbidity.

Suicide — Many depressed patients kill themselves [144]. 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 [125].

Many risk factors for suicide have been identified. In a meta-analysis of results from 28
articles (n >12,000 suicides, 3,000,000 controls), the risk factor that was most strongly
associated with suicide was prior history of suicide attempt (odds ratio 5, 95% CI 3-7) [145].
Other risk factors included male sex, family history of psychiatric disorder, more severe
depression, hopelessness, and comorbidity. As an example, traumatic brain injury is
associated with an increased risk of suicide [146,147].

Additional information about suicide is discussed separately. (See "Suicidal ideation and
behavior in adults".)

Homicide — Mortality due to homicide is elevated in patients with depressive syndromes. A

retrospective study of Swedish national registries compared the risk of homicidal death
among individuals with a lifetime history of unipolar depression and no history of substance
use, to the risk among individuals with no history of mental disorders [148]. After controlling
for sociodemographic factors, the risk of death due to homicide among depressed patients
:
was 2.6-fold higher (hazard ratio 3, 95% CI 2-4). However, the absolute risk was small.

Accidental death — Depressed patients may be at increased risk of dying from accidents
(eg, motor vehicle accidents, falls, or accidental poisoning). In a Swedish national registry
study, which compared depressed patients (n >200,000) with the general population (n >6.9
million) and controlled for sociodemographic factors and substance use disorders,
accidental deaths were two fold greater among depressed patients [149].

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

● Major depressive disorder (unipolar major depression) (table 1) and persistent

depressive disorder (dysthymia) (table 2) represent depressive syndromes that are
distinguished by the type and number of symptoms that occur as well as their duration.
(See 'Definitions' above and "Unipolar depression in adults: Assessment and
diagnosis".)

● Patients who are initially and correctly diagnosed with major depressive disorder may
eventually change diagnosis to bipolar disorder or schizophrenia. (See 'Diagnostic
stability' above.)

● The median time to recovery from a major depressive episode is approximately 20

weeks. However, episodes may remit quickly. Thus, for mild to moderate depression
with recent onset and no suicidality or psychosis, reassurance and watchful waiting with
short-term follow-up (eg, two weeks) may be a reasonable alternative to antidepressant
treatment. 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.)

● 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 thereafter 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.)

● 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.)

● Depression is associated with poor psychosocial and physical functioning. (See

'Functioning' above.)

● Although most episodes of dysthymia resolve, recurrences are common. Most patients
with dysthymia have exacerbations that meet criteria for a major depressive episode.
(See 'Persistent depressive disorder (dysthymia)' above.)

● Depression is associated with coronary heart disease, diabetes mellitus, and stroke,
and with worse outcomes in comorbid general medical illnesses. (See 'Morbidity'
above.)

● Depression is associated with increased all-cause mortality, completed suicide,

homicidal death, and accidental death. (See 'Mortality' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

:
REFERENCES

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorde

rs, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.

2. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291
diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global
Burden of Disease Study 2010. Lancet 2012; 380:2197.

3. Phillips JL, Batten LA, Tremblay P, et al. A Prospective, Longitudinal Study of the
Effect of Remission on Cortical Thickness and Hippocampal Volume in Patients with
Treatment-Resistant Depression. Int J Neuropsychopharmacol 2015; 18.

4. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on
response and remission in major depressive disorder. Neuropsychopharmacology
2006; 31:1841.

5. Eaton WW, Shao H, Nestadt G, et al. Population-based study of first onset and
chronicity in major depressive disorder. Arch Gen Psychiatry 2008; 65:513.

6. Judd LL, Akiskal HS, Maser JD, et al. A prospective 12-year study of subsyndromal
and syndromal depressive symptoms in unipolar major depressive disorders. Arch
Gen Psychiatry 1998; 55:694.

7. Keitner GI, Posternak MA, Ryan CE. How many subjects with major depressive
disorder meet eligibility requirements of an antidepressant efficacy trial? J Clin
Psychiatry 2003; 64:1091.

8. Zimmerman M, Chelminski I, Posternak MA. Generalizability of antidepressant efficacy

trials: differences between depressed psychiatric outpatients who would or would not
qualify for an efficacy trial. Am J Psychiatry 2005; 162:1370.

9. Zimmerman M, Mattia JI, Posternak MA. Are subjects in pharmacological treatment

trials of depression representative of patients in routine clinical practice? Am J
:
 Psychiatry 2002; 159:469.

10. Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-
analysis and exploration of heterogeneity. J Epidemiol Community Health 2007;
61:631.

11. Chen L, Eaton WW, Gallo JJ, Nestadt G. Understanding the heterogeneity of
depression through the triad of symptoms, course and risk factors: a longitudinal,
population-based study. J Affect Disord 2000; 59:1.

12. Jabben N, Penninx BW, Beekman AT, et al. Co-occurring manic symptomatology as a
dimension which may help explaining heterogeneity of depression. J Affect Disord
2011; 131:224.

13. Coryell W, Akiskal HS, Leon AC, et al. 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. Arch Gen Psychiatry 1994; 51:405.

14. Solomon DA, Keller MB, Leon AC, et al. Recovery from major depression. A 10-year
prospective follow-up across multiple episodes. Arch Gen Psychiatry 1997; 54:1001.

15. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive
disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA
2003; 289:3095.

16. Ratheesh A, Davey C, Hetrick S, et al. A systematic review and meta-analysis of

prospective transition from major depression to bipolar disorder. Acta Psychiatr Scand
2017; 135:273.

17. Chen MH, Chen YS, Hsu JW, et al. Comorbidity of ADHD and subsequent bipolar
disorder among adolescents and young adults with major depression: a nationwide
longitudinal study. Bipolar Disord 2015; 17:315.

18. Bukh JD, Andersen PK, Kessing LV. Rates and predictors of remission, recurrence and
conversion to bipolar disorder after the first lifetime episode of depression--a
:
 prospective 5-year follow-up study. Psychol Med 2016; 46:1151.

19. Clayton PJ, Guze SB, Cloninger CR, Martin RL. Unipolar depression: diagnostic
inconsistency and its implications. J Affect Disord 1992; 26:111.

20. Kessing LV. Diagnostic stability in depressive disorder as according to ICD-10 in

clinical practice. Psychopathology 2005; 38:32.

21. Schwartz JE, Fennig S, Tanenberg-Karant M, et al. Congruence of diagnoses 2 years

after a first-admission diagnosis of psychosis. Arch Gen Psychiatry 2000; 57:593.

22. Tsuang MT, Woolson RF, Winokur G, Crowe RR. Stability of psychiatric diagnosis.
Schizophrenia and affective disorders followed up over a 30- to 40-year period. Arch
Gen Psychiatry 1981; 38:535.

23. Salvatore P, Baldessarini RJ, Tohen M, et al. McLean-Harvard International First-

Episode Project: two-year stability of ICD-10 diagnoses in 500 first-episode psychotic
disorder patients. J Clin Psychiatry 2011; 72:183.

24. Bromet EJ, Kotov R, Fochtmann LJ, et al. Diagnostic shifts during the decade following
first admission for psychosis. Am J Psychiatry 2011; 168:1186.

25. Khan A, Dager SR, Cohen S, et al. Chronicity of depressive episode in relation to
antidepressant-placebo response. Neuropsychopharmacology 1991; 4:125.

26. Quitkin FM, Rabkin JG, Ross D, Stewart JW. Identification of true drug response to
antidepressants. Use of pattern analysis. Arch Gen Psychiatry 1984; 41:782.

27. Holma KM, Holma IA, Melartin TK, et al. Long-term outcome of major depressive
disorder in psychiatric patients is variable. J Clin Psychiatry 2008; 69:196.

28. Angst J, Preisig M. Course of a clinical cohort of unipolar, bipolar and schizoaffective
patients. Results of a prospective study from 1959 to 1985. Schweiz Arch Neurol
Psychiatr (1985) 1995; 146:5.

29. Keller MB, Klerman GL, Lavori PW, et al. Long-term outcome of episodes of major
:
 depression. Clinical and public health significance. JAMA 1984; 252:788.

30. Szádóczky E, Rózsa S, Zámbori J, Füredi J. Predictors for 2-year outcome of major
depressive episode. J Affect Disord 2004; 83:49.

31. Swindle RW Jr, Cronkite RC, Moos RH. Risk factors for sustained nonremission of
depressive symptoms: a 4-year follow-up. J Nerv Ment Dis 1998; 186:462.

32. Lamers F, Beekman AT, van Hemert AM, et al. Six-year longitudinal course and
outcomes of subtypes of depression. Br J Psychiatry 2016; 208:62.

33. Falola MI, Limdi N, Shelton RC. Clinical and Genetic Predictors of Delayed Remission
After Multiple Levels of Antidepressant Treatment: Toward Early Identification of
Depressed Individuals for Advanced Care Options. J Clin Psychiatry 2017; 78:e1291.

34. Angst J. The course of affective disorders. Psychopathology 1986; 19 Suppl 2:47.

35. Coryell W, Leon A, Winokur G, et al. Importance of psychotic features to long-term

course in major depressive disorder. Am J Psychiatry 1996; 153:483.

36. Goldberg JF, Harrow M. Consistency of remission and outcome in bipolar and unipolar
mood disorders: a 10-year prospective follow-up. J Affect Disord 2004; 81:123.

37. Salzman C. The APA Task Force report on benzodiazepine dependence, toxicity, and
abuse. Am J Psychiatry 1991; 148:151.

38. Coryell W, Endicott J, Winokur G. Anxiety syndromes as epiphenomena of primary

major depression: outcome and familial psychopathology. Am J Psychiatry 1992;
149:100.

39. Coryell W, Fiedorowicz JG, Solomon D, et al. Effects of anxiety on the long-term
course of depressive disorders. Br J Psychiatry 2012; 200:210.

40. Kelly KM, Mezuk B. Predictors of remission from generalized anxiety disorder and
major depressive disorder. J Affect Disord 2017; 208:467.

41. Grilo CM, Stout RL, Markowitz JC, et al. Personality disorders predict relapse after
:
 remission from an episode of major depressive disorder: a 6-year prospective study. J
Clin Psychiatry 2010; 71:1629.

42. Skodol AE, Grilo CM, Keyes KM, et al. Relationship of personality disorders to the
course of major depressive disorder in a nationally representative sample. Am J
Psychiatry 2011; 168:257.

43. Bukh JD, Andersen PK, Kessing LV. Personality and the Long-Term Outcome of First-
Episode Depression: A Prospective 5-Year Follow-Up Study. J Clin Psychiatry 2016;
77:e704.

44. Scott J, Eccleston D, Boys R. Can we predict the persistence of depression? Br J

Psychiatry 1992; 161:633.

45. Hirschfeld RM, Klerman GL, Andreasen NC, et al. Psycho-social predictors of
chronicity in depressed patients. Br J Psychiatry 1986; 148:648.

46. Steunenberg B, Beekman AT, Deeg DJ, Kerkhof AJ. Personality predicts recurrence of
late-life depression. J Affect Disord 2010; 123:164.

47. Hoertel N, Blanco C, Oquendo MA, et al. A comprehensive model of predictors of

persistence and recurrence in adults with major depression: Results from a national 3-
year prospective study. J Psychiatr Res 2017; 95:19.

48. Sherrington JM, Hawton K, Fagg J, et al. Outcome of women admitted to hospital for
depressive illness: factors in the prognosis of severe depression. Psychol Med 2001;
31:115.

49. Solomon DA, Leon AC, Coryell W, et al. Predicting recovery from episodes of major
depression. J Affect Disord 2008; 107:285.

50. Spijker J, de Graaf R, Bijl RV, et al. Determinants of persistence of major depressive
episodes in the general population. Results from the Netherlands Mental Health
Survey and Incidence Study (NEMESIS). J Affect Disord 2004; 81:231.

51. Gilman SE, Trinh NH, Smoller JW, et al. Psychosocial stressors and the prognosis of
:
 major depression: a test of Axis IV. Psychol Med 2013; 43:303.

52. Stegenga BT, Geerlings MI, Torres-González F, et al. Risk factors for onset of multiple
or long major depressive episodes versus single and short episodes. Soc Psychiatry
Psychiatr Epidemiol 2013; 48:1067.

53. Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of

illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry 2012;
169:141.

54. Garcia-Toro M, Rubio JM, Gili M, et al. Persistence of chronic major depression: a
national prospective study. J Affect Disord 2013; 151:306.

55. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third
Edition, 2010. http://www.psych.org/MainMenu/PsychiatricPractice/PracticeGuidelines
_1.aspx (Accessed on May 29, 2011).

56. Depression: The Treatment and Management of Depression in Adults, National Clinica
l Practice Guideline 90, 2010 http://guidance.nice.org.uk/CG90 (Accessed on May 29,
2011).

57. Bulloch A, Williams J, Lavorato D, Patten S. Recurrence of major depressive episodes

is strongly dependent on the number of previous episodes. Depress Anxiety 2014;
31:72.

58. Hardeveld F, Spijker J, De Graaf R, et al. Recurrence of major depressive disorder and
its predictors in the general population: results from the Netherlands Mental Health
Survey and Incidence Study (NEMESIS). Psychol Med 2013; 43:39.

59. Solomon DA, Keller MB, Leon AC, et al. Multiple recurrences of major depressive
disorder. Am J Psychiatry 2000; 157:229.

60. Keller MB, Lavori PW, Lewis CE, Klerman GL. Predictors of relapse in major
depressive disorder. JAMA 1983; 250:3299.

61. Pintor L, Torres X, Navarro V, et al. Is the type of remission after a major depressive
:
 episode an important risk factor to relapses in a 4-year follow up? J Affect Disord
2004; 82:291.

62. Giles DE, Jarrett RB, Biggs MM, et al. Clinical predictors of recurrence in depression.
Am J Psychiatry 1989; 146:764.

63. Kessing LV. Severity of depressive episodes according to ICD-10: prediction of risk of
relapse and suicide. Br J Psychiatry 2004; 184:153.

64. Maj M, Veltro F, Pirozzi R, et al. Pattern of recurrence of illness after recovery from an
episode of major depression: a prospective study. Am J Psychiatry 1992; 149:795.

65. Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major
depressive disorder during 15 years of observational follow-up. Am J Psychiatry 1999;
156:1000.

66. ten Doesschate MC, Bockting CL, Koeter MW, et al. Prediction of recurrence in
recurrent depression: a 5.5-year prospective study. J Clin Psychiatry 2010; 71:984.

67. Karsten J, Hartman CA, Smit JH, et al. Psychiatric history and subthreshold symptoms
as predictors of the occurrence of depressive or anxiety disorder within 2 years. Br J
Psychiatry 2011; 198:206.

68. Colman I, Naicker K, Zeng Y, et al. Predictors of long-term prognosis of depression.

CMAJ 2011; 183:1969.

69. van Loo HM, Aggen SH, Gardner CO, Kendler KS. Multiple risk factors predict
recurrence of major depressive disorder in women. J Affect Disord 2015; 180:52.

70. Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission of
major depressive disorder with citalopram and risk of relapse: a STAR*D report.
Psychol Med 2010; 40:41.

71. Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first lifetime
major depressive episode herald a chronic course of illness? Am J Psychiatry 2000;
157:1501.
:
72. Kiosses DN, Alexopoulos GS. The prognostic significance of subsyndromal symptoms
emerging after remission of late-life depression. Psychol Med 2013; 43:341.

73. de Zwart PL, Jeronimus BF, de Jonge P. Empirical evidence for definitions of episode,
remission, recovery, relapse and recurrence in depression: a systematic review.
Epidemiol Psychiatr Sci 2019; 28:544.

74. Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: a prospective study
of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect
Disord 1998; 50:97.

75. Judd LL, Schettler PJ, Rush AJ, et al. A New Empirical Definition of Major Depressive
Episode Recovery and Its Positive Impact on Future Course of Illness. J Clin
Psychiatry 2016; 77:1065.

76. Coryell W, Endicott J, Keller MB. Predictors of relapse into major depressive disorder
in a nonclinical population. Am J Psychiatry 1991; 148:1353.

77. Eaton WW, Anthony JC, Gallo J, et al. Natural history of Diagnostic Interview
Schedule/DSM-IV major depression. The Baltimore Epidemiologic Catchment Area
follow-up. Arch Gen Psychiatry 1997; 54:993.

78. Zisook S, Lesser I, Stewart JW, et al. Effect of age at onset on the course of major
depressive disorder. Am J Psychiatry 2007; 164:1539.

79. Wiegand HF, Godemann F. Increased Treatment Complexity for Major Depressive
Disorder for Inpatients With Comorbid Personality Disorder. Psychiatr Serv 2017;
68:524.

80. Abravanel BT, Sinha R. Emotion dysregulation mediates the relationship between
lifetime cumulative adversity and depressive symptomatology. J Psychiatr Res 2015;
61:89.

81. Fekadu A, Wooderson SC, Markopoulo K, et al. What happens to patients with
treatment-resistant depression? A systematic review of medium to long term outcome
:
 studies. J Affect Disord 2009; 116:4.

82. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in
depressed outpatients requiring one or several treatment steps: a STAR*D report. Am
J Psychiatry 2006; 163:1905.

83. Olin B, Jayewardene AK, Bunker M, Moreno F. Mortality and suicide risk in treatment-
resistant depression: an observational study of the long-term impact of intervention.
PLoS One 2012; 7:e48002.

84. de Jonge P, Conradi HJ, Kaptein KI, et al. Duration of subsequent episodes and
periods of recovery in recurrent major depression. J Affect Disord 2010; 125:141.

85. Kennedy N, Abbott R, Paykel ES. Longitudinal syndromal and sub-syndromal

symptoms after severe depression: 10-year follow-up study. Br J Psychiatry 2004;
184:330.

86. Angst J, Gamma A, Sellaro R, et al. Recurrence of bipolar disorders and major
depression. A life-long perspective. Eur Arch Psychiatry Clin Neurosci 2003; 253:236.

87. Coryell W, Solomon D, Leon A, et al. Does major depressive disorder change with
age? Psychol Med 2009; 39:1689.

88. van Loo HM, Cai T, Gruber MJ, et al. Major depressive disorder subtypes to predict
long-term course. Depress Anxiety 2014; 31:765.

89. Coryell W, Endicott J, Winokur G, et al. Characteristics and significance of untreated

major depressive disorder. Am J Psychiatry 1995; 152:1124.

90. Leon AC, Solomon DA, Mueller TI, et al. The Range of Impaired Functioning Tool
(LIFE-RIFT): a brief measure of functional impairment. Psychol Med 1999; 29:869.

91. Trivedi MH, Morris DW, Wisniewski SR, et al. Increase in work productivity of
depressed individuals with improvement in depressive symptom severity. Am J
Psychiatry 2013; 170:633.
:
 92. van der Voort TY, Seldenrijk A, van Meijel B, et al. Functional versus syndromal
recovery in patients with major depressive disorder and bipolar disorder. J Clin
Psychiatry 2015; 76:e809.

93. IsHak WW, Mirocha J, James D, et al. Quality of life in major depressive disorder
before/after multiple steps of treatment and one-year follow-up. Acta Psychiatr Scand
2015; 131:51.

94. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorde
rs, Fourth Edition, Text Revision, American Psychiatric Association, Washington DC 20
00.

95. McCullough JP Jr, Klein DN, Keller MB, et al. Comparison of DSM-III-R chronic major
depression and major depression superimposed on dysthymia (double depression):
validity of the distinction. J Abnorm Psychol 2000; 109:419.

96. McCullough JP Jr, Klein DN, Borian FE, et al. Group comparisons of DSM-IV subtypes
of chronic depression: validity of the distinctions, part 2. J Abnorm Psychol 2003;
112:614.

97. Klein DN, Shankman SA, Lewinsohn PM, et al. Family study of chronic depression in a
community sample of young adults. Am J Psychiatry 2004; 161:646.

98. Yang T, Dunner DL. Differential subtyping of depression. Depress Anxiety 2001; 13:11.

99. Gonzales LR, Lewinsohn PM, Clarke GN. Longitudinal follow-up of unipolar
depressives: an investigation of predictors of relapse. J Consult Clin Psychol 1985;
53:461.

100. Klein DN, Shankman SA, Rose S. Ten-year prospective follow-up study of the
naturalistic course of dysthymic disorder and double depression. Am J Psychiatry
2006; 163:872.

101. Klein DN, Taylor EB, Dickstein S, Harding K. Primary early-onset dysthymia:
comparison with primary nonbipolar nonchronic major depression on demographic,
clinical, familial, personality, and socioenvironmental characteristics and short-term
:
 outcome. J Abnorm Psychol 1988; 97:387.

102. Keller MB, Lavori PW, Endicott J, et al. "Double depression": two-year follow-up. Am J
Psychiatry 1983; 140:689.

103. Keller MB, Klein DN, Hirschfeld RM, et al. Results of the DSM-IV mood disorders field
trial. Am J Psychiatry 1995; 152:843.

104. Klein DN, Schwartz JE, Rose S, Leader JB. Five-year course and outcome of
dysthymic disorder: A prospective, naturalistic follow-up study. Am J Psychiatry 2000;
157:931.

105. Hayden EP, Klein DN. Outcome of dysthymic disorder at 5-year follow-up: the effect of
familial psychopathology, early adversity, personality, comorbidity, and chronic stress.
Am J Psychiatry 2001; 158:1864.

106. Klein DN, Shankman SA, Rose S. Dysthymic disorder and double depression:
prediction of 10-year course trajectories and outcomes. J Psychiatr Res 2008; 42:408.

107. Shankman SA, Klein DN. The impact of comorbid anxiety disorders on the course of
dysthymic disorder: a 5-year prospective longitudinal study. J Affect Disord 2002;
70:211.

108. Coryell W, Endicott J, Keller M. Outcome of patients with chronic affective disorder: a
five-year follow-up. Am J Psychiatry 1990; 147:1627.

109. Pincus HA, Pettit AR. The societal costs of chronic major depression. J Clin Psychiatry
2001; 62 Suppl 6:5.

110. Mueller TI, Keller MB, Leon AC, et al. Recovery after 5 years of unremitting major
depressive disorder. Arch Gen Psychiatry 1996; 53:794.

111. Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease management
model for depressed patients with persistent symptoms. J Clin Psychiatry 2006;
67:1412.
:
112. Evans DL, Charney DS, Lewis L, et al. Mood disorders in the medically ill: scientific
review and recommendations. Biol Psychiatry 2005; 58:175.

113. Jackson JL, DeZee K, Berbano E. Can treating depression improve disease
outcomes? Ann Intern Med 2004; 140:1054.

114. Krishnan KR. Depression as a contributing factor in cerebrovascular disease. Am

Heart J 2000; 140:70.

115. Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and
depression. Biol Psychiatry 2003; 54:227.

116. Musselman DL, Betan E, Larsen H, Phillips LS. Relationship of depression to diabetes
types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry 2003; 54:317.

117. Carnethon MR, Biggs ML, Barzilay JI, et al. Longitudinal association between
depressive symptoms and incident type 2 diabetes mellitus in older adults: the
cardiovascular health study. Arch Intern Med 2007; 167:802.

118. Golden SH, Lazo M, Carnethon M, et al. Examining a bidirectional association

between depressive symptoms and diabetes. JAMA 2008; 299:2751.

119. Shen CC, Tsai SJ, Perng CL, et al. Risk of Parkinson disease after depression: a
nationwide population-based study. Neurology 2013; 81:1538.

120. Cui X, Lyness JM, Tu X, et al. Does depression precede or follow executive
dysfunction? Outcomes in older primary care patients. Am J Psychiatry 2007;
164:1221.

121. Steffens DC, Otey E, Alexopoulos GS, et al. Perspectives on depression, mild
cognitive impairment, and cognitive decline. Arch Gen Psychiatry 2006; 63:130.

122. Singh-Manoux A, Akbaraly TN, Marmot M, et al. Persistent depressive symptoms and
cognitive function in late midlife: the Whitehall II study. J Clin Psychiatry 2010;
71:1379.
:
123. Simões do Couto F, Lunet N, Ginó S, et al. Depression with melancholic features is
associated with higher long-term risk for dementia. J Affect Disord 2016; 202:220.

124. Gallo JJ, Bogner HR, Morales KH, et al. Depression, cardiovascular disease, diabetes,
and two-year mortality among older, primary-care patients. Am J Geriatr Psychiatry
2005; 13:748.

125. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders:
follow-up over 34-38 years. J Affect Disord 2002; 68:167.

126. Cuijpers P, Vogelzangs N, Twisk J, et al. Differential mortality rates in major and
subthreshold depression: meta-analysis of studies that measured both. Br J Psychiatry
2013; 202:22.

127. Markkula N, Härkänen T, Perälä J, et al. Mortality in people with depressive, anxiety
and alcohol use disorders in Finland. Br J Psychiatry 2012; 200:143.

128. Gale CR, Batty GD, Osborn DP, et al. Association of mental disorders in early
adulthood and later psychiatric hospital admissions and mortality in a cohort study of
more than 1 million men. Arch Gen Psychiatry 2012; 69:823.

129. Gilman SE, Sucha E, Kingsbury M, et al. Depression and mortality in a longitudinal
study: 1952-2011. CMAJ 2017; 189:E1304.

130. Cuijpers P, Vogelzangs N, Twisk J, et al. Comprehensive meta-analysis of excess

mortality in depression in the general community versus patients with specific
illnesses. Am J Psychiatry 2014; 171:453.

131. Walker ER, McGee RE, Druss BG. Mortality in mental disorders and global disease
burden implications: a systematic review and meta-analysis. JAMA Psychiatry 2015;
72:334.

132. Laursen TM, Musliner KL, Benros ME, et al. Mortality and life expectancy in persons
with severe unipolar depression. J Affect Disord 2016; 193:203.

133. Zivin K, Ilgen MA, Pfeiffer PN, et al. Early mortality and years of potential life lost
:
 among Veterans Affairs patients with depression. Psychiatr Serv 2012; 63:823.

134. Cuijpers P, Vogelzangs N, Twisk J, et al. Is excess mortality higher in depressed men
than depressed women?, A meta-analytic comparison. J Affect Disord 2014.

135. Chang CK, Hayes RD, Perera G, et al. Life expectancy at birth for people with serious
mental illness and other major disorders from a secondary mental health care case
register in London. PLoS One 2011; 6:e19590.

136. Lawrence D, Hancock KJ, Kisely S. The gap in life expectancy from preventable
physical illness in psychiatric patients in Western Australia: retrospective analysis of
population based registers. BMJ 2013; 346:f2539.

137. Carney RM, Freedland KE, Jaffe AS, et al. Depression as a risk factor for post-MI
mortality. J Am Coll Cardiol 2004; 44:472; author reply 473.

138. Frasure-Smith N, Lespérance F, Talajic M. Depression following myocardial infarction.

Impact on 6-month survival. JAMA 1993; 270:1819.

139. Carney RM, Freedland KE, Steinmeyer B, et al. Depression and five year survival
following acute myocardial infarction: a prospective study. J Affect Disord 2008;
109:133.

140. Mykletun A, Bjerkeset O, Overland S, et al. Levels of anxiety and depression as

predictors of mortality: the HUNT study. Br J Psychiatry 2009; 195:118.

141. Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease progression and
mortality in cancer patients: a meta-analysis. Cancer 2009; 115:5349.

142. Pan A, Lucas M, Sun Q, et al. Increased mortality risk in women with depression and
diabetes mellitus. Arch Gen Psychiatry 2011; 68:42.

143. Hoertel N, Limosin F, Leleu H. Poor longitudinal continuity of care is associated with an
increased mortality rate among patients with mental disorders: results from the French
National Health Insurance Reimbursement Database. Eur Psychiatry 2014; 29:358.
:
144. Hawton K, van Heeringen K. Suicide. Lancet 2009; 373:1372.

145. Hawton K, Casañas I Comabella C, Haw C, Saunders K. Risk factors for suicide in
individuals with depression: a systematic review. J Affect Disord 2013; 147:17.

146. Fazel S, Wolf A, Pillas D, et al. Suicide, fatal injuries, and other causes of premature
mortality in patients with traumatic brain injury: a 41-year Swedish population study.
JAMA Psychiatry 2014; 71:326.

147. Fralick M, Thiruchelvam D, Tien HC, Redelmeier DA. Risk of suicide after a
concussion. CMAJ 2016; 188:497.

148. Crump C, Sundquist K, Winkleby MA, Sundquist J. Mental disorders and vulnerability
to homicidal death: Swedish nationwide cohort study. BMJ 2013; 346:f557.

149. Crump C, Sundquist K, Winkleby MA, Sundquist J. Mental disorders and risk of
accidental death. Br J Psychiatry 2013; 203:297.

Topic 14693 Version 30.0

:
GRAPHICS

DSM-5 diagnostic criteria for a major depressive episode

A. Five (or more) of the following symptoms have been present during the same two-week period and
represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood
or (2) loss of interest or pleasure.

NOTE: Do not include symptoms that are clearly attributable to another medical condition.

1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg,
feels sad, empty, hopeless) or observations made by others (eg, appears tearful). (NOTE: In children
and adolescents, can be irritable mood.)

2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every
day (as indicated by either subjective account or observation)

3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body
weight in a month), or decrease or increase in appetite nearly every day. (NOTE: In children, consider
failure to make expected weight gain.)

4) Insomnia or hypersomnia nearly every day

5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective
feelings of restlessness or being slowed down)

6) Fatigue or loss of energy nearly every day

7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every
day (not merely self-reproach or guilt about being sick)

8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by their
subjective account or as observed by others)

9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific
plan, or a suicide attempt or a specific plan for committing suicide

B. The symptoms cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.

C. The episode is not attributable to the direct physiological effects of a substance or to another medical
condition.

NOTE: Criteria A through C represent a major depressive episode.

NOTE: Responses to a significant loss (eg, bereavement, financial ruin, losses from a natural disaster, a
serious medical illness or disability) may include the feelings of intense sadness, rumination about the
loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive
episode. Although such symptoms may be understandable or considered appropriate to the loss, the
presence of a major depressive episode in addition to the normal response to a significant loss should also
be carefully considered. This decision inevitably requires the exercise of clinical judgement based on the
individual's history and the cultural norms for the expression of distress in the context of loss.

D. The occurence of the major depressive episode is not better explained by schizoaffective disorder,
schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified
schizophrenia spectrum and other psychotic disorders.

E. There has never been a manic or hypomanic episode.

NOTE: This exclusion does not apply if all of the manic-like or hypomanic-like epsidoes are substance-
:
 induced or are attributable to the physiological effects of another medical condition.

Specify:

With anxious distress

With mixed features

With melancholic features

With atypical features

With psychotic features

With catatonia

With peripartum onset

With seasonal pattern

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright © 2013). American Psychiatric Association. All Rights Reserved.

Graphic 89994 Version 12.0

:
 DSM-5 diagnostic criteria for persistent depressive disorder (dysthymia)

A. Depressed mood for most of the day, for more days than not, as indicated either by subjective account
or observation by others, for at least two years.

NOTE: In children and adolescents, mood can be irritable and duration must be at least one year.

B. Presence, while depressed, of two (or more) of the following:

1) Poor appetite or overeating.

2) Insomnia or hypersomnia.

3) Low energy or fatigue.

4) Low self-esteem.

5) Poor concentration or difficulty making decisions.

6) Feelings of hopelessness.

C. During the two-year period (one year for children or adolescents) of the disturbance, the individual has
never been without the symptoms in Criteria A and B for more than two months at a time.

D. Criteria for a major depressive disorder may be continuously present for two years.

E. There has never been a manic episode or a hypomanic episode, and criteria have never been met for
cyclothymic disorder.

F. The disturbance is not better explained by a persistent schizoaffective disorder, schizophrenia,

delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder.

G. The symptoms are not attributable to the physiological effects of a substance (eg, a drug of abuse, a
medication) or another medical condition (eg, hypothyroidism).

H. The symptoms cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.

NOTE: Because the criteria for a major depressive episode include four symptoms that are absent from
the symptom list for persistent depressive disorder (dysthymia), a very limited number of individuals will
have depressive symptoms that have persisted longer than two years but will not meet criteria for
persistent depressive disorder. If full criteria for a major depressive episode have been met at some point
during the current episode of illness, they should be given a diagnosis of major depressive disorder.
Otherwise, a diagnosis of other specified depressive disorder or unspecified depressive disorder is
warranted.

Specify if:

With anxious distress

With mixed features

With melancholic features

With atypical features

With mood-congruent psychotic features

With mood-incongruent psychotic features

With peripartum onset

Specify if:
:
 In partial remission

In full remission

Specify if:

Early onset: If onset is before 21 years.

Late onset: If onset is at age 21 years or older.

Specify if (for most recent two years of persistant depressive disorder):

With pure dysthymic syndrome: Full criteria for a major depressive episode have not been met in at
least the preceding two years.

With persistent major depressive episode: Full criteria for a major depressive episode have been
met throughout the preceding two-year period.

With intermittent major depressive episodes, with current episode: Full criteria for a major
depressive episode are currently met, but there have been periods of at least eight weeks in at least
the preceding two years with symptoms below the threshold for a full major depressive episode.

With intermittent major depressive episodes, without current episode: Full criteria for a major
depressive episode are not currently met, but there has been one or more major depressive episodes in
at least the preceding two years.

Specify current severity:

Mild

Moderate

Severe

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright © 2013). American Psychiatric Association. All Rights Reserved.

Graphic 91114 Version 5.0

:
 Time to recovery in patients and nonclinical individuals with
unipolar major depression

Time to recovery from the first prospectively observed episode of major

depression in patients (squares, N = 359) and nonclinical individuals (triangles,
N = 216) with major depressive disorder.

Reproduced with permission from: Coryell W, HS Akiskal, AC Leon, et al. 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. Arch Gen Psychiatry 1994; 51:405.
Copyright © 1994 American Medical Association. All rights reserved.

Graphic 73080 Version 11.0

:
 Time to recovery in patients with unipolar major depression

Time to recovery from the first (squares, N = 314) and second (triangles, N =
181) prospectively observed episodes of major depression in patients with
major depressive disorder.

Reproduced with permission from: Coryell W, HS Akiskal, AC Leon, et al. 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. Arch Gen Psychiatry 1994; 51:405.
Copyright © 1994 American Medical Association. All rights reserved.

Graphic 53095 Version 11.0

:
 Mean proportions of weeks in depressive episodes over five-year
periods by age group

Height of rectangle indicates the mean proportion, and error bar indicates +/- 1.00 standard
error.

Reproduced with permission from: Coryell W, Solomon D, Leon A, et al. Does major depressive
disorder change with age? Psychol Med 2009; 39:1689. Copyright © 2009 Cambridge University
Press.

Graphic 60472 Version 1.0

:
Contributor Disclosures
William Coryell, MD Grant/Research/Clinical Trial Support: Jannsen [Major depressive disorder]. Peter
P Roy-Byrne, MD Employment: Mass Medical Society. David Solomon, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for references
to be provided to support the content. Appropriately referenced content is required of all authors and
must conform to UpToDate standards of evidence.

Conflict of interest policy

: