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: Mar 2017. | This topic last updated: Dec 21,
2016.

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: Treatment of 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 diagnoses.

Patients with bipolar disorder may suffer one or more episodes of major depression prior
to their first manic or hypomanic syndrome, and initially receive a diagnosis of major
depressive disorder. As an example, a prospective observational study assessed 550
patients with major depressive disorder at least annually for up to 31 years, and found
that 20 percent eventually changed diagnoses to bipolar disorder [16]. The probability of
switching diagnoses was higher in patients with the following:

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)
Decreased need for sleep
Unusually high energy
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 [30-32]
Psychotic features (ie, delusions and/or hallucinations) [33-35]
Higher levels of anxiety [30,36-39]
Pre-existing comorbid disorders [29,31], including personality disorders [27,30,40-
42]
High levels of neuroticism [42-45]
Poorer psychosocial functioning [30,39,46-50]
Childhood maltreatment [39,49,51,52]

Recurrence Major depressive disorder is highly recurrent [5,53-55]:

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 [56]:
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 [57]. 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 [57]:

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
[40,56-67]. As an example, a prospective study of 318 patients found that each
recurrence increased the risk of a subsequent recurrence by 16 percent [57].
Residual depressive symptoms This is another potent risk factor [59,62,64,65,67-
70]. 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) [71,72].
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 [51].
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 [56].
Other factors such as:
Greater severity (intensity) of the preceding depressive episode [18,27,56,59,73]
Younger age at time of assessment [56,59,73,74]
Younger age of onset of major depressive disorder [60,75]
Comorbid personality disorder [40,42]
Poorer psychosocial functioning [50,56]
Feeling that life circumstances are beyond ones control (ie, low mastery) [66]
Emotional dysregulation and repeated exposure to adversity [67,76]

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 [77]. 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
[78]. 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 [77,79]. 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 [14,57,80]. 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 [13,14,81,82]:

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
[83]. 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 [84].

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 [85].

Functioning Although psychosocial functioning typically improves in patients who

recover from a major depressive episode [86], functional recovery often takes longer than
syndromal recovery [87]. 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 [88]. 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 ones 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 [89]. 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 [90]. 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 [91-94]. 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 [95]:

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 [96].
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 [96].

Also, patients with dysthymic disorder recovered more slowly than patients with non-
chronic major depression [95]. 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) [97].

Observational studies of dysthymic disorder found that patients usually had exacerbations
that met criteria for a major depressive episode, a phenomenon labelled double
depression [98]. 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) [96,99]. 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 [98,100]. (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 [96,101]

High neuroticism scores [101]
Comorbid anxiety disorder [102,103]

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 [90]. 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
[104]. Nevertheless, patients with chronic major depression recovered [104,105]:

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 [106].
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 [52].

Thus, clinicians should encourage patients to continue treatment and efforts to manage
their illness despite persistent symptoms [107].

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 [104].
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 [108].
Depression is associated with coronary heart disease, diabetes mellitus, Parkinson
disease, stroke, and with worse outcomes in comorbid general medical illnesses [109-
115]. In addition, depression in later life may be an independent risk for subsequent
cognitive decline [116-118]. (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 [119-123]. 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 [124]
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 [125]
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
[126]. 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 [127]. 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 '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 [128]. 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 [129,130].

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 [131-
133]:
 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) [134].
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) [135].
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) [136].

Continuity of care with the same psychiatrist for major depression is associated with
decreased all-cause mortality [137].

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 [138]. 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 [120].

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)
[139]. Other risk factors included male sex, family history of psychiatric disorder, more
severe depression, hopelessness, and comorbidity.

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 [140]. 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 [141].
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 diagnoses 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.)
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 REFERENCES

American Psychiatric Association. Diagnostic and Statistical Manual of Mental

1 Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA
2013.
Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291
2 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global
Burden of Disease Study 2010. Lancet 2012; 380:2197.
Phillips JL, Batten LA, Tremblay P, et al. A Prospective, Longitudinal Study of the
3 Effect of Remission on Cortical Thickness and Hippocampal Volume in Patients with
Treatment-Resistant Depression. Int J Neuropsychopharmacol 2015; 18.
Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on
4 response and remission in major depressive disorder. Neuropsychopharmacology
2006; 31:1841.
Eaton WW, Shao H, Nestadt G, et al. Population-based study of first onset and
5
chronicity in major depressive disorder. Arch Gen Psychiatry 2008; 65:513.
Judd LL, Akiskal HS, Maser JD, et al. A prospective 12-year study of subsyndromal
6 and syndromal depressive symptoms in unipolar major depressive disorders. Arch
Gen Psychiatry 1998; 55:694.
Keitner GI, Posternak MA, Ryan CE. How many subjects with major depressive
7 disorder meet eligibility requirements of an antidepressant efficacy trial? J Clin
Psychiatry 2003; 64:1091.
Zimmerman M, Chelminski I, Posternak MA. Generalizability of antidepressant
8 efficacy trials: differences between depressed psychiatric outpatients who would or
would not qualify for an efficacy trial. Am J Psychiatry 2005; 162:1370.
Zimmerman M, Mattia JI, Posternak MA. Are subjects in pharmacological treatment
9 trials of depression representative of patients in routine clinical practice? Am J
Psychiatry 2002; 159:469.
Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-
10 analysis and exploration of heterogeneity. J Epidemiol Community Health 2007;
61:631.
Chen L, Eaton WW, Gallo JJ, Nestadt G. Understanding the heterogeneity of
11 depression through the triad of symptoms, course and risk factors: a longitudinal,
population-based study. J Affect Disord 2000; 59:1.
Jabben N, Penninx BW, Beekman AT, et al. Co-occurring manic symptomatology as
12 a dimension which may help explaining heterogeneity of depression. J Affect Disord
2011; 131:224.
Coryell W, Akiskal HS, Leon AC, et al. The time course of nonchronic major
depressive disorder. Uniformity across episodes and samples. National Institute of
13
Mental Health Collaborative Program on the Psychobiology of Depression--Clinical
Studies. Arch Gen Psychiatry 1994; 51:405.
Solomon DA, Keller MB, Leon AC, et al. Recovery from major depression. A 10-
14
year prospective follow-up across multiple episodes. Arch Gen Psychiatry 1997;
 54:1001.
Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive
15 disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA
2003; 289:3095.
Fiedorowicz JG, Endicott J, Leon AC, et al. Subthreshold hypomanic symptoms in
16 progression from unipolar major depression to bipolar disorder. Am J Psychiatry
2011; 168:40.
Chen MH, Chen YS, Hsu JW, et al. Comorbidity of ADHD and subsequent bipolar
17 disorder among adolescents and young adults with major depression: a nationwide
longitudinal study. Bipolar Disord 2015; 17:315.
Bukh JD, Andersen PK, Kessing LV. Rates and predictors of remission, recurrence
18 and conversion to bipolar disorder after the first lifetime episode of depression--a
prospective 5-year follow-up study. Psychol Med 2016; 46:1151.
Clayton PJ, Guze SB, Cloninger CR, Martin RL. Unipolar depression: diagnostic
19
inconsistency and its implications. J Affect Disord 1992; 26:111.
Kessing LV. Diagnostic stability in depressive disorder as according to ICD-10 in
20
clinical practice. Psychopathology 2005; 38:32.
Schwartz JE, Fennig S, Tanenberg-Karant M, et al. Congruence of diagnoses 2 years
21
after a first-admission diagnosis of psychosis. Arch Gen Psychiatry 2000; 57:593.
Tsuang MT, Woolson RF, Winokur G, Crowe RR. Stability of psychiatric diagnosis.
22 Schizophrenia and affective disorders followed up over a 30- to 40-year period. Arch
Gen Psychiatry 1981; 38:535.
Salvatore P, Baldessarini RJ, Tohen M, et al. McLean-Harvard International First-
23 Episode Project: two-year stability of ICD-10 diagnoses in 500 first-episode
psychotic disorder patients. J Clin Psychiatry 2011; 72:183.
Bromet EJ, Kotov R, Fochtmann LJ, et al. Diagnostic shifts during the decade
24
following first admission for psychosis. Am J Psychiatry 2011; 168:1186.
Khan A, Dager SR, Cohen S, et al. Chronicity of depressive episode in relation to
25
antidepressant-placebo response. Neuropsychopharmacology 1991; 4:125.
Quitkin FM, Rabkin JG, Ross D, Stewart JW. Identification of true drug response to
26
antidepressants. Use of pattern analysis. Arch Gen Psychiatry 1984; 41:782.
Holma KM, Holma IA, Melartin TK, et al. Long-term outcome of major depressive
27
disorder in psychiatric patients is variable. J Clin Psychiatry 2008; 69:196.
Angst J, Preisig M. Course of a clinical cohort of unipolar, bipolar and
28 schizoaffective patients. Results of a prospective study from 1959 to 1985. Schweiz
Arch Neurol Psychiatr (1985) 1995; 146:5.
Keller MB, Klerman GL, Lavori PW, et al. Long-term outcome of episodes of major
29
depression. Clinical and public health significance. JAMA 1984; 252:788.
Szdczky E, Rzsa S, Zmbori J, Fredi J. Predictors for 2-year outcome of major
30
depressive episode. J Affect Disord 2004; 83:49.
Swindle RW Jr, Cronkite RC, Moos RH. Risk factors for sustained nonremission of
31
depressive symptoms: a 4-year follow-up. J Nerv Ment Dis 1998; 186:462.
 Lamers F, Beekman AT, van Hemert AM, et al. Six-year longitudinal course and
32
outcomes of subtypes of depression. Br J Psychiatry 2016; 208:62.
33 Angst J. The course of affective disorders. Psychopathology 1986; 19 Suppl 2:47.
Coryell W, Leon A, Winokur G, et al. Importance of psychotic features to long-term
34
course in major depressive disorder. Am J Psychiatry 1996; 153:483.
Goldberg JF, Harrow M. Consistency of remission and outcome in bipolar and
35 unipolar mood disorders: a 10-year prospective follow-up. J Affect Disord 2004;
81:123.
Clayton PJ, Grove WM, Coryell W, et al. Follow-up and family study of anxious
36
depression. Am J Psychiatry 1991; 148:1512.
Coryell W, Endicott J, Winokur G. Anxiety syndromes as epiphenomena of primary
37 major depression: outcome and familial psychopathology. Am J Psychiatry 1992;
149:100.
Coryell W, Fiedorowicz JG, Solomon D, et al. Effects of anxiety on the long-term
38
course of depressive disorders. Br J Psychiatry 2012; 200:210.
Kelly KM, Mezuk B. Predictors of remission from generalized anxiety disorder and
39
major depressive disorder. J Affect Disord 2017; 208:467.
Grilo CM, Stout RL, Markowitz JC, et al. Personality disorders predict relapse after
40 remission from an episode of major depressive disorder: a 6-year prospective study. J
Clin Psychiatry 2010; 71:1629.
Skodol AE, Grilo CM, Keyes KM, et al. Relationship of personality disorders to the
41 course of major depressive disorder in a nationally representative sample. Am J
Psychiatry 2011; 168:257.
Bukh JD, Andersen PK, Kessing LV. Personality and the Long-Term Outcome of
42 First-Episode Depression: A Prospective 5-Year Follow-Up Study. J Clin Psychiatry
2016; 77:e704.
Scott J, Eccleston D, Boys R. Can we predict the persistence of depression? Br J
43
Psychiatry 1992; 161:633.
Hirschfeld RM, Klerman GL, Andreasen NC, et al. Psycho-social predictors of
44
chronicity in depressed patients. Br J Psychiatry 1986; 148:648.
Steunenberg B, Beekman AT, Deeg DJ, Kerkhof AJ. Personality predicts recurrence
45
of late-life depression. J Affect Disord 2010; 123:164.
Sherrington JM, Hawton K, Fagg J, et al. Outcome of women admitted to hospital for
46 depressive illness: factors in the prognosis of severe depression. Psychol Med 2001;
31:115.
Solomon DA, Leon AC, Coryell W, et al. Predicting recovery from episodes of major
47
depression. J Affect Disord 2008; 107:285.
Spijker J, de Graaf R, Bijl RV, et al. Determinants of persistence of major depressive
48 episodes in the general population. Results from the Netherlands Mental Health
Survey and Incidence Study (NEMESIS). J Affect Disord 2004; 81:231.
Gilman SE, Trinh NH, Smoller JW, et al. Psychosocial stressors and the prognosis of
49
major depression: a test of Axis IV. Psychol Med 2013; 43:303.
 Stegenga BT, Geerlings MI, Torres-Gonzlez F, et al. Risk factors for onset of
50 multiple or long major depressive episodes versus single and short episodes. Soc
Psychiatry Psychiatr Epidemiol 2013; 48:1067.
Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of
51 illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry 2012;
169:141.
Garcia-Toro M, Rubio JM, Gili M, et al. Persistence of chronic major depression: a
52
national prospective study. J Affect Disord 2013; 151:306.
Practice Guideline for the Treatment of Patients with Major Depressive Disorder,
Third Edition,
53
2010. http://www.psych.org/MainMenu/PsychiatricPractice/PracticeGuidelines_1.asp
x (Accessed on May 29, 2011).
Depression: The Treatment and Management of Depression in Adults, National
54 Clinical Practice Guideline 90, 2010 http://guidance.nice.org.uk/CG90 (Accessed on
May 29, 2011).
Bulloch A, Williams J, Lavorato D, Patten S. Recurrence of major depressive
55 episodes is strongly dependent on the number of previous episodes. Depress Anxiety
2014; 31:72.
Hardeveld F, Spijker J, De Graaf R, et al. Recurrence of major depressive disorder
56 and its predictors in the general population: results from the Netherlands Mental
Health Survey and Incidence Study (NEMESIS). Psychol Med 2013; 43:39.
Solomon DA, Keller MB, Leon AC, et al. Multiple recurrences of major depressive
57
disorder. Am J Psychiatry 2000; 157:229.
Keller MB, Lavori PW, Lewis CE, Klerman GL. Predictors of relapse in major
58
depressive disorder. JAMA 1983; 250:3299.
Pintor L, Torres X, Navarro V, et al. Is the type of remission after a major depressive
59 episode an important risk factor to relapses in a 4-year follow up? J Affect Disord
2004; 82:291.
Giles DE, Jarrett RB, Biggs MM, et al. Clinical predictors of recurrence in
60
depression. Am J Psychiatry 1989; 146:764.
Kessing LV. Severity of depressive episodes according to ICD-10: prediction of risk
61
of relapse and suicide. Br J Psychiatry 2004; 184:153.
Maj M, Veltro F, Pirozzi R, et al. Pattern of recurrence of illness after recovery from
62
an episode of major depression: a prospective study. Am J Psychiatry 1992; 149:795.
Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major
63 depressive disorder during 15 years of observational follow-up. Am J Psychiatry
1999; 156:1000.
ten Doesschate MC, Bockting CL, Koeter MW, et al. Prediction of recurrence in
64
recurrent depression: a 5.5-year prospective study. J Clin Psychiatry 2010; 71:984.
Karsten J, Hartman CA, Smit JH, et al. Psychiatric history and subthreshold
65 symptoms as predictors of the occurrence of depressive or anxiety disorder within 2
years. Br J Psychiatry 2011; 198:206.
66 Colman I, Naicker K, Zeng Y, et al. Predictors of long-term prognosis of depression.
 CMAJ 2011; 183:1969.
van Loo HM, Aggen SH, Gardner CO, Kendler KS. Multiple risk factors predict
67
recurrence of major depressive disorder in women. J Affect Disord 2015; 180:52.
Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission
68 of major depressive disorder with citalopram and risk of relapse: a STAR*D report.
Psychol Med 2010; 40:41.
Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first lifetime
69 major depressive episode herald a chronic course of illness? Am J Psychiatry 2000;
157:1501.
Kiosses DN, Alexopoulos GS. The prognostic significance of subsyndromal
70 symptoms emerging after remission of late-life depression. Psychol Med 2013;
43:341.
Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: a prospective study
71 of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect
Disord 1998; 50:97.
Judd LL, Schettler PJ, Rush AJ, et al. A New Empirical Definition of Major
72 Depressive Episode Recovery and Its Positive Impact on Future Course of Illness. J
Clin Psychiatry 2016; 77:1065.
Coryell W, Endicott J, Keller MB. Predictors of relapse into major depressive
73
disorder in a nonclinical population. Am J Psychiatry 1991; 148:1353.
Eaton WW, Anthony JC, Gallo J, et al. Natural history of Diagnostic Interview
74 Schedule/DSM-IV major depression. The Baltimore Epidemiologic Catchment Area
follow-up. Arch Gen Psychiatry 1997; 54:993.
Zisook S, Lesser I, Stewart JW, et al. Effect of age at onset on the course of major
75
depressive disorder. Am J Psychiatry 2007; 164:1539.
Abravanel BT, Sinha R. Emotion dysregulation mediates the relationship between
76 lifetime cumulative adversity and depressive symptomatology. J Psychiatr Res 2015;
61:89.
Fekadu A, Wooderson SC, Markopoulo K, et al. What happens to patients with
77 treatment-resistant depression? A systematic review of medium to long term outcome
studies. J Affect Disord 2009; 116:4.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in
78 depressed outpatients requiring one or several treatment steps: a STAR*D report. Am
J Psychiatry 2006; 163:1905.
Olin B, Jayewardene AK, Bunker M, Moreno F. Mortality and suicide risk in
79 treatment-resistant depression: an observational study of the long-term impact of
intervention. PLoS One 2012; 7:e48002.
de Jonge P, Conradi HJ, Kaptein KI, et al. Duration of subsequent episodes and
80
periods of recovery in recurrent major depression. J Affect Disord 2010; 125:141.
Kennedy N, Abbott R, Paykel ES. Longitudinal syndromal and sub-syndromal
81 symptoms after severe depression: 10-year follow-up study. Br J Psychiatry 2004;
184:330.
82 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.
Coryell W, Solomon D, Leon A, et al. Does major depressive disorder change with
83
age? Psychol Med 2009; 39:1689.
van Loo HM, Cai T, Gruber MJ, et al. Major depressive disorder subtypes to predict
84
long-term course. Depress Anxiety 2014; 31:765.
Coryell W, Endicott J, Winokur G, et al. Characteristics and significance of untreated
85
major depressive disorder. Am J Psychiatry 1995; 152:1124.
Leon AC, Solomon DA, Mueller TI, et al. The Range of Impaired Functioning Tool
86
(LIFE-RIFT): a brief measure of functional impairment. Psychol Med 1999; 29:869.
Trivedi MH, Morris DW, Wisniewski SR, et al. Increase in work productivity of
87 depressed individuals with improvement in depressive symptom severity. Am J
Psychiatry 2013; 170:633.
van der Voort TY, Seldenrijk A, van Meijel B, et al. Functional versus syndromal
88 recovery in patients with major depressive disorder and bipolar disorder. J Clin
Psychiatry 2015; 76:e809.
IsHak WW, Mirocha J, James D, et al. Quality of life in major depressive disorder
89 before/after multiple steps of treatment and one-year follow-up. Acta Psychiatr Scand
2015; 131:51.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental
90 Disorders, Fourth Edition, Text Revision, American Psychiatric Association,
Washington DC 2000.
McCullough JP Jr, Klein DN, Keller MB, et al. Comparison of DSM-III-R chronic
91 major depression and major depression superimposed on dysthymia (double
depression): validity of the distinction. J Abnorm Psychol 2000; 109:419.
McCullough JP Jr, Klein DN, Borian FE, et al. Group comparisons of DSM-IV
92 subtypes of chronic depression: validity of the distinctions, part 2. J Abnorm Psychol
2003; 112:614.
Klein DN, Shankman SA, Lewinsohn PM, et al. Family study of chronic depression
93
in a community sample of young adults. Am J Psychiatry 2004; 161:646.
Yang T, Dunner DL. Differential subtyping of depression. Depress Anxiety 2001;
94
13:11.
Gonzales LR, Lewinsohn PM, Clarke GN. Longitudinal follow-up of unipolar
95 depressives: an investigation of predictors of relapse. J Consult Clin Psychol 1985;
53:461.
Klein DN, Shankman SA, Rose S. Ten-year prospective follow-up study of the
96 naturalistic course of dysthymic disorder and double depression. Am J Psychiatry
2006; 163:872.
Klein DN, Taylor EB, Dickstein S, Harding K. Primary early-onset dysthymia:
comparison with primary nonbipolar nonchronic major depression on demographic,
97
clinical, familial, personality, and socioenvironmental characteristics and short-term
outcome. J Abnorm Psychol 1988; 97:387.
98 Keller MB, Lavori PW, Endicott J, et al. "Double depression": two-year follow-up.
 Am J Psychiatry 1983; 140:689.
Keller MB, Klein DN, Hirschfeld RM, et al. Results of the DSM-IV mood disorders
99
field trial. Am J Psychiatry 1995; 152:843.
Klein DN, Schwartz JE, Rose S, Leader JB. Five-year course and outcome of
10
dysthymic disorder: A prospective, naturalistic follow-up study. Am J Psychiatry
0
2000; 157:931.
Hayden EP, Klein DN. Outcome of dysthymic disorder at 5-year follow-up: the effect
10
of familial psychopathology, early adversity, personality, comorbidity, and chronic
1
stress. Am J Psychiatry 2001; 158:1864.
10 Klein DN, Shankman SA, Rose S. Dysthymic disorder and double depression:
2 prediction of 10-year course trajectories and outcomes. J Psychiatr Res 2008; 42:408.
Shankman SA, Klein DN. The impact of comorbid anxiety disorders on the course of
10
dysthymic disorder: a 5-year prospective longitudinal study. J Affect Disord 2002;
3
70:211.
10 Coryell W, Endicott J, Keller M. Outcome of patients with chronic affective disorder:
4 a five-year follow-up. Am J Psychiatry 1990; 147:1627.
10 Pincus HA, Pettit AR. The societal costs of chronic major depression. J Clin
5 Psychiatry 2001; 62 Suppl 6:5.
10 Mueller TI, Keller MB, Leon AC, et al. Recovery after 5 years of unremitting major
6 depressive disorder. Arch Gen Psychiatry 1996; 53:794.
Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease management
10
model for depressed patients with persistent symptoms. J Clin Psychiatry 2006;
7
67:1412.
10 Evans DL, Charney DS, Lewis L, et al. Mood disorders in the medically ill: scientific
8 review and recommendations. Biol Psychiatry 2005; 58:175.
10 Jackson JL, DeZee K, Berbano E. Can treating depression improve disease
9 outcomes? Ann Intern Med 2004; 140:1054.
11 Krishnan KR. Depression as a contributing factor in cerebrovascular disease. Am
0 Heart J 2000; 140:70.
11 Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and
1 depression. Biol Psychiatry 2003; 54:227.
Musselman DL, Betan E, Larsen H, Phillips LS. Relationship of depression to
11
diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry 2003;
2
54:317.
Carnethon MR, Biggs ML, Barzilay JI, et al. Longitudinal association between
11
depressive symptoms and incident type 2 diabetes mellitus in older adults: the
3
cardiovascular health study. Arch Intern Med 2007; 167:802.
11 Golden SH, Lazo M, Carnethon M, et al. Examining a bidirectional association
4 between depressive symptoms and diabetes. JAMA 2008; 299:2751.
11 Shen CC, Tsai SJ, Perng CL, et al. Risk of Parkinson disease after depression: a
5 nationwide population-based study. Neurology 2013; 81:1538.
11 Cui X, Lyness JM, Tu X, et al. Does depression precede or follow executive
6 dysfunction? Outcomes in older primary care patients. Am J Psychiatry 2007;
164:1221.
11 Steffens DC, Otey E, Alexopoulos GS, et al. Perspectives on depression, mild
7 cognitive impairment, and cognitive decline. Arch Gen Psychiatry 2006; 63:130.
Singh-Manoux A, Akbaraly TN, Marmot M, et al. Persistent depressive symptoms
11
and cognitive function in late midlife: the Whitehall II study. J Clin Psychiatry 2010;
8
71:1379.
Gallo JJ, Bogner HR, Morales KH, et al. Depression, cardiovascular disease,
11
diabetes, and two-year mortality among older, primary-care patients. Am J Geriatr
9
Psychiatry 2005; 13:748.
12 Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders:
0 follow-up over 34-38 years. J Affect Disord 2002; 68:167.
Cuijpers P, Vogelzangs N, Twisk J, et al. Differential mortality rates in major and
12
subthreshold depression: meta-analysis of studies that measured both. Br J Psychiatry
1
2013; 202:22.
12 Markkula N, Hrknen T, Perl J, et al. Mortality in people with depressive, anxiety
2 and alcohol use disorders in Finland. Br J Psychiatry 2012; 200:143.
Gale CR, Batty GD, Osborn DP, et al. Association of mental disorders in early
12
adulthood and later psychiatric hospital admissions and mortality in a cohort study of
3
more than 1 million men. Arch Gen Psychiatry 2012; 69:823.
Cuijpers P, Vogelzangs N, Twisk J, et al. Comprehensive meta-analysis of excess
12
mortality in depression in the general community versus patients with specific
4
illnesses. Am J Psychiatry 2014; 171:453.
Walker ER, McGee RE, Druss BG. Mortality in mental disorders and global disease
12
burden implications: a systematic review and meta-analysis. JAMA Psychiatry 2015;
5
72:334.
12 Laursen TM, Musliner KL, Benros ME, et al. Mortality and life expectancy in
6 persons with severe unipolar depression. J Affect Disord 2016; 193:203.
12 Zivin K, Ilgen MA, Pfeiffer PN, et al. Early mortality and years of potential life lost
7 among Veterans Affairs patients with depression. Psychiatr Serv 2012; 63:823.
12 Cuijpers P, Vogelzangs N, Twisk J, et al. Is excess mortality higher in depressed men
8 than depressed women?, A meta-analytic comparison. J Affect Disord 2014.
Chang CK, Hayes RD, Perera G, et al. Life expectancy at birth for people with
12
serious mental illness and other major disorders from a secondary mental health care
9
case register in London. PLoS One 2011; 6:e19590.
Lawrence D, Hancock KJ, Kisely S. The gap in life expectancy from preventable
13
physical illness in psychiatric patients in Western Australia: retrospective analysis of
0
population based registers. BMJ 2013; 346:f2539.
13 Carney RM, Freedland KE, Jaffe AS, et al. Depression as a risk factor for post-MI
1 mortality. J Am Coll Cardiol 2004; 44:472; author reply 473.
13
2