Never-Ending Winter: Chronic Depression

September 15, 2007

Mood disorders are among the most prevalent forms of mental illness. Serious depression is especially common; based on a face-to-face survey conducted from December 2001 to December 2002, the past-year prevalence rate of clinically significant major depressive disorder (MDD) was estimated to be 6.6%, affecting at least 13.1 to 14.2 million Americans.

Mood disorders are among the most prevalent forms of mental illness. Serious depression is especially common; based on a face-to-face survey conducted from December 2001 to December 2002, the past-year prevalence rate of clinically significant major depressive disorder (MDD) was estimated to be 6.6%, affecting at least 13.1 to 14.2 million Americans.1 Although many patients with recurrent episodes of illness have good symptom remission between episodes, with few residual symptoms, approximately a quarter of patients with major depression have chronic residual depressive symptoms of varying severity with only incomplete remission for many years.2 There is evidence that chronic depression is more familial, more refractory to treatment, and more impairing than episodic major depression.

Diagnostic criteria

Current nosologies of depressive illnesses do not, however, do a very good job of categorizing chronic depression. In DSM-IV, there are 2 major categories for depressive illness: MDD, for which there are a number of subcategories and qualifiers; and dysthymic disorder, conceptualized as a more chronic but less severe depressive illness (Table). (DSM-IV also lists minor depressive disorder and recurrent brief depressive disorder among the "criteria sets . . . for further study.")

DSM-IV relies heavily on lists of symptoms to define the categories. For MDD, 5 symptoms are required to make a diagnosis of a major depressive episode: low mood; anhedonia; changes in appetite, weight, sleep, or psychomotor activity; feelings of guilt or worthlessness; cognitive problems (such as poor concentration); and recurrent thoughts of death or suicide. For dysthymic disorder, depressed mood, along with a similar list of symptoms is specified: changes in appetite, weight, or sleep; low energy; low self-esteem; cognitive problems; and hopelessness. Minor depressive disorder requires fewer of the same symptoms as MDD.

When DSM-IV addresses the course of illness, the situation becomes much more confusing and complicated. For MDD, symptoms must be present continuously for 2 weeks and may be characterized by a single episode or be recurrent. Either can be chronic if symptoms present continuously for 2 years. The qualifier, without full interepisode recovery, can be added as well. For dysthymic disorder, symptoms must present for 2 years (1 year in children and adolescents) with no absence of symptoms lasting more than 2 months. Also, there can be no major depressive episode during the first 2 years of the disturbance (1 year for children and adolescents).

When the validity of these distinctions is examined, it becomes apparent that this multitude of diagnoses does not reflect the clinical reality of chronic depressive illnesses. The term "double depression" was introduced by Keller and colleagues3 in 1982 to describe patients with MDD and a preexisting chronic minor depression (now called dysthymic disorder). Although this term appears commonly in the clinical literature and comes closest to reflecting the clinical reality of chronic depression, it is not a DSM diagnosis and must be captured in DSM-IV by assigning 2 diagnoses (MDD and dysthymia).

The natural history of chronic depression was well described in the work of the NIH Collaborative Study on the Psychobiology of Depression. In one report from that project, 431 patients with a major depressive episode were monitored for 12 years, assessed every 6 months, and assigned to 1 of 4 symptom levels of depressive illness: major depression, dysthymia, subsyndromal symptoms, or no symptoms.2 The authors reported that 23% of patients were never symptom-free and that 88% of patients spent some follow-up weeks at 3 or 4 different symptom levels with level changes 2 to 3 times per year. They concluded that "the traditional . . . focus on MDD level of symptoms represents only the tip of the iceberg of this common, chronic and disabling disease." These data further support the idea that rather than a collection of diagnoses, chronic depressive illness is best understood as a fluctuating condition with different levels of severity over time.

McCullough and colleagues4 compared 681 outpatients with chronic depression for a broad range of demographic, clinical, psychosocial, family history, and treatment response variables. Using DSM-IV criteria, they assigned participants to 4 categories of chronic depression:

  • Those who had a chronic major depressive episode lasting longer than 2 years.
  • Those who had suffered at least 2 major depressive episodes but without full interepisode recovery.
  • Those who had dysthymia and a major depressive episode (double depression).
  • Those who had both dysthymia and a chronicmajor depressive episode.

The investigators found almost no significant differences among the groups and concluded that "chronic depression is best viewed as a single broad condition that can assume a variety of clinical course configurations."4

Familial impact on chronicity of illness

It may be a truism that chronicity predicts chronicity in depressive illness, but it is one supported by studies of long-term illness. In a 5-year naturalistic follow-up study of 86 outpatients with the chronic depressive illness dysthymic disorder who had an onset before age 21, Klein and colleagues5 found that the 5-year recovery rate was only 53%. In that study, about half of the patients who did recover had a relapse within 2 years; patients spent an average of 70% of the follow-up period meeting full criteria for a mood disorder; and in about three fourths of the patients who had never had a major depressive episode, one developed during the 5-year period. Interestingly, 6% of the patients experienced mania or hypomania during the follow-up period. Based on a 10-year prospective follow-up study of the naturalistic course of dysthymic disorder and double depression, these investigators also reported that chronic depressive illness was unlikely to become episodic over time and that an episodic illness was unlikely to become chronic.6,7

Our current nosologies of chronic depressive illness, like those of DSM-IV, are hampered by categories that focus on minor distinctions in severity or an array of symptoms. This approach obscures an important underlying unitary concept: that of chronic depressive illness as opposed to episodic depressive illness.

In 1970, Robins and Guze8 suggested that "the finding of an increased prevalence of the same disorder among the close relatives of the original patients strongly indicates that one is dealing with a valid entity." Numerous studies have found family clustering of chronic forms of depression. Klein and colleagues9 reported that rates of MDD were significantly greater among the relatives of young adult probands with chronic depressive disorders (dysthymic disorder and chronic MDD) than among the relatives of probands with episodic major depressive disorder. They also found an increased rate of chronic major depression in relatives of probands with chronic major depression, although this finding did not reach statistical significance. In that study, and in a previous study,10 these investigators found elevated rates of the chronic depressive illness dysthymia in relatives of probands with dysthymia.

My colleagues and I11 recently reported that lifetime chronicity of depressive symptoms (substantial mood symptoms most or all of the time) showed strong familial aggregation in 638 pedigrees from the Genetics of Recurrent Early-onset Depression (GenRED) project. We found that persons with chronic depression had an earlier age of illness onset and higher rates of attempted suicide, panic disorder, and substance abuse than persons with episodic depression. Analysis yielded an odds ratio (OR) of 2.52 for the likelihood of a proband with chronicity predicting this feature in a relative. If the proband's illness started before the age of 13, the OR was 6.16. The results of these studies suggest that chronic illness may identify a more genetically determined subtype of a depressive disorder.

Again using the GenRED data set, we compared the family clustering of depressive illness using different definitions of "chronic depression" and reported further evidence of the inadequacy of DSM-IV nosology for chronic depression.12 In 1750 affected patients we applied 3 definitions of chronicity and determined ORs for the likelihood of chronicity in a proband predicting chronicity in an affected relative using each definition. We found greater family clustering of chronicity as determined by a clinician's global assessment of lifetime course of illness (OR, 2.54) than by DSM-IV definition of chronic major depressive episode (OR, 1.93) or dysthymic disorder (OR, 1.76). In families with probands who had preadolescent onset of MDD, familiality was increased by all definitions but with a much larger increase observed for chronicity by lifetime course (ORs were 6.14 for lifetime chronicity, 2.43 for chronic major depressive episode, and 3.42 for comorbid dysthymic disorder). Interestingly, agreement between these definitions of chronicity was only fair.

Treatment resistance

There is evidence that individuals with chronic depressive illness are more impaired in their functioning than persons with episodic depression. These patients have been shown to have worse long-term outcomes than patients without chronic symptoms, to have a greater number of relapses into periods of incapacitating depression, and to have worse occupational and social functioning over the long term.

Is chronicity merely another way of describing treatment resistance? There are some data suggesting that it is not. Researchers for the STAR*D project noted that depressed patients with a more prolonged or chronic illness course (longer overall duration of illness and greater length of current episode) were less likely to achieve remission with any acute treatment; thus, chronicity seemed to predict treatment resistance.13 When they attempted to characterize their patients with the most treatment-resistant depression, a familiar pattern emerged. They found an association between early age at onset, chronicity, and severity of impairment. Patients coming into this treatment study with early-onset MDD had a longer duration of illness, longer current episodes, more episodes, more suicidality, greater symptom severity, more comorbidity, and more significant negative psychosocial consequences such as lower educational attainment and lower rates of marriage.14

What about bipolar disorder? Akiskal and colleagues15 found that patients in whom bipolar II disorder developed took twice as long to recover from the index major depressive episode as did patients with mania or depression only (52 vs 24 weeks); they had an earlier age at onset of first major depressive episode, a longer duration of illness before study entry, and poorer long-term adjustment (job instability, long periods of unemployment). They concluded that the bipolar II subtype is best understood as mood lability intruding into chronic depressive episodes.

Long-term outcomes

Unfortunately, there are no data that suggest a particular treatment approach to chronic depressive illness. In 1992, Keller and colleagues16 reported that 11.5% of patients with MDD who were monitored for 5 years as part of the NIMH Collaborative Depression Study never recovered from their index episode despite receiving psychiatric care at tertiary-care academic medical centers. In 2003, Kennedy and colleagues17 reported that nearly the same proportion of patients (8%) never recovered from an episode of major depression over a period of 8 to 11 years, despite "quite high levels of antidepressant maintenance, compliance, and psychological therapies." They gloomily concluded that for patients chronically impaired by depressive illness, "the long-term outcome of depression . . . does not appear to have changed in the last 20 years."

Recently reported results from the STAR*D trial show that fewer than one third of patients with severe major depression responded to modern first-line treatment (an SSRI)18 and that after an additional intervention consisting of switching drugs or augmenting with a second agent, about half had still not achieved remission of symptoms.19,20 How many of these patients will remain unwell following the additional steps of the STAR*D protocol remains to be seen, but one would anticipate, based on common clinical experience as well as available data on long-term outcomes from naturalistic studies, that about 10% of the participants will continue to be depressed and severely impaired by depression.


Although several decades of epidemiological research have consistently identified a group of patients with chronic depression, nearly 50 years of treatment trials have failed to have an impact on their illness. The modern antidepressant armamentarium can arguably be described as composed of mere refinements of compounds that were seren- dipitously discovered in the 1950s to have antidepressant efficacy, albeit with important reductions in toxicity and adverse-effect burdens. Modern antidepressants may be safer but they are no more effective than drugs that have been available for more than 50 years.21,22 Clearly, novel pharmacotherapeutic approaches are sorely needed for patients with chronic depression.

Many patients with recurrent episodes of illness have good symptom remission between episodes with few residual symptoms; however, a substantial minority of those with serious depression have chronic residual depressive symptoms of varying severity and only incomplete remission over many years. Compared with persons with episodic depression characterized by full remission and few residual symptoms, these patients are younger at illness onset and have higher rates of attempted suicide, as well as more comorbidities such as panic disorder and substance abuse. Their illness is more refractory to treatment and they are more impaired in their social and occupational functioning than are persons with episodic illness. This course of illness appears to define a subtype of depressive illness that is more familial and thus more genetic in its origins.




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