Chronic forms of depression were once understood as mainly a characterological or personality disorder (1). However, as these depressive states have been more closely studied over the last three decades, it has been more widely recognized that these conditions are better classified along with the other affective disorders. Chronic depressive disorders include dysthymic disorder, chronic major depressive episode, major depressive episode superimposed on dysthymic disorder (double depression), as well as recurrent major depressive disorder without full interepisode recovery. These subforms of chronic depression are included in DSM-IV either as specifiers or as independent diagnostic category (e.g., dysthymic disorder). However, a broader category called “chronic depression” is being proposed for DSM-5, with the intent to encompass all forms of longstanding depression other than a chronic major depressive episode (2).

The majority of the available information on this subject derives from studies on dysthymic disorder, which is the most frequently studied entity among the various forms of chronic depression. However, when possible, specific clinical and epidemiologic characteristic for each subform of chronic depression will be highlights throughout the manuscript.

An individual with a longstanding, low-grade depression (i.e., dysthymia) has been classically portrayed as habitually gloomy, introverted, brooding, overly conscientious, incapable of fun, and preoccupied with personal inadequacy and failure (3). The concept of dysthymia has gone through different stages of development and was officially included as an axis I condition in DSM-III, essentially replacing the DSM-II diagnosis of neurotic depression (4, 5). As an “independent” condition, dysthymic disorder was defined as a subsyndromal state (i.e., too few symptoms to meet criteria for a major depressive episode), with a protracted duration of at least 2 years in adults. It was characterized by an insidious onset, often in childhood or adolescence, and a persistent, intermittent, or fluctuating course (6). As seen in Table 1, the diagnosis of dysthymic disorder requires the presence of predominantly depressed mood for at least 2 years (criterion A; irritability and 1-year duration will satisfy criteria in children and adolescents) and at least two or more criterion B features (i.e., change in appetite, change in sleep, decreased energy, low self-esteem, difficulties concentrating or making decisions, or hopelessness). The presence of either a symptom-free period lasting longer than 2 months or the presence of a major depressive episode during the first 2 years of the onset of the condition (1 year for children and adolescents) rule out the diagnosis (criterion C and D). Although some people with bipolar disorder also experience longstanding mild depressions, the diagnosis of dysthymic disorder cannot be made when an individual has a history of mania, hypomania, mixed affective episodes, or cyclothymia (criterion E). A history of psychotic symptoms does not rule out a diagnosis of dysthymic disorder as long as mood symptoms are not exclusively present during psychotic episodes (criterion F). As is true of other DSM-IV affective disorders diagnoses, the symptoms should not be a direct consequence of substance abuse or a medical condition, and a significant functional impairment should be present as a consequence of the symptoms (criterion G and H) (7). In the current classification, several specifiers can be used to further describe the disorder, including early versus late onset (21 years being the cutoff point) and presence of atypical features (7). The distinction between early- and late-onset dysthymia is thought to have particularly important prognostic implications (7).

Clinical similarities and frequent coexistence with the various forms of major depressive disorder (MDD) can lead to diagnostic difficulties. In this regard, adults who meet criteria for MDD can be diagnosed with dysthymic disorder as long as the dysthymic disorder has been evident for at least 2 years before the onset of the major depressive episode or the major depressive episode has been in full remission for 2 months before onset of dysthymia. In fact, across a lifetime, most people with dysthymic disorder will experience superimposed major depressive episodes and, conversely, at least 20% of people with MDD will have a history of antecedent dysthymic disorder (8). Whether such “double depressions” are a truly unique entity or more simply reflect the waxing and waning of single condition has been a topic of some interest to mood disorders nosologists for the past 30 years.

As illustrated above, to diagnose dysthymic disorder one should consider not only the chronicity of the symptoms but also the characteristic number and intensity of the symptoms. By convention, a hallmark of dysthymic disorder is that the symptom burden across any and all 2-week intervals is below the threshold for diagnosis of MDD. This convention, in turn, is why the specifier “chronic” is used to describe major depressive episodes that last 2 years or longer (i.e., chronic major depressive episode) in people with MDD or bipolar affective disorder (7). Patients with MDD can also have a chronic course of illness because of failure to achieve full remission of symptoms. As such, they would not meet criteria for dysthymia or chronic major depressive episode, but instead they would be diagnosed as recurrent major depression without full interepisode recovery (7).

Although the presence of chronic depressive symptoms is no longer thought of as a form of personality disorder, axis II conditions are not uncommon among people with early onset chronic forms of depression, with cluster C or “internalizing” personality disorders being the most common. In one study of patients with chronic forms of MDD, nearly one-half of the patients had at least one co-occurring personality disorder, even though patients with borderline and more severe antisocial personality disorders were excluded from this study (9).

Not all conditions associated with chronic depressive symptoms are classifiable as mood disorders. For example, entities such as prolonged grief disorder and chronic adjustment disorder with depressed mood can also present with protracted depressive symptoms but at this juncture are not formally considered forms of chronic depression.

The presence of medical conditions as perpetuating or etiologic factors should always be explored when evaluating a patient with chronic depression. Such conditions include endocrine disturbances (e.g., hypothyroidism, low testosterone, or protracted perimenopausal changes), anemia, hyponatremia, autoimmune disturbances, tumors (e.g., pancreatic, brain, and lung cancer), infections (including human immunodeficiency virus infection), and neurological conditions like epilepsy, Parkinson’s disease, and multiple sclerosis. Chronic mood symptoms can be caused or perpetuated by the abuse of drugs or alcohol and can be induced iatrogenically by antihypertensives, oral contraceptives, steroids, analgesics, antimicrobials, retinoic acid, benzodiazepines, and other medications (10, 11).

The diagnostic validity of chronic forms of depression has been an area of controversy, with most of the work done in patients with dysthymia. Biological research initially was used to help establish the validity of dysthymia as a subtype of depressive disorder. Findings that support a biological basis for this condition included sleep cycle abnormalities that are characteristic of MDD (reduced rapid eye movement [REM] latency, increased REM sleep, and abnormal theta bursts) and abnormalities in central nervous system electrophysiological functions (electroencephalogram during waking state, electrodermal activity, and evoked potentials) (12). Other markers suggesting its biological independence from major depressive disorder include differences in growth hormone secretion and in hypothalamic pituitary axis function (12). However, little has been found when exploring for differences in demographic variables, symptom patterns, treatment response or family history between the different forms of chronic depression (13). In light of that, the depressive disorders work group for DSM-5 has proposed the substitution of dysthymia for a broader category named “chronic depression” (2). The proposed criteria for DSM-V chronic depression are the same as the DSM-IV criteria for dysthymic disorder except for minor modifications to criteria D and E, which are intended to decrease the impact of the chronically depressed patient’s recall bias. The proposed DSM-5 criteria focuses in the last 2 years of symptoms (instead of the first 2) when exploring the presence of chronic major depressive episode or cyclothymia (2).

It is estimated that chronic forms of depression affect 3%–6% of adults in the United States (14, 15). Chronic courses are expected in up to 20% of patients with major depressive disorder (14, 15). Prevalence of dysthymic disorder is relatively high in primary care settings (7%) (16) and even higher in psychiatric outpatient clinics (36%) (17). Chronic courses of depressive symptoms are associated with a higher degree of occupational and psychosocial maladjustment and more frequent suicide attempts than the more episodic forms of depression (18). For example, although by definition dysthymia is a condition of low-grade severity, it is associated with significant functional impairment. In fact, patients with dysthymia are more likely to have supplemental social security income and Medicaid status and less likely to work full time than individuals with nonchronic forms of MDD (19). Patients with dysthymic disorder are more likely to have coexisting axis I conditions with a comorbidity rate of up to 75% in which major depressive disorder, anxiety disorders, and substance abuse are more frequently present (20). By itself, dysthymia is a risk factor for the development of a major depressive episode and (21) its presence is associated with poorer prognosis and more treatment resistance in patients with major depressive disorder (22).

The presence of chronic depressive symptoms, even when subthreshold for major depressive episode, is associated with worse prognosis in patients with coronary heart disease (23) and pregnancy. Newborns of mothers with dysthymia are more likely to have shorter gestational age, a lower birth weight, shorter birth length, and less optimal obstetric outcomes (24).

Given the significant potential for deleterious effects, chronic forms of depression should be promptly recognized by healthcare and mental health providers and aggressively treated.

As part of the zeitgeist to validate dysthymic disorder and other forms of chronic depression as mood disorders, a number of randomized clinical trials of antidepressants were conducted in the 1980s and 1990s. The first large-scale, randomized, placebo-controlled trial of an antidepressant for chronic forms of depression was published in the late 1980s by Kocsis et al. and reported an encouraging 59% response rate with imipramine (as compared with a 13% response rate with placebo) in a sample of 76 subjects in which 84% had courses greater than 5 years (25). Significant benefits were subsequently reported in a large scale, placebo-controlled multicenter study contrasting imipramine and the selective serotonin reuptake inhibitor (SSRI) sertraline (26). In that study, both types of antidepressants were effective, with the SSRI showing better tolerability. The advantage of active pharmacotherapy over placebo in the treatment of chronic forms of depression has been replicated by other investigators and most recently confirmed by meta-analyses. In one recent meta-analysis, for example, Levkovitz et al. reported response rates of up to 52.4% and a number needed to treat of 4.4 was calculated in a sample of 1,454 dysthymic patients receiving monotherapy with a broad range of antidepressants agents including imipramine, fluoxetine, sertraline, and moclobemide (a reversible inhibitor of monoamine oxidase A that, although available in many countries, is not approved for use in the United States), as well as the experimental compounds ritanserin and amisulpride (27). Antidepressant response rates in dysthymia are comparable to those of patients with major depressive disorder even in the presence of negative prognostic indicators such as axis II comorbidities (9). Although the available evidence does not identify a single best type of antidepressant for the treatment of chronic depression, the evidence is strongest for tricyclic antidepressants and selective serotonin reuptake inhibitors (28). These classes of antidepressants may benefit different patients and those who do not respond to one type may still benefit from an adequate trial of the other class of medication. For example, in one study of chronic forms of depression (average duration >6 years), patients showed similar response rates to an initial, 12-week course of double-blind treatment with either sertraline or imipramine monotherapy (52% with sertraline and 51% with imipramine) (29). Nonresponders were then switched to the alternate medications and over one-half responded and about one-quarter remitted (29). As expected, given its more favorable safety and tolerability profile, selective serotonin reuptake inhibitors are more frequently used.

When antidepressants are effective, continuation of treatment beyond acute response and remission is necessary to lower the risk of relapse in patients with chronic depression (30–32). It is not known whether treatment should be continued indefinitely or can be tapered after an extended period of recovery without great hazard of recurrence. In practice, such decisions should be made on a case-by-case basis, considering both the costs and side effects of ongoing pharmacotherapy and the potential risks of a recurrence following withdrawal of the antidepressant.

Frequent comorbid personality disorders as well as possible changes in personality resulting from years or even decades of depression have long made psychotherapy an important consideration for individuals with chronic forms of depression. The general range of response rates in small studies of patients with double depression and dysthymia receiving cognitive behavioral therapy has been reported to be above 30% (33), and there is ample clinical experience that many patients with longstanding depressions can benefit from cognitive, behavioral, interpersonal, and psychodynamic psychotherapies. However, meta-analyses of randomized clinical trials suggest that antidepressant medications (including sertraline, fluoxetine, and nortriptyline) may—on average—convey greater symptomatic benefits over psychotherapies across the first 3-4 months of treatment (34–36).

Although widely practiced and often recommended, combination therapy (i.e., medication plus psychotherapy) has not always been shown in randomized controlled trials to convey a significant advantage compared with medications alone in randomized controlled trials. For example, in two large trials of dysthymic disorder conducted in Canada, no advantages for combining interpersonal psychotherapy (IPT) (37) or group cognitive behavioral (38) therapies with sertraline were found in comparison to pharmacotherapy with sertraline alone. An advantage was found in a large study of patients with chronic forms of MDD (681 subjects). In this trial, patients were randomly assigned to 12 weeks of treatment with the antidepressant nefazodone, a form of psychotherapy developed specifically for chronic depression known as CBASP (cognitive behavioral analysis system of psychotherapy), or their combination. Patients receiving the monotherapies had a 48% response rate (i.e., drug and psychotherapy were almost identically effective at week 12), whereas there was a 73% response rate in combination treatment group (18). A similarly large advantage was shown for chronically depressed inpatients in a German study that contrasted the combination of interpersonal psychotherapy (IPT) and treatment as usual (i.e., pharmacotherapy and milieu therapies) as compared with treatment as usual alone (39). However, no advantage for combined treatment was observed in a third trial known by the acronym REVAMP (Research Evaluating the Value of Augmenting Medication With Psychotherapy). This outpatient study, which randomly assigned 491 patients with chronic forms of major depression who had not remitted with an initial prospective course of algorithm-guided course of pharmacotherapy, found that the addition of psychotherapy (either brief supportive psychotherapy or CBASP) to medications did not result in significantly better outcomes as compared with pharmacotherapy alone (40). Nonetheless, psychotherapy remains and important element when treating chronic depression, and combination therapy continues to be an appropriate option for many patients with persistent and disabling depressive disorders that have not responded to pharmacotherapy alone (41).

As illustrated by this brief review and based on the available evidence and our clinical experience, chronic forms of depression are prevalent and even those with low grade severity can lead to significant functional impairment if untreated. Therefore chronic depression should be considered when evaluating patients with dysphoria even in the presence of significant characterological traits. Clinical benefit from using psychopharmacologic agents alone or in combination with psychotherapy for the treatment of chronic depression is supported in the literature and should be pursued when taking care of patients with chronic depressive symptoms.