Download Persistent Depressive Disorder, Dysthymia, and Chronic Depression

Persistent Depressive Disorder, Dysthymia, and Chronic Depression: Update on
Published on Physicians Practice (http://www.physicianspractice.com)
Persistent Depressive Disorder, Dysthymia, and Chronic
Depression: Update on Diagnosis, Treatment
July 31, 2014
By Rudolf Uher, MUDr, PhD [1]
An update on the diagnosis, causation, and treatment of chronic depressive problems. The focus is
on the recently introduced diagnostic category of persistent depressive disorder.
Since the classic descriptions, depression has been conceived as an episodic and recurrent illness.
Depressive episodes with clear onset and offset and sharp contrast with one’s usual mood and
behaviors are perhaps the most conspicuous feature of severe mood disorders. However, systematic
studies of unselected samples have been telling a different story: a large proportion of individuals
suffer from low mood, lack of interest, and other symptoms of depression chronically, with some
fluctuations but no clearly demarcated episodes.1 Chronic patterns of symptoms are often
under-recognized and undertreated in the community.2
This article provides an update on the diagnosis, causation, and treatment of chronic depressive
problems, with a focus on the recently introduced diagnostic category of persistent depressive
disorder (PDD).
Diagnosis
In DSM-III and DSM-IV, the protracted forms of depression have been conceptualized as dysthymia
and by the chronic specifier of major depressive episodes. Dysthymia was characterized by milder
symptoms not fully meeting criteria for MDD, but lasting 2 years or longer and meriting clinical
attention because of the cumulative burden of long-standing symptoms. The symptomatic criteria for
dysthymia differed in part from those for major depressive episode, with an emphasis on low
self-esteem and hopelessness (Table 1).
In DSM-III and DSM-IV, dysthymia was trumped by MDD and was only diagnosed if the threshold for a
major depressive episode was not met in the initial 2 years of symptoms. Major depressive episodes
could be specified as chronic if the full criteria were continuously met for 2 years or longer.
The validity of dysthymia and its separation from MDD has been repeatedly discussed and
questioned.3 When individuals with dysthymia were followed over long periods, it became clear that
most of them also developed major depressive episodes, which suggests that dysthymia and major
depressive episodes are phases of the same disorder rather than separate conditions.4 Dysthymia
and MDD also run in the same families and respond to the same treatments. On the other hand, both
dysthymia and chronic depression are associated with more impairment, comorbidity, and suicide
risk than less persistent forms of depression.5
Chronic depression and dysthymia were merged into PDD in DSM-5. This new division of depressive
disorders gives more weight to duration than to severity of symptoms. DSM-5 defines PDD on the
basis of the set of symptoms for dysthymia, with the assumption that most individuals who meet the
full symptoms for MDD also meet criteria for dysthymia. However, because of differences in
symptomatic criteria, some individuals with chronic major depressive episodes will not meet the
DSM-5 criteria for PDD.6
While the merger of dysthymia and chronic depression into PDD is well justified by their strong
sequential comorbidity and similar implications for prognosis and treatment, several aspects of the
new diagnosis are not well supported by evidence and may not be useful. Why do we need 2
different sets of symptomatic criteria for MDD and PDD? The reliability and validity of the dysthymia
criteria has not been formally tested, prompting concerns about the value of the new diagnosis.3
The assumption that most individuals with chronic depression also fulfill the dysthymia criteria may
not hold consistently enough—it creates a group of individuals who suffer from chronic depression
but do not receive the PDD diagnosis. While it is undisputable that prolonged duration and
nonepisodic character are relevant, there is no good justification for the 2-year cutoff. In fact, some
of the work used to justify the validity of persistent depression is based on a duration of 1 year or
longer.7 For clinical and prognostic purposes, it is important to emphasize that duration of depressive
symptoms is important both below and above the 2-year mark regardless of whether the depression
Page 1 of 6
Persistent Depressive Disorder, Dysthymia, and Chronic Depression: Update on
Published on Physicians Practice (http://www.physicianspractice.com)
or dysthymia/PDD criteria are met.
How common are the persistent forms of depression?
According to a large general population survey, 2.7% of Americans experience chronic MDD, 2.5%
fulfill the diagnostic criteria for dysthymia, and 4.1% experience either chronic depression or
dysthymia over their lifetime.8 Yet, only approximately 3.4% of Americans receive a lifetime
diagnosis of DSM-5 PDD (Table 2). The difference between the intended definition of PDD (chronic
depression or dysthymia) and the actual DSM-5 definition of PDD (dysthymia not trumped by MDD) is
because approximately 1% of adults fulfill criteria for MDD with a chronic major depressive episode
but do not meet the dysthymia criteria required for PDD. Because of the chronic nature and resulting
impairment, persons who have persistent forms of depression are disproportionately represented
among primary care and mental health service patients.9
Causation
Since chronic forms of depression have typically been studied jointly with the episodic forms of
depressive disorders, relatively less is known about the causation of PDD. However, existing data
indicate partly overlapping and partly specific genetic and environmental factors. Persistent forms of
depression run in families jointly with episodic recurrent depression.5,6 In addition to a general
familial disposition to depressive disorders, there also appears to be a specific familial contribution to
chronicity.10
Familial disposition to dysthymia also overlaps with liability for personality disorders.11,12 Findings
from a study of twins suggest that the overlap is due to genetic factors.13 One study of severe
hospital-ascertained MDD in twins found that stronger heritability was associated with a greater
number but shorter duration of episodes, which suggests that persistent depression might be less
heritable than episodic depression.14 It is therefore likely that some of the familial aggregation of
persistent forms of depression is due to environmental factors that are also shared within families.
Environmental adversity is associated with depression in general and even more so with persistent
depression. A history of childhood maltreatment, including physical abuse, sexual abuse, and
emotional abuse and neglect, is especially strongly associated with persistent forms of depression.15
Regardless of treatment, patients with a history of childhood maltreatment were more likely to have
a chronic course of illness. The long-term relationship between childhood maltreatment and
perpetuation of depression into a chronic course appears to be strong, robust, and independent of
environmental risk factors measured in adulthood.7
The genetic and environmental factors that contribute to persistent depression are unlikely to be
independent of each other. The short variants of the serotonin transporter gene promoter length
polymorphism specifically sensitize individuals to develop chronic and persistent, but not transient or
episodic, depression in adulthood following childhood exposure to maltreatment.16,17 This
gene-environment interaction is perhaps the first example of a distinct causative mechanism specific
to PDD. It remains to be established whether the knowledge of causation can inform and improve
treatment.
Treatment of persistent depression
Many clinicians intuitively assumed that because of its long-standing nature and strong role of
environmental factors, persistent depression may require a primarily psychological treatment, which
may need to be different from that for episodic MDD. None of these assumptions have been borne
out by evidence; antidepressants are at least as effective for PDD as for MDD, and psychological
treatment designed specifically for PDD has not delivered consistent benefits.
The overall rate and degree of treatment success are lower in chronic depression than in non-chronic
depression. For example, in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study,
individuals with a current chronic depressive episode improved less and had a lower probability of
achieving remission than those with non-chronic depression, whether they were treated with
escitalopram or with nortriptyline.18 However, because of a low placebo response, the relative
benefit of antidepressant medication over placebo may actually be larger in PDD then in non-chronic
depression.19,20
A recent meta-analysis evaluated the efficacy and tolerability of treatments for persistent depression
on the basis of direct and indirect comparisons and demonstrated that multiple compounds are
effective for persistent depression.21 Drugs with strong efficacy and good tolerability included the
antidepressants moclobemide (not approved for use in the US) and sertraline as well as the
antipsychotic amisulpride (not licensed in the US or Canada). Imipramine also had strong efficacy
supported by a large body of evidence, but it was less well tolerated. The large effect size of benefit
from high-dose (mean, 675 mg/d) moclobemide and the results of a study showing that phenelzine
may outperform imipramine in chronic depression suggest that MAOIs may be an underutilized but
Page 2 of 6
Persistent Depressive Disorder, Dysthymia, and Chronic Depression: Update on
Published on Physicians Practice (http://www.physicianspractice.com)
effective option in the treatment of PDD.21,22
The finding that psychotherapy is less effective than medication for dysthymia may appear
surprising and has to be qualified by more detailed analyses.23 It is important to note that the
meta-analyses included no study of cognitive-behavioral therapy (CBT), the most extensively tested
psychological treatment for depression. Most of the results were based on interpersonal therapy
(IPT) and the cognitive behavioral analysis system of psychotherapy (CBASP).
IPT was significantly less effective than antidepressants and added only marginally significant
benefits when combined with antidepressant treatment.21 CBASP was developed specifically to
address the interpersonal patterns that presumably underlie the maintenance of chronic depression.
In a large study, CBASP combined with the antidepressant nefazodone led to a response rate of 85%,
a remarkable success in chronic depression.24 However, adding CBASP to antidepressants showed no
significant benefit in a second, even larger study, in spite of intensive therapist training and
adequate adherence to the CBASP protocol.25 The difference of CBASP performance in the two
studies was so large that it has led to heterogeneity and statistically significant differences in a
meta-analysis.21 Such inconsistent results suggest poor generalisability and the need to test the
efficacy of treatments that have shown benefits across multiple studies. The obvious candidate is
CBT.
Adding 12 sessions of individual CBT to antidepressants more than doubled response rates among
patients with MDD resistant to antidepressants; 59% of the patients had a chronic depressive
episode at baseline (and over three-quarters had depression lasting for a year or more).26 Another
study showed the benefits of group CBT among chronically depressed patients with alcohol use
disorder.27 These findings suggest that therapeutic effects of CBT will likely extend to persistent
forms of depression. CBT for persistent depression should be explicitly evaluated.
Persistent depression will require a combination of antidepressant medication and high-quality,
structured psychotherapy to achieve good long-term outcomes. A collaborative approach involving
both a psychiatrist and clinical psychologist or CBT therapist in the care of the same patient is
essential for delivery of effective treatment. One gap in evidence is the concurrent or sequential
indication for medication and psychological treatment. In most research studies, the two treatments
are started at the same time. This is unusual in clinical care.
The most common scenario in our specialized units for mood disorders is to first optimize
pharmacotherapy (often with the use of MAOIs or augmentation of antidepressants) to achieve at
least partial response and then start a course of CBT focusing on residual symptoms, individual
maintaining factors (rumination, avoidance), and comorbid anxiety disorders. The case vignette
provides an example to this approach. Future care may benefit from rigorous comparisons including
sequential and stepped approaches to persistent depression.
CASE VIGNETTE
Caroline, a 50-year-old divorced mother of 2 adult children, is referred because of chronic
depression, insomnia, and anxiety that has not responded to a number of antidepressants,
augmentation attempts, and psychotherapy. During the assessment, she is tense, unable to relax,
and anhedonic, with low energy and reduced affective reactivity. She states, “I have been depressed
for 40 years.”
Her score is 24 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and 35 on the Beck
Depression Inventory (BDI). She meets DSM-5 criteria for PDD (with current major depressive
episode), generalized anxiety disorder, and social anxiety disorder. She is currently taking 10 mg/d
of escitalopram, 100 mg/d of lamotrigine, and 25 mg of quetiapine at bedtime. Titration of
lamotrigine and quetiapine to therapeutic doses (250 mg and 200 mg, respectively) proves
unsuccessful. Escitalopram is discontinued and after a washout period of 3 weeks, phenelzine is
introduced and titrated to 15 mg 3 times daily (the last dose taken at 4 pm to reduce sleep problems
and following dietary restrictions for MAOIs). After taking phenelzine for 8 weeks, Caroline has partial
improvement (MADRS 14, BDI 23).
Caroline is assessed by a clinical psychologist and CBT is initiated, with a focus on activity
scheduling, problem solving, and rumination. This is followed by a course of CBT for generalized
anxiety disorder and for social anxiety disorder, including behavioral experiments and videofeedback
(25 sessions total). After 8 months of treatment with phenelzine and CBT, Caroline’s depression
(MADRS 5, BDI 9) and social anxiety symptoms remit. She is able to return to full-time employment
and enjoy sports activities.
Conclusion
PDD, including previous categories of dysthymia and chronic depression, is associated with adverse
Page 3 of 6
Persistent Depressive Disorder, Dysthymia, and Chronic Depression: Update on
Published on Physicians Practice (http://www.physicianspractice.com)
prognostic indicators, including high rates of comorbidity, impairment, and suicide attempts. PDD
can be effectively treated with antidepressant medication. Clinicians may want to consider MAOIs, at
least in patients who do not respond to SSRIs. Adding structured psychological therapy, such as CBT,
should be considered if remission is not achieved with medication.
Table 2: Lifetime prevalence rates of persistent
forms of depression i...
Table 1: DSM-5 criteria for major depressive
disorder and persistent d...
Disclosures:
Dr Uher is Associate Professor and Canada Research Chair in the department of psychiatry at
Dalhousie University in Halifax, Nova Scotia. He reports no conflicts on interest concerning the
subject matter of this article.
References:
1. 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;55:694-700.
2. Weissman MM, Klerman GL. The chronic depressive in the community: unrecognized and poorly
treated. Compr Psychiatry. 1977;18:523-532.
3. Rhebergen D, Graham R. The re-labelling of dysthymic disorder to persistent depressive disorder
in DSM-5: old wine in new bottles? Curr Opin Psychiatry. 2014;27:27-31.
4. 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;163:872-880.
5. Gilmer WS, Trivedi MH, Rush AJ, et al. Factors associated with chronic depressive episodes: a
preliminary report from the STAR-D project. Acta Psychiatr Scand. 2005;112:425-433.
6. Uher R, Payne JL, Pavlova B, Perlis RH. Major depressive disorder in DSM-5: implications for clinical
practice and research of changes from DSM-IV. Depress Anxiety. 2014;31:459-471.
7. Brown GW, Craig TK, Harris TO. Parental maltreatment and proximal risk factors using the
Childhood Experience of Care & Abuse (CECA) instrument: a life-course study of adult chronic
depression. J Affect Disord. 2008;110:222-233.
8. National Comorbidity Survey. http://www.hcp.med.harvard.edu/ncs. Accessed June 6, 2014.
9. Young AS, Klap R, Shoai R, Wells KB. Persistent depression and anxiety in the United States:
prevalence and quality of care. Psychiatr Serv. 2008;
59:1391-1398.
Page 4 of 6
Persistent Depressive Disorder, Dysthymia, and Chronic Depression: Update on
Published on Physicians Practice (http://www.physicianspractice.com)
10. Mondimore FM, Zandi PP, Mackinnon DF, et al. Familial aggregation of illness chronicity in
recurrent, early-onset major depression pedigrees. Am J Psychiatry. 2006;163:1554-1560.
11. Klein DN, Riso LP, Donaldson SK, et al. Family study of early-onset dysthymia: mood and
personality disorders in relatives of outpatients with dysthymia and episodic major depression and
normal controls. Arch Gen Psychiatry. 1995;52:487-496.
12. Riso LP, Klein DN, Ferro T, et al. Understanding the comorbidity between early-onset dysthymia
and cluster B personality disorders: a family study. Am J Psychiatry. 1996;153:900-906.
13. Røysamb E, Kendler KS, Tambs K, et al. The joint structure of DSM-IV Axis I and Axis II disorders.
J Abnorm Psychol. 2011;120:198-209.
14. McGuffin P, Katz R, Watkins S, Rutherford J. A hospital-based twin register of the heritability of
DSM-IV unipolar depression. Arch Gen Psychiatry. 1996;53:129-136.
15. Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and
treatment outcome in depression: a meta-analysis [published correction appears in Am J Psychiatry.
2012;169:439]. Am J Psychiatry. 2012;169:141-151.
16. Uher R, Caspi A, Houts R, et al. Serotonin transporter gene moderates childhood maltreatment’s
effects on persistent but not single-episode depression: replications and implications for resolving
inconsistent results. J Affect Disord. 2011;135:56-65.
17. Brown GW, Ban M, Craig TK, et al. Serotonin transporter length polymorphism, childhood
maltreatment, and chronic depression: a specific gene-environment interaction. Depress Anxiety.
2013;30:5-13.
18. Uher R, Maier W, Hauser J, et al. Differential efficacy of escitalopram and nortriptyline on
dimensional measures of depression [published correction appears in Br J Psychiatry. 2009;195:87].
Br J Psychiatry. 2009;194:252-259.
19. Levkovitz Y, Tedeschini E, Papakostas GI. Efficacy of antidepressants for dysthymia: a
meta-analysis of placebo-controlled randomized trials. J Clin Psychiatry. 2011;72:509-514.
20. von Wolff A, Hölzel LP, Westphal A, et al. Selective serotonin reuptake inhibitors and tricyclic
antidepressants in the acute treatment of chronic depression and dysthymia: a systematic review
and meta-analysis. J Affect Disord. 2013;144:7-15.
21. Kriston L, von Wolff A, Westphal A, et al. Efficacy and acceptability of acute treatments for
persistent depressive disorder: a network meta-analysis. Depress Anxiety. 2014 Jan 21; [Epub ahead
of print].
22. Stewart JW, McGrath PJ, Quitkin FM, et al. Chronic depression: response to placebo, imipramine,
and phenelzine. J Clin Psychopharmacol. 1993;13:391-396.
23. Cuijpers P, Sijbrandij M, Koole SL, et al. The efficacy of psychotherapy and pharmacotherapy in
treating depressive and anxiety disorders: a meta-analysis of direct comparisons. World Psychiatry.
2013;12:137-148.
24. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive
behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic
depression [published correction appears in N Engl J Med. 2001;345:232]. N Engl J Med.
2000;342:1462-1470.
25. Kocsis JH, Gelenberg AJ, Rothbaum BO, et al. Cognitive behavioral analysis system of
psychotherapy and brief supportive psychotherapy for augmentation of antidepressant nonresponse
in chronic depression: the REVAMP Trial. Arch Gen Psychiatry. 2009;66:1178-1188.
Page 5 of 6
Persistent Depressive Disorder, Dysthymia, and Chronic Depression: Update on
Published on Physicians Practice (http://www.physicianspractice.com)
26. Wiles N, Thomas L, Abel A, et al. Cognitive behavioural therapy as an adjunct to
pharmacotherapy for primary care based patients with treatment resistant depression: results of the
CoBalT randomised controlled trial. Lancet. 2013;381:375-384.
27. Watkins KE, Hunter SB, Hepner KA, et al. An effectiveness trial of group cognitive behavioral
therapy for patients with persistent depressive symptoms in substance abuse treatment. Arch Gen
Psychiatry. 2011;68:577-584.
Source URL:
http://www.physicianspractice.com/special-reports/persistent-depressive-disorder-dysthymia-and-chr
onic-depression
Links:
[1] http://www.physicianspractice.com/authors/rudolf-uher-mudr-phd
Page 6 of 6