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Molecular Psychiatry (2000) 5, 242–261
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REVIEW ARTICLE
Dysthymia: a review of pharmacological and behavioral
factors
J Griffiths1, AV Ravindran1, Z Merali1,2 and H Anisman1,3
1
Department of Psychiatry, University of Ottawa, Ottawa, Canada; 2Institute of Cellular and Molecular Medicine, Ottawa,
Canada; 3Institute of Neuroscience, Carleton University, Ottawa, Canada
Although dysthymia, a chronic, low-grade form of depression, has a morbidity rate as high
as that of major depression, and increases the risk for major depressive disorder, limited
information is available concerning the etiology of this illness. In the present report we review
literature concerning the biological and characterological features of dysthymia, the effectiveness of antidepressant treatments, the influence of stressors in the precipitation and maintenance of the disorder, and both quality of life and psychosocial correlates of the illness. We
also provisionally suggest that dysthymia may stem from disturbances of neuroendocrine
and neurotransmitter functioning (eg, corticotropin releasing hormone and arginine vasopressin within the hypothalamus, or alternatively monoamine variations within several extrahypothalamic sites), and may also involve cytokine activation. The central disturbances may reflect
phenotypic variations of neuroendocrine processes or sensitization of such mechanisms. It
is suggested that chronic stressor experiences or stressors encountered early in life lead to
the phenotypic neurochemical alterations, which then favor the development of the dysthymic
state. Owing to the persistence of the neurochemical disturbances, vulnerability to double
depression is increased, and in this instance treatment with antidepressants may attenuate
the symptoms of major depression but not those of the basal dysthymic state. Moreover, the
residual features of depression following treatment may be indicative of underlying neurochemical disturbances, and may also serve to increase the probability of illness recurrence
or relapse. Molecular Psychiatry (2000) 5, 242–261.
Keywords: depression; antidepressants; corticotropin releasing hormone; arginine vasopressin;
stress; illness recurrence; residual features
Introduction
Dysthymia, a chronic, low-grade form of depression,
occurs in a substantial portion of the population, and
increases the risk for major depressive disorder. Yet,
relative to major depression, limited information is
available concerning the behavioral concomitants, as
well as the physiological correlates of dysthymia. Dysthymia and major depression share several features
regarding stress/coping, and the response to pharmacotherapy. However, it appears that they can be distinguished from one another with respect to hypothalamic-pituitary-adrenal (HPA) functioning, and there is
evidence that these depressive subtypes can be differentiated with regard to their cytokine correlates. Yet,
there is reason to suppose that, owing to its chronic
nature, dysthymia may be associated with persistent
functional changes of HPA activity, as well as several
adjunctive features, including altered stressor and
uplift perceptions, coping styles, and quality of life.1–4
Together, these factors may perpetuate the illness, pro-
Correspondence: H Anisman, Institute of Neuroscience, Life
Science Research Centre, Ottawa, Ontario, K1S 5B6, Canada.
E-mail: hanisman얀ccs.carleton.ca
Received 10 June 1999; revised and accepted 30 September 1999
mote relapse following treatment, and increase the risk
for
superimposed
major
depression
(double
depression).
The broad purpose of the present review is to elucidate several behavioral, neuroendocrine and immune/
cytokine characteristics of dysthymia. To this end, we
provide an overview of the characteristics of dysthymia, including a description of the clinical and epidemiological aspects of the illness, comorbid features of
dysthymia, as well as a review of the data suggesting
a role for genetic factors. Given that dysthymia, or at
least some subtypes of the illness, may involve biological underpinnings, a brief review is provided regarding
the neuroendocrine, neurochemical and cytokine correlates of dysthymia, and an overview is provided concerning the efficacy of pharmacotherapy in the treatment of this disorder.
It is proposed that dysthymia may be related to subtle effects of stressors and inadequate coping styles,
and may be exacerbated by the presence of ongoing
psychosocial impairments. A highly provisional model
is proposed concerning the etiological processes subserving dysthymia, including various facets of the HPA
axis (eg, phenotypic variations of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP),
down-regulation of adrenal functioning) and forebrain
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J Griffiths et al
serotonergic mechanisms. However, given the paucity
of data concerning the effects of various challenges (eg,
dexamethasone, ACTH, CRH, TSH, stressors, as well as
challenges in the presence or absence of metyrapone)
on HPA hormones among dysthymic individuals, the
conclusions that can be derived are tentative and must
necessarily await further data.
Dysthymia: clinical and epidemiological features
Dysthymia, literally meaning ‘being of bad mood’ or
‘ill-humor’ is an illness characterized by a number of
affective, neurovegetative and cognitive symptoms.
The diagnosis of dysthymic disorder was introduced
in the third edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-III) to characterize
chronic depression of 2 or more years and to
encompass disorders which had previously been considered characterologically based, including neurotic
depression, chronic minor depression, and characterological depression.5 While the severity of dysthymia is
usually less profound than that of acute major depressive disorder, symptoms may fluctuate in intensity. Furthermore, several subtypes of dysthymia have been
proposed based on specific symptoms, family history,
and age of onset; subaffective dysthymia is thought to
be of biological origin, while character spectrum dysthymia is more personality-based.6,7 Currently, DSMIV stipulates that a diagnosis of dysthymia includes
depressed mood, coupled with two or more of the following: poor appetite or overeating, insomnia or hypersomnia, low energy/fatigue, low self-esteem, poor concentration or difficulty making decisions, and feelings
of hopelessness.5 Dysthymia also frequently has an
early and insidious onset, and is associated with pathology of character, albeit these may not play an etiological role. There has been some debate as to whether
these symptoms are, in fact, most characteristic of dysthymia, and based on field trials, the DSM-IV
(Appendix B) offers an alternative set of criteria. These
include: (a) low self-esteem, self confidence, or feelings
of inadequacy; (b) feelings of pessimism, despair, and
hopelessness; (c) anhedonia (generalized loss of interest or pleasure); (d) social withdrawal; (e) chronic
fatigue or tiredness; (f) feelings of guilt, or brooding
about the past; (g) irritability or excessive anger; (h)
reduced activity, effectiveness, or productivity; and (i)
difficulty in thinking, as reflected by poor concentration, memory or decisiveness.
Like the DSM-IV, the ICD-10 defines dysthymia as a
chronic depression which fails to meet the severity and
duration criteria for recurrent depressive disorder.
However, depressive illness, of at least mild duration,
may have occurred previously.8 According to the ICD10, dysthymia often begins early in adult life, and
when late onset dysthymia occurs it is often secondary
to a severe major depressive disorder or in response to
environmental stressors (eg, bereavement). Moreover,
dysthymia is thought to include persistent anxietydepression, depressive neurosis, depressive person-
ality disorder, as well as neurotic depression of more
than 2 years duration.7
The characteristics of dysthymia in many ways overlap with those of major depression, although in dysthymia, symptoms outnumber signs (ie, objective characteristics such as vegetative symptoms and psychomotor
changes are typically absent).9 Relative to major
depressive disorder, symptoms occur at a lower frequency in dysthymic patients, but are qualitatively
similar. Moreover, relative to neurovegetative and psychomotor features, social-motivational impairments
tend to be more characteristic of dysthymia.3,10 In many
dysthymic patients an intermittent emergence of major
depression may occur (double depression), with the
dysthymic state usually recurring upon remission of
the major depressive episode.9 Likewise, dysthymia
may emerge as a residual syndrome of acute
depression;6,11 however, the diagnosis of dysthymia
would not be applied if the initial episode of chronic
depressive symptoms met the criteria for and was sufficiently severe to be diagnosed as a major depressive
episode.
Dysthymia is more common among women than
among men (2:1), has a 1-year prevalence rate (for the
United States) estimated as high as 5.4%,12 and the
highest life-time prevalence of the affective disorders.13
However, only a relatively small proportion of dysthymic individuals seek treatment for their illness,
likely owing to the mild nature of the symptoms and
their insidious onset, coupled with the individual’s
lack of insight. Indeed, the illness often appears in
childhood and adolescence,14,15 and as a result of the
long-term, low-grade nature of the illness, dysthymia
might not be perceived as differing from the individual’s norm. It is of interest to note that in a study of a
fairly large number of dysthymic patients, only 41%
had received any form of pharmacotherapy, and just
56% had received psychotherapy, attesting to the
under-treatment of this disorder.16
Although it had been suggested that pharmacotherapy may be less effective in the treatment of dysthymia relative to major depressive disorder, recent
evidence has indicated that such intervention may, in
fact, be a treatment of choice for dysthymia. However,
the treatment response may vary with the specific subtype of the illness.4,17 Indeed, it appeared that
pharmacotherapy was less effective in ‘pure dysthymia’ than in dysthymia with a history of major
depression or in patients with concurrent major
depression.18 Because dysthymia was initially thought
to be more of a characterological disturbance than a
biologically-based illness, and because of the oft-noted
superiority of pharmacotherapy in major depression
relative to that observed in dysthymia,17 the illness was
typically treated using different forms of psychotherapy.19–21 As such, the lack of controlled studies
comparing the relative efficacy of psychotherapy and
pharmacotherapy (either alone or in combination) is
surprising. It was recently reported, however, that in
the short-run, pharmacotherapy (using a selective serotonin reuptake inhibitor) was more efficacious than
243
Molecular Psychiatry
Dysthymia
J Griffiths et al
244
group cognitive behavior therapy (CBT) in alleviating
symptoms of dysthymia,22 although CBT attenuated
several functional aspects of the illness. Using a somewhat more protracted regimen (16 weeks), CBT was
effective in a study involving a small number of dysthymic subjects. While this effect appeared to be
somewhat reduced relative to that associated with
fluoxetine, the effects of the treatments were not significantly different.23
Symptom and illness comorbidity
The presence of comorbid features with dysthymia can
be related to any number of factors. On the one hand,
the comorbidity may simply reflect the nosology of the
syndromes, which have overlapping symptoms.1 On
the other hand, comorbidity may reflect common
underlying mechanisms, or in the case of debilitating
medical conditions, the dysthymic state may represent
a subsyndromal depression resulting from the primary
illness. It is possible, as well, that the development of
dysthymia may be secondary to features such as personality disorders or to excessive anxiety, or conversely, dysthymia may give rise to these features.
Whatever the case, it is of obvious diagnostic and
therapeutic value to discern the presence and progression of comorbid features.1
Major depression is often superimposed on a dysthymic state (double depression), and is associated
with a high rate of illness recurrence.24,25 In their epidemiological study, Weissman et al26 reported that
40% of dysthymic patients exhibited comorbid major
depression, while more recent evidence suggested that
as many as 62% of dysthymic patients met criteria for
current major depression, and 80% for lifetime major
depression.14 Treatment outcome was significantly better in major depressives than among double depressives, as was the recurrence rate over 2 years.25 It has
been suggested that the chronology of dysthymia relative to major depression may influence subsequent
treatment response. For example, it was reported that
patients who had experienced dysthymia subsequent
to their first major depressive episode, showed a
reduced treatment response relative to those patients
in whom onset of dysthymia had preceded their first
major depression.27
As many as 75% of dysthymic patients suffer from
some comorbid psychiatric disorder, of which
depression, anxiety, and substance abuse are the most
common.26 Indeed, approximately one-half (50.7%) of
Shelton et al’s16 sample of 410 dysthymic patients
reported a history of major depression, while 26.3%
had a history of substance abuse, and 68.2% were diagnosed with a comorbid personality disorder. With
respect to comorbid anxiety, it was demonstrated that
while social phobia and panic attacks were significantly more common among unipolar and bipolar
depressives (respectively) than dysthymic patients, the
latter exhibited a higher prevalence of generalized anxiety disorder.28 As such, dysthymia ought to be more
closely scrutinized for comorbid anxiety disorder, as it
Molecular Psychiatry
might be associated with a more severe and enduring
symptom profile, as observed in major depression with
co-existing anxiety disorder,29 and might thus require
adjunctive forms of pharmacotherapy. In fact, it was
recently reported that a coexisting anxiety disorder
may indicate increased risk for persistent depression.30
In addition to comorbid anxiety, dysthymia often coexists with personality disorders.31 As well, more double depressive patients than pure dysthymics met criteria for at least one personality disorder. Conversely,
compared to episodic major depressives, significantly
more dysthymics met criteria for an axis II disorder.
Interestingly, dysthymic patients scored significantly
higher than major depressive patients on all of the 13
dimensions of the Personality Disorder Examination,
with the most common axis II disorders being borderline, avoidant and histrionic.31 Essentially, dysthymic
subjects were found to display personality disorders in
the DSM cluster B (antisocial, narcissistic, borderline
and histrionic)31,32 although high rates of avoidant and
dependent personality disorders were also apparent.31–33
Indeed, it was reported that subaffective and character
spectrum dysthymics could be distinguished from one
another on the basis of DSM cluster C characteristics,
with subaffective subjects exhibiting greater avoidant
personality and dependent personality relative to
character spectrum patients.34 It was further reported
that the occurrence of such personality disorder comorbidity was particularly notable in early-onset dysthymic patients.35,36 Finally, it appeared that depressive personality disorder (DPD) was more closely
aligned with dysthymia than with major depression.37
As in the case of other depressive syndromes,38
substance abuse was found to occur at a fairly high rate
among dysthymic patients. For instance, it has been
reported that subjects in alcohol treatment programs
frequently met the criteria for dysthymic disorder.39
In a sample of subjects with substance-related disorder,
a substantial portion (苲10%) exhibited comorbid
dysthymia.40,41 The dysthymic group also had a surprisingly early age of first use of caffeine (7.3 ± 7.0
years), and the investigators speculated that this may
have constituted an early attempt to self-medicate.40
In considering comorbid features, it may be
important to distinguish between subtypes of dysthymia based on age of illness onset. It had been reported
that early- and late-onset dysthymic patients with
superimposed major depression did not differ with
respect to several clinical, psychosocial and cognitive
indices, nor in terms of family history of depression
and alcoholism.42 Subsequent studies, however, indicated that early-onset dysthymics exhibited greater use
of emotion-focused coping strategies, a higher frequency of personality disorders, and increased lifetime substance abuse disorder than their late-onset
counterparts.36,43–50 Further, a greater number of earlyonset dysthymic patients had a family history of a
mood disorder, and displayed earlier onset and longer
duration of the index major depressive episode.36,50 To
be sure, as indicated by Klein et al,36 the earlier onset
of the index major depressive episode might simply
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J Griffiths et al
reflect greater opportunity for such an occurrence given
that dysthymia increases the risk of major depression.
Moreover, early onset dysthymia being associated with
poor interpersonal and psychosocial skills, may have
favored the development of personality disorders and
substance abuse. Yet, there is reason to suppose that
biological factors may be more closely aligned with
early onset of the illness, while late onset may be associated with character spectrum disorder.4 In fact, as
will be discussed shortly, there have been several
reports indicating that these subgroups may differ with
respect to several neuroendocrine substrates, as well as
in response to some antidepressant medications.
In addition to the high psychiatric comorbidity, dysthymia has also been associated with various other
medical conditions. Given the similarity between dysthymia and chronic fatigue syndrome (CFS), particularly with respect to lethargy, lassitude, impaired
concentration, and diminished drive, the possibility
exists that a subgroup of chronic fatigue patients represents a variant of dysthymia.51 Indeed, it was
reported that patients identified with fatigue were
between six and 10 times more likely to suffer from
dysthymia than the population at large.52 Similarly,
fibromyalgia syndrome, which overlaps with CFS, has
been associated with major depression and dysthymia.53,54 Interestingly, fibromyalgia syndrome has been
associated with adverse childhood experiences. Moreover, specific personality traits which may be related
to such adverse experiences (eg, unstable self-esteem),
may also be associated with fibromyalgia, just as they
are associated with dysthymia.54 It is unclear, however,
whether dysthymia is associated simply with the
symptom of chronic fatigue, as opposed to the syndrome.51 It is significant, as will be discussed shortly,
that dysthymia is associated with elevated production
of interleukin-1 (IL-1␤),55 a cytokine released by activated macrophages, just as CFS has been associated
with an elevation of this cytokine.56,57
In addition to CFS, like other mood and anxietyrelated disorders, dysthymia has also been associated
with increased co-occurrence of migraine (with aura),
tension, and non-organic headaches.58–60 In this
respect, it was reported that of the mood disorders, the
prevalence of coexisting dysthymia was particularly
notable.60 These data raise the possibility that headache and dysthymia share common underlying processes (eg, serotonergic mechanisms, given that both
are positively influenced by serotonin reuptake
inhibitors) or that environmental triggers, such as stressors, may be associated with both pathologies.
Comorbidity involving CFS and headaches in dysthymia is not unexpected given the potential for common mechanisms or environmental precipitants. More
surprising, however, was the finding that a large number of patients suffering from Parkinson’s disease exhibited concurrent major depressive disorder and/or dysthymia. Of course, such comorbidity might be
predicted given that the stress of the neurodegenerative
disturbance might lead to depressive affect. Interestingly, however, in a recent review of this literature,
depressive features, including introversion and
inflexibility, were reported to serve as premorbid predictors of the onset of Parkinson’s disease or an accelerated cognitive decline.61 These investigators have
gone so far as to suggest that psychological and pharmacological interventions may be appropriate in the
treatment of Parkinsonian depression.
As in the case of neurodegenerative disorders,
patients suffering from traumatic brain injury (TBI)
reportedly suffer from a higher prevalence of mood disorders than the general population (ie, 25–50% major
depression, 15–30% dysthymia, 9% mania).62 Given
the large number of brain regions that may be primarily
or secondarily influenced by head trauma, it is difficult
to identify the specific nuclei or pathways subserving
the depression. However, since brain trauma is associated with focal increases of IL-1,63 as are neurodegenerative disorders, the possibility should be considered
that the behavioral effects observed in TBI and
Parkinsonian patients are associated with heightened
cytokine levels.
245
Biological aspects of dysthymia
Depression has been associated with a variety of neurochemical changes, including deficiencies of norepinephrine (NE),64 serotonin (5-HT)65,66 and dopamine
(DA),67–69 or to variations of DA autoreceptors, 5-HT2
receptors, ␣1-NE or ␤-NE receptors.70–72 Of course,
depression is likely a biochemically heterogeneous disorder, such that the neurochemical underpinnings for
the illness, as well as the symptom profile exhibited,
vary across subjects.66,73 Moreover, given the abnormal
responses to various endocrine challenges (eg, the
dexamethasone suppression test (DST), CRH, as well
as thyroid releasing hormone (TRH) challenges), there
is reason to suppose that hormonal variations contribute to the provocation or expression of depressive
symptoms, and that considerable interindividual variability exists with respect to the contribution of these
endocrine factors.74–77
It has been suggested that stressful events or failure
experiences are associated with depressive illness.78–80
Such an outcome may stem from the stressor experience provoking the formation of attributions, which
give rise to negative expectancies of future performance and may result in the development of cognitive
disturbances, such as helplessness.81,82 Alternatively,
stressor experiences may give rise to neurochemical
alterations that favor depressed mood.83,84
It is difficult, using animals, to adequately model
depressive illness let alone to reflect dysthymia. Nevertheless, it may be productive to examine some of the
neurochemical correlates of stressors. Although
environmental insults initiate a series of neurochemical changes that may be of adaptive significance, when
these neurochemical alterations are insufficient to deal
with environmental demands (or neurochemical adaptation does not occur readily), vulnerability to pathology is increased.83 Indeed, animal studies indicated
that stressors will induce many of the central neuroMolecular Psychiatry
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J Griffiths et al
246
transmitter alterations (eg, variations of NE, DA and
5-HT turnover and levels) that have been proposed to
subserve the depressive symptoms in humans.
Specifically, in response to acute stressors the
increased utilization of NE, DA and 5-HT is ordinarily
met by adequate synthesis and hence transmitter levels
remain stable. However, under conditions that favor
amine utilization exceeding synthesis (ie, if the stressor
is sufficiently severe and uncontrollable), amine levels
may decline in several brain regions.83–86 These amine
alterations typically persist for only a few hours,
depending on the stressor severity and several organismic variables (eg, age, species).84,87,88 However,
re-exposure to a mild stressor enhances the utilization
of hypothalamic NE89,90 and mesocortical DA
(sensitization effect),91–93 even if the re-exposure
involves a different stressor.94–96
Since humans typically encounter chronic, intermittent and unpredictable stressors, it may be more relevant to assess the effects of such regimens in animal
studies. In contrast to the amine reductions induced
by acute stressors, transmitter levels equal or exceed
control values following protracted or repeated stressors,93,97–100 owing to increased amine synthesis and/or
moderation of excessive utilization.98,101 Moreover,
chronic insults affect the amine variations engendered
by later stressors. Specifically, in addition to a sensitization with respect to amine utilization (as seen following acute stressors), chronic stressors also induce sensitization of amine synthesis, thereby assuring adequate
transmitter levels upon later stressor encounters.99 In
addition, a chronic stressor may result in the downregulation of ␤-NE receptor activity and the NE-sensitive cAMP response.102 Interestingly, upon application
of a chronic unpredictable stressor the neurochemical
adaptation was slower to develop.83,103 It has been suggested that when inadequate neurochemical coping
mechanisms are generated (eg, in genetically vulnerable animals, and when the stressor occurs unpredictably and involves a series of different insults),
depressive-like characteristics may evolve.104 In fact,
Anisman and Merali105 indicated that a regimen of
mild, unpredictable stressors may be precisely the
antecedent events most closely aligned with dysthymic-like states. It is important to emphasize at this
juncture that while some degree of behavioral and
neurochemical adaptation may occur in response to
chronic stressor experiences, the view has been
expressed that the wear and tear induced by attempts
to adapt to a chronic stressor (allostatic load), when
sufficiently protracted and/or intense, may culminate
in pathological outcomes.106 As will be discussed later,
chronic insults may, in fact, promote persistent neurochemical alterations which favor the development of
depressive characteristics.
While there is considerable evidence supporting a
relationship between major depression and central
neurochemical disturbances,107–110 scant information is
available regarding the biological substrates of dysthymia. However, the frequent abnormal DSTs seen in
major depressive patients were absent in dysthymia,2,4
Molecular Psychiatry
and the latter might actually be associated with hypocortisol responding.111 Indeed, it has been reported that
the elevated salivary cortisol associated with exercise
in pre-adolescent children was not apparent among
dysthymic children of the same age.112 Paralleling
these alterations of pituitary-adrenal activity, differences appeared between major depression and dysthymia in growth hormone secretion in response to
physiological challenges, as well as TSH blunting in
the TRH stimulation test.113
As part of a study assessing the role of psychosocial
and biological variables in chronic and non-chronic
major depression and dysthymia, a lower rate of DST
non-suppression was observed in dysthymic patients
(52% vs 8.5% non-suppression in major depression vs
dysthymia). However, the rate of DST non-suppression
was higher in the early-onset than in the late-onset dysthymics,113 although, when double depressives were
excluded from the analysis (39 of the 75 dysthymic
patients), there was no difference between early and
late onset groups (9% and 8% respectively). Interestingly, paralleling the DST response, among late-onset
dysthymics, the blunted TSH response to TRH administration was absent, whereas early-onset dysthymics
(who parenthetically reported more traumatic and frustrating childhood backgrounds) had a higher rate of
DST nonsuppression, and more frequently exhibited a
blunted TSH response. In effect, these data suggest that
early-onset dysthymia may represent a biologically distinct subgroup of chronically depressed patients.113
Indeed, it was noted that early-onset dysthymics
responded preferentially to moclobemide relative to
imipramine, while no such distinction was found
among the late-onset dysthymics, suggesting that
monoamine oxidase A might be more imbalanced
among early-onset dysthymics.114
While limited attention has been devoted to the
analysis of monoamine abnormalities in dysthymia,
reduced levels of plasma NE coupled with elevated
platelet and free 5-HT were evident in dysthymia.115
Further, following exercise, changes of epinephrine
levels were relatively modest in dysthymic patients
relative to control subjects. Thus, it was posited that
dysthymia may be associated with altered adrenal
responsivity to environmental challenges, as well as
heightened sympathetic tone as reflected by the elevated free 5-HT levels. Ravindran et al111 observed
reduced platelet MAO activity in primary, early-onset
dysthymics relative to control subjects. Moreover,
MAO activity prior to treatment was lower among nonresponders than among the drug responders. Along the
same line, relative to endogenous depressives, MAO
levels were low among neurotic depressives,116 while
MAO activity correlated positively with clinical state
in the endogenous group. Thus, low MAO activity may
represent a marker for vulnerability to neurotic
depression. Consistent with the potential involvement
of serotonergic mechanisms in dysthymia, prior to
treatment, lower urinary 5-hydroxyindoleacetic acid
(5-HIAA) levels were observed among treatment
responders relative to nonresponders, and the reduced
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J Griffiths et al
levels in responders normalized following treatment.117
There have been few studies that assessed the electrophysiological correlates of dysthymia. However, it
was reported that in anticipation of aversive stimuli,
dysthymics exhibited hyporesponsiveness of skin conductance, and displayed subtle cognitive processing
disturbances (possibly reflecting difficulties in the processing of complex information), as reflected by evoked
potentials in response to task-relevant stimuli. It was
posited that dysthymia may be associated with an
impoverished ability to respond appropriately to external task demands, possibly owing to inappropriate
allocation of processing resources. Furthermore, it was
suggested that owing to their impaired resource allocation strategies, dysthymic subjects may be more generally impaired in their ability to cope with day-today stressors.118,119
Akiskal et al120,121 reported differences in the sleep
architecture between subtypes of dysthymic patients.
While subaffective dysthymics exhibited shortened
REM latencies relative to controls, this was not the case
among character spectrum disorder patients. In
addition, dysthymia was associated with excessive and
abnormal distribution of REM during the early part of
the night121 as observed in major depression.2,122 However, while the major depressive patients displayed
reduced total sleep time, sleep latency, morning wake
time and sleep efficiency, the sleep architecture of dysthymics in terms of stage percentages, and REM sleep
features, were identical to those of major depressives.
In effect, these data are consistent with the notion that
the two disorders are variants of the same illness,123 or
share common underlying mechanisms.
Pharmacological contributions to the analysis of
dysthymia
The most persuasive data favoring a biological substrate for dysthymia originate from studies which
assessed pharmacological agents in the treatment of
dysthymic illness. The early pharmacological studies
in dysthymia revealed that although MAO inhibitors
and tricyclic antidepressants (TCAs) had superior
therapeutic efficacy to placebo, their effects were not
as marked as in major depression.4,17,124–130 However,
it appears that reliable and impressive effects of antidepressant medications can be garnered in dysthymia.
This stems from the development of medications, such
as selective serotonin reuptake inhibitors (SSRIs),
which have fewer side effects, thus permitting the use
of higher doses. Moreover, it has been suggested that
optimal drug effects would be obtained when administered primarily to patients with subaffective, rather
than character spectrum disorder.4 In fact, studies
which employed rigorous diagnostic criteria,
established the efficacy of tricyclic agents, such as
imipramine and desipramine,131–137 MAOIs,136,138,139
the reversible monoamine oxidase inhibitor, moclobemide,114,137,140–143 SSRIs, such as fluoxetine and sertraline,22,23,111,132,134,144–146 as well as other agents, such
as the 5HT2 antagonist, ritanserin,147,148 the selective
norepinephrine reuptake inhibitor, reboxetine,149 and
the serotonin/norepinephrine reuptake inhibitor
(SNRI), venlafaxine150,151 (Table 1). The use of well tolerated compounds, including moclobemide and sertraline, may be effective in the long-term management of
dysthymia. This is particularly important since discontinuation of antidepressant treatment was found to be
associated with an 89% rate of relapse in a 4-year
maintenance study.18
In addition to the effects of the aforementioned antidepressants, hormonal manipulations have also been
shown to influence dysthymic symptoms. Specifically,
in a crossover-study involving a small number of subjects, it was observed that administration of the adrenal
androgen, dehydroepiandrosterone, alleviated dysthymic symptoms, primarily comprising anhedonia,
loss of motivation and energy, inability to cope, worry,
emotional numbness, and sadness.163 Interestingly,
these effects were obtained after only 3 weeks of treatment. Furthermore, the thyroid hormone, thyroxine,
potentiated the effects of a variety of antidepressant
medications in dysthymic and treatment-resistant
chronic depressive patients.164 Moreover, in a small
study of five patients it was observed that chromium
supplementation enhanced the antidepressant effects
of more traditional therapeutic agents.165
As indicated earlier, we observed in a double-blind
placebo-controlled study, that sertraline was generally
more effective than group CBT in treating the symptoms of dysthymia, as measured by the Hamilton
Depression Scale.22 Of course, these data need to be
considered as highly provisional, since the trial was
short-term (12 weeks), and the CBT consisted of group
rather than individual treatment. It is possible that
individual CBT, or a program designed specifically for
dysthymia may be more conducive to the treatment of
the disorder. Further, given that anhedonia is a characteristic and persistent feature of dysthymia, it may have
been beneficial to employ cognitive techniques which
focused specifically on the inability of patients to
experience or perceive positive events. Indeed, using
cognitive behavioral psychotherapy, which focuses on
the helplessness and hopelessness associated with dysthymia, and also teaches adaptive coping skills,
McCullough21 reported that nine of 10 dysthymic
patients were still in remission after a 2-year period.
Given the high rate of depressive relapse/recurrence
ordinarily observed following cessation of treatment,
it will be interesting to establish whether combination
therapy minimizes recurrence of illness relative to that
seen among patients who had received only pharmacotherapy. This is particularly the case since group CBT
enhanced the effects of sertraline with respect to some
functional behaviors (eg, cognitive coping styles, and
several indices of quality of life) which, in turn, may
have important implications with respect to illness
recurrence.22
Owing to dysthymia’s fluctuating and chronic nature, several studies evaluated the efficacy of antidepressants in the maintenance treatment of the illness.
247
Molecular Psychiatry
Dysthymia
J Griffiths et al
248
Table 1
Pharmacological studies of DSM-III/DSM-III-R/DSM-IV diagnosed dysthymia
Reference
Medication
Outcome
Placebo-controlled
Stewart et al (1985)130
Harrison et al (1986)152
Kocsis et al (1988)133
Tyrer et al (1988)153
Stewart et al (1989)154,a
Desipramine
Phenelzine
Imipramine
Doxepin
Imipramine, phenelzine
Costa-e-Silva et al (1990)155
Bersani et al (1991)148
Botte et al (1992)141,b
Versiani et al (1992)137
Hellerstein et al (1993)144
Stewart et al (1993)136,a
Versiani (1993)143
Bakish et al (1993)147
Kocsis et al (1994)134
Thase et al (1996)145
Vanelle et al (1997)146
Lecrubier et al (1997)156,a
Versiani (1997)114,a
Boyer et al (1999)157
Ravindran et al (1999)22
Amisulpride
Ritanserin
Moclobemide
Moclobemide, imipramine
Fluoxetine
Imipramine, phenelzine
Moclobemide, imipramine
Ritanserin, imipramine
Sertraline, imipramine
Sertraline, imipramine
Fluoxetine
Amisulpride, imipramine
Moclobemide, imipramine
Amisulpride, amineptine
Sertraline
Desipramine = placebo
Phenelzine ⬎ placebo
Imipramine ⬎ placebo
Doxepin ⬎ placebo
Imipramine ⬎ placebo; phenelzine = placebo;
imipramine = phenelzine
Amisulpride ⬎ placebo
Ritanserin ⬎ placebo
Moclobemide ⬎ placebo
Moclobermide = imipramine ⬎ placebo
Fluoxetine ⬎ placebo
Imipramine ⬎ placebo = phenelzine
Moclobemide ⬎ placebo; imipramine ⬎ placebo
Ritanserin = imipramine ⬎ placebo
Sertraline = imipramine ⬎ placebo
Sertraline = imipramine ⬎ placebo
Fluoxetine ⬎ placebo
Amisulpride = imipramine ⬎ placebo
Moclobemide ⬎ placebo; imipramine ⬎ placebo
Amisulpride = amineptine ⬎ placebo
Sertraline ⬎ CBT = placebo
Non-placebo-controlled
Vallejo et al (1987)139
Baumhackl et al (1989)140,b
Ravindran et al (1994)158
Marin et al (1994)135,a
Friedman et al (1995)159,a
Kocsis et al (1996)160,a
Dunner et al (1996)23
Dunner et al (1997)150
Keller et al (1998)132,c
Santagostino et al (1998)161
Smeraldi (1998)162
Ravindran et al (1998)151
Imipramine, phenelzine
Moclobemide, imipramine
Fluoxetine
Desipramine
Desipramine
Desipramine
Fluoxetine
Venlafaxine
Sertraline, imipramine
Alprazolam
Amisulpride, fluoxetine
Venlafaxine
Phenelzine ⬎ imipramine
Moclobemide = imipramine
65% response
70% response
61% response
71% response
Fluoxetine = CBT
⬎70% response
Sertraline = imipramine
73% response
Amisulpride = fluoxetine
73% response
a
Involved dysthymic and double depressive patients for whom data are reported independently (or authors indicate comparable
effects in the two populations).
b
Neurotic depression.
c
Major depressive or double depressive patients were assessed.
Kocsis et al166 indicated that the higher relapse rate in
those dysthymic patients who were randomized to placebo exceeded that of patients who continued on the
maintenance desipramine treatment. Paralleling these
findings, symptom improvement was sustained, and
the rate of relapse reduced, among dysthymic patients
who were maintained on either trazodone or fluoxetine
over a 40-week interval compared to those who discontinued medication.167 Commensurate with the notion
that a long-standing illness, such as dysthymia, might
require prolonged pharmacotherapy, continuous
improvement was observed among dysthymic patients
treated over a 6-month period,146 while Kocsis et al160
found a substantially reduced rate of relapse (11%)
among dysthymic patients maintained on desipramine
over a 2-year period, relative to the 52% relapse rate
in the placebo group. Although these data do not
necessarily speak to the mechanisms subserving dysMolecular Psychiatry
thymia, the results from these controlled clinical trials
are congruent with the proposition that antidepressants are effective for a substantial portion of dysthymic
patients (primarily the subaffective variety), and that
prolonged maintenance treatment may be beneficial.
While most antidepressant trials have focused on the
effects of 5-HT and NE manipulations on the symptoms
of dysthymia and major depression, there have been
several studies implicating a role for dopamine (DA).
Since DA has been thought to subserve reward processes,168 and anhedonia is a characteristic feature of
depression, the view has been taken that reduced DA
activity might contribute to the depressive profile.104,169,170 It will be recalled, however, that in contrast to major depression, anhedonia is not one of the
fundamental symptoms of dysthymia according to the
DSM-IV criteria. Yet, it has been suggested that
anhedonia may be a cardinal feature of dysthymic indi-
Dysthymia
J Griffiths et al
viduals.4 Unfortunately, there have been few studies
that evaluated the effects of DA manipulations in dysthymia. The administration of the selective D2 and D3
antagonist amisulpride, an agent most often used as an
antipsychotic when administered in high doses (400–
1200 mg), has agonistic DA properties at low doses
(50 mg), likely owing to preferential presynaptic binding. Consistent with the proposition that DA may play
a role in dysthymia, amisulpride was effective in attenuating the symptoms of both dysthymia and major
depressive illness.154–156,169,171,172 In fact, amisulpride
was as effective as imipramine in alleviating depressive symptoms in dysthymia, and both agents were significantly better than placebo in this respect (Table 1).
Genetic factors in dysthymia
Since the prevalence rates of various affective illnesses
differ in families with dysthymic, major depressive and
double depressive probands, it was suggested that dysthymia and major depression are independent disorders.2,47 While dysthymia may represent a trait factor
predicting increased risk for major depression, it may
be important to distinguish between early- and lateonset illness. In fact, while major depression and dysthymia appear to be distinct illnesses, relatives of probands with early-onset depression were at increased
risk for both major depression and dysthymia.173 Likewise, Goodman and Barnhill174 reported the results of
a study comparing the rates of dysthymia in relatives
of probands with either panic disorder, major
depression, or both conditions (a subset of 33 patients
were also dysthymic). Increased rates of dysthymia
were observed in relatives of early-onset major depressives, and among relatives of dysthymic probands, thus
supporting a relationship between early-onset major
depression and dysthymia. Unfortunately, the small
number of subjects tested makes it difficult to discern
whether the risk of dysthymia varies as a function of
early- vs late-onset of the disorder in the dysthymic
proband. Paralleling these findings, rates of major
depression in relatives of early-onset dysthymics compared to relatives of controls, confirmed a familial
association between dysthymia and major depression.
It was also observed that relatives of the dysthymics
had higher rates of chronic depression than relatives
of episodic depressives. Thus, there appears to be support for familial aggregation in dysthymia, as well as
for the validity of dysthymia as a distinct diagnostic
category.175
Donaldson et al176 found higher rates of dysthymia
among relatives of pure dysthymics and of double
depressives, than among relatives of major depressive
probands and normal controls. Furthermore, the rates
of pure dysthymia did not differ between relatives of
pure dysthymics and those of double depressives, nor
did they differ between relatives of major depressive
and normal control probands. Once again, these data
are consistent with the notion that while dysthymia
may be distinct from major depressive disorder, dysthymia and double depression may be more closely
related. The conclusions are clouded, however, by the
finding that there was a higher rate of pure major
depression among the relatives of pure major depressive probands, as well as among the relatives of double
depressives, than among normal controls. These investigators suggested that dysthymia may be associated
with two distinct etiological profiles. That is: (a)
increased vulnerability to depression occurs in all relatives of unipolar depressive illness, irrespective of subtype; and (b) that risk for dysthymia may be particularly notable among relatives of dysthymic patients
and those suffering from double depression.
The high comorbidity of dysthymia with personality
disorders has consistently been noted.177 It has also
been reported that the relatives of dysthymic patients,
regardless of the presence of cluster B personality disorder (antisocial, borderline, histrionic, narcissistic) in
the proband, exhibited increased frequency of dysthymia with and without cluster B personality disorder,
as well as cluster B personality disorder without dysthymia. Thus, these results supported the notion that
dysthymia and cluster B personality disorder share
etiological factors such as genetic or familial factors, or
early home environment.178
The contribution of genetic factors to dysthymia
prompted Akiskal6 to categorize patients, in part, on
the basis of genetic history. It was suggested that subaffective dysthymics frequently had a family history of
depression, whereas character spectrum dysthymics
tended to have a significant family history of
alcoholism/drug abuse, but not of depressive disorder.
Partial support for Akiskal’s classification of subaffective vs character spectrum disorder was obtained from
the finding that there was a higher rate of alcoholism
among the relatives of the character spectrum disorder
dysthymics, while the subaffective dysthymics exhibited higher rates of depressive symptoms, as well as
personality and cognitive features.34 Unlike Akiskal’s
classification, however, these investigators did not
observe differences between groups with respect to
early home environment, family history of mood disorders, gender, or personality disorder.
Few studies have examined the genotypic expression
of factors that might be related to dysthymia. However,
it was demonstrated in a Japanese sample, that patients
diagnosed with depressive disorders exhibited higher
rates of genotypes coding for low activity catechol-omethyltransferase relative to non-depressed controls.179 Although only five dysthymic patients were
represented in the sample, the results obtained were
consistent with those observed in a larger set of major
depressive patients (n = 66) in this study. Of course,
given the small number of subjects tested, these data
must be considered cautiously. Nevertheless, they are
suggestive of disturbances of enzyme activity related to
catecholamine function in dysthymic patients, just as
such effects may occur in major depressive disorder.
While the preceding studies supported a genetic contribution to dysthymia, other studies challenged this
conclusion. For instance, monozygotic and dizygotic
twins did not differ in their concordance rates for dys-
249
Molecular Psychiatry
Dysthymia
J Griffiths et al
250
thymic illness (7.4% vs 8.7% respectively) as they did
with respect to major depression.180 It was concluded
that the shared or family environment may contribute
more to the etiology of dysthymia than to major
depression. It was argued that severity of depression
and early-onset of the illness may be aligned with a
genetic association, while the milder depressive illness
spectrum (including dysthymia) may be more closely
tied to environmental factors. As the dysthymic
patients were not subdivided into character spectrum
vs subaffective, it is unclear from these data whether
the conclusion applies to both subtypes equally.
Psychosocial factors and stressors in major
depressive disorder and dysthymia
There is considerable evidence supporting the contention that a relationship exists between stressful events,
coping deficits, and the development or exacerbation of
major depressive disorder. These data have frequently
been reviewed and thus will not be reiterated
here.78,81,181 In view of the shared attributes between
dysthymia and major depression, it is somewhat surprising how little information is available concerning
the contribution of stress to the provocation of dysthymic disorder. However, inasmuch as dysthymia is
a chronic illness, it may be difficult to identify specific
life events that precipitated illness onset. Nevertheless,
it would not be unreasonable to propose that some
adverse life events, particularly the inability to cope
with day-to-day annoyances, or alternatively chronic
stressor experiences, may precipitate or aggravate the
illness.
Not unexpectedly, some stressors are conducive to
the provocation of depressive symptoms (eg, social
loss),78,182 whereas others are more closely aligned with
anxiety disorders (eg, threats or impending stress).183
Although major life events often precede depression,
the antecedents of affective illness may involve a series
of minor stressors (day-to-day hassles). Indeed, these
stressors may have particularly profound effects when
applied onto a backdrop of major stressors.182,184 Of
course, the potency of a stressor in promoting
depression may be related to characteristics of the
individual, coupled with the nature of the stressor
encountered.78,185,186 Finally, as alluded to earlier,
acute stressors may have very different implications
than chronic predictable or chronic intermittent stressors.182 Chronic intermittent stressors may not lend
themselves to neurochemical adaptation and may be
most likely to result in behavioral disturbances.83,104
It has been reported that dysthymic patients, like
major depressives, perceived a markedly greater frequency of day-to-day annoyances than did nondepressed subjects. In contrast, stressful life events
were only marginally greater in the depressive groups.
The elevated stress perception was accompanied by
coping styles wherein emotion-based strategies predominated (eg, blame, emotional expression, emotional
containment, avoidance/denial). With successful pharmacotherapy, the elevated stress perceptions were
Molecular Psychiatry
reduced, and the reliance on maladaptive coping was
attenuated.187,188 It is unclear whether these effects
reflect changes in appraisal processes and consequently altered coping styles, or simply a proportionate
decline in the reliance upon emotion-focused coping.
Of course, these data do not suggest that altered stress
perception and coping were etiological factors in dysthymia, as they may simply have been correlates of
the illness.
Interestingly, in a prospective study of dysthymic
patients over a 9-month period, McCullough et al189
identified several features that distinguished the remitters from the nonremitters. Specifically, the nonremitters tended to exhibit a stable depressive attributional
style and tended to employ inappropriate coping strategies. Additionally, the nonremitters did not deal with
their major stresses effectively, and tended to use emotion-focused coping (eg, wishing away their problems,
blame) and social support seeking rather than a problem-focused style. These individuals also displayed an
interpersonal style characterized by shyness and lack
of sociability, coupled with submissiveness and compliance. It was suggested that this profile represents a
maladaptive behavioral pattern that predisposes the
individual to the persistent nature of dysthymia.
While there is reason to suppose that stressful events
contribute to the provocation of dysthymia, prospective studies have not been conducted to assess the contribution of life stressors to this illness. Several studies,
however, reported that stressful life events preceded
the onset of both neurotic and non-neurotic
depression.190,191 Given the frequent early onset of dysthymia, coupled with its chronic nature, the paucity of
prospective studies concerning the stressful antecedents of the illness is not surprising. However, it was
reported that among adults who acted as care-givers for
a spouse with a progressive dementia (care-giving itself
is a profound stressor), the incidence of major
depression and dysthymia greatly exceeded that seen
in a matched control sample.192 Thus, dysthymia, like
major depression, may be provoked by chronic uncontrollable stressor conditions. It remains to be established whether a chronic regimen of minor stressors
would likewise be associated with dysthymic symptoms.
In addition to altered stress perception and coping
styles, perceived daily positive or uplifting events were
reduced in dysthymic individuals relative to controls.187,188 This effect, however, was not limited to
day-to-day uplift perception, but was also evident with
respect to several quality of life indices, including
social interaction, health perception, cognitive functioning, alertness, energy/vitality, and life satisfaction.
Among responders to treatment (either pharmacotherapy or group CBT), each of these quality of life
indices increased significantly.22,159,193–195 Studies that
focused on social and interpersonal impairments likewise indicated marked deficits among dysthymic
patients.22,159,193,196–199 These reports indicated that
social impairment correlated positively with increasing
severity and chronicity of the illness, and worsened
Dysthymia
J Griffiths et al
with onset of double depression. In addition to alleviating the depressive symptoms, antidepressants attenuated the social impairment characteristic of dysthymic
patients. Markowitz et al200 demonstrated that acute
treatment (10 weeks) with desipramine significantly
improved interpersonal functioning in dysthymics, as
measured by the Inventory of Interpersonal Problems
(IIP). While improvement continued over a 16-week
maintenance phase, this was not significant, and
although the social impairment scores approached normative values, they did not attain this level. Further to
this point, life satisfaction and psychosocial functioning improved among dysthymics who responded to
antidepressant treatment. Thus, it was posited that the
reduced capacity to enjoy leisure time may be a state
marker of chronic depression.131,159,201
It is interesting that while significant improvement
in quality of life was observed among dysthymic
patients treated with either imipramine or sertraline
over 12 weeks,202 self-reported social functioning
showed greater improvement than did participation in
leisure activity. It was suggested that the delayed
alleviation of certain aspects of psychosocial functioning may have been due to the relatively short duration of pharmacotherapy relative to the patients’ often
life-long impairment. Further to this same point, it
should also be considered that the well entrenched
anhedonia and impaired psychosocial functioning
among dysthymics may contribute to the unremitting
nature of the illness. In this respect, it also appears that
the response to desipramine was inferior among dysthymic patients characterized by the most pronounced
overall social impairment and family dysfunction.131
Despite the fact that antidepressant treatment diminished the functional impairments characteristic of dysthymic patients, it is of particular interest that the
stress profile, although improved, continued to show
significant residuum. For instance, while antidepressant medication was associated with reduced daily hassle perception, increased uplift perception, diminished
reliance on emotion-focused coping styles, and
reduced feelings of loneliness, none of these behavioral
parameters had returned to levels of nondepressed subjects.188 Similarly, Klein et al203 reported that adolescents with a history of dysthymia displayed persistent perception of increased daily hassles, difficulties
in psychosocial functioning, and residual symptoms of
depression. Finally, although improvement of psychosocial functioning was apparent among chronic
depressive patients within 4 weeks of sertraline or
imipramine treatment, the level of functioning typically did not reach that of a community control population.204 However, among those patients who displayed full remission, psychosocial functioning was
comparable to that of a community sample. Thus, it
appeared that in some chronically depressed patients,
antidepressant medication effectively alleviated the
functional psychosocial disturbances. Indeed, it was
recently observed that among patients who received
either sertraline, CBT, or a combination of the two
treatments, only a modest overall elevation of uplift
perception and quality of life was observed. However,
when these scores were assessed among treatment
responders, it was clear that uplift perception and
quality of life scores approached or reached those of
nondysthymic controls.22
As indicated earlier, it has been suggested that
depressive illness, and particularly dysthymia, may be
a life-long disorder. Moreover, the high rate of recurrence of major depressive disorder may stem from
undertreatment of the illness, as reflected by the persistence of residual symptoms.20,205–207 It is similarly
possible that those treatments which permit residual
dysthymic features to persist (eg, inadequate antidepressant dosage or insufficient duration of treatment)
may also favor recurrence of this illness. It is certainly
conceivable that by virtue of its effects on the secondary features of dysthymia, CBT may act to limit illness
recurrence. Yet, as will be discussed later, the neurochemical underpinnings of dysthymia may persist
despite a positive treatment response, thus necessitating sustained maintenance treatment.
One further issue warrants some consideration. It has
been observed that among dysthymic patients treated
with sertraline, the reduction of clinician-rated
depression scores (Hamilton Depression, Montgomery–
Asberg, and Cornell Dysthymia Rating Scales) was
greater than among patients treated with group CBT.
The scores in the latter group were, in fact, no different
from those of placebo-treated subjects. However, like
drug-treated patients who showed a positive treatment
response, the CBT patients who showed significant
clinical improvement also reported a marked increase
of quality of life. In contrast, no such increase was
apparent in placebo responders (ie, their quality of life
was comparable to treatment nonresponders). Thus,
despite the comparable clinical depression scores, the
functional effects of drug treatment, CBT, and placebo
were readily distinguishable. Given that quality of life
changes may be a fundamental characteristic in identifying the efficacy of treatment response,22 such a functional measure may also be useful in distinguishing
genuine drug responders from drug-treated patients
actually exhibiting a placebo-like response, and thus
may prove to be a valuable tool in predicting relapse.
251
Cytokines and depressive illness
Increasing evidence has indicated that depressive illness is accompanied by immune dysregulation. While
it had typically been assumed that depression promoted immunosuppression, it has been argued that the
compromised immunity may actually be secondary to
an initial immune activation. Furthermore, this notion
has led to the possibility that products of an activated
immune system may come to promote central neurochemical changes, hence provoking depressive symptoms.208 Commensurate with this view, depressed
patients exhibited signs of immune activation, including increased plasma concentrations of complement
proteins, C3 and C4, and immunoglobulin (Ig) M, as
well as positive acute phase proteins, haptoglobin, ␣1Molecular Psychiatry
Dysthymia
J Griffiths et al
252
antitrypsin, ␣1 and ␣2 macroglobulin, coupled with
reduced levels of negative acute phase proteins. Also,
depression was accompanied by an increased number
of activated T cells (CD25+ and HLA-DR+), secretion of
neopterin, prostaglandin E2 and thromboxane. Furthermore, it appears that depression may be associated
with variations of either circulating cytokine levels (ie,
cell signalling factors released from activated
macrophages), or cytokine production from mitogenstimulated lymphocytes, including interleukin-2 (IL-2),
soluble IL-2 receptors (sIL-2R), IL-1␤, IL-1 receptor
antagonist (IL-1Ra), IL-6, soluble IL-6 receptor (sIL-6R),
and ␥-interferon (IFN).209–216 While there have been
reports that the elevated levels of IL-1␤, IL-6 and ␣1acid glycoprotein normalized with antidepressant
medication,217 the unregulated production of sIL-2R,
IL-6 and sIL-6R was not attenuated with antidepressant
agents, leading to the suggestion that the latter factors
may be trait markers of the illness.208
Although severity of depressive illness is likely fundamental in determining cytokine levels,208 the possibility cannot be ignored that chronic depression (or
chronic stress) may induce cytokine changes to a
greater extent than those observed following acute episodes (as in the case of major depression). Consistent
with reports in melancholic patients,208 levels of
mitogen-stimulated IL-1␤ production were enhanced
in dysthymia.55 However, in this particular study, IL1␤ production was stimulated by the T cell mitogen,
phytohemagglutinin (PHA), and thus may have
reflected primarily T cell rather than macrophage-produced IL-1␤. While not excluding the possibility that
illness severity may be a pertinent feature in promoting
the enhanced IL-1␤ production, it seems likely that illness chronicity or age of onset may also be important
in this respect. Indeed, it was observed that age of onset
was inversely related to IL-1␤ production, while duration of illness was directly related to production of
this cytokine. Additionally, the altered IL-1␤ production was evident irrespective of whether a typical
or atypical (reversed neurovegetative) profile was evident. Thus, it is unlikely that the altered cytokine production was related to the neurovegetative alterations
that may appear in depression. It might be noted, as
well, that IL-1␤ production was not markedly reduced
with the alleviation of dysthymic symptoms following
12 weeks of SSRI treatment.55,218 However, given that
dysthymia is a long-standing illness, it is certainly
possible that more prolonged treatment would have
been necessary to realize changes of IL-1␤, just as relatively protracted treatment was previously reported to
promote variations of circulating natural killer cells.219
In contrast to the elevated IL-1␤ in supernatants of
mitogen-stimulated lymphocytes, we observed that circulating serum IL-1␤, presumably derived from macrophages and T cells, was not increased in either typical
major depressive or in dysthymic patients. However,
among atypical major depressive patients, circulating
IL-1␤ levels were greatly increased, and normalized
with treatment response.220 It could be assumed that
the elevated levels of serum IL-1␤ in atypical
Molecular Psychiatry
depression were secondary to the neurovegetative features of this depressive subtype. However, animal studies have shown that IL-1␤ provokes some symptoms
characteristic of atypical depression (including,
increased sleep and fatigue),99 and thus it is just as
likely that elevated circulating IL-1␤ contributes to the
neurovegetative features of this depressive subtype.
The finding that illnesses involving atypical depressive
features (eg, chronic fatigue syndrome) may be associated with HPA disturbances (eg, reduced plasma cortisol, increased ACTH, and reduced ACTH release following oCRH challenge),221,222 coupled with the fact
that IL-1␤ is a potent stimulator of CRH release,223,224
raises the possibility that elevated circulating IL-1␤
levels contribute to the pathophysiology of atypical
depressive symptoms.
In support of the immune activation view of depressive illness, Maes225 indicated that in addition to the
altered cytokine, acute phase protein, and hormonal
changes ordinarily elicited as part of the inflammatory
response, elevations of IL-1␤ may be evident in
depression associated with a variety of medical illnesses. These include not only infectious diseases
(influenza, herpes virus, HIV, Borna virus), but also
numerous noninfectious illnesses, such as neurodegenerative disorders, autoimmune disorders and brain
injury.61,225 Thus, it was suggested that the cytokine
activation associated with these illnesses and/or injuries may have provoked variations of HPA activity, as
well as central neurochemical alterations, which may
then have favored the development of depression. In
effect, these comorbid conditions may have contributed to the illness owing to the cascade of cytokine,
hormone and transmitter alterations engendered. It
will be recalled that dysthymia likewise is associated
with a large number of comorbid conditions, such as
neurodegenerative disorders,1,61 traumatic brain
injury,62 and illnesses potentially involving viral
components, such as fibromyalgia syndrome and
chronic fatigue syndrome.53,54 As such, the possibility
ought to be considered that such coexisting illnesses
are not simply correlates of the mood disorder, but may
actually act to either precipitate or aggravate dysthymia.
The data presently available concerning cytokine
changes in depressive illness (ie, studies showing elevations of the cytokines in severe major depression) are
largely correlational. Thus, it is unclear whether the
cytokine alterations seen in affective disorders are secondary to the illness (or the stress associated with the
illness), or play an etiological role in the provocation of
the disorder. Yet, administration of high doses of IL-2,
IFN-␣ and tumor necrosis factor-␣ (TNF-␣) in humans
undergoing immunotherapy have been shown to
induce
neuropsychiatric
symptoms,
including
depression, and these effects were related to the cytokine treatment rather than to the primary illness.226–229
Of course, the doses administered in these studies were
in the pathophysiological range, and thus their relevance to depression per se must be interpreted cautiously. However, as indicated by Meyers,230 even
Dysthymia
J Griffiths et al
when administered at relatively low doses, cytokines
such as IFN-␣ may elicit depressive-like symptoms.
A provisional model of chronic depressive illness
It is clear from the preceding sections that limited data
are available concerning the mechanisms underlying
dysthymia. Because of dysthymia’s chronic, low-grade
nature, animal models of the illness have yet to be
developed. Nevertheless, data derived from animal
studies offer some clues as to the potential persistent
effects of stressor experiences that may be relevant to
dysthymia. In particular, it seems that in addition to
any immediate consequences, stressors may also proactively influence the neurochemical response to subsequently encountered aversive stimuli (sensitization),
hence favoring long-term behavioral repercussions.
Post and Weiss231 indicated that although the variations of certain peptides persist for relatively brief
periods following a single stressor session, with
repeated challenges the release of some peptides will
be more readily induced and will be more persistent
(eg, CRH, and to a greater extent TRH). It was suggested
that depressive illness may initially stem from the neuroendocrine alterations provoked by a stressor. However, with each subsequent stressor experience, or with
each episode of depression, the sensitization becomes
more pronounced, such that progressively less intense
psychosocial stressors are required to provoke the
onset of a depressive episode. Ultimately, episodes of
depression may occur in the absence of obvious stress
triggers. In fact, it was reported that unlike the initial
episode, recurrence was less likely to be preceded by
antecedent stressors196,232 and even occurred spontaneously.233,234 Of course, it is often difficult to identify significant or meaningful stressors that may be pertinent to a given individual, thus conclusions
concerning the presence or absence of stressful precipitants of depression may be difficult to validate. It is
also conceivable that in addition to stressors of a
psychological nature, a physiological stressor, such as
a virus, may be interpreted by the CNS in the same way
as a psychosocial stressor, hence triggering the cascade
of events resulting in neuroendocrine, cytokine, and
mood alterations.235
Although it is often thought that HPA disturbances
are likely only a reflection of depression, it has been
proposed that alterations of HPA activity could be the
primary abnormality in depression, rather than simply
an illness response.236,237 Moreover, it has been suggested that among biologically predisposed individuals, chronic stressors may come to promote sustained
HPA activation which leads to adverse effects.74 As
alluded to earlier, the view has even been offered that
the monoamine variations often associated with
depression may actually stem from endocrine alterations.236,237 In this respect, it was suggested that stressful events promote CRH variations in the central amygdala, which in turn may affect forebrain serotonin
alterations. The former may reflect a basic stress-
response, while the latter, presumably, entails the
appraisal of the stressor situation.238
While the model developed by Post and Weiss231 was
meant to accommodate recurrent depression, it may
also be applicable to the analysis of dysthymia. In this
respect, however, it is important to underscore that
sensitization effects are not limited to the neuroendocrine factors discussed by Post, nor is such a sensitization limited to antecedent stressors. In fact, it has been
demonstrated that several neurochemical alterations
associated with stressors, psychostimulant use
(amphetamine and cocaine), and electrical stimulation
of the amygdala or the piriform cortex, may permanently enhance the neuronal response to subsequent
manipulations (sensitization).239 As will be seen
shortly, this applies to the effects of cytokine treatments as well.
In modelling dysthymic disorders, several features of
this illness need to be considered, and it is important
to distinguish these from other types of depression.
Depressive disorders may be associated with profound
interindividual differences in the symptoms subserving the illness, the response to pharmacotherapy,
as well as the neuroendocrine correlates of the disorder. Further, subtypes of depression may differ in
terms of their response to specific pharmacological
treatments, and with respect to their neuroendocrine
factors. For instance, major depression is characterized
by HPA alterations, including elevated plasma ACTH
and cortisol levels, nonsuppression of cortisol release
following dexamethasone challenge, and a blunted
ACTH response to CRH challenge.222,240 While limited
data are available, it appears that in illnesses involving
atypical features (eg, bulimia, seasonal affective disorder, and chronic fatigue syndrome) the elevated
ACTH levels are accompanied by reduced cortisol, a
blunted ACTH response to CRH challenge,221,222,240,241
and absence of the CRH hypersecretion characteristic
of typical depression.240 Among dysthymic patients the
profile is different yet again, and as indicated earlier,
there is reason to believe that cortisol levels may actually be reduced,4 although a contradictory finding has
been reported with respect to plasma cortisol and CRH
concentrations.242 Moreover, in response to a stressor
challenge, the cortisol response may be minimal in
dysthymic patients relative to that seen in other types
of depression and in nondepressed subjects.112 It
remains to be established whether subaffective and
character-spectrum dysthymia can be distinguished on
the basis of these parameters. In any event, in providing a model of the mechanisms subserving dysthymia
it needs to be understood why this disorder is not associated with cortisol abnormalities like those seen in
major depressive illness. Furthermore, with respect to
double depression, it would be of obvious benefit to
determine why, following successful treatment,
patients typically return to their dysthymic states
rather than to an euthymic state.
The sensitization model described earlier introduces
an important facet of stressor actions that may be relevant to understanding the relationship between
253
Molecular Psychiatry
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J Griffiths et al
254
stressor-induced neurochemical alterations and
chronic depressive illness. Tilders and his associates243–246 indicated that in response to repeated
stressor experiences, or with the passage of time following a stressor or IL-1␤ challenge,247 phenotypic
variations may occur within hypothalamic neurons
that are ordinarily responsive to stressors. In particular,
increased coexpression of CRH and AVP was observed
within CRH containing neurons originating in the paraventricular nucleus (PVN) and having terminals in the
external zone of the median eminence. As the coreleased peptides act synergistically to promote ACTH
secretion, the chronic stressor regimen increases the
potential for elevated HPA functioning.243,246 It is of
particular significance, as well, that the altered coexpression of CRH and AVP was exceptionally long
lasting, and was even evident as long as 60 days following stressor exposure.
Given the chronic nature of dysthymia, characterized
by increased stress perception and inadequate coping
styles, it is conceivable that this illness would be
accompanied by the neuroendocrine characteristics
ordinarily associated with chronic stressors. For
instance, dysthymia may be associated with increased
CRH and AVP coexpression within the external zone
of the median eminence, as occurs with chronic stressors,246 and this may represent a permanent (or
persistent) characteristic. The fact that dysthymic
patients do not exhibit increased ACTH and cortisol,
however, raises the possibility that the protracted
CRH/AVP may have given rise to the down-regulation
of pituitary and adrenal sensitivity. Clearly, this
suggestion is highly speculative given that experiments
have not been performed to assess, in detail, the
characteristics of HPA functioning in dysthymic
patients. Since an abnormal DST response has typically not been noted in dysthymia, it was taken for
granted that this illness is not accompanied by any
HPA disturbances. Yet, it may be the case that dysthymia is associated with adrenal hypofunctioning (as
observed in atypical depression), rather than the hyperfunctioning seen in major depressive disorder.4 There
are few neuroendocrine studies, however, that
observed distinctive differences between dysthymic
and non-depressed subjects. In part, this may stem
from the subtle pathophysiological disturbances in
dysthymia, and the use of neuroendocrine analyses
that tap circulating hormonal levels rather than the
dynamic, temporal patterns of hormone release.1 Also,
assessment of HPA functioning in dysthymia requires
evaluation of the effects of various challenges (eg,
ACTH, CRH, AVP, as well as serotonergic acting
agents) in order to identify the nature of any dysregulation that may exist.107,248 Further, it is essential to
evaluate these processes independently in the character-spectrum and subaffective variants of the illness.
Inasmuch as dysthymia is a chronic illness, often of
mild-moderate severity and typically without clear
precipitating events, it is unlikely that it is related to
a single strong stressor experience. It is more reasonable to speculate that dysthymia reflects the actions of
Molecular Psychiatry
more sustained, variable, and probably less intense
stressors, coupled with the use of inadequate or inappropriate methods of coping, culminating in the
phenotypic CRH/AVP coexpression. Thus, it would
not be altogether surprising to find that double
depression may be related to the superimposition of a
further stressor on the backdrop of dysthymia, which
would then promote the increased release of these peptides (and the ensuing neurochemical cascade). Given
this scenario, it might further be expected that after
treatment of double depression, the CRH/AVP coexpression would persist and hence the dysthymic profile would be maintained. In these individuals the risk
for further major depressive episodes would, of course,
be heightened. In effect, we are suggesting that dysthymia may reflect a chronic state of altered endocrine and
central neurotransmitter functioning which may be
related to sustained stressor experiences together with
inadequate coping. Indeed, even with the remission of
symptoms, the persistent neuropeptide disturbances
would increase the likelihood of symptom recurrence.249 Obviously, it would be of particular interest to
establish whether the alleviation of double depressive
symptoms would be accompanied by abnormal
responses to CRH challenge, and whether such an
effect differed from that seen following recovery from
a major depressive episode. These factors, coupled
with the long standing nature of the disorder, and the
comorbid features discussed earlier, may necessitate a
more sustained regimen of pharmacotherapy. Moreover, given the personality disturbances and the maladaptive cognitive coping strategies characteristic of dysthymia, in the absence of cognitive therapy or
psychotherapy (as adjunctive or maintenance
treatment) susceptibility to recurrence of illness may
be increased. Indeed, we have shown previously that
in spite of clinical improvement following pharmacotherapy, functional disturbances (as reflected by
compromised quality of life, anhedonia) may persist in
dysthymia. It was hypothesized that these residual features may actually be predictive of illness recurrence
following cessation of pharmacotherapy.22
In relating stressful events to the mechanisms underlying dysthymia, we have defined stressors in a fairly
broad way. As discussed earlier, it has been posited
that, among other things, the immune system acts like
a sensory organ informing the brain of antigenic challenge.250,251 Furthermore, given the nature of the neurochemical changes elicited by antigens and cytokines, it
was suggested that immune activation may be interpreted by the CNS as a stressor.44,223,235,251 To be sure,
the effects of systemic stressors (eg, those associated
with viral insults, bacterial endotoxins, cytokines) are
not entirely congruous with those elicited by processive stressors (ie, those involving higher order sensory processing).252 Nevertheless, cytokines may be
part of a regulatory loop that, by virtue of their effects
on CNS functioning, might influence behavioral outputs and may even contribute to the symptoms of
behavioral pathologies, including mood and anxietyrelated disorders.44,235,253 It is certainly the case that
Dysthymia
J Griffiths et al
both processive and systemic stressors effectively
increase HPA activity. However, while processive
stressors do so via limbic circuits, the HPA alterations
elicited by systemic stressors may result from limbicindependent processes.245 Yet, it ought to be underscored that systemic stressors, including IL-1␤, IL-2
and TNF␣ have all been shown to influence central
monoamine activity at both hypothalamic and extrahypothalamic sites, including hippocampal 5-HT
activity, as well as that of NE and DA in hypothalamus,
locus coeruleus and mesolimbic regions.235,254–256
Thus, the possibility exists that cytokine elevations, by
virtue of these monoamine effects, may come to promote or exacerbate depressive disorders, quite apart
from any actions involving the HPA axis. It remains
to be determined whether the IL-1␤ variations seen in
dysthymia are secondary to the illness or, in fact, play
an etiological role. Yet, as indicated earlier, this cytokine provokes behavioral changes, some of which are
reminiscent of the characteristics of atypical
depression, including increased sleep, lethargy and
reduced locomotor activity,257 and may provoke anxiety.235 Given that the production of IL-1␤ in mitogenstimulated lymphocytes is greater among dysthymic
than among major depressive patients, particularly in
those reporting early onset of the illness,55 the possibility exists that dysthymia may be associated with
excessive cytokine reactivity. Increased IL-1␤ activation would then stimulate CRH functioning, and the
ensuing neuroendocrine cascade. In effect, it may be
that in dysthymic patients, stressors in the form of viral
or bacterial challenges, may be particularly potent in
provoking major depressive symptoms and hence promoting double depression.
Concluding remarks
The paucity of data from human studies, coupled with
the lack of a suitable animal model for dysthymia, have
limited the conclusions that can be drawn concerning
the etiology of this disorder. Nevertheless, the available
data have made it clear that elucidation of the mechanisms underlying dysthymia, and the development of
adequate treatment strategies, will require that several
fundamental features be included in experimental
analyses. Foremost in this respect is the need to subtype subjects according to definite criteria. In particular, it will be of obvious advantage to distinguish
between pure dysthymia, double depression, and other
forms of chronic depression. Additionally, patients
need to be characterized into homogeneous subgroups
(eg, early- vs late-onset; subaffective vs characterspectrum), and the symptom profile of the dysthymic
patients ought to be considered (vis-à-vis the presence
of typical or atypical neurovegetative symptoms).
Although genetic factors likely contribute to the
expression of dysthymia, there is also reason to believe
that experiential factors play a cogent role in this
respect. There is no information, however, as to
whether early-life experiences contribute to the biological (subaffective) type of dysthymia. It is interest-
ing, however, that studies in rodents have indicated
that early life maternal deprivation may give rise to a
cascade of neurochemical alterations much like those
purported to occur in dysthymia. These include
increased CRH mRNA expression in the amygdala and
CRH concentrations in the median eminence, as well
as increases of CRH receptors in the prefrontal cortex,
amygdala, hypothalamus and cerebellum. As adults,
rats that had undergone maternal deprivation display
increased stress-elicited arousal and elevated HPA
functioning.258,259 The possibility ought to be explored
that in humans, early-life stress or ‘neglect’ may give
rise to these neurochemical disturbances, hence
increasing vulnerability to later stressor-induced neuroendocrine and neurotransmitter alterations and ultimately the dysthymic profile. Of course, the failure to
establish appropriate coping strategies (and this
includes affiliation, attachment and support systems,
particularly with parents) may augment stressor
effects, thereby encouraging the development of dysthymia.
Finally, the identification of subtypes of dysthymia
may be an important feature in determining the optimal treatment strategy employed. From the outset, it
must be acknowledged that because dysthymia is a
chronic condition, relatively sustained treatment may
be required to alleviate the symptoms.260 Thus, drugs
that are relatively well tolerated will be most efficacious in treatment, particularly when these agents do
not elicit sexual dysfunction or somatic complaints,
symptoms which themselves typically are not characteristic of dysthymia.18 Further, it is likely, as indicated
earlier, that the effectiveness of various treatment strategies may be related to factors such as age of onset,
and the presence of characterological features. In this
respect, determining whether a given episode is associated with neuroendocrine disturbances (eg, reduced
cortisol secretion secondary to excessive CRH
activation) may offer insights into whether pharmacotherapy (and the type of agents used) would be most
efficacious in treating the disorder. Of course, family
history of psychiatric illness and the effectiveness of
specific pharmacotherapy therein, would be of obvious
value in planning a treatment strategy. Finally, it ought
to be underscored that the effectiveness of cognitive
therapy has not been extensively evaluated in dysthymic patients. Nevertheless, it would appear that this
therapeutic modality may be useful in treating some
dysthymic patients. It remains to be established what
characteristics of the illness might be predictive of
those patients who would benefit most from this form
of therapy. In this respect, it may be useful to consider
functional parameters related to quality of life (eg, cognitive disturbances, social interaction, life satisfaction),
as opposed to relying simply on clinical indices of
depression. Given the particularly high rate of relapse
in dysthymia upon cessation of pharmacotherapy,18 the
possibility ought to be considered that cognitive therapy, particularly when focusing on residual functional
disturbances, would be useful as an adjunctive or
maintenance treatment strategy.
255
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J Griffiths et al
256
Acknowledgements
This work was supported by the Medical Research
Council of Canada. HA is an Ontario Mental Health
Foundation Senior Research Fellow.
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