Dysthymia: a review of pharmacological and behavioral factors

Molecular Psychiatry (2000) 5, 242–261 2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00

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REVIEW ARTICLE

Dysthymia: a review of pharmacological and behavioralfactorsJ Griffiths1, AV Ravindran1, Z Merali1,2 and H Anisman1,3

1Department 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 highas that of major depression, and increases the risk for major depressive disorder, limitedinformation is available concerning the etiology of this illness. In the present report we reviewliterature concerning the biological and characterological features of dysthymia, the effective-ness of antidepressant treatments, the influence of stressors in the precipitation and mainte-nance of the disorder, and both quality of life and psychosocial correlates of the illness. Wealso provisionally suggest that dysthymia may stem from disturbances of neuroendocrineand neurotransmitter functioning (eg, corticotropin releasing hormone and arginine vasopres-sin within the hypothalamus, or alternatively monoamine variations within several extrahypo-thalamic sites), and may also involve cytokine activation. The central disturbances may reflectphenotypic variations of neuroendocrine processes or sensitization of such mechanisms. Itis suggested that chronic stressor experiences or stressors encountered early in life lead tothe phenotypic neurochemical alterations, which then favor the development of the dysthymicstate. Owing to the persistence of the neurochemical disturbances, vulnerability to doubledepression is increased, and in this instance treatment with antidepressants may attenuatethe symptoms of major depression but not those of the basal dysthymic state. Moreover, theresidual features of depression following treatment may be indicative of underlying neuro-chemical disturbances, and may also serve to increase the probability of illness recurrenceor 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, andincreases the risk for major depressive disorder. Yet,relative to major depression, limited information isavailable concerning the behavioral concomitants, aswell as the physiological correlates of dysthymia. Dys-thymia and major depression share several featuresregarding stress/coping, and the response to pharmaco-therapy. However, it appears that they can be dis-tinguished from one another with respect to hypothal-amic-pituitary-adrenal (HPA) functioning, and there isevidence that these depressive subtypes can be differ-entiated with regard to their cytokine correlates. Yet,there is reason to suppose that, owing to its chronicnature, dysthymia may be associated with persistentfunctional changes of HPA activity, as well as severaladjunctive features, including altered stressor anduplift perceptions, coping styles, and quality of life.1–4

Together, these factors may perpetuate the illness, pro-

Correspondence: H Anisman, Institute of Neuroscience, LifeScience Research Centre, Ottawa, Ontario, K1S 5B6, Canada.E-mail: hanismanKccs.carleton.caReceived 10 June 1999; revised and accepted 30 September 1999

mote relapse following treatment, and increase the riskfor superimposed major depression (doubledepression).

The broad purpose of the present review is to eluci-date several behavioral, neuroendocrine and immune/cytokine characteristics of dysthymia. To this end, weprovide an overview of the characteristics of dysthy-mia, including a description of the clinical and epide-miological aspects of the illness, comorbid features ofdysthymia, as well as a review of the data suggestinga role for genetic factors. Given that dysthymia, or atleast some subtypes of the illness, may involve biologi-cal underpinnings, a brief review is provided regardingthe neuroendocrine, neurochemical and cytokine cor-relates of dysthymia, and an overview is provided con-cerning the efficacy of pharmacotherapy in the treat-ment of this disorder.

It is proposed that dysthymia may be related to sub-tle effects of stressors and inadequate coping styles,and may be exacerbated by the presence of ongoingpsychosocial impairments. A highly provisional modelis proposed concerning the etiological processes sub-serving dysthymia, including various facets of the HPAaxis (eg, phenotypic variations of corticotropin releas-ing hormone (CRH) and arginine vasopressin (AVP),down-regulation of adrenal functioning) and forebrain

DysthymiaJ Griffiths et al

243serotonergic mechanisms. However, given the paucityof data concerning the effects of various challenges (eg,dexamethasone, ACTH, CRH, TSH, stressors, as well aschallenges in the presence or absence of metyrapone)on HPA hormones among dysthymic individuals, theconclusions that can be derived are tentative and mustnecessarily 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 ofaffective, neurovegetative and cognitive symptoms.The diagnosis of dysthymic disorder was introducedin the third edition of the Diagnostic and StatisticalManual of Mental Disorders (DSM-III) to characterizechronic depression of 2 or more years and toencompass disorders which had previously been con-sidered characterologically based, including neuroticdepression, chronic minor depression, and characterol-ogical depression.5 While the severity of dysthymia isusually less profound than that of acute major depress-ive disorder, symptoms may fluctuate in intensity. Fur-thermore, several subtypes of dysthymia have beenproposed based on specific symptoms, family history,and age of onset; subaffective dysthymia is thought tobe of biological origin, while character spectrum dys-thymia is more personality-based.6,7 Currently, DSM-IV stipulates that a diagnosis of dysthymia includesdepressed mood, coupled with two or more of the fol-lowing: poor appetite or overeating, insomnia or hyper-somnia, low energy/fatigue, low self-esteem, poor con-centration or difficulty making decisions, and feelingsof hopelessness.5 Dysthymia also frequently has anearly and insidious onset, and is associated with path-ology of character, albeit these may not play an etiolog-ical role. There has been some debate as to whetherthese symptoms are, in fact, most characteristic of dys-thymia, and based on field trials, the DSM-IV(Appendix B) offers an alternative set of criteria. Theseinclude: (a) low self-esteem, self confidence, or feelingsof inadequacy; (b) feelings of pessimism, despair, andhopelessness; (c) anhedonia (generalized loss of inter-est or pleasure); (d) social withdrawal; (e) chronicfatigue or tiredness; (f) feelings of guilt, or broodingabout the past; (g) irritability or excessive anger; (h)reduced activity, effectiveness, or productivity; and (i)difficulty in thinking, as reflected by poor concen-tration, memory or decisiveness.

Like the DSM-IV, the ICD-10 defines dysthymia as achronic depression which fails to meet the severity andduration criteria for recurrent depressive disorder.However, depressive illness, of at least mild duration,may have occurred previously.8 According to the ICD-10, dysthymia often begins early in adult life, andwhen late onset dysthymia occurs it is often secondaryto a severe major depressive disorder or in response toenvironmental stressors (eg, bereavement). Moreover,dysthymia is thought to include persistent anxiety-depression, depressive neurosis, depressive person-

Molecular Psychiatry

ality disorder, as well as neurotic depression of morethan 2 years duration.7

The characteristics of dysthymia in many ways over-lap with those of major depression, although in dysthy-mia, symptoms outnumber signs (ie, objective charac-teristics such as vegetative symptoms and psychomotorchanges are typically absent).9 Relative to majordepressive disorder, symptoms occur at a lower fre-quency in dysthymic patients, but are qualitativelysimilar. Moreover, relative to neurovegetative and psy-chomotor features, social-motivational impairmentstend to be more characteristic of dysthymia.3,10 In manydysthymic patients an intermittent emergence of majordepression may occur (double depression), with thedysthymic state usually recurring upon remission ofthe major depressive episode.9 Likewise, dysthymiamay emerge as a residual syndrome of acutedepression;6,11 however, the diagnosis of dysthymiawould not be applied if the initial episode of chronicdepressive symptoms met the criteria for and was suf-ficiently severe to be diagnosed as a major depressiveepisode.

Dysthymia is more common among women thanamong men (2:1), has a 1-year prevalence rate (for theUnited States) estimated as high as 5.4%,12 and thehighest life-time prevalence of the affective disorders.13

However, only a relatively small proportion of dys-thymic individuals seek treatment for their illness,likely owing to the mild nature of the symptoms andtheir insidious onset, coupled with the individual’slack of insight. Indeed, the illness often appears inchildhood and adolescence,14,15 and as a result of thelong-term, low-grade nature of the illness, dysthymiamight not be perceived as differing from the individ-ual’s norm. It is of interest to note that in a study of afairly large number of dysthymic patients, only 41%had received any form of pharmacotherapy, and just56% had received psychotherapy, attesting to theunder-treatment of this disorder.16

Although it had been suggested that pharmaco-therapy may be less effective in the treatment of dys-thymia relative to major depressive disorder, recentevidence has indicated that such intervention may, infact, be a treatment of choice for dysthymia. However,the treatment response may vary with the specific sub-type of the illness.4,17 Indeed, it appeared thatpharmacotherapy was less effective in ‘pure dysthy-mia’ than in dysthymia with a history of majordepression or in patients with concurrent majordepression.18 Because dysthymia was initially thoughtto be more of a characterological disturbance than abiologically-based illness, and because of the oft-notedsuperiority of pharmacotherapy in major depressionrelative to that observed in dysthymia,17 the illness wastypically treated using different forms of psycho-therapy.19–21 As such, the lack of controlled studiescomparing the relative efficacy of psychotherapy andpharmacotherapy (either alone or in combination) issurprising. It was recently reported, however, that inthe short-run, pharmacotherapy (using a selective sero-tonin reuptake inhibitor) was more efficacious than


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group cognitive behavior therapy (CBT) in alleviatingsymptoms of dysthymia,22 although CBT attenuatedseveral functional aspects of the illness. Using a some-what more protracted regimen (16 weeks), CBT waseffective in a study involving a small number of dys-thymic subjects. While this effect appeared to besomewhat reduced relative to that associated withfluoxetine, the effects of the treatments were not sig-nificantly different.23

Symptom and illness comorbidity

The presence of comorbid features with dysthymia canbe related to any number of factors. On the one hand,the comorbidity may simply reflect the nosology of thesyndromes, which have overlapping symptoms.1 Onthe other hand, comorbidity may reflect commonunderlying mechanisms, or in the case of debilitatingmedical conditions, the dysthymic state may representa subsyndromal depression resulting from the primaryillness. It is possible, as well, that the development ofdysthymia may be secondary to features such as per-sonality disorders or to excessive anxiety, or con-versely, dysthymia may give rise to these features.Whatever the case, it is of obvious diagnostic andtherapeutic value to discern the presence and pro-gression of comorbid features.1

Major depression is often superimposed on a dys-thymic state (double depression), and is associatedwith a high rate of illness recurrence.24,25 In their epi-demiological study, Weissman et al26 reported that40% of dysthymic patients exhibited comorbid majordepression, while more recent evidence suggested thatas many as 62% of dysthymic patients met criteria forcurrent major depression, and 80% for lifetime majordepression.14 Treatment outcome was significantly bet-ter in major depressives than among double depress-ives, as was the recurrence rate over 2 years.25 It hasbeen suggested that the chronology of dysthymia rela-tive to major depression may influence subsequenttreatment response. For example, it was reported thatpatients who had experienced dysthymia subsequentto their first major depressive episode, showed areduced treatment response relative to those patientsin whom onset of dysthymia had preceded their firstmajor depression.27

As many as 75% of dysthymic patients suffer fromsome comorbid psychiatric disorder, of whichdepression, anxiety, and substance abuse are the mostcommon.26 Indeed, approximately one-half (50.7%) ofShelton et al’s16 sample of 410 dysthymic patientsreported a history of major depression, while 26.3%had a history of substance abuse, and 68.2% were diag-nosed with a comorbid personality disorder. Withrespect to comorbid anxiety, it was demonstrated thatwhile social phobia and panic attacks were signifi-cantly more common among unipolar and bipolardepressives (respectively) than dysthymic patients, thelatter exhibited a higher prevalence of generalized anx-iety disorder.28 As such, dysthymia ought to be moreclosely scrutinized for comorbid anxiety disorder, as it

might be associated with a more severe and enduringsymptom profile, as observed in major depression withco-existing anxiety disorder,29 and might thus requireadjunctive forms of pharmacotherapy. In fact, it wasrecently reported that a coexisting anxiety disordermay indicate increased risk for persistent depression.30

In addition to comorbid anxiety, dysthymia often co-exists with personality disorders.31 As well, more dou-ble depressive patients than pure dysthymics met cri-teria for at least one personality disorder. Conversely,compared to episodic major depressives, significantlymore dysthymics met criteria for an axis II disorder.Interestingly, dysthymic patients scored significantlyhigher than major depressive patients on all of the 13dimensions of the Personality Disorder Examination,with the most common axis II disorders being border-line, avoidant and histrionic.31 Essentially, dysthymicsubjects were found to display personality disorders inthe DSM cluster B (antisocial, narcissistic, borderlineand histrionic)31,32 although high rates of avoidant anddependent personality disorders were also apparent.31–33

Indeed, it was reported that subaffective and characterspectrum dysthymics could be distinguished from oneanother on the basis of DSM cluster C characteristics,with subaffective subjects exhibiting greater avoidantpersonality and dependent personality relative tocharacter spectrum patients.34 It was further reportedthat the occurrence of such personality disorder comor-bidity was particularly notable in early-onset dys-thymic patients.35,36 Finally, it appeared that depress-ive personality disorder (DPD) was more closelyaligned 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 rateamong dysthymic patients. For instance, it has beenreported that subjects in alcohol treatment programsfrequently met the criteria for dysthymic disorder.39

In a sample of subjects with substance-related disorder,a substantial portion (|10%) exhibited comorbiddysthymia.40,41 The dysthymic group also had a sur-prisingly early age of first use of caffeine (7.3 ± 7.0years), and the investigators speculated that this mayhave constituted an early attempt to self-medicate.40

In considering comorbid features, it may beimportant to distinguish between subtypes of dysthy-mia based on age of illness onset. It had been reportedthat early- and late-onset dysthymic patients withsuperimposed major depression did not differ withrespect to several clinical, psychosocial and cognitiveindices, nor in terms of family history of depressionand alcoholism.42 Subsequent studies, however, indi-cated that early-onset dysthymics exhibited greater useof emotion-focused coping strategies, a higher fre-quency of personality disorders, and increased life-time substance abuse disorder than their late-onsetcounterparts.36,43–50 Further, a greater number of early-onset dysthymic patients had a family history of amood disorder, and displayed earlier onset and longerduration of the index major depressive episode.36,50 Tobe sure, as indicated by Klein et al,36 the earlier onsetof the index major depressive episode might simply


245reflect greater opportunity for such an occurrence giventhat dysthymia increases the risk of major depression.Moreover, early onset dysthymia being associated withpoor interpersonal and psychosocial skills, may havefavored the development of personality disorders andsubstance abuse. Yet, there is reason to suppose thatbiological factors may be more closely aligned withearly onset of the illness, while late onset may be asso-ciated with character spectrum disorder.4 In fact, aswill be discussed shortly, there have been severalreports indicating that these subgroups may differ withrespect to several neuroendocrine substrates, as well asin response to some antidepressant medications.

In addition to the high psychiatric comorbidity, dys-thymia has also been associated with various othermedical conditions. Given the similarity between dys-thymia and chronic fatigue syndrome (CFS), parti-cularly with respect to lethargy, lassitude, impairedconcentration, and diminished drive, the possibilityexists that a subgroup of chronic fatigue patients rep-resents a variant of dysthymia.51 Indeed, it wasreported that patients identified with fatigue werebetween six and 10 times more likely to suffer fromdysthymia than the population at large.52 Similarly,fibromyalgia syndrome, which overlaps with CFS, hasbeen associated with major depression and dysthy-mia.53,54 Interestingly, fibromyalgia syndrome has beenassociated with adverse childhood experiences. More-over, specific personality traits which may be relatedto such adverse experiences (eg, unstable self-esteem),may also be associated with fibromyalgia, just as theyare associated with dysthymia.54 It is unclear, however,whether dysthymia is associated simply with thesymptom of chronic fatigue, as opposed to the syn-drome.51 It is significant, as will be discussed shortly,that dysthymia is associated with elevated productionof interleukin-1 (IL-1b),55 a cytokine released by acti-vated macrophages, just as CFS has been associatedwith an elevation of this cytokine.56,57

In addition to CFS, like other mood and anxiety-related disorders, dysthymia has also been associatedwith increased co-occurrence of migraine (with aura),tension, and non-organic headaches.58–60 In thisrespect, it was reported that of the mood disorders, theprevalence of coexisting dysthymia was particularlynotable.60 These data raise the possibility that head-ache and dysthymia share common underlying pro-cesses (eg, serotonergic mechanisms, given that bothare positively influenced by serotonin reuptakeinhibitors) or that environmental triggers, such as stres-sors, may be associated with both pathologies.

Comorbidity involving CFS and headaches in dys-thymia is not unexpected given the potential for com-mon mechanisms or environmental precipitants. Moresurprising, however, was the finding that a large num-ber of patients suffering from Parkinson’s disease exhi-bited concurrent major depressive disorder and/or dys-thymia. Of course, such comorbidity might bepredicted given that the stress of the neurodegenerativedisturbance might lead to depressive affect. Interest-ingly, however, in a recent review of this literature,


depressive features, including introversion andinflexibility, were reported to serve as premorbid pre-dictors of the onset of Parkinson’s disease or an accel-erated cognitive decline.61 These investigators havegone so far as to suggest that psychological and phar-macological interventions may be appropriate in thetreatment 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 dis-orders than the general population (ie, 25–50% majordepression, 15–30% dysthymia, 9% mania).62 Giventhe large number of brain regions that may be primarilyor secondarily influenced by head trauma, it is difficultto identify the specific nuclei or pathways subservingthe depression. However, since brain trauma is associa-ted with focal increases of IL-1,63 as are neurodegener-ative disorders, the possibility should be consideredthat the behavioral effects observed in TBI andParkinsonian patients are associated with heightenedcytokine levels.

Biological aspects of dysthymia

Depression has been associated with a variety of neuro-chemical changes, including deficiencies of norepi-nephrine (NE),64 serotonin (5-HT)65,66 and dopamine(DA),67–69 or to variations of DA autoreceptors, 5-HT2

receptors, a1-NE or b-NE receptors.70–72 Of course,depression is likely a biochemically heterogeneous dis-order, such that the neurochemical underpinnings forthe illness, as well as the symptom profile exhibited,vary across subjects.66,73 Moreover, given the abnormalresponses to various endocrine challenges (eg, thedexamethasone suppression test (DST), CRH, as wellas thyroid releasing hormone (TRH) challenges), thereis reason to suppose that hormonal variations contrib-ute to the provocation or expression of depressivesymptoms, and that considerable interindividual varia-bility exists with respect to the contribution of theseendocrine factors.74–77

It has been suggested that stressful events or failureexperiences are associated with depressive illness.78–80

Such an outcome may stem from the stressor experi-ence provoking the formation of attributions, whichgive rise to negative expectancies of future perform-ance and may result in the development of cognitivedisturbances, such as helplessness.81,82 Alternatively,stressor experiences may give rise to neurochemicalalterations that favor depressed mood.83,84

It is difficult, using animals, to adequately modeldepressive illness let alone to reflect dysthymia. Never-theless, it may be productive to examine some of theneurochemical correlates of stressors. Althoughenvironmental insults initiate a series of neurochem-ical changes that may be of adaptive significance, whenthese neurochemical alterations are insufficient to dealwith environmental demands (or neurochemical adap-tation does not occur readily), vulnerability to pathol-ogy is increased.83 Indeed, animal studies indicatedthat stressors will induce many of the central neuro-


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transmitter alterations (eg, variations of NE, DA and5-HT turnover and levels) that have been proposed tosubserve the depressive symptoms in humans.Specifically, in response to acute stressors theincreased utilization of NE, DA and 5-HT is ordinarilymet by adequate synthesis and hence transmitter levelsremain stable. However, under conditions that favoramine utilization exceeding synthesis (ie, if the stressoris sufficiently severe and uncontrollable), amine levelsmay decline in several brain regions.83–86 These aminealterations typically persist for only a few hours,depending on the stressor severity and several organ-ismic variables (eg, age, species).84,87,88 However,re-exposure to a mild stressor enhances the utilizationof hypothalamic NE89,90 and mesocortical DA(sensitization effect),91–93 even if the re-exposureinvolves a different stressor.94–96

Since humans typically encounter chronic, intermit-tent and unpredictable stressors, it may be more rel-evant to assess the effects of such regimens in animalstudies. In contrast to the amine reductions inducedby acute stressors, transmitter levels equal or exceedcontrol values following protracted or repeated stres-sors,93,97–100 owing to increased amine synthesis and/ormoderation of excessive utilization.98,101 Moreover,chronic insults affect the amine variations engenderedby later stressors. Specifically, in addition to a sensitiz-ation with respect to amine utilization (as seen follow-ing acute stressors), chronic stressors also induce sensi-tization of amine synthesis, thereby assuring adequatetransmitter levels upon later stressor encounters.99 Inaddition, a chronic stressor may result in the down-regulation of b-NE receptor activity and the NE-sensi-tive cAMP response.102 Interestingly, upon applicationof a chronic unpredictable stressor the neurochemicaladaptation was slower to develop.83,103 It has been sug-gested that when inadequate neurochemical copingmechanisms are generated (eg, in genetically vulner-able animals, and when the stressor occurs unpre-dictably and involves a series of different insults),depressive-like characteristics may evolve.104 In fact,Anisman and Merali105 indicated that a regimen ofmild, unpredictable stressors may be precisely theantecedent events most closely aligned with dys-thymic-like states. It is important to emphasize at thisjuncture that while some degree of behavioral andneurochemical adaptation may occur in response tochronic stressor experiences, the view has beenexpressed that the wear and tear induced by attemptsto adapt to a chronic stressor (allostatic load), whensufficiently protracted and/or intense, may culminatein pathological outcomes.106 As will be discussed later,chronic insults may, in fact, promote persistent neuro-chemical alterations which favor the development ofdepressive characteristics.

While there is considerable evidence supporting arelationship between major depression and centralneurochemical disturbances,107–110 scant information isavailable regarding the biological substrates of dysthy-mia. However, the frequent abnormal DSTs seen inmajor depressive patients were absent in dysthymia,2,4

and the latter might actually be associated with hypo-cortisol responding.111 Indeed, it has been reported thatthe elevated salivary cortisol associated with exercisein pre-adolescent children was not apparent amongdysthymic children of the same age.112 Parallelingthese alterations of pituitary-adrenal activity, differ-ences appeared between major depression and dysthy-mia in growth hormone secretion in response tophysiological challenges, as well as TSH blunting inthe TRH stimulation test.113

As part of a study assessing the role of psychosocialand biological variables in chronic and non-chronicmajor depression and dysthymia, a lower rate of DSTnon-suppression was observed in dysthymic patients(52% vs 8.5% non-suppression in major depression vsdysthymia). However, the rate of DST non-suppressionwas higher in the early-onset than in the late-onset dys-thymics,113 although, when double depressives wereexcluded from the analysis (39 of the 75 dysthymicpatients), there was no difference between early andlate onset groups (9% and 8% respectively). Interest-ingly, paralleling the DST response, among late-onsetdysthymics, the blunted TSH response to TRH admin-istration was absent, whereas early-onset dysthymics(who parenthetically reported more traumatic and frus-trating childhood backgrounds) had a higher rate ofDST nonsuppression, and more frequently exhibited ablunted TSH response. In effect, these data suggest thatearly-onset dysthymia may represent a biologically dis-tinct subgroup of chronically depressed patients.113

Indeed, it was noted that early-onset dysthymicsresponded preferentially to moclobemide relative toimipramine, while no such distinction was foundamong the late-onset dysthymics, suggesting thatmonoamine oxidase A might be more imbalancedamong early-onset dysthymics.114

While limited attention has been devoted to theanalysis of monoamine abnormalities in dysthymia,reduced levels of plasma NE coupled with elevatedplatelet and free 5-HT were evident in dysthymia.115

Further, following exercise, changes of epinephrinelevels were relatively modest in dysthymic patientsrelative to control subjects. Thus, it was posited thatdysthymia may be associated with altered adrenalresponsivity to environmental challenges, as well asheightened sympathetic tone as reflected by the elev-ated free 5-HT levels. Ravindran et al111 observedreduced platelet MAO activity in primary, early-onsetdysthymics relative to control subjects. Moreover,MAO activity prior to treatment was lower among non-responders than among the drug responders. Along thesame line, relative to endogenous depressives, MAOlevels were low among neurotic depressives,116 whileMAO activity correlated positively with clinical statein the endogenous group. Thus, low MAO activity mayrepresent a marker for vulnerability to neuroticdepression. Consistent with the potential involvementof serotonergic mechanisms in dysthymia, prior totreatment, lower urinary 5-hydroxyindoleacetic acid(5-HIAA) levels were observed among treatmentresponders relative to nonresponders, and the reduced


247levels in responders normalized following treat-ment.117

There have been few studies that assessed the elec-trophysiological correlates of dysthymia. However, itwas reported that in anticipation of aversive stimuli,dysthymics exhibited hyporesponsiveness of skin con-ductance, and displayed subtle cognitive processingdisturbances (possibly reflecting difficulties in the pro-cessing of complex information), as reflected by evokedpotentials in response to task-relevant stimuli. It wasposited that dysthymia may be associated with animpoverished ability to respond appropriately to exter-nal task demands, possibly owing to inappropriateallocation of processing resources. Furthermore, it wassuggested that owing to their impaired resource allo-cation strategies, dysthymic subjects may be more gen-erally impaired in their ability to cope with day-to-day stressors.118,119

Akiskal et al120,121 reported differences in the sleeparchitecture between subtypes of dysthymic patients.While subaffective dysthymics exhibited shortenedREM latencies relative to controls, this was not the caseamong character spectrum disorder patients. Inaddition, dysthymia was associated with excessive andabnormal distribution of REM during the early part ofthe night121 as observed in major depression.2,122 How-ever, while the major depressive patients displayedreduced total sleep time, sleep latency, morning waketime and sleep efficiency, the sleep architecture of dys-thymics in terms of stage percentages, and REM sleepfeatures, were identical to those of major depressives.In effect, these data are consistent with the notion thatthe two disorders are variants of the same illness,123 orshare common underlying mechanisms.

Pharmacological contributions to the analysis ofdysthymia

The most persuasive data favoring a biological sub-strate for dysthymia originate from studies whichassessed pharmacological agents in the treatment ofdysthymic illness. The early pharmacological studiesin dysthymia revealed that although MAO inhibitorsand tricyclic antidepressants (TCAs) had superiortherapeutic efficacy to placebo, their effects were notas marked as in major depression.4,17,124–130 However,it appears that reliable and impressive effects of anti-depressant medications can be garnered in dysthymia.This stems from the development of medications, suchas selective serotonin reuptake inhibitors (SSRIs),which have fewer side effects, thus permitting the useof higher doses. Moreover, it has been suggested thatoptimal drug effects would be obtained when adminis-tered primarily to patients with subaffective, ratherthan character spectrum disorder.4 In fact, studieswhich employed rigorous diagnostic criteria,established the efficacy of tricyclic agents, such asimipramine and desipramine,131–137 MAOIs,136,138,139

the reversible monoamine oxidase inhibitor, moclo-bemide,114,137,140–143 SSRIs, such as fluoxetine and ser-traline,22,23,111,132,134,144–146 as well as other agents, such


as the 5HT2 antagonist, ritanserin,147,148 the selectivenorepinephrine reuptake inhibitor, reboxetine,149 andthe serotonin/norepinephrine reuptake inhibitor(SNRI), venlafaxine150,151 (Table 1). The use of well tol-erated compounds, including moclobemide and sertra-line, may be effective in the long-term management ofdysthymia. This is particularly important since discon-tinuation of antidepressant treatment was found to beassociated with an 89% rate of relapse in a 4-yearmaintenance study.18

In addition to the effects of the aforementioned anti-depressants, hormonal manipulations have also beenshown to influence dysthymic symptoms. Specifically,in a crossover-study involving a small number of sub-jects, it was observed that administration of the adrenalandrogen, dehydroepiandrosterone, alleviated dys-thymic 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 treat-ment. Furthermore, the thyroid hormone, thyroxine,potentiated the effects of a variety of antidepressantmedications in dysthymic and treatment-resistantchronic depressive patients.164 Moreover, in a smallstudy of five patients it was observed that chromiumsupplementation enhanced the antidepressant effectsof more traditional therapeutic agents.165

As indicated earlier, we observed in a double-blindplacebo-controlled study, that sertraline was generallymore effective than group CBT in treating the symp-toms of dysthymia, as measured by the HamiltonDepression Scale.22 Of course, these data need to beconsidered as highly provisional, since the trial wasshort-term (12 weeks), and the CBT consisted of grouprather than individual treatment. It is possible thatindividual CBT, or a program designed specifically fordysthymia may be more conducive to the treatment ofthe disorder. Further, given that anhedonia is a charac-teristic and persistent feature of dysthymia, it may havebeen beneficial to employ cognitive techniques whichfocused specifically on the inability of patients toexperience or perceive positive events. Indeed, usingcognitive behavioral psychotherapy, which focuses onthe helplessness and hopelessness associated with dys-thymia, and also teaches adaptive coping skills,McCullough21 reported that nine of 10 dysthymicpatients were still in remission after a 2-year period.Given the high rate of depressive relapse/recurrenceordinarily observed following cessation of treatment,it will be interesting to establish whether combinationtherapy minimizes recurrence of illness relative to thatseen among patients who had received only pharmaco-therapy. This is particularly the case since group CBTenhanced the effects of sertraline with respect to somefunctional behaviors (eg, cognitive coping styles, andseveral indices of quality of life) which, in turn, mayhave important implications with respect to illnessrecurrence.22

Owing to dysthymia’s fluctuating and chronic nat-ure, several studies evaluated the efficacy of antide-pressants in the maintenance treatment of the illness.


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Table 1 Pharmacological studies of DSM-III/DSM-III-R/DSM-IV diagnosed dysthymia

Reference Medication Outcome

Placebo-controlledStewart et al (1985)130 Desipramine Desipramine = placeboHarrison et al (1986)152 Phenelzine Phenelzine . placeboKocsis et al (1988)133 Imipramine Imipramine . placeboTyrer et al (1988)153 Doxepin Doxepin . placeboStewart et al (1989)154,a Imipramine, phenelzine Imipramine . placebo; phenelzine = placebo;

imipramine = phenelzineCosta-e-Silva et al (1990)155 Amisulpride Amisulpride . placeboBersani et al (1991)148 Ritanserin Ritanserin . placeboBotte et al (1992)141,b Moclobemide Moclobemide . placeboVersiani et al (1992)137 Moclobemide, imipramine Moclobermide = imipramine . placeboHellerstein et al (1993)144 Fluoxetine Fluoxetine . placeboStewart et al (1993)136,a Imipramine, phenelzine Imipramine . placebo = phenelzineVersiani (1993)143 Moclobemide, imipramine Moclobemide . placebo; imipramine . placeboBakish et al (1993)147 Ritanserin, imipramine Ritanserin = imipramine . placeboKocsis et al (1994)134 Sertraline, imipramine Sertraline = imipramine . placeboThase et al (1996)145 Sertraline, imipramine Sertraline = imipramine . placeboVanelle et al (1997)146 Fluoxetine Fluoxetine . placeboLecrubier et al (1997)156,a Amisulpride, imipramine Amisulpride = imipramine . placeboVersiani (1997)114,a Moclobemide, imipramine Moclobemide . placebo; imipramine . placeboBoyer et al (1999)157 Amisulpride, amineptine Amisulpride = amineptine . placeboRavindran et al (1999)22 Sertraline Sertraline . CBT = placebo

Non-placebo-controlledVallejo et al (1987)139 Imipramine, phenelzine Phenelzine . imipramineBaumhackl et al (1989)140,b Moclobemide, imipramine Moclobemide = imipramineRavindran et al (1994)158 Fluoxetine 65% responseMarin et al (1994)135,a Desipramine 70% responseFriedman et al (1995)159,a Desipramine 61% responseKocsis et al (1996)160,a Desipramine 71% responseDunner et al (1996)23 Fluoxetine Fluoxetine = CBTDunner et al (1997)150 Venlafaxine .70% responseKeller et al (1998)132,c Sertraline, imipramine Sertraline = imipramineSantagostino et al (1998)161 Alprazolam 73% responseSmeraldi (1998)162 Amisulpride, fluoxetine Amisulpride = fluoxetineRavindran et al (1998)151 Venlafaxine 73% response

aInvolved dysthymic and double depressive patients for whom data are reported independently (or authors indicate comparableeffects in the two populations).bNeurotic depression.cMajor depressive or double depressive patients were assessed.

Kocsis et al166 indicated that the higher relapse rate inthose dysthymic patients who were randomized to pla-cebo exceeded that of patients who continued on themaintenance desipramine treatment. Paralleling thesefindings, symptom improvement was sustained, andthe rate of relapse reduced, among dysthymic patientswho were maintained on either trazodone or fluoxetineover a 40-week interval compared to those who discon-tinued medication.167 Commensurate with the notionthat a long-standing illness, such as dysthymia, mightrequire prolonged pharmacotherapy, continuousimprovement was observed among dysthymic patientstreated over a 6-month period,146 while Kocsis et al160

found a substantially reduced rate of relapse (11%)among dysthymic patients maintained on desipramineover a 2-year period, relative to the 52% relapse ratein the placebo group. Although these data do notnecessarily speak to the mechanisms subserving dys-

thymia, the results from these controlled clinical trialsare congruent with the proposition that antidepress-ants are effective for a substantial portion of dysthymicpatients (primarily the subaffective variety), and thatprolonged maintenance treatment may be beneficial.

While most antidepressant trials have focused on theeffects of 5-HT and NE manipulations on the symptomsof dysthymia and major depression, there have beenseveral studies implicating a role for dopamine (DA).Since DA has been thought to subserve reward pro-cesses,168 and anhedonia is a characteristic feature ofdepression, the view has been taken that reduced DAactivity might contribute to the depressive pro-file.104,169,170 It will be recalled, however, that in con-trast to major depression, anhedonia is not one of thefundamental symptoms of dysthymia according to theDSM-IV criteria. Yet, it has been suggested thatanhedonia may be a cardinal feature of dysthymic indi-


249viduals.4 Unfortunately, there have been few studiesthat evaluated the effects of DA manipulations in dys-thymia. The administration of the selective D2 and D3

antagonist amisulpride, an agent most often used as anantipsychotic when administered in high doses (400–1200 mg), has agonistic DA properties at low doses(50 mg), likely owing to preferential presynaptic bind-ing. Consistent with the proposition that DA may playa role in dysthymia, amisulpride was effective in atten-uating the symptoms of both dysthymia and majordepressive illness.154–156,169,171,172 In fact, amisulpridewas as effective as imipramine in alleviating depress-ive symptoms in dysthymia, and both agents were sig-nificantly better than placebo in this respect (Table 1).

Genetic factors in dysthymia

Since the prevalence rates of various affective illnessesdiffer in families with dysthymic, major depressive anddouble depressive probands, it was suggested that dys-thymia and major depression are independent dis-orders.2,47 While dysthymia may represent a trait factorpredicting increased risk for major depression, it maybe important to distinguish between early- and late-onset illness. In fact, while major depression and dys-thymia appear to be distinct illnesses, relatives of pro-bands with early-onset depression were at increasedrisk for both major depression and dysthymia.173 Like-wise, Goodman and Barnhill174 reported the results ofa study comparing the rates of dysthymia in relativesof probands with either panic disorder, majordepression, or both conditions (a subset of 33 patientswere also dysthymic). Increased rates of dysthymiawere observed in relatives of early-onset major depres-sives, and among relatives of dysthymic probands, thussupporting a relationship between early-onset majordepression and dysthymia. Unfortunately, the smallnumber of subjects tested makes it difficult to discernwhether the risk of dysthymia varies as a function ofearly- vs late-onset of the disorder in the dysthymicproband. Paralleling these findings, rates of majordepression in relatives of early-onset dysthymics com-pared to relatives of controls, confirmed a familialassociation between dysthymia and major depression.It was also observed that relatives of the dysthymicshad higher rates of chronic depression than relativesof episodic depressives. Thus, there appears to be sup-port for familial aggregation in dysthymia, as well asfor the validity of dysthymia as a distinct diagnosticcategory.175

Donaldson et al176 found higher rates of dysthymiaamong relatives of pure dysthymics and of doubledepressives, than among relatives of major depressiveprobands and normal controls. Furthermore, the ratesof pure dysthymia did not differ between relatives ofpure dysthymics and those of double depressives, nordid they differ between relatives of major depressiveand normal control probands. Once again, these dataare consistent with the notion that while dysthymiamay be distinct from major depressive disorder, dys-thymia and double depression may be more closely


related. The conclusions are clouded, however, by thefinding that there was a higher rate of pure majordepression among the relatives of pure major depress-ive probands, as well as among the relatives of doubledepressives, than among normal controls. These inves-tigators suggested that dysthymia may be associatedwith two distinct etiological profiles. That is: (a)increased vulnerability to depression occurs in all rela-tives of unipolar depressive illness, irrespective of sub-type; and (b) that risk for dysthymia may be parti-cularly notable among relatives of dysthymic patientsand those suffering from double depression.

The high comorbidity of dysthymia with personalitydisorders has consistently been noted.177 It has alsobeen reported that the relatives of dysthymic patients,regardless of the presence of cluster B personality dis-order (antisocial, borderline, histrionic, narcissistic) inthe proband, exhibited increased frequency of dysthy-mia with and without cluster B personality disorder,as well as cluster B personality disorder without dys-thymia. Thus, these results supported the notion thatdysthymia and cluster B personality disorder shareetiological factors such as genetic or familial factors, orearly home environment.178

The contribution of genetic factors to dysthymiaprompted Akiskal6 to categorize patients, in part, onthe basis of genetic history. It was suggested that subaf-fective dysthymics frequently had a family history ofdepression, whereas character spectrum dysthymicstended to have a significant family history ofalcoholism/drug abuse, but not of depressive disorder.Partial support for Akiskal’s classification of subaffec-tive vs character spectrum disorder was obtained fromthe finding that there was a higher rate of alcoholismamong the relatives of the character spectrum disorderdysthymics, while the subaffective dysthymics exhib-ited higher rates of depressive symptoms, as well aspersonality and cognitive features.34 Unlike Akiskal’sclassification, however, these investigators did notobserve differences between groups with respect toearly home environment, family history of mood dis-orders, gender, or personality disorder.

Few studies have examined the genotypic expressionof factors that might be related to dysthymia. However,it was demonstrated in a Japanese sample, that patientsdiagnosed with depressive disorders exhibited higherrates of genotypes coding for low activity catechol-o-methyltransferase relative to non-depressed con-trols.179 Although only five dysthymic patients wererepresented in the sample, the results obtained wereconsistent with those observed in a larger set of majordepressive patients (n = 66) in this study. Of course,given the small number of subjects tested, these datamust be considered cautiously. Nevertheless, they aresuggestive of disturbances of enzyme activity related tocatecholamine function in dysthymic patients, just assuch effects may occur in major depressive disorder.

While the preceding studies supported a genetic con-tribution to dysthymia, other studies challenged thisconclusion. For instance, monozygotic and dizygotictwins did not differ in their concordance rates for dys-


250


thymic illness (7.4% vs 8.7% respectively) as they didwith respect to major depression.180 It was concludedthat the shared or family environment may contributemore to the etiology of dysthymia than to majordepression. It was argued that severity of depressionand early-onset of the illness may be aligned with agenetic association, while the milder depressive illnessspectrum (including dysthymia) may be more closelytied to environmental factors. As the dysthymicpatients were not subdivided into character spectrumvs subaffective, it is unclear from these data whetherthe conclusion applies to both subtypes equally.

Psychosocial factors and stressors in majordepressive disorder and dysthymia

There is considerable evidence supporting the conten-tion that a relationship exists between stressful events,coping deficits, and the development or exacerbation ofmajor depressive disorder. These data have frequentlybeen reviewed and thus will not be reiteratedhere.78,81,181 In view of the shared attributes betweendysthymia and major depression, it is somewhat sur-prising how little information is available concerningthe contribution of stress to the provocation of dys-thymic disorder. However, inasmuch as dysthymia isa chronic illness, it may be difficult to identify specificlife events that precipitated illness onset. Nevertheless,it would not be unreasonable to propose that someadverse life events, particularly the inability to copewith day-to-day annoyances, or alternatively chronicstressor experiences, may precipitate or aggravate theillness.

Not unexpectedly, some stressors are conducive tothe provocation of depressive symptoms (eg, socialloss),78,182 whereas others are more closely aligned withanxiety disorders (eg, threats or impending stress).183

Although major life events often precede depression,the antecedents of affective illness may involve a seriesof minor stressors (day-to-day hassles). Indeed, thesestressors may have particularly profound effects whenapplied onto a backdrop of major stressors.182,184 Ofcourse, the potency of a stressor in promotingdepression may be related to characteristics of theindividual, coupled with the nature of the stressorencountered.78,185,186 Finally, as alluded to earlier,acute stressors may have very different implicationsthan chronic predictable or chronic intermittent stres-sors.182 Chronic intermittent stressors may not lendthemselves to neurochemical adaptation and may bemost likely to result in behavioral disturbances.83,104

It has been reported that dysthymic patients, likemajor depressives, perceived a markedly greater fre-quency of day-to-day annoyances than did non-depressed subjects. In contrast, stressful life eventswere only marginally greater in the depressive groups.The elevated stress perception was accompanied bycoping styles wherein emotion-based strategies pre-dominated (eg, blame, emotional expression, emotionalcontainment, avoidance/denial). With successful phar-macotherapy, the elevated stress perceptions were

reduced, and the reliance on maladaptive coping wasattenuated.187,188 It is unclear whether these effectsreflect changes in appraisal processes and conse-quently altered coping styles, or simply a proportionatedecline in the reliance upon emotion-focused coping.Of course, these data do not suggest that altered stressperception and coping were etiological factors in dys-thymia, as they may simply have been correlates ofthe illness.

Interestingly, in a prospective study of dysthymicpatients over a 9-month period, McCullough et al189

identified several features that distinguished the remit-ters from the nonremitters. Specifically, the nonremit-ters tended to exhibit a stable depressive attributionalstyle and tended to employ inappropriate coping stra-tegies. Additionally, the nonremitters did not deal withtheir major stresses effectively, and tended to use emo-tion-focused coping (eg, wishing away their problems,blame) and social support seeking rather than a prob-lem-focused style. These individuals also displayed aninterpersonal style characterized by shyness and lackof sociability, coupled with submissiveness and com-pliance. It was suggested that this profile represents amaladaptive behavioral pattern that predisposes theindividual to the persistent nature of dysthymia.

While there is reason to suppose that stressful eventscontribute to the provocation of dysthymia, prospec-tive studies have not been conducted to assess the con-tribution of life stressors to this illness. Several studies,however, reported that stressful life events precededthe onset of both neurotic and non-neuroticdepression.190,191 Given the frequent early onset of dys-thymia, coupled with its chronic nature, the paucity ofprospective studies concerning the stressful ante-cedents of the illness is not surprising. However, it wasreported that among adults who acted as care-givers fora spouse with a progressive dementia (care-giving itselfis a profound stressor), the incidence of majordepression and dysthymia greatly exceeded that seenin a matched control sample.192 Thus, dysthymia, likemajor depression, may be provoked by chronic uncon-trollable stressor conditions. It remains to be estab-lished whether a chronic regimen of minor stressorswould likewise be associated with dysthymic symp-toms.

In addition to altered stress perception and copingstyles, perceived daily positive or uplifting events werereduced in dysthymic individuals relative to con-trols.187,188 This effect, however, was not limited today-to-day uplift perception, but was also evident withrespect to several quality of life indices, includingsocial interaction, health perception, cognitive func-tioning, alertness, energy/vitality, and life satisfaction.Among responders to treatment (either pharmaco-therapy or group CBT), each of these quality of lifeindices increased significantly.22,159,193–195 Studies thatfocused on social and interpersonal impairments like-wise indicated marked deficits among dysthymicpatients.22,159,193,196–199 These reports indicated thatsocial impairment correlated positively with increasingseverity and chronicity of the illness, and worsened


251with onset of double depression. In addition to allevi-ating the depressive symptoms, antidepressants attenu-ated the social impairment characteristic of dysthymicpatients. Markowitz et al200 demonstrated that acutetreatment (10 weeks) with desipramine significantlyimproved interpersonal functioning in dysthymics, asmeasured by the Inventory of Interpersonal Problems(IIP). While improvement continued over a 16-weekmaintenance phase, this was not significant, andalthough the social impairment scores approached nor-mative values, they did not attain this level. Further tothis point, life satisfaction and psychosocial func-tioning improved among dysthymics who responded toantidepressant treatment. Thus, it was posited that thereduced capacity to enjoy leisure time may be a statemarker of chronic depression.131,159,201

It is interesting that while significant improvementin quality of life was observed among dysthymicpatients treated with either imipramine or sertralineover 12 weeks,202 self-reported social functioningshowed greater improvement than did participation inleisure activity. It was suggested that the delayedalleviation of certain aspects of psychosocial func-tioning may have been due to the relatively short dur-ation of pharmacotherapy relative to the patients’ oftenlife-long impairment. Further to this same point, itshould also be considered that the well entrenchedanhedonia and impaired psychosocial functioningamong dysthymics may contribute to the unremittingnature of the illness. In this respect, it also appears thatthe response to desipramine was inferior among dys-thymic patients characterized by the most pronouncedoverall social impairment and family dysfunction.131

Despite the fact that antidepressant treatment dimin-ished the functional impairments characteristic of dys-thymic patients, it is of particular interest that thestress profile, although improved, continued to showsignificant residuum. For instance, while antidepress-ant medication was associated with reduced daily has-sle perception, increased uplift perception, diminishedreliance on emotion-focused coping styles, andreduced feelings of loneliness, none of these behavioralparameters had returned to levels of nondepressed sub-jects.188 Similarly, Klein et al203 reported that ado-lescents with a history of dysthymia displayed persist-ent perception of increased daily hassles, difficultiesin psychosocial functioning, and residual symptoms ofdepression. Finally, although improvement of psycho-social functioning was apparent among chronicdepressive patients within 4 weeks of sertraline orimipramine treatment, the level of functioning typi-cally did not reach that of a community control popu-lation.204 However, among those patients who dis-played full remission, psychosocial functioning wascomparable to that of a community sample. Thus, itappeared that in some chronically depressed patients,antidepressant medication effectively alleviated thefunctional psychosocial disturbances. Indeed, it wasrecently observed that among patients who receivedeither sertraline, CBT, or a combination of the twotreatments, only a modest overall elevation of uplift


perception and quality of life was observed. However,when these scores were assessed among treatmentresponders, it was clear that uplift perception andquality of life scores approached or reached those ofnondysthymic controls.22

As indicated earlier, it has been suggested thatdepressive illness, and particularly dysthymia, may bea life-long disorder. Moreover, the high rate of recur-rence of major depressive disorder may stem fromundertreatment of the illness, as reflected by the per-sistence of residual symptoms.20,205–207 It is similarlypossible that those treatments which permit residualdysthymic features to persist (eg, inadequate anti-depressant dosage or insufficient duration of treatment)may also favor recurrence of this illness. It is certainlyconceivable that by virtue of its effects on the second-ary features of dysthymia, CBT may act to limit illnessrecurrence. Yet, as will be discussed later, the neuro-chemical underpinnings of dysthymia may persistdespite a positive treatment response, thus necessitat-ing sustained maintenance treatment.

One further issue warrants some consideration. It hasbeen observed that among dysthymic patients treatedwith sertraline, the reduction of clinician-rateddepression scores (Hamilton Depression, Montgomery–Asberg, and Cornell Dysthymia Rating Scales) wasgreater than among patients treated with group CBT.The scores in the latter group were, in fact, no differentfrom those of placebo-treated subjects. However, likedrug-treated patients who showed a positive treatmentresponse, the CBT patients who showed significantclinical improvement also reported a marked increaseof quality of life. In contrast, no such increase wasapparent in placebo responders (ie, their quality of lifewas comparable to treatment nonresponders). Thus,despite the comparable clinical depression scores, thefunctional effects of drug treatment, CBT, and placebowere readily distinguishable. Given that quality of lifechanges may be a fundamental characteristic in ident-ifying the efficacy of treatment response,22 such a func-tional measure may also be useful in distinguishinggenuine drug responders from drug-treated patientsactually exhibiting a placebo-like response, and thusmay prove to be a valuable tool in predicting relapse.

Cytokines and depressive illness

Increasing evidence has indicated that depressive ill-ness is accompanied by immune dysregulation. Whileit had typically been assumed that depression pro-moted immunosuppression, it has been argued that thecompromised immunity may actually be secondary toan initial immune activation. Furthermore, this notionhas led to the possibility that products of an activatedimmune system may come to promote central neuro-chemical changes, hence provoking depressive symp-toms.208 Commensurate with this view, depressedpatients exhibited signs of immune activation, includ-ing increased plasma concentrations of complementproteins, C3 and C4, and immunoglobulin (Ig) M, aswell as positive acute phase proteins, haptoglobin, a1-


252


antitrypsin, a1 and a2 macroglobulin, coupled withreduced levels of negative acute phase proteins. Also,depression was accompanied by an increased numberof activated T cells (CD25+ and HLA-DR+), secretion ofneopterin, prostaglandin E2 and thromboxane. Fur-thermore, it appears that depression may be associatedwith variations of either circulating cytokine levels (ie,cell signalling factors released from activatedmacrophages), or cytokine production from mitogen-stimulated lymphocytes, including interleukin-2 (IL-2),soluble IL-2 receptors (sIL-2R), IL-1b, IL-1 receptorantagonist (IL-1Ra), IL-6, soluble IL-6 receptor (sIL-6R),and g-interferon (IFN).209–216 While there have beenreports that the elevated levels of IL-1b, IL-6 and a1-acid glycoprotein normalized with antidepressantmedication,217 the unregulated production of sIL-2R,IL-6 and sIL-6R was not attenuated with antidepressantagents, leading to the suggestion that the latter factorsmay be trait markers of the illness.208

Although severity of depressive illness is likely fun-damental in determining cytokine levels,208 the possi-bility cannot be ignored that chronic depression (orchronic stress) may induce cytokine changes to agreater extent than those observed following acute epi-sodes (as in the case of major depression). Consistentwith reports in melancholic patients,208 levels ofmitogen-stimulated IL-1b production were enhancedin dysthymia.55 However, in this particular study, IL-1b production was stimulated by the T cell mitogen,phytohemagglutinin (PHA), and thus may havereflected primarily T cell rather than macrophage-pro-duced IL-1b. While not excluding the possibility thatillness severity may be a pertinent feature in promotingthe enhanced IL-1b production, it seems likely that ill-ness chronicity or age of onset may also be importantin this respect. Indeed, it was observed that age of onsetwas inversely related to IL-1b production, while dur-ation of illness was directly related to production ofthis cytokine. Additionally, the altered IL-1b pro-duction was evident irrespective of whether a typicalor atypical (reversed neurovegetative) profile was evi-dent. Thus, it is unlikely that the altered cytokine pro-duction was related to the neurovegetative alterationsthat may appear in depression. It might be noted, aswell, that IL-1b production was not markedly reducedwith the alleviation of dysthymic symptoms following12 weeks of SSRI treatment.55,218 However, given thatdysthymia is a long-standing illness, it is certainlypossible that more prolonged treatment would havebeen necessary to realize changes of IL-1b, just as rela-tively protracted treatment was previously reported topromote variations of circulating natural killer cells.219

In contrast to the elevated IL-1b in supernatants ofmitogen-stimulated lymphocytes, we observed that cir-culating serum IL-1b, presumably derived from macro-phages and T cells, was not increased in either typicalmajor depressive or in dysthymic patients. However,among atypical major depressive patients, circulatingIL-1b levels were greatly increased, and normalizedwith treatment response.220 It could be assumed thatthe elevated levels of serum IL-1b in atypical

depression were secondary to the neurovegetative fea-tures of this depressive subtype. However, animal stud-ies have shown that IL-1b provokes some symptomscharacteristic of atypical depression (including,increased sleep and fatigue),99 and thus it is just aslikely that elevated circulating IL-1b contributes to theneurovegetative features of this depressive subtype.The finding that illnesses involving atypical depressivefeatures (eg, chronic fatigue syndrome) may be associa-ted with HPA disturbances (eg, reduced plasma cor-tisol, increased ACTH, and reduced ACTH release fol-lowing oCRH challenge),221,222 coupled with the factthat IL-1b is a potent stimulator of CRH release,223,224

raises the possibility that elevated circulating IL-1blevels contribute to the pathophysiology of atypicaldepressive symptoms.

In support of the immune activation view of depress-ive illness, Maes225 indicated that in addition to thealtered cytokine, acute phase protein, and hormonalchanges ordinarily elicited as part of the inflammatoryresponse, elevations of IL-1b may be evident indepression associated with a variety of medical ill-nesses. These include not only infectious diseases(influenza, herpes virus, HIV, Borna virus), but alsonumerous noninfectious illnesses, such as neurodegen-erative disorders, autoimmune disorders and braininjury.61,225 Thus, it was suggested that the cytokineactivation associated with these illnesses and/or injur-ies may have provoked variations of HPA activity, aswell as central neurochemical alterations, which maythen have favored the development of depression. Ineffect, these comorbid conditions may have contrib-uted to the illness owing to the cascade of cytokine,hormone and transmitter alterations engendered. Itwill be recalled that dysthymia likewise is associatedwith a large number of comorbid conditions, such asneurodegenerative disorders,1,61 traumatic braininjury,62 and illnesses potentially involving viralcomponents, such as fibromyalgia syndrome andchronic fatigue syndrome.53,54 As such, the possibilityought to be considered that such coexisting illnessesare not simply correlates of the mood disorder, but mayactually act to either precipitate or aggravate dysthymia.

The data presently available concerning cytokinechanges in depressive illness (ie, studies showing elev-ations of the cytokines in severe major depression) arelargely correlational. Thus, it is unclear whether thecytokine alterations seen in affective disorders are sec-ondary to the illness (or the stress associated with theillness), or play an etiological role in the provocation ofthe disorder. Yet, administration of high doses of IL-2,IFN-a and tumor necrosis factor-a (TNF-a) in humansundergoing immunotherapy have been shown toinduce neuropsychiatric symptoms, includingdepression, and these effects were related to the cyto-kine treatment rather than to the primary illness.226–229

Of course, the doses administered in these studies werein the pathophysiological range, and thus their rel-evance to depression per se must be interpreted cau-tiously. However, as indicated by Meyers,230 even


253when administered at relatively low doses, cytokinessuch as IFN-a may elicit depressive-like symptoms.

A provisional model of chronic depressive illness

It is clear from the preceding sections that limited dataare available concerning the mechanisms underlyingdysthymia. Because of dysthymia’s chronic, low-gradenature, animal models of the illness have yet to bedeveloped. Nevertheless, data derived from animalstudies offer some clues as to the potential persistenteffects of stressor experiences that may be relevant todysthymia. In particular, it seems that in addition toany immediate consequences, stressors may also pro-actively influence the neurochemical response to sub-sequently encountered aversive stimuli (sensitization),hence favoring long-term behavioral repercussions.Post and Weiss231 indicated that although the vari-ations of certain peptides persist for relatively briefperiods following a single stressor session, withrepeated challenges the release of some peptides willbe more readily induced and will be more persistent(eg, CRH, and to a greater extent TRH). It was suggestedthat depressive illness may initially stem from the neu-roendocrine alterations provoked by a stressor. How-ever, with each subsequent stressor experience, or witheach episode of depression, the sensitization becomesmore pronounced, such that progressively less intensepsychosocial stressors are required to provoke theonset of a depressive episode. Ultimately, episodes ofdepression may occur in the absence of obvious stresstriggers. In fact, it was reported that unlike the initialepisode, recurrence was less likely to be preceded byantecedent stressors196,232 and even occurred spon-taneously.233,234 Of course, it is often difficult to ident-ify significant or meaningful stressors that may be per-tinent to a given individual, thus conclusionsconcerning the presence or absence of stressful precipi-tants of depression may be difficult to validate. It isalso conceivable that in addition to stressors of apsychological nature, a physiological stressor, such asa virus, may be interpreted by the CNS in the same wayas a psychosocial stressor, hence triggering the cascadeof events resulting in neuroendocrine, cytokine, andmood alterations.235

Although it is often thought that HPA disturbancesare likely only a reflection of depression, it has beenproposed that alterations of HPA activity could be theprimary abnormality in depression, rather than simplyan illness response.236,237 Moreover, it has been sug-gested that among biologically predisposed individ-uals, chronic stressors may come to promote sustainedHPA activation which leads to adverse effects.74 Asalluded to earlier, the view has even been offered thatthe monoamine variations often associated withdepression may actually stem from endocrine alter-ations.236,237 In this respect, it was suggested that stress-ful events promote CRH variations in the central amyg-dala, which in turn may affect forebrain serotoninalterations. The former may reflect a basic stress-


response, while the latter, presumably, entails theappraisal of the stressor situation.238

While the model developed by Post and Weiss231 wasmeant to accommodate recurrent depression, it mayalso be applicable to the analysis of dysthymia. In thisrespect, however, it is important to underscore thatsensitization effects are not limited to the neuroendo-crine factors discussed by Post, nor is such a sensitiz-ation limited to antecedent stressors. In fact, it has beendemonstrated that several neurochemical alterationsassociated with stressors, psychostimulant use(amphetamine and cocaine), and electrical stimulationof the amygdala or the piriform cortex, may perma-nently enhance the neuronal response to subsequentmanipulations (sensitization).239 As will be seenshortly, this applies to the effects of cytokine treat-ments as well.

In modelling dysthymic disorders, several features ofthis illness need to be considered, and it is importantto distinguish these from other types of depression.Depressive disorders may be associated with profoundinterindividual differences in the symptoms sub-serving the illness, the response to pharmacotherapy,as well as the neuroendocrine correlates of the dis-order. Further, subtypes of depression may differ interms of their response to specific pharmacologicaltreatments, and with respect to their neuroendocrinefactors. For instance, major depression is characterizedby HPA alterations, including elevated plasma ACTHand cortisol levels, nonsuppression of cortisol releasefollowing dexamethasone challenge, and a bluntedACTH response to CRH challenge.222,240 While limiteddata are available, it appears that in illnesses involvingatypical features (eg, bulimia, seasonal affective dis-order, and chronic fatigue syndrome) the elevatedACTH levels are accompanied by reduced cortisol, ablunted ACTH response to CRH challenge,221,222,240,241

and absence of the CRH hypersecretion characteristicof typical depression.240 Among dysthymic patients theprofile is different yet again, and as indicated earlier,there is reason to believe that cortisol levels may actu-ally be reduced,4 although a contradictory finding hasbeen reported with respect to plasma cortisol and CRHconcentrations.242 Moreover, in response to a stressorchallenge, the cortisol response may be minimal indysthymic patients relative to that seen in other typesof depression and in nondepressed subjects.112 Itremains to be established whether subaffective andcharacter-spectrum dysthymia can be distinguished onthe basis of these parameters. In any event, in provid-ing a model of the mechanisms subserving dysthymiait needs to be understood why this disorder is not asso-ciated with cortisol abnormalities like those seen inmajor depressive illness. Furthermore, with respect todouble depression, it would be of obvious benefit todetermine why, following successful treatment,patients typically return to their dysthymic statesrather than to an euthymic state.

The sensitization model described earlier introducesan important facet of stressor actions that may be rel-evant to understanding the relationship between


254


stressor-induced neurochemical alterations andchronic depressive illness. Tilders and his associ-ates243–246 indicated that in response to repeatedstressor experiences, or with the passage of time fol-lowing a stressor or IL-1b challenge,247 phenotypicvariations may occur within hypothalamic neuronsthat are ordinarily responsive to stressors. In particular,increased coexpression of CRH and AVP was observedwithin CRH containing neurons originating in the para-ventricular nucleus (PVN) and having terminals in theexternal zone of the median eminence. As the co-released peptides act synergistically to promote ACTHsecretion, the chronic stressor regimen increases thepotential for elevated HPA functioning.243,246 It is ofparticular significance, as well, that the altered co-expression of CRH and AVP was exceptionally longlasting, and was even evident as long as 60 days follow-ing stressor exposure.

Given the chronic nature of dysthymia, characterizedby increased stress perception and inadequate copingstyles, it is conceivable that this illness would beaccompanied by the neuroendocrine characteristicsordinarily associated with chronic stressors. Forinstance, dysthymia may be associated with increasedCRH and AVP coexpression within the external zoneof the median eminence, as occurs with chronic stres-sors,246 and this may represent a permanent (orpersistent) characteristic. The fact that dysthymicpatients do not exhibit increased ACTH and cortisol,however, raises the possibility that the protractedCRH/AVP may have given rise to the down-regulationof pituitary and adrenal sensitivity. Clearly, thissuggestion is highly speculative given that experimentshave not been performed to assess, in detail, thecharacteristics of HPA functioning in dysthymicpatients. Since an abnormal DST response has typi-cally not been noted in dysthymia, it was taken forgranted that this illness is not accompanied by anyHPA disturbances. Yet, it may be the case that dysthy-mia is associated with adrenal hypofunctioning (asobserved in atypical depression), rather than the hyper-functioning seen in major depressive disorder.4 Thereare few neuroendocrine studies, however, thatobserved distinctive differences between dysthymicand non-depressed subjects. In part, this may stemfrom the subtle pathophysiological disturbances indysthymia, and the use of neuroendocrine analysesthat tap circulating hormonal levels rather than thedynamic, temporal patterns of hormone release.1 Also,assessment of HPA functioning in dysthymia requiresevaluation of the effects of various challenges (eg,ACTH, CRH, AVP, as well as serotonergic actingagents) in order to identify the nature of any dysregul-ation that may exist.107,248 Further, it is essential toevaluate these processes independently in the charac-ter-spectrum and subaffective variants of the illness.

Inasmuch as dysthymia is a chronic illness, often ofmild-moderate severity and typically without clearprecipitating events, it is unlikely that it is related toa single strong stressor experience. It is more reason-able to speculate that dysthymia reflects the actions of

more sustained, variable, and probably less intensestressors, coupled with the use of inadequate or inap-propriate methods of coping, culminating in thephenotypic CRH/AVP coexpression. Thus, it wouldnot be altogether surprising to find that doubledepression may be related to the superimposition of afurther stressor on the backdrop of dysthymia, whichwould then promote the increased release of these pep-tides (and the ensuing neurochemical cascade). Giventhis scenario, it might further be expected that aftertreatment of double depression, the CRH/AVP co-expression would persist and hence the dysthymic pro-file would be maintained. In these individuals the riskfor further major depressive episodes would, of course,be heightened. In effect, we are suggesting that dysthy-mia may reflect a chronic state of altered endocrine andcentral neurotransmitter functioning which may berelated to sustained stressor experiences together withinadequate coping. Indeed, even with the remission ofsymptoms, the persistent neuropeptide disturbanceswould increase the likelihood of symptom recur-rence.249 Obviously, it would be of particular interest toestablish whether the alleviation of double depressivesymptoms would be accompanied by abnormalresponses to CRH challenge, and whether such aneffect differed from that seen following recovery froma major depressive episode. These factors, coupledwith the long standing nature of the disorder, and thecomorbid features discussed earlier, may necessitate amore sustained regimen of pharmacotherapy. More-over, given the personality disturbances and the malad-aptive cognitive coping strategies characteristic of dys-thymia, in the absence of cognitive therapy orpsychotherapy (as adjunctive or maintenancetreatment) susceptibility to recurrence of illness maybe increased. Indeed, we have shown previously thatin spite of clinical improvement following pharmaco-therapy, functional disturbances (as reflected bycompromised quality of life, anhedonia) may persist indysthymia. It was hypothesized that these residual fea-tures may actually be predictive of illness recurrencefollowing cessation of pharmacotherapy.22

In relating stressful events to the mechanisms under-lying dysthymia, we have defined stressors in a fairlybroad way. As discussed earlier, it has been positedthat, among other things, the immune system acts likea sensory organ informing the brain of antigenic chal-lenge.250,251 Furthermore, given the nature of the neuro-chemical changes elicited by antigens and cytokines, itwas suggested that immune activation may be inter-preted by the CNS as a stressor.44,223,235,251 To be sure,the effects of systemic stressors (eg, those associatedwith viral insults, bacterial endotoxins, cytokines) arenot entirely congruous with those elicited by pro-cessive stressors (ie, those involving higher order sen-sory processing).252 Nevertheless, cytokines may bepart of a regulatory loop that, by virtue of their effectson CNS functioning, might influence behavioral out-puts and may even contribute to the symptoms ofbehavioral pathologies, including mood and anxiety-related disorders.44,235,253 It is certainly the case that


255both processive and systemic stressors effectivelyincrease HPA activity. However, while processivestressors do so via limbic circuits, the HPA alterationselicited by systemic stressors may result from limbic-independent processes.245 Yet, it ought to be under-scored that systemic stressors, including IL-1b, IL-2and TNFa have all been shown to influence centralmonoamine activity at both hypothalamic and extra-hypothalamic sites, including hippocampal 5-HTactivity, 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, byvirtue of these monoamine effects, may come to pro-mote or exacerbate depressive disorders, quite apartfrom any actions involving the HPA axis. It remainsto be determined whether the IL-1b variations seen indysthymia are secondary to the illness or, in fact, playan etiological role. Yet, as indicated earlier, this cyto-kine provokes behavioral changes, some of which arereminiscent of the characteristics of atypicaldepression, including increased sleep, lethargy andreduced locomotor activity,257 and may provoke anxi-ety.235 Given that the production of IL-1b in mitogen-stimulated lymphocytes is greater among dysthymicthan among major depressive patients, particularly inthose reporting early onset of the illness,55 the possi-bility exists that dysthymia may be associated withexcessive cytokine reactivity. Increased IL-1b acti-vation would then stimulate CRH functioning, and theensuing neuroendocrine cascade. In effect, it may bethat in dysthymic patients, stressors in the form of viralor bacterial challenges, may be particularly potent inprovoking major depressive symptoms and hence pro-moting double depression.

Concluding remarks

The paucity of data from human studies, coupled withthe lack of a suitable animal model for dysthymia, havelimited the conclusions that can be drawn concerningthe etiology of this disorder. Nevertheless, the availabledata have made it clear that elucidation of the mech-anisms underlying dysthymia, and the development ofadequate treatment strategies, will require that severalfundamental features be included in experimentalanalyses. Foremost in this respect is the need to sub-type subjects according to definite criteria. In parti-cular, it will be of obvious advantage to distinguishbetween pure dysthymia, double depression, and otherforms of chronic depression. Additionally, patientsneed to be characterized into homogeneous subgroups(eg, early- vs late-onset; subaffective vs character-spectrum), and the symptom profile of the dysthymicpatients ought to be considered (vis-a-vis the presenceof typical or atypical neurovegetative symptoms).

Although genetic factors likely contribute to theexpression of dysthymia, there is also reason to believethat experiential factors play a cogent role in thisrespect. There is no information, however, as towhether early-life experiences contribute to the bio-logical (subaffective) type of dysthymia. It is interest-


ing, however, that studies in rodents have indicatedthat early life maternal deprivation may give rise to acascade of neurochemical alterations much like thosepurported to occur in dysthymia. These includeincreased CRH mRNA expression in the amygdala andCRH concentrations in the median eminence, as wellas increases of CRH receptors in the prefrontal cortex,amygdala, hypothalamus and cerebellum. As adults,rats that had undergone maternal deprivation displayincreased stress-elicited arousal and elevated HPAfunctioning.258,259 The possibility ought to be exploredthat in humans, early-life stress or ‘neglect’ may giverise to these neurochemical disturbances, henceincreasing vulnerability to later stressor-induced neur-oendocrine and neurotransmitter alterations and ulti-mately the dysthymic profile. Of course, the failure toestablish appropriate coping strategies (and thisincludes affiliation, attachment and support systems,particularly with parents) may augment stressoreffects, thereby encouraging the development of dys-thymia.

Finally, the identification of subtypes of dysthymiamay be an important feature in determining the opti-mal treatment strategy employed. From the outset, itmust be acknowledged that because dysthymia is achronic condition, relatively sustained treatment maybe required to alleviate the symptoms.260 Thus, drugsthat are relatively well tolerated will be most effi-cacious in treatment, particularly when these agents donot elicit sexual dysfunction or somatic complaints,symptoms which themselves typically are not charac-teristic of dysthymia.18 Further, it is likely, as indicatedearlier, that the effectiveness of various treatment stra-tegies may be related to factors such as age of onset,and the presence of characterological features. In thisrespect, determining whether a given episode is asso-ciated with neuroendocrine disturbances (eg, reducedcortisol secretion secondary to excessive CRHactivation) may offer insights into whether pharma-cotherapy (and the type of agents used) would be mostefficacious in treating the disorder. Of course, familyhistory of psychiatric illness and the effectiveness ofspecific pharmacotherapy therein, would be of obviousvalue in planning a treatment strategy. Finally, it oughtto be underscored that the effectiveness of cognitivetherapy has not been extensively evaluated in dys-thymic patients. Nevertheless, it would appear that thistherapeutic modality may be useful in treating somedysthymic patients. It remains to be established whatcharacteristics of the illness might be predictive ofthose patients who would benefit most from this formof therapy. In this respect, it may be useful to considerfunctional parameters related to quality of life (eg, cog-nitive disturbances, social interaction, life satisfaction),as opposed to relying simply on clinical indices ofdepression. Given the particularly high rate of relapsein dysthymia upon cessation of pharmacotherapy,18 thepossibility ought to be considered that cognitive ther-apy, particularly when focusing on residual functionaldisturbances, would be useful as an adjunctive ormaintenance treatment strategy.


256


Acknowledgements

This work was supported by the Medical ResearchCouncil of Canada. HA is an Ontario Mental HealthFoundation Senior Research Fellow.

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Dysthymia: a review of pharmacological and behavioral factors

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