Dysthymia: a Review of Pharmacological and Behavioral Factors J Grifﬁths1, AV Ravindran1, Z Merali1,2 and H Anisman1,3

Home , Amisulpride, Anhedonia, Anxiety disorder, Atypical depression, Bulimia nervosa, Double depression

Molecular Psychiatry (2000) 5, 242–261  2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00 www.nature.com/mp REVIEW ARTICLE Dysthymia: a review of pharmacological and behavioral factors J 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 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 extrahypo- thalamic 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 mote relapse following treatment, and increase the risk for superimposed major depression (double Dysthymia, a chronic, low-grade form of depression, depression). occurs in a substantial portion of the population, and The broad purpose of the present review is to eluci- increases the risk for major depressive disorder. Yet, date several behavioral, neuroendocrine and immune/ relative to major depression, limited information is cytokine characteristics of dysthymia. To this end, we available concerning the behavioral concomitants, as provide an overview of the characteristics of dysthy- well as the physiological correlates of dysthymia. Dys- mia, including a description of the clinical and epide- thymia and major depression share several features miological aspects of the illness, comorbid features of regarding stress/coping, and the response to pharmaco- dysthymia, as well as a review of the data suggesting therapy. However, it appears that they can be dis- a role for genetic factors. Given that dysthymia, or at tinguished from one another with respect to hypothal- least some subtypes of the illness, may involve biologi- amic-pituitary-adrenal (HPA) functioning, and there is cal underpinnings, a brief review is provided regarding evidence that these depressive subtypes can be differ- the neuroendocrine, neurochemical and cytokine cor- entiated with regard to their cytokine correlates. Yet, relates of dysthymia, and an overview is provided con- there is reason to suppose that, owing to its chronic cerning the efficacy of pharmacotherapy in the treat- nature, dysthymia may be associated with persistent ment of this disorder. functional changes of HPA activity, as well as several It is proposed that dysthymia may be related to sub- adjunctive features, including altered stressor and tle effects of stressors and inadequate coping styles, uplift perceptions, coping styles, and quality of life.1–4 and may be exacerbated by the presence of ongoing Together, these factors may perpetuate the illness, pro- psychosocial impairments. A highly provisional model is proposed concerning the etiological processes subserving dysthymia, including various facets of the HPA Correspondence: H Anisman, Institute of Neuroscience, Life Science Research Centre, Ottawa, Ontario, K1S 5B6, Canada. axis (eg, phenotypic variations of corticotropin releas- E-mail: hanismanȰccs.carleton.ca ing hormone (CRH) and arginine vasopressin (AVP), Received 10 June 1999; revised and accepted 30 September 1999 down-regulation of adrenal functioning) and forebrain Dysthymia J Griffiths et al 243 serotonergic mechanisms. However, given the paucity ality disorder, as well as neurotic depression of more of data concerning the effects of various challenges (eg, than 2 years duration.7 dexamethasone, ACTH, CRH, TSH, stressors, as well as The characteristics of dysthymia in many ways over- challenges in the presence or absence of metyrapone) lap with those of major depression, although in dysthy- on HPA hormones among dysthymic individuals, the mia, symptoms outnumber signs (ie, objective charac- conclusions that can be derived are tentative and must teristics such as vegetative symptoms and psychomotor necessarily await further data. changes are typically absent).9 Relative to major depressive disorder, symptoms occur at a lower frequency in dysthymic patients, but are qualitatively Dysthymia: clinical and epidemiological features similar. Moreover, relative to neurovegetative and psychomotor features, social-motivational impairments Dysthymia, literally meaning ‘being of bad mood’ or tend to be more characteristic of dysthymia.3,10 In many ‘ill-humor’ is an illness characterized by a number of dysthymic patients an intermittent emergence of major affective, neurovegetative and cognitive symptoms. depression may occur (double depression), with the The diagnosis of dysthymic disorder was introduced dysthymic state usually recurring upon remission of in the third edition of the Diagnostic and Statistical the major depressive episode.9 Likewise, dysthymia Manual of Mental Disorders (DSM-III) to characterize may emerge as a residual syndrome of acute chronic depression of 2 or more years and to depression;6,11 however, the diagnosis of dysthymia encompass disorders which had previously been con- would not be applied if the initial episode of chronic sidered characterologically based, including neurotic depressive symptoms met the criteria for and was suf- depression, chronic minor depression, and characterol- ficiently severe to be diagnosed as a major depressive ogical depression.5 While the severity of dysthymia is episode. usually less profound than that of acute major depress- Dysthymia is more common among women than ive disorder, symptoms may fluctuate in intensity. Fur- among men (2:1), has a 1-year prevalence rate (for the thermore, several subtypes of dysthymia have been United States) estimated as high as 5.4%,12 and the proposed based on specific symptoms, family history, highest life-time prevalence of the affective disorders.13 and age of onset; subaffective dysthymia is thought to However, only a relatively small proportion of dys- be of biological origin, while character spectrum dysthymic individuals seek treatment for their illness, thymia is more personality-based.6,7 Currently, DSM- likely owing to the mild nature of the symptoms and IV stipulates that a diagnosis of dysthymia includes their insidious onset, coupled with the individual’s depressed mood, coupled with two or more of the fol- lack of insight. Indeed, the illness often appears in lowing: poor appetite or overeating, insomnia or hyper- childhood and adolescence,14,15 and as a result of the somnia, low energy/fatigue, low self-esteem, poor con- long-term, low-grade nature of the illness, dysthymia centration or difficulty making decisions, and feelings might not be perceived as differing from the individ- of hopelessness.5 Dysthymia also frequently has an ual’s norm. It is of interest to note that in a study of a early and insidious onset, and is associated with path- fairly large number of dysthymic patients, only 41% ology of character, albeit these may not play an etiolog- had received any form of pharmacotherapy, and just ical role. There has been some debate as to whether 56% had received psychotherapy, attesting to the these symptoms are, in fact, most characteristic of dys- under-treatment of this disorder.16 thymia, and based on field trials, the DSM-IV Although it had been suggested that pharmaco- (Appendix B) offers an alternative set of criteria. These therapy may be less effective in the treatment of dys- include: (a) low self-esteem, self confidence, or feelings thymia relative to major depressive disorder, recent of inadequacy; (b) feelings of pessimism, despair, and evidence has indicated that such intervention may, in hopelessness; (c) anhedonia (generalized loss of inter- fact, be a treatment of choice for dysthymia. However, est or pleasure); (d) social withdrawal; (e) chronic the treatment response may vary with the specific sub- fatigue or tiredness; (f) feelings of guilt, or brooding type of the illness.4,17 Indeed, it appeared that about the past; (g) irritability or excessive anger; (h) pharmacotherapy was less effective in ‘pure dysthy- reduced activity, effectiveness, or productivity; and (i) mia’ than in dysthymia with a history of major difficulty in thinking, as reflected by poor concen- depression or in patients with concurrent major tration, memory or decisiveness. depression.18 Because dysthymia was initially thought Like the DSM-IV, the ICD-10 defines dysthymia as a to be more of a characterological disturbance than a chronic depression which fails to meet the severity and biologically-based illness, and because of the oft-noted duration criteria for recurrent depressive disorder. superiority of pharmacotherapy in major depression However, depressive illness, of at least mild duration, relative to that observed in dysthymia,17 the illness was may have occurred previously.8 According to the ICD- typically treated using different forms of psycho- 10, dysthymia often begins early in adult life, and therapy.19–21 As such, the lack of controlled studies when late onset dysthymia occurs it is often secondary comparing the relative efficacy of psychotherapy and to a severe major depressive disorder or in response to pharmacotherapy (either alone or in combination) is environmental stressors (eg, bereavement). Moreover, surprising. It was recently reported, however, that in dysthymia is thought to include persistent anxiety- the short-run, pharmacotherapy (using a selective sero- depression, depressive neurosis, depressive person- tonin reuptake inhibitor) was more efficacious than

Molecular Psychiatry Dysthymia J Griffiths et al 244 group cognitive behavior therapy (CBT) in alleviating might be associated with a more severe and enduring symptoms of dysthymia,22 although CBT attenuated symptom profile, as observed in major depression with several functional aspects of the illness. Using a some- co-existing anxiety disorder,29 and might thus require what more protracted regimen (16 weeks), CBT was adjunctive forms of pharmacotherapy. In fact, it was effective in a study involving a small number of dys- recently reported that a coexisting anxiety disorder thymic subjects. While this effect appeared to be may indicate increased risk for persistent depression.30 somewhat reduced relative to that associated with In addition to comorbid anxiety, dysthymia often co- fluoxetine, the effects of the treatments were not sig- exists with personality disorders.31 As well, more dou- nificantly different.23 ble depressive patients than pure dysthymics met criteria for at least one personality disorder. Conversely, compared to episodic major depressives, significantly Symptom and illness comorbidity more dysthymics met criteria for an axis II disorder. The presence of comorbid features with dysthymia can Interestingly, dysthymic patients scored significantly be related to any number of factors. On the one hand, higher than major depressive patients on all of the 13 the comorbidity may simply reflect the nosology of the dimensions of the Personality Disorder Examination, syndromes, which have overlapping symptoms.1 On with the most common axis II disorders being border- the other hand, comorbidity may reflect common line, avoidant and histrionic.31 Essentially, dysthymic underlying mechanisms, or in the case of debilitating subjects were found to display personality disorders in medical conditions, the dysthymic state may represent the DSM cluster B (antisocial, narcissistic, borderline a subsyndromal depression resulting from the primary and histrionic)31,32 although high rates of avoidant and illness. It is possible, as well, that the development of dependent personality disorders were also apparent.31–33 dysthymia may be secondary to features such as per- Indeed, it was reported that subaffective and character sonality disorders or to excessive anxiety, or con- spectrum dysthymics could be distinguished from one versely, dysthymia may give rise to these features. another on the basis of DSM cluster C characteristics, Whatever the case, it is of obvious diagnostic and with subaffective subjects exhibiting greater avoidant therapeutic value to discern the presence and pro- personality and dependent personality relative to gression of comorbid features.1 character spectrum patients.34 It was further reported Major depression is often superimposed on a dys- that the occurrence of such personality disorder comor- thymic state (double depression), and is associated bidity was particularly notable in early-onset dys- with a high rate of illness recurrence.24,25 In their epi- thymic patients.35,36 Finally, it appeared that depress- demiological study, Weissman et al26 reported that ive personality disorder (DPD) was more closely 40% of dysthymic patients exhibited comorbid major aligned with dysthymia than with major depression.37 depression, while more recent evidence suggested that As in the case of other depressive syndromes,38 as many as 62% of dysthymic patients met criteria for substance abuse was found to occur at a fairly high rate current major depression, and 80% for lifetime major among dysthymic patients. For instance, it has been depression.14 Treatment outcome was significantly bet- reported that subjects in alcohol treatment programs ter in major depressives than among double depress- frequently met the criteria for dysthymic disorder.39 ives, as was the recurrence rate over 2 years.25 It has In a sample of subjects with substance-related disorder, been suggested that the chronology of dysthymia rela- a substantial portion (ෂ10%) exhibited comorbid tive to major depression may influence subsequent dysthymia.40,41 The dysthymic group also had a sur- treatment response. For example, it was reported that prisingly early age of first use of caffeine (7.3 ± 7.0 patients who had experienced dysthymia subsequent years), and the investigators speculated that this may to their first major depressive episode, showed a have constituted an early attempt to self-medicate.40 reduced treatment response relative to those patients In considering comorbid features, it may be in whom onset of dysthymia had preceded their first important to distinguish between subtypes of dysthy- major depression.27 mia based on age of illness onset. It had been reported As many as 75% of dysthymic patients suffer from that early- and late-onset dysthymic patients with some comorbid psychiatric disorder, of which superimposed major depression did not differ with depression, anxiety, and substance abuse are the most respect to several clinical, psychosocial and cognitive common.26 Indeed, approximately one-half (50.7%) of indices, nor in terms of family history of depression Shelton et al’s16 sample of 410 dysthymic patients and alcoholism.42 Subsequent studies, however, indi- reported a history of major depression, while 26.3% cated that early-onset dysthymics exhibited greater use had a history of substance abuse, and 68.2% were diag- of emotion-focused coping strategies, a higher fre- nosed with a comorbid personality disorder. With quency of personality disorders, and increased life- respect to comorbid anxiety, it was demonstrated that time substance abuse disorder than their late-onset while social phobia and panic attacks were signifi- counterparts.36,43–50 Further, a greater number of early- cantly more common among unipolar and bipolar onset dysthymic patients had a family history of a depressives (respectively) than dysthymic patients, the mood disorder, and displayed earlier onset and longer latter exhibited a higher prevalence of generalized anx- duration of the index major depressive episode.36,50 To iety disorder.28 As such, dysthymia ought to be more be sure, as indicated by Klein et al,36 the earlier onset closely scrutinized for comorbid anxiety disorder, as it of the index major depressive episode might simply

Molecular Psychiatry Dysthymia J Griffiths et al 245 reflect greater opportunity for such an occurrence given depressive features, including introversion and that dysthymia increases the risk of major depression. inflexibility, were reported to serve as premorbid pre- Moreover, early onset dysthymia being associated with dictors of the onset of Parkinson’s disease or an accel- poor interpersonal and psychosocial skills, may have erated cognitive decline.61 These investigators have favored the development of personality disorders and gone so far as to suggest that psychological and phar- substance abuse. Yet, there is reason to suppose that macological interventions may be appropriate in the biological factors may be more closely aligned with treatment of Parkinsonian depression. early onset of the illness, while late onset may be asso- As in the case of neurodegenerative disorders, ciated with character spectrum disorder.4 In fact, as patients suffering from traumatic brain injury (TBI) will be discussed shortly, there have been several reportedly suffer from a higher prevalence of mood dis- reports indicating that these subgroups may differ with orders than the general population (ie, 25–50% major respect to several neuroendocrine substrates, as well as depression, 15–30% dysthymia, 9% mania).62 Given in response to some antidepressant medications. the large number of brain regions that may be primarily In addition to the high psychiatric comorbidity, dys- or secondarily influenced by head trauma, it is difficult thymia has also been associated with various other to identify the specific nuclei or pathways subserving medical conditions. Given the similarity between dys- the depression. However, since brain trauma is associa- thymia and chronic fatigue syndrome (CFS), parti- ted with focal increases of IL-1,63 as are neurodegener- cularly with respect to lethargy, lassitude, impaired ative disorders, the possibility should be considered concentration, and diminished drive, the possibility that the behavioral effects observed in TBI and exists that a subgroup of chronic fatigue patients rep- Parkinsonian patients are associated with heightened resents a variant of dysthymia.51 Indeed, it was cytokine levels. reported that patients identified with fatigue were between six and 10 times more likely to suffer from Biological aspects of dysthymia dysthymia than the population at large.52 Similarly, fibromyalgia syndrome, which overlaps with CFS, has Depression has been associated with a variety of neuro- been associated with major depression and dysthy- chemical changes, including deficiencies of norepi- mia.53,54 Interestingly, fibromyalgia syndrome has been nephrine (NE),64 serotonin (5-HT)65,66 and dopamine 67–69 associated with adverse childhood experiences. More- (DA), or to variations of DA autoreceptors, 5-HT2 ␣ ␤ 70–72 over, specific personality traits which may be related receptors, 1-NE or -NE receptors. Of course, to such adverse experiences (eg, unstable self-esteem), depression is likely a biochemically heterogeneous dis- may also be associated with fibromyalgia, just as they order, such that the neurochemical underpinnings for are associated with dysthymia.54 It is unclear, however, the illness, as well as the symptom profile exhibited, whether dysthymia is associated simply with the vary across subjects.66,73 Moreover, given the abnormal symptom of chronic fatigue, as opposed to the syn- responses to various endocrine challenges (eg, the drome.51 It is significant, as will be discussed shortly, dexamethasone suppression test (DST), CRH, as well that dysthymia is associated with elevated production as thyroid releasing hormone (TRH) challenges), there of interleukin-1 (IL-1␤),55 a cytokine released by acti- is reason to suppose that hormonal variations contrib- vated macrophages, just as CFS has been associated ute to the provocation or expression of depressive with an elevation of this cytokine.56,57 symptoms, and that considerable interindividual varia- In addition to CFS, like other mood and anxiety- bility exists with respect to the contribution of these related disorders, dysthymia has also been associated endocrine factors.74–77 with increased co-occurrence of migraine (with aura), It has been suggested that stressful events or failure tension, and non-organic headaches.58–60 In this experiences are associated with depressive illness.78–80 respect, it was reported that of the mood disorders, the Such an outcome may stem from the stressor experi- prevalence of coexisting dysthymia was particularly ence provoking the formation of attributions, which notable.60 These data raise the possibility that head- give rise to negative expectancies of future perform- ache and dysthymia share common underlying pro- ance and may result in the development of cognitive cesses (eg, serotonergic mechanisms, given that both disturbances, such as helplessness.81,82 Alternatively, are positively influenced by serotonin reuptake stressor experiences may give rise to neurochemical inhibitors) or that environmental triggers, such as stres- alterations that favor depressed mood.83,84 sors, may be associated with both pathologies. It is difficult, using animals, to adequately model Comorbidity involving CFS and headaches in dys- depressive illness let alone to reflect dysthymia. Never- thymia is not unexpected given the potential for com- theless, it may be productive to examine some of the mon mechanisms or environmental precipitants. More neurochemical correlates of stressors. Although surprising, however, was the finding that a large num- environmental insults initiate a series of neurochem- ber of patients suffering from Parkinson’s disease exhi- ical changes that may be of adaptive significance, when bited concurrent major depressive disorder and/or dys- these neurochemical alterations are insufficient to deal thymia. Of course, such comorbidity might be with environmental demands (or neurochemical adap- predicted given that the stress of the neurodegenerative tation does not occur readily), vulnerability to pathol- disturbance might lead to depressive affect. Interest- ogy is increased.83 Indeed, animal studies indicated ingly, however, in a recent review of this literature, that stressors will induce many of the central neuro-

Molecular Psychiatry Dysthymia J Griffiths et al 246 transmitter alterations (eg, variations of NE, DA and and the latter might actually be associated with hypo- 5-HT turnover and levels) that have been proposed to cortisol responding.111 Indeed, it has been reported that subserve the depressive symptoms in humans. the elevated salivary cortisol associated with exercise Specifically, in response to acute stressors the in pre-adolescent children was not apparent among increased utilization of NE, DA and 5-HT is ordinarily dysthymic children of the same age.112 Paralleling met by adequate synthesis and hence transmitter levels these alterations of pituitary-adrenal activity, differ- remain stable. However, under conditions that favor ences appeared between major depression and dysthy- amine utilization exceeding synthesis (ie, if the stressor mia in growth hormone secretion in response to is sufficiently severe and uncontrollable), amine levels physiological challenges, as well as TSH blunting in may decline in several brain regions.83–86 These amine the TRH stimulation test.113 alterations typically persist for only a few hours, As part of a study assessing the role of psychosocial depending on the stressor severity and several organ- and biological variables in chronic and non-chronic ismic variables (eg, age, species).84,87,88 However, major depression and dysthymia, a lower rate of DST re-exposure to a mild stressor enhances the utilization non-suppression was observed in dysthymic patients of hypothalamic NE89,90 and mesocortical DA (52% vs 8.5% non-suppression in major depression vs (sensitization effect),91–93 even if the re-exposure dysthymia). However, the rate of DST non-suppression involves a different stressor.94–96 was higher in the early-onset than in the late-onset dys- Since humans typically encounter chronic, intermit- thymics,113 although, when double depressives were tent and unpredictable stressors, it may be more rel- excluded from the analysis (39 of the 75 dysthymic evant to assess the effects of such regimens in animal patients), there was no difference between early and studies. In contrast to the amine reductions induced late onset groups (9% and 8% respectively). Interest- by acute stressors, transmitter levels equal or exceed ingly, paralleling the DST response, among late-onset control values following protracted or repeated stres- dysthymics, the blunted TSH response to TRH admin- sors,93,97–100 owing to increased amine synthesis and/or istration was absent, whereas early-onset dysthymics moderation of excessive utilization.98,101 Moreover, (who parenthetically reported more traumatic and frus- chronic insults affect the amine variations engendered trating childhood backgrounds) had a higher rate of by later stressors. Specifically, in addition to a sensitiz- DST nonsuppression, and more frequently exhibited a ation with respect to amine utilization (as seen follow- blunted TSH response. In effect, these data suggest that ing acute stressors), chronic stressors also induce sensi- early-onset dysthymia may represent a biologically dis- tization of amine synthesis, thereby assuring adequate tinct subgroup of chronically depressed patients.113 transmitter levels upon later stressor encounters.99 In Indeed, it was noted that early-onset dysthymics addition, a chronic stressor may result in the down- responded preferentially to moclobemide relative to regulation of ␤-NE receptor activity and the NE-sensi- imipramine, while no such distinction was found tive cAMP response.102 Interestingly, upon application among the late-onset dysthymics, suggesting that of a chronic unpredictable stressor the neurochemical monoamine oxidase A might be more imbalanced adaptation was slower to develop.83,103 It has been sug- among early-onset dysthymics.114 gested that when inadequate neurochemical coping While limited attention has been devoted to the mechanisms are generated (eg, in genetically vulner- analysis of monoamine abnormalities in dysthymia, able animals, and when the stressor occurs unpre- reduced levels of plasma NE coupled with elevated dictably and involves a series of different insults), platelet and free 5-HT were evident in dysthymia.115 depressive-like characteristics may evolve.104 In fact, Further, following exercise, changes of epinephrine Anisman and Merali105 indicated that a regimen of levels were relatively modest in dysthymic patients mild, unpredictable stressors may be precisely the relative to control subjects. Thus, it was posited that antecedent events most closely aligned with dys- dysthymia may be associated with altered adrenal thymic-like states. It is important to emphasize at this responsivity to environmental challenges, as well as juncture that while some degree of behavioral and heightened sympathetic tone as reflected by the elev- neurochemical adaptation may occur in response to ated free 5-HT levels. Ravindran et al111 observed chronic stressor experiences, the view has been reduced platelet MAO activity in primary, early-onset expressed that the wear and tear induced by attempts dysthymics relative to control subjects. Moreover, to adapt to a chronic stressor (allostatic load), when MAO activity prior to treatment was lower among non- sufficiently protracted and/or intense, may culminate responders than among the drug responders. Along the in pathological outcomes.106 As will be discussed later, same line, relative to endogenous depressives, MAO chronic insults may, in fact, promote persistent neuro- levels were low among neurotic depressives,116 while chemical alterations which favor the development of MAO activity correlated positively with clinical state depressive characteristics. in the endogenous group. Thus, low MAO activity may While there is considerable evidence supporting a represent a marker for vulnerability to neurotic relationship between major depression and central depression. Consistent with the potential involvement neurochemical disturbances,107–110 scant information is of serotonergic mechanisms in dysthymia, prior to available regarding the biological substrates of dysthy- treatment, lower urinary 5-hydroxyindoleacetic acid mia. However, the frequent abnormal DSTs seen in (5-HIAA) levels were observed among treatment major depressive patients were absent in dysthymia,2,4 responders relative to nonresponders, and the reduced

Molecular Psychiatry Dysthymia J Grifﬁths et al

147,148 247 levels in responders normalized following treat- as the 5HT2 antagonist, ritanserin, the selective ment.117 norepinephrine reuptake inhibitor, reboxetine,149 and There have been few studies that assessed the elec- the serotonin/norepinephrine reuptake inhibitor trophysiological correlates of dysthymia. However, it (SNRI), venlafaxine150,151 (Table 1). The use of well tol- was reported that in anticipation of aversive stimuli, erated compounds, including moclobemide and sertra- dysthymics exhibited hyporesponsiveness of skin con- line, may be effective in the long-term management of ductance, and displayed subtle cognitive processing dysthymia. This is particularly important since discon- disturbances (possibly reflecting difficulties in the pro- tinuation of antidepressant treatment was found to be cessing of complex information), as reflected by evoked associated with an 89% rate of relapse in a 4-year potentials in response to task-relevant stimuli. It was maintenance study.18 posited that dysthymia may be associated with an In addition to the effects of the aforementioned anti- impoverished ability to respond appropriately to exter- depressants, hormonal manipulations have also been nal task demands, possibly owing to inappropriate shown to influence dysthymic symptoms. Specifically, allocation of processing resources. Furthermore, it was in a crossover-study involving a small number of sub- suggested that owing to their impaired resource allo- jects, it was observed that administration of the adrenal cation strategies, dysthymic subjects may be more gen- androgen, dehydroepiandrosterone, alleviated dys- erally impaired in their ability to cope with day-to- thymic symptoms, primarily comprising anhedonia, day stressors.118,119 loss of motivation and energy, inability to cope, worry, Akiskal et al120,121 reported differences in the sleep emotional numbness, and sadness.163 Interestingly, architecture between subtypes of dysthymic patients. these effects were obtained after only 3 weeks of treat- While subaffective dysthymics exhibited shortened ment. Furthermore, the thyroid hormone, thyroxine, REM latencies relative to controls, this was not the case potentiated the effects of a variety of antidepressant among character spectrum disorder patients. In medications in dysthymic and treatment-resistant addition, dysthymia was associated with excessive and chronic depressive patients.164 Moreover, in a small abnormal distribution of REM during the early part of study of five patients it was observed that chromium the night121 as observed in major depression.2,122 How- supplementation enhanced the antidepressant effects ever, while the major depressive patients displayed of more traditional therapeutic agents.165 reduced total sleep time, sleep latency, morning wake As indicated earlier, we observed in a double-blind time and sleep efficiency, the sleep architecture of dys- placebo-controlled study, that sertraline was generally thymics in terms of stage percentages, and REM sleep more effective than group CBT in treating the symp- features, were identical to those of major depressives. toms of dysthymia, as measured by the Hamilton In effect, these data are consistent with the notion that Depression Scale.22 Of course, these data need to be the two disorders are variants of the same illness,123 or considered as highly provisional, since the trial was share common underlying mechanisms. 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 Pharmacological contributions to the analysis of dysthymia may be more conducive to the treatment of dysthymia the disorder. Further, given that anhedonia is a charac- The most persuasive data favoring a biological sub- teristic and persistent feature of dysthymia, it may have strate for dysthymia originate from studies which been beneficial to employ cognitive techniques which assessed pharmacological agents in the treatment of focused specifically on the inability of patients to dysthymic illness. The early pharmacological studies experience or perceive positive events. Indeed, using in dysthymia revealed that although MAO inhibitors cognitive behavioral psychotherapy, which focuses on and tricyclic antidepressants (TCAs) had superior the helplessness and hopelessness associated with dys- therapeutic efficacy to placebo, their effects were not thymia, and also teaches adaptive coping skills, as marked as in major depression.4,17,124–130 However, McCullough21 reported that nine of 10 dysthymic it appears that reliable and impressive effects of anti- patients were still in remission after a 2-year period. depressant medications can be garnered in dysthymia. Given the high rate of depressive relapse/recurrence This stems from the development of medications, such ordinarily observed following cessation of treatment, as selective serotonin reuptake inhibitors (SSRIs), it will be interesting to establish whether combination which have fewer side effects, thus permitting the use therapy minimizes recurrence of illness relative to that of higher doses. Moreover, it has been suggested that seen among patients who had received only pharmaco- optimal drug effects would be obtained when adminis- therapy. This is particularly the case since group CBT tered primarily to patients with subaffective, rather enhanced the effects of sertraline with respect to some than character spectrum disorder.4 In fact, studies functional behaviors (eg, cognitive coping styles, and which employed rigorous diagnostic criteria, several indices of quality of life) which, in turn, may established the efficacy of tricyclic agents, such as have important implications with respect to illness imipramine and desipramine,131–137 MAOIs,136,138,139 recurrence.22 the reversible monoamine oxidase inhibitor, moclo- Owing to dysthymia’s fluctuating and chronic nat- bemide,114,137,140–143 SSRIs, such as fluoxetine and ser- ure, several studies evaluated the efficacy of antide- traline,22,23,111,132,134,144–146 as well as other agents, such pressants in the maintenance treatment of the illness.

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 Desipramine Desipramine = placebo Harrison et al (1986)152 Phenelzine Phenelzine Ͼ placebo Kocsis et al (1988)133 Imipramine Imipramine Ͼ placebo Tyrer et al (1988)153 Doxepin Doxepin Ͼ placebo Stewart et al (1989)154,a Imipramine, phenelzine Imipramine Ͼ placebo; phenelzine = placebo; imipramine = phenelzine Costa-e-Silva et al (1990)155 Amisulpride Amisulpride Ͼ placebo Bersani et al (1991)148 Ritanserin Ritanserin Ͼ placebo Botte et al (1992)141,b Moclobemide Moclobemide Ͼ placebo Versiani et al (1992)137 Moclobemide, imipramine Moclobermide = imipramine Ͼ placebo Hellerstein et al (1993)144 Fluoxetine Fluoxetine Ͼ placebo Stewart et al (1993)136,a Imipramine, phenelzine Imipramine Ͼ placebo = phenelzine Versiani (1993)143 Moclobemide, imipramine Moclobemide Ͼ placebo; imipramine Ͼ placebo Bakish et al (1993)147 Ritanserin, imipramine Ritanserin = imipramine Ͼ placebo Kocsis et al (1994)134 Sertraline, imipramine Sertraline = imipramine Ͼ placebo Thase et al (1996)145 Sertraline, imipramine Sertraline = imipramine Ͼ placebo Vanelle et al (1997)146 Fluoxetine Fluoxetine Ͼ placebo Lecrubier et al (1997)156,a Amisulpride, imipramine Amisulpride = imipramine Ͼ placebo Versiani (1997)114,a Moclobemide, imipramine Moclobemide Ͼ placebo; imipramine Ͼ placebo Boyer et al (1999)157 Amisulpride, amineptine Amisulpride = amineptine Ͼ placebo Ravindran et al (1999)22 Sertraline Sertraline Ͼ CBT = placebo

Non-placebo-controlled Vallejo et al (1987)139 Imipramine, phenelzine Phenelzine Ͼ imipramine Baumhackl et al (1989)140,b Moclobemide, imipramine Moclobemide = imipramine Ravindran et al (1994)158 Fluoxetine 65% response Marin et al (1994)135,a Desipramine 70% response Friedman et al (1995)159,a Desipramine 61% response Kocsis et al (1996)160,a Desipramine 71% response Dunner et al (1996)23 Fluoxetine Fluoxetine = CBT Dunner et al (1997)150 Venlafaxine Ͼ70% response Keller et al (1998)132,c Sertraline, imipramine Sertraline = imipramine Santagostino et al (1998)161 Alprazolam 73% response Smeraldi (1998)162 Amisulpride, ﬂuoxetine Amisulpride = ﬂuoxetine Ravindran et al (1998)151 Venlafaxine 73% response

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

Kocsis et al166 indicated that the higher relapse rate in thymia, the results from these controlled clinical trials those dysthymic patients who were randomized to pla- are congruent with the proposition that antidepress- cebo exceeded that of patients who continued on the ants are effective for a substantial portion of dysthymic maintenance desipramine treatment. Paralleling these patients (primarily the subaffective variety), and that findings, symptom improvement was sustained, and prolonged maintenance treatment may be beneficial. the rate of relapse reduced, among dysthymic patients While most antidepressant trials have focused on the who were maintained on either trazodone or fluoxetine effects of 5-HT and NE manipulations on the symptoms over a 40-week interval compared to those who discon- of dysthymia and major depression, there have been tinued medication.167 Commensurate with the notion several studies implicating a role for dopamine (DA). that a long-standing illness, such as dysthymia, might Since DA has been thought to subserve reward pro- require prolonged pharmacotherapy, continuous cesses,168 and anhedonia is a characteristic feature of improvement was observed among dysthymic patients depression, the view has been taken that reduced DA treated over a 6-month period,146 while Kocsis et al160 activity might contribute to the depressive profound a substantially reduced rate of relapse (11%) file.104,169,170 It will be recalled, however, that in con- among dysthymic patients maintained on desipramine trast to major depression, anhedonia is not one of the over a 2-year period, relative to the 52% relapse rate fundamental symptoms of dysthymia according to the in the placebo group. Although these data do not DSM-IV criteria. Yet, it has been suggested that necessarily speak to the mechanisms subserving dys- anhedonia may be a cardinal feature of dysthymic indi-

Molecular Psychiatry Dysthymia J Griffiths et al 249 viduals.4 Unfortunately, there have been few studies related. The conclusions are clouded, however, by the that evaluated the effects of DA manipulations in dys- finding that there was a higher rate of pure major thymia. The administration of the selective D2 and D3 depression among the relatives of pure major depress- antagonist amisulpride, an agent most often used as an ive probands, as well as among the relatives of double antipsychotic when administered in high doses (400– depressives, than among normal controls. These inves- 1200 mg), has agonistic DA properties at low doses tigators suggested that dysthymia may be associated (50 mg), likely owing to preferential presynaptic bind- with two distinct etiological profiles. That is: (a) ing. Consistent with the proposition that DA may play increased vulnerability to depression occurs in all rela- a role in dysthymia, amisulpride was effective in atten- tives of unipolar depressive illness, irrespective of sub- uating the symptoms of both dysthymia and major type; and (b) that risk for dysthymia may be parti- depressive illness.154–156,169,171,172 In fact, amisulpride cularly notable among relatives of dysthymic patients was as effective as imipramine in alleviating depress- and those suffering from double depression. ive symptoms in dysthymia, and both agents were sig- The high comorbidity of dysthymia with personality nificantly better than placebo in this respect (Table 1). 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 dis- Genetic factors in dysthymia order (antisocial, borderline, histrionic, narcissistic) in Since the prevalence rates of various affective illnesses the proband, exhibited increased frequency of dysthy- differ in families with dysthymic, major depressive and mia with and without cluster B personality disorder, double depressive probands, it was suggested that dys- as well as cluster B personality disorder without dysthymia and major depression are independent dis- thymia. Thus, these results supported the notion that orders.2,47 While dysthymia may represent a trait factor dysthymia and cluster B personality disorder share predicting increased risk for major depression, it may etiological factors such as genetic or familial factors, or be important to distinguish between early- and late- early home environment.178 onset illness. In fact, while major depression and dys- The contribution of genetic factors to dysthymia thymia appear to be distinct illnesses, relatives of pro- prompted Akiskal6 to categorize patients, in part, on bands with early-onset depression were at increased the basis of genetic history. It was suggested that subaf- risk for both major depression and dysthymia.173 Like- fective dysthymics frequently had a family history of wise, Goodman and Barnhill174 reported the results of depression, whereas character spectrum dysthymics a study comparing the rates of dysthymia in relatives tended to have a significant family history of of probands with either panic disorder, major alcoholism/drug abuse, but not of depressive disorder. depression, or both conditions (a subset of 33 patients Partial support for Akiskal’s classification of subaffec- were also dysthymic). Increased rates of dysthymia tive vs character spectrum disorder was obtained from were observed in relatives of early-onset major depres- the finding that there was a higher rate of alcoholism sives, and among relatives of dysthymic probands, thus among the relatives of the character spectrum disorder supporting a relationship between early-onset major dysthymics, while the subaffective dysthymics exhib- depression and dysthymia. Unfortunately, the small ited higher rates of depressive symptoms, as well as number of subjects tested makes it difficult to discern personality and cognitive features.34 Unlike Akiskal’s whether the risk of dysthymia varies as a function of classification, however, these investigators did not early- vs late-onset of the disorder in the dysthymic observe differences between groups with respect to proband. Paralleling these findings, rates of major early home environment, family history of mood dis- depression in relatives of early-onset dysthymics com- orders, gender, or personality disorder. pared to relatives of controls, confirmed a familial Few studies have examined the genotypic expression association between dysthymia and major depression. of factors that might be related to dysthymia. However, It was also observed that relatives of the dysthymics it was demonstrated in a Japanese sample, that patients had higher rates of chronic depression than relatives diagnosed with depressive disorders exhibited higher of episodic depressives. Thus, there appears to be sup- rates of genotypes coding for low activity catechol-o- port for familial aggregation in dysthymia, as well as methyltransferase relative to non-depressed con- for the validity of dysthymia as a distinct diagnostic trols.179 Although only five dysthymic patients were category.175 represented in the sample, the results obtained were Donaldson et al176 found higher rates of dysthymia consistent with those observed in a larger set of major among relatives of pure dysthymics and of double depressive patients (n = 66) in this study. Of course, depressives, than among relatives of major depressive given the small number of subjects tested, these data probands and normal controls. Furthermore, the rates must be considered cautiously. Nevertheless, they are of pure dysthymia did not differ between relatives of suggestive of disturbances of enzyme activity related to pure dysthymics and those of double depressives, nor catecholamine function in dysthymic patients, just as did they differ between relatives of major depressive such effects may occur in major depressive disorder. and normal control probands. Once again, these data While the preceding studies supported a genetic con- are consistent with the notion that while dysthymia tribution to dysthymia, other studies challenged this may be distinct from major depressive disorder, dys- conclusion. For instance, monozygotic and dizygotic thymia and double depression may be more closely twins did not differ in their concordance rates for dys-

Molecular Psychiatry Dysthymia J Griffiths et al 250 thymic illness (7.4% vs 8.7% respectively) as they did reduced, and the reliance on maladaptive coping was with respect to major depression.180 It was concluded attenuated.187,188 It is unclear whether these effects that the shared or family environment may contribute reflect changes in appraisal processes and conse- more to the etiology of dysthymia than to major quently altered coping styles, or simply a proportionate depression. It was argued that severity of depression decline in the reliance upon emotion-focused coping. and early-onset of the illness may be aligned with a Of course, these data do not suggest that altered stress genetic association, while the milder depressive illness perception and coping were etiological factors in dys- spectrum (including dysthymia) may be more closely thymia, as they may simply have been correlates of tied to environmental factors. As the dysthymic the illness. patients were not subdivided into character spectrum Interestingly, in a prospective study of dysthymic vs subaffective, it is unclear from these data whether patients over a 9-month period, McCullough et al189 the conclusion applies to both subtypes equally. identified several features that distinguished the remit- ters from the nonremitters. Specifically, the nonremitters tended to exhibit a stable depressive attributional Psychosocial factors and stressors in major style and tended to employ inappropriate coping stra- depressive disorder and dysthymia tegies. Additionally, the nonremitters did not deal with There is considerable evidence supporting the conten- their major stresses effectively, and tended to use emotion that a relationship exists between stressful events, tion-focused coping (eg, wishing away their problems, coping deficits, and the development or exacerbation of blame) and social support seeking rather than a prob- major depressive disorder. These data have frequently lem-focused style. These individuals also displayed an been reviewed and thus will not be reiterated interpersonal style characterized by shyness and lack here.78,81,181 In view of the shared attributes between of sociability, coupled with submissiveness and com- dysthymia and major depression, it is somewhat sur- pliance. It was suggested that this profile represents a prising how little information is available concerning maladaptive behavioral pattern that predisposes the the contribution of stress to the provocation of dys- individual to the persistent nature of dysthymia. thymic disorder. However, inasmuch as dysthymia is While there is reason to suppose that stressful events a chronic illness, it may be difficult to identify specific contribute to the provocation of dysthymia, prospec- life events that precipitated illness onset. Nevertheless, tive studies have not been conducted to assess the con- it would not be unreasonable to propose that some tribution of life stressors to this illness. Several studies, adverse life events, particularly the inability to cope however, reported that stressful life events preceded with day-to-day annoyances, or alternatively chronic the onset of both neurotic and non-neurotic stressor experiences, may precipitate or aggravate the depression.190,191 Given the frequent early onset of dys- illness. thymia, coupled with its chronic nature, the paucity of Not unexpectedly, some stressors are conducive to prospective studies concerning the stressful ante- the provocation of depressive symptoms (eg, social cedents of the illness is not surprising. However, it was loss),78,182 whereas others are more closely aligned with reported that among adults who acted as care-givers for anxiety disorders (eg, threats or impending stress).183 a spouse with a progressive dementia (care-giving itself Although major life events often precede depression, is a profound stressor), the incidence of major the antecedents of affective illness may involve a series depression and dysthymia greatly exceeded that seen of minor stressors (day-to-day hassles). Indeed, these in a matched control sample.192 Thus, dysthymia, like stressors may have particularly profound effects when major depression, may be provoked by chronic uncon- applied onto a backdrop of major stressors.182,184 Of trollable stressor conditions. It remains to be estab- course, the potency of a stressor in promoting lished whether a chronic regimen of minor stressors depression may be related to characteristics of the would likewise be associated with dysthymic symp- individual, coupled with the nature of the stressor toms. encountered.78,185,186 Finally, as alluded to earlier, In addition to altered stress perception and coping acute stressors may have very different implications styles, perceived daily positive or uplifting events were than chronic predictable or chronic intermittent stres- reduced in dysthymic individuals relative to con- sors.182 Chronic intermittent stressors may not lend trols.187,188 This effect, however, was not limited to themselves to neurochemical adaptation and may be day-to-day uplift perception, but was also evident with most likely to result in behavioral disturbances.83,104 respect to several quality of life indices, including It has been reported that dysthymic patients, like social interaction, health perception, cognitive func- major depressives, perceived a markedly greater fre- tioning, alertness, energy/vitality, and life satisfaction. quency of day-to-day annoyances than did non- Among responders to treatment (either pharmaco- depressed subjects. In contrast, stressful life events therapy or group CBT), each of these quality of life were only marginally greater in the depressive groups. indices increased significantly.22,159,193–195 Studies that The elevated stress perception was accompanied by focused on social and interpersonal impairments like- coping styles wherein emotion-based strategies pre- wise indicated marked deficits among dysthymic dominated (eg, blame, emotional expression, emotional patients.22,159,193,196–199 These reports indicated that containment, avoidance/denial). With successful phar- social impairment correlated positively with increasing macotherapy, the elevated stress perceptions were severity and chronicity of the illness, and worsened

Molecular Psychiatry Dysthymia J Griffiths et al 251 with onset of double depression. In addition to allevi- perception and quality of life was observed. However, ating the depressive symptoms, antidepressants attenu- when these scores were assessed among treatment ated the social impairment characteristic of dysthymic responders, it was clear that uplift perception and patients. Markowitz et al200 demonstrated that acute quality of life scores approached or reached those of treatment (10 weeks) with desipramine significantly nondysthymic controls.22 improved interpersonal functioning in dysthymics, as As indicated earlier, it has been suggested that measured by the Inventory of Interpersonal Problems depressive illness, and particularly dysthymia, may be (IIP). While improvement continued over a 16-week a life-long disorder. Moreover, the high rate of recur- maintenance phase, this was not significant, and rence of major depressive disorder may stem from although the social impairment scores approached nor- undertreatment of the illness, as reflected by the per- mative values, they did not attain this level. Further to sistence of residual symptoms.20,205–207 It is similarly this point, life satisfaction and psychosocial func- possible that those treatments which permit residual tioning improved among dysthymics who responded to dysthymic features to persist (eg, inadequate anti- antidepressant treatment. Thus, it was posited that the depressant dosage or insufficient duration of treatment) reduced capacity to enjoy leisure time may be a state may also favor recurrence of this illness. It is certainly marker of chronic depression.131,159,201 conceivable that by virtue of its effects on the second- It is interesting that while significant improvement ary features of dysthymia, CBT may act to limit illness in quality of life was observed among dysthymic recurrence. Yet, as will be discussed later, the neuro- patients treated with either imipramine or sertraline chemical underpinnings of dysthymia may persist over 12 weeks,202 self-reported social functioning despite a positive treatment response, thus necessitat- showed greater improvement than did participation in ing sustained maintenance treatment. leisure activity. It was suggested that the delayed One further issue warrants some consideration. It has alleviation of certain aspects of psychosocial func- been observed that among dysthymic patients treated tioning may have been due to the relatively short dur- with sertraline, the reduction of clinician-rated ation of pharmacotherapy relative to the patients’ often depression scores (Hamilton Depression, Montgomery– life-long impairment. Further to this same point, it Asberg, and Cornell Dysthymia Rating Scales) was should also be considered that the well entrenched greater than among patients treated with group CBT. anhedonia and impaired psychosocial functioning The scores in the latter group were, in fact, no different among dysthymics may contribute to the unremitting from those of placebo-treated subjects. However, like nature of the illness. In this respect, it also appears that drug-treated patients who showed a positive treatment the response to desipramine was inferior among dys- response, the CBT patients who showed significant thymic patients characterized by the most pronounced clinical improvement also reported a marked increase overall social impairment and family dysfunction.131 of quality of life. In contrast, no such increase was Despite the fact that antidepressant treatment dimin- apparent in placebo responders (ie, their quality of life ished the functional impairments characteristic of dys- was comparable to treatment nonresponders). Thus, thymic patients, it is of particular interest that the despite the comparable clinical depression scores, the stress profile, although improved, continued to show functional effects of drug treatment, CBT, and placebo significant residuum. For instance, while antidepress- were readily distinguishable. Given that quality of life ant medication was associated with reduced daily has- changes may be a fundamental characteristic in ident- sle perception, increased uplift perception, diminished ifying the efficacy of treatment response,22 such a func- reliance on emotion-focused coping styles, and tional measure may also be useful in distinguishing reduced feelings of loneliness, none of these behavioral genuine drug responders from drug-treated patients parameters had returned to levels of nondepressed sub- actually exhibiting a placebo-like response, and thus jects.188 Similarly, Klein et al203 reported that ado- may prove to be a valuable tool in predicting relapse. lescents with a history of dysthymia displayed persistent perception of increased daily hassles, difficulties Cytokines and depressive illness in psychosocial functioning, and residual symptoms of depression. Finally, although improvement of psycho- Increasing evidence has indicated that depressive ill- social functioning was apparent among chronic ness is accompanied by immune dysregulation. While depressive patients within 4 weeks of sertraline or it had typically been assumed that depression pro- imipramine treatment, the level of functioning typi- moted immunosuppression, it has been argued that the cally did not reach that of a community control popu- compromised immunity may actually be secondary to lation.204 However, among those patients who dis- an initial immune activation. Furthermore, this notion played full remission, psychosocial functioning was has led to the possibility that products of an activated comparable to that of a community sample. Thus, it immune system may come to promote central neuro- appeared that in some chronically depressed patients, chemical changes, hence provoking depressive symp- antidepressant medication effectively alleviated the toms.208 Commensurate with this view, depressed functional psychosocial disturbances. Indeed, it was patients exhibited signs of immune activation, includ- recently observed that among patients who received ing increased plasma concentrations of complement either sertraline, CBT, or a combination of the two proteins, C3 and C4, and immunoglobulin (Ig) M, as treatments, only a modest overall elevation of uplift well as positive acute phase proteins, haptoglobin, ␣1-

Molecular Psychiatry Dysthymia J Griffiths et al 252 antitrypsin, ␣1 and ␣2 macroglobulin, coupled with depression were secondary to the neurovegetative fea- reduced levels of negative acute phase proteins. Also, tures of this depressive subtype. However, animal stud- depression was accompanied by an increased number ies have shown that IL-1␤ provokes some symptoms of activated T cells (CD25+ and HLA-DR+), secretion of characteristic of atypical depression (including, neopterin, prostaglandin E2 and thromboxane. Fur- increased sleep and fatigue),99 and thus it is just as thermore, it appears that depression may be associated likely that elevated circulating IL-1␤ contributes to the with variations of either circulating cytokine levels (ie, neurovegetative features of this depressive subtype. cell signalling factors released from activated The finding that illnesses involving atypical depressive macrophages), or cytokine production from mitogen- features (eg, chronic fatigue syndrome) may be associa- stimulated lymphocytes, including interleukin-2 (IL-2), ted with HPA disturbances (eg, reduced plasma cor- soluble IL-2 receptors (sIL-2R), IL-1␤, IL-1 receptor tisol, increased ACTH, and reduced ACTH release fol- antagonist (IL-1Ra), IL-6, soluble IL-6 receptor (sIL-6R), lowing oCRH challenge),221,222 coupled with the fact and ␥-interferon (IFN).209–216 While there have been that IL-1␤ is a potent stimulator of CRH release,223,224 reports that the elevated levels of IL-1␤, IL-6 and ␣1- raises the possibility that elevated circulating IL-1␤ acid glycoprotein normalized with antidepressant levels contribute to the pathophysiology of atypical medication,217 the unregulated production of sIL-2R, depressive symptoms. IL-6 and sIL-6R was not attenuated with antidepressant In support of the immune activation view of depress- agents, leading to the suggestion that the latter factors ive illness, Maes225 indicated that in addition to the 208 may be trait markers of the illness. altered cytokine, acute phase protein, and hormonal Although severity of depressive illness is likely fun- changes ordinarily elicited as part of the inflammatory 208 damental in determining cytokine levels, the possi- response, elevations of IL-1␤ may be evident in bility cannot be ignored that chronic depression (or depression associated with a variety of medical ill- chronic stress) may induce cytokine changes to a nesses. These include not only infectious diseases greater extent than those observed following acute epi- (influenza, herpes virus, HIV, Borna virus), but also sodes (as in the case of major depression). Consistent 208 numerous noninfectious illnesses, such as neurodegen- with reports in melancholic patients, levels of erative disorders, autoimmune disorders and brain mitogen-stimulated IL-1␤ production were enhanced 61,225 55 injury. Thus, it was suggested that the cytokine in dysthymia. However, in this particular study, IL- activation associated with these illnesses and/or injur- 1␤ production was stimulated by the T cell mitogen, ies may have provoked variations of HPA activity, as phytohemagglutinin (PHA), and thus may have well as central neurochemical alterations, which may reflected primarily T cell rather than macrophage-pro- then have favored the development of depression. In duced IL-1␤. While not excluding the possibility that effect, these comorbid conditions may have contrib- illness severity may be a pertinent feature in promoting uted to the illness owing to the cascade of cytokine, the enhanced IL-1␤ production, it seems likely that ill- hormone and transmitter alterations engendered. It ness chronicity or age of onset may also be important will be recalled that dysthymia likewise is associated in this respect. Indeed, it was observed that age of onset with a large number of comorbid conditions, such as was inversely related to IL-1␤ production, while dur- neurodegenerative disorders,1,61 traumatic brain ation of illness was directly related to production of 62 this cytokine. Additionally, the altered IL-1␤ pro- injury, and illnesses potentially involving viral components, such as fibromyalgia syndrome and duction was evident irrespective of whether a typical 53,54 or atypical (reversed neurovegetative) profile was evi- chronic fatigue syndrome. As such, the possibility dent. Thus, it is unlikely that the altered cytokine pro- ought to be considered that such coexisting illnesses duction was related to the neurovegetative alterations are not simply correlates of the mood disorder, but may that may appear in depression. It might be noted, as actually act to either precipitate or aggravate dysthymia. well, that IL-1␤ production was not markedly reduced The data presently available concerning cytokine with the alleviation of dysthymic symptoms following changes in depressive illness (ie, studies showing elev- 12 weeks of SSRI treatment.55,218 However, given that ations of the cytokines in severe major depression) are dysthymia is a long-standing illness, it is certainly largely correlational. Thus, it is unclear whether the possible that more prolonged treatment would have cytokine alterations seen in affective disorders are sec- been necessary to realize changes of IL-1␤, just as rela- ondary to the illness (or the stress associated with the tively protracted treatment was previously reported to illness), or play an etiological role in the provocation of promote variations of circulating natural killer cells.219 the disorder. Yet, administration of high doses of IL-2, In contrast to the elevated IL-1␤ in supernatants of IFN-␣ and tumor necrosis factor-␣ (TNF-␣) in humans mitogen-stimulated lymphocytes, we observed that cir- undergoing immunotherapy have been shown to culating serum IL-1␤, presumably derived from macro- induce neuropsychiatric symptoms, including phages and T cells, was not increased in either typical depression, and these effects were related to the cyto- major depressive or in dysthymic patients. However, kine treatment rather than to the primary illness.226–229 among atypical major depressive patients, circulating Of course, the doses administered in these studies were IL-1␤ levels were greatly increased, and normalized in the pathophysiological range, and thus their rel- with treatment response.220 It could be assumed that evance to depression per se must be interpreted cau- the elevated levels of serum IL-1␤ in atypical tiously. However, as indicated by Meyers,230 even

Molecular Psychiatry Dysthymia J Griffiths et al 253 when administered at relatively low doses, cytokines response, while the latter, presumably, entails the such as IFN-␣ may elicit depressive-like symptoms. appraisal of the stressor situation.238 While the model developed by Post and Weiss231 was meant to accommodate recurrent depression, it may A provisional model of chronic depressive illness also be applicable to the analysis of dysthymia. In this respect, however, it is important to underscore that It is clear from the preceding sections that limited data sensitization effects are not limited to the neuroendo- are available concerning the mechanisms underlying crine factors discussed by Post, nor is such a sensitiz- dysthymia. Because of dysthymia’s chronic, low-grade ation limited to antecedent stressors. In fact, it has been nature, animal models of the illness have yet to be demonstrated that several neurochemical alterations developed. Nevertheless, data derived from animal associated with stressors, psychostimulant use studies offer some clues as to the potential persistent (amphetamine and cocaine), and electrical stimulation effects of stressor experiences that may be relevant to of the amygdala or the piriform cortex, may perma- dysthymia. In particular, it seems that in addition to nently enhance the neuronal response to subsequent any immediate consequences, stressors may also pro- manipulations (sensitization).239 As will be seen actively influence the neurochemical response to sub- shortly, this applies to the effects of cytokine treat- sequently encountered aversive stimuli (sensitization), ments as well. hence favoring long-term behavioral repercussions. In modelling dysthymic disorders, several features of Post and Weiss231 indicated that although the vari- this illness need to be considered, and it is important ations of certain peptides persist for relatively brief to distinguish these from other types of depression. periods following a single stressor session, with Depressive disorders may be associated with profound repeated challenges the release of some peptides will interindividual differences in the symptoms sub- be more readily induced and will be more persistent serving the illness, the response to pharmacotherapy, (eg, CRH, and to a greater extent TRH). It was suggested as well as the neuroendocrine correlates of the dis- that depressive illness may initially stem from the neu- order. Further, subtypes of depression may differ in roendocrine alterations provoked by a stressor. How- terms of their response to specific pharmacological ever, with each subsequent stressor experience, or with treatments, and with respect to their neuroendocrine each episode of depression, the sensitization becomes factors. For instance, major depression is characterized more pronounced, such that progressively less intense by HPA alterations, including elevated plasma ACTH psychosocial stressors are required to provoke the and cortisol levels, nonsuppression of cortisol release onset of a depressive episode. Ultimately, episodes of following dexamethasone challenge, and a blunted depression may occur in the absence of obvious stress ACTH response to CRH challenge.222,240 While limited triggers. In fact, it was reported that unlike the initial data are available, it appears that in illnesses involving episode, recurrence was less likely to be preceded by atypical features (eg, bulimia, seasonal affective dis- antecedent stressors196,232 and even occurred spon- order, and chronic fatigue syndrome) the elevated taneously.233,234 Of course, it is often difficult to ident- ACTH levels are accompanied by reduced cortisol, a ify significant or meaningful stressors that may be per- blunted ACTH response to CRH challenge,221,222,240,241 tinent to a given individual, thus conclusions and absence of the CRH hypersecretion characteristic concerning the presence or absence of stressful precipi- of typical depression.240 Among dysthymic patients the tants of depression may be difficult to validate. It is profile is different yet again, and as indicated earlier, also conceivable that in addition to stressors of a there is reason to believe that cortisol levels may actu- psychological nature, a physiological stressor, such as ally be reduced,4 although a contradictory finding has a virus, may be interpreted by the CNS in the same way been reported with respect to plasma cortisol and CRH as a psychosocial stressor, hence triggering the cascade concentrations.242 Moreover, in response to a stressor of events resulting in neuroendocrine, cytokine, and challenge, the cortisol response may be minimal in mood alterations.235 dysthymic patients relative to that seen in other types Although it is often thought that HPA disturbances of depression and in nondepressed subjects.112 It are likely only a reflection of depression, it has been remains to be established whether subaffective and proposed that alterations of HPA activity could be the character-spectrum dysthymia can be distinguished on primary abnormality in depression, rather than simply the basis of these parameters. In any event, in provid- an illness response.236,237 Moreover, it has been sug- ing a model of the mechanisms subserving dysthymia gested that among biologically predisposed individ- it needs to be understood why this disorder is not asso- uals, chronic stressors may come to promote sustained ciated with cortisol abnormalities like those seen in HPA activation which leads to adverse effects.74 As major depressive illness. Furthermore, with respect to alluded to earlier, the view has even been offered that double depression, it would be of obvious benefit to the monoamine variations often associated with determine why, following successful treatment, depression may actually stem from endocrine alter- patients typically return to their dysthymic states ations.236,237 In this respect, it was suggested that stress- rather than to an euthymic state. ful events promote CRH variations in the central amyg- The sensitization model described earlier introduces dala, which in turn may affect forebrain serotonin an important facet of stressor actions that may be rel- alterations. The former may reflect a basic stress- evant to understanding the relationship between

Molecular Psychiatry Dysthymia J Griffiths et al 254 stressor-induced neurochemical alterations and more sustained, variable, and probably less intense chronic depressive illness. Tilders and his associ- stressors, coupled with the use of inadequate or inap- ates243–246 indicated that in response to repeated propriate methods of coping, culminating in the stressor experiences, or with the passage of time fol- phenotypic CRH/AVP coexpression. Thus, it would lowing a stressor or IL-1␤ challenge,247 phenotypic not be altogether surprising to find that double variations may occur within hypothalamic neurons depression may be related to the superimposition of a that are ordinarily responsive to stressors. In particular, further stressor on the backdrop of dysthymia, which increased coexpression of CRH and AVP was observed would then promote the increased release of these pep- within CRH containing neurons originating in the para- tides (and the ensuing neurochemical cascade). Given ventricular nucleus (PVN) and having terminals in the this scenario, it might further be expected that after external zone of the median eminence. As the co- treatment of double depression, the CRH/AVP co- released peptides act synergistically to promote ACTH expression would persist and hence the dysthymic pro- secretion, the chronic stressor regimen increases the file would be maintained. In these individuals the risk potential for elevated HPA functioning.243,246 It is of for further major depressive episodes would, of course, particular significance, as well, that the altered co- be heightened. In effect, we are suggesting that dysthy- expression of CRH and AVP was exceptionally long mia may reflect a chronic state of altered endocrine and lasting, and was even evident as long as 60 days follow- central neurotransmitter functioning which may be ing stressor exposure. related to sustained stressor experiences together with Given the chronic nature of dysthymia, characterized inadequate coping. Indeed, even with the remission of by increased stress perception and inadequate coping symptoms, the persistent neuropeptide disturbances styles, it is conceivable that this illness would be would increase the likelihood of symptom recur- accompanied by the neuroendocrine characteristics rence.249 Obviously, it would be of particular interest to ordinarily associated with chronic stressors. For establish whether the alleviation of double depressive instance, dysthymia may be associated with increased symptoms would be accompanied by abnormal CRH and AVP coexpression within the external zone responses to CRH challenge, and whether such an of the median eminence, as occurs with chronic stres- effect differed from that seen following recovery from sors,246 and this may represent a permanent (or a major depressive episode. These factors, coupled persistent) characteristic. The fact that dysthymic with the long standing nature of the disorder, and the patients do not exhibit increased ACTH and cortisol, comorbid features discussed earlier, may necessitate a however, raises the possibility that the protracted more sustained regimen of pharmacotherapy. More- CRH/AVP may have given rise to the down-regulation over, given the personality disturbances and the malad- of pituitary and adrenal sensitivity. Clearly, this aptive cognitive coping strategies characteristic of dys- suggestion is highly speculative given that experiments thymia, in the absence of cognitive therapy or have not been performed to assess, in detail, the psychotherapy (as adjunctive or maintenance characteristics of HPA functioning in dysthymic treatment) susceptibility to recurrence of illness may patients. Since an abnormal DST response has typi- be increased. Indeed, we have shown previously that cally not been noted in dysthymia, it was taken for in spite of clinical improvement following pharmaco- granted that this illness is not accompanied by any therapy, functional disturbances (as reflected by HPA disturbances. Yet, it may be the case that dysthy- compromised quality of life, anhedonia) may persist in mia is associated with adrenal hypofunctioning (as dysthymia. It was hypothesized that these residual fea- observed in atypical depression), rather than the hyper- tures may actually be predictive of illness recurrence functioning seen in major depressive disorder.4 There following cessation of pharmacotherapy.22 are few neuroendocrine studies, however, that In relating stressful events to the mechanisms under- observed distinctive differences between dysthymic lying dysthymia, we have defined stressors in a fairly and non-depressed subjects. In part, this may stem broad way. As discussed earlier, it has been posited from the subtle pathophysiological disturbances in that, among other things, the immune system acts like dysthymia, and the use of neuroendocrine analyses a sensory organ informing the brain of antigenic chal- that tap circulating hormonal levels rather than the lenge.250,251 Furthermore, given the nature of the neuro- dynamic, temporal patterns of hormone release.1 Also, chemical changes elicited by antigens and cytokines, it assessment of HPA functioning in dysthymia requires was suggested that immune activation may be inter- evaluation of the effects of various challenges (eg, preted by the CNS as a stressor.44,223,235,251 To be sure, ACTH, CRH, AVP, as well as serotonergic acting the effects of systemic stressors (eg, those associated agents) in order to identify the nature of any dysregul- with viral insults, bacterial endotoxins, cytokines) are ation that may exist.107,248 Further, it is essential to not entirely congruous with those elicited by pro- evaluate these processes independently in the charac- cessive stressors (ie, those involving higher order sen- ter-spectrum and subaffective variants of the illness. sory processing).252 Nevertheless, cytokines may be Inasmuch as dysthymia is a chronic illness, often of part of a regulatory loop that, by virtue of their effects mild-moderate severity and typically without clear on CNS functioning, might influence behavioral out- precipitating events, it is unlikely that it is related to puts and may even contribute to the symptoms of a single strong stressor experience. It is more reason- behavioral pathologies, including mood and anxiety- able to speculate that dysthymia reflects the actions of related disorders.44,235,253 It is certainly the case that

Molecular Psychiatry Dysthymia J Griffiths et al 255 both processive and systemic stressors effectively ing, however, that studies in rodents have indicated increase HPA activity. However, while processive that early life maternal deprivation may give rise to a stressors do so via limbic circuits, the HPA alterations cascade of neurochemical alterations much like those elicited by systemic stressors may result from limbic- purported to occur in dysthymia. These include independent processes.245 Yet, it ought to be under- increased CRH mRNA expression in the amygdala and scored that systemic stressors, including IL-1␤, IL-2 CRH concentrations in the median eminence, as well and TNF␣ have all been shown to influence central as increases of CRH receptors in the prefrontal cortex, monoamine activity at both hypothalamic and extra- amygdala, hypothalamus and cerebellum. As adults, hypothalamic sites, including hippocampal 5-HT rats that had undergone maternal deprivation display activity, as well as that of NE and DA in hypothalamus, increased stress-elicited arousal and elevated HPA locus coeruleus and mesolimbic regions.235,254–256 functioning.258,259 The possibility ought to be explored Thus, the possibility exists that cytokine elevations, by that in humans, early-life stress or ‘neglect’ may give virtue of these monoamine effects, may come to pro- rise to these neurochemical disturbances, hence mote or exacerbate depressive disorders, quite apart increasing vulnerability to later stressor-induced neur- from any actions involving the HPA axis. It remains oendocrine and neurotransmitter alterations and ulti- to be determined whether the IL-1␤ variations seen in mately the dysthymic profile. Of course, the failure to dysthymia are secondary to the illness or, in fact, play establish appropriate coping strategies (and this an etiological role. Yet, as indicated earlier, this cyto- includes affiliation, attachment and support systems, kine provokes behavioral changes, some of which are particularly with parents) may augment stressor reminiscent of the characteristics of atypical effects, thereby encouraging the development of dys- depression, including increased sleep, lethargy and thymia. reduced locomotor activity,257 and may provoke anxi- Finally, the identification of subtypes of dysthymia ety.235 Given that the production of IL-1␤ in mitogen- may be an important feature in determining the opti- stimulated lymphocytes is greater among dysthymic mal treatment strategy employed. From the outset, it than among major depressive patients, particularly in must be acknowledged that because dysthymia is a those reporting early onset of the illness,55 the possi- chronic condition, relatively sustained treatment may bility exists that dysthymia may be associated with be required to alleviate the symptoms.260 Thus, drugs excessive cytokine reactivity. Increased IL-1␤ acti- that are relatively well tolerated will be most effi- vation would then stimulate CRH functioning, and the cacious in treatment, particularly when these agents do ensuing neuroendocrine cascade. In effect, it may be not elicit sexual dysfunction or somatic complaints, that in dysthymic patients, stressors in the form of viral symptoms which themselves typically are not charac- or bacterial challenges, may be particularly potent in teristic of dysthymia.18 Further, it is likely, as indicated provoking major depressive symptoms and hence pro- earlier, that the effectiveness of various treatment stra- moting double depression. tegies 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 asso- Concluding remarks ciated with neuroendocrine disturbances (eg, reduced The paucity of data from human studies, coupled with cortisol secretion secondary to excessive CRH the lack of a suitable animal model for dysthymia, have activation) may offer insights into whether pharma- limited the conclusions that can be drawn concerning cotherapy (and the type of agents used) would be most the etiology of this disorder. Nevertheless, the available efficacious in treating the disorder. Of course, family data have made it clear that elucidation of the mech- history of psychiatric illness and the effectiveness of anisms underlying dysthymia, and the development of specific pharmacotherapy therein, would be of obvious adequate treatment strategies, will require that several value in planning a treatment strategy. Finally, it ought fundamental features be included in experimental to be underscored that the effectiveness of cognitive analyses. Foremost in this respect is the need to sub- therapy has not been extensively evaluated in dys- type subjects according to definite criteria. In parti- thymic patients. Nevertheless, it would appear that this cular, it will be of obvious advantage to distinguish therapeutic modality may be useful in treating some between pure dysthymia, double depression, and other dysthymic patients. It remains to be established what forms of chronic depression. Additionally, patients characteristics of the illness might be predictive of need to be characterized into homogeneous subgroups those patients who would benefit most from this form (eg, early- vs late-onset; subaffective vs character- of therapy. In this respect, it may be useful to consider spectrum), and the symptom profile of the dysthymic functional parameters related to quality of life (eg, cog- patients ought to be considered (vis-a`-vis the presence nitive disturbances, social interaction, life satisfaction), of typical or atypical neurovegetative symptoms). as opposed to relying simply on clinical indices of Although genetic factors likely contribute to the depression. Given the particularly high rate of relapse expression of dysthymia, there is also reason to believe in dysthymia upon cessation of pharmacotherapy,18 the that experiential factors play a cogent role in this possibility ought to be considered that cognitive ther- respect. There is no information, however, as to apy, particularly when focusing on residual functional whether early-life experiences contribute to the bio- disturbances, would be useful as an adjunctive or logical (subaffective) type of dysthymia. It is interest- maintenance treatment strategy.

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Molecular Psychiatry