dysthymia clinical picture, extent of overlap with chronic fatigue.pdf

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Journal of Affective Disorders 52 (1999) 275290

Special article

Dysthymia: clinical picture, extent of overlap with chronic fatiguesyndrome, neuropharmacological considerations, and new

therapeutic vistas

a ,b , c d e f g*N. Brunello , H. Akiskal , P. Boyer , G.L. Gessa , R.H. Howland , S.Z. Langer ,h j k a ,m l

J. Mendlewicz , M. Paes de Souza , G.F. Placidi , G. Racagni , S. WesselyaCenter of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy

bDepartment of Pharmaceutical Sciences, University of Modena, Modena, Italy

cDepartment of Psychiatry, University of California, San Diego, CA, USA

dINSERM, Paris, France

eDepartment of Neuroscience, University of Cagliari, Cagliari, Italy

fWestern Psychiatric Institute and Clinic University of Pittsburgh, Pittsburgh PA, USA

gSynthelabo Recherche, Bagneux, France

hDepartment of Psychiatry, Erasme Hospital, University of Brussels, Brussels, Belgium

jHospital Santa Maria, Lisbon, Portugal

kInstitute of Psychiatric Clinic, University of Pisa, Pisa, Italy

lDepartment of Psychological Medicine, Kings College Hospital, London, UK

mI.R.C.C.S. Centro San Giovanni di Dio Fate benefratelli, Brescia, Italy

Received 17 November 1997; received in revised form 12 August 1998; accepted 18 September 1998

Abstract

Dysthymia, as defined in the American Psychiatric Association and International Classification of Mental Disorders, refers

to a prevalent form of subthreshold depressive pathology with gloominess, anhedonia, low drive and energy, low self-esteem

and pessimistic outlook. Although comorbidity with panic, social phobic, and alcohol use disorders has been described, the

most significant association is with major depressive episodes. Family history is loaded with affective, including bipolar,

disorders. The latter finding explains why dysthymia, especially when onset is in childhood, can lead to hypomanic switches,

both spontaneously and upon pharmacologic challenge in as many as 30%. Indeed, antidepressants from different classes tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase A

(RIMAs), selective serotonin-reuptake inhibitors (SSRIs) and, more recently, amisulpride, and spanning noradrenergic,

serotonergic as well as dopaminergic mechanisms of action have been shown to be effective against dysthymia in an

average of 65% of cases. This is a promising development because social and characterologic disturbances so pervasive in

dysthymia often, though not always, recede with continued pharmacotherapy beyond acute treatment. Despite symptomatic

overlap of dysthymia with chronic fatigue syndrome especially with respect to the cluster of symptoms consisting of low

drive, lethargy, lassitude and poor concentration neither the psychopathologic status, nor the pharmacologic response

*Corresponding author. Tel: 1 39-2-20488331; fax: 1 39-2-29403673.

E-mail address: [email protected] (N. Brunello)

0165-0327/ 99/ $ see front matter 1999 Elsevier Science B.V. All rights reserved.

P I I : S 0 1 6 5 - 0 32 7 ( 9 8 ) 0 0 1 6 3 - 3


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276 N. Brunello et al. / Journal of Affective Disorders 52 (1999) 275290

profile of the latter syndrome is presently understood. Chronic fatigue today is where dysthymia was two decades ago. We

submit that the basic science clinical paradigm that has proven so successful in dysthymia could, before too long, crack

down the conundrum of chronic fatigue as well. At a more practical level, we raise the possibility that a subgroup within the

chronic fatigue group represents a variant of dysthymia. 1999 Elsevier Science B.V. All rights reserved.

Keywords: Dysthymia; Neurasthenia; Chronic fatigue syndrome; Neuropharmacology

1. Introduction 2. Spectrum of subsyndromal, dysthymic, and

major depressions

Although the roots of what today we calldysthymic disorder (American Psychiatric Associa- The core clinical manifestations of dysthymia

tion, 1994) go back into nineteenth century continen- consist of gloominess, anhedonia, low drive and

tal European psychiatry (Brieger and Marneros, energy, low self-confidence and pessimism (Akiskal,

1997), systematic research on the psychopathology 1983b). As such, dysthymia differs from melancholia

and treatment of this disorder has been accomplished characterized by profound disturbances in psychomo-

only during the past two decades (Akiskal et al., tor and vegetative functions. This is a familiar

1980; Akiskal and Cassano, 1997). This consensus classical dichotomy in depression contrasting endog-

statement summarizes current knowledge of this enous and neurotic depression. As opposed to the

disorder and emerging data on its treatment. episodic full-syndromal course of endogenous de-

Several documents have recently appeared on the pression, neurotic depression pursues a more fluc-

clinical picture and advances in the pharmacotherapy tuating low-grade course (Akiskal et al., 1978). Until

of this disorder (Burton and Akiskal, 1990; WPA 1980, patients in the latter group were considered asDysthymia Working Party, 1995; Kocsis and Klein, suffering from a character neurosis. Because of the

1995; Lecrubier and Smeraldi, 1996; Akiskal and frequently chronic nature of their condition, their

Cassano, 1997). The present statement goes beyond entire existence seemed immersed in melancholy,

these documents to address new developments on the hence they were also often subsumed under the

relationship of dysthymia to other disorders within rubric of existential depression. The thesis that

the affective spectrum, biochemical considerations of these chronic neurotic conditions represented sub-

the rationale for the pharmacotherapy of dysthymia, threshold or subaffective expressions initially came

including the possible relevance of the dopamine from studies conducted at the University of Tennes-

system to the core pathology of dysthymia; we also see at Memphis (Akiskal et al., 1980), demonstrating

consider chronic fatigue syndrome and its treatment sleep EEG findings, pharmacological response pro-

and whether it fits into the concept of an affective file, and family history patterns similar to those ofspectrum. major affective disorders for a large proportion of

The term consensus as used herein does not these patients, justifying their inclusion as a form of

necessarily imply that the authors of this document mood disorder under the rubric of dysthymia

agreed on all fronts. We felt that the time was ripe ( 5 bad humor or mood). Many of these patients had

and auspicious to delineate provocative links be- insidious onset in late childhood, but developed

tween basic neuropharmacology and clinical practice major affective episodes postpubertally and in young

in the domain of dysthymia, but not to the exclusion adulthood (Kovacs et al., 1994). Such data further

of a discussion of discrepant findings in the litera- testified to the affective origin of dysthymic disorder.

ture. Other studies have demonstrated the existence of a


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N. Brunello et al. / Journal of Affective Disorders 52 (1999) 275290 277

pattern of chronicity that results from failure of

recovery from major depressive disorders without

antecedent dysthymia (Akiskal, 1982). In the NIMH

Collaborative Depression Study (Keller et al., 1983),

the joint pattern of dysthymic and major depressivedisorders has been described as double-depressive.

Pharmacological studies (Stewart et al., 1988; Ravin-

dran et al., 1995; Kocsis et al., 1997) demonstrating

efficacy of various antidepressants for this spectrum

of disorders have also revealed significant benefits in

improving the social and interpersonal impairments

which characterize these patients, further justifyingFig. 1. Relationship of dysthymia to other affective spectrum

the primary nature of the mood disturbance inconditions.

dysthymia.

Related developments stemming from observa-

tions in US and Swiss epidemiological samples We lack the definitive studies regarding whether(Weissman et al., 1988; Angst et al., 1990), medical we are dealing with one or more spectra of disorders.

settings (Wells et al., 1989), and the inter-episodic What is clear is that the heterogeneity of depressive

phase of major depressive disorder (Judd et al., disorders can no longer be sub-classified on the basis

1994), have demonstrated the existence of a preva- of the severity of the clinical symptomatology. That

lent group of less-than-dysthymic subthreshold de- is, depressive symptoms of varying severity seem to

pressions which have been dubbed minor, or constitute the fluctuating life course of many depres-

subsyndromal symptomatic. Like dysthymia, these sive disorders, ranging from brief and subsyndromal

conditions are associated with impairment and are at to dysthymic and major episodic or visa versa

risk for developing major depressive disorders during (Akiskal, 1983a). This is shown in Fig. 1.

prospective observation. Briefer depressions of a few Dysthymia can thus pursue a course with a

days duration, which nonetheless recur at a severe double depressive pattern, fluctuating in and out of

symptom level, have also been more recently de- major depression, or pursue a relatively independentscribed (Angst et al., 1990) and appear to belong to a course of pure dysthymia. The former constitutes

broad affective spectrum. two-thirds of dysthymias in psychiatric settings and

Genetic models (Kendler et al., 1992) that have the latter two-thirds of subjects in community and

explored the relationship between narrowly and general medical settings (Weissman et al., 1988).

broadly defined affective phenotypes suggest that the Curiously, the ICD-10 (1992) concept of dysthymia

two lie on a continuum or spectrum. Comorbidity of is closer to community cases where superimposed

dysthymia with such conditions as panic disorder, major depression, if any, is mild and uncommon;

social phobia, alcohol abuse (just to name a few) is DSM-IV (American Psychiatric Association, 1994),

not uncommon (Markowitz et al., 1992; Akiskal, by contrast, liberally permits the double depressive

1994). More often than not, dysthymia is chronologi- pattern of dysthymia fluctuating in and out of major

cally the primary disorder in such comorbid cases depression. Both manuals agree, however, that low-(Lewinsohn et al., 1991). Indeed, follow-up of low- grade depression woven into the habitual self of the

grade depressive symptoms of dysthymia represent patient represents the essence of dysthymia, whether

powerful prospective risk factors for major depres- or not major depressions supervene.

sion in adults (Broadhead et al., 1990; Horwath et

al., 1992) and children (Kovacs et al., 1994). Finally,

ongoing studies in San Diego (Judd et al., 1998) 3. Relationship of dysthymia to the bipolar

show that subsyndromal symptomatology of a spectrum

dysthymic nature represents the modal lifetime con-

dition of a patient with depressive illness. Although both DSM-IV and ICD-10 specifically


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preclude a diagnosis of dysthymia in cases compris- and bipolar spectrum disorders is further suggested

ing the occurrence of previous manic, mixed, hypo- by reports of brief hypomanic switches after antide-

manic episodes or a cyclothymic disorder, systematic pressant therapy (Rosenthal et al., 1980) or sleep

clinical observation, and family and prospective deprivation (Rihmer, 1990), or even occurring

studies in adults and children have provided growing spontaneously (Klein et al., 1988). In addition, theevidence of subtle links between dysthymia and studies of Kovacs et al. (1984a), (1984b); Kovacs

bipolar spectrum disorders. and Gastsonis (1989) on depressive disorders in

As early as 1978, a prospective follow-up study by childhood appear to substantiate the link between

Akiskal et al. demonstrated that neurotic depres- dysthymia and bipolar spectrum disorder. In chil-

sives developed major depressive episodes, half of dren, dysthymic disorder was associated with a

which converted to bipolar II Akiskal et al., 1978. In greater risk of developing major depression as well

their subsequent studies of a large cohort of chronic as bipolar disorder with hypomanic, manic or mixed

neurotic depressives, these authors postulated the episodes (Kovacs et al., 1994).

existence of subaffective dysthymic disorders as Cassano and Savino (1993), compared a group of

chronic intermittent subsyndromal manifestations of dysthymics with a group of chronic major depres-

primary major affective illness, many of which sives on the basis of clinical and demographicrespond to antidepressants, and in selected cases, to characteristics, affective temperamental dysregula-

lithium (Akiskal et al., 1980, 1981). Nearly a third of tions, and first-degree family history. Dysthymic

these subaffective patients were postulated to lie on a patients differed from major chronic depressives in

nosological continuum with soft bipolar disorders showing an earlier age at onset and index age,

because of hypomanic switches on antidepressant subsyndromic features, a lower incidence of pre-

pharmacotherapy as well as bipolar family history. morbid affective temperament, and similar rates of

Other clinical studies on neurotic, characterologi- bipolar family history. These features were found to

cal or masked depression have also suggested a be closer to bipolar major depression than to unipolar

relationship between low-grade depressive pathology depression, justifying the claim by Akiskal et al.

and bipolar spectrum disorders (Eastwood and (1980) that as many as a third of patients with

Stiasny, 1978; Stone, 1978; Rihmer et al., 1983; dysthymia might belong to the bipolar spectrum.

Bronisch et al., 1985). The current controversies surrounding theFindings on patterns of familial aggregation in the nosologic status of dysthymia pertain to dimensional

relatives of probands with dysthymia have shown vs. categorical classification of depressions on the

high rates of mood disorders (Rosenthal et al., 1980; one hand, and the unipolarbipolar dichotomy on the

Angst and Wicki, 1990; Murphy and Checkly, other (Akiskal, 1983b). Dysthymia reflects these

1990): a family history of bipolar disorder was controversies in that it represents a possible trait or

reported in a higher percentage of patients with dimensional (constitutionally-based) depression on

dysthymia than with unipolar major depression the one hand, and a subsymptomatic depressive

(Rosenthal et al., 1980; Kocsis et al., 1986; Klein et condition with links to soft bipolarity on the other.

al., 1988). Akiskal et al. (1980) have gone so far as labeling the

In a sample of juvenile offspring or siblings of latter condition as sub-bipolar dysthymia.

bipolar adults, Akiskal et al. (1985) showed a high In summary, although a unipolar course is thepercentage of subjects with an insidious intermittent most typical and prevalent expression of dysthymia,

onset classified as cyclothymic and dysthymic; dur- studies in clinical settings and cases of childhood

ing follow-up, some of the dysthymic patients de- onset do suggest that as many as a third of

veloped bipolar II disorder. More recently, Klein et dysthymics might have links to the soft bipolar

al. (1995) reported a higher rate of bipolar disorder spectrum. This subtle link to bipolarity might explain

among the relatives of dysthymic probands with a in part why asthenia, lethargy and low drive char-

history of major depression compared to the relatives acterize a subgroup of dysthymics (Akiskal et al.,

of normal controls. 1980). A factor-analytic Italian study (Serretti et al.,

The relationship between dysthymic conditions in press) has likewise demonstrated the existence of


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a dysthymic subgroup where chronic fatigue is the most of the emotional-cognitive disturbances occur-

hallmark. These neurasthenic or deficit symptoms ring in dysthymic conditions.

in turn might be linked to a putative dopamine The currently available antidepressants possess

neurotransmitter pathology further elaborated in this diverse chemical structures and apparently varying

paper. biochemical actions upon acute administration. Allof these antidepressants take 23 weeks or longer

before clinical improvement occurs, therefore recent

4. Recent neurochemical considerations in studies on the mechanism of action of antidepres-

depression sants have investigated the long- term effect of these

compounds with respect to receptor changes and

We now shift to putative biochemical considera- modification of intracellular events. On the other

tions as pathophysiological bases for dysthymia and hand, the in vitro receptor affinity and the acute

related illnesses. The pivotal role of biogenic amines action of antidepressants better correlates with their

(noradrenaline, dopamine and serotonin) in the mech- side effect profile: TCAs lack specificity in their

anism of action of antidepressant agents (Brunello et pharmacological action and are associated with

al., 1994; Table 1) and the pathophysiology of antimuscarinic, antihistaminic anda

-adrenergicdepressive disorders was hypothesized nearly 30 blocking effects that account for many unwanted side

years ago (Schildkraut, 1965; Bunney and Davis, effects; SSRIs have little or no affinity for the

1965, Coppen, 1967). Since that time a large number foregoing neurotransmitter receptors, with their most

of investigators have conducted studies on the bio- common side effect being related to 5HT stimula-2logical mechanisms involved in the action of antide- tion (Cookson, 1993).

pressant agents and the information deriving from Research during the last 1015 years has begun to

these studies has led to a number of revised and provide a more complete understanding of the role

more refined theories on the biochemical abnor- played by second messengers and intracellular signal

malities of mood disorders (Healy et al., 1983; transduction pathways in those adaptive neural

Siever and Davis, 1985; Leonard, 1986; Stahl, 1996). mechanisms that underlie behavioral phenomena

Examination of Table 1 will reveal that putative relevant to depression and in the long-term effects of

neurotransmitter dysregulation involves not only the antidepressant pharmacotherapy. Thus, chronic ad-somatic features of depression, but also pertains to ministration of antidepressant drugs influences the

density and function of noradrenergic (Banerjee et

al., 1977), dopaminergic (Serra et al., 1992) andTable 1 serotonergic receptors (Peroutka and Snyder, 1980)Correlation between depressive symptoms and monoaminergic

following persistent elevated levels of neurotrans-systems involved in depression

mitter. Such changes in receptors occur via adapta-Noradrenaline Serotonin Dopamine tions of postreceptor signal transduction systems and

Vigilance 1 1 1 1 1 1 regulation of gene expression. Since some of theAttention 1 1 1 1 1 1 1 same intracellular sites may subserve different re-Cognitive functions 1 1 1 1 1 1 1 1

ceptors, intracellular adaptations could representMood 1 1 1 1 1 1 1

common postreceptor sites for antidepressant treat-Affectivity 1 1 1 1 1 1 1ment that differentially affect these neurotransmittersPsychomotor activities 1 1 1 1 1

Pain 1 1 1 1 1 acutely (Duman et al., 1994; Hyman and Nestler,Suicidal ideation 1 1 1 1 1996). Even if adaptations of beta-adrenergic, dopa-Avoidance 1 1 1 1 1

minergic and serotonergic receptors per se may notImpulsivity 1 1 1 1 1

underlie the therapeutic action of antidepressantAggressiveness 1 1 1 1 1 1 1agents, it is conceivable that adaptations of theAnxiety 1 1 1 1 1 1 1

Sleep 1 1 1 1 1 1 1 cAMP intracellular signal transduction pathway, orSexual functions 1 1 1 1 1 1 1 of cellular proteins regulated by the cAMP pathway,Appetite 1 1 1 1 1 1 1

are involved in the action of such. In fact it has


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recently been reported that chronic administration of 5. Does dopamine play a role in dysthymia?

antidepressants alters the cAMP-dependent phos-

phorylation system (Perez et al., 1989, 1991; New studies of the dopamine (DA) system until

Racagni et al., 1992); this action could result in recently the least favored putative substrate of de-

regulation of nuclear transcription factors thus in- pression have given rise to plausible psycho-fluencing the expression of additional neuronal pro- biologic explanations. These studies (summarized by

teins (Nibuya et al., 1995). Other types of receptor Fibiger, 1995) indirectly support the hypothesis that

regulation in response to chronic antidepressant reduced neurotransmission in the mesolimbic dopa-

treatment have been detected. Electrophysiological mine system may sustain some of the symptoms of

studies suggest in fact that the delayed onset of depressive conditions, including dysthymia. Ex-

action of SSRIs is due to the time necessary for perimental evidences indicate that mesolimbic DA

5-HT autoreceptors to desensitize, leading over plays a crucial role in controlling incentive motiva-1Atime to an enhanced postsynaptic serotonergic neuro- tion and reward. Finally, some antidepressants, irre-

transmission (Blier and de Montigny, 1994). spective of their acute action on the uptake of

Many adaptive modifications at receptor sites, norepinephrine or serotonin, have the common prop-

beyond receptor level and in monoamine turnover erty when given chronically to potentiate behavioralhave been reported after chronic antidepressant response to DA agonists. The DA hypothesis of

administration; however, the relevance of these depression (Gessa, 1996) offers an explanation for

changes in the mechanism of action of antidepres- the antidepressive effect of pharmaceutical agents

sants and in the pathophysiology of depression is such as sulpiride and amisulpride given at low doses,

disputed by the lack of adequate animal models, by that preferentially block DA autoreceptors and there-

the uncertain ability to generalize experimental find- by increase DA output ( Costa e Silva, 1990; Boc-

ings in laboratory animals to humans, by the inability chetta et al., 1993).

to measure changes in monoamine synaptic activity It is well established that presynaptic autoreceptors

in specific brain areas of patients and by the ques- in dopaminergic cells modulate the rate of firing

tionable relevance of biological markers in peripheral (somatodendritic) and of transmitter release (terminal

blood elements to neurons in the brain. The idea that autoreceptors). In dopaminergic neurons of several

biochemical abnormalities in the neuronal transduc- species, including man, presynaptic autoreceptors aretion mechanisms may underlie depressive psycho- of the D / D subtype (Mercuri et al., 1992). Selec-2 3pathology is further supported by new studies in- tive blockade of DA presynaptic terminal autorecep-

dicating that G-proteins and cAMP phosphorylation tors produce an increase in neurotransmitter release.

system may be altered in certain group of depressed Amisulpride is a selective D / D antagonist2 3patients (Schreiber et al., 1991; Manji et al., 1995; which preferentially blocks the presynaptic dopamine

Perez et al., 1995). autoreceptors which modulate the release of the

In conclusion, the elucidation of intracellular transmitter through a negative feed-back mechanism.3

signaling pathways and their effect on gene regula- Thus, in vitro amisulpride enhances H-dopamine

tion has begun to provide a better understanding of release from brain slices during electrical stimula-

the pathophysiology of depressive disorders. From tion. These nanomolar concentrations of amisulpride3

the available clinical and preclinical data it thus block the inhibitory effects of 7-OH-DPAT on H-appears that the future of antidepressant therapies dopamine release elicited by electrical stimulation.

may lie in the development of pharmaceutical agents Concentrations about 30 times higher are needed for

which modulate signal transduction by acting on blockade of postsynaptic receptors by amisulpride.

G-proteins or even at sites distal to the receptor- The preferential blockade by amisulpride of pre-

second messenger complex (Broekkamp et al., synaptic dopamine autoreceptors can also be demon-

1995). How these molecular events are linked to strated in vivo. Amisulpride increases dose-depen-

psychologically-defined stress and precarious adap- dently the release of dopamine from the rat nucleus

tive mechanisms implicated in trait and state depres- accumbens (dialysis in awake freely moving rats).

sions is still a formidable challenge to psychobiolo- These effects are obtained at 0.3, 1.0 and 3.0 mg / kg

gy. of amisulpride. On the other hand, doses of 10.0 and


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30.0 mg / kg of amisulpride are required to antagon- treatment with the possible exception of atypical

ize the postsynaptic effects of apomorphine (apomor- depressions to MAOIs, as exemplified in the work of

phine induced climbing). Thus, amisulpride is a the Columbia group (Klein et al., 1980).

selective and potent antagonist of presynaptic inhib- Akiskal et al. (1980), who found sleep EEG and

itory DA receptors both in vitro and in vivo. The familial evidence linking dysthymia to major depres-overall effect of low doses of amisulpride is to sion, were the first to report in an open study that

enhance dopaminergic neurotransmission (Guyon et secondary amine TCAs (e.g. desipramine and nor-

al., 1993). triptyline) could be effective in a subgroup of

dysthymics. It was based on a bold hypothesis

supported by external validating strategies, and it

6. Rationale for the pharmacological treatment went against the prevailing opinions of both psycho-

of dysthymia analytic authors and biologic thinking of the day.

Now, nearly 20 years later, the Pittsburgh group

Chronic depression for many decades was consid- (Thase et al., 1997) has shown that depressed

ered to be a milder form of depression, the conse- patients with abnormal sleep EEG are unlikely to

quence of a character neurosis and therefore to be respond to psychotherapy alone. This is reminiscenttreated primarily with psychotherapy (Arieti and of the situation of dysthymic patients that Akiskal

Bemporad, 1978). However, evidence for the effica- and colleagues described in 1980: the tricyclic-re-

cy of psychotherapy as monotherapy for dysthymia sponsive dysthymics, who had abnormal sleep EEG,

is weak at best, if not disappointing (Weissman and had failed to respond to past courses of long-term

Akiskal, 1984; Paykel, 1994; Markowitz, 1994). psychotherapy.

Although counter-intuitive, the evidence for the With the publication of DSM-III, dysthymia

efficacy of pharmacotherapy in dysthymia is strong, became more formally recognized as distinct clinical

and is documented below. entities with specific diagnostic criteria. Both DSM-

Systematic studies of pharmacotherapy in IV and ICD-10 have now officially sanctioned

dysthymic conditions have paralleled the gradual dysthymia. As a result, the need to find efficacious

evolution in our conceptual understanding of these treatments for this prevalent and pervasive affective

forms of depression. This has resulted in a shift from disorder became compelling. Clinical trials of pa-viewing chronic depressions as personality or charac- tients with dysthymia (most of whom had double

terological conditions to their being better viewed as depression) found a positive response to TCAs, even

related to affective disorders. As summarized by among patients with mild symptoms (e.g., 813

Akiskal (1994), this conceptual shift is based on Hamilton depression scores). Additional studies of

several lines of evidence along external validating double depression with MAOIs, including (phenel-

strategies including family history, sleep EEG zine) and reversible agents (moclobemide), also

studies, positive response to sleep deprivation, as found significant response rates comparable to TCAs

well as brief hypomanic switches upon pharmaco- and superior to placebo. More recent placebo con-

therapy; most importantly, both community and trolled studies using moclobemide and imipramine in

clinical studies have demonstrated progression of pure dysthymia have found significant drugplacebo

dysthymia to major depression. differences, but no evidence for superior efficacy of Early therapeutic trials in chronic depressions had a particular antidepressant (Versiani et al., 1997).

typically shown poor responses to TCAs, although This and other representative controlled studies of

these studies could now be criticized because of their dysthymia are summarized in Table 2.

lack of formal diagnostic criteria, inadequate medica- Another rationale for pharmacologic trials in

tion doses, poor study design and poor outcome dysthymia derived from basic and clinical research

measures or criteria. Naturalistic studies also showed on so-called deficit symptoms. Besides depressive

poor remission rates from chronic mild depressions symptoms, patients with dysthymia have been char-

compared to major depression. The results from acterized by poor motivation, anhedonia, anergy, loss

these early studies suggested that milder forms of of activity and fatigue. These symptoms are similar

depression did not respond well to antidepressant to those described in animals with low or poor


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Table 2

Representative controlled studies in dysthymia

Authors Diagnosis No. patients Treatment Improvement (%)

Vallejo et al., 1987 Dysthymia 32 Phenelzine High doses of phenelzine

Imipramine better than imipramineKocsis and Francis, 1988 Dysthymia, early 75 Imipramine 45

onset, moderate Placebo 12

Lepine, 1992 Dysthymia 250 Toloxatone 70

Fluoxetine 75

Guelfi et al., 1992 Dysthymia 164 Toloxatone 69

Viloxazine 54

Hellerstein et al., 1993 Dysthymia 35 Fluoxetine 62.5

Placebo 18.8

Versiani, 1994 Dysthymia 315 Moclobemide 67

Imipramine 68

Placebo 31

Thase et al., 1996 Dysthymia 416 Sertraline 59

Imipramine 64

Placebo 44

Lecrubier et al., 1997 Dysthymia 219 Amisulpride 72.2

Imipramine 68.6

Placebo 33.3

of standard antidepressants. This conclusion is up-mesolimbic dopamine transmission (Gessa, 1996).held in a recently published large-scale double-blindFor example, animals exposed to chronic mild stressItalian study (Smeraldi, 1998).have a generalized attenuation of response to reward,

Interest in the pharmacotherapy of dysthymia haslow psychomotor activity and poor motivation which

increased tremendously during the 1990s. The qual-can be reversed by chronic antidepressant treatmentity and variety of antidepressant treatment studies ofor by selective blockade of presynaptic D / D2 3dysthymia has also increased during this time.autoreceptors that lead to enhanced dopamine trans-SSRIs, widely used in depression, represented amission (Willner, 1995). This line of research is

rational choice, such as the study by Hellerstein et al.relevant to a putative neurochemical dimension that

(1993) with fluoxetine. A large number of placebo-cuts across schizophrenic and certain depressive

controlled studies (a representative selection is sum-conditions. These considerations underlie the interest

marized in Table 2) have shown that various antide-to use agents, such as amisulpride that enhancepressants are effective in the acute treatment ofdopamine transmission by DA autoreceptor antagon-dysthymia. Large-scale and rigorously designedism, as putative antidepressants in patients withplacebo-controlled randomized study of the acutedysthymia (Lecrubier and Boyer, 1995). Amisul-

treatment of dysthymia found that sertraline andpride, in low doses of 2550 mg, selectively blocksimipramine were significantly more effective thandopamine autoreceptors, and is known to enhance

placebo and that sertraline was significantly betterdopamine transmission with reversal of anhedonia,

tolerated than imipramine (Kocsis et al., 1994; Thaseamotivation, and poor response to reward. Clinical

et al., 1996). A much smaller number of studies haveplacebo-controlled studies of amisulpride compared

examined the post-acute continuation treatment ofto amineptine and to imipramine in dysthymia founddysthymia (Kocsis et al., 1996; Versiani et al., 1997;that all active agents were significantly better thanVanelle et al., 1997). The foregoing double blind andplacebo. These results suggest that antidepressantnaturalistic studies cumulatively suggest that TCAs,agents that enhance dopamine transmission are effec-Reversible Inhibitors of Monoamine Oxidase Ative in dysthymia and are comparable to the efficacy


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(RIMAs) and SSRIs are not only effective acutely, until 1988 by the Centers for Disease Control (CDC,

but also in preventing the relapse of depressive Holmes et al., 1988) and subsequently revised in

symptoms in remitted dysthymics. This is a critical 1994 (Fukuda et al., 1994; Wessely, 1994). Although

point, given the high risk of relapse in dysthymia. chronic fatigue is common (Manu et al., 1992), CFS

Several interesting acute treatment studies of as defined by the CDC is less so, although stillputative atypical antidepressants and related agents frequently found in primary care (Wessely, 1995).

(i.e., tianeptine, amisulpride, flupenthixol and minap- CFS refers to patients with severe unexplained

rine) have found them to be effective in dysthymia fatigue and exhaustion both mental and physical

(Guelfi et al., 1989; Geisler et al., 1992). These occurring after minimal effort, and accompanied

agents tend to enhance serotonin and/ or dopamine by substantial disability (Fukuda et al., 1994).

transmission, although their mechanism of action The etiology of CFS remains uncertain. Some

differ. The antidepressants bupropion and venlafax- patients show immunological abnormalities, such as

ine, which in addition to noradrenaline, also enhance increased memory cells or low levels of natural killer

serotonin and dopamine transmission, have not been cells, but these are inconsistent and non-specific.

studied in dysthymia in a prospective design. Ven- They are not related to clinical disability, and do not

lafaxine in particular, has shown promise in the influence outcome (Swanink et al., 1996).treatment of refractory depression (Nierenberg et al., The role of viral infection is unclear, but has

1994), including patients with chronic symptoms. probably been overestimated. Several early studies

Further research on the acute treatment of dysthymia suggested that the enterovirus family was implicated

with bupropion and venlafaxine are therefore war- in CFS, but later investigations have not confirmed

ranted. In addition, such commonly used clinical these findings (Swanink et al., 1994). In a large

strategies as lithium and thyroid augmentation for primary care cohort study we were unable to show

refractory depression have not been formally studied any role for common viral infections as etiological

in treatment-resistant dysthymia; it is of interest that factors (Wessely et al., 1995). Viral meningitis

in their original open trial of antidepressants, Akiskal appears to be a risk factor for subsequent CFS, but

et al. (1980) used lithium on the grounds of positive probably more as a non-specific severe stressor than

family history in a third of dysthymic patients via a direct biological mechanism (Hotopf et al.,

(Rosenthal et al., 1980). 1996). Only Epstein Barr virus (EBV) appears to beFinally, combined pharmacotherapypsychothera- associated with a direct post-infectious fatigue

py deserves systematic investigation in dysthymia. syndrome specific to that virus (White et al., 1995).

Although psychotherapy alone has not been found Most patients who fulfill criteria for CFS and are

particularly effective in dysthymia, because of the seen in specialist samples also fulfill criteria for

chronicity of the disorder, combination therapy may psychiatric diagnoses, chiefly depression (David,

confer some advantages over antidepressants alone. 1991). Controlled studies have shown that these rates

Both interpersonal and cognitive-behavioral ap- cannot be explained as a consequence of physical

proaches (Markowitz, 1994) deserve consideration in disability (Wessely and Powell, 1989; Katon et al.,

future studies that attempt to augment pharmaco- 1991). As similar associations are also found in

therapy. primary care, selection bias is also not an explana-

tion (McDonald et al., 1993; Wessely et al., 1996).Instead such overlap may be an inevitable conse-

7. The question of chronic fatigue syndrome quence of the overlap between the diagnostic criteria

for major depression and those for CFS.

Chronic fatigue syndrome (CFS), also known as Subjects identified with fatigue in the epi-

myalgic encephalomyelitis, chronic fatigue immuno- demiological catchment area (ECA) studies were

deficiency syndrome or post-viral syndrome consti- between six and ten times more likely to fulfill

tutes a major challenge for the clinician. Heir to the criteria for dysthymia (Walker et al., 1993). Some

nineteenth century American concept of neuras- authors who investigate chronic fatigue, particularly

thenia (Beard, 1881), it was not formally defined in Britain, use diagnostic systems that fail to recog-


10/16


nize dysthymia (Lane et al., 1991); even in the US it anxiety and depression (Goldberg and Huxley,

is 11% (Katon et al., 1991). In one of the few 1992).

systematic follow up studies, the presence of Interest in possible hypothalamuspituitary axis

dysthymia was associated with a worse outcome for (HPA) abnormalities in CFS was generated by the

fatigue (Bombardier and Buchwald, 1995). similarities between symptoms in Addisons diseaseDysthymia is possibly related to chronic fatigue (primary adrenal insufficiency) and CFS. Demitrack

rather than CFS. et al. (1991) showed that CFS patients had a low

Most studies and reviews on the subject of CFS evening plasma cortisol level, and decreased 24-h

and psychiatric disorder, have tended to emphasize urinary free cortisol output, suggestive of mild

the role of depressive rather than anxiety disorders. hypocortisolism. Pituitary responsiveness to CRH

However, this is probably unjustified. Anxiety dis- was reduced, while the adrenal cortices were hy-

orders are also common (Fischler et al., 1997), and perresponsive to low doses of administered ACTH.

current formulations of CFS emphasize the key role However, at higher doses the adrenal cortisol re-

played by fearful cognitions in determining avoid- sponse was impaired. This was interpreted as evi-

ance behavior and disability. The neurobiology may dence of mild hypocortisolism of central origin.

also show closer overlap with anxiety rather than Cortisol is closely related to central 5-HT systems;depressive disorders. To emphasize depression at the stress induced CRH secretion is partially controlled

expense of anxiety may reflect both the hierarchical by 5-HT neurones projecting to the hypothalamus1Anature of psychiatric disorder, the demise of the rich (McEwen, 1995). In a recent study central 5-HT

historical tradition of neurocirculatory asthenia, ef- function was assessed in CFS patients without

fort syndrome, Soldiers heart and their close as- comorbid depression by measuring the prolactin

sociations with anxiety disorders (Paul, 1987; Fava response to D-fenfluramine (Cleare et al., 1995): CFS

et al., 1994), and the general shift of fashion and patients showed higher 5-HT mediated responses

diagnostic preference from anxiety to depression than controls, with lower circulating cortisol levels.

(Young, 1989). Depressed patients showed the opposite. Increased

Despite these links, it would be an error to assume central 5-HT responsiveness was also found in a

that CFS is simply a misdiagnosed psychiatric previous study (Bakheit et al., 1992). The explana-

disorder. In every study between one third to one tion of these observations is not straightforward. Ithalf of cases do not fulfill criteria for any psychiatric may be that they reflect the observed differences

disorder (assuming one discounts neurasthenia as a between CFS patients, characterized by hypersomnia,

diagnosis). Even within depressed cases, there are appetite gain and fatigue, and classic major depres-

phenomenological differences between CFS and sion, with insomnia, anorexia and agitation; it is also

major depression. Some of these, such as relative possible the neuroendocrine changes are simply

absence of guilt and preservation of self esteem, epiphenomena of these functional differences (Leese

might be explained on the basis of the external, as et al., 1996). The similarity between the preliminary

opposed to internal, attributions made by most CFS neuroendocrine profiles found in CFS and those

patients in specialist care (Powell et al., 1990). observed in disorders closer to anxiety than depres-

Quite how one considers dysthymia and neuras- sion, such as post-traumatic stress disorder, is also

thenia is unclear. Modern epidemiological studies are intriguing (Yehuda et al., 1991). One formulation ofbeginning to determine the prevalence of operation- disability places greater emphasis on the role of

ally defined neurasthenia: it is common in the exercise avoidance, fear and conditioned responses

community (Merikangas and Angst, 1994), and rather than simple mood disorder, suggesting that

could be diagnosed in virtually everyone who attends depression per se may be an inadequate explanation

a specialist CFS clinic (Farmer et al., 1995). Rather of CFS. This conceptualization also suggests that

than attempting more fine-tuned distinctions between CFS (in the absence of depression) lies at one end of

CFS, neurasthenia and dysthymia, a population a spectrum of HPA activity, in which major depres-

perspective is likely to conclude that all three lie in sion is found at the other.

dimensional space on an axis somewhere between Several magnetic resonance imaging (MRI)


11/16


studies of CFS have been published (Cope and A double-blind, placebo-controlled trial of fluoxetine

David, 1996). Cerebral white matter abnormalities and a graded exercise program for CFS has been

have been reported in some, but not all. (Cope et al., conducted (Wearden et al., 1998), showing a signifi-

1995). Functional neuroimaging techniques such as cant treatment effect, either with fluoxetine or exer-

SPECT in CFS have generated inconsistent results. cise. Fluoxetine was associated with a significantThe most widely publicized study found that brain- change in fatigue scale scores as well as on anxiety

stem perfusion was significantly reduced in CFS and depression measures; however, there was no

subjects compared to controls, with depressed pa- change on functional work capacity.

tients showing intermediate values (Costa et al., Oxford researchers (Wessely et al., 1991; Surawy

1995). This study requires independent replication et al., 1995; Sharpe, 1996) have suggested a heuristic

(Cope and David, 1996). model for understanding chronic fatigue syndrome

To summarize the literature thus far reviewed, the which provides a psychotherapeutic rationale. At the

pathogenesis of CFS is unknown. Several reports heart is the message that whatever triggers CFS may

stressed viral causes or immune dysfunction imply- not perpetuate it. For example, an ordinary viral

ing either the central nervous system or a neuro infection may precipitate fatigue which, for the

muscular impairment. However, no findings have majority of the population, is resolved when abeen consistently replicated. No biological marker or normal recovery is made. However, on rare occa-

reliable test has been validated and the diagnosis still sions the presence of perpetuating factors (such as

relies on clinical case definition. psychosocial stressors, rapid deconditioning, failure

Given the somatic emphasis in the etiology of to rest adequately or concurrent depression) may

CFS, many compounds such as antiviral agents, delay or impede recovery. Fatigue then becomes

immune modifiers, vitamins, minerals, essential fatty chronic, persisting long after the departure of the

acids etc. have been reported anecdotally or in open original trigger and maintained by new variables.

trial to be effective. However, no therapy has been This would suggest the potential utility of cognitive-

demonstrated to be reproducibly useful in double- behavioral approaches, as is beginning to be con-

blind, placebo-controlled clinical trials with an firmed by early trials.

adequate duration of follow-up (Blondel et al.,

1993). In particular, replication and controlledstudies are needed for most therapies with claimed 8. Conclusions

efficacy such as carnitine, magnesium supplements,

high dose essential fatty acid supplements etc. Dysthymia refers to low grade intermittent, typi-

CFS is frequently associated with depression, cally chronic, possibly constitutionally-based affec-

especially dysthymic-type low-grade symptoms. tive pathology characterized by gloominess,

However, the observed response to antidepressants in anhedonia, low drive and energy, low confidence and

CFS is insufficient by itself to support the position pessimistic outlook (Akiskal, 1996). Such patients,

that CFS is just a variant of major depression. One constituting 36% of the community, are quite

possible logical conclusion to date is that CFS may prevalent in general medical settings where they

share some overlap of symptoms and neurochemical present with unexplained physical symptoms (espe-

mechanisms with major depression (Goodnick and cially low energy) and psychiatric settings whereSandoval, 1993). they present with complaints related to an anhedonic

The association between CFS and depression led life-style or its complications (including interperson-

to open trials with antidepressants in these disorders. al and occupational disturbances and sometimes

There are several reports of clinical benefits from suicidal ideation or attempts). Long-considered

antidepressants on CFS (Behan et al., 1994; Good- characterologic in origin, recent data suggest that this

nick et al., 1992), but there is no published positive disorder represents a variant in the course of primary

controlled trial yet. The first randomized, double- affective illness in as much as many purse a double

blind, placebo- controlled study of fluoxetine in CFS depressive course (dysthymia plus major depression)

was resoundingly negative (Vercoulen et al., 1996). or a pure dysthymic course. In many cases, especial-


12/16


ly those with childhood onset, brief hypomanic Acknowledgements

switches do occur either spontaneously or upon

antidepressant challenge. This paper has been produced by a group of

Although traditionally the domain of long-term experts under the patronage of the International

psychotherapy and psychoanalysis, psychotherapy Academy for Biomedical and Drug Research.even in its most practical cognitive-behavioral and

interpersonal forms has not been shown to be

effective in monotherapy. By contrast, most classesReferencesof antidepressants (including TCAs, MAOIs,

RIMAs, SSRIs as well as atypical antidepressantsAkiskal, H.S., 1983a. Diagnosis and classification of affectiveand amisulpride) have been shown in double blind

disorders: New insights from clinical and laboratory ap-studies to be effective against placebo in an averageproaches. Psychiatr. Devel. 1, 123160.

of 65% of dysthymic patients. Naturalistic as well asAkiskal, H.S., 1983b. Dysthymic disorder: psychopathology of

double-blind long term extension of several of these proposed chronic depressive subtypes. Am. J. Psychiatry 140,studies over 2 years and even beyond (Akiskal, 1993; 1120.

Akiskal, H.S., 1993. La dysthymie et son traitement. Encephale

Kocsis et al., 1996; Versiani et al., 1997) have shown 19, 375378.continued benefit from several of these agents. WeAkiskal, H.S., 1994. Dysthymia: clinical and external validity.need new studies to determine whether cognitive-

Acta Psychiatr. Scan. Suppl. 383, 1923.behavior and interpersonal psychotherapies can en-

Akiskal, H.S., 1996. Dysthymia as a temperamental variant ofhance the benefit of long-term pharmacotherapy. affective disorder. Eur. Psychiatry 11 (suppl 3), 117s122s.New pharmacotherapies with either more specific Akiskal, H.S., Cassano, G.B., ( Eds.), 1997. Dysthymia and the

spectrum of chronic depressions. New York, Guilford Press.neurotransmitter action or favorable profile of side-Akiskal, H.S., Bitar, A.H., Puzantian, V.R., Rosenthal, T.L.,effects (e.g. SSRI, RIMA and amisulpride) have

Walker, P.W., 1978. The nosological status of neurotic depres-considerably facilitated the long-term clinical man-

sions: a prospective three-to four-year follow-up examinationagement of dysthymic patients. in the light of the primarysecondary and the unipolarbipolar

In this consensus statement we have also consid- dichotomies. Arch. Gen. Psychiatry 35, 756766.Akiskal, H.S., Rosenthal, T.L., Haykal, R.F., Lemmi, H., Rosenth-ered new biochemical developments which may

al, R.H., Scott-Straus, A., 1980. Characterological depressions:provide a putative pathophysiologic substrate forClinical and sleep EEG findings separating subaffective

selected aspects of the dysthymic pathology, espe-dysthymias from character spectrum disorders. Arch. Gen.

cially low drive, anhedonic-anergic manifestations. Psychiatry 37, 777783.Whether some patients with chronic fatigue belong Akiskal, H.S., King, D., Rosenthal, T.L., Robinson, D., Scott-

Straus, A., 1981. A Chronic depressions. Part 1. Clinical andto this category of patients is presently unknown.familial characteristics in 137 probands. J. Affective Disord. 3,What is clear is that many patients with dysthymic-297315.type pathology (including low energy and fatigue not

Akiskal, H.S., 1982. Factors associated with incomplete recoverynecessarily meeting the stringent criteria for chronic

in primary depressive illness. J. Clin. Psychiatry 43, 266271.fatigue syndrome) do present to general practition- Akiskal, H.S., Downs, J., Jordan, P., Watson, S., Daugherty, D.,ers and psychiatrists. New, more specific pharmaco- Pruitt, D.B., 1985. Affective disorders in referred children and

younger siblings of manic-depressives. Arch. Gen. Psychiatrylogic treatments, possibly combined with new psy-42, 9961003.

chotherapeutic approaches, have provided new hope American Psychiatric Association, 1994. Diagnostic and Statisticalfor this group of patients previously deemed re-

Manual of Mental Disorders, 4th Edition. Washington D.C.,calcitrant to treatment. This hope is presently closer American Psychiatric Press.to practice reality in the clinical management of Angst, J., Wicki, W., 1990. The Zurich study, XI: is dysthymia a

separate form of depression? Results of the Zurich Cohortdysthymia. We have considered CFS, not because weStudy. Eur. Arch. Psychiatry Clin. Neurosc. 240, 349354.believe it is isomorphic with the concept of

Angst, J., Merikangas, K., Scheidegger, P., Wicki, W., 1990.dysthymia, but to underscore our conviction that theRecurrent brief depression: A new subtype of affective disor-

basic scienceclinical practice paradigm that has der. J. Affect. Disord. 19, 8798.been so successful in dysthymia could be equally Arieti, S., Bemporad, J. 1978. Severe and mild depression. Newfruitful in the conundrum of chronic fatigue. York, Basic Books.


13/16


Bakheit, A., Behan, P., Dinan, T., Gray, C., OKeane, V., 1992. functioning and magnetic resonance imaging in chronic fatigue.

Possible upregulation of hypothalamic 5-hydroxytryptamine Br. J. Psychiat. 167, 8694.

receptors in patients with postviral fatigue syndrome. Br. Med. Coppen, A., 1967. The biochemistry of affective disorders. Br. J.J. 304, 10101012. Psychiatry 113, 12371264.

Banerjee, S.P., Kung, L.S., Riggi, S.S., Chanda, S.K., 1977. Costa, D., Tannock, C., Brostoff, J., 1995. Brainstem perfusion is

Development of beta adrenergic receptor subsensitivity by impaired in patients with myalgic encephalomyelitis/ chronicantidepressants. Nature 268, 455456. fatigue syndrome. Quart. J. Med. 88, 767773.

Beard, G.M. 1881. A practical treatise on nervous exhaustion Costa e Silva, J.A., 1990. Traitement des dysthymies par de

(neurasthenia). W. Wood, New York. faibles doses damisulpride. Ann. Psychiatry 5, 242249.

Behan, P.O., Hannifah, B., Doogan, D., 1994. A pilot study of David, A.S., 1991. Postviral fatigue syndrome and psychiatry. Br.

Sertraline for the treatment of chronic fatigue syndrome. Clin. Med. Bull. 47, 966988.

Infec. Dis. 18 ((Suppl 1)), S111. Demitrack, M., Dale, J., Straus, S.E., Lane, E., Listwak, S.J.,

Blier, P., de Montigny, C., 1994. Current advances and trends in Kruesi, M.J., Chrousos, G.P., Gold, P.W., 1991. Evidence for

the treatment of depression. Trends Pharmacol. Sci. 15, 220 impaired activation of the hypothalamic pituitary adrenal

226. axis in patients with chronic fatigue syndrome. J. Clin. End.

Blondel-Hill, E., Shafran, S.D., 1993. Treatment of the chronic Metab. 73, 12241234.

fatigue syndrome. A review and practical guide. Drugs 46, Duman, R.S., Heninger, G.R., Nestler, E.J., 1994. Molecular

639651. psychiatry. Adaptations of receptor coupled signal transduction

Bocchetta, A., Bernardi, F., Burrai, C., Peddizzi, M., Del Zompo, pathways underlying stress-and drug-induced neural plasticity.

M., 1993. A double-blind study of L-sulpiride versus ami- J. Nerv. Ment. Disease 182, 692700.

triptyline in lithium maintained bipolar depressives. Acta Eastwood, M.R., Stiasny, S., 1978. Psychiatric disorder, hospital

Psychiatr. Scand 88, 434439. admission, and season. Arch. Gen. Psychiatry 35, 769771.

Bombardier, C., Buchwald, D., 1995. Outcome and prognosis of Farmer, A., Jones, I., Hillier, J., Llewelyn, M., Borysiewicz, L.,

patients with chronic fatigue vs chronic fatigue syndrome. Smith, A., 1995. Neuraesthenia revisited: ICD-10 and DSM-

Arch. Intern. Med. 155, 21052110. III-R Psychiatric Syndromes in Chronic Fatigue Patients and

Broadhead, W.E., Blazer, D.G., George, L.K., Tse, C.K., 1990. Comparison Subjects. Br. J. Psychiat. 167, 503506.

Depression, disability, and days lost from work in a prospective Fava, G.A., Magelli, C., Savron, G., Conti, S., Bartolucci, G.,

epidemiological survey. J. Am. Med. Assoc. 264, 25242528. Grandi, S., Semprini, F., Saviotti, F.M., Belluardo, P., Mag-

Brieger, P., Marneros, A., 1997. Dysthymia and cyclothymia: nani, B., 1994. Neurocirculatory asthenia: a reassessment using

historical origins and contemporary development. J. Affect. modern psychosomatic criteria. Acta Psychiatrica Scand. 89,

Disord 45, 117126. 314319.

Broekkamp, C.L.E., Leysen, D., Peeters, B.W.M.M., Pinder, R.M., Fibiger, H.C., 1995. Neurobiology of depression: focus on dopa-

1995. Prospects for improved antidepressants. J. Med. Chem. mine. Biochem. Psychopharmacol. 49, 117.38, 46154633. Fischler, B., Cluydts, R., De Gucht, Y., Kaufman, L., DeMeirleir,

Bronisch, T., Wittchen, H.U., Krieg, C., Rupp, H.U., von Zerssen, K., 1997. Generalized anxiety disorders in chronic fatigue

D., 1985. Depressive neurosis. A long-term prospective and syndrome. Acta Psychiat. Scand. 95, 405413.

retrospective follow-up study of former inpatients. Acta Fukuda, K., Straus, S., Hickie, I., Sharpe, M., Dobbins, J.,Psychiatr. Scand. 71, 237248. Komaroff, A., 1994. The chronic fatigue syndrome: a com-

Brunello, N., Langer, S.Z., Perez, J., Racagni, G., 1994. Current prehensive approach to its definition and study. Ann. Int. Med.

understanding of the mechanism of action of classic and newer 121, 953959.

antidepressant drugs. Depression 2, 119126. Geisler, A., Mygind, S., Riis Knudsen, O., Sloth-Nielsen, M.,

Bunney, W.E., Davis, J.M., 1965. Norepinephrine in depressive 1992. Ritanserin and flupenthixol in dysthymic disorder. Nord.

reaction. Arch. Gen. Psychiatry 13, 483494. J. Psychiatry 46, 237243.

Burton, S.W., Akiskal, H.S. (Eds.), 1990. Dysthymic Disorder, Gessa, G.L., 1996. Dysthymia and depressive disorders: dopamine

Gaskell, London. hypothesis. Eur. Psychiatry 11 (Suppl 3), 123s127s.

Cassano, G.B., Savino, M., 1993. Chronic major depressiveGoldberg, D., Huxley, P. 1992. Common Mental Disorders: Aepisode and dysthymia comparison of demographic and clinical Biosocial Model, Tavistock, London.

characteristics. Eur. Psychiatry 8 (5), 277279. Goodnick, P.J., Sandoval, R., Brickman, A., Klimas, N.G., 1992.

Cleare, A.J., Bearn, J., Allain, T., McGregor, A., Wessely, S., Bupropion treatment of fluoxetine-resistant chronic fatigue

Murray, R.M., OKeane, V., 1995. Contrasting neuroendocrine syndrome. Biol. Psychiatry 32, 834838.

responses in depression and chronic fatigue syndrome. J. Goodnick, P.J., Sandoval, R., 1993. Psychotropic treatment ofAffect. Disord. 34, 283289. chronic fatigue syndrome and related disorders. J. Clin. Psychi-

Cookson, J., 1993. Side effects of antidepressants. Br. J. Psychi- atry 54, 1320.

atry 163, 2024. Guelfi, J.D., Pitchout, P., Dreyfus, J.F., 1989. Efficacy of tianep-

Cope, H., David, A., 1996. Neuroimaging in chronic fatigue tine in anxiousdepressed patients: Results of a controlled

syndrome. J. Neurol. Neurosurg. Psychiatry 60, 471473. multicenter trial versus amitriptyline. Neuropsychobiology 22,

Cope, H., Pernet, A., Kendall, B., David, A., 1995. Cognitive 4148.


14/16


Guelfi, J.D., Favre, J.D., Von Frenckell, R., Caille, Ph. 1992. Essai Klein, D.N., Lawrence, P., Donaldson, S.K., Schwartz, J.E., et al.,

comparatif en double insu de la toloxatone versus viloxazine 1995. Family study of early-onset dysthymia. Arch. Gen.

chez 164 patients presentant une dysthymie, Symposium, Psychiatry 52, 487496.

Humeur depressive et troubles dysthymiques, Opio, p. 21. Kocsis, J.H., Klein, D.N. 1995 Diagnosis and treatment of chronic

depression. Guilford Press, New York.Guyon, A., Assouly-Besse, F., Biala, G., Puech, A.J., Thiebot,

Kocsis, J.H., Frances, A.J., 1988. Imipramine for the treatment ofM.H., 1993. Potentiation by low doses of selected neurolepticschronic depression. Arch. Gen. Psychiatry 45, 253257.of food-induced conditioned place preference in rats. Psycho-

Kocsis, J.H., Voss, C., Mann, J., Frances, A.J., 1986. Chronicpharmacology-Berl. 110, 460466.depression: demographic and clinical characteristics. Psycho-Healy, D., Carney, P.A., Leonard, B.E., 1983. Monoamine relatedpharmacol. Bull. 22 (1), 192195.markers of depression. J. Psychiatr. Res 7, 251258.

Kocsis, J.H., Thase, M.E., Koran, L., Halbreich, U., Yonkers, K.Hellerstein, D.J., Yanowitch, P., Rosenthal, J., Samstaf, L.W.,1994. Pharmacotherapy of pure dysthymia: sertraline vs.Maurer, M., Kasch, K., Burrows, L., Poster, M., Cantillon, M.,imipramine and placebo, VIIth ECNP, Jerusalem, Elsevier,Wiston, A., 1993. A randomized double-blind study of fluox-1622 October, p. 204.etine versus placebo in the treatment of dysthymia. Am. J.

Kocsis, J.H., Friedman, R.A., Markowitz, J.C., Leon, A.C., Miller,Psychiatry 150, 11691175.N.L., Gniwesch, L., Parides, M., 1996. Maintenance therapyHolmes, G.P., Kaplan, J.E., Gantz, N.M., Komaroff, A.L., Schon-for chronic depression: a controlled clinical trial of desip-berger, L.B., Straus, S.E., Jenos, J.F., Dubois, R.E., Cunnin-ramine. Arch. Gen. Psychiatry 53, 769774.gham-Rundles, C., Pahwa, S., et al., 1988. Chronic fatigue

Kocsis, J.H., Zisook, S., Davidson, J., Shelton, R., Yonkers, K.,syndrome a working case definition. Ann. Intern. Med. 108,Hellerstein, D.J., Rosenbaum, J., Halbreich, U., 1997. Double-387389.blind comparison of sertraline, imipramine, and placebo in theHorwath, E., Johnson, J., Klerman, G.L., Weissman, M.M., 1992.treatment of dysthymia: psychosocial outcomes. Am. J. Psychi-Depressive symptoms as relative an attributable risk factors foratry 154, 390395.first onset major depression. Arch. Gen. Psychiatry 49, 817

Kovacs, M., Feinberg, T.L., Crouse-Novak, M.A., Paulauskas,823.S.L., Pollock, M., Finkelstein, R., 1984. Depressive disordersHotopf, M., Noah, N., Wessely, S., 1996. Chronic fatigue andin childhood, I: A longitudinal prospective study of characteris-minor psychiatric morbidity after viral meningitis: a controlledtics and recovery. Arch. Gen. Psychiatry 41, 229237.study. J. Neurol. Neurosurg. Psychiatry 60, 504509.

Kovacs, M., Feinberg, T.L., Crouse-Novak, M.A., Paulauskas,Hyman, S.E., Nestler, E.J., 1996. Initiation and adaptation: aS.L., Pollock, M., Finkelstein, R., 1984. Depressive disordersparadigm for understanding psychotropic drug action. Am. J.in childhood, II part: a longitudinal study of risk for aPsychiatry 153, 151162.subsequent major depression. Arch. Gen. Psychiatry 41, 643Judd, L.L., Akiskal, H.S., Maser, J.D., Zeller, P.J., Endicott, J.,649.Coryell, W., Paulus, M.P., Kunovac, J.L., Leon, A.C., Mueller,

Kovacs, M., Gastsonis, C. 1989. Stability and change in child-T.I., Rice, J.A., Keller, M.B., 1998. A prospective 12-year hood: onset of depressive disorder: longitudinal course as astudy of sub-syndromal and syndromal depressive symptoms indiagnostic validator. In: L.N. Robins, J.E. Barret, (Eds.), Theunipolar major depressive disorders. Arch. Gen. Psychiatry 55,Validity of Psychiatric Diagnosis, Raven Press, New York, pp.694700.5773.

Judd, L.L., Rapaport, M.H., Paulus, M.P., Brown, J.L., 1994.Kovacs, M., Akiskal, H.S., Gatsonis, C., Parrone, P.L., 1994.

Subsyndromal symptomatic depression: A new mood disor-Childhood-onset dysthymic disorder: Clinical features and

der?. J. Clin. Psychiatry 55, 1828.prospective naturalistic outcome. Arch. Gen. Psychiatry 51,

Katon, W., Buchwald, D., Simon, G., Russo, J., Mease, P., 1991.365374.

Psychiatric illness in patients with chronic fatigue andLane, T., Manu, P., Matthews, D., 1991. Depression and somatiza-

rheumatoid arthritis. J. Gen. Intern. Med. 6, 277285.tion in the chronic fatigue syndrome. Am. J. Med. 91, 335

Keller, M.B., Lavori, P.W., Endicott, J., Coryell, W., Klerman,344.

G.L., 1983. Double depression: Two year follow-up. Am. J.Lecrubier, Y., Boyer, P., 1995. Dopaminergic influence on motiva-

Psychiatry 140, 689694.tional processes: improving positive and / or negative symp-

Kendler, K.S., Neale, M.C., Kessler, R.C., Heath, A.C., Eaves, toms. Eur. Neuropsychopharmacol. 5, 214215.L.J., 1992. A population-based twin study of major depressionLecrubier, Y., Smeraldi, E., 1996. (coordinators), Pharmacotherapy

in women: The impact of varying definitions of illness. Arch.of dysthymia: Recent perspectives. Eur. Psychiatry 11 (suppl

Gen. Psychiatry 49, 257266.3), 111s147s.

Klein, D.F., Gittleman, R., Quitkin, F., Rifkin, A. 1980 DiagnosisLecrubier, Y., Boyer, P., Turjanski, S., Rein, W., and the Amisul-

and drug treatment of psychiatric disorders, ed 2. Williams &pride Study Group, 1997. Amisulpride versus imipramine and

Wilkins, Baltimore.placebo in dysthymia and major depression, J. Affect Dis-

Klein, D.N., Taylor, E.T., Dickstein, S., Harding, K., 1988.orders, 43, 95103.

Primary early onset dysthymia: comparison with primary nonLeese, G., Chattington, P., Fraser, W., Vora, J., Edwards, R.,

bipolar non chronic major depression on demographic, clinical,Williams, G., 1996. Short-term night-shift working mimics the

familial, personality and socioenvironmental characteristics andpituitary-adrenocortical dysfunction of chronic fatigue

short term outcome. J. Abnorm. Psychol. 97, 387398.syndrome. J. Clin. End. Metab. 81, 18671870.


15/16


Lepine, J.P. 1992. Essai clinique multicentrique randomise en Perez, J., Zanardi, R., Mori, S., Gasperini, M., Smeraldi, E.,

double insu toloxatone versus fluoxetine dans les dysthymies Racagni, G., 1995. Abnormalities of cAMP-dependent endog-

du DSM III-R en medecine ambulatoire, Symposium, Humeur enous phosphorylation in platelets from patients with Bipolar

depressive et troubles dysthymiques, Opio, France, p. 22. Disorder. Am. J. Psychiatry 152, 12041206.

Peroutka, S.J., Snyder, S.H., 1980. Long term antidepressantLeonard, B.E., 1986. Neurotransmitter receptors, endocrine re-

treatment decreases spiroperidol labeled serotonin receptorsponses and the biological substrates of depression: a review.binding. Science 210, 8890.Hum. Psychopharmacol. 1, 318.

Powell, R., Dolan, R., Wessely, S., 1990. Attributions and self-Lewinsohn, P.M., Rohde, P., Seeley, J.R., Hops, H., 1991.

esteem in depression and chronic fatigue syndromes. J. Psycho-Comorbidity of unipolar depression I: Major depression with

som. Res. 34, 665673.dysthymia. J. Abnorm. Psychol. 100, 205213.

Racagni, G., Brunello, N., Tinelli, D., Perez, J., 1992. NewManji, H.K., Chen, G., Shimon, H., Hsiao, J.K., Potter, W.Z.,

biochemical hypotheses on the mechanism of action of antide-Belmaker, R.H., 1995. Guanine nucleotide-binding proteins in

pressant drugs: cAMP-dependent phosphorylation system.bipolar affective disorder. Effect of long-term lithium treat-

Pharmacopsychiatry 25, 5155.ment. Arch. Gen. Psychiatry 52, 135144.

Ravindran, A.V., Griffiths, J., Waddell, C., Anisman, H., 1995.Manu, P., Lane, T.J., Matthews, D.A., 1992. Chronic fatigue

Stressful life events and coping styles in relation to dysthymiasyndromes in clinical practice. Psychother. Psychosom. 58,

and major depressive disorder: Variations associated with6068.

alleviation of symptoms following pharmacotherapy. Prog.Markowitz, J.C., 1994. Psychotherapy of dysthymia. Am. J.

Neuro-Psychopharm. Biol. Psychiatr. 19, 637653.Psych. 151, 11141121.

Rihmer, Z., Szadoszky, E., Arato, M., 1983. DexamethazoneMarkowitz, J.C., Moran, M.E., Kocsis, J.H., Frances, A.J., 1992.

suppression test in masked depression. J. Affect. Disord. 5,Prevalence and comorbidity of dysthymic disorder among

293296.psychiatric outpatients. J. Affec. Disord. 24, 6371.

Rihmer, Z. 1990. Dysthymia: a clinicians perspective. In: S.W.McDonald, E., David, A., Pelosi, A., Mann, A., 1993. ChronicBurton, H.S. Akiskal (Eds.), Dysthymic Disorder pp. 112123.fatigue in general practice attenders. Psychol. Med. 23, 987

Rosenthal, T.L., Akiskal, H.S., Scott-Strauss, A., Rosenthal, R.H.,998.

David, M., 1980. Familial and developmental factors inMcEwen, B., Neuroendocrine Interactions, In: F. Bloom, D.

characterological depressions. J. Affect. Disord. 3, 183192.Kupfer, (Eds.), 1995. Psychopharmacology: the Fourth Genera-

Schreiber, G., Avissar, S., Danon, A., Belmaker, R.H., 1991.tion of Progress, Raven Press, New York.

Hyperfunctional G proteins in mononuclear leukocytes ofMercuri, N.B., Calabresi, P., Bernardi, G., 1992. The electro-

patients with mania. Biol. Psychiatry 29, 273280.physiological actions of dopamine and dopaminergic drugs on

Schildkraut, J.J., 1965. The catecholamine hypothesis of affectiveneurons of the substantia nigra pars compacta and ventral

disorders: a review of supporting evidence. Am. J. Psychiatrytegmental area. Life Sci. 51, 711718.

122, 509522.Merikangas, K., Angst, J., 1994. Neurasthenia in a longitudinalSerra, G., Collu, M., DAquila, P.S., Gessa, G.L., 1992. Role ofcohort study of young adults. Psychol. Med. 24, 10131024.

the mesolimbic dopamine system in the mechanism of actionMurphy, D.G.M., Checkly, S.A. 1990. Dysthymia presenting toof antidepressants. Pharmacol. Toxicol. 71, 7285.the emergency clinic of the Mudsley Hospital, S.W. Burton,

Serretti, A., Jori, M.G., Cassadei, G., Ravizza, L., Smeraldi, E.,H.S. Akiskal, (Eds.), Dysthymic Disorder, Gaskell, London,

Akiskal, H.S. Delineating psychopathologic clusters withinpp. 3748.

dysthymia: Analysis of depressive and anxiety symptoms, J.Nibuya, M., Morinobu, S., Duman, R.S., 1995. Regulation ofAffect. Disorders, in press.BDNF and trkB mRNA by chronic electroconvulsive seizure

Sharpe, M., 1996. Chronic Fatigue Syndrome. Psychiatric Clinicsand antidepressant drug treatment. J. Neurosci. 15, 75397547.

of North America 19, 549573.Nierenberg, A.A., Feighner, J.P., Rudolph, R., Cole, J.O., Sullivan,

Siever, L.J., Davis, K.L., 1985. Overview: toward a dysregulationJ., 1994. Venlafaxine for treatment-resistant unipolar depres-

hypothesis of depression. Am. J. Psychiatry 142, 10171031.sion. J. Clin. Psychopharmacol. 14, 419423.

Smeraldi, E., 1998. Amisulpride versus fluoxetine in patients withPaul, O., 1987. Da Costas syndrome or neurocirculatory asthenia.

dysthymia or major depression in partial remission: A double-Br. Heart J. 58, 306315. blind, comparative study. J. Affect. Disord. 48, 4756.Paykel, E., 1994. Psychological therapies [dysthymia]. Acta

Stahl, M. 1996. Essential Psychopharmacology: NeuroscientificPsychiatr. Scand. 89 (Suppl. 383), 3541.

Basis and Practical Applications. Cambridge University Press,Perez, J., Tinelli, D., Brunello, N., Racagni, G., 1989. cAMP-New York.dependent phopsphorylation of soluble and crude microtubule

Stewart, J.W., Quitkin, F.M., McGrath, P.J., et al., 1988. Socialfractions of rat cerebral cortex after prolonged desmethyl-

functioning in chronic depression: Effect of 6 weeks ofimipramine treatment. Eur. J. Pharmacol. Mol. Pharmacol. Sec.

antidepressant treatment. Psychiatry Res. 25, 213222.172, 305316.

Stone, M.H., 1978. Toward early detection of manic-depressivePerez, J., Tinelli, D., Bianchi, E., Brunello, N., Racagni, G., 1991.

illness in psychoanalytic patients. Am. J. Psychother. 32, 427cAMP binding proteins in the rat cerebral cortex after adminis-

439.tration of selective 5-HT and NE reuptake blockers with

Surawy, C., Hackmann, A., Hawton, K., Sharpe, M., 1995.antidepressant activity. Neuropsychopharmacology 4, 5764.


16/16


Chronic fatigue syndrome: A cognitive approach. Behav. Res. Weissman, M.M., Akiskal, H.S., 1984. The role of psychotherapy

Ther. 33, 535544. in chronic depression: a proposal. Comprehensive Psychiatry,

Swanink, C., Melchers, W., van der Meer, J., Vercoulen, J.H., 25, 2331.

Bleijenberg, G., Fennis, J.F., Galama, J., 1994. Enteroviruses Wearden, A.J., Morriss, R.K., Mullis, R., Strickland, P.L., Pearson,and the chronic fatigue syndrome. Clin. Infect. Dis. 19, 860 D.J., Appleby, L., Campbell, I.T., Morris, J.A., 1998. Random-

864. ized, double-blind, placebo-controlled trial of fluoxetine and aSwanink, C., Vercoulen, J.H., Galama, J., Roos, M.T., Meyard, L., graded exercise for chronic fatigue syndrome. Br. J. Psychiatry

van der Ven Jongekrijk, J., deNijs, R., Bleijenberg, G., Fennis, 172, 485490.J.F., Miedema, F., van der Meer, J.W., 1996. Lymphocyte Weissman, M.M., Leaf, P.J., Bruce, M.L., Florio, L., 1988. Thesubsets, apoptosis and cytokines in patients with chronic epidemiology of dysthymia in five communities: Rates, risks,fatigue syndrome. J. Infect. Dis. 173, 460463. comorbidity, and treatment. Am. J. Psychiatry 145, 815819.

Thase, M.E., Fava, M., Halbreich, U., Kocsis, J.H., Koran, L.,Wells, K.B., Stewart, A., Hays, R.D., Burnam, M.A., Rogers, W.,

Davidson, J., Rosenbaum, J., Harrison, W., 1996. A placebo-Daniels, M., Berry, S., Greenfield, S., Ware, J., 1989. The

controlled randomized clinical trial comparing sertraline andfunctioning and well-being of depressed patients: results from

imipramine for the treatment of dysthymia. Arch. Gen. Psychi-the medical outcomes study. J. Am. Med. Assoc. 262, 914

atry 53, 777784.919.

Thase, M.E., Buysse, D.J., Cherry, C.R., Cornes, C.L., Mallinger,Wessely, S. 1994. The history of chronic fatigue syndrome. In: S.A.G., Kupfer, D.J., 1997. Which patients will respond to

Straus (ed.), Chronic Fatigue Syndrome, Mark Dekker, Newinterpersonal psychotherapy? The role of abnormal elec-

York, pp. 4182.troencephalographic sleep profiles. Am. J. Psychiatry 154,Wessely, S., 1995. The epidemiology of chronic fatigue syndrome.502509.

Epidemiol. Rev. 17, 139151.The ICD-10: Classification of mental and behavioural disorders.Wessely, S., Powell, R., 1989. Fatigue syndromes: a comparisonClinical descriptions and diagnostic guidelines. 1992. Geneva,

of chronic postviral fatigue with neuromuscular and affectiveWorld Health Organization.

disorder. J. Neurol. Neurosurg. Psychiatry 52, 940948.The WPA Dysthymia Working Party, Dysthymia in clinical

practice, Br. J. Psychiatry, 166 (1995) 174-183. Wessely, S., Butler, S., Chalder, T., David, A. 1991. The cognitiveVallejo, J., Gasto, C., Catalan, R., Salamero, M., 1987. Double- behavioral management of the post-viral fatigue syndrome. In:

blind study of imipramine versus phenelzine in melancholias R. Jenkins, J. Mowbray, ( Eds.), Postviral Fatigue Syndrome,and dysthymic disorders. Br. J. Psychiatry 151, 639642. Wiley, Chichester, pp. 305334.

Vanelle, J., Attar-Levy, D., Poirier, M., Bouhassira, M., Blin, P., Wessely, S., Chalder, T., Hirsch, S., Pawlikowska, T., Wallace, P.,Olie, J., 1997. Controlled efficacy study of fluoxetine in Wright, D., 1995. Post infectious fatigue: a prospective study in

dysthymia. Br. J. Psychiatry 170, 351357. primary care. Lancet 345, 13331338.

Vercoulen, J.H., Swanink, C.M., Zitman, F.G., Vreden, S.G., Wessely, S., Chalder, T., Hirsch, S., Wallace, P., Wright, D., 1996.Hoofs, M.P., Fennis, J.F., Galama, J.M., van der Meer, J.W.,Psychological symptoms, somatic symptoms and psychiatric

Bleijenberg, G., 1996. Randomized, double-blind, placebo-disorder in chronic fatigue and chronic fatigue syndrome: a

controlled study of fluoxetine in chronic fatigue syndrome.prospective study in primary care. Am. J. Psychiatry 153,

Lancet 347, 858861.10501059.

Versiani, M., 1994. Pharmacotherapy of dysthymia: a controlledWhite, P., Thomas, J., Amess, J., Grover, S., Kangro, H., Clare,

study with imipramine, moclobemide or placebo. Neuro-A., 1995. The existence of a fatigue syndrome after glandular

psychopharmacology 10, 298s.fever. Psychol. Med. 25, 907916.

Versiani, M., Amrein, R., Stabl, M., 1997. Moclobemide andWillner, P., 1995. Pharmacology of anhedonia. Eur. Neuro-imipramine in chronic depression (dysthymia): an international

psychopharmacol. 5, 214.double-blind, placebo-controlled trial. International Collabora-Yehuda, R., Giller, E., Southwick, S., Lowy, M., Mason, J., 1991.tive Study Group. Intl. Clin. Psychopharmacology 12, 183

Hypothalamicpituitaryadrenal dysfunction in post-traumatic193.stress disorder. Biol. Psych. 30, 10311048.Walker, E., Katon, W., Jemelka, R., 1993. Psychiatric disorders

and medical care utilization among people who report fatigue Young, D., 1989. Neurasthenia and related problems. Cul. Med.in the general population. J. Gen. Intern. Med. 8, 436440. Psych. 13, 131138.

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