Biological studies of Dysthymia

B~OL ~YCH|ATRY

~3

REVIEW

Biological Studies of Dysthymia Robert H. Howland and Michael E. Thase

Dysthymic disorder (DD; is a chronic subsyndromal depressive condition that has generated increasing interest since its formal introduction into the p~¢chiatric nomenclature in 1980. Although DD was included among the affective disorders in DSM-IH, this classification was controversial. Some clinical and family studies support an association beaveen DD and major ~tepression disorder ¢MDD). but there has been little additional research firmly establishing the diagnostic vaiidir¢ of DD or clari~'ing its relation to MDD and to personalio, disorders. In this article, the literature on the biology of DD is reviewed. Studies of rapid eye mo~ ement ¢REM) latenc},, electrodermal activity, and the thyroid a.ris show similarities between DD and MDD, but the findings are m~ed. Other investigations, including the Dexamethasone Suppression Test (DST), catecholamines, and several other electroencephalogram (EEG) sleep variables, show more consistent differences between DD and MDD. These findings suggest that DD manifests primarily trait characteristics of depression, thus differentiating it from the state characteristics of MDD. The methodological problems and implications of these studies, and suggestions for fiaure research, are discussed.

Introduction There is increasing recognition that chronic affective conditions, especi~ly depressive illness, are a common and significant clinical problem for psychiatrists. Chronic depression has been identified by many labels in the psychiatric literature, including neurotic depression, characterologic depression, depressive personalty, chromc dysphoria, and mild .,-,.~u.,.,~ d e pr e s s ion. Alth ou gh th ese u~ag.u~u~ .,: . . . . .:_ catego fi es oit~, _c. . . . . , ~ a, a ~ a . . ~ ,~.,. . . . a ~,~,. . . . .o~.vj.,,., ~,;°~., ,,,,. variable interpretations by clinicians ~see, e.g., Klerman et al 1979), they g e n e ~ l y describe a depression that is long standing and is typically less severe than melancholia. In addition, several of these terms also imply that the depression is intimately associated with character pathology. As a result, they axe sometimes characterized as "nonbiological" disorders for which pharmacotherapy is not primarily indicated and for which psychotherapy is believed to be the treatment of choice (e.g., Chodoff 1972). However, the efficacy of psychotherapy in chronic depression has not been rigorously evaluated (Weissman and Akiskal 1984).

From the Western Psychiatric Institute and Clinic. Department of Psychiatry. University of Pittsburgh School of Medicine. Pittsburgh. PA. Address reprint requests to Dr. Robert H. Howla~. Wes,.e~ ~ychiatr/c Institute and Clinic. Depattamnt of P s y c h . University of Pittsburgh School of Medicine, 3811 O'Hara Street. Pittsburgh. PA 15213. Received June 26. 1990. revised October 24. 1990.

1991 Socie~' of Biological Psychiatry

0006-3223/91/$03.50

2:84

BIOL PSYCHIATRY 1991; ~ : 2 8 3 ~

R.H. Howland and M.E. Thase

In the 1970s, Akiskal et al began to study the ~nomenology, course, treatment, and psychobiology of chronic depression. This group argued that the character pathology in these patients was not necessarily the primary etiology of their depressive symptoms, but might be a manifestation of a subsyndromal affective disorder (Akiskal 1984). Subsequent work has confirmed the hazards of attempting to diagnose personality disorders in symptomatic depressives (Hirschfeld et al 1983). B ~ on their findings from the family history, electroencephalo~m (EEG) sleep studies, and response to treatment with thymoleptic drugs, Akiskai's group proposed that a subgroup of patients with chronic mild depression had a biologically based illness ( ~ i s k a l et al 1980; Akiskal et al 1981). From this work emerged the concept of dysthymic disorder (DD), described in DSM-Ill and DSM-III-R (American Psychiatric Association 1980, 1987). In these classification schemes DD is conceptualized as an affective disorder; associated personality features are then noted on Axis II as is done for all Axis I disorders. The creation of a new diagnostic category for DD was controversial. However, a separate category emphasizes recognition of chronic depression for clinical practice and as an important area for both clinical practice and research. Furthermore, the formulation of criteria for DD was based on limited empirical evidence of its validity (Kocsis and Frances 1987); only recently has there been any research using the validation strategy of Robins and Guze (1970) to establish the diagnostic validity of DD. Two major areas of interest regarding the classification of DD are its relation to major depression disorder (MDD) and its relation to personality disorders (Akiskal 1990). The comorbidity of DD and MDD is so common that some authors have suggested it may not be possible to distinguish between these conditions (Keller and Lavori 1984; Keller and Sessa 1990). The comorbidity of DD and personality disorders also is quite common (Hirschfeld 1990), raising the issue of whether some types of DD are a variant of personality disorders (Kocsis and Frances 1987). Clarifying the relationship among DD, affective disorders, and personality disorders thus has important implications for treatment and for understanding the pathophysiology of depression. Two approaches to examining the relationship between DD and major affective disorders are family history studies and treatment studies. Many family history and offspring studies provide substantial evidence to support an association between DD and both unipolar and bipolar disorder (Akiskal et al 1981, 1985; Kocsis et al 1986; Klein et al 1988a, 1988b, 1988c, 1988d). Most pharmacotherapy studies have found also that antidepressant treatment is effective in DD, but the response rate may be less than that seen in acute depression (Howland, 1991). In this article we will review the biology of DD as one way of comparing and contrasting it with other psychiatric disorders. The study of biological processes is an important way to establish the validity of psychiatric diagnoses, especially construct validity, and provides at. opportunity to understand the underlying pathophysiology of the disorder. This information can be used to distinguish between diagnostically similar conditions such as DD and MDD, promote the development of effective treatments for chronic depression, and elucidate the factors that might describe meaningful subtypes of DD, that better characterize the phenomenology of the condition, and that predict the response to treatment (Kupfer and Thase 1987). This review will include sleep and neurophysiology, neuroendocrinology, neurochemistry, and other biological studies. Because DD is a relatively new diagnostic entity, some of the work that is reviewed will nezessarily use non-DSMIll terminology. For example, the Research Diagnostic Criteria (RDC) for minor or

Biological Studies of Dysthymia

B ~ ~¥OUATRY

28.5:

intermittent depression have been commonly used in affective disorders re"~-~,.rch(Spitzer et al 1978). Therefore, we have tried to include in this review only those stt~es using relatively unambiguous clinical descriptions of chronic depressive states nat are simil~ to DD.

Neurophysiology Sleep Studies Electroencephalographic (EEG) studies have been an i m p o ~ t and fruitful research tool in affective disorders. Four types of EEG sleep abnormalities are commoMy found in MDD. Sleep continuity disturbances arid diminished slow wave sleep are common in depression, but are nonspecific and have been found in many other ~ d i c a l and psychiatric conditions (Kupfer and Thase 1983). Increased rapid eye movement ( ~ M ) density and reduced REM latency have been found to be somewhat more specific to affective disorders and have been widely replicated (see, e.g., Thase and Kupfer 1987). Although mast EEG sleep research has focused on MDD, Akiskai et M generated interest in the biology of DD primarily by the use of EEG sleep studies. The sleep studies reviewed here are summarized in Table 1. Akiskal et al (1980) initially reported from their work with chronic ~ l d depressives that a subgroup (which they labeled "subaffective dyst.hymia') could be distinguished by a reduced gEM latency period similar to that seen in MDD. However, reduced REM latency was not consistently found in a larger group of their patients who had DSM-HI DD (divided into subgroups having chronic primary and secondary depressionL suggesting heterogeneity ivt this condition (Akiskal 1982). Reduced REM latencies in DD have been reported in several other in,:estigations (Akiskal et al 1984; Hauri and Sateia 1984; Cluydts et al 1989), but this has not been confirmed by all researchers (Paiva et M 1986; Gupta and Moldofsky 1986; Paiva et a| !988; Appelboom-Fondu et al 1988; Arriaga et al 1990). However, Gupta and Moldofsky (1986) reported a reduced REM latency on the second of three sleep study nights, and Paiva et al (1986, i988) and Gupta mad Moldofsky (1986) studied a small number of subjects and did not utilize normal controls, which may have obscured any positive findings. Also, Appelboom-Fondu et M (1988) studied adolescents, a group that does not reliably manifest REM sleep abnormMities (Ryan and Puig-Antich 1986). Finally, Quitkin et al (1985) found reduced REM latency in a group of patients with chronic atypical depression. This study is pertinent because most of these subjects also would meet criteria for DD. Other EEG sleep variables have been investigated in DD, but not all studies have used appropriate controls (i.e., MDD or normals). Several studies have found an increased percentage of REM sleep in DD (Hanri and Sateia 1984; Akiskal et al 1984; Quitkin et al 1985, Paiva et al 1986), but other studies have found no differences compared to controls (Gupta and Moldofsky 1986; Appelboom-Fondu et al 1988; Arriaga et al 1990). Reduced slow-wave sleep and diminished sleep e;fi¢ienc2; also have been reported in DD (Paiv~ et ai 1986, 1988; Arriaga et al 1990), but this has not been c o n ~ e d by other research groups (Gupta and Moldofsky 1986; Appelboom-Fondu et al 1988). Of note. Akiskal et al (1984) reported a significantly diminished sleep efficiency in their DD group during the first, but not the second, sleep study night. Finally, Gupta and Moldofsky

286

R.H. Howland and M.E, lhase

BIOL PSYCHIATRY

Table I. EEG Sleep Studies in Dysthymia Study Akiska~ et al 1980

Akiskal et al 1984

Akiskal 1982

Hauri et al 1984 Paiva et a! !986 Gupta et al I~6

Paiva et al 1988 Cluydts et al 1987 Arriaga et at 1990 AppelboomFondu et al 1988 Quitkin et al 1985

n

Diagnosis

5 7 6 8 20 22 II I! 5 21 i0 9 i0 12 6

Subaffective" ~ e r MDD Normal Dysthymia" Anxious Medical L ~ i c ~ primary MDD Chronicsecondary Normal Subaffective" Character Dysthymia Dysthymia Medical" Dysth~a Minor" Dysthymia Normal RDC minor RDC MDD N ~ Atypical" RI'~rC MDD Normal

6

10 78 23 22 12 9 12 26 19 2!

REM.L (rain)

REM%

SE%

Delta%

5Y

26'

9O~

19~

99 89

21 19

89 93

20 18

57.6~ 59 I01

59.6~ 52.2 89.0 97.0

27"

"F~

105

53"

20

80

79 t 71 126 67%'

I~

24 17

87 y 95 93

21y 21 25

q2* 96 95" 86 92 94/ 89 92

21 i

66.3 j

20 f

99.3

19

I~.:

19~

125 133 66.9~ 53.9 92.8

16 16 2F ~ 18

26 27 26 5 6

REM-L = REM latency, SE -- sleep efficiency, ~Most patients with atypical depr~sion had dysthymia. ~ANOVA p < 0.001. 'ANOVA p < 0,01. '~ANOVA not significant. •p < 0.01. ~p not significant, ~Data not reported, No difference from historical MDD group. 'Data not reported, Reduced compared with hislorical group, '67qt of subjects had REM latency less than 60 rain. 'Trend signihcance, p < O.I.

7,<0o5.

(1986) reported increased theta bursts during stage 2 sleep, a fiading that has recently been replicated by Arriaga et al (1990) in a study of DD and normal subjects. In summary, several similarities between patients with DD and MDD have been suggested by EEG sleep studies. The variability of the findings may be due in part to the choice of patient control groups in many of the s~adies. In addition, the variable re~u|ts also suggest heterogeneity among patients with DD. Reduced REM latency is a relatively consistent finding across these studies. This finding is consistent with the suggestion that reduced REM latency represents a trait marker of depression (Kupfer and Ehlers 1989). In thi~ regard, it is of interest that Akiskal reported a favorable response to thymoleptic treatmei.~ in DD with reduced REM latency, because Rush et al (1989) and Thase and Simons (1990) also found a more favorable outcome in MDD with reduced REM iateucy

Biological Studies of Dysthymia

I~,K~LPS'~C~AI~I~Y |YO|~283+

287

values. Also of interest are the reports of increased REM percent in DD. ~ REM sleep has been suggested as a characteristic of ~u-~:~gichypersomic dep~ssion ~Thase et al 1989} and hypersomnia has been reported in many patients with DD (Akiska] et 1980, 1984; Keller and Lavori 1984), thus providing a clinicopatholo-gical link between DD and this EEG sleep abnormality. Finally, the investigation of sleep microsm~ture, in which abnormal ~heta bursts have been noted in DE), has been suggested as a potentially useful research approach (Arriaga et al 1990)o These factors need to be e x ~ i n e d further in additional sleep studies of DD, especially in comparison with other affective nonaffective conditions {such as various anxiety states). In particular, longitudinal, studms that assess these wariables throughout the course of DD, and during the subsequent development and remission of MDD, would be important.

Other Neurophysiologicai Studies The research literature is replete with various neuro~ysio|ogical studies (e.g., evoked potentials, electrodermal activity, and waking EEG) of depressive illness (see, e.g., ~ n 1986). Some of these studies have included patients with "'neurotic" depression, many of whom would likely meet diagnostic criteria for DD. However, because of ~ clinical and diagnostic heterogeneity of neurotic depression, no attempt will be made to review those particular studies. The remaining studies that pertain to the neurophysiology of DD are quite limited. Foni et al (1986) compared four groups of patients (DD, major affective disorder, paranoid schizophrenia, and a heterogeneous group of geriatric patients) using quantitative EEG measures during the waking state. They found no significant difference between the DD and major affecfive disorders groups with .espect to power or coherence variables. However, the combined affective {"depressed") grouping differed from the other two groups (i.e., alpha coherence was increased in the paranoid group and decreased in the geriatric group). The authors suggested that this might reflect differences in central nervous system {CNS) arousal among different psychiatric conditions, which has also been found in other studies (Pollock and Schneider 1990). In a comparison of the w ~ n g EEG in DD and borderline personality, Snyder and Pins (1984) found an a b ~ a l EEG in 13% (which is similar to the proportion of abnormal EEG studies in n o ~ populations) and 38%, respectively, with a nonsignificant trend for lateralization to the right hemisphere in DD. The lateralization finding in DD is similar to that reported for MDD (Abrams ~ Taylor 1979), although its clinical and pathophysiological significance is unclear. Electrodermal activity was assessed in various DSM-IH subgroups of depression by Thoreli et al (1984) who found no significant difference between DD and MDD, although both manifested reduced activity. Ward and Doen" (1985) found abnormally low resting skin conductance levels in DD patients which was similar to MDD. These findings, which suggest the commonality of DD and MDD, may provide ~urther support for the idea that reduced electrodermai activity may represent a trait marker for depression because lacono e'. al ~i983) found that the abnormality persisted into clinical remission. Shagass et ai (1985) conducted a study ~+f evoked potentials in a large samp|e of psychiatric patients and controls, including patients with "neuroses," personality disorders, schizophrenia, schizotypal/borderline disorders, MDD, and mania. Although the patients initially were enrolled in the study using DSM-II criteria, the authors stated that the group of neuroses was comprised of many dysthymic patients. Using discriminant analyses, they reported a significant differer~ee between the neurotic group and each group of

288

BIOL ~YCHIATRY

R.H. H o w ~ and M.E. Tiuue

controls, MDD, and schizotypal/borderline patients. Giese-Davis and Miller (198/) examined EEG-evoked potentials in a study comparing DD, normal controls, and a group of patients selected for anhedonia. They found differences among ~ groups on several components of the evoked potential waveform, including N200 and P300. These researchers also reported differences betw~n these patients in a study of ~ time and cardiac response to various stimuli (Miller and ~ee 1985). In a subsequent study, Yee and Miller (1988) c o m ~ normal and DD subjects, and found severad differences in cardiac response, skin conductance, and event.related potentials. Each of these studies support the finding of neurophysiologica! d;.ff:rcr,ces between DD and ~ controls, although their specificity is limited by the failure to include ~ a t e MDD controls. Finally, visual flicker sensitivity has been investigated in DD, MDD, end normal controls, but no significant differences were found (Herskovic et al 1986). The results from these studies are very difficult to interpret, although the consistency of findings suggests that psychiatric conditions are characterized by abnormal CNS electrophysiological function, which distinguishes them from normals. Moreover, the pattern of electrophysiological abnormalities may differ among psychiatric conditions (e.g., affective versus psychotic symptoms), which would imply that the abnormalities are not simply a manifestation of a nonspecific CNS process (Shagass et al 1985), nor are they state dependent (Henriques and Davidson 1990). For the affective d i ~ , including DD, such electrophysiological abnormalities might fit within a general information Wocessing model of depression (Otto et al 1987; Yee and Miller 1988). For example, in a study of cognitive information processing in sc~zophrenic and dysthymic "neurotic" patients, both groups showed significant impairment during several test conditions compared with normal controls, but the d y ~ y m i c s were less impaired than the schizophrenics (Weller and Bum 1984). There are few neurophysiologicai studies of DD providing any definitive conclusions, although the similarities to MDD and differences from controls suggest areas for future research. Investigation of electrodermal activity in DD and MDD have shown similar reductions in skin conductivity, which is consistent with the suggestion that abnormal skin conductance may be a general trait phenomenon of depression (Ward et al 1983).

Neuroendocrinology Hylu~thatamic-Pimitary-Adrenal Axis Investigation of various neuroendocrine abnormalities has been an active area of research in biological p~ychiatry, especially in the affective disorders. The hypothalamic-pituitaryad~na| ~HPA) axis in particular has been extensively studied in depression lwsing the dexamethasoi~e suppression test (DST). These studies have been done much more often in MDD than in DD. Ten studies using DSM-III criteria have compared the DST in DD, MDD, and other psychiatric d~..,rders in adults (Beck-Fnis et al 1985; Lu et al 1985, 1986, 1988; Roy et al 1985c; Roy 1988; Magni et al 1986; Miller et al 1986; Henry et ai 1987; Vallejo et al 1987). These studies used similar procedu~s for performing the DST. Considered together, 33 of 243 (!,4%) dysthymics, 131 of 221 (59%) major depressives, 30 of 89 (34%) schizophrenics, i0 of 31 (32%) borderline personalities, and 4 of 72 (6%) controls had an abnormal DST, rates that are significantly different (chi-square = 138, df = 4, p < 0.001). In addition, the rate of DST nonsuppression was significantly different

Biological Studies of Dysthymia

BIOL PSYOI|ATRY

between DD and MDD (chi-square = 106, df = I, p < 0.001), but ~ between DD and normal controls (p > 0.05, Fisber's Exact Test). One of ~ studies ( ~ ~ al 1985)

combined the DD and control groups in their analysis, but this did not change ~ above findings. Of interest, two of the studies (Beck-Friis et al 1985; Miller et al 1986) compared ~'double depressives" (MDD superimposed upon DD) with unipola.r dewessive~ ~ found no statistically significant difference in the rate of DST nonsuppression, suggesting that the development of an episode of MDD in DD is associated with activation of the HPA axis. However, the small number of DD patients in the study by Beck-Friis et al (1985) may have obscured any significant differences. These studies are s u ~ z e d in Table 2. Additional studies have examined the DST in children and adolescents using DSMill criteria. Petty et ~'! (1985) and Brambilla et al (1989) found no significant difference in DST nonsuppression among children with MDD, DD, nonelective psychiatric disorders, or normal controls. By contrast Casat et al (1989) found significant differences among adolescents with MDD, DD, =~d ,or~affective psychiatric disorders in a metaanalytic study. These results suggest that the different rates of DST nonsuppression in MDD and DD may be due in part to the effects of age, with a greater separation between groups in adolescence than in childhood. A second group of studies used RDC criteria to compare the DST in m i ~ ~ MDD (see Table 2). In three of the studies together, 3 of 42 minor depressives (7%), 47 of 165 major depressives (28%), I of 13 psychiatric controls (8%), ~ none of 12 normal controls had an abnormal DST, rates that are significantly different (chi-square = 15,0. df = 3, p < 0.005) (Carroll et al 1980: Holsboer et al 1980; Steardo et al 1984). A fourth study reported DST nonsuppression in 12 of 16 (75%) ~ n o r depressives, w~ich is a higher rate than is commonly seen in MDD, but there were no control groups to evaluate this finding (Rihmer et al 1983). When this study is included in ~ above analysis, the findings are no longer statistically significant (chi-square = 6.9, af = 3, p > 0.05). This study did not report Hamilton depression scores, although patients +,vere characterized as having "'masked" depression with multiple somatic complaints. Further, 69% of the sample responded to tricyclic antidepressants (TCA). These findings from studies using RDC criteria are consistent with the studies using DSM-m criteria reviewed above. Another group of studies also used DSM-III criteria in their investigation of the DST in DD, but combined the dysthymics and patients with adjustznent disorder and/or atypical depression to form a group with "minor" depression for their analyses. These studies reported significant differences in post-DST cortisol levels (Thase et al 1985; Maes et al 1986a, 1987b, 1988, 1989a) and rates of DST nonsuppression (Nelson et al 1984; Thase et ai i985; Cluydts et al 1987; Poirier et al 1987) between patients with MDD and minor depression, which is consistent with the studies previously reviewed, but they are confounded because of the heterogeneity of the minor depression group. These studies also are summarized in Table 2. Several studies have investigated the adrenal response to other exogenous physiological challenges in DD. These investigations include the use of corticotropin-releasing hormone (CRH) (Leake et al 1989), fenfluramine (Lopez-lbor et ~ 1989), 5-hydroxytryptophan (Maes et al 1987a), L-t~3,ptophan (Maes et al 1989c), and dextroamphetamine (S:ewart et al 1984). In general, significant differences are found between DD and MDD, but not between DD and norTaal controis, which is consistent with the D3T studies+ To summarize tb:se findings, there are significant differences between patients with

BIOL PSYCHIATRY I ~ I ;30:283--3(14

R.H. H o w l a n d and M,E, Thase

Table 2, Dexamethasone Suppression Tes: in Dysthymia

Study Beck-Friis et al 1985

l,u et al 1985

Roy et al 1985c Lu et al 1986 Magnt e.' al 1986

Miller et al 1986 Hem3' et al 1987

Vallejo et al 1987 Lu et al 1988

Roy 1988

Carroll et al 1980 Holslx~er 1980

Rihmer et ai i983 Steardo et al 1984

Nelson e~ al 1984

Thas¢ et al 1985 Cluydts ct al 1987 Poirier et al 1987

n 12 20 i0 I0 32 12 25 il !I i0 19 18 15 18 39 3~ 103 !7 28 32 32 16 20 51 19 36 !3 50 43 13 72 19 74 9 i6 IO 19 !2 65 157 !4 28 12 14 117 16 57

Diagnosi~ D,~ble depression Nondysthymic depression Dysthymia

HDRS

DST %~'

p

'~

33.3 65.O

NS

"

IO,tY

<0.0OI

Normal

MDD BPD~ Schizophrenia Dystilymia Normal Dysthymia MDD Dysthymia MDD Medical Double depression MDD Dysthymia MDD Schiz. ehrenia Dysthymm MDD Dysthymia Normal MDD BPIY Schizophrenia Dysthymia MDD Normal RDC minor RDC MDD RDC minor RDC MDD Schizophrenia RDC minor RDC minor RDC MDD Normal Mixed minord MDD Schizophrenia Alcoholism Mixed minors MDD Mixed minor:' Mixed minora MDD

?~alue nol roll,tied, "DSM-Ill cnlcna unless ~rher~is~ ,pe~.llied ~Percentage of DST non~uppress~ 'D)sthymta and r~omlaigrouv, combined. JMixed re|+er~,to combined ~ltan depressive c~mdmon~ "~5otderhnePer~nahty Di~rder

9.9 24.3 29.0 o

22.5 22.8

20.5 ~,1 23.O 1.5 .6 24.8 13.4 9.0 24.7 '~ 19.1 26.1 24,5 21.8 24.3 "~

'~

'~ '? 45.0 51.0

65.6 33,3 40,0 18.2 0.0 IO.O 73.7 ! i.O 73.O I ! .0 36.0 47.0 18.0 53.O ~.O 3. I 40.6 12.5 I0.0 62.7 31.6 36.1 15.4 56.0 4.6 O.O 28.O 15.7 21.6 ! i.i 75.O 0.O 58.O 0.0 20.0 63. ! 28.6 39.3 25.O 64.O 25.O 19.0 42.0

NS <0.005 <0.005

NS

NS


<0.001

<0.05 NS



0.05

NS

Biological Studies of Dysthymia

tooL, p s v ~ i A ~ Y

29t

Table 3. T R H Stimulation Test in D y s t h y m i a

Study Langer el ai 1986 Kennedy et a| 1987 Roy et a| i 985c Brambilla et a| 1987 Maes e! a| 1989a Kahn | 988

Brambilla et al 1989

n i0 73 26 6 !2 I1 |I 10 lO 19 26 I5 15 41 6 24 7 8

8

Diagnosis RDC minor RDC MDD Nonr~ RDC minor RDC M D D Dysthymia Non~| Dyslhymm Nonna| Mixed minor MDD Melancholia Dys~ynua~ MDD Adjustment disorder Conduct disorder Substance a b u ~ Dysfllmia~

HDRS

TSW

23,0 24,0 °~ '~ 0.9 ? '~'

8,4 5.9 ~2,4 ~1.7 t0.8 ~35 ~0.7 "

~6.6 2 I. 7 28. | | 3.0 t~ 19.0 9.0

8.4 6.6 3.6 |0,2 10.3 | 2.0

8.0 | 1.0

[ 3,3 9.9 '

'>

p

< 0 , 0 5 ~' NS NS NS

<0.01 a

< 0.05 ~

NS

Normal

?Valee ~ ~xmed. ~Result is the mean or median change in TSH in mU;L ~Significantdifference between (t~ressi~es and ~ r m ~ s ~'lEy. q~o significant diffe~,~e in degree of TSH blunting. dSngnificam difference between melancholia and both minor and MDD groups only. "Children and adolescents. ~BD! ~-oce. rSignificant difference bet~,een dysthyrma and MDD.

DD and MDD in HPA axis activity. Further, most of these studies also find few significant differences between DD and normal controls. The DST studies in DD suggest that hyperactivity of the HPA axis may be related to age and to the development of a superimposed MDD. This is consistent with the idea that DE) is a subsyndromal disorder prevalent in young adult life, and therefore is less likely to manifest a state-dependent abnormality, such as DST nonsuppression, which is more c o - - m y found in melancholic forms of MDD. However, the relationship among DST nonsuppression, DD, and melancholia warrants further study because Klein et al (1988c, 19~8d) have found melancholia more frequently in their patients with DD than in a comparison group of patients with nonchronic MDD.

T.~yroid K~is Another major focus of neuroendocrinology research in affective di~orde~ involves the hypothalamic-pituitary-thyroid (HPT) axis, but only a s ~ l number of studies have been done in DD. Using the thyrotropin-releasing hormone ( ~ ) stimulation test in children, adole~ents, or adults, some studies have found similarities to (|.anger et al 1986; Kennedy et al 1987) and differences with (Kahn 1988, Maes etal 1989a) MDD or similarities te normal controls (Roy et ai 1985c; Brambilla etal 1987, 1989). These sm~ies are summarized in Table 3.

292

B I ~ ~YCHIATRY

R.H. Howland and M.E. Thase

In an interesting study of geriatric patients, Tappy et al (1987) found that 4 of 23 (15%) with DD. none of 13 with major affective disorders, and 2 of 104 (2%) with nonpsychiatric medical conditions were hypothyroid, which is a statistically significant difference. This finding is consistent ~ith another study that found that a history of thyroid dysfunction was more common in chronic MDD than in acute MDD (Scott et al 1988), which suggests that thyroid abnormalities ~her than TRH blunting may be relevant in chronic depressive states. Clearly, studies of the HPT axis have not shown conclusive differences between DD and either MDD or normals. This finding is inconsistent with claims that TRH blunting might be related to the chronicity of depression (Taka.hashi et al 1974) or might be a trait phenomenon in some patients (Targum 1983), rat,her than a state-dependent abnormality during acute MDD episodes (Ballenger 1988). However, several studies suggest that chronic depressives might be at higher risk for low-grade hypothyroidism.

Other Neuroendocrine Studies A small number of stoics have e x a m i ~ other neuroendocrine functions in addition to the HPA and HPT axes. With respect to growth hormone (GH) secretion, Brambilla et ai (1987) found a significantly higher beseline level in DD compared with normal controls: 2 of !0 dysthymics also had an increased GH response to TRH. Ansseau et al (1988) found a significantly reduced GH respons~ to ~ clonidine end apomorphine challenge in 15 RDC MDD com!xared with 15 minor depressives. Likewise, Lopez-~,~-et al (1989) reported a significantly reduced GH response to fenfluramine stimulation in 26 with MDD compared with 8 with DD. Finally, Brambilla et al (1989), in a study of DD and normal children and adole~ents, found no signific~t difference in GH response to cionidinc, but noted that 5 of 8 with DD showed abnormal GH increases with TRH challenge. Several studies have investigated other hormones irl DD and minor depression, but also are inconclusive. These investigations include prolactin secretior (Brambilla et al 1987: Maes et al 1989b; Lopez-lbor et al 1989), nocturnal melatonin t:. "'v~"-+" , ~ (B~k-Friis et ai 1985), proopiomelanocortin hormone (Leake et al 1989), cerebrospinal fluid (CSF) sommos,atin (Rubinow 1986), and gonadotropic hormones (Brambiila et al 1987). Although interesting, these studies are too few to provide useful information regarding the relationship of DD and MDD at present. in summary, many neuroendocrine functions have been investigated in DD and related minor depressions. The most consistent finding has been a significant difference between DD and MDD with the DST. These studies indicate that DST nonsuppression is uncommon in DD, unless there is also a superimposed MDD episode, which supports the idea that HPA axis alterations are state-dependent phenomena of severe depression. By contrast, studies involving the HPT a~is have yielded mixed results, although some data suggest that TRH abnormalities might be a stable trait of depression or might be related to chronicity. Finally, several other hormones have been studied in DD. With the exception of GH, these studies are too few to provide definitive information. The studies of GH regulation suggest impo~ant differences between MDD and DD, which is consistent with the DST findings. Differen~:cs also were found between DD and normal controls in some of the studies. Longitudinal investigations of these neuroendocrine variables are needed to evaluate possible biological state and trait markers among different depressive conditions. In addi+~ion+ studies of DD also should take into account the presence of superimposed MDD episode, which might confound the findings.

Biological Studies of Dysthymia

l~to~ PS¥O~tATRY

293

i991 ~30~2~3- 3~3~

Table 4. Urinary Catecholamines in Dysthymia Study Roy et al 1986b

C o m m i c! a| 1989

Schiidkra~lt et al 1977 Maes el al 1987b Maes et al 198~ M a e s el al 1989a

n 8 7 8 25 |4 14 31 13 9 15 29 54 i2 2! 24 19 26 15

Dmgnos~s

NE

MHPG

VMA

DA

Dyslhym~a MDD

1.39 ~ ! 25 ~

7.8l ~ 5.05 ~

5. [ ~ 4.68~.:

27.39 ~ ~.6~'

Mclancholm Normal Dys|hym~a MDD-SE ° MDD-R ° L2hnm~c~ MDD Bmpolat Mixed minor MDD M~xed minor MDD N~rmal Mixed m m m MDD Me|ancholia

I ~96~ I~ | 3 ~

6~74 ~ 8, 5 I 16~ |.2~'

28.~ 26.6g '~ 29,47 ~,

4.33 ~ 4.20,

2~.~I ~ 24,2~

1.5,2

HVA

4.26 ¢ 4.~

18 | 4 ~ |7~9 ~ 12[ | 2,497" 22l | O. 52 | O. 2 4 ~ O. 643 29,54 38.04 59.84 ~

215,~: ~ [9[ .73 19l. [6

~Not s~gmficamly different fn~n t ~ m ~ . embossed as mz~n~o~ ~2.t b.r ~Sigmficanll.~~dfffercm from m~'nmd. ~SE ~single episodeL R ~mcmtem). •~Significaml.~, different from MDD-R. e x ~ as ~ g m g c r c ~ m ~ "No significant d~ffenmce [n~n MI:)D-R ~quond: char~-',e~l~icd e l m ~ a (Sch~Idk~ut ~ Kiem |975~ 'Signific~attiy d i f f e r f ~ m bipolar group, e x ~ s s ~ as p g 2 4 hr. ~No significam diffe~nce, e x l ~ s e d as rag:24 hr. ~Significamly diffL~nl from mixed manor and nocmal, e~,pt~ssed as rag/24 hr ~Significanli~ diffcren! from mixed t m ~ and ~ . e~ptes_.,,~ as n~ 24 hr ~•o significam difference, e~gmessed as t t ~ m i

Neurochemistry

Catecholamines Perhaps the first biological theory regarding the pathophysioIogy of affective disov~rs postulated changes in CNS neurochemica~s, a theory t.ha~ takes into account the ~ w n bi~hemicai effe~:ts of antidepressant drugs. The catecholami~s norepinephrine (NE) and dopamine (DA), and their metabolites, have been extensively investigated in ,&e urine, plasma, and CSF of depressed patients, and more recently, in DD. Several research groups have studied urinary catecholamine excretion in DD (Roy et al 1986b; Corona et al 1989), in chronic characterotogic depression (Schildkraut e~: al 1977), and in a heterogeneous group of minor depressions, including DD (Maes e~ al 1987b, 1989a, 1989c). These studies are summarized in Table 4. Plasma catecholamines, including epinephrine (E), also have been investigated in s e v e n studies of DD (Roy et al 1985b, 1986a; Kennedy et al 1987; Corona et al 1989) and are s u ~ z e d in Table 5. These studies of NE and its metabolites show little evidence of dismrb0stce in DD. Delimitation of such abnormalities to the most severe depressive states supports theft relationship to state-dependent clinical characteristics such as psychomotor agitation. ~ais finding is perhaps related to the role of catecholamines in the regulation of CRH, which also is increased in MDD (Holsboer 1988).

294

R.H. H o w ~

BIOl. PSYCIHATRY

and M,E, Thas¢

Table 5, Plasma Catecholamines in Dysthymia Study Roy et al 1985b

Corona et al 1989

Kennedy et al 1987

Roy et al 1986a

n

Diagnosis

NE

II 10 !7 7 41 14 14 31 6 8 4 II 12 28 43

Dysthymia MDD Melancholia Bipolar Normal Dysthymia MDD-SE MDD-R RDC minor RDC MDD RDC bipolar Dysthymia MDD Melancholia Normal

0.98 i.30 2.19" 0.72 0.87

°Significantlydifferent fmrn tahcr groups, expressed as pmol/m|. ~No sign|ficant dtfl¢rencc an~ng groups, values no~ reported. 'Plasma NE respon~ to TRH stimulation significantlyg~ater in b~polar~ , mNosignificantdifferencearr~mg groups. ~Signiticantlydifferent from other groups, expres.,uxlas ng/ml.

E

MHPG

b

c

d

2.7 2.6 3.9" 3.2

valug,s not reported.

A single study has examined CSF catecholamine levels in DD (Roy et al 1985a). The levels of NE and MHPG did not differ among DD, MDD, and melancholics, but dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were significantly lower in the patients with melancholia, which might be related to the clinical state of psychomotor retardation that is commonly seen in ~nelancbolia (Ballenger 1988). To summarize the studies of catecholamines in DD, there appears to be no difference among patients with DD, nonmelancholic MDD, and normal controls. The catecholamine findings seem to distinguish among affective states much better when melancholia or psychomotor disturbance is present. Therefore, catecholamine abnormalities might he best viewed as state-dependent phenomena in more severe depressive episodes and, as such, they would not be expected in a subsyndromal disorder such as DD. A study that compares patients with "double" depression to these other affective disorder groups might clarify this issue further.

Indoleamines A second area of neurochemicai research involves serotonin, which is a subject of some significance for depression because of its potential role in the pathophysiology of affective disorders and because of the development of newer antidepressants having specific effects on ~rotonergic activity. Plasma tryptophan levels (i.e., a possible precursor of CNS serotonin) were found to fall significantly more in MDD than in DD or normal controls immediately in response to insulin-induced hypoglycemia, but this difference did not persist over time (Menna-Perper et al 1983). Pringuey et al (1986) reported that red blood cell transport of tryptophan was higher in both DD and MDD relative to bipolar depression. Unfo,unately, this study did not utilize normal controls, so that it is unclear whether the values observed in DD are elevated or reduced compared with normal values. Finally. one research group has studied the plasma ratio of tryntophan to valine plus leucine in depression. This ratio was lower in MDD compared with minor depression in one study

Biological Studies of Dysthymia

B~

PSYC|[~A~Y

295

(Maes et al 1986bL but not in a subsequent report by the same group (Ma~s et al 1988). However, as noted earlier, their group of minor depressions was com~sed of patients with DD, adjustment disorders, and atypic.~! depressions, which could confou~ imerpretation of this study. One study examining CSF levels of 5-hydroxyindo[eacetic ~ i d (5-HIAA) found no difference among patients with DD, MDD, or ~lancholia (Roy et ai 1985a). Finally, two studies have investigated severn| other aspects of s e r ~ i : n activity. Roy et al (1987) found no difference in platele~ serotonin u~ake or imipramine binding in MDD, bipolar depressives, DD, or normal controls. A postmortem study of ~rotonin receptors in depressed subjects who had died of natural causes found slightly i~reased binding in MDD compared with DD and normal controls, but ~is was not statistic~ly significant (McKeith et al 1987). They also reported a nonsignificant trend for reduced brain concentrations of 5-HIAA in the two groups of depressives compared with controls. The studies of serotonin metabolism in DD are limited, but tend to show few differences between DD and MDD. This finding may be especially relevant to ur~erstanding the relationship between chronicity and treatment resistance, because ~onard (1988) has postulated a serotonergic abnormality in resistant ~pression. In addition, ntanserm, a serotonergic antidepressant, is effective in treating DD (Amaga et al [986; Reyntjens et al 1986), and fluoxetine, a potent serotonin reuptake blocker, has been f o u ~ to be effective than imipramine in chronic depression (Reimherr et al 1984). Additional studies are thus warranted.

Other Neurochemical Studies Investigations of neurochemical abnormalities besides catecholamines and serotonin in DD are limited. These studies include erythrocyte transport of tyrosine (Pringuey et al 1986). platelet monoami~e oxidase activity (Poirier et al 1987L eEvthrocyte catechol-omethyitransferase activity (Karege et a] 1987), and salivary prostaglandins (Ohishi et al 1988; Nishino et al 1989). These results generally show significant differences between DD and MDD, but not between DD and normal controls. In summary, most neurochemical parameters are similar in DD and nonrnelancholic MDD. However, many findings in melancholia differ from both DD and nonmelancholic MDD, again suggesting that severity of illness might be an i m p o ~ t factor. It would be interesting to ascertain whether and how these neurochemicals change d ~ n g the progression from DD to "'double" depression and back again. Certainly, additional studies ate needed to investigate th: ~e findings further.

Other Biological Studies in addition to the major areas of biological research reviewed above, other types of biological investigation have been applied to the affective disorders more recently, such as brain imaging. However. these studies are limited in DD research. Regional cerebral blood flow (rCBF) was studied in P.DC major, minor, and bipolar depressives and in normal controls (Uytdenhoef et al 1983). Significant differences were found between the minor and MDD. but not between the minor depressives and controls. Warren et al (1984) also studied rCBF in 18 depressed patients and i 8 normal controls. Nine of the depressed patients met criteria for DSM-III DD. and the remainder had a MDD. l'he depressed group as a whole had a lower resting blood flow than the normal controls, but the distributi, ~ ff blood flow and the response to a mental task did not differ between the

2~

i~lOL PSYCHIATRY

R.H. Howland and M~E~ Thas¢

groups. Unfortunately. this study did not analyze the rCBF result.s in DD and MDD separately, in a computed tomographi¢ study, the ventricular brain ratio did not differ among DD. MDD. or controls in a study by Rossi et al (1987). Finally, Cosyns et al ( 1989} compared the mitogen-induced lymphocyte response in MDD and minor depression. The MDD had a significantly reduced response to stimulation compared with the minor depressives, but the latter group included a mixture of DD and adjustment disorders. To our knowledge, none of these investigations has been replicated, and they represent other possible ~ a s for future research in DD. Discussion Interest in chronic depressive states, including DD, has been demonstrated by recent work in epidemiology (Weissman et al 1988), treatment (Kocsis et al 1988; Howland 1991L psychosocial research (Brown et al 1988), and clinical phenomenology (Kovacs et ai 1984: Klein et al 1988b). In this article, we have reviewed the growing body of information regarding the biological ch,',,~acteristicsof DD. in contrast to the large number of studies examining the biology of major affective disorders (see, e.g., Thase and Howland 1991 ), there are only a relatively small number of studies to provide comparable data about DD. Nevertheless, the available studies provide important insights into the pathophysiology of these chronic depressive conditions and suggest directions for future research. Several conclusions can be drawn from the findings in this review. The most consistent results are from neuroenc~ocrinology research, where differences in GH secretion and DST nonsuppression have been reported between DD and MDD. However, other neuroendocrine studies, including those inves,igating the HPT axis, have yielded mixed results. The findings from neurophysiology research also have been mixed. Many EEG sleeF i~vestigations in DD have found reduced REM latency that is comparable to MDD. although others have found no difference from normal controls. The small number of studies evaluating other neurophysiological variables, such as electrodermal activity, report some similarities to MDD and differences from controls. In neurochemistry research, most studies in DD have examh,ed noradrenergic function. These noradrenergic investigations suggest that neither nonmelancholic nonbipolar MDD nor DD differ from normal controls. Also, studies of serotonin metabolites tend to show more similarities than differences between DD and MDD, with little conclusive evidence that these conditions differ from normals. Finally, negative results have been reported in many other biological investigations of DD, ranging from monoamine enzymes and prostaglandins to brain imaging and psychoimmunology, but the number of these studies is small. The significance of these research findings is limited by some important methodological problems. First, considerable diagnostic variability is evident across man) of these studies. The use of DSM-ilI, DSM-III-R, RDC, or other structured diagnostic criteria define slightly different groups of patients having chronic subsyndromal depressions. Also, because of the frequent comorbidity of MDD in these patients, it is not clear in some studies whether the investigators were examining "pure" DD or "double" depression. This distinction might have important implications for research on those biological variables that are known to vary with the severity of depressive symptomatology (e.g., the DST). A second methodological concern is the practice in some studies of combining DD with other minor depressives, such as adjustment disorders, to create a single category

Biological Studies of Dysthymia

a~

~¥CHIA~Y

~7

for comparison with MDD. Our review suggests that such an ~mixture of m i ~ depressions is not an appropriate comparison group in biological research (e.g., Kovacs et al 1984) and this practice ma~~confound or obscure importar~t findings. A third concern with this work is the small number of sub~ects in ~ y of the ~udies. As a result, because of limited statistical power, significar:: differe~es anxmg groups may not be apparent in such studies. Also, a lack of replication studies ~ e s some of the findings tentative. A final methodological concern is the use of control subjects in these s~dies. Many different comparison groups have been used~ including norton[s, m~or affective disorder, and other psychiatric conditions, but they have not been used in all studies. T ~ use of both MDD and normal controls in research on DD is vitally important to determine whether DD is an entity biologically distinct from other depressive conditions or is merely a ,...,,.co, variant of MDD. Despite these methodological problems, there remains the task of interpreting the biological data available in these studies. The studies reviewed reveal several biological similarities and differences among DD, MDD. and n o ~ a l controls, and also some ambiguous or mixed findings. A possible explanation for ~ese diverse findings is ~at DD is a heterogeneous group of conditions ,twhich i~ probab!y *~ae of MDD as wel!) This point has been stressed by other authors (i.e., Akiskal 1983; Kocsis and Frances |987; Akiskal 1990), and criteria for subtypir,g DD has been incorporated into the DSMIII-R classification system to reflect the clinical heterogeneity. Recent family studies have reported different rates of major affccti~,c disorder in the ~e|atives of patients with different D D subtypes (Klein et al 1988b), which is consistent with heterogeneity in DD and suggests that the use of clinical subtypes would be fruitful in biological research. Unfortunately, beyond the work of Akiskal and his colleagues, the biological studies reviewed here have not adequately addressed this issue and, thus, validation of the DSM-III-R schema awaits further study. A second possible interpretation of the data might be that DD and MDD are simply different aspects of the same disorder, such that the v ~ o u s biological similarities and differences are a reflection of measurements taken at different stages or phases of the depres~. ~e state. This interpretatio, ~s supported by longitudinal studies of DD demonstrating that the subsequent development of MDD occurs in more than ~ of case.s (Keller and Lavori 1984). In this review, several studies c o m p i n g double depression and MDD found similar rates of DST nonsuppression (Beck-Friis et al 1985; Miller et al 1986), whereas most of the other studies (presumably comparing pure DD with MDD) found significant differences. This also supp:~rts the notion that different biological abnormalities among patients may reflect state-dependent changes during the course of the illness, rather than imply different disorders. Whether these conditions (i.e., DD, MDD, and double depression) are different aspects of the same disorder is also related to the issue of severity of illness (i.e., how illness severity may be manifested by any of these biological abnormalities). The neurochemical studies, for example, suggest that endogeneity (perhaps representing the broader construct of illness severity) may be an important determinant of how closely DD is related to MDD for a particular biological abnormality. However, other studies have not found that a biological abnormality (i.e., DST nonsuppression) is necessarily correlated with the severity of depression (e.g., Steardo et ai 1994; Lu el al 1988). Moreover, of interest, dysthymics may be at greater risk to develop melancholic MDD episodes (Klein et al 1988c, 1988d), further complicating the relationship among depressive subtype, illness chronicity, illness severity, and biological abnormalities. This issue may depend in part

~8

BIOL PsY~IA'I'RY I~1 ~+):21+3+304

R.H. Howland and M.E. Tnase

on how severity is defined, and it would be useful to ~ l a t e different biological variables with various measures of illness severity (e.g., endogenous symptoms, psychosis, and BDI or HRSD scores). In addition, the effects of age on these biological variables also must be taken into account when i n t e ~ n g ~ s e research studies. A third possible interpretation of the mixed results ~ these studies is that DD and MDD are different disorders. However, a great majority of patients with DD develop MDD, although the converse is not true. Therefore, perhaps more accurately, double depression is independent of a MDD that is not ~ l i c a t e d by an underlying DD. Conceptualized this way, the many similar and dissimilar biological findings would be a manifestation of different underlying pathophysiological ~ s s e s in each condition. Understanding this distinction is important in considering the problem of why some depressions are self-limited and relatively easier to treat, whereas other depressions are more persistent and relatively less responsive to ~ t m e n t . Family studies also provide some evidence that DD and MDD may be independent disorders, because they show that the prevalence rates of various affective disorders are different in families with DD and MDD probands (Akiskal et al 1981; Klein et al 1988c, 1988d). The general pattern of biological findings in DD (i.e., normal DST and catecholamine metabolism, but increased risk of reduced RF_M latency and neurophysiological dysfunction) suggests that this condition might be a depressive "trait" disorder that has a high risk for developing MDD. it is exciting, from a research consultant standpoint, to thus view DD as potentially manifesting the substrate of biological vulnerability to MDD. Such vulnerability also might be related to its early age of onset and high genetic loading, suggesting a highly penetrant genetic depressive phenotype. A complete understanding of the biological relationship between DD and MDD is not yet possible. Investigations completed to date are primarily cross-sectional studies, using biok~gical probes at a single point in time to measure conditions that are dynamic and may or may not form a continuum. A mor~ informative cross-sectional study design would simultaneously compare normal controls with patients meeting criteria for pure DD, double depression, chronic MDD, and MDD alone, using various biological probes while evaluating other variables such as clinical characteristics, family history, and treatment response. Alternatively, a longitudinal study design with serial biological measurements would ~ovide usefu2 information about how these biological variables change during the course of illness (e.g., with the deve|opmc~t of MDD or following recovery), and. . .how . . . . . they . . might l.~v.,related to each .~,~," . . . . . •Iv"'""...,and ..-.o~e . . . . llJ,m~. 7~,p. Tl',,c stability or-" any biological similarities or differences among the groups could be determined, and the measures could be used to distinguish among diagnostically similar disorders. Future research in DD should carefully consider these issues, which will enhance our understanding of the biological L;ata that these ea~!ier studies have generated. Finally, the findings from this review have several important implications for research and for clinical practice. First, a sampling of the research literature in affective disorders reveals that some studies of depression utilize subject samples that combine DD and other depressive disorders. Our review suggests that there are enough differences between MDD and DD to confound the results of any study using such a heterogeneous group of research subjects. We strongly recommend tha g this practice should be avoided. Second, a popular notion is that chronic depressions are primarily characterological, and not biological, conditions. However, the studies we have considered in this review provide reasonable evidence that some of the characteristic biological abnormalities of MDD also exist in DD patients. A better understanding of these abnormalities may elucidate some

Biological Studies of Dysthymia

B~L I~YC~T~Y

mechanisms involved in the development and maintenance of chxonicity, Last, ~ ~ n g of biological abnormalities in DD provides additional support for the use of pham-~cotherapy in these patients. There is evidence that antidepressants are effective but underutilized in this disonJer (Howland, 1991), and our review should lead to a reconside~ion of this practice, if not encourage a more aggressive treatment approach in DD. We thank Ms. Katen Heal am] Mrs° Lisa Stupat for their V"rO~m | ~ wepata~ Of the n',~m~npc,

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1 !:83-

iacono WG. Lykken DT, Peloquin LJ. Lumry AE, Valentine RH, Tuason VB (1983): Eiectrodcrrnal , ...... ;,,,,--~~40:557-565. activit3 i~i eu~.hymic unipoIar and bipolar affective disorders. Arch Gen P~ch

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