Child and adolescent clinical features as forerunners of adult-onset major depressive disorder:...

www.elsevier.com/locate/jadJournal of Affective Disorders 82 (2004) 9–20

Research report

Child and adolescent clinical features as forerunners of

adult-onset major depressive disorder: retrospective evidence

from an epidemiological sample

Holly C. Wilcoxa,b,*, James C. Anthonyb

aDepartment of Psychiatry and Behavioral Sciences, Center for Family Research, George Washington University, Washington, DC 20037, USAbDepartment of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, 624 N. Broadway, Room 888, Baltimore,

MD 21205, USA

Received 24 September 2002; accepted 17 October 2003

Abstract

Background: Adult-onset cases of DSM-III-R major depressive disorder (MDD) often have had a history of mood

disturbances and allied clinical features during childhood or adolescence. This study seeks to illuminate these early-life

disturbances, as recalled and reported by adult-onset MDD cases (i.e. those whose first episode of MDD occurred after age 18)

and non-cases. Methods: Our research group has re-assessed survivors in the Baltimore Epidemiologic Catchment Area (ECA)

community sample roughly 13.5 years after first diagnostic assessments in 1981. Of the 1920 participants, 150 were found to

have a history of adult-onset MDD; 1755 were sub-threshold with respect to DSM criteria or reported few or no depression-

related problems. Survival analysis was used to plot and study the cumulative occurrence of each clinical feature of depression

from age 6 through 18 years for cases of adult-onset MDD versus non-cases. Results: The earliest and most frequently occurring

forerunners of adult-onset MDD were persistent depressed mood, anhedonia, feelings of worthlessness, and thoughts of death or

suicide, with persistent anhedonia and worthlessness having a special prognostic value. One-third of adult-onset cases of MDD

reported at least one clinical feature before age 19 versus only 7.3% of non-cases. Limitations: The study’s estimates are based

on retrospective recall, although a life chart methodology sought to reduce recall inaccuracies. Conclusions: The ECA follow-

up sample data, though based on retrospection, provide new details about early forerunners of adult-onset depression from a

sample of survivors. When they appear in children or adolescents, persistent anhedonia and persistent feelings of worthlessness

merit special attention. These two clinical features, in particular, may help predict later risk of adult-onset major depression.

D 2003 Elsevier B.V. All rights reserved.

Keywords: Major depression; Epidemiologic studies; Survival analysis; Natural history; Adolescent; Children

0165-0327/$ - see front matter D 2003 Elsevier B.V. All rights reserved.

doi:10.1016/j.jad.2003.10.007

* Corresponding author. Department of Mental Health, Bloom-

berg School of Public Health, Johns Hopkins University, 624 N.

Broadway, Room 888, Baltimore, MD 21205, USA. Tel.: +1-410-

614-2852; fax: +1-410-955-9088.

E-mail address: [email protected] (H.C. Wilcox).

1. Introduction

Our aim in this study is to use epidemiological and

field survey diagnostic methods in order to identify

specific early markers or precursors that may help

clinicians identify young people at excess risk for

developing adult-onset major depressive disorder

H.C. Wilcox, J.C. Anthony / Journal of Affective Disorders 82 (2004) 9–2010

(MDD). A specific focus is upon persistent anhedonia

and persistent feelings of worthlessness, two clinical

features recently identified by Pine et al. (1999) and

Murphy et al. (2002) as having special prognostic

significance.

Three features differentiate this study from virtu-

ally all previous work of this type. First, we use

survival analysis and generalized estimating equation

(GEE) methods to reconstruct the emergence of dis-

turbed mental life during the years of childhood and

adolescence. This statistical approach, sometimes re-

ferred to as, ‘multivariate response profile analysis’,

takes the interdependencies of other clinical features

into account while estimating risk of adult-onset

MDD for each clinical feature and adjusting for

possible confounding by age, sex, and race-ethnic

minority status. Second, while other studies of this

type have recruited from clinical samples, this re-

search is based upon an epidemiological sample.

More than one-half of the community cases of major

depression in this sample had never received treat-

ment for their depression. Third, we compared char-

acteristics of 1755 young people who did not develop

MDD to 150 individuals who did develop MDD. All

cases and non-cases were drawn from the same

community sample.

Dryman and Eaton (1991), in an analysis of 1-

year follow-up data from ECA samples assessed in

the early 1980s, found that adult-onset MDD was

most strongly associated with prior feelings of

worthlessness, trouble concentrating, diminished sex

drive, and either sleep disturbance (women) or

fatigue (men). More recently, Pine et al. (1999)

extended this line of inquiry by studying a longitu-

dinal community sample of young adults in New

York State, first observed in childhood or adoles-

cence during two waves and then followed to a

mean age of 22 years (range 17–26). In this re-

search, the experience of anhedonia and thoughts of

death during childhood or adolescence helped pre-

dict which individuals subsequently developed MDD

by age 22. However, since the peak risk for adult-

onset major depression is after age 22 years, it is

very likely that most cases of adult-onset MDD were

not identified by these investigators (Eaton et al.,

1989).

The finding on early-life anhedonia was somewhat

of a surprise because prior clinical and epidemiolog-

ical studies of MDD had not suggested that anhedonia

was a common forerunner of adult-onset MDD. An-

hedonia has been found to increase with age, but has

been one of the less common clinical features of MDD

in clinical sample research on childhood and adoles-

cent patients with MDD (e.g. see Roberts et al., 1995).

The experience of general anhedonia was not a

prominent characteristic of MDD cases identified by

Dryman and Eaton (1991) nor by Weissman et al.

(1991) in the prior ECA studies of adults, although

Dryman and Eaton identified ‘‘loss of interest in sex’’

as a noteworthy predictive feature.

In the present study, we use the terms ‘forerunner’

and ‘antecedent’ in order to convey our uncertainty

about the associations linking the earlier clinical

features that emerge before adulthood with the later

major depressive episodes that occur in adulthood. If

the strength of association is large, many youngsters

who report the forerunner or antecedent will become

MDD cases as adults. From an epidemiological stand-

point, we might assert that the positive predictive

value (PPV) of each clinical feature approaches

100%. If so, the clinical feature might be part of the

MDD prodrome (e.g. see Eaton et al., 1995). Due to

recently published evidence, we give special attention

to the clinical features of persistent anhedonia (see

Pine et al., 1999) and persistent feelings of worthless-

ness (see Murphy et al., 2002), which may have

special prognostic significance as forerunners or ante-

cedents of adult-onset major depression, or as part of

the MDD prodrome.

2. Methods

2.1. Sample

This study makes use of data from the longitudi-

nal follow-up of the Baltimore sample of the Epide-

miologic Catchment Area Survey (ECA). More

detailed reports of the Baltimore ECA follow-up

methodology have appeared elsewhere (Eaton et

al.,; Badawi et al., 1999; 1997; Neumark et al.,

2000; Rosenberg and Anthony, 2001). The ECA

program began with five epidemiological surveys

carried out by independent research teams in collab-

oration with National Institute of Mental Health

(NIMH) staff; the ECA sites were Los Angeles,

H.C. Wilcox, J.C. Anthony / Journal of Affective Disorders 82 (2004) 9–20 11

New Haven, St. Louis, the Raleigh-Durham Pied-

mont area and Baltimore City. The ECA program

was designed to assess occurrence of psychiatric

disorders and the use of mental health services

(Eaton et al., 1981). The methods of the ECA

program are described in more detail elsewhere

(Eaton and Kessler, 1985; Robins and Regier, 1991).

For the Baltimore ECA site, standard survey tech-

niques were used to select and assess a multi-stage

probability sample of 3481 household members who

were aged 18 years or older at the time of recruitment

in 1981. A total of 1920 Baltimore ECA respondents,

almost 75% of the survivors, were traced and re-

assessed roughly 13–15 years later in 1993–1996

(Fig. 1). Major depression, as measured in the ECA

project has not been strongly related to premature

mortality, loss to follow-up, or refusal to be inter-

viewed (Badawi et al., 1999). At the time of initial

assessment as well as the follow-up assessments,

participants consented to participate in accord with a

protocol approved by the local IRB (Committee on

Human Research).

Fig. 1. Flow chart for Baltimore ECA screening and diagn

2.2. Variables and measures

In the longitudinal follow-up in 1993–1996, an

adapted version of the NIMH Diagnostic Interview

Schedule (DIS) was used to gain a retrospective

assessment of the history and levels of depression,

clinical features associated with depression, age of

onset of each clinical feature, as well as the recency

(Robins et al., 1981, 1994). This version of the DIS

method assigns respondents to subgroups of cases and

non-cases based on the diagnostic criteria of the

DSM-III-R, taking into account main clinical features

reported and their times of occurrence. For the present

analysis, 19 specific questions have been grouped in

relation to nine clinical features outlined in the DSM

criteria: anhedonia, depressed mood, weight/appetite

disturbance, sleep disturbance, motor disturbance,

tiredness, worthlessness/guilt, diminished ability to

think/concentrate, and thoughts of death/suicide. Each

grouping of clinical features was comprised of 1–4

depression items. The self reported age of onset of

each clinical feature was assessed, and for each of the

ostic procedures. MDD, major depressive disorder.


groups, the earliest reported age of onset for the 1–4

items was considered the age of onset for the clinical

features grouping. Clinical features groups were stud-

ied individually, not in combination.

A note about the persistence or prominence of

clinical features is in order, which will help clarify

the distinctions between the ‘clinical features’ under

study here versus the ‘symptoms of MDD’ that count

toward DSM criteria. In general, the DSM criteria for

MDD require a disturbance of mental life or behavior

that is either persistent or impairing. Most typically, the

DSM criteria require the presence of a full 2 weeks of a

disturbance of mental life or behavior, but an exception

is a single suicide attempt, which is sufficient to satisfy

DSM criteria. Hereinafter, when we refer to ‘‘feelings

of worthlessness’’ or other clinical features with the

exception of suicide attempt, the respondent has

reported clinical features pertinent to mood disturban-

ces that have persisted for 2 weeks or more.

However, suppose an MDD case (or a non-case)

has experienced 2 weeks of feeling worthless, but

never has suffered impairment as a result, and neither

told a doctor nor sought help for this particular clinical

feature. In this instance, the experience of the clinical

feature would not meet the impairment or help-seek-

ing standards that are imposed if a clinical feature is to

be counted toward the MDD diagnosis (e.g. see

Narrow et al., 2002). However, the DIS age of onset

question is asked anyway, which has allowed us to

plot the experience of each clinical feature in relation

to the age of the case (or non-case). As such, this is

research on ‘clinical features’, some of which do not

qualify formally as ‘symptoms’ of an underlying

MDD and do not count toward fulfillment of DSM

diagnostic criteria.

We also note that the DIS assessment of age of onset

of each clinical feature is not specific with respect to

issues of presumed etiology. That is, if the clinical

feature is to be counted toward DSM criteria, it must

occur without attribution to known etiological factors

such as the use of alcohol and other drugs, or to general

medical conditions such as pregnancy or malignancies.

This issue of etiological specificity has been found to

account for some of the observed mismatch between

DIS diagnoses of major depression and standardized

clinical examination diagnoses made by board-eligible

psychiatrists. For this reason, some observers prefer to

eschew DIS diagnoses in favor of standardized assess-

ments by clinicians (e.g. see Anthony et al., 1985).

Moreover, the DIS questions about age of onset of

MDD clinical features do not require the degree of

etiological specificity that might be achieved in a

thorough clinical examination. In the balance, howev-

er, a reliance on DIS diagnoses frees the research from a

diagnostic work-up bias that might be created when

clinicians conduct diagnostic assessments for research

purposes. Namely, unless special precautions are taken

to constrain ordinary diagnostic practices, clinicians

might probe more deeply for MDD when a respondent

reports an early suicide ideation or attempt. This form

of potential work-up bias is constrained when lay

interviewers use the DIS method because they are not

permitted to probe and cross-examine in a work-up

process that is one of the real strengths of a psychia-

trist’s diagnostic examination (e.g. see Anthony et al.,

1985).

As described in detail by Lyketsos et al. (1994), the

follow-up methodology sought to address the problem

of deterioration of recall by means of a standardized

procedure called the Life Chart Interview. At the start

of every interview, the Life Chart Interview method

generates age and calendar linked personal memory

cues for the respondent by means of an interactive

visually oriented life calendar that focuses the respon-

dent’s attention on designated time periods during the

follow-up.

At the time of the follow-up assessment for DSM-

III-R major depression during 1993–1996, a total of

150 Baltimore ECA respondents had ever qualified

for adult-onset MDD (i.e. met DSM-III-R criteria as

evaluated by the adapted DIS, and reported first

episode as having occurred after age 18). A total of

1755 people had few or no depression-related prob-

lems, and had not developed MDD by the time of the

follow-up, when the median age and minimum age of

ECA interviewees were 50 and 27 years, respectively.

To sharpen this study’s focus on the early-life expe-

riences of adult-onset MDD, we have excluded the 15

cases whose experience of the onset of the first

episode of MDD occurred before age 19.

2.3. Statistical analyses

Kaplan–Meier survival analyses were used to plot

and estimate the cumulative occurrence of each clin-

ical feature from age 6 through 18 years, contrasting

Table 1

Sociodemographic characteristics of adults with and without adult-

onset MDD, data from the Baltimore ECA follow-up sample,

1981–1993/1996

No past history of

MDD* (n= 1755)

MDD case, both recent

and past (n= 150)*

Sex

Female 1093 (62%) 110 (73%)

Male 662 (38%) 40 (27%)

Age at 1993–1996 assessment

27–39 412 (23%) 44 (29%)

40–49 436 (24%) 59 (39%)

50–59 232 (13%) 28 (19%)

60–69 213 (12%) 8 (5%)

70 + 472 (27%) 11 (7%)

Race

White,

non-Hispanic

1100 (63%) 103 (69%)

Other** 655 (37%) 47 (31%)

*As explained in accompanying text and footnote to Fig. 1,

there were 15 MDD cases with child or adolescent onset MDD.

These early-onset cases were excluded from this study of predictors

for adult-onset MDD.

**Mainly African–American.


the 150 adult-onset MDD cases and the non-cases.

Making use of information about each respondent’s

age at assessment and the reported age of onset of

each clinical feature, this actuarial approach estimates

annual occurrence by calculating the years at risk for

individuals as they pass through ages 6–18 years.

This approach provides a graphical display of infor-

mation about the retrospectively recalled experiences

of adult-onset cases and non-cases of MDD, as these

experiences emerged during childhood and adoles-

cence. In this way, it has been possible to reconstruct

the progression of features of depression over time,

displaying features that appear most rapidly and at an

increased occurrence.

For these analyses, clinical features with first onset

at ages 1–5 were recoded to age 6.5, which we

designated as the start of the observation interval of

primary interest to us. Twenty-eight individuals met

criteria for childhood or adolescent dysthymic disor-

der that preceded adult-onset MDD; these cases were

retained in the analyses because their exclusion might

have distorted our findings on anhedonia. Dysthmia

was not studied with MDD because the evolution and

clinical course is distinct from MDD (Akiskal, 1994).

Overall results (based on all male and female cases)

and female results are presented to explore potential

differences in the frequency and onset of clinical

features. Results specific for males are not presented

because there were too few cases for precise estimates

(n = 40 male adult-onset cases). Consistent with stan-

dard survival analysis conventions (Lawless, 1982),

the time of occurrence of clinical features was spec-

ified in relation to the midpoint through the age-year

reported by the respondent as the ‘age of onset’ (i.e. at

age 16.5 for someone who reported onset at 16 years

of age).

Multivariate response modeling (GLM/GEE), with

application of the general linear model and the gener-

alized estimating equations, was used to estimate the

association that links each early clinical feature to

occurrence of adult-onset MDD, based on methods

described by Liang et al. (1992) and as illustrated in

Andrade et al. (1994), Chen and Anthony (2003), and

others. This statisticalmethod, sometimes referred to as,

‘GEE multivariate response profile analysis’, takes the

interdependencies of the binary responses into account,

with statistical adjustments for covariates (here, birth

cohort, sex, and race-ethnicminority status). The result-

ing estimates are in the form of the familiar odds ratio

(i.e. the covariate-adjusted odds of reporting a given

clinical feature for cases with adult-onset MDD vs. the

corresponding odds for adults without MDD). To aid in

interpretation, 95% confidence intervals (CI) and P-

values are presented, with variance estimators based

upon a GEE exchangeable working correlation struc-

ture and robust specification for variance estimation.

3. Results

3.1. Description of study sample

In general, as described previously (Eaton et al.,

1997; Chen et al., 2000), major depression was more

prevalent among females, younger people, and Cau-

casians as compared to other race-ethnicity subgroups

in the Baltimore ECA follow-up sample (Table 1). Of

the 150 adult-onset cases of MDD, 110 are females

and 40 are males. It is important to note that, at the

time of follow-up, the youngest person in the sample

was 27 years old, and when the study began in 1981

all the respondents were 18 years of age or older. This


community sample had generally received little for-

mal clinical intervention for depression. When evalu-

ated in 1993–1996, a total of 47% of cases of MDD

had ever spoken with a doctor or mental health

professional about depression; fewer had been in

treatment for depression.

3.2. Survival analysis

Within the Baltimore ECA sample, there were

1755 adults who had not developed DSM-III-R major

depression by the time of follow-up in the 1990s.

Among the 1755 MDD non-cases, a total of 128 (7–

8%) reported at least one clinical feature of depression

before age 19. In comparison, among the 150 adults

who had developed MDD by the time of follow-up, a

total of 50 (i.e. one-third) had experienced at least one

clinical feature of depression by age 19.

Survival analysis curves for adult-onset MDD

cases and non-cases depict estimated cumulative oc-

currence of clinical features, with separate curves used

to display male– female differences (Fig. 2a–d).

Kaplan–Meier life-table estimates were derived, and

curves were plotted, in order to depict the cumulative

incidence of each clinical feature by two groups

defined in terms of adult-onset MDD status. This

method produced a cumulative age-specific estimate

of the probability of each clinical feature among those

with and without adult-onset MDD at each age under

study. Persistent anhedonia was reported by 5–6% of

female cases before age 19 years (vs. 0.2% for female

non-cases), and by 2–3% of male cases (vs. 0.5% for

male non-cases; Fig. 2a). (An inset figure was placed

in Fig. 2a to show more refined details about early

anhedonia while maintaining the same scale of the

main figure for direct comparison to other clinical

features.)

Before age 19 years, suicidal thoughts or behav-

iors were reported by 20% of female cases (vs. 2–

3% of female non-cases) and by 15% of male cases

(vs. 1–2% of male non-cases as depicted in Fig.

2b). Persistent depressed mood was reported by 21–

22% female cases (vs. almost 3% of non-cases) and

by 10% of male cases (vs. 2–3% of male non-

cases; as depicted in Fig. 2c). When we considered

all clinical features in the same analyses, a total of

36–37% of female MDD cases had experienced at

least one clinical feature of depression before age

19; for male adult-onset cases, this value was 25%.

Corresponding values for female and male non-cases

were in the 6–8% range (Fig. 2d). For most adult-

onset cases of MDD, the first disturbances occurred

after age 12 years, and occurred more frequently

among female cases than male cases.

3.3. Multivariate response modeling (GLM/GEE)

The next analysis in our series is one that expresses

the occurrence of a multivariate profile of child–

adolescent disturbances as a function of membership

in the adult-onset MDD case group versus the non-

case group, first with females and males combined,

followed by separate GEE profile analyses for

females. As explained in our Section 2, this multivar-

iate response analysis is important because it takes the

interdependencies of these reported disturbances into

account and provides an analogue to multivariate

analysis of covariance, with an allowance for statisti-

cal adjustments (i.e. for birth cohort, sex, race-ethnic-

ity). Results are presented in order of strength of

association. Table 2a provides evidence that confirms

the earlier report of Pine et al. (1999) with respect to

persistent anhedonia. Here, within the context of the

multivariate analysis, persistent anhedonia in child-

hood and adolescence is observed some 17 times

more often among adult-onset MDD cases than

among non-cases (P < 0.001), and there is no more

than modest attenuation of this association with sta-

tistical adjustment for birth cohort, sex, and race-

ethnicity (estimated relative risk (RR) = 14.1; 95%

CI = 4.5, 44.8; P < 0.001).

Table 2a also shows the overall results for other

clinical features strongly associated with MDD, such

as persistent feelings of worthlessness (RR = 19.8;

95% CI = 7.5, 51.8; P < 0.001) and diminished ability

to think or concentrate (RR = 13.8; 95% CI = 5.8,

33.1; P < 0.001). The associations with occurrence

of adult-onset MDD were not appreciably altered with

statistical adjustment for cohort, sex and race

(RR = 11.4; 95% CI = 4.8, 27.5; P < 0.001, respective-

ly). Weight/appetite disturbance in adolescence was

the clinical feature group least associated with devel-

oping adult-onset MDD after adjusting for demo-

graphic variables. Adolescents reporting weight or

appetite problems were about three to four times more

likely to develop MDD as adults than adolescents not

Fig. 2. (a) Estimated cumulative occurrence of anhedonia during the child and adolescent years, cross-classified to show the different

experiences of adult-onset MDD cases and non-cases, males and females. Data from Baltimore ECA sample, 1993–1996.* Inset figure is a plot

of the same data, but with a rescaled y-axis. (b) Estimated cumulative occurrence of thoughts of death/suicide and/or suicide attempt during the

child and adolescent years, cross-classified to show the different experiences of adult-onset MDD cases and non-cases, males and females. Data

from Baltimore ECA sample, 1993–1996. (c) Estimated cumulative occurrence of depressed mood during the child and adolescent years, cross-

classified to show the different experiences of adult-onset MDD cases and non-cases, males and females. Data from Baltimore ECA sample,

1993–1996 *. (d) Estimated cumulative occurrence of any clinical feature during the child and adolescent years, cross-classified to show the

different experiences of adult-onset MDD cases and non-cases, males and females. Data from Baltimore ECA sample, 1993–1996 *.


Fig. 2 (continued).


reporting these clinical features (RR = 4.3; 95%

CI = 2.3, 8.1; P < 0.001).

Table 2b provides separate estimates for females.

Based on these exploratory sex-specific analyses, the

association linking earlier anhedonia to later onset of

MDD is quite pronounced for females, who were about

31 times more likely to develop MDD as adults than

their female peers who did not suffer from anhedonia

(RR = 31.5; P < 0.001). Even after adjusting for demo-

graphic variables, women who had experienced per-

Table 2

Estimated association between the occurrence of each observed clinical feature before age 19 and the development of adult-onset MDD

Clinical features Unadjusted Adjusted for cohort, sex and race

RR P-value 95% CI RR P-value 95%CI

(a) Both sexes combined

Worthlessness 19.8 < 0.001 7.5–51.8 16.4 < 0.001 6.2–43.2

Anhedonia 17.1 < 0.001 5.4–54.6 14.1 < 0.001 4.5–44.8

Think/concentrate 13.8 < 0.001 5.8–33.1 11.4 < 0.001 4.8–27.5

Sleep disturbance 11.2 < 0.001 5.3–23.4 9.3 < 0.001 4.4–19.8

Death/suicide 10.1 < 0.001 6.0–17.0 8.5 < 0.001 5.1–14.3

Tiredness 7.9 < 0.001 3.4–18.7 6.6 < 0.001 2.8–15.4

Depressed mood 7.6 < 0.001 4.7–12.6 6.5 < 0.001 3.9–10.8

Motor disturbance 6.7 0.001 2.2–20.2 5.5 0.003 1.8–16.6

Weight/appetite 4.3 < 0.001 2.3–8.1 3.6 0.001 1.9–6.9

Any feature 6.4 < 0.001 4.3–9.3 5.5 < 0.001 3.7–8.2

Clinical features Unadjusted Adjusted for cohort and race

RR P-value 95% CI RR P-value 95% CI

(b) For females

Anhedonia 31.5 < 0.001 6.3–158.0 27.0 < 0.001 5.4–134.7

Worthlessness 21.4 < 0.001 6.3–72.2 18.3 < 0.001 5.4–62.5

Think/concentrate 15.5 < 0.001 5.8–41.7 13.3 < 0.001 5.0–35.7

Death/suicide 9.9 < 0.001 5.4–18.1 8.6 < 0.001 4.7–15.6

Sleep disturbance 9.0 < 0.001 3.8–21.4 7.7 < 0.001 3.2–18.6

Depressed mood 9.0 < 0.001 5.1–15.9 7.8 < 0.001 4.3–14.0

Motor disturbance 7.6 0.008 1.7–34.6 6.5 0.015 1.4–29.3

Tiredness 6.7 < 0.001 2.5–17.6 5.7 < 0.001 2.2–15.2

Weight/appetite 5.2 < 0.001 2.5–10.7 4.5 < 0.001 2.1–9.5

Any feature 6.8 < 0.001 4.3–10.6 6.0 < 0.001 3.8–9.6


sistent anhedonia were 27 times more likely to develop

MDD as adults (RR= 27.0; P < 0.001). Other obser-

vations of possible note with respect to females in-

volve persistent feelings of worthlessness during

childhood or adolescence (RR= 21.4; 95% CI = 6.3,

72.2; P < 0.001) and periods of diminished ability to

think or concentrate during childhood or adolescence,

which were also highly associated with increased risk

of developing MDD as adults (RR = 15.5; 95%

CI = 5.8, 41.7; P < 0.001) (see Table 2b). There was

no appreciable shift in the summary estimates when

terms were added to include statistical adjustment for

cohort and race (RR = 18.3; 95% CI = 5.4, 62.5;

P < 0.001; RR= 13.3; 95% CI = 5.0, 35.7; P < 0.001,

respectively).

3.4. Positive predictive value (PPV)

Sample-based PPVs were calculated as an indica-

tion of how often the early-life appearance of each

clinical feature was followed by adult-onset MDD.

Estimates of PPVs for each clinical feature were

calculated for the total sample and for females. Over-

all, the PPV estimate for persistent anhedonia was

58%, which means that 58% of adolescents reporting

anhedonia had developed MDD as adults. In the case

of female adolescents, the PPV was notably higher

(75%). For persistent feelings of worthlessness, the

estimated PPV was 61% overall and 67% for females.

The estimated PPV for persistent problems with

concentration was the next highest with 52% overall

and 59% for females. The lowest PPV was for

persistent weight/appetite disturbances, 25% overall

and 32% for females.

4. Discussion

There are four main findings: first, an estimated

33% of adult-onset cases of MDD reported early-life


clinical features before age 19, whereas only 7% of

non-cases reported clinical features. Females were

more likely than males to report disturbances in mood

and allied clinical features before age 19 years; 36%

of female cases and 25% of male cases reported at

least one clinical feature. Second, an estimated 75% of

females with child–adolescent anhedonia were found

to have developed adult-onset MDD, and for males

and females combined, the PPV estimate was about

60%. Third, persistent anhedonia in childhood and

adolescence is observed some 17 times more often

among adult-onset MDD cases than among non-cases,

and some 31–32 times more often for females.

Fourth, in the multivariate response profile analysis,

persistent feelings of worthlessness were most strong-

ly associated with MDD. Almost 70% of females with

childhood–adolescent persistent feelings of worth-

lessness later developed MDD in adulthood, whereas

the PPV for both sexes combined was about 60%.

Before detailed discussion of these results, several

limitations merit attention. First, because the range of

ages in the ECA sample did not include adolescents,

this study’s estimates are based upon an adult’s

retrospective recall of the age of onset of individual

clinical features, and are subject to errors of recall and

accuracy in reporting, although the life chart method-

ology was used to address the problem of deteriora-

tion of recall. The ECA has a prospective design, but

the age of onset questions were not administered for

each clinical feature until the ECA follow-up in

1993–1996.

A second limitation is the modest number of MDD

cases, especially male cases, which places a limit on

what can be learned from the Baltimore ECA sample,

despite its large sample, with coverage of many adult

years of life. A third limitation involves diagnostic

criteria and methods of assessment (e.g. orientation to

DSM-III-R as opposed to DSM-IV, and reliance on

the DIS, as mentioned in our Section 2). It is possible

that different results might be obtained with the DSM-

IV or ICD-10 diagnostic criteria, or with standardized

clinical examinations by psychiatrists. We must also

acknowledge a possibility that some of our adult-onset

MDD cases actually were adolescent-onset cases, with

our assessment of age-of-onset subject to a distortion

in the measurement process. Finally, we will mention

the distinction we have drawn between the ‘clinical

feature’ age of onset information that is elicited by our

survey questions versus the ‘symptom’ age of onset.

As noted in our description of methods, age of onset

questions about ‘clinical features’ are less specific

than age of onset questions about ‘symptoms’, and

not all of the experiences tallied in our Kaplan–Meier

analyses and survival plots would qualify as a ‘symp-

tom of MDD’ if an experienced psychiatrist were to

have conducted a careful examination. Some readers

may prefer to see a study focused more specifically on

‘symptoms’ of MDD, which might well lead to even

greater separation of survival curves and subgroup

differences to the extent that ‘MDD symptoms’ are

defined as observable self-report manifestations of the

underlying pathology of MDD.

Despite limitations such as these, several features of

the study’s evidence merit attention. The results of this

new study help to strengthen and confirm the thesis

advanced by Pine et al. (1999) with respect to the

prognostic significance of persistent anhedonia when it

appears before young adulthood. These new results

also help to strengthen and confirm the thesis ad-

vanced by Murphy et al. (2002) with respect to

appearance of feelings of worthlessness in children

or adolescents. Results are generally consistent with

studies of a rather insidious or slow MDD onset. These

results are also consistent with the literature on MDD

clinical features as predictors of onset among adults

(Dryman and Eaton, 1991; Horwath et al., 1992).

As to the meaning or potential clinical utility of

these findings, we note that the results provide some

support for clinical observation that early depression-

like clinical features in childhood and adolescence

have a prognostic significance with respect to later

adult-onset MDD, and it might be useful to pose

questions about distinguishing these clinical features

from variations in ‘‘normal’’ development. As such,

these early features may be a manifestation of sus-

ceptibility for later adult-onset psychiatric disturban-

ces (Pine et al., 1999; Orvaschel et al., 1995; Aronen

and Soininen, 2000). This study may also stimulate

interest in dimensional conceptualizations of depres-

sive disorder as characterized by a dynamic fluctuat-

ing course with a common disease process whereby

clinical features of depression are neither normal nor

non-specific variations of normal mood, but rather are

clinical markers of significance (e.g. see Judd and

Akiskal, 2000). From a public health standpoint,

identifying specific early clinical features of MDD


might make it possible to provide anticipatory guid-

ance or other early interventions that might prevent or

reduce the impact of the disorder.

Working along these lines, Costello (1992) as well

as Eaton et al. (1995) have discussed the importance

of studying the earliest clinical features in the screen-

ing and prevention of mental disorders. However,

definitive evidence on potentially distinctive child

and adolescent elements of an MDD prodrome may

require periodic follow-up assessments of a large

epidemiological sample from the childhood years

through the full period of risk for MDD. What is

needed is a longitudinal community study, similar to

the work by Pine et al. (1999) but with more frequent

assessments and with follow-up into and through the

periods of peak MDD risk in adulthood.

A word of caution may be necessary about the

current public health applications of this study’s find-

ings. The prospective study by Pine et al. (1999) and

our own retrospective study both highlight persistent

anhedonia (and other clinical features) as forerunner

experiences of adult-onset major depression. Grimes

and Schulz (2002) recently outlined a rationale to be

cautious about launching mass screening initiatives on

the basis of early epidemiological evidence of this type.

Until there is more evidentiary support, these findings

merit attention in new investigations, but not premature

application in the context of public health work. Ulti-

mately, the clinical and public health significance of

these findings will be demonstrated if early interven-

tion before or during the prodromal interval is effective

and leads to reduced risk, severity, duration, or disabil-

ity associated with adult-onset major depression.

5. Uncited references

Eaton, 1995; Lewinsohn et al., 1994.

Acknowledgements

We thank Dr. Li-Shiun Chen and Dr. William W.

Eaton for their assistance. This work was funded by

research training grants T32 DA07292 and F31

DA14454 from the National Institute on Drug Abuse

and research grant R01 MH47447 from the National

Institute of Mental Health.

References

Akiskal, H.S., 1994. Dysthymia: clinical and external validity. Acta

Psychiatr. Scand. 89 (Suppl. 383), 19–23.

Andrade, L., Eaton, W.W., Chilcoat, H., 1994. Lifetime comorbid-

ity of panic attacks and major depression in a population-based

study: symptom profiles. Br. J. Psychiatry 165, 363–369.

Anthony, J.C., Folstein, M., Romanoski, A.J., Von Korff, M.R.,

Nestadt, G.R., Chahal, R., Merchant, A., Brown, C.H., Sha-

piro, S., Kramer, M., Gruenberg, E.M., 1985. Comparison of

the lay Diagnostic Interview Schedule and a standardized psy-

chiatric diagnosis. Experience in eastern Baltimore. Arch. Gen.

Psychiatry 42 (7), 667–675.

Aronen, E.T., Soininen, M., 2000. Childhood depressive symptoms

predict psychiatric problems in young adults. Can. J. Psychiatry

45, 465–470.

Badawi, M., Eaton, W.W., Myllyluoma, J., Weimer, L.G., Gallo, J.,

1999. Psychopathology and attrition in the Baltimore ECA 15-

year follow-up 1981–1996. Soc. Psychiatry Psychiatr. Epide-

miol. 34, 91–98.

Chen, C.Y., Anthony, J.C., 2003. Possible age-associated bias in

reporting of clinical features of drug dependence: epidemiolo-

gical evidence on adolescent-onset marijuana use. Addiction 98

(1), 71–82.

Chen, L., Eaton, W.W., Gallo, J.J., Nestadt, G., 2000. Understan-

ding the heterogeneity of depression through the triad of symp-

toms, course and risk factors: a longitudinal, population-based

study. J. Affect. Disord. 59, 1–11.

Costello, C.G., 1992. Research on symptoms versus research on

syndromes: arguments in favour of allocating more research

time to the study of symptoms. Br. J. Psychiatry 160, 304–308.

Dryman, A., Eaton, W.W., 1991. Affective symptoms associated

with the onset of major depression in the community: findings

from the US National Institute of Mental Health Epidemiologic

Catchment Area Program. Acta Psychiatr. Scand. 84, 1–5.

Eaton, W.W., 1995. Studying the natural history of psychopatho-

logy. In: Tsuang, M., Tohen, M., Zahner, G. (Eds.), Textbook

in Psychiatric Epidemiology. Wiley-Liss Inc, New York, NY,

pp. 157–177.

Eaton, W.W., Kessler, L.G. (Eds.), 1985. Epidemiological Field

Methods in Psychiatry: The NIMH Epidemiological Catchment

Area Program. Academic Press, Orlando, FL.

Eaton, W.W., Regier, D.A., Locke, B.Z., Taube, C.A., 1981. The

Epidemiologic Catchment Area Program of the National Insti-

tute of Mental Health. Public Health Rep. 96, 319–325.

Eaton, W.W., Kramer, M., Anthony, J.C., Dryman, A., Shapiro, S.,

Locke, B.Z., 1989. The incidence of specific DIS/DSM-III men-

tal disorders: data from the NIMH Epidemiologic Catchment

Area Program. Acta Psychiatr. Scand. 79 (2), 163–178.

Eaton, W.W., Badawi, M., Melton, B., 1995. Prodromes and pre-

cursors: epidemiologic data for primary prevention of disorders

with slow onset. Am. J. Psychiatry 152, 967–972.

Eaton, W.W., Anthony, J.C., Gallo, J., Cai, G., Tien, A., Romanos-

ki, A., Lyketsos, C., Chen, L.S., 1997. Natural history of Diag-

nostic Interview Schedule/DSM-IV major depression. The

Baltimore Epidemiologic Catchment Area follow-up. Arch.

Gen. Psychiatry 54, 993–999.


Grimes, D.A., Schulz, K.F., 2002. Uses and abuses of screening

tests. Lancet 359, 881–884.

Horwath, E., Johnson, J., Klerman, K., Weissman, M., 1992.

Depressive symptoms as relative and attributable factors for

first onset depression. Arch. Gen. Psychiatry 49, 817–823.

Judd, L.L., Akiskal, H.S., 2000. Delineating the longitudinal struc-

ture of depressive illness: beyond clinical subtypes and duration

thresholds. Pharmacopsychiatry 33, 3–7.

Lawless, J.F., 1982. Statistical Models and Methods for Lifetime

Data. Wiley, New York, NY.

Lewinsohn, P.M., Clarke, G., Seeley, J.R., Rohde, P., 1994. Major

depression in community adolescents: age at onset, episode

duration, and time to recurrence. J. Am. Acad. Child Adolesc.

Psychiatry 33, 809–818.

Liang, K.Y., Zeger, S.L., Qaqish, B., 1992. Multivariate regression

analyses for categorical data. J. R. Stat. Soc. Ser. B—Methodo-

logical 54, 3–40.

Lyketsos, C.G., Heithoff, K., Nesdadt, G., Cwi, J., Eaton, W.W.,

1994. The life-chart interview: a standardized method to describe

the course of psychopathology. Int. J. Methods Psychiatr. Res. 4,

143–155.

Murphy, J.M., Nierenberg, A.A., Monson, R.R., Laird, N.M.,

Sobol, A.M., Leighton, A.H., 2002. Self-disparagement as

feature and forerunner of depression: findings from the Stirling

County Study. Compr. Psychiatry 43 (1), 13–21.

Narrow, W.E., Rae, D.S., Robins, L.N., Regier, D.A., 2002. Revised

prevalence estimates of mental disorders in the United States:

using a clinical significance criterion to reconcile 2 surveys’

estimates. Arch. Gen. Psychiatry 59 (2), 115–123.

Neumark, Y.D., Van Etten, M.L., Anthony, J.C., 2000. Drug de-

pendence and death: survival analysis of the Baltimore ECA

sample from 1981–1995. Substance Use Misuse 35, 313–327.

Orvaschel, H., Lewinsohn, P.M., Seeley, J.R., 1995. Continuity of

psychopathology in a community sample of adolescents. J. Am.

Acad. Child Adolesc. Psychiatry 34, 1525–1535.

Pine, D.S., Cohen, E., Cohen, P., Brook, J., 1999. Adolescent

depression symptoms as predictors of adult depression: moodi-

ness or mood disorder? Am. J. Psychiatry 156, 133–135.

Roberts, R.E., Lewinsohn, P.M., Seeley, J.R., 1995. Symptoms of

DSM-III-R major depression in adolescence: evidence from an

epidemiological survey. J. Am. Acad. Child Adolesc. Psychiatry

34, 1608–1617.

Robins, L.N., Regier, D.A., 1991. Psychiatric Disorders in Amer-

ica. Free Press, New York.

Robins, L.N., Helzer, J.E., Croughan, J., Ratcliff, K.S., 1981.

National Institute on Mental Health Diagnostic Interview

Schedule: its history, characteristics, and validity. Arch. Gen.

Psychiatry 38, 381–389.

Robins, L.N., Helzer, J.E., Croughan, J., Ratcliff, K.S., 1994. Na-

tional Institute on Mental Health Diagnostic Interview Schedule.

In: Mezzich, J.E., Jorge, M.R., Salloum, I.M. (Eds.), Psychiatric

Epidemiology: Assessment, Concepts and Methods. The Johns

Hopkins University Press, Baltimore, MD.

Rosenberg, M.F., Anthony, J.C., 2001. Early clinical manifestations

of cannabis dependence in a community sample. Drug Alcohol

Depend. 64, 123–131.

Weissman, M.M., Bruce, M.L., Leaf, P.J., Florio, L.P., Holzer III, C.

1991. Affective disorders. In: Robins, L.N., Regier, D.A. (Eds.),

Psychiatric Disorders in America. The Free Press, New York,

NY, pp. 53–80.

Child and adolescent clinical features as forerunners of adult-onset major depressive disorder:...

Documents

Transcript of Child and adolescent clinical features as forerunners of adult-onset major depressive disorder:...