the clinical characteristics of unipolar vs. bipolar major depression in adhd youth

www.elsevier.com/locate/jad

Journal of Affective Disorde

Research report

The clinical characteristics of unipolar vs. bipolar major

depression in ADHD youthB

Janet Wozniak*, Thomas Spencer, Joseph Biederman, Anne Kwon,

Michael Monuteaux, Jeffrey Rettew, Kathryn Lail

Pediatric Psychopharmacology Research Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

Received 8 September 2003; accepted 19 May 2004

Abstract

Objective: To investigate the characteristics of unipolar vs. bipolar depression in youth using a sample of children referred for a

study on attention deficit hyperactivity disorder (ADHD).

Methods: We compared children with unipolar depression (N=109) to those with bipolar depression (N=43) using boys and girls

(N=280) referred for a study on ADHD. Comparisons were made in characteristics of depression, comorbidity and family

history. All diagnoses were made using the KSADS-E.

Results: In comparison to children with unipolar depression, children with bipolar depression were more likely to have met

criteria for depression due to both bsadQ and bmadQ mood states as stated in the KSADS-E, have severe depression with

suicidality, anhedonia and hopelessness. Children with bipolar depression were more likely to have comorbid conduct disorder,

severe oppositional defiant disorder, agoraphobia, obsessive compulsive disorder and alcohol abuse, compared to children with

unipolar depression. Bipolar depressed children had lower GAF scores and higher rates of hospitalization. Bipolar depression is

associated with higher levels of psychiatric disorders in first-degree relatives.

Conclusions: In youth, bipolar depression is distinct from unipolar depression in quality and severity of symptoms, comorbidity

and family history. This presentation can aid clinicians in identifying children and adolescents with bipolar disorder.

D 2004 Elsevier B.V. All rights reserved.

0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.jad.2004.05.013

B Supported by the Johnson and Johnson Pediatric Psycho-

pharmacology Research Center at Massachusetts General Hospital.

* Corresponding author. Massachusetts General Hospital ACC

725, Boston, MA 02114, United States. Tel.: +1 617 724 5600; fax:

+1 617 503 1060.

E-mail address: [email protected] (J. Wozniak).

1. Introduction

When a child or adolescent presents with a severe

disturbance of mood, both unipolar major depression

(MDD) and bipolar disorder should be considered in

the differential diagnosis. While mania and depression

can be distinguished from each other, differentiating

between unipolar and bipolar forms of depression

poses unique clinical and therapeutic challenges.

rs 82S (2004) S59–S69

J. Wozniak et al. / Journal of Affective Disorders 82S (2004) S59–S69S60

Although a few studies suggest that childhood onset

MDD is associated with the development of bipolar

disorder, questions remain as to which clinical

characteristics of MDD should alert clinicians to the

likelihood of a bipolar disorder clinical picture. As the

use of antidepressants may precipitate manic symp-

toms when used for bipolar depression, differentiating

unipolar from bipolar depression is of high clinical

relevance.

In a prospective longitudinal study of 60 hospi-

talized, depressed adolescents aged 13–16 years,

Strober et al. (1993) found that 20% switched to

bipolar disorder at 3–4-year follow-up and was

predicted by the rapid onset of depressive symptoms,

psychomotor retardation, mood-congruent psychotic

features, a family history of bipolar illness and a

history of pharmacologically induced hypomania.

Geller et al. (1994, 2001) followed-up 79 children

(80% prepubertal) with major depression and found

that 32% switched to mania by an average age of 11

years and 50% by the age of 21 years and the conduct

disorder symptom of bullying and family history were

predictors of switching. Luby and Mrakotsky (2003)

found early risk factors for switching to mania in a

group of depressed preschoolers. These authors

concluded that increased rates of restlessness in the

depressed preschoolers with a family history of

bipolar disorder may represent a precursor of bipolar

disorder. Taken together, these findings suggest that

juvenile MDD especially with a family history of

bipolar disorder is strongly associated with the

development of later mania.

The identification of characteristics of pediatric

depression that could predict the presence of manic

episodes is of high clinical importance. In a natural-

istic chart review by Biederman et al. (2000), these

authors found that prescribing an antidepressant to a

child with mania results in manic exacerbation, but in

addition prescribing an antidepressant to a child with

an earlier, distant history of mania also results in

manic exacerbation. Given concerns that the treat-

ments for depression may exacerbate bipolar disorder

in children with bipolar depression, early recognition

of bipolar depression can aid clinicians in the

management of such patients.

To this end, this study investigated whether

unipolar and bipolar depression in youth can be

distinguished from each other in terms of clinical

features and correlates. Based on the literature, we

hypothesized that bipolar depression as compared to

unipolar depression would be characterized by earlier

onset, family history of bipolar disorder and comor-

bidity, especially with conduct disorder. To our

knowledge, this effort represents the most compre-

hensive evaluation of this subject.

2. Methods

Study subjects were children and adolescents with

major depression, stratified by the presence or absence

of bipolar disorder. Controls without depression or

bipolar disorder were included in some analyses for

comparative purposes. All youth had been diagnosed

with ADHD and had been referred for a family

genetic study of ADHD, which is described in

previous publications (Biederman et al., 1992; Bieder-

man et al., 1996; Biederman et al., 1999; Faraone et

al., 1993; Faraone et al., 2000). These youth were all

index cases of ADHD (probands), and were com-

prised of Caucasian, non-Hispanic males (N=140) and

females (N=140) between the ages of 6 and 17 years.

Referrals were obtained from two independent sour-

ces, psychiatrists and pediatricians. Psychiatrically

referred probands with ADHD were obtained through

consecutive referrals to the Pediatric Psychopharma-

cology Clinic at the Massachusetts General Hospital

(MGH), Boston. Pediatrically referred probands con-

sisted of pediatric patients from the Harvard Com-

munity Health Plan, a large health maintenance

organization (HMO).

Potential probands were excluded if they had been

adopted or if their nuclear family was unavailable for

study. We also excluded probands if they had major

sensorimotor handicaps (e.g., paralysis, deafness,

blindness), psychosis, autism or a Full-Scale IQ less

than 80. All of the probands with ADHD met

diagnostic criteria for current ADHD when clinically

referred. All subjects gave written informed consent

prior to enrollment in the study.

All diagnostic assessments were made using DSM-

III-R-based structured interviews. Psychiatric assess-

ments of probands and siblings were made with the

childhood version of the Schedule for Affective

Disorders and Schizophrenia, Epidemiologic version

(Kiddie-SADS-E) (Orvaschel and Puig-Antich, 1987).

J. Wozniak et al. / Journal of Affective Disorders 82S (2004) S59–S69 S61

Diagnoses were based on independent interviews with

the mothers and direct interviews of probands and

siblings, except for children younger than 12 years,

who were not directly interviewed. Psychiatric assess-

ments of parents and adult siblings were made using

the Structured Clinical Interview for DSM-III-R

(SCID) (Spitzer et al., 1990). For every diagnosis,

information was also gathered regarding the ages at

onset and offset of symptoms, number of episodes and

treatment history.

Interviews were conducted by raters with under-

graduate degrees in psychology who had been trained

to high levels of interrater reliability. We computed jcoefficients of agreement by having three experi-

enced, board-certified child and adult psychiatrists

diagnose subjects from audiotaped interviews made

by the assessment staff. Based on 175 interviews, all

disorders achieved j’s higher than 0.82. The mean jwas 0.90. We attained a j of 1.0 for ADHD and 0.91

for BPD. The reliability of maternal reports of these

disorders over a 1-year period was also high, with j’sfor ADHD and BPD being 0.95 and 0.71 (Faraone et

al., 1995).

All diagnoses were reviewed blindly by a diag-

nostic sign-off committee chaired by the service chief

(JB) who reviewed both the items endorsed during the

interview along with detailed notes taken by the

interviewer. Diagnoses of depression and mania

underwent extensive review. Diagnoses presented

for review were considered positive only if a con-

sensus was achieved that criteria were met to a degree

that would be considered clinically meaningful. By

bclinically meaningfulQ, we mean that the data

collected from the structured interview indicated that

the diagnosis should be a clinical concern due to the

nature of the symptoms, the associated impairment

and the coherence of the clinical picture. Because the

anxiety disorders compose many syndromes with a

wide range of severity, we also report results for two

or more anxiety disorders to index the presence of a

clinically meaningful anxiety syndrome. For children

older than 12 years, data from direct and indirect

interviews were combined by considering a diagnos-

tic criterion positive if it was endorsed in either

interview. Since the structured interviews generate

diagnostic information about both past and current

disturbances, the rates of illness reported herein are

lifetime prevalences.

Families were considered intact if there was no

divorce or separation in the proband’s family of origin.

Socioeconomic status was assessed with the Hollings-

head Four-Factor Index of Social Status (Hollings-

head, 1975), which uses parental education and

occupation to determine a family’s composite social

status. We also obtained information regarding cog-

nitive functioning using subtests from the Wechsler

Intelligence Scale for Children (WISC-R) (Wechsler,

1991). To evaluate school functioning, we assessed

three straightforward indices of school failure, based

on parent reports: placement in special classes, in-

school tutoring and repeated grades. Psychosocial

functioning was assessed using the DSM-III-R Global

Assessment of Functioning (GAF: 0=worst to

90=best). Scores for the Social Adjustment Inventory

(SAICA) (John et al., 1987) were obtained (where

higher scores indicate poorer functioning).

2.1. Statistical analysis

Comparisons were made between three groups (all

with ADHD): subjects with MDD only (unipolar

depression), subjects with MDD who fulfilled criteria

for mania (bipolar depression) and control subjects

without depression or bipolar disorder. Logistic or

ordinary least squares regression models were used to

predict clinical outcomes. Pairwise comparisons

between groups were also conducted if omnibus tests

were found to be significant. Omnibus analyses were

adjusted for SES and family intactness, while unipolar

vs. bipolar depression comparisons were adjusted for

gender and family intactness. Two-tailed tests were

used and statistical significance was set at the 0.05

level for omnibus statistics and 0.01 level for pairwise

comparisons.

3. Results

The three groups for comparison were ADHD boys

and girls meeting KSADS-E structured interview

criteria for MDD, but not for mania (unipolar depres-

sion group, N=109), meeting criteria for MDD plus

mania (bipolar depression, N=43), and ADHD boys

and girls without MDD or mania (control, N=128). In

the bipolar depressed group, 55% had a mixed

presentation and others had a biphasic presentation.

Table 2

Clinical characteristics of unipolar and bipolar depression probands

Unipolar

depression

(N=109)

Bipolar

depression

(N=43)

Test statistic,

p-valuea

MDD characteristics

Age of onset 7.8F4.2 6.5F3.9 Z=1.01, p=0.314

Age of onsetV12 96 (89) 39 (91) v(1)2 =0.11, p=0.744

Severe impairment 47 (43) 33 (77) Z=3.11, p=0.002

Screening symptoms

Sad at all 73 (69) 34 (79) Z=1.3, p=0.19

Sad only 16 (15) 2 (5) Z=�1.6, p=0.106

Irritable at all 79 (75) 38 (88) Z=1.55, p=0.122

Irritable only 22 (21) 6 (14) Z=�1.3, p=0.193

Both sad and

irritable

57 (54) 32 (74) Z=2.3, p=0.022

Anhedonia 74 (70) 37 (86) Z=2.1, p=0.035

Symptoms

Appetite and weight

changes

68 (65) 30 (71) Z=1.07, p=0.283

Sleep disturbances 86 (82) 37 (88) Z=1.07, p=0.283

Psychomotor

disturbance

83 (79) 39 (93) Z=1.93, p=0.053

Fatigue, loss of

energy

63 (60) 19 (45) Z=�1.19, p=0.233

Worthlessness,

excessive guilt

95 (90) 36 (86) Z=�0.48, p=0.631

(Lack of)

concentration/

indecision

97 (92) 41 (98) Z=1.52, p=0.128

Diurnal mood

variation

59 (56) 26 (62) Z=0.79, p=0.527

Irritability/anger 87 (83) 39 (93) Z=1.53, p=0.126

Hopelessness/

pessimistic

71 (69) 37 (88) Z=2.37, p=0.018

Multiple physical

complaints

57 (54) 26 (62) Z=1.27, p=0.205

Social withdrawal 65 (62) 22 (52) Z=�1.17, p=0.242

Reactivity of mood 21 (20) 11 (26) Z=0.8, p=0.422

Evidence of 25 (26) 13 (33) Z=0.89, p=0.376


Also of the bipolar group, 47% presented with MDD

first and then mania, 30% presented with mania first

and then MDD, and 23% had a simultaneous mixed

onset on mania and MDD (Table 1).

Youth with unipolar depression vs. those with

bipolar depression had a mean age of 13.2 and 13.5

years, respectively, while controls reported a mean age

of 12.4 years. There were no significant differences in

age or gender among the three groups. Control and

unipolar depressed subjects had higher rates of

familial intactness ( p=0.039) and slightly higher

SES ( p=0.038) compared to subjects with bipolar

depression.

After controlling for family intactness and gender,

bipolar depression was significantly more likely to

present with severe MDD impairment (77% vs. 43%;

Z=3.11, p=0.002) vs. moderate or mild impairment as

measured by the KSADS-E. Both the MDD KSADS-

E screening symptom of anhedonia and the combina-

tion of both sad and irritable symptoms were found to

be higher in bipolar depression subjects (Z=2.1,

p=0.035 and Z=2.3, p=0.022, respectively). Bipolar

depression was also associated with a higher rate of

suicidality (69% vs. 50% in MDD only; Z=2.21,

p=0.027) and feelings of hopelessness or pessimism

(Z=2.37, p=0.018) (Table 2).

Unipolar depression subjects reported significantly

greater use of therapy or counseling alone without

medication treatment than bipolar depression subjects

(Z=�2.2, p=0.03). Bipolar depression subjects

reported significantly greater rates of hospitalization

(Z=3.2, p=0.001) (Tables 2 and 3).

Bipolar depressed youth generally presented with

higher rates of comorbid psychiatric disorders com-

precipitation

Suicidality

(ideation/attempts)

52 (50) 29 (69) Z=2.21, p=0.027

Total MDD symptom

count

8.5F3.0 9.4F2.9 t(79)=�1.7, p=0.09

Treatment history

Therapy/

counseling only

34 (49) 9 (23) Z=�2.2, p=0.03

Hospitalization 4 (6) 14 (36) Z=3.2, p=0.001

Medication only 5 (7) 0 (0) p=0.158b

Combined medication

or therapy

27 (39) 16 (41) Z=0.36, p=0.716

All values in table represent meanFS.D. or frequency (%).a Analyses adjusted for gender and familial intactness.b Using Fisher’s exact test.

Table 1

Demographic information in unipolar and bipolar depression

probands

Control

(ADHD)

(N=128)

Unipolar

depression

(N=109)

Bipolar

depression

(N=43)

Omnibus test

statistic, p-value

Age 12.4F4.1 13.2F3.1 13.5F3.2 F=2.1, p=0.125

AgeV12 40 (36) 45 (44) 20 (52) v(2)2 =8.3, p=0.016

SES 1.8F0.8 1.9F1.1 2.2F1.1 F=3.3, p=0.038

Gender

(male)

59 (46) 53 (49) 28 (65) v(2)2 =4.9, p=0.088

Intactness 98 (78) 79 (72) 24 (56) v(2)2 =6.5, p=0.039

All values in table represent meanFS.D. or frequency (%).

Table 3

Psychiatric comorbidity of unipolar and bipolar depression

probands

Control

(ADHD)

(N=128)

Unipolar

depression

(N=109)

Bipolar

depression

(N=43)

Omnibus

test statistic,

p-valuea

Disruptive disorders

Conduct disorder 11 (9) 13 (12) 25 (60)b,c v(4)2 =47.35,

pb0.0001

Oppositional

disorder

19 (15) 33 (30)d 27 (63)b,c v(4)2 =34.54.

pb0.0001

Mood disorders

Dysthymia 14 (11) 19 (17) 7 (16) v(4)2 =2.6,

p=0.622

Anxiety disorders

Multiple (z2)

anxieties

23 (19) 50 (46)d 24 (57)b v(4)2 =35.33,

pb0.0001

Panic disorder 2 (2) 10 (9) 4 (10) v(4)2 =10.2,

p=0.037

Agoraphobia 13 (11) 20 (18) 17 (41)b,c v(4)2 =18.1,

p=0.001

Overanxious

disorder

23 (19) 52 (48)d 25 (60)b v(4)2 =36.14,

pb0.0001

Social phobia 11 (9) 32 (29)d 12 (29)b v(4)2 =20.74,

p=0.0004

Simple phobia 23 (19) 35 (32) 17 (43)b v(4)2 =12.41,

p=0.015

Separation

anxiety

24 (20) 36 (33) 19 (45)b v(4)2 =11.86,

p=0.018

OCD 5 (4) 9 (8) 8 (20)b v(4)2 =12.95,

p=0.012

Substance disorders

Any substance use 11 (9) 18 (17) 12 (28)b v(4)2 =12.9,

p=0.012

Alcohol abuse 9 (7) 6 (6) 9 (21)b,c v(4)2 =10.8,

p=0.029

Alcohol

dependence

3 (2) 5 (5) 4 (9) v(4)2 =4.0,

p=0.411

Drug abuse 8 (6) 10 (9) 8 (19) v(4)2 =5.4,

p=0.245

Drug dependence 5 (4) 9 (8) 4 (9) v(4)2 =3.4,

p=0.500

Other disorders

Psychosis 3 (2) 7 (6) 3 (7) v(4)2 =4.9,

p=0.302

Smoking 13 (10) 22 (20) 13 (30)b v(4)2 =11.6,

p=0.021

Tic disorder/

Tourette’s

16 (31) 17 (32) 11 (42) v(4)2 =1.1,

p=0.903

Tic disorder 4 (7) 6 (11) 2 (7) v(4)2 =2.0,

p=0.741

All values in table represent frequency (%).a Analyses adjusted for SES and familial intactness.b pb0.01 for bipolar depression vs. control.c pb0.01 for unipolar depression vs. bipolar depression.d pb0.01 for unipolar depression vs. control.


pared to their unipolar depressed and control counter-

parts. Significantly greater rates were found in the

bipolar depression group compared to the unipolar

depression group for conduct disorder (Z=5.17,

pb0.001), severe ODD (Z=2.88, p=0.004), alcohol

abuse (Z=2.7, p=0.007) and agoraphobia (Z=2.9,

p=0.004).

Likewise, higher rates of psychiatric disorders were

found in the relatives of the bipolar depression

subjects compared to relatives of unipolar depression

and control subjects (Table 4). Omnibus comparisons

among all three groups were significant for MDD

( p=0.003), multiple anxiety disorders ( p=0.0002),

bipolar disorder ( p=0.003), conduct disorder

( p=0.0001) and oppositional disorder ( p=0.0002;

severe ODD, p=0.044). Unipolar depression to

bipolar depression comparisons also reached signifi-

cance for MDD (Z=2.81, p=0.005), multiple anxiety

disorders (Z=3.17, p=0.002), BPD (Z=2.6, p=0.008),

conduct disorder (Z=3.3, p=0.001), oppositional

defiant disorder (ODD) (Z=3.1, p=0.002) and severe

ODD (Z=2.4, p=0.02).

Unipolar depression and control youth were found

to have better psychosocial functioning, and reported

Table 4

Psychiatric comorbidity in relatives of unipolar and bipolar

depression probands

Control

(ADHD)

(N=536)

Unipolar

depression

(N=339)

Bipolar

depression

(N=146)

Omnibus

test statistic,

p-value

MDD 132 (43) 115 (45) 72 (62)a,b v(2)2 =11.6,

p=0.003

MDD, severe 47 (30) 13 (12) 25 (60) v(2)2 =5.8,

p=0.055

Multiple anxiety

disorders

69 (23) 33 (30) 27 (63)a,b v(2)2 =17.5,

p=0.0002

ADHD 68 (17) 56 (17) 25 (18) v(2)2 =0.06,

p=0.971

BPD 18 (7) 18 (8) 18 (20)a,b v(2)2 =11.4,

p=0.003

Conduct

disorder

25 (9) 26 (12) 29 (31)a,b v(2)2 =17.8,

p=0.0001

Oppositional

disorder

43 (16) 47 (20) 41 (43)a,b v(2)2 =16.8,

p=0.0002

Oppositional

disorder,

severe

17 (6) 13 (6) 16 (17) v(2)2 =6.3,

p=0.044

All values in table represent frequency (%).a pb0.01 for bipolar depression vs. control.b pb0.01 for unipolar depression vs. bipolar depression.


higher GAF scores than bipolar depression youth

(past GAF: omnibus pb0.0001, current GAF: omni-

bus pb0.0001). Subjects with bipolar depression

reported poorest functioning in most SAICA scores,

with significantly higher scores (worse functioning)

for school behavior (t=2.8, p=0.007), problems with

peers (t=2.8, p=0.006), problems and activity with

siblings (Z=2.3, p=0.023; t=2.4, p=0.02) and prob-

lems with parents (t=�2.6, p=0.011) compared to

subjects with unipolar depression. Unipolar

depressed youth reported significantly greater prob-

lems with boy–girl relationships (t=�2.6, p=0.012)

(Table 5).

Although the omnibus statistics for the WISC-R

and WRAT subscales reached statistical significance

for many of the items, pairwise comparisons between

unipolar and bipolar depression subjects did not reach

statistical significance at the 0.01 level. There was a

trend towards significance on the block design WISC-

R subscale in unipolar depression youth (Z=�2.2,

p=0.03). There were no significant differences among

the groups for learning disabilities (arithmetic or

reading) or school failure (repeated grade and tutor-

Table 5

Psychosocial outcome in unipolar and bipolar depression probands

Control (ADHD)

(N=128)

Unipolar dep

(N=109)

GAF scores

Past GAF 51.3F7.1 47.1F6.5b

Current GAF 63.3F6.3 60.3F6.1b

Social Adjustment Inventory scale

School behavior 2.5F0.8 2.7F0.8

Spare-time activities 1.9F0.6 2.2F0.6b

Spare-time problems 1.9F0.7 2.4F0.8b

Activity with peers 1.9F0.8 2.2F0.7b

Problems with peers 1.8F0.8 2.3F0.7b

Boy–girl relationship 2.3F0.9 2.6F0.8

Problems with opposite sex 1.3F0.6 1.7F0.9b

Activity with sibling 1.7F0.8 1.8F0.9

Problems with siblings 1.8F0.9 1.9F0.9

Relationship with mother 1.4F0.6 1.6F0.7

Relationship with father 1.6F0.8 1.8F0.8

Problems with parents 1.8F0.8 2.2F0.8b

All values in table represent meanFS.D.a All analyses adjusted for SES and familial intactness.b pb0.01 for unipolar depression vs. control.c pb0.01 for bipolar depression vs. control.d pb0.01 for unipolar depression vs. bipolar depression.

ing) (all p=NS), with the exception of placement in a

special class, which was higher for unipolar and

bipolar depression subjects compared to controls

(both comparisons, pb0.01) (Table 6).

4. Discussion

In children and adolescents, determining the polar-

ity of a mood disorder presentation is a common

clinical dilemma. Indeed, youth presenting with MDD

may go on to develop bipolar disorder. In this sample,

47% of the bipolar individuals had MDD present prior

to mania. However, 23% had a simultaneous onset of

mania and depression while 55% had mixed clinical

pictures during their illness. Children presenting with

mixed states pose a particular clinical challenge.

Especially at this time in history when most child

and adolescent psychiatrists have been trained in the

recognition of MDD, but not in mania, a child

presenting with mixed symptoms may be mistakenly

identified as having unipolar rather than bipolar

disorder.

ression Bipolar depression

(N=43)

Omnibus test statistic,

p-valuea

40.0F7.4c,d F(4,275)=23.11, pb0.0001

55.6F6.3c,d F(4,275)=14.7, pb0.0001

3.1F0.6c,d F(4,262)=7.6, pb0.0001

1.9F0.6 F(4,262)=2.4, p=0.048

2.6F0.8c F(4,262)=11.1, pb0.0001

2.2F0.7c F(4,262)=3.4, p=0.01

2.7F0.8d F(4,262)=11.7, pb0.0001

2.0F0.8 F(4,97)=1.3, p=0.268

1.6F0.7 F(4,91)=3.5, p=0.011

2.1F1.0 F(4,251)=3.5, p=0.009

2.3F1.1c F(4,251)=3.8, p=0.006

1.8F0.8c F(4,262)=3.0, p=0.018

2.1F1.0c F(4,262)=6.2, p=0.0001

2.5F0.7c F(4,262)=9.2, pb0.0001

Table 6

Cognitive functioning, school functioning and learning disabilities in unipolar and bipolar depression

Control (ADHD)

(N=128)

Unipolar depression

(N=109)

Bipolar depression

(N=43)

Omnibus test statistic,

p-value**Analyses

adjusted for SES and

familial intactness

WISC-R subscales

Vocabulary 11.3F3.1 11.4F3.2 10.5F3.1 F(4,273)=9.74, pb0.0001

Block design 12.4F3.4 12.5F3.7 11.4F3.5 F(4,273)=7.9, pb0.0001

Digit symbol 11.1F3.1 10.5F3.4 10.4F3.1 F(4,271)=2.0, p=0.095

Digit span 9.3F2.9 9.4F3.2 9.6F3.3 F(4,272)=0.1, p=0.868

Oral arithmetic 10.5F2.7 10.7F3.1 10.7F3.0 F(4,273)=4.6, p=0.001

Estimated full-scale IQ 105.3F9.9 105.1F10.7 101.4F8.9 F(4,274)=15.2, pb0.0001

Freedom from distractibility 101F12.9 99.8F16.2 100.3F16.0 F(4,272)=6.5, pb0.0001

WRAT subscales

Arithmetic 99.8F14.5 98.7F14.8 98.4F18.5 F(4,272)=7.2, pb0.0001

Reading 104.6F12.9 102.4F16.6 99.6F16.1 F(4,245)=8.0, pb0.0001

Learning disabilities

Arithmetic 4 (6) 3 (5) 2 (13) v(4)2 =1.8, p=0.618

Reading 3 (4) 3 (5) 1 (7) v(4)2 =0.9, p=0.925

School failure

Repeated grade 32 (25) 41 (38) 14 (33) v(4)2 =9.4, p=0.052

Tutoring 103 (81) 91 (83) 36 (84) v(4)2 =0.8, p=0.939

Special class 32 (25) 48 (44)a 27 (63)b v(4)2 =38.8, pb0.0001

All values in table represent meanFS.D. or frequency (%).a pb0.01 for unipolar depression vs. control.b pb0.01 for bipolar depression vs. control.


In this sample, 30% of the pediatric subjects had

mania onset prior to MDD. This clinical picture

requires the clinician to obtain a distant history of

mania in the child or adolescent presenting with

MDD. In a child aged 6 or 7 years old (the average

age of onset of MDD in this sample), this may require

an inquiry into preschool thinking, feeling and

behavior. In older children and adolescents, a retro-

spective history may be unreliable. The features of

depression noted in this study can alert clinicians to

probe especially carefully with those depressed

children who are most likely to have a distant, current

or future episode of mania and aid in fashioning the

most effective treatment plan.

In this study examining the features of depression

in ADHD youth with and without mania, we found

that in contrast to unipolar depression, bipolar

depression was more likely to present with severe

impairment, suicidality, both irritability and sadness,

and higher levels of comorbidity with CD, ODD,

alcohol abuse and agoraphobia. While the differences

between the two groups reached statistical signifi-

cance, many of those with unipolar depression,

however, did present with these characteristics.

Comorbidity with CD is consistent with findings

from Geller et al who noted higher rates of bullying in

MDD youth who switched (Geller et al., 1994). Both

greater family intactness and higher SES were noted

in those with unipolar depression vs. those with

bipolar depression, suggesting that having a child with

bipolar disorder vs. unipolar disorder is more likely to

lead to dysfunction in family relationships and

occupational functioning.

As noted in the literature, family history was

helpful in distinguishing youth with unipolar from

bipolar depression (Geller et al., 1994; Strober and

Carlson, 1982). A family history of bipolar disorder

was more likely to be present in bipolar (20%) vs.

unipolar (8%) depressed youth. In addition, relatives

of youth with bipolar depression had greater levels

of MDD (62%) vs. unipolar youth (45%), whose

rates of MDD approximated that of non-MDD, non-


BPD ADHD youth (43%). Relatives of youth with

bipolar depression also had higher rates of other

disorders when compared to relatives of youth with

unipolar depression including multiple anxiety dis-

orders (63% vs. 30%), CD (31% vs. 12%) and ODD

(43% vs. 20%). While work by Strober (1992) and

Strober et al. (1988) indicates that early onset bipolar

disorder carries with it a greater genetic loading for

bipolar disorder, little is written on the loading for

other disorders. Our study, consistent with an

emerging literature addressing the family genetics

of conditions which frequently present comorbidly

with pediatric bipolar disorder (Wozniak et al., 2001,

2002), not only finds high levels of bipolar disorder

in family members, but high levels of other

conditions as well when compared to relatives of

probands with unipolar depression. This finding

supports the concept of heterogeneity of bipolar

disorder with the pediatric onset form presenting

with distinct features, including a strong family

history of various psychiatric disorders.

In comparison to youth with unipolar depression,

youth with bipolar depression were more likely to

endorse both the sad and irritable screens (as opposed

to one or the other) on the KSADS structured

interview and require both medication treatment and

counseling (rather than counseling alone, which was

seen among more unipolar youth). Based on GAF

scores, hospitalization, KSADS severity rating and the

presence of suicidality, bipolar depression in youth

appears to present with much greater morbidity than

unipolar depression. This may not be surprising, as

manic states bring with them greater levels of

impulsivity and aggression, which could be directed

against the self as well as outward. However, the only

study to examine severity done with an adult

population, Mitchell et al. (2001) found no difference

in severity between unipolar and bipolar depression

based on Hamilton Rating Scale Score for Depression.

This may in part be due to the fact that the severity

outcome measure was limited to the Hamilton score

only and also that the sample included a large number

of subjects who were already hospitalized (and thus

more severely affected), whereas this sample is

entirely an outpatient sample. This may also indicate

that findings in adults regarding differences in

unipolar vs. bipolar depression cannot be extrapolated

to youth.

This study finds a higher rate of suicidality

(ideation and attempts) among youth with bipolar

depression than among youth with unipolar depres-

sion. This is consistent with findings from Brent et al.

(1988) who found that suicide victims (N=27)

compared to those with ideation or suicide attempt

(N=56) were more likely to suffer from bipolar

disorder with a trend toward higher comorbidity with

ADHD, a condition which combines mood instability

with high degrees of impulsivity. The finding of

higher levels of suicidality in those with bipolar

disorder is important from a clinical, scientific and

public health perspective. From a clinical perspective,

when evaluating children and adolescents for suicide

risk and the attendant need for precautions or

hospitalization, including questions regarding symp-

toms of mania may be important. From a public health

perspective, this finding could lead to more efficient

screening of children and adolescents at risk. From a

scientific standpoint, when evaluating the genetics of

suicide a possible link to bipolar disorder should be

explored.

While our study focused on a pediatric popula-

tion, Mitchell et al. (2001) compared clinical features

of depression in 39 matched pairs of inpatients and

outpatients adults meeting DSM IV criteria for

unipolar and bipolar depression. In this study, the

bipolar patients were more likely to have psycho-

motor-retarded melancholic features and atypical

depressive features (mood reactivity, reversed sleep

and appetite disturbances, psychomotor disturbance)

as well as previous episodes of psychotic depres-

sion. In contrast, our study of children and adolescents

did not find the atypical features of depression to

be useful in distinguishing unipolar from bipolar

depression.

One reason these findings may not extrapolate to

the pediatric population is the observation that child-

hood depression in general may be more likely to be

characterized by atypicality as compared to adult

depression, thus rendering this feature less useful in

distinguishing between unipolar and bipolar depres-

sion in youth. Consistent with this idea, in their study

of the characteristics of depressed youth who

switched, Geller et al. (1994) note that atypical

features of depression were not predictive of switch-

ing. While some studies of adults which compare

unipolar and bipolar depression have found lower age


at onset, more comorbidity and more atypical features

associated with bipolar depression, other studies find

few differences. (Goodwin and Jamison, 1990) Con-

flicting findings have been reported regarding the

presence or absence of psychomotor retardation and

agitation, suicidal behavior and chronic course

(Benazzi et al., 1999a,b, 2003; Kuhs and Reschke,

1992). In a study comparing psychotic bipolar and

unipolar depression, no differences in any of these

variables was found (Benazzi, 1999).

The findings from this study and others may be

useful to clinicians in the important clinical decision of

whether to use an antidepressant or a mood stabilizer

with an antidepressant in a child or adolescent

presenting with severe mood disturbance suggestive

of depression. Recent data suggesting that the anti-

depressant paroxetine should not be used in individuals

under the age of 18 due to increased suicidality only

highlights the importance of this issue (Waechter,

2003). Studies of adults with bipolar disorder have

begun to extensively examine the issue of the use of

antidepressants in bipolar individuals. Such studies

indicate that adult bipolar disorder is more likely to be

characterized by the depressive than the manic phase of

the illness (Altshuler et al., 2003a,b, 2002; Post et al.,

1977, 2001, 2003). Furthermore, these studies indicate

that the extended use of an antidepressant can treat the

depressive phase of the illness without exacerbating

mania in many individuals (Altshuler et al., 2003b).

The field awaits further studies which address whether

depression in youth with bipolar disorder can be

effectively treated without exacerbating mania.

In summary, although a few studies suggest that

childhood onset MDD is associated with the develop-

ment of bipolar disorder, questions remain as to which

clinical characteristics of depression should alert

clinicians to the likelihood of bipolar disorder. A

limitation of this study is that it is a cross-sectional

examination of the features of MDD in individuals

who have and have not already developed mania.

Therefore, it may assist in determining whether an

individual with MDD is unipolar or bipolar, but

whether the features described offer any predictive

value regarding switching is less certain. Because this

is an ADHD sample, differences in rates of ADHD

could not be examined between the groups with

unipolar and bipolar depression. However, as early

onset bipolar disorder is characterized by high rates of

comorbid ADHD, any bipolar sample is likely to have

high rates of ADHD. The universal presence of ADHD

in both the unipolar and bipolar groups may have

dampened our ability to detect differences in cognitive

and school functioning. As psychosis was an exclu-

sionary criteria in the original sample of ADHD

children, the reported rates of psychosis are lower

than would be anticipated. This exclusionary charac-

teristic of the sample also renders it impossible to test

the hypothesis that bipolar depression is more likely

than unipolar depression to be accompanied by mood-

congruent psychotic features (Strober et al., 1993).

Future work would benefit from examining unipolar

and bipolar depression in an unselected sample. As the

sample is young, not all individuals have passed

through the age of risk for developing bipolar disorder

and some portion of the unipolar group may actually

be bpre-bipolarQ.In addition, for this study, we have set the

statistical significance level at p=0.01, consistent with

a Bonferroni correction for pairwise comparisons. As

many statistical comparisons were made overall, the

possibility that our findings are due to chance alone

are increased. However, as this study is hypothesis

generating and represents the only such comparison of

its kind between unipolar and bipolar depression in

youth, we felt the findings are of clinical and research

interest nonetheless.

The symptoms found to differentiate bipolar from

unipolar depression, while statistically significant,

were often not greater than 20% between the two

groups (e.g. anhedonia was present in 86% of the

bipolar depressed group vs. 70% of the unipolar

depressed group). In addition, the differentiating

symptoms were often present in at least 50% of the

unipolar depressed group. Thus, from a clinical

standpoint, these symptoms and characteristics

should be viewed as aids in distinguishing these

groups and not as specific and unique to bipolar

depression.

Despite its limitations, this study represents the

first attempt to our knowledge to identify features of

MDD uniquely associated with bipolarity in a

pediatric population. Severe impairment, poor func-

tioning, suicidality, hospitalization, irritability and

sadness, high levels of comorbidity with CD, ODD

and agoraphobia as well as high rates of psychiatric

disorders in first degree relatives are all features which


distinguish bipolar from unipolar depression in this

sample of ADHD youth. These features can alert

clinicians to those patients at highest risk of manic

exacerbation when treated with antidepressants.

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