www.elsevier.com/locate/jad

Journal of Affective Disorders 78 (2004) 81–84

Preliminary report

Earlier onset of bipolar disorder in children by antidepressants or

stimulants? An hypothesis

Catrien G. Reicharta,*, Willem A. Nolenb

aDepartment of Child and Adolescent Psychiatry, Sophia Children’s Hospital/Erasmus University of Rotterdam, Dr. Molewaterplein 40,

Rotterdam 3015 GD, The NetherlandsbDepartment of Psychiatry, University Medical Center Utrecht and Altrecht Institute for Mental Health Care, Utrecht, The Netherlands

Received 17 January 2002; received in revised form 15 May 2002; accepted 27 May 2002

Abstract

Among adults and adolescents, bipolar disorder (BD) has a similar prevalence in the US and in the Netherlands. However,

among pre-pubertal children, BD is frequently diagnosed in the US and seldomly in the Netherlands. This suggests that, among

children, the prevalence of BD is lower in the Netherlands than in the US, indicating an earlier onset of BD in the US than in the

Netherlands. It is hypothesized that this may be related to the greater use of antidepressants and stimulants for depression or

attention deficit disorder with hyperactivity by US children. In those children who are genetically at risk to develop BD, these

drugs may lead to a switch into mania.

D 2002 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder; Children; Antidepressants; Stimulants

1. Possible different prevalence of bipolar 1995). Onset before puberty is controversial. The only

disorder among children in the US and the

netherlands

Bipolar disorder (BD) has a life-time prevalence of

about 1.5–2%, with similar prevalence rates among

both adults and adolescents in the United States (US)

and the Netherlands (Regier et al., 1993; Kessler et al.,

1994; Bijl et al., 1998; Verhulst et al., 1997). In most

patients the illness starts after puberty, with an onset

before 20 years in around 25% of cases (Goodwin and

Jamison, 1990; Ten Have et al., 2002; Faedda et al.,

0165-0327/$ - see front matter D 2002 Elsevier B.V. All rights reserved.

doi:10.1016/S0165-0327(02)00180-5

*Corresponding author. Tel.: +31-10-463-4551; fax: +31-10-

463-3217.

E-mail address: reichart@psyd.azr.nl (C.G. Reichart).

epidemiological study among pre-pubertal children,

performed in the US, found a 3-month prevalence

among 9–13-year-old children of 0.1% for hypoman-

ic cases (i.e. bipolar II disorder) and no manic cases

(Costello et al., 1996).

In 2001, we performed a survey among all 325

members of the Child and Adolescent Section of the

Dutch Psychiatric Association, and asked them to

report on children with BD below 13 years they have

seen or treated during the last year. Around 50% of

them responded and they reported only 39 cases,

indicating a yearly prevalence of BD among pre-

pubertal children as detected by child and adolescent

psychiatrists of less than 0.001%. Obviously, such a

survey is not an adequate method to assess the

C.G. Reichart, W.A. Nolen / Journal of Affective Disorders 78 (2004) 81–8482

prevalence of a disorder in the general population, but

even after correcting for non-response and possible

underreporting, the prevalence of BD among children

appears to be far less in the Netherlands than in the

US. If true, what might be the reason for this

difference?

2. Possible earlier onset of bipolar disorder in

the US

A first explanation is poor recognition of BD by

the Dutch child and adolescent psychiatrists. Diag-

nosing BD in children is difficult. Typical manic

symptoms as seen in adults, such as euphoria, gran-

diosity and pressured speech, are less common among

children with BD. While they do show predominantly

hyperactivity, irritability, temper tantrums and mood

lability, their mood changes are typically relative brief

(hours or days), and one can see non-episodic and

mixed states (Wozniak et al., 1995; Faedda et al.,

1995). Therefore, it is very difficult to discriminate

BD from oppositional disorder, conduct disorder and,

especially, attention deficit disorder with hyperactivity

(ADHD). In a US study, 91% of children with BD

also fulfilled the criteria for ADHD, while 19% of

children with ADHD were also diagnosed as BD

(Geller et al., 2001). Similar findings from other US

studies were reported in a US round table conference

on prepubertal BD (Anonymous, 2001). It is still not

clear whether or not ADHD precedes bipolar disorder

in children, or is only a comorbid disorder.

Another explanation is that our US colleagues

over-diagnose BD in children. However, after having

seen several videotapes of US children diagnosed as

BD, we agreed that the children on these tapes were

definitely manic and also very ill. We were also

convinced that the children on these tapes would

definitely be recognized as such by Dutch child and

adolescent psychiatrists. Moreover, in the Netherlands

we use the same diagnostic instruments (both self-

reports and structured interviews) and classification

system (DSM-IV) as our US colleagues.

Thus, we conclude that, although we cannot rule

out some under-diagnosis in the Netherlands and

some over-diagnosis in the US, this is unlikely the

complete explanation. Taking into account both the

similar prevalence of BD among adults and adoles-

cents and the lower prevalence among children, this

indicates that, in the US, the age of onset of BD is

advanced compared to the Netherlands, at least in a

subgroup of patients. If this is true, what might be the

reason?

First of all, there might be a difference between the

populations of the US and the Netherlands, e.g. a

difference in the genetic pool. We are not aware of

data supporting this, but we cannot rule this factor out.

Another difference between the US and the Nether-

lands is related to different treatment approaches.

3. Different treatment approaches between the

US and The Netherlands

Several reports have indicated that BD develops

gradually. Most patients with BD report depressive

episodes or other prodromal symptoms such as sub-

syndromal states and mood lability starting (mean) 6–

8 years prior to the onset of the first manic or

hypomanic episode (Akkerhuis et al., 2000). In pre-

pubertal children, these early manifestations can be

either full depressive episodes and subsyndromal

states or periods with hyperactivity leading to a

diagnosis of ADHD (Faedda et al., 1995). Therefore,

in these children there may be an indication for

treatment of either depression with antidepressants

or ADHD with stimulants. However, these treatments

also bear the risk of a switch into (hypo)mania.

Among adults it is well documented that antide-

pressants can trigger a manic episode in patients with

unipolar or bipolar depression (Altshuler et al., 1995).

Depression in children is often the first episode of BD.

When treated with antidepressants these children have

a greatly increased risk to switch into a manic episode.

As young adults, up to 50% may have developed BD

(Geller et al., 2001). A recent study among children

and adolescents with BD showed that those who

received prior antidepressants or stimulants had an

earlier diagnosis (10.7F 3.1 years) than those who

were never exposed to these medications (12.7F 4.3

years) (El-Mallakh et al., 2001). In our survey, Dutch

child and adolescent psychiatrists reported on 228

children younger than 13 years who they treated with

antidepressants in the previous year, resulting in 10

switches (4.4%) into (hypo)mania, corresponding to

26% of the 39 BD children they have seen.

C.G. Reichart, W.A. Nolen / Journal of Affective Disorders 78 (2004) 81–84 83

With regard to stimulants, it has also been sug-

gested that these drugs can cause mania (Vitiello,

2001). Two recent reports indicate that they indeed

can lead to a switch. In a recent study into the

treatment of 42 children and adolescents with a manic

episode, 30 (71%) of the children had co-morbid

ADHD (Kowatch et al., 2000). How many of these

children had been treated with stimulants was not

reported, but the demographic data of this study show

a mean age of onset of ADHD of 5.5 (F 2.7) years, a

mean age of beginning with stimulants of 6.9 (F 2.8)

years, and a mean age of onset of bipolar (hypomanic

or manic) symptoms of 7.1 (F 3.4) years. In another

study of 34 adolescents hospitalized with mania, sub-

jects with a history of stimulant exposure had an earlier

age of onset of BD than those without prior stimulants,

10.7 (F 3.9) versus 13.9 (F 3.9) years, respectively

(DelBello et al., 2001).

Therefore, there are arguments that support the

notion that antidepressants and stimulants can trigger

a (hypo)manic episode in children. But can this explain

the possible earlier onset of BD in the US compared to

the Netherlands? We have taken into account two other

differences between these countries: the treatment

rates with antidepressants and with stimulants.

Compared to the Netherlands, the prescription of

antidepressants and stimulants to children in the US is

much higher. A recent study in Dutch pharmacies

revealed that, between 1995 and 1999, each year

0.44% of children aged 0–19 years received at least

one prescription for an antidepressant and that the use

of stimulants in this period increased from 0.15 to

0.74% (Schirm et al., 2001). In the US in 1995, 2.8%

of 5–18 year olds used stimulants (Safer et al., 1996),

while the estimated prescription of antidepressants

was about half, i.e. 1–1.5% (Jensen et al., 1999).

Based on these figures we assume that, in the US,

relatively more children diagnosed with depression or

ADHD are treated with either antidepressants or

stimulants compared to the Netherlands, resulting in

relatively more switches into hypo(mania). Probably,

some of these children have their depression or

ADHD as a prodromal phase of BD and these children

may be at risk for a switch, with possible severe

clinical consequences such as hospitalization and an

increased suicide risk, and social consequences such

as disturbed relations with family and peers and

interrupted school careers.

4. Tentative conclusion

We now come to our hypothesis: in children

genetically predetermined to develop bipolar disorder,

the use of antidepressants and/or stimulants may

advance the onset of bipolar disorder even before

puberty.

Obviously, this is still only an hypothesis for which

we have only circumstantial evidence. Clearly, further

research is needed. However, if proven true, physi-

cians should be careful when prescribing antidepres-

sants or stimulants to children with ADHD or

depression when there is a positive family history of

BD or when these drugs have been shown to be

ineffective in a particular child.

Acknowledgements

This work was made possible by generous support

from the Stanley Medical Research Institute.

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