‘Do not mistake a child for his symptom.’
In this issue, Tijssen and colleagues
report a study examining whether early expressions of subthreshold
hypomanic or depressive symptoms from childhood through to early adulthood
(‘common bipolar experiences’) are predictive of subsequent conversion to formal
bipolar disorder and mental health service attendance. If a valid and distinctive
signal, then there are obvious implications, particularly in advancing an argument
for early intervention as an extension of the arguments we muster for improving
formal detection. For example, many studies (see e.g. Hadjipavlou et
) have quantified substantive subjective distress and disability, as well as
considerable collateral damage (i.e. failure to maintain jobs and relationships,
and increased risks of suicide, hospitalisation and drug and alcohol misuse) when
the bipolar disorders remain undiagnosed and/or inadequately managed.
Although such arguments are persuasive for providing early intervention following
formal onset of bipolar disorder, they may or may not hold for addressing
indicative or prodromal symptom states. But does the study by Tijssen and
colleagues make or advance such a case?
Are early episodes indicative of later disorders and service use?
The researchers recruited a community-based adolescent sample with a mean age
of 18 years at baseline assessment and, after excluding those with established
bipolar disorder and mental health facility attendees at baseline or at early
follow-up stages, they assessed outcome at a mean follow-up period of 8 years.
Outcome variables were (i) onset of DSM-defined hypomanic or manic episodes
(DSM (hypo)manic episodes) and (ii) mental healthcare attendance.
Hypomanic or manic episodes
Those who had never experienced two or more hypomanic or manic symptoms
before baseline assessment had a 0.7% risk of developing DSM (hypo)manic
disorders at follow-up and a 9.4% risk of using mental healthcare services.
As pre-baseline symptoms increased in number, the rate of DSM (hypo)manic
episode conversion increased (but only to a maximum rate of 3.2%).
Similarly, the more persistent such pre-baseline symptoms, the higher the
DSM (hypo)manic episodes and mental healthcare services use transition
The authors also examined the impact of pre-baseline depressive symptoms and
again showed a ‘dose’ impact: the greater the number and persistence of
depressive symptoms, the higher the subsequent DSM (hypo)manic episodes and
mental healthcare services use rates but, as might be anticipated,
depressive symptoms had less impact and less of a ‘dose’ effect than
pre-baseline hypomanic or manic symptoms.
Early manic symptoms in adolescents – what may they signify?
The first refutability question is whether the predictor and outcome variables
were confounded by artefactual issues. In essence, might those who ‘converted’
to full clinical diagnosis at follow-up have already had their bipolar disorder
at baseline assessment, with some assessment nuance (e.g. person biases such as
denial, rater biases emerging from interviewers only rating symptoms ‘noticed
by others’ or causing ‘problems’, limitations to the screening measure,
imperfect test–retest reliability to ‘caseness’ estimates of mood disorders)
accounting for (false) subclinical classification at an early stage and
(correct) clinical status at follow-up. The study's finding of dose effects
(with more pre-baseline symptoms and greater symptom persistence increasing the
‘conversion’ rates) does not entirely negate that caveat, as milder and briefer
pre-baseline symptomatology would risk false negative assignment at that
Second, although we recognise that bipolar disorder can commence in adolescence
and in pre-pubertal children – with studies indicating that initial bipolar
symptoms commence in one-half to two-thirds of individuals prior to the age of
– the impact of age on phenotypic expression in younger individuals is
unclear, both in terms of pattern and severity. Most reviews (e.g. Youngstrom
) indicate age-based differences (e.g. irritability, hyperactivity and
‘mixed states’ being over-represented in younger individuals) as well as some
similarities. Hence, were the subclinical symptoms in study participants truly
subclinical or, alternately, did they more reflect age-specific phenotypic
manifestations of true bipolar status at a younger age – in essence,
Thus, did the presence of ‘common adolescent bipolar experiences’ reflect an
incipient state as implied by Tijssen and colleagues – or more reflect the
early expression of actual bipolar disorder? Until we know how to accurately
stage and define the bipolar disorders (particularly in adolescents), we may
assume that, in those who develop bipolar disorder later, some will show no
early warning signs, some will meet full criteria in adolescence and earlier,
some will show non-specific symptoms, some will show forme fruste symptoms and
states (e.g. anxiety and eating disorders), and some will show subclinical or
subthreshold symptoms – with only the last reflecting the logic of Tijssen
et al's study. If the reality is that quite variegated
longitudinal patterns occur, any signal from subsyndromal symptoms will be
compromised by the other patterns.
Is early intervention in adolescents justifiable?
Tijssen and colleagues concluded that their findings may indicate ‘a window for
intervention’, and referenced several studies indicating that early onset
predicts a worse outcome for bipolar disorder. Can that next step be argued by
their paper or is such a conclusion premature?
The latter is suggested – both by the theoretical issues noted above and by the
quantitative analyses. First, for study participants who showed the greatest
number of pre-baseline hypomanic subthreshold symptoms and the highest rate of
symptom persistence, rates of conversion to a full bipolar diagnosis were 3.2%
at most (in comparison to a conversion rate of less than 1% for those not
reporting symptoms or 2.0% for those having brief symptoms). Essentially, the
signal had low predictive power. As an analogy – although mental health
professionals prioritise averting suicide, our capacity to predict the very
small percentage of suicidally depressed individuals who go on to kill
themselves is well recognised. If hospital admission protected against suicide,
we would have to admit 100 such depressed individuals (for some quite variable
period) to prevent the suicide of two or three. Such an analogy is relevant
here when we compare the very low rates of conversion in comparison groups. The
signal quantified in this study is weak and, when the much higher mental
healthcare services use than DSM (hypo)manic episodes follow-up rates are
considered, insufficiently specific to argue a case for intervention.
A risky path
Some general concerns about intervening for preclinical states can be briefly
overviewed. Many clinicians have great difficulty in making a bipolar disorder
diagnosis even in those with established conditions (particularly the
non-psychotic bipolar II disorders). Apart from failing to detect a bipolar
pattern, many clinicians will interpret such patterns as reflecting normal mood
swings, attention-deficit hyperactivity disorder, emotional dysregulation or a
personality disorder. Other clinicians hold to a spectrum model for the bipolar
disorders and risk including many with unipolar disorders as well as those who
merely have colourful or ebullient personalities. Such risks of underdiagnosis
and overdiagnosis are likely to be increased when assessing prodromal symptoms
(by the nature of their low severity or non-specificity) – particularly in
children and adolescents, as a consequence of their argot, response biases
(e.g. denial), lack of worldly experiences and lifestyles. Let us consider the
last only. DSM–IV hypomania criteria include inflated self-esteem, decreased
need for sleep, pressured talk, distractibility and excessive involvement in
pleasurable activities. Many adolescents would meet such individual DSM
criteria as a consequence of a wide range of activities – including falling in
love, extensive socialisation or studying for exams – all risking false
positive diagnoses. The reported rise of 4000% in the diagnosis of bipolar
disorder over the past decade in those under 18 years of age in the USA
may reflect better detection up to a point, but we must also be
suspicious of overdiagnosis.
Low predictability and false positive interpretation of adolescent ‘symptoms’
would risk interventions (drug and non-drug) being provided to many who would
never have developed the disorder. Further, if a drug intervention is to be
offered, how to proceed when the evidence base across the differing drug
classes for managing adolescent bipolar disorder is negligible?
A further risk to providing early intervention is the impact of labelling and
stigma. The distinguished psychiatrist Norman Sartorius recounted a salutary
personal story in his book dealing with mental illness stigma.
At the age of 8 he experienced distinct visual and auditory
hallucinations. He received no treatment and the hallucinations went away, but
he contemplates the impact on his subsequent schooling, socialisation and
working life if, alternatively, he had been admitted to hospital or
While Tijssen et al raise (in the Discussion) an argument for
intervention, their summary has a differing emphasis – noting there that the
‘non-clinical bipolar phenotype’ is ‘common and usually transitory’. In the
early phases of the study, 28% of the sample experienced hypomanic or manic
symptoms, while 60% experienced depressive symptoms. Yet only 1.1% met formal
criteria for bipolar disorder at follow-up. Their data weight that
interpretation – one or two bipolar symptoms in adolescence do not a case make,
either for indicating the probability of incipient formal bipolar disorder or
for intervention. The researchers have illuminated a key issue, but the signal
requires much greater definition.
Tijssen, MJA, van Os, J, Wittchen, H-U, Lieb, R, Beesdo, K, Mengelers, R, et al. Prediction of transition from common
adolescent bipolar experiences to bipolar disorder: 10-year
study. Br J Psychiatry
Hadjipavlou, G, Yatham, LN. Bipolar II disorder in context: epidemiology,
disability and economic burden. In Bipolar II
Disorder: Modelling, Measuring and Managing (ed Parker, G): 61–74. Cambridge
University Press, 2008.
Chang, K. Adult bipolar disorder is continuous with pediatric
bipolar disorder. Can J Psychiatry
2007; 52: 418–25.
Youngstrom, EA, Birmaher, B, Findling, RL. Pediatric bipolar disorder: validity, phenomenology,
and recommendations for diagnosis. Bipolar
Moreno, C, Laje, G, Blanco, C, Jiang, H, Schmidt, AB, Olfson, M. National trends in the outpatient diagnosis and
treatment of bipolar disorder in youth. Arch Gen
2007; 64: 1032–9.
Sartorius, N, Schulze, H. Reducing the Stigma of Mental Illness: A Report from a
Global Programme of the World Psychiatric Association.
Cambridge University Press,