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Early interventions for youths at high risk for bipolar
disorder: a developmental approach
Xavier Benarous, Angèle Consoli, Vanessa Milhiet, David Cohen
To cite this version:
Xavier Benarous, Angèle Consoli, Vanessa Milhiet, David Cohen. Early interventions for youths at
high risk for bipolar disorder: a developmental approach. European Child and Adolescent Psychiatry,
Springer Verlag (Germany), 2016, 25 (3), pp.217-233. �10.1007/s00787-015-0773-6�. �hal-01303787�
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Early interventions for youths at high risk for bipolar
disorder: A developmental approach
Xavier Benarous
1
, Angèle Consoli
12
, Vanessa Milhiet
1
, David Cohen
13
1
Service de Psychiatrie de l’Enfant et de l’Adolescent, Hôpital Pitié-Salpêtrière, 47-83
Boulevard de l’Hôpital, 75013 Paris, France
2
INSERM U-669, PSIGIAM, Paris, France
3
CNRS UMR 7222, Institut des Systèmes Intelligents et Robotiques
Address of correspondence: Xavier Benarous, Service de Psychiatrie de l’Enfant et de
l’Adolescent, Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, AP-HP, 47-83,
Boulevard de l’Hôpital, 75013, Paris, France
Email: xavierbenarous@gmail.com
Telephone: +33(0)603260193
Fax number: +33(0)142162331
Abbreviated title: Early interventions for bipolar disorder
Conflict of interest: On behalf of all authors, the corresponding author states that there is no
conflict of interest.
2
Early interventions for youths at high risk for bipolar disorder: A
developmental approach
Abstract
In recent decades, ongoing research programs on primary prevention and early identification
of bipolar disorder (BD) have been developed. The aim of this article is to review the
principal forms of evidence that support preventive interventions for BD in children and
adolescents and the main challenges associated with these programs. We performed a
literature review of the main computerised databases (MEDLINE, PUBMED) and a manual
search of the literature relevant to prospective and retrospective studies of prodromal
symptoms, premorbid stages, risk factors, and early intervention programs for BD. Genetic
and environmental risk factors of BD were identified. Most of the algorithms used to measure
the risk of developing BD and the early interventions programs focused on the familial risk.
The prodromal signs varied greatly and were age-dependent. During adolescence, depressive
episodes associated with genetic or environmental risk factors predicted the onset of
hypomanic/manic episodes over subsequent years. In prepubertal children, the lack of
specificity of clinical markers and difficulties in mood assessment were seen as impeding
preventive interventions at these ages. Despite encouraging results, biomarkers have not thus
far been sufficiently validated in youth samples to serve as screening tools for prevention.
Additional longitudinal studies in youths at high risk of developing BD should include
repeated measures of putative biomarkers. Staging models have been developed as an
integrative approach to specify the individual level of risk based on clinical (e.g., prodromal
symptoms and familial history of BD) and non-clinical (e.g., biomarkers and neuroimaging)
data. However, there is still a lack of empirically validated studies that measure the benefits
of using these models to design preventive intervention programs.
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Keywords: Early onset bipolar disorder; high-risk study; prevention; early intervention;
children; staging models
Introduction
Over the past few decades, preventive interventions have been proposed to prevent or limit
the consequences of bipolar disorder (BD) in adults. Because more than half of adult patients
with BD present their first episode before the age of 18 [1,2], these programs would mainly
concern children and adolescents. This concern is of particular importance with regard to the
high level of functional impairment in affected children and adolescents. BD is the fourth
leading cause of disability among youths aged 10-24 worldwide and is associated with an
increased risk of suicide [3,4]. In this paper, the evidence that supports the development of
such interventions at these ages is discussed. First, to understand the growing interest in the
development of a preventive approach, the natural course of BD is discussed. Second, we
examine whether the following criteria for the development of an effective prevention of BD
in paediatric samples have been met: (i) genetic and environmental risk factors for BD must
be identified in view of defining a target population; (ii) clinical markers that predict the
onset and/or the course of the disease must be determined; (iii) endophenotypes or
biomarkers that reflect an early pathological process could help to identify individuals who
require special attention, and (iv) the effectiveness of preventive interventions must be
evaluated. Finally, the use of staging models that were previously developed for psychosis,
has been proposed for BD. These models were conceived as tools based on clinical (e.g.,
symptoms and family history of BD) and non-clinical (e.g., neuroimaging and biological
markers) parameters for measuring the risk of progression over the course of the disease. It is
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seen as a rational approach to adapting treatments with potential side-effects to a specific
situation according to the individual level of risk. However, despite a theoretical framework
that supports the use of staging models in BD, few studies have examined the empirical
evidence. This review will examine the internal and external validity of models that focus on
the transition from a non-symptomatic at-risk status to the first manic episode.
1. The life-time course of bipolar disorder
Although BD has traditionally been described as a cyclical disorder with euthymic periods, in
recent decades, the clinical importance of inter-episode symptoms has been highlighted. It
has been noted that symptom-free periods are actually rare in bipolar patients, who continue
to report subsyndromal affective symptoms between episodes [5]. An aggravation of the
disease with more severe symptoms and shorter periods between relapse is observed
throughout the course of BD in a sizeable proportion of patients [6-9]. The concepts of
kindling and neuro sensitisation were coined to describe the phenomenon of a progressive
increase in episode frequencies as the mood episodes repeated [8,9]. Although this concept
have largely been cited in support of the promotion of early interventions in BD, this
assumption has been contradicted by empirical evidences [10,11]. In a 30 year follow-up
study among outpatients with BD (N=220), Angst and Selloro found that a shortening of
cycle length only occurred in the first few, but not in later episodes [10]. In addition to
subthreshold symptoms, some degree of cognitive impairment also persists during euthymic
periods in patients with BD [12-14]. Increasing cognitive difficulties have been reported over
the course of the disorder and are correlated with the number of manic episodes [15].
Longitudinal studies in adults have supported the assumption that inter-episode functioning
