Research reportChildhood-compared to adolescent-onset bipolar disorder has more statistically significant clinical correlates
Introduction
Bipolar disorder (BD) is a common condition characterized by recurrent episodes of mood elevation and depression that inflict considerable human and economic costs (Dilsaver, 2011). The substantial phenomenological and biological heterogeneity of bipolar disorder makes diagnosis and treatment challenging. Over the past several decades, there have been important advances in the nosology of psychiatric disorders in general, and in bipolar disorder in particular (American Psychiatric Association, DSM-5 Task Force, 2013). There has also been increasing appreciation of the need for better understanding of neurobiology and the development of biomarkers (Teixeira et al., 2013). Further, researchers have sought to identify specific characteristics, such as temperament, that may mediate the putative influence of genotype on phenotypic outcome in early-onset affective disorders (Akiskal, 1995). However, symptom-based classifications of patients into more homogeneous subgroups, such as unipolar versus bipolar mood disorders, as well as bipolar I versus bipolar II disorders, have not yielded robust relationships with biological markers (Escamilla and Zavala, 2008). In contrast, onset age has been identified as a clinical marker that may define more homogenous, neurobiologically distinctive subgroups (Benazzi, 2009, Etain et al., 2012). For example, childhood-onset bipolar disorder has been associated with an increased rate of having a first-degree relative with a mood disorder in most (9/13) recent studies (Baldessarini et al., 2012, Bellivier et al., 2001, Bellivier et al., 2003, Benazzi, 2009, Hamshere et al., 2009, Leverich et al., 2007, Lin et al., 2006, Ortiz et al., 2011, Rende et al., 2007), but not in a minority (4/13) of such studies (Carter et al., 2003, Ernst and Goldberg, 2004, Javaid et al., 2011, Tozzi et al., 2011).
Juvenile onset of bipolar disorder has been associated with both diagnostic challenges and delays to appropriate treatment (Leverich et al., 2007). Researchers have struggled to delineate a clear clinical picture of childhood onset bipolar disorder, particularly owing to the complex contributions of temperament and age-dependent affective presentations, as well as the extensive potentially confounding influences of substance use, anxiety, and personality disorder comorbidities (Akiskal, 1998). Given the dramatic social consequences of delayed treatment in bipolar disorder, researchers have sought particularly to identify which genetic factors, environmental influences, and subtle psychopathological features may predispose individuals to the development of full-blown affective episodes (Akiskal, 1995, Akiskal et al., 1985). As such, recent studies have commonly focused upon relationships between early age at onset and multiple unfavorable illness characteristics (Jacobs et al., 2014). Significant associations were found between early-onset bipolar disorder and lifetime history of suicide attempt in twelve (Azorin et al., 2013, Bellivier et al., 2001, Carter et al., 2003, Coryell et al., 2013, Etain et al., 2012, Hamshere et al., 2009, Lin et al., 2006, Moor et al., 2012, Ortiz et al., 2011, Perlis et al., 2009, Rende et al., 2007, Tozzi et al., 2011) of fifteen (Ernst and Goldberg, 2004, Javaid et al., 2011, Manchia et al., 2008) studies, worse mood outcome in seven (Azorin et al., 2013, Baldessarini et al., 2012, Benazzi, 2009, Coryell et al., 2013, Leverich et al., 2007, Ortiz et al., 2011, Perlis et al., 2009) of seven studies, substance use disorders in ten (Azorin et al., 2013, Carter et al., 2003, Coryell et al., 2013, Ernst and Goldberg, 2004, Etain et al., 2012, Javaid et al., 2011, Leverich et al., 2007, Lin et al., 2006, Perlis et al., 2009, Rende et al., 2007) of twelve (Moor et al., 2012, Ortiz et al., 2011) studies, prior year rapid cycling in seven (Carter et al., 2003, Ernst and Goldberg, 2004, Hamshere et al., 2009, Leverich et al., 2007, Lin et al., 2006, Ortiz et al., 2011, Perlis et al., 2009) of nine (Coryell et al., 2013, Etain et al., 2012) studies, anxiety disorder in five (Azorin et al., 2013, Leverich et al., 2007, Moor et al., 2012, Ortiz et al., 2011, Perlis et al., 2009) of eight (Carter et al., 2003, Coryell et al., 2013, Etain et al., 2012) studies, and alcohol use disorder in two (Azorin et al., 2013, Lin et al., 2006) of eight (Carter et al., 2003, Coryell et al., 2013, Etain et al., 2012, Javaid et al., 2011, Leverich et al., 2007, Moor et al., 2012) studies.
In contrast to the consistency of studies finding early-onset bipolar disorder associated with higher rates of unfavorable illness characteristics, there has been substantial variation in definitions (e.g. first mood episode (Benazzi, 2009; Ernst and Goldberg, 2004; Leverich et al., 2007)) versus first reliable diagnosis (Javaid et al., 2011, Manchia et al., 2008) of early-onset. Further variability has existed in selection of boundaries between onset age subgroups. However, fifteen (Azorin et al., 2013, Baldessarini et al., 2012, Bellivier et al., 2001, Bellivier et al., 2003, Benazzi, 2009, Coryell et al., 2013, Etain et al., 2012, Hamshere et al., 2009, Lin et al., 2006, Manchia et al., 2008, Moor et al., 2012, Ortiz et al., 2011, Perlis et al., 2009, Rende et al., 2007, Tozzi et al., 2011) of nineteen (Carter et al., 2003, Ernst and Goldberg, 2004, Javaid et al., 2011, Leverich et al., 2007) studies published since 2000 with at least one finding that was replicated by a different group used three onset age groups. Most studies have used an aggregated childhood/adolescent/±early adulthood-onset definition of early-onset, with a majority of such studies using upper age bounds for early-onset ranging between 21 and 23 years (Azorin et al., 2013, Bellivier et al., 2001, Bellivier et al., 2003, Benazzi, 2009, Carter et al., 2003, Coryell et al., 2013, Ernst and Goldberg, 2004, Etain et al., 2012, Hamshere et al., 2009, Javaid et al., 2011, Lin et al., 2006, Manchia et al., 2008, Ortiz et al., 2011, Tozzi et al., 2011). In contrast, a minority of studies, mostly based in the United States, have defined separate childhood- and adolescent-onset groups, setting upper bounds for childhood-onset groups at the commencement of puberty (12–13 years of age) (Baldessarini et al., 2012, Leverich et al., 2007, Moor et al., 2012, Perlis et al., 2009, Rende et al., 2007). To date, findings of studies using aggregated childhood/adolescent/±early adulthood- compared to separate childhood- and adolescent-onset groups have largely overlapped, but no study has directly compared childhood- and adolescent-onset groups considered separately versus in aggregate.
Some investigators used developmental stages to define onset age groups, yielding separate very early- (i.e. childhood, age<13 years) and early-onset (i.e. adolescent, age 13–18 years) groups to compare to adult-onset (age>18 years) groups (Baldessarini et al., 2012, Leverich et al., 2007, Moor et al., 2012, Perlis et al., 2009, Rende et al., 2007). However, other investigators used larger single early-onset (i.e. pooled childhood/adolescent, age ≤18 years or ≤21 years) groups to compare to adult-onset (age >18 years or >21 years) groups (Coryell et al., 2013, Etain et al., 2012). Other investigators still used admixture analyses, which yielded even larger early-onset (e.g. pooled childhood/adolescent/young adult, e.g. age ≤23 years) groups to compare to groups of patients with yet later onset (Azorin et al., 2013, Bellivier et al., 2001, Bellivier et al., 2003, Benazzi, 2009, Carter et al., 2003, Ernst and Goldberg, 2004, Hamshere et al., 2009, Javaid et al., 2011, Lin et al., 2006, Manchia et al., 2008, Ortiz et al., 2011, Tozzi et al., 2011).
We assessed naturalistic, observational data to test the hypothesis that using childhood-onset rather than adolescent-onset or pooled childhood/adolescent-onset to define early-onset would yield more robust associations with unfavorable illness characteristics.
Section snippets
Methods
We performed a PubMed search using the keywords “bipolar disorder” AND “onset age,” “age at onset,” “childhood onset,” OR “early onset.” Studies published after 2000 reporting at least one positive association between early-onset and an unfavorable illness characteristic that was also found by at least one other study published after 2000 were included. Studies using age at first hospitalization as the definition for onset were excluded. Primary unfavorable illness characteristic measures were
Results
Our literature review confirmed that most studies used three onset age groups, though onset age group definitions varied. Nineteen studies involving 15,924 patients published since 2000 had at least one finding that was replicated in at least one other such report (Table 1). Among such studies, most (14/19, involving 9583 patients) were based outside of the United States, and used aggregated childhood/adolescent/±early adulthood as early-onset groups that comprised 41.8% of these 9583 patients,
Discussion
The childhood-onset definition of early-onset bipolar disorder was sensitive for detecting relationships with unfavorable illness characteristics. Specifically, childhood-onset compared to adolescent-onset and pooled childhood/adolescent-onset yielded statistically significant associations with more unfavorable illness characteristics than previously found to be related to early-onset bipolar disorder.
Thus, considering childhood- and adolescent-onset separately rather than in aggregate may be a
Limitations
Our study has the strengths of using a validated instrument to assess bipolar diagnosis, illness subtype, and illness characteristics, and including a substantial number of patients. However, our study also has noteworthy limitations. First, our primarily Caucasian, relatively affluent, insured, suburban, low substance abuse, American specialty clinic-referred sample limits the generalizability of our findings to more ethnically and geographically diverse populations. Most studies using a
Role of funding source
This research was conducted with support from the Pearlstein Family Foundation and the Mitchell Foundation. There was no pharmaceutical company funding. The funding sources did not influence the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the article for publication.
Conflict of interest
Disclosures for the last 36 months are as follows: Ms. Holtzman and Drs. Hooshmand and Wang, and Shelley Hill report no financial relationships with commercial interests. Dr. Miller has received an honorarium from Pamlab, Inc. Dr. Chang has received grant/research Support from GlaxoSmithKline and Merck & Co., Inc.; has been an unpaid consultant for GlaxoSmithKline, Eli Lilly and Company, Bristol Myers Squibb, and serves on a data safety monitoring board for Sunovion Pharmaceuticals. Dr. Rasgon
Acknowledgments
These data were presented at the 16th Annual Conference of the International Society for Bipolar Disorders, Seoul, South Korea, March 18–21, 2014, and at the 167th Annual Meeting of the American Psychiatric Association, United States, May 3–7, 2014.
References (40)
Developmental pathways to bipolarity: are juvenile-onset depressions pre-bipolar
J. Am. Acad. Child Adolesc. Psychiatry
(1995)- et al.
Characteristics and profiles of bipolar I patients according to age-at-onset: findings from an admixture analysis
J. Affect. Disord
(2013) - et al.
Age at onset versus family history and clinical outcomes in 1,665 international bipolar-I disorder patients
World Psychiatry
(2012) Classifying mood disorders by age-at-onset instead of polarity
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2009)- et al.
Life stress and kindling in bipolar disorder: review of the evidence and integration with emerging biopsychosocial theories
Clin. Psychol. Rev.
(2011) - et al.
Age of onset and the prospectively observed course of illness in bipolar disorder
J. Affect. Disord.
(2013) An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009
J. Affect. Disord.
(2011)- et al.
Clinical features related to age at onset in bipolar disorder
J. Affect. Disord.
(2004) - et al.
Reconsideration of bipolar disorder as a developmental disorder: importance of the time of onset
J. Physiol. Paris
(2013) - et al.
Age-at-onset in bipolar-I disorder: mixture analysis of 1369 cases identifies three distinct clinical sub-groups
J. Affect. Disord.
(2009)
A three generations nation-wide population study of family load estimates in bipolar disorder with different age at onset
J Affect. Disord.
The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders
J Affect. Disord.
The poor prognosis of childhood-onset bipolar disorder
J. Pediatr.
Prevalence and correlates of eating disorders in 875 patients with bipolar disorder
J Affect. Disord.
Effects of comorbidity and early age of onset in young people with bipolar disorder on self harming behaviour and suicide attempts
J Affect. Disord.
An admixture analysis of the age at index episodes in bipolar disorder
Psychiatry Res.
Sensitization and kindling phenomena in mood, anxiety, and obsessive–compulsive disorders: the role of serotonergic mechanisms in illness progression
Biol. Psychiatry
Childhood-onset bipolar disorder: evidence for increased familial loading of psychiatric illness
J. Am. Acad. Child Adolesc. Psychiatry
Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD)
Biol. Psychiatry
Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP
Psychiatry Res.
Cited by (41)
Neural abnormalities of reward processing in adolescents with bipolar disorders: An ERP study
2023, Biological PsychologySubstance use disorders in bipolar disorders: Clinical correlates and treatment response to mood stabilizers
2022, Journal of Affective DisordersDouble jeopardy in the United States: Early onset bipolar disorder and treatment delay
2020, Psychiatry ResearchNeurodevelopmental pathways in bipolar disorder
2020, Neuroscience and Biobehavioral ReviewsProof-of-concept study of a multi-gene risk score in adolescent bipolar disorder
2020, Journal of Affective Disorders