The Journal of Pediatrics
Volume 150, Issue 5 , Pages 485-490, May 2007

The Poor Prognosis of Childhood-Onset Bipolar Disorder

Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health, Biological Psychiatry Branch, Bethesda, MD; Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH; Mental Health Care Line and General Clinical Research Center, Cincinnati VA Medical Center, Cincinnati, OH; Department of Psychiatry and Biobehavioral Science, David Geffen School of Medicine, University of California Los Angeles and West Los Angeles VA Medical Center, Los Angeles, CA; Altrecht Institute for Mental Health Care, Utrecht, The Netherlands; Department of Psychiatry, University Hospital, Groningen, The Netherlands; University of Texas-Southwestern Medical Center, Dallas; and Psychiatrische Klinik der LMU, Munich, Germany.

Received 3 March 2006; received in revised form 3 August 2006; accepted 27 October 2006.

Article Outline

Objective

We examined age of onset of bipolar disorder as a potential course-of-illness modifier with the hypothesis that early onset will engender more severe illness.

Study design

A total of 480 carefully diagnosed adult outpatients with bipolar disorder (mean age, 42.5 ± 11.6 years) were retrospectively rated for age of illness onset, time to first pharmacotherapy, and course of illness. Clinicians prospectively rated daily mood fluctuations over 1 year.

Results

Of the 480 patients, 14% experienced onset in childhood (12 years or younger); 36% in adolescence (13 to 18 years); 32% in early adulthood (19 to 29 years); and 19% in late adulthood (after 30 years). Childhood-onset bipolar illness was associated with long delays to first treatment, averaging more than 16 years. The patients with childhood or adolescent onset reported more episodes, more comorbidities, and rapid cycling retrospectively; prospectively, they demonstrated more severe mania, depression, and fewer days well.

Conclusions

This study demonstrates that childhood onset of bipolar disorder is common and is associated with long delays to first treatment. Physicians and clinicians should be alert to a possible bipolar diagnosis in children in hopes of shortening the time to initiating treatment and perhaps ameliorating the otherwise adverse course of illness.

Abbreviations: ADHD, Attention deficit hyperactivity disorder, NIMH-LCM, National Institutes of Mental Health Life Chart Method, SCID, Structured Clinical Interview for DSM-IV Axis I Disorders

 

The recent follow-up studies of Geller et al1, 2 suggest a relatively difficult course of illness in children with bipolar disorder treated naturalistically in the community. Although 65% of the patients studied recovered for 2 weeks by the end of 2 years, 55% relapsed within this 2-year period, and 64% relapsed during the 4-year follow-up. Birmaher et al3 reported extremely long delays to achieving acute remission, along with relatively high subsequent relapse rates, in children with bipolar I, bipolar II, and especially bipolar NOS (not otherwise specified) disorders. Controlled clinical trial findings in long-term prophylaxis of childhood bipolar illness have reported high dropout rates due to inefficacy of either lithium or valproate monotherapy.4

See editorial, p 459

There remains much controversy about the quality of symptoms and severity/duration thresholds sufficient for diagnosing childhood-onset bipolar illness.5, 6, 7, 8 Given this ongoing controversy, many children with bipolar illness are not being identified until after many years of psychopathology. In some instances, these children are being treated with stimulants or antidepressants for their comorbid attention deficit hyperactivity disorder (ADHD) without the recommended coverage of a mood stabilizer or atypical antipsychotic.6

Much of the diagnostic controversy derives from the lack of characteristic discrete episodes so often seen in adult-onset bipolar disorder.9 In contrast, many of the youngest children with otherwise profound manic and depressive mood and behavioral swings associated with considerable social or educational dysfunction show brief bursts and rapid changes in mood, sometimes several times within a 24-hour period, a phenomenon called “ultradian” cycling.1, 2, 10, 11 A second reason underlying the controversy is that the extremes of activation, impulsivity, irritability, and anger that these children exhibit can occur in other childhood disorders, such as ADHD, oppositional defiant disorder, or major depressive disorder.12

In this article, we examine the proportion of adults who had childhood and adolescent onset of their illness and assess the illness outcomes related to these different ages of onset. One retrospective study by Perlis et al13 based on the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort of 983 patients found that 27.7% had on onset of bipolar illness in childhood (age ≤ 12) while another 37.6% had their onset in adolescence (from ages 13 to 18). They found that both of these groups had a much more difficult course of illness compared with those with adult onset, including faster cycling, more days depressed, greater number lifetime of manic and depressive episodes, an increased risk of substance abuse and other comorbidities, and a greater lifetime risk of suicide attempts. We also revisit this issue in another adult outpatient cohort with several new methodological approaches. We obtained daily prospective clinician ratings for 1 year during naturalistic treatment of adult bipolar illness by experts to supplement the retrospective self-report findings. We also examined data on the lag between the onset of first symptoms likely meeting DSM-IV diagnostic criteria and the onset of first drug treatment for either mania or depression.

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Methods 

The methods of study of this outpatient cohort have been presented in detail elsewhere.14, 15, 16, 17, 18 Outpatients were recruited between 1995 and 2002 largely from local advertisements and outpatient settings located near 4 research clinic sites in the United States (Los Angeles, Dallas, Cincinnati, and Bethesda) and 3 sites in Europe (Utrecht, Freiburg, and Munich). All patients provided informed written consent for participation in naturalistic follow-up. The population was a broad and representative sample, because patients were not excluded for the presence of comorbidities; the only exclusions were for active ongoing substance abuse that required separate treatment in another facility or other serious medical illnesses that might preclude participation in subsequent treatment protocols if this became necessary.

Patients were diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID)19 and completed questionnaires about the extent of their previous course of illness.16, 17, 18, 20 The self-report questions included (1) age of onset of first depressive symptoms associated with dysfunction, (2) age of onset of first hypomanic or manic symptoms, and (3) age of first treatment for either mania or depression. Age of onset was also obtained from the SCID19 interviews by trained clinicians based on an assessment of when symptoms similar to those experienced in adulthood first occurred. Ages of onset as assessed by these 2 methods were highly correlated (r = .80; P ≤ .001). In this study, we used patients’ self-reported age, because it was derived from the same patient assessment instrument that also provided retrospective data on course of illness and time to first treatment.

The 480 patients were assessed on various cross-sectional measures18, 20 during each visit, as well as on the daily prospective National Institutes of Mental Health Life Chart Method (NIMH-LCM).21 Because the severity of mania and depression ratings on the NIMH-LCM are based on the degree of mood-related functional impairment in a patient’s usual social, educational, or occupational roles,21 they are readily remembered by the patient and rated by a clinician during the clinical interview. Such prospective NIMH-LCM clinician ratings are highly reliable over a period of several weeks to 1 month between visits and have been validated against more conventional cross-sectional rating scales, as described by Denicoff et al.22, 23

Sequentially admitted patients who also had a full year of prospective daily clinician ratings were included in the analysis. Because preliminary analysis suggested potential nonlinear relationships between age of onset and various outcome measures, age of onset was divided into 4 groups as was done by Perlis et al.13 Onset at age 0 to 12 years was considered childhood onset; at 13 to 18 years, adolescent onset; at 19 to 29 years, early-adult onset; and after 30 years, late-adult onset.

Average severity of days ill (with euthymic days included) for the prospective year was calculated using the mood ratings for mania and depression on the NIMH-LCM on a scale of 0 to 4, with 0 = euthymic (not ill); 1 = mild severity, with little or no role dysfunction; 2 = low moderate (some dysfunction); 3 = high moderate (much dysfunction); and 4 = severe (essentially incapacitated).21 Days with ultradian cycling (ie, switching between mania and depression within a 24-hour period) were recorded separately and not counted in the assessment of number of episodes.

The normality of continuous measures was examined using the Kolmogorov-Smirnov test, and homogeneity of variance was examined using Levene’s test. Continuous demographic and outcome measures were examined using 1-way analysis of variance with the 4 onset groups. Bonferroni-corrected pairwise comparisons were used post hoc. A χ2 test was used with categorical measures, with omnibus significance followed up with a 2 × 2 χ2 test to determine the location of differences. All P values were evaluated for significance at <.05 (2-tailed). Results were Bonferroni-corrected for the 15 measures compared across onset groups.

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Results 

The mean age at network entry (42.5 ± 11.6 years) was not significantly different among the patients with childhood, adolescent, and early-adult onset; however, the late-adult onset group was significantly older at network entry than the other groups (Table I). Of the 480 individuals with at least 1 year of complete prospective daily ratings, 65 (14%) reported onset at age 12 years or younger, 171 (36%) reported onset during adolescence, 154 (32%) reported early-adult onset, and 90 (19%) reported late-adult onset.

Table I. Patient demographics and retrospective illness variables as a function of age of onset
VariableChildhood (0 to 12 years)Adolescent (13 to 18 years)Early adulthood (19 to 29 years)Late adulthood (30+ years)χ2P
n (percent)65(14%)171(36%)154(32%)90(19%)
Mean age at first symptom, years ± SD9.57±215.92±222.60±338.51±7
Mean age at network entry, years ± SD39.95±1140.37±1240.95±1151.20±9F = 24.06<.001
Female42(65)98(57)78(51)45(50)4.87.18
Bipolar type 3.57.31
I54(83)132(80)125(83)63(73)
II11(17)33(20)26(17)23(27)
Married/cohabitating28(46)82(50)78(30)49(50)0.82.84
Parental history of bipolar disorder23(47)52(37)27(21)12(17)21.62<.001
Parental history of depression25(52)60(43)39(29)18(25)14.06<.001
Physical abuse as a child22(36)36(22)21(15)10(12)16.22.001
Sexual abuse as a child19(31)33(20)15(11)8(10)17.63.001
Dysphoric mania48(79)94(59)68(46)46(52)19.40<.001
Rapid cycling (lifetime)45(70)83(51)66(45)35(40)15.92.001
Number of mood episodes (>20 lifetime)50(83)105(66)63(44)30(38)43.14<.001
Comorbidities:
Lifetime anxiety disorder38(60)63(37)56(37)21(24)21.07<.001
Lifetime alcohol abuse or dependence27(42)60(35)46(30)22(25)5.77.12
Lifetime drug abuse (excluding alcohol)16(25)42(25)30(20)7(8)11.14.01

Includes patients with 1 full year (365 days) of prospective life chart data.

The duration from onset of illness to first pharmacologic treatment for depression or mania, available in 420 patients, was strongly inversely related to age of onset (Figure). The lag averaged 16.8 ± 10 years in those with childhood onset and 11.5 ± 10 years in those with adolescent onset. In contrast, those with onsets in early and late adulthood received their first treatment after average delays of only 4.6 ± 7 years and 2.6 ± 5 years, respectively.

  • View full-size image.
  • Figure. 

    Childhood- and adolescent-onset bipolar disorders are associated with extremely long delays from first symptoms to first treatment for either manic or depressive symptoms. Total n = 420. Plotted is the average delay per onset group ± 1 standard error of the mean.

As shown in Table I, patients with childhood-onset bipolar disorder had the highest incidence of parental history of bipolar illness and unipolar depression, and these percentages declined progressively in patients with later age of onset. Environmental adversity, also a potential vulnerability factor,24, 25, 26 was higher in those with early onsets of bipolar disorder, as revealed by the incidence of physical or sexual abuse in childhood.

A higher percentage of patients with childhood and adolescent onset reported having more than 20 affective episodes before network entry compared with those with adult onset. The incidence of dysphoric (as opposed to euphoric) mania was also substantially higher in patients with childhood onset (ie, mania was unpleasant, with more anxious and depressive symptoms). Among the comorbidities, patients with childhood onset had a higher prevalence of lifetime anxiety disorders and of drug abuse, with a nonsignificant trend in the same direction for alcohol abuse.

As shown in Table II, in the first year of daily prospective ratings during naturalistic treatment, patients with childhood onset remained substantially more ill than those with adult onset. The childhood-onset group had greater severity of both mania and depression, as well as more days depressed and days with ultradian cycling. They also had more total affective episodes during the prospective year and fewer days well (euthymic).

Table II. Outcome in childhood- and adolescent-onset bipolar disorder: One-year prospective follow-up on the NIMH-LCM (n = 480)
VariableChildhood (0 to 12 years)Adolescent (13 to 18 years)Early adulthood (19 to 29 years)Late adulthood (30+ years)FP
Total days (hypo-) manic51.4±4951.9±5934.7±4339.7±5137.56.01
Total days depressed162.2±97139.3±96108.5±98128.6±1055.29.001
Days cycling26.7±5011.6±328.7±234.6±186.59<.001
Days euthymic125.74±91162.18±103213.14±108192.19±11212.97<.001
Mean severity of depression⁎2.2±1.541.7±1.371.4±1.511.6±1.625.23<.01
Mean severity of mania⁎0.72±0.880.59±0.680.45±0.570.43±0.634.35<.01
Mean number of episodes (DSM IV)5.4±3.724.1±3.432.6±2.482.8±3.3415.78<.001

⁎1, mild; 2, low moderate; 3, high moderate; 4, severe on the NIMH-LCM.

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Discussion 

Our findings reveal that approximately 50% of adult outpatients with bipolar disorder had an onset of illness in either childhood or adolescence (ie, before age 19), and these individuals had long lags before initial treatment for mania or depression. These findings in a clinically identified cohort are convergent with recent epidemiologic data reported by Kessler et al27 demonstrating a substantial incidence of early onset and long lag to treatment. However, Kessler et al could not determine whether or not the lag to first treatment reflected the presence of mild symptomatology and had little functional impact. Our combined retrospective and prospective data indicate that early onset of bipolar disorder is associated with an adverse lifetime course of illness that extends into 1 year of naturalistic treatment in adulthood. When we analyzed data by site, we found that the sites in the United States had a significantly greater rate of childhood- and adolescent-onset bipolar disorder than those in Europe, as discussed in detail elsewhere.28 When considering only the US sites, our findings (62% onset in childhood or adolescence) are even more similar to those of Perlis et al,13 who found this onset pattern in 65% of their US participants.

Our data are also consistent with findings of Perlis et al13 indicating that earlier age of onset was associated with a more difficult and complicated course of illness, including faster cycling, more days depressed, greater lifetime manic and depressive episodes, increased risk of substance abuse and other comorbidities, and greater lifetime risk of suicide attempts. In our study, those with childhood onset had more mood episodes, as well as more anxiety disorder and substance abuse comorbidity (Table I). Furthermore, they also experienced more dysphoric mania and more ultradian cycling than the other groups.

These 2 retrospective accounts and the report by Lish et al29 of a more severe course of bipolar disorder in patients with earlier illness onset are now validated by clinician-rated daily prospective follow-up as adults. During naturalistic treatment (i.e., treatment as usual), those patients with early onset had more time depressed and more severe mania and depression, as well as less time well. The fact that these patients experienced a greater number of episodes in this 1 year of prospective follow-up indicates that the greater proportion of early-onset patients with high numbers of episodes reported retrospectively is not just an artifact of a greater number of years of potential exposure (ie, duration of illness).

Kessler et al,30, 31 in their epidemiologic data from 983 community survey participants in the National Comorbidity Study Replication, found that 13% of bipolar patients had an onset of illness by age 10 and that time lags between illness onset and first treatment correlated inversely with age of onset.

The data from our cohort and that of Perlis et al13 indicate that 14% to 28% of patients with bipolar disorder experience onset of illness before age 13 and that 50% to 67% experience onset before age 19. Lish et al,29 in a study of bipolar patients surveyed from an affective illness advocacy group, also found that early onset of illness and long delay to appropriate diagnosis and treatment were very common. All of these findings taken together with the longest lags in onset of first treatment in those with the earliest onsets27, 28, 29 suggest that very–early-onset bipolar disorder was quite common even a generation ago, but was relatively underrecognized and undertreated at that time. Lange and McGinnis32 reviewed evidence likely indicating both cohort (year of birth) and anticipation (generational) effects in childhood-onset bipolar illness, possibly yielding even more children with early onset today than were found several decades ago when the adults in our study were at risk.

Consequently, providers who assess and treat children and adolescents in various health care settings, including primary and family practice, pediatrics, and neurology, who see many children with ADHD and other externalizing disorders, should be particularly alert to the possibility of bipolar disorder in the differential diagnosis. Such vigilance may begin to shorten what were the extraordinary long delays to first treatment some 20 years ago. Keep in mind, however, that even in adults, in whom there is much less diagnostic controversy, only 9.8% of those in a primary care clinic who screened positive for bipolar symptomatology were recognized as potentially having this disorder.33 Similarly, the underdiagnosis and treatment of bipolar illness in adults is apparent in epidemiologic samples.27, 28, 29, 34, 35 Most strikingly, even when bipolar illness is diagnosed, adults in the community are often given antidepressants without concomitant mood stabilizers,36 contrary to the recommendation in most treatment guidelines.36, 37, 38, 39, 40

Instead of being a diagnosis of exclusion and last resort in children, as has often been the case, bipolar disorder should be actively considered and ruled in or out. This is particularly important in children at high risk due to having 1 or both parents with a diagnosis of bipolar illness (as seen in this study and in the studies of Lapalme et al41 and Pavuluri et al12) or the presence of environmental stressors, such as the occurrence of traumatic events in childhood.24, 25, 26

Most children with bipolar disorder also have a comorbid diagnosis of ADHD, whereas the vast majority of children with ADHD do not have bipolar disorder.6, 12, 42, 43 Nonetheless, in patients with apparent ADHD and additional indicators of extreme mood lability and behavioral dyscontrol (especially in the presence of periods of euphoria, decreased need for sleep, increased sexual interest or acts, delusions, hallucinations, or suicidal behaviors), providers should carefully consider the possibility of bipolar disorder before initiating treatment with stimulants and antidepressants alone, because first treatment with mood stabilizers or atypical antipsychotics is the recommended approach in consensus guidelines.6

Inadequate recognition, diagnosis, and treatment of adult-onset bipolar illness in clinical samples and in the community now appear to be paralleled by equal problems in recognizing and treating childhood-onset bipolar illness, particularly in the United States. Given the likely adverse consequences of long periods of untreated or inadequately treated mood-related symptomatology, as seen in this and other studies,44, 45 efforts to ensure earlier diagnosis and institution of treatment are important. Whether such earlier intervention will in fact ameliorate the long-term difficulties associated with childhood-onset bipolar disorder remains to be ascertained.

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Additional statistical support was provided by Sun Hwang at the Department of Biostatistics, School of Public Health, UCLA, Los Angeles, CA. We thank Chris Gavin for his editorial support.

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 Supported by the National Institutes of Mental Health and the Stanley Medical Research Institute.

PII: S0022-3476(06)01039-0

doi:10.1016/j.jpeds.2006.10.070

Refers to article:

  • Childhood Onset Bipolar Disorder: A Role for Early Recognition and Treatment

    Russell E. Scheffer
    The Journal of Pediatrics May 2007 (Vol. 150, Issue 5, Pages 459-460)

The Journal of Pediatrics
Volume 150, Issue 5 , Pages 485-490, May 2007

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