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Clinical characteristics of bipolar disorder in very young children
Journal of Affective Disorders 97 (2007) 51 – 59 www.elsevier.com/locate/jad
Research report
Clinical characteristics of bipolar disorder in very young children Arman Danielyan a,⁎, Sanjeev Pathak a,b , Robert A. Kowatch a,b , Sarah P. Arszman a , Erin S. Johns a a
Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, D-3014, Cincinnati, OH 45229, United States b Department of Psychiatry, University of Cincinnati Medical Center, United States Received 10 February 2006; received in revised form 17 May 2006; accepted 25 May 2006 Available online 5 July 2006
Abstract Background: Clinical information about bipolar disorder (BPD) in preschool-age (3–7 years old) children is extremely limited. This study examined clinical presentations, applicability of the DSM-IV diagnostic criteria, comorbidity, recovery and relapse rates, as well as some treatment strategies used in the management of BPD in preschoolers. Methods: The charts of 26 outpatient children, ages 3–7, refereed to a child psychiatry outpatient clinic with mood and behavioral symptoms, were retrospectively reviewed. Results: The majority of the patients were referred with the tentative diagnosis of ADHD but the most common diagnoses made by child and adolescent psychiatrists at the time of initial evaluation were BPD NOS (61.5%), followed by BPD I (26.9%), and mood disorder NOS (23.1%). Thirty-eight percent of the patients had one or more comorbid diagnoses. The most common presenting symptoms were irritability (84.6%) and aggression (88.5%). The most widely prescribed class of medications after diagnosis in the clinic was atypical antipsychotics and mood stabilizers. Twenty-six percent of the patients were treated with a combination of atypical antipsychotics and mood stabilizers. Limitations: Retrospective design; small sample size; lack of a comparison group. Conclusions: The course of BPD with onset in preschool years is complicated with high recovery and relapse rates. The questions of development of age-appropriate diagnostic criteria, long-term prognosis and treatment strategies used in this population require further intensive investigation. © 2006 Elsevier B.V. All rights reserved. Keywords: Mania; Pediatric bipolar disorder; Preschool; Diagnostic criteria; Pharmacotherapy; Comorbidity
1. Introduction A growing number of publications during recent years have challenged the assertion that bipolar disorder (BPD) in young children is an extremely rare or a nonexistent condition (Akiskal et al., 1985; Biederman, 1998; Carlson, 1995; Craney and Geller, 2003; Dilsaver ⁎ Corresponding author. Tel.: +1 513 636 1838; fax: +1 513 636 4283. E-mail address: [email protected] (A. Danielyan). 0165-0327/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2006.05.028
and Akiskal, 2004; Geller et al., 2000a; Geller et al., 2004; Geller et al., 2000b; Kowatch, 1998; Luby et al., 2002; Weller et al., 2003a; Weller et al., 1986). Wozniak et al. (1995) reported that 16% of children clinically referred for psychiatric evaluation had a bipolar disorder. Of those, 70% have the onset of manic symptoms at age 5 or younger. In 23% of these children, symptoms of mania were reported as being “always present” (Wozniak and Biederman, 1997). However, despite an increased attention during the recent years to the phenomenon of the early onset bipolar disorder
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(EOBPD), there is a paucity of data regarding the phenomenology, diagnostic criteria, naturalistic course, comorbidity, and the treatment of BPD in children with an onset of this illness before age 7 years. As a result, EOBPD is probably under- and misdiagnosed due to the lack of age-appropriate diagnostic criteria for BPD in young children. Despite some improvements in diagnostic criteria for mania in DSM-IV compared to previous versions of DSM, which applied “adult” criteria to diagnose mania in children, mania in childhood is still frequently underdiagnosed or misdiagnosed (Weller et al., 2003a). Current DSM-IVTR criteria require a distinct period of abnormally and persistently elevated, expansive, or irritable mood, with a duration of 4 days for a hypomanic episode, or 7 days for a manic episode. The application of episode-duration criteria developed for adult BPD, with mania presenting as discrete episodes, limits the chance of diagnosing BPD in very young children (Faedda et al., 2004). Recent studies demonstrate that in contrast to adult BPD, EOBPD most commonly presents with frequent daily mood swings, characterized by frequent short episodes of intense mood liability, hostile aggressive behavior, and chronic irritability rather than classic euphoric mania (Biederman et al., 1998a; Geller et al., 1998; Kowatch et al., 2005; Weller et al., 2003a; Weller et al., 2003b). Several recent research studies have demonstrated that discrete episodes of mania in young children are often not present and the cycling pattern of these patients may best be described as ultrarapid or ultradian cycling (Geller et al., 2000b). EOBPD is sometimes misdiagnosed as attention-deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety, oppositional-defiant disorder (ODD) and conduct disorders (CD). There is a lack of definite diagnostic criteria to diagnose and treat this population of very young children, who often have more severe and developmentally complicated subtype of BPD, characterized by complex episodes, poorer course, and fewer remissions (Carlson et al., 2000). Although several recent studies described the clinical characteristics and phenomenology of pediatric bipolar disorder (Biederman et al., 2004; Dilsaver and Akiskal, 2004; Findling et al., 2001; Geller et al., 2004; Kowatch et al., 2005; Scheffer and Niskala Apps, 2004), the majority of these studies have focused on the 7 to 17 year age group. The effect of pharmacotherapy on the course and outcome of the EOBPD is even less well described with no controlled studies of any medications in children ages 3–7 years with BPD. The questions of the clinical presentation, diagnostic criteria, treatment, recovery, and relapse rates in very young (3–7 years old) children remain controversial and largely understudied.
The objective of this retrospective chart review was to examine the referral pattern and clinical characteristics of bipolar disorder in children between the ages of 3 and 7 years. 2. Methods This study was approved by the local Institutional Review Board and adhered to the privacy requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). The medical charts of 26 children, who were referred for behavior problems, treated as outpatients at the Cincinnati Children's Hospital Medical Center (CCHMC), Division of Psychiatry during the calendar years from 2000 to 2004, were ≤ 7 years old at initial evaluation and diagnosed with a Bipolar Disorder, including BPD I, BPD II, BPD NOS and mood disorder NOS, were retrospectively reviewed. A structured chart review form was utilized to collect data. The data gathering and review included a comprehensive review of all available clinical information, including the child psychiatrists' notes, previous discharge summaries, medication logs and physician's orders. All treating physicians were board-certified/ eligible child and adolescent psychiatrists. Demographic and clinical data obtained included sex, age and race. The variables examined included referral diagnoses, symptoms profile at the time of initial presentation, diagnosis at the time of treatment and number of previous hospitalizations, if any. We also examined how long it took for a diagnosis of BPD to be made by a child and adolescent psychiatrist, after the first appearance of clinically significant symptoms. We evaluated the time to respond to treatment after the initial evaluation by assigning retrospectively a Clinical Global Impression Scale-Severity (CGI-S) and the Clinical Global Impression Scale-Improvement (CGI-I) to each subject's course, along with the Clinical Global Assessment Scale (CGAS, 1 = poor functioning to 100 = outstanding functioning) (Shaffer et al., 1983). A positive response to treatment was defined as a CGI-I score of 1 (Very Much Improved) or 2 (Much Improved) and CGI-S score of 1 to 3 (Symptoms Not Present–Mild Symptoms Not Clinically Significant) for ≥ 2 weeks. A CGI-I score of 3 was defined as a partial response. Relapse was defined as meeting syndromal criteria for mania or hypomania with CGI-S score of ≥ 5 (Moderate Symptoms, Clinically Significant Symptoms Necessitating Intervention) and CGI-I score of ≥ 3 (Minimally Improved) for at least 2 weeks. Clinical impairment was also defined as the Children's Global Assessment Scale
A. Danielyan et al. / Journal of Affective Disorders 97 (2007) 51–59 Table 1 Diagnoses made by referring physicians versus the diagnoses made by a child and adolescent psychiatrist at the time of initial outpatient evaluation
BPD I BPD II BPD NOS Mood disorder NOS Major depressive disorder ADHD Oppositional defiant disorder Adjustment disorder Post-traumatic stress disorder Intermittent explosive disorder Reactive attachment disorder
Diagnoses the patients were referred with
Diagnoses made by child and adolescent psychiatrist at the time of initial evaluation
n
%
n
%
0 0 0 2 1 10 5 2 3 1 1
0 0 0 7.7 3.8 38.5 19.2 7.7 11.5 3.8 3.8
7 0 16 6 0 8 3 1 1 0 0
26.9 0 61.5 23.1 0 30.8 11.5 3.8 3.8 0 0
score of ≤60 for ≥ 2 weeks. In those patients who relapsed after initially responding to treatment, we studied duration of being a responder (CGI-S = 1 or 2; CGAS ≥ 60) before relapse, and the duration of relapse. We also evaluated the main treatment strategies, e.g., dose change, augmentation or change of medications, implemented by treating psychiatrists. We also elected to report three additional pediatric symptom clusters of BPD, based on the “cardinal symptoms” of mania described by Craney and Geller (2003) in the study of 10 year old prepubertal children with BPD. 3. Results A total of 26 charts were reviewed. The male to female ratio was 3:1 (73.1% versus 26.9% respectively). Twenty-four out of twenty-six patients were Caucasian (92.3%), one African-American and one biracial (3.8% each). The mean age of the subjects at the time of initial study evaluation by a child and adolescent psychiatrist was 5.3 ± 1.3 years. 3.1. Diagnostic profile The most common diagnosis (by DSMIV TR) made by treating child and adolescent psychiatrist (CAP) at the time of initial evaluation at the CCHMC was BPD NOS (n = 16; 61.5%), followed by BPD I (n = 7; 26.9%),
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and Mood Disorder NOS (n = 6; 23.1%). None of the patients were diagnosed with BPD II by CAP at the time of initial evaluation. None of the subjects had a diagnosis of BPD I made by a referring physician. Two subjects were diagnosed with mood disorder NOS by their referring physician. In both cases, however, the referral diagnosis was not confirmed by CAP at the time of initial evaluation at the CCHMC, and both of these patients were diagnosed with BPD NOS. Comparison of the diagnoses made by referring physician versus diagnoses made by CAP is illustrated in Table 1. Since clear diagnostic criteria are lacking for cases of BPD with very early onset, we assumed that some children with BPD might in fact be diagnosed as having mood disorder NOS and included the charts of these patients in our review. Out of 26 charts, 22 were diagnosed with BPD according to the DSM-IV categories. Four patients, however, were diagnosed with BPD without clarification of its subtype. None of these four patients met diagnostic criteria for BPD-I or BPD-II. After reviewing these 4 charts, we assigned a diagnosis of bipolar disorder NOS to these subjects based on the clinical presentation, which included multiple daily mood swings without clearly defined episodes. The prevailing symptoms included severe irritability and aggression, increased energy, decreased sleep, distractibility, grandiosity and poor judgment. Out of 10 subjects diagnosed with ADHD by a referring physician, after the initial diagnostic evaluation in the clinic by child and adolescent psychiatrists, the diagnosis of ADHD was confirmed, and the diagnosis of BPD was added in four patients. Ten patients (38.5%) had at least one DSM IV axis I comorbid diagnosis and 5 patients (19.2%) had two or more comorbid diagnoses after initial evaluation by a child and adolescent psychiatrist. The most common comorbid conditions were (in descending order): ADHD (8, 31%); ODD (3, 11%); PTSD (3, 11%); Table 2 Frequency of manic symptoms by categories (in descending order)
DSM-IV mania criteria Sleep disturbances Elated mood Grandiosity Racing thought
n
%
17 8 2 0
65.4 30.8 7.7 0
WASH-U-KSADS items for DSM-IV poor judgment criterion Silliness 5 Hypersexuality 4 Daredevil acts 4 Poor judgment 2
19.2 15.4 15.4 7.7
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Fig. 1. The most frequent presenting symptoms in descending order (in %).
Adjustment Disorder (1, 3.8%) and Reactive Attachment Disorder (1, 4%). 3.2. Symptom profile The first category of symptoms that was reviewed included DSM-IV cardinal symptoms of mania by Craney and Geller (2003) (Table 2). In our sample, the prevalence of these symptoms in the clinic in descending order was: sleep disturbances (65.4%), elated mood (30.8%), grandiosity (7.7%) and racing thoughts (0%). We also examined the WASH-U-KSADS items for
DSM-IV poor judgment criteria, in our subjects. The rates were: silliness (19.2%), hypersexuality (15.4%), daredevil acts (15.4%) and poor judgment (7.7%). Overall, the most prevalent symptoms were aggression (88.5%), irritability (84.6%), increased energy (50%) and distractibility (19.2%). Three out of 26 subjects (11.5%) also had psychotic features, i.e., hallucinations. One patient had suicidal ideation (Fig. 1). We also looked at specific distribution of symptoms in children with BPD only versus children with BPD with comorbid ADHD. ADHD is a very common comorbid disorder in children with BPD (Geller et al.,
Fig. 2. DSM-IV mania-specific symptoms comparison (the numbers are given in %).
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2002; Wozniak et al., 1995), and this differential diagnosis is often difficult. In this sample, children both with BPD alone and with BPD with comorbid ADHD had the same levels of aggression and irritability as main symptoms, followed by decreased sleep and increased energy. Grandiosity, decreased sleep, increased energy, distractibility, accelerated speech, and poor judgment were more prevalent in bipolar children with comorbid ADHD. From the DSM-IV mania symptoms, 65.4% of the subjects had sleep disturbances, which could be a sign of various other psychiatric conditions. Elated mood was observed only in 30.8% of our sample, followed by grandiosity (7.7%, Fig. 2). 3.3. Illness course On the average, it took over 1 year (mean 12.9 months, SD 11.6) for patients to be diagnosed with BPD after they were seen by a health care professional with their first mood symptoms. The CGI-S mean score of this sample at the baseline was 6.5 ± 1.4 (moderate to severe symptoms) and their CGAS score was 41.4 ± 7.4, both indicating severe symptoms. The scores at the last clinic visit were: CGI-S score of 4.0 ± 1.8 (mild to moderately ill range) and CGAS score of 56.35 ± 11.5, indicating some overall improvements in patients' conditions. 3.4. Pharmacotherapy course Seventeen subjects (65.4%) were drug naive at the time of initial evaluation in the clinic. Of those who had already been treated pharmacologically at the time of admission, two were taking mood stabilizers (MS) (one patient was taking valproate, and another one was on carbamazepine). Three patients were taking AA (risperidone n = 2; quetiapine n = 1), including one patient who was taking bupropion and adderall in addition to risperidone. From stimulants, three patients were on Adderrall®, including one on Adderall plus clonidine, one patient was taking methylphenidate, and two patients were taking Strattera. Independent of the diagnosis, the most commonly used psychotropic was risperidone (80.8%), followed by DVP (38.5%). The other frequently prescribed antipsychotics were quetiapine (19.2%) and aripiprazole (19.2%). Only one patient was taking lithium at the time of initial evaluation. None of our patients were prescribed lithium by a child and adolescent psychiatrist at the baseline. Atypical antipsychotics were the most frequent class of medications used in the management of bipolar
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spectrum disorders in very young children, with risperidone being overall the most frequently prescribed medication (80.8% of patients) that was also used for the longest duration of time. The second most frequently used psychotropic in our study was valproate (38.5%). Risperidone was also the most frequently used agent to add on to other psychotropics after relapse. Mean duration of treatment with risperidone was 35.8 ± 38.4 weeks versus 20.9 ± 30 weeks for DVP. Combined use of several psychotropics was common in this sample. At least seven patients (26.9%) were treated with a combination of AA and MS; two patients were taking two AAs and one patient was prescribed two MSs. Six patients (23.1%) were taking at least two psychotropics (e.g., AAs, MSs, SSRIs or psychostimulants) simultaneously, and eight patients (30.8%) were treated with three concomitant medications. 4. Discussion Despite controversies surrounding the question of validity of the diagnosis of BPD in very young children, growing clinical and scientific evidence suggests that children in the age group 3 to 7 years are being referred for psychiatric evaluations and are diagnosed with BPD (Luby and Mrakotsky, 2003; Scheffer and Niskala Apps, 2004). The diagnostic process, however, is then complicated due to a paucity of data on the age-specific diagnostic criteria, clinical presentation and the course of BPD with very early onset. In many cases, the clinicians do not limit the diagnostic process by simply trying to apply current DSM-IV criteria, but also rely heavily on individual clinician's diagnostic impressions based on presenting clinical signs and symptoms. Dilsaver and Akiskal (2004) state that there should be no contradiction in applying these two approaches, i.e., structured diagnostic interview and clinical interview, by a sophisticated physician. However, confusion still exists among many physicians in assigning diagnosis of EOBPD, its subtypes, and its differentiation from comorbid conditions. Despite the complex variation in clinical symptoms in children with EOBPD, thorough review of clinical cases and reports conclude that the most frequently reported clinical symptoms in the age group of 3–7 year olds are mania non-specific, with irritability being the main source of diagnostic mistakes. Irritability rather than euphoria was the most common reason for hospitalization in the sample of 262 children, 12 years or younger, reported by Wozniak et al. (1995). Irritability reported in children with BPD is usually described by different authors as very severe, “extreme,
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explosive”, “completely wild”, “extremely aggressive,” “creating a war zone”, and is often associated with violence (Carlson, 1984; Wozniak et al., 1995; Wozniak et al., 2005). High levels of severe irritability, absence of episodes, and high levels of hyperactivity as characteristic of prepubertal mania are also described by Carlson (1984). One hundred percent of children, diagnosed with BPD, had irritability as presenting symptom in a retrospective chart review of kids under age of 5 years old (Scheffer and Niskala Apps, 2004). In our sample results were pretty similar. Such symptom polymorphism could obviously become a major barrier in diagnosing these patients by pediatricians and child psychiatrists. In our study, 7 out of 26 patients were diagnosed with different types of BPD even though they did not have DSM-IV first rank symptoms of mania. Two of these patients were diagnosed with BPD based on the symptoms of aggression, increased energy and irritability. The remaining five patients were diagnosed with BPD NOS and the presenting symptoms included aggression, irritability, distractibility, and poor judgment. High levels of irritability and aggression, along with presence of high levels of mania non-specific mood dysregulations, are reported by numerous studies to be a result of presence of comorbid ADHD. Studies report presence of comorbid ADHD in as much as 98% of children with BPD (Geller et al., 2000b; Kowatch, 1998; Scheffer and Niskala Apps, 2004; Weller et al., 2003b; Wozniak et al., 1995). In our study, however, the rates of comorbid ADHD were much lower (30.8%). This could be indicative of a considerable overlap of clinical symptoms in cases with very early onset, including overexpression of mania nonspecific and underexpression of true mania symptoms, which may further complicate differential diagnosis. Children with the diagnosis of ADHD often present with newly developed or with worsening of previously present mood swings and irritability after being treated with stimulant medications. There is also a point of view that early treatment with stimulants can result in earlier onset of mania and a more severe course of BPD (DelBello et al., 2001; Soutullo et al., 2002). It is probable that the comorbid ADHD seen in these patients may be cases of mania without any concurrent illness, as most symptoms of ADHD can be explained by mania itself. Results of our study are in accordance with work of other groups, reporting recovery rates from index episodes ranging from 65% to 100% and relapse rates from 40% to 67% (Biederman et al., 1998b; Geller et al., 2001; Geller et al., 2000c; Srinath et al., 1998; Strober et
al., 1995). In our study, 25 out of 26 patients responded to the treatment initially. However, 61.5% of the patients have then relapsed during the course of treatment, with some patients having two or more consecutive relapses. Median time to respond to initial treatment in our study was 4 weeks (mean 12.88; S.D. = 26.27), which is close to the range of 0.4 to 27.4 weeks (median 4 weeks), reported by Jairam et al. (2004) in 25 children, aged 9– 16 years, with BPD. In contrast, the time to recovery was 60.2 ± 47.5 weeks in a sample of 86 prepubertal children aged 10.8 ± 2.7 in the study of Geller et al. (2004). Since Geller's study involved only patients with BPD I with at least one cardinal symptoms of mania, whereas the patient population in our study had more “mixed”, non-specific picture, these results could indicate that a clear bipolar I phenotype shows more delayed response to treatment. There could also be a possibility that in cases with very early onset of bipolar illness, early intervention could lead to earlier response. Interestingly, however, the time to relapse after recovery was much shorter in our patients compared to the sample in above-mentioned study of Geller et al. (2004) (19.69 ± 18.4 versus 40.4 ± 33.4 weeks respectively). Only one patient in our study remained symptom-free for more than a year. 31.25% of the patients remained responders for up to 2 months; 50% for up to 6 months; and 12.5% for up to 1 year. There are no controlled studies of psychotropic medication in this age group. There is one, open prospective study of olanzapine and risperidone for the treatment of BPD in preschool-age children (Biederman et al., 2005). However, despite the fact that there is no data on efficacy and safety of either acute or maintenance treatment of BPD in preschoolers (Greenhill, 1998; Minde, 1998; Vitiello, 1998, 2001), various classes of psychotropics, including combined use of two or more psychotropics, are widely used in this age group (Kowatch et al., 2003; Pathak et al., 2004; Zito et al., 2000). In our study this was evidenced by a variety of psychotropics taken by the patients at the time of initial evaluation, suggesting that practitioners are still lacking clear guidelines on how to treat mood dysregulations in this age group. Interestingly, none of our patients were treated with lithium. The reason could be unfavorable side effect profile for the lithium, as well as difficulties associated with the maintenance of therapeutic plasma level. The patients in our study were often treated with 2 or even 3 psychotropics simultaneously (23.1% and 30.8% respectively), which was probably due to unresponsiveness of the patients to monotherapy or the presence of comorbid conditions. This, in fact, could be another
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reason for low level of comorbid ADHD reported in our study. Seventy-five percent of patients with diagnosed comorbid ADHD at the initial visit received multiple psychotropics, whereas 77.8% of patients without comorbid ADHD received multiple psychotropics (including atypical antipsychotics, stimulants and mood stabilizers). This difference was not statistically significant. This further emphasizes the significance of conducting controlled trials of mono- and polypharmacotherapy of BPD in this young age group. In a summary, one of the major pitfalls in a long pathway of helping this group of patients is the absence of clearly defined diagnostic criteria as evidenced by a large diversity of bipolar-spectrum diagnoses in our subjects, with prevailing number of kids with the diagnosis of BPD NOS and mood disorder NOS. Hence, it is crucially important to characterize features of BPD in this age group and to develop precise, ageappropriate diagnostic guidelines to assist physicians in the diagnostic process. This will help to identify and intervene at early stages of the development of this chronic illness, which seriously disrupts the lives of children and adolescents, with studies showing poorer academic performance, disturbed interpersonal relationships, increased rates of substance abuse, legal difficulties, multiple hospitalizations, and increased rates of both suicide attempts and completions (Akiskal et al., 1985; Carlson et al., 2002; Geller and Luby, 1997; Lewinsohn et al., 1995; Strober et al., 1995). Although this population does respond initially to psychopharmacological treatment, the relapse rates are pretty high, with only 2 out of 26 patients maintaining remission for more than 1 year in our study. This could be a result of either developing tolerance/tachyphylaxis to the treatment with a specific drug or a problem of genetic “matching” of specific medications. Future research in the field of psychopharmacogenetics should be crucial in understanding this phenomenon. 5. Limitations Generalization of the present results may be limited by the following: (a) use of retrospective design; (b) relatively small sample size; (c) lack of a comparison group. The diagnoses listed could be different if structured and semi-structured (e.g., WASH-UKSADS) instruments were applied. CGI and CGAS ratings were also applied retrospectively, which limits its reliability. The majority of the patients in our study were from outpatient clinics and results may be different if compared to the inpatient samples. Changes in the CGI scores could be related to an
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additional use of psychosocial treatments which we did not document. Family history data, which could be a very valuable source for confirming diagnosis of BPD in these children due to already documented high risk of BPD in first degree relatives, is also missing. And finally, the data presented did not elaborate on psychosocial factors that could influence the recovery and relapse rates. Acknowledgments The authors acknowledge Drs. Michael Sorter and Pamela Campbell for their contribution. Disclosure: Dr. Kowatch has financial affiliations with Bristol-Myers Squibb, Glaxo-Smith Kline, Janssen, Astra-Zeneca, Cephalon Inc., Abbott and Pfizer. Dr. Pathak has research funding from Forest Laboratories Inc. and Cephalon Inc. The other authors have no financial relationships to disclose. References Akiskal, H.S., Downs, J., Jordan, P., Watson, S., Daugherty, D., Pruitt, D.B., 1985. Affective disorders in referred children and younger siblings of manic-depressives. Mode of onset and prospective course. Archives of General Psychiatry 42, 996–1003. Biederman, J., 1998. Resolved: mania is mistaken for ADHD in prepubertal children. Journal of the American Academy of Child and Adolescent Psychiatry 37, 1096–1098. Biederman, J., Klein, R.G., Pine, D.S., Klein, D.F., 1998a. Resolved: mania is mistaken for ADHD in prepubertal children. Journal of the American Academy of Child and Adolescent Psychiatry 37, 1091–1096. Biederman, J., Mick, E., Bostic, J.Q., Prince, J., Daly, J., Wilens, T.E., Spencer, T., Garcia-Jetton, J., Russell, R., Wozniak, J., Faraone, S.V., 1998b. The naturalistic course of pharmacologic treatment of children with manic-like symptoms: a systematic chart review. Journal of Clinical Psychiatry 59, 628–637. Biederman, J., Mick, E., Faraone, S.V., Van Patten, S., Burback, M., Wozniak, J., 2004. A prospective follow-up study of pediatric bipolar disorder in boys with attention-deficit/hyperactivity disorder. Journal of Affective Disorders 82, S17–S23. Biederman, J., Mick, E., Hammerness, P., Harpold, T., Aleardi, M., Dougherty, M., Wozniak, J., 2005. Open-label, 8-week trial of olanzapine and risperidone for the treatment of bipolar disorder in preschool-age children. Biological Psychiatry 58, 589–594. Carlson, G.A., 1984. Classification issues of bipolar disorders in childhood. Psychiatric Developments 2, 273–285. Carlson, G.A., 1995. Identifying prepubertal mania. Journal of the American Academy of Child and Adolescent Psychiatry 34, 750–753. Carlson, G.A., Bromet, E.J., Sievers, S., 2000. Phenomenology and outcome of subjects with early- and adult-onset psychotic mania. American Journal of Psychiatry 157, 213–219. Carlson, G.A., Bromet, E.J., Driessens, C., Mojtabai, R., Schwartz, J.E., 2002. Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. American Journal of Psychiatry 159, 307–309.
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Kowatch, R.A., 1998. Mania in young children [comment]. Journal of the American Academy of Child and Adolescent Psychiatry 37, 1003–1005. Kowatch, R.A., Sethuraman, G., Hume, J.H., Kromelis, M., Weinberg, W.A., 2003. Combination pharmacotherapy in children and adolescents with bipolar disorder. Biological Psychiatry 53, 978–984. Kowatch, R.A., Fristad, M., Birmaher, B., Wagner, K.D., Findling, R.L., Hellander, M., Child Psychiatric Workgroup on Bipolar, D., 2005. Treatment guidelines for children and adolescents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 44, 213–235. Lewinsohn, P.M., Klein, D.N., Seeley, J.R., 1995. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. Journal of the American Academy of Child and Adolescent Psychiatry 34, 454–463. Luby, J.L., Mrakotsky, C., 2003. Depressed preschoolers with bipolar family history: a group at high risk for later switching to mania? Journal of Child and Adolescent Psychopharmacology 13, 187–197. Luby, J.L., Heffelfinger, A.K., Mrakotsky, C., Hessler, M.J., Brown, K.M., Hildebrand, T., 2002. Preschool major depressive disorder: preliminary validation for developmentally modified DSM-IV criteria [see comment]. Journal of the American Academy of Child and Adolescent Psychiatry 41, 928–937. Minde, K., 1998. The use of psychotropic medication in preschoolers: some recent developments. Canadian Journal of Psychiatry-Revue Canadienne de Psychiatrie 43, 571–575. Pathak, S., Arszman, S.P., Danielyan, A., Johns, E.S., Smirnov, A., Kowatch, R.A., 2004. Psychotropic utilization and psychiatric presentation of hospitalized very young children. Journal of Child and Adolescent Psychopharmacology 14, 433–442. Scheffer, R.E., Niskala Apps, J.A., 2004. The diagnosis of preschool bipolar disorder presenting with mania: open pharmacological treatment. Journal of Affective Disorders 82, S25–S34. Shaffer, D., Gould, M.S., Brasic, J., Ambrosini, P., Fisher, P., Bird, H., Aluwahlia, S., 1983. A children's global assessment scale (CGAS). Archives of General Psychiatry 40, 1228–1231. Soutullo, C.A., DelBello, M.P., Ochsner, J.E., McElroy, S.L., Taylor, S.A., Strakowski, S.M., Keck Jr., P.E., 2002. Severity of bipolarity in hospitalized manic adolescents with history of stimulant or antidepressant treatment. Journal of Affective Disorders 70, 323–327. Srinath, S., Janardhan Reddy, Y.C., Girimaji, S.R., Seshadri, S.P., Subbakrishna, D.K., 1998. A prospective study of bipolar disorder in children and adolescents from India. Acta Psychiatrica Scandinavica 98, 437–442. Strober, M., Schmidt-Lackner, S., Freeman, R., Bower, S., Lampert, C., DeAntonio, M., 1995. Recovery and relapse in adolescents with bipolar affective illness: a five-year naturalistic, prospective follow-up. Journal of the American Academy of Child and Adolescent Psychiatry 34, 724–731. Vitiello, B., 1998. Pediatric psychopharmacology and the interaction between drugs and the developing brain. Canadian Journal of Psychiatry-Revue Canadienne de Psychiatrie 43, 582–584. Vitiello, B., 2001. Psychopharmacology for young children: clinical needs and research opportunities. Pediatrics 108, 983–989. Weller, R.A., Weller, E.B., Tucker, S.G., Fristad, M.A., 1986. Mania in prepubertal children: has it been underdiagnosed? Journal of Affective Disorders 11, 151–154. Weller, E.B., Weller, R.A., Danielyan, A.K., 2003a. Mood disorders in prepubertal children. In: Wiener, J., Dulcan, M. (Eds.), The
A. Danielyan et al. / Journal of Affective Disorders 97 (2007) 51–59 American Psychiatric Publishing Textbook of Child and Adolescent Psychiatry. American Psychiatric Publishing, Incorporated, Washington, DC, pp. 411–435. Weller, E.B., Weller, R.A., Lau, K.C., Weller, A.E., Danielyan, A.C., Zilber, I., 2003b. Diagnosing mania in children and adolescents. Biological Psychiatry 53, 13S (Supplement). Wozniak, J., Biederman, J., 1997. Childhood mania: insights into diagnostic and treatment issues. Journal of the Association for Academic Minority Physicians 8, 78–84. Wozniak, J., Biederman, J., Kiely, K., Ablon, J.S., Faraone, S.V., Mundy, E., Mennin, D., 1995. Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children [see
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comments]. Journal of the American Academy of Child and Adolescent Psychiatry 34, 867–876. Wozniak, J., Biederman, J., Kwon, A., Mick, E., Faraone, S., Orlovsky, K., Schnare, L., Cargol, C., van Grondelle, A., 2005. How cardinal are cardinal symptoms in pediatric bipolar disorder? An examination of clinical correlates. Biological Psychiatry 58, 583–588. Zito, J.M., Safer, D.J., dosReis, S., Gardner, J.F., Boles, M., Lynch, F., 2000. Trends in the prescribing of psychotropic medications to preschoolers [see comment]. JAMA 283, 1025–1030.
Research report
Clinical characteristics of bipolar disorder in very young children Arman Danielyan a,⁎, Sanjeev Pathak a,b , Robert A. Kowatch a,b , Sarah P. Arszman a , Erin S. Johns a a
Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, D-3014, Cincinnati, OH 45229, United States b Department of Psychiatry, University of Cincinnati Medical Center, United States Received 10 February 2006; received in revised form 17 May 2006; accepted 25 May 2006 Available online 5 July 2006
Abstract Background: Clinical information about bipolar disorder (BPD) in preschool-age (3–7 years old) children is extremely limited. This study examined clinical presentations, applicability of the DSM-IV diagnostic criteria, comorbidity, recovery and relapse rates, as well as some treatment strategies used in the management of BPD in preschoolers. Methods: The charts of 26 outpatient children, ages 3–7, refereed to a child psychiatry outpatient clinic with mood and behavioral symptoms, were retrospectively reviewed. Results: The majority of the patients were referred with the tentative diagnosis of ADHD but the most common diagnoses made by child and adolescent psychiatrists at the time of initial evaluation were BPD NOS (61.5%), followed by BPD I (26.9%), and mood disorder NOS (23.1%). Thirty-eight percent of the patients had one or more comorbid diagnoses. The most common presenting symptoms were irritability (84.6%) and aggression (88.5%). The most widely prescribed class of medications after diagnosis in the clinic was atypical antipsychotics and mood stabilizers. Twenty-six percent of the patients were treated with a combination of atypical antipsychotics and mood stabilizers. Limitations: Retrospective design; small sample size; lack of a comparison group. Conclusions: The course of BPD with onset in preschool years is complicated with high recovery and relapse rates. The questions of development of age-appropriate diagnostic criteria, long-term prognosis and treatment strategies used in this population require further intensive investigation. © 2006 Elsevier B.V. All rights reserved. Keywords: Mania; Pediatric bipolar disorder; Preschool; Diagnostic criteria; Pharmacotherapy; Comorbidity
1. Introduction A growing number of publications during recent years have challenged the assertion that bipolar disorder (BPD) in young children is an extremely rare or a nonexistent condition (Akiskal et al., 1985; Biederman, 1998; Carlson, 1995; Craney and Geller, 2003; Dilsaver ⁎ Corresponding author. Tel.: +1 513 636 1838; fax: +1 513 636 4283. E-mail address: [email protected] (A. Danielyan). 0165-0327/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2006.05.028
and Akiskal, 2004; Geller et al., 2000a; Geller et al., 2004; Geller et al., 2000b; Kowatch, 1998; Luby et al., 2002; Weller et al., 2003a; Weller et al., 1986). Wozniak et al. (1995) reported that 16% of children clinically referred for psychiatric evaluation had a bipolar disorder. Of those, 70% have the onset of manic symptoms at age 5 or younger. In 23% of these children, symptoms of mania were reported as being “always present” (Wozniak and Biederman, 1997). However, despite an increased attention during the recent years to the phenomenon of the early onset bipolar disorder
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(EOBPD), there is a paucity of data regarding the phenomenology, diagnostic criteria, naturalistic course, comorbidity, and the treatment of BPD in children with an onset of this illness before age 7 years. As a result, EOBPD is probably under- and misdiagnosed due to the lack of age-appropriate diagnostic criteria for BPD in young children. Despite some improvements in diagnostic criteria for mania in DSM-IV compared to previous versions of DSM, which applied “adult” criteria to diagnose mania in children, mania in childhood is still frequently underdiagnosed or misdiagnosed (Weller et al., 2003a). Current DSM-IVTR criteria require a distinct period of abnormally and persistently elevated, expansive, or irritable mood, with a duration of 4 days for a hypomanic episode, or 7 days for a manic episode. The application of episode-duration criteria developed for adult BPD, with mania presenting as discrete episodes, limits the chance of diagnosing BPD in very young children (Faedda et al., 2004). Recent studies demonstrate that in contrast to adult BPD, EOBPD most commonly presents with frequent daily mood swings, characterized by frequent short episodes of intense mood liability, hostile aggressive behavior, and chronic irritability rather than classic euphoric mania (Biederman et al., 1998a; Geller et al., 1998; Kowatch et al., 2005; Weller et al., 2003a; Weller et al., 2003b). Several recent research studies have demonstrated that discrete episodes of mania in young children are often not present and the cycling pattern of these patients may best be described as ultrarapid or ultradian cycling (Geller et al., 2000b). EOBPD is sometimes misdiagnosed as attention-deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety, oppositional-defiant disorder (ODD) and conduct disorders (CD). There is a lack of definite diagnostic criteria to diagnose and treat this population of very young children, who often have more severe and developmentally complicated subtype of BPD, characterized by complex episodes, poorer course, and fewer remissions (Carlson et al., 2000). Although several recent studies described the clinical characteristics and phenomenology of pediatric bipolar disorder (Biederman et al., 2004; Dilsaver and Akiskal, 2004; Findling et al., 2001; Geller et al., 2004; Kowatch et al., 2005; Scheffer and Niskala Apps, 2004), the majority of these studies have focused on the 7 to 17 year age group. The effect of pharmacotherapy on the course and outcome of the EOBPD is even less well described with no controlled studies of any medications in children ages 3–7 years with BPD. The questions of the clinical presentation, diagnostic criteria, treatment, recovery, and relapse rates in very young (3–7 years old) children remain controversial and largely understudied.
The objective of this retrospective chart review was to examine the referral pattern and clinical characteristics of bipolar disorder in children between the ages of 3 and 7 years. 2. Methods This study was approved by the local Institutional Review Board and adhered to the privacy requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). The medical charts of 26 children, who were referred for behavior problems, treated as outpatients at the Cincinnati Children's Hospital Medical Center (CCHMC), Division of Psychiatry during the calendar years from 2000 to 2004, were ≤ 7 years old at initial evaluation and diagnosed with a Bipolar Disorder, including BPD I, BPD II, BPD NOS and mood disorder NOS, were retrospectively reviewed. A structured chart review form was utilized to collect data. The data gathering and review included a comprehensive review of all available clinical information, including the child psychiatrists' notes, previous discharge summaries, medication logs and physician's orders. All treating physicians were board-certified/ eligible child and adolescent psychiatrists. Demographic and clinical data obtained included sex, age and race. The variables examined included referral diagnoses, symptoms profile at the time of initial presentation, diagnosis at the time of treatment and number of previous hospitalizations, if any. We also examined how long it took for a diagnosis of BPD to be made by a child and adolescent psychiatrist, after the first appearance of clinically significant symptoms. We evaluated the time to respond to treatment after the initial evaluation by assigning retrospectively a Clinical Global Impression Scale-Severity (CGI-S) and the Clinical Global Impression Scale-Improvement (CGI-I) to each subject's course, along with the Clinical Global Assessment Scale (CGAS, 1 = poor functioning to 100 = outstanding functioning) (Shaffer et al., 1983). A positive response to treatment was defined as a CGI-I score of 1 (Very Much Improved) or 2 (Much Improved) and CGI-S score of 1 to 3 (Symptoms Not Present–Mild Symptoms Not Clinically Significant) for ≥ 2 weeks. A CGI-I score of 3 was defined as a partial response. Relapse was defined as meeting syndromal criteria for mania or hypomania with CGI-S score of ≥ 5 (Moderate Symptoms, Clinically Significant Symptoms Necessitating Intervention) and CGI-I score of ≥ 3 (Minimally Improved) for at least 2 weeks. Clinical impairment was also defined as the Children's Global Assessment Scale
A. Danielyan et al. / Journal of Affective Disorders 97 (2007) 51–59 Table 1 Diagnoses made by referring physicians versus the diagnoses made by a child and adolescent psychiatrist at the time of initial outpatient evaluation
BPD I BPD II BPD NOS Mood disorder NOS Major depressive disorder ADHD Oppositional defiant disorder Adjustment disorder Post-traumatic stress disorder Intermittent explosive disorder Reactive attachment disorder
Diagnoses the patients were referred with
Diagnoses made by child and adolescent psychiatrist at the time of initial evaluation
n
%
n
%
0 0 0 2 1 10 5 2 3 1 1
0 0 0 7.7 3.8 38.5 19.2 7.7 11.5 3.8 3.8
7 0 16 6 0 8 3 1 1 0 0
26.9 0 61.5 23.1 0 30.8 11.5 3.8 3.8 0 0
score of ≤60 for ≥ 2 weeks. In those patients who relapsed after initially responding to treatment, we studied duration of being a responder (CGI-S = 1 or 2; CGAS ≥ 60) before relapse, and the duration of relapse. We also evaluated the main treatment strategies, e.g., dose change, augmentation or change of medications, implemented by treating psychiatrists. We also elected to report three additional pediatric symptom clusters of BPD, based on the “cardinal symptoms” of mania described by Craney and Geller (2003) in the study of 10 year old prepubertal children with BPD. 3. Results A total of 26 charts were reviewed. The male to female ratio was 3:1 (73.1% versus 26.9% respectively). Twenty-four out of twenty-six patients were Caucasian (92.3%), one African-American and one biracial (3.8% each). The mean age of the subjects at the time of initial study evaluation by a child and adolescent psychiatrist was 5.3 ± 1.3 years. 3.1. Diagnostic profile The most common diagnosis (by DSMIV TR) made by treating child and adolescent psychiatrist (CAP) at the time of initial evaluation at the CCHMC was BPD NOS (n = 16; 61.5%), followed by BPD I (n = 7; 26.9%),
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and Mood Disorder NOS (n = 6; 23.1%). None of the patients were diagnosed with BPD II by CAP at the time of initial evaluation. None of the subjects had a diagnosis of BPD I made by a referring physician. Two subjects were diagnosed with mood disorder NOS by their referring physician. In both cases, however, the referral diagnosis was not confirmed by CAP at the time of initial evaluation at the CCHMC, and both of these patients were diagnosed with BPD NOS. Comparison of the diagnoses made by referring physician versus diagnoses made by CAP is illustrated in Table 1. Since clear diagnostic criteria are lacking for cases of BPD with very early onset, we assumed that some children with BPD might in fact be diagnosed as having mood disorder NOS and included the charts of these patients in our review. Out of 26 charts, 22 were diagnosed with BPD according to the DSM-IV categories. Four patients, however, were diagnosed with BPD without clarification of its subtype. None of these four patients met diagnostic criteria for BPD-I or BPD-II. After reviewing these 4 charts, we assigned a diagnosis of bipolar disorder NOS to these subjects based on the clinical presentation, which included multiple daily mood swings without clearly defined episodes. The prevailing symptoms included severe irritability and aggression, increased energy, decreased sleep, distractibility, grandiosity and poor judgment. Out of 10 subjects diagnosed with ADHD by a referring physician, after the initial diagnostic evaluation in the clinic by child and adolescent psychiatrists, the diagnosis of ADHD was confirmed, and the diagnosis of BPD was added in four patients. Ten patients (38.5%) had at least one DSM IV axis I comorbid diagnosis and 5 patients (19.2%) had two or more comorbid diagnoses after initial evaluation by a child and adolescent psychiatrist. The most common comorbid conditions were (in descending order): ADHD (8, 31%); ODD (3, 11%); PTSD (3, 11%); Table 2 Frequency of manic symptoms by categories (in descending order)
DSM-IV mania criteria Sleep disturbances Elated mood Grandiosity Racing thought
n
%
17 8 2 0
65.4 30.8 7.7 0
WASH-U-KSADS items for DSM-IV poor judgment criterion Silliness 5 Hypersexuality 4 Daredevil acts 4 Poor judgment 2
19.2 15.4 15.4 7.7
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Fig. 1. The most frequent presenting symptoms in descending order (in %).
Adjustment Disorder (1, 3.8%) and Reactive Attachment Disorder (1, 4%). 3.2. Symptom profile The first category of symptoms that was reviewed included DSM-IV cardinal symptoms of mania by Craney and Geller (2003) (Table 2). In our sample, the prevalence of these symptoms in the clinic in descending order was: sleep disturbances (65.4%), elated mood (30.8%), grandiosity (7.7%) and racing thoughts (0%). We also examined the WASH-U-KSADS items for
DSM-IV poor judgment criteria, in our subjects. The rates were: silliness (19.2%), hypersexuality (15.4%), daredevil acts (15.4%) and poor judgment (7.7%). Overall, the most prevalent symptoms were aggression (88.5%), irritability (84.6%), increased energy (50%) and distractibility (19.2%). Three out of 26 subjects (11.5%) also had psychotic features, i.e., hallucinations. One patient had suicidal ideation (Fig. 1). We also looked at specific distribution of symptoms in children with BPD only versus children with BPD with comorbid ADHD. ADHD is a very common comorbid disorder in children with BPD (Geller et al.,
Fig. 2. DSM-IV mania-specific symptoms comparison (the numbers are given in %).
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2002; Wozniak et al., 1995), and this differential diagnosis is often difficult. In this sample, children both with BPD alone and with BPD with comorbid ADHD had the same levels of aggression and irritability as main symptoms, followed by decreased sleep and increased energy. Grandiosity, decreased sleep, increased energy, distractibility, accelerated speech, and poor judgment were more prevalent in bipolar children with comorbid ADHD. From the DSM-IV mania symptoms, 65.4% of the subjects had sleep disturbances, which could be a sign of various other psychiatric conditions. Elated mood was observed only in 30.8% of our sample, followed by grandiosity (7.7%, Fig. 2). 3.3. Illness course On the average, it took over 1 year (mean 12.9 months, SD 11.6) for patients to be diagnosed with BPD after they were seen by a health care professional with their first mood symptoms. The CGI-S mean score of this sample at the baseline was 6.5 ± 1.4 (moderate to severe symptoms) and their CGAS score was 41.4 ± 7.4, both indicating severe symptoms. The scores at the last clinic visit were: CGI-S score of 4.0 ± 1.8 (mild to moderately ill range) and CGAS score of 56.35 ± 11.5, indicating some overall improvements in patients' conditions. 3.4. Pharmacotherapy course Seventeen subjects (65.4%) were drug naive at the time of initial evaluation in the clinic. Of those who had already been treated pharmacologically at the time of admission, two were taking mood stabilizers (MS) (one patient was taking valproate, and another one was on carbamazepine). Three patients were taking AA (risperidone n = 2; quetiapine n = 1), including one patient who was taking bupropion and adderall in addition to risperidone. From stimulants, three patients were on Adderrall®, including one on Adderall plus clonidine, one patient was taking methylphenidate, and two patients were taking Strattera. Independent of the diagnosis, the most commonly used psychotropic was risperidone (80.8%), followed by DVP (38.5%). The other frequently prescribed antipsychotics were quetiapine (19.2%) and aripiprazole (19.2%). Only one patient was taking lithium at the time of initial evaluation. None of our patients were prescribed lithium by a child and adolescent psychiatrist at the baseline. Atypical antipsychotics were the most frequent class of medications used in the management of bipolar
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spectrum disorders in very young children, with risperidone being overall the most frequently prescribed medication (80.8% of patients) that was also used for the longest duration of time. The second most frequently used psychotropic in our study was valproate (38.5%). Risperidone was also the most frequently used agent to add on to other psychotropics after relapse. Mean duration of treatment with risperidone was 35.8 ± 38.4 weeks versus 20.9 ± 30 weeks for DVP. Combined use of several psychotropics was common in this sample. At least seven patients (26.9%) were treated with a combination of AA and MS; two patients were taking two AAs and one patient was prescribed two MSs. Six patients (23.1%) were taking at least two psychotropics (e.g., AAs, MSs, SSRIs or psychostimulants) simultaneously, and eight patients (30.8%) were treated with three concomitant medications. 4. Discussion Despite controversies surrounding the question of validity of the diagnosis of BPD in very young children, growing clinical and scientific evidence suggests that children in the age group 3 to 7 years are being referred for psychiatric evaluations and are diagnosed with BPD (Luby and Mrakotsky, 2003; Scheffer and Niskala Apps, 2004). The diagnostic process, however, is then complicated due to a paucity of data on the age-specific diagnostic criteria, clinical presentation and the course of BPD with very early onset. In many cases, the clinicians do not limit the diagnostic process by simply trying to apply current DSM-IV criteria, but also rely heavily on individual clinician's diagnostic impressions based on presenting clinical signs and symptoms. Dilsaver and Akiskal (2004) state that there should be no contradiction in applying these two approaches, i.e., structured diagnostic interview and clinical interview, by a sophisticated physician. However, confusion still exists among many physicians in assigning diagnosis of EOBPD, its subtypes, and its differentiation from comorbid conditions. Despite the complex variation in clinical symptoms in children with EOBPD, thorough review of clinical cases and reports conclude that the most frequently reported clinical symptoms in the age group of 3–7 year olds are mania non-specific, with irritability being the main source of diagnostic mistakes. Irritability rather than euphoria was the most common reason for hospitalization in the sample of 262 children, 12 years or younger, reported by Wozniak et al. (1995). Irritability reported in children with BPD is usually described by different authors as very severe, “extreme,
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explosive”, “completely wild”, “extremely aggressive,” “creating a war zone”, and is often associated with violence (Carlson, 1984; Wozniak et al., 1995; Wozniak et al., 2005). High levels of severe irritability, absence of episodes, and high levels of hyperactivity as characteristic of prepubertal mania are also described by Carlson (1984). One hundred percent of children, diagnosed with BPD, had irritability as presenting symptom in a retrospective chart review of kids under age of 5 years old (Scheffer and Niskala Apps, 2004). In our sample results were pretty similar. Such symptom polymorphism could obviously become a major barrier in diagnosing these patients by pediatricians and child psychiatrists. In our study, 7 out of 26 patients were diagnosed with different types of BPD even though they did not have DSM-IV first rank symptoms of mania. Two of these patients were diagnosed with BPD based on the symptoms of aggression, increased energy and irritability. The remaining five patients were diagnosed with BPD NOS and the presenting symptoms included aggression, irritability, distractibility, and poor judgment. High levels of irritability and aggression, along with presence of high levels of mania non-specific mood dysregulations, are reported by numerous studies to be a result of presence of comorbid ADHD. Studies report presence of comorbid ADHD in as much as 98% of children with BPD (Geller et al., 2000b; Kowatch, 1998; Scheffer and Niskala Apps, 2004; Weller et al., 2003b; Wozniak et al., 1995). In our study, however, the rates of comorbid ADHD were much lower (30.8%). This could be indicative of a considerable overlap of clinical symptoms in cases with very early onset, including overexpression of mania nonspecific and underexpression of true mania symptoms, which may further complicate differential diagnosis. Children with the diagnosis of ADHD often present with newly developed or with worsening of previously present mood swings and irritability after being treated with stimulant medications. There is also a point of view that early treatment with stimulants can result in earlier onset of mania and a more severe course of BPD (DelBello et al., 2001; Soutullo et al., 2002). It is probable that the comorbid ADHD seen in these patients may be cases of mania without any concurrent illness, as most symptoms of ADHD can be explained by mania itself. Results of our study are in accordance with work of other groups, reporting recovery rates from index episodes ranging from 65% to 100% and relapse rates from 40% to 67% (Biederman et al., 1998b; Geller et al., 2001; Geller et al., 2000c; Srinath et al., 1998; Strober et
al., 1995). In our study, 25 out of 26 patients responded to the treatment initially. However, 61.5% of the patients have then relapsed during the course of treatment, with some patients having two or more consecutive relapses. Median time to respond to initial treatment in our study was 4 weeks (mean 12.88; S.D. = 26.27), which is close to the range of 0.4 to 27.4 weeks (median 4 weeks), reported by Jairam et al. (2004) in 25 children, aged 9– 16 years, with BPD. In contrast, the time to recovery was 60.2 ± 47.5 weeks in a sample of 86 prepubertal children aged 10.8 ± 2.7 in the study of Geller et al. (2004). Since Geller's study involved only patients with BPD I with at least one cardinal symptoms of mania, whereas the patient population in our study had more “mixed”, non-specific picture, these results could indicate that a clear bipolar I phenotype shows more delayed response to treatment. There could also be a possibility that in cases with very early onset of bipolar illness, early intervention could lead to earlier response. Interestingly, however, the time to relapse after recovery was much shorter in our patients compared to the sample in above-mentioned study of Geller et al. (2004) (19.69 ± 18.4 versus 40.4 ± 33.4 weeks respectively). Only one patient in our study remained symptom-free for more than a year. 31.25% of the patients remained responders for up to 2 months; 50% for up to 6 months; and 12.5% for up to 1 year. There are no controlled studies of psychotropic medication in this age group. There is one, open prospective study of olanzapine and risperidone for the treatment of BPD in preschool-age children (Biederman et al., 2005). However, despite the fact that there is no data on efficacy and safety of either acute or maintenance treatment of BPD in preschoolers (Greenhill, 1998; Minde, 1998; Vitiello, 1998, 2001), various classes of psychotropics, including combined use of two or more psychotropics, are widely used in this age group (Kowatch et al., 2003; Pathak et al., 2004; Zito et al., 2000). In our study this was evidenced by a variety of psychotropics taken by the patients at the time of initial evaluation, suggesting that practitioners are still lacking clear guidelines on how to treat mood dysregulations in this age group. Interestingly, none of our patients were treated with lithium. The reason could be unfavorable side effect profile for the lithium, as well as difficulties associated with the maintenance of therapeutic plasma level. The patients in our study were often treated with 2 or even 3 psychotropics simultaneously (23.1% and 30.8% respectively), which was probably due to unresponsiveness of the patients to monotherapy or the presence of comorbid conditions. This, in fact, could be another
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reason for low level of comorbid ADHD reported in our study. Seventy-five percent of patients with diagnosed comorbid ADHD at the initial visit received multiple psychotropics, whereas 77.8% of patients without comorbid ADHD received multiple psychotropics (including atypical antipsychotics, stimulants and mood stabilizers). This difference was not statistically significant. This further emphasizes the significance of conducting controlled trials of mono- and polypharmacotherapy of BPD in this young age group. In a summary, one of the major pitfalls in a long pathway of helping this group of patients is the absence of clearly defined diagnostic criteria as evidenced by a large diversity of bipolar-spectrum diagnoses in our subjects, with prevailing number of kids with the diagnosis of BPD NOS and mood disorder NOS. Hence, it is crucially important to characterize features of BPD in this age group and to develop precise, ageappropriate diagnostic guidelines to assist physicians in the diagnostic process. This will help to identify and intervene at early stages of the development of this chronic illness, which seriously disrupts the lives of children and adolescents, with studies showing poorer academic performance, disturbed interpersonal relationships, increased rates of substance abuse, legal difficulties, multiple hospitalizations, and increased rates of both suicide attempts and completions (Akiskal et al., 1985; Carlson et al., 2002; Geller and Luby, 1997; Lewinsohn et al., 1995; Strober et al., 1995). Although this population does respond initially to psychopharmacological treatment, the relapse rates are pretty high, with only 2 out of 26 patients maintaining remission for more than 1 year in our study. This could be a result of either developing tolerance/tachyphylaxis to the treatment with a specific drug or a problem of genetic “matching” of specific medications. Future research in the field of psychopharmacogenetics should be crucial in understanding this phenomenon. 5. Limitations Generalization of the present results may be limited by the following: (a) use of retrospective design; (b) relatively small sample size; (c) lack of a comparison group. The diagnoses listed could be different if structured and semi-structured (e.g., WASH-UKSADS) instruments were applied. CGI and CGAS ratings were also applied retrospectively, which limits its reliability. The majority of the patients in our study were from outpatient clinics and results may be different if compared to the inpatient samples. Changes in the CGI scores could be related to an
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additional use of psychosocial treatments which we did not document. Family history data, which could be a very valuable source for confirming diagnosis of BPD in these children due to already documented high risk of BPD in first degree relatives, is also missing. And finally, the data presented did not elaborate on psychosocial factors that could influence the recovery and relapse rates. Acknowledgments The authors acknowledge Drs. Michael Sorter and Pamela Campbell for their contribution. Disclosure: Dr. Kowatch has financial affiliations with Bristol-Myers Squibb, Glaxo-Smith Kline, Janssen, Astra-Zeneca, Cephalon Inc., Abbott and Pfizer. Dr. Pathak has research funding from Forest Laboratories Inc. and Cephalon Inc. The other authors have no financial relationships to disclose. References Akiskal, H.S., Downs, J., Jordan, P., Watson, S., Daugherty, D., Pruitt, D.B., 1985. Affective disorders in referred children and younger siblings of manic-depressives. Mode of onset and prospective course. Archives of General Psychiatry 42, 996–1003. Biederman, J., 1998. Resolved: mania is mistaken for ADHD in prepubertal children. Journal of the American Academy of Child and Adolescent Psychiatry 37, 1096–1098. Biederman, J., Klein, R.G., Pine, D.S., Klein, D.F., 1998a. Resolved: mania is mistaken for ADHD in prepubertal children. Journal of the American Academy of Child and Adolescent Psychiatry 37, 1091–1096. Biederman, J., Mick, E., Bostic, J.Q., Prince, J., Daly, J., Wilens, T.E., Spencer, T., Garcia-Jetton, J., Russell, R., Wozniak, J., Faraone, S.V., 1998b. The naturalistic course of pharmacologic treatment of children with manic-like symptoms: a systematic chart review. Journal of Clinical Psychiatry 59, 628–637. Biederman, J., Mick, E., Faraone, S.V., Van Patten, S., Burback, M., Wozniak, J., 2004. A prospective follow-up study of pediatric bipolar disorder in boys with attention-deficit/hyperactivity disorder. Journal of Affective Disorders 82, S17–S23. Biederman, J., Mick, E., Hammerness, P., Harpold, T., Aleardi, M., Dougherty, M., Wozniak, J., 2005. Open-label, 8-week trial of olanzapine and risperidone for the treatment of bipolar disorder in preschool-age children. Biological Psychiatry 58, 589–594. Carlson, G.A., 1984. Classification issues of bipolar disorders in childhood. Psychiatric Developments 2, 273–285. Carlson, G.A., 1995. Identifying prepubertal mania. Journal of the American Academy of Child and Adolescent Psychiatry 34, 750–753. Carlson, G.A., Bromet, E.J., Sievers, S., 2000. Phenomenology and outcome of subjects with early- and adult-onset psychotic mania. American Journal of Psychiatry 157, 213–219. Carlson, G.A., Bromet, E.J., Driessens, C., Mojtabai, R., Schwartz, J.E., 2002. Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. American Journal of Psychiatry 159, 307–309.
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