Diagnostic stability in pediatric bipolar disorder

Research report

Diagnostic stability in pediatric bipolar disorder

Lars Vedel Kessing a,n, Eleni Vradi b, Per Kragh Andersen b

a Psychiatric Center Copenhagen, Department O, 6233 Blegdamsvej 9, 2100 Copenhagen, Denmark and University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark b Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark

a r t i c l e i n f o

Article history: Received 25 March 2014 Received in revised form 20 October 2014 Accepted 20 October 2014 Available online 29 October 2014

Keywords: Mania Bipolar disorder Diagnostic stability ICD-10 Children and adolescents

a b s t r a c t

Background: The diagnostic stability of pediatric bipolar disorder has not been investigated previously. The aim was to investigate the diagnostic stability of the ICD-10 diagnosis of pediatric mania/bipolar disorder. Methods: All patients below 19 years of age who got a diagnosis of mania/bipolar disorder at least once in a period from 1994 to 2012 at psychiatric inpatient or outpatient contact in Denmark were identified in a nationwide register. Results: Totally, 354 children and adolescents got a diagnosis of mania/bipolar disorder at least once; a minority, 144 patients (40.7%) got the diagnosis at the first contact whereas the remaining patients (210; 59.3%) got the diagnosis at later contacts before age 19. For the latter patients, the median time elapsed from first treatment contact with the psychiatric service system to the first diagnosis with a manic episode/ bipolar disorder was nearly 1 year and for 25% of those patients it took more than 2½ years before the diagnosis was made. The most prevalent other diagnoses than bipolar disorder at first contact were depressive disorder (21.4%), acute and transient psychotic disorders or other non-organic psychosis (19.2%), reaction to stress or adjustment disorder (14.8%) and behavioral and emotional disorders with onset during childhood or adolescents (10.9%). Prevalence rates of schizophrenia, personality disorders, anxiety disorder or hyperkinetic disorders (ADHD) were low. Limitations: Data concern patients who get contact to hospital psychiatry only. Conclusions: Clinicians should be more observant on manic symptoms in children and adolescents who at first glance present with transient psychosis, reaction to stress/adjustment disorder or with behavioral and emotional disorders with onset during childhood or adolescents (F90–98) and follow these patients more closely over time identifying putable hypomanic and manic symptoms as early as possible.

& 2014 Elsevier B.V. All rights reserved.

1. Introduction

One criterion for validating psychiatric diagnoses is that of diag- nostic stability (Robins and Guze, 1970). Diagnostic stability may be defined as the degree to which a diagnosis is confirmed at subsequent assessment points (Fennig et al., 1994). Surprisingly, the diagnostic stability of the diagnosis of pediatric bipolar disorder has never been investigated in any larger long-term study. The National Institute of Mental (NIMH) funded “Phenomenology and Course of Pediatric Bipolar Disorder” study (Geller and Tillman, 2005; Geller et al., 2008) has never addressed in detail what proportion of the sample continues to have the same diagnosis, as recently highlighted (Carlson, 2011), although it is mentioned that “subjects remained bipolar and did not develop schizophrenia, ADHD or other psychiatric disorders during 4-year prospective follow-up” (Geller and Tillman, 2005). In fact, there is one study only including 91 children and adolescents with bipolar disorder, which found that 86% fulfilled criteria for mania

or hypomania at 6-month follow-up, but this study presented no data on diagnostic shift (Geller et al., 2000). Only two studies on children and adolescents with first episode psychosis have included bipolar disorder patients and reported on diagnoses during follow-up. One study including 13 patients with first episode psychotic bipolar disorder found a 92% diagnostic stability after ½-year follow-up (Castro-Fornieles et al., 2011) and another study including 8 patients with first episode psychotic bipolar disorder revealed a 57% diagnostic stability after 1 year (Fraguas et al., 2008).

Based on the importance of the question of diagnostic stability and the very limited amount of research within the area we find it important to report data from Danish psychiatric case registers on all children and adolescents diagnosed with mania/bipolar dis- order within psychiatry and during a period of 16 years.

The aim of the present study was to investigate the diagnostic stability of the ICD-10 diagnosis of pediatric mania/bipolar dis- order as made by clinicians within psychiatry using a nationwide register based sample of out- and inpatients from psychiatric settings and further to estimate the gender and age associations with time to first diagnosis of bipolar disorder.

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Journal of Affective Disorders

http://dx.doi.org/10.1016/j.jad.2014.10.037 0165-0327/& 2014 Elsevier B.V. All rights reserved.

n Corresponding author. Tel.: þ45 38 64 70 81. E-mail address: lars.vedel.kessing@regionh.dk (L. Vedel Kessing).

Journal of Affective Disorders 172 (2015) 417–421

2. Method

2.1. The register

The Danish Psychiatric Central Research Register (DPCRR) is nation-wide with registration of all psychiatric hospitalizations in Denmark for the 5.3 million inhabitants (Munk-Jorgensen and Mor- tensen, 1997). From January 1, 1995 the register included information on patients in psychiatric ambulatories and community psychiatry centers, also. General practitioners and private practicing psychiatrist do not report to the DPCRR.

All inhabitants in Denmark have a unique person identification number (Civil Person Registration number, CPR-number) that can be logically checked for errors; so it can be established with great certainty if a patient has had contact to psychiatric service previously, irrespective of changes in name etc.

No private psychiatric inpatient hospitals or department are in operation in Denmark, all are organized within public services and reporting to the DPCRR. The International Classification of Dis- eases, 10th Revision (World Health Organization, 1992) has been used in Denmark from January 1, 1994.

2.2. The sample

The study sample was defined as all children and adolescents o19 years with a contact as outpatient (patients in psychiatric ambulatories and community psychiatry centers) or inpatient (patients admitted during daytime or overnight to a psychiatric hospital) with at least one main diagnosis of mania/bipolar disorder (ICD-10, code DF30-31.9) during the study period from January 1, 1994 to December 31, 2012. Outpatients were included in a period from January 1, 1995 to December 31, 2012 (as these data are available for this period, only) and inpatients in the entire ICD-10 period (from January 1, 1994 to December 31, 2012).

2.3. Statistical analysis

Categorical data were analyzed with the chi-square test (2-sided) and continuous data were analyzed with the Mann–Whitney test for

two independent groups. Po0.05 was used to indicate statistical significance.

3. Results

Totally, 354 patients below 19 years of age got a main diagnosis of a manic episode (F30) or bipolar affective disorder (F31) at least once during the study period from 1994 to 2012. The annual rate of incident mania or bipolar disorder was approximately 0.003% in 2010 for both sexes. Fig. 1 shows age at first diagnosis of mania/bipolar disorder for boys and girls. There was no significant difference between boys and girls at age at first diagnosis of mania/bipolar disorder (P¼0.6).

Among the 354 patients, 144 patients (40.7%) got the main diagnosis at the end of the first contact period whereas the remaining patients (210¼59.3%) got the diagnosis at later contacts. There was no difference in the proportions of boys and girls who got the diagnosis of mania/bipolar disorder at first contact (36.7% of girls versus 45.8% of boys, P¼0.08).

3.1. Change from bipolar disorder to other diagnoses

Among the 144 patients with the diagnosis of mania/bipolar disorder at the first contact ever in a period from 1994 to 2012, 60 (41.7%) were treated during outpatient settings and 84 (58.3%) during psychiatric hospitalization; 50.7% were girls. Median age at first contact was 17.4 years (quartiles: 16.3–18.2 years) and follow up time from first contact with a diagnosis of mania/bipolar disorder to end of study or 19th birthday was 1.31 years (quartiles: 0.65–2.48).

Table 1 presents main diagnoses at subsequent contact periods for the 144 patients with a main diagnosis of mania/bipolar disorder at first contact. As can be seen, 98 patients had a second contact period, 41.7% had a third contact period, etc. At the end of the second contact period, 79.6% got a main diagnosis of bipolar disorder and this proportion was rather stable at subsequent contact period. The most prevalent other diagnosis during follow-up was within neurotic, stress-related and somatoform diagnoses with an increase to 9.1% at the 5th psychiatric contact. There was no tendency to an increase in other main diagnoses for which the prevalence was 5% or below.

Fig. 1. Age at first diagnosis of mania/bipolar disorder for boys and girls.

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3.2. Change from other diagnoses to bipolar disorder

Table 2 presents data the other way around as the main diagnosis at first contact for the 210 patients who got a main diagnosis of mania/ bipolar disorder at subsequent contact periods but not at the first contact period. A large proportion of the patients got a main diagnosis of depressive episode or recurrent depressive disorder (22.9%) at first discharge. However, 22.9% got a main diagnosis within F20—mainly acute and transient psychotic disorder (14.8%) and other non-organic psychosis (4.3%). Notably, only 1.4% got a diagnosis of schizophrenia at first contact. A total of 19.5% got a main diagnosis within neurotic, stress related and somatoform disorder (F40), among which the major proportion was reaction to stress or adjustment disorder (14.8%).

For the 210 patients who got the diagnosis at later contacts, the median time from the first diagnosis with a manic episode/bipolar disorder back to first treatment contact within the psychiatric service system was 0.93 years (quartiles: 0.38–2.52). This time lag was numerically longer for boys (1.04 years (quartiles: 0.29–2.67)) than for girls (0.87 years (quartiles: 0.43–2.32)) but the difference was not statistically significant (P¼0.9).

4. Discussion

This is the first study investigating the diagnostic stability of pedi- atric mania/bipolar disorder in clinical practice. The study included a Danish nationwide sample of all in- and outpatients treated for pediatric mania/bipolar disorder at least once in psychiatric settings. In Denmark, doctors are obliged to make a diagnosis when a treat- ment period is terminated, i.e. at discharge from hospital or at the end of an ambulatory treatment period, and all diagnoses are reported to the Danish Psychiatric Central Research Register.

The most striking finding is that only 40.7% of the patients got the diagnosis of mania/bipolar disorder at the first in- or outpatient contact whereas 59.3% got the diagnosis at later contacts. This 40.7% proportion of pediatric patients who got the diagnosis at first contact was substantially lower than the corresponding proportion among adult patients in a similar study from our group with exactly the same design and type of analyses, namely 56.2% (Kessing, 2005).

In the present study, for the patients who got their first diagnosis of a manic episode/bipolar disorder at a later contact, the median time elapsed since first treatment contact with the psychiatric service

Table 1 Main diagnoses at subsequent contact periods for 144 patients with a main diagnosis of a manic episode/bipolar disorder at first contact.

N¼144 2nd contact 3rd contact 4th contact 5th contact

Number of patients (% of total) 98 (68.1) 60 (41.7) 36 (25) 22 (15.3) Organic 0 0 0 0 Psychoactive substance use 2.1 3.3 0 4.6 Schizophrenia, schizotypal and delusional 3.1 1.7 5.6 4.6 Bipolar disorder 79.6 76.7 83.3 77.3 Affective disorders, other (F32–39) 5.1 5.0 2.8 4.5 Neurot, stress-rel. and somatof. 4.1 8.3 2.8 9.1 Personality disorders 3.1 0 2.8 0 Pervasive development disorders (F84–89) 1.0 0 0 0 Behavioral and emotional disorders (F90–98) 2.0 5.0 2.8 0

Table 2 Main diagnoses at first contact for 210 patients with a main diagnosis of a manic episode/bipolar disorder at subsequent contact periods.

%, total for group Major sub-diagnoses within group % of total

Organic F00–09 0 Dementia (F00–039) 0 Psychoactive substance use F10–19 2.9 Alcohol use (F10) 0

Cannabinoids (F12) 1.0 Cocaine (F14.55) 0.5 Multiple drug or psychoactive substances (F19) 1.4

Schizophrenia, etc. F20–29 22.9 Schizophrenia (F20) 1.4 Schizotypal disorder (F21) 0.5 Persistent delusional disorder (F22) 1.4 Acute and transient psychotic disorders (F23) 14.8 Schizoaffective disorders (F25) 0.5 Other non-organic psychosis (F28.9þ29.9) 4.3

Affective disorder F32–39 22.9 Depressive episode or recurrent depressive disorder (F32–33) 21.4 Affective disorder, unspecified (F38.8þ39.9) 1.5

Neurot, stress-rel. and somatof. F40–49 19.5 Phobic anxiety disorders (F40) 0 Other anxiety disorders (F41) 2.9 Obssesive–compulsive disorder (F42) 1.4 Reaction to severe stress, and adjustment disorders (F43) 14.8 Dissociative disorders (F44) 0.5 Somatoform disorders (F45) 0

Personality disorders F60–69 1.0 Emotionally unstable personality disorder, borderline type (F60.31) 0 Schizoid personality disorder (F60.1) 0.5 Personality disorder, unspecified (D60.9) 0.5

Pervasive developmental disorders (F84–89) 7.1 Childhood autism, atypical autism (F84.0–84.1) 1.4 Rett’s syndrome (F84.2) 0 Others 5.7

Behavioral and emotional disorders (F90–98) 10.9 Hyperkinetic disorders (F90) 3.8 Conduct disorder (F91–92) 2.9 Emotional disorders (F93) 1 Disorders of social functioning (F94) 1.9 Others 1.3

L. Vedel Kessing et al. / Journal of Affective Disorders 172 (2015) 417–421 419

system was nearly 1 year and for 25% of the patients it took more than 2½ years before the diagnosis was made. These figures are very similar to those found in the study among adult patients (Kessing, 2005), and although this diagnostic lag is critical for all individuals regardless of age it may be even more critical for children and adolescents with as untreated mania or bipolar disorder may have substantial negative influence on the development of personality, intellectual and school capability and social competencies. The most prevalent other diagnoses than bipolar disorder at first contact were depressive disorder (21.4%), acute and transient psychotic disorders or other non-organic psychosis (totally 19.2%), reaction to stress or adjustment disorder (14.8%) and behavioral and emotional disorders with onset during childhood or adolescents (10.9%, F90–98). Also among adults, the most frequent misdiagnosis of bipolar disorder is unipolar depression (Hirschfeld et al., 2003; Kessing, 2005) although acute and transient psychotic disorders as well as reaction to stress or adjustment disorders also are frequent initial diagnoses prior to the diagnosis of mania/bipolar disorder (Kessing, 2005). The high pre- valence of depressive episodes is in accordance with the natural history of bipolar disorder with prevalent onset of depressive epi- sodes prior to first hypomania/mania. However, the other figures illustrate great difficulties in identifying initial presentations of mania/ bipolar disorder, which seems even more pronounced among chil- dren and adolescents than among adults. This may be due to uncertainty among doctors or psychiatrists so they do not identify possible manic symptoms or bipolar disorder behind these syn- dromes or alternatively that bipolar disorder in a substantial propor- tion of cases initially present with prodromal syndromes such as transient psychosis, reaction to stress/adjustment disorder or beha- vioral and emotional disorders (F90–98) and that these conditions later on may develop into bipolar disorder. In addition, for some children and adolescents symptoms of mania may emerge more slowly and with mixed and/or shifting depressive and manic symp- toms complicating the diagnostic process (Youngstrom et al., 2008). It is most likely that these phenomena may co-occur.

In contrast to this diagnostic uncertainty, clinicians did not seem to be unsure regarding differentiation of mania/bipolar disorder from schizophrenia, personality disorders, anxiety disorder or hyperkinetic disorders (ADHD). Thus, as can be seen from Table 2, remarkably few patients had a main diagnosis of schizophrenia (1.4%) or schizoaffective disorder (0.5%) at first contact and only 1.0% were diagnosed with a main diagnosis of personality disorders and 1.4% with OCD and 2.9% with other anxiety disorder. In addition, hyperkinetic disorders (corresponding to the DSM ADHD diagnosis) were surprisingly low at first contact (3.8%, Table 2) and at subsequent contacts (2–5%, Table 1). Although early studies have suggested high comorbidity between ADHD and child and adoles- cents mania/bipolar disorder (Geller et al., 1995; Geller and Luby, 1997) longitudinal data (Craney and Geller, 2003; Youngstrom et al., 2008) as well as studies with more careful diagnostic sorting of symptoms (Arnold et al., 2011) have revealed lower comorbidity and supported the differentiation of child and adolescents mania/ bipolar disorder from hyperkinetic disorder/ADHD in accordance with our findings. As argued by Arnold et al. (2011), “Indeed, if one automatically count such symptoms as hyperactivity and impaired attention towards both disorders without noting association with mood episodes, and especially if one does not require episodicity for bipolar disorder it may artificially inflate the comorbidity rate”. To identify episodicity longitudinal observation is an advantage. In this way our longitudinal results seem to confirm the observation that even though the symptoms may not be so different between mania and ADHD, the clinical presentation and the illness course with an episodic course in bipolar disorder and a more chronic course in ADHD differ between the disorders (Carlson and Klein, 2014).

When the diagnosis of mania/bipolar disorder was made at first psychiatric contact, this diagnosis was rather stable over successive

contacts as 76–83% also got this diagnosis during follow-up in this way suggesting that the initial diagnosis was correct (the follow up time from first contact with a diagnosis of mania/bipolar disorder to end of study or 19th birthday was 1.31 years (quartiles: 0.65–2.48)). No other studies have presented data on diagnostic shifts of patients initially diagnosed with mania/bipolar disorder; however, a study of 91 children and adolescents with bipolar disorder found that 86% fulfilled criteria for mania or hypomania at 6-month follow-up (Geller et al., 2000). In addition, two studies on children and adolescents with first episode psychotic bipolar disorder revealed 92% diagnostic stability after ½-year follow-up of 13 patients (Castro-Fornieles et al., 2011) and 57% diagnostic stability after 1 year of 8 patients (Fraguas et al., 2008). These three mentioned studies used research based DSM-IV diagnoses according to the Kiddie-Schedule for Affec- tive disorders and Schizophrenia (Kaufman et al., 1997) but the level of diagnostic stability among patients with a first diagnosis of mania/ bipolar disorder was rather similar to the diagnostic stability in our study, in this way validating the clinical diagnoses made in our study.

4.1. Advantages of the present study

Diagnostic stability has never been systematically investigated before but compared to three mentioned follow-up studies above, the sample size was considerable larger and the study period longer in our study. The study comprises an observation period of up to 16 years of the whole Danish population (5.3 million inhabitants) and further, the population is ethnically and socially homogeneous and with a very low migration rate. The entire population (approxi- mately 100%) of patients treated in psychiatric settings in a whole country during in- or outpatient settings was included. Psychiatric care is well developed in Denmark so persons with mania or bipolar disorder can easily come in contact with psychiatric community centers or hospitals. Also, as psychiatric treatment in Denmark is free of charge, the study is not biased by socioeconomic differences.

4.2. Limitations of the present study

It may be argued that the psychiatrists who made the clinical diagnoses were not blinded for diagnoses given at previous contacts and that the study consequently may have overestimated the diag- nostic stability of bipolar disorder. We do not find, however, that the clinical situation in this respect differs from the situation making research based diagnoses using e.g. the Kiddie-Schedule for Affective disorders and Schizophrenia, as the latter diagnoses also are best estimate diagnoses based on all available data frequently including case files and diagnoses from previous contacts or detailed information from the patient regarding such data. Nevertheless, it should be emphasized that the clinical ICD-10 diagnoses of mania/bipolar dis- order used in the Danish Psychiatric Central Research Register has not been validated against research based diagnoses such as the Kiddie- Schedule for Affective disorders and Schizophrenia. Despite these caveats, the diagnostic stability was rather similar in our study as in the three other studies that have used research based diagnoses and presented data on the level of diagnostic stability among patients with a first diagnosis of mania/bipolar disorder (Geller et al., 2000; Castro- Fornieles et al., 2011; Fraguas et al., 2008), also for the only study that used a blinded approach (92% at½-year follow-up, (Geller et al., 2000)).

It should be noted that the study included patients who have passed the threshold for treatment to psychiatric outpatient settings (psychiatric ambulatories and community centers) or to psychiatric hospitalization, only. Although the vast majority of children and adolescents with bipolar disorders are treated in these hospital setting as in- or outpatients some patients with milder types of the illness may be treated within private psychiatric practice. Such patients are not included in the study, as private psychiatric practice does not

L. Vedel Kessing et al. / Journal of Affective Disorders 172 (2015) 417–421420

report to the DPCRR. General practitioners do not treat children and adolescents with bipolar disorder in Denmark.

As the Danish Psychiatric Central Research Register started to include information on out-patient treatment in January 1, 1995, some patients may have had an outpatient psychiatric contact before this date without this being recorded in the register. Thus, a minor proportion of these patients and of the patients who were recorded in the register with a first hospitalization contact may have had an out-patient contact before January 1, 1995. We cannot exclude the possibility that the diagnostic stability is underestimated somewhat in the present study due to this minor misclassification but we do not believe that it has substantially affected our results.

The causal relation between diagnostic stability and the num- ber of psychiatric contacts is unknown. Patients who have many psychiatric contacts may present with more unstable psychiatric illness leading to more diagnostic variation. On the other hand, it may be that clinicians have problems with diagnosing some patients accurately and that this may lead to less effective treat- ment and more psychiatric contacts for these patients.

It should be noted that the diagnosis of bipolar disorder in ICD- 10 includes both bipolar disorder I and bipolar disorder II but does not discriminate between the two subtypes, as ICD-10 bipolar disorder is defined as a disorder with at least two mood episodes among which at least one is a hypomanic or a manic episode. It is most likely that the majority of the 354 patients in the present study suffered from bipolar disorder, type I, as patients were included via their contact to hospital psychiatric settings.

Frequent comorbid conditions in bipolar disorder such as anxiety disorders, hyperkinetic disorders and substance use may complicate the diagnostic process. It should be stressed that the present study focused on the diagnostic change in the main diagnoses as the aim was to investigate changes in the main diagnostic picture over time as evaluated in clinical practice. The main diagnosis is given for the main illness leading to investiga- tion and treatment. The main diagnoses are given according to the diagnostic hierarchy in ICD-10 giving priority to diagnoses with lower ICD-10 codes (World Health Organization, 1992). According to the diagnostic guidelines, a comorbid illness should be recorded as an auxiliary diagnosis only when the comorbid illness is independent of the primary illness. Auxiliary diagnoses are seldom recorded in Denmark. Thus among patients with a main diagnosis of bipolar disorder at first contact, only between 20.8% (at the first contact) and 13.6% (at the 5th contact) got an auxiliary diagnosis of any kind. Including such small figures of auxiliary diagnoses in the analyses would only have changed our results marginally.

5. Conclusion

In conclusion, in a nationwide sample of all children and adolescents who got an ICD-10 diagnosis of mania/bipolar disorder at least once in a period from 1994 to 2012 during in- or outpatients psychiatric treatment it was found that a minority of patients (40.7%) got the diagnosis at the initial contact and the majority (59.3%) got the diagnosis at later contacts. Approximately 24% of patients with an initial diagnosis of mania/bipolar disorder eventually changed diag- nosis during follow-up. Substantial proportions of patients initially presented with depression or prodromal syndromes such as acute and transient psychosis, reaction to stress/adjustment disorder or mental or behavioral and emotional disorders with onset during childhood or adolescents that subsequently developed into bipolar disorder. Clinicians should be more observant on hypomanic and manic symptoms who as first glance present with these conditions and follow these patients more closely over time identifying putable hypomanic and manic symptoms as early as possible. On the other

hand, clinicians seem to be able to differentiate child and adolescent mania/bipolar disorder from schizophrenia, anxiety disorders and hyperkinetic disorder/ADHD.