We conducted a longitudinal follow-up study of a clinic sample of youth with SMD and narrowly defined BD to answer an important question related to the pediatric BD debate—namely, whether children commonly evolve from a phenotype characterized by severe, nonepisodic irritability to a more classic presentation of BD by developing distinct episodes of (hypo-)mania. We found that (hypo-)manic or mixed episodes were significantly less likely to occur in youth with SMD compared with BD.
It is important to note that SMD was created for the purpose of studying children presenting with severe nonepidsodic irritability.8
SMD overlaps with ODD in that both ascertain temper outbursts, irritability, and anger. Crucially, however, SMD does not include the symptoms of defiance and annoyance that are also included in ODD—this distinction between headstrong and irritable dimensions in ODD has been shown to have important differential predictions.16,17
In addition, the criteria for SMD define irritability much more specifically than do those for ODD, requiring a high frequency of outbursts, and the SMD criteria require that impairing irritability be present in at least two settings, although a child can meet criteria for ODD with impairment in only one setting. Thus, whereas most children with SMD meet criteria for ODD, most with ODD do not meet criteria for SMD, and SMD, but not ODD, ascertains a population that is as impaired as are youth with BD. For these reasons, we undertook this line of research using the SMD criteria, rather than those for ODD. Finally, it should be noted that SMD, as originally proposed,8
contains sadness as an alternative to anger for the criterion of negatively valenced mood. Nonetheless, all SMD youth meet the criteria of at least three outbursts per week, so that irritability is one of its prominent features, regardless of whether the negatively valenced mood is anger or sadness.
One of the main questions about SMD relates to the extent to which it is a developmental presentation of BD. If it were, one would expect that, over time, youth with SMD would manifest manic or hypomanic episodes meeting DSM-IV criteria. However, only one of 84 SMD subjects manifested an episode of (hypo-)mania at follow-up. The difference between SMD and BD is of an order of magnitude: the probability for a (hypo-)manic episode occurring in BD subjects was more than 50 times higher than in those with SMD. Moreover, the lower confidence limit of the probability of a (hypo-)manic episode in BD was more than six times higher than the upper confidence limit for manic episodes in SMD.
Our finding that only one youth with SMD experienced an episode of (hypo)mania over the follow-up period contrasts with the high conversion rate for short-episode bipolar disorder–not otherwise specified (BD-NOS) noted in the Course and Outcome of Bipolar Illness in Youth (COBY) study.18
The diagnosis of BD-NOS is poorly specified in DSM-IV; in child psychiatry, it is frequently assigned to two distinct clinical presentations: youth with severe, nonepisodic irritability (a presentation that we operationalized as SMD), and those with distinct (hypo-)manic episodes that are shorter than 4 days in duration. This distinction between these different presentations is important, given its potential implications for pathophysiology treatment, and nosologic classification. Youth with the short-duration episodes were followed longitudinally in the COBY study, in which approximately 25% of the BD-NOS subjects experienced a full-duration hypomanic or manic episode over the course of a 3-year follow-up18
In contrast, in the present study, 1.2% of SMD subjects converted from SMD to BD-I or BD-II within an approximate 2-year follow-up. Of note, the AACAP guidelines for BD recommend considering both the “short episode” and the “nonepisodic” phenotypes to be BD-NOS presentations.19
In contrast, our data, in concert with those from the COBY study, suggest that, whereas the “short-episode” phenotype may be a manifestation of BD and thus may warrant the diagnosis of BD-NOS, such a conclusion is considerably less clearly justified in the case of the nonepisodic presentation that is characteristic of SMD. Importantly, our study did not include youth with brief (hypo-)manic episodes, like those in the COBY study. Because we included only the SMD phenotype (i.e., severe, nonepisodic irritability), our data do not speak to the longitudinal course of any of the other possible bipolar spectrum phenotypes.
Our finding here is consistent with previous results using SMD-proxy phenotypes in community samples9,10
as well as with a preliminary family history study.20
These studies indicate that irritable youth are at risk for developing depressive and anxiety disorders in adulthood, and that youth with SMD are less likely than those with BD to have a parent with BD.20
Moreover, our findings are in keeping with those of a recent clinic study showing that, for children with severe persistent irritability, a diagnosis of BD is rarely justified upon careful clinical assessment.21
However, it should be noted that the current study was not designed to test the hypothesis that the occurrence of (hypo-)manic or mixed episodes in SMD was no more than would occur by chance; this would require a much larger sample. Moreover, our findings do not exclude the possibility that BD and SMD have common pathophysiologic features. Indeed, previous studies suggest that the two share behavioral deficits in emotion labeling processing14,22
and cognitive flexibility,23
although the neural mechanisms mediating these deficits may differ between the two patient groups.24
In sum, to the extent that the question, “Is SMD a developmental presentation of BD?” is framed categorically, the conclusion from this and previous studies9,20,24
is “no.” Because treatment decisions are categorical, there is value to framing the question categorically. That is, if a clinician views SMD as a BD phenotype, that clinician might prescribe atypical antipsychotic and/or mood-stabilizing medication for youth with this clinical presentation. Alternatively, if the clinician views SMD as a phenotype of anxiety and/or unipolar depression, coupled with ADHD, that individual might consider prescribing antidepressant medication coupled with a stimulant (these are medications that are relatively contraindicated in BD). Unfortunately, no published data currently exist on the safety or effectiveness of anti-depressant or stimulant medication in the SMD phenotype, and that is an important question for future study. So far, the only clinical trial in SMD is a pilot study of lithium, which was not effective.25
Additional treatment trials in youth with severe, nonepisodic irritability are a pressing public health need, given that an SMD proxy phenotype occurred with a prevalence of 3.3% in an epidemiologic sample in the United States9
and mood lability occurred in more than 5% of the population of children and adolescents in a sample in the United Kingdom.26
Although it is important to frame the question, “Is SMD a developmental presentation of BD?” categorically, it is equally important to ask the question dimensionally. Recent data demonstrate convincingly that DSM-IV diagnoses may not necessarily be pathophysiologically distinct: there is considerable genetic overlap between BD and schizophrenia27
and between BD and MDD.28
As noted, BD and SMD appear to share pathophysiological mechanisms, making it possible that the SMD phenotype will ultimately be placed on a pathophysiological spectrum between BD and MDD and/or other depressive syndromes. Accordingly, we found that depressive episodes were significantly more common in the BD group; a possible post hoc
explanation for this finding is that, consistent with previous data,10
SMD may be linked with depressive phenotypes not characterized by episodicity, such as dysthymia. The findings of this study are relevant to researchers who study the early development of BD and inform their choices for the phenotypes to use, for example in genetic studies of early onset BD.
This study has a number of strengths. It is the first to report a follow-up of subjects with well-characterized SMD. Moreover, in comparison with previous community-based studies on SMD9
and mood lability,20
in which BD and SMD are relatively rare, the present clinic sample is enriched with cases of both SMD and BD and thus in reducing the likelihood of recall bias.
However, there are a number of important limitations. First, there is considerable attrition. Therefore, we cannot exclude the possibility that the conversion rate from SMD to BD has been underestimated. Secondly, from a psychometric point of view, it is conceivable that the prominence of nonepisodic irritability in those with SMD has generated “background noise” affecting on our instrument's ability to detect episodes. Although we cannot exclude this possibility, the effect size of the difference between SMD and BD is very large and therefore unlikely to be the result of a reduced signal-to-noise ratio. Third, it was not feasible to have the follow-up assessments be conducted blindly, so assessment bias cannot be excluded. However, follow-up was performed by experienced clinicians, who were 1) particularly attuned to the clinical importance of establishing (hypo-)manic and mixed episodes and 2) instructed to have a low threshold for their ascertainment. Importantly, parents were aware that, should an SMD child develop manic or hypomanic symptoms, the child and his/her family could continue to participate in the study, so that there should be no concern that reporting such an episode would result in exclusion. Fourth, follow-up interviews were only conducted only with the patient's parents and not with the children themselves. Given the generally low parent–child agreement in reporting symptoms of mania and depression, this may conceivably underestimate symptoms.29,30
However, we consider it unlikely that full-blown (hypo-)manic or mixed episodes would have gone unnoticed by parents. Fifth, it is important to reiterate that this study focuses on the comparison between narrowly defined BD and only one phenotype of several that have been described as BD–NOS. That is, although SMD captures children with nonepisodic irritability, this study did not include children with episodes of manic symptoms that are too short to meet DSM-IV criteria for hypomania. Thus, clinicians and researchers should not extrapolate from these results to other BD-NOS presentations, in particular to children with episode durations of less than 4 days. Finally, we used a narrow phenotype to ascertain cases of BD at baseline, in that we required abnormally elevated or expansive mood during an episode; the presence of irritability on its own30,31
was not a sufficient Criterion A for (hypo-)mania in this study. It is therefore possible that the BD cases in this study might not be representative of all cases of pediatric BD. However, two findings argue against this. First, the patterns of our results regarding the course of BD are in keeping with those of a recent large longitudinal study,32
i.e., episodes of depression were most common. Second, a recent study comparing patients with BD and abnormally elevated or expansive mood and/or grandiosity as the only Criterion A to those with either episodic irritability-only or with episodes characterized by both irritability and elevated or expansive mood suggests these groups are similar on important variables.33
In conclusion, our results suggest that research efforts should continue to focus on the pathophysiology of SMD and BD, as well as on the treatment of both conditions, given that both groups continued to exhibit significant psychopathology. In addition, studies should address the overlap and distinctions between SMD and ODD. Finally, studies using larger samples with longer follow-ups of SMD subjects, replicated in other centers, are required.