Considerable public attention has focused recently on the question of why there has been a rather dramatic upsurge recently in the rate at which the diagnosis of bipolar disorder (BD) is being assigned to children. In large part the upsurge appears to be due to the fact that children with extremely severe irritability, but without distinct manic episodes, are receiving the diagnosis of BD. At the inception of this project, we defined criteria that would allow us to identify reliably children in this controversial diagnostic group. We called the syndrome severe mood and behavioral dysregulation (SMD), and defined it in terms of impairing symptoms that include abnormal baseline mood (i.e. irritability, anger, and/or sadness), hyperarousal (e.g. insomnia, agitation, distractibility), and increased reactivity to negative emotional stimuli. The specific goals of this project are 1) to identify reliably a group of children with severe mood and behavioral dysregulation in order to characterize them clinically and behaviorally, and follow them longitudinally, 2) to compare the brain function of SMD children (assessed with functional MRI and standardized behvioral testing) to that of children with unequivocal BPD;3) to test appropriate treatments for SMD. The latter is particularly important, since if youth with SMD are found to have a form of BD that would dictate one course of treatment, whereas if they are found to have (for example) a variant of depression, anxiety, and/or attention deficit hyperactivity disorder, this would dictate a rather different plan for treatment. Since the inception of this project, approximately 150 youth with SMD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. In past years, we demonstrated that youth with SMD are at risk for major depression, rather than necessarily BD, in early adulthood, and that they are less likely than youth with BD to have a parent with BD. A limitation of those data were that subjects were only followed untl the age of 18, which is not through the age of risk for BD. In work published this year, we examined associations between chronic irritability, as one would see in SMD, and psychopathology in an epidemiologic sample followed from age 13 to age 33. Importantly, the latter is through the major age of risk for BD. Once again, we found an association between chronic irritability and risk for unipolar depressive disorders and anxiety disorders, but not BD. This further bolsters the argument that, at least from a categorical perspective, SMD should not be considered to be a developmental phenotype of BD. In previous years, we had demonstrated that youth with BD or SMD, but not those with attention deficit hyperactivity disorder (ADHD), anxiety disorders, or unipolar depression, have deficits in face emotionl labeling. This year we are preparing for publication data which indicate that, while BD and SMD have similar behavioral deficits, the neural dysfunction mediating that dysfunction differs between groups. Specifically, the nature of amygdala dysfunction during face emotion processing differs among youth with BD, SMD, and ADHD. Ongoing work is designed to further specify the precise nature of the amygdala dysfunction in these groups, and to ascertain whether explicit labeling is needed in order to elicit between-group differences in amygdala activity (preliminary data suggest that it is not). Finally, from a public health perspective, it is essential to determine whether the distinction between SMD and BD, which is evident in terms of clinical course, family history, and neural circuitry, is also associated with between-group differences in treatment response. In previous work, we found that lithium was not effective in the treatment of SMD. This year, we began a doubel-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor antidepressant) plus stimulant is more effective than placebo puls stimulant in the treatment of SMD. The choice of citalopram and stimulant was motivated by three considerations: 1) youth with SMD meet criteria for ADHD;2) youth with SMD frequently meet current criteria for anxiety disorders, and data indicated that serotonergic reuptake inhibitor antidepressants are effective in the treatment of pediatric anxiety disorders;and 3) youth with SMD are at increased risk to develop unipolar depressive disorders and anxiety disorders as they mature, and both these conditions can be treated by serotonergic reuptake inhibitor antidepressants. Data collection is currently onoging.