Hypomanic Episode

Participants were recruited from the community and area mental health clinics (via fliers, Internet postings, etc.), on the basis of symptoms of anxiety and depression. In keeping with the aims of RDoC, we did not use a cutoff to demarcate between normal and abnormal levels of internalizing symptoms (Cuthbert, 2014 (link); Cuthbert & Insel, 2013 (link)). Instead, we used minimal symptom-based inclusion and exclusion criteria, and aimed to recruit a sample with a broad range of internalizing symptomatology. However, to ensure the clinical relevance of the sample, we also oversampled from individuals with severe psychopathology. Thus, the goal was to recruit a sample with normally distributed internalizing symptoms but with a mean more severe than the mean of the general population. Prior to their involvement in the study, participants were screened via telephone using the Depression, Anxiety, and Stress Scale (DASS; Lovibond & Lovibond, 1995 ), a brief (21-item) measure of broad internalizing psychopathology (the measure was used to ensure that the sample had the above-mentioned distribution on internalizing symptoms). As manic and psychotic symptoms have been shown to be separable from internalizing disorders (Watson, 2005 (link)), probands and siblings were excluded during screening if they had a personal or 1st degree family history of a manic/hypomanic episode or psychotic symptoms, assessed via items from the Structured Clinical Interview for DSM–IV (SCID; First, Spitzer, Gibbon, & Williams, 1996). Participants were also excluded if they were unable to read or write English, had a history of head trauma with loss of consciousness, or were left-handed. Potential participants were not excluded based on current psychotropic medication use, or current substance use.
Participants were eligible for the study if they were between the ages of 18 and 30, and had a full sibling between the ages of 18 and 30 who was also interested in participating. We opted to recruit siblings rather than other relatives because this approach allowed us to have siblings and probands matched on mean age. We restricted the age of the probands and siblings to 18-30 because we were interested in risk for internalizing psychopathology. It was therefore critical that ‘healthy’ (or low symptom) siblings were not out of the peak risk period for internalizing disorders (through age 45; Kessler et al., 2005 (link)). The premise of examining whether healthy or low-symptom siblings of symptomatic probands have abnormal neural responses is that even though siblings have not developed significant symptoms, they still may carry the vulnerability marker (Zubin & Spring, 1977 (link)). However, if a low symptom sibling was significantly past the peak risk period (e.g., age 50) and still had not developed symptoms, they may be less likely to carry the vulnerability marker, or may even be characterized by some resilience process that counteracted their vulnerability.
Participants were only included in the analyses that follow if complete ERP and self-report data were available from both members of the sibling pair (n = 160). Of these, 10 individuals (from 10 families) were excluded as a result of excessive noise in the ERP data, leaving a final sample of n = 140 individuals, from 70 sibling pairs. The final sample was 59% female, and was racially diverse (43.5% Caucasian-American, 28% Hispanic, 13.4% African-American, 7% Asian, 3.7 % Middle Eastern, 2.4% “Other”, and 2.4 % Mixed Race), well-educated (48.7% had completed at least some college education; 21.5% had completed four years of college) and relatively young (Age M = 22.54, SD = 3.15). All procedures were approved by the University of Illinois–Chicago Institutional Review Board.

Usable fMRI data were acquired from subjects with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) as well as healthy comparison subjects (N=37). Participants, ages 8 to 17 years, were enrolled in an Institutional Review Board-approved study at the National Institute of Mental Health. Parents and youths gave written informed consent/assent. Patients were recruited through advertisements to mental health support groups and mental healthcare professionals. Healthy comparison subjects were recruited by advertisement and had no lifetime psychiatric diagnoses and no first-degree relatives with a mood disorder.
Subjects were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL) (35 (link)). Interviewers were master's- and doctoral-level clinicians, with excellent interrater reliability (κ>0.9 for all diagnoses, including differentiating bipolar disorder from severe mood dysregulation). Diagnoses were based on best-estimate procedures generated in a consensus conference led by two psychiatrists. Youths with bipolar disorder met “narrow phenotype” criteria, with at least one DSM-IV full-duration hypomanic/manic episode characterized by abnormally elevated mood and at least three B mania symptoms (1 (link)). Youths with severe mood dysregulation had nonepisodic irritability, overreactivity to negative emotional stimuli ≥3 times per week, and hyperarousal (i.e., at least three of the following symptoms: insomnia, distractibility, psychomotor agitation, racing thoughts/flight of ideas, pressured speech, intrusiveness). Symptoms began before age 12; were present for at least 1 year, with no symptom-free periods exceeding 2 months; and caused severe impairment in at least one setting (i.e., home, school, peer) and mild impairment in another. Euphoric mood or distinct episodes lasting more than 1 day were exclusionary (1 (link)). Youths with ADHD met DSM-IV criteria for ADHD but not for severe mood dysregulation or any mood disorder. In the ADHD group, anxiety disorders were exclusionary, except for separation anxiety and social phobia.
The Wechsler Abbreviated Scale of Intelligence was administered to determine IQ. To evaluate mood in patients with bipolar disorder or severe mood dysregulation, clinicians with interrater reliability (κ>0.9) administered the Children's Depression Rating Scale and the Young Mania Rating Scale to the parent and child within 48 hours of scanning. Elevated Young Mania Rating Scale scores in patients with severe mood dysregulation reflect hyperarousal symptoms because, by definition (1 (link)), patients with this type of mood dysregulation cannot meet criteria for hypomania, mania, or a mixed episode.
Exclusion criteria for all subjects were an IQ <70, a history of head trauma, a neurological disorder, a pervasive developmental disorder, an unstable medical illness, or substance abuse/dependence. Patients with ADHD taking short-acting stimulants were included but were medication-free for ≥48 hours before scanning. Thus, both healthy comparison subjects and ADHD patients were medication-free at testing. Patients receiving medication for bipolar disorder or severe mood dysregulation were included. For ethical reasons, only those patients who were not responding to current psychotropic medication were withdrawn from treatment.
One hundred eighty-six subjects were scanned, yielding 127 (68.3%) usable scans. Groups differed in the proportion of excluded scans (p=0.02) but not in reasons for exclusion. Relative to patients with bipolar disorder, more severe mood dysregulation patients (p<0.01) and healthy comparison subjects (p=0.02) had unusable scans. Of the 59 excluded scans, 25 were excluded for poor behavioral data (no response ≥7 times), 22 for a >3.5-mm movement in any plane, and 12 for technical malfunction. Data from 20 bipolar disorder patients and 12 healthy comparison subjects have been published previously (11 (link)). Thus, among the 127 participants studied, data from 95 have not been presented previously.