This study was approved by Stony Brook’s Committee on Research Involving Human Subjects. All parents/caregivers gave consent at admission to permit observations and ratings of a possible rage episode, as well as permission to use liquid risperidone with their child if needed. No one refused, but 3 children were not included in the medication aspect because they had had previous dystonic reactions taking risperidone. (Two ultimately never required risperidone).
A comprehensive, semistructured diagnostic interview was completed with parents/guardians of all admitted children based on their having completed the Child Symptom Inventory, a DSM IV-based rating scale, in advance (16
). Endorsed items from this rating scale were then reviewed with parents. A history of the presence/absence and frequency of rage outbursts at home was also obtained at admission. The diagnostic assessment has been described elsewhere (18
). For study purposes, a best estimate diagnosis (19
), was made by the first author (GAC) and the inpatient medical director (ZG), and included parent- provided history and child mental status, hospital course, and nurse and inpatient teacher observations. Since 141 (93.4%) admissions lasted more than one week, adequate observation of children after admission was possible in most cases. Diagnostic reliability was assessed in a random sub-sample of 25% of cases (between authors GAC and DM) using the procedure of Klein et al (20
). Cohen’s kappas for the diagnostic categories relevant to this study were: for mania, learning and language disorders, externalizing disorder (either or both attention deficit hyperactivity disorder and oppositional defiant/conduct disorder) and psychosis, k=1.0; attention deficit disorder (ADHD), k=0.94; pervasive developmental disorder (PDD), k=0.91, anxiety k=0.85, depression k=0.83, oppositional defiant/conduct disorder k=0.74.
For this report, the diagnosis of bipolar disorder was examined from 5 viewpoints to address both broad and narrow diagnostic approaches to bipolar disorder: 1) bipolar diagnosis made by referring clinician; 2) DSM IV manic symptoms (elated/irritable mood + any of the “B” criteria) with or without episodes elicited from parent/guardian at admission 3) “narrow phenotype” mania/bipolar disorder (BP) requiring a clearly defined current episode with symptoms of mania described by parents and concurrent symptoms observed by the child psychiatrist, child psychologist or nursing staff as occurring most of the day and fulfilling unmodified DSM IV criteria (21
); 4) The diagnosis of BP NOS/possible mania made if DSM IV symptoms of mania were transient, i.e, periods of behavior that lasted an hour or less. (The current operationalization of BPNOS (22
) was not available when this study began); 5) Severe Mood Dysregulation (SMD), because it has been the subject of investigation as a possible “broad bipolar phenotype” (3
). However, since this study was designed before SMD criteria were published, the condition was assigned retrospectively if the child had a history of chronic aggression lasting at least a year, frequent rages at home of sufficient severity and frequency that hospitalization resulted (i.e. markedly increased reactivity to negative emotional stimuli), and a history of irritability and 3 or more of the following: insomnia, agitation, distractibility, flight of ideas, pressured speech, intrusiveness as elicited in obtaining a history of manic symptoms, ADHD and/or oppositional defiant/conduct disorder.
In terms of safety, laboratory tests (CBC, electrolytes, BUN, creatinine, liver function tests, thyroid panel, cholesterol), and an EKG are done routinely on all admissions. No additional lab work was done with children who had rage outbursts. Any child who was given oral risperidone was evaluated for sedation and sleepiness as part of an Agitation Inventory developed for use in this project (19
). The Abnormal Involuntary Movements Scale (AIMS, 24), Simpson-Angus scale for extrapyramidal symptoms (SAS, 25) and Barnes Akathisia Scale (BAS, 26) were completed within 2 hours of the end of each rage outburst for children who received liquid risperidone.
A rage outburst was defined as sufficient agitation and loss of control such that the child was unable to “time out” (i.e. sit in a chair for 10 minutes on being told to do so) or was a danger to himself or others and a higher level of intervention was needed. In order to compare the efficacy of medication against usual treatment (i.e. seclusion/restraint), a first rage outburst in the hospital was treated non-medically; that is, the child was placed in an isolation room. The door remained open if the child was able to regain control and take the time out in the room; otherwise the door was closed. If there was a second episode, the child was told “You need some medicine to help you get back in control. Take this medicine or we may have to give you a shot”. If agreeable, the child was given 0.015 mg/kg of liquid risperidone.
Four highly experienced day and evening nursing “shift leaders” were trained to a reliability of K>0.8 to use the Children’s Agitation Inventory (23
), an observational list developed to code the presence or absence of specific tantrum behaviors at 5, 15, 30, 60, 90 and 120 minutes or termination of the rage. Behaviors rated included physical aggression (e.g. hitting, kicking, pushing, throwing things), verbal aggression (e.g. cursing, screaming, threatening), other behaviors like throwing self on the floor and stamping feet, and mood and psychiatric symptoms (e.g. crying, pacing, being withdrawn and unresponsive, reporting or appearing to be having hallucinations). Also noted was whether the child was sedated or asleep. Reliability ranged from k=0.66 for pacing/psychomotor agitation to k=1.0 for physical and verbal aggression.
If the patient showed no evidence of improvement by 30 minutes following drug administration, the dose for a next rage was increased to 0.02 mg/kg. Since children were also often taking other scheduled atypical antipsychotics, the IRB required a ceiling dose on total amount of risperidone (or equivalent) that could be administered in one day. The ceiling dose was based on the child’s weight and ranged from 1.4 mg in a child weighing 20–24 kg to 4 mg in a child of 60–64 kg. We examined improvement using time to behavioral control or if there was the need for a 2nd intervention (locked door seclusion or, if the child was in danger of injuring himself, intramuscular dyphenhydramine which had been the rescue medication used prior to starting this study).
Adverse events such as sedation (as noted on the Agitation Inventory), extrapyramidal symptoms and akathisia were measured at the end of a rage outburst in which medication was administered using the coding inventory described above (24
Sample characteristics, and rates of SMD, parent-described manic symptoms and referring clinician-diagnosed BP rates prior to each admission, best estimate BP diagnoses and classes of discharge medication were compared using the Chi square statistic between admissions with no rages, one to two, and three or more rages. For BP, current mania and BP NOS were counted separately from lifetime mania since the former were the object of treatment. The paired t-test was used to calculate significance between non-medicated and maximally-medicated rage durations. The duration of rages in children with two or more liquid risperidone administrations were compared to those from the non-medicated state to account for any effect of the novelty of intervention.