This study seeks to characterize symptoms of severe mood and behavioral dysregulation (SMBD) in children and adolescents. The study will also evaluate the effectiveness of lithium as a treatment for this condition while subjects participate in day-treatment or inpatient care.

Children with SMBD display chronic anger, sadness, irritability, hyperarousal symptoms (such as insomnia, distractibility) and extreme responses to frustration. Participants will be screened as outpatients using medical and psychiatric history and interview, physical examination, blood and urine tests, and an electrocardiogram.

Children with SMBD have current medications gradually withdrawn over 1- to 3-weeks and then are randomly assigned to receive either lithium or a placebo (sugar pill).

The treatment phase is 8 weeks and is provided on a children's inpatient unit or day treatment center, depending on clinical considerations. All children will receive placebos for at least 2 weeks during some part of the 8-week trial. During treatment, participants are rated on mood, behavior, and medication side effects. Blood tests are obtained weekly or as clinically indicated. At the end of the 8 week randomized trial, children who took placebo may be offered lithium. Children who took lithium but did not respond will be stabilized before returning to care in the community. Schooling is provided in the inpatient and day treatment programs.

Patients receive neuropsychological testing, experimental psychophysiological studies, magnetic resonance imaging (MRI) scans of brain structure, and research magnetic resonance spectroscopy (MRS) scans. . Patients are asked to wear activity monitors on their wrist. Information on family medical and psychiatric history is also obtained.

Patients are asked to return for follow-up visits once every 2 years for repeat interviews, medical, psychiatric and school histories, questionnaires, physical examination, blood work, and structural MRI. Participants will be followed over time and their symptoms will be compared with those of children with bipolar disorder (BPD) and healthy volunteers (controls).

Condition	Treatment or Intervention	Phase
Mood Disorder	Drug: Lithium	Phase IV

Further Study Details: 

Expected Total Enrollment:  160

Recently, researchers and clinicains have focused increased attention on a group of children with severe mood and behavioral dysregulation. These children are characterized by 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. Because this syndrome shares many clinical features with bipolar disorder (BPD), there is considerable debate as to whether these children should be diagnosed with BPD. However, children with this syndrome lack the cardinal symptoms of BPD (i.e. euphoria, elation, grandiosity, decreased need for sleep, and increased goal-directed activity). Similrly, while many of these children fit diagnostic criteria for other DSM-IV diagnoses (including attention deficit hyperactivity, oppositional defiant, major depressive and/or conduct disorders), these diagnoses capture heterogeneous clinical populations that include many children who do not exhibit the symptoms noted above. Therefore, the first goal of this project is to identify reliably a group of children with severe mood and behavioral dysregulation in order to characterize them clinically and follow them longitudinally. In addition, since there are no controlled trials to guide treatment of these severely impaired children, we will conduct a double-blinded, placebo controlled trial of lithium. The goals of this trial will be to test the efficacy of lithium, and to investigate whether lithium response, which has been associated with neurotrophic effects and with changes in phosphoinositide signaling in bipolar patients, has similar effects in this group of patients. Finally we will test two preliminary hypotheses regarding the possible pathophysiology of their symptoms. To do so, we will use affect-modulated startle techniques parallel to those being used in a study of children with unequivocal BPD (Protocol # 00-M-0198) as well as functional MRI.

Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

INCLUSION CRITERIA:
1. Ages 7-17
2. Abnormal mood (specifically anger, sadness, and/or irritability), present at least half of the day most days, and of sufficient severity to be noticeable by people in the child's environment (e.g. parents, teachers, peers).
3. Hyperarousal, as defined by at least three of the following symptoms: insomnia, agitation, distractibility, racing thoughts or flight of ideas, pressured speech, intrusiveness.
4. Compared to his/her peers, the child exhibits markedly increased reactivity to negative emotional stimuli that is manifest verbally or behaviorally. For example, the child responds to frustration with extended temper tantrums (inappropriate for age and/or precipitating event), verbal rages, and/or aggression toward people or property. Such events occur, on average, at least three times a week for the past four weeks.
5. The symptoms in # 2, 3, and 4 above are currently present and have been present for at least 12 months without any symptom-free periods exceeding two months. The onset of symptoms must be prior to age 12 years.
6. The symptoms are severe in at least in one setting (e.g. violent outbursts, assaultiveness at home, school, or with peers). In addition, there are at least mild symptoms (distractibility, intrusiveness) in a second setting.
7. If the child meets DSM-IV criteria for major depressive disorder, he/she must have had an adequate trial of an SSRI antidepressant (defined as four weeks of consecutive treatment in minimally effective doses among adults: paroxetine 20 mg; fluoxetine 20 mg; citalopram 20 mg; fluvoxamine 150 mg; sertraline 50 mg). His/her response to the treatment must have been no more than minimal (i.e. CGI-I greater than 2).
8. If the child meets DSM-IV criteria for attention deficit hyperactivity disorder, he/she must have had an adequate trial of methylphenidate (defined as two consecutive weeks of Ritalin, Metadate, Methylin, or Concerta, at least 30 mg/day if adverse effects present, and at least 60 mg/day if dose not limited by adverse effects), and an adequate trial of amphetamines two consecutive weeks of Adderall 20 mg/day or dextroamphetamine 40 mg/day). His/her response to the treatment must have been no more than minimal (i.e. CGI-I greater than 2).
9. Currently in treatment with a psychiatrist for the symptoms.
10. The child is failing his/her treatment. To meet this criterion:
a) The child's current CGAS score must be less than or equal to 60.
b) The child's psychiatrist must agree that the child's response to his/her current treatment is no more than minimal (i.e. CGI-I greater than 2). According to this criterion, it would be clinically appropriate to change the child's current treatment.
c) On the basis of record review and interviews with child and parent, the research team agrees that the child's response to his/her current treatment is no more than minimal (i.e. CGI-I greater than 2).
INCLUSION CRITERIA - CONTROLS:
Control subjects will be age- and sex- matched to the patients. They will have normal physical and neurological examinations and an identified primary care physician. Both control subjects and their first-degree relatives must be free of current or past psychopathology.
EXCLUSION CRITERIA:
1. The individual exhibits any of these cardinal bipolar symptoms:
Elevated or expansive mood;
Grandiosity or inflated self-esteem;
Decreased need for sleep;
Increase in goal-directed activity (this can result in excessive involvement in pleasurable activities that have a high potential for painful consequences)
2. The symptoms occur in distinct periods lasting more than 4 days , and therefore meet criteria for hypomania or mania.
3. Meets criteria for schizophrenia, schizophreniform disorder, schizoaffective illness, PDD, or PTSD.
4. Meets criteria for substance use disorder in the three months prior to randomization.
5. IQ less than 80
6. The symptoms are due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition.
7. Currently pregnant or lactating, or sexually active without using a barrier method of contraception.
8. Contraindications to treatment with lithium (e.g. renal, thyroid, cardiac disease, seizure disorder).
9. Previous adequate trial of treatment with lithium that did not have beneficial clinical effects. An adequate trial is defined as at least 6 weeks of treatment with a blood level of greater than or equal to 0.8 mEq/L.
EXCLUSION CRITERIA - CONTROLS:
I.Q. less than 80; ongoing medical illness; neurologic disorder (including seizures); pregnancy; meeting past or present criteria for any diagnosis on the K-SADS-PL(7); meeting the criteria for severe mood and behavioral dysregulation; meeting criterion of post-traumatic stress disorder (exposure to a traumatic event).

Maryland
      National Institute of Mental Health (NIMH), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  020021; 02-M-0021
Record last reviewed:  December 7, 2004
Last Updated:  December 21, 2004
Record first received:  October 31, 2001
ClinicalTrials.gov Identifier:  NCT00025935
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08