Psychosomatics 46:254-258, June 2005
© 2005 The Academy of Psychosomatic Medicine
Risperidone Treatment of Three Seriously Medically Ill Children With Secondary Mood Disorders
Judith M. Bealke, M.D., and
Karen G. Meighen, M.D.
Received June 9, 2004; revision received Oct. 16, 2004; accepted Nov. 15, 2004. From the Section of Child and Adolescent Psychiatry, Department of Psychiatry, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis. Address correspondence and reprint requests to Dr. Meighen, James Whitcomb Riley Hospital for Children, 702 Barnhill Dr., Rm. 4300, Indianapolis, IN 46202-5200; kmeighen{at}iupui.edu (e-mail).
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INTRODUCTION
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Atypical antipsychotics are increasingly used in child and adolescent populations for a variety of psychiatric disorders. Compared to conventional antipsychotics, their appeal is at least twofold: tolerability and unique neurotransmitter receptor affinities that translate into applicability beyond schizophrenia and other psychotic disorders. We present three cases from a child and adolescent consultation-liaison psychiatry service where risperidone was used to treat significant mood disorders secondary to serious medical conditions. These cases represent novel uses of risperidone because of the very young ages of the children and the diagnoses being treated.
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Case Reports
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Case 1
Arnie was a 30-month-old Caucasian boy with a history of complex single-ventricle congenital heart defect. He was admitted to a tertiary care children’s hospital for corrective cardiac surgery (the Fontan procedure) and had a complicated postoperative course, including prolonged ventilator support. Arnie suffered a hypoxic event at one point during his 2 -month hospital stay, after which he demonstrated decreased responses to visual, auditory, and tactile stimuli. He exhibited a regression in fine and gross motor skills. Subclinical seizures were found on an EEG, and treatment with phenytoin was started. Magnetic resonance imaging (MRI) of the brain revealed an old infarction involving the watershed area and diffuse volume loss in the thalami and basal ganglia.
A child psychiatry consultation was sought 71 days after completion of the Fontan procedure with the concern being persistent irritability and agitation. Arnie had been extubated. Sedative-hypnotic medicines had been tapered and discontinued except lorazepam, as needed. At the time of his psychiatric evaluation, Arnie had become progressively more irritable, had poor oral intake, and would writhe in bed for hours. He cried almost all day and had been getting only 2 or 3 hours of sleep a night. Arnie had been having nightly episodes of fever associated with increased motor agitation, tachypnea, tachycardia, and hypertension. No physiological explanation for these episodes could be found. Neurological consultants believed that the periods of fever could be due to hypothalamic dysfunction. Possible occult infection remained a concern. His phenytoin level was found to be within the therapeutic range. Before this hospitalization, Arnie’s parents described him as having an easygoing temperament with a tolerance for multiple medical interventions.
Adequate trials of diphenhydramine, chloral hydrate, chlorpromazine, morphine sulfate, and lorazepam were of no benefit in decreasing Arnie’s irritability or episodes of fever with agitation.
A mental status examination revealed an alert, mildly overweight young child. He constantly rocked his head back and forth and held his arms tightly flexed at the elbows. His hands were clenched. His legs were loosely held flexed at the knees and ankles. His tongue thrusts were rhythmic and continuous. He did not appear to visually track objects. He did not respond to auditory stimuli. The only evidence of response to tactile stimulation was a brief period during which Arnie made chewing motions when he was orally stimulated. His affect was restricted and irritable.
Arnie was diagnosed with a mood disorder secondary to a general medical condition; his hypoxic brain insult was implicated as the cause. Risperidone was started at 0.25 mg every morning and 0.75 mg every night through a gastrostomy tube. The next day, Arnie was more relaxed and was better able to engage in physical therapy. He slept 4 consecutive hours without any episodes of fever overnight. His risperidone dose was gradually increased to 0.25 mg in the morning and 1.0 mg at night through a gastrostomy tube and careful monitoring since the initial doses had caused a slight decrease in his diastolic blood pressure. After this increase, Arnie was found to be alert and calm. His head rocking and tongue thrusting had disappeared. There was no evidence of motor tension or agitation. He was more responsive to tactile stimuli. He had a euthymic affect. He had reportedly slept 6 consecutive hours and had no fever episodes overnight. His blood pressure was only minimally affected by subsequent doses of risperidone, with his diastolic measures dropping an average of 4 to 6 mm Hg. Arnie was maintained on this dosage and progressed physically to the point at which he could be discharged to a pediatric rehabilitation facility by the fourth day of treatment.
Case 2
Brian was a 17-month-old Caucasian boy with a history of complex congenital heart disease that had been repaired during the first year of life. He was brought to the emergency department of a tertiary care children’s hospital in respiratory distress followed by cardiac arrest. Brian was taken to the operating suite, where a left ventricular assist device was placed. He remained intubated and heavily sedated for about 6 weeks before he underwent a cardiac transplant. Before the transplant, a computerized tomography (CT) scan of his head was obtained that showed global atrophy and a chronic subdural hematoma with areas of acute hemorrhage. An EEG showed severe encephalopathy. Premorbidly, Brian was small for his age and had mild developmental delays in language and fine and gross motor skills. There were no reports of neurological deficits or behavioral or mood disturbances before this hospitalization. After the cardiac transplant, Brian was easily extubated and removed from sedating medications. The child psychiatry consultation-liaison service was then asked to be involved because of his extreme agitation. He was constantly in motion, causing large abrasions over both elbows because of friction against his bed linens. He had not slept in several days and was not responsive to soothing by his parents or to environmental changes. Haloperidol was implemented in scheduled intravenous doses, to a maximum of 16.25 mg in 24 hours. This provided some consolidation of sleep periods at night and wakeful daytime periods during which Brian appeared partially responsive to his parents’ interactions. A cross-taper with risperidone through a gastrostomy tube was accomplished within the next 2 weeks. The maximum dose of risperidone was 1 mg in the morning and 3 mg at bedtime. No dystonia or extrapyramidal side effects were observed. A significant improvement in mood was noted with risperidone. He became much calmer and was able to sleep. Brian had only brief episodes of agitation occurring with medical procedures and therapies. He appeared to attend to auditory stimuli and parental soothing but did not clearly track visually. Repeat CT scans of his head showed diffuse atrophy with enlarged CSF spaces and no change from the previous study, left-sided subdural hemorrhage with evolving appearance but without mass effect, and evidence of prior periventricular ischemic injury thought to be related to his history of left ventricular device and/or transplantation. A repeat EEG was abnormal because of the presence of a focus of epileptiform discharges over the right central-temporal region and a severely slow background rhythm suggestive of severe encephalopathy. Brian’s postoperative change in functioning appeared to be related to ischemic injury. His psychiatric diagnosis was mood disorder secondary to this injury. He was transferred to a pediatric rehabilitation unit when it was determined that his cardiovascular status was stable. His weight at that time was 8.3 kg. He had been receiving risperidone monotherapy for 3 weeks. While in rehabilitation, Brian demonstrated small but significant gains in motor control and tracking, decreased irritability with easier consolation when he was frustrated, improved alertness during the day, and fairly good sleep patterns at night. Risperidone was decreased to 3 mg at bedtime with no change in irritability, and Brian was able to return home.
Case 3
Corey was a 3-year-old African American boy who was admitted to the hematology/oncology service of a tertiary care children’s hospital. He had a history of acute lymphoblastic leukemia diagnosed 4 months earlier and was given methotrexate, vincristine, 6-mercaptopurine, and dexamethasone 14 days before his hospitalization. His admission was prompted by the onset of fever (102.8°F), irritability, left eye pain, and an unstable gait accompanied by nasal congestion, sneezing, and a runny nose. Corey had been throwing temper tantrums any time he did not get his way and began to have difficulty sleeping.
A child psychiatry consultation was sought because of the medical team’s concerns about his severe agitation and irritability. Corey would dislodge intravenous lines, scream, curse, and strike out at anyone attempting to provide him with care.
During the psychiatric evaluation, Corey’s father described him as premorbidly having a happy, playful demeanor. In the past, he had reportedly tolerated medical procedures and chemotherapy without significant emotional or behavioral problems. He had not had any past psychiatric treatment. His past medical history was negative except for the diagnosis of acute lymphoblastic leukemia. The acute lymphoblastic leukemia was thought to be in remission at the time of Corey’s hospitalization. His medications at the time of the initial consultation included a trial of oral diphenhydramine, 25 mg every 6 hours, as needed, for agitation and a trial of oral lorazepam, 0.5 mg–1.0 mg every 4 hours, as needed, for agitation. Neither of the medicines was effective in reducing Corey’s irritability or aggression.
At his mental status examination, Corey was minimally cooperative and easily agitated. He held a toy and pounded it onto his bed. He appeared restless and fidgety. He gave mostly "no" answers, and he made no eye contact. No involuntary or abnormal motor movements were seen. His affect was blunted and irritable. He reported no thoughts of self-harm or harm to others, and there was no evidence of psychosis. He was oriented to self and place.
An extensive medical workup was undertaken, including a normal blood volatile screen, a drug screen, a prothrombin time, a partial thromboplastin time, a comprehensive metabolic panel, a CBC with differential, measures of magnesium and phosphorus levels; a blood culture, serum protein electrophoresis, and studies for Epstein Barr virus and Mycoplasma pneumoniae. Pleiocytosis was found upon examination of Corey’s CSF, raising concerns about an infectious or inflammatory etiology for Corey’s symptoms. An MRI showed hyperintensities bilaterally in the posteromedial thalamus, which were thought to be toxic, metabolic, or ischemic in origin.
A psychiatric diagnosis of mood disorder secondary to a general medical condition was made, given the abnormalities found that related to the CNS. Specifically, a diagnosis of acute disseminated encephalomyelitis was ultimately given, based on his presentation and the final results of his medical workup. Oral risperidone, 0.25 mg every morning and 0.50 mg every evening, was started. The next day, Corey was calmer and more receptive to the examiner. He had slept 5 hours consecutively and awoke in a less irritable mood. He tolerated medical procedures with minor complaints but no aggression. Oral risperidone was then increased to 0.25 mg every morning and 0.75 mg every evening.
By day 5 of his hospitalization, Corey was more playful and easily redirected. He remained fussy during medical interventions but did not demonstrate physical resistance. In order to treat his acute disseminated encephalomyelitis, he was started on a 3-day course of intravenous methylprednisolone that he tolerated without adverse effects. Oral risperidone was decreased to 0.5 mg every evening on hospital day 7 then discontinued. His irritability, agitation, pain, and ataxia had improved markedly. His eating and sleeping patterns had returned to normal. Oral prednisolone was started at 30 mg/day on hospital day 8. Corey was judged to be at his baseline of neurological and emotional functioning by the ninth day of inpatient care and was discharged home.
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Discussion
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Each of the children in these cases experienced an insult to the CNS that resulted in extreme irritability, agitation, decreased sleep, and decreased social responsiveness, which we have diagnosed as a mood disorder secondary to a medical condition. These insults were documented on an MRI and were temporally related to the evolution of psychiatric symptoms. The sudden onset and dramatic presentations precluded adjustment disorders and disruptive behavioral disorders, which often accompany chronic illness. In each case, the diagnosis of delirium was carefully considered but ultimately ruled out because the criteria could not be fully met. Changes in cognition and perceptual disturbances could not be demonstrated in any of the cases, and the one possible disturbance in consciousness (the case of Arnie) was actually a complex static sensory loss. In each case, the addition of risperidone yielded improvements that could not be obtained with other agents; in two cases, the response was overnight. In the third case, it is important to note that dramatic changes in mood and behavior occurred before the initiation of methylprednisolone, which can also affect mood and behavior. A review of the literature shows that this use of risperidone is novel, both in treating a mood disorder secondary to a general medical condition and in treating this very young age group, as young as 17 months in the case of Brian. Two cases have been reported of children with autism treated with risperidone who were of similar ages, 29 and 23 months old, respectively.1 In two open-label studies of risperidone2,3 and in one other published case report,4 the age of the children treated was as young as 3 years. In all other published data concerning risperidone treatment, the age of inclusion for study has generally been 5 years and older. The adult literature shows potential for mood stabilization with risperidone, particularly in bipolar disorder, but its use in depressive disorders has not been studied as extensively. In 1998, Schreier5 reported on 11 children, six of whom had a confirmed or suspected diagnosis of either bipolar I disorder, bipolar II disorder, or cyclothymic disorder. He observed marked improvement in four of these children, moderate improvement in one, and no improvement in depressive symptoms associated with bipolar disorder in one other child. The children exhibiting good responses were generally agitated, aggressive, and/or blatantly manic. An open-label trial of risperidone added to lithium in adolescents with acute psychotic mania6 showed improvements in Young Mania Rating Scale and Clinical Global Improvement scores with the addition of an antipsychotic in this population. Published reports have shown the potential efficacy of risperidone in treating children and adolescents with schizophrenia, pervasive developmental disorders, and behavioral disturbances7; subaverage IQ and behavioral disturbances8; conduct disorder9; and Tourette’s syndrome.10 These are all chronic conditions without the specific mood component that was seen in our three reported cases. The tolerability of risperidone has been established11 and was supported by these cases. The most serious adverse effects reported have been tardive dyskinesia and neuroleptic malignant syndrome, but these have been rare. More commonly, extrapyramidal symptoms have been observed with the use of risperidone, especially with doses higher than 6 mg/day. The most common side effects are sedation, hyperprolactinemia with prolonged use, and most significantly, weight gain with a risk for hyperlipidemia and type II diabetes. Relevant to these cases is the report of a 23-month-old with dose-related persistent tachycardia and QTc prolongation.1 Both of the cardiology patients described in this report were, of course, carefully monitored, and no cardiac effects of risperidone were observed. The lowering of diastolic blood pressure was the only side effect worthy of note in any of the three cases, and it had no real clinical significance. Haloperidol has previously been reported in the literature to be effective in treating agitation in critically ill children.12,13 These children and adolescents were similar to our cases in the acuity of their medical illnesses (e.g., burn injuries, acute respiratory distress, peritonitis); however, mood symptoms were not delineated by these authors. The targeted symptoms for haloperidol were anxiety, agitation, confusion, and disorientation. Intravenous haloperidol has proven useful as an acute intervention for agitation because of its ease of administration when there is an impairment of consciousness; however, the long-term tolerability of conventional antipsychotics is a concerning issue, especially in young children. In addition, haloperidol has not been reported to have mood-enhancing effects. Haloperidol was used initially in the case of Brian. When his gastrostomy tube was accessible and functional, the switch was made to risperidone because of potential side effects from haloperidol, as well as incomplete resolution of his symptoms. In a critically ill child, risperidone can be administered in liquid form through a nasogastric or gastrostomy tube, and that is one of its current advantages over other atypical antipsychotics. In summary, the child and adolescent psychiatry consultation/liaison service of a tertiary referral children’s hospital was able to implement risperidone successfully in three critically ill children who had significant symptoms related to a new-onset mood disorder, in each case secondary to a cerebral insult. The doses were tailored to individual need and in one case discontinued before discharge. No significant adverse effects were noted. Although the literature supports the use of risperidone in children, few published reports have been made on children this young, and no reports have been made for this specific indication. As with all off-label use of medications in children, caution and vigilance should be exercised if this application of risperidone is to be used until further data are obtained. Prior studies indicating the effectiveness of risperidone in conditions where there is brain-based pathology in combination with agitation make it a reasonable approach to the patients described in these case reports.
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REFERENCES
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- Posey DJ, Walsh KA, Wilson GA, McDougle CJ: Risperidone in the treatment of two very young children with autism. J Child Adolesc Psychopharmacol 1999; 9:273–276[Medline]
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- Schreier HA: Risperidone for young children with mood disorders and aggressive behavior. J Child Adolesc Psychopharmacol 1998; 8:49–59[Medline]
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- Gaffney GR, Perry PJ, Lund BC, Bever-Stille KA, Arndt S, Kuperman S: Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 2002; 41:330–336[CrossRef][Medline]
- Stigler KA, Potenza MN, McDougle CJ: Tolerability profile of atypical antipsychotics in children and adolescents. Paediatric Drugs 2001; 3:927–942[CrossRef][Medline]
- Harrison AM, Lugo RA, Lee WE, Appachi E, Bourdakos D, Davis SJ, McHugh MJ, Weise KL: The use of haloperidol in agitated critically ill children. Clin Pediatr 2002; 41:51–54[Free Full Text]
- Brown RL, Henke A, Greenhalgh DG, Warden GD: The use of haloperidol in the agitated, critically ill pediatric patient with burns. J Burn Care Rehabil 1996; 17:34–38[Medline]
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M. Pao, E. D. Ballard, D. L. Rosenstein, L. Wiener, and A. S. Wayne
Psychotropic Medication Use in Pediatric Patients With Cancer
Arch Pediatr Adolesc Med,
August 1, 2006;
160(8):
818 - 822.
[Abstract]
[Full Text]
[PDF]
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INTRODUCTION
Case Reports
