JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
`Volume 10, Number 1, 2000
`Mary Ann Liebert, Inc.
`Pp. 45-49
`
`Case Report
`Mood Stabilizer Augmentation with Olanzapine in
`Acutely Manic Children
`
`KIKI D. CHANG, M.D. and TERENCE A. KETTER, M.D.
`
`ABSTRACT
`We report on three cases of acutely manic prepubertal children diagnosed with bipolar dis-
`order who were treated with olanzapine in addition to their existing mood stabilizer regi-
`mens. All three had marked improvement of their manic symptoms within 3-5 days of be-
`ginning olanzapine therapy as measured by clinician-rated instruments. Adverse effects
`included sedation and weight gain. These results suggest that olanzapine may have an anti-
`manic or mood stabilizing effect in acutely manic children with bipolar disorder.
`
`INTRODUCTION
`
`Antipsychotics have been routinely used in the acute and chronic treatment of bipolar disorder (Tohen
`
`and Zarate 1998). Due to their low incidence of tardive dyskinesia, atypical antipsychotics may be at-
`tractive alternatives to typical antipsychotics. The advent of atypical antipsychotics has also raised the pos-
`sibility of these agents having antimanic, ant.i.d.epressant, or mood stabilizing properties. Olanzapine is an
`atypical antipsychotic similar in structure and receptor affinity to clozapine, but without the side effects of
`agranulocytosis, seizures, or hypotension. In open studies and case reports, researchers have found olanza-
`pine useful as augmentation to traditional mood stabilizers in acutely manic adults (Ketter et al. 1998; McEl-
`roy et al. 1998). Olanzapine has been suggested to be effective monotherapy in some adults with mania
`(Ravindran et al. 1997) and has been reported to work rapidly to alleviate mixed mania (Ketter et al. 1998).
`A double blind placebo controlled study recently found olanzapine monotherapy superior to placebo in
`manic adults (Tohen et al. 1999). However, there have also been reports of manic symptoms, including ag-
`gression and agitation, induced by treatment with olanzapine (John et al. 1998; Lindenmayer and Klebanov
`1998; London 1998), possibly due to agitation secondary to discontinuation of traditional antipsychotics.
`Thus, the efficacy olanzapine in treating mania has not yet been fully established.
`There have been fewer reports of olanzapine use in children and adolescents. Olanzapine was found to
`be moderately effective in eight children with schizophrenia in an open label study (Kumra et al. 1998).
`However, a recent study reported discontinuation of open olanzapine treatment in five children with vari-
`ous psychiatric disorders due to persistent side effects (sedation, weight gain, and akathesia) and lack of
`significant improvement of symptoms (Krishnamoorthy and King 1998). Bipolar disorder was among the
`
`Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
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`Alkermes, Ex. 1018
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`

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`CHANG AND KETTER
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`differential diagnoses for three of these children, but it was not clear that any of them were experiencing a
`manic state due to bipolar disorder. In another open case series, five out of seven adolescents with manic
`episodes were reported to have responded well to either addition of olanzapine to their medication regi-
`mens or, in one case, olanzapine monotherapy (Soutullo et al. 1999). There have been no reports of mood
`stabilizer augmentation with olanzapine in acutely manic prepubertal children. Here, we report on three
`cases of acutely manic prepubertal children with bipolar disorder who responded to olanzapine's being
`added to their existing mood stabilizer regimen.
`
`CASE REPORTS
`
`Case 1
`R.C, a 12-year-old boy, was first diagnosed with attention-deficit hyperactivity disorder (ADHD) at age
`6. His family history was significant for his mother's having bipolar disorder and numerous maternal rela-
`tives with depression. After 3 years of therapy with sustained release methylphenidate 20 mg QD, he be-
`gan to experience increasingly labile mood, with frequent bouts of depressed mood alternating with extreme
`irritability and tantrums; however, no other medications were tried.
`At age 11 years, R.C. presented to our outpatient clinic with extreme irritability, racing thoughts, initial
`insomnia, hypersexuality, and hyperactivity. He was tapered off of the methylphenidate over 2 weeks, but
`these symptoms continued and worsened over the next month. He was diagnosed with bipolar disorder,
`rapid cycling, and begun on divalproex, eventually titrated to 500 mg qhs (serum level 98 ¿ig/mL). RC re-
`sponded partially with less irritability, insomnia, and racing thoughts. However he still experienced mood
`lability, hyperactivity, inattention, and significant depressed mood. Sustain release methylphenidate 20 mg
`QD was added back to his regimen along with lithium carbonate 300 mg b.i.d. Over the next 3 weeks,
`R.C.'s condition improved, with an euthymic mood, decreased mood lability, and decreased hyperactivity.
`Lithium was discontinued after 1 month of treatment, however, due to an elevated serum thyroid stimulat-
`ing hormone (TSH) level of 7.9 /j,IU/mL. Levothyroxine 0.1 mg was started, resulting in a TSH level of
`2.1 juIU/L in 1 month, and was maintained at this dose. R.C. continued in a euthymic condition for 2 months,
`until, during a trip to Europe, he experienced severe initial insomnia and began sleeping only 3 hours per
`night. After 1 week, he was floridly manic, with increased speech, euphoric mood, hyperactivity, grandios-
`ity, eccentric behavior, and poor judgment, including yelling at strangers in museums and having paranoid
`delusions. Upon his return to the United States, he was evaluated at our clinic, and he had a Young Mania
`Rating Scale (YMRS) score of 25 and Global Assessment of Function (GAF) score of 55. Olanzapine 2.5
`mg qhs was added to his current medications. After 2 days, in which he slept a total of 24 hours, his con-
`dition improved dramatically, with a resolution to his baseline condition. He began to sleep normally, achiev-
`ing 9 hours of sleep per night. His YMRS after 4 days was 4. His Clinical Global Impression (CGI) was
`rated as Markedly Improved. Thyroid studies were performed to rule out iatrogenic hyperthyroidism: serum
`TSH level was 3.5 /uIU/mL and free thyroxine level was 1.1 ng/dL, both within the normal reference range.
`Over the next month, RC continued to do well, but gained 18 lb. This weight gain was a 22% increase
`from his initial weight of 81 lb, but placed him at his ideal body weight (perhaps due to prior low weight
`secondary to appetite suppression with methylphenidate treatment). Olanzapine was then discontinued to
`prevent further weight gain, and R.C. continued to do well at a 1-month follow-up.
`
`Case 2
`M.L. was a 10-year-old boy diagnosed with ADHD and bipolar disorder, being treated with divalproex
`(serum level 102 /¿g/mL) and lithium carbonate (0.7 mEq/L). Psychiatric family history revealed his mother's
`having bipolar disorder. He was receiving home schooling due to a past protracted hospitalization and was
`doing well for the prior 3 months. However, during his parents' divorce proceedings, he began to experi-
`ence bursts of giddiness, irritability, racing thoughts, and unusual behavior. He became extremely dysphoric
`and began having intermittent paranoid delusions that unspecified people were planning to hurt him.
`Upon presentation in our clinic, his YMRS score was 22, GAF was 55, and he was diagnosed as acutely
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`Alkermes, Ex. 1018
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`

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`OLANZAPINE IN ACUTELY MANIC CHILDREN
`
`manic. Olanzapine 2.5 mg qhs was added to his regimen, which was increased to 5 mg qhs the next day.
`M.L. experienced mild sedation and increased sleep over the next 3 days. By the fifth day, he was notice-
`ably improved, with decreased rate of speech and decreased racing thoughts, and he remained only mildly
`irritable. There were no further episodes of psychotic behavior. YMRS score was 5, and M.L. was consid-
`ered Markedly Improved on the CGI. M.L. was continued on olanzapine 5 mg qhs for 1 week and then
`eventually tapered to 2.5 mg qhs. He had no further manic episodes for 2 months subsequently on the same
`medication regimen. During treatment with olanzapine, he reported initial sedation for the first 3 days and
`no other adverse effects.
`
`Case 3
`D.T. was a 9-year-old boy who presented to our clinic with a prior diagnosis of depression and ADHD.
`His prior psychiatrist had prescribed sertraline 150 mg QD and sustained release methylphenidate 20 mg
`b.i.d. for the past 2 years and, for unclear reasons, gabapentin 300 mg t.i.d. for the past month. However,
`D.T. was experiencing racing thoughts, hyperactivity, irritability, and severe initial insomnia. All medica-
`tions were tapered over 2 weeks and eventually discontinued. However, he continued to display manic
`symptoms for 2 weeks and was diagnosed with bipolar disorder NOS, as it was unclear whether or not these
`agents had precipitated the mania. Divalproex was started and titrated up to 250 mg QAM and 375 mg qhs,
`with a serum level of 78 ¿ig/iriL over the next 4 weeks. There was mild improvement in initial insomnia
`and irritability, but D.T. continued to have episodic bursts of extreme irritability as well as racing thoughts
`and hyperactivity. His YMRS score at this time was 19.
`After D.T.'s parents declined institution of a second mood stabilizer (lithium or carbamazepine), olan-
`zapine 2.5 mg was added at bedtime. The parents reported dramatic improvement in D.T.'s condition after
`3 days. Upon réévaluation after 7 days, D.T. was noticeably less irritable, appearing euthymic, and reported
`cessation of racing thoughts. He was not hyperactive and was compliant with the psychiatric evaluation for
`the first time. His YMRS score was 1, and his CGI was rated as Markedly Improved. D.T. continued on
`olanzapine and divalproex and was doing well 6 weeks after institution of olanzapine. He gained 10 lb,
`from an initial weight of 79 lbs., and continued to experience mild daytime sedation.
`
`DISCUSSION
`
`We report on three prepubertal children with bipolar disorder and acute mania who all responded dra-
`matically within 5 days to augmentation of their mood stabilizers with olanzapine. They were all managed
`as outpatients, and all were maintained on lithium and/or valproate during the olanzapine trial. This rapid-
`ity of response to olanzapine in acute mania is similar to two adult case reports by Ketter et al. (1998). All
`three patients also experienced considerable sedation in the first few days after beginning olanzapine treat-
`ment and slept more than their normal amount (over 10 hours per night). Disruption of sleep-wake cycles
`has been purported to be involved in triggering mania or exacerbating rapid cycling in bipolar patients
`(Kasper and Wehr 1992; Wehr et al. 1982), and restoration of normal sleep patterns may resolve mania
`fairly rapidly (Nowlin-Finch et al. 1994; Robertson and Tanguay 1997). Thus, resolution of their manic
`symptoms may have also been facilitated by a return of a normal sleep cycle. This may have been espe-
`cially pertinent in case 1, in which R.C. suffered jet lag and subsequent disruption of his sleep cycle while
`in Europe.
`Furthermore, all three children were maintained on their previous mood stabilizers during the olanzap-
`ine trial. In case 3, it is possible that D.T. may have continued to have increasing benefit from divalproex
`during treatment with olanzapine, as he had only begun on divalproex 4 weeks prior. However, the rapid
`time course of improvement with olanzapine addition suggests this agent was important in achieving re-
`mission. The two other patients had been maintained on a constant dose of lithium and divalproex for at
`least 2 months prior to their manic episode, again suggesting the role of olanzapine in their rapid remis-
`sion.
`The adverse effects experienced by our patients after olanzapine addition were predominantly seda-
`tion and weight gain. This is consistent with case reports of olanzapine use in prepubertal children, in
`47
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`CHANG AND KETTER
`
`which 50% gained at least 16 lb (Krishnamoorthy and King 1998).
`In a larger trial of olanzapine in
`bipolar adults, the mean weight gain over 4 weeks was 4.6 lbs (2.1 kg; Tohen et al. 1999), substantially
`less than the 10 or 18 lb reported here. However, the children in our report were also being treated with
`either lithium or divalproex, both of which may have contributed to the weight gain. It remains to be
`seen if younger children are in some way more susceptible to this particular adverse effect of olanzap-
`ine.
`Other agents have historically been used temporarily in conjunction with standard mood stabilizers (i.e.,
`lithium or valproate) to treat acute manic states. Typical antipsychotics, such as haloperidol or chlorpro-
`mazine, have a long history of use in both acute and chronic treatment of mania (Tohen and Zarate 1998).
`Benzodiazepines, such as lorazepam or clonazepam, have also been used adjunctively. The efficacy of these
`medications supports the possibility of sedation or restoration of sleep as a major contributor to resolution
`of acute mania. However, typical antipsychotics have a significant adverse effect profile, including poten-
`tial for extrapyramidal symptoms and tardive dyskinesia. Benzodiazepines do not share these adverse ef-
`fects, but in children may cause behavioral disinhibition (Graae et al. 1994; Reiter and Kutcher 1991). Olan-
`zapine, as of yet, does not appear to have significant potential for these particular adverse effects, suggesting
`that it may be an attractive alternative to typical antipsychotics or benzodiazepines for acute, or possibly
`chronic, treatment of childhood mania.
`The rapid response of all three acutely manic children in this report to olanzapine addition supports the
`possibility of olanzapine's having antimanic or mood stabilizing properties. Further research needs to be
`conducted to determine if olanzapine is effective in children with acute mania, whether in monotherapy or
`adjunctive therapy to conventional mood stabilizers.
`
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`Ketter TA, Winsberg ME, DeGolia SG, Dunai M, Täte DL, Strong CM: Rapid efficacy of olanzapine augmentation in
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`OLANZAPINE IN ACUTELY MANIC CHILDREN
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`Soutullo CA, Sorter MT, Foster KD, McElroy SL, Keck PE: Olanzapine in the treatment of adolescent acute mania: A
`report of seven cases. J Affect Disord 53:279-283, 1999
`Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, Petty F, Centorrino F, Wang R, Grundy
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`zapine HGEH Study Group. Am J Psychiatry 156:702-709, 1999
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`
`Address reprint requests to:
`Kiki D. Chang, M.D.
`Stanford University School of Medicine
`Division of Child and Adolescent Psychiatry
`401 Quarry Road
`Stanford, CA 94305-5540
`E-mail: kchang88@leland.stanford.edu
`
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`(cid:8)(cid:15)(cid:32)(cid:3)(cid:43)(cid:32)(cid:27)(cid:13)(cid:12)(cid:25)(cid:9)(cid:12)(cid:15)(cid:26)(cid:25)(cid:6)(cid:3)(cid:15)(cid:16)(cid:17)(cid:18)(cid:19)(cid:3)(cid:10)(cid:20)(cid:19)(cid:3)(cid:21)(cid:19)(cid:22)(cid:18)(cid:12)(cid:23)(cid:24)(cid:12)(cid:20)(cid:13)(cid:3)(cid:25)(cid:23)(cid:14)(cid:24)(cid:16)(cid:17)(cid:10)(cid:13)(cid:6)(cid:17)(cid:24)(cid:3)(cid:15)(cid:18)(cid:17)(cid:20)(cid:17)(cid:24)(cid:23)(cid:3)(cid:22)(cid:11)(cid:3)(cid:26)(cid:22)(cid:6)(cid:13)(cid:16)(cid:3)(cid:21)(cid:27)(cid:12)(cid:6)(cid:17)(cid:24)(cid:10)(cid:3)(cid:22)(cid:23)(cid:18)(cid:3)(cid:49)(cid:5)(cid:5)(cid:4)(cid:49)(cid:59)(cid:49)(cid:6)(cid:3)(cid:51)(cid:22)(cid:24)(cid:27)(cid:25)(cid:25)(cid:45)(cid:12)(cid:38)(cid:52)
`(cid:59)(cid:6) (cid:7)(cid:27)(cid:15)(cid:8)(cid:26)(cid:23)(cid:8)(cid:15)(cid:3)(cid:22)(cid:3)(cid:58)(cid:38)(cid:12)(cid:14)(cid:38)(cid:12)(cid:24)(cid:18)(cid:3)(cid:45)(cid:27)(cid:57)(cid:12)(cid:24)(cid:26)(cid:3)(cid:43)(cid:3)(cid:60)(cid:27)(cid:46)(cid:8)(cid:26)(cid:9)(cid:23)(cid:18)(cid:3)(cid:47)(cid:12)(cid:13)(cid:14)(cid:25)(cid:25)(cid:8)(cid:3)(cid:58)(cid:3)(cid:29)(cid:12)(cid:13)(cid:53)(cid:12)(cid:13)(cid:13)(cid:27)(cid:6)(cid:3)(cid:34)(cid:35)(cid:35)(cid:48)(cid:6)(cid:3)(cid:37)(cid:23)(cid:12)(cid:3)(cid:11)(cid:25)(cid:12)(cid:3)(cid:27)(cid:38)(cid:3)(cid:8)(cid:15)(cid:26)(cid:14)(cid:28)(cid:25)(cid:33)(cid:9)(cid:23)(cid:27)(cid:26)(cid:14)(cid:9)(cid:25)(cid:3)(cid:14)(cid:15)(cid:3)(cid:9)(cid:23)(cid:14)(cid:13)(cid:32)(cid:24)(cid:12)(cid:15)(cid:3)(cid:8)(cid:15)(cid:32)(cid:3)(cid:8)(cid:32)(cid:27)(cid:13)(cid:12)(cid:25)(cid:9)(cid:12)(cid:15)(cid:26)(cid:25)
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