Olanzapine in the treatment of adolescent acute mania: a report of seven cases

Journal of Affective Disorders 53 (1999) 279–283

Preliminary communication

Olanzapine in the treatment of adolescent acute mania: a report of seven cases Cesar A. Soutullo

a ,b ,

*, Michael T. Sorter a , Keith D. Foster a , Susan L. McElroy b , Paul E. Keck a ,b

a

b

Division of Child and Adolescent Psychiatry, Children’ s Hospital Medical Center, Cincinnati, OH, USA Department of Psychiatry, Biological Psychiatry Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA Received 9 December 1997; received in revised form 27 April 1998; accepted 5 June 1998

Abstract Background: Clozapine may be effective in adults and adolescents with treatment-resistant bipolar disorder. Olanzapine has a receptor affinity profile similar to that of clozapine. Methods: The responses of seven consecutive adolescents (ages 12–17) with DSM-IV bipolar disorder, manic episode, treated with olanzapine were evaluated. Response to olanzapine was rated as marked, moderate, minimal, none or worse. Results: Five (71%) adolescents showed a marked or moderate response. The mean6SD olanzapine dose was 0.14660.086 mg / kg / day (1166 mg / day). Conclusion: Olanzapine may have antimanic effects in some adolescents with acute mania. Controlled studies of olanzapine in adolescent bipolar disorder appear to be warranted.  1999 Elsevier Science B.V. All rights reserved. Keywords: Olanzapine; Bipolar disorder; Mania; Adolescent; Treatment-resistant; Atypical; Antipsychotic

1. Background Substantial clinical data suggest that the atypical antipsychotic clozapine may be effective in the acute and prophylactic treatment of some patients with treatment-resistant bipolar disorder (McElroy et al., 1991; Zarate et al., 1995; Calabrese et al., 1996; *Corresponding author. Biological Psychiatry Program, P.O. Box 670559, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267-0559, USA. Tel.: 1 513-58-1132; Fax: 1 513-558-2882.

Suppes et al., 1996; Frye et al., 1998), including adolescents (Kowatch et al., 1995; Fuchs, 1994). The new atypical antipsychotic olanzapine has a pharmacological and receptor affinity profile similar to that of clozapine (binding potently to dopamine D 1 , D 2 , D 4 , histamine H 1 , muscarinic M 1 , serotonin 5-HT 2C , 5-HT 6 , 5-HT 7 and a 1 -noradrenergic receptors) (Keck et al., 1997; Frye et al., 1998), but is devoid of clozapine’s more serious adverse effects (e.g., agranulocytosis). Olanzapine blocks 5-HT 2A receptors more potently than D 2 receptors by a ratio of 3:1 (Keck et al., 1997). Preliminary data suggest that

0165-0327 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 98 )00119-0

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olanzapine, like clozapine, may have mood-stabilizing properties in adults with schizoaffective disorder, bipolar type (Tohen et al., 1997; Tollefson et al., 1997) and treatment-resistant bipolar disorder (McElroy et al., 1998). However, experience with olanzapine in adolescents with bipolar disorder is limited. To our knowledge, there have been no reports on the use of olanzapine in the treatment of children or adolescents with bipolar disorder. To investigate the efficacy and tolerability of olanzapine in adolescent patients with bipolar disorder, we evaluated the response of all adolescents (n 5 6) hospitalized with acute mania who received treatment with olanzapine for persistent affective symptoms at the Children’s Hospital Medical Center Adolescent Psychiatry Unit. We also evaluated the response of adolescents with acute mania treated with olanzapine by the authors at affiliated outpatient clinics (n 5 1).

2. Methods All patients admitted to the Children’s Hospital Medical Center’s Adolescent Psychiatry Unit, or followed by the authors at affiliated outpatient clinics, with DSM-IV (American Psychiatric Association, 1994) bipolar disorder, manic or mixed episode, who received treatment with olanzapine were included in this analysis. These records were reviewed by the child psychiatrist responsible for each patient’s care. Four patients were evaluated retrospectively and three patients prospectively. Overall response of the episode to olanzapine was rated by the treating physicians using the Clinical Global Improvement Scale (CGI) (U.S. National Institute of Mental Health, 1985) as marked, moderate, minimal, none or worse.

3. Results Six consecutive hospitalized patients and one outpatient with bipolar I disorder, manic episode, treated with olanzapine were identified over a period of twelve months. Demographic and clinical characteristics of these patients are shown in Table 1. The patients’ mean age6SD (range) was 1561 (12–17)

years. All seven patients (three males and four females) met DSM-IV criteria for a manic episode. Two patients met criteria for rapid cycling, and four also displayed psychotic features. Two patients displayed significant depressive symptoms but did not meet full criteria for a mixed episode. All seven patients displayed persistent affective symptoms that impaired their functioning. The six hospitalized adolescents had olanzapine added to their ongoing stable pharmacologic regimen 665 days (mean6SD) after admission, due to inadequate response. Patients were discharged 661 days (mean6SD) after olanzapine was added. As shown in Table 1, olanzapine was added to pre-existing psychotropic regimens in six patients. Olanzapine was chosen as an adjunctive therapy due to its minimal risk for extrapyramidal symptoms (EPS), lack of prolactin elevation, probable lower risk of tardive dyskinesia compared to standard antipsychotic drugs (Keck et al., 1997) and possible mood stabilizing properties in adults (Tohen et al., 1997; Tollefson et al., 1997; McElroy et al., 1998). One patient (no. 7) was treated with olanzapine monotherapy due to family refusal of mood stabilizer treatment. Four patients (nos. 2, 4, 5 and 6) had not responded to, or could not tolerate prior antipsychotic trials. One of them (no. 6) became manic on lithium plus carbamazepine after perphenazine was discontinued due to severe cognitive impairment. Two patients (nos. 1 and 3) were treated with stimulants for attention deficit hyperactivity disorder (ADHD). One of them (no. 1) was also taking sertraline for depressive symptoms; both patients had their stimulants discontinued (the treatment of patient no. 1 is described in detail below). Five (71%) patients showed a marked or moderate response, and two (26%) patients showed a minimal response. All six hospitalized patients were discharged on olanzapine. The single outpatient maintained a marked response to olanzapine at six months follow-up. The most common side-effect was sedation, occurring in five (71%) patients. Sedation resolved within two days in one patient despite continued treatment at the same dose and was mild in another patient. The patients received a mean6SD (range) olanzapine dose of 0.14660.086 (0.055– 0.303) mg / kg / day or 1166 (5–20) mg / day. The response of other DSM-IV comorbid conditions to olanzapine was not formally evaluated. Two patients

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281

Table 1 Clinical characteristics of seven adolescents with acute mania treated with olanzapine Pat ] ient

Age / sex

Primary

Comorbid

Admission

Discharge

Olanzapine dose

/ race

diagnoses

diagnoses

medications

medications

mg / day

mg / kg / day

Response

Side-effects

1

12 / M / W a

BP-I, M PF c

ADHD

Methylphenidate Sertraline

Divalproex Olanzapine

15

0.197

Marked

Sedation (transient)

2

15 / M / W

BP-I, M PF, RC

Tourette’s OCD ADHD

Lithium Sertraline Risperidone Propranolol Alprazolam

Lithium Olanzapine Sertraline Propranolol Alprazolam

5

0.074

Mild

Sedation

3

15 / F / B

BP-I, M PF

ADHD enuresis

Methylphenidate Clonidine

Olanzapine Clonidine

10

0.096

Marked

None

4

17 / F / W b

BP-I, M PF

LSD, cocaine and marijuana abuse

Perphenazine Benztropine

Divalproex Olanzapine Clonazepam

20

0.303

Moderate

Sedation (mild)

5

14 / F / W a

BP-I, M RC

Alcohol and marijuana abuse Conduct disorder

Divalproex Risperidone

Divalproex Olanzapine

5

0.055

Mild

Sedation

6

16 / M / W c

BP-I, M

ADHD

Carbamazepine Lithium

Lithium Olanzapine Methylphenidate

15

0.215

Marked

None

7

14 / F / B d

BP-I, M PF

None

None

Olanzapine

5

0.085

Marked

Sedation

Key: BP-I 5 bipolar I disorder; M 5 manic; PF 5 psychotic features; ADHD 5 attention deficit hyperactivity disorder; RC 5 rapid cycling; OCD 5 obsessive compulsive disorder. a Patients 1 and 5 had significant depressive symptoms but did not fill criteria for a mixed episode. b Failed inpatient trial of divalproex plus haloperidol. c Patient no. 6 was treated as an outpatient. d Patient no. 7 had a prior episode of major depressive disorder and presented with her first manic episode with psychotic symptoms. Her mother refused a mood stabilizer trial.

who displayed marked or moderate responses are presented as examples.

4. Case reports

4.1. Patient A Patient A (Table 1, no. 1), a 12 year-old male with a two-year history of ADHD was hospitalized with a one-year history of gradually worsening euphoric and irritable mood, decreased sleep, rapid speech, loose associations, mild grandiosity, psychomotor agitation, auditory hallucinations and delusions. Over

the prior two months he also exhibited depressed mood and suicidal ideation. He had significant academic and behavioral problems at school, and behavioral problems at home. At the time of admission, he was receiving methylphenidate (40 mg / day) and sertraline (50 mg / day). His mother had schizoaffective disorder, depressed type. After admission, patient A’s methylphenidate and sertraline were discontinued and he was given divalproex at a dose of 1500 mg / day (163 mg / l plasma concentration). The divalproex dose was reduced to 1000 mg / day (115 mg / l). However, after five days at therapeutic levels and prn lorazepam, up to 4 mg / day, he remained extremely irritable, with rapid

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speech, psychomotor agitation, decreased sleep and inappropriate laughing. Due to the lack of response, olanzapine (10 mg / day) was added to divalproex, with rapid improvement of his symptoms within 48 h. His mood became less irritable, his speech slowed, his auditory hallucinations and delusions improved and eventually disappeared, and his psychomotor agitation gradually resolved. Over the next eight days, his symptoms continued to improve and his initial sedation resolved. He reported that the addition of olanzapine helped him to clear his mind of racing thoughts, ‘to think better’, and his mood gradually improved to mildly euphoric. Due to residual euphoric mood, mild psychomotor agitation and religious preoccupation, his dose was increased to 15 mg / day, with good tolerability and complete resolution of symptoms.

4.2. Patient B Patient B (Table 1, no. 4), a 17 year-old female, three months post-miscarriage, was hospitalized because of extremely irritable, euphoric and labile mood, uncontrollable aggressive behavior, and grandiose delusions. She also displayed psychomotor agitation, decreased need for sleep, increased energy, rapid speech, flight of ideas and disorganized thinking. The onset of these symptoms was six months prior to admission, during the first trimester of her pregnancy. She was hospitalized then but treated only with prn haloperidol. She had a miscarriage as a result of physical violence in the fifth month of her pregnancy. She continued displaying gradually worsening psychotic and affective symptoms, which did not respond to consecutive inpatient trials of chlorpromazine and perphenazine. This was her fourth psychiatric hospitalization in six months, and the third one in the past month. She had concurrent LSD, cocaine and marijuana abuse. She was treated with a combination of divalproex, 1750 mg / day (77–113 mg / l, plasma concentration) and haloperidol, up to 13 mg / day, showing signs of EPS. Additional clonazepam (3 mg / day) and prn lorazepam, up to 4 mg / day, were not helpful. After 14 days in the hospital and receiving this regimen, she was still irritable, euphoric, delusional, with psychomotor agitation, poor sleep and disorganized thinking. Olanzapine was added and titrated up to 20

mg / day, and haloperidol was gradually tapered and discontinued. She displayed a moderate response and seven days later she was discharged to a crisis stabilization unit with mild irritability, mild grandiosity, occasional delusional ideation, but was much improved, with better sleep and much less psychomotor agitation.

5. Discussion Of seven adolescents aged between 12 to 17 years with bipolar I disorder, manic episode, who received open-label treatment with olanzapine, five (71%) displayed moderate or marked improvement. These findings suggest that olanzapine, like clozapine, may have antimanic properties in some adolescents with bipolar disorder. These preliminary observations are limited by several methodological shortcomings. Most importantly, data were obtained without blindedness or a randomized control group. Thus, the possibility that the observed favorable response to olanzapine was in fact due to a placebo effect, rater or patient bias, or spontaneous remission cannot be excluded. Second, in six of seven patients, olanzapine was added to ongoing psychotropic regimens. It is therefore uncertain whether the observed mood stabilizing response after olanzapine addition was due to olanzapine alone, a late response to concurrently administered psychotropics, or a synergistic response to olanzapine and concurrently administered psychotropics. Also, our patient source is not homogeneous, as it includes hospitalized and nonhospitalized patients. These findings must therefore be regarded as highly provisional, pending substantiation in controlled trials. However, even when these limitations are considered, the response observed in five (71%) of seven patients with bipolar disorder was promising. Six of these patients had failed to respond to at least one mood stabilizer, and two were on a concurrent antipsychotic. If proven to have antimanic or moodstabilizing properties in controlled trials, olanzapines’s favorable pharmacokinetic and side effect profile relative to classic antipsychotics, and lack of need for regular blood monitoring relative to the atypical antipsychotic clozapine, would make it an

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extremely useful addition to the therapeutic armamentarium for adolescent bipolar disorder.

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