High-Dose Olanzapine Orally Disintegrating Tablets for Treatment-Resistant Psychosis

Sir: Olanzapine is a thienobenzodiazepine antipsychotic that has a broad in vitro affinity for several receptors, including serotonergic, cholinergic, dopaminergic, and adrenergic receptors.¹ Olanzapine is approved for treatment of psychoses at doses up to 20 mg/day.² New research suggests benefits of higher doses of olanzapine.³ Anecdotal case reports highlight the benefits of olanzapine at 50 mg/day in patients with refractory schizoaffective disorders.⁴ In the United Kingdom, a trial of high-dose olanzapine (range, 20–60 mg/day) showed moderate to marked clinical improvement in patients with clozapine-resistant schizophrenia.⁵

Treatment-resistant psychosis is generally treated with clozapine, which requires frequent blood tests and is associated with several side effects, including weight gain, sedation, and agranulocytosis. Regular blood draws and the myriad of side effects often contribute to poor compliance with clozapine. However, when patients fail clozapine, few other options exist. We describe a patient who, after failing clozapine treatment, responded to the orally disintegrating formulation of high-dose olanzapine.

Case report. Mr. A, a 44-year-old man, had a long history of schizoaffective disorder, bipolar type (DSM-IV criteria). Symptoms started at the age of 21 years and included auditory hallucinations, delusions of grandeur, and hyper-religiosity. He was hospitalized multiple times and, at the time of the presentation described here (1999), was being treated in an assertive community training (ACT) program.

After several medication failures, including trials of risperidone, quetiapine, ziprasidone, and olanzapine, he started clozapine treatment. All previous antipsychotic medications were administered for an adequate duration at an adequate dose; the maximum dose of olanzapine prescribed in the past was 20 mg/day. He developed disabling fatigue soon after initiation of treatment with clozapine. He often missed his appointments because of his dislike of frequent blood tests; however, after staff members from ACT began working closely with Mr. A, his compliance improved, as demonstrated by therapeutic serum clozapine levels, but his psychosis continued. He subsequently stopped clozapine and had a relapse of symptoms, including an increase in hallucinations and delusions that required hospitalization.

During hospitalization, Mr. A was administered the orally disintegrating formulation of olanzapine; this formulation improved his medication adherence, but his psychotic symptoms continued. After 2 weeks of treatment with olan-zapine, the dose was increased to 40 mg daily. He reported a decrease in auditory hallucinations and hyper-religiosity and continued to deny side effects. His family reported improvement in his social functioning and cognition. On the basis of his symptoms, olanzapine was titrated further to 60 mg daily. His condition improved, and he experienced no side effects.

Over the next 3 months, his psychosis continued to decrease. His Brief Psychiatric Rating Scale⁶ score decreased from l4 (with clozapine) to 3 (with orally disintegrating olanzapine) on objective evaluation and from 6 to 2 on subjective evaluation. Disorganized thoughts and somatic preoccupations decreased significantly. His serum olanzapine level was 108.3 ng/mL (therapeutic range: 20–60 ng/mL).

Mr. A had gained weight from 210 lb to 276 lb while taking a combination of valproic acid and clozapine prior to initiation of olanzapine. Weight gain and glucose dysregulation are known side effects associated with use of olanzapine.^7–9 Several measures, including periodic monitoring of weight, diet management, and encouragement for regular exercise, were provided as part of the ACT program to counter the above-mentioned side effects. Mr. A was compliant with the recommendations and lost 10 lb over a period of 2 years. Periodic glucose monitoring showed no glucose dysregulation. Over the next year, he required no hospitalization, his level of independent functioning improved, and he resumed his education at a community college.

The patient's improvement was probably multifactorial, but higher doses of olanzapine and the orally disintegrating formulation might have played a part. Use of olanzapine was not accompanied by the fatigue associated with clozapine and improved medication adherence. Prescribing guidelines for olanzapine suggest a maximum dose of 20 mg/day. Higher-dose olanzapine treatment has not been well researched, but in our patient, it was efficacious and produced fewer side effects than clozapine. Further, obviating the need for blood draws and use of orally disintegrating pills improved medication adherence and reduced the need for monitoring. Most importantly, the patient's symptoms improved without additional side effects. Since he had previously not responded to low-dose olanzapine, clinical improvement after starting higher doses of olanzapine suggests causality.

Although more clinical trials are needed to establish the benefits of high-dose olanzapine treatment, it may be an option for patients with treatment-resistant psychosis. High-dose olanzapine in the orally disintegrating formulation offers several advantages, including ease of administration, limited need for blood draws, and potential for improved mood stabilization.