Very-high-dose olanzapine for treatment-resistant schizophrenia

doi:10.4236/ojpsych.2012.24037

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Open Journal of Psychiatry, 2012, 2, 269-271 OJPsych

http://dx.doi.org/10.4236/ojpsych.2012.24037 Published Online October 2012 (http://www.SciRP.org/journal/ojpsych/)

Very-high-dose olanzapine for treatment-resistant

schizophrenia

Jean-Marie Batail1,2*, Sophie Bleher1, Clément Lozachmeur1,2, Gabriel Robert1,2, Bruno Millet1,2,

Dominique Drapier1,2

1Adult Psychiatry Department, Guillaume Régnier Hospital, Rennes, France

2Behavior and Basal Ganglia Unit, Rennes University Hospital, University of Rennes I, Rennes, France

Email: *[email protected]

Received 25 June 2012; revised 27 July 2012; accepted 6 August 2012

ABSTRACT

Treatment-resistant schizophrenia has an extremely

negative impact on mental health and social life. If

clozapine, the gold standard treatment, fails, there

are very few options left. The literature suggests that

high-dose olanzapine (20 - 60 mg/day) is a possible

alternative. We report two cases in which very high

doses of olanzapine were administered, with signifi-

cant clinical improvements above 60 mg/day. Clini-

cal, metabolic and cardiac tolerance was good. This

report highlights the usefulness of very-high-dose

olanzapine in treatment-resistant schizophrenia. The

main hypotheses concerning the psychopharmacolo-

gical mechanisms of very-high-dose olanzapine are d is-

cussed.

Keywords: Schizophrenia; Treatment Resistance;

High-Dose Olanzapine; Treatment Tolerance

1. INTRODUCTION

According to Kane’s criteria (1988), treatment-resistant

schizophrenia is defined as clinical resistance (PANSS

decrease of less than 20%) after the administration of

three antipsychotic drugs from at least two different che-

mical classes at optimum doses and over sufficiently

long periods.

Clozapine is currently the gold standard treatment for

refractory schizophrenia [1,2]. Nevertheless, its prescrip-

tion sometimes has to be stopped due to either lack of

efficacy or intolerance (agranulocytosis). If clozapine

fails, there are few treatment options left, although treat-

ment-resistant delusions appear to be alleviated by elec-

troconvulsive therapy, and refractory auditory hallucina-

tions by transcranial magnetic stimulation of the tem-

poroparietal junction [2]. Over the past few years, seve-

ral studies and case reports have identified high-dose

olanzapine (>20 mg/day) as a pharmacological alterna-

tive to clozapine. We report two cases illustrating the

usefulness of very high doses (≥60 mg/day) of olanzap-

ine in the management of treatment-resistant schizophre-

nia.

2. CASE STUDY 1

Mr. A, currently aged 29 years, was diagnosed with schi-

zophrenic disorder in 2003. There was no family history

of schizophrenia. Most of his hospitalizations were due

to severe positive symptoms. A set of crystallized delu-

sions with religious or esoteric themes interfered with the

patient’s ability to lead a normal everyday life. Auditory

and cenesthesic hallucinations were frequent. Between

2004 and 2006, there were many hospitalizations owing

to behavioral problems associated with delusions. Many

antipsychotics were tried at adequate doses over suffi-

ciently long periods, including pipotiazine, risperidone

(depot form), olanzapine (20 mg), haloperidol (depot

form), aripiprazole, amisulpride and zuclopenthixol (de-

pot form). All these medications had to be stopped, either

because of their lack of efficacy in treating refractory

hallucinations or because of intolerance (extrapyramidal

syndrome). Electroconvulsive therapy was prescribed

with good results, but the effect could not be maintained

over time. In 2008, clozapine was prescribed. Reduced

delusions, better conceptual organization and improved

social relations were observed. Unfortunately, 11 months

later, the patient had a bout of fever with agranulocytosis,

which meant that the clozapine had to be stopped. He

was hospitalized due to a fresh upsurge of delusions and

hallucinations.

In this context, it was decided to gradually introduce

high-dose olanzapine. Clinical (monthly weight and

waist measurements), biological (monthly blood lipid

and glucose tests, weekly blood counts) and electrocar-

diogram (weekly) monitoring was performed. No clinical

effects were observed up to 60 mg/day (administered

three times per day). From 80 mg/day, however, positive

*Corresponding autho

OPEN ACCESS

J.-M. Batail et al. / Open Journal of Psychiatry 2 (2012) 269-271

270

symptoms such as delusions, hallucinations and beha-

vioral problems decreased. Although the dose was in-

creased to 100 mg/day, we failed to observe any signifi-

cant improvements in negative symptoms, such as im-

paired social relations or emotional withdrawal. Clinical

tolerance was good, and no side effects (e.g., extrapyra-

midal syndrome, weight gain) were reported. Biologi-

cally, a slight neutropenia (1300 - 1700/mm3) was re-

corded over a 6-week period, but it was well tolerated.

After three months of treatment at 100 mg/day, the blood

lipid level was slightly increased for cholesterol (6.3

mmol/l), but was still normal for triglycerides (0.52

mmol/l). No normalization was observed during the pa-

tient’s hopitalization. Blood sugar level have been

checked and was normal, no glycosylated hemoglobin

have been assessed. Olanzapine blood level was 197.2

ng/ml. Mr. A’s improved clinical condition has remained

stable since 2009. He completed a psychosocial rehab

program and has not been hospitalized for two years.

3. CASE STUDY 2

Mr. B, currently aged 21 years, experienced early-onset

schizophrenia. His first schizophrenic symptoms appeared

at around the age of 14 years. He developed persecutive,

intuitive and interpretative delusions. The functional im-

pact on his work and social relations was massive and

forced him to quit secondary school. No auditory hallu-

cinations were ever described. The main symptoms were

psychic, affective and behavioral disorganization, proba-

bly masking the previously reported delusions. He was

treated with risperidone, first in its oral form, then in its

depot one (50 mg/2 weeks). He received this treatment

for two years, but then returned to hospital due to an

acute episode. During a 7-month hospitalization, zu-

clopenthixol, aripiprazole, and haloperidol were success-

sively tried at adequate doses and over sufficiently long

periods without any significant clinical improvement. In

this case of resistant early-onset schizophrenia, we de-

cided to try an alternative to clozapine for this young

man. Treatment with high-dose olanzapine was thus be-

gun. No effect on the positive and disorganization sym-

ptoms was observed until the dose reached 70 mg/day.

After three weeks at 80 mg/day, an improvement in the

persecutory ideas and a reduction in hostility were ob-

served. After six weeks, remission was diagnosed, de-

spite two residual symptoms (i.e., apragmatism and apa-

thy). Following his 7-month hospitalization, Mr. B joined

a psychosocial rehab program. After six months of

treatment at 80 mg/day, the patient had gained 10 kg, but

his weight remained stable thereafter. Biological toler-

ance remained good (cholesterol = 4.82 mmol/l, triglyc-

erides = 1.59 mmol/l, glycosylated hemoglobin = 5.7% -

5.9%). Olanzapine blood level was 106 ng/ml.

4. DISCUSSION

As far as we know, these are the first two reports of olan-

zapine administration at doses higher than 60 mg/day.

Olanzapine is an atypical antipsychotic, with a pharma-

cological structure close to that of clozapine. Olanzap-

ine shares several aspects of clozapine’s in vivo phar-

macological profile, including a high affinity for 5-HT2,

muscarinic and histamine receptors [3]. Its 5-HT2A an-

tagonism is associated with fewer extrapyramidal sym-

ptoms and less tardive dyskinesia than other antipsy-

chotics, thus allowing high doses to be administered

[4].

To our knowledge, there have been no controlled stud-

ies of such high doses of olanzapine in treatment-resi-

stant schizophrenia, and only a handful of case reports

have been published on doses of olanzapine between 20

and 60 mg. Sheitman et al. reported a lack of efficacy for

positive symptoms, but with doses below 60 mg/day [5].

Other reports have indicated an improvement in social

functioning and cognition, and decreased auditory hallu-

cinations at 40 and 50 mg/day [6,7]. All reports have

emphasized its good tolerance. There are conflicting data

concerning the relative efficacy of high-dose olanzapine

compared with clozapine in treatment-resistant schizo-

phrenia. Some randomized, double-blind studies have

demonstrated the superiority of clozapine in refractory,

early-onset schizophrenia [8], whereas others have found

no difference at all between the two [1,9]. Prospective

studies have shown that olanzapine at doses of 15 - 60

mg/day is a good alternative to clozapine for treatment-

resistant patients [10-13]. The clinching argument for

switching from clozapine to olanzapine is the latter’s

tolerability.

The present case report also highlights the question of

the link between clinical response and olanzapine blood

level. Why did these two treatment-resistant patients

display a clinical improvement at very high doses despite

resistance at low doses of olanzapine? There are diver-

gent data about the relationship between clinical re-

sponse and olanzapine plasma concentration. Perry et al.

suggested that a minimum concentration of 23 ng/ml was

needed to be effective, but did not draw any link with

improvements in BPRS scores [14]. Mauri et al. de-

scribed a curvilinear relationship with clinical efficacy

between 20 and 50 ng/ml of olanzapine serum concentra-

tion [15]. Lane et al., however, failed to establish any

correlation between olanzapine blood level and improve-

ments in schizophrenic symptoms, although they did find

one for depressive symptoms, with a plasma concentra-

tion of 36 ng/ml being a good predictor of response [16].

We can hypothesize that olanzapine’s serotonin antago-

nism plays a key role in the antidepressant effect.

Finally, at doses of 5 - 40 mg/d, striatal dopamine D2

J.-M. Batail et al. / Open Journal of Psychiatry 2 (2012) 269-271

271

[8] Kumra, S., Kranzler, H., Gerbino-Rosen, G., Kester, H.M.,

De Thomas, C., Kafantaris, V., Correll, C.U. and Kane,

J.M. (2008) Clozapine and “high dose” olanzapine in re-

fractory early-onset schizophrenia: A 12-week random-

ized and double-blind comparison. Biological Psychiatry,

63, 524-529. doi:10.1016/j.biopsych.2007.04.043

receptor occupancy ranges from 50% to 90% [3,17,18].

At these doses, the relationship between dopamine D2

occupancy and both dose and plasma level seems to be

represented by a hyperbolic saturation curve [3]. The

psychopharmacological mechanism of the therapeutic

response at very high doses remains unclear. Are other

cerebral targets saturated at such high doses? Are recep-

tors other than dopamine D2/D3 involved?

[9] Meltzer, H., Bobo, W., Roy, A., Jayathilake, K., Chen, Y.,

Ertugrul, A., Anil Yagcioglu, A.E. and Small, J.G. (2008)

A randomized, double-blind comparison of clozapine and

high dose olanzapine in treatment-resistant patients with

schizophrenia. The Journal of Clinical Psychiatry, 69, 274-

285. doi:10.4088/JCP.v69n0214

In conclusion, very-high-dose olanzapine seems to be

a good alternative in treatment-resistant schizophrenia.

Its use at such high doses needs to be closely monitored,

due to poor data on its clinical and biological tolerance.

Most studies suggest that the dose range is correlated

with improvements in organization (lower doses) and

positive symptoms (higher doses). Nevertheless, more

data are needed to confirm its relative efficacy at higher

doses for different symptom dimensions, compared with

clozapine, in treatment-resistant schizophrenia. This could

be achieved by conducting randomized double-blind trials

with larger samples of participants. Furthermore, clinical

data need to be correlated with imaging data in order to

investigate a potential correlation between clinical im-

provement and the D2/D3 occupancy profile at such very

high doses.

[10] Baldacchino, A.M., Stubbs, J.H. and Nevison-Andrews,

D. (1998) The use of olanzapine in non-compliant or

treatment-resistant clozapine populations in hospital. Phar-

maceutical Journal, 260, 207-209.

[11] Dursun, S., Gardner, D., Bird, D. and Flinn, J. (1999) Olan-

zapine for patients with treatment-resistant schizophrenia:

A naturalistic case-series outcome study. Canadian Jour-

nal of Psychiatry, 44, 701-704.

[12] Martin, J., Gomez, J.C., Garcia-Bernardo, E., Cuesta, M.,

Alvarez, E. and Gurpegui, M. (Spanish Group for the

Study of Olanzapine in Treatment-Refractory Schizophre-

nia Spain) (1997) Olanzapine in treatment-refractory

schizophrenia: Results of an open label study. Journal of

Clinical Psychiatry, 58, 479-483.

doi:10.4088/JCP.v58n1103

[13] Rodriguez-Perez, V., Lopez, A., Blanco, C., Pena, C.,

Lopez, A., Gomez, Y., Ferreiro, M.J., Rego, C., Lopez,

A., Cudeiro, F., Alvarez, V., Prieto, R. and Ciudad, A.

(2002) Olanzapine for the treatment of chronic refractory

schizophrenia: A 12-month follow-up naturalistic study.

Progress in Neuropsycholopharmacology and Biological

Psychiatry, 26, 1055-1062.

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