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
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
r
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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,
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(2002) Olanzapine for the treatment of chronic refractory
schizophrenia: A 12-month follow-up naturalistic study.
Progress in Neuropsycholopharmacology and Biological
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