Bibliography of references to dose-related Zyprexa side effects

Amann BL, et al.
      EEG abnormalities associated with antipsychotics:
      a comparison of quetiapine, olanzapine, haloperidol and healthy subjects.
      Human Psychopharmacology, 2003, vol.18, no. 8, pp. 641-6.
Abnormal EEGs were observed in 5% of the quetiapine group, 35% of the olanzapine group, 23% of
the haloperidol group, and 7% of controls. The only group to demonstrate epileptiform activity was
olanzapine patients (11%). Furthermore, EEG abnormalities increased significantly with dose in the
olanzapine group, compared with patients treated with haloperidol, quetiapine, or controls.

Ballesteros S, et al.
      A severe case of olanzapine overdose with analytical data.
      Clinical Toxicology, 2007, vol. 45, no. 4, pp. 412-415.
Because of the capacity-limited isozyme cytochrome P540, large overdoses result in nonlinear
pharmacokinetic behavior, with disproportionate increases in the serum concentration relative
to dose and potentially severe adverse effects.

Bever KA, Perry PJ.
      Olanzapine: a serotonin-dopamine-receptor antagonist for antipsychotic therapy.
      American Journal of Health-System Pharmacy, 1998, vol. 55, no. 10, pp. 1003-16.
Constipation and dry mouth occur as dose-dependent ADRs.

Briggs G, Freeman R, Yaffe S.
      Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk,
      Lippincott Williams & Wilkins, 8th Edition, 2008, p. 1355.
Olanzapine is not an animal teratogen in two species, but dose-related embryo and fetal toxicity was observed.

Cadario B.
      Olanzapine (Zyprexa): suspected serious reactions.
      Canadian Adverse Reaction Newsletter, July 2000, vol. 10, no. 3, pp. 2-3.
Two other patients who had fatal cardiac reactions (myocardial infarction and arrhythmia)
had received an olanzapine dose 25-30 mg/d at the time of death. This amount exceeds current
dosing recommendations, which range from 5 to 20 mg/d. The safety of dosages above 20 mg/d
has not been evaluated.

Chue P, Singer P.
      A review of olanzapine-associated toxicity and fatality in overdose.
      Journal of Psychiatry & Neuroscience, 2003, vol.28, no. 4, pp. 253-61.
The rate of metabolism of olanzapine can vary up to 20-fold among individuals, and because of
extensive first-pass metabolism (up to 40%), large overdoses result in nonlinear pharmacokinetics
leading to significant increases in blood concentrations.

Deshauer D, Erwin L, Karagianis J.
      Case Report: Edema related to olanzapine therapy.
      Canadian Family Physician, May 10, 2006, vol. 52, no. 5, pp. 620-621.
In this case, a pre-existing tendency to develop edema was exacerbated by olanzapine.
This exacerbation was dose related.

Duggal HS, Gates C, Pathak PC.
      Olanzapine-Induced Neutropenia: Mechanism and Treatment.
      Journal of Clinical Psychopharmacology, April 2004, vol. 24, no. 2, pp. 234-235.
This patient most likely had a dose-related adverse reaction to increase in dosage of olanzapine.
The rapid return of this patient's blood count to normal levels after discontinuation of olanzapine
further supports a causal relationship between neutropenia and increase in olanzapine dose.

Eli Lilly and Company (USA).
      Zyprexa® Prescribing Information.
      Package insert, revised January 27, 2010.
Safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials.
Dose-dependent adverse reactions included: akathisia, akinesia, asthenia, cogwheel rigidity, dizziness,
dry mouth, extrapyramidal syndrome, fatigue, hyperkinesia, hypertonia, hypokinesia, prolactin elevation,
masked facies, nausea, prolactin elevation, somnolence, tremor and weight gain.

Kodesh A, Finkel B, Lerner AG, Kretzmer G, Sigal M.
      Dose-dependent olanzapine-associated leukopenia: three case reports.
      International Clinical Psychopharmacology, 2001, vol.16, no. 2, pp. 117-9.
In each case, the leukopenia was dose-dependent. Reduction in the dose of olanzapine was
followed by normalization of the white blood count which allowed continuation of the medication.
These cases suggest the possibility that, in some patients, leukopenia or agranulocytosis during
olanzapine treatment might be dose-related.

Mamo C, Kapur S.
      Antipsychotic Drugs.
      In Encyclopedia of Molecular Pharmacology,
      Offermans S and Rosenthal W, eds.; Springer; 2nd edition, 2008, p. 181.
At least in the case of risperidone and olanzapine (and possibly also ziprasidone),
this 'atypical' nature appears to be lost in a dose-dependant manner resulting in the
appearance of EPS and sustained hyperprolactinemia at higher doses.

Morgan P.
      Audit of Olanzapine Plasma Concentration Testing.
      12th Multi-Disciplinary POWYS Research & Innovation Conference,
      Builth Wells, Wales, Dec. 11, 2007.
Dose-related side effects: somnolence, dizziness, peripheral oedema, postural hypotension, akathisia.

Naber D, Kasper S.
      The importance of treatment acceptability to patients.
      International Journal of Psychiatry in Clinical Practice, Dec. 2000, vol. 4, no. 3, pp. s25-s34.
The incidence of EPS observed with risperidone and olanzapine is dose-related.

Nemeroff, C.B.
      Dosing the antipsychotic medication olanzapine.
      Journal of Clinical Psychiatry, 1997, vol. 58, suppl. 10, pp. 45-49.
Olanzapine patients had a dose-related increase in weight, achieving after 1 year a mean weight gain of
approximately 12 kg with a high dose (12.5-17.5 mg/day), compared with a mean weight gain of 3 kg
with a low dose (1 mg/day).

Robertson M, McMullin M.
      Olanzapine Concentrations in Clinical Serum and Postmortem Blood Specimens --
      When Does Therapeutic Become Toxic?
      Journal of Forensic Science, 2000, vol. 42, pp. 418-421.
Olanzapine is extensively metabolized by the liver enzymes CYP1A2 and 2D6; hence any reduction
of enzyme-mediated metabolism, a result of pathophysiological processes or drug interaction,
may inadvertently raise olanzapine concentrations in the blood, possibly resulting in toxicity.

Sadock V, Kaplan H, Sadock B.
      Kaplan and Sadock's Concise Textbook of Clinical Psychiatry,
      Lippincott Williams & Wilkins, 3rd Edition, 2008, p. 544.
Higher doses are associated with increased extrapyramidal and other adverse effects, and doses
greater than 20 mg a day were not studied in the pivotal trials that led to the approval of olanzapine.

Samuels S, Marin D.
      Late-Life Psychosis.
      In Geriatric medicine: an evidence-based approach,
      Cassel C, Leipzig R, Cohen H, editors, Springer, 4th edition, 2003, pp. 1185-95.
Approximately 10% of patients treated with olanzapine have increases in their ALT and GGT
that are dose related and reverse after drug discontinuation.

Schatz RA.
      Olanzapine for Psychotic and Behavioral Disturbances in Alzheimer Disease.
      Annals of Pharmacotherapy, 2003, vol. 37, no. 9, pp. 1321-1324.
Adverse effects that occurred with significantly greater frequency than placebo (p < 0.05) were
somnolence and abnormal gait, which were dose related.

Semaan WE, Doyon J, Jolicoeur F, Duchesneau J.
      Dose-dependent urinary retention following olanzapine administration.
      Annals of Pharmacotherapy, 2006, vol. 40, no. 9, p. 1693.
The temporal sequence of events described is consistent with a probable and dose-dependent
association between use of olanzapine and urinary retention.

Sharpley A, et al.
      Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT2C receptors in vivo.
      Biological Psychiatry, 2000, vol. 47, no. 5, pp. 468-470.
Olanzapine (5 mg and 10 mg) produced substanial (59.1% and 83.3%) and highly significant dose-related
increases in SWS in humans probably via blockade of brain 5-HT2C receptors.

Waring WS, Wrate J, Bateman DN.
      Olanzapine overdose is associated with acute muscle toxicity.
      Human & experimental toxicology, 2006, vol. 25, no.12, pp. 735-40.
The risk of acute muscle toxicity progressively increased with higher stated quantities of
ingested olanzapine, suggesting a dose-dependent effect.

Wichniak A, et al.
      Electroencephalogram slowing, sleepiness and treatment response in patients with schizophrenia during olanzapine treatment.
      Journal of Psychopharmacology, 2006, vol. 20, no. 1, pp. 80-85.
Analysing EEG recordings of patients receiving olanzapine monotherapy we found a dose-related increase
in EEG abnormality rates. Patients at the olanzapine dose >10mg/day (n=28) tended to have more EEG
abnormalities than those (n=26) receiving the doses<=10mg/day (82.1% vs. 57.7%, respectively, p<0.074).
The most pronounced difference was found in the rates of paroxysmal slow wave discharges (25.0% vs.
3.8%, p<0.052). The patients treated with high olanzapine doses showed also an increased incidence of
sharp waves (32.1% vs. 11.5%), many theta waves (64.3% vs. 42.3%), and increased sensitivity to activation
with hyperventilation (positive in 35.7% of patients in the high-dose group and only in 15.4% of those in
the low-dose group).