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Olanzapine: Safety profile and dosing strategies
Journal of the American Psychiatric Nurses Association
Olanzapine: Safety Profile and Dosing Strategies Karen C. Tugrul, RN, BSN, and Jerry A. Bennett, Pharm D
1998, six new antipsychotic medications may be available for the treatment of psychosis, each with different side effect profiles. Nurses have an obligation to be educated about new treatments, including their indications and safety profiles, to better provide optimal patient care. A novel antipsychotic, olanzapine (Zyprexa), developed by Eli Lilly and Co., has recently become available for prescription use for the treatment of psychosis. The efficacy and safety data compiled thus far are substantial, warranting a careful examination by the psychiatric nurse. Safety data, dosing strategies, and available formulations will be specifically described in this manuscript. B y
PHARMACOKINETICS Olanzapine is well absorbed and achieves peak concentrations in approximately 5 hours. Nearly 40% of the drug is metabolized before entering the systemic circulation. Olanzapine is metabolized to a 10-N glu-
Karen C. Tugrul is Clinical Research Nurse Coordinator in the Department of Psychiatry of the Biological Psychiatry Program at the University of Cincinnati College of Medicine in Cincinnati, Ohio. Jerry A. Bennett is an Associate Professor of Clinical Pharmacy and Psychiatry in the Department of Psychiatry of the Biological Psychiatry Program at the University of Cincinnati College of Medicine in Cincinnati, Ohio. Reprint requests: Karen C. Tugrul, RN, BSN, Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati, College of Medicine, 231 Bethesda Ave., PO Box 670559, Cincinnati, OH 45267-0559. J A m Psychiatr Nurses Assoc [1997]. 3, $14-$1 Z Copyright © 1997 by the American Psychiatric Nurses Association. 1078-3903/97
$14
$5.00 + 0 66/0/80201
Tugrul a n d Bennett
curonide compound, which is the main inactive metabolite (Ring et al., 1996). Four other minor metabolites are produced by oxidation and are also inactive. All metabolites are produced from different enzyme systems (CYP 2D6, FM03, CYPIA2), suggesting a low potential for drug interactions. Carbamazepine, an anticonvulsant with mood stabilizing properties, however, can cause an increase in the clearance of olanzapine by approximately 50% (Keck & McElroy,
The efficacy and safety data compiled thus far are substantial, warranting a careful examination by the psychiatric nurse. 1996). Olanzapine has a mean half-life of 30 hours and displays linear kinetics over the clinical dosing range. Olanzapine is extensively distributed throughout the body, with 93% of the agent being bound to plasma proteins. Only 7% of the drug is excreted unchanged in the urine. The extensive metabolism and amount excreted unchanged mean that a dose reduction is probably not required in renal insufficiency. (Ring et al., 1996; Tran, Beasley, & Tollefson, 1995).
SAFETY PROFILE One of the four pivotal studies conducted with olanzapine is Study 2 (S2), or the North American doubleblind trial (American Psychiatric Association, 1994; Beasley, Tollefson, et al., 1996). In this study three dosage ranges of olanzapine, 5 + 2.5 mg/day (Olzlow dose), 10 + 2.5 mg/day (Olz-moderate dose), and olanzapine 15 + 2.5 mg/day (Olz-high dose) were compared with haloperidol 15 + 5 rag/day (Hal) and Vol. 3, No. 1
Journal o f the American Psychiatric Nurses Association
placebo in the treatment of 335 patients diagnosed with schizophrenia according to DSM-IV criteria. One limitation of this trial was that the duration of treatment was limited to 6 weeks. Data from extended
The most common treatmentemergent adverse events were somnolence, agitation, asthenia, and nervousness. treatment trials have not yet been published. Safety results from the $2 protocol are summarized in the following text.
Central Nervous System Adverse Effects The most common treatment-emergent adverse events were somnolence, agitation, asthenia, and nervousness. Agitation and nervousness may have been due to psychopathology as opposed to a medication-related origin. Agitation and nervousness may have been due to manifestations of the illness and medicationrelated. No seizure activity occurred during the doubleblind therapy. Agitation, akathisia, paranoid reaction, schizophrenia reaction, and suicide attempt were adverse events leading to discontinuation in patients treated with placebo. These were all considered to be either a manifestation or exacerbation of preexisting psychiatric symptoms.
Extrapyramidal Symptoms The instruments used to evaluate extrapyramidal side effects included the Simpson-Angus Scale for parkinsonism (Simpson et al., 1964) and the Barnes Akathisia (Barnes & Braude, 1985) Scale for akathisia. All patient groups treated with olanzapine displayed a reduction in their scores on these scales from baseline. Akathisia occurred in the patients treated with highdose olanzapine at approximately half the rate observed in the patients treated with haloperidol. Similarly, patients treated with haloperidol had statistically significant worsening of scores on both scales compared with baseline. Scores for all treatment groups on the Involuntary Movement Scale (Anonymous, 1980) to assess tardive dyskinesia improved slightly except in those patients treated with low-dose olanzapine. Antipsy-
February 1997
chotic medication is known to mask tardive dyskinesia (Jeste & Wyatt, 1979), thus possibly accounting for the decrease in scores. Patients treated with olanzapine (moderate and high-dose groups) had greater improvement in scores on the Involuntary M o v e m e n t Scale. It is not yet clear w h e t h e r olanzapine will alleviate tardive dyskinesia similarly to clozapine. Long-term experience with olanzapine will be required to determine this agent's propensity to induce tardive dyskinesia. The availability of an antipsychotic medication with a greatly reduced likelihood of extrapyramidal symptoms has important clinical implications. Neurologic side effects (extrapyramidal side effects, akathisia) are major reasons underlying patient noncompliance with antipsychotic medications (Van Putten, 1974). Akathisia is not only extremely uncomfortable, it is also often confused with agitation and is sometimes seen as a sign of decompensation. Nurses must make careful assessments to determine the presence of akathisia, which can lead to noncompliance and contribute to deterioration of a patient's condition.
Hematologic Adverse Effects Therapy for one patient being treated with low-dose olanzapine and for one patient being treated with haloperidol was discontinued because of leukopenia. In the patient treated with olanzapine there was a marked decrease in total white blood cell count before entering the study. This patient's white blood cell count continued to decrease during double-blind treatment. The patient being treated with haloperidol showed a decrease in white blood cell count during the double-blind therapy.
Akathisia is not only extremely uncomfortable, but it is also often confused with agitation and is sometimes seen as a sign of decompensation. Thirty-two subjects with a history of clozapine-associated hematotoxicity received olanzapine; no blood dyscrasias reoccurred in these patients (Eli Lilly Co., personal communication). Because there is no evidence of hematotoxicity with olanzapine, weekly blood count monitoring is not necessary.
Tugrul and Bennett
S15
Journal o f the American Psychiatric Nurses Association
Table 1. Anticholinergic Adverse Events in Study 2 (%)
than those associated with haloperidol and not statistically different from placebo.
Anttcholinerglc event
Hepatic Adverse Effects
Constipation Dry mouth
Hal
Olz-L
OIz-M
5.8 4.3
6.2 3.1
7.8 4.7
Olz-H Placebo
14.5 13.0
0.0 4.4
Data from Beasley, et al,, 1996.
Cardiovascular Adverse Effects Clinically significant orthostatic hypotension or any clinically significant change in vital signs was not associated with olanzapine treatment. High-dose olanzapine caused a slight but asymptomatic decrease in the mean orthostatic blood pressure. No clinically significant cardiac rate or rhythm disturbance was associated with olanzapine.
Anticholinergic Adverse Effect Because of olanzapine's affinity for muscarinic (M1) receptors, a relatively high incidence of anticholinergic side effects (constipation and dry mouth) might be expected. Clinically, these events were dose-dependent and occurred relatively infrequently. The percentage of patients who had these side effects is summarized in Table 1. No patients were discontinued as a result of anticholinergic adverse events. No cases of anticholinergic delirium have been reported with olanzapine to date.
Therapy for six patients being treated with olanzapine was discontinued because of elevated hepatic transaminase (ALT) values. No clinical signs of hepatic dysfunction were seen. Hepatic transaminase levels returned to normal in all patients who discontinued olanzapine treatment. Some patients who remained on olanzapine therapy showed normalized transaminase levels despite continued treatment.
Safety Data Conclusion Olanzapine appears to be well tolerated with no acute dystonia, few other treatment-emergent acute extrapyramidal symptoms, no evidence of blood dyscrasias, and no clinical signs of hepatic disease. Results from the other three pivotal studies, S1 (Beasley, Sanger, et al., 1996), $3 (Tran, Lu, Sanger, Beasley, & Tollefson, 1996), and $4 (Tollefson et al., 1996) were consistent with these safety data. To confirm these findings additional studies will be needed.
DOSING AND FORMULATION
The recommended starting dose of olanzapine is 5 to 10 mg/day with a target dose of 10 mg/day within several days. This dosage is currently considered a therapeutic dose. Subsequent dose changes, up to 20 mg/ Gastrointestinal Adverse Effects day, may be made based on an individual patient's Weight gain (6% of patients treated with olanzapine response. Steady state concentrations occur with daily vs 1% of patients treated with placebo) was associadministration of olanzapine in approximately I week. ated with olanzapine treatNo withdrawal syndrome ment. Weight gain was was associated with abrupt more frequently seen with Weight gain was more frequently discontinuation of olanzahigher dosages, with an seen with higher dosages. pine treatment. Olanzapine average of approximately may be taken with or with2 kg. Most of the patients out food. who gained weight were below their ideal body Only limited information is available on olanzaweight to begin with. Follow-up data are required to pine overdoses. In one case in which a patient indetermine whether this rate of weight gain persists gested 300 mg, only drowsiness and slurred speech beyond 6 weeks of treatment. were seen. Accidental or intentional overdoses in 67 patients have not resulted in any adverse changes in Endocrinologic Adverse Effects electrocardiography, vitals signs, or routine laboraAcute and long-term adverse effects (e.g., amenortory analysis (Zyprexa package insert, 1996). rhea, galactorrhea, gynecomastia, impotence) have Olanzapine is available in 5 mg, 7.5 mg, and 10 mg been associated with persistent elevation of plasma unscored white tablets. Tablets should be stored at prolactin concentrations. Mild, transient, dose-related room temperature. Crushing the tablets is not recomelevations in prolactin levels were observed. Howmended by the manufacturer. Granules for oral susever, the frequency and magnitude were much lower pension will be available in the near future. $16
Tugrul a n d Bennett
Vol. 3, No. ]
Journal o f the American Psychiatric Nurses Association
Approximately one third of patients treated with standard agents respond poorly (Kane, 1989) or have distressing side effects, which may lead to medication discontinuation and relapse. Olanzapine offers patients with psychosis a novel effective treatment option with a favorable side effect profile and simple dosage regimen. References American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders. (4th ed.). Washington, DC: Author. Anonymous. (1980). Tardive dyskinesia scales in current use, in Fann, W., Smith, R. C., Davis, J. M. et al. (editors): Tardive dyskinesia research and treatment (pp. 243-267). Jamaica, NY: Spectrum Publications. Barnes, T. R., & Braude, W. M. (1985). Akathisia variants and tardive dyskinesia. Archives of General Psychiatry, 42, 874-878. Beasley, C, M., Sanger, T., Satterlee, W., Tollefson, G., Tran, E, Hamilton, S., & The Olanzapine HGAP Study Group. (1996). Olanzapine versus placebo: Results of a double-blind, fixed dose olanzapine trial. Psychopharmacology, 124, 159-167. Beasley, C. M., Tollefson, G., Tran, P., Satterlee, W., Sanger, T., & Hamilton, S. (1996). Olanzapine versus placebo and haloperidol. Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology, 14, 113-122. Jeste, D. V., & Wyatt, R.J. (1979). In search of treatment for tardive dyskinesia: Review of the literature. Schizophrenia Bulletin, 5, 253-293.
February 1997
Kane, J. M. (1989). The current status of neuroleptic therapy, Journal of ClinicaI Psychiatry, 50, 322-328. Keck, P. E. Jr., & McElroy, S. L. (1996). Olanzapine: A novel antipsychotic medication. Todays Therapeutic Trends, 14, 3-75. Ring, B. J., Catlou, J., Lindsay, T. J., Gillespie, T., Roskos, L. K., Lerimele, B. D., Swanson, S. P., Hammon, M. A., & Wrighton, S, A. (1996). Identification of the human cytochromes P-450 responsible for the in vitro formation of the antipsychotic
olanzapine. Journal of Pharmacology and Experimental Therapeutics, 276, 658-666. Simpson, G. M., Amuso, D., Blair, J. H., & Farhas, T. (1964). Phenothiazine produced extrapyramidal disturbance. Archives General Psychiatry, 10, 127-136. Tollefson, G., Beasley, C. M., Tran, P., Dellva, M. A., Krueger, J., & Tamura, R. (1996, May/June). Olanzapine versus haloperdiol: Acute results of the multi-center international trial. New Clinical Drug Evaluation Unit Program abstract. Poster session presented at the New Clinical Drug Evaluation Unit Program, Boca Raton, FL. Tran, P. V., Beasley, C. M., & Tollefson, G. D. (1995, December). Olanzapine. Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico. Tran, P., Lu, Y., Sanger, T., Beasley, C. M., & Tollefson, G. (1996, May/June). Olanzapine in the treatment of schizoaffective disorder. Poster session presented at the New Clinical Drug Evaluation Unit Program, Baca Raton, FL. Van Putten, T. (1974). Why schizophrenic patients refuse their medication. Archives of General Psychiatry, 31, 67-72. Zyprexa (olanzapine) Package Insert. (1996). Indianapolis, IN: Eli Lilly and Co.
Tugrul a n d B e n n e t t
$17
Olanzapine: Safety Profile and Dosing Strategies Karen C. Tugrul, RN, BSN, and Jerry A. Bennett, Pharm D
1998, six new antipsychotic medications may be available for the treatment of psychosis, each with different side effect profiles. Nurses have an obligation to be educated about new treatments, including their indications and safety profiles, to better provide optimal patient care. A novel antipsychotic, olanzapine (Zyprexa), developed by Eli Lilly and Co., has recently become available for prescription use for the treatment of psychosis. The efficacy and safety data compiled thus far are substantial, warranting a careful examination by the psychiatric nurse. Safety data, dosing strategies, and available formulations will be specifically described in this manuscript. B y
PHARMACOKINETICS Olanzapine is well absorbed and achieves peak concentrations in approximately 5 hours. Nearly 40% of the drug is metabolized before entering the systemic circulation. Olanzapine is metabolized to a 10-N glu-
Karen C. Tugrul is Clinical Research Nurse Coordinator in the Department of Psychiatry of the Biological Psychiatry Program at the University of Cincinnati College of Medicine in Cincinnati, Ohio. Jerry A. Bennett is an Associate Professor of Clinical Pharmacy and Psychiatry in the Department of Psychiatry of the Biological Psychiatry Program at the University of Cincinnati College of Medicine in Cincinnati, Ohio. Reprint requests: Karen C. Tugrul, RN, BSN, Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati, College of Medicine, 231 Bethesda Ave., PO Box 670559, Cincinnati, OH 45267-0559. J A m Psychiatr Nurses Assoc [1997]. 3, $14-$1 Z Copyright © 1997 by the American Psychiatric Nurses Association. 1078-3903/97
$14
$5.00 + 0 66/0/80201
Tugrul a n d Bennett
curonide compound, which is the main inactive metabolite (Ring et al., 1996). Four other minor metabolites are produced by oxidation and are also inactive. All metabolites are produced from different enzyme systems (CYP 2D6, FM03, CYPIA2), suggesting a low potential for drug interactions. Carbamazepine, an anticonvulsant with mood stabilizing properties, however, can cause an increase in the clearance of olanzapine by approximately 50% (Keck & McElroy,
The efficacy and safety data compiled thus far are substantial, warranting a careful examination by the psychiatric nurse. 1996). Olanzapine has a mean half-life of 30 hours and displays linear kinetics over the clinical dosing range. Olanzapine is extensively distributed throughout the body, with 93% of the agent being bound to plasma proteins. Only 7% of the drug is excreted unchanged in the urine. The extensive metabolism and amount excreted unchanged mean that a dose reduction is probably not required in renal insufficiency. (Ring et al., 1996; Tran, Beasley, & Tollefson, 1995).
SAFETY PROFILE One of the four pivotal studies conducted with olanzapine is Study 2 (S2), or the North American doubleblind trial (American Psychiatric Association, 1994; Beasley, Tollefson, et al., 1996). In this study three dosage ranges of olanzapine, 5 + 2.5 mg/day (Olzlow dose), 10 + 2.5 mg/day (Olz-moderate dose), and olanzapine 15 + 2.5 mg/day (Olz-high dose) were compared with haloperidol 15 + 5 rag/day (Hal) and Vol. 3, No. 1
Journal o f the American Psychiatric Nurses Association
placebo in the treatment of 335 patients diagnosed with schizophrenia according to DSM-IV criteria. One limitation of this trial was that the duration of treatment was limited to 6 weeks. Data from extended
The most common treatmentemergent adverse events were somnolence, agitation, asthenia, and nervousness. treatment trials have not yet been published. Safety results from the $2 protocol are summarized in the following text.
Central Nervous System Adverse Effects The most common treatment-emergent adverse events were somnolence, agitation, asthenia, and nervousness. Agitation and nervousness may have been due to psychopathology as opposed to a medication-related origin. Agitation and nervousness may have been due to manifestations of the illness and medicationrelated. No seizure activity occurred during the doubleblind therapy. Agitation, akathisia, paranoid reaction, schizophrenia reaction, and suicide attempt were adverse events leading to discontinuation in patients treated with placebo. These were all considered to be either a manifestation or exacerbation of preexisting psychiatric symptoms.
Extrapyramidal Symptoms The instruments used to evaluate extrapyramidal side effects included the Simpson-Angus Scale for parkinsonism (Simpson et al., 1964) and the Barnes Akathisia (Barnes & Braude, 1985) Scale for akathisia. All patient groups treated with olanzapine displayed a reduction in their scores on these scales from baseline. Akathisia occurred in the patients treated with highdose olanzapine at approximately half the rate observed in the patients treated with haloperidol. Similarly, patients treated with haloperidol had statistically significant worsening of scores on both scales compared with baseline. Scores for all treatment groups on the Involuntary Movement Scale (Anonymous, 1980) to assess tardive dyskinesia improved slightly except in those patients treated with low-dose olanzapine. Antipsy-
February 1997
chotic medication is known to mask tardive dyskinesia (Jeste & Wyatt, 1979), thus possibly accounting for the decrease in scores. Patients treated with olanzapine (moderate and high-dose groups) had greater improvement in scores on the Involuntary M o v e m e n t Scale. It is not yet clear w h e t h e r olanzapine will alleviate tardive dyskinesia similarly to clozapine. Long-term experience with olanzapine will be required to determine this agent's propensity to induce tardive dyskinesia. The availability of an antipsychotic medication with a greatly reduced likelihood of extrapyramidal symptoms has important clinical implications. Neurologic side effects (extrapyramidal side effects, akathisia) are major reasons underlying patient noncompliance with antipsychotic medications (Van Putten, 1974). Akathisia is not only extremely uncomfortable, it is also often confused with agitation and is sometimes seen as a sign of decompensation. Nurses must make careful assessments to determine the presence of akathisia, which can lead to noncompliance and contribute to deterioration of a patient's condition.
Hematologic Adverse Effects Therapy for one patient being treated with low-dose olanzapine and for one patient being treated with haloperidol was discontinued because of leukopenia. In the patient treated with olanzapine there was a marked decrease in total white blood cell count before entering the study. This patient's white blood cell count continued to decrease during double-blind treatment. The patient being treated with haloperidol showed a decrease in white blood cell count during the double-blind therapy.
Akathisia is not only extremely uncomfortable, but it is also often confused with agitation and is sometimes seen as a sign of decompensation. Thirty-two subjects with a history of clozapine-associated hematotoxicity received olanzapine; no blood dyscrasias reoccurred in these patients (Eli Lilly Co., personal communication). Because there is no evidence of hematotoxicity with olanzapine, weekly blood count monitoring is not necessary.
Tugrul and Bennett
S15
Journal o f the American Psychiatric Nurses Association
Table 1. Anticholinergic Adverse Events in Study 2 (%)
than those associated with haloperidol and not statistically different from placebo.
Anttcholinerglc event
Hepatic Adverse Effects
Constipation Dry mouth
Hal
Olz-L
OIz-M
5.8 4.3
6.2 3.1
7.8 4.7
Olz-H Placebo
14.5 13.0
0.0 4.4
Data from Beasley, et al,, 1996.
Cardiovascular Adverse Effects Clinically significant orthostatic hypotension or any clinically significant change in vital signs was not associated with olanzapine treatment. High-dose olanzapine caused a slight but asymptomatic decrease in the mean orthostatic blood pressure. No clinically significant cardiac rate or rhythm disturbance was associated with olanzapine.
Anticholinergic Adverse Effect Because of olanzapine's affinity for muscarinic (M1) receptors, a relatively high incidence of anticholinergic side effects (constipation and dry mouth) might be expected. Clinically, these events were dose-dependent and occurred relatively infrequently. The percentage of patients who had these side effects is summarized in Table 1. No patients were discontinued as a result of anticholinergic adverse events. No cases of anticholinergic delirium have been reported with olanzapine to date.
Therapy for six patients being treated with olanzapine was discontinued because of elevated hepatic transaminase (ALT) values. No clinical signs of hepatic dysfunction were seen. Hepatic transaminase levels returned to normal in all patients who discontinued olanzapine treatment. Some patients who remained on olanzapine therapy showed normalized transaminase levels despite continued treatment.
Safety Data Conclusion Olanzapine appears to be well tolerated with no acute dystonia, few other treatment-emergent acute extrapyramidal symptoms, no evidence of blood dyscrasias, and no clinical signs of hepatic disease. Results from the other three pivotal studies, S1 (Beasley, Sanger, et al., 1996), $3 (Tran, Lu, Sanger, Beasley, & Tollefson, 1996), and $4 (Tollefson et al., 1996) were consistent with these safety data. To confirm these findings additional studies will be needed.
DOSING AND FORMULATION
The recommended starting dose of olanzapine is 5 to 10 mg/day with a target dose of 10 mg/day within several days. This dosage is currently considered a therapeutic dose. Subsequent dose changes, up to 20 mg/ Gastrointestinal Adverse Effects day, may be made based on an individual patient's Weight gain (6% of patients treated with olanzapine response. Steady state concentrations occur with daily vs 1% of patients treated with placebo) was associadministration of olanzapine in approximately I week. ated with olanzapine treatNo withdrawal syndrome ment. Weight gain was was associated with abrupt more frequently seen with Weight gain was more frequently discontinuation of olanzahigher dosages, with an seen with higher dosages. pine treatment. Olanzapine average of approximately may be taken with or with2 kg. Most of the patients out food. who gained weight were below their ideal body Only limited information is available on olanzaweight to begin with. Follow-up data are required to pine overdoses. In one case in which a patient indetermine whether this rate of weight gain persists gested 300 mg, only drowsiness and slurred speech beyond 6 weeks of treatment. were seen. Accidental or intentional overdoses in 67 patients have not resulted in any adverse changes in Endocrinologic Adverse Effects electrocardiography, vitals signs, or routine laboraAcute and long-term adverse effects (e.g., amenortory analysis (Zyprexa package insert, 1996). rhea, galactorrhea, gynecomastia, impotence) have Olanzapine is available in 5 mg, 7.5 mg, and 10 mg been associated with persistent elevation of plasma unscored white tablets. Tablets should be stored at prolactin concentrations. Mild, transient, dose-related room temperature. Crushing the tablets is not recomelevations in prolactin levels were observed. Howmended by the manufacturer. Granules for oral susever, the frequency and magnitude were much lower pension will be available in the near future. $16
Tugrul a n d Bennett
Vol. 3, No. ]
Journal o f the American Psychiatric Nurses Association
Approximately one third of patients treated with standard agents respond poorly (Kane, 1989) or have distressing side effects, which may lead to medication discontinuation and relapse. Olanzapine offers patients with psychosis a novel effective treatment option with a favorable side effect profile and simple dosage regimen. References American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders. (4th ed.). Washington, DC: Author. Anonymous. (1980). Tardive dyskinesia scales in current use, in Fann, W., Smith, R. C., Davis, J. M. et al. (editors): Tardive dyskinesia research and treatment (pp. 243-267). Jamaica, NY: Spectrum Publications. Barnes, T. R., & Braude, W. M. (1985). Akathisia variants and tardive dyskinesia. Archives of General Psychiatry, 42, 874-878. Beasley, C, M., Sanger, T., Satterlee, W., Tollefson, G., Tran, E, Hamilton, S., & The Olanzapine HGAP Study Group. (1996). Olanzapine versus placebo: Results of a double-blind, fixed dose olanzapine trial. Psychopharmacology, 124, 159-167. Beasley, C. M., Tollefson, G., Tran, P., Satterlee, W., Sanger, T., & Hamilton, S. (1996). Olanzapine versus placebo and haloperidol. Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology, 14, 113-122. Jeste, D. V., & Wyatt, R.J. (1979). In search of treatment for tardive dyskinesia: Review of the literature. Schizophrenia Bulletin, 5, 253-293.
February 1997
Kane, J. M. (1989). The current status of neuroleptic therapy, Journal of ClinicaI Psychiatry, 50, 322-328. Keck, P. E. Jr., & McElroy, S. L. (1996). Olanzapine: A novel antipsychotic medication. Todays Therapeutic Trends, 14, 3-75. Ring, B. J., Catlou, J., Lindsay, T. J., Gillespie, T., Roskos, L. K., Lerimele, B. D., Swanson, S. P., Hammon, M. A., & Wrighton, S, A. (1996). Identification of the human cytochromes P-450 responsible for the in vitro formation of the antipsychotic
olanzapine. Journal of Pharmacology and Experimental Therapeutics, 276, 658-666. Simpson, G. M., Amuso, D., Blair, J. H., & Farhas, T. (1964). Phenothiazine produced extrapyramidal disturbance. Archives General Psychiatry, 10, 127-136. Tollefson, G., Beasley, C. M., Tran, P., Dellva, M. A., Krueger, J., & Tamura, R. (1996, May/June). Olanzapine versus haloperdiol: Acute results of the multi-center international trial. New Clinical Drug Evaluation Unit Program abstract. Poster session presented at the New Clinical Drug Evaluation Unit Program, Boca Raton, FL. Tran, P. V., Beasley, C. M., & Tollefson, G. D. (1995, December). Olanzapine. Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico. Tran, P., Lu, Y., Sanger, T., Beasley, C. M., & Tollefson, G. (1996, May/June). Olanzapine in the treatment of schizoaffective disorder. Poster session presented at the New Clinical Drug Evaluation Unit Program, Baca Raton, FL. Van Putten, T. (1974). Why schizophrenic patients refuse their medication. Archives of General Psychiatry, 31, 67-72. Zyprexa (olanzapine) Package Insert. (1996). Indianapolis, IN: Eli Lilly and Co.
Tugrul a n d B e n n e t t
$17