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Safety metanalysis of olanzapine-fluoxetine combination versus olanzapine
P.1. Affective disorders and antidepressants
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Metanalysis of olanzapine-fluoxetine use in treatment-resistant depression
S. Dube, S.W. Andersen, S. Paul, S.A. Corya, L.E. Van Campen, T.M. Sanger, L. Welge, J. Nanos, G.D. Tollefson. Eli Lilly and
Company, Indianapolis, Indiana, US.A. Background and Objective: Up to 30% of patients with major
depression are resistant to conventional antidepressant treatment (Amsterdam and Hornig-Rohan, 1996). Subsequent therapy options may include augmenting an antidepressant with an antipsychotic (Robertson and Trimble, 1982). The efficacy of olanzapinefluoxetine combination (OFC) was compared with that of olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD). TRD was defined as a retrospective SSRI failure and a prospective non-SSRI failure. Methods: A metanalysis was performed on one 8-week, and one 12-week double-blind study using mixed-model, repeated measures analysis. Subjects (n=797) with nonpsychotic, unipolar treatment-resistant major depression were randomized to OFC, or olanzapine or fluoxetine monotherapy treatment groups. MADRS was the primary efficacy measure. Results: OFC patients achieved significantly greater total score improvement at Week 1 (-7.31) than olanzapine (-5.18, p=0.013) or fluoxetine (-5.26, p=0.004) patients and maintained the significant effect throughout 8 weeks of treatment (-11.60; -7.55, p<0.001; -8.73, p<0.001). OFC patients had a significantly greater endpoint response rate than olanzapine (37.3%, 21.1%) patients and significantly greater endpoint remission rates than olanzapine or fluoxetine (24.9%, 13.1%, 15.2%). Moreover, OFC showed significantly greater reductions in MADRS scores than olanzapine or fluoxetine for a subset of patients (n=253) with a history of SSRI failure in their current episode (-11.78; -7.91, p=.021; -6.40, p<.001). Conclusion: OFC showed rapid improvement in depressive symptoms by Week 1 of treatment and sustained treatment effect throughout 8 weeks of therapy. OFC demonstrated greater reductions in depressive symptoms than olanzapine or fluoxetine, as well as better response rates and remission rates. The combination represents a promising treatment for patients with TRD.
References [1] Amsterdam, J.D., Hornig-Rohan, M., 1996. Treatment algorithms in treatment-resistant depression. Psychiatr. Clin. North. Am. 19, 371386. [2] Robertson, M.M., Trimble, M.R., 1982. Major tranquillisers used as antidepressants: A review. J. Affect. Disord. 4, 173-193.
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Safety metanalysis of olanzapine-fluoxetine combination versus olanzapine
S. Corya, S.W. Andersen, S. Paul, L.E. Van Campen, T.M. Sanger, G.D. Tollefson, S. Dube. Eli Lilly and Company, Indianapolis,
Indiana, U.S.A. and Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) enhances antidepressant effects in difficult-to-treat depressions such as treatment-resistant depression (TRD) and psychotic depression. The safety data for OFC were evaluated for any new side effects that are not seen in olanzapine monotherapy. Methods: Metanalysis of safety data from five 8-week, doubleblind studies (n=762) was performed. OFC was compared with Background
olanzapine for treating TRD (three studies) and psychotic depression (two studies). Frequency and severity of adverse events including extrapyramidal symptoms (EPS) measured by the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale, changes in vital signs, electrocardiography (ECG), and laboratory analytes were analyzed. Results: Of the adverse events occurring in >10% of OFC patients, no significant differences were seen between OFC and olanzapine patients. A significant, but small proportion of OFC patients (3.0%) had low supine diastolic blood pressure compared with olanzapine (0.7%; p=0.032) patients. Categorical changes in laboratory analytes, ECG, heart rate, and EPS measures were not significantly different between OFC and olanzapine patients. Conclusion: No significant adverse effects were seen when giving OFC compared with olanzapine monotherapy, and the OFC safety profile was consistent with those expected for component monotherapies (Beasley et al., 2000; Bhana et al., 2001). These results support the acute safety and tolerability of OFC.
References [1] Beasley, C.M., Koke, S.C., Nilsson, M.E., Gonzales, J.S., 2000. Adverse event and treatment discontinuationsin clinical trials of fluoxetine in major depressivedisorder: An updated meta-analysis.Clin. Ther. 22, 1319-1329. [2] Bhana, N., Foster, R.H., Olney,R., Plosker, G.L., 2001. Olanzapine:An updated review of its use in the management of schizophrenia. Drugs 61, 111-161.
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Olanzapine-fluoxetine combination for psychotic major depression
S. Dube 1 , A. Rothschild 2, S.W. Andersen 1 , T.M. Sanger 1, D.B. Clemow 1, M. Tohen1, G.D. Tollefson1. 1Eli Lilly
and Company, Indianapolis, Indiana, U.S.A.; 2University of Massachusetts Medical School, Worcester, Massachusetts, US.A. Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) has enhanced antidepressant qualities compared with monotherapies and is a promising treatment option for difficult-to-treat depressions such as bipolar depression, treatmentresistant depression, and psychotic depression. The present study examined efficacy and safety of a combination of olanzapine and the antidepressant fluoxetine compared to olanzapine monotherapy or placebo for treatment of major depressive disorder (MDD) with psychotic features. Methods: Two parallel, 8-week double-blind trials, with an optional 48-week open-label extension, were conducted. Subjects (n=249) with MDD with psychotic symptoms were randomized to one of three treatment groups: olanzapine-fluoxetine combination (OFC; 5-20 mg/day and 20-80 mg/day, respectively; n=48), olanzapine (5-20 mg/day; n=101) or placebo (n=100). The 24item Hamilton Depression Rating Scale (HAMD-24) was used to monitor primary efficacy. Results: Pooled data showed a significantly greater HAMD24 total score decrease at 8 weeks with OFC (-18.3) than PLA (-11.4, p<.001) and trended toward a greater decrease with OLZ (-14.4, p=.072). Eight-week endpoint response (>50% decrease in HAMD-24 total score) to OFC was significantly greater than OLZ or PLA (56%, 36% [p=.041], and 30% [p=.005], respectively). Seventy-one percent of acute OFC responders maintained response in the open-label phase. More OFC partial responders (>25% total score decrease at 2 weeks) achieved full endpoint response compared with OLZ or PLA (64%, 35%, 32%). OFC
S180
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Metanalysis of olanzapine-fluoxetine use in treatment-resistant depression
S. Dube, S.W. Andersen, S. Paul, S.A. Corya, L.E. Van Campen, T.M. Sanger, L. Welge, J. Nanos, G.D. Tollefson. Eli Lilly and
Company, Indianapolis, Indiana, US.A. Background and Objective: Up to 30% of patients with major
depression are resistant to conventional antidepressant treatment (Amsterdam and Hornig-Rohan, 1996). Subsequent therapy options may include augmenting an antidepressant with an antipsychotic (Robertson and Trimble, 1982). The efficacy of olanzapinefluoxetine combination (OFC) was compared with that of olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD). TRD was defined as a retrospective SSRI failure and a prospective non-SSRI failure. Methods: A metanalysis was performed on one 8-week, and one 12-week double-blind study using mixed-model, repeated measures analysis. Subjects (n=797) with nonpsychotic, unipolar treatment-resistant major depression were randomized to OFC, or olanzapine or fluoxetine monotherapy treatment groups. MADRS was the primary efficacy measure. Results: OFC patients achieved significantly greater total score improvement at Week 1 (-7.31) than olanzapine (-5.18, p=0.013) or fluoxetine (-5.26, p=0.004) patients and maintained the significant effect throughout 8 weeks of treatment (-11.60; -7.55, p<0.001; -8.73, p<0.001). OFC patients had a significantly greater endpoint response rate than olanzapine (37.3%, 21.1%) patients and significantly greater endpoint remission rates than olanzapine or fluoxetine (24.9%, 13.1%, 15.2%). Moreover, OFC showed significantly greater reductions in MADRS scores than olanzapine or fluoxetine for a subset of patients (n=253) with a history of SSRI failure in their current episode (-11.78; -7.91, p=.021; -6.40, p<.001). Conclusion: OFC showed rapid improvement in depressive symptoms by Week 1 of treatment and sustained treatment effect throughout 8 weeks of therapy. OFC demonstrated greater reductions in depressive symptoms than olanzapine or fluoxetine, as well as better response rates and remission rates. The combination represents a promising treatment for patients with TRD.
References [1] Amsterdam, J.D., Hornig-Rohan, M., 1996. Treatment algorithms in treatment-resistant depression. Psychiatr. Clin. North. Am. 19, 371386. [2] Robertson, M.M., Trimble, M.R., 1982. Major tranquillisers used as antidepressants: A review. J. Affect. Disord. 4, 173-193.
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Safety metanalysis of olanzapine-fluoxetine combination versus olanzapine
S. Corya, S.W. Andersen, S. Paul, L.E. Van Campen, T.M. Sanger, G.D. Tollefson, S. Dube. Eli Lilly and Company, Indianapolis,
Indiana, U.S.A. and Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) enhances antidepressant effects in difficult-to-treat depressions such as treatment-resistant depression (TRD) and psychotic depression. The safety data for OFC were evaluated for any new side effects that are not seen in olanzapine monotherapy. Methods: Metanalysis of safety data from five 8-week, doubleblind studies (n=762) was performed. OFC was compared with Background
olanzapine for treating TRD (three studies) and psychotic depression (two studies). Frequency and severity of adverse events including extrapyramidal symptoms (EPS) measured by the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale, changes in vital signs, electrocardiography (ECG), and laboratory analytes were analyzed. Results: Of the adverse events occurring in >10% of OFC patients, no significant differences were seen between OFC and olanzapine patients. A significant, but small proportion of OFC patients (3.0%) had low supine diastolic blood pressure compared with olanzapine (0.7%; p=0.032) patients. Categorical changes in laboratory analytes, ECG, heart rate, and EPS measures were not significantly different between OFC and olanzapine patients. Conclusion: No significant adverse effects were seen when giving OFC compared with olanzapine monotherapy, and the OFC safety profile was consistent with those expected for component monotherapies (Beasley et al., 2000; Bhana et al., 2001). These results support the acute safety and tolerability of OFC.
References [1] Beasley, C.M., Koke, S.C., Nilsson, M.E., Gonzales, J.S., 2000. Adverse event and treatment discontinuationsin clinical trials of fluoxetine in major depressivedisorder: An updated meta-analysis.Clin. Ther. 22, 1319-1329. [2] Bhana, N., Foster, R.H., Olney,R., Plosker, G.L., 2001. Olanzapine:An updated review of its use in the management of schizophrenia. Drugs 61, 111-161.
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Olanzapine-fluoxetine combination for psychotic major depression
S. Dube 1 , A. Rothschild 2, S.W. Andersen 1 , T.M. Sanger 1, D.B. Clemow 1, M. Tohen1, G.D. Tollefson1. 1Eli Lilly
and Company, Indianapolis, Indiana, U.S.A.; 2University of Massachusetts Medical School, Worcester, Massachusetts, US.A. Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) has enhanced antidepressant qualities compared with monotherapies and is a promising treatment option for difficult-to-treat depressions such as bipolar depression, treatmentresistant depression, and psychotic depression. The present study examined efficacy and safety of a combination of olanzapine and the antidepressant fluoxetine compared to olanzapine monotherapy or placebo for treatment of major depressive disorder (MDD) with psychotic features. Methods: Two parallel, 8-week double-blind trials, with an optional 48-week open-label extension, were conducted. Subjects (n=249) with MDD with psychotic symptoms were randomized to one of three treatment groups: olanzapine-fluoxetine combination (OFC; 5-20 mg/day and 20-80 mg/day, respectively; n=48), olanzapine (5-20 mg/day; n=101) or placebo (n=100). The 24item Hamilton Depression Rating Scale (HAMD-24) was used to monitor primary efficacy. Results: Pooled data showed a significantly greater HAMD24 total score decrease at 8 weeks with OFC (-18.3) than PLA (-11.4, p<.001) and trended toward a greater decrease with OLZ (-14.4, p=.072). Eight-week endpoint response (>50% decrease in HAMD-24 total score) to OFC was significantly greater than OLZ or PLA (56%, 36% [p=.041], and 30% [p=.005], respectively). Seventy-one percent of acute OFC responders maintained response in the open-label phase. More OFC partial responders (>25% total score decrease at 2 weeks) achieved full endpoint response compared with OLZ or PLA (64%, 35%, 32%). OFC