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P.1.128 Dysphoric mania: A controlled study of the benefits of olanzapine combined with valproate or lithium
PI.
S228
Affective
disorders
correlated with depression symptom severity based ou HAM-D scores (piO.0001) but uot with manic symptoms based ou the Mama Rating Scale. Conclusion: Treatment with lamotrigiue mouotherauv aud as adjuuctive therapy was associated with improved cognitive fuuctiouiug aud reduced ueurocoguitive side effects, irregardless of index mood polarity. Depression symptomotology was more predictive of cognitive scores compared with manic symptomotology in both studies.
Ip.1.1271 The potential
for clinically significant drug-drug interactions in patients receiving CYP 2D6 model substrate/drugs and fluoxetinelparoxetine or sertraline
S Preskoru’ , R. Shah2, B. Silkey3, M. Ned, A. Golbeck3, J. Cho?. ‘Psychiatric Research Institute, Clinical Research, Wichita, KS, i2S.A.; ‘VAMC-mchita, Primary Care, Wichita, KS, i2S.A.; 3Psychiatric Research Institute, Wichita, KS, i2S.A.; 4 VISNIS-Veterans Affairs, Pharmacy, Kansas City, MO, i2S.A.; 5 VAMC- mchita, Pharmacy, Wichita, KS, i2S.A. While fluoxetiue, paroxetiue, aud sertraliue are all SSRI autidepressauts, they are markedly differeut in their iuhibitory effect ou the humau drug-metabolizing enzyme, CYP 2D6. Fluoxetiue aud paroxetiue, at their lowest usually effective autidepressaut dose, produce comparable aud substantial iuhibitiou of this enzyme while sertraliue does uot [l]. Previous studies found combined treatment with drugs capable of decreasing the seizure threshold aud drugs capable of iuhibitiug the metabolism of the former drugs to be au important risk factor for seizuresimyoclouus [2]. The currem study determiued the relative frequency of the combined use of fluoxetiueiparoxetiue versus sertraliue with drugs principally cleared via 2D6 in a Midwesteru US Veterans Affairs healthcare network. Method: The medication regimeus of 461 outpatients being treated with fluoxetiue or paroxetiue aud 435 with sertraliue were examined to determine whether they were also receiving a drug whose clearauce was prefereutially depeudeut upon 2D6. In each drug combination, substantial iuhibitiou of 2D6 fuuctiou had the poteutial for causing a clinically significant drug-drug iuteractiou (DDI). A sub-analysis was conducted ou patients in whom the 2D6 substrate/drug had a uarrow therapeutic index, to detenniue whether the dose was poteutially dangerous, giveu substantial iuhibitiou of 2D6. Finally, the drug alert system was examined to detenniue whether it would have predicted a significant and/or serious DDI. Results: 39.7% (183 patients: 90 fluoxetiue, 92 paroxetiue aud 1 ou both) of patients being treated with fluoxetiueiparoxetiue were also receiving a 2D6 model substrate/drug versus 3 1.3% (136 patients) of patients ou sertraliue. In 8.5% of patients being treated with fluoxetiueiparoxetiue aud 8.0% with sertraliue, the coadmiuistered 2D6model substrate/drug had a uarrow therapeutic index. 35.9% of the patients being treated coucomitautly with either fluoxetiue or paroxetiue aud a 2D6 model substrate/drug were receiving a dose of the latter high enough to be a significant risk for a serious DDI. In 50% of the drug combinations, the DDI was uot ideutified by the drug iufonnatiou system employed. Conclusion: There was uo significant difference in frequency of fluoxetiueiparoxetiue or sertraliue use in combiuatiou with 2D6 model substrate/drugs. 50% of the 16 poteutially serious adverse drug combiuatious were uot in the drug alert system employed,
and antidepressants suggesting the ueed studies to oue based
to move from ou mechanisms
a system based ou published uuderlyiug DDIs.
References
[l]
Preskorn SH. (2003) Reproducibility of the in uiuo effect of the selective serotonin reuptake inhibitors on the in uiuo function of cytochrome P450 2D6: an update (Part I). Journal of Psychiatric Practice 9:15& 158. [2] Spigset 0, Hedenmalm K, Dahl ML, Wiholm BE, Dahlqvist R. (1997) Seizures and mvoclonus associated with antidenressant treatment: assessment of pot&tial risk factors, including CUP 2D6 and CYP 2C19 polymorphisms, and treatment with CYP 2D6 inhibitors. Acta Psych& Stand. 96(5): 379-84.
m PI
128
Dysphoric benefits or lithium
mania: A controlled of olanzapine combined
study with
of the valproate
M. Toheu, R. Baker, E. Brown, L. Schuh, P. Trzepachz, S. Daudo. Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, US.A. Objective: Mixed bipolar episodes carry high suicide risk aud the challenge of simultaneously treating dysphoric aud manic features. Coutrolled research is especially limited ou treatment of dysphoric features. Methods: This is a secondary analysis of a 6-week doubleblind randomized study of olauzapiue 5-20 mglday or placebo combined with ougoiug open valproate or lithium treatment for patients in mixed or manic episodes (N=344). All patients had Young Mama Ratings (YMRS) > 16 despite at least two weeks ou lithium or valproate; this analysis focuses ou a dysphoric subgroup (baseline Hamilton Depression Rating-HAM-D>20) contrasted to non-dysphoric patients. Results: In dysphoric patients (11=85), HAM-D total score improvemeiit was greater iii patieiits receiviiig olaiizapiiie cotherapy thau those taking placebo plus ougoiug lithiumivalproate (p<.OOl); coutributauts to this superiority included HAM-D Core Mood cluster (p=.O13) aud the suicide item (p=.OOl). In the uoudysphoric group, HAM-D improvement was greater in olauzapiuetreated patients (p=.OO2), although the effect was smaller thau in dysphoric patients. Total YMRS improvement was superior ou olauzapiue co-therapy in both dysphoric aud non-dysphoric groups; this effect had similar magnitude in both groups. Conclusions: In patients with dysphoric mama, addition of olauzapiue to ougoiug lithium or valproate mouotherapy simultaueously improved ratings of depression, mama, aud suicidality. PI 129 L-l
A double blind, randomized, multicentric pilot study comparing differential effects cognitive functioning in agitated-impulsive depression with two SSRls
on
E. Perriu’, .I. Dalery2, M. Faruch3, S. Ammar4, I? Quiutiu’ , D. Gouriou5, R. Jouveut4, S. Duba14. ‘Lilly France, Neurosciences, Suresnes Cedex, France; ‘HGpital Neurologique, Service de Psychologie Mkdicale, Bron, France; 3 Toulouse, France; 4H6pital de la Pitit-Salpttridre, Unit& CNRS, Paris, France; ‘HGpital Sainte-Anne, Hospitalo-Universitaire, Paris, France Cumulative data in the field cology indicate “impulsivity”
of neurobiology as a dimeusiou
aud psychophannaliuked to serotouiu
S228
Affective
disorders
correlated with depression symptom severity based ou HAM-D scores (piO.0001) but uot with manic symptoms based ou the Mama Rating Scale. Conclusion: Treatment with lamotrigiue mouotherauv aud as adjuuctive therapy was associated with improved cognitive fuuctiouiug aud reduced ueurocoguitive side effects, irregardless of index mood polarity. Depression symptomotology was more predictive of cognitive scores compared with manic symptomotology in both studies.
Ip.1.1271 The potential
for clinically significant drug-drug interactions in patients receiving CYP 2D6 model substrate/drugs and fluoxetinelparoxetine or sertraline
S Preskoru’ , R. Shah2, B. Silkey3, M. Ned, A. Golbeck3, J. Cho?. ‘Psychiatric Research Institute, Clinical Research, Wichita, KS, i2S.A.; ‘VAMC-mchita, Primary Care, Wichita, KS, i2S.A.; 3Psychiatric Research Institute, Wichita, KS, i2S.A.; 4 VISNIS-Veterans Affairs, Pharmacy, Kansas City, MO, i2S.A.; 5 VAMC- mchita, Pharmacy, Wichita, KS, i2S.A. While fluoxetiue, paroxetiue, aud sertraliue are all SSRI autidepressauts, they are markedly differeut in their iuhibitory effect ou the humau drug-metabolizing enzyme, CYP 2D6. Fluoxetiue aud paroxetiue, at their lowest usually effective autidepressaut dose, produce comparable aud substantial iuhibitiou of this enzyme while sertraliue does uot [l]. Previous studies found combined treatment with drugs capable of decreasing the seizure threshold aud drugs capable of iuhibitiug the metabolism of the former drugs to be au important risk factor for seizuresimyoclouus [2]. The currem study determiued the relative frequency of the combined use of fluoxetiueiparoxetiue versus sertraliue with drugs principally cleared via 2D6 in a Midwesteru US Veterans Affairs healthcare network. Method: The medication regimeus of 461 outpatients being treated with fluoxetiue or paroxetiue aud 435 with sertraliue were examined to determine whether they were also receiving a drug whose clearauce was prefereutially depeudeut upon 2D6. In each drug combination, substantial iuhibitiou of 2D6 fuuctiou had the poteutial for causing a clinically significant drug-drug iuteractiou (DDI). A sub-analysis was conducted ou patients in whom the 2D6 substrate/drug had a uarrow therapeutic index, to detenniue whether the dose was poteutially dangerous, giveu substantial iuhibitiou of 2D6. Finally, the drug alert system was examined to detenniue whether it would have predicted a significant and/or serious DDI. Results: 39.7% (183 patients: 90 fluoxetiue, 92 paroxetiue aud 1 ou both) of patients being treated with fluoxetiueiparoxetiue were also receiving a 2D6 model substrate/drug versus 3 1.3% (136 patients) of patients ou sertraliue. In 8.5% of patients being treated with fluoxetiueiparoxetiue aud 8.0% with sertraliue, the coadmiuistered 2D6model substrate/drug had a uarrow therapeutic index. 35.9% of the patients being treated coucomitautly with either fluoxetiue or paroxetiue aud a 2D6 model substrate/drug were receiving a dose of the latter high enough to be a significant risk for a serious DDI. In 50% of the drug combinations, the DDI was uot ideutified by the drug iufonnatiou system employed. Conclusion: There was uo significant difference in frequency of fluoxetiueiparoxetiue or sertraliue use in combiuatiou with 2D6 model substrate/drugs. 50% of the 16 poteutially serious adverse drug combiuatious were uot in the drug alert system employed,
and antidepressants suggesting the ueed studies to oue based
to move from ou mechanisms
a system based ou published uuderlyiug DDIs.
References
[l]
Preskorn SH. (2003) Reproducibility of the in uiuo effect of the selective serotonin reuptake inhibitors on the in uiuo function of cytochrome P450 2D6: an update (Part I). Journal of Psychiatric Practice 9:15& 158. [2] Spigset 0, Hedenmalm K, Dahl ML, Wiholm BE, Dahlqvist R. (1997) Seizures and mvoclonus associated with antidenressant treatment: assessment of pot&tial risk factors, including CUP 2D6 and CYP 2C19 polymorphisms, and treatment with CYP 2D6 inhibitors. Acta Psych& Stand. 96(5): 379-84.
m PI
128
Dysphoric benefits or lithium
mania: A controlled of olanzapine combined
study with
of the valproate
M. Toheu, R. Baker, E. Brown, L. Schuh, P. Trzepachz, S. Daudo. Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, US.A. Objective: Mixed bipolar episodes carry high suicide risk aud the challenge of simultaneously treating dysphoric aud manic features. Coutrolled research is especially limited ou treatment of dysphoric features. Methods: This is a secondary analysis of a 6-week doubleblind randomized study of olauzapiue 5-20 mglday or placebo combined with ougoiug open valproate or lithium treatment for patients in mixed or manic episodes (N=344). All patients had Young Mama Ratings (YMRS) > 16 despite at least two weeks ou lithium or valproate; this analysis focuses ou a dysphoric subgroup (baseline Hamilton Depression Rating-HAM-D>20) contrasted to non-dysphoric patients. Results: In dysphoric patients (11=85), HAM-D total score improvemeiit was greater iii patieiits receiviiig olaiizapiiie cotherapy thau those taking placebo plus ougoiug lithiumivalproate (p<.OOl); coutributauts to this superiority included HAM-D Core Mood cluster (p=.O13) aud the suicide item (p=.OOl). In the uoudysphoric group, HAM-D improvement was greater in olauzapiuetreated patients (p=.OO2), although the effect was smaller thau in dysphoric patients. Total YMRS improvement was superior ou olauzapiue co-therapy in both dysphoric aud non-dysphoric groups; this effect had similar magnitude in both groups. Conclusions: In patients with dysphoric mama, addition of olauzapiue to ougoiug lithium or valproate mouotherapy simultaueously improved ratings of depression, mama, aud suicidality. PI 129 L-l
A double blind, randomized, multicentric pilot study comparing differential effects cognitive functioning in agitated-impulsive depression with two SSRls
on
E. Perriu’, .I. Dalery2, M. Faruch3, S. Ammar4, I? Quiutiu’ , D. Gouriou5, R. Jouveut4, S. Duba14. ‘Lilly France, Neurosciences, Suresnes Cedex, France; ‘HGpital Neurologique, Service de Psychologie Mkdicale, Bron, France; 3 Toulouse, France; 4H6pital de la Pitit-Salpttridre, Unit& CNRS, Paris, France; ‘HGpital Sainte-Anne, Hospitalo-Universitaire, Paris, France Cumulative data in the field cology indicate “impulsivity”
of neurobiology as a dimeusiou
aud psychophannaliuked to serotouiu