CaseReports RESUMEN DEL CASO: Una pacientede 56 aiiosde edad, hospitalizadacon mieloma multiple,desarro1l6 convulsionescl6nicas y de tipo gran mal despuesde la administraci6n intravenosade mas de 400 mg/h de morfinacon bisulfitos6dico. Las convulsionesresolvieronal discontinuarla morfina,administraragentes anticonvulsivos y cambiar la terapia a fentanyl intravenososin preservativo. DISCUStON: Se discuten los factores potencialmente asociadoscon esta reacci6nadversaal igual que la literaturarespectoa los efectos adversos de los opioidesy sulfitossobre el sistema nerviosocentral. CONCLUSIONES: La rnorfinay el bisulfitos6dico en altas dosis pueden producirconvulsiones. Si pacientesrequirenla administraci6n intravenosa de altas dosis de morfina,es razonable usar una formulaci6n sin preservativos para evitar posiblestoxicidadesaditivas 0 sinergisticas. CHRISTINA DALMADY-ISRAEL RESUME
OBJF£IlF: IIlustrerun cas de convulsionssurvenuespendant l'administration d'une perfusionde hautes doses de morphine,laquelle solutioncontenaitdu bisulfitede sodium 11 titre d'agent de conservation.
RESUME DU CAS: Une femme de 56 ans hospitalisee pour myelomes multiplesa developpedes convulsionsde type cloniqueet grand-mal suite 11 l'administrationde doses de morphinecontenantdu bisulfitede sodium comme agent de conservation, doses superieures 11 400 mg par heure.Ces convulsionssont disparues 11 l'arret de la perfusionde morphine; des anticonvulsivants ont ete administreset la morphine a par la suite ete remplaceepar une perfusionde fentanylne renfermantpas de preservatif DISCUSSION: Les facteurs potentielsassocies11 cet effet indesirable rnedicamenteux sont mentionneset la litterature pertinentesur les effets indesirables des opiaces et des sulfitessur Ie systeme nerveuxcentralest revue. CONCLUSIONS: Les hautesdoses intraveineuses de morphinecontenant des sulfitescomme agent de conservation peuvent etre associees11 l'apparition de convulsions. Lorsqu'un patient requiertde hautesdoses intraveineuses de morphine,il serait preferabled'utiliser une solutionne renfermantaucun preservatifafin d'eviter une toxiciteau niveaudu systeme nerveuxcentral additiveou synergique. DENYSE DEMERS
ABNORMAL PLATELET AGGREGATION ASSOCIATED WITH FLUOXETINE THERAPY Christopher P. Alderman, Claire K. Moritz, and David I. Ben-Tovim
OBJECTIVE: To document the development of abnormal hemostasis in a patient treated with fluoxetine. CASE SUMMARY: A 49-year-old man developed a release-type defect in platelet aggregation during treatment with fluoxetine. Abnormal platelet aggregation was observed during platelet viability testing, in which adenosine diphosphate, epinephrine, ristocetin, arachidonic acid, and collagen were used as agonists. Two days after the withdrawal of fluoxetine, platelet function returned to normal. DISCUSSION: F1uoxetineis an antidepressant that is thought to act through inhibition of serotonin reuptake in the central nervous system. F1uoxetinealso inhibits the reuptake of serotonin in platelets, significantly decreasing granular storage and potentially influencing platelet aggregation characteristics. Clinical manifestations of abnormal platelet function have been reported in association with fluoxetine therapy. CONCLUSIONS: The rapid normalization of platelet aggregation after the withdrawal of fluoxetine in this patient does not conform to the known clinical pharmacokinetics of norfluoxetine. The half-life of fluoxetine is shorter, suggesting that the parent drug (rather than norfluoxetine) was the causative agent. Serum fluoxetine and norfluoxetine concentrations were not measured in this patient.
Ann Pharmacother 1992;26:1517-9.
CHRISTOPHER P. ALDERMAN, B.Pharm., is a Clinical Pharmacist (Psychiatry). Repatriation General Hospital. Daws Rd., Daw Park. South Australia 5041; CLAIRE K. MORITZ, B.App.Sc., is a Principal Hospital Scientist (Haematology); and DAVID I. BEN-TOVIM, Ph.D., M.B.B.S., M.R.C.Psych., FRANZCP, is an Associate Professor and Director, Department of Psychiatry, Repatriation General Hospital. Reprints: Christopher P. Alderman, B.Pharm.
fluoxetine is a very widely prescribed antidepressant. Clinical experience with a large number of patients in various countries has indicated that the drug's adverse effects profile is distinctly different from that of older antidepressant agents. I Fluoxetine diminishes granular storage of serotonin in platelets, and has been associated with clinical manifestations of defects in hemostasis.' We report the case of a man who developed defective platelet aggregation during fluoxetine treatment. THE SEROTONIN REUPTAKE INHIBITOR
CASE REPORT
A 49-year-oldman was hospitalized after an overdoseof temazepam. On admission the patient was drowsy but arousable, with pupils equal and reactive to light. An electrocardiogram revealed sinus bradycardia(55 beats/min).Venous access was established and hydration was begun with NaCl 0.9%. The following morning the patient was alert, oriented, and adequately hydrated, and was subsequently referredfor psychiatricassessment. The patient was well known to the staff of the unit and had a long-standing psychiatric history of anorexia nervosa with concurrent narcissistic personality disorder, both of which fulfilled the relevantdiagnosticcriteria withinthe Diagnostic and Statistical Manual, 3rd edition-revised. The patient was 180em tall and weighed 43 kg on admission. Physical examination revealed severe cachexia; however, the cardiovascular,neurologic,and respiratorysystems were unremarkable. Abdominalexaminationrevealed no organomegaly.The patient had no medicationtherapy prescribed at the time of admission. Laboratory investigationon admissionrevealed an elevated serum urea concentration of 11.5 mmol/L (range 3.0--8.0), with other electrolytes within normal
The Annals ofPharmacotherapy
•
1992 December, Volume 26 •
1517
limits. Thyroid function tests, serum vitamin B 12 and folate concentrations, and red cell folate and transketolase concentrations were normal. The results of a complete blood count (CBC) performed 30 days prior to admission were within normal limits. Mental state examination revealed a gaunt and kyphotic man dressed in very loose clothing. Conversation was slow but appropriate. The affect was blunted and depressed, but the patient revealed no perceptual abnormalities or cognitive defect. Memory, orientation, attention, and abstraction were intact. The patient was admitted to the hospital for further assessment and a structured treatment program for his anorexia nervosa was formulated. Disordered eating behavior continued, and 14 days after admission the patient's weight had further decreased to 41 kg. In light of persistent agitation, anxiety, and the emergence of paranoid delusions, haloperidol 5 mg bid was begun. Other drug therapy included benztropine 1-2 mg bid pm for extrapyramidal adverse effects and multivitamin capsules. Although this treatment produced some improvement in symptoms, one week later it was thought that sufficient indication did exist for a trial of antidepressant medication. The patient had previously failed to tolerate the anticholinergic adverse effects of dothiepin; therefore, desipramine was selected for its relative lack of antimuscarinic activity. Treatment with haloperidol was discontinued at this time. The CBC performed the day before desipramine treatment was initiated was normal (platelets 147 x 109!L). After two days of treatment with desipramine the platelet count fell to 115 x 109!L, with all other blood elements remaining within normal limits. The CBC was repeated the following day and revealed a platelet count of 112 x 109!L.The hemoglobin and mean red cell volume were normal. The white blood cell count had decreased from its previous level of9.8 x 1Q6!L to 5.4 x IQ6!L, and desipramine was withheld in order to determine whether this drug was responsible for the changes in the CBC. Two days later, alternative antidepressant treatment was begun with f1uoxetine 20 mg/d. In view of the long-standing nature of psychopathology in this patient, it was acknowledged that further treatment with other tricyclic antidepressants may be necessary, and that the changes in the CBC that occurred during desipramine therapy should be further investigated. A CBC obtained two days after the commencement of fluoxetine therapy was normal (platelets 222 x 109!L)and two days later a blood sample was obtained for the purpose of screening for desipramine-related antiplatelet antibodies using platelet aggregometry. The viability of platelets was studied first using adenosine diphosphate, epinephrine, ristocetin, arachidonic acid, and collagen as agonists, and at this time a release-type defect in platelet aggregation was observed. The potential for f1uoxetine to produce this pattern of aggregation defects was noted and further therapy with this drug was withheld. When aggregation studies were repeated 48 hours later, the defect had largely resolved, with normal responses to most agonists. Furthermore, investigations at this stage failed to demonstrate desipramine-related antiplatelet antibodies. The results of the platelet aggregation tests performed during and after f1uoxetine treatment are summarized in Table I. Alternative therapy was initiated using increasing doses of dothiepin, and the patient again tolerated tricyclic antidepressant treatment poorly because of anticholinergic adverse effects. He was discharged from the hospital nearly ten weeks after admission, and at this time was not taking antidepressant medication.
Fluoxetine is thought to produce its antidepressant effects through selective inhibition of serotonin reuptake in the central nervous system.' Extensive clinical experience with this drug has revealed a profile of adverse effects most frequently characterized by gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and central nervous system excitation (e.g., agitation, anxiety, insomnia).' The association of this drug with reactions such as the intensification of suicidal ideation is less clear,' Fluoxetine is notable for its lack of anticholinergic activity and adverse effects that are usually associated with other antidepressant drugs. 1518 •
The Annals ofPharmacotherapy •
Table 1. Platelet Aggregation During and After Treatment with Fluoxetine PLATELET AGGREGATION (percentage of maximum)" AGONIST (final concentration)
DURING FLUOXETINE TREATMENT
48hAFrER FLUOXETINE
Adenosine disphosphate 31lmol 51lmo1 Epinephrine Ristocetin Arachidonic acid Collagen
23 26 3 69 32 18
44 75 72 44 68 75
"Normal
=>50 percent.
Fluoxetine is known to decrease the granular storage of serotonin in platelets, and this effect has been proposed as a mechanism for a previously reported prolongation of skin bleeding time.' There has been at least one report of death resulting from hemorrhage associated with abnormal bleeding time during fluoxetine therapy.' Another group of investigators reported a series of patients in whom fluoxetine therapy was associated with hemorrhagic complications such as bruising and malena. It is noteworthy that nearly all the patients in this report were treated with doses greater than 20 mg/d." It is feasible that the postulated effects of fluoxetine on platelet aggregation may be dose related, and that the magnitude of this effect is related to the serum concentration of fluoxetine or one of its metabolites. There is evidence to suggest that the maintenance dose of fluoxetine should not exceed 20 mg/d and that dosages higher than this are associated with an increase in adverse effects, without enhanced therapeutic efficacy.' We observed a defect in platelet aggregation associated with fluoxetine 20 mg/d. The CBC and platelet count were normal during the assessment of platelet aggregation. Given the low body weight of the patient, it is possible that a low volume of distribution leading to high concentrations of fluoxetine or its metabolite may have accounted for the platelet dysfunction. However, the rapid normalization of platelet aggregation after the discontinuation of fluoxetine does not conform to the known clinical pharmacokinetics of norfluoxetine, which has a half-life of7-lS days.' The half-life of fluoxetine is shorter (1-3 d), suggesting that the pattern of resolution here is more likely to implicate the parent drug (rather than norfluoxetine) as a causative agent in platelet dysfunction. Serum fluoxetine and norfluoxetine concentrations were not measured in this patient. ~ References I. Cooper GL. The safety of fluoxetine-an update. Br J Psychiatry 1988; I53(suppl 3):77-86. 2. Humphries JE, Wheby MS, Vandenberg SR. F1uoxetine and the bleeding time. Arch Pathol Lab Med 1990;114:727-8. 3. Bergstrom RF, Lemberger L, Farid NA, Wolen RL. Clinical pharmacology and pharmacokinetics of fluoxetine: a review. Br J Psychiatry 1988;153(suppl 3):47-50. 4. McGrath BJ, Stoukides CA. Fluoxetine and suicidal ideation. DICP
Ann PharmacotherI991;25:607-9. 5. Evans TG, Buys SS, Rodgers GM. (letter). N Engl J Med 1991;324:1671. 6. Yaryura-Tobias JA, Kirschen H, Ninan P, Mosberg HJ. Fluoxetine and bleeding in obsessive-compulsive disorder (letter). Am J Psychiatry 1991;148:949.
1992 December, Volume 26
Case Reports 7. Altamura AC, Montgomery SA, Wernicke JF. The evidence for 20mg a day of fluoxetine as the optimaldose in the treatment of depression. Br J Psychiatry 1988; I 53(suppl 3):109-12.
EXTRACfO
Documentarel desarrollo de una hemostasis anormal en un paciente tratado con fluoxetin.
OBJETIVO:
RFSUMEN DEL CASO: Un hombre de 49 afios desarro1l6 un defecto de liberaei6nque afecta la agregaci6nde plaquetas durante el tratamiento con fluoxetin. La agregaci6nanormal de plaquetas se observ6 durante una prueba de viabilidadde plaquetas,donde se utilizaroncomo agonistasdifosfatode adenosina,epinefrina, restocetina,acido araquidonico, y colageno, Dos dfas luego de descontinuarfluoxetin la funci6n plaquetaria se normaliz6.
Fluoxetines un medicamentoantidepresivoque se cree acnia mediante la inhibici6nde la recaptaci6nde serotoninaen el sistema nervioso central. Fluoxetin tambien inhibe la recaptaci6nde serotonina en plaquetas,disminuye significativamente el almacenamientogranular, y potencialmenteafecta las caracterfsticas de agregaci6n plaquetaria. DISCUSION:
En este caso la rapida normalizaci6nde la agregaci6nde plaquetas luego de descontinuar fluoxetin no concuerda con los parametres clinicos farmacocineticos de su metabolito norfluoxetin. La vida media de fluoxetin es corta, 10 que sugiere que el patron observado en este caso debe estar relacionadoal medicamento y no a su metabolito. No se midieron concentraciones sericas de fluoxetin 0 de norfluoxetinen este paciente. Los autores planifican realizar un estudio prospectivocon un cohorte de pacientes donde se evalue la agregaci6n de plaquetas y se midan las concentracionessericas de fluoxetin y norfluoxetinconcurrentemente,si es posible. CONCLUSIONF.s:
RESUME
Documenter la presence d'une hemostase anormale chez un patient traite 11 la fluoxetine,
OBJECTIF:
RFSUME DU CAS: Un homme age de 49 ans a developpe un probleme d'agregation plaquettairependant un traitementavec la fluoxetine. L' agregationplaquettaireanormale a ete observee pendant un test d'evaluation de la viabilitedes plaquettes,au cours duquelle diphosphate d' adenosine, I'epinephrine, la ristocetine, I' acide arachidoniqueet Ie collagene ont servi d' agonistes. Deux jours apres avoir cesse Ie traitement 11 la fluoxetine, la fonction plaquettaireetait redevenue normale.
La fluoxetine est un antidepresseurqui agit en inhibantIe recaptagede la serotonine au systeme nerveux central. La fluoxetine inhibe aussi Ie recaptage de la serotonine dans les plaquettes, diminuant ainsi de facon significativeles quantites de serotonineemmagasinees dans les granules. Tout ceci peut influencerou modifier l'agregation plaquettaire.Des manifestationsc1iniques d'un fonctionnement plaquettaireanormal ont deja ete rapporteeset associees 11 la prise de fluoxetine. DISCUSSION:
La normalisationrapide de l'agregation plaquettairesuite 11 I' arret de la fluoxetine dans ce cas, ne peut pas s' expliqueren fonction des donnees de pharrnacocinetique c1inique concernantla norfluoxetine, La demi-vie de la fluoxetine est plus courte, ce qui nous incite 11 croire que ce medicament, plutot que la norfluoxetine, serait responsabledes anomalies fonctionnelles au niveau plaquettaire. Les concentrations seriques de fluoxetine et de norfluoxetinen' ont pas ete determineeschez ce patient. Les auteurs prevoient mener une etude prospective portant sur I' evaluationde I' agregationplaquettaire, et comportant si possible, la determinationconcomitante des concentrationsseriques de fluoxetineet de norfluoxetine. CONCLUSIONS:
JOEllE SAINT-PIERRE
ANNETIE PEREZ
The Annals ofPharmacotherapy
•
1992 December, Volume 26 •
1519
OBJF£IlF: IIlustrerun cas de convulsionssurvenuespendant l'administration d'une perfusionde hautes doses de morphine,laquelle solutioncontenaitdu bisulfitede sodium 11 titre d'agent de conservation.
RESUME DU CAS: Une femme de 56 ans hospitalisee pour myelomes multiplesa developpedes convulsionsde type cloniqueet grand-mal suite 11 l'administrationde doses de morphinecontenantdu bisulfitede sodium comme agent de conservation, doses superieures 11 400 mg par heure.Ces convulsionssont disparues 11 l'arret de la perfusionde morphine; des anticonvulsivants ont ete administreset la morphine a par la suite ete remplaceepar une perfusionde fentanylne renfermantpas de preservatif DISCUSSION: Les facteurs potentielsassocies11 cet effet indesirable rnedicamenteux sont mentionneset la litterature pertinentesur les effets indesirables des opiaces et des sulfitessur Ie systeme nerveuxcentralest revue. CONCLUSIONS: Les hautesdoses intraveineuses de morphinecontenant des sulfitescomme agent de conservation peuvent etre associees11 l'apparition de convulsions. Lorsqu'un patient requiertde hautesdoses intraveineuses de morphine,il serait preferabled'utiliser une solutionne renfermantaucun preservatifafin d'eviter une toxiciteau niveaudu systeme nerveuxcentral additiveou synergique. DENYSE DEMERS
ABNORMAL PLATELET AGGREGATION ASSOCIATED WITH FLUOXETINE THERAPY Christopher P. Alderman, Claire K. Moritz, and David I. Ben-Tovim
OBJECTIVE: To document the development of abnormal hemostasis in a patient treated with fluoxetine. CASE SUMMARY: A 49-year-old man developed a release-type defect in platelet aggregation during treatment with fluoxetine. Abnormal platelet aggregation was observed during platelet viability testing, in which adenosine diphosphate, epinephrine, ristocetin, arachidonic acid, and collagen were used as agonists. Two days after the withdrawal of fluoxetine, platelet function returned to normal. DISCUSSION: F1uoxetineis an antidepressant that is thought to act through inhibition of serotonin reuptake in the central nervous system. F1uoxetinealso inhibits the reuptake of serotonin in platelets, significantly decreasing granular storage and potentially influencing platelet aggregation characteristics. Clinical manifestations of abnormal platelet function have been reported in association with fluoxetine therapy. CONCLUSIONS: The rapid normalization of platelet aggregation after the withdrawal of fluoxetine in this patient does not conform to the known clinical pharmacokinetics of norfluoxetine. The half-life of fluoxetine is shorter, suggesting that the parent drug (rather than norfluoxetine) was the causative agent. Serum fluoxetine and norfluoxetine concentrations were not measured in this patient.
Ann Pharmacother 1992;26:1517-9.
CHRISTOPHER P. ALDERMAN, B.Pharm., is a Clinical Pharmacist (Psychiatry). Repatriation General Hospital. Daws Rd., Daw Park. South Australia 5041; CLAIRE K. MORITZ, B.App.Sc., is a Principal Hospital Scientist (Haematology); and DAVID I. BEN-TOVIM, Ph.D., M.B.B.S., M.R.C.Psych., FRANZCP, is an Associate Professor and Director, Department of Psychiatry, Repatriation General Hospital. Reprints: Christopher P. Alderman, B.Pharm.
fluoxetine is a very widely prescribed antidepressant. Clinical experience with a large number of patients in various countries has indicated that the drug's adverse effects profile is distinctly different from that of older antidepressant agents. I Fluoxetine diminishes granular storage of serotonin in platelets, and has been associated with clinical manifestations of defects in hemostasis.' We report the case of a man who developed defective platelet aggregation during fluoxetine treatment. THE SEROTONIN REUPTAKE INHIBITOR
CASE REPORT
A 49-year-oldman was hospitalized after an overdoseof temazepam. On admission the patient was drowsy but arousable, with pupils equal and reactive to light. An electrocardiogram revealed sinus bradycardia(55 beats/min).Venous access was established and hydration was begun with NaCl 0.9%. The following morning the patient was alert, oriented, and adequately hydrated, and was subsequently referredfor psychiatricassessment. The patient was well known to the staff of the unit and had a long-standing psychiatric history of anorexia nervosa with concurrent narcissistic personality disorder, both of which fulfilled the relevantdiagnosticcriteria withinthe Diagnostic and Statistical Manual, 3rd edition-revised. The patient was 180em tall and weighed 43 kg on admission. Physical examination revealed severe cachexia; however, the cardiovascular,neurologic,and respiratorysystems were unremarkable. Abdominalexaminationrevealed no organomegaly.The patient had no medicationtherapy prescribed at the time of admission. Laboratory investigationon admissionrevealed an elevated serum urea concentration of 11.5 mmol/L (range 3.0--8.0), with other electrolytes within normal
The Annals ofPharmacotherapy
•
1992 December, Volume 26 •
1517
limits. Thyroid function tests, serum vitamin B 12 and folate concentrations, and red cell folate and transketolase concentrations were normal. The results of a complete blood count (CBC) performed 30 days prior to admission were within normal limits. Mental state examination revealed a gaunt and kyphotic man dressed in very loose clothing. Conversation was slow but appropriate. The affect was blunted and depressed, but the patient revealed no perceptual abnormalities or cognitive defect. Memory, orientation, attention, and abstraction were intact. The patient was admitted to the hospital for further assessment and a structured treatment program for his anorexia nervosa was formulated. Disordered eating behavior continued, and 14 days after admission the patient's weight had further decreased to 41 kg. In light of persistent agitation, anxiety, and the emergence of paranoid delusions, haloperidol 5 mg bid was begun. Other drug therapy included benztropine 1-2 mg bid pm for extrapyramidal adverse effects and multivitamin capsules. Although this treatment produced some improvement in symptoms, one week later it was thought that sufficient indication did exist for a trial of antidepressant medication. The patient had previously failed to tolerate the anticholinergic adverse effects of dothiepin; therefore, desipramine was selected for its relative lack of antimuscarinic activity. Treatment with haloperidol was discontinued at this time. The CBC performed the day before desipramine treatment was initiated was normal (platelets 147 x 109!L). After two days of treatment with desipramine the platelet count fell to 115 x 109!L, with all other blood elements remaining within normal limits. The CBC was repeated the following day and revealed a platelet count of 112 x 109!L.The hemoglobin and mean red cell volume were normal. The white blood cell count had decreased from its previous level of9.8 x 1Q6!L to 5.4 x IQ6!L, and desipramine was withheld in order to determine whether this drug was responsible for the changes in the CBC. Two days later, alternative antidepressant treatment was begun with f1uoxetine 20 mg/d. In view of the long-standing nature of psychopathology in this patient, it was acknowledged that further treatment with other tricyclic antidepressants may be necessary, and that the changes in the CBC that occurred during desipramine therapy should be further investigated. A CBC obtained two days after the commencement of fluoxetine therapy was normal (platelets 222 x 109!L)and two days later a blood sample was obtained for the purpose of screening for desipramine-related antiplatelet antibodies using platelet aggregometry. The viability of platelets was studied first using adenosine diphosphate, epinephrine, ristocetin, arachidonic acid, and collagen as agonists, and at this time a release-type defect in platelet aggregation was observed. The potential for f1uoxetine to produce this pattern of aggregation defects was noted and further therapy with this drug was withheld. When aggregation studies were repeated 48 hours later, the defect had largely resolved, with normal responses to most agonists. Furthermore, investigations at this stage failed to demonstrate desipramine-related antiplatelet antibodies. The results of the platelet aggregation tests performed during and after f1uoxetine treatment are summarized in Table I. Alternative therapy was initiated using increasing doses of dothiepin, and the patient again tolerated tricyclic antidepressant treatment poorly because of anticholinergic adverse effects. He was discharged from the hospital nearly ten weeks after admission, and at this time was not taking antidepressant medication.
Fluoxetine is thought to produce its antidepressant effects through selective inhibition of serotonin reuptake in the central nervous system.' Extensive clinical experience with this drug has revealed a profile of adverse effects most frequently characterized by gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and central nervous system excitation (e.g., agitation, anxiety, insomnia).' The association of this drug with reactions such as the intensification of suicidal ideation is less clear,' Fluoxetine is notable for its lack of anticholinergic activity and adverse effects that are usually associated with other antidepressant drugs. 1518 •
The Annals ofPharmacotherapy •
Table 1. Platelet Aggregation During and After Treatment with Fluoxetine PLATELET AGGREGATION (percentage of maximum)" AGONIST (final concentration)
DURING FLUOXETINE TREATMENT
48hAFrER FLUOXETINE
Adenosine disphosphate 31lmol 51lmo1 Epinephrine Ristocetin Arachidonic acid Collagen
23 26 3 69 32 18
44 75 72 44 68 75
"Normal
=>50 percent.
Fluoxetine is known to decrease the granular storage of serotonin in platelets, and this effect has been proposed as a mechanism for a previously reported prolongation of skin bleeding time.' There has been at least one report of death resulting from hemorrhage associated with abnormal bleeding time during fluoxetine therapy.' Another group of investigators reported a series of patients in whom fluoxetine therapy was associated with hemorrhagic complications such as bruising and malena. It is noteworthy that nearly all the patients in this report were treated with doses greater than 20 mg/d." It is feasible that the postulated effects of fluoxetine on platelet aggregation may be dose related, and that the magnitude of this effect is related to the serum concentration of fluoxetine or one of its metabolites. There is evidence to suggest that the maintenance dose of fluoxetine should not exceed 20 mg/d and that dosages higher than this are associated with an increase in adverse effects, without enhanced therapeutic efficacy.' We observed a defect in platelet aggregation associated with fluoxetine 20 mg/d. The CBC and platelet count were normal during the assessment of platelet aggregation. Given the low body weight of the patient, it is possible that a low volume of distribution leading to high concentrations of fluoxetine or its metabolite may have accounted for the platelet dysfunction. However, the rapid normalization of platelet aggregation after the discontinuation of fluoxetine does not conform to the known clinical pharmacokinetics of norfluoxetine, which has a half-life of7-lS days.' The half-life of fluoxetine is shorter (1-3 d), suggesting that the pattern of resolution here is more likely to implicate the parent drug (rather than norfluoxetine) as a causative agent in platelet dysfunction. Serum fluoxetine and norfluoxetine concentrations were not measured in this patient. ~ References I. Cooper GL. The safety of fluoxetine-an update. Br J Psychiatry 1988; I53(suppl 3):77-86. 2. Humphries JE, Wheby MS, Vandenberg SR. F1uoxetine and the bleeding time. Arch Pathol Lab Med 1990;114:727-8. 3. Bergstrom RF, Lemberger L, Farid NA, Wolen RL. Clinical pharmacology and pharmacokinetics of fluoxetine: a review. Br J Psychiatry 1988;153(suppl 3):47-50. 4. McGrath BJ, Stoukides CA. Fluoxetine and suicidal ideation. DICP
Ann PharmacotherI991;25:607-9. 5. Evans TG, Buys SS, Rodgers GM. (letter). N Engl J Med 1991;324:1671. 6. Yaryura-Tobias JA, Kirschen H, Ninan P, Mosberg HJ. Fluoxetine and bleeding in obsessive-compulsive disorder (letter). Am J Psychiatry 1991;148:949.
1992 December, Volume 26
Case Reports 7. Altamura AC, Montgomery SA, Wernicke JF. The evidence for 20mg a day of fluoxetine as the optimaldose in the treatment of depression. Br J Psychiatry 1988; I 53(suppl 3):109-12.
EXTRACfO
Documentarel desarrollo de una hemostasis anormal en un paciente tratado con fluoxetin.
OBJETIVO:
RFSUMEN DEL CASO: Un hombre de 49 afios desarro1l6 un defecto de liberaei6nque afecta la agregaci6nde plaquetas durante el tratamiento con fluoxetin. La agregaci6nanormal de plaquetas se observ6 durante una prueba de viabilidadde plaquetas,donde se utilizaroncomo agonistasdifosfatode adenosina,epinefrina, restocetina,acido araquidonico, y colageno, Dos dfas luego de descontinuarfluoxetin la funci6n plaquetaria se normaliz6.
Fluoxetines un medicamentoantidepresivoque se cree acnia mediante la inhibici6nde la recaptaci6nde serotoninaen el sistema nervioso central. Fluoxetin tambien inhibe la recaptaci6nde serotonina en plaquetas,disminuye significativamente el almacenamientogranular, y potencialmenteafecta las caracterfsticas de agregaci6n plaquetaria. DISCUSION:
En este caso la rapida normalizaci6nde la agregaci6nde plaquetas luego de descontinuar fluoxetin no concuerda con los parametres clinicos farmacocineticos de su metabolito norfluoxetin. La vida media de fluoxetin es corta, 10 que sugiere que el patron observado en este caso debe estar relacionadoal medicamento y no a su metabolito. No se midieron concentraciones sericas de fluoxetin 0 de norfluoxetinen este paciente. Los autores planifican realizar un estudio prospectivocon un cohorte de pacientes donde se evalue la agregaci6n de plaquetas y se midan las concentracionessericas de fluoxetin y norfluoxetinconcurrentemente,si es posible. CONCLUSIONF.s:
RESUME
Documenter la presence d'une hemostase anormale chez un patient traite 11 la fluoxetine,
OBJECTIF:
RFSUME DU CAS: Un homme age de 49 ans a developpe un probleme d'agregation plaquettairependant un traitementavec la fluoxetine. L' agregationplaquettaireanormale a ete observee pendant un test d'evaluation de la viabilitedes plaquettes,au cours duquelle diphosphate d' adenosine, I'epinephrine, la ristocetine, I' acide arachidoniqueet Ie collagene ont servi d' agonistes. Deux jours apres avoir cesse Ie traitement 11 la fluoxetine, la fonction plaquettaireetait redevenue normale.
La fluoxetine est un antidepresseurqui agit en inhibantIe recaptagede la serotonine au systeme nerveux central. La fluoxetine inhibe aussi Ie recaptage de la serotonine dans les plaquettes, diminuant ainsi de facon significativeles quantites de serotonineemmagasinees dans les granules. Tout ceci peut influencerou modifier l'agregation plaquettaire.Des manifestationsc1iniques d'un fonctionnement plaquettaireanormal ont deja ete rapporteeset associees 11 la prise de fluoxetine. DISCUSSION:
La normalisationrapide de l'agregation plaquettairesuite 11 I' arret de la fluoxetine dans ce cas, ne peut pas s' expliqueren fonction des donnees de pharrnacocinetique c1inique concernantla norfluoxetine, La demi-vie de la fluoxetine est plus courte, ce qui nous incite 11 croire que ce medicament, plutot que la norfluoxetine, serait responsabledes anomalies fonctionnelles au niveau plaquettaire. Les concentrations seriques de fluoxetine et de norfluoxetinen' ont pas ete determineeschez ce patient. Les auteurs prevoient mener une etude prospective portant sur I' evaluationde I' agregationplaquettaire, et comportant si possible, la determinationconcomitante des concentrationsseriques de fluoxetineet de norfluoxetine. CONCLUSIONS:
JOEllE SAINT-PIERRE
ANNETIE PEREZ
The Annals ofPharmacotherapy
•
1992 December, Volume 26 •
1519
