Download PDF
Pharmacopsychiatry 2004; 37: 70-78
DOI: 10.1055/s-2004-815513
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Blood Dyscrasias Induced by Psychotropic Drugs

S. Stübner1 , R. Grohmann1 , R. Engel1 , B. Bandelow2 , W.-D. Ludwig3 , G. Wagner1 , B. Müller-Oerlinghausen4 , H.-J. Möller1 , H. Hippius1 , E. Rüther2
  • 1Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany
  • 2Department of Psychiatry and Psychotherapy, Georg-August University, Göttingen, Germany
  • 3HELIOS Klinikum Berlin, Department of Hematology, Oncology, and Tumor Immunology, Charité (Campus Berlin-Buch), Humboldt-University of Berlin, Germany
  • 4Drug Commission of the German Medical Association, Berlin/Cologne, Germany
Further Information

Publication History

Publication Date:
30 March 2004 (online)

Also available at
    Permissions and Reprints

Drugs can cause a variety of blood dyscrasias, e. g., by interfering with hematopoiesis in the bone marrow or damaging mature blood cells by antibodies.

Although numerous reports on the risks of adverse hematological effects associated with psychotropic drugs have led to stringent monitoring requirements for some compounds, particularly neuroleptics, it is still difficult to estimate the true prevalence of such risks.

Sixteen episodes of thrombocytopenia, 63 of neutropenia, 22 of agranulocytosis, 4 episodes of severe neutro- and thrombocytopenia, and 2 of pancytopenia were documented by the drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der Psychiatrie) in a population of 122,562 patients between 1993 and 2000. All cases were related to the epidemiological data provided for this population and systematically analyzed as regards history of medication, co-medication, and the clinical course. Putative risk rates for the main groups of medications and a number of drugs could be estimated with this database.

Most changes in the white blood cell counts, which were rated as probably or definitely drug-induced, were attributed to clozapine (0.18 % of patients exposed), carbamazepine (0.14 %) and perazine (0.09 %).

In patients on newer atypical neuroleptics, we documented neutropenia assumed to be probably or definitely drug-related in five patients during treatment with olanzapine and in one case with risperidone. In all five olanzapine-related cases, the drugs were the sole cause of the adverse drug reactions.

All surveyed patients who received clozapine showed no difference in age and gender distribution from those who developed hematological changes.

Incidences of hematological changes for antidepressants were much lower (about 0.01 %).

Although the methodological accuracy of these findings has to be critically discussed these data could be of considerable clinical relevance and should be helpful in making clinical treatment decisions.

References

  • 1 Agresti A, Coull B A. Approximate is better than ”exact” for interval estimation of binominal proportions.  The American Statistician. 1998;  52 119-126
    PubMedSearch in Google Scholar
  • 2 Alvir J MJ, Liebermann J A, Saffermann A Z, Schwimmer J L, Schaaf J A. Clozapine-induced agranulocytosis: increased and risk factors in the United States.  New Engl J Med. 1993;  329 162-167
    CrossrefPubMedSearch in Google Scholar
  • 3 Assion H J, Kolbinger H M, Rao M L, Laux G. Lymphocytopenia and thrombocytopenia during treatment with risperidone or clozapine.  Pharmacopsychiatry. 1996;  29 227-228
    PubMedSearch in Google Scholar
  • 4 Benedetti F, Cavallaro R, Smeraldi E. Olanzapine-induced neutropenia after clozapine-induced neutropenia.  Lancet. 1999;  354 567
    CrossrefPubMedSearch in Google Scholar
  • 5 Bondolfi G, Morena P, Dascal D -R, Bertschy G. Risperidone and reversible neutropenia: a negative rechallenge.  Europ Neuropsychopharmacol. 1996;  6 257
    PubMedSearch in Google Scholar
  • 6 Buchman N, Strous R D, Ulman A -M, Lerner M, Kotler M. Olanzapine-induced leukopenia with human leukocyte antigen profiling.  Int Clin Psychopharmacol. 2001;  16 55-57
    CrossrefPubMedSearch in Google Scholar
  • 7 Clopper C J, Pearson E S. The use of confidence of fiducial limits illustrated in the case of the binominal.  Biometrika. 1934;  26 404-413
    CrossrefPubMedSearch in Google Scholar
  • 8 Dettling M, Cascorbi I, Roots I, Mueller-Oerlinghausen B. Genetic Determinants of Clozapine-Induced Agranulocytosis: Recent Results of HLA Subtyping in a Non-Jewish Caucasian Sample.  Arch Gen Psychiatry. 2001;  58 93
    PubMedSearch in Google Scholar
  • 9 Dettling M, Cascorbi R, Hellweg R, Deicke U, Weise L, Müller-Oerlinghausen B. Genetic Determinants of Drug-Induced Agranulocytosis: Potential Risk of Olanzapine?.  Pharmacopsychiatry. 1999;  32 110-112
    PubMedSearch in Google Scholar
  • 10 Dettling M, Schaub R T, Mueller-Oerlinghausen B, Roots I, Cascorbi I. Further evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry.  Pharmacogenetics. 2000;  10 1-7
    CrossrefPubMedSearch in Google Scholar
  • 11 Dvernovsek M, Tavcar R. Olanzapine appears haematologically safe in patients who developed blood dyscrasia on clozapine and risperidone.  Int Clin Psychopharmacol. 2000;  15 237-238
    PubMedSearch in Google Scholar
  • 12 Felber W, Naumann R, Schuler U. et al . Are There Genetic Determinants of Olanzapine-Induced Agranulocytosis?.  Pharmacopsychiatry. 2000;  33 197-198
    PubMedSearch in Google Scholar
  • 13 Finkel B, Lerner A G, Oyfee I, Sigal M. Risperidone-associated agranulocytosis.  Am J Psychiatry. 1998;  155(6) 855-856
    PubMedSearch in Google Scholar
  • 14 Finkel B, Lerner A G, Oyffe I, Rudinski D, Sigal M, Weizman A. Olanzapine treatment in patients with typical and atypical neuroleptic-associated agranulocytosis.  Int Clin Psychopharmacol. 1998;  13 133-135
    PubMedSearch in Google Scholar
  • 15 Flynn S, Altmann S, Macewan G W, Black L L, Greenidge L L, Horner W G. Prolongation of clozapine.induced graulocytopenia associated with olanzapine.  J Clin Psychopharmacol. 1997;  17 494-495
    CrossrefPubMedSearch in Google Scholar
  • 16 Godleski L I, Sernyak M. Agranulocytosis afterAddition of Risperidone to Clozapine Treatment.  Am J Psychiatry. 1996;  153(5) 735-736
    PubMedSearch in Google Scholar
  • 17 Grohmann R, Hippius H, Helmchen H, Rüther E, Schmidt L. The AMÜP study for drug surveillance in psychiatry - a summary of inpatient data.  Pharmacopsychiatry. 2004;  37 Suppl 1 S16-26
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Grohmann R, Rüther E, Engel R, Hippius H. Assessment of adverse reactions with the AMSP drug safety program: Methods and first results on tricyclic antidepressants and SSRI.  Pharmacopsychiatry. 1999;  31 1-8
    PubMedSearch in Google Scholar
  • 19 Grohmann R, Schmidt L, Spiess-Kiefer C, Rüther E. Agranulocytosis and significant luecopenia with neuroleptic drugs: results from the AMÜP program.  Psychopharmacology. 1989;  99 (109-112)
    PubMedSearch in Google Scholar
  • 20 Heimpel H. When should the clinician suspect a drug-induced blood dyscrasia, and how should he proceed?.  Eur J Haematol. 1996;  60(suppl) 11-15
    PubMedSearch in Google Scholar
  • 21 Hippius H, Kanig K. Die Agranulocytose unter neuro-psychiatrischer Phenothiazin-Therapie.  Ärztliche Wochenschrift. 1958;  13(23) 501-507
    PubMedSearch in Google Scholar
  • 22 Horler A R. Blood disorders. In: Davies DM, ed Textbook of adverse Drug Reactions 3. ed Oxford; Oxford University Press 1985: 578-594
    Search in Google Scholar
  • 23 Kaufman D W, Kelly J P, Jurgelon J. et al . Drugs in the aetiology of agranulocytosis and aplastic anaemia.  Eur-J-Haematol. 1996;  60 Suppl 23-30
    PubMedSearch in Google Scholar
  • 24 King D J, Wager E. Haematological safety of antipsychotic drugs.  J Psychopharmacol. 1998;  12(3) 283-288
    CrossrefPubMedSearch in Google Scholar
  • 25 Krupp P, Barnes P. Clozapine-induced agranulocytosis: risk and aetiology.  British Journal of Psychiatry. 1992;  160 38-40
    PubMedSearch in Google Scholar
  • 26 Lambert T. Olanzapine after clozapine: the rare case of prolongation if graulocytopaenia.  Aust NZ J Psychiatry. 1998;  32 591-592
    PubMedSearch in Google Scholar
  • 27 Lorenz M, Evering W E, Provencher A. et al . Atypical antipsychotic-induced neutropenia in dogs.  Toxicology and Applied Pharmacology. 1998;  155 227-236
    PubMedSearch in Google Scholar
  • 28 Mahmood T, Silverstone T, Spittle B. Risperidone appears safe in patients with antipsychotic-induced blood dyscrasias.  Int Clin Psychopharmacol. 1996;  11 53-54
    PubMedSearch in Google Scholar
  • 29 Meissner W, Schmidt T, Kupsch A, Trottenberg T, Lempert T. Reversible Leucopenia related to Olanzapine.  Movement Disorders. 1999;  14 872
    CrossrefPubMedSearch in Google Scholar
  • 30 Meylan C, Bondolfi G, Aubert A -C, Baumann P. Reversible neutropenia during a cold: possible involvement of risperidone?.  Europ Neuropsychopharmacol. 1995;  5 1-2
    PubMedSearch in Google Scholar
  • 31 Naumann R, Felber W, Heilemann H, Reuster T. Olanzapine-induced agranulocytosis.  Lancet. 1999;  354 566-567
    PubMedSearch in Google Scholar
  • 32 Oyewumi L K, Al-Seman Y. Olanzapine: Safe during Clozapine-Induced Agranulocytosis.  J Clin Psychopharmacol. 2000;  20(2) 279-281
    CrossrefPubMedSearch in Google Scholar
  • 33 Pisciotta A V. Agranulocytosis induced by certain phenothiazine derivates.  JAMA. 1969;  208 1862
    CrossrefPubMedSearch in Google Scholar
  • 34 Pisciotta A V. Drug-induced agranulocytosis.  Drugs. 1978;  15 132
    PubMedSearch in Google Scholar
  • 35 Rizvi M A, Shah S R, Raskob G E, George J N. Drug-induced thrombocytopenia.  Curr-Opin-Hematol. 1999;  6(5) 349-53
    PubMedSearch in Google Scholar
  • 36 Grohmann R, Engel R, Rüther E, Hippius H. The AMSP Drug Safety Program: Methods and Global Results.  Pharmacopsychiatry. 2004;  37 Suppl 1 S4-11
    Thieme ConnectPubMedSearch in Google Scholar
  • 37 Schuld A, Kraus T, Hinze-Selch D, Haack M, Pollmächer T. Granulocyte colony-stimulating factor plasma levels during clozapine- and olanzapine-induced granulocatopenia.  Acta Psychiatr Scand. 2000;  102 153-155
    CrossrefPubMedSearch in Google Scholar
  • 38 Steinwachs A, Grohmann R, Pedrosa F, Rüther E, Schwerdtner I. Two Cases of Olanzapine-Induced Reversible Neutropenia.  Pharmacopsychiatry. 1999;  32 154-156
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Strom B L, Carson J L, Schinnar R, Snyder E S, Shaw M. Descriptive epidemiology of agranulocytosis.  Arch Intern Med. 1992;  152 1475-1480
    CrossrefPubMedSearch in Google Scholar
  • 40 Swartz J R, Ananth J, Smith M W, Burgyone K S, Gadasally R, Arai Y. Olanzapine Treatment After Clozapine-Induced Granulocytopenia in 3 Patients.  J Clin Psychiatry. 1999;  60(2) 119-121
    PubMedSearch in Google Scholar
  • 41 Teter C J, Early J J, Frachtling R J. Olanzapine-Induced Neutropenia in Patients With History of Clozapine Treatment; Two Case Reports From a State Psychiatric Institution.  J Clin Psychiatry. 2000;  61(11) 872-873
    PubMedSearch in Google Scholar
  • 42 Tolosa C, Ruiz A, Mari B, Naval E. Olanzapine-Induced Agranulocytosis.  Int J Neuropsychopharmacol. 2000;  suppl 1 S93
    PubMedSearch in Google Scholar
  • 43 Wray C -M, Sztuke-Fournier A. Olanzapine: hematological reactions.  CMAJ. 1998;  159(1) 81-82
    PubMedSearch in Google Scholar

Dr. med. Susanne Stübner

Psychiatrische Klinik und Poliklinik

Abteilung für Forensische Psychiatrie

Nussbaumstraße 7

80336 München

Germany

Phone: +49-89-5160-2736

Fax: +49-89-5160-3389

Email: susanne.stuebner@med.uni-muenchen.de