Vol 6 n° 1 - Predictors of Response to Treatment in Neuropsychiatry
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espite the proven efficacy of antipsychotic med- ications and despite the additional advantages of the new- generation antipsychotics,1-5 one-fifth to one-half of schiz- ophrenia   patients   are   classified   as   refractory   to pharmacological treatment6-13 and this proportion remains consistent  over  time.3 The  management  of  treatment- refractory  schizophrenia  (TRS)  is  a  persistent  public health problem, because a substantial number of inpatient psychiatric  beds14  and  resources  are  devoted  to  these patients,15 and because they experience the worst out- comes, such as suicide16 and homelessness.17 TRS can man- ifest itself as failure to achieve remission from the initial episode of psychosis, failure to maintain remission, or grad- ual deterioration in the context of successive relapses.18 For classification and descriptive purposes, as well as for enrollment into trials of experimental treatments, TRS patients are grouped on the basis of predefined criteria. However, there is considerable variability within this population, in terms of specific domain of treatment refractoriness as well as degree of refractoriness (sever- ity of persistent symptoms). Defining treatment refractoriness Since treatment with antipsychotic drugs has been the most accepted and effective treatment intervention in schizophrenia over the last 40 years, the traditional def- P h a r m a c o l o g i c a l   a s p e c t s 6 1 Treatment-refractory schizophrenia Asaf Caspi, MD; Michael Davidson, MD; Carol A. Tamminga, MD D Between one-third and one-half of the individuals who meet diagnostic criteria for schizophrenia remain actively ill despite optimal pharmacological treatment. These indi- viduals tend to progressively deteriorate in terms of social and vocational functioning despite major public and pri- vate investments in their rehabilitation. For patients who do not respond to the first prescribed antipsychotic drug, current clinical practice is to switch to a second and a third drug, and eventually to clozapine, the only antipsy- chotic drug proven to be effective in treatment-refrac- tory schizophrenia (TRS). Occasionally, two antipsychotics are given concomitantly or psychotropic drugs are added to antipsychotic drugs; however, very few empirical data exist to support this practice. Although there are many exceptions, patients who do not benefit from the first prescribed drug will not benefit from any pharmacolog- ical intervention. Therefore, efforts are under way to determine the reason for lack of response to available treatments and devise novel, more effective treatments. To be successful these efforts must result in a more spe- cific definition of TRS, as well as in a better understand- ing of the illness pathophysiology and the mechanism of action of the drugs. © 2004, LLS SAS Dialogues Clin Neurosci. 2004;6:61-70. Keywords: schizophrenia; treatment; antipsychotic agent; mechanism for treat- ment-refractory schizophrenia Author affiliations: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (Asaf Caspi, Michael Davidson); Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA (Carol A. Tamminga) Address  for  correspondence:  Michael  Davidson,  MD,  Chaim  Sheba  Medical Center, Beitan 39A, Tel-Hashomer 52621, Israel (e-mail: davidso@netvision.net.il) Copyright © 2004 LLS SAS.  All rights reserved www.dialogues-cns.org