Progress in Neuro-Psychopharmacology and Biological Psychiatry
Combination of “atypical” antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder
Introduction
Antipsychotic medication is effective in the treatment of psychotic symptoms. However, between 20% and 40% of schizophrenic patients exhibit inadequate or poor response. This appears to be the case not only with the use of “typical” or classical antipsychotic medications, but also with the use of the newer “atypical” antipsychotic medications such as clozapine, olanzapine, quetiapine, risperidone, remoxipride, sertindole, amisulpride, sulpiride, tiapride, and ziprasidone Barnes et al., 1996, Toren et al., 1998. While the precise definition labeling an antipsychotic medication “atypical” remains controversial, several have suggested that the “atypicality” of an antipsychotic medication refers to its antipsychotic effect without associated extrapyramidal effects and minor (if any) increases in prolactin levels, as well as hypothesized effects on negative symptoms. Their unique mechanism of action, in contradistinction to “typical” antipsychotics, includes combined serotonin 5-HT2/dopamine D2 occupancy thresholds with a high ratio of serotonin type 2 (5HT2) to dopamine type 2 (D2) receptor inhibition Meltzer et al., 1989, Gerlach and Peacock, 1995, Kapur and Remington, 1996, Waddington et al., 1997. In addition, they exhibit a greater specificity for the mesolimbic dopamine system than for the striatal dopamine system (Goldstein, 2000). Although evidence as to their absolute superiority in the management of treatment-resistant illness remains controversial, many believe that atypical antipsychotic medication may be more effective that typical antipsychotic medications Chouinard et al., 1993, Marder and Meibach, 1994, Tollefson et al., 1997.
Considering that the problem of treatment-resistant psychosis in this subpopulation of patients is an important and difficult one, several approaches have been considered by clinicians in order to deal with the clinical challenge. These have included switching treatment-resistant patients from a classical neuroleptic drug to an “atypical” antipsychotic or to an alternative “typical” agent from a differing chemical class, the use of electroconvulsive therapy, adding another psychotropic drug such as benzodiazepines, lithium, or anticonvulsants, or to combine high and low potency antipsychotic medication (Zarate et al., 1995). However, this practice appears to have been based more on clinical impression, experience, and published guidelines rather than any controlled clinical trials Fleischhacker and Hummer, 1997, Stern et al., 1997, Stahl, 1999a, Stahl, 1999b, Meltzer and Kostakoglu, 2000. Thus, the quest for more safe and effective methods to treat resistant psychotic conditions remains.
Since the development and introduction of “atypical” antipsychotic medication into routine clinical management, the use of combinations of antipsychotic drugs to treat schizophrenia has appeared to gain new impetus. Since the newer “atypical” antipsychotic medications exhibit a more novel neuroreceptor profile, the assumption became that combination with a second either “typical” or “atypical” antipsychotic medication would provide a more efficacious profile. Interestingly, however, while the recommendation is usually to avoid polypharmacy and most clinical trials are conducted with monotherapy, recent evidence demonstrates that in practice more than 20% of patients are taking two or more drugs (Stahl, 1999c). Despite the observation that clinicians now readily combine an “atypical” with a “typical” antipsychotic or combine two “atypical” antipsychotics, there remains little, if any, systematic evidence to clearly support this practice (Conley and Buchanan, 1997).
In this article, the authors summarize and review the results of combination antipsychotic medication management of resistant schizophrenia and schizoaffective disorder, with a focus on combinations of “atypical” antipsychotic drugs in the treatment of this patient subpopulation. While combinations of typical and atypical antipsychotic medications are frequently administered to patients as referred to above Freudenreich and Goff, 2002, Stahl, 2002, Weissman, 2002, Tapp et al., 2003, we focus on combinations of “atypical” antipsychotic medications since they are being increasingly dispensed to patients, and limited information describing their use and efficacy, if any, exists in the academic literature.
Section snippets
Method
Since “atypical” antipsychotic medications first became readily available for clinical use towards the end of 1980, the authors performed a computerized literature search (National Library of Medicine/MEDLINE) for the years ranging from 1985 to 2003, including both English and non-English language articles. A search of the following key words was conducted: resistant/refractory schizophrenia, resistant/refractory schizoaffective disorder, “atypical” antipsychotic, clozapine, risperidone,
Results
The selective review of literature relating to treatment-resistant schizophrenic and schizoaffective patients managed with combination (coadministration) “atypical” antipsychotic drugs revealed only 28 articles and two abstracts from 202 publications dealing with treatment resistance. The reports were carefully reviewed and are presented in Table 1. Nineteen of the references were case reports, 8 were open study, and only 1 reporting a double-blind placebo-controlled trial. Of seven “atypical”
Discussion
Since the first advent of antipsychotic medications in the early 1950s, mental health practitioners have used drug combinations to manage schizophrenic patients, although this approach has frequently provoked controversy (Anonymous, 2000). While most treatment guidelines recommend pharmacological monotherapy, little is known about the extent to which psychiatrists actually comply with this advice. For example in Austria, Rittmannsberger et al. (1999) observed that only approximately 8–22% of
Conclusion
Combinations of “atypical” antipsychotic medications are well tolerated in the most reviewed reports and may be effective in the management of treatment refractory schizophrenia and schizoaffective disorder. However, further double-blind placebo-controlled trials are required in order to test and confirm these observations.
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