Vol 4 n° 4 - Drug Development
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Keywords: atypical neuroleptic; monotherapy; dose–response relationship; optimal dose; schizophrenia Author   affiliations:   Nathan   S.   Kline   Institute   for   Psychiatric Research, Orangeburg, NY, USA Address for correspondence: Fabien Trémeau, MD, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY 10962, USA
(ftremeau@nki.rfmh.org) he use of atypical neuroleptics in psychotic dis- orders has steadily increased since 1989, and atypical neu- roleptics have become the first line of treatment for psy- chotic disorders. Since the marketing of clozapine in 1989 in  the  USA, several  other  atypical  neuroleptics  have become available to clinicians there, and this has extended and diversified the prescriptions of atypical neuroleptics. However, no newer atypical neuroleptic has yet shown greater efficacy than clozapine. In addition, many patients have improved only partially with these newer atypical neuroleptics. Clinicians often face difficult choices when patients do not respond or partially respond to these newer atypicals. Several strategic possibilities are then available to clinicians: (i) increasing the dosage of the antipsychotic; (ii) switching to another neuroleptic; (iii) augmenting treatment with a mood stabilizer; and (iv) using polypharmacy (meaning adding a second antipsy- chotic medication). Before adding any other medication, or changing to another neuroleptic, a fundamental ques- tion should be answered: has the current neuroleptic been optimally used? This question can be divided into two dif- ferent questions: has the length of the medication trial been long enough, and has the patient received an opti- mal dosage? In this presentation, we will focus on the second question: what is the optimal dosage for the atypical neuroleptics? We will limit the neuroleptics to the atypical agents cur- rently available in the USA (clozapine, risperidone, olan- zapine, quetiapine, ziprasidone, and aripiprazole), and thus we will not discuss dosing issues regarding other atypicals such as sertindole or amisulpride. Lessons from typical neuroleptics The issue of optimal dosage with typical neuroleptics has been the focus of frequent debates. For example, in the seventies, very high doses of haloperidol were routinely P h a r m a c o l o g i c a l   a s p e c t s 4 3 8 Optimizing dosing in atypical neuroleptic monotherapy Fabien Trémeau, MD; Leslie Citrome, MD, MPH T Atypical neuroleptics have become the first line of treat- ment for psychotic disorders, but some questions remain: what are their optimal dosages and is more medication more efficacious? For clozapine, it is recommended to aim for a plasma level above 350 ng/mL for nonresponders and partial responders. It should be specified that this plasma level should be obtained exactly 12 h after the last dose. For risperidone, optimal daily doses range between 4 and 8 mg, and there is no indication that a higher dose would bring additional improvement. For olanzapine, a quite different situation is encountered. There is a good indication that daily doses of 30 and 40 mg can increase clinical response. It appears that plasma levels above 23 ng/mL may predict response. For quetiapine, reports on the utility of dosages greater than 800 mg/day are anec- dotal at this point, and more studies should be conducted. For ziprasidone, dosages above 40 mg/day should be used, but daily doses above 200 mg have not yet been system- atically investigated. Dialogues Clin Neurosci. 2002;4:438-443.