Letters to the Editor
Re: Atypical Antipsychotics Mechanisms of Action
Dear Editor:
Dr Seeman’s hypothesis with regard to the mechanism by which the atypical antipsychotics (APs) improve psychosis with a “minimum” of extrapyramidal side effects (EPSEs) is thought-provoking (1). Nevertheless, important observations remain unexplained. For example, according to this hypothesis, amoxapine should be atypical; however, it is not—at least, not in Parkinson’s disease (PD) patients (2). Pimozide, which is most similar clinically to haloperidol in terms of EPSEs, should in theory be more atypical than risperidone. Olanzapine, which certainly worsens parkinsonism in PD patients (thus illustrating its extrapyramidal effects), has very little effect on prolactin levels, in contrast to risperidone and the typicals. According to their D2 binding, molindone and loxapine should be more atypical than risperidone, yet they seem to lack any special benefits other than those previously accorded to low-potency neuroleptics. Perhaps most intriguing is the observation that olanzapine treatment, which PD patients tolerate poorly owing to motor dysfunction, is virtually free from acute dystonic reactions—a property shared by quetiapine and clozapine, but not by risperidone.
Significant conflicting reports complicate efforts to interpret the EPSEs of these drugs, with studies reporting either major or no parkinsonism from olanzapine and risperidone (3). One study even reports that, when compared, neuroleptic-naïve young patients receiving equal dosages of either risperidone or haloperidol showed no differences in parkinsonism, acute dystonia, and akathisia (4).
While the “fast-off-D2” theory may be important, it does not completely explain the effects of the atypical APs, which all act on a myriad of neurotransmitters. The suggestion that thioridazine may be “relatively free” of EPSEs is speculative and, if true, not clearly related to its anticholinergic properties. There are clear limits to the benefits of anticholinergics in alleviating the signs and symptoms of neuroleptic-induced parkinsonism: concurrent treatment with anticholinergics reduces, but does not eliminate, parkinsonism. Conversely, clozapine’s anticholinergic action is not mirrored in systemic side effects (for example, dry mouth, constipation, blurred vision, or impaired memory). Clozapine has potent antitremor effects in PD patients, and it works in patients who failed to respond to anticholinergics at higher dosages.
It is also apparent that formulating hypotheses is limited by conflicting data on just what motor side effects these drugs have.
I close by asking about the relevance of data suggesting preferential binding of drugs in and out of the striatum.
References
1. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002;47:27–38.
2. Sa DS, Kapur S, Lang AE. Amoxapine shows an antipsychotic effect but worsens motor function in patients with Parkinson’s disease and psychosis. Clin Neuropharmacol 2001;4:242–4.
3. Friedman JH, Factor SA. Atypical antipsychotcs in the treatment of drug induced psychosis in Parkinson’s disease. Mov Disord 2000;15:201–11.
4. Rosebush PI, Mazurek MF. Neurologic side effects in neuroleptic-naïve patients treated with haloperidol or resperidone. Neurology 1999;52:782–5.
Joseph H Friedman, MD
Pawtucket, Rhode Island
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