The paper reviewed here is ‘Predicting Age-Specific Dosing of Antipsychotics’ by Uchida and colleagues. This is an opinion piece rather than a systematic review or research study which thus affords it more flexibility in the approach to the subject although firmer conclusions can be expected in other types of article in the evidence-base hierarchy. The authors consider the interaction between age and the loading dose for antipsychotics which the authors point out is especially important given the recent studies and reports on antipsychotics in specific populations (see here for example)*.
The authors argue citing evidence in the process, that with increasing age there is a loss both of the clearance of a drug (specific example given) and a decrease in the number of D2 receptors available for binding, a figure which decreases linearly with each passing decade. They also argue that surveys of prescribing data show age associated changes in the prescribed dose of antipsychotics for people with schizophrenia which supports the hypothesis that lower doses of antipsychotics should be prescribed in older age. This in turn is in keeping with various expert consensus guidelines. However there are obvious cultural factors that influence such prescribing and the authors note these confounders. The authors then outline a strategy for making predictions of D2 occupancy based on the plasma levels of an antipsychotic and to ensure this is applied across the lifespan. They have further studies in preparation.
Having such data is obviously extremely important and would imply that plasma levels would become clinically meaningful. There are several complexities that occur in this regards however. In older adults, polypharmacy is common relative to the population of younger adults which has the potential to influence plasma drug levels. While it can be argued that if there is a linear relationship between D2 occupancy and plasma drug levels the measured values still give useful information, such interactions may produce fluctuations in these drug levels which in turn would be expected to influence D2 occupancy. Nevertheless this argument would need supporting data. Another complexity here is that the drug clearance is influenced both by renal pathology and a number of other factors. This leads onto the point that with increasing age, comorbidity and polypharmacy may lead to an increasingly heterogenous population. This in turn may make it difficult to utilise a single model effectively and may necessitate solutions which organise this complexity in ways which facilitate prediction. This speculation also is in need of supporting data. Finally, particularly with the atypical antipsychotics, the actions have been argued to be effected not just at the D2 receptors but at a range of other receptors including other dopamine receptor subtypes, serotonin receptors, histamine receptors and so on. Thus it could be argued that an investigation of the same relationship between occupancy status and plasma drug levels could provide data contributing to more complex and realistic models.
The approach to studying lifespan changes in loading dose of antipsychotics is encouraging and it will be interesting to see the development of comprehensive age-related pharmacodynamic and pharmacokinetic models which are of clinical relevance and which can be combined with changes in practice to improve outcomes.
* The authors declare a potential conflicts of interests which include financial support from several pharmaceutical companies.
Uchida H, Pollock B G, Bies R R and Mamo D C. Predicting Age-Specific Dosing of Antipsychotics. Clinical Pharmacology and Therapeutics. Vol 86. Number 4. October 2009. 360-362.
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