D. Layton.
Background
In the UK, the Ready Reckoner algorithm is a tool used in psychiatric clinical practice to monitor antipsychotic dosing in patients with complex antipsychotic regimens. For each patient, the dose of each antipsychotic can be converted to percentage of relevant maximum dose according to each indication and titration stage as specified in the Summary of Prescribing Characteristics (SPC). Total dose percentage (TD%) >100% identifies patients at risk. A nested case control (NCC) study was undertaken as part of a post authorisation safety study (PASS) program to explore possible dose- event response for somnolence/sedation (SS) after starting a new formulation of an antipsychotic, with a focus on evaluating total daily dose (TDD)> 600mg.
Objectives
An exploratory analysis to evaluate use of the Ready Reckoner algorithm as an alternative indication-adjusted dose metric to model antipsychotic treatment effects
Methods
An incidence density matched NCC study used data from a primary care based observational cohort study (N=13276) identified between September 2008 and February 2013. Of 756 cases, 212(28%) were randomly selected and 170 risk sets created. For all subjects, the reported TDD (start, maintenance, and event) were converted to TD% in accordance with the Ready Reckoner algorithm; for off label indications the SPC dose range for major depression was used. Fractional polynomial (FP) logistic models explored functional form; empirical and fitted within-person Ordinary least Squares (OLS) dose trajectories described patterns over time
Results
SS cases tended have higher reported TDD vs controls at start [median 300 (IQR 200,600) vs 200mg (IQR 100,300), p<0.01] but the inverse was seen when the TD% metric was applied (median 50% (IQR 16,100) vs 75% (33,100), p=0.02). At maintenance & event, similar relationships were observed for reported TDD and TD% variables. SS risk was a negative function of TDD and TD%. No deviation from linear assumption was apparent for start and maintenance doses (FP2 vs linear, P>0.05), but was non-linear for TD% at event (p=0.04). In exploring pattern over time, the general trend was decreasing for both cases and controls, although slower for controls.
Conclusion
This exploratory analysis demonstrates the feasibility of the Ready Reckoner algorithm as an alternative method of calculating an indication-adjusted variable suitable for analysing dose- related effects, particularly where multiple indications may exist that use various dose ranges. Analytical advantages include avoiding creation of strata of small sample sizes. Limitations include possible metric under-estimation from missing data for other concomitant antipsychotics.