Pharmacokinetic and pharmacodynamic contributions to EPS

The consensus, based on meta-analyses of placebo controlled trials of risperidone in people with psychosis in Alzheimer's disease, is that 1 mg/day risperidone may optimally balance efficacy and adverse effects.^{Reference Tampi, Tampi, Balachandran and Srinivasan3,Reference Katz, de Deyn, Mintzer, Greenspan, Zhu and Brodaty7,Reference Schneider, Dagerman and Insel21} However, meta-analyses can only inform the ‘average’ dose requirements, but are less able to identify subgroups who are most susceptible to side-effects. In this analysis we have investigated the pharmacokinetic (dose–concentrations) and pharmacodynamic (concentration–outcome) contribution to EPS, to guide safer prescribing.

We estimated that 22% of patients were functionally poor metabolisers, and observed an independent effect of age on risperidone clearance. Pharmacokinetic biomarkers were robust predictors of EPS, with higher trough concentrations of 9-OH-risperidone and active moiety providing the best fit for the data. Lower MMSE, a marker of more severe global cognitive impairment, was an independent predictor of EPS. Model-based simulations suggest that, for functionally normal metabolisers aged 75 years with an MMSE of 15 (moderate Alzheimer's disease severity), 1 mg/day would be associated with minimal risk of EPS, but a dose reduction to 0.5 mg/day would be required for those with an MMSE of 5. For those aged 85 years, a 50% dose reduction would be required and, for those who are functionally poor metabolisers, alternate day dosing would be required to avoid excessive exposure.

Drug metabolism is a major contributor to pharmacokinetic variability and, in older adults, the relative importance of genotype is difficult to disentangle from physiological and clinical factors.^{Reference de Leon15} In the absence of information on CYP2D6 genotype, the extent of any genetic contribution to functional metaboliser status is unclear, although estimates of risperidone clearance in participants who were functionally poor metabolisers and functionally normal metabolisers were broadly consistent with estimates for CYP2D6-predicted ‘intermediate’ and ‘extensive’ metabolisers,^{Reference Feng, Pollock, Coley, Marder, Miller and Kirshner10} with a single patient having a risperidone/9-OH-risperidone ratio greater than one (suggestive of a genetically poor metaboliser).^{Reference de Leon15}

Age was independently associated with risperidone clearance and, when incorporated into the model, led to the reassignment of six patients who were initially categorised as being functionally poor metabolisers. Although previous research has not shown an effect of age specifically on risperidone clearance,^{Reference Feng, Pollock, Coley, Marder, Miller and Kirshner10} a 30% decrease in hepatic metabolism in those aged over 70 years has been observed for other CYP2D6 substrates^{Reference Sotaniemi, Arranto, Pelkonen and Pasanen22} and it is thus likely that our findings are explained by the older age of CATIE-AD participants. The long t_1/2 (27 h) of 9-OH-risperidone in the sample as a whole is consistent with age-related impairment in renal clearance in CATIE-AD participants, which resulted in high trough concentrations of 9-OH-risperidone. This is important as the association between trough active moiety concentrations and EPS was largely explained by 9-OH-risperidone.^{Reference Vandenberghe, Guidi, Choong, von Gunten, Conus and Csajka12}

The absence of an association between pharmacokinetic biomarkers and sedation warrants further consideration, as it may reflect the fact that distinct pharmacological mechanisms underpin sedation and EPS. However, methodological limitations need to be taken into account, as sedation was not measured using a standardised scale, but was identified solely from the adverse event log. This is important as only eight participants were rated as having EPS in the adverse event log, compared with the 14 identified using SAS and BAS scores. Prior exposure to antipsychotic drugs before randomisation also needs to be considered, as this may have reduced our ability to detect a relationship between sedation and pharmacokinetic biomarkers. This was not the case for EPS, as patients who scored above the threshold cut-off on SAS or BAS at baseline were excluded from further analysis.

Statistical modelling of the relationship between risperidone active moiety plasma concentrations and D_2/3 receptor occupancy^{Reference Uchida, Takeuchi, Graff-Guerrero, Suzuki, Watanabe and Mamo23} in adults with schizophrenia, suggests that trough concentrations of 10.5–38.2 ng/mL are associated with 60–78% occupancy in the striatum, and 6.5 ng/mL (95% CI, 3–10 ng/mL) is associated with 50% occupancy. In CATIE-AD participants, EPS emerged from trough active moiety concentrations of 3.4 ng/mL (of which 3.2 ng/mL was 9-OH- risperidone), and concentrations exceeded 10 ng/mL (60% occupancy) in 8 of 14 patients with EPS. In the absence of occupancy data, it is unclear whether the emergence of EPS at such low concentrations signifies a leftwards shift in the concentration–occupancy curve, similar to that observed during amisulpride treatment.^{Reference Reeves, McLachlan, Bertrand, D'Antonio, Brownings and Nair5} This is possible, as risperidone and 9-OH-risperidone are substrates for P-glycoprotein,^{Reference Wang, Ruan, Taylor, Donovan, Markowitz and DeVane24} a blood–brain barrier efflux transporter that is marked reduced in older people with Alzheimer's disease.^{Reference van Assema, Lubberink, Bauer, van der Flier, Schuit and Windhorst25} However, age- or disease-specific changes in brain–drug distribution, clearance and competition with endogenous dopamine at receptor sites need to be considered.^{Reference Reeves, McLachlan, Bertrand, D'Antonio, Brownings and Nair5}

Pharmacodynamic changes (reduced D_2/3 receptor reserve, altered signal transduction) that lead to a greater functional outcome for a given occupancy are also important. We have previously observed EPS at low striatal D_2/3 receptor occupancies (60% compared with 80% in young people), in older people with schizophrenia taking risperidone,^{Reference Uchida, Suzuki, Graff-Guerrero, Mulsant, Pollock and Arenovich26,Reference Graff-Guerrero, Rajji, Mulsant, Nakajima, Caravaggio and Suzuki27} and older people with psychosis in Alzheimer's disease taking amisulpride.^{Reference Reeves, McLachlan, Bertrand, D'Antonio, Brownings and Nair5} Given the error margin of occupancy predictions, we cannot rule out the possibility that occupancy was underestimated in a proportion of those with active moiety concentrations less than 10 ng/mL.^{Reference Uchida, Takeuchi, Graff-Guerrero, Suzuki, Watanabe and Mamo23}

The observed association between lower MMSE score, a marker of greater neuropathological change, and emergent EPS is consistent with previous clinical observations in patients taking risperidone.^{Reference de Leon15} Furthermore, an association between agitation, antipsychotic use and death in those with more severe dementia has been reported in a recently published cohort study.^{Reference Aworinde, Werbeloff, Lewis, Livingston and Sommerlad28} The mechanisms of antipsychotic-induced EPS are not fully understood, but D_2/3 receptor antagonism of inhibitory dopaminergic inputs to striatal medium spiny neurons and cholinergic interneurons may play a key role.^{Reference Ohno, Kunisawa and Shimizu2} It is unclear whether the risk of EPS in those with lower MMSE scores reflects greater impairment in networks that modulate motor control, or is associated with as yet unidentified factors that potentiate EPS.

Limitations

Limitations to the analysis include sparse sampling, which meant it was not possible to estimate within-participant variability in clearance of risperidone or 9-OH-risperidone, or to investigate the contribution of concomitant medications to pharmacokinetic variability. Neither was it possible to investigate the contribution of comorbid medical conditions to variability in pharmacokinetics or emergent side-effects. The lack of information on renal function is a major limitation, given the significant association between plasma concentrations of the renally eliminated metabolite and emergent EPS. This needs to be addressed in future studies.

We cannot account for the fact that those with emergent EPS were more likely to have been prescribed concomitant trazodone, given the small sample size and uncertain exposure (dose, continuity of the prescribed drug) of individual participants to trazodone. However, we cannot rule out the possibility of potential drug–drug interactions, including an interaction with P-glycoprotein, for which trazodone is a substrate. Preclinical studies have shown that selective serotonin reuptake inhibitors potentiate antipsychotic-induced EPS and this may be relevant as trazodone acts as a weak reuptake inhibitor.^{Reference Ohno, Kunisawa and Shimizu2} The issue of polypharmacy is an important one, as antipsychotic drugs are often initiated alongside other drug treatments, including sedating antidepressants and the downstream effects of central drug–drug interactions are poorly understood. Other limitations relate to the CATIE-AD study design, which may have reduced our ability to detect associations between pharmacokinetic indices and clinical outcome. This includes flexibility in starting dose (low or high), and the option of making adjustments or of discontinuing a phase, based on clinician judgement.

Dose adjustments needed to avoid treatment-emergent EPS

This analysis represents a step towards safer risperidone prescribing and argues strongly for age- and MMSE- related dose reductions. From a pragmatic perspective, clinicians should ‘start low go slow’ (0.5–1 mg/day) in those aged 75 years with moderate stage Alzheimer's disease, and ‘start low, stay low’ (maximum 0.5 mg/day) in those aged 75 years with severe Alzheimer's disease. For those aged 85 years, the dose should be halved, and alternate daily dosing should be considered if side-effects emerge, as it is likely that the person has slower active moiety clearance.

Personalised prescribing should ideally incorporate knowledge of genetic, environmental and personal variables to determine dosing. This is not currently happening in clinical practice and there has been a lack of empirical data in older people to justify the use of routine therapeutic drug monitoring. A recently proposed personalised prescribing algorithm for risperidone suggests that high trough concentration-to-dose ratios are indicative of slower active moiety clearance, as a result of the combined effect of CYP2D6, 3A4 and renal clearance.^{Reference de Leon15} Our analysis, which used model-based estimates of trough concentrations, were consistent with this recommendation and suggested that alternate daily dosing may be required in those with higher concentration-to-dose ratios to avoid emergent EPS. Therapeutic drug screening offers the opportunity to guide dose adjustments with more precision, as the concentration-to-dose ratio of the active moiety could be derived from a single steady state trough plasma sample, to identify those at higher risk of excessive exposure. It will, however, be important to replicate these findings in a larger data-set that includes information on renal function, and allows further investigation of the impact of antidepressant use on the observed associations. Alongside this, future studies should evaluate the feasibility and clinical utility of therapeutic drug screening in older people with Alzheimer's disease.