Olanzapine and risperidone plasma concentration therapeutic drug monitoring: A feasibility study

Abstract

Background:

This study aimed to develop a clinically acceptable method of therapeutic drug monitoring (TDM) for olanzapine and risperidone and to evaluate the feasibility of its implementation.

Method:

A non-randomised study of inpatients from five Mental Health Trusts was conducted, with a clinical interview at the time of TDM and a subsequent 6-week follow-up review of clinical notes. The TDM intervention comprised: (a) a venous blood sample taken 12 hours post-dose, 7–10 days after drug initiation, and (b) rapid results feedback, with interpretation algorithm guidance.

Results:

Thirty-two participants provided samples (19 prescribed olanzapine, 13 risperidone). Twenty-six participants remained on the target drug at study end, with seven experiencing a dose change, for whom only four of the TDM results were confirmed as having been checked. Mean dose increased for olanzapine (0.9 mg/day, range 0–10) and decreased for risperidone (-0.3 mg/day, range -4–3).

Conclusion:

TDM can be implemented as part of routine clinical practice for both drugs. However, the lack of robust supporting evidence for or against antipsychotic TDM has probably led to a lack of enthusiasm for and interest in the results. Nevertheless, the advent of less invasive measures and the targeting of patients who might be more likely to benefit may facilitate uptake.

Keywords

Antipsychotics schizophrenia dose therapeutic drug monitoring plasma concentration olanzapine risperidone

Introduction

Therapeutic drug monitoring (TDM) can aid in the optimisation of antipsychotic prescribing, through the monitoring of an individual’s plasma drug concentrations to assess adherence and guide dose (Hiemke et al., 2011). European guidelines (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie; AGNP) ‘strongly recommend’ the use of TDM for several second-generation antipsychotics (SGAs), including olanzapine and risperidone (Hiemke et al., 2011). These recommendations are supported by data from the UK that demonstrated significant inter-patient variability in the plasma concentrations of olanzapine and of ‘total risperidone’ (risperidone + total 9-hydroxyrisperidone), allowing for dose (Bowskill et al., 2012; Patel et al., 2011). However, a recent systematic review, including clinical trial data, recommended a more limited role for olanzapine TDM (Bishara et al., 2013).

Likely future use of antipsychotic TDM has been found to be influenced by psychiatrists’ attitudes and perceived potential barriers (Patel et al., 2014b), which include the strength of the evidence base, difficulty in interpreting TDM results and patients’ acceptance of TDM methods (Best-Shaw et al., 2014). Currently, clozapine is the only SGA for which TDM is more routinely used in clinical practice in the UK, despite psychiatrists holding mainly positive attitudes to TDM for other SGAs (Best-Shaw et al., 2014; Conca et al., 2011; Patel et al., 2014b). This may be a result of weak evidence that TDM can improve clinical outcomes for other SGAs as compared with clozapine (Lopez and Kane, 2013). Furthermore, current schizophrenia treatment guidelines do recommend the use of TDM for clozapine when response is suboptimal (Buchanan et al., 2010; Hasan et al., 2012), particularly prior to augmenting with another antipsychotic (National Institute for Health and Care Excellence, 2014).

In essence, TDM is rarely used in normal clinical practice for olanzapine and risperidone, despite favourable findings from large cross-sectional studies (Bowskill et al., 2012, Patel et al., 2011), psychiatrists’ positive attitudes towards TDM and also strong recommendations from European TDM guidelines (Hiemke et al., 2011). Neglecting to use TDM for olanzapine and risperidone may constitute a missed opportunity for improving symptom control. Further, high-dose prescribing is commonplace (Patel et al., 2014a) and yet there is little evidence that it confers additional benefit over standard doses, but the increasing likelihood of problematic side effects is apparent (Paton et al., 2008; Prescribing Observatory for Mental Health, 2012).

An important step towards integrating TDM for antipsychotics other than clozapine into routine practice is to conduct an intervention study to test the clinical utility of TDM for SGAs with stronger evidence for potential benefit, such as olanzapine and risperidone. This small-scale pilot study aimed to investigate the feasibility of, and develop a methodology for, a subsequent randomised controlled trial (RCT). Feasibility was examined with regard to acceptability of the TDM intervention for patients and the practicalities of the TDM procedure, including feedback of results to clinicians, as well as testing the proposed primary outcome. Given the high doses commonly prescribed in routine practice, we hypothesised that TDM would highlight the lack of need for further increasing the dose and so participants receiving the intervention would more likely have a reduction, rather than an increase, in target antipsychotic (olanzapine or risperidone) dose to a minimum effective dose.

Method

Study design

A non-randomised, intervention feasibility study of TDM for patients prescribed either olanzapine or risperidone was conducted with a clinical interview assessment at the time of TDM (baseline) and a subsequent 6-week follow-up review of clinical notes.

Setting and sample

Patients were recruited from five Mental Health Trusts in London and south-east England. A sample size of 30 was originally planned, with approximately 10–15 participants per drug being considered sufficient to determine feasibility of the TDM intervention and inform further sample size calculations for a future definitive RCT (Julious, 2005).

Inclusion criteria were: age 18–65 years, inpatients admitted in the preceding 8 weeks, with a diagnosis of schizophrenia or schizoaffective disorder, current acute psychotic symptoms, and initiated on oral risperidone or olanzapine in the preceding 4 weeks. Exclusion criteria were: clozapine prescription within the past 12 months; currently regularly prescribed a second antipsychotic (although pro re nata (PRN) prescriptions and other medications, including other psychotropics, were allowed).

Intervention

The intervention comprised: (a) a venous blood sample (taken into EDTA) 12 hours post-dose for TDM analysis, 7–14 days after initial drug initiation; (b) rapid feedback of TDM results to clinicians, accompanied by a newly developed algorithm offering interpretation and advice for individual patient antipsychotic dose management (Figure 1); and (c) up to two further blood tests to check plasma analyte concentrations following a dose change. The algorithm was based on target ranges and time to steady state (olanzapine 20–40 ng/mL, 7 days (Bishara et al., 2013); total risperidone 20–60 ng/mL, 5 days (Bowskill et al., 2012)). TDM results were fed back via an online system with the interpretation algorithm.

Olanzapine and total risperidone assay

Plasma olanzapine and total risperidone (risperidone + total 9-hydroxyrisperidone [(+)-9-hydroxyrisperidone and (-)-9-hydroxyrisperidone]) were measured by liquid chromatography-tandem mass spectrometry after extraction into methyl tert-butyl ether at pH 10.6 (Fisher et al., 2013).

Measures

Baseline

To characterise the samples’ current mental and physical wellbeing, symptomatology, functional ability, quality of life, attitudes towards medication and antipsychotic side effects were assessed (Table 1). To identify potential factors which might impact on metabolism, the following were recorded: smoking status (classified as ‘current’ if the participant had used tobacco in the past 12 months); illicit drug use; alcohol use; and the prescription of concomitant medication, including psychotropic and other medication prescribed. Body mass index (BMI), waist to hip ratio and blood pressure were measured to assess risk of metabolic syndrome.

Table 1.

Sample baseline sociodemographic and clinical characteristics.

483.307 pt	Olanzapine(n = 19^a)			Risperidone(n = 13^b)			Total(n = 32^c)
	n	%		n	%		n	%
Sex
Male	16	84.2		9	69.2		25	78.1
Female	3	15.8		4	30.8		7	21.9
Ethnicity
White	7	36.8		5	38.5		12	37.5
Other ethnic group	12	63.2		8	61.5		20	62.5
Education level
No qualifications	2	10.5		2	15.4		4	12.5
GCSE^d level or higher	14	73.7		7	53.8		21	65.6
Missing	3	15.8		4	30.8		7	21.9
Employment status
Employed	3	15.8		1	7.7		4	12.5
Not employed	15	78.9		11	84.6		26	81.3
Missing data	1	5.3		1	7.7		2	6.2
Relationship status
Single/other	17	89.5		11	84.6		28	87.5
Married/steady relationship	2	10.5		1	7.7		3	9.4
Missing data	0	0		1	7.7		1	3.1
Accommodation status
Living alone/sole occupancy bed-sit	11	57.9		4	30.8		15	46.9
Living with others/sheltered	8	42.1		9	69.2		17	53.1
Diagnosis
Schizophrenia	16	84.2		13	100		29	90.6
Schizoaffective disorder	3	15.8		0	0		3	9.4
Smoking
Current smoker	13	68.4		10	76.9		23	71.9
Previous smoker	2	10.5		1	7.7		3	9.4
Never smoked	4	21.1		2	15.4		6	18.7
	Mean	SD	Range	Mean	SD	Range	Mean	SD	Range
PANSS
Total PANSS	62.2	12.7	42–90	68.3	13.4	39–92	64.6	31.1	39–92
Positive	16.5	5.4	7–27	17.8	5.4	8–26	17.0	5.4	7–27
Negative	14.5	5.7	7–24	16.0	4.8	8–25	15.1	5.3	7–25
General psychopathology	31.2	7.2	19–47	34.5	5.4	23–42	32.5	6.6	19–47
GAF	48.6	17.4	24–75	47.5	13.6	26–67	48.2	15.8	24–75
SF-36
Physical composite	51.0	9.8	30.0–63.7	48.0	11.3	26.0–63.4	49.7	10.4	26.0–63.7
Mental composite	36.7	14.1	6.5–60.1	40.3	15.7	10.7–62.3	38.2	14.6	6.5–62.3
DAI	4.5	2.5	0–8	5.7	2.6	1–9	5.0	2.6	0–9
AUDIT	4.3	4.9	0–15	4.1	6.5	0–24	4.2	5.5	0–24
ANNSERS
Total number of present side effects	8.4	5.4	3–23	11.8	7.7	2–27	9.8	6.5	2–27
Weighted score	13.6	11.6	4–47	21.8	14.4	2–44	16.9	13.2	2–47
BARS
Objective and subjective ratings	0.6	1.6	0–6	0.5	1.1	0–4	0.6	1.4	0–6
Global clinical assessment	0.4	0.9	0–3	0.2	0.6	0–2	0.3	0.8	0–3
SAS	0.4	0.4	0–1.3	0.4	0.7	0–2	0.4	0.5	0–2
	n	%		n	%		n	%
AIMS
Positive AIMS examination score	2	10.5		1	7.7		3	9.4
Negative AIMS examination score	17	89.5		12	92.3		29	90.4

Including three who discontinued olanzapine

Including three who discontinued risperidone

Three participants were excluded due to protocol violation and poor data quality

National examinations when aged 16 years

PANSS: Positive and Negative Syndrome Scale (Kay et al., 1987); GAF: Global Assessment of Functioning (Frances and Pincus, 1994); SF-36: Short Form (36) Health Survey (Ware et al., 1993); DAI-10: Drug Attitude Inventory 10-item version (Awad, 1993); AUDIT: Alcohol Use Disorders Identification Test (Saunders et al., 1993); ANNSERS: Antipsychotic Non-Neurological Side-Effect Rating Scale (Ohlsen et al., 2008); BARS: Barnes Akathisia Rating Scale (Barnes, 1989); SAS: Simpson–Angus scale (Simpson and Angus, 1970); AIMS: Abnormal Involuntary Movement scale (Guy, 1976).

Primary outcome

Change in target antipsychotic (olanzapine or risperidone) total daily prescribed dose from baseline to 6-week follow-up.

TDM intervention feasibility

The feasibility of the TDM procedure was assessed through checking sample timing after the last dose (trough level) and whether steady state was achieved prior to sampling, the proportion of blood samples collected that were analysed, and the timely feedback of results. The acceptability of the method of feedback of TDM results was assessed using data from focus groups. Untoward events experienced by the participants during the course of the study were also recorded.

Procedure

Participant recruitment was conducted from August 2011 to October 2012. Participants were provided with an information sheet and written informed consent was obtained. Clinical and research staff and participants were not blinded as there was no comparison control group. The baseline clinical interview was conducted and blood was taken and sent for laboratory analysis. Clinicians were asked to confirm whether they checked the results. Six-week follow-up data were collected by review of the clinical notes. Two focus groups were conducted to explore patient participants’ acceptability of the methods used. The study was approved by an independent ethics committee and local governance policies were adhered to.

Data analysis

The data were captured and managed online using the InferMed MACRO database system and analysed using Stata version 11. Descriptive analyses were conducted for means and frequencies. For scales with missing items, the within-participant mean was used to replace the missing items if missingness was ⩽ 20% whereas the total score was treated as missing if the proportion was > 20%.

Results

Sample

Of 35 consenting participants (olanzapine: 22, risperidone: 13), three were excluded from further analysis due to problematic data quality at baseline. Thirty-two participants provided a blood sample (olanzapine: 19, risperidone: 13) and 26 remained on the target drug at study end (olanzapine: 16, risperidone: 10), including three for whom there were no TDM results (Figure 2).

Baseline measures

For the 32 participants who provided a blood sample, initial statistical analyses indicated that there were no significant differences in sociodemographic and clinical variables between the olanzapine and risperidone groups (Table 1). The mean score on the Positive and Negative Syndrome Scale was 64.6 (SD 13.1, range 39–92). The use of cannabis (31.3%) and club drugs (6.2%) was reported in the past 30 days. Concomitant medication included olanzapine PRN (15.8%), haloperidol PRN (15.8%), benzodiazepines (63.2%), antidepressants (26.3%), hypnotics (10.5%), mood stabilisers (15.8%) and other non-psychotropic medication (50.0%). The most commonly reported side effects on the Antipsychotic Non-Neurological Side-Effect Rating Scale included lethargy/lassitude (65.6%), loss of energy/drive (59.4%) and weight gain (50.0%). Eleven (34.4%) participants had a BMI in the overweight or obese categories and 53.1% had high blood pressure (systolic > 140 and/or diastolic > 90), indicating a risk for metabolic syndrome.

Primary outcome

Olanzapine

For the participants who provided a blood sample and remained on olanzapine throughout the study (n = 16, including two for whom there were no TDM results), there was a mean increase in olanzapine dose of 0.9 mg/day (SD 2.7, range 0–10; baseline mean dose 13.8 mg/day (4.7, 5–20); 6-week follow up mean dose 14.7 mg/day (5.0, 5–20)). For the three participants who discontinued olanzapine during the study, the baseline mean dose was 14.2 mg/day.

Risperidone

Conversely, for the participants who provided a blood sample and remained on risperidone throughout the study (n = 10, including one for whom there was no TDM result), there was a mean decrease in risperidone dose of -0.3 mg/day (SD 2.0, range -4–3; baseline mean dose 4.1 mg/day (1.3, 2–6); 6-week follow-up mean dose 3.8 mg/day (1.5, 2–6). For the three participants who discontinued risperidone during the study, the baseline mean dose was 3 mg/day (Table 2).

Table 2.

Therapeutic drug monitoring (TDM) results and antipsychotic dose change from baseline to 6-week follow-up^a.

	Olanzapine (n = 16)						Risperidone (n = 10)
	Direction of dose change (n)			Dose pre TDM (mg/day)	Dose at 6 weeks (mg/day)	Dose change (mg/day)	Direction of dose change (n)			Dose pre TDM (mg/day)	Dose at 6 weeks (mg/day)	Dose change (mg/day)
	↑	↓	Δ	Mean (SD, range)	Mean (SD, range)	Mean (SD, range)	↑	↓	Δ	Mean (SD, range)	Mean (SD, range)	Mean (SD, range)
Medication dose	2	0	14	13.8 (4.7, 5–20)	14.7 (5.0, 5–20)	0.9 (2.7, 0–10)	2	3	5	4.1 (1.3, 2–6)	3.8 (1.5, 2–6)	−0.3 (2.0, –4–3)
Clinician guidance
Dose reduction advised (> 60 ng/mL or > 80ng/mL)	0	0	1	20.0 (–)	20.0 (–)	0 (–)	−	−	−	−	−	−
Maintain if good clinical response + tolerance (41–60 ng/mL or 61–80ng/mL)	0	0	1	20.0 (–)	20.0 (–)	0 (–)	−	−	−	−	−	−
Maintain unless poor clinical response or non-tolerance (20–40 ng/mL or 20–60 ng/mL)	2	0	1	11.7 (2.9, 10–15)	16.7 (5.8,10–20)	5.0 (5.0, 0–10)	1	2	1	5.3 (1.0, 4–6)	4.3 (1.7, 2–6)	−1.0 (2.6, –4–2)
Partial adherence likely (2–19 ng/mL)	0	0	9	11.7 (3.5, 5–15)	11.7 (3.5, 5–15)	0 (0, 0–0)	1	1	2	3.5 (0.6, 3–4)	3.8 (1.7, 2–6)	0.3 (2.1, -2–3)
Non–adherence likely (< 2ng/mL)	−	−	−	−	−	−	0	0	1	4.0 (–)	4.0 (–)	0 (–)
TDM results not available	0	0	2	20.0 (0, 20–20)	20.0 (0, 20–20)	0 (0, 0–0)	0	0	1	2.0 (–)	2.0 (–)	0 (–)

Excludes six patients who discontinued the target drug before study end

↑: Increase in dose; ↓: decrease in dose; Δ: no change in dose.

TDM intervention feasibility

For participants for whom time of last dose and time of blood sample data were available, a trough level was achieved for all, but this was measured at steady state for only 78.1% of participants. It was not possible for the laboratory to analyse three blood samples due to: sample haemolysis (n = 1); incorrect lab assay (n = 1); and sample unlabelled (n = 1). Of the remaining 29, 16 (55.2%) TDM results were reported within 3 working days. Of the 32 participants who provided blood samples, only seven (21.9%) experienced a dose change, for whom only four of the TDM results were confirmed as having been checked by the clinician.

Only one participant experienced an adverse event throughout the course of the study that was deemed ‘remotely related’ to TDM, which consisted of verbal and physical abuse. Seven patient participants were involved in the focus groups; they believed TDM was a ‘good idea’ and could aid clinicians when prescribing medication, for example ‘…you know, be more accurate with their dosage, rather than hit or miss’, although one participant was slightly sceptical: ‘I’m a bit of a cynic on this, I just never did know how anyone would be able to find out what’s going on in someone’s body’. All focus group participants reported that the doctor/ward staff did not discuss the results of the blood test with them, and that the dose of their medication did not change following the blood sample being taken.

Discussion

Dose change and the prescriber’s role

Following antipsychotic TDM, only three participants experienced a decrease in antipsychotic dose. The lack of dose decrease may be due to the TDM results rarely supporting a dose reduction; indeed, the majority of results indicated either partial adherence or for the current dose to be maintained or increased until a minimum effective dose was reached (Hiemke et al., 2011). However, few clinicians confirmed that they had checked the TDM results, even though most results were reported within 4 days, which was considered to be an appropriate time frame (Best-Shaw et al., 2014). Clinicians may have been inadvertently unaware that the results were available. Alternatively, clinicians’ negative attitudes and expectations regarding antipsychotic TDM or the perceived barriers (Patel et al., 2014b) may account for their reluctance to check the results. This reluctance may have been the result of: (a) a perceived lack of clinical indication, given the modest doses used by collaborating clinicians to warrant the need for TDM; and/or (b) that current schizophrenia guidelines do not recommend the use of TDM for olanzapine or risperidone (Buchanan et al., 2010; Hasan et al., 2012). Thus, even when provided with a TDM result and clinical algorithm to aid with interpretation, clinicians seemingly chose to forgo such objective measures and select a dose only according to the patient’s symptoms and side-effect profile (National Institute for Health and Care Excellence, 2014). It is also conceivable that participation in the study itself improved clinicians’ attention to prescribing, thus circumventing some of the benefits of TDM.

Limitations

As this was a feasibility study, there was no intervention comparison group and so the true utility or impact of TDM on clinical practice could not be more fully explored. However, although the sample size was small, it was adequate to examine the acceptability of the measures used. Some TDM results are at risk of spurious interpretation, due to blood samples being taken before steady state was achieved. Such results could lead to undue dose increases, with an associated risk of dose-related side effects and subsequent non-adherence (Hiemke et al., 2011).

The success of implementing the TDM intervention was limited by the small number of clinicians who reported checking the TDM results. One reason for this low rate of clinician checking may be that there was insufficient ‘buy-in’ from clinicians, as the TDM intervention was not targeted towards patients who had a clinical need for TDM. However, this number may be an underestimation due to the use of verbal self-report rather than more objective measures. Verification of whether or not TDM results had been checked, via the internet-based reporting system, was not possible. Nonetheless, that clinicians did not check the TDM results renders the primary outcome of dose change more difficult to interpret, as it is unclear whether the TDM results were useful to clinicians and actually informed their decisions on dose. Further, the chosen primary outcome did not provide sufficient insight into whether antipsychotic plasma concentrations were in the target range after the TDM intervention and any resultant changes to dose.

Future directions

Subsequent research could evaluate ways to make the TDM results more meaningful for clinicians and facilitate their checking of the results. This may include focusing on clinical populations where antipsychotic TDM is clinically indicated, such as those most likely to have plasma concentrations outside the therapeutic range (e.g. where there is high dose prescribing or concerns regarding suboptimal medication adherence). Additionally, more emphasis could be placed on the clinician’s role in TDM in the development of future studies, which may investigate whether or not dose was adjusted by clinicians once they had been given TDM results.

Important implications for future practice include the importance of laboratories highlighting where information (date of last dose adjustment, time of last dose and time of blood sample) is lacking, thus indicating the risk of potentially misleading results. The appeal of the TDM process for antipsychotics may be improved by the introduction of non- or less invasive methods such as oral fluid or dried blood spot testing (Fisher et al., 2013; Mangalore and Knapp, 2007) and/or more rapid reporting of results through, for example, the use of a bedside finger-stick (capillary blood) test (clinicaltrials.gov, 2014).

Conclusions

TDM can be feasibly implemented as part of routine clinical practice for both olanzapine and risperidone, and may aid dose optimisation. However, the lack of robust supporting evidence either for or against antipsychotic TDM from pharmacological efficacy trials in research settings has probably led to lack of enthusiasm for and interest in the results of TDM even within a pragmatic evaluation. Hence, given the current state of knowledge, uptake of TDM is likely to be slow were it to become widely available. In light of the feasibility shown here and general positive attitudes (Best-Shaw et al., 2014), it is also likely that less invasive measures and the targeting of specific patients (who might be more likely to benefit) would facilitate uptake of TDM in many inpatient units.

Footnotes

Acknowledgements

With grateful thanks to all participants and their clinical teams. We also acknowledge and thank Athanasios Prountzos, Lauren Best-Shaw, Simon Handley, Sandra O’Sullivan, Drs Deborah Stevenson, Manal El Maraghy and Lawrence Ratna, and Professors David Taylor, Shitij Kapur and Thomas Barnes, as well as the Mental Health Research Network.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MXP has received consultancy fees, lecturing honoraria, and/or research funding from Janssen, Lilly, Endo, Lundbeck, Otsuka and Wyeth. MXP has previously or is currently working on clinical drug trials or studies for Janssen, Amgen and Lundbeck. ASD and SaL receive salary support from the National Institute for Health Research Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. ASD has received honoraria and lecture fees from Novartis, Janssen and Lilly. RJF has received honoraria and lecture fees from Novartis, Janssen and Lilly. SuL, MG, NM and DR have no declarations of interest. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Clinician Scientist Award (grant number NIHR/CS/009/010) for MXP from the National Institute for Health Research. ISRCTN: 71305621.

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. (1993) SF-36 Health Survey Manual and Interpretation Guide. Boston, MA: New England Medical Centre, The Health Institute.