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Abstract

Background:

This study aimed to explore predictive factors for future use of therapeutic drug monitoring (TDM) and to further examine psychiatrists’ current prescribing practices and perspectives regarding antipsychotic TDM using plasma concentrations.

Method:

A cross-sectional study for consultant psychiatrists using a postal questionnaire was conducted in north-west England. Data were combined with those of a previous London-based study and principal axis factor analysis was conducted to identify predictors of future use of TDM.

Results:

Most of the 181 participants (82.9%, 95% confidence interval 76.7–87.7%) agreed that ‘if TDM for antipsychotics were readily available, I would use it’. Factor analysis identified five factors from the original 35 items regarding TDM. Four of the factors significantly predicted likely future use of antipsychotic TDM and together explained 40% of the variance in a multivariate linear regression model. Likely future use increased with positive attitudes and expectations, and decreased with potential barriers, negative attitudes and negative expectations. Scientific perspectives of TDM and psychiatrist characteristics were not significant predictors.

Conclusion:

Most senior psychiatrists indicated that they would use antipsychotic TDM if available. However, psychiatrists’ attitudes and expectations and the potential barriers need to be addressed, in addition to the scientific evidence, before widespread use of antipsychotic TDM is likely in clinical practice.

Keywords

antipsychotics attitude dose plasma concentration schizophrenia therapeutic drug monitoring

Introduction

Current schizophrenia guidelines do not generally offer specific recommendations regarding antipsychotic dose choice, other than suggesting a lower dose for patients experiencing their first psychotic episode [Buchanan et al. 2010; Hasan et al. 2012; National Institute for Health and Care Excellence, 2014]. Thus, when selecting dose, clinicians often rely on dose equivalency data [Patel et al. 2013] and clinical experience [Correll et al. 2011; Patel et al. 2003, 2010]. Antipsychotic dosing is further complicated by the significant variation between patients’ steady-state antipsychotic plasma concentrations for a given dose [Hiemke et al. 2011]. In part, this variation for clozapine and olanzapine can be accounted for by differences in age, sex, smoking habit, and genetically determined hepatic drug metabolizing enzyme activity [Bishara et al. 2013; Rostami-Hodjegan et al. 2004]. Therapeutic drug monitoring (TDM) is the use of whole blood plasma or serum drug (or metabolite) concentration measurements to assess adherence, guide dose, and minimise the risk of toxicity [Hiemke et al. 2011] and has been shown to accurately predict the D₂ occupancy for a number of antipsychotics [Uchida et al. 2011].

The schizophrenia Patient Outcomes Research Team recommend the use of TDM when clozapine response is insufficient [Buchanan et al. 2010]. Whereas UK schizophrenia guidelines only recommend the use of TDM prior to clozapine augmentation with another antipsychotic [National Institute for Health and Care Excellence, 2014], which is a common management strategy for treatment-resistant schizophrenia [Miyamoto et al. 2014]. In contrast, European guidelines, Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsy-chiatrie (AGNP), ‘strongly recommend’ the use of TDM for specific second-generation antipsychotics (SGAs), namely clozapine, risperidone, olanzapine and amisulpride [Hiemke et al. 2011]. However, the robustness of the underlying evidence base is debatable. Data from a TDM service in the UK have illustrated the value of TDM for risperidone [Bowskill et al. 2012a], olanzapine [Patel et al. 2011], and amisulpride [Bowskill et al. 2012b] in specific instances, whereas findings from systematic reviews, including clinical trial data, have suggested a more limited role for TDM for both olanzapine [Bishara et al. 2013] and amisulpride [Sparshatt et al. 2009]. TDM was not as strongly recommended by the AGNP for either quetiapine or aripiprazole [Hiemke et al. 2011], which is consistent with more recent evidence [Handley et al. 2013; Sparshatt et al. 2010]. Further, evidence suggesting that TDM for SGAs other than clozapine improves clinical outcome is limited [Lopez and Kane, 2013].

Consultant psychiatrists in London (sampled 2011–2012) generally had positive attitudes towards antipsychotic TDM, with most reporting they would use TDM if it were readily available [Best-Shaw et al. 2014]. Despite this, antipsychotic TDM is used infrequently, potentially due to practical issues, such as the cost and availability of local laboratory services and the requirement for phlebotomy, as well as concerns as to the strength of the evidence base, the absence of a role for TDM of first-generation antipsychotics and incomplete knowledge [Conca et al. 2011]. Exploration of the relative impact of these factors and whether other concerns or negative clinician attitudes might limit uptake of TDM services is a necessary precursor to developing clinical practice in this field.

This study aimed to explore potential predictive factors for the likely future use of TDM, thus furthering our original study [Best-Shaw et al. 2014], which only examined current prescribing practices and psychiatrists’ perspectives regarding antipsychotic TDM. We predicted that most participants would agree with the statement ‘if TDM for antipsychotics were readily available, I would use it’. We also hypothesized, speculatively, that participants’ perspectives regarding TDM and not their characteristics would predict its likely future use.

Materials and methods

Design

A cross-sectional study for consultant psychiatrists using a previously developed structured postal questionnaire [Best-Shaw et al. 2014] was conducted. Data were combined with those from the previous study conducted in the London region [Best-Shaw et al. 2014].

Setting and sample

Participants were recruited from three geographically defined Mental Health providers (Trusts) in north-west (NW) England. Pre-existing data collected from four Mental Health Trusts in London were also used [Best-Shaw et al. 2014]. The lists of potential participants included senior psychiatrists who prescribe antipsychotics for adults with schizophrenia. Consultants working in Child and Adolescent Mental Health Services, liaison psychiatry and psychotherapy were excluded.

Questionnaire

A previously developed questionnaire was used [Best-Shaw et al. 2014]. Information regarding participants’ demographics, clinical setting and caseload was requested. Participants’ views regarding antipsychotic prescribing, including antipsychotic preference, optimum dose selection, titration method and switching were elicited. Patient and illness factors potentially warranting a dose decrease were examined [Gardner et al. 2010]. Perspective regarding antipsychotic TDM were assessed using the statement ‘If TDM for antipsychotics was readily available, I would use it’, in addition to 35 items based upon four a priori themes: perceived potential benefits and negative aspects of TDM, perceptions of likely attitudes of patients, the impact of routine TDM on changing clinical practice, and possible barriers to TDM. Level of agreement with the statements was assessed using a six-point Likert scale (strongly disagree, disagree, vaguely disagree, vaguely agree, agree or strongly agree).

Procedure

The questionnaire and information sheet were posted to potential participants with a stamped reply envelope in NW England from November 2012 to May 2013. Approximately 3 and 6 weeks later, nonresponders were emailed the information and questionnaire. Ethics approval was granted and research governance procedures were adhered to. The London study data collection was conducted from April 2011 to May 2012.

Analysis

Data were analysed using SPSS (version 20). Descriptive analyses were conducted for participant characteristics. The results from the London and NW England groups were compared using χ² and t tests. Proportions were calculated for individual questionnaire items. The 95% confidence interval (CI) was calculated for the proportion of participants who agreed with the statement ‘If TDM for antipsychotics was readily available, I would use it’. The internal consistency of the four original TDM themes was checked. Two themes showed good internal consistency (Cronbach’s α ⩾ 0.7) [George and Mallery, 2003]: perceived possible benefits and negative aspects of TDM (0.74) and impact of routine TDM on changing clinical practice (0.73); and two did not: perceptions of likely attitudes of patients (0.31) and potential barrier to TDM (0.46). Thus, a principal axis factoring (PAF) analysis was conducted and only included items with a Pearson’s correlation coefficient greater than 0.3 for three or more items. Sampling adequacy was verified with the Kaiser–Mye–Olkin measure. Pairwise deletion was used for missing data. Where an item loaded on more than one factor (varimax rotation), it was allocated to the factor for which it had the highest absolute value. Internal consistency of the factors was tested using Cronbach’s α. Potential predicative factors for the likely future use of TDM including consultant participant characteristics and the factors identified by the PAF were considered in a linear regression analysis.

Results

Sample and participant characteristics

There were 147 eligible participants from NW England, of whom 76 (51.7%) returned the questionnaire fully completed. These were combined with pre-existing data from 105 senior psychiatrists in London [Best-Shaw et al. 2014] to give a total of 181 participants (Figure 1). Prior to combining the two samples, group characteristics were compared and found only to differ by age and clinical setting. The London group was younger (χ² = 8.7, p = 0.03), with more participants in the 30–49 age category (London: 77.1% versus NW England 69.7%), and more likely to work in an outpatient only setting (42.8% versus 25.0%, χ² = 7.2, p = 0.01). The sociodemographic and clinical characteristics of the total sample are displayed in Table 1.

Figure 1.

Flow diagram of the recruitment and formation of the study sample. NW, north west.

Table 1.

Participant characteristics (n = 181).

	Total sample
	n	%
Sex
Male	121	66.9
Female	55	30.4
Missing	5	2.8
Age
30–39	44	24.3
40–49	90	49.7
50–59	35	19.3
60+	11	6.1
Missing	1	0.6
Place qualified
UK/Eire	118	65.2
Other	54	29.8
Missing	9	5.0
Clinical specialty
General adult	113	62.4
Other	65	35.9
Missing	3	1.7
Clinical setting
Outpatient only	64	35.4
Other	96	53.0
Inpatient	42	23.2
Inpatient and outpatient	31	17.1
Home treatment	17	9.4
Other	6	3.4
Missing	21	11.6
	mean	SD	range
Years of experience (n = 167)	17.6	7.5	1–44

Current prescribing practices

Optimum dose was mainly determined by a psychiatrist’s usual dosing regimen for patients presenting in a similar way (84.5%) and patients’ goals and responsibilities (89.5%). Further, 72.9% agreed that their perspective of equivalent dose would determine optimum dose. The preferred titration method was starting at a low-dose and increasing over 2–4 weeks until a target dose is reached (78.5%). Most (66.9%) would prescribe a perceived adequate dose for 4–6 weeks before considering it ineffective. Following an acute relapse of schizophrenia, half (50.3%) would wait 6 months to 1 year before considering a dose reduction. Half (50.8%) believed that there was no maximum to the number of times it is acceptable to switch antipsychotics per year. When asked for the likely reasons for switching between antipsychotics (with no limit of choices) the most common responses were: nontolerance (99.4%), patient preference (98.9%), nonefficacy (98.3%), and nonadherence (91.2%). A dose decrease was most likely to be suggested for certain comorbid medical conditions, including hepatic disease (92.8%), as well as increasing age (76.1%), and first-episode psychosis (62.7%). However, a dose decrease was also suggested for overweight patients (37.2%) and chronicity of psychotic illness (17.2%).

TDM

Factor analysis

The correlation matrix for the 35 TDM items revealed that 13 items had insufficient item–item correlation, and so were excluded from the PAF analysis. The PAF was conducted and the Kaiser–Myer–Olkin measure (0.9) was greater than 0.5, which is considered acceptable [Field, 2000]. Two further items were excluded from the final model as their absolute values were less than 0.4. Five factors were identified with an eigenvalue at least 1, comprising 20 items, which together explained 46.2% of the variance, with factor A explaining substantially more variance than the other factors (Table 2). All five factors had good internal consistency (Cronbach’s α) and were subsequently labelled as: positive attitudes and expectations (factor A, α=0.82), potential barriers (factor B, 0.66), negative attitudes (factor C, 0.78), negative scientific perspective (factor D, 0.70), and negative expectations (factor E, 0.67).

Factors, with example items and level of agreement, are further described below:

Factor A (6 items): TDM would reduce likelihood of relapse (63.5%) and reduce arguments about dose between patients and doctors (51.9%).

Factor B (4 items): TDM requires too many blood tests for every dose change (43.6%) and patients would complain of being treated like ‘guinea pigs’ or ‘rats’ if TDM were suggested (32.0%).

Factor C (5 items): TDM is a bad idea (12.2%) and plasma concentrations are not relevant for drug action in the brain (26.5%).

Factor D (3 items): The scientific evidence for TDM for risperidone (68.0%) and olanzapine (63.5%) is weak and interpretation of the TDM results for antipsychotics is straightforward (24.9%).

Factor E (2 items): TDM will have no impact on dose related decision making (11.6%) and doctors will ignore TDM results when considering dose (21.5%).

Items not included in the PAF model (15 items): The scientific evidence base for TDM for clozapine is strong (82.9%), they routinely use TDM for clozapine (85.6%), and they had used TDM for antipsychotics other than clozapine (41.4%).

Table 2.

Principal axis factoring analysis (35 TDM items).

	Total sample		Cronbach’s α	Factors
	Agree (%)	Missing (%)		A	B	C	D	E
Rotation sum of squares loadings: total				6.3	1.7	0.9	0.7	0.5
Rotation sum of squares loadings: % of variance				28.6	7.8	4.0	3.3	2.4
Rotation sum of squares loadings: cumulative %				28.6	36.4	40.4	43.7	46.2
				Factor score (varimax rotation)
A. Positive attitudes and expectations			0.82
TDM for antipsychotics will improve clinical outcomes	70.7	1.1		0.8
TDM for antipsychotics will reduce likelihood of clinical relapse	63.5	0		0.7
TDM for antipsychotics will reduce arguments about dose between doctors and patients	51.9	0		0.6
TDM for antipsychotics directly enables individualized prescribing of antipsychotics	70.7	0.6		0.6
TDM for antipsychotics can assist in minimizing the risk of dose-related side effects	81.2	0		0.5
TDM for antipsychotics helps the clinician to avoid subtherapeutic dosing	79.0	0.6		0.4
B. Potential barriers			0.66
TDM for antipsychotics requires too many blood tests for every dose change	43.6	0.6			0.7
Patients will complain of being tested like ‘guinea pigs’ or ‘rats’ if I suggest TDM	32.0	1.7			0.5
Doctors will only use TDM results for antipsychotics to check for medication adherence	37.6	0			0.5
I do not have time to wait for an antipsychotic TDM result before changing dose	34.8	1.1			0.5
C. Negative attitudes			0.78
Antipsychotic plasma concentration levels are not relevant for drug action in the brain	26.5	0.6				0.6
TDM for antipsychotics does not help the clinician to minimize the risk of toxicity	18.2	0				0.5
TDM for antipsychotics is a bad idea	12.2	1.7				0.5
TDM for antipsychotics will increase length of stay for acutely psychotic inpatients	18.2	1.7				0.5
TDM for antipsychotics will cost your NHS Trust more money than it might save by its use	47.0	1.7				0.4
D. Negative scientific perspective			0.70
The scientific evidence for TDM for olanzapine is weak	63.5	3.9					0.7
The scientific evidence for TDM for risperidone is weak	68.0	6.1					0.6
The interpretation of the TDM results for antipsychotics is straightforward	24.9	0.6					−0.6
E. Negative expectations			0.67
TDM for antipsychotics will have no impact on dose-related decision-making	11.6	0						0.6
Doctors will ignore the results of TDM for antipsychotics when considering dose	21.5	0.6						0.5
Items not included in the PAF (absolute value < 0.4)
TDM for antipsychotics is only a very small contributory factor to guiding dose choice	71.3	0
The scientific evidence for TDM for clozapine is strong	82.9	1.1
Pearson’s correlation coefficient < 0.3
I routinely use TDM for clozapine	85.6	0.6
I have never used TDM for antipsychotics other than clozapine	41.4	0.6
TDM directly enables individualized prescribing of mood stabilizers	68.0	2.2
Patients will only want to know the TDM results if it suggests dose reduction not increase	24.9	1.1
Doctors will primarily use TDM results for antipsychotic to guide dose	47.5	0.6
Obtaining a blood sample from a psychotic patient is as easy as with any other patient	32.0	0.6
Patients will request TDM testing to prove they have been taking their medication	44.2	0
TDM should only be optional and not compulsory for patients	77.3	0
Patients with psychosis will never agree to TDM for antipsychotics	2.8	0
There is a laboratory to which I can readily send sample for antipsychotic TDM testing	47.0	1.1
It is impossible to take a morning TDM blood sample before the morning dose is taken	11.6	0.6
The TDM laboratory should take no longer than 4 days to provide a sample test result	83.4	1.1
Patients will readily request TDM for antipsychotics	18.2	1.1

TDM, therapeutic drug monitoring.

Regression analysis

Most (82.9%, 95% CI 76.7–87.7%) of the sample agreed with the statement ‘if TDM for antipsychotics was readily available, I would use it’. Unadjusted linear regression, based on the responses using the six-point Likert scale for likely future use, revealed that consultant participant characteristics (sex, age, place qualified, clinical setting and specialty) each did not significantly predict the response to the above statement. However, four out of the five factors identified by the PAF were significant predictors for likely future use (Table 3). Thus, factors A, B, C and E were entered into a final adjusted linear regression model, whereby all four factors were taken into account, and together these explained 40% of the variance in the responses to the statement ‘if TDM for antipsychotics was readily available, I would use it’ (R² = 0.40, p < 0.01, n = 158). Level of agreement for likely future use increased with positive attitudes and expectations (factor A), and decreased with perceived potential barriers (factor B), negative attitudes (Factor C) and negative expectations (factor E).

Table 3.

Linear regression analysis exploring potential predictive factors for likely future use of TDM.

	Unadjusted			Adjusted*
	B	SE	p value	B	SE	p value
Constant	–	–	–	3.54	0.07	<0.001
Factor A: positive attitudes and expectations	0.56	0.08	<0.001	0.51	0.07	<0.001
Factor B: potential barriers	−0.37	0.10	<0.001	−0.27	0.08	0.002
Factor C: negative attitudes	−0.47	0.10	<0.001	−0.33	0.09	<0.001
Factor D: negative scientific perspective	−0.06	0.11	0.591	–	–	–
Factor E: negative expectations	−0.35	0.11	0.001	−0.26	0.09	0.003
Male	0.28	0.18	0.121	–	–	–
Age (reference category: 30–39)
40–49	0.03	0.20	0.865	–	–	–
50–59	0.15	0.25	0.560	–	–	–
60+	0.09	0.37	0.806	–	–	–
UK/Eire	0.11	0.18	0.525	–	–	–
General adult	−0.10	0.17	0.549	–	–	–
Outpatient only	0.23	0.18	0.187	–	–	–
Years of experience	−0.01	0.01	0.539	–	–	–

n = 158.

SE, standard error; TDM, therapeutic drug monitoring.

Discussion

Principal findings

Current antipsychotic prescribing practices were influenced by many elements, including patient factors and psychiatrists’ experiences. Attitudes and expectations regarding antipsychotic TDM were mainly positive, with most agreeing that they would use it if it were readily available. Four of the five factors, identified in the factor analysis, predicted likely future use of antipsychotic TDM. Likely future use increased with positive attitudes and expectations, and decreased with perceived potential barriers, negative attitudes and negative expectations. Negative perspectives regarding the scientific evidence for TDM and participant characteristics were not significant predictors.

Strengths and limitations

Responses from the combined sample allowed for investigation, by way of factor analysis, of potential predictive factors from the psychiatrist’s perspective for the likely future use of TDM. Responses were from senior psychiatrists working in a variety of specialties across multiple mental health providers. Further, the responses from the NW England sample were broadly similar to those from the London sample, suggesting that the findings are representative. However, variations in local policy and the patient populations are potential confounding factors. The response rate from the NW England sample was 51.7%, which although low, is double that of a similar study [Conca et al. 2011]. Additionally, every effort was made to contact nonresponders in an attempt to minimize self-selection bias. The use of self-report measures may have introduced social desirability bias, as actual antipsychotic prescribing behaviour does not always reflect current good practice [Miles et al. 2011].

Prescribing practices

Guideline recommendations for antipsychotic prescribing are endorsed by most, including prescribing an adequate dose for 4–6 weeks before making changes [Joint Formulary Committee, 2012]. However, guidelines lack specificity regarding dose choice, and this may account for high-dose prescribing [Lelliott et al. 2002], polypharmacy [Hori et al. 2013] and frequent switching [Faries et al. 2009], which are common, but potentially ineffective, prescribing behaviours. Further, clinicians perceive that certain patient and illness factors, such as age and first-episode psychosis, warranted a dose decrease, which is in keeping with previous findings [Gardner et al. 2010].

TDM

TDM is an objective measure upon which prescribing decisions can in part be based. The limited use of TDM in clinical practice for antipsychotics other than clozapine may be due to the lack of scientific evidence confirming that TDM is indicated, for example if there is a narrow therapeutic window [Flanagan, 2011], or the lack of a direct linear relationship between dose and plasma concentration [Bishara et al. 2013; Sparshatt et al. 2010], or whether a widely accepted target plasma range exists [Handley et al. 2013]. Thus, psychiatrists appear to use other factors, such as their subjective perspectives of prescribing to influence dose choice. This is consistent with previous questionnaire-based research on clinicians views of antipsychotic prescribing namely that: the prescription of long-acting injections increased when clinicians held favourable patient-centred attitudes [Patel et al. 2003, 2010] and decreased if clinicians perceived that patients were unwilling to consider a long-acting injection [Heres et al. 2011]; antipsychotic polypharmacy rates increased if clinicians believed polypharmacy was not problematic [Correll et al. 2011]; and clozapine prescribing was less likely if clinicians had greater concerns regarding safety and beliefs that patients prescribed clozapine were less satisfied [Nielsen et al. 2010].

Potential barriers found to influence the likely future use of antipsychotic TDM included the clinician’s perception as to whether TDM had adverse patient appeal as well as the limited flexibility of use and subsequent impact of the intervention in clinical practice [Nelson and Steele, 2008]. Similarly, barriers to switching from long-acting injection to oral SGAs included staffing levels and social changes required to implement the switch [Lambert et al. 2003]. Conversely, a previous study reported that the general use of TDM for drugs, such as lithium, was rare even when no barriers were identified [Conca et al. 2011].

The perceived strength of the scientific evidence base did not predict future use of antipsychotic TDM, which confirms former findings [Conca et al. 2011]. This may be partly due to the questionnaire only asking about the strength of the evidence for TDM for two of the many available antipsychotics. Admittedly the strength of the available evidence recommending the use of TDM is subject to debate, particularly in light of the conflicting finding for olanzapine and amisulpride from naturalistic data [Bowskill et al. 2012b; Patel et al. 2011] and systematic reviews [Bishara et al. 2013; Sparshatt et al. 2009], which may in part be due to naturalistic studies being based on data from patients where clinicians already felt there was a clinical problem indicating the need for TDM. The resultant lack of clear and conclusive evidence may account for why current schizophrenia guidelines do not recommend the use of TDM for antipsychotics other than clozapine [Buchanan et al. 2010; Hasan et al. 2012; National Institute for Health and Care Excellence, 2014].

Implications and conclusion

The data presented here suggest that most psychiatrists would use TDM for antipsychotics, with likely future use being influenced by psychiatrists’ attitudes and expectations. However, future work should explore whether or not psychiatrists’ attitudes predict actual behaviour rather than just likely future behaviour. The attitudes and expectations of patients and carers should also be explored to understand the wider impact of routine antipsychotic TDM. Further it seems that some psychiatrists do not appraise the evidence base as clearly supporting TDM for antipsychotics other than clozapine. Thus, more robust studies are necessary; this should perhaps include the role of TDM prior to switching between two antipsychotics due to poor clinical response. Psychiatrists are also aware of the potential practical difficulties and negative reactions from patients. Although the current evidence base is modest, there will always be a call for antipsychotic TDM in specific instances, for example if nonadherence is the suspected reason for nonresponse [Patel et al. 2011]. Nevertheless, psychiatrists’ attitudes and expectations and the potential barriers need to be addressed, in addition to the scientific evidence, before widespread use of antipsychotic TDM is likely in clinical practice.

Footnotes

Acknowledgements

With grateful thanks to all participants, Mr Altaf Sumra for data collection support, Dr Mizanur Khondoker for advice on factor analysis, and Ms Lauren Best-Shaw, Ms Jessica Negar and Ms Maria Gudbrandsen for their role in the former London-based study. We also acknowledge and thank Professors Diana Rose, Thomas R. Barnes, Sabrina Landau, David Taylor and Shitij Kapur, as well as the Mental Health Research Network, and National Institute for Health Research in supporting this work.

Funding

This study was funded by a Clinician Scientist Award (NIHR/CS/009/010) for Dr Maxine Patel from the National Institute for Health Research.

Conflict of interest statement

The authors declare that there is no conflict of interest.

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Antipsychotic therapeutic drug monitoring: psychiatrists’ attitudes and factors predicting likely future use

Abstract

Background:

Method:

Results:

Conclusion:

Keywords

Introduction

Materials and methods

Design

Setting and sample

Questionnaire

Procedure

Analysis

Results

Sample and participant characteristics

Current prescribing practices

TDM

Factor analysis

Regression analysis

Discussion

Principal findings

Strengths and limitations

Prescribing practices

TDM

Implications and conclusion

Footnotes

Acknowledgements

Funding

Conflict of interest statement

References