Barriers to using clozapine in treatment-resistant schizophrenia: systematic review
Saeed Farooq Abid Choudry Dan Cohen Farooq Naeem Muhammad Ayub
- Correspondence
Saeed Farooq (Sfarooqlrh@yahoo.com)
- date
2019-2
- Abstract
Aims and method
To systematically review the literature on barriers to the use of clozapine and identify any interventions for optimizing clozapine use in treatment-resistant schizophrenia. Journal databases were searched from 1972 to March 2018. The following search terms were used: treatment-resistant schizophrenia, clozapine, barriers, use, prescription rates, implementation, clozaril and prescribing practices. Following a review of the literature, 15 papers were included in the review.
Results
The major barriers that were identified included mandatory blood testing, fear of serious side-effects and lack of adherence by the patients, difficulty in identifying suitable patients, service fragmentation, and inadequate training in or exposure to using clozapine.
Clinical implications
In view of consistent evidence across the studies on inadequate knowledge and skills as a significant barrier, we suggest that a certification requiring competence in initiating and managing side-effects of clozapine becomes a mandatory requirement in training programmes.
Declarations of interest
None.
Clozapine use in schizophrenia
Clozapine is the only medication licensed for treatment-resistant schizophrenia (TRS), which affects about one-third of those suffering from the disorder. Recently, there has been increased interest in redefining the role of clozapine in the treatment of schizophrenia in view of the evidence of superior efficacy and safety, despite serious side-effects.1 Meta-analyses have demonstrated that clozapine is significantly better at treating symptoms than first-generation antipsychotics and some (but not all) second-generation antipsychotics.2 This superior efficacy was also supported by two large, independently funded studies.3,4 Clozapine also appears to have broader effects, with evidence for efficacy in suicidality, aggression and substance misuse.1 In the USA, clozapine is approved by the Food and Drug Administration for the management of suicidality in people with schizophrenia or schizoaffective disorder. In addition, clozapine has been shown to have anti-aggressive properties5 and may also be effective in diminishing substance misuse.6,7 Tiihonen et al7 found, using a large database, that that people regularly taking clozapine had the lowest risk of premature mortality compared with both those on other antipsychotics and those not taking regular medication, despite the fact that the drug is associated with a number of serious adverse side-effects.7
Potential barriers and delays in clozapine use
Despite the evidence of superior efficacy and recommendations by different treatment guidelines, the drug is grossly underutilised.8 Studies based on prescription patterns in routine practice almost universally show lower prescriptions of clozapine in individuals with Schizophrenia, even after taking into account potential barriers such as inadequate service provision.9 There is also substantial evidence that the use of clozapine is delayed for several years, which may result in less than optimal efficacy for the drug. A study by Howes et al10 showed that the mean theoretical delay from meeting the National Institute for Health and Care Excellence (NICE) criteria for TRS and starting clozapine was about 4 years. In New Zealand the theoretical delay was almost 10 years.11 In the USA, only six states reported that more than 10% of Medicaid-eligible patients with schizophrenia had received a prescription of clozapine.12
The reasons for such suboptimal use of clozapine remain obscure, and may include several factors related to patients, carers and clinicians. These may include the perception of the drug as a dangerous medicine1 or difficulties associated with initiating and maintaining the treatment. The life-threatening side-effects of clozapine and mandatory requirement for white blood cell (WBC) counts may partly account for the less than optimal use of the drug in clinical practice. Experience in using clozapine may be an important factor. A study by Nielsen et al13 of the attitudes and knowledge of 137 psychiatrists in Denmark, including 100 consultant psychiatrists, revealed that some had never prescribed clozapine despite having worked for over 5 years. The barriers to effective use of clozapine have not been reviewed systematically.
We therefore aimed to review the literature on barriers to the effective use of clozapine in clinical practice for TRS. We also wanted to identify any interventions that could potentially improve the use of clozapine. This systematic review aimed to answer the following questions. •What barriers or factors have been identified that prevent the optimal use of clozapine in TRS, based on the current literature?•What strategies have been explored to promote the effective use of clozapine in TRS?•What is the methodological quality of the evidence that is available exploring the barriers to optimal use of clozapine?
Method
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines.14 A protocol defining the key methodological parameters was developed prior to the literature search and was registered at the International Prospective Register of Systematic Reviews (PROSPERO).15
Search strategy
Electronic databases (PsycINFO, Medline, PubMed, AMED, CINHAL and EMBASE) from 1972 onwards were searched, followed by a search of the reference lists of the full texts of the retrieved articles for further relevant articles. The following search terms were used: treatment-resistant schizophrenia, clozapine, barriers, use, prescription rates, implementation, clozaril and prescribing practices. These keywords were searched for in the title, keywords, or abstract. Truncations and related terms were used as appropriate based on individual database procedures. The search was last updated in March 2018.
All study types (intervention, observational and descriptive) were included in the review if the following inclusion criteria were met. •Adult populations with a diagnosis of TRS for whatever indication. Clozapine has been used for other diagnoses; however, we limited our present review to TRS.•Included primary research information on the outcome variables, i.e. barriers or factors associated with low use or implementation strategies.•Published between 1972 and 2018.
Studies that examined the pattern of use of clozapine, the rate of prescriptions, or its efficacy and effectiveness were excluded, unless these provided data on the barriers or factors associated with low or high use of clozapine.
There is no agreed definition of the ‘optimal use’ of clozapine. However, a number of studies9–11,16 indicate that the optimal use is determined on the basis of time since the start of the first antipsychotics (considering that clozapine is used after failure to respond to two antipsychotics) and the prevalence of clozapine prescription relative to total antipsychotic prescriptions (based on fact that about 30% of those suffering from schizophrenia develop TRS). These provide useful guidance but do not take into practical factors such as patient willingness to start clozapine or non-availability, or the cost of clozapine in low- and middle-income country settings. We used these parameters as a broad guideline for our review, but we will also report clozapine use and how it is defined as adequate or optimal by different studies.
Data extraction
The screening for searches examining the relevant abstracts, examination of full-text articles and data extraction were done by two reviewers independently, as outlined in the protocol.15 Any disagreements were resolved by consensus and, where appropriate, by consultation with the third reviewer. A data extraction sheet was developed based on the pre-specified outcomes and relevant data were extracted on to this sheet. We planned a meta-analysis of primary and secondary outcomes, but it was not possible to statistically summarise the data owing to the heterogeneity of studies, lack of adequate data and low quality of studies. We instead provide a descriptive summary of main findings.
Results
The electronic searches returned 253 relevant abstracts and titles; no further articles were identified from the other sources. We screened the titles and abstracts, and excluded any studies that were not directly relevant to the objectives of the review. After screening these titles and abstracts and removal of duplicates, we further examined 47 full-text papers. Finally, we included 15 papers in the review. The details of the search yield and reasons for excluding full-text articles are provided in Fig. 1. Fig. 1Summary of the abstracts reviewed to identify papers relevant for the review.
Characteristics of included studies
The studies were conducted in a number of different populations, settings and periods, and also used diverse methodologies. Owing to the diverse methodologies and number of variables examined across studies, it was inappropriate to pool the data to produce a statistical summary. We therefore describe the main findings and produce a narrative summary of results.
Fifteen studies met the inclusion criteria. Twelve of these studies focused on barriers or factors associated with clozapine use. These comprised surveys (n = 5), case note reviews (n = 4), and semi/structured interviews and consultations with stakeholders (n = 3). The majority of these studies (n = 8) involved eliciting views from clinicians, particularly consultant psychiatrists. Three studies described interventions or quality improvement initiatives to facilitate the use of clozapine. These are described separately.
In survey-based studies, response rates varied from 8.8 to 76%. The mean response rate from the papers which had figures available (n = 5) was 52.3%. The total number of males from the studies providing this information (n = 6) was 608, and the number of females was 402. The populations in these studies comprised 902 psychiatrists, 68 trainees, 49 pharmacy staff and 15 nursing staff or staff in mental health leadership positions. One database study reviewed the Medicaid patients on antipsychotic medication using records of 629 800 patients in the analysis.
In the three intervention studies, 158 participants were involved. One study did not provide details of sample size.
Barriers to the use of clozapine in TRS
It was possible to classify the barriers in three groups with some overlap: •barriers related to patients and the drug;•clinician-related barriers;•health system-related factors.
Discussion
This was the first systematic review aiming to examine the barriers to effective use of clozapine. The following major barriers or factors related were identified: the mandatory blood testing requirement; fear of serious side-effects, lack of familiarity in use of clozapine; lack of clarity in diagnosis and difficulty in identifying suitable patients; service fragmentation; and lack of adequate training in or exposure to using clozapine. Only one educational intervention was available that showed some effect on clozapine prescription rate. POC testing using capillary blood was more acceptable to patients than traditional blood sampling, being less painful and less time consuming, but no studies tested whether it increased the uptake of clozapine.
A conservative estimate suggests that TRS adds more than $34 billion in annual direct medical costs in the USA.31 In the UK, NICE has included the extent and the degree of clozapine use in the quality criteria for commissioners when commissioning services for mental health.32 However, initiatives to overcome this major service need are rare.
Almost all studies highlighted routine blood monitoring as the top-ranking barrier to initiating and maintaining clozapine treatment. Two randomised cross-over trials showed that blood testing using a simple finger prick that was undertaken as part of routine assessment by psychiatric staff, either in the patient’s home or at a psychiatric out-patient clinic, was feasible and convenient for patients. However, none of these trials looked at the effect of POC testing on prescription rates. The POC devices will also need to comply with regulatory requirements for monitoring blood counts.
It appears that there is a common perception amongst clinicians that clozapine is a dangerous drug, and that patients will not adhere to it or would not like to consider it as a treatment option. The findings in this review suggest that these negative beliefs about clozapine result from a lack of experience and knowledge, owing to the current limited use of clozapine. A self-perpetuating cycle can ensue, as practitioners do not see the benefits of clozapine, and thus do not develop confidence in its use.1 This is consistent with the study by Stroup et al which showed that higher clozapine initiation was significantly associated with patients residing in areas associated with historically high clozapine usage and higher concentrations of psychiatrists (>15 per 100 000 population).25
The NASMHPD published 36 recommendations on its website for expanding the use of clozapine.33 One important recommendation included improving residency trainee standards. Considering the disease burden resulting from TRS and the central role of clozapine in its treatment, we suggest that training in the use of clozapine becomes a mandatory requirement for all psychiatry residence and continuing professional development programmes. A certification requiring competence in initiating, maintaining and managing side-effects of clozapine is required, based on clinical experience, similar to the certification that is now required for electroconvulsive therapy.
The use of clozapine is alarmingly low in many developing countries. In Pakistan, for example, about 1300 patients were receiving clozapine as recorded in the Clozaril Patient Monitoring System. Although generic clozapine has become available recently, numbers are still very low, considering that the country has a population of about 200 million (R. U. Rahman, personal communication, 2016; data available from the authors on request). To put this prescription rate into perspective, The Netherlands, with a population of about 17 million, has over 12000 patients on clozapine, which is 0.07% of the population (https://www.gipdatabank.nl/). This means that, at current rates of use, there is a more than 100-fold difference between the two countries. This situation requires a public health intervention to improve access to clozapine in certain countries.
The major limitation of the review was the low quality of the included studies. Studies were based on surveys, which are prone to a number of biases, including selection bias of respondents, and lacked control groups. The low numbers of studies from a few countries also limit the generalisation of results. None of the studies defined the optimal use of clozapine. The lack of patient perspectives is striking, considering that a number of studies suggested patient-related factors as major barriers.
Despite these limitations, this systematic review indicates that there is broad agreement on the major barriers that hinder the effective use of clozapine. There is certainly a need to improve the methodological quality of studies and the way these are reported, but the present study identifies gaps in clinical practice and health services that can be addressed in intervention studies. Use of POC devices, educational interventions targeting clinicians and shared decision-making involving patients need to be evaluated using controlled study designs. Future research should be guided by the implementation science methods and behaviour change principles that have successfully been used in implementing and evaluating evidence-based interventions in medicine.