Article Text
PDF
Abstract
Objectives This study aimed to investigate the perspectives of clozapine-naïve outpatients with treatment-resistant schizophrenia on clozapine commencement and the barriers and facilitators of it.
Design A mixed-methods convergent design was employed using both qualitative and quantitative data on the same items.
Setting In-home visits or meetings at three Mental Health outpatient facilities in Region Zealand East, Denmark.
Participants Clozapine-eligible, yet clozapine-naïve, outpatients with schizophrenia. A convenience sample of 206 patients with schizophrenia treated with antipsychotic polypharmacy (APP) was screened for clozapine eligibility. Clozapine eligibility included recurrent/continued prescription of APP throughout the past year, ≥ 3 different antipsychotics (APs) trialled at a therapeutic dose and ≥2 APs trialled adequately before current treatment. All eligible patients able to provide written informed consent were invited to participate.
Methods The participants’ perspectives were assessed qualitatively through semistructured interviews and quantitatively with closed-ended questions, numerical scale ratings, and standardised patient-reported outcome measures. Moreover, the participants’ sociodemographic and clinical characteristics were collected through case files, participant questionnaires, and clinical ratings made by the participants’ treating clinicians. Interviews were transcribed verbatim and analysed thematically. Quantitative data were analysed with descriptive statistics. Finally, qualitative and quantitative results were compared and merged to draw meta-inferences.
Results Eighteen patients were included, 10 (56%) were men and the median age was 30.0 years (IQR 24.8–37.8). Nine participants (50%) were willing to commence clozapine if offered now, nine were not. No apparent clinical or socioeconomic differences were observed between refusers and acceptors; however, the acceptors rated their subjective recovery on the Brief INSPIRE-O significantly lower than the refusers did, and qualitatively, they all expressed subjective distress due to their current symptoms. Three themes characterised the refusers’ reasons for not accepting clozapine: ‘Reconciliation with the current situation warrants no change in treatment’, ‘Clozapine is a last-resort treatment for last-resort people’ and ‘Permanent or situational reluctance due to practical aspects of treatment’. In the vast majority of cases, blood sampling had little or no impact on the participants’ current willingness to commence clozapine, and quantitatively, blood sampling ranked lowest of the suggested barriers, whereas hospital admission for clozapine commencement ranked highest. The adverse side effects of clozapine, sedation and, weight gain in particular, were considered a major barrier if previously encountered with ineffective AP trials. The introduction of individualised commencement plans mitigating personal barriers was highlighted as the facilitator with the greatest impact on clozapine willingness, able to turn refusals into acceptance.
Conclusions Patients tend to prefer the predictability in status quo over switching to clozapine if they previously have trialled multiple APs with inadequate symptom reduction and subsequent deterioration/rehospitalisation or AP-induced weight gain and sedation. Moreover, the impression that clozapine treatment was unmanageable or a last-resort option further accentuated their reluctance to switch. Antipsychotic-trial fatigue and the stigma of clozapine as a last-resort treatment should be avoided by adhering to guidelines, thereby limiting the number of antipsychotics trialled before offering clozapine. Fortunately, it seems as if the patient’s willingness to trial clozapine is positively impressionable to the conversation about customised commencement plans offering commencement on the patient’s terms. For patients with subjective distress due to their symptoms, such plans can even reverse an initial clozapine refusalCite Now
- Schizophrenia & psychotic disorders
- Patient Reported Outcome Measures
- QUALITATIVE RESEARCH
- Patient-Centered Care
Data availability statement
Data are available in a public, open access repository. The qualitative and sociodemographic data supporting these findings are not openly available due to reasons of sensitivity. All other quantitative data informing this study are available on the OSF data repository: https://osf.io/r35cb/.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
- Schizophrenia & psychotic disorders
- Patient Reported Outcome Measures
- QUALITATIVE RESEARCH
- Patient-Centered Care
STRENGTHS AND LIMITATIONS OF THIS STUDY
No previous studies have qualitatively assessed the perspectives of clozapine-naïve, yet clozapine-eligible, patients with schizophrenia on clozapine commencement.
The assessment of both qualitative and quantitative aspects of the same questions has provided a more in-depth understanding of the subject than any of the methods would have been able to on their own.
Some patients were too unwell to participate, and therefore, we do not know how the most severely ill patients would respond to the study questions.
The number of participants (n=18) was more than adequate for qualitative purposes though small in a classic quantitative sense. Hence, the quantitative results of this study can serve only for data triangulation and hypothesis-generating purposes.
Introduction
The atypical antipsychotic (AP) clozapine is indicated (labelled and off-labelled) for a range of psychiatric and neurological disorders,1–3 first-line for the treatment of treatment-resistant schizophrenia (TRS).4 However, clozapine is continuously underused,5–9 while the non-evidence-based practice of antipsychotic polypharmacy is widely and increasingly10 employed. Decades of research and discussions on how to address the underutilisation issue have found that some of the most frequently mentioned barriers to clozapine treatment are the patients’ and/or prescribers’ concerns about adverse side effects and mandatory blood tests.11 In contrast, real-world data suggest that most patients accept an offer of clozapine treatment.8 Unfortunately, there is a lack of studies exploring the patients’ perspectives on the matter. A recent scoping review12 showed that, to date, only one study has assessed the perspectives of clozapine-eligible, yet clozapine-naïve, patients’ attitudes toward clozapine commencement. This was a quantitative study, an interviewer-administered survey, on inpatients with schizophrenia or schizoaffective disorder and acute deterioration.13 No studies, quantitative nor qualitative, have assessed the views of clozapine-eligible, yet clozapine-naïve, outpatients with schizophrenia on clozapine commencement. Considering that outpatients and inpatients might have different views on clozapine commencement, it seems highly relevant to assess the perspectives of the clozapine-eligible outpatients as well, asking them how they would respond to an offer of clozapine treatment, why they would give such a response and what initiatives, if any, would make them more prone to trial it. To that end, we have conducted this mixed-methods study.
Methods
Design
The study was carried out using a mixed-methods convergent design14 (also referred to as the concurrent, parallel or simultaneous design)15 with a special emphasis on the qualitative strand. Following this design, qualitative in-depth interview data were compared and contrasted with quantitative data on the same items (counts and proportions, numerical scale ratings) to comprehensively investigate the participants’ perspectives on the research question (ie, how do treatment-resistant, yet clozapine-naïve, outpatients with schizophrenia respond to an offer of clozapine commencement and what are their perspectives on barriers and facilitators of it?). The qualitative and the quantitative data were collected simultaneously (ie, within the same session per participant), processed and analysed separately, and the results then mixed/merged in the final integration analysis.16
Several pragmatic considerations led to the choice of study design: (1) the objective of the study (to generate practical and actionable knowledge about a complex, real-world clinical challenge) lends itself to mixed-methods research17; (2) the dual dataset was considered necessary to provide an authentic description of the participants’ perspectives, taking into consideration the severity of their illness (TRS, expectedly) and its likely impact on their ability to express themselves qualitatively and/or quantitatively to varying degrees; and (3) the addition of the quantitative strand to the qualitative core enhanced the description of the participants’ perspectives within a context and enabled comparison with quantitative results from similar studies. Thus, the convergent design was an obvious and suitable choice of design.
Checklists for the Good Reporting of A Mixed Methods Study18 and Standards for Reporting Qualitative Research19 are submitted with the manuscript.
Participants
A convenience sample of 206 outpatients with a diagnosis of schizophrenia (International Classification of Diseases, Tenth Revision) and a prescription of non-clozapine antipsychotic polytherapy (APP) was screened for clozapine-eligible patients.
The 206 APP patients were affiliated with one of three local outpatient facilities and identified on May 8, 2020, as part of a quality assessment project reported elsewhere.8
Patients were considered likely to be treatment-resistant and hence eligible for clozapine treatment if they, 1 year later (as of May 8, 2021), had:
A current prescription of non-clozapine APP (indicating a recurrent or continued insufficient response to AP monotherapy),
Trialled ≥3 different non-clozapine APs at a therapeutic dose (as defined in the manufacturer’s product labelling),
Trialled ≥2 APs adequately (at a therapeutic dose for at least 6 weeks/4 months if prescribed as a long-acting injectable) prior to current treatment, excluding treatment periods described with questionable compliance,
Not yet trialled clozapine.
Following the identification of eligible patients, the clinicians responsible for their treatment were asked for permission to contact the patients regarding study participation. None of the authors carried treatment responsibilities for patients identified as eligible for study participation.
All eligible patients able to provide written informed consent were invited to participate.
Material
For all patients consenting to participate, and for the patients who, by their primary treating clinician, were considered too unwell to be contacted, clinician-perceived scores of functioning (Global Assessment of Functioning (GAF-F)) and illness severity (Clinical Global Impression-Severity, (CGI-S)) were collected. Ratings made by both the treating psychiatrist and the primary clinical care provider were collected, if possible, to form a mean clinician rating.
Furthermore, data regarding the time of first diagnosis of schizophrenia as well as on current and former AP treatment were retrieved from the medical records.
The interviews were conducted at a place of the participant’s own choice (at home, at the local outpatient facility, etc). The lead investigator (MIJ) retrieved the data from medical files and performed the interviews.
Before the interview, the participants were asked to complete a battery of interviewer-administered patient-reported outcome measures (PROMs). The battery consisted of:
A questionnaire with demographic and socioeconomic questions constructed for this study (see online supplemental file 1) for an English version of the questionnaire,
An assessment of subjective well-being (the WHO Well-Being Index (WHO-5),20 a five-item rating scale with total scores ranging from 0 to 100),
An assessment of subjective recovery (the Brief INSPIRE-O,21 a five-item rating scale with total scores ranging from 0 to 100),
An assessment of drug attitude (the Drug Attitude Inventory-10-item version (DAI-10) (derived from the 30-item version22), with total scores ranging from −10 to 10),
An assessment of subjective disability (the Sheehan’s Disability Scale (SDS),23 a 3-item rating scale with sum scores ranging from 0 to 30),
An assessment of insight (the Beck Cognitive Insight Scale (BCIS),24 a 15-item self-report, consisting of two subscales. Cognitive insight is reflected by a composite index between the two subscales (the sum of one subscale subtracted by the sum of the other subscale). The composite index ranges from −18 to 27.
Supplemental material
The instruments in the battery were chosen based on their presumed impact on willingness to trial clozapine, either due to suggestions in previous literature (insight and symptom severity)25 or due to the authors’ own presumptions.
The interviews were semistructured and assessed the participants’ willingness to trial clozapine if offered now as well as the context affecting their beliefs. The interviews were constructed to obtain both qualitative and quantitative responses to the same questions, by first asking open-ended questions about each item and then probing the participants to more specific questions to which they also provided quantitative, categorical answers (‘yes’, ‘maybe’, ‘no’, ‘don’t know’) or ratings on Likert or 0–10 scales. The scale ratings were aided by visual scale analogues.
The online supplemental file 2 shows the interview guide translated into English.
Supplemental material
The interview comprised three sections:
Section 1, assessing the participants’ experience of their illness course and current symptoms, perception of current and former antipsychotic treatment, former experience or knowledge about clozapine, their perception of clozapine after receiving information about it during the interview and their willingness to trial clozapine if offered now.
The patient information sheet on clozapine used for this study was a slightly paraphrased version of the information sheet used in a study by Gee et al.13 It was read out loud to the participants (who were also given a printed version) and informed about the primary indication for clozapine treatment, efficacy, common and severe adverse side effects related to clozapine treatment, the monitoring regimen and the possible requirement of hospital admission for clozapine commencement (see S2, page 6).
Section 2, specifically assessing the perceived impact of frequently mentioned barriers to clozapine treatment (blood sampling, adverse side effects and hospital admission) on the participants’ willingness to trial clozapine.
The wording and scales of the quantitative questions were aligned with the questions used in the Gee study on inpatients.13
Section 3, assessing the participants’ perspective on eight proposed clozapine-facilitating initiatives.
All interviews were audio-recorded and transcribed verbatim by an experienced research assistant.
After each interview, the interviewer asked supplementary questions from the SCI-PANSS interview guide26 to assess the presence and severity of current symptoms. The interviewer then rated the severity of the participant’s illness (CGI-S) based on these answers and on the symptoms and their impact on daily living and well-being as reported by the participant during the interview. The interviewer-assessed CGI-S served as a pseudomeasure for the participant-reported severity of current symptoms.
Patient and public involvement
The preliminary version of the interview guide was pre-trialled on three external outpatients with schizophrenia. The final version of the interview guide is modified according to their answers and feedback on content and wording.
Analyses
Quantitative analyses
Quantitative data were analysed with descriptive statistics using Microsoft Excel (V.2013)27 and the statistical software R28 and RStudio.29 Answers to questions assessed as a nominal outcome with four or five possible answers: ‘yes’, ‘maybe’, ‘no’, ‘don’t know’ and ‘other’ were collated to form a dichotomous categorical variable: positive answers (yes+maybe) and negative answers (no+don’t know).
Differences between groups (eg, between participants accepting a trial with clozapine vs participants not accepting a trial of clozapine) were tested with the non-parametric Mann-Whitney U test for ordinal and continuous data and with the Fisher’s exact test, or the Binomial exact test, for categorical data. Differences within groups (eg, changes in repeated assessments of willingness) were tested with the non-prametric Wilcoxon signed rank test. All p values were two-tailed with a significance level of<0.05.
Qualitative analyses
Interview transcripts were imported to the qualitative data analysis software NVivo (V.14)30 and analysed thematically by the lead investigator (MIJ) in accordance with the framework developed by Braun and Clarke.31 First, field notes and transcripts were read through in their entire length to obtain an overall understanding of the data. The transcripts were divided into acceptors and refusers according to their quantitative responses to clozapine willingness, and text passages were then coded deductively according to focus area (ie, reason for acceptance/refusal of clozapine, context for willingness to trial clozapine, impact of blood sampling on willingness, impact of side effects on willingness and impact of hospital admission on willingness) to which the text was collated. Collated text on each focus area was subsequently coded inductively and then organised into preliminary themes and subthemes. The formation of themes and subthemes was further adapted in an iterative process. To address the issue of trustworthiness, the selection of representative participant citations was carried out in collaboration with an experienced qualitative researcher (SFA). This further helped ensure that the formed themes were grounded within the data.
Integration of qualitative and quantitative results
The results of each dataset were summarised, side-by-side, in a joint display to compare the qualitative and quantitative results for convergence and to draw meta-inferences (ie, the overall understanding based on both datasets).
Ethics and permissions
According to Danish legislation, the project does not need ethical approval.
The Regional Data Agency approved the use and storage of study data (ID: REG-092–2020), and the Regional legal authorities permitted the retrieval of data from medical records for screening purposes and for the retrieval of clinical data regarding patients who were considered too unwell to be contacted for study participation (ID: R-21013123). These patients served as a reference group for the included participants in terms of functioning and severity of illness. Patients considered well enough to be contacted were included only if they provided written informed consent. Patients received a payment of 500 DKK (~72.5 USD) before taxes for the interview participation. All patient data have subsequently been anonymised.
Results
Participants
Forty-three patients fulfilled our criteria for clozapine eligibility (see figure 1 for a flowchart of the screening and inclusion process), of which 17 patients, by their primary treating clinician, were considered too unwell to be contacted for study participation. Of the remaining 26 patients, 18 agreed to participate with both clinical data and interviews. The clinical and sociodemographic characteristics of the 18 interviewed participants are summarised in table 1. Their median age was 30.0 years with an IQR of 24.8–37.8 years and a full range of 22–68 years. Fifteen participants (83%) had been ill for at least 5 years, half the sample (nine participants (50%)) for at least 10 years.
Screening and inclusion of clozapine-eligible, yet clozapine-naïve, patients. The flowchart shows the process of screening for and inclusion of eligible patients from a convenience sample of APP-treated outpatients with schizophrenia. ICD10, International Classification of Diseases, Tenth Revision. 1As defined in the manufacturer’s product labelling. 2Therapeutic dose ≥6 weeks for oral prescriptions and ≥ 4 months for long-acting injections.
Participant characteristics
All participants were considered at least moderately ill (CGI-S ≥4, full range 4–7) by their treating clinicians, and most participants (15 participants (83%)) were considered to have serious or major functional impairment (GAF-F ≤50, full GAF-F range 25–75).
The clinician-rated CGI-S and GAF-F scores differed significantly between the interviewed participants, and the patients considered too unwell to be contacted: CGI-SInterviewed 5.0 (IQR 4.6–5.5) versus CGI-SToo_unwell 6.0 (IQR 5.0–7.0); p=0.013, and GAF-FInterviewed 39.3 (IQR 33.5–45.0) versus GAF-FToo_unwell 25.0 (IQR 19.0–32.5); p<0.001.
Quantitative results
Willingness to trial clozapine and quantifications of context
Nine of the 18 participants (50%) responded positively in terms of trialling clozapine if offered now (n=7 ‘yes’, n=2 ‘maybe’), while nine participants (50%) said that they would not accept a trial of clozapine right now. Five participants had previously been offered a trial of clozapine which they had declined at the time.
The participant-reported degree of current symptom severity (ie, the interviewer-assessed CGI-S level), the degree of participant-perceived helpfulness of current APs and the number of participants reporting adverse side effects with their current APs differed between the participants willing to trial clozapine now (acceptors) and the participants not willing to trial clozapine now (refusers). However, only the difference in participant-reported symptom severity (CGI-S) was statistically significant (p=0.03). Table 2 shows the quantitative assessments of the participants’ willingness to trial clozapine, and its context, divided by clozapine acceptance/refusal.
Quantitative assessments of eligible outpatients’ perspectives on current symptoms, antipsychotic treatment, prior experience with and willingness to trial clozapine
In addition to the sociodemographic questionnaire and the closed-ended and scale-rated interview questions, the participants completed five standardised PROM instruments assessing the context for their willingness (see table 3). Marked differences in subjective well-being (WHO-5), self-rated recovery (Brief INSPIRE-O) and self-rated drug attitude (DAI-10) were observed between the participants willing to trial clozapine now and the participants not willing to trial clozapine now. However, only the difference in self-rated recovery showed statistically significant (table 3).
Standardised patient-reported outcome measures (PROMs) used as quantitative assessments of context for clozapine willingness
Tales showing the individual quantitative answers to the interview questions and the PROMs are available on the OSF data repository at https://doi.org/10.17605/OSF.IO/R35CB in the file named ‘Individual quantitative data’.32
No apparent differences in terms of clinical or sociodemographic factors were observed between clozapine acceptors and refusers (see online supplemental file 3 for an overview of clinical and sociodemographic participant characteristics divided by clozapine acceptance/refusal).
Supplemental material
Impact of suggested barriers on willingness
When asked specifically about the impact of frequently mentioned barriers (blood sampling, adverse side effects and hospital admission) on the willingness to trial clozapine, the barrier with the highest median impact on the 1–5 Likert scale was hospital admission (3.0 (IQR 3.0–4.0)), while blood sampling ranked lowest (1.5 (IQR 1.0–2.8)) (table 2). This distribution remained the same when answers were divided by acceptance/refusal of clozapine; no statistical differences were observed between the groups (table 2). However, the clozapine-refusing sample showed a larger spread in ratings, with two refusers (22%) rating blood sampling five on the Likert scale (= ‘this would preclude me from trying clozapine’), one refuser (11%) rating side effects five on the scale and two refusers (22%) rating hospital admission five on the scale (individual quantitative data).32 In contrast, only one acceptor (11%) rated a barrier (in this case hospital admission) five on the impact Likert scale (see "Individual quantitative data").32
Clozapine-facilitating initiatives
The participants were presented with eight suggestions of initiatives and asked whether these initiatives would make them more prone to commencing clozapine. They were also asked if they, themselves, had any further suggestions.
The participants’ responses to these questions are summarised in table 4. In total, 17 of the 18 interviewed participants responded that one or more initiatives would make them more prone to trial clozapine. The initiatives most frequently stated as possible facilitators of clozapine acceptance were the “Individualisation of blood sampling location according to the patients’ preferences’ (n=13 (72%)), ‘Clozapine commencement as an outpatient’ (n=12 (67%)) and ‘Listening to peer patients sharing their personal experiences with clozapine treatment’ (n=12 (67%)). There was no obvious preference for in-person versus video presentation of peers' clozapine experiences (n=7 vs. n=5, p= 0.77) amongst those choosing the peer option as a facilitator ("Individual quantitative data").32
Distribution of positive* patient responses to the question ‘do you think that the following initiative would make you more prone to trial clozapine?’
No statistically significant differences in preferences were observed between the clozapine-accepting and refusing participants either; however, the facilitator most frequently chosen as a possible influencer on clozapine willingness by acceptors was from the ‘Individualised blood sampling location’ category (n=8 (89%)), whereas the refusers most frequently chose the peer option (n=7 (78%)) (table 4).
Changes in willingness to trial clozapine
At the end of the interview, eight participants (five clozapine-accepting and three refusing participants) reported a positive change in their perspective on clozapine; however, a change in the score of willingness was observed for 10 participants (five clozapine-accepting and five refusing participants) ("Individual quantitative data").32 The median score of willingness had changed from 8.0 (IQR 7.0–8.0) to 8.0 (IQR 8.0–9.0) for the acceptors and from 0 (IQR 0–2.0) to 1.0 (IQR 0–2.0) for the refusers. The change was significant for the refusers only, p=0.04 versus p=0.41.
Qualitative results
During the first part of the interview, the participants’ perceptions of their current symptoms and impact on life, their perceptions of antipsychotic treatment and any prior experience of/knowledge about clozapine were assessed and, within this context, their willingness and reasons for trialling or not trialling clozapine if offered to them now.
A thematic analysis was applied to the qualitative responses divided by acceptors and refusers to understand and characterise the underlying reasons why seemingly eligible patients either accept or refuse a trial of clozapine.
Willingness to trial clozapine if offered now
In total, six themes described the participants’ reasons for accepting or refusing clozapine treatment. Three themes characterised the clozapine-accepting participants’ reasons for acceptance, and three themes characterised the refusers’ reasons for non-acceptance. See figure 2 for a visual presentation of the analysis.
Patient perspectives on clozapine willingness. Thematic map showing the identified themes and subthemes describing the participating patients’ reasons for accepting or refusing clozapine treatment. Themes describing the perspectives of clozapine-accepting patients are coloured green, and themes describing the perspectives of clozapine-refusing patients are coloured red.
Clozapine-accepting patients’ reasons for acceptance
Theme 1: clozapine offers hope of improvement
The vast majority of acceptors expressed inadequate symptom control with both current and former APs. They were not necessarily dissatisfied with their current treatment, but their residual symptoms were perceived as being distressful and affecting them negatively in their daily life:
My meds are ok. They take most of the, um…very bad thoughts, but I'm still not functioning because my head is still all over the place—I can’t concentrate on doing anything. (Patient 13)
The voices in my head and my anxiety…It makes it difficult for me to get out of the house and… it limits me in being social. (Patient 17)
Furthermore, they all expressed wishes for symptom relief and/or to regain control of themselves and their lives:
I wish they didn’t control my life that way—the voices I mean. And that the visions went away… (Patient 10)
I just wish that the medicine would take some of the thoughts so I could focus and do stuff. By myself, you know. (Patient 13)
Not all acceptors spontaneously expressed hope of improvement, and some patients thought their current situation to be as good as possible; however, when introduced to the patient information about clozapine, all acceptors expressed such hopes due to their positive impressions of clozapine’s efficacy and/or side effect profile. The latter was often noticed, in positive terms, as being manageable and/or without the presence of previously experienced extrapyramidal side effects:
It sounds like it actually works…Even in your bad periods. And you can practically treat almost all the common side effects listed here. You can’t do that with what I’m having now (…) I have experienced being really badly affected by side effects (…) In my muscles. (Patient 15)
It’s nothing (referring to the list of common adverse side effects)…I mean, it’s not something that I haven’t already tried. Yes, there are side effects, but, to me, it sounds like maybe it’s a drug that could help me somehow, um…because that’s what’s been the problem with all the others, you know, they haven’t really helped me. (Patient 16)
Theme 2: confidence in the necessity of the doctors’ orders
Another major theme was the acceptors’ confidence in the professionalism of their psychiatrists and hence in the relevancy and necessity of their recommendations:
If it was a doctor who suggested it then I would do it, yes. Because then I know that the doctor would have put some thoughts into it. (Patient 15)
Most acceptors expressed their intention to follow such recommendations, whether they, themselves, had thought about changing medications:
I trust the doctors to know what they are talking about and that it is right for me. (Patient 14)
Theme 3: customised plans for commencement provide reassurance in the necessity and feasibility of clozapine treatment
Some of the acceptors had previously been offered clozapine treatment and refused it. These participants had recently been offered clozapine again—and this time they had accepted to commence it (not yet commenced at the time of the interview). The ‘turned’ participants expressed perspectives within the themes mentioned above; however, the ‘game changer’ in terms of their current acceptance was the fact that efforts had been made to customise the plans of their commencement to mitigate or even remediate the specific barriers that had precluded them from accepting clozapine in the first place:
I can’t do public transportation or waiting rooms (…) so, had it been regular outpatient commencement I wouldn’t have been able to do it. But now that it all can be done from home, I can manage. (Patient 10)
Because my tutor (community caretaker)…she was with me at the meeting with the doctor, and she also said it was a good idea and that she would help me with all of that (ie, remembering appointments, drug compliance, accompanied blood sampling, reporting fevers, etc). (Patient 13)
Clozapine-refusing patients’ reasons for refusal
Theme 1: reconciliation with the current situation warrants no change in treatment
The vast majority of refusers expressed drug-trial fatique and the perception that their symptoms currently were that much in control, or at least that stable, that they were able to live with their illness and accept their current situation:
I still have, uh…voices and stuff, it’s just that it’s changed, it’s kind of faded into the background, so, now I can put up with it. (Patient 05)
Most refusers attributed this stability to their current AP treatment, which they considered the best they had trialled so far because it seemed to work (more or less), and/or lacked the burden of the previously encountered adverse side effects, sedation and weight gain:
None of the medications I’ve tried have been able to solve all my problems. What I’m having now is the closest I’ve come (…) I think that I am as well treated as I can be right now, so I don’t think there is any reason to change the medicines. (Patient02)
It (clozapine) sounds like some of the old drugs that I have tried (…) I remember feeling really bad and sedated (…) I don’t want that. Then I’d rather have what I’m having now. (Patient 01)
I’ve been through it all and tried several things twice (…) Nothing worked. I’m satisfied with the treatment I’m having now (…) it doesn’t cause weight gain. Once, I gained 30 kg in 4 months. I think I've lost 8 of them, the rest aren’t going anywhere. (Patient 03)
Some refusers did express subjective distress due to their current symptoms and a longing for symptom reduction; however, their previous experiences with changes in AP treatment comprised several instances of illness deterioration and hospital admission without significant improvement in symptoms, which now precluded them from any new changes in medications:
Sometimes it’s not enough (the medicine), I spent a lot of time in my bed, but I'm pretty good, mentally, for most parts (…) and the road to get there has been with so many hospitalisations and different medications…and many downs. (Patient 04)
Right now, my symptoms come all the time, so it doesn’t take all of it (…) it helps a little. I would like it to take away…all the bad things I experience (…) But no, I don’t dare to try any more new medicines…now I’ve had this for so long (Patient 08)
Some refusers also described worries about changing from their current medication because they previously had experienced being ‘trapped’ on antipsychotics that were not right for them:
They gave me all different kinds of antipsychotic medications, which just didn’t work, not for me anyway, and the last one I was on for 1.5 years before I was allowed to switch…even though I almost constantly, at every doctor’s appointment, said that I was feeling bad, and I would like a change in my medication. (Patient 07)
Theme 2: clozapine is a last-resort treatment for last-resort people
The impression of clozapine being a last-resort treatment was mentioned as a barrier to acceptance. Some refusers stated that they knew clozapine as a treatment option for patients much worse than themselves and that they did not identify themselves as candidates for clozapine just yet:
I knew someone who was on Leponex (clozapine). He was in a really bad shape, much worse than me… (Patient 02)
In some cases, the alienation from clozapine candidacy was enhanced by the negative impressions of relatives:
I’ve been told about clozapine, that it’s if you are really ill. It’s like a “last resort”…quite strong medicine (…) It’s not that bad with me, I think. (…) My mom said that too. Make sure never to take that drug she said. And I won’t. (Patient 01)
However, the majority of refusers (n=5) stated that they would consider clozapine treatment if their symptoms deteriorated:
Now, if we said that the medicine I’m having now stopped working, then I'd be like nine or ten (on the 0–10 scale of willingness) (…) I think that a lot of schizophrenia people get desperate at some point and need something that works…then we're willing to try anything. (Patient 03)
Theme 3: permanent or situational reluctance due to practical aspects of treatment
A rarely mentioned, albeit distinct, reason for refusing clozapine treatment was the reluctance to have blood drawn. Some (n=2) refusers mentioned that they had previously declined an offer of clozapine treatment due to the requirements of haematological monitoring—although for very different reasons. As in the cases of prior refusals among acceptors, one refuser explained his prior refusal due to blood sampling as situational (eg, from a time with lower mental capacity than now) and linked to practical concerns other than the blood sampling itself:
It was unmanageable, having to have blood drawn every 4 weeks. It was mostly that…and that it’s dangerous to have a fever (…) that you’d have to call it in… I couldn’t keep track of all the things that followed. (Patient 04)
However, one participant mentioned the reluctance to have blood drawn as a permanent barrier and the reason for refusing clozapine now as well. In this case, the reason was the fear of blood sampling itself:
I don’t like having blood drawn and being poked with needles (…) It’s not that it hurts. It doesn't hurt that much (…) it’s more that it (the needle) has to enter me and stuff like that. I can’t have it. (Patient 09)
Impact of suggested barriers on willingness to trial clozapine
The need for blood sampling, the specific adverse side effects of clozapine and the potential need for hospitalisation for clozapine commencement have been mentioned as reasons for patients to refuse clozapine treatment. Therefore, the participants were asked specifically about their perspectives on these suggested barriers and their impact on the participants’ willingness to trial clozapine. The results of the thematic analysis on each of the suggested barriers will be summarised in the following. Figure 3 provides a visual overview (a thematic map) of the results. Some themes were shared by both refusers and acceptors, and some were specific to one group or the other. In the following, quotes from both refusers and acceptors are included as ‘evidence’ of shared themes, and quotes are therefore labelled ‘refuser’ or ‘acceptor’ for clarity:
Patient perspectives on suggested barriers to clozapine commencement. Thematic map showing the participating patients’ perspectives on frequently mentioned barriers to clozapine commencement and their impact on willingness to trial clozapine. Themes describing the clozapine-accepting patients’ perspectives are coloured green, and themes describing the clozapine-refusing patients' perspectives are coloured red. Themes shared by both acceptors and refusers are coloured in both colours.
Perspectives on the requirement for blood sampling and its impact on clozapine willingness
When asked specifically about their perspectives on blood sampling and the impact of the requirements of frequent blood sampling on their willingness to trial clozapine, two themes reflected the participants’ perspectives. One theme reflected both the clozapine-accepting and the clozapine-refusing participants’ perspectives, and one theme was specific to the refusers (figure 3):
Theme 1 (common theme): several aspects of blood sampling may be a burden—not a deal breaker
The vast majority of participants stated that they did not consider the blood sampling itself to be a problem and showed their tattoos or piercings as part of their response:
It doesn’t bother me that much to be honest, having blood drawn…it’s just a prick. (Patient 13, acceptor)
I’ve been on long-acting medications for…I don’t know how long now, so a little blood sampling doesn’t bother me at all. (Patient 03, refuser)
However, a substantial proportion of the participants expressed difficulties with the practical aspects of blood sampling (eg, remembering appointments, being on time, finding transportation) or with the need for being with other people during public transportation and/or while sitting in the waiting room:
The thing about remembering it and getting there on time (…) I would probably need help with that. (Patient 18, acceptor)
It’s not that really about the prick itself (…) it’s more about all that follows…about sitting in the waiting room and that you’re never called in on time and…it’s probably the uncertainty of everything that surrounds it. (Patient 04, refuser)
Others expressed that it was the frequency by which they had to accommodate these requirements that troubled them the most:
It’s not about getting up there. It’s about having to do so, so frequently. (Patient 13, acceptor)
I wouldn’t mind that (having blood drawn), it’s more about having to go back and forth so often. I don’t like that. (Patient 02, refuser)
As a result, some participants acknowledged that the need for blood sampling did affect their degree of willingness to some extent; however, all of the clozapine-accepting, and most of the refusing, participants stated that the need for blood sampling would not prevent them from trialling clozapine, or as some of the refusers stated, not if their symptoms deteriorated:
It would bother me quite a bit, but I would still be willing to try it. You can say, luckily, it’s only the first 4 months, but it’s still a bit inhibiting on everyday life that you would have to make an appointment once a week at a hospital where it’s already difficult to get appointments. (Patient 15, acceptor)
If I got really ill, I'd readily take it though. (Patient 02, refuser)
Theme 2 (refusers only): the need for blood sampling is a showstopper
One of the clozapine-refusing participants stated that the need for blood sampling would put him off trialling clozapine entirely, regardless of finger-prick (point-of-care) sampling or reduced frequency of sampling being available options for individualised treatment:
No, I’m completely panicking (when having blood drawn). I don’t like them sticking needles in me. I can’t have that at all (…) I wouldn’t do it. (Patient09, refuser)
Perspectives on the adverse side effects of clozapine and their impact on clozapine willingness
When asked about their perspectives on adverse side effects and the impact of such on their willingness to trial clozapine, three themes reflected the participants’ perspectives. One theme described both the clozapine-accepting and the clozapine-refusing participants’ perspectives, one theme was specific to the acceptors and one theme was specific to the refusers (figure 3):
Theme 1 (common theme): concerns about side effects are not specific to clozapine treatment
The majority of participants were generally concerned about side effects when commencing new drugs and expressed concerns unrelated to clozapine treatment:
Yes, side effects worry me because I have previously experienced being really badly affected by side effects. (Patient 15, acceptor)
Yes, when I start something new (medications), I’m always worried about how I will react; whether I can tolerate it, and such. I’m not afraid of dying from it, but I’m nervous beforehand because I know how strongly one can react, especially on antipsychotics. It’s not exactly candy we have to eat, you know. (Patient 03, refuser)
Some of the refusers had even turned down treatment with other kinds of medicines (non-APs) due to the risk of adverse side effects:
So, uh, at one point there was some talk about me having to switch to some other drugs, uh, and there were these three drugs that I didn't want (…) because of the side effects. (Patient 06, refuser)
Theme 2 (acceptors only): knowledge about the adverse side effects of clozapine does not deter patients from trialling it
All the clozapine-accepting participants stated that their current knowledge about the adverse side effects of clozapine would not prevent them from trialling it:
No, it doesn’t worry me at all, because I don’t know if I’ll get the side effects until I’ve taken it for a while anyway. (Patient 16, acceptor)
The acceptors noticed different side effects with clozapine, in most cases the weight-inducing properties or the impact on leucocyte counts but weighted the side effects differently. To some acceptors, the side effects carried at least a slight concern; to others, they were perceived as a positive and welcomed effect:
The thing about, uh, the weight gain…and the dizziness, I probably wouldn’t want to have that one either, but there’s not really something that I would be afraid of. And the fatigue…well, that one is a plus for me. (Patient 14, acceptor)
The acceptors who previously had been offered a trial of clozapine stated that they had received much more information about the clozapine side effects and their impact on treatment and monitoring than they had about any other drugs and that the received information had scared them to such an extent at the time that they had declined the treatment on that account. However, as they, later on, gained more information about the relative risks and the possibility of handling the adverse side effects, they now felt more relaxed about it:
I have received more information about clozapine than about the other drugs…about side effects and that it works well for most people who take it (…) I was spooked (earlier) when they told me about the risks of it. Especially about the ones with the fastened heartbeat and the white blood cells. I also have anxiety so I can get thoughts about…well, death (…) Now I have searched a lot on clozapine on the internet and read some experiences with it (…) Most of the bad things that can happen are “worst-case scenarios”…a result of no one reacting, so, if I just react to it, I think it will be alright. (Patient 10, acceptor)
Theme 3 (refusers only): previously encountered adverse side effects resembling those of clozapine affect willingness
A substantial proportion of the clozapine-refusing participants explained that they previously had experienced adverse side effects resembling the ones related to clozapine, sedation and weight gain in particular, and were reluctant to trial medications with these side effects again:
I make sure to ask about the side effects that I don't want to experience again, to ensure that they are not part of it (…) I don’t want anything that causes weight gain again for example. (Patient 03, refuser)
One refuser stated that the adverse side effects of clozapine would put her off trialling it entirely, one refuser mentioned the witnessed sedative effect on a peer as the reason for a clozapine refusal in the past and some refusers stated that the mentioned side effects would impact their current willingness a lot. However, the majority of refusers stated that their knowledge about clozapine side effects would only affect them to some extent and that it would not prevent them from trialling it if their symptoms got worse:
Well, I would definitely have to think about it (…) but I would still, like, be willing to try it (…) it wouldn’t be the side effects that prevented me from trying it no. (Patient 05, refuser)
Perspectives on hospital admission for commencement and its impact on clozapine willingness
One overarching theme covered the participants’ perspectives on hospital admission for clozapine commencement:
Theme 1 (common theme): a barrier in practice if not in emotion
To some participants, being admitted to a hospital for the commencement of a new drug was perceived as a welcomed safety precaution although not always doable due to work or home obligations:
If I didn’t have a pet, I would probably choose to be hospitalised in the beginning (of the commencement), because I am so afraid of adverse side effects (…) it’s safer in there. (Patient 10, acceptor)
To others, the attitude towards hospitalisation was more ambiguous and coupled with both negative and positive experiences:
Most of the times that I have been hospitalised, it has worked (…) and I have felt quite good afterwards (…) But sometimes I just feel that I get more unwell being in there… (Patient 09, refuser)
However, the majority of participants stated that it was unpleasant to be hospitalised and preferred it avoided if not warranted by proper justifications:
I don’t like planned hospitalisations, because I don’t see any logic in having to be among people that unwell if you're not in such a bad shape that you have to be in there yourself. (Patient 15, acceptor)
The way I see it, hospitalisation is the last resort. Something you have to, only if you’re really ill. (Patient 02, refuser)
Despite that, most participants said that the prospect of hospital admission would not preclude them from trialling clozapine, although it would affect their willingness negatively to some extent:
I would still be willing to try it (clozapine), but I really want to avoid it (the hospitalisation). (Patient13, acceptor)
I would think that it was very uncool, but I would do it if necessary. (Patient 04, refuser)
Integration of qualitative and quantitative results
The mixing stage of the mixed-methods convergent design occurs when the results of the quantitative and qualitative data are merged and compared to determine whether they converge or not. From this comparison, overall interpretations (meta-inferences) are made about what has been learnt from the combined data. Summaries of the quantitative and qualitative results, the meta-inferences drawn from their comparison, and statements of convergence/divergence are shown in table 5.
Joint display
Discussion
With this study, we sought to understand the underlying reasons why some clozapine-eligible patients accept a trial of clozapine, whereas others do not.
The study was carried out as a mixed-methods convergent design,14 in which qualitative interview data were complemented with quantitative data (ie, counts and proportions, numerical scale-ratings) on the same items to comprehensively investigate the participants’ perspectives on clozapine commencement. The incorporation of selected questions from previous research (willingness to trial clozapine and Likert scales on specific barriers) into our quantitative dataset furthermore allowed us to compare the answers of our outpatients with the answers of inpatients from the few previous (quantitative) studies on the subject.13 25
We found that clozapine-eligible outpatients with schizophrenia in general seem positive about trialling clozapine treatment. Half of the participants stated that they would be willing to try it if offered now. In comparison, only 25–30% of the patients in previous studies on eligible inpatients would accept a trial of clozapine.13 25 For those 50% of our participants who did not want to try it now, clozapine itself was rarely the reason. In some cases, the participant’s own perception of being adequately treated was stated as the main reason for refusal; however, the majority expressed drug-trial fatigue and an acceptance of their current situation as ‘as good as it gets’. They explained that they had tried so many different APs without adequate efficacy, but with the same bothersome side effects as with clozapine (weight gain in particular) or with subsequent deterioration of symptoms and rehospitalisation, that they preferred living with their now stably unwell condition on their current APP treatment, rather than trialling a new drug with the same adverse side effects or negative consequences as encountered before. Furthermore, when clozapine treatment was heard of beforehand, it was often perceived as a last-resort treatment, and several of the refusers stated that they did not identify themselves as in need of ‘the last resort’ just yet. The practical aspects of clozapine treatment also constituted a barrier to treatment for various reasons. The majority of patients who had refused an offer of clozapine in the past mentioned practical aspects of treatment (eg, public transportation for blood sampling, remembering frequent appointments, calling in fevers) or the sum of them, as their reason for refusing clozapine at the time. The patients for whom these practical barriers had been mitigated were now about to commence clozapine. Hospitalisation for ‘practical purposes’ (ie, for clozapine commencement) was not spontaneously mentioned as a reason for clozapine refusal by any of the participants, and most participants stated that it would not ultimately preclude them from trialling clozapine. However, as in the Gee study,13 it was the highest-weighted barrier when specifically asked about the impact of ‘hospitalisation’, ‘side effects’ and ‘blood sampling’ on willingness (ie, partial convergence between probed and non-probed answers, and between qualitative and quantitative answers), regardless of whether the participant was a clozapine accepter or refuser.
Some patients mentioned that they previously had been overwhelmed by the frequency of blood sampling or by the thereof perceived danger of clozapine. However, the requirements of blood sampling only rarely affected the participants’ current willingness to try clozapine substantially (decisive for one participant only). This was further reflected in the low preference for suggestions such as ‘finger-prick (POC) sampling’ or ‘reduced frequency of blood tests’ as facilitators of clozapine treatment. A similar conclusion was drawn in the Gee study13 in which blood sampling also ranked lowest of three suggested barriers (hospitalisation, adverse side effects and blood sampling).
Interestingly, these results are in contrast to the findings from a previous study by Swinton and Ahmed,25 in which 75% of the inpatients refused to try a drug that would require them to have blood drawn regularly (although not otherwise informed about the drug, nor that it was called clozapine). Furthermore, Swinton and Ahmed25 found that the reluctance was related to both increasing symptom severity and low insight scores.
In our study, there were no obvious sociodemographic or clinical differences between clozapine refusers and acceptors. However, the participants who were willing to trial clozapine were often more subjectively affected by their symptoms and felt less helped by their current medication than the refusers did (qualitatively expressed), which, quantitatively, was reflected in differences between their CGI-SInterview scores (used as a pseudo-measure for the self-reported symptom severity), WHO-5 scores, INSPIRE-O scores and DAI-10 scores. Hence, we found convergence between the qualitative and quantitative findings. Only the differences in CGI-SInterview and INSPIRE-O scores were statistically significant. The lack of statistical significance is most likely attributed to the small sample size (type 2 error); however, it is important to keep in mind that some of the refusers did express severe distress and affected well-being due to their current symptoms albeit too afraid of negative consequences to accept another AP trial. Such patients could have diminished the overall difference between refusers and acceptors in some regards.
In a parallel study,33 we assessed the very same patients’ eligibility for clozapine treatment as rated by their treating clinicians. It is noteworthy, how the clinicians rated many of these participants as well-treated/as well-treated as possible (meaning stably unwell and without subjective distress due to their symptoms)33 and therefore not eligible for clozapine treatment. The presence of subjective distress is not a requirement for the TRS status (the primary indication for clozapine treatment) according to the Treatment Response and Resistance in Psychosis (TRRIP) consensus guideline,4 nor should it be. However, it should raise the question of whether the patient is as well-treated as possible and if a change in medication is warranted. So should low levels of functioning regardless of stability. Taking into consideration that all of the clozapine-accepting participants were subjectively affected by their symptoms (though stably ill and not necessarily recognised as in distress by their treating clinicians nor spontaneously informing their clinicians about it), maybe subjective distress ought to be given more attention in everyday clinical care as measured by formal instruments, that is, PROMs. If nothing else, this study highlights that clinicians could be better at spotting residual distress and that we need to include other measures than the clinician-perceived efficacy of treatment or burden of symptoms when considering clozapine candidacy. A suggestion to help the clinicians identify suitable clozapine candidates in the clinic could therefore be routine CGI screening at each consultation and interviews based on the patients’ completion of the Brief INSPIRE-O, as these instruments seem sensitive to subjective distress due to inadequate efficacy of current AP treatment—and therefore to clozapine willingness. Additionally, these instruments are all short and intuitive and thus manageable to both patients and clinicians. Future, and larger, studies should seek to replicate these results and investigate whether any cut-off limits exist for the relevant instruments to indicate inadequate symptom control and/or prediction of clozapine-willingness.
Another way to identify clozapine candidates in the clinic would be to simply just discuss clozapine treatment with the patients. The participants expressed a general inclination to follow their doctors’ recommendations, and some participants did not reveal their wishes for changes in their AP treatment until they learnt that an effective alternative existed. Furthermore, the study showed that the clozapine conversation (the interview) itself positively influenced the participants’ attitudes towards clozapine. The clozapine-refusing participants were generally more positive towards clozapine at the end of the interview than at the beginning of it, and several participants stated that they would accept an offer of clozapine if they were to get worse. Thus, clinicians should not be afraid to talk with their patients about clozapine treatment—nor with patients who previously have refused a trial of clozapine. Clozapine refusals are not necessarily permanent but changeable with time, place and circumstances, especially when individual considerations have been applied to mitigate specific personal barriers and thereby ease feasibility. In our study, the participants called for several different facilitating interventions such as positive experiences from relatable peers, reassurance that side effects can and will be acted upon, and an easier and more manageable approach to the practical aspects of commencement and blood sampling (eg, assisted drug compliance or transportation for ECG and blood sampling, in-home sampling or sampling at another, to the patient, more convenient location to avoid the psychological burden of public transportation and social interaction). In summary, personalised treatment was the main request in terms of clozapine-facilitating interventions, and it was the most important factor leading to current clozapine acceptance by the participants who had previously refused a trial of clozapine but now agreed to commence.
Maybe in the future, even refusals due to previously experienced AP-induced weight gain can be reversed by the offer of an effective new-generation weight loss medication, and at the same time improve the patients' cardio-metabolic risk status.34–37
All clinicians should bear the positive impact of conversation and personalised treatment in mind so that patients, who meet the eligibility criteria, are offered clozapine as soon as possible without excessive AP trials, and refusers are offered clozapine more than once—preferably motivated with customised commencement plans.
Our study clearly shows that patients initially do tend to accept APs with adverse side effects such as weight gain and sedation, but that the exposure to several of these APs to which only suboptimal responses are reached, risks exhausting and even deterring the patients from trialling new medications later on. Furthermore, patients (and their relatives/caregivers) should be informed that clozapine is not a last-resort option and that the chances of responding to clozapine treatment are reduced if they wait too long to trial it.38 This message is also important to disseminate to the clinicians—if the stigma of clozapine as a ‘last-resort treatment for last-resort patients’ is allowed to live on, and the offer of clozapine treatment is pushed until the state of ultra-resistance or chronicity has been reached, the patients end up deprived of that improvement in both symptoms and quality of life that clozapine could have given them.
Strengths and limitations
A clear strength of this study is the population included. No previous studies have assessed the perspectives of clozapine-naïve, yet clozapine-eligible, outpatients with schizophrenia on clozapine commencement. The study intended to explore the perspectives of TRS patients, to what end we used inclusion criteria guided by the TRRIP consensus guideline.4 As the inclusion criteria primarily build on retrospective data from case files, we furthermore added the requirements of an extra AP trial at an effective dose as well as the recurrent or sustained need for APP (ie, indicating an inadequate treatment response to AP monotherapy) for an elongated period of time (1 year), as a means to rule out ‘false positive’ TRS inclusions. However, we acknowledge the possibility of ‘false-positive TRS inclusions’ and the inclusion of treatment-intolerant patients instead, and therefore we have used the term ‘clozapine-eligible’ instead of ‘treatment-resistant’ throughout the text.
Another strength of the study is its comprehensiveness. The assessment of both quantitative and qualitative aspects of the same questions have provided a much more nuanced picture of the subject than any of the methods would have been able to on their own.
Several steps were undertaken to enhance the trustworthiness of the qualitative analysis: to improve the credibility of the analysis, prolonged engagement with the material and the collection of information from different sources such as interviews and questionnaires (data triangulation) was undertaken. To promote transferability, detailed demographics and psychopathology of participants were provided along with thick descriptions of the participants’ different perspectives on clozapine. To address confirmability, a clear process (audit trail) for conducting the thematic analysis was outlined. Finally, themes were discussed and reviewed by a second, qualitative researcher (SFA) and quotes that were considered reflective of the themes selected in collaboration.
Some study limitations also need to be acknowledged: the patients included for interview in this study were significantly better in terms of clinician-rated illness severity and functioning than the clozapine-eligible patients deemed too unwell to be contacted for study participation. Therefore, we do not know how the most severely ill patients would respond to the study questions. Future studies assessing the willingness and perspectives of those patients are warranted.
The number of participants (n=18) was more than adequate for qualitative purposes though small in a classic quantitative sense. However, the quantitative strand was not the main focus of the study, and the data did not stand alone; instead, they served a descriptive purpose outlining the context for and complementing the qualitative component of the study and for hypothesis generation. Furthermore, we only used non-parametric tests, and the observed differences, or lack of same, were compared with the qualitative results of the same outcomes and, in most cases, verified by them (convergence between qualitative and quantitative findings).
For the same reasons, no correction was applied for multiple statistical comparisons.
Conclusion
Clozapine-eligible outpatients with schizophrenia seem positive toward clozapine commencement. Half (50%) of the 18 interviewed outpatients stated that they would accept a trial of clozapine if offered now, and half would not. Clozapine itself, or the need for blood sampling, was rarely the reason for refusal, and a substantial part of the refusing patients (n=5 (56%) stated that they would consider clozapine if their condition deteriorated. The general difference between clozapine refusers and acceptors was that the refusers either perceived themselves as somewhat in recovery or preferred being stably ill on their current non-clozapine APP treatment over trialling yet another drug and thereby risking subsequent illness deterioration and/or reoccurrence of previously experienced side effects, weight gain and sedation in particular. In contrast, the acceptors quantitatively and qualitatively expressed subjective distress due to their illness and wished for symptom relief regardless of side effects or risks of deterioration. Hence, this study highlights the need to include PROMs, e.g. on subjective recovery, when assessing clozapine eligibility in the clinic. It also highlights the importance of timely offers of clozapine to eligible patients and the consequences in terms of treatment exhaustion and discouragement to trial new drugs when handling clozapine as a last-resort treatment, exposing the patients to numerous non-clozapine AP(P) trials without proper antipsychotic efficacy but with some of the same adverse side effects. Clinicians should be aware that talking with their patients about their subjective well-being and the possibility of clozapine treatment seems to be a clozapine-facilitating intervention in its own right and therefore not to be avoided. Furthermore, they should be aware that clozapine refusals are dynamic and situationally determined, positively impressionable to the promise of individualised treatment with the patient in focus. In conclusion, this study suggests that even clozapine utility is a matter of patient-centred care.
Data availability statement
Data are available in a public, open access repository. The qualitative and sociodemographic data supporting these findings are not openly available due to reasons of sensitivity. All other quantitative data informing this study are available on the OSF data repository: https://osf.io/r35cb/.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants but was not approved by According to Danish law, the project does not need ethical approval.The Regional Data Agency approved the use and storage of study data (ID: REG-092-2020) and the Regional legal authorities permitted the retrieval of data from medical records for screening purposes and for the retrieval of clinical data regarding patients who were considered too unwell to be contacted for study participation (ID: R-21013123). These patients served as a reference/control group for the participants in terms of functioning and severity of illness. Patients considered well enough to be contacted were included only if they provided written informed consent. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We sincerely thank the included patients for their participation and endurance. We also thank our research assistant Augusta Holst for her work on transcribing the audio recordings and the pretest participants for their feedback on the interview guide and the study's relevance.
References
Footnotes
Contributors All authors participated in conceptualising the study. MIJ collected, managed and analyzed the data and drafted the sociodemographic questionnaire and interview guide in Danish and English, as well as all versions of the manuscript including tables and figures. SFA and JN critically reviewed the draft of the interview guide, and SFA further oversaw the analysis of the qualitative data. All authors have critically reviewed the manuscript and approved the final version for submission. MIJ acts as guarantor for this submission.
Funding This work was part of a cross-regional PhD project39 and supported by the Mental Health Services of Region Zealand Psychiatry East, Roskilde, Denmark, The Psychiatric Research Unit, Region Zealand Psychiatry, Slagelse, Denmark, and the Psychiatric Centre Glostrup, Unit for Complicated Schizophrenia, Mental Health Services of The Capital Region of Denmark, in collaboration. Grant numbers not applicable. Due to the funding by the Psychiatric Research Unit, Region Zealand Psychiatry, the study is partially funded by a private donation favouring patient-oriented research within the region.
Competing interests JN has previously received teaching honorariums from H. Lundbeck and Radiometer. The other authors have nothing to declare.
Patient and public involvement Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer-reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.