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Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation

  • Oliver D. Howes (a1), Francis Vergunst (a2), Siobhan Gee (a3), Philip McGuire (a1), Shitij Kapur (a1) and David Taylor (a4)...

Abstract

Background

Clozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of clozapine and other antipsychotics have been disseminated to clinicians.

Aims

To determine the theoretical delay to clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment.

Method

Clinico-demographic data were extracted from the treatment records of all patients commencing clozapine in our centre between 2006 and 2010.

Results

Complete records were available for 149 patients. The mean theoretical delay in initiating clozapine was 47.7 months (s.d. = 49.7). Before commencing clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (β = 0.7, P<0.001) but did not differ by gender or ethnicity.

Conclusions

Substantial delays to clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to clozapine, despite treatment guidelines.

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Copyright

Corresponding author

Oliver D. Howes, Box 067, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. Email: oliver.howes@kcl.ac.uk

Footnotes

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These authors contributed equally to the work.

See editorial, pp. 425-427, this issue.

Declaration of interest

D.T. has received consultancies fees, lecturing honoraria and/or research funding from AstraZeneca, Janssen-Cilag, Servier, Sanofi-Aventis, Lundbeck, Bristol-Myers Squibb (BMS), Novartis, Eli Lilly and Wyeth. O.D.H. has been a speaker at meetings organised by and/or received investigator-initiated charitable research funding from Astra-Zeneca, BMS, Eli Lilly, and Jansenn-Cilag. S.K. has received grant support from AstraZeneca and GSK, and has served as consultant and/or speaker for AstraZeneca, Bioline, BMS-Otsuka, Eli Lilly, Janssen (J&J), Lundbeck, NeuroSearch, Pfizer, Roche, Servier and Solvay Wyeth.

Footnotes

References

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Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation

  • Oliver D. Howes (a1), Francis Vergunst (a2), Siobhan Gee (a3), Philip McGuire (a1), Shitij Kapur (a1) and David Taylor (a4)...
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eLetters

Identifying treatment refractory schizophrenia

Oliver D. Howes, Psychiatrist
01 February 2013

We thank Professor Mortimer for raising some important issues. The first was about the absence of a control group. Our study was observational, designed to determine clinical practice in antipsychotic prescribing prior to clozapine relative to treatment guidelines, which is why there is no control group. Prescribing in patients who have treatment refractory illnesses but have never received clozapine is an important issue but outside the scope of our study. The second issue was that the paper implies that any patient for whom a third antipsychotic is considered ought to be considered for clozapine. Our study specifically selected patients who went on to be prescribed clozapine, predominantly because the illness was treatment refractory (see page 481 in the paper(Howes, Vergunst, Gee, et al, 2012)). As such it is relevant to treatment refractory patients, and in no way should be taken to imply thatall patients who are being considered for a third antipsychotic should automatically be considered for clozapine. It is important to note that our design could not confirm the illness was treatment refractory at the point at which two antipsychotics had been used and, whilst treatment resistance can be evident from the first episode(Agid, Remington, Kapur, et al, 2007), it may potentially emerge later in some patients (this is discussed further in the paper(Howes, Vergunst, Gee, et al, 2012), page 483). For this reason, the delay is described as the maximum theoretical delay (see 482 in the paper(Howes, Vergunst, Gee, et al, 2012)). We agree with Professor Mortimer that it is currently not possible to predict whichpatients will have treatment refractory illness or will respond to clozapine, although the development of pathophysiologically specific markers may enable this(Bose, Turkheimer, Howes, et al, 2008; Demjaha, Murray, Kapur, et al, 2011; Howes, Bose, Turkheimer, et al, 2011; Howes, Bose, Valli, et al, 2011). Likewise we agree with Professor Mortimer that clozapine is not the only option for treatment resistance, although it hasthe best evidence base and this is reflected in its pre-eminence in treatment guidelines. However, we found that over one third of patients had received antipsychotic polypharmacy, and a third had received high dose antipsychotic treatment prior to clozapine treatment(Howes, Vergunst,Gee, et al, 2012). This indicates that poorly evidenced strategies are commonly used in preference to clozapine and, to echo Professor Mortimer, this is a disservice to our patients.

Dr Oliver D. Howes, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. Email: oliver.howes@kcl.ac.uk; Ms Siobhan Gee, The Pharmacy Department, The Maudsley Hospital, Denmark Hill, Camberwell, London, SE5 8AZ, UK; Professor David Taylor, Institute of Psychiatry, London, UK

Reference List

Agid, O., Remington, G., Kapur, S., et al (2007) Early use of clozapine for poorly responding first-episode psychosis. Journal of clinical psychopharmacology, 27, 369-373.Bose, S. K., Turkheimer, F. E., Howes, O. D., et al (2008) Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging. Schizophr Res, 106, 148-155.Demjaha, A., Murray, R. M., Kapur, S., et al (2011) Dopaminergic function in treatment resistant schizophrenia. Schizophr Bull.Howes, O., Bose, S., Turkheimer, F., et al (2011) Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Molecular psychiatry, 16, 885-886.Howes, O. D., Bose, S., Valli, I., et al (2011) Dopamine synthesis capacity before onset of psychosis: a prospective [18]-DOPA PET imaging study. Am J Psychiatry, 168, 1311-1317.Howes, O. D., Vergunst, F., Gee, S., et al (2012) Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior toclozapine initiation. The British journal of psychiatry : the journal of mental science, 201, 481-485.

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Conflict of interest: O.D.H. has been on the speaker bureaux and/or received investigator-initiated charitable research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Jansenn-Cilag. D.T. has received consultancies fees, lecturing honoraria and/or research funding from AstraZeneca, Janssen-Cilag, Servier, Sanofi-aventis, Lundbeck, Bristol-Myers Squibb, Novartis, Eli Lilly and Wyeth. SG has no potential conflicts of interest.

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Delay in clozapine initiation: widely prevalent yet neglected issue

Naresh Nebhinani, Psychiatrist
19 December 2012

Firstly, I would like to complement Howes & colleagues1 for theirvaluable contribution in this clinically relevant area, as clozapine is the only medication licensed for treatment-resistant schizophrenia, with robust evidence of effectiveness in suicidality, aggression and substance misuse.2 Authors have reported the mean delay of nearly 4 years in initiation of clozapine in this study1 and 5 years in their previous study.3 One-third patients were also receiving antipsychotic polypharmacy and high dose antipsychotic treatment prior to clozapine therapy.1 Authorshave nicely reiterated the lesser adherence to guidelines for treatment ofschizophrenia. Since it was a retrospective chart review, it has several inherent limitations mainly due to nature of the study. There is lack of data on following important parameters like reasons of clozapine initiation; details about prior antipsychotic prescription; reported side-effects with clozapine; efficacy of clozapine treatment; use of augmentingagents in case of clozapine non-responsiveness; and most importantly patients' perception about clozapine therapy- before and after this treatment, as they might have apprehension about its side effects, which might have been an important reason for refusing or delaying this therapy.There are typological errors at two places; in statistics, the Kolmogorov-Smirnov Z test (K-S test) is wrongly spelt; and in table-1, demography data of excluded patients (N=78) is incomplete as it's mentioned for 75 patients. Health professionals' knowledge and attitude towards clozapine are mentioned as important reasons for this substantial delay in clozapineinitiation. Majority of health professionals' are much concerned about thepotential side-effects, such as agranulocytosis, metabolic syndrome and cardiovascular risk with clozapine but surprisingly clozapine has shown the lowest risk of premature mortality compared to other antipsychotics inan 11 year follow-up study of patients with schizophrenia in a population based cohort.4 The underutilization, delayed initiation, suboptimal dosing, cigarette smoking, coupled with polypharmacy and high dose treatment would further complicate the course and outcome of schizophreniadue to lesser efficacy as well as greater side-effects of the prescribed drugs. There is definite need for more research in this area to manage this widely prevalent yet neglected issue of improper utilization of this broad-spectrum antipsychotic. Farooq & Taylor2 has rightly mentioned that clozapine should not be considered a treatment of last resort but drug of first choice as soon as non-responsiveness to established first- line treatments is evident.

Reference 1. Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry 2012;201:481-5. 2. Farooq S, Taylor M. Clozapine: dangerous orphan or neglected friend? Br J Psychiatry 2011;198:247-9. 3. Taylor DM, Young C, Patron C. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. J Clin Psychiatry 2003;64:30-4. 4. TiihonenJ, L?nnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374:620-7.

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Conflict of interest: None declared

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Re: Delay in Starting clozapine and treatment guidelines

Oliver D Howes
14 December 2012

Delay in initiating clozapine for treatment resistant psychoses

We thank Dr Sharma for the letter commenting on our study. The first point raised is that the delay to clozapine initiation may not be a true reflection of the actual delay because patients may have been offered clozapine but refused it. This, of course, depends on what delay you are interested in. In our study we used the delay from the point at which treatment guidelines recommend a patient start clozapine(1). In our view this is the key clinically relevant delay. However, Dr Sharma is right in suggesting that this delay does not necessarily mean that clinicians have delayed offering clozapine, although if this were the case it implies thatit has taken on average four years for patients to agree to start clozapine. In practice it seems likely that there are a number of patient,clinician and service factors that may underlie the delay we observed in our study. Understanding these will be important if delays are to be reduced in the future. The availability of biomarkers for treatment resistance, as indicated by a recent study(2), could also contribute to identifying resistant patients earlier. Dr Sharma also rightly raises the issue that duration of untreated psychosis was not assessed in our study. Consequently we cannot exclude the possibility that the duration of illness was in fact longer in our sample and thus that the delay to effective treatment was in fact longer.

Dr Oliver Howes, MRCPsych PhD; Professor David Taylor, PhDInstitute of Psychiatry, Camberwell, London SE5 8AF

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Conflict of interest: Prof. Taylor has received consultancies fees, lecturing honoraria and/or research funding from AstraZeneca, Janssen-Cilag, Servier, Sanofi-aventis, Lundbeck, Bristol-Myers Squibb, Novartis, Eli Lilly and Wyeth. Dr Howes has been on the speaker bureaux and/or received investigator-initiated charitable research funding from Astra-Zeneca, BMS, Eli Lilly, and Jansenn-Cilag.

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Dealy in Starting clozapine and treatment guidelines

Akhilesh Sharma, Psychiatrist
05 December 2012

There is reasonable level of information to suggest that clozapine iseffective in patients who have treatment resistant schizophrenia. Hence, clozapine should be started at the right time so that the patients can draw maximum benefit from the same. In this line the article by Howes et al1, provides important insights into the clinical practice with regard touse of clozapine. The authors showed that clozapine is delayed by about a period of 4 years and many patients are treated with polypharmacy and receive higher than recommended doses, which are contrary to the recommendations made by several practice guidelines. However, it is important to note that the conclusions drawn about the delay in starting of clozapine might not be true reflection of actual delay, because many a times, patients who are offered clozapine, refuse to take the same. Hence,some of the delay may be due to lack of agreement of the patient and this in general does not reflect the delay in the clinician offering the medication. It would have been better if the authors would have extracted the data pertaining to initial offering of clozapine, number of patients who refused clozapine at the first instance as part of this study. This would have actually given the true clinical picture. Another issue is the definition of duration of illness used by the authors in their paper. The authors have defined duration of illness as "the time from the first recording of the diagnosis of a psychotic illness by a clinician to the present", which may not be a true reflection of duration of illness, because there may be varying periods of duration of untreated psychosis and this can have its own treatment implications. Despite these shortcomings, findings of the study suggest that despite organised National Health Care System in place and of wider dissemination of treatment guidelines, still there is only a modest impact of these on real clinical practice. The possible effect of treatment guidelines is reflected by the fact that in recent time's patients receive fewer trials of other antipsychotics (2.8 versus 4 trials) before being started on clozapine compared to earlier2.

References:1.Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D. Adherence totreatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry. 2012 Sep 6. [Epub ahead of print]2.Taylor DM, Young C, Paton C. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. J Clin Psychiatry 2003; 64: 30-4.

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Conflict of interest: None declared

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