TRS in the UK

Defining TRS

The National Institute for Health and Care Excellence (NICE) defines ‘treatment resistance’ in schizophrenia patients as the lack of satisfactory clinical improvement following sequential treatment with at least two different antipsychotic drugs, including at least one second-generation (atypical) antipsychotic.1

TRS is common among schizophrenia patients

Treatment resistance is a significant barrier to effective treatment. A review of several cohort studies estimates that 20-30% of patients with schizophrenia meet the criteria for treatment resistant schizophrenia (TRS).2

Given that an estimated 25‒50% of schizophrenia patients attempt suicide and 10% eventually achieve this goal,3 it is essential that patients with TRS are identified in a timely manner so that they can receive appropriate therapy.

NICE recommends clozapine as first-line treatment for TRS

NICE guidelines recommend that clozapine should be offered first-line to schizophrenia patients who have not shown satisfactory clinical improvement following sequential treatment with at least two different antipsychotic drugs, including at least one second-generation (atypical) antipsychotic.1

Clozapine is under-prescribed in the UK

The National Clinical Audit of Psychosis (NCAP), was carried out in 2018 by the Royal College of Psychiatrists and involved 62 organisations4. Found that:

  • The NICE guideline also recommends that patients who have not responded adequately after trials of at least two different antipsychotic medications should be offered clozapine. Of the 1,872 patients who were not in remission, 1,380 (74%) were not currently being prescribed clozapine.

  • Less than half (42%) of patients were screened for 5 cardiovascular risk factors.

  • 1 in 3 patients (34%) had no documentation on why they were prescribed high dose medication.

  • Less than 30% of patients were given accessible information about their prescribed medication.

The national audit of schizophrenia (NAS), which was carried out in 2014 by the Royal College of Psychiatrists and involved all 64 Mental Health Trusts in England and Health Boards in Wales, found that more than 1 in 4 (28%) patients with schizophrenia who failed on at least two antipsychotics, and whose condition may have benefitted from clozapine treatment, were not prescribed it.5

This audit identified three main causes for the under-prescription of clozapine:5

  • More than two antipsychotics are being tried before prescribing clozapine

  • More than half (57%) of schizophrenia patients taking clozapine in 2014 had been prescribed three or more different antipsychotic drugs before initiating treatment with clozapine.

  • Polypharmacy is employed to improve response, rather than moving to clozapine

  • More than 1 in 10 (11%) people with schizophrenia (who were not taking clozapine) were being prescribed more than one type of antipsychotic at the same time. In some areas, this practice occurred in as many as 24% of schizophrenia patients.

  • Patients are treated with higher than recommended doses of antipsychotics

  • One in 10 people are being prescribed antipsychotic drugs – other than clozapine – at a higher dose than that recommended by the British National Formulary.

Blood monitoring while on Clozaril® is mandatory

White blood cell abnormalities are possible with clozapine treatment so all patients receiving it must be monitored regularly for white blood cell (WBC) count and absolute neutrophil count (ANC).6

Pre-treatment blood testing

WBC and differential blood counts must be performed within 10 days prior to initiating Clozaril® treatment to ensure that only patients with normal WBC count (≥3500/mm3 [3.5x109/l]) and ANC (≥2000/mm3 [2.0x109/l]) receive Clozaril®.6

Blood monitoring after Clozaril® initiation

After the start of Clozaril® treatment, regular WBC count and ANC must be performed and monitored weekly for the first 18 weeks, and at least four-weekly thereafter.

Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Clozaril® or until haematological recovery has occurred. WBC and differential blood counts must be performed immediately if any symptoms or signs of an infection occur.6

Action if a patient has low WBC count/ANC

If a patient develops a low WBC count and /or low ANC while on Clozaril® treatment, monitoring must be increased to at least twice weekly until counts recover to within an accepted range. If WBC count and ANC fall below a specific threshold, Clozaril® must be discontinued immediately.6

Table 1 summarizes the actions required for WBC counts and ANC thresholds.

Table 1. Blood cell parameters and actions required for patients receiving Clozaril®6

Blood cell count

Action required
WBC/mm3 (/l) ANC/mm3 (/l)

≥3500 (≥3.5x109)

≥2000 (≥2.0x109)

Continue Clozaril® treatment

Between ≥3000 and <3500 (≥3.0x109 and <3.5x109)

Between ≥1500 and <2000 (≥1.5x109 and <2.0x109)

Continue Clozaril® treatment, sample blood twice weekly until counts stabilise or increase.

<3000 (<3.0x109)

<1500 (<1.5x109)

Immediately stop Clozaril® treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient.

If Clozaril has been withdrawn and either a further drop in the WBC count below 2000/mm3 (2.0x109/l) occurs or the ANC falls below 1000/mm3 (1.0x109/l), the management of this condition must be guided by an experienced haematologist.

References

  1. National Institute for Health and Care Excellence (NICE). Psychosis and schizophrenia in adults: prevention and management. Clinical guideline CG178. February 2014. Available at: https://www.nice.org.uk/guidance/cg178/chapter/1-Recommendations#first-episode-psychosis-2(accessed February 2021).
  2. Elkis H, Meltzer HY. Refractory schizophrenia. Rev Bras Psiquiatr. 2007; 29: S41-7.
  3. Stahl, S. 2013 Stahl's Essential Psychopharmacology - 4th Edition. Cambridge University Press.
  4. The Royal College of Psychiatrists (2018) National Clinical Audit of Psychosis – National Report for the Core Audit 2018. London: Healthcare Quality Improvement Partnership.
  5. National Audit of Schizophrenia (NAS). Second National Audit of Schizophrenia: What you need to know. The Royal College of Psychiatrists, 2014.
  6. Clozaril® Summary of Product Characteristics (SmPC). Available at www.medicines.org.uk/emc/ (UK) or www.medicines.ie (Ireland) (last accessed July 2021).

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