Should We Use Clozapine Second Line in the Treatment of Schizophrenia? – Highlights from RCPsychIC 2019

Posted on:August 16, 2019
Last Updated: December 8, 2021
Time to read: 3 minutes

This article is based on the talk by Dr James MacCabe at the RCPsych IC 2019.

1.The current NICE guidelines for treating schizophrenia are complicated, and patients are required to be prescribed two different drugs with a failed response to both before being offered clozapine. This is consistent with the recommendations by the RANZCP guidelines for schizophrenia.

2. In reality, patients are often offered up to five different drugs, including a combination of drugs, which perpetuates until the patient is eventually offered clozapine. Such treatment methods lead to a delay in clozapine treatment of approximately four years.

3. A study showed that when patients were prescribed clozapine within the first 2.8 years of their illness, the response rate to clozapine was in the order of 80%. Patients who had clozapine prescribed later than 2.8 years after the onset of illness had a response rate of approximately 30%. [Yoshimura B et al., 2017]

4. The duration of active psychosis should be limited as far as possible to ensure a good treatment response.

5. Arguments for clozapine as a 3rd-line treatment include historical reasons [Kane J et al., 1988], safety issues [Lahdelma L.,2012] and a belief that the superiority of clozapine is confined to treatment-resistance with no better outcomes than other antipsychotics on first-episode.[Girgis R et al.,2011]

6. Studies investigating clozapine as a 1st- or 2nd-line antipsychotic have been reviewed recently with risperidone, chlorpromazine, and thioridazine as comparators. All studies taken together in a systematic review and meta-analysis concluded that clozapine is superior to comparator drugs. [Okhuijsen-Pfeifer C et al., 2018]. The authors conclude:


  • As a first‐ or second‐line treatment option clozapine outperforms other antipsychotics in schizophrenia spectrum disorders.

  • Compared to first‐line risperidone, clozapine is more effective in schizophrenia spectrum disorders.


7. Two recent studies have investigated the benefit of a second antipsychotic before prescribing clozapine, and whether switching antipsychotics or the early use of clozapine affects patient outcomes in first-episode schizophrenia.

The first study by Agid O et al., 2011, concluded:

A high response rate (75%) to initial antipsychotic treatment in first-episode schizophrenia. A considerably lower response rate (< 20%) occurs with a second antipsychotic trial. Results here were specific to olanzapine and risperidone, suggesting clinical differences (ie, olanzapine more effective than risperidone).

The second more recent study by Kahn et al., 2018, concluded:

For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation.

8. If clozapine became the 2nd-line treatment, most patients would likely continue to receive clozapine as either 2nd- or 3rd-line therapy. However, the delay in introducing clozapine would decrease, and some patients would receive the treatment much earlier in their illness.

9. RCTs comparing clozapine as 2nd- vs 3rd-line therapy are needed, along with pharmacoeconomic studies related to relieving current health service costs.