Delay in Starting Clozapine in Treatment Resistant Schizophrenia – Why it Matters

Clozapine was first introduced into practice in the 1960s. However, in 1976, there were reports of fatal agranulocytosis (drastic reduction in white blood cells), which resulted in its complete withdrawal from the market.

Then, in 1990, it was again approved but only as a third-line agent in the treatment of TRS and with the caveat of routine blood testing to monitor white blood cell and absolute neutrophil counts to reduce the risk of any further fatal agranulocytosis.

Clozapine use can be associated with severe side effects of agranulocytosis, neutropenia, and myocarditis, which are monitored during treatment.

However, an 11-year follow-up study of over 66 000 patients with schizophrenia in Finland concluded that clozapine was the most effective antipsychotic in reducing mortality compared to other SGA’s. [Tiihonen et al., 2009]

Clozapine is a dopamine and serotonin antagonist (5HT2A) with a few unique differences compared to other SGA’s.

Clozapine has much greater antagonistic activity on cortical and limbic dopamine D₄ than D₂ receptors.

It also antagonises 5HT2 serotonergic receptor subtypes (5HT2A & 5HT_2C) and adrenergic (α1), histamine (H₁) and muscarinic receptors (M₁).

The combination of relatively high D₁, low D₂, and very high 5-HT2 receptor occupancy rates is unique to Clozapine and may explain its lower propensity for Extrapyramidal side effects.

It may also explain why it is used as a treatment for Tardive Dyskinesia.

There have been several studies that have shown the superiority of clozapine over other Second-Generation Antipsychotics (SGA’s) on various outcomes such as response to treatment, adherence to medication, and patient satisfaction.

Even though clinical practice guidelines endorse clozapine therapy in TRS, there seems to be a continuing resistance by clinicians to prescribe clozapine at a suitable time point.

A recently published paper at the Okayama Psychiatric Medical Center in Japan attempted to understand the critical nature of the clozapine treatment window in TRS. They aimed to determine the symptomatic outcomes of TRS and the delay in initiating clozapine treatment.

The study was a retrospective observational review of 90 patients with TRS in the inpatient ward of the Okayama Psychiatric Medical Center.

Schizophrenia was determined to be TRS when there were two previously failed trials of chlorpromazine and a Global Assessment of Functioning score of < 41 in each trial. TRS patients started clozapine between January 1^st, 2010 and February 28^th, 2015 and had to remain on clozapine for at least 3 months to be included in the study.

The duration of illness was defined from the onset of the first psychotic episode to the initiation of clozapine, whereas medication delay was defined as the onset of TRS to initiation of clozapine treatment.

Relapse was considered when the patient was either hospitalised because of psychotic symptoms or when psychotic symptoms were rated as much worse when using the Clinical Global Impressions – Improvement (CGI-I) scale.

A multiple linear regression analysis was applied to a previously published observational study to determine the predictive and discriminative ability of clozapine treatment delay on TRS symptoms. Statistically, this was assessed using a receiver operating characteristic (ROC) curve to measure the overall discriminative power of the critical treatment window.

The researchers determined that initiating clozapine treatment and the duration of clozapine treatment were independent contributors to improvement in TRS symptoms. Furthermore, ROC curve analysis showed that 2.8 years was the cutoff for predicting clozapine efficacy at treating TRS symptoms.

This data showed that patients who received clozapine within 2.8 years of the onset of TRS had a treatment response rate of 81.6% if the patient received clozapine with a greater than 2.8 years delay, they had a response rate of only 30.8%.

In addition, patients who received clozapine within 2.8 years were less likely to then receive electroconvulsive treatment (5%) than compared to patients who received clozapine 2.8 years after onset (23%). [Yoshimura et al., 2017]

1. Small study from one institution
2. Unblinded rating by physician
3. Measurement of short-term symptomatic outcomes

Overall, these findings suggest that a delay in clozapine treatment may be detrimental to patients suffering from TRS with a clinical outcome similar to untreated psychosis.

According to the authors –

Following the above study, a systematic review of the available literature echoed the findings that there is a possible link between delay in clozapine use and poorer treatment outcomes in patients with treatment-resistant schizophrenia.

Clozapine is a gold standard antipsychotic for TRS with a substantial evidence base. Its initiation as a treatment for TRS is often delayed despite guidelines advocating its use earlier in treatment resistance.

Evidence suggests that before commencing clozapine treatment, clinicians are more inclined to recommend polypharmacy or high dose treatment: both of which have little to no evidence to support these strategies. [Howes et al., 2012]

Polypharmacy and high-dose strategies come with an increased risk of complications as well as more severe side effects.

In routine clinical practice, clozapine initiation had a mean delay of 47 months, with 36.2% of the studied patients previously on antipsychotic polypharmacy, while 34.2% of patients had previously been provided with high-dose treatment above and beyond the licensed maximum dose. [Howes et al., 2012]

In another retrospective study, Üçok and colleagues showed that the mean delay in clozapine treatment after a TRS diagnosis was 29 months.

Further analysis showed that those who showed good improvements after clozapine initiation had a mean delay of only 21 months.

For those patients who were reported to have little to no response to clozapine treatment, the mean delay in clozapine initiation was closer to 47 months. [Üçok et al., 2015]

A systematic review and meta-analysis showed the following variables were significantly associated with a better response to clozapine: [Griffiths et al., 2021]

• Shorter duration of illness
• Later illness onset
• Younger age at clozapine initiation
• Fewer hospitalizations
• Fewer antipsychotic trials prior to clozapine initiation

A recent study in the American Journal of Psychiatry demonstrated a nearly two-fold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine than clozapine-treated individuals. [Wimberley et al., 2017]

Another study (population-based cohort of 2,370 individuals with treatment-resistant schizophrenia) showed a nearly twofold higher mortality rate (HR – 1.88) among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. [Wimberley et al., 2017]

In a study involving 159 individuals with schizophrenia or schizoaffective disorder, most of whom were male (64.2%), Chinese (85.5%), and with a mean age of 40.01 years, findings revealed that 23.3% achieved symptom remission and 63.5% achieved functional remission.

The median number of antipsychotic trials before clozapine initiation was 6. Notably, patients in remission exhibited shorter periods and fewer antipsychotic trials before initiating clozapine. [Law et al., 2023]

Further evidence supporting the early use of clozapine was shown in a recent Japanese study. [Hatano et al., 2023]

Patients were divided into 3 groups based on clozapine initiation: 

• Early (≤ 9 years)
• Intermediate (10-19 years)
• Late (≥ 20 years)

Incidence rates of rehospitalisation within three years: 

• 32.3% for early, 29.7% for intermediate, and 62.2% for late initiation of clozapine, respectively.
• Late initiation had a significantly higher risk of psychiatric rehospitalisation than early initiation (HR, 2.94).

The incidence rate of all-cause clozapine discontinuation within three years :

• 13.0% for early
• 10.6% for intermediate
• 20.1% for late initiation.

According to Patel –

A 2018 systematic review identifying barriers to using clozapine (the majority of studies obtained views from consultant psychiatrists) in treatment-resistant schizophrenia found the major barriers to be: [Farooq et al., 2019]

1. Mandatory blood testing
2. Fear of serious side-effects
3. Lack of adherence by the patients
4. Difficulty in identifying suitable patients
5. Service fragmentation and;
6. Inadequate training in or exposure to using clozapine.

The most recent study from Acta Psychiatr Scand 2018 showed that the protective effect of clozapine in patients with treatment-resistant schizophrenia (TRS) on all-cause mortality was significant (adjusted hazard ratio 0.61; 95% confidence interval 0.38-0.97; P = 0.04).

The study concluded that Clozapine reduces the risk of mortality in patients who meet the criteria for TRS. Thus improving access to clozapine in TRS is likely to reduce the mortality gap in schizophrenia. [Cho et al., 2018]

A nationwide Finnish register-based cohort study of 62,250 patients showed the cumulative mortality rates during a maximum follow‐up of 20 years were 46.2% for no antipsychotic use, 25.7% for any antipsychotic use, and 15.6% for clozapine use. [Taipale H et al., 2020]

Even in patients where clozapine is discontinued for undefined reasons, clozapine (besides olanzapine) is the most effective and safest option. [Luykx J et al., 2020]

The concerns around the delay in initiation of clozapine have been debated for over a decade. Clinical practice, however, does not seem to have shifted. Could this clinician hesitation be costing patients their lives?