Clozapine and Covid-19 – What should Psychiatrists Know?

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Clozapine and COVID:

Clozapine is associated with neutropenia and agranulocytosis.

Patients with COVID-19 may have reduced blood counts that can impact on the ongoing prescribing of clozapine.

The Australian Commission on Safety and Quality in Healthcare position statement suggests that during the COVID-19 pandemic, to ensure uninterrupted supply of clozapine:

The frequency of Absolute Neutrophil Count (ANC) monitoring may be reduced to every 3 months for people fulfilling all of the following criteria:

Continuous clozapine treatment for >1 year
Have never had an ANC <2000/μl (or <1500/μl if patient has a history of benign ethnic neutropenia)
No safe or practical access to ANC testing

GUIDANCE FOR THE MANAGEMENT OF CLOZAPINE AND BLOOD DYSCRASIAS IN PATIENTS WITH CORONAVIRUS

The following guidance is from the RCPsych based on the South London and Maudsley NHS Trust article.

According to guidance from the RCPsych

It appears likely that patients with COVID-19 infection will have a low WCC. This seems to be largely due to reduced lymphocytes.

As the monitoring parameters for clozapine include total WCC, a reduction may result in patients registering results that, under normal circumstances, require interruption of clozapine treatment. However, the purpose of interrupting clozapine treatment is to protect patients from neutropenia and agranulocytosis.

Where a low WCC count occurs in the presence of a normal or non-dangerous neutrophil level in the context of COVID-19 infection, it is reasoned that clozapine can be safely continued. It is also important to consider the risk of discontinuing an effective antipsychotic treatment such as clozapine at a time when uncontrolled psychotic symptoms (which are unlikely to be treated by other drugs) may present challenges in safely managing an infected patient. So, continuation of clozapine treatment is the imperative unless low neutrophil counts dictate treatment cessation.

All clozapine patients with symptoms of COVID-19 must have a blood sample taken immediately for WCC and ANC and clozapine plasma concentration.

CLOZAPINE PATIENTS WITH A HISTORY OR SUSPICION OF CLOZAPINE RELATED BLOOD DYSCRASIA

2.0 (BEN: > 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms. (Values are 1o^9 /l)

Continue Clozapine and monitor FBC as normal:

< 2.0 (BEN: < 1.5)

STOP Clozapine
Monitor FBC TWICE WEEKLY.
Restart clozapine when two consecutive ANC results are > 2.0 unless there is a clear contraindication to doing so

CLOZAPINE PATIENTS ON WEEKLY MONITORING

2.0 (BEN: > 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

Continue clozapine with weekly monitoring

1.5 – 2.0 (BEN: 1.0 – 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

Continue clozapine Monitor FBC TWICE WEEKLY until two consecutive ANC results are > 2.0

<1.5 (BEN: < 1.0)

STOP clozapine
Monitor FBC TWICE WEEKLY.
Restart clozapine when two consecutive ANC results are >1.5, but only after consultation with COVID physician

CLOZAPINE PATIENTS ON TWO WEEKLY OR MONTHLY MONITORING

2.0 (BEN: < 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

Continue clozapine and continue to monitor FBC as normal

1.5 – 2.0 (BEN: 1.0 – 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

Continue clozapine
Monitor FBC TWICE WEEKLY until two consecutive ANC results are > 2.0

<1.5 (BEN: < 1.0)

STOP clozapine
Monitor FBC TWICE WEEKLY.
Restart clozapine when two consecutive ANC results are >1.5, but only after consultation with COVID physician

CLOZAPINE LEVELS AND COVID

Covid-19 infection can increase clozapine levels due to smoking cessation and /or downregulation of CYP1A2. With inflammation, cytokines are increased, and interleukin 1β (IL-1β), IL-6, tumour necrosis factor-α (TNF-α), interferon-α (IFN-α), and IFN-γ, in particular, seem to inhibit the activity of CYP1A2. [Tio et al., 2021]

COVID VACCINES AND CLOZAPINE

Vaccines and Clozapine:

Most COVID-19 vaccines could downregulate CYP1A2 and CYP3A4 enzymes, both of which are involved in clozapine metabolism and could increase clozapine levels.
A case study showed that the administration of mRNA COVID-19 vaccine (BNT162b2) could cause increased clozapine and CRP levels. [Thompson et al., 2021]
Clinicians should thus be vigilant following COVID-19 vaccine administration of such potential interactions and monitor absolute neutrophil counts and clozapine serum concentrations closely in patients using clozapine.[Bayraktar et al., 2021]