Clozapine is strongly associated with the risk of pneumonia and inflammation

Abstract

Clinicians need to remember that (1) systemic inflammations can increase clozapine level; (2) clozapine, by itself, can cause inflammation, particularly during titration that is too rapid for that patient; (3) clozapine may increase the risk of infection; and (4) more specifically, clozapine may be particularly strongly associated with the risk of pneumonia. Pneumonia appears to be associated with high mortality in clozapine patients around the world. Clinicians who are alert to the risk of pneumonia in clozapine patients may significantly decrease mortality in clozapine patients. There is no data on COVID-19 infections in clozapine patients, but based on what we know about clozapine pharmacology, we can hypothesise that clozapine, possibly by impairing immunological mechanisms, may increase the risk of pneumonia in infected patients. More importantly, once fever and/or pneumonia develops, the clozapine dose should be cut in half to decrease the risk of clozapine intoxication. If there is any doubt that in spite of halving the dose there are still signs of clozapine intoxication, completely stopping clozapine may be indicated. Once the signs of inflammation and fever have disappeared, the clozapine dose can be increased to the prior dosage level.

COVID-19 in adult patients with pre-existing chronic cardiac, respiratory and metabolic disease: a critical literature review with clinical recommendations

“…The importance of safeguarding access to clozapine monitoring clinics and depot antipsychotic injections for patients with chronic schizophrenia has been highlighted by the psychiatric profession [96]. While there are currently no data on the COVID-19 in clozapine-treated patients, clinicians should be vigilant for signs of infection in these patients [97]. Delirium is a common, but oft overlooked, clinical manifestation of COVID-19.…”

COVID-19 Infection May Cause Clozapine Intoxication: Case Report and Discussion

“…In patients treated with clozapine, COVID-19 infection may result in complications including an increased risk of pneumonia, clozapine toxicity, and disruption to clozapine treatment by COVID-19 induced lymphopenia. [1][2][3] Patients treated with clozapine are at greater risk of pneumonia and may, therefore, be at increased risk of deterioration during COVID-19 infection. 1 De Leon et al offer a thorough review of the risk of pneumonia and clozapine intoxication associated with infection, recommending clozapine dose reduction during fever and/or pneumonia including in the context of COVID-19.…”

“…1 De Leon et al offer a thorough review of the risk of pneumonia and clozapine intoxication associated with infection, recommending clozapine dose reduction during fever and/or pneumonia including in the context of COVID-19. 2 This risk of intoxication is reflected in the RCPsych (UK) policy on clozapine and blood dyscrasias in patients with COVID-19, where it is advised that clozapine levels are taken in all patients with suspected symptoms of COVID-19. 3 A 38-year-old male on an inpatient mental health rehabilitation ward treated with 325 mg per day of clozapine for organic psychosis developed a cough, headache, and reduced oxygen saturation of 94% on room air.…”

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

“…The major mechanisms of CLZ intoxication induced by inflammation were supported by preclinical findings that both the expression and activities of cytochromes P450 (CYP)1A2 and CYP3A4 [ 64 ] were reduced by some pro-inflammation cytokines, i.e., interleukin-1 (IL-1), IL-2, IL-4, IL-6, tumour necrosis factor (TNF)-α, TNF-β, interferon (IFN)-α, and IFN-γ [ 65 ]. Therefore, the lethality of pneumonia in CLZ patients was explained in that CLZ likely contributes to the pathomechanism of pneumonia, and the development of pneumonia can cause CLZ intoxication [ 66 ]. In other words, bidirectional interaction between pneumonia and CLZ intoxication is highly lethal.…”