Clozapine is a second-generation, antipsychotic, neuroleptic dibenzodiazepan drug that is prescribed for schizophrenia patients who are unresponsive to frequently used antipsychotics or have other psychotic disorders[4]. It is the most frequently used antipsychotic drug in mainland China, although its prescription rate seems to have decreased recently[5]. In some regions of China, clozapine is prescribed to almost 76.1% of the schizophrenia patients[6]. Acute clozapine intoxication is a serious condition with a mortality rate of 12%. However, no systematic study so far has focused on the characteristics and outcomes of acute clozapine intoxication.
Clozapine can bind to a multitude of receptors and pharmacologically active metabolites. However, the exact mechanism underlying its antipsychotic effects is unknown. Clozapine has a minor affinity for the dopamine D2 receptor but relatively higher affinity for both D1 and D4 receptors. In addition, clozapine also has a high affinity for the 5-HT2A receptor, along with partial agonistic action, which likely contributes to the low risk of EPS. The strong binding affinity of clozapine for muscarinic receptors, as well as the partial and full agonistic activity of its metabolite desmethylclozapine on some muscarinic receptor subtypes, may contribute its the unique mechanism. Furthermore, clozapine is an agonist of the NMDA receptor glycine site and improves glutamatergic homeostasis through different pathways[7–9].
The acceptable serum concentration of clozapine in schizophrenia patients is 350–400ng/mL. However, considerable variations have been observed in the symptomatic responses and side effects of individual patients. Although the definite serum concentration of clozapine that is associated with toxicity remains unclear, adverse effects are more likely to occur when the serum levels are above 600–1000ng/ml[10]. However, a peak serum level of 24,000ng/mL is the highest reported dose of clozapine with a non-fatal outcome. Our patient was pregnant and had been taking clozapine 100mg/d over a long period of time. She was brought to the emergency department four hours after ingesting 200 clozapine 25 mg tablets. After hospitalization, the levels of clozapine and norclozapine levels were 5930.75ng/ml and 1048.47ng/ml respectively. Although it is controversial whether prolonged clozapine intake increases the tolerance of patients to acute intoxication, it is reasonable to hypothesize that pre-treatment with clozapine will affect the severity of intoxication. However, a retrospective study of 73 cases with acute clozapine mono-intoxication did not confirm this hypothesis, and showed no significant correlation between clozapine pre-treatment and the severity of intoxication[11].
In addition to drug–drug interactions, smoking, caffeine consumption, infection and inflammation contribute to clozapine intoxication[12–13]. During pregnancy, the cardiovascular, hematological, digestive and urinary systems undergo considerable changes, which affect drug pharmacokinetics. After 12 weeks of pregnancy, the serum levels of clozapine and norclozapine gradually increase due to the decrease in the concentration of drug binding proteins in the plasma[14]. Clozapine use during pregnancy may increase the risk of obesity, hypertension and gestational diabetes.However, the data on common pregnancy and birth complications, such as miscarriage, stillbirth, preterm birth, small for gestational age, neonatal adaption and childhood neurodevelopment, are overall insufficient to provide confident estimates of the effect of taking clozapine during pregnancy[15]. Our patient was diagnosed with gestational diabetes, which is consistent with previous studies[16].
Patients with clozapine poisoning typically present with altered consciousness ranging from somnolence to coma or agitation, along with delirium, tachycardia, blood pressure abnormalities and seizures. Fatal intoxication may manifest as cardiorespiratory arrest or severe respiratory depression, or may be the consequence of aspiration pneumonia. Cardiac side-effects such as hypotension, tachycardia, myocarditis and prolonged QT interval are also observed with clozapine, which is an atypical neuroleptic[17–18]. Blood pressure abnormalities due to clozapine intake are presumably due to its antagonistic effect on alpha-adrenergic receptor and calcium ions, inhibition of the central pressor reflex and weakened myocardial contractility. Peripheral vasodilation and the anticholinergic effect of clozapine can lead to tachycardia. In addition, clozapine affects cardiac electrical activity by blocking the ion channels of myocardial cells, including fast sodium influx channel (FINA), slow calcium influx channel (ICA) and potassium outflow channel (IK), and blocks the fast activation delayed integration potassium (IKr)[19–20]. Our patient presented with severe tachycardia, fatal hypotension and significantly decreased peripheral vascular resistance, all of which are consistent with clozapine-associated cardiotoxicity. On the basis of hemodynamic monitoring, we gave the patient esmolol, a short acting and highly selective β1 receptor blocker, to reduce heart rate. In addition, the a2 receptor agonist norepinephrine and the selective V1 receptor agonist terlipressin were also given in combination to constrict the blood vessels and increase peripheral vascular resistance.
The current guidelines for treating clozapine intoxication recommend treatment selection based on the clinical symptoms[21]. There is currently no specific antidote for acute clozapine intoxication. A combination of symptomatic treatment and blood purification can alleviate the effects of poisoning by reducing drug absorption and accelerating drug clearance[22]. HP is an extracorporeal drug removal intervention wherein blood is passed over an adsorbent structure to directly remove the toxic substances. It is particularly effective against drugs with high protein binding capacity, high molecular weight, lipid solubility and small volume of distribution. Clozapine is a lipid-soluble compound of molecular mass 326.83d and protein binding rate > 90%. Therefore, it meets 3 criteria for HP, with the exception for its large volume distribution (2–5 L/kg)[23]. In a retrospective chart review, patients with clozapine poisoning who underwent HP regained consciousness significantly faster than their counterparts with the same plasma level of clozapine (> 2000 ng/mL) who did not undergo the procedure. A combination of HP and symptomatic treatment is the best therapeutic option when plasma clozapine concentration is high. Blood samples were drawn regularly during hospitalization to measure serum levels of clozapine/norclozapine continuously and dynamically. Both decreased significantly before and after HP. Once HP removes a large amount of clozapine from the plasma, it is redistributed to maintain its concentration, resulting in decreased levels in the vital organs[24].
The patient also underwent plasma exchange, an extracorporeal process wherein a large volume of whole venous blood is drawn, and the plasma is separated. The remaining blood components are infused back into the patient. Replacement fluids such as albumin or fresh-frozen plasma may be used. Plasma exchange can remove toxins that bind to plasma proteins, reduce the toxicological effects of any residual drug and prevent drug redistribution[25]. In order to remove other small and medium-sized toxins and inflammatory mediators, we also performed continuous veno-venous hemofiltration (CVVH).
To summarize, we have described a case of a 32-year-old pregnant woman who developed life-threatening clozapine toxicity at 28 weeks of gestation. The levels of clozapine and norclozapine in the serum were high due lower concentrations of drug binding proteins. We therefore initiated HP and other detoxification therapies to remove the drug. The patient had severely dilated peripheral blood vessels, which led to cardiac symptoms such as fatal hypotension and uncontrollable tachycardia, resulting in very high cardiac output and elevated ScvO2. According to the hemodynamic parameters monitored by PICCO, we administered the β1 receptor blocker esmolol, a2 receptor agonist norepinephrine, and selective V1 receptor agonist terlipressin. Pharmacological intervention significantly improved the hemodynamics.
Once the clozapine binding sites are saturated, the concentration of the free drug in the plasma increases significantly, which is responsible for recurrent hemodynamic instability. Interestingly, only one study has reported severe hemodynamic instability due to clozapine toxicity. Based on our findings in the current case, we hypothesize that hemodynamic instability in patients with clozapine intoxication can indirectly reflect the serum concentration of clozapine. Hemodynamic monitoring before and after blood detoxification can help assess the efficacy and guide treatment.