Clozapine Intoxication in a Dog
Intoxication with clozapine in a dog, suspected from history and clinical signs at presentation, was confirmed by demonstration of decreasing serum levels of this drug. Clozapine is a tricyclic dibenzodiazepine used for treatment of human schizophrenia, and clinical signs of intoxication in humans include tachycardia, seizures, muscle fasciculations, agitation, and sialorrhea. This dog showed ptyalism, hyperthermia, tachycardia, and was easily excited by tactile or auditory stimulation. The calculated peak concentration of clozapine in this dog was approximately 6,000 ng/mL, and the elimination half-life (t1/2) was 5 hours. Charcoal administration and supportive care led to a successful outcome in this patient.
Introduction
Clozapine, a tricyclic dibenzodiazepine classified as an atypic neuroleptic, is used in cases of human schizophrenia1 that are refractory to treatment with other neuroleptics.2 Clozapine blocks dopamine (D4) receptors and serotonin (5-HT) receptors in the brain in a complex interaction.2 The drug does not cause significant extrapyramidal side effects, in contrast to other neuroleptics, but it has been associated with agranulocytosis, which is the primary reason for limited use of the drug.12 Clozapine is rapidly absorbed after oral administration in humans, and peak concentrations occur in approximately 1 hour.23 Several cases of human intoxication with clozapine have been reported,4–15 but to the authors’ knowledge, there are no previous reports of clozapine intoxication in clinical canine cases.
Clinical signs commonly reported with clozapine intoxication in humans include coma, tachycardia, seizures, dystonia or tonic convulsions, muscle fasciculations, agitation, and sialorrhea.14–68–15 Other signs of acute overdose include eosinophilia, enuresis or inability to urinate, extrapyramidal reaction, delirium, cognitive dysfunction, nausea, emesis, hypoglycemia, hypo- or hypertension, disorientation, ataxia, nystagmus, torticollis, serum hypotonicity, Parkinson’s-like syndrome, and hepatic toxicity.1
No antidote is available; therefore, supportive treatment directed at clinical signs and drug elimination including decontamination with gastric lavage and activated charcoal are recommended.1
This report describes the observed clinical signs of clozapine intoxication in a dog and the pharmacokinetics of drug elimination in this case.
Case Report
History
A 6-year-old, 10.6-kg, spayed female miniature schnauzer was presented to the Veterinary Teaching Hospital emergency service at Washington State University. The owner had found the dog in close proximity to a vial of clozapine (100-mg tablets). The vial had originally contained 30 to 45 tablets, but only four tablets remained. A small amount of partially chewed remnants of tablets were found next to the chewed vial. The owner estimated that the incident occurred between 1 and 8 hours prior to presentation.
Clinical Effects
On physical examination, the dog appeared depressed but nervous and was easily excited by auditory and tactile stimulation. She showed ptyalism, hyperthermia (40.1°C), tachycardia (heart rate, 200 beats per minute [bpm]) with normal pulse quality, and tachypnea (respiratory rate, 40 breaths per minute). No murmurs or abnormal lung sounds were ausculted. No other clinical signs were detected.
Therapy
Activated charcoala was administered immediately after the initial physical examination (22.6 mL/kg body weight; total dose, 240 mL per os [PO]) and was repeated every 6 hours (11.3 mL/kg body weight; total dose, 120 mL PO) for a total of three doses.
After consultation of the literature regarding mechanism of action of clozapine and possible adverse effects after overdose,16 an intravenous (IV) infusion of lactated Ringer’s solution (2.3 mL/kg body weight per hour; 25 mL per hour) was started. The treatment and monitoring plan for this patient were based on information from humans, since no information was available for veterinary species. Cardiovascular, respiratory, and central nervous system parameters (such as mental state and seizure activity) were monitored closely for signs of progressing toxicity. However, further workup was postponed until the next day, because the owner expressed concerns about financial constraints. After 5 hours of the aforementioned supportive treatment, the dog gradually became less depressed, and the heart rate normalized at 120 to 130 bpm. Normalization of respiratory rate and temperature occurred simultaneously and in concert with the normalizing heart rate.
Diagnostic Procedures
A complete blood count (CBC) performed 10 hours after presentation showed leukocytosis (17.4 × 103/μL; reference range, 5.8 to 11.7 × 103/μL) with mature neutrophilia (16.9 × 103/μL; reference range, 3.0 to 7.1 × 103/μL) and lymphopenia (0/μL; reference range, 1.1 to 5.1 × 103/μL), consistent with a stress leukogram. The number and morphology of red blood cells (RBCs) and platelets were within reference ranges. A serum biochemical profile demonstrated lipemic serum with an increased alanine aminotransferase (ALT, 90 U/L; reference range, 21 to 67 U/L), alkaline phosphatase (ALP, 827 U/L; reference range, 14 to 72 U/L), serum total carbon dioxide (6 mmol/L; reference range, 18 to 24 mmol/L), anion gap (32 mEq/L; reference range, 15 to 25 mEq/L), hypercholesterolemia (490 mg/dL; reference range, 123 to 363 mg/dL), mild hyperglycemia (186 mg/dL; reference range, 70 to 117 mg/dL), hypernatremia (167 mEq/L; reference range, 147 to 157 mEq/L), hyperchloremia (133 mEq/L; reference range, 111 to 122 mEq/L), hypokalemia (3.5 mEq/L; reference range, 4.4 to 5.3 mEq/L), and decreased serum urea nitrogen (SUN, 4 mg/dL; reference range, 9 to 27 mg/dL). The increase in liver enzymes and the hypercholesterolemia were attributed to an acute hepatopathy with intrahepatic cholestasis. However, preexisting hepatic disease or hyperadrenocorticism could not be ruled out. Due to the magnitude of the increase in ALP, a stress response was thought to be a less likely cause of this abnormality. The sample was centrifuged prior to the assays in a high-speed centrifuge to remove the lipid; however, lipid interference with the assays cannot be totally ruled out and could be partially responsible for the increase in ALP. The mild hyperglycemia was attributed to the lipemic serum, and on subsequent analyses normoglycemia was present. Clinical signs consistent with idiopathic hyperlipidemia in schnauzers (e.g., vomiting, diarrhea, abdominal pain, or inappetence)17 were not present in this case, but this could not be ruled out as a cause of hypercholesterolemia. Serum triglyceride levels were not evaluated in this case. The observed abnormalities in electrolytes in this case were interesting but somewhat difficult to explain. The hypernatremia and hyperchloremia could possibly be attributed to free water loss caused by hypersalivation, considering the low content of sodium and chloride in saliva even during hypersalivation.18 The hypokalemia could be attributed to loss through hypersalivation due to the high potassium content in this type of secretion.18 Alternatively, contributing causes of the hypokalemia might have been catecholamine release due to the stress from intoxication and subsequent intracellular translocation of potassium. The metabolic acidosis might have increased the serum potassium concentration, and it is possible that an even more severe intracellular depletion of potassium was present. Clozapine-induced hypokalemia has not been reported but cannot be totally ruled out as a cause of hypokalemia. The observed decrease in SUN was not associated with a corresponding decrease in serum creatinine. Increased renal excretion of SUN is therefore a less likely explanation for this abnormality, even though the lack of a urinalysis in the present study makes conclusions regarding polyuria hard to make. A preexisting underlying liver disease, causing decreased urea production, could not be ruled out. Serum levels of creatine kinase, creatinine, total protein, calcium, and phosphorus were all within reference ranges. A decreased serum total carbon dioxide and an increased anion gap were detected, indicating a metabolic acidosis. Increased liver enzymes4 as well as metabolic acidosis5 have been associated with clozapine intoxication in human case reports.
Because neurological abnormalities are commonly reported in human cases of clozapine overdose, a neurological examination was performed after admission, and fine tremors of all limbs were detected. No truncal or head tremors were detected. Flexor reflex response was diminished in all limbs, and all other spinal and cranial nerve reflexes were normal. Additionally, since hypertension is associated with clozapine intoxication in humans, blood pressure was determined 2 hours after admission by oscillometric measurement.b The mean arterial blood pressure from nine measurements over 10 minutes was 89.4 mm Hg (range, 73 to 114 mm Hg), with a mean systolic pressure of 122.2 mm Hg (range, 118 to 141 mm Hg; reference range, 80 to 180 mm Hg) and a mean diastolic pressure of 79 mm Hg (range, 39 to 105 mm Hg; reference range, up to 100 mm Hg).
An electrocardiogram was performed 2 hours after admission and showed sinus rhythm with normal QRS complexes.
Hypersalivation and fine muscle tremors were apparent for at least 12 hours after admission. These signs resolved without specific treatment, and 24 hours after admission the dog appeared normal with all parameters in the physical examination within normal limits. The dog was discharged from the hospital 36 hours after admission.
Pharmacokinetics
Blood was collected for measurement of clozapine and norclozapine (active metabolite) levels at 8 and 27 hours after admission to the hospital (9 to 16 hours and 28 to 35 hours, respectively, after exposure). The blood was centrifuged at 3,500 rpm for 5 minutes, and serum was collected. Serum was stored at 2°C to 8°C prior to submission for clozapine analysis. Analysis was performed by gas chromatography.c Serum clozapine levels were 1,500 ng/mL and 180 ng/mL in the two consecutively collected samples [Figure 1]. Levels of norclozapine were 420 and 220 ng/mL, respectively. Total clozapine-norclozapine concentrations were 1,920 and 400 ng/mL at 8 and 27 hours, respectively, after admission.
Follow-Up
The dog was reexamined at the teaching hospital 7, 21, and 40 days after initial admission. The physical examination was normal each time; however, the owner reported that both dogs in the household had wheezing breath sounds. No abnormalities attributed to the respiratory system were found during physical examination in either of the dogs, and the wheezing was presumptively attributed to the owner’s heavy smoking in the home.
A CBC was performed at the 7- and 21-day reexaminations. Seven days after initial presentation, the total white blood cell (WBC) count (11.5 × 103/μL) was within reference ranges, the segmented neutrophil count (9.9 × 103/μL) was elevated, and lymphopenia (920/μL) was present; these results were again interpreted as a stress leukogram. A mild thrombocytopenia (132 × 103/μL; reference range, 157 to 394 × 103/μL) of unknown origin was also found. The RBC count and morphology were within reference ranges.
At 21 days after initial presentation, the total WBC count (9.7 × 103/μL) was within reference ranges, the segmented neutrophil count (7.7 × 103/μL) was slightly elevated, and the lymphocyte count (1.5 × 103/μL) was within reference ranges. The platelet count (198 × 103/μL) was also within reference ranges. The RBC count and morphology were again within reference ranges.
At reexamination after 40 days, a CBC and serum biochemical profile were performed. The total WBC count, the segmented neutrophil count, and the RBC count and morphology were all within reference ranges. A very mild lymphopenia (936/μL, interpreted as a stress response) and thrombocytopenia (155 × 103/μL) of unknown origin were detected. An increase in ALP (722 U/L) was the only abnormality detected on the serum biochemical profile. The dog did not show any clinical signs associated with disorders of liver, biliary tract, intestines, or bone. No clinical signs of hyperadrenocorticism were present, and the dog was not, according to the owner, receiving any drugs. The owner declined further investigation of this problem.
Discussion
In humans, mice, and dogs,19 clozapine is metabolized by the hepatic microsomal enzyme system into desmethyl-clozapine (i.e., norclozapine) and clozapine N-oxide, both with lower pharmacological activity than the parent compound.2 In humans, absorption of clozapine after oral administration is rapid.2 The drug is highly protein-bound (95%) and excreted in feces and urine.1 The plasma decay half-life after oral administration in two healthy beagles was determined to be approximately 7 hours, using data published by Gaush and Michaelis.19 In humans, therapeutic plasma concentrations of clozapine are considered to be 200 to 400 ng/mL,1 and intoxication in adults can occur with concentrations of the parent drug over 2,000 ng/mL.1 However, survival has been reported with plasma concentrations as high as 20,000 ng/mL.6 Intoxication in children has been associated with plasma concentrations >500 ng/mL.7 The elimination half-life (t1/2) in humans is 4.5 to 7.5 hours,1 but as long as 18 hours has been reported in cases of overdose.58
Many of the clinical signs exhibited by this patient were consistent with signs of clozapine intoxication in humans.1681012–15 The clinical signs in combination with the strong indication of clozapine exposure led to a presumptive diagnosis of clozapine intoxication. The diagnosis was confirmed by measurement of clozapine serum concentrations. Based on the two clozapine concentrations in this patient, the calculated t1/2 of clozapine was 5 hours. Since ingestion occurred at least 9 hours prior to the first plasma sample, it is reasonable to assume that the estimated t1/2 represents the actual t1/2 in this patient. Using the calculated t1/2, one can predict the initial peak concentration. The concentration of clozapine in the first serum sample from this patient (1,500 ng/mL) was obtained 9 to 16 hours (two to three half-lives) after ingestion occurred. Based on a conservative estimated time of exposure, the calculated peak concentration of clozapine was approximately 6,000 ng/mL. Therefore, it is not surprising that this patient initially exhibited clinical signs of clozapine intoxication.3
The case described here displayed significant electrolyte abnormalities and metabolic acidosis as sequelae to clozapine intoxication. The cause of the observed hypernatremia, hyperchloremia, and hypokalemia is not totally clear but could possibly reflect the ion distribution in saliva, which is low in sodium and chloride but rich in potassium.18 The severe hypersalivation in this case might have been at least partially responsible for these electrolyte abnormalities, which have not been described in human cases of clozapine intoxication. Hypernatremia can be of clinical concern, due to the possibility of neuronal swelling if rapid correction occurs. In the present case, a replacement type of fluid (i.e., lactated Ringer’s solution) was administered at a maintenance rate that was unlikely to correct hypernatremia too rapidly. Frequent monitoring of the electrolytes would have been ideal but was declined by the owner, since all clinical signs were diminishing. The observed metabolic acidosis could have resulted in ion exchange with an increase in extracellular potassium and depletion of intracellular potassium. However, since the dog was eating with good appetite within 12 hours after admission, IV potassium supplementation was deemed unnecessary. Severe metabolic acidosis has been described in a human case report of clozapine intoxication, showing acidosis with increased blood lactate concentrations.5 No mechanism for the acidosis was suggested by the previous authors.
All parameters in the serum biochemical profile, except for ALP, were within reference ranges in this patient 40 days after the intoxication. The dog’s health prior to the incident is unknown, but the dog displayed no clinical signs indicating liver dysfunction. Since the owner declined further workup, the liver function in this dog was not investigated. This patient did not experience agranulocytosis, which is one of the most severe side effects of clozapine intoxication in human patients.1
Conclusion
The observed clinical signs of clozapine intoxication in this case correspond to reported symptoms of intoxication in humans. In this case, the calculated peak concentration of clozapine was approximately 6,000 ng/mL, and the t1/2 was 5 hours. Charcoal administration and supportive care led to a successful outcome. This represents the first report of a clinical case of clozapine intoxication in a dog. Despite the severity of the intoxication, supportive treatment was all that was necessary for a successful outcome.
ToxiBan; Vet-A-Mix, Inc., Shenandoah, IA
HP M1205A OmniCare Component Monitoring system Model 24; Hewlett-Packard, Palo Alto, CA
Pathology Associated Medical Laboratories, Spokane, WA
Citation: Journal of the American Animal Hospital Association 38, 5; 10.5326/0380421
Logarithmic plasma clozapine concentration versus estimated time after ingestion in a 6-year-old schnauzer with a history and clinical signs consistent with clozapine ingestion.
Contributor Notes
