Abstract
OBJECTIVE:
To report a case of seizures in a patient with Alzheimer disease, who was receiving quetiapine for psychoses.
CASE SUMMARY:
A 75-year-old white man with Alzheimer disease was observed to have seizures while receiving quetiapine 500 mg/d and carbamazepine 200 mg/d. He had been taking quetiapine for 18 months prior to the event. No other toxic, metabolic, or anatomic abnormalities were identified to explain the seizures. After cessation of quetiapine treatment, the patient remained seizure free. An objective causality assessment revealed that the adverse drug reaction was possible.
DISCUSSION:
The patient was taking a relatively high dose of quetiapine. An increased risk of seizures has been associated with Alzheimer disease. Using a relatively high dose of quetiapine may have resulted in seizures in our patient with Alzheimer disease.
CONCLUSIONS:
As with other antipsychotics, quetiapine should be used cautiously in elderly patients with conditions that can lower the seizure threshold, and special monitoring should be performed for this serious adverse effect.
Antipsychotic agents are often given to patients with dementia for psychosis and aggression, which are seen in up to 70% and 40% of patients, respectively. 1 Clozapine, olanzapine, and quetiapine are the most commonly used agents for this purpose. As with other atypical antipsychotics, quetiapine has a low incidence of extrapyramidal reactions, but its insignificant anticholinergic effect differentiates quetiapine from the others. Anticholinergic properties are particularly undesirable in patients with Alzheimer disease, especially for those in mild to moderate stages, because they worsen cognitive abilities and may offset the benefits of cholinesterase inhibitors. 1 Atypical antipsychotics such as clozapine and olanzapine have been reported to induce seizures.2,3 Such an effect has been explained by the lowering of the seizure threshold.2,4,5 Seizures associated with quetiapine have been reported.6–8 We report a case involving seizures witnessed in a patient with Alzheimer disease receiving concurrent quetiapine and carbamazepine treatment.
Case Report
In April 1999, a 75-year-old white man was admitted to our neurology outpatient clinic with a 1-year history of forgetfulness, confusing his children's names, and confusing times, dates, and places. The patient had no recent history of stroke, alcohol abuse, or head trauma, as well as no documented systemic diseases such as diabetes mellitus, hypertension, and cardiac or pulmonary disease. Neuropsychological examination showed a marked deficit in short-term memory and mild anomic aphasia. He scored 22/30 on the Mini-Mental State Examination (MMSE). Cranial nerve examination was unremarkable. Muscle bulk, muscle strength, and deep tendon reflexes were normal. There were no abnormal reflexes except palmar grasp reflex bilaterally. Complete blood cell count, serum biochemical analysis, serologic analysis for hepatitis B and C viruses and HIV, urine, and cerebrospinal fluid investigations were negative for infectious (herpes simplex virus), metabolic, toxic, or inflammatory causes. An electroencephalogram (EEG) showed mild, diffuse background slowing at 7–8 Hz. Computed tomography scan and magnetic resonance imaging of the brain showed diffuse cortical atrophy. The patient was diagnosed as having probable Alzheimer disease according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders criteria. 9
Treatment with donepezil 5 mg/d was introduced. Twenty-one days after initiating donepezil, the dose was increased to 5 mg twice daily, but the patient developed nausea and vomiting. The dose was then tapered to 5 mg/d and such adverse effects did not recur.
Neuropsychological examination after 12 months of donepezil treatment showed a marked cognitive decline, and the patient scored 18/30 on the MMSE. He was not able to recognize his family members in the evenings and, in the last months, had become lost twice near his home. The patient was also severely affected by symptoms of agitation and aggressive behavior in the evenings. Donepezil was thought to be ineffective and was withdrawn over 2 weeks; rivastigmine 3 mg/d was administered for 4 weeks and the dose was then escalated to 6 mg/d. No adverse effects were reported during rivastigmine treatment.
The patient ignored his wife's death, did not talk to family members, and often refused to eat. He sometimes showed aggressive behavior toward his daughter. Nocturnal agitation was incapacitating for the family, and carbamazepine 200 mg/d was added to the treatment regimen in September 2000. The agitation and aggressiveness resolved significantly with carbamazepine therapy. After 6 months of rivastigmine therapy, no benefit could be observed and rivastigmine was withdrawn.
In November 2000, the patient developed visual hallucinations and delusions, and quetiapine 25 mg/d was initiated for these psychotic symptoms. The dose of quetiapine was increased to 100 mg by 25-mg increments every 3 days. With this dose, the psychotic symptoms subsided significantly. In February 2001, 3 months after starting quetiapine treatment, an exacerbation of behavioral symptoms was observed and the quetiapine dose was increased in 25-mg increments every 3 days to 200 mg/d. Symptom control was not achieved; therefore, the quetiapine dose was increased to 500 mg/d with 25-mg increments every 3 days in a 1-month period, and the psychotic symptoms diminished significantly. The patient gained 6 kg during quetiapine treatment. The other reported adverse effect of quetiapine was sedation, but it was not disabling. Treatment with quetiapine 500 mg/d and carbamazepine 200 mg/d was maintained between March 2001 and April 2002, and the patient remained free from behavioral symptoms. He did not take herbal medicine or nutritional supplements during the treatment.
In April 2002, the patient was admitted to the emergency department due to a generalized tonic–clonic seizure. The seizure activity was witnessed by the patient's daughter. When he was admitted, he still had clonic activity. The seizure lasted approximately 10 minutes and postictal confusion lasted 1 hour. Routine hemogram, electrolyte, and liver and renal function tests were within normal limits and computed cranial tomography was unremarkable. The serum carbamazepine concentration was 6.7 mEq/L. An EEG obtained 6 hours following the seizure showed nonspecific generalized slowing at 6–7 Hz. The patient was discharged from the hospital, and the next day he developed a new generalized tonic–clonic seizure. At this time, the dose of carbamazepine was increased to 400 mg/d. Ten days after the first seizure, the patient developed another generalized tonic–clonic seizure and the serum concentration of carbamazepine was 9.1 mEq/L. It was thought that these seizures might have occurred as a result of quetiapine treatment. Because of this possibility, the dose of quetiapine was lowered to 150 mg/d; the tapering was performed within a week by 50-mg/d decrements, and the drug was slowly withdrawn over 2 weeks. The patient continued taking carbamazepine, and risperidone at 0.5 mg/d was introduced for his behavioral symptoms 1 month after the withdrawal of quetiapine. The patient did not experience seizure recurrence in the last 6 months of follow-up. This patient's seizures constitute a possible adverse drug reaction according to the Naranjo probability scale. 10
Discussion
Quetiapine is an antagonist of serotonin 5-HT1A and 5-HT2, dopamine 1 and dopamine 2, histamine H1, and adrenergic α1 and α2 receptors. 11 Quetiapine is rapidly absorbed after an oral dose, with peak plasma concentration reached between 60 and 90 minutes after ingestion. It has linear pharmacokinetics, and steady-state pharmacokinetics appear to be the same for both men and women. 12 The mean half-life of a 375-mg dose is 6.9 hours. 12 Quetiapine is metabolized in the liver by the CYP3A4 isoenzyme. 11 It is eliminated primarily in the form of metabolites, with 73% excreted in the urine and 21% excreted in the feces. 12 Clearance in elderly patients is reduced by about 40% compared with younger patients, and is also reduced in patients with renal or hepatic impairment. 12
Atypical antipsychotics such as clozapine have been reported to lower the seizure threshold, and increased seizure risk associated with clozapine is dose dependent.2,4 There have been reports that another atypical antipsychotic, olanzapine, which had a premarketing seizure rate of 0.9%, 13 can induce seizures. 3 One fatal case has also been described. 14 In a clinical trial with 3700 patients, the occurrence of seizures in patients treated with quetiapine was no greater than that observed in patients receiving placebo. 15 Recently, a case of a new-onset seizure associated with concurrent use of olanzapine and quetiapine was described. 6 The patient in that report was taking a stable dose of olanzapine when quetiapine 100 mg/d was added. The patient was also taking clonazepam and, after starting quetiapine, clonazepam was discontinued. Two days after the cessation of clonazepam, and 1 day after starting quetiapine, the patient had a generalized seizure. After discontinuation of quetiapine, no additional seizures occurred. The patient was also taking sertraline, a drug with seizure threshold–lowering potential. The authors concluded that this situation describes a fairly typical scenario: overlapping atypical antipsychotic use, benzodiazepine dose adjustments, and the presence of other psychotropic medications that lower the seizure threshold.
In a study investigating short-term efficacy and safety of quetiapine in autistic children, 1 patient was reported to have dropped out because of a possible seizure during the fourth week of treatment. 7 Recently, a case of seizure activity causing death associated with alcohol withdrawal and multiple drug use including tramadol, venlafaxine, trazodone, and quetiapine was reported. 8
Our patient was using carbamazepine and quetiapine concurrently. Recently, an interaction between quetiapine and carbamazepine was described. 16 According to this report, 2 patients who were receiving carbamazepine experienced markedly elevated concentrations of its active metabolite, carbamazepine-10,11-epoxide (CBZ-E), after starting quetiapine therapy. The CBZ-E/carbamazepine ratio increased three- to fourfold in each patient. Concentrations of CBZ-E returned to baseline after discontinuation of this combination. One of the patients experienced ataxia and agitation while receiving quetiapine that resolved after carbamazepine was switched to oxcarbamazepine. The metabolite contributes to both seizure control and toxicity, including drowsiness, confusion, dizziness, ataxia, and exacerbation of seizures.
Quetiapine may inhibit epoxide hydrolase and/or glucuronidation of carbamazepine-10,11-trans-diol. 16 Phenytoin also causes a marked increase in the apparent oral clearance of quetiapine when the drugs are coadministered. 17 Carbamazepine and phenytoin are hepatic enzyme inducers and, if quetiapine is added, increased doses of quetiapine may be required to maintain antipsychotic efficacy.
Drugs with inhibitory effects on γ-aminobutyric acid (GABA) current may also lower the seizure threshold and induce seizures in a dose-dependent manner. Recently, Yokota et al. 18 investigated the effects of certain neuroleptics, including haloperidol, clozapine, quetiapine, olanzapine, risperidone, zotepine, and chlorpromazine, on GABA-in-duced chloride current in rat dorsal root ganglion neurons. Their results showed that quetiapine and haloperidol did not affect the peak amplitude of the GABA-induced chloride current.
Other neuroleptics that have been studied inhibited the GABA-induced chloride current. The inhibitory effects of neuroleptics on GABA current were ranked clozapine > zotepine > chlorpromazine > olanzapine > risperidone. These inhibitory effects were correlated with the clinical incidences of seizure during treatment with neuroleptics. 18 These data support clinical observations and may explain their seizure threshold–lowering effects. Quetiapine has little affinity for GABAergic receptors. The possible seizure-lowering effect of quetiapine remains to be studied.
EEG findings in Alzheimer disease are highly dependent on timing. The EEG is initially normal or shows an α rhythm (8–12 Hz) at or just below the lower limits of normal. 19 Generalized slowing appears as the disease progresses. The initial EEG of our patient on admission and those performed after the seizures occurred showed generalized slowing and were interpreted as being insignificant. Healthy elderly people also show a slightly increased amount of slow activity.
There are also reports that Alzheimer disease and other dementias are associated with an increased risk of epilep-sy.20,21 Using a relatively high dose of quetiapine and having Alzheimer disease might have resulted in seizures in our patient. After cessation of the quetiapine treatment, the patient remained seizure free. Most studies with quetiapine have involved younger schizophrenic patients, with effective doses ranging from 150 to 750 mg/d.22,23 Although studies with quetiapine at low doses in elderly patients with Alzheimer disease showed promising results,1,24 efficacy and safety in this age group require confirmation with a larger scale, double-blind study.
Summary
Possible explanation for seizures in our patient can be the dose-dependent drug-induced lowering of the seizure threshold. As with other antipsychotics, quetiapine should be used cautiously in patients with a history of seizures or with conditions that can lower the seizure threshold, such as Alzheimer disease. While using quetiapine, as well as other antipsychotics in the elderly population who are prone to develop seizures or at high risk for seizures, close monitoring should be undertaken for this serious adverse effect.