Effectiveness of carbamazepine for benzodiazepine-resistant impulsive aggression in a patient with frontal infarctions

Authors


Tomoyuki Nagata, MD, Department of Psychiatry, Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa, Chiba 277-8567, Japan. Email: t.nagata@jikei.ac.jp

Abstract

Abstract  Anticonvulsants have been used for the treatment of impulsive aggression since the 1980s. A 50-year-old man suffered from irritability and agitation after developing a right ipsilateral frontal lobe infarction as a result of Moyamoya disease; these symptoms caused difficulties with his working and interpersonal relationships. The patient had been treated using multiple benzodiazepine agents for 2 years but his symptoms had not improved. However, after treatment with carbamazepine (CBZ; 200 mg) was begun, the patient's irritability and agitation gradually decreased. The efficacy of CBZ treatment in this patient suggests a method for controlling benzodiazepine-resistant impulsive aggression.

INTRODUCTION

Impulsive aggression is defined as impulsive anger or aggression that manifests as a result of even a slight environmental stressor or frustration; therefore subjects with impulsive aggression often have difficulties establishing interpersonal relationships or participating in social activities.1,2 In the 1980s anticonvulsants were discussed as a candidate pharmacotherapy for aggression related to temporal epilepsy. In recent clinical studies oxycarbazepine, which is structurally similar to carbamazepine (CBZ), was reported to be effective for the treatment of impulsive aggression.3

Herein we report a case in which CBZ treatment improved benzodiazepine-resistant impulsive aggression related to right frontal lobe damage, enabling the patient to cease receiving two benzodiazepine agents without experiencing withdrawal. CBZ has not been previously reported to be effective for the treatment of benzodiazepine-resistant impulsive aggression caused by stroke as a result of Moyamoya disease. To maintain patient privacy all personal information has been altered; the patient's written informed consent was obtained.

CASE REPORT

The patient was a 50-year-old man who had not experienced any significant problems with growth, development, or medication or substance abuse. No significant family medical history was present. He experienced sudden onset of left hemiparesthesia and was admitted to the neurosurgical department of another hospital. Other neurological findings were normal but magnetic resonance imaging (MRI) studies indicated a high-intensity lesion on T2-weighted images of the white and gray matter in the right frontal lobe, including the superior frontal gyrus and the middle frontal gyrus. Magnetic resonance angiography (MRA) demonstrated numerous distal branches of a right frontal lobe lesion and a weak appearance of the right anterior and middle cerebral arteries. Based on these findings he was diagnosed as having Moyamoya disease; conservative treatment with antiplatelet and anti-edematous drugs was started.

Over the course of 1 week his left hemiparesthesia gradually disappeared, but he began to feel irritable and agitated. Therefore treatment with benzodiazepine agents (diazepam 2 mg/day) was prescribed by a neurosurgeon. These drugs were initially effective for controlling his irritability but he gradually developed a tolerance to them.

At the age of 52 years the patient was taking several kinds of benzodiazepine agents: diazepam 20–30 mg/day and etizolam 1.5–2.5 mg/day. He was also using flunitrazepam (2 mg/day) and triazolam (0.25 mg/day) as hypnotics. In addition he was taking ticlopidine 200 mg/day and amlodipine 5.0 mg/day. He sometimes was unable to control his impulsive aggression; consequently, he was unable to continue performing office work.

The neurosurgeon advised him to visit the psychiatric department of Jikei University Kashiwa Hospital. His appearance and expression were normal but he complained that he could not control his emotions (e.g. trivial daily episodes made him irritated or aggressive, and he argued with other people). Moreover, he complained of subjective forgetfulness during the daytime. According to his wife his previous temperament had been much more moderate. His consciousness and orientation were intact, and other neurological and physical findings were normal. Laboratory data were within the normal ranges, except for a high total glyceride level of 288 mg/dL. He had a Mini-Mental State Examination (MMSE) score of 29 points, and a Frontal Assessment Battery (FAB: cut-off point of 11–12)4 score of 12 points. A Wechsler Memory Scale-Revised test showed a verbal memory quotient of 77, a visual memory quotient of 79, an attention/concentration quotient of 87, and a delayed memory quotient of 74. MRI showed an extensive old cerebral infarction in the right frontal lobe, and MRA showed poor expression of bilateral middle cerebral artery and the right anterior cerebral artery. Technetium-99m-ethyl cysreinate dimer single-photon emission computed tomography showed hypoperfusion of relative cerebral blood flow between the right frontal lobe cortex and the parietal lobe cortex. Electroencephalogram was unremarkable.

We decided to prescribe low-dose CBZ (200 mg/day) to treat his irritability and agitation. At the time he was informed that CBZ was a drug for the treatment of epilepsy or manic state and that he might experience several side-effects; he then consented to take the drug. Because his irritability gradually subsided after approximately 2 weeks, the dose of etizolam and diazepam was decreased. After approximately 4 weeks his irritability and agitation disappeared completely, and he no longer required etizolam and diazepam during the daytime. We succeeded in controlling his impulses using only CBZ 300 mg/day (his serum CBZ concentration was 5.5 μ/mL). However, his sleep disorder did not improve so he was unable to stop using the other two hypnotics. After approximately 16 weeks he was able to resume work but his FAB and MMSE scores remained the same and his subjective forgetfulness has not yet improved. Although the dose of CBZ (300 mg) has been maintained for approximately 1 year, no remarkable side-effects have occurred, including pancytopenia, agranulocytosis, hemolytic anemia, or somnolence.

DISCUSSION

Using the DSM-IV criteria, the patient was diagnosed as having a combined type (aggression and labile) personality change as the result of a cerebral infarction and a cognitive disorder not otherwise specified (Axis I). Regarding the putative mechanisms underlying the patient's symptoms, we speculated that the damage to his right frontal lobe might have resulted in an inability to control his impulses and a mild memory disorder (delayed and verbal memory). In other previous studies acquired impulsivity or sensitivity were thought to be associated with focal prefrontal frontal cortex (PFC) involvement or orbitofrontal or dorsolateral PFC.5,6 Such impulsive aggression also was thought to originate as a result of executive dysfunction with frontal damage.7

Propranolol, CBZ, and risperidone have been approved as pharmacological approaches for acquired impulsive aggression (organic brain injury or dementia etc.).2 Divalproex sodium and selective serotonin re-uptake inhibitors have also been reported to be effective for the treatment of impulsive aggression observed in subjects with cluster B personality disorders, but not in subjects with other diseases.2 CBZ's mechanism of action is thought to be related to the inhibition of repeated excitation of brain structures in the temporal lobe and limbic system.8 Regarding the anti-aggressive effect of CBZ, its inhibition of γ-aminobutyric acid or a reduction in 5-hydroxytriptophan synthesis in some brain regions has been considered.9,10

CBZ has been suggested to be effective in benzodiazepine-addicted or withdrawn patients with gradually tapered discontinuation.11,12 CBZ is thought to competitively bind to benzodiazepine receptors rather than central receptors associated with chloride channels, and to displace binding at peripheral receptors associated with calcium channels.12–14 These competitive actions may explain CBZ's antiwithdrawal effect. The present patient exhibited impulsive aggression with benzodiazepine resistance or a tolerance to benzodiazepine agents; therefore CBZ was chosen to control his impulsivity and to prevent benzodiazepine withdrawal. This case suggests that CBZ may be effective as an alternative psychotropic for patients with benzodiazepine-resistant impulsive aggression as a result of organic brain damage.

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