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We describe a patient with Alzheimer's disease who developed coma a few days after starting low dose trazodone associated with ginkgo biloba. Coma was reversed by flumazenil, a specific antagonist of the benzodiazepine (BDZ) receptor. The finding is relevant in that, although the sedative effects of trazodone are well known, the drug is inactive on the BDZ receptor. On the other hand, ginkgo is active on the receptor, but sedation has so far never been reported.
In March 1999, an 80 year old woman was first evaluated in our facility and given a diagnosis of probable Alzheimer's disease (NINCDS-ADRDA criteria) of a moderate severity (mini mental state examination of 10/30). She had no physical comorbidity or vascular risk factors. At the time of observation she was taking 3.5 mg bromazepam for mild restlessness, anxiety, and irritability, with only partial benefit (neuropsychiatric inventory: anxiety 4/12, irritability/lability 3/12). A dose of 5 mg donepezil at bedtime was added with the aim of improving both cognitive function and behaviour, together with 600 mg vitamin E twice daily.
After 3 months, no improvement of cognitive function, behaviour, or daily function could be detected. Donepezil was discontinued. Vitamin E was also discontinued due to the development of ecchimotic bruises on all limbs. Ginkgo biloba ((Egb 761) 80 mg) twice daily was added. Rivastigmine was not considered a feasible option because it was not possible to have frequent clinical follow up visits during the titration phase. For a better control of behavioural disturbances, bromazepam was replaced with 20 mg trazodone twice daily.
The day after the visit, the new therapeutical regimen was initiated. Sedation or other adverse effects did not appear, and the care giver reported improvement of anxiety. On the next day, the improvement of behavioural disturbances was sustained, still in the absence of sedation. At 600 pm of the third day, the patient developed instability of gait and drowsiness. At 700 pm she fell asleep. The care giver tried to wake her by slapping her face, but without success. Overall, she had taken 100 mg trazodone and 320 mg Egb 761 in about 50 hours. A physician on call found that blood pressure was 120/55 mm Hg and her Glasgow coma scale was 6/15. The patient was taken to the nearest hospital, where 1 mg flumazenil intravenously was administered. The patient awoke immediately.
Medicine bottles at the patient's home were examined. The medications remaining in the containers were consistent with the prescribed doses, and medications other than those prescribed were not found anywhere in the house.
Trazodone and ginkgo were discontinued and bromazepam was resumed. The patient was re-evaluated 2 months later. Cognitive functions and behaviour were unchanged.
The pathogenesis of coma would have remained unexplained in this patient had not flumazenil been fortuitously administered. This led to an investigation of the links among trazodone, ginkgo, and the GABAergic system.
Ginkgo biloba is active on cognition in Alzheimer's disease through its antioxidant properties. Flavonoids represent the major active component of the extract and possess GABAergic activity through action at the BDZ binding site as partial agonists.1 However, ginkgo alone does not have clinically sedative effects.
Trazodone is an antidepressant widely used for its hypnotic and sedative effects to treat behavioural disturbances in the demented. Drowsiness is a dose dependent effect due to a direct antagonism at the α1 adrenergic receptor level, and in elderly people it has been reported with doses greater than 75 mg daily. Trazodone is metabolised by an isoform of cytochrome P-450 (CYP3A4) into an active compound 1-(m-chlorophenyl)piperazine (mCPP). Through an agonistic action on presynaptic 5-HT2 and α2 receptors located on GABAergic nerve terminals,2 mCPP enhances the release of GABA.3 4 The activity of CYP3A4 can be increased by flavonoids.5
We hypothesise that, in our patient, on the one hand flavonoids provided a subclinical increase of the GABAergic activity through a direct effect on the BDZ receptor, whereas on the other increased CYP3A4 function and mCPP production, inducing a further enhancement of GABAergic activity that became clinically apparent. Flumazenil might have blocked the direct effect of flavonoids, thus causing GABAergic activity to fall below the threshold of clinical manifestation (figure).
Ginkgo is widely used and is thought to be a harmless food supplement. Although we warn that the adverse effects of the simultaneous administration of trazodone and ginkgo should be further confirmed, we think that natural compounds such as ginkgo can have, in some clinical circumstances, adverse effects of similar magnitude as traditional drugs.