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Thirteen patients with treatment-resistant major depression were given venlafaxine, at doses ranging from 150 mg to 375 mg, combined with ECT. Propofol was used as an anesthetic. Ten of 13 (76.9%) were considered responsive to combined ECT-venlafaxine treatment, and positive responses were not associated with venlafaxine doses. An asystole episode was observed in 4 patients; these patients had received significantly higher doses of venlafaxine (P<0.01). Treatment seems to be safe at venlafaxine doses <300 mg/day. At higher doses, with propofol used as anesthetic, the possibility of asystole cannot be ruled out. A possible additive effect of high-dose venlafaxine and propofol-blocking sodium channels are discussed.