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Venlafaxine‐associated serotonin syndrome and manic episode in a geriatric depressive patient

Venlafaxine has been considered a safe choice in treating major depressive episode for patients with bipolar II disorder. 8 However, sporadic cases have been reported to have venlafaxine-induced ‘manic and hypomanic switches’. 9–12 In a MEDLINE search, we have not located any report describing a patient who has both serotonin syndrome and manic episode simultaneously after venlafaxine use. Here, we report a geriatric depressive patient, who developed both conditions rapidly after having received two doses of 37.5 mg venlafaxine on the top of her existing medications. Ms. A is a 69-year-old married female, who was diagnosed with major depressive disorder 1 year ago in the outpatient department. She was devoid of any other medical illness. During the follow-up clinic visits at the outpatient clinic, her depressive symptoms did not respond after she received monotherapy with fluoxetine, trazodone or amitriptyline in adequate dose and duration. She appeared to have partial response when she took fluoxetine 20 mg/day and trazodone 150 mg/ day for depressive mood, buspirone 20 mg/day and zolpidem 10 mg/day for anxiety symptoms and sleep disturbances. In an attempt to improve the partial response after a 2-month combination treatment, she was given venlafaxine 37.5 mg twice a day on top of her regular medications. On the next day, she developed fever, tremor, muscle cramping pain, diarrhea, ataxia, irritability, consciousness disturbance, disorientation to time, place and people, and behavior disturbance. Under the guise of serotonin syndrome, she was then admitted to the acute psychiatric ward and all her medications were discontinued. The symptoms of serotonin syndrome (including consciousness disturbance) subsided gradually over 3 days. Then, she developed a fullbrown manic episode with symptoms and signs of elated mood, irritability, decrease of sleep need, hyperactivity, grandiose delusion, flight of ideation, and giving sexually oriented speech. The level of her consciousness was clear and she was oriented to time, person and place under the close observation on the unit. She received only supportive treatment without giving any mood stabilizing agents or psychotropic drugs. She got all the symptoms of manic episode remitted in 2 weeks. Any drug or combination of drugs that increase CNS serotonin neurotransmission, can produce serotonin syndrome. Different biochemical mechanisms, including inhibition of serotonin reuptake or serotonin metabolism, stimulation of serotonin synthesis or release, and direct stimulation to serotonin receptors, are thought to activate serotonergic neurotransmission, 13 such as trazodone and buspirone, the agonist of serotonin receptor. Furthermore, venlafaxine is dependent on CYP2D6 and CYP3A3/4 for its phase I biotransformation, while fluoxetine can inhibit many isozymes including CYP2D6 and CYP3A3/4. The serum level of venlafaxine might increase rapidly with coadministered fluoxetine. 1 The combination use of venlafaxine, fluoxetine, trazodone and buspirone has the potential for pharmacodynamic and pharmacokinetic drug interactions, which result in increasing CNS serotonin transmission and inducing serotonin syndrome. Venlafaxine has been considered as a safe choice of causing ‘manic switching’ for patients with bipolar II disorder. 8 However, sporadic cases have been reported that venlafaxine is implicated to cause antidepressantinduced mania. 9–12 There is no exact standard treatment for patients with antidepressant-induced manic episode. In our case, the manic episode, which developed after having two 37.5 mg doses of venlafaxine, remitted in 2 weeks after all her medications were discontinued. This case is reported to alert psychiatrists about producing accumulative serotonergic effects from combined use of psychoactive drugs and recognizing other risk factors, such as elderly patients, for the drug adverse effects. 2,3,14,15