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Critical Use of Venlafaxine Serology to Uncover Genetic Rapid Metabolism

Key Words: Venlafaxine • Depression • Metabolism

SIR: A 17-year-old male with three serious overdose suicide attempts in two years and intractable major depression (MD) was successfully treated only with the high dose of 500 mg of venlafaxine per day. His experience illustrates the benefit of dual-action antidepressants, the critical utility of peak venlafaxine serum levels in selected patients, and the utility of knowing familial metabolic rates.

Case Report
An adolescent failed to improve from consecutive trials of 50 mg per day of fluoxetine and 200 mg of sertraline, each for months. Venlafaxine was started for its dual neurotransmitter action, possibly resulting in faster and fuller remission.^1,2

The youth's baseline Inventory to Diagnose Depression³ score (IDD) was 51 (0–10 is normal). He suffered daily suicidal ideation and profound anhedonia. He was titrated to 375 mg per day of venlafaxine over 2 weeks with only transient anorexia. He improved in 2 weeks, with a peak venlafaxine level of 310 ng/ml and an O-desmethylvenlafaxine (ODV) level of 210 ng/ml. In 3 weeks, he had an IDD of 24.

After 5 weeks he worsened, in the absence of stressors. A prompt follow-up plasma venlafaxine level was only 79 ng/ml, with an ODV of only 170 ng/mg. The dose was increased to 425 mg/day in divided doses, with moderate improvement in his MD over 10 weeks. Plasma venlafaxine was 450 ng/mg, with ODV 480 ng/mg. Eventually the dosage was increased to 500 mg (slow-release form) in two doses, at which level the patient had only transient vivid dreams. After 2 months, his IDD scores were normal. Serum levels after 1 year were venlafaxine 650 ng/ml and ODV 590 ng/ml, approximately within the expected peak ranges.

Eventually, his father began treatment and was also started on venlafaxine. He also initially had a therapeutic benefit on 200 mg per day, followed by a marked loss of benefit and a significant drop in baseline serum levels. Increasing his dose to 375 mg per day almost put him in full MD remission, with serum levels in the therapeutic range. Both pharmacokinetic and pharmacodynamic response may run in families.

Comment
Reasonable laboratory standards for venlafaxine and ODV^4,5 blood levels exist. It seems useful to use blood levels to confirm compliance, to monitor polypharmacy in treatment-resistant patients, and to assess patients with initial clear benefits that are suddenly lost, perhaps because of marked metabolism. Understanding this patient's rapid metabolism kept us from aborting a therapeutic medication and yielded meaningful remission in an otherwise treatment-resistant patient with a history of suicide attempts and severe MD.

REFERENCES

1. Nelson JC, Mazure CM, Bowers MB, et al: A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 1991; 48:303–307[Abstract]
2. Silverstone PH, Ravindran AR: Once-daily venlafaxine extended release (xr) compared with fluoxetine in outpatients with depression and anxiety. J Clin Psychiatry 1999; 60:22–28
3. Zimmerman M, Coryell M, Corenthal C, Wilson S: A self-report scale to diagnose major depressive disorder. Arch Gen Psychiatry 1986; 43:1076–1086
4. Clement EM, Odontiadis J, Franklin M: Simultaneous measurement of venlafaxine and its major metabolite, oxydesmethylvenlafaxine, in human plasma by high-performance liquid chromatography with coulometric detection and utilisation of solid-phase extraction. J Chromatography B 1998; 705:303–308
5. Hicks DR, Wolaniuk D, Russell A, et al: A high-performance liquid chromatographic method for the simultaneous determination of venlafaxine and O-desmethylvenlafaxine in biological fluids. Therapeutic Drug Monitoring 1994; 16:100–107[Medline]

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