Controlled Double-Blind Trial of Phenytoin vs. Fluoxetine in Major Depressive Disorder
J Clin Psychiatry 2005;66(5):586-590
© Copyright 2017 Physicians Postgraduate Press, Inc.
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Background: Phenytoin was the first nonsedative
anticonvulsant introduced and is still the anticonvulsant most
widely used worldwide in neurology. Given the efficacy of the
anticonvulsant lamotrigine in the depressed phase of bipolar
disorder, a critical theoretical question is whether other
anticonvulsants used in treating bipolar disorder might be
similarly effective. We therefore undertook a controlled trial of
phenytoin versus fluoxetine in major depressive disorder.
Method: Data were collected from July 2001 to
July 2003. Thirty-three subjects entered the study. All patients
met DSM-IV criteria for major depressive disorder and scored a
minimum of 18 on the 24-item Hamilton Rating Scale for Depression
(HAM-D) at baseline. After a 3-day washout of any previous
medications, patients were randomly assigned to fluoxetine or
phenytoin in identical capsules. Each capsule contained phenytoin
100 mg or fluoxetine 7 mg plus cornstarch. Patients started with
1 tablet daily and increased every other day until they were
taking 1 tablet 3 times daily with meals. Blood phenytoin levels
were taken after 1 week, 3 weeks, and 6 weeks, and dosage was
adjusted to achieve blood levels of 10 to 20 mg/mL, to a maximum
dose of 4 capsules per day or a minimum dose of 2 capsules per
day. Fluoxetine patients were assigned dummy blood phenytoin
levels by the control psychiatrist such that the treating
physician would raise the number of capsules to at least 3 per
day (20 mg of fluoxetine).
Results: Thirty-three patients entered the
study, and 28 (N = 14 in each treatment group) completed at least 3
weeks and were included in the data analysis. Patients who
dropped out after week 3 (3 patients) were included in the study
as last value carried forward. There was no difference between
treatment groups in overall rate of response or speed of
Conclusion: The absence of a placebo
arm in our study allows for the possibility that
neither treatment was more effective than placebo.
However, the exclusion of past fluoxetine
nonresponders and the minimum HAM-D score
at baseline of 18 make this possibility unlikely.