Topiramate Augmentation in Major Depression

Molecular Model of the Drug Topiramate

Currently available antidepressants provide significant relief from major depression in many patients.  However, a significant number of patients receive little or limited relief following an initial trial of a standard first-line drug from the selective serotonin re-uptake inhibitor class of agents.


A common clinical strategy after initial drug non-response and non-remission is to consider pharmacological augmentation.  Augmentation options for clinicians include lithium carbonate, triiodthyronine (thyroid hormone), a second antidepressant, an atypical antipsychotic or adding psychotherapy if it is not already being provided.


Despite the number and range of augmentation options, additional options need to be explored given the persistence of depressive symptoms in many individuals.  A small study from Iran suggests one alternative to consider may be the drug topiramate.


Topiramate is a drug approved by the FDA for the treatment of epilepsy and migraine headaches  in the United States.  It is not approved for the treatment of any primary psychiatric disorder.  The exact mechanism of action for topiramate is unknown although it is known to have effects on the sodium channel, gamma-amino butyric acid (GABA) receptors, glutamate receptors and act as a carbonic anhydrase inhibitor.


Mowla and Kardeh have published a small study of 42 subjects randomized to topiramate or placebo.  The key elements of the study include:

• Subjects: Adults with DSM-IV major depressive disorder who had failed to respond to eight weeks of treatment with an SSRI drug (fluoxetine, citalopram or sertraline)
• Drug: Topiramate 25 mg per day increased by 25 mg per week throughout the trial (mean dosage 175 mg/day) or placebo
• Clinical trial design: Double-blind, randomized controlled trial with primary outcome measure the Hamilton Depression Rating scale (HAM-D) administered by a psychologist not involved in treatment

Fifty three subjects started the study with 11 dropouts (six in the topiramate group and five in the placebo group).  HAM-D scores statistically decreased more in the topiramate group (21.6 at baseline to 14.7 at 8 weeks) than in the placebo group (21.9 at baseline to 20.8 at 8 weeks).


Since a score of seven or more is considered remission in MDD, the mean score of 14.7 in the topiramate groups suggests significant residual symptomatology.  The authors do not provide the number of subjects meeting remission criteria in the topiramate and placebo groups by 8 weeks.


Nevertheless, topiramate has some potential significant advantages in the treatment-resistant major depression population.  First, it is a generic drug and would have some cost advantages in comparison to some of the other options.  Second, topiramate it typically weight neutral or produces a slight weight reduction.  Most antidepressants increase weight over time so this might be an important advantage.  Third, topiramate might hold an advantage in treatment of MDD populations with migraine or epilepsy--disorders with an indication for the drug.


This study is too small to change clinical practice patterns or guidelines.  Additional larger replication studies need to be considered.  

Molecular model of the drug topiramate from Wikipedia Creative Commons file released to the public domain.  Author of the model is: Fvansconsellos

Mowla A, & Kardeh E (2011). Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial. Progress in neuro-psychopharmacology & biological psychiatry, 35 (4), 970-3 PMID: 21291943