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

Common Neuropsychiatric Problems in Epilepsy

Epilepsy represents a complex neuropsychiatric condition with significant public health impact.  The prevalence estimates of active epilepsy range from about 1 to 4% of the general population.  Like other medical conditions, epilepsy appears to increase the risk for a variety of secondary (or cormorbidity problems).  Understanding these related risks can aid patients, families and clinicians in understanding symptoms, common presentation conundrums and best treatment approaches. A recent epidemiology survey published by Ottman and colleagues of a large sample of the general population in the U.S. provides insight into the range and relative risk for variety of disorders in those with epilepsy.  The key elements of this survey include the following key design items:

• Data part of Epilepsy Comorbidity and Health (EPIC) Survey
• Mail survey to random households in the United States
• Case definition of epilepsy a yes response to the following question: “Have you ever been told you have a seizure disorder or epilepsy?”.
• Those who reported being diagnosed with epilepsy (2.0% of those surveyed) were compared to those without a self-reported diagnosis
• Surveyed other neuropsychiatric, pain and other medical conditions included: anxiety disorder, depression, bipolar affective disorder, ADHD, sleep disorder/apnea, tremor/movement disorder, migraine, fibromyalgia, chronic pain, neuropathic pain, asthma, diabetes, high blood pressure
• Risk ratios controlled for a variety of potential confounding variables including: sex, age, income, population density,census region, prior head injury, and prior stroke

The comorbid conditions with the highest relative risks (that were statistically significant) are shown in the accompanying summary figure.   A prevalence ratio of 2.0 would mean those with epilepsy are twice as likely to have the diagnosis compared to controls without epilepsy. ADHD, bipolar disorder, movement disorder/tremor and fibromyalgia led the rank list of diagnoses.  A significant number of the disorders showed statistically significant associations between a risk of 1.0 to 2.0.   The only disorders that showed no link to a diagnosis of epilepsy were diabetes and high blood pressure.

The primary weaknesses of these types of studies is reliance on self-report diagnosis by a the respondents.  One way to exam the validity of diagnoses is to conduct more detailed direct interviews and examinations of a subset of study participants.  Also the rates of self-reported diagnoses can be compared to known direct interview studies.  Here are the rates of self-reported neuropsychiatric diagnoses in those without epilepsy in the current study: depression 25.6%, anxiety 13.9%, bipolar disorder 6.8%, ADHD 5.5%.   The bipolar disorder self-report rates seem unexpectedly high and the implications for the validity of this study is unclear.

The authors note their study demonstrating a lifetime self-report prevalence rate of 2.0% is consistent with previous other population-based surveys.  Neuropsychiatric comorbidities were common in those reporting epilepsy ranging from a low of 8.7% for neuropathic pain to 32.5% for depression.  The authors note this study will aid those caring for epilepsy and help target comprehensive assessment and managment.

Ottman R, Lipton RB, Ettinger AB, Cramer JA, Reed ML, Morrison A, & Wan GJ (2011). Comorbidities of epilepsy: Results from the Epilepsy Comorbidities and Health (EPIC) Survey. Epilepsia PMID: 21269285