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

Phentermine/Topiramate Combo for Obesity

Molecular Model of Topiramate

Previous Brain Posts summarized some of the pharmacologic agents in the pipeline for weight loss as well as some drug combinations.  A recent research study published in Lancet provides additional data on one of the drug combinations being studied: phentermine and topiramate.

This new study is important because it looked at 56 weeks of treatment and target obese individuals with at least two obesity-related medical complications.  Subjects were required to have significant obesity (BMI 27-45 kg/m2) and at least two of the following:  hypertension, dyslipidemia, diabetes or prediabetes, abdominal obesity).  Each of these factors increases the risk of mortality associated with being overweight.

The key findings from the study--number of pounds lost at 56 weeks:

• placebo-- 3.1 pounds (1.4 kg)
• phentermine 7.5mg/topiramate 46 mg-- 17.8 pounds (8.1 kg)
• phentermine 15.0mg/topiramate 92 mg-- 22.4 pounds (10.2 kg)

The weight loss outcome in the highest dose group was approximately 10% of body weight--a significantly positive result in light of previous single agent trials.

One area of outcome caught my eye, the change in physiological and metabolic parameters over the course of the study.  Waist circumference decreased about an inch (2.4 cm) in the control group but three (7.6 cm) to three and one half inches (9.2 cm) in the low dose and high dose treatment group.  Blood lipid changes were also pretty impressive with LDL and triglycerides falling more in the treatment groups while good cholesterol values (HDL) increased more with the active drug combination.  Fasting insulin levels dropped significantly more in the active groups also.

Given historical problems with use of weight loss drugs, safety issues are important to monitor closely.  The most common adverse events in the active agent groups with rates higher than placebo were dry mouth (21%), paresthesias (numbness and tingling) (21%),  constipation (17%), dysguesia (10%), insomnia (10%), dizziness (10%), anxiety (4%) and irritability (3%).  Although infrequent (1%) depression was noted in the high dose group more than placebo.  One potential red flag with this combination was report of 11 cases of renolithiasis (kidney stones) in the high dose active agent group.

Topiramate inhibits the action of carbonic anhydrase.  This effect can cause decreases in serum bicarbonate and potassium as well as increasing risk of renolithiasis.  The rate of renolithiasis was lower in the low dose group suggesting a dose-related effect.  Additional, inhibitors of carbonic anhydrase have been noted to cause alterations in sensation (paresthesias) and in taste (dysguesia).

The authors note several relevant areas of caution.  Subjects with clinically relevant depression were excluded from the study due to concern about drug-induced depression.  Also some subjects noted cognitive adverse events, attention or memory problems, and this needs to be monitored in those more prone to such effects.  Additionally, the first application to approve this combination of phentermine and topiramate was turned down for lack of long-term cardiac safety data and data on risk of use during pregnancy.  This additional data is likely being collected for analysis and possible re-application given the impressive level of weight loss associated with this combination.

Molecular model of topiramate from Wikipedia Creative Commons, Author fvasconcellos.

Kishore M Gadde, David B Allison, Donna H Ryan, Craig A Peterson, Barbara Troupin, Michael L Schwiers, Wesley W Day (2011). Eff ects of low-dose, controlled-release, phentermine plus
topiramate combination on weight and associated
comorbidities in overweight and obese adults (CONQUER):
a randomised, placebo-controlled, phase 3 trial Lancet : 10.1016/S0140- 6736(11)60205-5