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

Real-Time fMRI Psychotherapy

Old World Psychotherapy: Sofa of Sigmund Freud

There has been a series of interesting research studies examining the effect of psychotherapy on brain structure and function.  These studies have typically shown that effective psychotherapy results in reduction of brain deficits or abnormalities associated with a specific neuropsychiatric disorder.

Now a study published in Plos One summarizes the results of study examining the use of real-time fMRI to provide neurofeedback during an amygdala activation task.

This research was completed by neuroscientists affiliated with the Laureate Institute of Brain Research in Tulsa, Oklahoma and George Mason University in Fairfax, Virginia. (Disclosure: The author of Brain Posts is employed by Laureate Institute of Brain Research but was not involved in the study reviewed in this post.)

The authors of this study noted the key role of the amygdala in the processing of emotions.   They developed a experimental paradigm to train control subjects to increase the activation of the brain left amygdala.  A group of young male subjects were instructed in a happy autobiographical memory task and provided real-time feedback on how successful they were in increasing blood flow to the left amygdala.

Subjects identified three key happy memories from their past.  During the experimental phase, they were instructed to recall these specific memories while being scanned using an fMRI scanner. They were provided real-time feedback on a monitor screen on the changes in left amygdala BOLD signal.  (Subjects were told prior to scanning that fMRI neurofeedback is delayed by a few seconds due to the brain hemodynamic process).

Subjects provided real-time feedback were more successful at increasing the left amygdala activation than those in a control group.  This increase in the experimental group correlated with increases in other brain areas known to have functional connectivity with the amygdala (fronto-temporo-limbic network).

New World Psychotherapy: Real Time fMRI

Additionally, the study identified six specific regions where functional connectivity identified correlations with the left amygdala activation:

• right medial frontal cortex
• bilateral dorsomedial prefrontal cortex
• left anterior cingulate cortex
• bilateral superior frontal gyrus

Subjects were selected based on being free of a history of neuropsychiatric disorders including anxiety and depression.  However, there was some variability in the level of change in left amygdala activation with neurofeedback training.  Subjects who scored high on the Difficulty Identifying Feelings scale had less increase in the left amygdala.  Additionally, subjects with higher scores on a scale of being susceptible to anger showed less increase.

This research is an very important advance in understanding the amygdala and regions connected with the amygdala.  Additionally, it raises the possibility that real-time fMRI may emerge as a tool to understand processes associated with psychotherapy and to be an emerging model for providing therapy under real-time neurofeedback conditions.  

The site of psychotherapy might be moving from the sofa model of Sigmund Freud to the fMRI scanner.  Both methods have subjects that lie down, but only the fMRI method provides real-time feedback of brain effects related to a psychotherapy intervention.

The authors note that this study was a type of "proof-of-concept" study since it focused on healthy control subjects.  They suggest that this type of model might be particularly relevant to cognitive behavioral treatment of conditions such as PTSD and major depression.

Photo of Sigmund Freud sofa from the Freud Museum in London from Wikipedia distributed under the GNU Free Documentation License.


Photo of Functional Magnetic Research Imaging device courtesy of the Laureate Institute for Brain Research. 

Zotev, V., Krueger, F., Phillips, R., Alvarez, R., Simmons, W., Bellgowan, P., Drevets, W., & Bodurka, J. (2011). Self-Regulation of Amygdala Activation Using Real-Time fMRI Neurofeedback PLoS ONE, 6 (9) DOI: 10.1371/journal.pone.0024522