Anti-seizure drug inhibits the glutamate system

By David Hodges

MONTREAL – The anticonvulsant topiramate (Topamax) may be an
effective second-line strategy for patients with obsessive-
compulsive disorder (OCD) who do not respond to serotonin reuptake
inhibitors (SRIs), concludes a preliminary study presented at the
Canadian Psychiatric Association meeting here.

Scientists at McMaster University found that topiramate works by
reducing levels of glutamate, a common brain chemical that has been
found in abnormally high concentrations in children with OCD.
Previous research has shown that a decrease in OCD symptom severity
was associated with a decrease in concentrations of glutamate
following SRI treatment.

"We looked at the drug topiramate, which is on the market for
seizures and convulsions. And so we gave it to these (OCD) patients
in the hope that this drug would work on the glutamate system and
improve the patient's symptoms. And low and behold in our
preliminary work . . . we did find that effect in almost two-thirds
of the people," said researcher Dr. Michael Van Ameringen, an
assistant professor in the department of psychiatry and behavioural
neurosciences, and co-director of the anxiety disorders clinic at
the Hamilton Health Sciences Corp.

"Topiramate inhibits the glutamate system," Dr. Van Ameringen
said. "We think there is a group of patients with OCD who get a very
robust effect from this. It clearly does not work in all OCD
patients, but there is a group who go from having very significant
symptoms to virtually nothing on this treatment. That's why were
excited about it."

For the study, Dr. Van Ameringen and colleagues investigated the
adjunctive use of topiramate in 16 consecutive OCD outpatients
referred to their institution's anxiety disorders clinic who were
partial or nonresponders to SRI monotherapy or to SRI combination
therapy with antipsychotics, antidepressants or benzodiazepines.
These patients had topiramate added over 14 to 26 weeks, and were
seen approximately every four weeks for the first 16 weeks or until
a treatment response was achieved. The sample included five men and
11 women who had a mean of age of 41 years, a mean age of onset of
14.9 years and a mean duration of illness of 26.2 years.

Patient responses were measured using the Clinical Global Impression
Scale for Severity (CGI-S), which rates patients' severity of
symptoms from one ("normal/not at all") to seven ("among the most
extremely ill patients"), and the Clinical Global Impressive Scale
for Improvement (CGI-I), which rates patient improvement from one
("very much improved") to seven ("very much worse").

Following a mean response time of 9.2 weeks, the researchers found
11 of the 16 patients (60%) responded to adjunctive topiramate, with
a CGI-I score of two ("much") or one ("very much improved"). The 60%
response rate was considered a good response, said researchers.

CGI-S scores also improved significantly, to an endpoint score of
4.6 ("moderately ill" to "markedly ill") from a mean baseline score
of 6.1 ("severely ill").

During the course of the study, adverse events were experienced by
13 of 16 patients, but no individual withdrew from the study because
of them. The most commonly reported adverse events included weight
loss, sedation and fatigue, memory and word-finding difficulties and
paresthesia (see table).

Some of Dr. Van Ameringen's previous research has also looked at the
adjunctive use of topiramate in women with OCD who were on the drug
and then had to stop taking it when they became pregnant. Within
four weeks of discontinuation, these women were getting all their
OCD symptoms back. But after resuming the drug following the
completion of pregnancy, their symptoms were again alleviated.

Right now, Dr. Van Ameringen and colleagues are working on a placebo-
controlled study of topiramate in obsessive-compulsion disorder
patients.

Pointing to other research initiatives, Dr. Van Ameringen said there
are also some new agents being studied in SRI-refractory OCD
patients that purely work on the glutamate system.

"These drugs may have some really big applications in this area," he
said.

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