Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 970–973

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Progress in Neuro-Psychopharmacology & Biological

Psychiatry
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p

Topiramate augmentation in patients with resistant major depressive disorder:

A double-blind placebo-controlled clinical trial
Arash Mowla ⁎, Ehsan Kardeh
Department of Psychiatry, Bushehr University of Medical Sciences, Bushehr, Iran

a r t i c l e i n f o a b s t r a c t

Article history: Background: Despite evolution of new antidepressant treatment, clinicians still encounter challenges in the
Received 27 September 2010 treatment of depressed patients. Looking for new medications that can potentiate the effects of current
Received in revised form 10 January 2011 antidepressants seems to be necessary. Our objective is to survey the efficacy of topiramate augmentation in
Accepted 22 January 2011 resistant major depressive disorder (MDD).
Available online 1 February 2011
Method: This augmentation trial was designed as an 8-week randomized, placebo-controlled, double-blind
study. Fifty three patients with DSM-IV diagnosis of MDD who had failed to respond to at least 8 weeks of
Keywords:
Anticonvulsant
treatment with an adequate dose of one of the SSRIs (fluoxetine, citalopram or serteraline) were included in
Major depression the study. Patients were randomized to receive a flexible dose of topiramate (100–200 mg/day) or placebo
Topiramate beside their current antidepressant medication for a period of eight weeks. Outcome measures were Hamilton
Depression Scale (HAM-D) and Clinical Global Impression (CGI).
Results: 42 patients completed the study and there were 6 and 5 dropouts in topiramate and placebo groups,
respectively. The topiramate group demonstrated significant improvement over the study period based on
mean HAM-D score at week 8 compared to baseline (P = .000, Z = 3.699). Those receiving topiramate
demonstrated to have a mean decrease of 32.0% in HAM-D score, compared to only 5.5% for those receiving
placebo. Depressed mood, suicidality, insomnia (early, middle and late), agitation and anxiety symptoms
were significantly improved in the topiramate group.
Conclusion: Our double-blind placebo-controlled study demonstrated that topiramate augmentation
potentiate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treatment of resistant major
depressive disorder. Of note is that our study is preliminary and larger double-blind studies are needed to
confirm the results.
© 2011 Elsevier Inc. All rights reserved.

1. Introduction
Major depressive disorder (MDD) is a severe, highly prevalent
illness that has a substantial impact on public health and human
functioning worldwide (Hasin et al., 2006; Mathers and Loncar, 2006,
Ustün et al., 2004). Although options for pharmacologic treatment
have expanded significantly in the past 20 years, between one and
two thirds of patients will not respond to the first antidepressant
prescribed, and 15 to 33% will not respond to multiple interventions
(Berlim et al., 2008; Cain, 2007). Patients may experience long periods
of depressive symptoms with modest or insufficient benefit from
treatment (Souery et al., 2006; Little, 2009). In the past several years
the focus on treatment resistant depression has increased sharply.
Abbreviations: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition; MDD, major depressive disorder; SSRI, specific serotonin reuptake
inhibitor; HAM-D, Hamilton Depression Scale; CGI, Clinical Global Impression; TSH,
thyroid stimulating hormone; FT4, free thyroxin 4.
⁎ Corresponding author. Tel: + 98 9173132001; fax: + 98 7712523123.
E-mail address: mowlaar@gmail.com (A. Mowla).
Looking for newer medication to deal with this large portion of
depressive population seems necessary.
The use of mood stabilizing antiepileptic drugs has increasingly
been explored for the treatment of different psychiatric conditions.
Among them, topiramate is a novel antiepileptic drug effective against
both partial and generalized seizures (Biton et al., 2001). Topiramate
has been shown to activate beta (2) or beta (3) subunit of GABA (A)
receptors (Simeone et al., 2006; Kuzniecky et al., 1998). It also may
inhibit brain excitatory glutamate release, by antagonizing α-amino-
3-hydroxy-5-methyl-4-isoxazolapropionate (AMPA) kainate type of
glutamate receptors, and may inhibit NA (+) and L-type Ca (2+)
channel neuronal activities (Gibbs et al., 2002; Coulter et al., 1993).
The rationale for use of topiramate in major depression comes from
several lines of evidence. First, some other anticonvulsants with
mechanism of action similar to topiramate have suggested antidepres-
sive effects (Vigo and Baldessarini, 2009). In this regard, carbamazepine
has some evidence of efficacy as treatment for unipolar depression in
controlled clinical trials (Small, 1990; Rybakowski et al., 1999). Valporic
acid has demonstrated efficacy in the treatment of depressive phase of
bipolar mood disorder (Davis et al., 1996). Lamotrigine also has shown

0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2011.01.016
 A. Mowla, E. Kardeh / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 970–973
beneficial effects for depressive phase of bipolar disorder (Geddes, et al.,
2009) and unipolar major depression (Thomas et al., 2010). Second,
some previous preliminary studies have shown topiramate to be
effective in unipolar or bipolar depression (Nickel et al., 2005; Carpenter
et al., 2002; Schmidt et al., 2002; McIntyre et al., 2002; Hussain et al.,
2001). Cochrane database systemic review indicates that studies
regarding the use of topiramate in bipolar and unipolar depression are
preliminary and more controlled studies are needed to clarify the effect
of topiramate in mood disorders (Vasudev et al., 2006). Our study moves
in this direction. Third, a review of literature has shown that topiramate
has increasingly been used in the treatment of numerous psychiatric
conditions (Danilo, 2005). Fourth, topiramate's favorable pharmacoki-
netics makes it a candidate for use as an adjunctive agent in clinical
psychopharmacology (Morris, 1998). However recent studies and FDA
statement on risk of suicidal acts or violent deaths associated with
anticonvulsants need to be considered (Patorno et al., 2010).
In this current study, our objective is to survey the efficacy of
topiramate in major depressive disorder. We would also study the effects
of topiramate on signs and symptoms of major depression specifically.
2. Methods
2.1. Patients
The patients were recruited from Abolfazl Psychiatric Clinic affiliated
to Bushehr University of Medical Sciences from December 2009 to July
2010. Patients were diagnosed according to DSM-IV criteria for MDD by
a board certified psychiatrist through Structured Clinical Interview for
DSM-IV, Clinical Version (SCID-I). The patients had failed to respond to at
least 8 weeks of treatment with an adequate and stable dose of one of
the SSRIs (fluoxetine, citalopram or serteraline), as reflected by a
baseline Hamilton Depression Scale of 18 or greater. All the patients had
at least one episode of major depression before their current episode.
The concurrent medications at baseline were fluoxetine (n=21, mean
dosage=50.6 (40–60 mg/d); citalopram (n=18, mean dosage 47.9 mg/
d (40–80 mg/d) and serteraline (n=14, mean dosage=201.5 mg/d
(150–300 mg/d).
Exclusion criteria were any other axis I and II diagnosis, major
medical problems (cardiovascular, pulmonary, renal or gastrointesti-
nal diseases), pregnancy and substance or alcohol abuse. Any patient
with anxiety disorders were specifically excluded from the study.
Given the mood stabilizing effect of topiramate, patients with bipolar
mood disorder were specially explored and excluded. To exclude
bipolar mood disorder the patients and their first degree relatives
were interviewed. A thorough history also was taken to explore
bipolar mood disorder in their other family members. Positive family
history also led to exclusion.
All patients provided informed consent and the study was
approved by the ethics committee of Bushehr University that adheres
to the Declaration of Helsinki Ethical Principles for Medical Research.
2.2. Procedure
The trial was designed as a randomized, placebo-controlled,
double-blind study. Major depressed patients referred to Abolfazl
psychiatry clinic were randomly assigned to receive either topiramate
Table 1
HAM-D scores at baseline and after 8 weeks in topiramate and placebo groups.
Topiramate group
Baseline mean (SD) 8 weeks mean (SD) p value mean (SD)
HAM-D 21.57 (6.5) 14.66 (8.3) .000
CGI 2.1 (.47)
HAM-D: Hamilton Depression Scale score.
CGI: efficacy index of Clinical Global Improvement.
971
(26 patients) or placebo (27 patients). We used a standard
randomization procedure generated by a computer to obtain random
sample sets. The placebo and topiramate tablets had the same shape
and color. The placebo tablets were prepared by Bushehr University
Pharmacology Unit. The patients and the examiner were both blind
about the consuming medication since the same number of similar
pills were provided. The ratings were done by an examiner who was a
psychologist and was unaware of adverse events.
The duration of treatment was 8 weeks. Topiramate was added to
the subject's current antidepressant regimen initially at 25 mg/d and
increased in 25-mg increments weekly. No dose escalation was
administered in the case of patient's intolerance or clinical response.
The mean dosage of topiramate was 173.15 mg/day (range of 100–
200 mg/day). The patients took the pills twice a day. Subjects were
interviewed at baseline, and at the end of weeks 2, 4 and 8. Safety and
tolerability were assessed using spontaneously reported adverse
event data and rates of premature termination for side effects.
During the study psychological interventions were not allowed. All
patients completed a general medical examination and blood
chemistry tests, including TSH, FT4, liver function test, renal function
test and complete blood count before the study.
Depressive symptoms were rated with the 21-item Hamilton
Depression Rating Scale (HAM-D) (Hamilton,1967). Ratings were
performed at baseline and at the end of the study. The HAM-D is a 21-
item scale that evaluates depressed mood, guilt feeling, suicidal
ideation, and somatic, vegetative, and cognitive symptoms of
depression. We did not include HAM-D items 18 to 21 in our analyses
The efficacy index of Clinical Global Improvement (CGI-2) was
employed at the end of the study.
2.3. Statistical analysis
We compared both demographic and clinical characteristics of the
groups at baseline using X2 and Mann–Whitney U tests. Mann–
Whitney U test was used to compare the 2 groups for significant
difference of effects, and the Wilcoxon signed ranks test computed the
differences within groups. Response rates were compared between
the groups at the endpoint. The analysis was performed only on
completers. All p values were two-tailed, and statistical significance
was set at the 5% level. Statistical assessments were performed by
SPSS for Windows version 12.0.
3. Result
Of 53 patients who were randomized to treatment, 42 patients
including 20 in the topiramate group and 22 in the placebo group
completed the trial. There were 11 dropouts consisting 6 dropouts in
the topiramate and 5 in the placebo group. The dropouts in the
topiramate group were mainly due to side effects. Loss of appetite
(33.3%), gastric disturbance (33.3%), memory problem (16.6%) and
akatasia (16.6%) were reported in this group. Loss of efficacy was the
major cause of dropout in the placebo group.
Table 1 shows HAM-D changes within treatment groups, and
Table 2 depicts significant differences between the two groups.
Treatment groups were comparable at baseline regarding sex, age,
Placebo group Comparison
of the groups
Baseline mean (SD) 8 weeks mean (SD) p value
21.9 (5.0) 20.73 (8.0) .181 .000
3.8 (.45) .000
972 A. Mowla, E. Kardeh / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 970–973
Table 2
Significant differences between topiramate and placebo groups on measures of
depression.
Statistic
P Z
HAM-D total score .000
Depressed mood .000
Suicidal ideation .000
Work and activity .000
Insomnia early .000
Insomnia middle .000
Insomnia late .000
Agitation .000
Psychological anxiety .000
Somatic anxiety .000
Loss of weight .000
HAM-D: Hamilton Depression Scale.
and depression severity. Mean age was 36.2 years and 56.8% were
women.
The HAM-D total score for the topiramate group was significantly
reduced at the end of the trial period (P = .00, Z = 3.699); however,
the placebo group did not show to have any significant improvement
(P = .1; Z = 1.312) [Table 1]. Twelve patients (60%) in the topiramate
group versus none in the placebo group were rated responders.
Those receiving topiramate demonstrated a mean decrease of
32.0% in HAM-D score, compared to only 5.5% for those receiving
placebo. Depressed mood, suicidality, insomnia (early, middle and
late), agitation and anxiety were specifically improved in the
topiramate group [Table 2].
The topiramate group also showed to have significant improve-
ment in the efficacy index of Clinical Global Improvement (P = .00,
Z = 3.337).
4. Discussion
Our randomized placebo-controlled double-blind study was
designed to survey the efficacy of topiramate augmentation in
treatment resistant major depression. We found that topiramate
may potentiate the SSRIs' effects in treatment of resistant depression.
In a thorough review of literature, only three studies were found
about the role of topiramate in treatment of major depression. One of
them was a randomized, double-blind study of 64 patients with MDD,
in which depression score (17-item HDRS) reduced by 17% (23.1 to
19.2) in the topiramate group compared to only 4% (22.9 to 22.0) in
the placebo group (p = .02) (Nickel et al., 2005).The second was a
chart review of 16 obese, depressed patients given topiramate (277 ±
101 mg/day) for 4–18 weeks in addition to their current antidepres-
sants. The results showed that CGI ratings of depressive symptoms
improved moderately (15%), with appreciable weight loss
(mean = 5.9 kg) (Carpenter et al., 2002). And finally, moderate
improvement in depressive symptoms after adding topiramate to
venlafaxine was observed in a case report (Schmidt et al., 2002). The
current study also demonstrated effectiveness for topiramate
augmentation.
Topiramate has demonstrated efficacy in treatment of bipolar
depression too. MacIntyre et al. (2002) in a single blind study
demonstrated that adjunctive topiramate (mean dose 176 mg/day)
reduced depression severity in acute bipolar depression. Furthermore,
topiramate (mean dose 275 mg/day) as adjunctive in patients with
bipolar disorder type I (N = 65) and II (N = 18) in a moderately severe
depressive phase, refractory to mood stabilizers has demonstrated
efficacy (Hussain et al., 2001).
Our study demonstrated that topiramate is specifically effective for
some signs and symptoms of major depression. For example,
insomnia (early, middle and late), agitation and anxiety (psycholog-
ical and somatic) were more improved in the topiramate group.
Topiramate enhancing the inhibitory GABAergic transmission and
reducing the excitatory glutamergic transmission may justify its
sedative, anti agitation and anti anxiety effects (Kuzniecky et al.,
1998; Gibbs et al., 2002; Coulter et al., 1993).
Topiramate often yields weight loss by unknown mechanisms
(Gordon and Price, 1999). In this line, our study revealed that weight
4.429
5.823 loss was more dominant in the topiramate group. Although weight
5.568 loss is not a positive point in treatment of depression, but it can be
5.453 desirable for the obese depressed patients.
5.723 Our study is a small trial; larger double-blind clinical trials are
5.670
5.681
needed to confirm the effectiveness of topiramate in major depres-
5.702 sion. Another shortage is that we used topiramate for a duration of
5.702 eight weeks; longer periods and higher doses may yield to other
5.689 results. The focus of this study was on the core symptoms of major
5.681
depression that are assessed with HAM-D. It is possible that other
domains, not assessed on this scale, might show different effects. And
finally lack of rating during follow ups is another pitfall of this
research.
In conclusion, our study indicates that topiramate augmentation
would potentiate the antidepressive effects of SSRIs. However, it
needs to be mentioned that our study is preliminary and larger
double-blind clinical trials are needed to confirm the results.
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