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

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Progress in Neuro-Psychopharmacology & Biological

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

0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
A. Mowla, E. Kardeh / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 970–973 971

beneficial effects for depressive phase of bipolar disorder (Geddes, et al., (26 patients) or placebo (27 patients). We used a standard
2009) and unipolar major depression (Thomas et al., 2010). Second, randomization procedure generated by a computer to obtain random
some previous preliminary studies have shown topiramate to be sample sets. The placebo and topiramate tablets had the same shape
effective in unipolar or bipolar depression (Nickel et al., 2005; Carpenter and color. The placebo tablets were prepared by Bushehr University
et al., 2002; Schmidt et al., 2002; McIntyre et al., 2002; Hussain et al., Pharmacology Unit. The patients and the examiner were both blind
2001). Cochrane database systemic review indicates that studies about the consuming medication since the same number of similar
regarding the use of topiramate in bipolar and unipolar depression are pills were provided. The ratings were done by an examiner who was a
preliminary and more controlled studies are needed to clarify the effect psychologist and was unaware of adverse events.
of topiramate in mood disorders (Vasudev et al., 2006). Our study moves The duration of treatment was 8 weeks. Topiramate was added to
in this direction. Third, a review of literature has shown that topiramate the subject's current antidepressant regimen initially at 25 mg/d and
has increasingly been used in the treatment of numerous psychiatric increased in 25-mg increments weekly. No dose escalation was
conditions (Danilo, 2005). Fourth, topiramate's favorable pharmacoki- administered in the case of patient's intolerance or clinical response.
netics makes it a candidate for use as an adjunctive agent in clinical The mean dosage of topiramate was 173.15 mg/day (range of 100–
psychopharmacology (Morris, 1998). However recent studies and FDA 200 mg/day). The patients took the pills twice a day. Subjects were
statement on risk of suicidal acts or violent deaths associated with interviewed at baseline, and at the end of weeks 2, 4 and 8. Safety and
anticonvulsants need to be considered (Patorno et al., 2010). tolerability were assessed using spontaneously reported adverse
In this current study, our objective is to survey the efficacy of event data and rates of premature termination for side effects.
topiramate in major depressive disorder. We would also study the effects During the study psychological interventions were not allowed. All
of topiramate on signs and symptoms of major depression specifically. patients completed a general medical examination and blood
chemistry tests, including TSH, FT4, liver function test, renal function
2. Methods test and complete blood count before the study.
Depressive symptoms were rated with the 21-item Hamilton
2.1. Patients 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-
The patients were recruited from Abolfazl Psychiatric Clinic affiliated item scale that evaluates depressed mood, guilt feeling, suicidal
to Bushehr University of Medical Sciences from December 2009 to July ideation, and somatic, vegetative, and cognitive symptoms of
2010. Patients were diagnosed according to DSM-IV criteria for MDD by depression. We did not include HAM-D items 18 to 21 in our analyses
a board certified psychiatrist through Structured Clinical Interview for The efficacy index of Clinical Global Improvement (CGI-2) was
DSM-IV, Clinical Version (SCID-I). The patients had failed to respond to at employed at the end of the study.
least 8 weeks of treatment with an adequate and stable dose of one of
the SSRIs (fluoxetine, citalopram or serteraline), as reflected by a
2.3. Statistical analysis
baseline Hamilton Depression Scale of 18 or greater. All the patients had
at least one episode of major depression before their current episode.
We compared both demographic and clinical characteristics of the
The concurrent medications at baseline were fluoxetine (n=21, mean
groups at baseline using X2 and Mann–Whitney U tests. Mann–
dosage=50.6 (40–60 mg/d); citalopram (n=18, mean dosage 47.9 mg/
Whitney U test was used to compare the 2 groups for significant
d (40–80 mg/d) and serteraline (n=14, mean dosage=201.5 mg/d
difference of effects, and the Wilcoxon signed ranks test computed the
(150–300 mg/d).
differences within groups. Response rates were compared between
Exclusion criteria were any other axis I and II diagnosis, major
the groups at the endpoint. The analysis was performed only on
medical problems (cardiovascular, pulmonary, renal or gastrointesti-
completers. All p values were two-tailed, and statistical significance
nal diseases), pregnancy and substance or alcohol abuse. Any patient
was set at the 5% level. Statistical assessments were performed by
with anxiety disorders were specifically excluded from the study.
SPSS for Windows version 12.0.
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 3. Result
were interviewed. A thorough history also was taken to explore
bipolar mood disorder in their other family members. Positive family Of 53 patients who were randomized to treatment, 42 patients
history also led to exclusion. including 20 in the topiramate group and 22 in the placebo group
All patients provided informed consent and the study was completed the trial. There were 11 dropouts consisting 6 dropouts in
approved by the ethics committee of Bushehr University that adheres the topiramate and 5 in the placebo group. The dropouts in the
to the Declaration of Helsinki Ethical Principles for Medical Research. topiramate group were mainly due to side effects. Loss of appetite
(33.3%), gastric disturbance (33.3%), memory problem (16.6%) and
2.2. Procedure akatasia (16.6%) were reported in this group. Loss of efficacy was the
major cause of dropout in the placebo group.
The trial was designed as a randomized, placebo-controlled, Table 1 shows HAM-D changes within treatment groups, and
double-blind study. Major depressed patients referred to Abolfazl Table 2 depicts significant differences between the two groups.
psychiatry clinic were randomly assigned to receive either topiramate Treatment groups were comparable at baseline regarding sex, age,

Table 1
HAM-D scores at baseline and after 8 weeks in topiramate and placebo groups.

Topiramate group Placebo group Comparison

of the groups
Baseline mean (SD) 8 weeks mean (SD) p value mean (SD) Baseline mean (SD) 8 weeks mean (SD) p value

HAM-D 21.57 (6.5) 14.66 (8.3) .000 21.9 (5.0) 20.73 (8.0) .181 .000
CGI 2.1 (.47) 3.8 (.45) .000

HAM-D: Hamilton Depression Scale score.

CGI: efficacy index of Clinical Global Improvement.
972 A. Mowla, E. Kardeh / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 970–973

Table 2 Topiramate enhancing the inhibitory GABAergic transmission and

Significant differences between topiramate and placebo groups on measures of reducing the excitatory glutamergic transmission may justify its
sedative, anti agitation and anti anxiety effects (Kuzniecky et al.,
Statistic 1998; Gibbs et al., 2002; Coulter et al., 1993).
P Z Topiramate often yields weight loss by unknown mechanisms
(Gordon and Price, 1999). In this line, our study revealed that weight
HAM-D total score .000 4.429
Depressed mood .000 5.823 loss was more dominant in the topiramate group. Although weight
Suicidal ideation .000 5.568 loss is not a positive point in treatment of depression, but it can be
Work and activity .000 5.453 desirable for the obese depressed patients.
Insomnia early .000 5.723 Our study is a small trial; larger double-blind clinical trials are
Insomnia middle .000 5.670
Insomnia late .000 5.681
needed to confirm the effectiveness of topiramate in major depres-
Agitation .000 5.702 sion. Another shortage is that we used topiramate for a duration of
Psychological anxiety .000 5.702 eight weeks; longer periods and higher doses may yield to other
Somatic anxiety .000 5.689 results. The focus of this study was on the core symptoms of major
Loss of weight .000 5.681
depression that are assessed with HAM-D. It is possible that other
HAM-D: Hamilton Depression Scale. domains, not assessed on this scale, might show different effects. And
finally lack of rating during follow ups is another pitfall of this
and depression severity. Mean age was 36.2 years and 56.8% were research.
women. In conclusion, our study indicates that topiramate augmentation
The HAM-D total score for the topiramate group was significantly would potentiate the antidepressive effects of SSRIs. However, it
reduced at the end of the trial period (P = .00, Z = 3.699); however, needs to be mentioned that our study is preliminary and larger
the placebo group did not show to have any significant improvement double-blind clinical trials are needed to confirm the results.
(P = .1; Z = 1.312) [Table 1]. Twelve patients (60%) in the topiramate
group versus none in the placebo group were rated responders. References
Those receiving topiramate demonstrated a mean decrease of
Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic
32.0% in HAM-D score, compared to only 5.5% for those receiving
treatment of resistant/refractory major depression: an overview. Ann Med
placebo. Depressed mood, suicidality, insomnia (early, middle and 2008;40:149–59.
late), agitation and anxiety were specifically improved in the Biton V, Edwards KR, Montouris GD, Sackellares JC, Harden CL, Kamin M. Topiramate
titration and tolerability. Ann Pharmacother 2001;35:173–9.
topiramate group [Table 2].
Cain RA. Navigating the sequenced treatment alternatives to relieve depression
The topiramate group also showed to have significant improve- (STAR*D) study: practical outcomes and implications for depression treatment in
ment in the efficacy index of Clinical Global Improvement (P = .00, primary care. Prim Care 2007;34:505–19.
Z = 3.337). Carpenter LL, Leon Z, Yasmin S, Price LH. Do obese depressed patients respond to
topiramate? A retrospective chart review. J Affect Disord 2002;69:251–5.
Coulter DA, Sombati S, DeLorenzo RJ. Selective effects of topiramate on sustained and
4. Discussion repetitive firing and spontaneous bursting in cultured hippocampus neurons.
Epilepsia 1993;34:123.
Danilo A. Review of the use of topiramate for treatment of psychiatric disorders. Ann
Our randomized placebo-controlled double-blind study was Gen Psychiatry 2005;4:5.
designed to survey the efficacy of topiramate augmentation in Davis LL, Kabel D, Patel D, Choate AD, Foslien-Nash C, Gurguis GN, et al. Valproate as an
treatment resistant major depression. We found that topiramate antidepressant in major depressive disorder. Psychopharmacol Bull 1996;32:
may potentiate the SSRIs' effects in treatment of resistant depression. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression:
In a thorough review of literature, only three studies were found independent meta-analysis and meta-regression of individual patient data from
about the role of topiramate in treatment of major depression. One of five randomised trials. Br J Psychiatry 2009;194:4–9.
Gibbs JW, Sombati S, DeLorenzo RJ, Coulter DA. Cellular actions of topiramate: blockade
them was a randomized, double-blind study of 64 patients with MDD, of kainite-evoked inward currents in cultured hippocampus neurons. Epilepsia
in which depression score (17-item HDRS) reduced by 17% (23.1 to 2002;41:S10–6.
19.2) in the topiramate group compared to only 4% (22.9 to 22.0) in Gordon A, Price LH. Mood stabilization and weight-loss with topiramate. Am J
Psychiatry 1999;156:968–9.
the placebo group (p = .02) (Nickel et al., 2005).The second was a
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin
chart review of 16 obese, depressed patients given topiramate (277 ± Psychol 1967;6:278–96.
101 mg/day) for 4–18 weeks in addition to their current antidepres- Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive
sants. The results showed that CGI ratings of depressive symptoms disorder: results from the National Epidemiologic Survey on Alcoholism and
Related Conditions. Arch Gen Psychiatry 2006;62:1097–106.
improved moderately (15%), with appreciable weight loss Hussain MZ, Chaudhry ZA, Hussain S. Topiramate in treatment of refractory bipolar
(mean = 5.9 kg) (Carpenter et al., 2002). And finally, moderate depression. Bipolar Disord 2001;3:43.
improvement in depressive symptoms after adding topiramate to Kuzniecky R, Hetherington H, Ho S, Pan J, Martin R, Gilliam F, et al. Topiramate increases
cerebral GABA in healthy humans. Neurology 1998;51:627–9.
venlafaxine was observed in a case report (Schmidt et al., 2002). The Little A. Treatment-resistant depression. Am Fam Physician 2009;80:167–72.
current study also demonstrated effectiveness for topiramate Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002
augmentation. to 2030. PLoS Med 2006;3:442.
McIntyre RS, Mancini DA, McCann S, Srinivasan J, Sagman D, Kennedy SH. Topiramate
Topiramate has demonstrated efficacy in treatment of bipolar versus bupropion SR when added to mood stabilizer therapy for the depressive
depression too. MacIntyre et al. (2002) in a single blind study phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord 2002;4:
demonstrated that adjunctive topiramate (mean dose 176 mg/day) 207–13.
Morris HH. Pharmacokinetics of new anticonvulsants in psychiatry. Cleve Clin J Med
reduced depression severity in acute bipolar depression. Furthermore, 1998;65 Suppl 1:SI15-20; discussion SI45-7. Review.
topiramate (mean dose 275 mg/day) as adjunctive in patients with Nickel C, Lahmann C, Tritt K, Muehlbacher M, Kaplan P, Kettler C, et al. Topiramate in
bipolar disorder type I (N = 65) and II (N = 18) in a moderately severe treatment of depressive and anger symptoms in female depressive patients: a
randomized, double-blind, placebo-controlled study. J Affect Disord 2005;87:
depressive phase, refractory to mood stabilizers has demonstrated
efficacy (Hussain et al., 2001). Patorno E, Bohn RL, Wahl PM, Avorn J, Patrick AR, Liu J, et al. Anticonvulsant
Our study demonstrated that topiramate is specifically effective for medications and the risk of suicide, attempted suicide, or violent death. JAMA
some signs and symptoms of major depression. For example, 2010;303:1401–9.
Rybakowski JK, Suwalska A, Chlopocka-Wozniak M. Potentiation of antidepressants
insomnia (early, middle and late), agitation and anxiety (psycholog- with lithium or carbamazepine in treatment-resistant depression. Neuropsycho-
ical and somatic) were more improved in the topiramate group. biology 1999;40:134–9.
A. Mowla, E. Kardeh / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 970–973 973

Schmidt D, Prado-Lima PA, Bacaltchuck J. Topiramate in treatment-resistant depression Thomas SP, Nandhra HS, Jayaraman A. Systematic review of lamotrigine augmentation
and binge-eating disorder. Bipolar Disord 2002;4:271–3. of treatment resistant unipolar depression. J Ment Health 2010;19:168–75.
Simeone TA, Wilcox KS, White HS. Subunit selectivity of topiramate modulation of Ustün TB, Ayuso-Mateos JL, Chatterji S, Mathers C, Murray CJ. Global burden of
heteromeric GABA(A) receptors. Neuropharmacology 2006;50:845–57. depressive disorders in the year 2000. Br J Psychiatry 2004;184:386–92.
Small JG. Anticonvulsants in affective disorders. Psychopharmacol Bull 1990;26: Vasudev K, Macritchie K, Geddes J, Watson S, Young A. Topiramate for acute affective
25–36. episodes in bipolar disorder. Cochrane Database Syst Rev 2006;25:CD003384.
Souery D, Papakostas G, Trivedi M. Treatment resistant depression. J Clin Psychiatry Vigo DV, Baldessarini RJ. Anticonvulsants in the treatment of major depressive
2006;67:16–22. disorder: an overview. Harv Rev Psychiatry 2009;17:231–41.