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Susan L. McElroy, Paul E. Keck: Chapter 40. Topiramate, in The American Psychiatric Publishing Textbook of

Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American

Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.414542. Printed 5/10/2009 from

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Textbook of Psychopharmacology >

Chapter 40. Topiramate

HISTORY AND DISCOVERY

Topiramate is a derivative of the naturally occurring monosaccharide D-fructose. It was originally

synthesized to be a structural analog of fructose-1,6-diphosphatase as part of a project to develop

agents that inhibit gluconeogenesis by inhibiting the enzyme fructose-1,6-biphosphatase (Shank et

1. 2000). To date, however, it has not been shown by clinical evidence to have direct hypoglycemic

activity. Topiramate contains a sulfamate moiety. The structural resemblance of this moiety to the

sulfonamide moiety in the established antiepileptic drug acetazolamide prompted researchers to

evaluate topiramate for possible anticonvulsant effects. Topiramate subsequently was shown to

have potent anticonvulsant properties in a broad range of preclinical epilepsy models (Shank et al.

2000).

The drug’s efficacy in patients with epilepsy was established in the early 1990s. These studies also

showed that topiramate had a favorable pharmacokinetic profile, had a high therapeutic index, was

not associated with hematological or hepatic abnormalities, did not require routine serum

concentration monitoring, and was associated with anorexia and weight loss (rather than appetite

stimulation and weight gain like some other antiepileptic drugs) (Langtry et al. 1997). Topiramate

was approved by the U.S. Food and Drug Administration (FDA) for the treatment of epilepsy in

1996. It was approved for migraine prevention in adults in 2004.

Reports appearing in the late 1990s of the drug having potential beneficial effects in bipolar

disorder led Johnson and Johnson Pharmaceutical Research and Development (PRD), the discoverer

and manufacturer of topiramate, to conduct a large clinical study program of topiramate in the

treatment of acute bipolar mania (McElroy and Keck 2004). Controlled trials of the drug in bipolar

adults with manic symptoms failed to demonstrate significant separation between the topiramate

and placebo groups (Chengappa et al. 2006; Kushner et al. 2006). However, topiramate has been

shown to be efficacious in placebo-controlled trials in several neuropsychiatric conditions often

comorbid with bipolar disorder, including, in addition to migraine, binge-eating disorder (BED),

bulimia nervosa, alcohol dependence, borderline personality disorder (BPD),

psychotropic-associated weight gain, and obesity.

STRUCTURE–ACTIVITY RELATIONS

Topiramate is a sulfamate-substituted monosaccharide derived from D-fructose (Figure 40–1). As

such, it is structurally distinct from other antiepileptic medications. Its sulfamate moiety is

essential for its pharmacological activity (Shank et al. 2000). It has been postulated that

topiramate’s multiple pharmacological properties (which are discussed in the following section) are

regulated by protein phosphorylation. Specifically, it has been hypothesized that topiramate

interacts with voltage-activated sodium channels, -aminobutyric acid (GABA) type A (GABAA)

receptors, -amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)/kainate glutamate

receptors, and high-voltage-activated calcium channels via formation of hydrogen bonds between

proton-accepting oxygens in its sulfamate moiety and proton donor groups in tetrapeptide

sequences in the latter (Shank et al. 2000).

FIGURE 40–1. Chemical structure of topiramate.Print: Chapter 40. Topiramate

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PHARMACOLOGICAL PROFILE

Topiramate has multiple pharmacological properties that may contribute to its anticonvulsant

effects, as well as its therapeutic effects in other neuropsychiatric disorders (Langtry et al. 1997;

Rho and Sankar 1999; Rosenfeld 1997; Shank et al. 2000; White 2002, 2005; White et al. 2007).

First, topiramate inhibits voltage-gated sodium channels in a voltage-sensitive, use-dependent

manner and thus suppresses action potentials associated with sustained repetitive cell firing

(Kawasaki et al. 1998; Shank et al. 2000).

Second, topiramate increases brain GABA levels, possibly by activating a site on the GABAA

receptor, thereby enhancing the inhibitory chloride ion influx mediated by the GABAA receptor and

potentiating GABA-evoked currents (Kuzniecky et al. 1998; Petroff et al. 2001; Simeone et al.

2006). Because this action is not blocked by the benzodiazepine antagonist flumazenil, it is thought

that topiramate exerts this effect via an interaction with the GABAA receptor that is not modulated

by benzodiazepines (White et al. 2000). This action may also be sensitive to GABA concentrations

and GABAA receptor subunit composition (Simeone et al. 2006).

Third, topiramate antagonizes glutamate receptors of the AMPA/kainate subtype and may

selectively inhibit glutamate receptor 5 (GluR5) kainate receptors (Kaminski et al. 2004). It has

essentially no effect on glutamate N-methyl-D-aspartate (NMDA) receptors. AMPA/kainate

receptors mediate fast excitatory postsynaptic potentials responsible for excitatory

neurotransmission; blockade of kainate-evoked currents decreases neuronal excitability.

Fourth, topiramate negatively modulates high-voltage-activated calcium channels (Zhang et al.

2000). Of note, Shank et al. (2000) proposed that topiramate’s combined effects on

voltage-activated sodium channels, GABAA receptors, AMPA/kainate receptors, and

high-voltage-activated calcium channels are unique as compared with those of other antiepileptic

drugs. Indeed, Schiffer et al. (2001) found that pretreatment with topiramate inhibited

nicotine-induced increases in mesolimbic extracellular dopamine and norepinephrine but not

serotonin. They hypothesized that this property was a result of the drug’s ability to affect both

GABAergic and glutamatergic function.

Fifth, topiramate has weak inhibitory actions against some carbonic anhydrase isoenzymes,

including subtypes II and VI. Carbonic anhydrase is essential for the generation of GABAA-mediated

depolarizing responses. By inhibiting carbonic anhydrase, topiramate has been shown to reversibly

reduce the GABAA-mediated depolarizing responses evoked by either synaptic stimulation or

pressure application of GABA (but not to modify GABAA-mediated hyperpolarizing postsynaptic

potentials) (Herrero et al. 2002). As a result of the effects of carbonic anhydrase inhibition on

intracellular pH, topiramate also may activate a potassium conductance (Herrero et al. 2002).

Finally, topiramate has been shown to have a number of other properties. These include an

interaction with glycine receptor channels (Mohammadi et al. 2005), effects on mitochondrial

permeability (Kudin et al. 2004), and antikindling properties in some animal models (Wauguier and

Zhou 1996).

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Topiramate has a favorable pharmacokinetic profile (Bialer et al. 2004; Doose and Streeter 2002;

Langtry et al. 1997; Rosenfeld 1997; Shank et al. 2000). It is rapidly and almost completely

absorbed after oral administration, with bioavailability estimated to be about 80%. Peak plasma

concentrations are reached within 2–4 hours. Plasma concentration increases in proportion to dose

over the pharmacologically relevant dose range.

The volume of distribution of topiramate is inversely proportional to the dose, with the drug

distributed primarily to body water. It is minimally protein-bound (9%–17%).

Topiramate is minimally metabolized by the liver in the absence of hepatic enzyme–inducing drugs.

It inhibits cytochrome P450 (CYP) enzyme 2C19 but not other hepatic CYP enzymes. Topiramate is

excreted mostly unchanged (approximately 70%) in the urine. The nonrenal (hepatic) clearance of

topiramate increases two- to threefold when the drug is administered with hepatic

enzyme–inducing drugs such as carbamazepine and phenytoin. Six minor metabolites have been

identified (Shank et al. 2000).

Topiramate’s elimination half-life is 19–25 hours, with linear pharmacokinetics in the dose range of

100–1,200 mg. The pharmacokinetics of topiramate in children are similar to those in adults, except

that clearance is 50% higher, resulting in 33% lower plasma concentrations. Moderate or severe

renal failure is associated with reduced renal clearance and increased elimination half-life of

topiramate. Moderate or severe liver impairment is associated with clinically insignificant increased

plasma concentrations of the drug.

MECHANISM OF ACTION

Although the mechanism of topiramate’s anticonvulsant action is unknown, it has been

hypothesized to be due to some combination of the drug’s multiple pharmacological properties (Rho

and Sankar 1999; Shank et al. 2000; White 2002, 2005; White et al. 2007).

As discussed, these include state-dependent blockade of voltage-activated sodium channels,

enhancement of GABA activity at the GABAA receptor via interaction with a nonbenzodiazepine

receptor site, antagonism of the AMPA/kainate glutamate receptor, antagonism of

high-voltage-activated calcium channels, and inhibition of carbonic anhydrase. For example, the

drug’s anticonvulsant profile, as well as its benefits in substance use and eating disorders, has been

hypothesized to be due to its dual actions on the GABAergic and glutamatergic systems (Johnson et

1. 2003, 2005; McElroy et al. 2003, 2007b; Rho and Sankar 1999; Schiffer et al. 2001). By contrast,

carbonic anhydrase inhibition is thought by some not to play a large role in topiramate’s

anticonvulsant properties despite acetazolamide’s clinical efficacy as an antiepileptic because of

topiramate’s much weaker potency as an inhibitor (Rho and Sankar 1999). Others, however, have

suggested that topiramate’s inhibition of carbonic anhydrase contributes to its anticonvulsant

properties via reduction of GABAA-mediated depolarizing responses and/or activation of a

potassium conductance (Herrero et al. 2002).

INDICATIONS AND EFFICACY

FDA-Approved Indications

Topiramate is currently indicated by the FDA as initial monotherapy in patients 10 years of age and

older with partial-onset or primary generalized tonic-clonic seizures; as adjunctive therapy for

adults and pediatric patients ages 2–16 years with partial-onset seizures or primary generalized

tonic-clonic seizures; and in patients 2 years of age and older with seizures associated with

Lennox-Gastaut syndrome (van Passel et al. 2006). It is also indicated for the prophylaxis of

migraine headache in adults (Brandes 2005; Bussone et al. 2006).

Other Indications

Topiramate is not currently approved by the FDA for use in the treatment of any psychiatric

disorder. Because the drug was widely used off-label in the treatment of bipolar disorder after it

came to market (see subsection “Bipolar Disorder” below), Johnson and Johnson PRD, the

discoverer of topiramate, conducted a large study program of topiramate in adults with acutePrint: Chapter 40. Topiramate

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bipolar mania. These placebo-controlled studies failed to demonstrate a significant benefit of

topiramate over placebo on the Young Mania Rating Scale (YMRS) (Chengappa et al. 2001a;

Kushner et al. 2006; McElroy and Keck 2004). In contrast, a placebo-controlled trial in pediatric

mania, which was prematurely discontinued in the aftermath of the failed adult trials, did show

significant efficacy results favoring topiramate based on a retrospective analysis of 56 patients

(DelBello et al. 2005).

Topiramate has been studied in the treatment of a variety of other neuropsychiatric disorders,

many of which co-occur with bipolar disorder. Data from placebo-controlled clinical trials suggest

that topiramate is efficacious in BED with obesity (McElroy et al. 2003, 2007b), bulimia nervosa

(Hedges et al. 2003; Hoopes et al. 2003; C. Nickel et al. 2005b), alcohol dependence (Johnson et al.

2003, 2007), psychotropic-induced weight gain (Ko et al. 2005; M. K. Nickel et al. 2005b), obesity

(McElroy et al. 2008), and neuropathic pain (Raskin et al. 2004). These and other studies will be

reviewed below.

Bipolar Disorder

Five randomized, placebo-controlled studies have shown that topiramate monotherapy is not

efficacious in the short-term treatment of acute manic or mixed episodes in adults with bipolar I

disorder (Kushner et al. 2006; McElroy and Keck 2004). All five studies used week 3 as the primary

endpoint; in addition, three studies had a week 12 secondary endpoint, two studies had lithium

comparator groups, and all trials measured weight as a secondary outcome. Analyses of the 3-week

data from all five trials were consistent. In each trial, the primary efficacy outcome—the change

from baseline to week 3 in the YMRS score—failed to show a statistically significant separation

between topiramate and placebo. There was also no drug–placebo separation in the three trials

with week 12 data. By contrast, in the two trials in which lithium was used, lithium did show

statistical superiority to placebo. Topiramate, however, showed significant separation from placebo

in weight loss, whereas lithium was associated with statistically significant weight gain.

Similarly, in the only placebo-controlled study of adjunctive topiramate in bipolar disorder, 287

outpatients experiencing a manic or mixed episode (by DSM-IV [American Psychiatric Association

1994] criteria) and a YMRS score 18 while taking therapeutic levels of valproate or lithium showed

similar reductions (40%) in baseline YMRS scores for both topiramate and placebo after 12 weeks

(Chengappa et al. 2006). Topiramate, however, was again associated with significant weight loss as

compared to placebo.

Despite the negative results of the adult acute mania trials, numerous clinical reports suggest that

topiramate may have a role in the management of bipolar disorder. In the only placebo-controlled

study of topiramate in pediatric bipolar I disorder, 56 children and adolescents (6–17 years) with

manic or mixed episodes were randomly assigned to topiramate (n = 29) or placebo (n = 27) for 4

weeks (DelBello et al. 2005). Initially designed to enroll approximately 230 subjects, the study was

prematurely discontinued when the adult mania trials were negative. Decrease in mean YMRS score

from baseline to final visit using last observation carried forward (LOCF) was not statistically

different between treatment groups (–9.7 ± 9.65 for topiramate vs. –4.7 ± 9.79 for placebo, P =

0.152). However, a post hoc repeated-measures linear regression model of the primary efficacy

analysis showed a statistically significant difference in the slopes of the linear mean profiles (P =

0.003).

No placebo-controlled study of topiramate has yet been done in acute bipolar depression. Results

from an 8 week single-blind comparison trial in which 36 outpatient adults with bipolar depression

were randomly assigned to receive either topiramate (mean dosage = 176 mg/day; range =

50–300 mg/day) or bupropion SR (sustained release) (mean dosage = 250 mg/day; range =

100–400 mg/day) suggested that the drug might have antidepressant properties in some bipolar

patients (McIntyre et al. 2002). The percentage of patients meeting a priori response criteria (50%

or greater decrease from baseline in mean total score on the 17-item Hamilton Rating Scale for

Depression [Ham-D]) was significant for both topiramate (56%) and bupropion SR (59%). There

were no cases of manic switching with either drug. Moreover, numerous open-label reports havePrint: Chapter 40. Topiramate

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described patients with milder forms of bipolarity (i.e., “soft” bipolar spectrum disorders), including

those with mixed states or rapid cycling, that respond to topiramate (McElroy and Keck 2004;

McElroy et al. 2000; McIntyre et al. 2005).

Finally, a number of open-label reports have described the successful topiramate treatment of

bipolar disorder with various comorbid psychiatric or general medical disorders (“complicated”

bipolar disorder). Comorbid psychiatric conditions in which improvement was seen included alcohol

abuse; anxiety disorders such as obsessive-compulsive disorder (OCD) and posttraumatic stress

disorder (PTSD); eating disorders such as bulimia nervosa, BED, and anorexia nervosa;

impulse-control disorders; and catatonia (Barzman and DelBello 2006; Guille and Sachs 2002;

Huguelet and Morand-Collomb 2005; McDaniel et al. 2006; McElroy et al. 2008; Shapira et al. 2000).

Comorbid general medical conditions in which improvement was seen included obesity,

psychotropic-induced weight gain, type 2 diabetes mellitus, tremor, and Tourette’s disorder

(Chengappa et al. 2001b; Guille and Sachs 2002; McIntyre et al. 2005; Vieta et al. 2002).

These observations call for controlled studies of topiramate in pediatric bipolar disorder, acute

bipolar depression, bipolar II disorder and other “softer” forms of bipolar disorder, and complicated

bipolar disorder. No controlled maintenance or prophylactic treatment studies of topiramate in

bipolar disorder have yet been completed.

Depressive Disorders

In the only controlled study of topiramate in a depressive disorder, 64 females with DSM-IV

recurrent major depressive disorder were randomly assigned to topiramate (n = 32) or placebo (n

= 32) for 10 weeks (C. Nickel et al. 2005a). Topiramate was superior to placebo in reducing

depressive and anger symptoms (as assessed by the Ham-D [P = 0.02] and the State-Trait Anger

Expression Inventory [STAXI; P <0.001 on all scales]), respectively, and on most scales of the

SF-36 Health Survey (all Ps between 0.15 and 0.001). The reduction in expression of anger

correlated significantly with changes on the Ham-D. Five subjects (2 topiramate, 3 placebo) were

lost to follow-up. Weight loss was greater in the topiramate group by 4.2 kg (P <0.001). All

subjects tolerated topiramate well, and there were no suicidal events.

Psychotic Disorders

Two randomized, placebo-controlled studies of topiramate targeting psychopathology in psychotic

disorders have been conducted. In the first, 26 patients with treatment-resistant schizophrenia had

topiramate (gradually increased to 300 mg/day) or placebo added to their ongoing treatment

(clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods

(Tiihonen et al. 2005). In the intent-to-treat analysis, topiramate was superior to placebo in

reducing general psychopathological symptoms as assessed by the Positive and Negative Syndrome

Scale (PANSS), but no significant improvement was observed in positive or negative symptoms.

In the second study, 48 patients with schizoaffective disorder, bipolar type, were randomly

assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate

(100–400 mg/day) or placebo (Chengappa et al. 2007). Patients who had achieved 20% decrease

from baseline in their PANSS total scores were given the opportunity to continue for an additional 8

weeks of double-blind treatment. Study medication dosage was continued unchanged from the

earlier 8-week study period. Adjunctive topiramate (nearly 275 mg/day) did not show increased

efficacy relative to placebo on the PANSS (the primary outcome measure) or on any of the

secondary outcome measures. Topiramate-treated patients lost significantly more body weight than

did placebo-treated patients, but they also experienced higher rates of paresthesias, sedation,

word-finding difficulty, sleepiness, and forgetfulness.

Case reports regarding topiramate’s effectiveness as an adjunct treatment in schizophrenia have

been inconsistent, with improvement, no change, and deterioration in clinical state all being

described (Citrome 2008). However, there are several case reports of the successful use of

topiramate to treat catatonia in patients with chronic psychotic disorders (McDaniel et al. 2006).Print: Chapter 40. Topiramate

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Eating Disorders

Five randomized, placebo-controlled studies have shown that topiramate reduces binge eating and

excessive body weight in 640 subjects with bulimia nervosa (n = 2 studies, 99 subjects) or BED (n

= 3 studies, 541 subjects). In the first study in bulimia nervosa, a 10-week trial in 69 subjects,

topiramate (median dosage = 100 mg/day; range = 25–400 mg/day) was superior to placebo in

reducing the frequency of binge and purge days (days during which at least one binge-eating or

purging episode occurred; P = 0.004); decreasing scores on the bulimia/uncontrollable overeating

(P = 0.005), body dissatisfaction (P = 0.007), and drive for thinness (P = 0.002) subscales of the

Eating Disorder Inventory; decreasing scores on the bulimia/food preoccupation (P = 0.019) and

dieting (P = 0.031) subscales of the Eating Attitudes Test; and reducing body weight (mean

decrease of 1.8 kg for topiramate vs. 0.2 kg mean increase for placebo; P = 0.004) (Hedges et al.

2003; Hoopes et al. 2003). Binge-eating/purging remission rates were 32% for topiramate and 6%

for placebo (P = NS). Dropout rates were 34% for topiramate and 47% for placebo. In the second

study, 60 subjects with DSM-IV bulimia nervosa for at least 12 months received 10 weeks of

topiramate (titrated to 250 mg/day in the sixth week) (n = 30) or placebo (n = 30) (C. Nickel et al.

2005b). Topiramate was associated with significant decreases in binge/purge frequency (defined

as a >50% reduction; 37% for topiramate and 3% for placebo), body weight (difference in weight

loss between the 2 groups = 3.8 kg), and all of the SF-36 Health Survey scales (all Ps <0.001). Five

(17%) subjects on topiramate and 6 (20%) subjects on placebo were dropouts.

In the first controlled study in BED, 61 subjects with DSM-IV BED and obesity (defined as a body

mass index [BMI] 30) received topiramate (n = 30) or placebo (n = 31) for 14 weeks (McElroy et

1. 2003). Topiramate was significantly superior to placebo in reducing binge frequency, as well as

global severity of illness, obsessive-compulsive features of binge-eating symptoms, body weight,

and BMI. Topiramate-treated subjects experienced a 94% reduction in binge frequency and a mean

weight loss of 5.9 kg, whereas placebo-treated subjects experienced a 46% reduction in binge

frequency and a mean weight loss of 1.2 kg. The dropout rate, however, was high—14 (47%)

subjects receiving topiramate and 12 (39%) subjects receiving placebo failed to complete the trial.

The second controlled study of topiramate in BED was a multicenter trial in which subjects with

DSM-IV BED and ±3 binge-eating days per week, a BMI ranging from 30 kg/m2 to 50 kg/m2 , and no

current psychiatric disorders or substance abuse were randomly assigned in a 1:1 ratio to

topiramate or placebo for 16 weeks (McElroy et al. 2007b). Of 407 subjects enrolled, 13 failed to

meet inclusion criteria; 95 topiramate and 199 placebo subjects were therefore evaluated for

efficacy. Topiramate significantly reduced binge-eating days per week (–3.5 ± 1.9 vs. –2.5 ± 2.1),

binge episodes per week (–5 ± 4.3 vs. –3.4 ± 3.8), weight (–4.5 ± 5.1 kg vs. 0.2 ± 3.2 kg), and BMI

(–1.6 ± 1.8 kg/m2 vs. 0.1 ± 1.2 kg/m2 ) compared with placebo (all Ps <0.001). The drug also

significantly decreased measures of obsessive-compulsive symptoms, impulsivity, hunger, and

disability. Fifty-eight percent of topiramate-treated subjects achieved remission compared with

29% of placebo-treated subjects (P <0.001). Discontinuation rates were 30% in each group;

adverse events were the most common reason for topiramate discontinuation (16%; placebo, 8%).

The third controlled study of topiramate in BED was another multicenter trial in which 73 patients

with BED and obesity were randomly assigned to 19 sessions of cognitive-behavior therapy in

conjunction with topiramate (n = 37) or placebo (n = 36) for 21 weeks (Claudino et al. 2007).

Compared with patients given placebo, patients given topiramate showed a significantly greater

rate of reduction in weight, the primary outcome measure, over the course of treatment (P

<0.001). Topiramate recipients also showed a significant weight loss (–6.8 kg) relative to placebo

recipients (–0.9 kg). Rates of reduction of binge frequencies and scores on the Binge Eating Scale

and BDI did not differ between the groups, but a greater percentage of topiramate-treated patients

(31 of 37) than of placebo-treated patients (22 of 36) attained remission of binge eating (P =

0.03). There was no difference between groups in completion rates, although one topiramate

recipient withdrew because of an adverse effect.

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with obesity; to reduce symptoms of BED, bulimia nervosa, and anorexia nervosa with comorbid

mood disorders; and to reduce nocturnal eating and overweight in patients with night-eating

syndrome and sleep-related eating disorders (Guille and Sachs 2002; McElroy et al. 2008;

Winkelman 2006). However, there is a report of topiramate possibly “triggering” a recurrent

episode of anorexia nervosa in a woman with epilepsy and several reports of eating disorder

patients misusing the drug to lose weight (McElroy et al. 2008).

Substance Use Disorders

Four randomized, placebo-controlled studies suggest that topiramate may have therapeutic effects

in alcohol, cocaine, and nicotine dependence. Two studies examined topiramate in alcohol

dependence. In the first, 150 subjects with alcohol dependence were randomly assigned to

topiramate (n = 75; up to 300 mg/day) or placebo (n = 75) for 12 weeks (Johnson et al. 2003). All

subjects received compliance enhancement therapy. At study end, subjects receiving topiramate,

compared with those on placebo, had 2.88 (95% CI = –4.50 to –1.27) fewer drinks per day (P =

0.0006), 3.10 (95% CI = –4.88 to –1.31) fewer drinks per drinking day (P = 0.0009), 27.6% fewer

heavy drinking days (P = 0.0003), 26.2% more days abstinent (P = 0.0003), and a log plasma

gamma-glutamyl transferase (GGT) ratio of 0.07 (–0.11 to –0.02) less (P = 0.0046). Changes in

craving were also significantly greater with topiramate than with placebo. In the second study, 371

subjects were randomly assigned to topiramate (up to 300 mg) or placebo, along with a weekly

compliance enhancement intervention, at 16 sites for 14 weeks (Johnson et al. 2007). Topiramate

was significantly superior to placebo in reducing the percentage of heavy drinking days and other

drinking outcomes, such as drinks per drinking day, percentage of days abstinent, and log plasma

GGT ratio (all Ps 0.002).

In the study in cocaine dependence, 40 subjects were randomly assigned to topiramate (titrated

gradually over 8 weeks to 200 mg/day) or placebo for 13 weeks (Kampman et al. 2004).

Topiramate-treated subjects were more likely to be abstinent from cocaine after week 8 compared

with placebo-treated subjects (P = 0.01). They were also more likely to achieve 3 weeks of

continuous abstinence from cocaine (P = 0.05).

In the first of two controlled studies in smoking cessation, topiramate (n = 45) was superior to

placebo (n = 49) in 94 male and female subjects with comorbid alcohol dependence (Johnson et al.

2005). This study was a subgroup analysis of the first controlled study of topiramate in alcohol

dependence (Johnson et al. 2003). In the second study, the drug (n = 43) was superior to placebo

(n = 44) for smoking cessation in male (n = 38), but not female (n = 49), subjects who had no

associated psychopathology (Anthenelli et al. 2008).

There have also been case reports of the successful use of topiramate in opiate and benzodiazepine

withdrawal, but these uses will need to be evaluated in placebo-controlled trials (Michopoulos et al.

2006; Zullino et al. 2004).

Anxiety Disorders

Topiramate has been evaluated in one controlled study of PTSD. Thirty-eight patients with

non-combat-related PTSD were randomly assigned to flexible doses of topiramate (median dosage

= 150 mg/day, range = 25–400 mg/day) or placebo for 12 weeks (Tucker et al. 2007). No

significant difference was found on the primary efficacy measure, the total Clinician-Administered

PTSD Scale (CAPS) score. However, significant or near significant effects were found in favor of

topiramate on the eight-item Treatment Outcome PTSD scale (TOP-8) (decrease in overall severity

68% vs. 41.6%; P = 0.025) and endpoint Clinical Global Impression Scale—Improvement (CGI-I)

scores (1.9 ± 1.2 vs. 2.6 ± 1.1; P = 0.055).

Open-label studies suggest that topiramate may have therapeutic effects in generalized social

phobia and OCD (Mula et al. 2007). In contrast, there are case reports of patients experiencing

panic attacks apparently induced by topiramate (Damsa et al. 2006).

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Three placebo-controlled studies, all conducted by the same group, have evaluated topiramate in

DSM-IV-defined BPD. In the first, 29 female subjects were randomly assigned in a 2:1 ratio to

topiramate (n = 21, analysis based on 19) or placebo (n = 10) for 8 weeks (M. K. Nickel et al.

2004). Topiramate dosage was increased to 250 mg/day over 6 weeks. At study end, significant

improvement on four subscales of the STAXI (state–anger, trait–anger, anger–out, and

anger–control) was observed for topiramate compared with placebo. In the second study, 42 male

subjects with BPD received topiramate (n = 22) or placebo (n = 20) for 8 weeks (M. K. Nickel et al.

2005a). Similar to the study in females, significant improvement on the same four subscales on the

STAXI was found for topiramate compared with placebo. In the third study, 56 women with BPD

received topiramate (n = 28) or placebo (n = 28) for 10 weeks (Loew et al. 2006). Topiramate was

titrated to 200 mg/day over 6 weeks and then held constant. Topiramate was superior to placebo

on the somatization, interpersonal sensitivity, anxiety, hostility, phobic anxiety, and Global Severity

Index subscales of the Symptom Checklist (SCL-90-R) (all Ps <0.001); all eight scales of the SF-36

Health Survey (all Ps <0.01); and four of eight scales of the Inventory of Interpersonal Problems

(all Ps <0.001). Four patients (1 on topiramate, 3 on placebo) dropped out. In all three studies,

topiramate was associated with significantly greater weight loss then placebo. It was also well

tolerated, and there were no psychotic or suicidal adverse events.

Psychotropic-Associated Weight Gain

Two placebo-controlled studies suggest that topiramate reduces antipsychotic-induced weight gain

in schizophrenia. In one study, 66 inpatients with schizophrenia receiving antipsychotic medication

and “carrying excess weight” were randomly assigned to topiramate 100 mg/day, topiramate 200

mg/day, or placebo for 12 weeks (Ko et al. 2005). Body weight, BMI, and waist and hip

circumference decreased significantly in the topiramate 200 mg/day group compared with the

topiramate 100 mg/day and placebo groups. Scores on the Clinical Global Impression

Scale—Severity of Illness (CGI-S) and the Brief Psychiatric Rating Scale (BPRS) were also

significantly decreased, but the decreases were not thought to be clinically meaningful. In the other

study, 43 women with mood or psychotic disorders who had gained weight while receiving

olanzapine were given topiramate (n = 25) or placebo (n = 18) for 10 weeks (Nickel et al. 2005b).

Weight loss was significantly greater (by 5.6 kg) in the topiramate group. Topiramate-treated

subjects also experienced significantly greater improvement in measures of health-related quality

of life and psychological impairment.

One placebo-controlled study and two randomized comparison trials suggest that topiramate may

be superior to placebo and at least as effective as bupropion and sibutramine in

psychotropic-associated weight gain in bipolar patients. In the controlled study in bipolar I manic

or mixed patients receiving lithium or valproate, adjunctive topiramate was ineffective for manic

symptoms but was associated with significantly greater reductions in body weight compared with

placebo (–2.5 vs. 0.2 kg, respectively; P <0.001) and BMI (–0.84 vs. 0.07 kg/m2 , respectively; P

<0.001) (Chengappa et al. 2006). In a single-blind comparator trial in 36 outpatients with bipolar

depression, adjunctive bupropion and topiramate showed similar rates of antidepressant response

(59% vs. 56%), but topiramate was associated with a greater mean weight loss (5.8 kg vs. 1.2 kg)

(McIntyre et al. 2002). In a 24-week open-label, flexible-dose comparison trial, 46 euthymic

outpatients with a bipolar disorder (types I, II, or not otherwise specified [NOS]) who had a BMI

30 kg/m2 , or a BMI 27 with obesity-related medical comorbidities, and psychotropic-associated

weight gain (defined as a weight gain of 10 lbs [4.5 kg] since initiation of their current

psychotropic regimen) were randomly assigned to receive topiramate (n = 28; 25–600 mg/day) or

sibutramine (n = 18; 5–15 mg/day) for 24 weeks (McElroy et al. 2007a). Patients receiving either

drug lost comparable amounts of weight (2.8 ± 3.5 kg for topiramate and 4.1 ± 5.7 kg for

sibutramine) and displayed similar rates of weight loss (0.82 kg/week and 0.85 kg/week,

respectively). However, only 4 (22%) patients receiving sibutramine and 6 (21%) patients

receiving topiramate completed the trial. In addition, the attrition patterns for the two drugs were

different, with patients discontinuing topiramate doing so early in treatment and patients

discontinuing sibutramine doing so throughout treatment.Print: Chapter 40. Topiramate

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Several open-label, prospective trials suggest that initiating treatment with the combination of

topiramate with either risperidone or olanzapine may successfully stabilize mood in patients with

bipolar disorder while preventing weight gain (Bahk et al. 2005; Vieta et al. 2003, 2004). Finally,

topiramate has also been used to treat weight gain in patients with major depression receiving

antidepressants, patients with anxiety disorders receiving selective serotonin reuptake inhibitors,

and patients with autism receiving antipsychotics (McElroy et al. 2008).

Obesity

Nine randomized, placebo-controlled trials have evaluated topiramate (Astrup et al. 2004; Bray et

1. 2003; Eliasson et al. 2007; Stenlöf et al. 2007; Tonstad et al. 2005; Toplak et al. 2007; Tremblay

et al. 2007; Wilding et al. 2004) or a controlled-release (CR) formulation of topiramate (Rosenstock

et al. 2007) for weight loss in subjects with obesity. In one study, subjects were required to have

comorbid essential hypertension (Tonstad et al. 2005); in four studies, subjects were required to

have concurrent type 2 diabetes (Eliasson et al. 2007; Rosenstock et al. 2007; Stenlöf et al. 2007;

Toplak et al. 2007). In all nine studies, topiramate was superior to placebo for weight loss at all

doses (range 64–400 mg/day) and at all endpoints (range 28 weeks to 1 year) evaluated. The four

long-term studies (duration 40 weeks to 1 year) showed that topiramate was associated with

weight loss that increased up to 1 year without plateauing (Astrup et al. 2004; Eliasson et al. 2007;

Stenlöf et al. 2007; Wilding et al. 2004). In the study of topiramate in obese subjects with comorbid

hypertension, there were significant decreases in diastolic, but not systolic, blood pressure in the

two groups receiving topiramate compared with the placebo group. In the four studies of

topiramate in obese subjects with comorbid type 2 diabetes, topiramate-treated patients showed

significant decreases in glycosylated hemoglobin (HbA1c) compared with placebo-treated patients.

Neuropathic Pain and Other Neurological Conditions

Five randomized, placebo-controlled studies of topiramate in painful diabetic neuropathy have

produced mixed results. Three similarly designed trials in 1,259 subjects with moderate or extreme

pain evaluating topiramate at 100 mg, 200 mg, or 400 mg/day did not find statistical separation on

the 100-mm Visual Analog Scale (VAS) after 18–22 weeks of treatment (Thienel et al. 2004).

Across all studies, 24% of topiramate-treated subjects and 8% of placebo-treated subjects

discontinued treatment due to adverse events; groups did not differ in the occurrence of serious

adverse events.

The other two controlled studies showed separation between topiramate and placebo in 345

subjects (Raskin et al. 2004). In the larger trial (N = 323), subjects with a pain visual analog (PVA)

scale score of at least 40 (on a scale of 0 [no pain] to 100 mm [worst possible pain]) were given

topiramate (up to 400 mg/day; n = 214) or placebo (n = 109) for 12 weeks (Raskin et al. 2004).

Topiramate was associated with significantly greater reductions in the PVA scale score (P = 0.038),

the worst pain intensity score (P = 0.003), and sleep disruption (P = 0.020). Topiramate also

reduced body weight (–2.6 vs. +0.2 kg for placebo; P <0.001) without disrupting glycemic control.

Regarding other neurological conditions, topiramate has been shown superior to placebo in

controlled trials in preventing pediatric migraine (Winner et al. 2005) and treating essential tremor

(Ondo et al. 2006). Open data suggest that topiramate may have beneficial effects in cluster

headache (Pascual et al. 2007).

SIDE EFFECTS AND TOXICOLOGY

The side-effect profile of topiramate may vary with the patient’s illness, mood state, and

concomitant medications. The most common side effects of topiramate in the initial dose-ranging

studies in patients with epilepsy when used in combination with other antiepileptic drugs at

dosages of 200–1,000 mg/day were related to the central nervous system and included dizziness,

somnolence, psychomotor slowing, nervousness, paresthesias, ataxia, difficulty with memory,

difficulty with concentration or attention, confusion, and speech disorders or related speech

problems (Langtry et al. 1997; Shorvon 1996). Other side effects were nystagmus, depression,

nausea, diplopia, abnormal vision, anorexia, language problems, and tremor. When used asPrint: Chapter 40. Topiramate

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monotherapy in patients with epilepsy, the most common side effects were dizziness, anxiety,

paresthesias, insomnia, somnolence, myalgia, anorexia, nausea, dyspepsia, and diarrhea. The most

common side effects of topiramate in the large registration trials for migraine (which used total

daily doses of 50, 100, and 200 mg) were paresthesias, fatigue, memory difficulties,

concentration/attention problems, and mood problems (Bussone et al. 2006). In the monotherapy

trials in adult mania, paresthesias, decreased appetite, dry mouth, and weight loss were more

common with topiramate than placebo (Kushner et al. 2006). In the adolescent mania trial, the

most common adverse events occurring with topiramate were decreased appetite, nausea,

diarrhea, paresthesias, somnolence, insomnia, and rash (DelBello et al. 2005). In the obesity trials,

events related to the central or peripheral nervous systems or to psychiatric disorders were most

commonly reported (Rosenstock et al. 2007). These included paresthesias; fatigue; difficulty with

attention, concentration and/or memory; taste perversion; and anorexia. Overall, paresthesias and

cognitive complaints are the most troublesome adverse events (van Passel et al. 2006).

The central nervous system and gastrointestinal effects of topiramate are usually mild to moderate

in severity and often decrease or resolve with time or dosage reduction (Meador et al. 2003;

Shorvon 1996). Also, they may be minimized by slow titration of topiramate dosage (Biton et al.

2001). However, topiramate may be associated with more cognitive impairment than some of the

other new antiepileptic drugs (Martin et al. 1999; Meador et al. 2003).

Infrequent but serious side effects of topiramate include nephrolithiasis, an ocular syndrome of

acute myopia with secondary angle-closure glaucoma, oligohydrosis and hyperthermia, and

metabolic acidosis (van Passel et al. 2006). The incidence of nephrolithiasis has been estimated to

be 1.5% (Shorvon 1996). In the epilepsy trials, more than 75% of the patients who developed

renal stones elected to continue treatment with topiramate (Reife et al. 2000). Nephrolithiasis is

thought to be related to topiramate exerting carbonic anhydrase inhibition in the kidney (Welch et

1. 2006).

The secondary angle-closure glaucoma associated with topiramate is characterized by acute onset

of bilateral blurred vision and ocular pain (Fraunfelder and Fraunfelder 2004; Fraunfelder et al.

2004). Ophthalmological findings include bilateral myopia, conjunctival hyperemia, anterior

chamber shallowing, and increased intraocular pressure. Most cases have occurred within 1 month

of topiramate initiation and fully resolve with drug discontinuation. Peripheral iridectomy or laser

iridotomy are not effective. The syndrome has been attributed to sulfamate-induced ciliary body

edema.

There were no clinically relevant changes in hepatic, renal, or hematological parameters in the

registration trials of topiramate, and laboratory monitoring was initially thought not to be required

(Reife et al. 2000; Sachdeo and Karia 2002). In addition, no treatment-related changes in physical

or neurological examinations (except body weight loss; see next paragraph), in the

electrocardiogram, or in ophthalmological or audiometric test results were noted. However, as a

carbonic anhydrase inhibitor, topiramate reduces serum bicarbonate levels, and it is believed that

this is the mechanism underlying reports of reversible metabolic acidosis in some patients (Sachdeo

and Karia 2002; van Passel et al. 2006; Welch et al. 2006). It is now recommended that baseline

and periodic serum bicarbonate levels be measured in patients receiving topiramate. A case of liver

failure in a young woman with epilepsy after addition of topiramate to carbamazepine (Bjoro et al.

1998) and a case of significant liver enzyme elevation in another young woman with bipolar

disorder and obesity after addition of topiramate to divalproex sodium, benztropine, risperidone,

clonazepam, and an oral contraceptive (Doan and Clendenning 2000) have been reported. To date,

no cases of liver failure have been reported with topiramate monotherapy.

A growing concern is the psychiatric adverse-event profile of antiepileptic drugs in patients with

epilepsy, including whether such drugs cause suicidality and psychosis. Although some data

suggest that a subgroup of epilepsy patients may be susceptible to such psychiatric adverse events,

other data indicate that topiramate may be associated with depression in epilepsy patients,

especially during rapid titration (Mula and Sander 2007). There are also isolated reports of the drugPrint: Chapter 40. Topiramate

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inducing mood and anxiety symptoms in psychiatric patients (Damsa et al. 2006; Klufas and

Thompson 2001). Moreover, one obesity study reported eight (6.2%) suicidal-related events

occurring in topiramate-treated subjects versus none in placebo-treated subjects (Rosenstock et al.

2007).

Body weight loss in patients enrolled in clinical trials for epilepsy was reported as an adverse event

in 7% of the patients receiving topiramate 200–400 mg/day and 13% of the patients receiving

topiramate 600–1,000 mg/day, compared with 3% of the placebo-treated patients (Reife et al.

2000). Weight loss was associated with anorexia and was more common in heavier patients.

Degree of weight loss was dose related; mean weight loss was 1.1 kg in patients receiving less than

200 mg/day of topiramate and 5.9 kg in patients receiving 800 mg/day or more (Langtry et al.

1997). Weight reduction usually plateaued after 15–18 months of treatment (Rosenfeld et al.

1997b).

DRUG–DRUG INTERACTIONS

Although topiramate is minimally metabolized by the liver, its clearance can be increased by the

coadministration of hepatic enzyme–inducing drugs (Bialer et al. 2004; Gidal 2002; Langtry et al.

1997; Rosenfeld et al. 1997a; van Passel et al. 2006). Thus, carbamazepine and phenytoin may

substantially decrease topiramate levels. Conversely, topiramate has mild enzyme-inducing

properties and may enhance metabolism of ethinyl estradiol. Available data suggest that at

topiramate doses of 200 mg/day or lower, this induction is insignificant, but at doses greater than

200 mg/day, induction becomes dose dependent and occurs to a great extent (Bialer et al. 2004).

Women taking combination oral contraceptive agents therefore need to be counseled about this

potential interaction.

There have been reports of topiramate causing increased lithium levels (Abraham and Owen 2004).

This effect appears to be rarely clinically significant. Indeed, pharmacokinetic studies suggest that

topiramate may slightly decrease serum lithium concentrations (Bialer et al. 2004).

CONCLUSION

Five controlled monotherapy trials and one adjunctive therapy trial indicate that topiramate is not

efficacious in the treatment of acute bipolar mania in adults. However, clinical reports suggest that

topiramate may be effective in other aspects of bipolar disorder, including juvenile mania, bipolar

depression, “soft” forms of bipolar spectrum disorder, and bipolar disorder with comorbid

conditions. Moreover, placebo-controlled trials suggest that topiramate is efficacious in

binge-eating disorder, bulimia nervosa, alcohol dependence, borderline personality disorder,

psychotropic-induced weight gain, and obesity. Further controlled clinical trials of topiramate in

mood, eating, substance use, and personality disorders are needed to more clearly delineate its role

as a psychotropic agent.

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