Adjunctive Topiramate and Weight Loss
By Arline Kaplan © 2000 (All Rights Reserved)
Patients with bipolar and related disorders often experience psychotropic-induced
weight gain. But adjunctive use of topiramate (Topamax) may counteract the weight
gain effect and promote appetite suppression and weight loss, according to findings
in recent open-label studies.
In A Five-Year Prospectus of the Stanley Foundation Bipolar Network, Post et
al. (2000) discussed the results of an open, add-on study of topiramate in bipolar
patients (McElroy et al., 2000). Besides noting that adjunctive topiramate was
seemingly effective in mania and cycling, but not acute depression, the researchers
observed "substantial degrees of weight loss" among the patients.
(However, McElroy and others in a pilot trial of adjunctive topiramate did find
four of eight (50%) bipolar depressed subjects were rated as improved [McElroy
et al., as cited in Chengappa et al., 1999]—Ed.)
"This drug continues to be explored as a possible agent to counter the
weight gain induced by a variety of other psychotropic agents, including lithium
[Eskalith, Lithobid], valproate [Depakote, Depakene], and the atypical neuroleptics,
particularly olanzapine [Zyprexa] and clozapine [Clozaril]," Post and colleagues
said. "Now that the potential utility for mood stabilization and weight
loss has been revealed for topiramate, a more formal randomized clinical trial
of its efficacy and tolerability in comparison with the newly approved weight
loss agent sibutramine (Meridia) has been formulated."
Post et al. (2000) said sibutramine has "shown some promise in unipolar
depression" but has not been studied in bipolar illness (unpublished data).
The multisite trial will compare the drugs in a bipolar population to assess
their relative efficacy for weight loss or liability for mood destabilization.
The study protocol has been completed, and the research centers are awaiting
approvals from institutional review boards.
Drug’s Profile
Topiramate
is a structurally and pharmacologically novel antiepileptic drug, approved by
the U.S. Food and Drug Administration as an adjunct in treating partial seizures
in patients with epilepsy. It is being used off-label for bipolar disorder.
It has a unique mechanism of action, including the ability to block the a-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid (AMPA) or kainate glutamate receptor subtypes as opposed to the
more widely recognized N-methyl-D-aspartate (NMDA) receptor subtype.
Adjunctive use of topiramate may be safer than some other combinations, because
topiramate has a favorable pharmacokinetic profile.
"It is minimally bound to plasma proteins and has few clinically relevant
pharmacokinetic interactions with other AEDs [antiepileptic drugs]," McElroy
and colleagues said. (The Physician’s Desk Reference [2000] notes
that topiramate may increase phenytoin [Dilantin], while phenytoin may substantially
decrease topiramate levels. Topiramate has little effect on carbamazepine [Tegretol],
but carbamazepine may substantially decrease topiramate levels. Additionally,
valproic acid [Depakene] and topiramate may slightly decrease each other’s
levels—Ed..
For their study, McElroy et al. gathered data on 56 outpatients with bipolar
illness who had been treated clinically with adjunctive topiramate in an open-label,
naturalistic fashion because they were either inadequately responsive to or
poorly tolerant of at least one standard mood stabilizer. Topiramate was openly
added to pre-existing psychotropic regimens and was generally begun at 25 mg/day
to 50 mg/day; doses were typically increased according the patient’s response
and side effects to the maximum dose utilized of 1200 mg/day. Patients were
generally seen every two weeks for the first 10 weeks of treatment and monthly
thereafter to assess response, weight and side effects. Response was assessed
with the Clinical Global Impressions Scale modified for Bipolar Illness (CGI-BP),
Young-Mania Rating Scale (Y-MRS) and Inventory of Depressive Symptoms (IDS).
Of the 54 patients who completed at least two weeks of topiramate treatment,
30 had manic, mixed or cyling symptoms, 11 had depressed symptoms and 13 were
relatively euthymic. Patients with manic symptoms at initiation of topiramate
treatment displayed significant decreases in CGI-BP-Mania and Y-MRS scores at
four weeks, 10 weeks of treatment and at their last evaluation. They also showed
significant decreases in IDS (but not CGI-BP-Depression) scores. In contrast,
patients who were initially depressed or euthymic showed no significant changes.
Thirty seven patients continued maintenance treatment with topiramate for more
than seven months. Of the 22 patients who had manic mood symptoms at topiramate’s
initiation, 12 (55%) were rated as much or very much improved. Of the five depressed
patients, one improved. Of the 10 initially euthymic patients, nine showed minimal
or no change and one became worse.
Adverse effects of topiramate were usually neurological or gastrointestinal,
often mild and transient, but sometimes leading to drug discontinuation. (In
the Physician’s Desk Reference [2000], placebo-controlled trials
of add-on topiramate [dose 200 mg/day to 400 mg/day] showed non-dose-related
adverse effects of somnolence, psychomotor slowing, dizziness, ataxia, speech
problems, paresthesias and nystagmus. Dose-related adverse events included tremor,
nervousness, impaired concentration/attention and confusion. The PDR also
noted that concomitant use of topiramate with other carbonic anydrase inhibitors,
like acetazolamide, may increase the risk of kidney stone formation and should
be avoided—Ed.)
"Topiramate treatment was associated with significant decreases in both
weight and body mass index (BMI) at four weeks of treatment, 10 weeks of treatment
and at the last evaluation for patients as a group," the authors said,
adding that most patients found this weight loss beneficial.
Chengappa Study
Similar
findings to the McElroy et al. study were reported by Chengappa et al. (1999).
The researchers evaluated topiramate as an add-on adjunctive treatment for mania
among patients with DSM-IV-defined bipolar I disorder (n=18) and schizoaffective
disorder-bipolar type (n=2). The majority of the subjects were inpatients who
had failed adequate trials of combinations of mood stabilizers and antipsychotic
and anxiolytic agents in the weeks prior to topiramate’s initiation. When
adjunctive topiramate was initiated, other medications were held constant for
at least five weeks. These other medications included lithium, valproate, carbamazepine,
gabapentin (Neurontin) and antipsychotic drugs. By five weeks, 12 (60%) of the
patients were viewed as responders, three were "minimally improved,"
four showed no change and one was "minimally worse." Response was
defined as a 50% or more reduction in Y-MRS score and a Clinical Global Impressing
rating of much or very much improved. Six patients had mild parasthesia, three
experienced fatigue and two had word finding difficulties. The side effects
were transient.
All patients lost weight with a mean of 9.4 pounds in five weeks. Body mass
index also was significantly reduced. Some of the subjects reported they did
not feel the urge to eat certain food to excess (e.g., chocolates, junk food).
Chengappa and colleagues noted that "anorexia and weight loss may be a
particularly advantageous property of topiramate" especially for bipolar
patients who are overweight or obese or at risk for diabetes, hypertension,
sleep apnea and other medical conditions.
Two other open-label studies exploring the adjunctive use of topiramate for
bipolar disorder (Kusumakar et al., 1999; Marcotte and Gullick, 1998) suggest
the anticonvulsant may have mood-stabilizing and appetite-suppression properties.
References
Chengappa
KNR, Rathmore D, Levine J et al. (1999), Topiramate as add-on treatment for
patients with bipolar mania. Bipolar Disord 1:42-53.
Kusumakar V, Lakshmi N, Yatham MB et al. (1999), Topiramate in rapid-cycling
bipolar women. Abstract (NR477) presented at the 152nd annual meeting of the
American Psychiatric Association. Washington, D.C., May 19.
Marcotte D, Gullick E (1998), Use of topiramate, a new antiepileptic drug as
a mood stabilizer. Presented as a poster at the 37th annual meeting of the American
College of Neuropsychopharmacology. Los Croabas, Puerto Rico, Dec. 14-18.
McElroy SL, Suppes T, Keck PE Jr. et al. (2000), Open-label adjunctive topiramate
in the treatment of bipolar disorder. Biol Psychiatry 47:1025-1033.
Physician’s Desk Reference (2000). Montvale, N.J.: Medical Economics Company,
Inc.
Post RM, Leverich GS, Altshuler L et al. (2000), A Five-Year Prospectus of the
Stanley Foundation Bipolar Network (SFBN). Available at www.bipolarnetwork.org/.
Accessed on Sept. 3, 2000.
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