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Epilepsy & Behavior 10 (2007) 268–271

www.elsevier.com/locate/yebeh

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Anticonvulsants in sports: Ethical considerations
Kenneth R. Kaufman *

Departments of Psychiatry and Neurology, UMDNJ—Robert Wood Johnson Medical School, 125 Paterson Street,
Suite 2200, New Brunswick, NJ 08901, USA

Received 10 October 2006; revised 4 December 2006; accepted 8 December 2006


Available online 26 January 2007

Abstract

Objective. Antidoping codes in sport are intended to deter and sanction athletes using performance-enhancing agents while promoting
an even playing field for all competitors. Although the World Anti-Doping Code (WADC) permits anticonvulsants in general, harmoniza-
tion of antidoping permits an international sport federation (IF) to prohibit specific medications within that IF. The anticonvulsants
levetiracetam, tiagabine, and lamotrigine may pose ethical dilemmas and could be considered violations of antidoping codes.
Method. This study is a literature review with analysis.
Results. Lamotrigine, with antiglutamatergic and sodium channel properties, is FDA-approved for maintenance treatment of bipolar
disorder, in addition to its use in the treatment of major depression, anxiety disorders, and schizophrenia. Tiagabine, a selective GABA
reuptake inhibitor, has mood-stabilizing and anxiolytic properties. Levetiracetam, whose unique mechanism involves the modulators
b-carboline and zinc, has anxiolytic and mood-stabilizing properties. Anxiolytics, antidepressants, and antipsychotics are banned in
archery; under strict liability, all three anticonvulsants violate WADC/IF for that specific sport and could result in disqualification unless
therapeutic use exemptions (TUEs) are obtained. Ethical issues regarding the use of anticonvulsants by athletes and the need to obtain
TUEs are addressed.
Conclusion. The WADC with harmonized IF policies are meant to prevent doping by athletes, but not appropriate medical treatment.
When anticonvulsants have other psychotropic properties, ethical issues arise. Athletes should list all medications taken with diagnoses,
obtain TUEs as indicated, and contact the appropriate IF or Olympic organization to determine the status of the proposed medication
(banned, restricted, nonbanned). Further, clinicians should be knowledgeable regarding these issues when treating athletes.
Ó 2006 Elsevier Inc. All rights reserved.

Keywords: Anticonvulsants; Sports; Ethics; Doping; Epilepsy; Psychiatry; Treatment; Therapeutic use exemption; Levetiracetam; Tiagabine; Lamotrigine

1. Introduction athlete, violation of the spirit of sport, or if the substance


could serve to mask another prohibited substance (WADC
The key to amateur athletics is the concept that all par- 4.3) [1]. Fundamental to the WADC is the concept of strict
ticipants compete on an even playing field without the ben- liability (WADC 2.1.1 and Comment 2.1.1) [1]. The athlete
efit of performance-enhancing substances. For this takes personal responsibility for any and all substances that
purpose, the World Anti-Doping Code (WADC) has been might enter his or her body whether or not he or she know-
created with far-ranging sanctions inclusive of simple ingly ingested such. If the athlete tests positive for a prohib-
warnings, competition disqualification, and lifetime sus- ited substance, whether she or he took such intentionally or
pensions [1]. The four main reasons for prohibiting sub- not, and even if that substance would have been detrimen-
stances are performance enhancement, danger to the tal and not enhancing to the athlete’s performance, so long
as that substance is listed as prohibited, the athlete is con-
q
sidered to have committed a doping offense and must suffer
This paper was presented at the 7th European Congress on Epilep-
tology, Helsinki, Finland, July 2–6, 2006.
the consequences. However, if a prohibited substance is
*
Fax: +1 732 235 7677. required for medical purposes, then the athlete can apply
E-mail address: kaufmakr@umdnj.edu for a therapeutic use exemption (TUE) [2].

1525-5050/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2006.12.004
K.R. Kaufman / Epilepsy & Behavior 10 (2007) 268–271 269

It is important for athletes and clinicians to realize that anxiety, and PTSD has also been reported [26–29]. Preliminary findings
the WADC list of prohibited substances is not all-inclusive from a retrospective chart review suggest that adjunctive tiagabine may be
beneficial in reducing symptoms of rage and aggression associated with mul-
[3]. Specifically, the concept of ‘‘related substance’’ [specific tiple psychiatric disorders [30]. An initial report on monotherapy tiagabine
wording is ‘‘other substances with a similar chemical struc- treatment of major depression with anxiety suggests that tiagabine may have
ture or similar biological effect(s)’’] exists in each category antidepressant properties in addition to being an anxiolytic [31]. Literature
to cover those substances with similar actions not yet clas- on the efficacy of tiagabine in bipolar disorder is mixed, though this may be
sified. A recent ‘‘related substance’’ (stimulant) example is secondary to titration; a series of articles suggest that tiagabine may be ben-
eficial as an adjunctive treatment for bipolar disorder and even for schizoaf-
modafinil, which resulted in disqualification, suspension, fective disorder [32–35].
and loss of medals for an elite female sprinter at the 2003
World Outdoor Track and Field Championships; the next
2.3. Lamotrigine
year, modafinil joined the list of prohibited substances [4].
Although the WADC permits anticonvulsants in gener- Lamotrigine has multiple mechanisms of action and properties, some
al, harmonization of antidoping permits an international believed to be more related to its efficacy as an anticonvulsant and others
sport federation (IF) to prohibit specific medications with- more related to its efficacy as a psychotropic; these include antiglutamater-
in that IF. Archery prohibits antidepressants, anxiolytics, gic, calcium channel-blocking, and sodium channel-blocking properties
[36–38]. Animal lamotrigine studies have addressed the antidepressant,
and antipsychotics [5,6]. In competitive archery, the anti- anxiolytic, and antimanic properties. Lamotrigine decreases immobility
convulsants levetiracetam, tiagabine, and lamotrigine may time in the mouse forced swimming test consistent with antidepressant
pose ethical dilemmas and could be considered violations effects [39]. The same study suggests that lamotrigine has postsynaptic 5-
of antidoping codes. Further, if the competitive archer is HT1A receptor activity [39]. In the conditioned emotional response test
found to have committed a doping infraction, all sanctions of anxiety in the rat, lamotrigine was noted to be anxiolytic with suggested
sodium channel mechanisms [40]. Lamotrigine as well as valproate and
(including suspensions) imposed by FITA (the IF for carbamazepine are effective in the rodent model of mania [41].
archery) are applicable to all signatories of WADC Lamotrigine is FDA-approved for both the treatment of epilepsy and
(WADC 10.9 and 15.4), rendering an elite athlete potential- the maintenance treatment of adults with Bipolar I disorder with a focus
ly ineligible for all athletic competitions [1]. on bipolar depression [42]. A series of retrospective chart reviews suggest
that lamotrigine is an effective augmenting agent for treatment-resistant
major depression [43–45]. A preliminary placebo-controlled randomized
2. Method trial noted the efficacy of lamotrigine in the treatment of PTSD [46].
Clinical studies also reveal that when used to augment clozapine, lamotri-
This study is a literature review with analysis. gine reduces positive symptoms of schizophrenia [47–49]. A small case
series reported the efficacy of lamotrigine monotherapy in the treatment
2.1. Levetiracetam of borderline personality [50].

Levetiracetam is a novel anticonvulsant whose unique mechanisms of


3. Discussion
action and properties include inhibition of the negative allosteric modula-
tors zinc and b-carboline, reduction of potassium currents, selective block-
age of N-type calcium channels, and binding to the synaptic vesicle protein Of the three anticonvulsants described in this article,
SV2A [7–10]. Animal studies involving chlordiazepoxide withdrawal, the only lamotrigine is FDA-indicated for treatment in psychi-
modified plus-maze animal test, and the Vogel conflict test all supported atry. Nonetheless all three anticonvulsants have been used
the anxiolytic properties of levetiracetam [11–13]. Further, levetiracetam
off-label as monotherapy or adjunctive therapy for major
was found to be effective in the animal behavioral model of mania, pro-
ducing results similar to those of the known mood stabilizers lithium, val- depression, bipolar disorder, generalized anxiety disorder,
proate, and carbamazepine [14]. This study confirmed the stereospecificity panic disorder, PTSD, social phobia, impulse control
of levetiracetam in that the R-enantiomer was not effective in the treat- disorders, schizoaffective disorder, schizophrenia, and
ment of manic behavior [14]. Preliminary clinical studies noted the efficacy borderline personality disorder.
of levetiracetam in adjunctive treatment of posttraumatic stress disorder
Although anticonvulsants are not on the WADC pro-
(PTSD) and in monotherapy treatment of social anxiety disorder
[15,16]. Further, preliminary reports have described the efficacy of leveti- hibited substance list, psychotropics are prohibited by
racetam in monotherapy and adjunctive treatment of refractory bipolar FITA [5,6]. Clearly, the anticonvulsants described in this
disorders, including depressive, mixed, manic, and rapid cycling presenta- article have significant psychotropic properties. In light of
tions [17–19]. the WADC rule of strict liability for a prohibited or ‘‘relat-
ed substance,’’ this creates an ethical dilemma concerning
2.2. Tiagabine the use of anticonvulsants by athletes competing in
archery.
Tiagabine is a novel anticonvulsant whose mechanism of action as a
selective GABA reuptake inhibitor (SGRI) increases the level of functional As anticonvulsants are not considered prohibited, it is
GABA in the synaptic cleft [20,21]. An animal study involving the elevated unlikely that an athlete with epilepsy competing in archery
plus-maze animal test revealed that acute and chronic administration of would apply for a TUE. However, the literature supports
tiagabine to rats had anxiolytic effects similar to those of acute administra- significant psychiatric comorbidity (especially anxiety and
tion of diazepam [22]. Further, cholecystokinin tetrapeptide-induced panic
mood disorders) in patients with epilepsy [51–54]. As anti-
and anxiety symptoms in healthy volunteers are reduced by tiagabine [23].
Clinical studies support the efficacy of tiagabine in monotherapy treatment convulsants are used to treat both epilepsy and psychiatric
of both generalized anxiety disorder and panic disorder with agoraphobia disorders, it is quite possible that the patient with epilepsy
[24,25]. Efficacy in augmentation treatment of anxiety, treatment-resistant on a specific anticonvulsant is being treated for two disor-
270 K.R. Kaufman / Epilepsy & Behavior 10 (2007) 268–271

ders: the epilepsy for which the anticonvulsant is not tions when treating athletes, as well as understand the pro-
prohibited and the psychiatric disorder for which the fessional responsibilities associated with a TUE. Further
anticonvulsant should be considered a prohibited ‘‘related research and education are required in the complex field
substance’’ [55]. of antidoping in sports medicine.
It is difficult to determine if an athlete has a specific ill-
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