Bipolar disorders are classified as a severe mental illness with a lifetime prevalence of 4.4% in the United States and 2.4% worldwide.1,2 A recent meta-analysis addressing prevalence in primary care noted a current prevalence of 3.7%.3 Bipolar disorders are associated with significant medical and psychiatric comorbidities,4 have a disproportionate global disease burden,5 and are frequently complicated by suicidal behaviors.6,7 Thus, early diagnosis with pharmacologic interventions is key to the long-term outcome for patients with bipolar disorders.

The goal of pharmacologic intervention in both research trials and clinical care is therapeutic outcome – maximal efficacy with minimal adverse effects.8 In treating bipolar disorders, this may be complicated by comorbidities and/or adjunctive medications required to address adverse effects. Optimal rational polypharmacy may maximize therapeutic outcome yet could create ethical issues in competitive sports.

The World Anti-Doping Code (WADC)9 and yearly published World Anti-Doping Code Prohibited List10 are intended to deter and sanction athletes using performance-enhancing agents while promoting an even playing field for all competitors. Criteria for including substances in the Prohibited List are outlined in WADC Section 4.3.1:

“4.3.1 A substance or method shall be considered for inclusion on the Prohibited List if WADA, in its sole discretion, determines that the substance or method meets any two of the following three criteria:

• 4.3.1.1 Medical or other scientific evidence, pharmacological effect or experience that the substance or method, alone or in combination with other substances or methods, has the potential to enhance or enhances sport performance;

• 4.3.1.2 Medical or other scientific evidence, pharmacological effect or experience that the Use of the substance or method represents an actual or potential health risk to the Athlete;

• 4.3.1.3 WADA's determination that the Use of the substance or method violates the spirit of sport described in the introduction to the Code.”9

The key word in Section 4.3 is “potential” and the Prohibited List refers to “and other substances with a similar chemical or biological effect(s).”9,10 As such, numerous substances not on the Prohibited List may meet these criteria. This is especially pertinent to bipolar disorders with comorbid conditions wherein psychotropics frequently are used off-label.11,12 Further, substances that were once monitored or considered “related” have been advanced to the Prohibited List.13 Since there is strict liability for doping violations, it is incumbent on athletes to list all substances and, as indicated, to obtain a Therapeutic Use Exemption (TUE).14 Criteria for obtaining a TUE include:

“4.1 An Athlete may be granted a TUE if (and only if) he/she can show that each of the following conditions is met:

• a.

  The Prohibited Substance or Prohibited Method in question is needed to treat an acute or chronic medical condition, such that the Athlete would experience a significant impairment to health if the Prohibited Substance or Prohibited Method were to be withheld.

• b.

  The Therapeutic Use of the Prohibited Substance or Prohibited Method is highly unlikely to produce any additional enhancement of performance beyond what might be anticipated by a return to the Athlete's normal state of health following the treatment of the acute or chronic medical condition.

• c.

  There is no reasonable Therapeutic alternative to the Use of the Prohibited Substance or Prohibited Method.”14

This paper presents three hypothetical examples in the treatment of bipolar disorders with comorbidities (comorbid ADHD, lithium-induced tremor, and comorbid pain) wherein unintended Prohibited List contravention would result in doping violation disqualifications without approved TUEs.

Hypothetical case analyses with literature review.

These hypothetical cases are unique and permit the development and discussion of key points in bipolar disorder, comorbid conditions, pharmacotherapy, and ethical considerations in sports as outlined in the WADC.

First, early-onset bipolar disorder has been associated with comorbid alcohol/substance dependence, comorbid anxiety, increased suicidal behaviors, and increased depressive severity all consistent with potentially poorer prognosis supporting the need for early diagnosis and intervention.15

Second, the significant degree of comorbid psychiatric conditions with bipolar disorders is often underestimated. Recent literature addressing prevalence rates for bipolar disorders and comorbid psychiatric conditions notes: >40% for any anxiety disorder,16 >20% for ADHD,17 and >20% for alcohol and substance use disorders.18,19 Presence of comorbidities may vary based on population age and setting with increased psychiatric comorbidities reported in pediatric bipolar disorder (>60% for anxiety disorders; >40% for ADHD).6 Further, in a national survey (N=34,653), 19.71% of those with anger had comorbid bipolar disorder and >60% of bipolar disorder depressed patients in a small study had anger attacks.20,21 These prevalence rates emphasize the need for clinicians to appreciate that bipolar disorder patients are at high risk for specific comorbid psychiatric disorders, to consider these conditions both at time of initial diagnosis and longitudinally, and to address pharmacologic interventions that may serve to treat multiple disorders.

Third, bipolar disorder pharmacotherapy requires minimization of adverse effects, especially in specific populations at risk. These populations include but are not limited to: women in child bearing years, pregnancy, patients with renal/hematopoietic/liver diseases, patients with comorbid medical and psychiatric conditions requiring minimal metabolic induction, patients with metabolic syndrome or family history of metabolic disorder, patients with history of drug reactions (Steven Johnson Syndrome), and geriatrics.

Fourth, suicidal behaviors (suicidal ideation, suicide attempt, and suicide) are a major concern in the illness course and treatment of bipolar disorders. Specifically, suicidal ideation has been reported in ∼50% and suicide attempts in ∼25% of bipolar patients, respectively, with a standardized mortality ratio for suicide of >20-fold than in the general population.6,7,22,23 Since suicide is the cause of death in 15–20% of all bipolar patients,24 treatment requires consideration of suicide prevention strategies. Multiple randomized controlled trials and meta-analyses report the significant anti-suicidal properties of lithium in mood disorders (suicide odds ratio of 0.13 compared to placebo25; lithium treatment with an 80% decrease in all suicidal acts with decreased lethality of acts26; lithium maintenance discontinuation with 20-fold increased risk of suicidal acts during the first year off lithium27).

Fifth, there is limited research addressing prevalence rates for psychiatric disorders among athletes, with no studies specifically addressing bipolar disorders.28 A small sports psychiatrist survey (N=40) noted the preferential use of lamotrigine for bipolar disorders.29 Sports and exercise are considered important for both physical and mental health wellbeing with improved quality of life measures, increased socialization and decreased stigma30,31; however, whether exercise is an appropriate treatment for bipolar disorder has been questioned and requires further research.32

Sixth, ethical considerations in sports require that all athletes adhere to the WADC with emphasis on the Prohibited List and obtaining TUEs as indicated. When obtaining a TUE, two questions need to be considered: (a) if the athlete has been stabilized with a prohibited medication for a severe illness or associated comorbidity, should that athlete be mandated to try an approved drug with a prior history of inferior response; (b) should in-competition prohibited medications be acutely discontinued for a given competition? The three cases address these points.

Seventh, psychostimulants (methylphenidate and mixed amphetamine salts) are preferential first-line treatments for ADHD followed by non-psychostimulants (atomoxetine and guanfacine).33,34 Psychostimulants are prohibited substances in competition (S6) whereas both atomoxetine and guanfacine are approved.10 In the ADHD case presented, atomoxetine was not effective and guanfacine had only partial benefit leading ultimately to successful treatment with methylphenidate-XR. Without obtaining a TUE, the WADC would require the gymnast either to take the historically inferior atomoxetine/guanfacine during competition or not take methylphenidate during competition. In the first instance the gymnast's ADHD would be only partially treated and in the second instance the ADHD would remain untreated with neither upholding the WADC goal of creating an even playing field.9 Competitive gymnasts must be attentive to avoid unnecessary, but costly, scoring deductions; consider that deductions can occur for each failure to present (acknowledge the panel judge) before and/or after an exercise (0.30), for not beginning an exercise within 30s of being signaled by judge or green light (0.30), for inappropriate attire (0.30), and for each overtime exercise (0.10).35 As criteria are met (4.1a, 4.1b, 4.1c), a TUE is indicated for this case.14

Eighth, beta-blockers (propranolol) and primidone are preferential first-line treatments for essential tremor (Class A) followed by gabapentin (B), topiramate (B) and other lower level evidenced-based interventions.36,37 Beyond dose reduction for lithium-induced tremors, with limited research studies, pharmacotherapies for lithium tremor mirror recommendations for essential tremor.38 Beta-blockers are Prohibited Substances both in-competition and out-of-competition for archery (P2) whereas primidone, gabapentin, and topiramate are approved.10 In the lithium-tremor case, lithium dose reduction diminished the tremor severity without increased subclinical inter-episode symptoms.39 Primidone, gabapentin and topiramate trials were not effective and benzodiazepines were avoided due to his history of polysubstance dependence. His lithium-induced tremor resolved with propranolol; however, without a TUE, he would be required to change his mood stabilizing agent as the other recognized treatments for this tremor had all been ineffective. This case is a classic example of poor prognosis – early-onset with comorbid substance dependence and suicidal behaviors. Within 7 years, there were 7 distinct episodes (3 manic and 4 depressive) including 4 suicide attempts. Numerous pharmacotherapies (3 anticonvulsants and 3 second generation antipsychotics individually, in combination, and with dose titrations) were effective for acute episodes only. With lithium maintenance, he had been stable for 5 years without further suicidal behaviors. In consideration of the significant bipolar-suicide literature, to request this athlete to change psychotropics would be contraindicated and could be life threatening with both increased suicidal behaviors and lethality of acts.26,27 As criteria are met (4.1a, 4.1b, 4.1c), a TUE is indicated for this case.14

Ninth, pain management is a complex issue balancing the need to decrease pain severity with both its negative impact on HRQoL40–43 and its significant inter-relationship with mental health44–47 while avoiding excessive interventions that might lead to dependence. With increased pain severity associated with disease progression, pain management may evolve from non-pharmacologic, to non-opiate pharmacologic, to opiate, to potential adjunctive cannabinoids, and even surgical treatments. The case described, osteoarthritic pain with a chronic post-trauma pain syndrome, is an example of treatment evolution to manage persistent pain. There are several unique aspects to this case. Oxcarbazepine in rodent models is noted to have a synergistic analgesic effect with both acetaminophen and NSAIDs.48,49 Tramadol, though a weak opioid with addictive properties, is not a Prohibited Substance but rather listed as part of the Monitoring Program50 – as such, tramadol is still approved for use by athletes.51 As narcotic analgesics are Prohibited Substances in competition (S8),10 the cyclist would not be permitted to use oxycodone which controlled her pain without a TUE; however, the cyclist had followed general guidelines for non-pharmacologic and non-narcotic pharmacologic pain control such that use of oxycodone should be permitted.52 Further, to minimize total narcotic analgesic dosing with the ultimate intent to switch from oxycodone back to tramadol, the cyclist added cannabinoids which is also a Prohibited Substance in competition (S9).10 Recent literature suggests that cannabinoids are beneficial in the treatment of chronic non-cancer pain including arthritis where in animal models it may modify disease progression suggesting that cannabinoids potentially could be used as treatment for the underlying disease process.53,54 As criteria are met (4.1a, 4.1b, 4.1c), a TUE is indicated for this case.14

Future research needs include: (a) prevalence rates in athletes of specific psychiatric illnesses, such as bipolar disorder, where there is a paucity of data28; (b) evidenced-based studies addressing whether athletes with specific psychiatric diseases when treated with a Prohibited Substance receive any performance enhancement (consider stimulants in ADHD); (c) evidenced-based studies determining if a Prohibited Substance beyond treating symptomatically can also modify disease progression (consider cannabinoids for pain in arthritis); (d) national and international data on which psychotropics are used for specific psychiatric diseases among athletes; (e) well-designed studies to determine the therapeutic benefit of exercise and sports for patients with bipolar disorders.32

The principal strength and limitation of this paper relates to the use of hypothetical bipolar disorder cases. With such cases, it is possible to develop complex presentations permitting a greater understanding of the illness process (comorbidities, prevalence, suicidal behaviors, treatment adverse effects) from which step-wise treatment options can be suggested for both the patient's wellbeing and safety in the context of the WADC. Yet hypothetical cases cannot be generalized and do not represent what decisions would be reached by the TUE Committee (TUEC) of a given National Anti-Doping Organization14 in real cases or whether national TUEC decisions would be consistent. It is important to assess real cases with decisions to have a better understanding as to what degree sport authorities recognize the health needs of the athlete. The clinician must always remember that the athletes are patients first and the WADC is not the arbiter of their health.

Patient-athletes with bipolar disorder and comorbidities require holistic approaches with appreciation of both the WADC and Prohibited List. Specifically, a physician's primary responsibility is the health, well-being, and safety of all patients, including patient-athletes. A secondary consideration pertinent to patient-athletes is the use of pharmacotherapies on the Prohibited List – this may be required based on the complexity of individual cases. An example from the hypothetical cases was the need for lithium treatment in a complex bipolar patient with a history of multiple suicide attempts as a means to maximize both mood stabilization and minimize any suicidal behaviors with resultant lithium-tremor that was responsive only to propranolol.

Athletes should list all medications with diagnoses, verify proposed medication status (banned/restricted/permitted) with appropriate International Federations and/or National Olympic Committees to avoid inadvertent doping violations, and obtain TUEs where indicated. Clinicians should be cognizant of these issues when treating patient-athletes, review all medications with possible implications for the Prohibited List, and, where indicated, assist with requested documentation.

There are no conflicts of interest to declare.