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Sports Pharmacology of Psychiatry and Behavioral Medicine


Introduction

  • Optimal treatment is determined through a collaborative approach, including team physicians, psychologists, psychiatrists, athletic trainers, academic advisors, coaches, teammates, parents, and administrative staff. More institutions are promoting an integrative approach to mental health and well-being using a wide variety of interventions:

    • Self-care: exercise, sleep, nutrition

    • Social connections: informal groups, team activities, interest-based communities

    • Online or self-directed tools: mental health apps, life hacks, relaxation, mindfulness

    • Group or support sessions: peer- or mentor-based, group counseling, life coaching

    • Individualized mental healthcare: counseling, medications, intensive outpatient or inpatient programs and reassess care plans frequently

  • Nonprescription therapies shown to be helpful:

    • Psychotherapy

    • Over-the-counter herbal and dietary supplements

    • Light therapy (seasonal affective disorder)

    • Electroconvulsive therapy (ECT) (treatment-resistant depression, mania, or psychosis)

  • Athletes often self-treat their conditions with:

    • Overtraining

    • Avoidance

    • Self-help information

    • Self-medication with over-the-counter medications, alcohol, and illicit drugs

  • Treatment with medications requires evaluation and monitoring:

    • Accurate diagnosis and identifying existing comorbidities

    • Suicidal ideation, self-harm, risk of harm to others, other safety concerns

    • Side effects and both positive and negative effects on school/work/sport performance

    • Efficacy and compliance

    • Attention to potential side effects that may affect athletic performance:

    • Daytime sedation

    • Orthostasis

    • Tremors

    • Arrhythmias

    • Nausea

    • Weight or appetite changes

  • Table 9.1 lists syndromes associated with the medications reviewed:

    • Neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and extrapyramidal symptoms (EPS)

    Table 9.1
    Syndromes Associated With Medications Used for Psychiatric Disorders
    Serotonin Syndrome (SS)
    (Italics distinguish from neuroleptic malignant syndrome)

    • Potentially fatal, caused by a net increase in serotonin

    • Occurs rapidly after medication change (usually within 24 hours)

    • Symptoms: anxiety, agitation, disorientation, and delirium; autonomic (dilated pupils, tachycardia, hypertension, hyperthermia, diaphoresis, vomiting, and diarrhea); and neuromuscular ( hyperrigidity , myoclonus , hyperreflexia , tremor , akathisia, ataxia , and shivering )

    • Treatment: discontinue serotonergic drugs; supportive management with intravenous fluids, oxygen, blood pressure control, benzodiazepine to control agitation, and cyproheptadine (if other treatments fail)

    Neuroleptic Malignant Syndrome (NMS)
    (Italics distinguish from serotonin syndrome)

    • May be a life-threatening emergency

    • Often develops over days

    • Symptoms: mental status changes (confusion, agitated delirium, mutism, and catatonic); muscular rigidity (lead-pipe rigidity/cogwheeling), bradyreflexia , hyperthermia, tremor, diaphoresis, tachycardia, and labile blood pressure

    • Treatment: hospitalization; discontinue offending agent; consider benzodiazepines, dantrolene, bromocriptine, or amantadine and supportive care

    Extrapyramidal Symptoms (EPS)

    • Range of movement disorders: dystonia (muscular spasms of neck, jaw, and back), akathisia (restlessness, nervousness, and anxiety), parkinsonism (rigidity, tremor, bradykinesia, shuffling gait, and masked facies), and tardive dyskinesia (involuntary muscle movements of distal extremities and face)

    • Treatment: consider anticholinergic drugs, beta-blockers, benzodiazepines, and pramipexole

  • Use caution with medication selection in athletes, pediatric, pregnant, potentially pregnant, or geriatric patients

Treatment for Major Depressive Disorder (MDD)

  • Table 9.2 summarizes antidepressant classifications and adverse effects.

    Table 9.2
    Medications Used For Depression and/or Anxiety
    Name (Brand) Mechanism, Adverse Effects (AEs), and Comments
    Selective Serotonin Reuptake Inhibitor (SSRI)

    • Sexual dysfunction, drowsiness, weight gain, insomnia, anxiety, dizziness, headache, dry mouth, blurred vision, rash, itching, tremor, constipation, and stomach upset

    • Caution with NSAIDs: gastrointestinal bleeding and serotonin syndrome

    Citalopram (Celexa)

    • Some antihistamine effect

    Escitalopram (Lexapro)

    • Best tolerated, fewest drug interactions

    Fluoxetine (Prozac)

    • Activating properties (avoid with insomnia, anxiety)

    • Lowest rate of withdrawal symptoms

    • Long half-life

    Paroxetine (Paxil)

    • Calming, good for anxiety

    Paroxetine CR (Paxil CR)

    • Highest rate of withdrawal symptoms

    • Highest rate of sexual AEs (16%)

    Sertraline (Zoloft)

    • Activating properties

    • Diarrhea

    Serotonin Noradrenergic Reuptake Inhibitor (SNRI)

    • Not interchangeable, have different levels of NE and 5HT action

    • Common: nausea, somnolence, dry mouth; dizziness, constipation, weakness; blurred vision, sweating

    Desvenlafaxine (Pristiq)

    • Hypertension may occur during titration

    • Withdrawal reaction

    • Headache, anxiety, insomnia, and diarrhea

    Duloxetine (Cymbalta)

    • Good for depression with chronic pain

    • Less risk of hypertension

    • 67% higher discontinuation due to AEs

    • Start twice daily then switch to daily

    Levomilnacipran (Fetzima)

    • Enantiomer of milnacipran

    • Most noradrenergic action of SNRIs

    Venlafaxine (Effexor)

    • First-line SNRI, most often prescribed

    • Hypertension may occur during titration

    • AE: 52% higher (nausea, vomiting), causing 40% higher risk of discontinuation, high rate of withdrawal symptoms

    • XR form lower in AE

    Serotonin Antagonist and Reuptake Inhibitor (SARI)

    • Mechanism: antagonize serotonin receptor and inhibit reuptake of serotonin, norepinephrine, or dopamine

    Trazodone (Desyrel, Oleptro)

    • Priapism

    • Lower dose increases somnolence (may improve sleep)

    Vilazodone (Viibryd)

    • SSRI and 5HT1A partial agonist action

    • Taken with food improves therapeutic level

    Other
    Mirtazapine (Remeron, Remeron SolTab)

    • Mechanism: noradrenergic and specific serotonergic antidepressant (NaSSA), some alpha-adrenergic and serotonergic properties

    • Weight gain (after 6–8 weeks), sedation

    • Faster onset of action

    • Sedation decreases with increased dose

    Bupropion (Wellbutrin)

    • Mechanism: norepinephrine and dopamine reuptake inhibitor (NDRI), is both an active drug and precursor

    • Not associated with weight gain or sexual dysfunction

    • Activating and energizing properties

    • Regular, SR, and XL preparations available

    Buspirone

    • Mechanism: selective serotonin 5HT1A receptor agonist and dopamine agonist/antagonist

    • May help treat anxiety if unable to tolerate SSRIs or SNRIs

    • Decreased efficacy if on long-term benzodiazepine

    • Multiple dosing may be a drawback

    Vortioxetine (Trintellix)

    • SSRI; 5HT1A agonist; 5HT1B partial agonist action; and antagonistic action on 5HT3A, 5HT1D, and 5HT7 receptors

    Brexanolone (Zulresso)

    • GABA-A modulator for postpartum depression

    • Used as an infusion in hospital settings

    Esketamine (Spravato)

    • NMDA receptor antagonist delivered IV and intranasally

    • For treatment-resistant depression

    Tricyclic Antidepressants (TCAs)
    (e.g., amitriptyline, nortriptyline, and clomipramine)

    • Dangerous and lethal in overdose (QT prolongation leading to arrhythmias)

    • Inhibits reuptake of primarily serotonin and norepinephrine

    • Rarely used because of side effects

    Monoamine Oxidase Inhibitors (MAOI)

    • Mild anticholinergic

    • Sedation, agitation, GI effects, weight gain, and suppressed REM sleep

    • Rarely used because of dietary restrictions, drug interactions, and AEs

    • Risk of SS

    Benzodiazepines(e.g., alprazolam, lorazepam, clonazepam, and diazepam)

    • Sedation, nausea, syndrome of inappropriate antidiuretic hormone secretion, blood dyscrasia, hyponatremia, anterograde amnesia, agitation, depression, cognitive impairment, hyponatremia, and extrapyramidal syndrome

    • Used in combination in acute settings of mania/hypomania, particularly to reduce agitation in patients with acute mania

    • Risk of tolerance and addiction

    • Monitor complete blood count and liver function for long-term use

    • Contraindicated in patients with myasthenia gravis or acute narrow-angle glaucoma

    • Caution in patients with substance abuse

    Anticholinergic: orthostatic hypotension, blurred vision, dizziness, urinary retention, constipation, dryness, abnormal heart rhythm.

  • Psychotherapy alone is effective for mild depression. For moderate to severe mood disorders, a combination of psychotherapy and pharmacologic treatment provides a better outcome.

  • Second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and other medications that target neurotransmitters with similar mechanisms of action.

  • Pharmacologic treatment is better than placebo in primary care practice settings (53% vs. 40%).

  • Second-generation antidepressants have similar efficacy and response rates (60%), with primary differences in their respective side-effect profiles.

  • Insufficient evidence to evaluate the comparative risk of suicidal thoughts and behaviors or rare but severe adverse events, such as seizures, cardiovascular events, hyponatremia, hepatotoxicity, and SS.

  • Treatment is administered in phases:

    • Acute phase: 4–8 weeks needed for initial therapy with close monitoring.

    • Continuation phase: continue to monitor, treat for 4–9 months for an acute episode.

    • Maintenance phase: continue to reduce the risk of relapse (greater if history of MDD or chronic MDD).

    • Discontinuation of treatment: taper over several days to weeks, choose optimal time of low stressors/risks or high outside support. Some patients experience discontinuation symptoms that mimic a depressive episode, and adjustment of the taper may be necessary.

  • If family history of previous successful antidepressant, consider that agent first.

  • Start with an SSRI or bupropion.

  • If failure with one SSRI agent occurs, consider another SSRI.

  • If failure with two SSRIs, try an SNRI or another class of antidepressant.

  • If partial response, optimize or augment treatment with a different class of antidepressant.

  • Patients with associated insomnia, SSRIs have similar effectiveness (trazodone as an adjunct is beneficial with insomnia).

  • Fluoxetine and bupropion are well tolerated in athletes.

  • Tricyclic antidepressants (TCAs), particularly imipramine and clomipramine, have reasonable efficacy, but adverse effects limit their use.

  • The only US Food and Drug Administration (FDA)–approved medications for adolescents are fluoxetine and escitalopram.

The Black Box Warning

  • Use of antidepressants in young patients under the age of 25 years should balance the risk of suicidal behavior and attempts along with the clinical need. Important considerations with the black box warning are:

    • Mental health disease without treatment carries inherent risks of suicide

    • It is important to monitor the patient frequently for their symptoms and response to medication in the first weeks of treatment

Treatment for Bipolar Disorder

  • Table 9.3 lists common medications used in bipolar disorder.

    Table 9.3
    Medications Used for Bipolar Disorder
    Medication Adverse Effects (AEs) and Comments
    Antidepressants (see Table 9.2 )

    • Concern with using antidepressants as monotherapy for the risk of converting to manic state

    Other (Mood Stabilizer)
    Lithium

    • Excessive thirst, polyuria, sedation, tremor, nausea, loose stools, cognitive effects, weight gain, hypothyroidism, and diabetes insipidus, renal disease, (avoid NSAIDs, ACE inhibitors and maintain hydration status)

    • Use: mania, depression

    • Before initiation, check/monitor: BMI, electrolytes, estimated glomerular filtration rate, thyroid, complete blood count, and consider ECG if risk factors for cardiovascular disease present

    • Monitor serum lithium levels 1–2 times in the first week and 1 week after dose change

    • Toxicity is dose dependent

    • Compared with valproate or carbamazepine, lithium lowers the risk of suicide

    • Protective against dementia

    Typical Antipsychotics (First-Generation Antipsychotics)
    (e.g., haloperidol and Thorazine)

    • Increased risk of dry mouth, sedation, EPS, NMS and tardive dyskinesia, restlessness, anxiety, headache, weight gain, insomnia, and depression

    • Use: psychosis, mania

    • Increase risk of cerebrovascular accident in older patients with dementia

    • Rarely used since emergence of second-generation antipsychotics

    Atypical Antipsychotics (Second-Generation Antipsychotics)

    • EPS and tardive dyskinesia (but lower risk than typical antipsychotics), anticholinergic symptoms, sedation, metabolic effects (weight gain, hyperglycemia, dyslipidemia, and hyperprolactinemia), cardiac effects, hypotension, cataracts, and sexual dysfunction

    • Rare: NMS, seizures, agranulocytosis, and hypersensitivity reactions

    • Before initiation: document, then monitor weight/BMI, vitals, lipid profile, fasting glucose, complete blood count, and consider ECG if cardiovascular risk factors are noted

    • Target doses often achieved within first week

    • Caution in obese patients

    Aripiprazole (Abilify)

    • Use: mania, mixed, psychosis, augmentation for bipolar depression

    • Used as monotherapy or combination with lithium or valproate

    • Used in adults and adolescents (aged 10–17 years)

    Olanzapine (Zyprexa)

    • Increased risk: weight gain, glucose intolerance, and diabetes more than other agents

    • Used in adults and adolescents (aged 13–17 years) for mania/mixed, in adults only for depression

    • Used for agitation in bipolar mania

    Olanzapine With Fluoxetine Combination (Symbyax)

    • Used in adults with depressive symptoms

    • Effective in preventing manic relapse

    Quetiapine (Seroquel)

    • Use: mania, mixed, depression, psychosis

    • Used in adult and adolescents (aged 10–17 years) for acute mania

    • Superior to monotherapy for maintenance if used with lithium or valproate

    Risperidone (Risperdal)

    • Monitor prolactin levels

    • Adults and adolescents (aged 10–17 years) can be used as short-term therapy for acute manic or mixed states

    Asenapine (Saphris)

    • D2 and 5HT2A receptor antagonist with low anticholinergic activity

    • Do not swallow. Avoid food or drink for 10 min after taking

    Iloperidone (Fanapt)

    • D2 and 5HT2a receptor antagonist

    • Twice-daily dosing with need for titration

    Cariprazine (Vraylar)

    • D2, D3 and 5HT1A receptor partial agonist, 5HT2A receptor antagonist

    Lumateperone (Caplyta)

    • Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects

    Paliperidone (Invega)

    • D2 and 5HT2A receptor antagonist

    • Patients may see intact capsules in stools but are empty pills (OROS delivery system)

    Brexpiprazole (Rexulti)

    • D2 and 5HT1A receptor partial agonist and serotonin 5HT2A receptor antagonist

    • Used also as an adjunct for depression

    Anticonvulsants

    • Monitor levels, check complete blood count and liver function

    Valproic Acid (Depakene, Divalproex, Depakote, Stavzor)

    • Tremor, sedation, weight gain, nausea, diarrhea, alopecia, leukopenia, increase in liver enzymes, liver failure, pancreatitis, and PCOS, caution with liver disease

    • Use: mania, depression, mixed

    • Not recommended for women of childbearing potential

    • More effective than lithium for mixed states

    Lamotrigine (Lamictal)

    • Anticholinergic, tremor, somnolence, headache, nausea, rash, (reduced risk slow titration), toxic epidermal necrolysis, leukopenia, thrombocytopenia, pancytopenia, aseptic meningitis

    • Use: mania, depression

    • Acceptable for pregnancy with monitoring

    • Black box warning for increased risk of Stevens–Johnson syndrome

    EPS, Extrapyramidal symptoms; NMS, neuroleptic malignant syndrome.

  • Bipolar disorder is often managed by or in consultation with a psychiatrist. Knowledge of treatment modalities may be helpful for the primary care physician, particularly to help stabilize patients waiting to consult with a psychiatrist.

  • Treatment guidelines include:

    • Adjunct therapies (e.g., cognitive behavioral therapy [CBT], dialectical behavior therapy [DBT])

    • Educate caregivers about early warning signs and support

  • Treatment protocol depends on presenting symptoms (mania, hypomania, mixed state, depression, or maintenance), comorbidities, adverse effects, whether the patient (or a family member) has successfully been treated for bipolar disorder before, and the cost of medication

  • Recovery rates improved with a combination of pharmacology and psychotherapy

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