Serotonin Syndrome Induced by Over-The-Counter Supplements

Introduction:

Recent times have witnessed an increased number of serotonin syndrome cases, especially after the invention of antidepressant medications. Serotonin syndrome can affect people of any age group. Serotonin is essential for the optimum functioning of the brain and the transmission of nerve impulses. Deficiency causes depression, whereas increased levels cause increased nerve activity. A person will develop serotonin syndrome when a new drug is taken, or an increased dosage of the drug increases the serotonin levels in the blood. At times, the body fails to process normal serotonin levels, which can also lead to serotonin syndrome.

What Is Serotonin Syndrome?

Serotonin syndrome is a potentially life-threatening medical emergency that occurs because of increased serotonin levels in the body leading to the manifestation of various clinical features ranging from mild symptoms like fever, nausea, and diarrhea to severe symptoms like seizures or high fever. Serotonin is a neurotransmitter that is produced by the brain cells and some other areas in the body. If not recognized in time, the condition can lead to fatal complications.

What Causes Serotonin Syndrome?

• Serotonin syndrome occurs due to excess intake of over-the-counter pills and herbal supplements. Increased usage causes overactivation of both the central and peripheral serotonin receptors, leading to higher levels of serotonin in the blood.

• Serotonin is also called (5-hydroxytryptamine) (5-HT). It is formed by the decarboxylation and hydroxylation of tryptophan (amino acid), is stored in the vesicles, and gets released into the synaptic cleft on stimulation. Eventually, 5-HT (serotonin) is metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid.

• Serotonin acts on both peripheral and central receptors.

• Enterochromaffin cells of the gastrointestinal (GI) tract produce peripheral serotonin, which causes vasoconstriction, uterine contraction, bronchoconstriction, GI motility, and platelet aggregation.

• Midline raphe nuclei of the brainstem from the midbrain to the medulla contain central serotonin receptors which mediate in inhibiting excitatory neurotransmission, alleviate weakness, initiate wakefulness, attention, anxiety, depression, and control sexual behavior, appetite, thermoregulation, motor tone, migraine, emesis, nociception, and aggression.

• The drugs that cause serotonin syndrome may act by following pathomechanisms:

  • Inhibition of serotonin uptake and decreased serotonin metabolism.

  • Increased serotonin synthesis.

  • Increased serotonin release and activation of serotonergic receptors.

  • Inhibition of certain enzymes that metabolize serotonin, like cytochrome P2D6 (CYP2D6) and cytochrome P3A4 (CYP3A4) by the SSRIs (selective serotonin reuptake inhibitors).

• This inhibition results in the accumulation of certain serotonergic drugs, increasing serotonergic activity and leading to classical clinical presentations of serotonin syndrome.

What Medications Cause Serotonin Syndrome?

Antidepressants are the most common culprits behind serotonin syndrome. The risk is higher if over-the-counter supplements are taken in excess, which may increase serotonin levels. The following drugs are most commonly involved:

• Selective Serotonin Reuptake Inhibitors (SSRIs): These are the most commonly prescribed antidepressants.

  • Citalopram.

  • Escitalopram.

  • Fluoxetine.

  • Fluvoxamine.

  • Paroxetine.

  • Sertraline.

• Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs): They also belong to the class of antidepressants, which include:

  • Desvenlafaxine.

  • Desvenlafaxine succinate.

  • Duloxetine.

  • Levomilnacipran.

  • Venlafaxine.

• Monoamine Oxidase Inhibitors (MAOIs):

  • Isocarboxazid.

  • Phenelzine.

  • Tranylcypromine.

  • Transdermal selegiline.

• Buspirone for treating anxiety disorders.

• Trazodone for treating depression or insomnia.

• Drugs Used to Treat Migraine Include:

  • Almotriptan.

  • Naratriptan.

  • Rizatriptan.

  • Sumatriptan.

  • Zolmitriptan.

• Painkillers (Opioids) and Other Medications Include:

  • Fentanyl.

  • Fentanyl citrate.

  • Meperidine.

  • Pentazocine.

  • Tramadol.

• Medications to Relieve Cough Include:

  • Dextromethorphan.

• Anti-emetic Medications:

  • Granisetron.

  • Metoclopramide.

  • Ondansetron.

• Antidepressants Acting on Multiple Serotonin Receptors:

  • Vilazodone.

  • Vortioxetine.

• Recreational Drugs:

  • Cocaine.

  • Lysergic acid diethylamide (LSD).

• Dietary Supplements:

  • St. John's wort.

  • Ginseng.

What Are the Clinical Features of Serotonin Syndrome?

• Nervousness and sweating.

• Nausea and vomiting.

• Diarrhea.

• Dilated pupils.

• Tremors.

• Agitation.

• Restlessness.

• Involuntary muscle spasms and muscle twitching.

• Muscular rigidity.

• Shivering.

• Involuntary eye movements.

• Confusion.

• Altered mental status.

• Tachycardia (increased heart rate).

• High blood pressure.

• Fever.

• Seizures.

• Arrhythmias (irregular heartbeat).

• Loss of consciousness.

How Is Serotonin Syndrome Diagnosed?

• Serotonin syndrome does not have specific diagnostic tests.

• Detailed medical and personal history of certain serotonergic drugs should be noted.

• A careful physical examination to rule out other possible conditions is done.

• Not to miss the history of any herbal supplements and recreational drugs taken. The healthcare provider may advise some laboratory investigations to confirm the diagnosis, which include,

  • Complete blood count (CBC).

  • Blood culture.

  • Thyroid function tests.

  • Drug screens measure the toxicity levels of the drug.

  • Kidney function tests.

  • Liver function tests.

What Are the Differential Diagnoses for Serotonin Syndrome?

• Neuroleptic malignant syndrome (NMS) is a life-threatening condition that occurs as an adverse effect of antipsychotic medications, causing altered mental status and muscle rigidity).

• Malignant hyperthermia (characterized by a dangerous increase in blood pressure due to some anesthetic medications).

• Anticholinergic toxicity (overdosing of the medications used to block the activity of a neurotransmitter called acetylcholine).

• Serotonergic discontinuation syndrome (adverse effects occurring due to discontinuation of antidepressants.

• Sympathomimetic drug intoxication (toxicity caused by overdose of sympathomimetic drug given to treat disorders of the sympathetic nervous system).

• Meningitis.

• Encephalitis (inflammation of the brain).

• Stroke.

• Central hyperthermia (injury of the brain causing increased high temperature).

How Is Serotonin Syndrome Treated?

• First and foremost, all the serotonergic drugs need to be discontinued.

• Supportive therapy includes stabilizing vital signs, administering oxygen to maintain oxygen saturation levels above 93 percent, and fluid resuscitation.

• Continuous cardiac monitoring is carried out meticulously.

• Benzodiazepines are given for sedation, and serotonin antagonists are given to counteract the serotonergic effects.

• Serotonin syndrome resolves within 24 hours if treated adequately.

• Diazepam is administered to treat mild cases of hypertension and tachycardia.

• Diazepam acts by reversing the serotonergic effects. So, Diazepam can be given to treat hypertension, tachycardia, and fever in addition to its sedative effects.

• Even though benzodiazepines are given, vital signs are not stabilized sometimes. Such cases require the administering of serotonin antagonists (5HT-2A receptor antagonists).

• Cyproheptadine is the more potent 5HT-2A receptor antagonist.

• Hyperthermia is treated by reducing excess muscle activity, and cooling measures are adopted.

• Antipyretics are of not much use in these cases as hyperthermia is most probably caused by increased muscular activity and not because of hypothalamic regulation in the brain.

• Patients suffering from hyperthermia (temperatures greater than 41.1°C) should be sedated, and a non-depolarizing agent should be given to reduce the uncontrolled muscular movements.

• Vecuronium is the most commonly used non-depolarizing drug.

Conclusion:

Early prompt recognition of clinical features and timely management of serotonin syndrome can harness better prognosis. In cases of confusion and still the diagnosis is questionable, discontinuing serotonergic drugs is feasible, and supportive therapy should be initiated. Patients with mild clinical presentations should be monitored regularly to prevent the disease progression. High clinical suspicion is encouraged in such cases as recent times have witnessed the widespread use of serotonergic drugs. Serotonin syndrome, if treated in time, can lower mortality and morbidity rates to a greater extent.