Serotonin Syndrome/Serotonin Toxicity

Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical neurotransmitter in the central and peripheral nervous systems that was discovered in 1940s. ¹ O ne of the most widely studied chemical messengers , serotonin influences many physiologic functions in humans, including regulation of mood, sleep-wake cycle, appetite suppression, memory, emesis, breathing, cognition, blood coagulation, libido, and many other functions. ² In 1992, Insel and colleagues first document ed the toxic symptoms produced from too much serotonin in the central and peripheral nervous systems , naming it serotonin syndrome. ^3,4

Serotonin Syndrome

Experts in the fields of psychiatry, pharmacy, and toxicology refer to these symptoms as serotonin toxicity, because the symptoms result from the toxic effects of too much serotonin.^5-9 The term toxicity instead of syndrome “clarifies that it is a form of poisoning, just as lithium toxicity is a form of poisoning.”⁶ Therefore, serotonin toxicity (ST) can develop with administration of any serotonin-enhancing medication, including therapeutic use, polypharmacy, or accidental/intentional drug overdose.

The incidence of ST has increased over the past decade.^5,6,10,11 Several reasons explain this increase: (1) ST mirrors the increase in depression in the US populations^10,12,13; (2) There has been an increase in off-label antidepressant prescribing by both primary care and mental health providers^14-16; (3) the increased use of illicit drugs¹³; (4) an increase in suicide attempts with antidepressants¹⁷; and (5) increased use of opioids for pain management, including both prescription and illicit use.^11,14 This paper reviews the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications; a presentation of symptoms from in utero to adult; diagnostic criteria; and recommended treatments.

The Veterans Health Administration (VHA) and non-VHA health care providers can play a key role in identifying and preventing serotonin syndrome/ST by keeping abreast of the latest updates of potentially lethal drug combinations. Commonly prescribed medications with the potential for a reaction include antidepressants, anxiolytics, pain medications, antinausea medications, herbal medications, and over-the-counter (OTC) medications, such as cough suppressants. Patients may be at increased risk for ST due to the growth of polypharmacy management of comorbidities.

Antidepressants

Over the past decade, antidepressant use has increased substantially in the US,United Kingdom, and Canada.¹⁴ Also the types of antidepressants prescribed has changed and been replaced with the newer agents. The selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have replaced the older tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) as first-line treatments for depression due to their improved comparative efficacy, reduced mortality following overdose, adverse effects (AEs) that are more tolerable for most patients, and the SSRIs have no anticholinergic properties (except paroxetine) (Table 1).¹⁸

In 2017 the National Institute of Mental Health reported that about 17 million adults and 3 million adolescents (aged 11-18 years) experienced at least 1 episode of major depression.¹⁹ About 40% of US veterans will experience depression, which is 3 times higher than the rate of the general US population.¹² A random sampling survey conducted of about 17,000 active-duty service members by the US Department of Defense (DoD) from November 2015 to April 2016 revealed 9.4% reported depression.²⁰ Antidepressant usage in the US and among veterans continues to increase.^12,16 In 2018, the list of top US prescribed drugs, included sertraline (14th), citalopram (21st), trazodone (24th), and escitalopram (26th).²¹ Antidepressant prescribing in the US increased 18% from 2012 to 2017.²² This trend also continues within the military with a 40% increase of antidepressant use in the past decade.¹⁶

One reason for the increase in antidepressant use is off-label prescribing.^14,23 A sampling of about 2 billion psychiatric outpatient visits in a western portion of the US found 12.9% of the prescriptions filled were off-label.¹⁵ In Minnesota, off-label prescribing of antidepressants was found to contribute to an increase in drug interactions in elderly nursing home residents.²⁴ An investigation by the Military Times of the military community revealed off-label prescribing occurs not only with antidepressant medications, but also with anticonvulsants, antipsychotics, anti-anxiety drugs, and antiepileptic medications.¹⁴

A case report that brought ST to the forefront occurred in the 1980s and involved a college student.²⁵ She was initially diagnosed with the flu. Her symptoms progressed over a 24-hour period despite treatment, leading to seizures, hyperthermia, generalized clonus, muscle rigidity, respiratory failure, and death because of unrecognized ST. Her combination of serotonin-elevating drugs included meperidine, phenelzine, chlorpheniramine, and haldol. On autopsy, there were traces of cocaine found in some of her tissue samples.