Episode 174: “Serotonin Toxicity”, Otherwise known as Serotonin Syndrome

Alexander Horwitz, M.D., Ken Gillman, M.D., David Puder, M.D.

Conflicts of interest for this episode: Dr. Gillman has equity interests in and is on the advisory board of NeuraWell Therapeutics, the company that has the patent for a modified form of tranylcypromine.

Introduction

In today’s episode of the podcast, we are joined by psychiatrist and neuropharmacologist Dr. Ken Gillman who is the founder and convener of the International MAOI (monoamine oxidase inhibitor) Expert Group and widely recognized as a world expert in serotonin toxicity. 

Serotonin toxicity (syndrome) is a rare as well as potentially lethal form of toxicity that results from excess serotonin within neuronal synapses. There are numerous poorly written/controlled case reports that have perpetuated misinformation about drugs that can cause serotonin toxicity. While the word “syndrome” is often used, toxicity is a more accurate description given that toxicity represents a spectrum of severity rather than a defined set of symptoms. In today’s podcast, we will discuss the pathophysiology, causes, clinical presentation, criteria, controversies, and medical management of serotonin toxicity. 

Definition and Clinical Presentation

Serotonin toxicity is a direct result of ingesting drugs that substantially increase brain concentrations of serotonin. It can be thought of as a drug-induced toxicity caused by serotonin poisoning. Toxicity is viewed as a more accurate description than syndrome for a variety of reasons. In medicine, the term syndrome is a broad definition often used to encompass a set of signs or symptoms without necessarily attributing them to a single identifiable pathogenesis. Syndrome is also often used to imply that something is idiosyncratic and occurs only in certain people and not others, such as neuroleptic malignant syndrome (NMS). Toxicity implies a spectrum as opposed to a circumscribed set of symptoms. Lithium overdose is not referred to as lithium syndrome – why should this be the case with serotonin?

Excess serotonin produces a spectrum of severity with clinical effects ranging from mild signs and symptoms (which may be underdiagnosed) such as tremor and diaphoresis, all the way to more serious effects including muscular hypertonicity and hyperthermia. It is useful to characterize serotonin toxicity as a clinical triad:

1. Neuromuscular abnormalities (particularly hyperactivity): hyperreflexia, hyperkinesia, tremor, clonus, and pyramidal rigidity (in severe cases)

2. Autonomic hyperactivity: mydriasis, hyperactive bowel sounds, tachycardia, tachypnea, hyperthermia, diaphoresis

3. Altered mental status: agitation and hyperarousal.

Symptoms of serotonin toxicity develop rapidly (over hours as opposed to days). Neuromuscular signs are often more observable in the lower limbs. While there are multiple non-specific symptoms associated with serotonin toxicity (e.g., diaphoresis and tachycardia), as discussed below, clonus is the single most important sign for diagnosing serotonin toxicity. Clonus often starts in the lower limbs and then becomes more generalized. 

Pathophysiology

Serotonin toxicity is mediated through 5-HT2A [5-HT = 5-hydroxytryptamine = serotonin] receptor agonism. It was initially thought that 5-HT1A agonism contributes to serotonin toxicity, but it was later shown that 5-HT1A antagonists have a negligible effect on the treatment of serotonin toxicity and that 5-HT1A agonists cause hypothermia (not hyperthermia). In order to induce serotonin toxicity, a drug must increase serotonin concentrations by 50-100 times above baseline. Severe toxicity will result in intrasynaptic serotonin concentrations 1000 times above baseline.

Dr. Gillman has noted three classes of drugs that, in certain combinations at therapeutic doses, can lead to severe serotonin toxicity: 

1. Monoamine oxidase inhibitors (MAOIs)

2. Serotonin reuptake inhibitors [including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs); given that the word “selective” in SSRI is largely a misnomer, moving forward, they will be referred to [S]SRIs]

3. Serotonin releasers [e.g. MDMA (“ecstasy”)]

While there are other combinations of drugs/medications that can possibly or rarely cause serotonin toxicity, with normal therapeutic doses, only [S]SRI plus MAOI is likely to lead to severe serotonin toxicity. The risk of an MAOI precipitating serotonin toxicity is related to its inhibition of monoamine oxidase A (MAO-A), which is responsible for the breakdown of serotonin in addition to norepinephrine and dopamine. Monoamine oxidase B (MAOI-B) does not metabolize serotonin.

The following diagram was taken from Dr. Gillman’s website, psychotropical.com, and is a schematic way of considering interactions between the three classes of drugs that can lead to severe serotonin toxicity:

Of note, [S]SRIs block the entry of MDMA into the serotonergic neuron via SERT and therefore prevent the release of excess serotonin and serotonin toxicity. 

Overdose with a single [S]SRI leads to moderate serotonin toxicity (requiring inpatient admission and medical treatment) in only 10-20% of cases, but with no fatalities or hyperthermia [i.e., temperature over 38.5 degrees Celsius or 101.3 degrees Fahrenheit].  Combining an MAOI with a [S]SRI leads to severe serotonin toxicity in about 50% of cases (even with therapeutic doses). 

Criteria

There are two major criteria for the diagnosis of serotonin toxicity: the Sternbach Criteria and the Hunter Criteria. The Sternbach Criteria were proposed by psychiatrist Dr. Harvey Sternbach in 1991. Dr. Sternbach reviewed a total of 38 cases from 10 case reports and two case series published in the literature to identify the most common signs and symptoms. In 2003, Professor Ian Whyte (a medical toxicologist) and colleagues published new criteria for serotonin toxicity. 

The Hunter Serotonin Toxicity Criteria published by Whyte and colleagues examined all patients admitted to the Hunter Area Toxicology Service (HATS) located in the Hunter Area of New South Wales, Australia, from January 1987 to February 2003 (n = 9960). Data collection was performed by a team of medical toxicologists, which yielded prospective data that was much more reliable than Sternbach’s 38 case reports. The 2003 paper identified 2222 cases of serotonin toxicity (thousands more cases have been subsequently added to the HATS database) and noted that only the following variables were required for accurately predicting serotonin toxicity: spontaneous clonus, inducible clonus, ocular clonus, agitation, diaphoresis, tremor, and hyperreflexia. It is important to note that serotonin toxicity represents a spectrum of symptoms that progress as follows: tremor