Liver enzymes

The cytochrome (CYP) 450 family of enzymes metabolises many serotonergic medicines (Scotton et al 2019). However, some medicines inhibit groups of CYP enzymes, thereby increasing the risk of serotonin syndrome because the serotonin is not sufficiently cleared (Volpi-Abadie et al 2013). For example, SSRIs and antibiotics such as ciprofloxacin and fluconazole can inhibit CYP enzymes and increase the risk of serotonin syndrome when used in combination (Francesangeli et al 2019). Jurek et al (2019) recommended that clinicians should be aware of the pharmacological interactions of medicines to reduce the risk of adverse effects.

Kidneys

Serotonin syndrome can cause dehydration due to hyperthermia and diaphoresis (excessive sweating). In severe cases, kidney injury results from the breakdown of muscle tissues and the subsequent presence of myoglobin (an oxygen-storing protein found in muscle tissue) in the urine (Boyer et al 2021). Adequate kidney function and hydration are required to ensure the kidneys can excrete excess serotonin metabolites (Hall and Chapman 2008b). People with reduced kidney function can develop elevated serotonin levels and complicated presentations (Alusik et al 2014).

Older people

Older people are at a higher risk of developing serotonin syndrome due to their reduced hepatic and renal capacity, alongside a depletion of serotonin receptors as part of the ageing process, which means that less serotonin is required to overstimulate the receptors (Alusik et al 2014). However, Hall and Chapman (2008a) emphasised that reduced serotonin synthesis may balance this risk.

Genetic factors

Isbister (2021) reported that there is little evidence that genetic variations affect serotonin syndrome. However, Volpi-Abadie et al (2013) argued that because serotonin syndrome can manifest in a variety of medicine combinations and doses, individual genetic factors have a significant role in this (Alusik et al 2014, Francesangeli et al 2019, Jurek et al 2019, Pandya et al 2020).

Medicines

Alusik et al (2014) proposed four processes by which serotonin receptors can become overstimulated: serotonin agonists, increased serotonin release, reduced serotonin reuptake and reduced serotonin breakdown. A wide range of serotonergic medicines may trigger serotonin syndrome (Table 1), the most common of which are antidepressant agents, such as SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants, which inhibit the reuptake of serotonin (Francesangeli et al 2019).

Serotonin agonists such as triptans and metoclopramide hydrochloride also increase serotonin receptor activity (Simon and Keenaghan 2021), while recreational drugs, such as 3,4-methylenedioxy-methamphetamine (MDMA), cocaine and amphetamines accelerate the release of serotonin and inhibit reuptake (Volpi-Abadie et al 2013). The most severe forms of serotonin syndrome are precipitated by MAOIs, which inhibit the metabolism of serotonin (Simon and Keenaghan 2021).

If there is a suspicion that a patient is experiencing serotonin syndrome, clinicians must take a thorough medicines history, including dose and formulation, recent dose changes and/or additional agents, including over-the-counter medicines, dietary supplements and recreational drugs (Simon and Keenaghan 2021). Polypharmacy, the use of serotonergic agents and pharmacological interactions can accelerate serotonin syndrome. Furthermore, there is significant comorbidity between depression and pain, therefore clinicians must be aware of patients who may be taking antidepressants alongside pain medicines that involve the serotonin pathways (Hall and Chapman 2008a).

Finally, patients who have intentionally overdosed on serotonergic medicines tend to ingest higher quantities and are therefore at greater risk of developing serotonin syndrome than those who have unintentionally overdosed (Boyer et al 2021).

Clinical presentation

Tina’s signs and symptoms were assumed quickly by her mental health team to be serotonin syndrome, which ensured prompt advice to attend an ED. However, the ED staff were unaware of the condition and instead focused on differentials such as a mental health crisis or recreational drug use. Werneke et al (2016) noted that most patients with signs and symptoms of serotonin syndrome present to EDs for treatment rather than to their usual care team, which emphasises the importance of increasing ED clinicians’ awareness.

The onset of serotonin syndrome is generally sudden and can occur within one hour of increasing the dosage of, or adding another, serotonergic medicine (Francesangeli et al 2019); however, it more typically develops within six to 24 hours (Boyer et al 2021). Onset can be delayed in older people, due to the aged-related reduction in neurotransmitter and receptor activity (Hall and Chapman 2008a), and in those who start taking serotonergic medicines without a sufficient ‘washout’ period – the time required between stopping one medicine and starting another to reduce the risk of adverse interactions (Alusik et al 2014).

Patients with serotonin syndrome typically present with a triad of: mental state changes, autonomic hyperactivity and neuromuscular abnormalities (Alusik et al 2014) (Table 2).

The signs and symptoms of serotonin syndrome range from mild to life-threatening (Jurek et al 2019), and are not necessarily all present or spread equally across the triad categories (Hall and Chapman 2008b). GI issues are not included in the triad, but Skopp (2020) suggested that their presence can support a diagnosis, particularly in the context of differentials such as anticholinergic toxicity (condition precipitated by use of anticholinergic medicines and with similar features to serotonin syndrome). Francesangeli et al (2019) cautioned that mild presentations of serotonin syndrome can be confused with influenza-like signs and symptoms, which is important to note in the context of COVID-19 and seasonal influenza. Other mild signs and symptoms such as restlessness, tremors and sweating can be attributed to the side effects of medicines, deteriorating mental health or a myriad of other conditions; however, if clinicians do not consider or identify serotonin syndrome and patients continue with their medicines regimen, the condition will advance.

Moderate signs and symptoms of serotonin syndrome include agitation, clonus (muscular spasms), hyperreflexia, tachycardia, hypotension and hyperthermia of 40°C. Patients can be highly unstable and deteriorate quickly, and in severe cases tachycardia can progress to hypotension and shock (Boyer et al 2021). Muscular contractions, spasms and rigidity are believed to be the main drivers of hyperthermia, with temperatures reaching as high as 41°C or more (Talton 2020).

There may also be an increase or decrease in blood pressure and pulse, and episodes of delirium (Jurek et al 2019). The most severe incidences of serotonin syndrome can result in metabolic acidosis, which progresses to rhabdomyolysis, in which patients’ muscle fibres begin to break down, releasing their contents into the blood stream (Jurek et al 2019), in turn leading to kidney damage caused by myoglobin in the urine (Talton 2020). Excess blood clotting secondary to tissue damage can occur throughout the body, which can progress to multiple organ failure, seizures, coma and death (Alusik et al 2014, Jurek et al 2019, Talton 2020).

Diagnosis

Diagnosis is based on clinical presentation, medicines history (Volpi-Abadie 2013), and diagnostic criteria (Dunkley et al 2003). A full medicines history is advised, including any illicit drug use.

Physical examination should focus on establishing the presence and extent of autonomic and mental state signs and symptoms (Table 2) and should include a neuromuscular examination (Isbister 2021), to assess the patient’s reflexes and muscle rigidity (Jurek et al 2019). Clonus is one of the most common features of the condition and most easily induced in the ankle. Patients with severe serotonin syndrome will present with spontaneous clonus or abnormally high muscle tone, termed hypertonicity (Isbister 2021). Ocular clonus (roving eye movements) is also a prominent feature and clinicians may also observe dilated pupils and continuous or spasmodic involuntary eye movements during examination (Jurek et al 2019). Tina developed distressing visual disturbances while in the ED and described seeing the floor ‘moving’, which made it challenging for her to walk.

Abdominal examination may reveal hyperactive bowel sounds. Hyperthermia indicates the need for immediate treatment, particularly if combined with neuromuscular signs and symptoms (Isbister 2021).

Additional investigations (Box 1) are not always required but can be used to exclude differential diagnosis (Isbister 2021).

The Hunter Serotonin Toxicity Criteria (Dunkely et al 2003) (Box 2) is the most commonly used diagnostic decision tool used for serotonin toxicity, although it has been criticised for relying too heavily on neuromuscular signs and symptoms, which may overlook atypical presentations (Skopp 2020), or more serious cases (Werneke et al 2016). Tina was diagnosed with serotonin syndrome by a liaison consultant psychiatrist using the Hunter Serotonin Toxicity Criteria, which identified her recent use of serotonergic agents, the presence of ocular clonus and psychomotor agitation.

Differential diagnoses

Serotonin syndrome has several differential diagnoses, which are shown in Box 3, although it is distinguished by neuromuscular stimulation, most commonly clonus, that is absent from the conditions detailed in Box 3 (Isbister 2021). Tina’s signs and symptoms were presumed initially by ED staff unfamiliar with serotonin syndrome to be a mental health crisis, or associated with drug or alcohol misuse. Tina told her CMHT that she felt distressed by being asked repeatedly about her mental health and substance use, and anxious that her insight into her own mental health was being questioned and her physical condition dismissed. Tina’s CMHT nurse had told her that her presentation could be due to excess serotonin, so she was able to ask ED staff assertively for this to be considered and subsequently a liaison consultant psychiatrist was contacted.

Treatment

First-line treatment for serotonin syndrome is to stop any serotonergic medicines even if serotonin syndrome is only suspected. In mild cases, stopping or reducing serotonergic agents is all that is required (Isbister 2021). Following this, it is important to identify pharmacological interactions and discuss ongoing medicines options with knowledgeable clinicians such as pharmacists, doctors or non-medical prescribers. Patients with moderate toxicity must be observed in appropriate clinical settings, for example EDs or as inpatients, for a minimum of six hours (Isbister 2021).

Supportive treatment is aimed at stabilising the patient’s signs and symptoms and continued monitoring of their heart rate, blood pressure, temperature and oxygen levels to avoid deterioration. Benzodiazepines can relieve agitation and decrease neuromuscular agitation, heart rate and blood pressure, with the aim of reducing the risk of hyperthermia (Boyer et al 2021). Fluids are recommended to treat dehydration and prevent a cascade of renal complications secondary to hyperthermia and neuromuscular excitation (Alusik et al 2014). Activated charcoal, which reduces the absorption of toxins, can be given to patients who have overdosed on serotonergic agents within one hour of ingestion (Isbister 2021).

Patients with severe serotonin syndrome must be managed in critical care (Isbister 2021), to control neuromuscular excitation and hyperthermia and prevent metabolic acidosis, rhabdomyolysis and organ failure (Talton 2020). Early sedation, intubation and ventilation is advised (Isbister 2021). Muscle paralysis reduces clonus and rigidity, and external cooling can bring down the patient’s core temperature; antipyretics are of little use as the hyperthermia is caused by muscle rigidity (Isbister 2021). Serotonergic antagonists can be used to shorten the progression of serotonin syndrome (Volpi-Abadie et al, 2013). For example, cyproheptadine hydrochloride is a sedative antihistamine with 5-HT-antagonist properties and can be effective in mild-to-moderate serotonin syndrome, although its usefulness in severe cases has not been researched adequately (Scotton et al 2019). Additionally, chlorpromazine hydrochloride, an antipsychotic with less potent 5-HT-antagonist activity, can be administered. Chlorpromazine works by blocking dopamine receptors; however, neuroleptic malignant syndrome is a rare reaction to antipsychotic medicines whereby increased blockade of dopamine receptors causes symptoms such as stiffness and tremor. If clinicians decided to administer chlorpromazine to a patient suspected of having serotonin syndrome, neuroleptic malignant syndrome would first need to be ruled out as a differential diagnosis because administering chlorpromazine could result in deteriorating neuroleptic malignant syndrome symptoms (Jurek et al 2019). Cyproheptadine also exerts some weak anticholinergic properties (Boyer et al 2021), therefore anticholinergic toxicity must be ruled out. As cyproheptadine and chlorpromazine can cause mild hypotension they should be administered with adequate hydration to offset this effect (Hall and Chapman 2008a).

Once Tina’s diagnosis of serotonin syndrome was confirmed, she was monitored for signs of deterioration and given diazepam 5mg for agitation and restlessness, which was effective. On discharge from the ED, Tina was advised to maintain her hydration, reduce her duloxetine to 60mg and seek an urgent review with her CMHT.

Duration

Francesangeli et al (2019) reported that 70% of mild-to-moderate cases of serotonin syndrome resolve within 24 hours of treatment initiation, although patients with severe signs and symptoms can take up to two weeks to recover (Hall and Chapman 2008b). Signs and symptoms can persist for longer when medicines have a long half-life, for example norfluoxetine, the metabolite of the SSRI fluoxetine, has a half-life of 16 days (Skopp 2020).

Tina’s signs and symptoms improved significantly within 24 hours and resolved fully within five days. She had an urgent medication review with her CMHT three days after ED discharge, at which it was agreed to maintain the doses of duloxetine at 60mg and trazadone at 150mg, which had been beneficial previously. Tina also had regular contact with the CMHT during her recovery to ensure that she was continuing to improve and there were no further adverse effects.