Presentation

Patients in mental health services are often treated with combinations of antidepressants and antipsychotics; the antagonistic role of olanzapine and risperidone at 5-HT_2A receptors and the partial agonism of many atypical antipsychotics at 5-HT_1A receptors is often disregarded. Further, it has been suggested that some people with psychiatric illness, especially those with schizophrenia, have abnormal thermoregulation, which includes an elevated baseline temperature (Reference Chang and CastleChang 2004). In susceptible individuals, serotonin syndrome may be precipitated when serotonin levels at specific synapses in the CNS are multiplied manifold.

In practice, serotonin syndrome usually results from drug interactions, classically secondary to the combined overdose of an SSRI with an (irreversible) monoamine oxidase inhibitor (MAOI), which in around 50% of cases is believed to result in severe serotonin syndrome. Moderate serotonin toxicity has been noted in 15% of people who took large quantities of SSRIs in overdoses (Reference Buckley, Dawson and IsbisterBuckley 2014). It can also occur where the drugs used have previously unrecognised serotonergic properties. Among others, anticonvulsants, anti-emetics, antimicrobials, anti-migraine and recreational drugs have been associated with serotonin syndrome (Reference GillmanGillman 2010b; Reference Monte, Chuang and BodmerMonte 2010; Reference Cooper and SejnowskiCooper 2013).

Severe serotonin toxicity can have a rapid onset and deterioration; death can ensue within 24 h. This may be alarming not only for the observer but also for the patient, who often remains alert in the early stages (Reference GillmanGillman 2005). Symptoms may be noted from 2 h and most present within 6–8 h of addition/ingestion of the relevant substance (Reference Ener, Sharon and MeglatheryEner 2003; Reference Haddad and DursunHaddad 2008). Chronic, less dramatic presentations have been described where the only symptom is anxiety, restlessness or diarrhoea, thus perhaps escaping recognition. In some cases symptoms may be misattributed to deterioration in mental state, with the risk of increasing or additional medication (Reference Ener, Sharon and MeglatheryEner 2003).

Serotonin syndrome: mechanism

Presynaptic neurons in the raphe nuclei, largely restricted to the basal plate of the pons and medulla, synthesise and release serotonin. The serotonin transporter (SERT) located on these cells plays a major role in reabsorption of much of this; some of this intrasynaptic serotonin also binds to autoreceptors, triggering a negative feedback loop, thus modulating its own release. Serotonergic medications through different mechanisms act on various steps of this process: SSRIs block the action of SERT, thereby increasing the available serotonin in the synaptic space by limiting the recycling process. Increased serotonin neurotransmission results, mainly at postsynaptic 5-HT_1A and 5-HT_2A receptors; currently both these subtypes, as well as peripheral and central serotonin, are implicated in the wide range of symptoms and signs in serotonin syndrome (Reference Haddad and DursunHaddad 2008).

There appears to be a sequential stimulatory effect in the presence of excess serotonin, which corresponds roughly to the spectrum of increasing toxicity. This may be observed clinically when the more abundant 5-HT_1A receptors are stimulated at lower levels, accounting for some of the less severe symptoms, including, initially, hypothermia. Overstimulation of 5-HT_2A receptors occurs at much higher serotonin concentrations; this subtype is now generally considered to be the mediator of the more severe, toxic aspects of serotonin syndrome, with marked pyrexia and neuromuscular hyperactivity. Not only is there a complex interplay between these two receptors, but also very high serotonin levels potentiate glutamatergic, noradrenergic and dopaminergic pathways, with progression to extreme toxic states; such toxicity may be precipitated subsequent to the ingestion of cocaine or 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) (Reference Haddad and DursunHaddad 2008).

There is support for the theory that a particular concentration of serotonin is a prerequisite for the development of serotonin syndrome. However, there is considerable inter-individual variation and this variability has its basis in genetic factors, which include polymorphisms of CYP2D6, SERT or the serotonin receptors themselves (Reference GillmanGillman 2005; Reference Fox, Jensen and GallagherFox 2007).

Diagnosis

Diagnosis is clinical and associated with a history of current or recent ingestion of a serotonergic drug(s). Measurement of serum serotonin levels does not add to the diagnosis; psychotropic drugs can accumulate in the brain in concentrations that are 10–40 times higher than in the serum. Acute medical presentations with generalised clonus (usually easier to elicit in the lower limbs) associated with rising temperature should prompt careful scrutiny of the pharmacotherapy and the consumption of certain foods and supplements, such as caffeine in its various forms, grapefruit juice and over-the-counter medicines such as St John’s wort. Other possible causes should be excluded. Serotonin syndrome should be considered when any patient presents with a combination of suggestive clinical features. In practice it can be difficult to identify clonus and hyperreflexia in severely toxic cases with progression to rigidity.

It may be simpler to consider the symptoms under three group headings:

1. neuromuscular: tremor, ocular clonus,Footnote a myoclonus, hyperreflexia, akathisia and muscular rigidity

2. autonomic: fever, flushed skin, tachycardia, diaphoresis, diarrhoea, abdominal cramps and tachypnoea

3. mental state/CNS: agitation, insomnia, hypomania,Footnote b hallucinations (visual), confusion and seizures.

Differential diagnosis

Before diagnosing serotonin toxicity it is important to consider neuroleptic (antipsychotic) malignant syndrome (Table 1) and other alternative or even comorbid possible causes, such as infection, metabolic upset and substance misuse/withdrawal states. Additional factors that may contribute to serotonin syndrome include dietary supplements, lithium ingestion, electroconvulsive therapy (ECT), hepatic or renal diseases, genetic defects in xenobioticFootnote c metabolising enzymes, and combinations of psychotropic medication with inhibitors of their enzymes, for example an SSRI with an MAOI.

TABLE 1 Comparison of clinical features of serotonin syndrome with those of neuroleptic malignant syndrome

Serotonin syndrome and interface with other specialties

Serotonin syndrome has been reported perioperatively as a result of serotonergic potentiation secondary to the coadministration of fentanyl during anaesthesia (Reference GillmanGillman 2005), to the use of methylene blue dye during parathyroid surgery (Reference GillmanGillman 2010b) and to the use of linezolid in the treatment of severe infection (Reference Shaikh, Krueper and MalinsShaikh 2011). Linezolid is a synthetic oxazolidinone antibiotic with a half-life of 5 h; it was originally developed for use as an antidepressant owing to its reversible non-selective MAO inhibitory properties. Its coincidental antimicrobial properties led to its further development and subsequent use in treating specific Gram-positive infections such as methicillin-resistant Staphylococcus aureus (MRSA) (Reference Jones, Athan and O'BrienJones 2004). Serotonin syndrome has recently been described following rewarming in patients who had been treated with therapeutic hypothermia for cardiac arrest (Reference Fugate, White and RabinsteinFugate 2014) and in a breastfed neonate whose mother had been taking 60 mg fluoxetine daily (Reference Morris and MatthesMorris 2015).

Management of serotonin syndrome

Treatment in mild to moderate cases consists of identifying and discontinuing the serotonergic medication(s), whereupon resolution usually follows within 1–3 days. There is currently no specific test to confirm the diagnosis of serotonin syndrome. Non-specific abnormalities, including raised white cell count, raised creatine kinase, and reduced magnesium, calcium and sodium levels, have been noted. However, monitoring of haematological and biochemical parameters, including a drug screen, may be useful where the diagnosis is unclear and in the treatment of patients who exhibit severe toxicity (Reference Iqbal, Miles and KaplanIqbal 2012). Maintain fluid balance, paying careful attention to urinary output and undertake regular observations of pulse, blood pressure and temperature (Reference Buckley, Dawson and IsbisterBuckley 2014).

An electrocardiogram (ECG) should be undertaken, for example where tricyclic antidepressants have been ingested; arrhythmias and postural hypo tension may not be self-evident. Liver toxicity may ensue either directly from large doses of lofepramine or as a secondary effect of the serotonin syndrome. An electroencephalogram may help in excluding non-convulsive epileptic states. Care should be taken where slow-release preparations or benzodiazepines have been ingested: observation times should be increased to 12 h or more in order to monitor for a delay in emergent side-effects. This should not detract from managing the patient’s immediate presenting symptoms in the meantime. Measurement of urinary dopamine and serotonin metabolites has been proposed as a possible adjunct to clinical assessment.

In moderate to severe serotonin syndrome individuals are likely to exhibit a degree of agitation and this can be treated with oral diazepam. However, it is important not to underestimate the possibility of rapid deterioration, especially in situations where even low doses of both an MAOI and an SSRI have been taken together, and input from the medical team should be sought. This should be done immediately if the patient has consumed large quantities of drugs, if there is doubt about the quantity or type of medication ingested, if novel psychoactive substances have been used, if combinations of medications have been taken or if there is suicidal intent with an unknown quantity of medication. There may also be cardiotoxic effects, such as prolonged QT interval, as in the case of overdose with citalopram. Norfluoxetine has a half-life of about 17 days, while its parent compound fluoxetine has a half-life of about 7 days. Together, the two compounds can precipitate serotonin syndrome several weeks after the last dose, especially if an irreversible MAOI is subsequently prescribed.

Drug screening should be undertaken and early contact with toxicology services considered. Benzodiazepines may help with muscle rigidity/hyperactivity, myoclonus, seizures and agitation. Lorazepam or oxazepam have been suggested as the most appropriate benzodiazepine, the rationale being their shorter duration of action and lack of active metabolites (Reference Ahuja and ColeAhuja 2009). Diazepam use has also been described (Reference Buckley, Dawson and IsbisterBuckley 2014). Prudence is required in the use of benzodiazepines in elderly patients, who may develop delirium or hypotension, especially where there is impaired liver or kidney function.

Common antipyretic drugs are not indicated in serotonin syndrome. Excess muscle activity contributes to the hyperthermia, so muscle paralysis may be required to curb this in extreme cases (Reference Boyer and ShannonBoyer 2005; Reference Volpie-Abadie, Kaye and KayeVolpie-Abadie 2013). Avoid the use of restraint, as active resistance can contribute to metabolic acidosis and lead to further rise in body temperature. Pyrexia of 38.5°C or higher, and/or markedly increased truncal rigidity may herald imminent respiratory distress: in such cases senior medical advice should be sought immediately, as rapid deterioration is likely to ensue (Reference Dunkley, Isbister and SibbrittDunkley 2003).

Further interventions include the antihistamine cyproheptadine (an antagonist at both 5-HT_1A and 5-HT_2A receptors) and chlorpromazine, a 5-HT_2A antagonist which may require prior fluid loading to prevent hypotension (Reference Buckley, Dawson and IsbisterBuckley 2014). Although both these drugs have recognised serotonin receptor antagonist properties, their use has been described on a theoretical basis only and they remain unlicensed for this purpose. Owing to the common symptom profile shared by serotonin syndrome and neuroleptic malignant syndrome, it may be prudent to confine the use of chlorpromazine to severe cases treated by experienced prescribers of the drug. There is a lack of supporting evidence for the use of propranolol or haloperidol in serotonin syndrome.

Highly toxic states, where the body temperature rises to over 40°C, are associated with a risk of multi -organ failure and death; active cooling is imperative (Reference Buckley, Dawson and IsbisterBuckley 2014). It has been suggested that lowering of body temperature reduces functionality of the 5-HT_2A receptors (Reference Krishnamoorthy, Ma and ZhangKrishnamoorthy 2010), which may minimise triggering of neurotoxic cascades (Reference Fugate, White and RabinsteinFugate 2014). Rapid cooling may be achieved by covering the body in ice packs in conjunction with the use of cooled fluids for bladder and/or peritoneal lavage and for intravenous administration. Disseminated intravascular coagulation, kidney failure, acidosis and acute respiratory distress syndrome are also possible secondary complications of severe serotonin syndrome and intensive supportive care is likely to be necessary.

Further management

A detailed review of the patient’s prescribed drugs should be undertaken 1–2 weeks after the serotonin syndrome has resolved. Alternatives should be considered where possible. Some of the causative medications may be individually retitrated, beginning at lower doses. Most SSRIs have a half-life of 12–36 h and require a washout period of 7–14 days before restarting. Where an MAOI was involved in the cause of serotonin syndrome, serotonergic agents should not be restarted for at least 14 days. Fluoxetine has active metabolites with a 5–7 day half-life, thereby requiring a 5-week washout period; serotonergic interactions may thus occur several weeks after its discontinuation. Patients should be monitored for increased anxiety, agitation, tremor, pulse, blood pressure, temperature, headache and reflexes. Care should be exercised; recurrence of serotonin syndrome following exposure to a different serotonergic drug has been described in the presence of pre-existing liver disease (Reference Tomaselli and ModestinTomaselli 2004).

Prognosis

The prognosis is good, especially where there has been early recognition, immediate discontinuation of the causal medication and rapid establishment of appropriate supportive measures (Reference Sun-Edelstein, Tepper and ShapiroSun-Edelstein 2008). A degree of confusion may persist for a few days, and sometimes muscle pain for longer. Reference ChechaniChechani (2002) reported four severe episodes of serotonin syndrome in the same woman; with two different SSRIS, she continued to experience muscle aches and tremors 2 months after resolution of the syndrome. This may be partly due to the necessity of abrupt cessation of potent CYP2D6 inhibitors such as paroxetine, or occasionally to SSRI-induced extrapyramidal side-effects of medications with long half-lives, such as fluoxetine, along with their active metabolites (Reference LaneLane 1998).

Prevention

We have an aging population often treated with complex regimens of multiple drugs. This poses particular challenges if several medical conditions co-occur. Reference Lingam and ScottLingam & Scott (2002) state that 10– 60% of patients do not take their antidepressant medication as prescribed; introduction of the SSRIs appears to have had little impact on this. Patterns of adherence to prescribed antidepressants vary from taking excessive amounts sporadically, to periodic use, to frequent stop–starts, to abrupt cessation; around a third of patients who discontinue their medication may not reveal this to their doctor. There is thus not only the risk of toxicity but of experiencing discontinuation symptoms, which include sleep disturbance, agitation, anxiety and depression (Reference Demyttenaere and HaddadDemyttenaere 2000). Patient- and/or illness-related factors may contribute to this; sensitively exploring patients’ attitudes, associated health beliefs and treatment expectations may be helpful in assessing the degree of medication adherence. Routine enquiry about various foods, including caffeine consumption, and the use of recreational drugs may assist in the face of apparent treatment non-response before prescribing second- or even third-line medication. The importance of advising patients against mixing other substances with prescribed drugs should not be underestimated. Medication reconciliation and communication with other people who may be prescribing for patients are key.

MCQs

Select the single best option for each question stem

1. 1 How many families of serotonin receptor subtype have been identified?

   1. a 3

   2. b 9

   3. c 2

   4. d 7

   5. e 5.

2. 2 Which body organ contains the highest density of the cytochrome P450 enzymes?

   1. a lungs

   2. b spleen

   3. c liver

   4. d kidneys

   5. e brain.

3. 3 Caffeine is both metabolised by and an inhibitor of which CYP enzyme?

   1. a CYP2D6

   2. b CYP1A2

   3. c CYP2C19

   4. d CYP2C9

   5. e CYP3A4.

4. 4 Which of the following was noted in severely toxic presentations of serotonin syndrome and added to the Hunter criteria?

   1. a tremor

   2. b diaphoresis

   3. c hyperreflexia

   4. d rigidity

   5. e agitation.

5. 5 Which treatment option has not been found to be useful in the clinical management of serotonin syndrome?

   1. a antipyretic medication

   2. b discontinuation of serotonergic medication

   3. c chlorpromazine

   4. d benzodiazepines

   5. e cyproheptadine.

MCQ answers

1

d

2

c

3

b

4

d

5

a