Serotonin syndrome I Case notes Serotonin syndrome in asymptomatic Huntington’s disease Verity Haffenden BSc, MBBS, Anish Patel MBChB, MRCPsych, MedEd(Cert) Serotonin syndrome is a rare Figure 1. Hunter’s Criteria (adapted from Boyer and Shannon, 2005)6 and serious condition most often resulting from iatrogenic insult; the prescriber’s pen is Has a serotonergic agent been administered in the past five weeks? sometimes the most poisonous. Here, Dr Haffenden and Dr No Yes Patel discuss a complex case of serotonin syndrome in a patient with genetically proven, but not Not serotonin Are any of the following symptoms yet symptomatic, Huntington’s syndrome present? disease and chronic renal Tremor and hyperreflexia impairment. A screening Spontaneous clonus process is proposed to recognise the multitude of No Muscle rigidity, temperature >38°C, and Yes precipitating factors, which either ocular clonus or inducible clonus aligned in this case, and could Ocular clonus and either agitation or either alter our prescribing or diaphoresis expedite recognition. Inducible clonus and either agitation or diaphoresis untington’s disease (HD), a Hprogressive neurodegenerative Not serotonin Serotonin disease, is clinically diagnosed with syndrome syndrome a triad of signs/symptoms: chorea; psychiatric illness, and dementia. Research has shown neurotransmit- surgery was performed using a Past medical history of note ter deficits in mice models of Hun- cadaveric specimen but his postoper- included a genetic, but not yet tington’s1 both before and after ative period was complicated by anti- symptomatic, diagnosis of HD and symptomatic disease presence2 – body-mediated rejection and past psychiatric history included namely a reduction in serotonin. A steroid-induced psychosis (resolved depression, for which he was taking review of the research demon- with reduction of steroids and admin- citalopram 20mg once daily. The strated a few cases of neuroleptic istration of PRN haloperidol). Six only other prescribed medication malignant syndrome (NMS)3 but weeks postoperatively the patient was with a psychotropic effect was tram- found no linked cases of serotonin improving and his creatinine had adol, prescribed for analgesia. syndrome (SS) and either sympto- fallen from 1006µmol to 368µmol Assessment and examination matic or asymptomatic HD. As such but he became acutely confused and revealed a diaphoresis, bilateral our patient sparked a lot of multi- was wandering the ward naked, trem- inducible clonus and hyperreflexia, disciplinary interest. ulous and clammy. Investigations, upper limb tremor and expressive including bloods, CT head and lum- dysphasia. Approximately 30 min- Case presentation bar puncture, did not uncover the utes prior to this episode the patient A 53-year-old male was admitted for aetiology and he was referred to our had received a stat dose of the renal transplant, due to renal failure liaison psychiatry service for assess- antiemetic ondansetron, 4mg intra- resulting from an IgA nephropathy, ment and diagnosis of this acute venous, as he was feeling nauseated. with a creatinine of 1006µmol/L. His alteration in his mental state. Blood tests revealed a chronic renal www.progressnp.com Progress in Neurology and Psychiatry I Vol. 22 Iss. 1 2018 I 21 Case notes I Serotonin syndrome impairment, hyperkalaemia, hyper- serotonin syndrome in patients with medication thus potentially pre- calcaemia, anaemia, raised lactate a previous psychiatric history who cipitating serotonin syndrome. and mild leucocytosis. were given ondansetron, linked to Our patient was taking citalo- With consideration of the symp- the concomitant use of pro-seroton- pram and given a stat dose of toms and use of three drugs with a ergic medications, but again high- ondansetron. Both of these med- serotonergic action model (citalo- lighting the role of ondansetron in ications work with CYP450 in pram, tramadol and ondansetron) patients who are predisposed to neu- some way; ondansetron is a sub- a working diagnosis of serotonin rotransmitter deficit.8 strate for the CYP1A2 enzyme, syndrome was made. Management We feel our case highlights the which is inhibited by citalo- was supportive with cessation of ser- combination of several predispos- pram.10 This interaction results in otonergic agents and IV hydration, ing factors making this patient accumulation of ondansetron. and complete recovery was seen more vulnerable to the use of mul- after approximately 48 hours. tiple serotonergic agents. These This complex interplay also empha- include: sises the desirability of a medication Discussion • Factors affecting renal clearance – interaction checking tool to aid safe This case highlights an example of ser- Reduced renal clearance leads to prescribing. With knowledge of otonin syndrome, a condition result- higher circulating plasma concen- these enzymes and the emerging ing in a number of symptoms, trations of serotonin. With a use of mechanistic models in pre- including hyperthermia, clonus, dia- chronic renal impairment it is likely dicting drug-drug interactions we phoresis, agitation and hyperreflexia. our patient was not able to clear ser- may in the future be able to predict An increased serum serotonin level otonin as one would expect. severe adverse reactions in specific does not predict the development of • Neurodegenerative conditions – There patient populations.11 serotonin syndrome and cannot be is evidence in the literature to suggest used to aid diagnosis.4 A useful and that patients with a neurodegenera- Implications for clinical care accurate diagnostic tool in these tive condition such as Parkinson’s dis- Our case not only adds to the litera- patients is Hunter’s criteria5 as out- ease are predisposed to the ture a previously unpublished case lined in Figure 1;6 with a sensitivity of development of serotonin syndrome.9 of serotonin syndrome associated 84% and a specificity of 97% this is Perhaps an already vulnerable brain is with HD. It also usefully illustrates now the accepted standard reference more easily influenced by small multiple predisposing and precipi- tool for diagnosis. Treatment of sero- changes in neurotransmitters. We pos- tating factors occurring together, tonin syndrome is conservative and tulate that the same is the case with that have been previously implicated supportive with discontinuation of ser- HD; although no reported cases were individually, in the development of otonergic agents, active cooling mech- found on review of the literature, we serotonin syndrome. Dissecting out anisms for hyperthermia, airway and were able to find evidence of cases these factors in an attempt to dis- volume support and benzodiazepines associating the equally lethal condi- cover why our patient developed ser- for agitation.4 This patient’s presenta- tion of NMS in four patients with HD.3 otonin syndrome helps to formulate tion met the suggested diagnostic cri- Although a different neurotransmit- a checklist that can prompt clini- teria for serotonin syndrome given the ter is implicated in the development cians to consider their prescribing acute onset of neuropsychiatric symp- of NMS, perhaps an association decisions. In the age of electronic toms and resolution of symptoms between the syndrome and a neurode- prescribing this could be an auto- upon cessation of serotonergic agents generative condition demonstrates an mated algorithm that produces an in the absence of any alternative element of vulnerability to subtle alert with the prescription of two or medical aetiology. changes in neurotransmitter levels. more serotonergic drugs with Although some of the literature • Pharmacokinetics – Certain increasing severity dependent on refutes the role of ondansetron in cytochrome P450 (CYP450) the patient’s creatinine, neurologi- the development of serotonin syn- enzymes have been implicated in cal vulnerability and psychiatric his- drome7 a clear temporal association the development of serotonin tory. Frequent prompting in this between ondansetron treatment and syndrome. These enzymes metab- manner would also increase aware- onset of serotonin toxicity is demon- olise multiple drugs and can also ness of serotonin syndrome amongst strated here in a neurologically vul- be inhibited by multiple drugs; prescribers and thus potentially nerable patient. There have been their inhibition may result in the expedite diagnosis and subsequent case reports of the development of accumulation of a serotonergic cessation of serotonergic agents. 22 I Progress in Neurology and Psychiatry I Vol. 22 Iss. 1 2018 www.progressnp.com Serotonin syndrome I Case notes Conclusion Liaison Psychiatrist, both at NBT 5. Dunkley EJ, Isbister GK, Sibbritt D, et al. The This case raises several points that Mental Health Liaison Team, South- Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin are of clinical importance. Firstly, it mead Hospital, Bristol. toxicity. QJM 2003;96(9):635–42. acts as a reminder of the serious 6. Boyer EW, Shannon M. The serotonin and potentially fatal serotonin syn- Declaration of interests syndrome. N Engl J Med 2005;352(11):1112–20. 7. Rojas-Fernandez CH. Can 5-HT3 Antagonists drome. Secondly, it highlights the No conflicts of interest were Really Contribute to Serotonin Toxicity? A Call need for adequate risk assessment declared. for Clarity and Pharmacological Law and Order. Drugs Real World Outcomes 2014;1(1):3–5. prior to the prescription of a sero- 8. Schuch LG, Yip A, Nouri KF, et al. Serotonin tonergic