Cristina, 55, doesn’t have an easy life. For fifteen years she has been suffering from a drug-resistant depression. In the last period she has been at home sick from her job as an employee and has started a treatment of transcranial electrical stimulation, without having had any benefits for now.
The days seem to pass all the same, until she is admitted in hospital to undergo the second cycle of transcranial electrical stimulation. Suddenly, without any particular symptoms or premonitory signs, Cristina was found by the nurse in her room in a state of confusion, with nystagmus and afinalistic movements of the four limbs. Fever has also appeared. On neurological examination there are no strength deficits.
The clinical picture is particularly impressive,and the woman is immediately taken to the emergency room of the local hospital.
The woman is treated with numerous drugs for her various disorders, in particular she is taking: delorazepam and sertraline, as well as betaistine dichlorhydrate, rosuvastatin, phenofibrate, macrogol, olmesartan medoxomil/amlodipine, pantoprazole and biperidene chlorohydrate.
Family members arrived in the emergency romm report the recent suspension of lurasidone, replaced by ademetionine, and the intake of trazodone the evening before the crisis that led her to the emergency room. They also point out that Cristina has been following a ketogenic diet for about a month.
The patient is tachycardic, normotensive, tachypnoic and feverish and, given the general conditions, is immediately transferred to the intensive care unit.
Laboratory tests carried out urgently revealed a marked neutrophilia, a marked increase in creatinine and CPK.
Chest x-ray, abdomen ultrasound and brain CT were negative for acute events, while the EEG showed signs of brain suffering prevalent in the left hemisphere.
It was decided to perform a rachycentesis: the chemical-physical examination of the CSF is normal, but there is the presence in the CSF of genomic sequences of HHV-6. On the basis of this data, the patient is treated with ganciclovir, although the likely contaminating nature of the positivity.
A thoracic-abdominal CT showed an area of parenchymal consolidation in the lungs, for which empirical antibiotic therapy is set up with ceftriaxone and levofloxacin, which in a few days leads to an improvement in the radiological picture, with the disappearance of fever.
In view of renal failure, an important hydrating therapy is also set up.
Given the doubtful signs of brain suffering in EEG, is asked for a cerebral magnetic resonance imaging with contrast medium that does not show focal lesions or other intracranial lesions that may explain the electroencephalographic picture. During hospitalization there is a progressive anaemia with reticulocytes within the normal limits, unconsumed haptoglobin, folates and vitamin B12 at the lower limits, in a picture interpreted as bone marrow toxicity by ganciclovir. The haematochemical controls show, in the weeks following the suspension of the drug, a progressive slow increase in haemoglobin values.
Also during the days of hospitalization appears an important hypokalaemia not corrected by intravenous infusion of about 80 mmol/day. Magnesemia is also extremely low. Therefore, magnesium supplementation is carried out with the resolution of both hypokalaemia and hypomagnesemia.
In all this, the antidepressant therapy that Cristina took before arriving in the emergency room is suspended as a precautionary measure, in the suspicion that it may have played a role in the syndrome presented by the patient: the picture of clonies, hyperthermia, nystagmus and mental agitation is compatible with a serotonergic syndrome while rhabdomyolysis may, at least in part, be attributable to the treatment with statin associated with fibrates.
At discharge, once the symptoms are resolved, Cristina’s mood appears only slightly flexed, despite the absence of antidepressant therapy.
So many symptoms a single cause?
The case of Cristina is a classic example of how numerous adverse drug effects can be combined in a complex and difficult to interpret clinical picture. We will focus exclusively on serotonergic syndrome. It is an adverse drug reaction, potentially life-threatening, secondary to excessive serotonergic activity at the level of the central and peripheral nervous system.1
It is not an idiopathic drug reaction, but a predictable consequence of the excessive agonist action induced by drugs at the receptors of the central nervous system and peripheral serotonergic receptors.2,3 The drugs most involved are antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), being also the most widely used.4
It is usually described as a clinical triad composed of: changes in mental status, autonomic hyperactivity and neuromuscular abnormalities (often clonies), but this symptoms cortege are not always present and this makes the diagnosis often difficult and the syndrome unknown.5,6
Signs of serotonin excess range from tremor (clonies) and diarrhea in mild cases, to delirium, neuromuscular stiffness and hyperthermia in potentially fatal cases. A great danger is that mild symptoms can be easily overlooked, particularly akathisia and anxiety, and can be mistakenly attributed to the patient’s underlying condition. However, it is in these cases that the possible addition of a drug with a serotonergic effect or an increase in the dosage of drugs already in use can cause dramatic clinical deterioration.1,6-8
In the case of Cristina some confusing factors caused a diagnostic delay: first of all the EEG report and the diagnostic hypothesis of viral encephalitis, only partially corroborated by the positive for HHV-6.
A review of the literature has revealed that the frequency of electroencephalographic alterations in patients with serotonergic syndrome is about 29%, but they are mostly non-specific.9
A key factor in the resolution of the case was the careful pharmacological history that allowed us to define how the interaction between the drugs taken by the patient in the days prior to hospitalization has triggered the syndrome. In particular, the possible interaction between sertraline and trazodone is reported, since both inhibit the reuptake of serotonin. Trazodone also has an activating effect on serotonin receptors. Therefore, the association between the two drugs is contraindicated.10
To these we have probably to add the effect of ademetionine, a coenzyme involved in the transfer of methyl groups that regulates numerous biological reactions including the biosynthesis of dopamine and serotonin and therefore could have contributed to the excess of serotonin for the onset of the syndrome.11,12
As for lurasidone, suspended from the patient 7 days before the onset of symptoms, it is a second-generation antipsychotic with a long half-life (about 20-40 hours) and a large volume of distribution (6,000 l). These pharmacokinetic properties make it susceptible to accumulation and it is possible that it was still present in the patient’s circulation despite the suspension. Since it is a relatively new drug, there are few literature data on it. In a recent analysis by the FDA Adverse Event Reporting System (FAERS) of the Food and Drug Administration (FDA), a statistically significant correlation between the syndrome and the use of the drug emerges.13
Finally, the ketogenic diet that Cristina was following before her admission deserves a mention; this diet is based on the principle of elimination of all carbohydrates in favour of proteins and lipids only, so it could have altered the levels of the metabolites of dopamine and serotonin. However, there are only preliminary data from trials conducted on animal models or on a small number of patients.14-16
In conclusion, the case of Cristina calls for doctors to be extremely careful in the use of drugs with central serotonergic activity. Interactions and summations of effects must be avoided by having a greater knowledge of the pharmacodynamic and pharmacokinetic properties of the drug used. Great caution must be exercised when introducing or replacing selective serotonin reuptake inhibitors (SSRIs) and great attention must be paid to the early recognition of symptoms of serotonergic syndrome.
Alessia Olivato, Cristiano Fava, Denise Marcon
Dipartimento di Medicina, Università di Verona, Unità di Medicina Generale e Ipertensione AOUI - “Policlinico G.B. Rossi”, Verona
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- Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13.
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- Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr 2002;76:1158S-61S.
- Mischoulon D, Alpert J, et al. Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder. J Clin Psychiatry 2012;DOI:10.4088/JCP.11m07139.
- Racz R, Soldatos T, et al. Association between serotonin syndrome and second-generation antipsychotics via pharmacological target-adverse event analysis. Clin Transl Sci 2018;11:322-9.
- Dahlin M, Månsson J, et al. CSF levels of dopamine and serotonin, but not norepinephrine, metabolites are influenced by the ketogenic diet in children with epilepsy. Epilepsy Res 2012;99:132-8.
- Kantak K, Wayner M, et al. Effects of various periods of food deprivation on serotonin synthesis in the lateral hypothalamus. Pharmacol Biochem Behav1978;9:535-41.
- Sheikh K, Camejo G, et al. Beyond lipids, pharmacological PPARα activation has important effects on amino acid metabolism as studied in the rat. Am J Physiol Metab 2007;292;E1157-65.