Analysis of Serotonin Syndrome - Thesis Example

Serotonin Syndrome [Pick the Serotonin syndrome, first mentioned in 1959 in a patient with tuberculosis, was not given much research space till much later and was even for a long time considered to be a disease restricted to animals. But since its presence first reported in man in 1982, the disease has been much investigated and has been found to be a potentially life threatening disease. The disease is iatrogenic, caused by administration of a combination of drugs or overdose of a single drug. The symptoms withdraw immediately post discontinuation of causative drugs, usually within 24 hrs and medication may be needed only in cases of severe complication. The determining factor in disease management is therefore, early recognition of the symptoms, which themselves are the major diagnostic factors. The essay is an outline of the researches contributing to an understanding of the various aspects of the disease. Keywords: Serotonin Syndrome, receptors, Serotonergic agents. Introduction: Serotonin syndrome is a combination of symptoms that occur as a result of overstimulation of specific serotonin receptors. It usually develops as a consequence of administration of more than one (rarely one) drug that is a serotonergic agent. Described as a possibility first in 1955 by Mitchell, in a tuberculosis patient administered iproniazid and meperidine simultaneously, the disease has been in existence since much longer. Initially studied as a behavioural disorder exclusively in animals (Grahame-Smith, 1971), the disease was much later associated with humans (Insel et al., 1982). The increase in incidences of the syndrome was reported as a consequence of prescribing selective serotonin reuptake inhibitors (SSRI) for treatment of depression, which lead to an interest in serotonin syndrome. The disease is characterized by restlessness, incessant twitching, excitement, agitation and tremor or shivering. The disease severity can vary from mild to intense, though severe cases of disease are rarely reported and can be treated by withdrawal of causative agents as well as use of serotonin antagonists. In its most severe form the disease can even be life threatening. Serotonin: Chemically 5-hydroxytryptamin or 5HT, Serotonin is a neurotransmitter formed by hydroxylation and decarboxylation of amino acid tryptophan. It is involved in the control and expression of a plethora of feelings ranging from depression and psychosis, to hunger and slumber. It also plays important role in body temperature, sexual behaviour, pain and memory. Serotonin secreting neurons are known as serotonergic. However, serotonin function is determined by its interaction with its receptors, a number of which have been identified till date viz. 5HT1 (subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E and 5HT1F), 5HT2 (SUBTYPES 5HT2A, 5HT2B and 5HT2C), 5HT3, 5HT4, 5HT5 (SUBTYPES 5HT5A & 5HT5B), 5HT6 and 5HT7 (Bijl, 2004). While some of the serotonin receptors are presynaptic (5HT1A, 5HT1B), others are post synaptic. Most serotonin receptors occur in association with G proteins except 5HT3, which is ion channel. With help of its wide array of receptors, serotonin also influences the activity of many other neurotransmitters. While a balanced level of serotonin can be a boon, elevated levels due to an overstimulation of serotonin receptors can have both positive and negative influences. This aspect of serotonin function becomes more important in the light of the fact that serotonin production is not only natural, but several drugs are known to cause overstimulation of serotonin receptors, leading to a hyperserotonergic state. Symptoms: Symptoms for the diagnosis of serotonin syndrome can broadly be classified into three categories (Birmes, 2003): Alteration in mental status Changes in functioning of autonomous nervous system specifically its hyperactivity such as diarrhoea, mydriasis and sweating. Neuromuscular disorders exhibited in form of muscular rigidity, clonus and hyperreflexia along with shivering in some cases. Different researchers have given different criteria for the diagnosis of serotonin syndrome on the basis of its symptoms as observed in various case reports. The oldest and still the most exhaustive set of symptoms was given by Sternbach (1991) on the basis of 12 reports of 38 cases studied in man as well as animals. The criteria are as shown in the table 1. Altered mental state Restlessness Myoclomus Hypereflexia Diaphoresis Shivering Tremor Fever Lack of coordination Diarrhoea Table 1: Symptoms of Serotonin syndrome, Sternbach (1991) Presence of any three of these criteria accompanied by a clinical history supporting the serotonin syndrome was has been considered as diagnostic by Sternbach (1991). This is a vague set of diagnostic features in terms of severity of disease compared to that of Birmes (2003). Mills (1997), on the basis of study of 127 cases has on the other hand reported a list of 34 criteria, based on their frequency of occurrence, as shown in pie charts below (figures 1, 2, 3 and 4). The disease is diagnosed on the basis of occurrence of three or four major and two minor symptoms (January, 2001). Figure 1 Figure 2 Figure 3 Figure 4 Symptoms of serotonin syndrome appear after one or two doses of causative medication which may either be in combination or excessively high doses of single causative drug. The appearance and progress of symptoms is fairly rapid and acute. While mild symptoms are rarely reported or even noticed, severe symptoms can even be fatal. Pathophysiology: Of the seven known serotonin receptors, the major ones involved in serotonin syndrome are 5HT1A and 5HT2A (figure 5). The 5HT1A receptors are unevenly present in human brain, with comparatively higher concentrations in hippocampus, frontal cortex, amygdala and raphe nuclei. They are known to be cause hyperactivity, hyperreflexia and anxiety upon hyperstimulation, and therefore are primarily implicated in occurrence of serotonin syndrome, the major influence being their overstimulation in central gray nuclei and medulla of human brain. The same has been proven by Izumi (2006) in rats. Other evidences for the probable involvement of these two receptors are the correlation between their influences when hyperstimulated and serotonin syndrome in man. 5HT1A binds to serotonin even at lower concentrations of serotonin since it has higher affinity for it, thus leading to the related symptoms of muscle rigidity and hypothermia. Next in turn is 5HT2A which needs higher levels of serotonin for binding. Figure 5: (Mills, 1997) Usually serotonin syndrome develops due to elevated levels of brain serotonin levels due to interaction of two or more drugs taken by an individual and may occur through following six mechanisms: Serotonin synthesis acceleration Induction of elevated levels of serotonin release Serotonin antagonism Serotonin reuptake inhibition Elevated post synaptic responses Serotonin degradation inhibition. Another mechanism, though still under speculation can be changes in relative concentration of neurotransmitters as a result of drug-drug interaction, which may lead to changes in non serotonin neurotransmitter levels, which can further affect higher serotonin release or receptor sensitivity (Ener et al., 2003). A list of drugs implicated in causing serotonin syndrome is tabulated with respect to their mechanisms in figure 6 and 7. Of the listed drugs the most prominent effect is of monoamine oxidase inhibitors (MOI), causing disease development post second serotonergic agent administration even after two weeks of discontinuation of MOIs. Another important class of interacting drugs that lead to serotonin syndrome are phenylpiperidine opiates and their analogues, though the mechanism of it is not yet clear. Some other drugs reported to cause the syndrome are fentanyl, pethidine, admetionine etc. Figure 6 Figure 7 Diagnosis: Serotonin syndrome is an iatrogenic disease, the origin following the administration of a certain combination or in some cases, single drug use. Thus diagnosis involves a study of the history of drug use, in case the symptoms of disease are noticed (Sternbach, 1991); along with parallel studies pointing towards exclusion of other diseases, or disorders. No specific tests can be done for diagnosis, however, serum electrolytes, glucose, renal function tests, CK and ECG are usually done for aid in diagnosis. To enable management of symptoms of hyperthermia, hypotension etc, liver function tests, platelet and arterial blood gases etc are obtained. Chest radiographs are required in individuals with CNS depression or hypoxia. The most important differential diagnosis need to be done with regard to neuroleptic malignant syndrome (NMS), which has similar signs and symptoms, however, NMS is slow to develop and exhibits dysphagia, hypersalivation, incontinence, extrapyramidal ‘lead pipe’ rigidity (Birmes et al., 2003). Treatment: Treatment of serotonin syndrome involves continuous monitoring, care and immediate discontinuation of all medication suspected to lead to the condition. In cases of severe to mild complication, medication is provided on the basis of type of complication. However no large scale, treatment studies with control trials have been undertaken to study medication for the syndrome. A few case studies have been reported with a list of medication, two of the most important of which are cyproheptadine and chlorpromazine (Boyer et al., 2005). Cyproheptadine is a histamine receptor antagonist with nonspecific antiserotonergic properties. Chloropromazine has 5HT1A and 5HT2A receptor antagonist properties and should be given after proper hydration of the patient. Another drug under study for treatment is gastric pentadecapeptide BPC 157, which has been hinted to influence serotonin levels and to overcome the disease symptoms in studies on rats (Boban Blagaic et al., 2005). However further research is needed before conclusive statement can be made. Prognosis: Most symptoms are seen to subside within 24 hours of withdrawal of causative medication and within two to four weeks some of the medication can cautiously be readministered at low doses. Duration of disease symptom persistence has been found to be dependent on the half life of the causative drug and the dosage at which the drug was administered. Conclusion: Serotonin syndrome is usually mild and damage can be minimised by early identification of symptoms and withdrawal of medication. The limiting factor is time, the management of which can prevent the severe or even moderate form of disease development. There is however, no other way in which the disease can be prevented because the drugs combinations which cause the syndrome, when taken individually do not show any serotonergic effects. It is hence, important to exercise caution when resorting to self medication, to prevent administration of combinations which are known to cause the syndrome or to avoid high dosage. References 1. 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Bijl, D. (2004). The serotonin syndrome. Neth J Med. 62(9), 309-313. 9. Ener, R. A., Meglathery, S. B., Van Decker, W. A., Gallagher, R. M. (2003). Serotonin syndrome and other serotonergic disorders. Pain Med. 4(1), 63-74. 10. Boyer, E. W., Shannon, M. (2005). The serotonin syndrome. N Engl J Med. 352(11), 1112-1120. [Erratum in: N Engl J Med 2007;356(23), 2437.] 11. Boban Blagaic, A., Blagaic, V., Mirt, M., et al. (2005). Gastric pentadecapeptide BPC 157 effective against serotonin syndrome in rats. Eur J Pharmacol. 512(2-3), 173-179. Read More