Central serotonin syndrome

MAOIs Theoretically central serotonin syndrome could occur... 

PHARMACOKINETIC/PHARMACODYNAMIC INTERACTIONS AND THE CENTRAL SEROTONIN SYNDROME... 

Central Serotonin Syndrome is manifest by autonomic, neuromuscular, and cognitive symptoms. Mild symptoms can include tremor, incoordination, and confusion. Moderate symptoms can manifest as shivering, sweating, hyperreflexia, and agitation, and severe symptoms include fever, myoclonus, and diarrhea. This syndrome is usually associated with two or more drugs that increase central serotonin transmission and affect the 5-HTia receptor (see Table 5.4). 

TABLE 5.4 Pro-serotonegic Agents Implicated in Central Serotonin Syndrome... 

Gillman, PK (1999) The serotonin syndrome and its treatment. J. Psychopharmacol. 13 100-109. Heal, DJ, Cheetham, SC, Prow, MR, Martin, KF and Buckett, WR (1998) A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying drugs. Brit. J. Pharmacol. 125 301-308. 

Monoamine Oxidase A MAOA Inhibition May induce severe hypertensive crisis (known as the Cheese reaction ) - Centrally mediated side effects such as the serotonin syndrome, dizziness, blurred vision and weakness. 

Serious toxic reactions with delirium can arise when specific serotonin reuptake inhibitors (SSRIs) are taken with other drugs that increase central and peripheral serotonergic activity. Known as the serotonin syndrome , this reaction consists of excitation, restlessness, fluctuations in consciousness, with tremor, rigidity, myoclonus, sweating, flushing, pyrexia, cardiovascular changes, and rarely coma and death (Sternbach, 1991). The syndrome has occurred when SSRIs have been combined with irreversible monoamine oxidase... 

Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome. There are several drug mechanisms that can cause serotonin toxicity. Serotonin toxicity can be a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure. 

TABLE 22.5. Drugs that Potentiate Serotonin in the Central Nervous System and Could Be Associated with Serotonin Syndrome... 

HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood. Serotonin syndrome is a condition associated with skeletal muscle contractions and precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class (SSRIs see Chapter 30). Although the hyperthermia of serotonin syndrome results from excessive muscle contraction, serotonin syndrome is probably caused by a central nervous system effect of these drugs (Table 16-4 and Serotonin Syndrome and Similar Syndromes). 

Bromination of LSD 25 yields 2-bromolysergic acid diethylamide which exerts practically no psychotomimetic effect (Fig. 8a) the central excitation syndrome is reduced, whereas the antiserotonin effect remains intact, but the effect on smooth muscle is practically absent. This compound is almost as potent as LSD 25 in antagonizing serotonin but does not elicit hallucinogenic effects. 

The tendency for MAO inhibitors to produce symptoms related to neuromuscular excitability, the serotonin syndrome, has been recognized in cases of overdose (SEDA-10, 18) and in interactions with other antidepressants or tryptophan (SEDA-10, 16, 17) (20). The authors of a thorough review of the preclinical and clinical literature have drawn attention to these phenomena, which occur at therapeutic doses with a MAO inhibitor alone, and have speculated that the mechanism is related to a combination of increased serotonergic tone and central disin-hibition of alpha motor neuron-mediated spinal activity (21). They discussed ten previous reports of myoclonus, hyper-reflexia, muscle twitching, and increased muscle tone in patients taking MAO inhibitors. These neuromuscular effects appear to occur in up to 15% or more of patients, and are more likely when tryptophan is given in combination. They usually appear after 10-14 days. Tolerance does not occur, but the effects may abate or... 

Central nervous system agents Dizziness, drowsiness, headache, hallucination, neuroleptic malignant syndrome, serotonin syndrome... 

Many reports have linked childhood hyperactivity to impaired central serotonin functions.89 In animals, the occurrence of a behavioral syndrome consisting of hyperactivity, stereotyped movements, and increase of temperature has been induced by L-tryptophan, as a serotonin precursor, by serotonin reuptake inhibitors, and by MAOIs.90 Most of these manifestations can be blocked specifically by pretreatment with an inhibitor of serotonin synthesis. In humans, the association of myoclonus, diarrhea, confusion, hypomania, agitation, hyperreflexia, shivering, incoordination, fever, and diaphoresis, when patients are treated with serotoninergic agents, could constitute a "serotonin syndrome." Such cases of serotonin syndrome were reported after treatments with L-tryptophan, MAOIs, serotonin reuptake inhibitors, and tricyclics, alone or in association. 

On theoretical grounds the manufacturers contraindicate the concurrent use of sibutramine with MAOIs, and they say that it should not be given with serotonei ic drugs because of the risk of the serious serotonin syndrome. The manufacturers say that the use of sibutramine with other centrally acting appetite suppressants is contraindicated and they caution the use of cold and flu remedies. No clinically relevant interactions have been seen between sibutramine and cimetidine, and no interaction occurs with oral contraceptives. 

Nierenberg DW, SemprebonM The central nervous system serotonin syndrome. Clin Pharmacol Ther (1993) 53,84-8. 

Drug-drug interactions Methylthioninium chloride is a monoamine oxidase inhibitor, and can cause serotonin toxicity when it is combined with drugs that increase central serotonin neurotransmission. It has been associated with a toxic metabolic encephalopathy in 26 cases [66 ]. Autonomic, neurological, and neuromuscular instability has been reported after infusion of methylthioninium chloride for parathyroidectomy, and the authors suggested that this was due to serotonin syndrome [67" ]. 

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