Clinical Geriatrics

This is the second part of a two-part series on central serotonin syndrome in the elderly that reviews the incidence, how central serotonin syndrome presents in the elderly, which psychiatric and nonpsychiatric medications interact to exacerbate or cause the syndrome, the pathophysiology of the disorder, and its treatment. Part I discussed the history and prevalence of the disorder, causative agents, presentations and diagnostic criteria, and ways to distinguish the condition from other conditions with which it might be initially confused, such as neuroleptic malignant syndrome. Part II focuses on its pathophysiology, opiate and psychiatric drug interactions, and the treatment of central serotonin syndrome in the elderly.

Pathophysiology
Serotonin is a biogenic amine synthesized from tryptophan and found in the periphery of the body (eg, gastrointestinal system, platelets) and the central nervous system (brain, spinal cord, with particularly high levels in the hypothalamus and basal ganglion) (Table I).1-4 Serotonin is not able to cross the blood-brain barrier, and is therefore synthesized both in the periphery and centrally.5,6 The central effects of serotonin are thought to include modulation of mood, the sleep-wake cycle, hormone secretion, nociception (pain), motor tone, sexual behavior, thermoregulation, and nausea.1,2,4,6-8 Serotonin syndrome is believed to be caused by increased 5-hydroxytryptamine at the intrasynaptic cleft as the result of the pharmacological effect of a drug or a combination of drugs (usually having two different mechanisms of action affecting serotonin levels or cell response).1,2,9 This increase in intrasynaptic serotonin has both a direct and an indirect effect on noradrenergic pathways, dopaminergic pathways, and the GABA adrenergic inhibitory pathways, which are also responsible for some of the symptoms that occur. These pathways are also involved in the genesis of symptoms by indirectly increasing central serotonin levels.6,10,11-13

Currently, there are at least seven types of identified serotonin receptors, each with several subclassifications.1,5,14 Although multiple neurotransmitters, feedback mechanisms, and receptor types are involved in producing serotonergic syndrome, the predominant receptors are thought to be 5HT1A (overstimulation may cause hyperactivity, hyperreflexia, and anxiety)1,2,8,15 and 5HT2A (associated with hyperthermia, incoordination, and neuromuscular excitement).1,6-8,16-20 5HT1A receptors are distributed heterogeneously in human brains, with increased concentrations in the hippocampus, frontal cortex, amygdala, and raphe nuclei.6,21 Overstimulation of 5HT1A receptors in the central gray nuclei and the medulla are thought to be primarily responsible for the major symptoms of serotonin syndrome.6,8 There is a clear association between the overstimulation of 5HT1A receptors and the serotonin behavioral syndrome that occurs in animals.16,20,21 Although there are several similarities between serotonin behavioral syndrome and human serotonin syndrome, some neuroscientists suggest caution in generalizing the findings from one condition to the other.16,20 5HT1A receptors have a higher affinity for serotonin than the 5HT2A receptors, causing them to become saturated when lower concentrations of serotonin exist at the synaptic cleft.16 This may explain why hyperthermia and muscle rigidity are seen more commonly in severe forms of the disease.