The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice

Abstract

The serotonin syndrome is a medication-induced condition resulting from serotonergic hyperactivity, usually involving antidepressant medications. As the number of patients experiencing medically-treated major depressive disorder increases, so does the population at risk for experiencing serotonin syndrome. Excessive synaptic stimulation of 5-HT_2A receptors results in autonomic and neuromuscular aberrations with potentially life-threatening consequences. In this review, we will outline the molecular basis of the disease and describe how pharmacologic agents that are in common clinical use can interfere with normal serotonergic pathways to result in a potentially fatal outcome. Given that serotonin syndrome can imitate other clinical conditions, an understanding of the molecular context of this condition is essential for its detection and in order to prevent rapid clinical deterioration.

Keywords: 5-hydroxytryptophan; antidepressants; genetic polymorphisms; polypharmacy; serotonin syndrome.

Figure 1

Signs and symptoms of the serotonin syndrome occur along a spectrum of severity. Mild symptoms may easily be overlooked, and may manifest as little more than diarrhea and flu-like symptoms. Unless the disease is recognized and the causative drugs are discontinued, it can rapidly progress to muscle rigidity, severe hyperthermia and death.

Figure 2

At normal serotonergic neurons, the concentration of serotonin at a synapse is determined by several processes, including synthesis, controlled release from the presynaptic neuron, reuptake, and metabolism. 5-HTP = 5-hydroxytryptophan; 5-HT = 5-hydroxytryptamine (serotonin); VMAT = vesicular monoamine transporter; SERT = serotonin reuptake transporter; 5-HIAA = 5-hydroxy indole acetic acid. Asterisk denotes the rate-limiting step in serotonin synthesis.