A patient taking an SSRI for depression is also prescribed tramadol for pain. Two days later he develops agitation, hyperthermia, diaphoresis, and clonus. The pathophysiological mechanism responsible is:

• A Dopaminergic excess in the nigrostriatal pathway causing neuroleptic malignant syndrome
• B Noradrenaline reuptake inhibition by tramadol potentiating the SSRI's adrenergic effects
• C CYP2D6 inhibition by the SSRI increasing tramadol's active metabolite to toxic levels
• D Excess serotonergic activity at 5-HT1A and 5-HT2A receptors due to combined serotonin reuptake inhibition and mu-opioid–mediated serotonin release ✓

Explanation

Serotonin syndrome results from excess serotonergic neurotransmission at central 5-HT1A and 5-HT2A receptors. SSRIs block serotonin reuptake via SERT, while tramadol itself inhibits serotonin reuptake and also has weak serotonin-releasing properties; together they produce serotonergic toxidrome characterised by the triad of altered mental status, autonomic instability, and neuromuscular abnormalities (clonus being pathognomonic). This differs from NMS by its acute onset and clonus/hyperreflexia.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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