The correct answer is Option 1: Tramadol combined with selective serotonin reuptake inhibitors (SSRIs).

Serotonin syndrome is a potentially life-threatening condition caused by excessive accumulation of serotonin in the central nervous system. It is usually precipitated by the use of medications that increase serotonin activity either by increasing its synthesis, release, or by inhibiting its metabolism or reuptake.

- Tramadol is an opioid analgesic that not only acts on mu-opioid receptors but also inhibits the reuptake of serotonin and norepinephrine. Because of this, tramadol has serotonergic properties.

- Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that increase serotonin levels by blocking its reuptake at the synaptic cleft.

When tramadol is combined with SSRIs, there is a significant increase in serotonergic activity, which raises the risk of developing serotonin syndrome.


Other options do not have significant serotonergic effects:
- Option 2: Ibuprofen (a nonsteroidal anti-inflammatory drug) combined with beta-blockers does not affect serotonin levels.
- Option 3: Metformin, an antidiabetic agent, combined with calcium channel blockers has no impact on serotonin metabolism.
- Option 4: Amoxicillin (an antibiotic) combined with proton pump inhibitors has no serotonergic effects.

Clinical features of serotonin syndrome include:
- Agitation
- Confusion
- Tachycardia
- Hyperthermia
- Myoclonus or tremor
- Hyperreflexia

Early recognition and withdrawal of serotonergic agents are critical to management.