LAUSR

&NA; We studied the effects of the multi‐modal antidepressant, vortioxetine and the SSRI, paroxetine on pineal melatonin and monoamine synthesis in a sub‐chronic tryptophan (TRP) depletion model of depression based on a low TRP diet. Female Sprague‐Dawley rats were randomised to groups a) control, b) low TRP diet, c) low TRP diet + paroxetine and d) low TRP diet + vortioxetine. Vortioxetine was administered via the diet (0.76 mg/kg of food weight) and paroxetine via drinking water (10 mg/kg/day) for 14 days. Both drugs resulted in SERT occupancies > 90%. Vortioxetine significantly reversed TRP depletion‐induced reductions of pineal melatonin and serotonin (5‐HT) and significantly increased pineal noradrenaline NA. Paroxetine did none of these things. Other studies suggest pineal melatonin synthesis may involve N‐methyl‐D‐aspartate (NMDA) receptors and glutamatergic modulation. Here observed changes may be mediated via vortioxetine's strong 5‐HT reuptake blocking action together with possible additional effects on glutamate neurotransmission in the pineal via NMDA receptor‐modulation and possibly with added impetus from increased NA output. HighlightsThe effects of vortioxetine and paroxetine on pineal melatonin and monoamines in a tryptophan depletion model of depression were studied.Adult female Sprague‐Dawley rats were used. Vortioxetine was administered via the diet and paroxetine via drinking water for 14 days.Vortioxetine reversed TRP depletion‐induced reductions of melatonin and 5‐HT and increased pineal NA. Paroxetine did not.Observed changes may be mediated via vortioxetine's 5‐HT reuptake blocking action.There may be additional effects on glutamate synthesis in the pineal via NMDA receptor‐modulation plus added impetus from increased NA output.