Ketamine, recently FDA-approved for treatment-resistant depression, does not work like traditional SSRIs at low doses. In fruit fly larvae, which have a serotonin system similar to mammals, 1 mM ketamine did not affect serotonin reuptake but increased locomotion and feeding. Low doses of SSRIs (escitalopram and fluoxetine) inhibited serotonin reuptake and also increased feeding and locomotion. At a high dose (100 mM), ketamine inhibited serotonin reuptake and increased serotonin concentrations but decreased locomotion and feeding due to anesthetic effects. Low doses of other NMDA receptor antagonists increased feeding, while serotonin receptor agonists increased locomotion, suggesting ketamine affects behavior through multiple mechanisms, not by blocking serotonin reuptake like SSRIs.
Ketamine, when given at very low (micro) doses, increases movement and feeding in fruit fly larvae, but through a different mechanism than standard antidepressants such as SSRIs. At 1 mM, ketamine did not alter serotonin levels yet still boosted locomotion and feeding, whereas low doses of the SSRIs escitalopram and fluoxetine inhibited the serotonin transporter (dSERT) and similarly increased these behaviors. At a high dose (100 mM), ketamine blocked dSERT and raised serotonin, but reduced movement and feeding due to anesthetic effects. Experiments with mutant flies and other drugs suggest ketamine's behavioral effects come from NMDA receptor antagonism (which increases feeding) and serotonin receptor activation (which increases locomotion), not from acting on the serotonin transporter like SSRIs.