If SSRIs raise serotonin within hours, why do they take weeks to work? · Grey Matter

Blocking the serotonin transporter raises serotonin around the raphe neurons first, where it acts on their 5-HT1A autoreceptors and slows their firing, so serotonin in the forebrain rises less than expected at the start.

If SSRIs raise serotonin within hours, why do they take weeks to work?

Blocking the serotonin transporter raises serotonin around the raphe neurons first, where it acts on their 5-HT1A autoreceptors and slows their firing, so serotonin in the forebrain rises less than expected at the start. Over two to several weeks those autoreceptors desensitise and the neurons fire normally again with the transporter still blocked, which is one classic explanation for the delay. Other proposed explanations involve slow changes downstream (plasticity, new gene expression, changes in how emotional information is processed), and the delay is probably the sum of several of them. The question matters because it shows that a drug's immediate chemical effect and its clinical effect can be separated by weeks of adaptation.