Pharmacology of rapid-onset antidepressant treatment strategies.

Long-term treatment with selective serotonin reuptake inhibitors (SSRIs) desensitizes inhibitory 5-HT1 autoreceptors, enhancing serotonin neurotransmission.

• SSRIs block the reuptake of serotonin rapidly, but their therapeutic effects are delayed.
• Feedback mechanisms mediated by 5-HT1A and 5-HT1B autoreceptors reduce serotonin neuron firing and release initially.
• Desensitization of these autoreceptors over time enhances serotonin neurotransmission, correlating with the delayed clinical action.
• The addition of pindolol, a 5-HT1A receptor blocker, may accelerate the antidepressant response by decoupling feedback inhibition.
• Mirtazapine, an alpha2-adrenoceptor antagonist, increases serotonin neurotransmission by disinhibiting norepinephrine activation of serotonin neurons.
• These mechanisms may explain the faster onset of action of mirtazapine compared to SSRIs.

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