What is the overall pharmacologic goal of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression?

Mechanism of Action of SSRIs in Depression Treatment

The overall pharmacologic goal of selective serotonin reuptake inhibitors (SSRIs) in treating depression is to increase the amount of serotonin found in the synapses. 1

Core Mechanism

SSRIs selectively block the presynaptic serotonin transporter, preventing reuptake of serotonin from the synaptic cleft; this inhibition raises synaptic serotonin levels and facilitates stimulation of postsynaptic serotonin receptors. 1

The mechanism works through the following pathway:

• SSRIs bind to and inhibit the serotonin transporter protein located on the presynaptic neuron membrane 2, 3
• This blockade prevents serotonin molecules from being removed from the synaptic space back into the presynaptic neuron 4, 5
• The resulting accumulation increases serotonin concentration in the synaptic cleft 1, 2
• Higher synaptic serotonin levels lead to enhanced stimulation of postsynaptic serotonin receptors 1

Why Therapeutic Effects Are Delayed

SSRIs require several weeks of continuous administration before their full therapeutic effect emerges because acute dosing has minimal impact on synaptic serotonin levels due to regulatory feedback mechanisms. 6

The delayed response occurs because:

• Somatodendritic 5-HT1A autoreceptors initially suppress serotonergic neuron firing rates 6
• Terminal 5-HT autoreceptors (5-HT1B/1D subtypes) initially inhibit serotonin release 6
• During prolonged SSRI administration (weeks), these feedback systems become desensitized and lose their regulatory effects 6
• Only after this desensitization do synaptic serotonin levels rise sufficiently to produce antidepressant effects 6, 3

Clinical Confirmation of Mechanism

Tryptophan depletion studies demonstrate that when serotonin is depleted in patients whose depression has remitted on an SSRI, the depressive symptoms rapidly return, confirming that increased synaptic serotonin is necessary for SSRI efficacy. 3

Answer to the Question

The correct answer is: Increase the amount of serotonin found in the synapses

The other options are incorrect:

• Decreasing synaptic serotonin would worsen depression 3
• GABA receptors are not the primary target of SSRIs 1
• Decreasing CNS dopamine is not the mechanism of SSRIs; some antidepressants like bupropion actually increase dopamine 1