Psychopharmacology of Selective Serotonin Re-uptake Inhibitors (SSRIs) – Mechanism of Action

Posted on: April 23, 2020
Last Updated: November 2, 2021

In this video, Dr Sanil Rege covers the mechanism of action and psychopharmacology of SSRIs.

Fluoxetine, Paroxetine, Sertraline, Escitalopram and Citalopram come under the banner of SSRIs. Read more on the mechanisms of action, doses and pharmacokinetics of SSRIs here.

SSRIs are evidence-based in the treatment of depression, anxiety and OCD. SSRIs block serotonin transporter (SERT) increasing extracellular levels of serotonin within the synaptic cleft.

The main receptors serotonin acts on are 5HT2A, 5HT2C, 5HT3 and 5HT1A autoreceptor. The initial activation of the post-synaptic 5HT2A, 5HT2C and 5HT3 receptors are responsible for side effects. These receptors downregulate in 1-2 weeks and the side effects wane.

The 5HT1A receptor also downregulates after a lag of 2-4 weeks (onset of action for SSRIs) which results in serotonin flowing down the presynaptic neuron and the neuron firing.

BDNF receptor: 

  • More recently, evidence suggests that SSRIs act at the TRKB receptor which is a BDNF receptor.
  • The binding of the BDNF receptor (the transmembrane domain of tyrosine kinase receptor 2 (TRKB)) facilitates increased expression and signalling of brain-derived neurotrophic factor (BDNF) which promotes neuronal plasticity and antidepressant responses. [Casarotto et al., 2021]. 
  • Serotonin (5HT)- BDNF systems act synergistically on synaptic plasticity and neurogenesis in brain areas implicated in depression [Martinowich and Lu, 2008].

Serotonin, BDNF and Neural Effects: 

Both 5-HT1A and 5-HT2A receptor agonists also upregulate BDNF protein and mRNA expression. [Jiang et al., 2016]

5-HT1A receptors are a major target for SSRI-induced increases in adult hippocampal neurogenesis which is correlated with antidepressant response.

A proposed model looking at SSRIs and downstream effects are as follows : [Samuels et al., 2015]

  • Chronic SSRI administration increases 5-HT levels
  • Increased serotonin results in the activation of 5-HT receptors on dentate gyrus granule cells.
  • Activation of 5HT1A receptors on mature granular cells results in the release of downstream growth factors such as BDNF, VEGF, and others, which bind to receptors on neural precursor cells (NPCs) in the subgranular zone.
  • Neural precursor/progenitor cells (NPCs) then proliferate and differentiate into young adult-born granule cells (ABGCs), which will begin to migrate, mature, and finally integrate into the granule cell layer.
  • However, the young ABGCs have distinct plasticity properties from the mature dentate gyrus granule cells and activate local GABAergic interneurons to evoke strong inhibitory input to the mature granule cells.
  • The inhibition of mature GCs via direct activation of 5HT1A receptors is therefore critical for the antidepressant response.

Astrocyte Modulation: 

Astrocyte dysfunction has recently been proposed to contribute to the pathogenesis of depression through several mechanisms:

  • Affecting the monoaminergic system
  • Modulating neuronal activity
  • Altering the excitatory-inhibitory balance
  • Disturbing the neurotrophic support of neuronal networks

Evidence has mainly focused on the astrocytic inward rectifier potassium channel 4.1 (Kir4.1 channel) as a possible contributor to depression. The channel is an important modulator of neuronal excitability and glutamate metabolism.

Serotonin can communicate with and modulate Kir4.1 activity although the exact interaction and effect are still a matter for further research. Evidence shows that Kir4.1 inhibition increases astrocyte secretion of BDNF.

SSRIs inhibit Kir 4.1 activity. Fluoxetine and sertraline displayed a stronger, voltage-independent effect, with respect to fluvoxamine, which instead inhibited Kir4.1 in a voltage-dependent manner.


  • Serotonin has proinflammatory effects by elevating cytokine levels, however, activation of the 5HT2A receptors has anti-inflammatory effects. [Wan et al., 2020]

SSRIs and SNRIs decrease neuroinflammation through multiple mechanisms: [Dionisie et al., 2021]

  • Reduction of blood or tissue cytokines
  • Regulating complex inflammatory pathways: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inflammasomes, Toll-like receptor 4 (TLR4) and peroxisome proliferator-activated receptor-gamma (PPARγ).
  • This property has been used in the treatment of Covid -19 with fluvoxamine. [Read more in the article on neuropsychiatric of covid]

In summary, SSRIs may have additional effects that are yet to be discovered beyond the serotonergic hypothesis of depression.