Latest Update on the Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs)

SEROTONIN NETWORKS

A recent article explored the relationship between large-scale brain activity and behavior, and how optogenetic activation can affect behaviors. The dorsal raphe (DR) serotonin neurons modulate the complex serotonin networks. [Salvan, 2022].

It examined the role of serotonin in regulating behavior, and how its spatial distribution and receptor types can affect brain-wide activity and behavior. The key findings were:

1. Serotonin is produced by a small proportion of neurons and is released widely throughout the brain.
2. There are individual variances in the functional connectivity of serotonin networks.
3. There seem to be two independent modes of population variation: the first is related to impulsivity, antisocial problems and feelings of aggression; the second is related to a negative bias in reward processing, depression and feelings of panic.
4. Serotonin has been associated with both behavioral inhibition and aversive processing.
5. Neuroimaging and gene expression maps can be used to extract brain-wide functional signatures associated with specific serotonin receptors.
6. The importance of serotonin receptor types’ brain-wide distribution patterns is not well understood and thus, the  mechanisms through which serotonin modulates human behavior remain still remains to be studied.

SSRIs AND SEROTONIN

• SSRIs block serotonin transporter (SERT), increasing extracellular levels of serotonin within the synaptic cleft.
• The main receptors serotonin acts on are 5-HT2A, 5-HT2C, 5-HT3 and 5-HT1A autoreceptor. The initial activation of the post-synaptic 5-HT2A, 5-HT2C and 5-HT3 receptors are responsible for side effects. However, these receptors downregulate in 1-2 weeks, and the side effects wane. [Not all side effects wane, and the propensity differs from individual to individual]
• The 5HT1A receptor also downregulates after a lag of 2-4 weeks (onset of action for SSRIs), resulting in serotonin flowing down the presynaptic neuron and the neuron firing.

SSRIs, NORADRENALINE (NA) AND DOPAMINE (DA)

• Long-term administration of SSRIs enhances 5-HT transmission in the locus coeruleus.
• 5-HT activates the 5-HT2A receptors on GABA neurons which in turn exert an inhibitory action on NA neurons through enhanced γ-aminobutyric acid (GABA) release. [Blier & El Mansari, 2013]
• Serotonin neurons also exert an inhibitory influence on DA neurons in the ventral tegmental area (VTA), which give rise to mesolimbic and mesocortical projections.
• SSRIs can therefore reduce frontal and mesolimbic dopamine.
• Reduction of NA in the amygdala may assist in reducing anxiety but at the same time be associated with emotional blunting.
• Reduction of frontal dopamine may be associated with emotional blunting and lack of therapeutic response in some cases of  depression (as DA plays an important role in the pathogenesis of depression)
• The serotonergic innervation to the amygdala is influenced by SSRIs and leads to positive shifts in the way the brain appraises emotionally-valenced information. This effect occurs very early in treatment, prior to clinical antidepressant effects. [Harmer et al., 2009]

SSRIs AND 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 5-HT1A 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: [Vecchia et al., 2021]

• 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.

ANTI-INFLAMMATORY EFFECTS

• 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.