What is the receptor profile of fluoxetine (selective serotonin reuptake inhibitor, SSRI)?

Receptor Profile of Fluoxetine

Fluoxetine is a highly selective serotonin reuptake inhibitor that primarily works by blocking the presynaptic reuptake of serotonin, with negligible binding affinity for other neurotransmitter receptors. 1, 2

Primary Mechanism of Action

• Fluoxetine selectively inhibits the serotonin transporter (SERT), blocking reuptake of serotonin at the synaptic cleft, which increases serotonin availability 3, 1
• This blockade eventually leads to downregulation of inhibitory serotonin autoreceptors, heightening serotonergic neuronal firing rates and increasing serotonin release 3
• The multistep process explains the delayed onset of therapeutic effects seen with fluoxetine treatment 3

Receptor Binding Profile

• Fluoxetine has high affinity and selectivity for the serotonin transporter with a Ki value of 1.4 nmol/L 4
• It has essentially no effect on norepinephrine reuptake or other neurotransmitters 5, 2
• Fluoxetine demonstrates minimal binding affinity for:
  • Muscarinic receptors 2
  • Histaminic H1 receptors 2
  • Serotonergic 5-HT1 or 5-HT2 receptors 2
  • Noradrenergic alpha-1 or alpha-2 receptors 2

Metabolite Activity

• Fluoxetine is metabolized to an active metabolite called norfluoxetine 5
• Norfluoxetine is also specific for inhibition of serotonin reuptake, maintaining the selective profile 5
• The active metabolite has an extremely long half-life (approximately 7 days after long-term administration), contributing to fluoxetine's persistent effects 6, 5

Unique Pharmacological Properties

• Fluoxetine is considered the most "activating" SSRI in the class, making it beneficial for patients with fatigue, hypersomnia, or psychomotor retardation 6
• Its stimulating properties are attributed partly to its long half-life and that of its active metabolite 6
• Fluoxetine's para-trifluoromethyl substituent is a pivotal structural element contributing to its selective interaction with the serotonin transporter 1
• The drug's molecular conformation resembles that of other serotonin uptake inhibitors, enabling high affinity and selective interaction with the serotonin transporter 1

Pharmacodynamic Effects

• Fluoxetine affects primarily the hSERT transport rate by reducing the availability of the transporter in the membrane 7
• This effect appears to be post-translational and independent of PKC and PKA activity 7
• Long-term fluoxetine treatment does not significantly alter total hSERT protein content or hSERT mRNA levels 7

Clinical Implications of Receptor Profile

• Fluoxetine's selective serotonergic action makes it useful for treating various conditions including depression, OCD, and anxiety disorders 3, 1
• Its activating profile may be beneficial for patients with fatigue but should be avoided in those with significant anxiety, agitation, or insomnia 6
• Morning administration is recommended to minimize insomnia due to its activating properties 6
• Fluoxetine's long half-life (4 days after long-term administration) and its active metabolite's even longer half-life (7 days) have implications for drug interactions and withdrawal effects 5

Pharmacogenetic Considerations

• CYP2D6 genetic variations can significantly affect fluoxetine metabolism and plasma concentrations 3
• Poor metabolizers (PMs) of CYP2D6 may experience 3.9-11.5 fold higher area under the curve (AUC) compared to extensive metabolizers (EMs) 3
• Long-term fluoxetine use at 20 mg/day can convert approximately 43% of EMs to PMs through enzyme inhibition 3
• The FDA has issued safety labeling changes for fluoxetine regarding QT prolongation risk in CYP2D6 poor metabolizers 3