Mechanism of Action Differences Between Atomoxetine and Fluoxetine
Atomoxetine is a selective norepinephrine reuptake inhibitor that primarily blocks norepinephrine transporters, while fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that primarily blocks serotonin reuptake—fundamentally different neurotransmitter systems with distinct therapeutic applications. 1, 2
Atomoxetine's Mechanism
Norepinephrine-Selective Action:
- Atomoxetine selectively inhibits presynaptic norepinephrine transporters, increasing synaptic noradrenaline levels throughout the brain 1, 3
- It has high affinity and selectivity for norepinephrine transporters but little or no affinity for serotonin transporters or other neurotransmitter receptors 3, 4
- In the prefrontal cortex specifically, norepinephrine transporters also regulate dopamine reuptake (since dopamine transporters are scarce in this region), resulting in increased both noradrenaline and dopamine concentrations in prefrontal cortex synapses 1
Secondary Effects:
- Atomoxetine increases cortical acetylcholine levels through norepinephrine alpha-1 and/or dopamine D1 receptor activation, which may contribute to its effects on attention and memory 5
- This procholinergic effect occurs in cortical but not subcortical brain regions 5
Clinical Application:
- FDA-approved for ADHD treatment in children, adolescents, and adults 1
- Modulates stress responses including alertness, arousal, attentiveness, and vigilance through noradrenergic pathways 2
Fluoxetine's Mechanism
Serotonin-Selective Action:
- Fluoxetine inhibits presynaptic reuptake of serotonin in the brain, increasing serotonin availability at the synaptic cleft 2
- This blockade leads to downregulation of inhibitory serotonin autoreceptors over time, eventually heightening serotonergic neuronal firing rate and increasing serotonin release 2
- Has little effect on norepinephrine or dopamine systems compared to its serotonergic effects 2
Clinical Application:
- Used primarily for depression and anxiety disorders, not ADHD 2
- Serotonergic function modulates fear, worry, stress, and facilitates cognitive processing of emotions 2
Critical Distinction in Classification
Important caveat: Although atomoxetine is sometimes grouped with SNRIs (serotonin-norepinephrine reuptake inhibitors) in some literature, it is more accurately classified as a selective norepinephrine reuptake inhibitor (NRI) because it has minimal serotonergic activity 2, 1. True SNRIs like venlafaxine and duloxetine inhibit reuptake of both norepinephrine and serotonin, whereas atomoxetine's effectiveness for anxiety as a primary disorder has not been established 2.