I read about long term use of these kinda antidepressants causing hippocampal neurogenesis and stuff like that but I'm focusing more on what long term use does to the various monoamine neurotransmitter pathways. I'll start with SSRIs because they are the simplest. Their main mechanism of action is inhibiting reuptake of serotonin. Would I be right in assuming that the surplus of serotonin in the synapse causes downregulation of 5-HT receptors? In my pharmacology book, they claimed that long term use of antidepressants cause downregulation of two of the subtypes (α2 and β1 I think it was) of adrenergic receptors but they didn't state what class of antidepressants do this. I can see why TCAs and other SNRIs would downregulate α and β receptors but I don't see why SSRIs would cause significant downregulation of adrenaline receptors. However, I know very little about what long term use of an SSRI does. SARIs (serotonin antagonist reuptake inhibitors) are an even bigger mystery to me. Two that I'm familiar with are trazodone and mirtazapine. Trazodone binds strongly (and antagonises) various 5-HT receptors, as well as α1 receptors. It also has mild affinity for the serotonin transporter. Mirtazapine has a similar binding profile but its much less selective (i.e. it has significant anticholinergic and antihistamine properties). Since these drugs block various monoamine receptors, what kinda long term effects do they produce? I can't see how they would downregulate receptors (since the antagonism should counteract the reuptake inhibition) or produce long term trophic effects such as hippocampal neurogenesis.