How Antidepressants Work: Mechanism of Action

Introduction

Antidepressants are medications designed to ease the symptoms of depression. Once a diagnosis of moderate to severe depressive episodes is confirmed, the standard next step is to prescribe an antidepressant.

Even with all the progress we've made in medicine, treatment outcomes still fall short of where we want them to be. Major studies have shown that after trying just one prescribed antidepressant, only about a third of patients reach remission—and even after cycling through various different options, that number only climbs to about two-thirds.

On the flip side, expectations for treatment are getting higher; nowadays, the goal isn't just basic remission, but a full return to normal life—what doctors call "cognitive remission."

While waiting to see if a specific medication actually works for a patient, precious time is lost, which only extends their suffering. Because of this, it would be a massive help to clinicians if there were clinical or biological markers available to predict which therapy a person is most likely to respond to.

Despite a mountain of research in this field, reliable biological indicators just don't exist yet. However, certain antidepressants tend to be more effective against specific symptoms due to their unique mechanism of action—which, naturally, also dictates their side effects.

The goal of this article is to provide a concise overview of how these antidepressants work.

Classifying Antidepressants
There’s quite a wide variety of antidepressants available today. They can be categorized based on their chemical makeup, their generation, or their specific mechanism of action. Most clinical classifications rely on how they actually work, which you can see laid out in Table 1.

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Keep in mind that these categories aren't set in stone—they can get pretty confusing for clinicians. The reality is that there's significant overlap in their mechanism of action. Plus, the way these drugs hit different receptors is highly dose-dependent.

Mechanism of Action in Antidepressants

Figure 1. The link between depressive symptoms and monoamine system dysfunction, alongside the anatomical locations of monoamine pathways

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Large-scale meta-analyses suggest that most antidepressants are roughly equal in terms of effectiveness when treating depression. That said, individual responses can vary wildly. These differences stem from both the heterogeneous nature of clinical presentations and the various mechanisms of action involved. Research has shown that specific depressive symptoms can often be tied back to deficits in certain monoamines, as illustrated in Figure 1.

However, we can't really look at any single system in isolation. Everything is tightly interwoven—both anatomically and functionally. There are countless receptors on all neurons that allow one group of neurons to regulate the activity of others, and vice versa.

Figure 2. Mechanisms through which antidepressants exert their effects

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Antidepressants change monoamine system activity in three primary ways:

Inhibition of transporters: Serotonin Transporter, NET, and the Dopamine Transporter (DAT)
Inhibition of enzymes that break down monoamines: MAO type A and B
Binding to various receptors—specifically serotonergic and noradrenergic (note that antidepressants don't bind to dopamine receptors)

Figure 2 illustrates these effects.

Treating depression essentially boils down to increasing monoamine activity in the brain. This can be achieved through several different routes, as shown in Table 2.

Table 2. Classification of antidepressants by the amines they target

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*TCAs differ among themselves regarding the degree of Serotonin Transporter blockade; at average doses, quvortioxetine and Trazodone have a weaker effect than SIPPSa.

** TCAs vary in their level of noradrenergic transporter blockade.

***This effect has been established "in vitro," though it's unclear how pronounced it is "in vivo" or how much it contributes to the antidepressant effect.

**** In the United States, this is only approved as an antiparkinsonian medication.

Looking at the table, you can see that while some antidepressants primarily affect just one monoamine system, others impact multiple systems. Some act solely on transporters or just on receptors (unimodal antidepressants), while others target both transporters and receptors (bimodal antidepressants). Below, I'll briefly go over the different groups of antidepressants and their specific mechanism of action.

Source: Post-Graduate Course I: Antidepressants in Clinical Practice
Led by:
Prof. Alma Mihaljević-Peleš, PhD
Marina Šagud, PhD

http://www.plivamed.net/aktualno/cla...ifikacija.html

Antidepressants that target multiple receptor types—plus those little extra additions to the mix.

To really get a handle on depression, you can't just look at the diagnosis in a vacuum—you have to tackle the co-occurring conditions and the specific life circumstances each patient is actually facing.

Mirtazapine.

Mirtazapine doesn't actually block any transporters or enzymes—instead, its whole mechanism of action relies entirely on blocking various receptors. If you look at Figure 1, you can see how the effects of Mirtazapine are concentration-dependent, meaning everything shifts based on the specific dose being used.

If you look at Figure 1, you'll see that at lower doses, Mirtazapine acts primarily as a sedative and hypnotic due to its antihistamine properties. However, once you ramp up to those higher doses, that sleepy effect actually fades away—instead, the antidepressant effects take center stage thanks to the antagonism of $\alpha$2 receptors.

I’ve been looking over this chart—it's quite interesting how those curves interact, isn't it? It really clarifies how certain medications start to pull their weight differently over time.

Trazodone—it’s one of those medications that really makes you feel the weight of its effects. Personally, I’ve found it to be quite a heavy hitter when it comes to sleep.

Trazodone hits its antidepressant stride through a dual-action approach:

At lower doses, you get much more receptor antagonism across several different types.
At higher dosages, especially when you factor in the blockade of the Serotonin Transporter—it changes the whole game.
If you look at Figure 2, you'll see that Trazodone works much like Mirtazapine—the effects are entirely dependent on concentration, which basically means it all comes down to the dosage you're taking.

At lower doses, Trazodone acts as an antagonist for both 5HT2A and 5HT2C receptors—it also hits those 5HT1A, H1, and α1/α2 receptors too. Since its affinity for the Serotonin Transporter is pretty weak, you’d only really expect that specific effect to kick in at higher dosages. That said, we don't actually know how much the Serotonin Transporter is being blocked in vivo, mostly because there just isn't any data from PET studies out there yet.

I’ve been looking into Trazodone lately—it’s an interesting one. It seems to have a pretty unique way of working compared to other options out there.

Vortioxetine

This category also includes vortioxetine and vilazodone—though the latter isn't actually used here in the States.

Vortioxetine works exclusively through the serotonergic system. It’s a pretty complex process—it involves inhibiting the Serotonin Transporter, though not nearly as much as SSRIs do (we're looking at roughly 50% at standard therapeutic doses)—and it also hits several different serotonin receptors, just like you can see in Figure 3.

It’s widely believed that combining these effects yields a pro-cognitive boost—largely because they modulate glutamate neuron activity within the hippocampus and the prefrontal cortex. This specific mechanism of action has been most thoroughly studied in relation to vortioxetine.

I’ve been looking over the data on Vortioxetine—it’s pretty fascinating stuff, honestly. It seems to have a really unique mechanism of action compared to what we're used to. Just seeing how it hits those various targets makes you realize how much more nuanced antidepressant treatment can be.

Tianeptine—it’s such an interesting one to look into, isn't it?

Tianeptine really throw a wrench into the whole monoamine theory of depression. It’s wild because this antidepressant doesn't actually block any of the well-known transporters, enzymes, or receptors we usually look at. Some people used to think it worked by increasing serotonin reuptake—basically doing the exact opposite of an SSRI—but even that theory is pretty shaky now. Most researchers are leaning toward the idea that it works indirectly by messing with the glutamate and dopamine activity in the mesolimbic system.

Antidepressant Characteristics and Clinical Indications

Table 1. Primary characteristics of receptor-acting antidepressants

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The following table outlines common indications for various antidepressants used here in the United States.

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Managing depression through pharmacology isn't always straightforward—we often run into issues like treatment resistance, side effect intolerance, or patients simply struggling to stick to their regimen. In my experience, we tend to see much poorer responses in patients dealing with comorbid anxiety, chronic pain, personality disorders, or alcoholism. It’s also much tougher when there's a history of abuse, high-stress life circumstances, thyroid issues, B12 or folate deficiencies, anemia, or even cortical atrophy. Still, our job remains the same: we have to provide care for these patients regardless of the complexity.

Next-Gen Antipsychotics

It’s been established for quite some time now that certain next-generation antipsychotics carry antidepressant properties—especially when used at lower doses than what's typically required for their antipsychotic effects. In fact, a meta-analysis covering 16 double-blind studies revealed that adding an atypical antipsychotic to an existing antidepressant regimen actually doubles the likelihood of remission compared to a placebo. Here in the United States, four specific antipsychotics have been approved for use as adjunctive therapy alongside antidepressants:

1) Aripiprazole: acts as a partial agonist at 5HT1A receptors, a partial dopamine agonist, and a 5HT7 receptor antagonist

2) Brexpiprazole: functions as a partial agonist at 5HT1A receptors, a partial dopamine agonist, an α2 and 5HT2A antagonist, and a moderate 5HT2C antagonist

3) Quetiapine extended-release: serves as a 5HT2A antagonist, while its metabolite, norquetiapine, acts as a potent NET blocker and a partial 5HT1A receptor agonist

4) Olanzapine: acts as a 5HT2A and 5HT2C antagonist

In America, only quetiapine extended-release has been approved as an add-on treatment for depression.

TCAs
The mechanism of action for TCAs involves inhibiting the reuptake of serotonin and norepinephrine, though the balance varies significantly between drugs. For instance, Clomipramine is most potent at blocking the Serotonin Transporter, while Amitriptyline, Nortriptyline, Desipramine, and Imipramine all inhibit both transporters—whereas Maprotiline specifically targets the NET. That said, they also hit various other receptors, including anticholinergic, antiadrenergic (α1), and antihistaminic (H1) effects, along with potential interference with myocardial conduction. Because of these side effects, TCAs are used much less frequently today, even though they were the go-to antidepressants for about 25 years before the discovery of SIPPSa.

Table 1. Overview of specific TCA properties

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MAO Is

The whole point of using an MAO I is to boost monoamine concentrations in the brain—which, at the end of the day, is pretty much what most other antidepressants aim to do. We generally categorize these drugs into reversible versus irreversible, and selective versus non-selective. When we talk about selectivity, we’re really just talking about how much affinity the drug has for either the A or B isoform. In the US, we really only see one type of MAO I being used, which is a reversible inhibitor of MAO A (RIMA) called moclobemide. Taking moclobemide typically results in about 74% occupancy of the MAO-A in the brain. It works by ramping up the levels of serotonin, norepinephrine, and dopamine.

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Serotonergic Antidepressants
SIPPSa

The primary goal of these medications is to ramp up serotonin activity—mostly by heavily inhibiting the Serotonin Transporter. At standard therapeutic doses, they typically occupy about 80% of these transporters. In the United States, just like in the rest of the world, there are six main antidepressants in this class; I've laid out their core characteristics in Table 3 below.

Table 3. Overview of individual SIPPSa properties.

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While all SIPPSa share that potent effect on the Serotonin Transporter, they aren't identical—there are some key differences between them, which you can see in Table 4.

Table 4. Characteristics of specific SIPPSa

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We can break down how SIPPSa work into two distinct phases:

Acute effects: This happens when there's a sudden surge of serotonin in the synapse. Because the effect hits all serotonin receptors non-selectively, it's a bit of a double-edged sword—you get acute side effects like nausea or agitation, while simultaneously seeing a drop in serotonin synthesis and release because those autoreceptors are being overstimulated.

Chronic effects: Eventually, the serotonin receptors begin to adapt. As the presynaptic autoreceptors desensitize, serotonin synthesis and release actually increase. Meanwhile, postsynaptic receptor changes help dampen or even eliminate those initial side effects, leading to the actual antidepressant effect. It’s interesting to note that while acute use of SIPPSa can be anxiogenic (causing anxiety), long-term use tends to be anxiolytic (reducing anxiety). Ultimately, the antidepressant benefit stems from complex intracellular processes, including shifts in gene expression and protein synthesis.

Table 5 outlines the various consequences of that non-selective stimulation of serotonin receptors.

Table 5. Effects of serotonin receptor stimulation and blockade

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Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Since these antidepressants block the Serotonin Transporter, they basically share everything we know about SSRIs. However, they also provide additional NET blockade, which brings four specific clinical implications to the table:

1) They might offer better efficacy when treating moderate to severe depression compared to SSRIs—plus, they can be great for patients dealing with lethargy, as they tend to boost energy levels and provide a bit of activation.

2) They can help manage chronic pain, something SSRIs just don't do.

3) Along with the serotonergic effects, you get some noradrenergic side effects—think things like increased blood pressure (depending on the dose), dry mouth, sweating, or dilated pupils. Because of this, doctors need to be extra careful with anyone dealing with hypertension or angle-closure glaucoma.

4) They show promise for people with bipolar depression, which is often linked to low noradrenergic activity. That said, there is a higher risk of triggering a manic episode, so using them in these patients requires really careful weighing of the risks and close monitoring.

Table 6 highlights the two most prominent representatives of this class.

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Noradrenergic Antidepressants

Reboxetine

The primary mechanism of action for Reboxetine is the inhibition of the NET. While norepinephrine plays a huge role in mood regulation, it seems like just inhibiting the NET isn't quite enough to get the full antidepressant effect we're looking for. Based on various meta-analyses, Reboxetine actually shows a weaker antidepressant effect compared to other options out there—it’s also prescribed much less frequently than most other antidepressants. It feels like the noradrenergic component works best as a supporting player alongside other mechanisms of action, rather than being a powerhouse on its own.

Dopaminergic and Noradrenergic Antidepressants

The lone representative here is bupropion, which acts as a moderate reuptake inhibitor for both norepinephrine and dopamine. At standard therapeutic doses, it manages to block the DAT in the striatum by somewhere between 20% and 26%. It looks like this effect is driven by the stimulation of dopamine D1 receptors—since blocking those receptors actually cancels out the whole thing. Bupropion also inhibits NET activity, though we don't really have specific data on just how much that happens.

Additionally, bupropion functions as an antagonist for neuronal nicotinic receptors located in the ventral tegmental area (VTA)—which, as many know, is the starting point for the mesolimbic dopamine pathway. This particular mechanism is exactly why bupropion helps people kick their smoking habit.

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Antidepressants during pregnancy and the link to autism

Depression is a common struggle for women of childbearing age—in fact, about 3% to 8% of pregnant women across America have used antidepressants during their pregnancy.

The thing is, all antidepressants cross the placental barrier and reach the fetus. In animal models, prenatal exposure to serotonergic antidepressants resulted in offspring displaying behaviors similar to autism, which naturally raised questions about whether we might see similar effects in humans.

In this prospective observational study, researchers tracked over 250,000 children between the ages of 4 and 17. Their mothers were split into three distinct groups: those with no psychiatric disorders who didn't take antidepressants, those who did take antidepressants during pregnancy, and those who had a psychiatric disorder but chose not to take medication. The primary outcome measured was a diagnosis of autism spectrum disorder.

Out of the 3,342 children exposed to antidepressants in utero, 4.1% were later diagnosed with autism. Compare that to the 2.9% found among the 12,325 children whose mothers had a psychiatric disorder but stayed off medication.

We still don't fully understand the causes of autism. While there is a statistical link between antidepressant exposure and autism, only about 2% of all autism cases in the general population would actually be prevented if women with psychiatric disorders avoided these medications entirely. It’s also highly possible that genetic factors play a much larger role here—something that definitely needs more deep-dive research.

http://www.bmj.com/content/358/bmj.j2811