Atypical antidepressants are unique from other classes of antidepressants based on pharmacological properties. These days, the most common antidepressants fit into one of a few categories: SSRIs/SNRIs, TCAs, and MAOIs. Respectively these are: selective-serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclics (TCAs), and monoamine oxidase inhibitors (MAOIs). SSRIs and SNRIs are considered the new “second generation” antidepressant drugs, while TCAs and MAOIs are of the “first generation” class.
From 2000 to 2010, the first-line treatment option for depression has always been an SSRI medication. It is thought that this class of medication carries less significant side effects when compared with the first generation drugs (TCAs and MAOIs). Throughout history, there have been antidepressants that don’t necessarily fit the protocol to fit within a classification – these drugs are referred to as being “atypical.”
Atypical Antidepressants: List of Examples
Below is a list of atypical antidepressants starting with the earliest approved and advancing to the latest.
1. Desyrel (Trazodone)
Approved in 1981, this antidepressant works as an antagonist at all of its receptor sites except 5-HT1A, where it acts as a partial agonist. It also works as an inhibitor of the serotonin transporters (5-HTT). This drug is largely considered an SARI (Serotonin Antagonist and Reuptake Inhibitor) and works similar to the drug Nefazodone.
In other words, this drug helps increase serotonin levels in the brain (reuptake inhibitor). It also blocks excess serotonin (at 5HT2A and 5HT2C receptors) and excess norepinephrine (at Alpha 1 noradrenergic receptors). The antihistamine properties of this drug are considered to pack a powerful punch.
2. Wellbutrin (Bupropion)
Approved in 1985, Wellbutrin is considered one of the first atypical antidepressants on the market. It works by preventing the reuptake of the neurotransmitters norepinephrine and dopamine (to a lesser extent). This allows levels in your brain to increase and soak in the synapses, which yields an antidepressant effect.
This is a popular antidepressant on its own because it doesn’t tend to result in unwanted side effects like weight gain, sexual dysfunction, and low energy. Many consider Wellbutrin the best antidepressant for weight loss. In addition to being a popular first-line treatment, it is also a commonly paired with an SSRI to patients that need more energy or to minimize SSRI side effects.
Specifically, the drug is described as a norepinephrine-dopamine reuptake inhibitor (NDRI), but the extent to which it affects dopamine is thought to be a lesser degree. Various research has suggested that it doesn’t significantly affect dopamine levels at doses used to treat depression.
It also acts as an antagonist at a few nicotinic acetylcholine receptors. In terms of structure, it is considered more of a stimulant and some doctors actually use Wellbutrin for ADHD with comorbid depression.
3. Remeron (Mirtazapine)
Approved 1996, Remeron is in a class of antidepressants that stimulate norepinephrine and serotonin release, while also blocking two serotonin receptors (5-HT2 and 5-HT3). In other words, this is the only noradrenergic and specific serotonergic antidepressant (NaSSA) that’s been approved in the United States.
What separates Remeron from SNRIs is that it is able to target where it works in the brain. It is an agonist at the 5-HT1A serotonin receptors and an antagonist at the 5-HT2A, 5-HT2C, and 5-HT3 sites. It also carries very potent antihistamine properties.
4. Serzone (Nefazodone)
Approved in 1994, this drug worked as a powerful antagonist at the 5-HT2A receptors and also slightly on the Alpha 1 adrenergic receptor and 5-HT1A receptor. It has a lesser effect on the Alpha 2 adrenergic receptor and the D2 dopamine receptor. In other words, this drug works as a relatively weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).
Many newer drugs called “Triple Reuptake Inhibitors” are attempting to work as more powerful SNDRIs than Serzone. The degree to which this drug acts as an antihistamine is inconclusive, but some sources suggest that in theory it should work quite well. When taking higher dosages of Serzone, it may prevent the reuptake of enough norepinephrine and dopamine to make a noticeable difference in mood. Unfortunately for this medication, it was removed from the market in 2003 due to cases of liver damage and failure.
5. Viibryd (Vilazodone)
Approved in 2011, this drug works as both an SSRI and partial agonist at the 5-HT1A receptor. Many experts still classify Viibryd as an SSRI, but its effect as an agonist makes it slightly different from other SSRIs. It’s similar to the combination of an SSRI and BuSpar. It is a relatively newer medication as well and supposedly touted as having less side effects than older selective-serotonin reuptake inhibitors.
6. Brintellix (Vortioxetine)
Approved in 2013, this drug functions primarily as a serotonin-modulator and stimulator (SMS). It has an effect by inhibiting reuptake of serotonin as well as norepinephrine to a lesser extent. It also acts as a partial agonist at various 5-HT receptors including: 5-HT3A, 5-HT1A, and 5-HT7. Researchers believe that it also could increase concentrations of acetylcholine as well as histamine in the brain.
It has only been approved to treat major depression, but is being studied for potential use in anxiety disorders. In a variety of studies for treating major depression, this drug has been found significantly superior to a placebo, but no more effective than other antidepressants. Research has suggested that this drug may cause less sexual dysfunction than Effexor.
Why are people prescribed “atypical” antidepressants?
In the past, a majority of individuals were prescribed atypical antidepressants only when they hadn’t gotten relief from an SSRI. These days, a person may actually be prescribed an atypical antidepressant as a first-line treatment option depending on the subtype of depression as well as the side effects a patient hopes to avoid.
- Others don’t work – Usually a person ends up trying an atypical antidepressant after they’ve already gone through an array of SSRIs without improvement in depression. Some psychiatrists make their patients try every mainstream SSRI until they’re convinced that a different class of drug may work better, while others may change medication class sooner.
- Neurotransmitters – If a person is experiencing depression because they have low arousal and low energy, a doctor may figure that serotonin may not be the culprit. Instead they may choose to prescribe a drug that has more of an influence on dopamine (read: dopamine vs. serotonin). Additionally, they may decide that a blend between serotonin and norepinephrine reuptake inhibition would be optimal for a certain individual (read: low norepinephrine and depression).
- Newer – When a new medication comes out, everyone wants to try it (e.g. Viibryd). Since certain drugs are newer, they are thought to be improved and carry less overall side effects. Newer means more appeal to consumers as well as greater profits for the doctors that prescribe them.
- Side effect profile – Perhaps the most favorable aspect about the majority of atypical antidepressants is that certain ones are not associated with as much weight gain and sexual dysfunction as SSRIs. Additionally most do not carry as many unwanted side effects brought on by using TCAs and MAOIs.