Atypical antidepressants are mainly used to treat major depressive disorder. This disorder causes a persistent feeling of sadness and loss of interest in everyday activities. Even though the exact cause of depression is still unknown, there's some evidence that suggests it’s related to low levels of neurotransmitters like serotonin, norepinephrine, and dopamine. Typical antidepressants like selective serotonin reuptake inhibitors or tricyclic antidepressants work by increasing the levels of serotonin and norepinephrine, while atypical antidepressants often have multiple mechanisms of action.
All right, now within the brain, there are many different types of neurons, but we’re going to focus only on three: serotonergic neurons, which produce serotonin; noradrenergic neurons, which produce norepinephrine; and dopaminergic neurons, which produce dopamine. Each of these neurons synthesizes and stores their neurotransmitters in small vesicles. So, when an action potential reaches the presynaptic membrane, these vesicles fuse with the membrane, releasing neurotransmitters into the synaptic cleft. Once released, serotonin (or 5-HT) binds to 5-HT2 receptors on the postsynaptic membrane, thereby increasing neural stimulation, and regulating mood, feeding, and reproductive behavior. On the other hand, norepinephrine binds to norepinephrine receptors on the postsynaptic membrane, boosting alertness. And finally, dopamine binds to dopamine receptors, thereby stimulating cognitive functions, motivation, and awakeness.
As long as there’s a high enough concentration of neurotransmitters in the synaptic cleft, the postsynaptic neurons will continue to fire. Now, serotonergic neurons on their presynaptic membrane have serotonin transporters (or SERT); noradrenergic neurons have norepinephrine transporters (or NET); while dopaminergic neurons have dopamine transporters (or DAT). These membrane proteins transport neurotransmitters from the synaptic cleft back into presynaptic neurons. This leads to a decreased neurotransmitter concentration within the synaptic cleft, causing the postsynaptic neurons to stop firing. Noradrenergic and serotonergic neurons are also rich in alpha 2 receptors. When stimulated, alpha 2 receptors inhibit the activity of the presynaptic neurons and decrease the release of norepinephrine or serotonin.
Now, in conditions such as major depressive disorder, atypical antidepressants are typically reserved for individuals that don’t respond to other antidepressants. Common medications in this group include mirtazapine, trazodone, nefazodone, vilazodone, vortioxetine, and bupropion. All right, first let’s start with mirtazapine. Mirtazapine binds and inhibits several receptors including alpha 2 receptors, 5-HT2A receptors, 5-HT3A receptors, and histamine H1 receptors. Its main antidepressant effect comes from the inhibition of alpha 2 receptors, which reduces the inhibition of the presynaptic neuron, leading to increased norepinephrine and serotonin release. Now mirtazapine is actually a serotonin antagonist, which might seem counterintuitive. But there are different types of 5-HT2 receptors; mirtazapine selectively blocks 5-HT2A and 5-HT3A receptors, so more serotonin can bind to 5-HT1A receptors; which have a stronger link to depression. Inhibition of 5-HT3A receptors also reduces nausea and vomiting. Lastly, inhibition of histamine H1 receptors leads to sedation, which could be desirable in depressed individuals with insomnia.
Other common side effects include dry mouth, increased appetite, and weight gain, which may be helpful for anorexic individuals. Next we have trazodone and nefazodone. These medications’ main antidepressant effect comes from their ability to bind 5-HT2A receptors, so more serotonin binds to 5-HT1A receptors. They are also weak inhibitors of serotonin reuptake transporters on the presynaptic neuron, thereby increasing the levels of serotonin within the synaptic cleft. They are strong H1 receptor inhibitors and are commonly used to treat insomnia. Finally they are also alpha 1 receptor inhibitors, which may cause orthostatic hypotension and priapism, which is a prolonged, unwanted erection of the penis. Nefazodone is also known to cause severe liver damage in rare cases.
Next we have vilazodone and vortioxetine, which are strong inhibitors of serotonin reuptake transporters on the presynaptic neuron just like SSRIs. However, these medications can also directly bind to and stimulate 5-HT1A receptors; vilazodone is a partial agonist, while vortioxetine is a full agonist. Since they enhance the effect of serotonin through 2 separate mechanisms, they can also cause serotonin syndrome, which is a life-threatening condition caused by serotonin accumulation and over stimulation of the nervous system. This syndrome is characterized by skin flushing, hyperthermia, agitation, muscle rigidity, seizure, and coma. It usually occurs in individuals treated with a combination of these medications and other antidepressants that increase serotonin levels, such as selective serotonin reuptake inhibitors. Treatment of serotonin syndrome consists of administration of cyproheptadine, which is a serotonin antagonist that blocks 5-HT2 receptors. These medications are anticholinergics and can cause atropine-like side effects such as sedation, blurred vision, orthostatic hypotension, urinary retention, and tachycardia. Vilazodone can also cause weight gain, while vortioxetine can cause abnormal dreams.