Atypical antidepressants

Antidepressants are often used to treat depression, although they may be prescribed to treat other conditions, such as anxiety disorders and insomnia. You might be prescribed an atypical antidepressant if other medications have not been effective or if you have experienced unpleasant side effects from other antidepressants.

What are atypical antidepressants?

There are four classes of antidepressant medications referred to as typical: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). Medications grouped within each of these classes share a similar mechanism of action ^[1].

Antidepressants that don’t fit into any of these classes are referred to as atypical antidepressants. These medications have various and unique mechanisms of action. Because of these differences, atypical antidepressants can be prescribed for treatment-resistant depression, to target specific symptoms, or to avoid undesirable side effects that other medications may cause ^[2].

Types of atypical antidepressants

There are several types of atypical antidepressants. The FDA has approved the use of the following atypical antidepressants in the treatment of major depressive disorder ^[3]:

• Bupropion: Bupropion is available as a tablet and can be prescribed as immediate-release, extended-release, or sustained-release tablets. Brand names include Wellbutrin, Aplenzin, and Zyban.
• Trazodone: Trazodone is available as a tablet. Brand names include Desyrel and Oleptro.
• Mirtazapine: Mirtazapine is available as a tablet that is swallowed whole and a tablet that disintegrates on the tongue. Brand names include Remeron.
• Nefazodone: Nefazodone is available as a tablet. Brand names include Serzone.
• Esketamine: This medication is administered as a nasal spray. It is available under the brand name Spravato.
• Vortioxetine and vilazodone: These medications are sometimes listed as SSRIs as they inhibit serotonin reuptake. However, they are also considered atypical as they also have additional actions, unlike other medications in the SSRI Vortioxetine is available as a tablet under the brand name Trintellix. Vilazodone is available as a tablet under the brand name Viibryd ^[4][5].

What are atypical antidepressants used to treat?

Atypical antidepressants are approved for use in the treatment of major depressive disorder (MDD). Many also have other uses, some approved by the FDA and others prescribed off-label.

Bupropion

Bupropion is approved by the FDA for use in the treatment of MDD. Compared to other antidepressants, it causes less sedation and fatigue, less weight gain, and less libido reduction ^[2].

As such, it may be prescribed as an alternative medication for individuals who have experienced these side effects. It can also be prescribed alongside other antidepressants to prevent sexual dysfunction side effects ^[6].

Bupropion (Zyban) is approved by the FDA to help with smoking cessation ^[7].

Off-label uses for bupropion include treating anxiety disorders and attention-deficit/hyperactivity disorder (ADHD) ^[6][8].

Trazodone

Trazodone is approved by the FDA for use in the treatment of major depressive disorder. Compared to other antidepressants, trazodone causes fewer issues with sleep or sexual functioning and less anxiety ^[2].

Trazadone is highly sedating, so it is commonly prescribed off-label to treat sleep disorders, such as insomnia. It is more often prescribed for this use than to treat depression, as it can cause unwanted drowsiness ^[8].

Trazadone is also prescribed off-label to treat anxiety disorders, chronic pain, bulimia nervosa, and schizophrenia ^[9].

Mirtazapine

Mirtazapine is approved by the FDA for use in the treatment of major depressive disorder. Compared to many other antidepressants, mirtazapine begins working more rapidly and causes fewer side effects relating to sexual dysfunction ^[2].

Mirtazapine is sometimes used off-label to treat sleep disturbances such as insomnia, although trazodone is more commonly prescribed for this ^[8].

Other off-label uses for mirtazapine include anxiety disorders and obsessive-compulsive disorder (OCD) ^[10]. It may also be used to treat depression in individuals with anorexia nervosa, as it can cause a significant increase in appetite and weight ^[11].

Nefazodone

Nefazodone is approved by the FDA for use in the treatment of major depressive disorder ^[3].

Nefazodone may be prescribed off-label to treat post-traumatic stress disorder (PTSD) ^[6].

Esketamine

Esketamine (Spravato) is approved by the FDA for use in the treatment of treatment-resistant depression and major depressive disorder with acute suicidal ideation. It should be used alongside an oral antidepressant medication and administered under professional supervision ^[3].

Vortioxetine and Vilazodone

Vortioxetine and vilazodone are approved by the FDA for use in the treatment of major depressive disorder ^[3].

How do atypical antidepressants work?

Antidepressants work by impacting the levels of certain neurotransmitters in the brain. The neurotransmitters typically targeted by antidepressants include ^[1][2]:

• Serotonin: Serotonin helps to regulate mood, behavior, libido, sleep, and appetite.
• Dopamine: Dopamine is involved in the pleasure and reward system in the brain and impacts motivation and decision-making abilities.
• Norepinephrine (also called noradrenaline): Norepinephrine is involved in the stress response, impacting heart rate and blood pressure. It also affects motor functioning, alertness, and energy levels.

Bupropion

Bupropion increases the levels of dopamine and norepinephrine by inhibiting the reuptake of these neurotransmitters, thus causing antidepressant effects ^[7].

Trazodone

Trazodone is a serotonin receptor antagonist and reuptake inhibitor (SARI) due to its effects on serotonin activity. Trazodone has antidepressant effects by increasing levels of serotonin and norepinephrine and has sedating effects due to its impact on histamine levels ^[2][6].

Mirtazapine

Mirtazapine enhances serotonin and norepinephrine by working as an antagonist of these neurotransmitter receptors, thus causing antidepressant effects. It also has some impact on histamine levels, which causes its sedating effects ^[10].

Nefazodone

Nefazodone works similarly to trazodone and is also a SARI due to its impact on serotonin. However, it differs from trazodone as it has a weaker effect on norepinephrine and does not cause as much sedation ^[12].

Esketamine

Esketamine is an NMDA glutamate receptor antagonist. Unlike other antidepressants, esketamine impacts glutamate levels and does not affect serotonin, dopamine, or norepinephrine. Glutamate is the most abundant neurotransmitter in the brain and affects mood, learning, memory, and communication between neurons ^[13].

Esketamine begins working within a few hours and increases treatment response when used alongside oral antidepressant medications ^[14].  

Vortioxetine and Vilazodone

Vortioxetine and vilazodone both inhibit serotonin reuptake, so they are often considered selective serotonin reuptake inhibitors (SSRIs). This action increases serotonin levels, causing an antidepressant effect. However, unlike other SSRIs, these medications also have other neurotransmitter effects.

Vortioxetine also impacts several serotoninergic receptors, further influencing serotonin levels, and also affects dopamine and norepinephrine ^[4].

Vilazodone also acts as a partial agonist on a serotoninergic receptor, adding to its effects on serotonin ^[5].

Because of their additional actions, these medications are found to cause fewer side effects commonly seen in SSRIs, such as weight gain and sexual dysfunction ^[4][5].

Atypical antidepressants precautions and interactions

Suicidal ideation

Many antidepressants have been found to cause an increase in suicidal ideation within the first few weeks of treatment. This risk is particularly high in individuals under the age of 24. When this happens, suicidal ideation will likely alleviate within a few months as the medication takes effect ^[1][3].

If you notice increased thoughts of self-harm or suicide when taking antidepressant medications, it is important to contact your doctor or mental health professional immediately. They can help to ensure your safety and provide appropriate support.

Pregnancy and breastfeeding

It is advised to consult with your doctor if you are pregnant or planning to become pregnant while taking antidepressant medication. There may be some risk of fetal harm, particularly in the third trimester ^[15][16]. It is essential to be aware of these risks, as well as the potential risks of discontinuing antidepressant treatment, to make an informed decision about medication use.

Similarly, you should consult your doctor if breastfeeding while taking antidepressant medication, as the medicine might be excreted in breast milk. Again, these risks should be weighed against the potential harm of discontinuing treatment ^[7][17].

Often, antidepressant use while pregnant or breastfeeding will depend on the individual’s preference, their symptoms, and the severity of their condition. If your condition is moderate to severe, you may be advised to continue your treatment or commence alternative treatment ^[3].  

Serotonin syndrome

Serotonin syndrome can occur when antidepressant medications cause a dangerously high level of serotonin, either when used in combination or alone. Serotonin syndrome can cause symptoms such as agitation, hallucinations, increased blood pressure, dizziness, confusion, stomach issues, and seizures, and can be fatal in some cases ^[15][16].

If serotonin syndrome occurs, seek medical attention. Antidepressant medication should be stopped immediately and treatment provided ^[1].

Heart, liver, and kidney disease

People who have experienced cardiac irregularities, or heart, liver, or kidney disease, should inform their doctor of their medical history before taking antidepressant treatment. Some medications may be unsafe to take, or your doctor may wish to prescribe you a reduced dose and ensure careful monitoring ^[7][16].

Drug interactions

Antidepressants can interact with several different medications, causing unpleasant or dangerous effects. This can include beta-blockers, anticonvulsants, heart medications, antivirals, antibiotics, antifungals, steroids, sedatives, other antidepressants, antipsychotics, blood thinners, and St. John’s wort ^[17][18].

It is advised to inform your doctor of all medications and supplements you are using (prescribed or over the counter) before commencing an antidepressant medication.

Stopping medication

You should never abruptly stop taking an antidepressant medication, as this can cause unpleasant withdrawal symptoms. If you wish to stop taking your medication, following your doctor’s advice is important, as they will likely gradually reduce your prescription to prevent withdrawal symptoms ^[3].

Additional precautions include:

• Bupropion: Bupropion can cause an increased risk of seizures, so people should not take it if they have a seizure disorder or are at high risk of seizures, such as those with anorexia or bulimia ^[7].
• Trazodone: Trazodone is strongly sedating, so it is advised not to drive while using this medication ^[17].
• Mirtazapine: Mirtazapine can cause an increase in appetite and weight ^[10].
• Nefazodone: Nefazodone can cause significant liver dysfunction that is potentially life-threatening in some cases. It is advised to be aware of and report any concerning symptoms that may indicate liver issues, such as yellowing of the skin, fatigue, and nausea ^[1][3].
• Esketamine: Esketamine is a controlled substance due to its potential for abuse and addiction. It should only be used if at least two other antidepressant medications have been tried with little or no effect. Esketamine can only be administered under professional supervision, followed by close monitoring for side effects ^[3][14].