How SSRIs Compare to MAOIs

Monoamine oxidase inhibitors (MAOIs) are considered perhaps the most effective antidepressant agents in the psychiatrist's medical arsenal. They work by inhibiting the enzyme monoamine oxidase in the brain, thereby increasing levels of norepinephrine, dopamine and serotonin.

Selective serotonin reuptake inhibitors (​SSRIs), on the other hand, are used to treat depression in addition to many anxiety-related illnesses, including panic disorder (PD). They work by inhibiting the reuptake of serotonin in the brain, causing an increase of serotonin.

How MAOIs Work

It is believed that the brain contains several hundred different types of chemical messengers called neurotransmitters that act as communication agents between different brain cells. These chemical messengers are molecular substances that can affect mood, appetite, anxiety, sleep, heart rate, temperature, aggression, fear, and many other psychological and physical functions.

Monoamine oxidase (MAO) is an enzyme that degrades or breaks down three neurotransmitters associated with mood and anxiety: serotonin, norepinephrine, and dopamine. MAOIs reduce the activity of the MAO enzyme, leading to higher levels of norepinephrine, serotonin, and dopamine in the brain. The benefits of these increases are improved mood and an anti-panic effect.

Some common MAOIs include:

• Emsam (selegiline)
• Marplan (isocarboxazid)
• Nardil (phenelzine)
• Parnate (tranylcypromine)

How SSRIs Work

Serotonin is a neurotransmitter that is important in modulating a variety of body functions and feelings, including our mood. According to research, low levels of serotonin transmission have been linked to depression. As the name implies, SSRIs inhibit the reuptake of serotonin in the brain. This causes an increase of serotonin in an area of the brain called the synaptic cleft, the small space between brain cells.

Examples of SSRIs include:

• Celexa (citalopram)
• Lexapro (escitalopram)
• Luvox (fluvoxamine)
• Paxil (paroxetine)
• Prozac (fluoxetine)
• Zoloft (sertraline)

Another medication called Viibryd (vilazodone) is not just an SSRI. It is both an SSRI and a serotonin 1α (5HT-1α) partial agonist (like the anti-anxiety medication buspirone), so it is classified as a multimodal serotonergic agent. Of note is that while fluvoxamine is an SSRI, it is also the most potent of the SSRI's at the σ-1 receptor, which may make it more effective in reducing severe anxiety and depression as well as aiding cognitive functioning.

Why SSRIs Prescribed More Often Than MAOIs

SSRIs are generally the first choice for treatment of depression because beyond their effectiveness, they generally cause fewer problems with side effects. Because of dietary restrictions and concerns over hypertensive reactions, as well as serotonergic crises from drug interactions (serotonin syndrome), MAOIs are often used only after other agents have failed.

People should try to avoid foods high in tyramine, which can be elevated due to MAOI use and may lead to critically high blood pressure. Foods to avoid include beef liver, hot dogs, bacon, sour cream, aged cheese, red wine, and brewer's yeast. The lowest dose of Emsam (6 mg), however, carries no dietary precautions.

Other common side effects of MAOIs include:

• Confusion
• Decreased sleep/insomnia
• Diarrhea
• Dizziness
• Dry mouth
• Edema (water retention)
• Hypertension (high blood pressure)
• Hypotension (low blood pressure)
• Muscle spasms
• Nausea
• Weight gain
• Sexual dysfunction
• Weakness

One of the attractions of SSRIs is that they are believed to be safer and produce fewer unwanted side effects than other classes of antidepressants. But any medication can cause side effects, especially at the beginning of treatment. Some common side effects of SSRIs include:

• Drowsiness
• Headache
• Insomnia
• Nausea
• Nervousness
• Sexual dysfunction, including reduced desire or orgasm difficulties
• Stomach upset
• Weight gain

Some of these side effects will be eliminated after your body adjusts to the medication. If they don’t and are bothersome, your doctor may try another SSRI. Although all SSRIs function by a similar mode of action, each drug is different. Certain side effects with one SSRI may not be a problem with another. Discussing the details with your doctor will help choose the best option for you.

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In general, primary care providers should not prescribe MAOIs unless they have experience with these medications.

Other Types of Antidepressants

In addition to MAOIs and SSRIs, there are other classes of antidepressant medications available, including serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and multimodal medications.

How SNRIs Work

Venlafaxine (Effexor) was approved in 1993 and was the first FDA-approved SNRI. SNRIs are often used to treat the chronic pain linked to depression as well as generalized anxiety, post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), panic disorder, and nerve pain associated with fibromyalgia. They work similarly to SSRIs, but they inhibit the reuptake of both norepinephrine and serotonin.

SNRI use can trigger a manic or hypomanic episode.

Examples of SNRIs include:

• Cymbalta (duloxetine)
• Effexor (venlafaxine)
• Fetzima (levomilnacipran)
• Pristiq (desvenlafaxine)
• Savella (milnacipran)

Common side effects of SNRIs include:

• Constipation
• Drowsiness
• Dry mouth
• Fatigue
• Nausea

How TCAs Work

Tricyclic antidepressants (TCAs), which are primarily used to treat depression, bipolar disorder, and other conditions such as chronic pain and insomnia, were first introduced in the 1950s. TCAs work similarly to reuptake inhibitors in that they block the absorption of serotonin and norepinephrine into nerve cells, however, these drugs are known to have more side effects than newer classes of antidepressants like SSRIs.

In a meta-analytic review, researchers found that patients with major depressive disorder (MDD) who took TCAs discontinued treatment 27% of the time due to side effects compared with 19% on SSRIs. The percentage was even greater in elderly patients—33% and 16%, respectively. 

When compared with MAOIs, TCAs have also been found less effective for treatment-resistant depression (TRD). However, TCAs still have their place in depression treatment.

Examples of TCAs include:

• Anafranil (clomipramine)
• Asendin (amoxapine)
• Elavil (amitriptyline)
• Norpramin (desipramine)
• Pamelor (nortriptyline)
• Sinequan (doxepin)
• Surmontil (trimipramine)
• Tofranil (imipramine)
• Vivactil (protriptyline)

Some side effects of TCAs include:

• Blurry vision
• Constipation
• Dizziness
• Drowsiness
• Dry mouth
• Irregular heartbeat
• Low blood pressure
• Seizures
• Weight gain

How Multimodal Medications Work

There are also multimodal medications such as Viibryd, Trintelix, bupropion (Wellbutrin), and mirtazapine (Remeron). These drugs work in unique ways so that they do not fit in the same classes as other antidepressants so they are often called atypical antidepressants or multimodal antidepressants.

Some different types of atypical antidepressants include:

• Bupropion (Wellbutrin)
• Mirtazapine (Remeron)
• Trazodone
• Vilazodone (Viibryd)
• Vortioxetine (Trintellix)

Possible side effects of atypical antidepressants include:

• Dry mouth
• Dizziness
• Increased or decreased appetite
• Sexual side effects
• Sleeping difficulties

A Word From Verywell

There's no one-size-fits-all treatment for depression and what works for someone else might not work for you. Since all antidepressants can help with symptoms of depression, deciding which one to take may come down to which side effects you can and can't tolerate. Other factors include your symptoms, treatment history, and current medications (including prescription drugs, over-the-counter medications, vitamins, and supplements).

If your side effects are intolerable and begin to interfere with your quality of life, call your doctor right away but don't stop treatment on your own. Stopping abruptly can cause withdrawal symptoms, including chills, dizziness, fever, headache, lethargy, nausea, and vomiting.