How SSRIs Compare to MAOIs

A Comparison Between Types of Antidepressants

zoloft, paxil, and prozac pills

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Monoamine oxidase inhibitors (MAOIs) are considered to be perhaps the most effective antidepressant agents in the psychiatrist's medical arsenal. They work by inhibiting the enzyme monoamine oxidase in the brain.

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 Do MAOIs Work?

It is believed that the brain contains several hundred different types of chemical messengers (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 occurrences.

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 enzyme MAO, leading to higher levels of norepinephrine, serotonin, and dopamine in the brain. This, in turn, leads to improved mood and an anti-panic effect.

The benefits of these increases are improved mood and an anti-panic effect.

Some common MAOIs include:

  • Phenelzine (nardil)
  • Tranylcypromine (parnate)
  • Isocarboxazid (marplan)
  • Selegiline (emsam)

How Do SSRIs Work?

Serotonin is a neurotransmitter that is important in modulating a variety of body functions and feelings, including our mood. Low serotonin levels have been linked to depression and anxiety. 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, which is a small space between brain cells.

Examples of SSRIs include:

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

Why Are SSRIs More Often Prescribed Than MAOIs?

SSRIs are generally the first choice for treatment of depression because, beyond just being effective, they have fewer problems with side effects. Because of dietary restrictions and concerns over hypertensive reactions, MAOIs are often used only after other agents have failed.

Other common side effects of MAOIs include:

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

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 during the beginning of treatment. Some common side effects of SSRIs include:

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

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 SSRIs function by a similar mode of action, they are 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.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

First approved by the FDA in 1992, 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 similar to SSRIs, but they inhibit the reuptake of both norepinephrine and serotonin, which may make them more effective than SSRIs for severe depression.

SNRIs are also less likely than SSRIs to exacerbate rapid mood cycling in people with bipolar depression. They are most often used for short-term therapy, however. This is because prolonged use can trigger a manic or hypomanic episode.

Examples of SNRIs include:

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

Common side effects of SNRIs include

  • Nausea
  • Drowsiness
  • Fatigue
  • Constipation
  • Dry mouth

Antidepressant

  • TCAs

  • SNRIs, TCAs

  • SSRIs, MAOIs

  • SSRIs, SNRIs, MAOIs, TCAs

  • SSRIs, SNRIs, MAOIs, TCAs

  • SSRIs, SNRIs, MAOIs, TCAs

  • SSRIs, SNRIs, TCAs

  • SSRIs, SNRIs, MAOIs, TCAs

  • SSRIs, SNRIs, TCAs

  • SSRIs, SNRIs, MAOIs, TCAs

  • SSRIs, MAOIs, TCAs

Side Effect

  • Blurry vision

  • Constipation

  • Diarrhea

  • Dizziness

  • Drowsiness

  • Dry mouth

  • Fatigue

  • Headache

  • Insomnia

  • Sexual dysfunction

  • Weight gain

Tricyclic Antidepressants (TCAs)

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 published in Drugs Context researchers found that patients with MDD on 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 treatment.

Examples of TCAs include:

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

Some side effects of TCs include:

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

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 of these 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 (prescription, over-the-counter, vitamins, and supplements).

When starting a new drug, do your best to have patience (it can take up to eight weeks to feel substantial improvement) and monitor any drug side effects.

If your side effects are intolerable and begin to interfere with your quality of life, call your doctor right away but never stop treatment on your own. Stopping abruptly can cause withdrawal symptoms, including chills, dizziness, fever, headache, lethargy, nausea, and vomiting.

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