What you need to know about SNRIs, MAOIs, tetracyclics, dopamine reuptake inhibitors and atypical neuroleptics for depression treatment

In addition to selective serotonin reuptake inhibitors (SSRIs) and tricyclics, here are some other antidepressants you should know about.


The action, efficacy, and side effects of drugs like maprotiline and mirtazapine (Remeron) are similar to those of the tricyclics. However, maprotiline is more likely to cause seizures than most other antidepressants. A version of Remeron is available that dissolves on the tongue and does not need to be chewed or swallowed whole.

Dopamine Reuptake Inhibitors

Wellbutrin decreases the reuptake of dopamine, a neurotransmitter and a precursor of other neurotransmitters. This drug causes less drowsiness and fewer side effects than the tricyclics (especially fewer sexual side effects), but on rare occasions it can cause seizures, particularly at higher doses. Wellbutrin XL is the first drug approved to prevent major depressive episodes in people with seasonal affective disorder (SAD).

Serotonin and Norepinephrine Reuptake Inhibitors

Medications like desvenlafaxine (Pristiq), duloxetine (Cymbalta), trazodone, and venlafaxine (Effexor) are serotonin and norepinephrine reuptake inhibitors (SNRIs). These medications work by raising brain concentrations of the neurotransmitters serotonin and norepinephrine. In December 2013, the U.S. Food and Drug Administration (FDA) approved the first generic versions of Cymbalta (duloxetine delayed-release capsules).

SNRIs are often the most effective drugs for older people.

Possible SNRI side effects include nausea, weakness, sweating, insomnia, drowsiness, dry mouth, dizziness, and constipation. Effexor may increase blood pressure and cholesterol levels in some people, so monitoring blood pressure and cholesterol is important for anyone taking this drug. Cymbalta, Effexor, and Pristiq taken in combination with triptan migraine medications may result in serotonin syndrome.

Monoamine Oxidase (MAO) Inhibitors

MAO inhibitors such as phenelzine (Nardil) and tranylcypromine (Parnate) increase brain levels of norepinephrine, serotonin, and dopamine by blocking the action of the enzyme MAO, which normally inactivates these three neurotransmitters. MAO inhibitors are effective in many depressed people, especially those whose depression is accompanied by marked anxiety, panic attacks, heightened appetite, or excessive sleeping.

People who should not take MAO inhibitors

MAO inhibitors can cause some of the same side effects as the tricyclics; side effects can be reduced in similar ways. But there are some individuals for whom MAO inhibitors pose greater risks.

MAOI Interactions

If you are a heavy drinker, have heart failure or severely impaired liver or kidney function, or take multiple medications for high blood pressure, you should not take an MAO inhibitor. In addition, MAO inhibitors can cause a sudden, extreme elevation in blood pressure (known as a hypertensive crisis) when people using them take certain drugs or consume foods or beverages containing tyramine. (Tyramine is found in nasal decongestants, cold or allergy medicines, very ripe bananas, beer, and aged or smoked meats, among other things.) People taking an MAO inhibitor must get a complete list of restricted foods and drugs from their doctor. Normally, the enzyme MAO breaks down any tyramine consumed in the diet, preventing its blood pressure-raising effect. This protective mechanism is disabled by MAO inhibitors, which block the action of MAO in the liver and intestine, allowing tyramine levels to rise and increase blood pressure.

Symptoms of a hypertensive crisis include severe chest pain, excruciating headache, sweating, clammy skin, nausea, and vomiting. Immediate treatment with blood pressure- lowering drugs is essential. Because of this risk and the dietary restrictions, MAO inhibitors are now only used as second-line drugs for the treatment of depression, despite their proven efficacy.

A skin patch of the MAO inhibitor Emsam is now available. At the lowest dose, Emsam does not interfere with the breakdown of tyramine in the digestive tract and can therefore be used without dietary restrictions.

Atypical Neuroleptic / Selective Serotonin Reuptake Inhibitor

In 2009, the FDA approved Symbyax, a combination of an atypical neuroleptic (olanzapine) already used for bipolar disorder and an SSRI (fluoxetine), to treat depression in people who have not responded to two other antidepressants. Like all neuroleptics, Symbyax increases the risk of death in elderly people with dementia. Symbyax is also associated with a risk of neuroleptic malignant syndrome.

Atypical Neuroleptics as Adjuncts to Antidepressants

Sometimes even after trying several different antidepressants, symptoms of depression remain. In this case, adding an atypical neuroleptic such as aripiprazole (Abilify) or risperidone (Risperdal) to a patient’s current medication often provides relief. These medications are approved by the FDA to treat symptoms of bipolar disorder and schizophrenia as well as for depression in combination with an antidepressant.

Side effects of neuroleptics include nausea, vomiting, constipation, headache, dizziness, an inner sense of restlessness or need to move (akathisia), anxiety, and insomnia. There is also the risk of more serious side effects including a condition called tardive dyskinesia, which causes abnormal or uncontrollable movements of the face, tongue, or other parts of the body, and neuroleptic malignant syndrome, which may cause severe muscle stiffness, fever, severe tiredness, or weakness. Elderly people with dementia who take neuroleptics are at increased risk of sudden cardiac death. Ask your healthcare provider about this and other risks if he or she suggests you take a neuroleptic.

Publication Review By: Karen L. Swartz, M.D.

Published: 03 Mar 2011

Last Modified: 16 Dec 2013