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Reviewed by: HU Medical Review Board | Last reviewed: September 2023

The first-line treatment for most cases of major depressive disorder (MDD) is an antidepressant drug. The most effective treatment plans often include at least 1 antidepressant drug along with some type of talk therapy (psychotherapy).1,2

The most common types of antidepressants for MDD are:1-3

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs)
  • Tricyclic and tetracyclic antidepressants (TCAs)
  • Monoamine oxidase inhibitors (MAOIs)
  • Atypical antidepressants

How do antidepressant drugs work?

All commonly used antidepressants in the United States act on neurotransmitters. Neurotransmitters are chemicals the brain uses to send messages to the rest of the body. These messages tell our bodies how to think and behave. They also control bodily functions like digestion, heart rate, blood pressure, and more.3,4

Experts think neurotransmitters play a big role in mood. Some think depression is directly linked to the balance of certain neurotransmitters. Others believe it is linked to brain processes that eventually change this balance down the line.1,2

Some common neurotransmitters impacted by antidepressants are:1,3

  • Serotonin
  • Norepinephrine
  • Dopamine
  • Histamine
  • Acetylcholine

For many people, symptoms respond well to antidepressant drugs. Some people even experience full relief (remission) of symptoms.1,2


SSRIs and SNRIs are both often used as the first options for treating MDD. They have many similarities. Both impact the neurotransmitter serotonin. But SNRIs also impact norepinephrine.1,3,5,6

Common examples of SSRIs include:5,7

  • Escitalopram (Lexapro®)
  • Fluoxetine (Prozac®)
  • Sertraline (Zoloft®)
  • Citalopram (Celexa®)
  • Paroxetine (Paxil®)

Common examples of SNRIs include:6,7

  • Venlafaxine (Effexor®)
  • Duloxetine (Cymbalta®)
  • Levomilnacipran (Fetzima®)
  • Desvenlafaxine (Pristiq®)


TCAs are an older drug class used to treat depression. They have many side effects and risks because they affect several neurotransmitters. TCAs affect serotonin, norepinephrine, histamine, acetylcholine, and other neurotransmitters. Some call TCAs broad-spectrum antidepressants.3,7,8

Today, TCAs are used when a person has not responded to other drugs, like SSRIs or SNRIs. Common examples of TCAs include:3,7,8

  • Amoxapine (Asendin®)
  • Amitriptyline (Elavil®)
  • Clomipramine (Anafranil®)
  • Desipramine (Norpramin®)
  • Nortriptyline (Pamelor®)
  • Doxepin (Sinequan®)
  • Trimipramine (Surmontil®)
  • Imipramine (Tofranil®)
  • Protriptyline (Vivactil®)
  • Maprotiline (Ludiomil®)


MAOIs are also an older class of antidepressants. Like TCAs, they have many risks and are most commonly used after newer drugs have been tried. MAOIs impact serotonin, norepinephrine, dopamine, and tyramine.3,9

Tyramine is a neurotransmitter that plays a role in blood pressure control. If a person taking an MAOI gets too much tyramine from their diet, they may have a life-threatening episode of high blood pressure. This is called a hypertensive crisis.3,9

Because of this risk, people on MAOIs may need to avoid certain foods and drinks. Some of these include aged cheeses, cured meats, draft beer, and fermented soy products like tofu.3,9

Common examples of MAOIs include:7,9

  • Selegiline (Emsam®)
  • Isocarboxazid (Marplan®)
  • Phenelzine (Nardil®)
  • Tranylcypromine (Parnate®)

Atypical antidepressants

Atypical antidepressants do not fall into 1 of the previously listed categories. Their effects on the body can vary. Atypical antidepressants may be good options for avoiding certain side effects or treating multiple issues at once.1,3,10,11

For example, trazodone is an atypical antidepressant that has fewer sexual side effects. Bupropion is another atypical drug that can also help with quitting smoking.1,3,10,11

Common examples of atypical antidepressants include:7,10,11

  • Bupropion (Wellbutrin®)
  • Mirtazapine (Remeron®)
  • Trazodone (Desyrel®)
  • Nefazodone (Serzone®)
  • Vortioxetine (Trintellix®)
  • Vilazodone (Viibryd®)

What are the possible side effects?

Side effects can vary depending on the specific drug you are taking. The exact side effects of an antidepressant depend on which neurotransmitters it impacts. But the most common side effects of antidepressants include:1,3,7

  • Trouble sleeping (insomnia)
  • Gastrointestinal issues, like nausea, constipation, or diarrhea
  • Dry mouth
  • Dizziness, especially when standing up
  • Blurry vision
  • Headache
  • Changes in appetite or weight
  • Extreme tiredness (fatigue)
  • Changes in the way the heart beats
  • Shakiness (tremors)
  • Problems with sexual function, including reduced desire, inability to maintain an erection, and trouble achieving orgasm

Antidepressants have a boxed warning, the strictest warning from the US Food and Drug Administration (FDA). They have this warning because they may increase suicidal thoughts or behaviors for people under age 25. This risk is highest for those who have just started treatment or who have recently changed drug doses.3,7

These are not all the possible side effects of antidepressants. Talk to your doctor about what to expect when taking 1 of these drugs. You also should call your doctor if you have any changes that concern you when taking an antidepressant.

Finding the right antidepressant for you

Finding the right antidepressant is often a trial-and-error process. For some, it can last weeks, months, or even longer. Many antidepressants have a slow onset of action. Some do not have noticeable effects for a long time. A typical trial of an antidepressant drug can be 6 weeks or longer.1,4

If you and your doctor think you are not responding to the drug you are on, it may be time to try a new one. This can be another drug in the same class or a different class. For example, you may first try sertraline, an SSRI. If your symptoms are not responding, you may be prescribed another SSRI, like citalopram. Or your doctor might recommend switching to an SNRI, like venlafaxine.1

It may take some time to find the right dose as well. Some antidepressants have a wide range of safe doses. In most cases, the goal is to use the lowest possible dose that helps symptoms so that side effects are reduced. Because of this, your doctor will often start you on a low dose. If your symptoms are not responding, they may slowly increase the dose until you notice an effect.1,3

If you reach a high dose but your symptoms are not improving or the side effects are hard to manage, it may be time to try a new drug.1,3

Treatment-resistant depression

Some people do not respond to antidepressant drugs. This is called having treatment-resistant depression. The exact definition of this condition can vary. But many experts agree that symptoms that do not respond to 2 or more different types of antidepressant drugs are considered treatment-resistant depression.1,12,13

People with treatment-resistant depression may be able to continue trying new drug options. But if many options have not worked, they may need to try nondrug options. Examples of nondrug options for treatment-resistant depression include electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and other brain stimulation treatments.2,12,13

Other things to know

Many antidepressants interact with other drugs, vitamins, and supplements. Some of these interactions can be dangerous. Some antidepressants can make existing health conditions worse. Before beginning treatment for MDD, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you take. This includes over-the-counter drugs.1,3

Most antidepressant drugs impact serotonin in some way. This can increase the risk of serotonin syndrome. Serotonin syndrome occurs when a person has too much serotonin activity in the body. Although increased serotonin may help with mood, too much can lead to dangerous effects.1,3,14

Serotonin syndrome can be life-threatening if not treated. Seek immediate medical care if you notice any signs of serotonin syndrome, including:1,3,14

  • Fever or feeling very hot
  • Muscle spasms or twitches
  • Irritation or agitation
  • Diarrhea
  • Anxiety or severe restlessness
  • Fast heart rate
  • Trouble thinking or confusion
  • High blood pressure

Before starting to take an antidepressant, tell your doctor if you are pregnant or planning to become pregnant. Some antidepressant drugs may cause harm to an unborn baby.1,9

Do not change or stop taking an antidepressant drug without talking with your doctor first. Stopping certain antidepressants suddenly can lead to withdrawal-like symptoms or be dangerous.1,9

If you notice you are having thoughts of harming yourself or others while taking an antidepressant, seek immediate support. Call or text the Suicide & Crisis Lifeline at 988. Crisis counselors are available 24 hours a day.15

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