How Different Antidepressants Work

Selective serotonin reuptake inhibitors (SSRIs) are probably the first medicine your doctor will try if you have major depressive disorder (MDD), PTSD, OCD, or an anxiety disorder. These specifically block serotonin (also called 5-hydroxytryptamine or 5-HT) from being reabsorbed by your nerve terminals. Serotonin is a neurotransmitter that helps regulate your behavior, mood, memory, and your gastrointestinal system.

SSRIs tend to have fewer adverse (or side) effects than older antidepressants. The higher your dose, the higher your risk of having these side effects. The most common SSRI adverse effects include:

• Sleep pattern changes, such as drowsiness and insomnia
• Sexual dysfunction, such as reduced sex drive, inability to reach orgasm, and ejaculation disorder
• Headache
• Excessive sweating
• Digestive problems, such as loss of appetite, nausea, vomiting, constipation, or diarrhea
• Weight changes
• Anxiety
• Dry mouth

Common SSRIs include:

Citalopram (Celexa). This SSRI was FDA-approved for the treatment of depression in adults in 1998. It's sometimes used off-label for conditions such as:

• OCD
• Panic disorder
• Alcohol use disorder
• Plaque buildup in your arteries
• Premenstrual dysphoric disorder
• Menopause symptoms

Citalopram isn't generally prescribed for children, teens, or young adults younger than 24 years because it may make their depression worse or increase their risk of suicidal ideation and suicide.

Escitalopram (Lexapro). This SSRI was FDA-approved in 2002 for the treatment of major depressive disorder in adults and teens aged 12 and older. It was also FDA-approved for generalized anxiety disorder in adults and children aged 7 and older in 2003. It's sometimes used off-label for:

• Social anxiety disorder
• OCD
• Panic disorder
• PTSD
• Premenstrual dysphoric disorder
• Menopause symptoms

Paroxetine isn't approved for children and teens under the age of 18 years because it can increase the risk of suicide. Sometimes, doctors use it off-label for OCD and social anxiety disorder in children and teens.

Sertraline (Zoloft). This SSRI is FDA-approved for MDD, OCD, panic disorder, PTSD, premenstrual dysphoric disorder, and social anxiety disorder. Doctors may use it off-label for:

• Binge eating disorder
• Body dysmorphic disorder
• Bulimia nervosa
• Generalized anxiety disorder
• Premature ejaculation

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a newer type of antidepressant. They block the reuptake of two neurotransmitters: serotonin and norepinephrine. Norepinephrine (also called noradrenaline) is a neurotransmitter that helps regulate your attention, alertness, cognitive function, and stress response. However, they may not target serotonin and norepinephrine equally. For instance, some increase your levels of serotonin more than norepinephrine.

You'll usually need to take SNRIs for about 6-8 weeks before you get the full effect.

Since SNRIs affect your serotonin levels, you have an increased risk of serotonin syndrome if you take them with other medicines that affect your serotonin levels. As with SSRIs, don't stop taking these suddenly because you can get antidepressant discontinuation syndrome.

Levomilnacipran (Fetzima). This SNRI was FDA-approved in 2013 to treat MDD in adults. Levomilnacipran isn't generally prescribed for children, teens, or young adults younger than 24 because it may make their depression worse or increase their risk of suicidal ideation and suicide.

Milnacipran (Savella). This SNRI was FDA-approved in 2009 to treat fibromyalgia in adults. Milnacipran isn't generally prescribed for children, teens, or young adults younger than 24 because it may make their depression worse or increase their risk of suicidal ideation and suicide.

Venlafaxine (Effexor). This SNRI was FDA-approved in 1993 to treat MDD and social anxiety disorder. It's since been FDA-approved for panic disorder. It's sometimes also used off-label for:

• Attention deficit disorder (ADD)
• Fibromyalgia
• Diabetic nerve pain
• Complex pain syndromes
• Hot flashes
• Migraine prevention
• PTSD
• OCD
• Premenstrual dysphoric disorder

What is the difference between SSRIs and SNRIs? 

SSRIs and SNRIs are both antidepressants used to treat MDD and some other mental health conditions, but they work in slightly different ways. SSRIs block serotonin reuptake into your nerve cells, while SNRIs block both serotonin and norepinephrine reuptake into your nerve cells. Since they work slightly differently, they have slightly different medication interactions and side effects.

One of the most serious side effects is that it can make you more likely to have seizures, so if you have a seizure disorder or risk factors for seizures, you may not be able to take bupropion. The higher-dose, immediate-release version seems to cause this side effect more than lower-dose and extended-release formulas.

As with many other antidepressants, it isn't generally prescribed for children, teens, or young adults younger than 24 because it may make their depression worse or increase their risk of suicidal ideation and suicide. Also, make sure your doctor knows all the medicines and supplements you take since they can interact with bupropion.

Cyclic Antidepressants

Cyclic antidepressants were among the first medicines used to treat MDD in the 1950s. They're called "cyclics" because they have rings in their chemical structure. There are two types: tricyclics and tetracyclics. Tricyclic antidepressants (TCAs) have three rings in their structure and tetracyclics have four rings.

These cyclic antidepressants work the same way as reuptake inhibitors, but they have a broader range of action on more kinds of brain chemicals. So, even though they work as well as the newer antidepressants for depression symptoms, they can have more serious side effects. They are also a lot easier to overdose on than newer antidepressants such as SSRIs and SNRIs. 

Side effects can include:

• Blurred vision
• Dizziness
• Confusion
• Drowsiness
• Dry mouth
• Constipation
• Increased appetite
• Weight gain
• Fast heart rate
• Low blood pressure when you change position, such as moving from lying down to sitting up
• Heart rhythm changes
• Risk of sudden death due to loss of heart function, especially if you already have heart disease
• Increased risk of seizures in people with epilepsy

Most TCAs aren't prescribed for children because they carry an increased risk of suicidal ideation and suicide, especially in people younger than 24 years old.

Doctors usually only turn to these drugs when newer and better-tolerated medicines haven't helped. But they can sometimes be very helpful for people with severe or treatment-resistant depression.

Because of the potential side effects, your doctor might periodically check your blood pressure, request an EKG, or recommend occasional blood tests to monitor the level of tricyclics in your system. These medicines might not be safe for people with certain heart rhythm problems.

Types of cyclic antidepressants include: 

Amitriptyline (Elavil). This tricyclic antidepressant is FDA-approved for MDD in adults. It's sometimes used off-label for:

• Anxiety
• PTSD
• Insomnia
• Chronic pain syndromes, such as diabetic nerve pain, fibromyalgia, interstitial cystitis (bladder pain syndrome), post-herpetic neuralgia (nerve pain from shingles), and post-COVID headaches
• Irritable bowel syndrome (IBS) 
• Migraine prevention
• Sialorrhea (too much spit)

Don't take amitriptyline with:

• Other medicines that can affect your heart rhythm, such as disopyramide and ibutilide
• Omeprazole (Prilosec) or cisapride, which are medicines used to treat gastroesophageal reflux disease (GERD)
• Other medicines that increase your serotonin levels, such as monoamine oxidase inhibitors, which include isocarboxazid and phenelzine

Amoxapine (Asendin). This tricyclic antidepressant is FDA-approved for depression. It's most often used for treatment-resistant depression after you've tried SSRIs and SRNIs and they haven't worked. It may also be used if you have depression along with another mood disorder, such as anxiety, agitation, psychosis, and neurosis. It's sometimes used off-label for chemotherapy-induced diarrhea (along with irinotecan) and nerve pain. Don't drink alcohol or take barbiturates (which you may take if you have migraine, tension headaches, or insomnia) while you take amoxapine.

Nortriptyline (Pamelor). This tricyclic antidepressant is FDA-approved for depression and may be used off-label for:

• Chronic pain
• Diabetic nerve pain
• Persistent myofascial pain
• Face pain (trigeminal neuralgia)
• Pain from shingles (postherpetic neuralgia)
• Smoking cessation
• Migraine prevention
• Chronic cough from overstimulation of the nerves in your throat and larynx

Maprotiline (Ludiomil) and mirtazapine (Remeron). These are tetracyclic antidepressants FDA-approved for MDD, bipolar disorder, and anxiety. Mirtazapine may be used off-label for:

• Insomnia
• Panic disorder
• PTSD
• OCD
• Generalized anxiety disorder
• Social anxiety disorder
• Headache disorders, including migraine

Serotonin Antagonist and Reuptake Inhibitor (SARIs)

Serotonin antagonist and reuptake inhibitors (SARIs) appear to work in a couple of different ways to increase the levels of serotonin in specific areas of your brain. First, like SSRIs, they prevent the reuptake of serotonin. Second, they redirect serotonin to specific places in your brain that help your nerve cells regulate your mood. They are mainly used to treat MDD, but they may be used off-label for insomnia and anxiety.

As with almost all antidepressants, they aren't prescribed for children because they carry an increased risk of suicidal ideation and suicide, especially in people younger than 24 years old.

SARIs include trazadone (Desyrel, Oleptro) and Nefazodone (Serzone). Both are FDA-approved for MDD either alone or in combination with other treatments. They may also be used off-label for:

• Insomnia and other sleep disorders
• Anxiety
• Alzheimer disease
• Substance misuse disorder
• Bulimia nervosa
• Fibromyalgia
• PTSD (if SSRIs don't work), especially if nightmares are associated with PTSD
• Nighttime breathing episodes in people with obstructive sleep apnea (OSA)

Research shows that trazadone works for MDD almost as well as SSRIs, SNRIs, and TCAs. Because it works slightly differently, it may have less risk of causing certain side effects, such as sexual dysfunction, insomnia, and anxiety. Other side effects may include:

• Headaches
• Fatigue
• Dizziness
• Drowsiness
• Dry mouth
• Low blood pressure when changing body position
• Fainting
• Heart rhythm changes
• An erection that won't go away (priapism)

Monoamine Oxidase Inhibitors (MAOIs)

MAOI antidepressants work by blocking the effects of the enzyme monoamine oxidase in your brain. Monoamine oxidase is a protein that breaks down the brain chemicals serotonin, epinephrine, dopamine, and tyramine. By preventing these brain chemicals from breaking down, it keeps their levels high in your brain. Because they work on several different neurotransmitters at once, they can have serious side effects and are easy to overdose on.

These are some of the earliest antidepressants invented, but they aren't used very often anymore. Your doctor may prescribe them if none of the other types of antidepressants have worked for you. Or, they may use them off-label for ADHD, treatment-resistant social anxiety disorder, treatment-resistant panic disorder, and atypical depression.

Unfortunately, neurotransmitters aren't the only thing that monoamine oxidase breaks down. So, MAOIs also prevent your body from breaking down some medicines (such as Sudafed, or stimulants) and an amino acid called tyrosine, which is found in certain foods such as aged meats and cheeses. This raises your risk for high blood pressure, among other things. For this reason, when you're taking MAOIs, your doctor may recommend you limit foods with high tyramine levels, including aged cheeses, soy sauce, cured fish, fermented sausages, salami, overripe fruits such as avocado and banana, fava beans, and sourdough bread.

Don't take MAOIs with other medicines that raise your serotonin levels, which include certain migraine medicines and pretty much any other antidepressant. This increases your risk for a buildup of serotonin (called "serotonin syndrome"), which can be life-threatening.

Types of MAOIs include

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

Nutraceuticals

"Nutraceuticals" are defined differently depending on where you are. In the U.S., nutraceuticals are usually food ingredients and dietary supplements used to treat or prevent some medical conditions.

For serious conditions such as depression, your doctor is unlikely to recommend that you treat your condition using only nutraceuticals. But they can help support your treatment when you take them alongside your antidepressant. 

Also, make sure that your doctor knows all the herbs and supplements you're taking because some can interact with your prescription medicine. 

Types of nutraceuticals

The nutraceuticals that seem to work the best for depression include:

• S-adenosyl-methionine (SAMe), which is a chemical your body makes from the amino acid methionine. It may help your body make neurotransmitters. People with depression may have lower levels of SAMe than people without depression. Increasing your levels of SAMe may help with the symptoms of depression.
• L-methylfolate, a form of folate (also known as vitamin B9) that can cross the blood-brain barrier. People with depression may have low levels of folate in their blood. Increasing the levels of folate in your blood and brain may help with the symptoms of depression.
• Omega-3s, especially eicosapentaoenoic acid (EPA). Omega-3s with EPA are dietary fats found mostly in fish oils. They have anti-inflammatory actions and may help decrease inflammation in the brain that may be associated with depression.
• Vitamin D, which your skin makes when it's exposed to sunlight. Vitamin D is another vitamin with anti-inflammatory properties.

Treatment-Resistant Depression: Getting the Most From Your Antidepressants

It's worth remembering that a lot of what we think about antidepressants is still based on assumptions. We don't really know if low levels of serotonin or other neurotransmitters "cause" depression or if your levels are low because you are depressed. But what doctors do know is that medicines that change the levels of serotonin, norepinephrine, and dopamine can make you feel better.

We also have a lot of research into how people with depression can get the most out of their medicines.

When taking any antidepressant, you have to be patient. Some people start an antidepressant and expect that it will work right away. But that's just not how antidepressants work. No one knows exactly why, but they can take weeks or months before they gain their full effect. When you're taking an antidepressant, it's important to adjust your expectations and be patient.

Takeaways

Experts don't know exactly how antidepressants work. But we do know that these medicines seem to increase the level of brain chemicals called neurotransmitters. Different types of antidepressants seem to increase the levels of neurotransmitters in different ways. For instance, SSRIs, some of the most commonly prescribed antidepressants, work by preventing one neurotransmitter, serotonin, from being taken back up for recycling once your brain has used it. This keeps your serotonin levels higher, which seems to help with the symptoms of depression as well as some other conditions.

How Antidepressants Work FAQs

What do antidepressants do to the brain?

Antidepressants seem to increase the levels of certain brain chemicals called neurotransmitters. They don't do this permanently, which is why they don't cure depression. However, they can help you manage the symptoms of depression, which can be very challenging to navigate as you go about your daily life.

What are the most common antidepressants?

Currently, the most commonly prescribed antidepressants are reuptake inhibitors, such as SSRIs and SNRIs. SSRIs mainly target serotonin, and SNRIs mainly target serotonin and norepinephrine. Some examples that you may be familiar with include fluoxetine (Prozac), an SSRI, and duloxetine (Cymbalta), an SNRI.