SSRIs vs. SNRIs: How Reuptake Inhibitors Work

In the abbreviations SSRI and SNRI, the "RI" stands for "reuptake inhibitor." Reuptake inhibitors are a type of drug used to treat depression, anxiety, and other psychiatric conditions. They work by increasing the concentration of certain brain chemicals, known as neurotransmitters, to alter mood.

There many types of reuptake inhibitors, including:

Selective serotonin reuptake inhibitors (SSRIs)
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Norepinephrine reuptake inhibitors (NRIs)
Norepinephrine-dopamine reuptake inhibitors (NDRIs)
Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs)

While the drugs all have similar mechanisms of action, they differ in which neurotransmitters they target. To understand how reuptake inhibitors work, you need to get a better sense of what neurotransmitters actually do.

Neurotransmitters and Mood

A neurotransmitter is a chemical messenger that carries, boosts, and balances signals between nerve cells (neurons) and target cells throughout the body. Billions of neurotransmitter molecules work to keep our brains functioning, managing everything from our breathing to a variety of psychological functions such as fear, mood, pleasure, and joy.

For the purpose of treating mood disorders, three specific neurotransmitters are targeted, each of which is associated with mood elevation:

Dopamine plays a central role in behavior by stimulating the emotional desire for a "reward" in the form of pleasure.
Norepinephrine works by mobilizing the brain and body for action, increasing alertness, focus, and the retrieval of memory.
Serotonin plays a regulatory role in moods, social behavior, appetite, sleep, memory, sexual desire, and sexual function.

It is strongly believed that low levels of these neurotransmitters (or the lack of cellular receptors able to receive the messages) play a pivotal role in mood disorders. Moreover, depending on which neurotransmitters or neuroreceptors are low, the type and severity of a mood disorder can differ.

What Reuptake Inhibitors Do

Reuptake means reabsorption. It is a normal mechanism by which the body controls how long a nerve signal lasts. However, if you have significantly low levels of a neurotransmitter, reuptake can be a problem as it restricts the amount of neurotransmitters being actively circulated in the brain.

To this end, limiting reuptake increases the extracellular concentrations of these chemicals and, by doing so, increases their ability to exert positive effects on your mood. Because reuptake inhibitors limit the reabsorption of certain neurotransmitters, these medications are able to increase the availability of these neurotransmitters in the brain.

Types of Reuptake Inhibitors

The reuptake inhibitors used to treat mood disorders are classified by the types of neurotransmitter pathway they block.

The drugs are able to do this by binding one or several different proteins, called transporters, which are responsible for carrying the chemical between cells. Some of these reuptake inhibitors are classified as selective because they only bind to certain proteins, while others are nonspecific because they bind to a broad range of proteins.

The choice of reuptake inhibitor depends largely on the condition being treated and the mechanism of action of the drug.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs work by blocking the serotonin transporter in neurons, which results in higher levels and greater activity of the feel-good chemical. They are typically used to treat major depressive disorder (MDD) and anxiety disorders.

While SSRIs are sometimes used to treat bipolar depression, there is some controversy as to how effective they are given their potential to exacerbate the rapid cycling of moods.

SSRI medications approved for use in the U.S. include:

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

There is also a two-in-one drug called Symbyax which combines Prozac with the antipsychotic Zyprexa (fluoxetine + olanzapine). Symbyax is specially approved for use in treating bipolar depression.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs block both the serotonin transporter and norepinephrine transporter. SNRIs can be used to treat bipolar depression, MDD, ADHD, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), chronic nerve pain, and fibromyalgia.

When compared to SSRIs, SNRIs are less likely to exacerbate rapid mood cycling in people with bipolar depression. However, they are commonly used for short-term therapy, as prolonged use may trigger a manic or hypomanic episode.

SNRI medications approved for use in the U.S. include:

Cymbalta (duloxetine), used for depression and chronic pain
Fetzima (levomilnacipran), used to treat depression
Pristiq (desvenlafaxine), used for depression and panic disorder
Savella (milnacipran), used to treat fibromyalgia

Norepinephrine Reuptake Inhibitors (NRIs)

NRIs work by blocking the action of the norepinephrine transporter. These are commonly used to treat MDD, anxiety, panic disorder, narcolepsy, and ADHD.

NRI medications approved for use in the U.S. include:

Ludiomil (maprotiline), used to treat depression and anxiety
Strattera (atomoxetine), used primarily to treat ADHD
Vivalan (viloxazine), used to treat narcolepsy

Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)

NDRIs block the action of both the norepinephrine transporter and the dopamine transporter. NDRIs are used for clinical depression, ADHD, and narcolepsy.

NDRI medications approved for use in the U.S. include:

Focalin (dexmethylphenidate), used to treat ADHD and depression
Ritalin (methylphenidate), used to treat ADHD
Wellbutrin (bupropion), used off-label to treat ADHD

Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRIs)

SNDRIs, also known as triple reuptake inhibitors, block the action of the serotonin transporter, norepinephrine transporter, and dopamine transporter. SNDRIs were developed to treat depression but can also be used to treat ADHD, chronic pain, and binge-eating disorder associated with obesity.

SNDRI medications approved for use in the U.S. include:

Effexor (venlafaxine), used to treat major MDD, generalized anxiety disorder (GAD), panic disorder, and social phobia
Mazanor (mazindol), used as an appetite suppressant
Serzone (nefazodone), used to treat depression

A Word From Verywell

While all these acronyms can be confusing, the good news is that there are many treatment options available for anxiety, depression, and other mood disorders. Work with your doctor to find a reuptake inhibitor that works best for you.