How SNRIs, SSRIs, and SNDRIs Differ in Treating Depression

Remembering the names of certain drugs can be difficult enough, but making sense of drug anagrams can be downright confusing, especially if they are meant to treat the same condition. Such is the case with a class of drugs known as reuptake inhibitors used to treat depression, anxiety, bipolar disorder, and other psychiatric conditions.

There many types of reuptake inhibitor which belong to one of five classes of drug:

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

While the drugs all have similar mechanisms of action—namely to increase the concentration of certain brain chemicals, known as neurotransmitters, to alter moods—they differ in the types of neurotransmitter they target.

To understand how reuptake inhibitors work, you need to get a better sense of what neurotransmitters actually do.

A neurotransmitter is a chemical secreted by a nerve cell at the behest of a nerve impulse which is then absorbed by an adjacent cell, thereby transferring the nerve impulse. The adjacent cell might be a nerve cell, which passes the chemical message along a nerve pathway, or other cells (such as muscle cells), which act upon the instructions of the chemical message.

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 reward-motivated 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) is at the heart of why mood disorders exist. Moreover, depending on which neurotransmitters or neuroreceptor are low, the type and severity of mood disorder can differ.

NRIs, NDRIs, SSRIs, SNRIs, and SNDRIs are all reuptake inhibitors. They work by blocking the reabsorption (reuptake) of a specific neurotransmitter after it has been excreted from a nerve cell.

Reuptake in 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 volume of neurotransmitters being actively circulated in the brain. 

To this end, inhibiting the reuptake increases their extracellular concentrations of these chemicals and, by doing so, increases their ability to exert positive effects on your mood.

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.

Norepinephrine Reuptake Inhibitors (NRIs)

NRIs work by blocking the action of the norepinephrine transporter (NET). NRIs are commonly used to treat major depressive disorder (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 (NET) and the dopamine transporter (DAT). 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

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs work by limiting, rather than blocking, the serotonin transporter (SERT). They are typically used to treat 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 (SERT) and norepinephrine transporter (NET). 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

Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRIs)

Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), also known as triple reuptake inhibitors, blocks the action of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). SNDRIs were developed to treat depression but can also be used to treat ADHD, chronic pain, and 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