NDRIs vs SSRIs: What's The Difference?

For those struggling with a depressive disorder, there are several ways to manage symptoms and find help in day-to-day life. One solution is antidepressants, but which ones are the right ones for you?

It can be challenging to understand how various antidepressants work and which is the best fit. Speaking with your healthcare provider is a good first step in finding more information about the antidepressants available and deciding which is the best choice.

But even trying to remember the names of some of these drugs — let alone their functions — can be confusing.

Two effective antidepressant medications prescribed for the treatment of depression are norepinephrine-dopamine reuptake inhibitors (NDRIs) and selective serotonin reuptake inhibitors (SSRIs).

Both are effective at treating the symptoms of depression (and, for some drugs, anxiety disorders as well).

But what are the differences between NDRIs vs SSRIs?

Let’s go into more detail on how SSRIs and NDRIs work to treat depression and anxiety, as well as the major differences between these two similar types of antidepressants.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant medication in the U.S.

SSRIs are commonly used as first-line treatments for major depressive disorder (MDD), as well as anxiety disorders such as generalized anxiety disorder (GAD), social anxiety disorder, panic disorder and post-traumatic stress disorder.

SSRIs first came onto the market in the late 1980s, with the first of these drugs — fluoxetine (Prozac®) — being approved in 1987 by the Food and Drug Administration (FDA). Compared to other antidepressants, SSRIs have fewer side effects while still being effective.

SSRIs are believed to work by blocking the brain from reabsorbing (or reuptaking) the neurotransmitter serotonin, thereby increasing serotonin levels.

Serotonin is responsible for managing your feelings, moods and thoughts, as well as regulating happiness and anxiety. Serotonin also plays a role in stimulating the parts of your brain that control sleep and waking.

Low levels of serotonin are believed to be associated with depression, anxiety, obsessive-compulsive disorder and mania.

Examples of SSRIs used to treat depression and anxiety include escitalopram (Lexapro®), citalopram (Celexa®), fluvoxamine (Luvox®), fluoxetine (Prozac), paroxetine (Paxil®), vilazodone (Viibryd®) and sertraline (Zoloft®).

Norepinephrine-dopamine reuptake inhibitors, or NDRIs, are a newer class of antidepressant medications primarily used to treat depression.

One of the first norepinephrine-dopamine reuptake inhibitors, bupropion (Wellbutrin®), was approved in 1989 by the FDA.

NDRIs are often used as a treatment for major depressive disorder for those who don’t respond well to SSRIs.

NDRIs may also be used “off-label” to treat seasonal affective disorder, Parkinson’s disease, attention-deficit hyperactivity disorder (ADHD) and to help quit smoking.

Anecdotal evidence suggests some NDRIs may also help treat symptoms of anxiety disorders, such as panic disorders and general anxiety disorder.

Sometimes referred to as dual reuptake inhibitors or dual-acting antidepressants, NDRIs prevent the brain from reabsorbing the neurotransmitters norepinephrine and dopamine.

Along with serotonin, norepinephrine and dopamine are also major neurotransmitters associated with the symptoms of depression.

Norepinephrine increases alertness and attention as well as affects your mood and sleep cycle.

Low levels of norepinephrine are linked with depression, anxiety and other mental health issues as well as headaches, memory problems, sleeping problems and more.

Dopamine is known as a “feel good” hormone and plays a role in several body functions, including pleasurable reward and motivation, movement, behavior, attention and more.

Low levels of dopamine may make someone feel tired, unmotivated or unhappy and are associated with depression as well as Parkinson’s disease and attention deficit hyperactivity disorder.

By preventing your brain from reuptaking norepinephrine and dopamine, NDRIs increase the levels and alter mood, alertness and more.

Only one NDRI is approved by the FDA to treat depression — bupropion (Wellbutrin®).

Along with the Wellbutrin moniker, bupropion is also sold under the brand names Wellbutrin SR® and Wellbutrin XL® to treat depression and seasonal affective disorder. When sold under the brand name Zyban®, it’s used as a medication to quit smoking.

Two other types of NDRI medications are dexmethylphenidate (Focalin®) and methylphenidate (Ritalin®), both of which are used to treat ADHD.

Like any medication, NDRIs and SSRIs can both cause side effects. Most of these are mild and transient, although some people might experience side effects that are persistent or severe.

Common side effects of NDRIs include:

• Dry mouth

• Nausea

• Insomnia

• Headache

• Anxiety 

• Sweating

• Loss of appetite 

NDRIs have been known to produce fewer side effects than other antidepressants, tend to be mild and disappear after a few weeks.

However, if any new side effects come up or if they persist, talk to your healthcare provider.

Common side effects of SSRIs include:

• Headaches

• Dizziness

• Difficulty sleeping or oversleeping

• Changes in appetite

• Decreased libido

• Weight loss

• Dry mouth

• Anxiety

Some SSRIs may cause more side effects than others. Be sure to talk with your healthcare provider about any new or persisting side effects if you start taking an SSRI. You can also check the drug labeling provided with your medication for a detailed list of potential side effects.

One serious, potentially life-threatening drug interaction involving SSRIs is serotonin syndrome, which develops when serotonin levels become dangerously high. Because of the effects on serotonin levels, SSRIs can cause drug interactions when used with other medications that increase serotonin.

Symptoms of serotonin syndrome include rapid heart rate, high body temperature, increase in blood pressure levels, shaking, sweating, involuntary movements and overactive reflexes.

Make sure to inform your healthcare provider about all medications, supplements and other substances you currently take or have recently taken before using any SSRI medications.

Prolonged use of NDRIs can cause dependency on the drug and make it difficult to stop using them.

You might experience some withdrawal symptoms when stopping the use of an NDRI, like headaches, anxiety, insomnia, tiredness, nausea and vomiting.

Additionally, bupropion can negatively interact with several other types of drugs and antidepressants. These include:

• Tricyclic antidepressants 

• Monoamine oxidase inhibitors

• Levodopa and amantadine

• Antipsychotics, theophylline, systemic steroids

• Beta-blockers and antiarrhythmics

If you’re prescribed an NDRI or SSRI and start to experience side effects, don’t stop taking the medication. Instead, let your healthcare provider know about how you’re feeling.

When it comes to major depressive disorder, there is no “perfect” prescription or one-size-fits-all approach. It’s even common to try different types of antidepressants before finding one that works for you.

SSRIs are commonly used as first-line treatments for depression, meaning they are the medications that healthcare providers prescribe first when treating people with clinical depression.

Although SSRIs are generally less likely to cause side effects than other antidepressants, side effects are still common for some people who use SSRIs to treat depression or anxiety. Some people may also not see improvement in their symptoms when taking SSRIs for depression.

Many people may use an NDRI like bupropion instead due to the effects on norepinephrine and dopamine levels as well as fewer side effects.

Most notably, research has shown that bupropion is less likely to cause sexual side effects than other antidepressant medications.

A 2005 review that compared bupropion to SSRIs found that both medications were equally effective in treating depression but the major difference was that SSRIs were more likely to cause sexual dysfunction.

NDRIs may often be used as an SSRI alternative or as a secondary medication in combination with an SSRI or SNRI. A 2016 systematic review of bupropion, which examined 51 studies, supported its use as an antidepressant prescribed on its own or with another antidepressant.

However, other possible side effects of NDRIs include loss of appetite and weight loss, so these medications are not recommended to those with eating disorders.

There are also currently more FDA-approved SSRI medications on the market for treating depression than NDRIs.

Remember that depression can vary significantly from person to person, both in terms of specific symptoms of depression and the severity of those symptoms.

Because SSRIs and NDRIs work differently, your healthcare provider may recommend one type of medication over the other if they think it’s a better match for your symptoms and needs.

SSRIs and NDRIs aren’t the only antidepressant medications available.

If you have a depressive disorder or other mental health disorder, your healthcare provider may also consider one of the following types of antidepressants:

• Tricyclic antidepressants (TCAs). These older antidepressants are equally as effective as SSRIs but have a higher risk of causing side effects. TCAs generally aren’t used as first-line depression treatments but are used off-label for issues such as chronic pain.

• Monoamine oxidase inhibitors (MAOIs). Another older class of antidepressants, MAOI medications are rarely used today due to their significant risk of causing side effects and interactions. However, they may be used if other medications aren’t effective.

• Serotonin-norepinephrine reuptake inhibitors (SNRIs). Similar to SSRIs, SNRIs work by inhibiting the reuptake of serotonin and norepinephrine. Some SNRI medications also increase dopamine levels, another brain chemical associated with depression. These may be prescribed to those who had unsuccessful treatment for depression using SSRIs.

While the acronyms can be confusing, the good news is that there are many treatment options available for anxiety, depression and other mood disorders.

If you’re feeling depressed, seeking help is essential. You can use our mental health resources for effective strategies from licensed therapists to better recognize and help alleviate symptoms of depression.

You can also talk to a licensed psychiatry provider online, where you’ll receive a personalized treatment plan and, if appropriate, medication to help you treat your symptoms. Depression may be overwhelming at times but getting help isn’t.