NDRIs: What Are They?

If you’re one of the 21 million U.S. adults affected by major depressive disorder, also known as depression, there’s a chance your healthcare provider prescribed antidepressants.

With over 13 percent of American adults taking antidepressants between 2015 and 2018, these medications are a common treatment for symptoms of depression as well as anxiety in some cases.

You may be familiar with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).

But while SSRIs and SNRIs are two of the more common antidepressant medications prescribed, there are other drugs used to treat and manage depression.

Another class of medication used to treat depression are norepinephrine-dopamine reuptake inhibitors (also known as NDRIs).

Norepinephrine-dopamine reuptake inhibitors are primarily used to treat depression and several other medical conditions.

Below, we cover what exactly NDRIs are and how they work as well as common side effects and potentially harmful drug interactions.

Norepinephrine-dopamine reuptake inhibitors are a newer class of antidepressants primarily used to treat depression.

These medications tend to have fewer side effects than other common antidepressants.

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

NDRIs may be prescribed to treat major depressive disorder for those who do not respond well to SSRIs or the side effects of SSRIs, which are the first-line treatment for depression.

Sometimes referred to as dual reuptake inhibitors or dual-acting antidepressants, NDRIs inhibit the reuptake of two neurotransmitters — norepinephrine and dopamine.

By preventing the brain from reabsorbing these two chemicals, higher levels of norepinephrine and dopamine are active.

Norepinephrine, dopamine and serotonin are the three major neurotransmitters believed to play a role in a depressive disorder and are associated with the symptoms of depression.

Norepinephrine increases alertness and attention as well as affects your mood and sleep cycle. This neurotransmitter is also part of the sympathetic nervous system, the body’s emergency response system to danger — more commonly known as the “fight-or-flight” response.

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

Dopamine plays a role in several body functions, including movement, behavior, attention, pleasurable reward and motivation and more. Known as a “feel good” hormone, dopamine gives a sense of pleasure as well as the motivation to do something when you feel pleasure.

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 increasing the amount of norepinephrine and dopamine in your body, NDRIs may relieve symptoms of depression over time.

NDRIs typically take two to four weeks to start showing signs of improvement in symptoms.

NDRIs are used to treat several medical conditions.

Many of these treatments are prescribed NDRIs “off-label” however (using an FDA-approved drug for a condition other than the condition it was approved for).

Seasonal Affective Disorder

Seasonal Affective Disorder (SAD) is a mood disorder and type of depression that occurs with seasonal changes, mostly in the fall and winter, and affects an estimated 10 million American adults.

Bupropion, an NDRI, is one treatment method for seasonal affective disorder.

Nicotine Addiction and Smoking Cessation

Norepinephrine-dopamine reuptake inhibitors are sometimes prescribed to help people quit smoking.

By preventing the brain from reabsorbing dopamine, an NDRI like bupropion stops the craving and anti-withdrawal effects of quitting smoking.

Some clinical trials have even shown that the use of an NDRI doubled the number of people who quit smoking in both short- and long-term periods compared to a nicotine patch or placebo.

Narcolepsy

Narcolepsy is a chronic sleep disorder that causes excessive drowsiness or sleepiness during the day.

In 2019 the FDA approved the norepinephrine-dopamine reuptake inhibitor solriamfetol (Sunosi®) for the treatment of narcolepsy. Solirameftol helps promote wakefulness in people with this condition.

Parkinson’s Disease

Parkinson’s disease is a chronic neurological disorder that affects the nervous system. This disorder can cause:

• Issues with balance and walking

• Tremors or shaking

• Stiff muscles

• Slow movement

Those struggling with long-term diseases may develop depression, as these diseases can trigger feelings about physical limits, symptoms and death. Up to 50 percent of people with Parkinson’s disease experience depression.

Parkinson’s disease may even directly cause depression, as the disease affects the brain chemicals norepinephrine, dopamine and serotonin that lead to mood disorders.

In some cases, NDRIs may be used to treat those diagnosed with Parkinson’s who are also struggling with depression.

Attention-Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders first diagnosed during childhood that can last well into adulthood. In 2020, ADHD affected over 360 million adults globally.

Those with ADHD may have extreme difficulty paying attention, controlling impulsive behaviors or staying organized.

Some healthcare providers may prescribe certain NDRIs off-label as a treatment for ADHD. Although stimulants are the first-line treatment for ADHD symptoms, a second-line NDRI treatment may be more appropriate for others.

Currently, only one norepinephrine-dopamine reuptake inhibitor is approved by the FDA to treat depression — bupropion.

Two other types of NDRIs are approved to treat different conditions, such as attention-deficit hyperactivity disorder.

Below we’ve listed three NDRIs approved by the FDA to treat symptoms of depression and other medical conditions.

Bupropion (Wellbutrin®)

Wellbutrin® is the brand name for bupropion, a prescription-only antidepressant sold in immediate-release tablet form.

Bupropion is considered an “atypical” antidepressant drug and belongs to a unique chemical class called aminoketones.

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 also used as a medication to quit smoking.

Bupropion prevents your body from reabsorbing the neurotransmitters dopamine and norepinephrine, which can lessen symptoms of depression and anxiety. Because of this, bupropion may also be used to treat anxiety as a result of depression.

Some healthcare providers may also prescribe Wellbutrin® off-label as a treatment for ADHD.

Dexmethylphenidate (Focalin®)

Dexmethylphenidate is a stimulant drug typically used for the treatment of ADHD.

The brand name version of dexmethylphenidate is Focalin® and is prescribed in tablet form. Focalin® is also believed to block the reuptake of norepinephrine and dopamine, although it is not recommended to treat depression due to withdrawal symptoms.

Methylphenidate (Ritalin®)

Methylphenidate is an FDA-approved first-line drug used to treat ADHD in adults and children, and as a second-line treatment option for narcolepsy in adults.

This NDRI is sold under the brand names Ritalin® as well as Concerta®, Methylin®, Metadate® and others. Methylphenidate comes in many different forms, from immediate- and extended-release tablets to liquid form.

By increasing dopamine levels, methylphenidate may  also slow or halt the progression of Parkinson’s disease.

All medications cause a variety of side effects, and NDRIs are no exception.

However, norepinephrine-dopamine reuptake inhibitors have been known to produce fewer side effects than other antidepressants.

Most notably, bupropion does not seem to produce a side effect of sexual dysfunction, as many other antidepressants tend to have.

Some of the common side effects of NDRIs include:

• Dry mouth

• Nausea

• Insomnia

• Headache

• Weight loss 

• Anxiety 

• Constipation

• Sweating

• Loss of appetite 

• Vomiting

Side effects of norepinephrine-dopamine reuptake inhibitors tend to be mild and disappear after a few weeks as your body adjusts to the drugs.

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

NDRIs are typically safe and effective medications that help to treat depression and other conditions with few issues. 

However, NDRIs may interact with other drugs and may also affect your health if you have existing conditions.

To reduce the risk of harmful interactions, tell your healthcare provider if you are taking any other medications or supplements before starting an NDRI.

Dependency and Withdrawal

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.

Bupropion Interactions

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

While NDRIs are one option for the treatment of a major depressive disorder, they may not be the best choice for everyone.

Some other antidepressants include:

• Selective serotonin reuptake inhibitors (SSRIs). SSRIs work by inhibiting serotonin reuptake and increasing serotonin levels. Medications of this type are commonly used as first-line treatments for depression and anxiety.

• 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.

• Tricyclic antidepressants (TCAs). TCAs are older antidepressants that are sometimes used when newer medications aren’t effective. They’re more likely to cause side effects and health issues than newer antidepressants.

• Monoamine oxidase inhibitors (MAOIs). MAOIs are another class of older medications for depression. They can cause significant side effects and interactions, meaning they’re generally only used when all other antidepressants are unsuccessful.

Major depressive disorder and anxiety often improve with psychotherapy, including options such as cognitive-behavioral therapy (CBT). 

Making certain changes to your lifestyle, such as exercising regularly, eating a healthy diet and practicing relaxation techniques, may also help improve depression and anxiety symptoms.

Dealing with depression can certainly be a struggle and can negatively impact your health and wellbeing. 

However, there are ways to manage the symptoms of depression and get help. There isn’t a one-size-fits-all approach to treating depression, and managing the symptoms can be a combination of different options.

Medication is one way to treat the symptoms of a depressive disorder and NDRIs may be part of the right treatment plan for you.

You can use our online psychiatry services to start a consultation with a licensed psychiatry provider and figure out the best treatment plan for you and your needs.