What to Know About Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)

Norepinephrine-dopamine reuptake inhibitors (NDRIs) are a class of drugs used primarily for the treatment of depression. They are also used to treat attention-deficit hyperactivity disorder (ADHD), narcolepsy, and Parkinson's disease. NDRIs are a newer class of antidepressants and tend to have fewer side effects than other common antidepressant drugs. 

How NDRIs Work

NDRIs work by inhibiting the reuptake of norepinephrine and dopamine in the brain. Norepinephrine regulates alertness and concentration, while dopamine regulates mood. When these chemical messengers malfunction, they can contribute to mood disorders such as depression and anxiety.

While similar to other reuptake inhibitor drugs like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), NDRIs focus on norepinephrine and dopamine instead of serotonin. They do this by blocking the actions of norepinephrine and dopamine transporters. 

Norepinephrine is involved in the body's fight-or-flight response, while dopamine is associated with the reward system. Low levels of these neurotransmitters may contribute to problems with mood and energy, so blocking their reuptake makes more of them available in the brain.

Uses for NDRIs

NDRIs are typically prescribed when other forms of antidepressants don’t produce effective results or cause bothersome side effects. They are used to treat the following conditions:

• Depression: NDRIs are known as second-generation antidepressants and, along with SSRIs and SNRIs, are one of the most common types of drugs recommended for the treatment of depression.
• ADHD: Antidepressants can be prescribed to help treat ADHD symptoms, as an alternative to stimulant medications. NDRIs may offer some value over other ADHD drugs, such as providing a more immediate and sometimes more effective response than SNRIs.
• Narcolepsy: Narcolepsy is a condition that causes excessive daytime sleepiness. In 2019, the FDA approved Sunosi (solriamfetol), which is an NDRI for the treatment of narcolepsy. Solirameftol helps promote wakefulness in people with this condition.
• Parkinson’s disease: Approximately 40% to 50% of people with Parkinson's disease will experience depressive symptoms due to brain chemistry changes characterized by this disease. In these cases, NDRIs might be used to treat depressive symptoms. 
• Drug and alcohol cessation: Individuals taking NDRIs report that they have reduced cravings for cigarettes, alcohol, and opioids while also having fewer withdrawal symptoms once quitting these drugs, including those related to mood.  

Types of NDRIs

There are currently three main types of NDRIs approved for use in the United States. 

Bupropion

Bupropion is currently the only NDRI approved for treating depression by the U.S. Food and Drug Administration (FDA). The most common brand name of bupropion available is Wellbutrin. It’s also available under other brand names like Zyban and Alpezin.

Wellbutrin is primarily used to treat major depressive disorder. It’s also commonly used off-label to treat ADHD. In 1997, the FDA approved Zyban for use as a smoking cessation aid, to help people with nicotine dependence quit smoking. 

A 2016 review on the effectiveness of bupropion as a treatment for depression, found that the medication was highly effective in treating depression symptoms both when used on its own or alongside other depression treatments.  Wellbutrin is often used together with an SSRI for treating depression.

Dexmethylphenidate 

Dexmethylphenidate is typically used for the treatment of ADHD. It is also sometimes used off-label to help treat certain forms of depression.

A review of several different studies concluded that dexmethylphenidate is effective for treating ADHD in children and adolescents. The review also noted that these drugs are typically well tolerated.

The brand name version of dexmethylphenidate is Focalin. It’s essential to know that Focalin can be habit-forming. So, you shouldn’t take it for longer than prescribed or take more quantities than your prescription advises.

Methylphenidate 

Methylphenidate is a drug used to treat ADHD in adults and children. It’s typically sold under the brand name Ritalin, which is also sometimes used for the treatment of narcolepsy in adults. You might recognize methylphenidate by other brand names like Concerta, Methylin, and Metadate.

Methylphenidate helps to increase the attention span and reduce symptoms of hyperactivity and impulsivity in people with this condition. It is typically used alongside other treatment options, such as behavior therapy, when used to treat ADHD.

Methylphenidate can be habit-forming. So, it's important to not take more than prescribed by your healthcare provider as dependence on this drug can develop.

Side Effects of NDRIs 

Norepinephrine-dopamine reuptake inhibitors are sometimes a preferred treatment for depression because they have fewer side effects that are common to other antidepressants, such as those related to sexual dysfunction.

However, NDRIs can cause some side effects that are mostly mild and tend to dissipate within a few weeks of use. Among the potential side effects of NDRIs are:

• Headache
• Weight loss 
• Anxiety 
• Dry mouth
• Constipation
• Insomnia
• Sweating
• Loss of appetite 
• Nausea
• Vomiting 

In rare cases, you might experience more serious side effects when taking NDRIs, such as high blood pressure, vision loss, seizures, and tremors. It's also possible to experience suicidal thoughts when taking these types of drugs.

NDRI Warnings 

It’s essential to keep an eye on your blood pressure when using this type of medication, as it might sometimes cause high blood pressure.

If you develop a dependency on NDRIs, your doctor may stop their use or reduce your dosage. When you stop using an NDRI after a dependency has developed, you might experience withdrawal symptoms such as headaches, anxiety, insomnia, tiredness, nausea, and vomiting. 

NDRI Interactions

Certain medications can interact with NDRIs. It is important to tell your doctor about any medications, supplements, vitamins, herbal remedies, or other substances that you are currently taking. Drug interactions can affect how well your medications work or lead to side effects.

Using an NDRI while taking monoamine oxidase inhibitors (MAOIs) is strongly cautioned against. In some cases, combining these two medications can cause serotonin syndrome, a potentially life-threatening condition. Using antipsychotic medications with NDRIs could also increase your risk of seizures. 

Other substances that may interact with NDRIs include:

• Other antidepressants
• Anticonvulsants
• Other stimulants
• Steroids
• Some antibiotics
• Sedatives
• Nicotine patches
• Antiarrhythmic medications
• Beta-blockers
• Insulin and some other diabetes medications
• Sleeping pills

Getting Help for Depression

Coping with depression can be hard, but talking to your doctor about your symptoms is an important first step. Antidepressant medications such as NDRIs can be an important part of your overall treatment plan. 

Your doctor may recommend medication as well as other changes, such as psychotherapy and lifestyle modifications. Cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and dialectical behavior therapy (DBT) are a few effective approaches. 

Lifestyle changes, such as eating a healthy diet, getting regular exercise, and finding social support, can help you cope and may improve your symptoms.