NDRIs: Uses, Side Effects, & Risks

What Are NDRIs?

Norepinephrine-dopamine reuptake inhibitors (NDRIs) are a class of antidepressants that work differently than many other common antidepressants. Drugs in this class work by increasing norepinephrine and dopamine in the brain.¹ These chemicals significantly influence mood regulation through their impacts on energy, motivation, and pleasure.

By increasing the levels of norepinephrine and dopamine in the brain, individuals with depression can see improvements in their symptoms. The only NDRI currently available for the treatment of depression is bupropion, which goes by many brand names, including Wellbutrin, Aplenzin, and Forvivo.^{2, 3}

What’s the Difference Between SSRIs & NDRIs?

Selective serotonin reuptake inhibitors (SSRIs) and norepinephrine-dopamine reuptake inhibitors (NDRIs) are both types of antidepressants, but they have different ways that they work in the body. SSRIs, such as fluoxetine and sertraline, work by increasing serotonin in the brain. Serotonin is an important chemical associated with mood regulation. In contrast, NDRIs work by increasing norepinephrine and dopamine in the brain. These chemicals impact mood through their effects on energy, motivation, and pleasure.

How Do NDRI Drugs Work?

NDRI drugs work by affecting the levels of norepinephrine and dopamine in the brain.¹ It’s thought that this impacts nerve cells, which may improve depressive symptoms. Increasing norepinephrine can improve attention and alertness, while increasing dopamine may improve behavior, motivation, and pleasure.

What Are NDRIs Used to Treat?

Bupropion is the only NDRI currently available in the United States used for the treatment of depression. Bupropion is FDA-approved for the treatment of major depressive disorder, seasonal affective disorder, and nicotine addiction.⁴ FDA-approval means that the U.S. Food and Drug Administration has evaluated the medication and has demonstrated its safety and effectiveness for specific conditions.

Bupropion is occasionally used off-label, meaning that it is used for a condition other than what is approved by the FDA. A prescriber may choose to use a medication off-label if, in their professional judgment, they believe it may offer benefit to someone. Off-label uses for bupropion include depressive episodes of bipolar disorder, attention deficit hyperactivity disorder (ADHD), sexual dysfunction, and obesity.^{4, 5}

NDRIs (specifically bupropion) may be used as an FDA-approved medication to treat:⁴

• Major depressive disorder (MDD) in adults
• Seasonal affective disorder
• Nicotine addiction

NDRIs (specifically bupropion) can also be used off-label (non-FDA-approved) for treating:^{4, 5}

• Depressive episodes of bipolar disorder
• Attention deficit hyperactivity disorder (ADHD)
• Sexual dysfunction
• Obesity

How Effective Are NDRIs?

NDRIs have been shown to be effective in treating depression, but individual responses can vary. One study compared the effectiveness of bupropion to other antidepressants and found that bupropion was just as effective in the treatment of depression.⁶ However, it is important to note that the level of efficacy may depend on factors such as the specific symptoms experienced and variations in individual responses.

Are NDRI Drugs More Effective Than SSRIs?

The effectiveness of NDRIs compared to selective serotonin reuptake inhibitors (SSRIs) varies among individuals and is influenced by the symptoms experienced. Both classes of antidepressants have demonstrated efficacy, but their impacts on the brain are different. Because of this, some individuals may respond better to one drug class in comparison to the other.

What Are the Most Common NDRIs?

Bupropion is the only NDRI available that has been FDA-approved for the treatment of depression. Bupropion goes by several brand names, including Wellbutrin, Aplenzin, and Forfivo.

Two other medications, methylphenidate and dexmethylphenidate, are also technically NDRIs. However, these medications are used for different purposes and are typically considered as part of the stimulant class of medications. These medications are most often used in the treatment of ADHD. Brand names of methylphenidate include Concerta, Metadate, and Ritalin. The brand name of dexmethylphenidate is Focalin.

Here are the available types of NDRI medications:

• Bupropion (Wellbutrin): Wellbutrin is the only NDRI that is FDA-approved for the treatment of depression. It is also commonly used for nicotine addiction and smoking cessation.
• Methylphenidate (Ritalin): Ritalin is not typically used for depression. Its most common use is for the treatment of ADHD.
• Dexmethylphenidate (Focalin): Focalin is not typically used for depression. Its most common use is for the treatment of ADHD.

What Happens If I Miss a Dose of NDRIs?

If you miss a dose of your NDRI, specifically bupropion, it is best to skip the missed dose and continue your regular dosing schedule. Never take a double dose to make up for a missed one.⁷

Side Effects of NDRI Antidepressants

NDRI antidepressants, specifically bupropion, can lead to various side effects due to their impact on chemicals in the brain and body. Typically, these side effects are mild and resolve over time as the body adjusts to the new medication. However, in some cases, side effects may persist or be severe, requiring adjustments in the medication.

Common Side Effects of NDRIs

The majority of side effects caused by NDRI antidepressants are generally mild and do not require medical intervention. Many of the common side effects will diminish or resolve over time as the body adjusts to the new medication. However, it is important to share any concerns or lingering side effects with your healthcare provider.

Common side effects of NDRIs include:^{1, 8}

• Rash
• Nausea
• Abdominal pain
• Headaches
• Dry mouth
• Dizziness
• Insomnia

*All medications, including NDRIs, can cause side effects which can be mild or serious. This is not a comprehensive list of all possible side effects. You should talk with your doctor about any questions you have and to understand the potential side effects and benefits of any medication.

Serious Side Effects of NDRIs

NDRIs, such as bupropion, can cause serious side effects, although these side effects are rare. Serious side effects may include allergic reactions, significant mood changes, and severe impacts on the brain and heart. It is crucial to be aware of these uncommon but potentially severe side effects and to seek immediate medical attention if they occur.

Serious side effects of NDRIs may include:^{1, 7, 8}

• Seizures
• Irregular heartbeat
• Hallucinations
• Swelling of the lips, face, or tongue
• Difficulty breathing

*All medications, including NDRIs, can cause side effects which can be mild or serious. This is not a comprehensive list of all possible side effects. You should talk with your doctor about any questions you have and to understand the potential side effects and benefits of any medication.

NDRI Antidepressant Discontinuation

Abruptly stopping an NDRI such as bupropion can lead to a rebound effect of symptoms, sometimes called antidepressant withdrawal. To prevent symptoms of antidepressant discontinuation, it is important to work closely with a physician to taper the medication gradually.

NDRIs Warnings & Precautions

It’s important to be aware of the specific warnings and precautions associated with NDRIs. Some individuals may be at a higher risk for severe side effects or reactions, and anyone taking these medications should be aware of them. Immediate medical attention may be necessary if any of the listed warnings develop.

Warnings and precautions for taking NDRIs include:^{1, 8}

• Taking NDRIs such as bupropion during pregnancy or breastfeeding: The risks of taking bupropion during pregnancy have not been well studied, but there is no evidence of indicating harm to a developing fetus. The decision to continue or stop the medication during pregnancy should be made in conjunction with your healthcare provider.
• Taking NDRIs when breastfeeding: NDRIs – specifically bupropion – are excreted in breast milk at a low level but would not be expected to cause any adverse effects in breastfed infants. However, this has not been well studied, and there may be a risk of causing seizures in breastfed infants. The decision to continue breastfeeding while on NDRIs should be discussed with your healthcare provider.
• Suicidal ideation: When starting antidepressants, some individuals may experience worsening of their depression or develop suicidal thoughts/behaviors. It is necessary to know how to spot the warning signs of suicide due to this potential risk.
• Psychiatric changes: Some individuals taking bupropion have reported severe mood changes. These changes may include depression, mania, psychosis, hallucinations, and more.
• Seizures: Bupropion can cause seizures, especially in individuals who have a seizure disorder.
• Hypertension: Bupropion can increase blood pressure, which should be monitored closely during treatment.
• Angle-closure glaucoma: Individuals with a history of glaucoma may experience a sudden worsening of this condition when taking bupropion.
• Allergic reactions: Severe allergic reactions have occurred in individuals taking bupropion. These symptoms may include hives, difficulty breathing, and swelling of the lips, mouth, or throat.

There may be additional warnings or precautions with this medication. Talk with your healthcare provider about all risks before you start taking this medication.

What to Avoid When Taking NDRIs

NDRIs, such as bupropion, have the potential to interact with various medications, substances, and herbs, possibly resulting in adverse effects. It is important to disclose all medications and supplements to your healthcare provider. NDRIs may interact with drugs used for psychiatric conditions, high blood pressure, or seizures.

Additionally, interactions with substances such as alcohol can occur. Open communication with your healthcare provider ensures a comprehensive understanding of the possible interactions, allowing you to make informed decisions and prevent side effects.

You may need to avoid or take precautions with NDRIs including:^{1, 4, 8}

• Blood thinners: Ticlopidine and clopidogrel, two medications used to prevent blood clotting, may impact the effectiveness of bupropion.
• Anti-seizure medications: Anti-seizure medications such as carbamazepine, phenobarbital, and phenytoin may decrease the effects of bupropion and may require a dose increase.
• HIV Medications: Medications used to treat HIV, such as ritonavir, lopinavir, and efavirenz, can decrease the effects of bupropion and may require a dose increase.
• Psychiatric medications: Many psychiatric medications may be less effective when taken with bupropion. These medications include antidepressants and antipsychotics.
• Heart medications: Some heart medications, including beta-blockers and antiarrhythmics, may be less effective if taken with bupropion.
• Anti-Parkinson medications: Drugs used to treat Parkinson’s disease may have an increased risk of side effects if taken with bupropion.
• Alcohol: Taking bupropion with alcohol can increase the risk and severity of side effects.

This is not a comprehensive list of the possible interactions with NDRIs. You should talk with your healthcare provider and your pharmacist about all prescription and over-the-counter medications, herbs, and supplements you take before starting NDRIs.

Can You Overdose on NDRIs?

Overdosing on NDRIs is possible if more than prescribed is taken at one time. This can lead to significant. even deadly. side effects. These effects may include hallucinations, coma, irregular heartbeat, and breathing difficulties.¹

What Should You Do If You Take Too Much NDRI Medication?

If you take too much of an NDRI medication, seek immediate medical attention or call 911 if severe symptoms occur, such as seizures, difficulty breathing, or coma. After getting emergency care, you may also call poison control at 1-800-222-1222 for more information about NDRI overdose.

Questions to Ask Your Healthcare Provider About NDRIs

If you are considering the use of an NDRI for depression and want to learn more, it’s important to have a conversation with your doctor, psychiatrist, and therapist. You may want to ask about the specific benefits and risks associated with NDRIs and how the medication may align with your symptoms.

Additionally, finding the right therapist can be a beneficial part of depression treatment. These professionals can help individuals explore the emotional aspects of their journey, develop coping strategies, and ensure a comprehensive approach to mental well-being.

Questions to ask your care team about NDRIs include:

• Can I use an NDRI along with therapy to treat depression?
• How soon might I notice side effects from taking an NDRI medication?
• Am I at risk for more severe symptoms if I am already taking other anxiety or depression medications?
• What is the best dosage to ensure fewer side effects?
• Are there drugs I am taking that could have harmful interactions with NDRIs?
• When should I reach out to you if I am experiencing side effects?
• Is there anything I should tell my therapist about this new medication?
• How can the medication be adjusted if I am not responding well or experiencing adverse effects?
• Are there lifestyle factors, such as diet or alcohol consumption, that may affect the medication’s effectiveness?
• How frequently will my progress be monitored?
• What steps can be taken if the current treatment plan proves ineffective?

How to Get an NDRI Prescription

NDRIs, such as bupropion, are only available as a prescription. Getting a prescription for an NDRI starts with an appointment with a healthcare provider who will thoroughly assess your symptoms, medical history, and lifestyle factors.

The prescriber will be able to provide the various treatment options and discuss their risks and benefits. For those exploring the option of NDRI for treatment, one convenient option to consider is an online psychiatry service. These services provide remote access to licensed psychiatrists and therapists.