How Are NDRI and SSRI Antidepressants Different?

When it comes to antidepressants, different classes of medications, like NDRIs and SSRIs, take separate approaches for treating symptoms of depression and other mental health conditions.

So, what makes each type of prescription medication unique ― and does one approach work better than the other? Let’s take a closer look with the help of psychiatric pharmacist Josh Maline, PharmD, BCPP.

NDRIs vs SSRIs

Both NDRIs (norepinephrine and dopamine reuptake inhibitors) and SSRIs (selective serotonin reuptake inhibitors) improve mood by affecting chemical messengers in your brain known as neurotransmitters.

In general, antidepressants influence three chemicals to influence emotions. They are:

• Serotonin (often called your body’s “feel-good” chemical)
• Norepinephrine (which increases energy and alertness as part of your body’s natural “fight-or-flight” response to danger)
• Dopamine (typically described as a “pleasure” chemical)

NDRIs and SSRIs target different chemicals to address and improve mood disorders.

Differences in how NDRIs and SSRIs work

NDRIs increase your brain’s levels of two of three mood-altering chemicals mentioned above ― norepinephrine and dopamine, says Dr. Maline. The medication does this by blocking the reuptake (or absorption) of the chemicals by nerve cells in your brain.

This process allows more of each chemical to stay active in your brain, which can lift spirits and increase attention.

NDRIs DO NOT affect serotonin, that third chemical that can guide emotions.

SSRIs, however, focus solely on boosting serotonin levels by blocking reuptake, explains Dr. Maline. That single point of emphasis is one of the reasons why SSRIs are the most frequently prescribed form of antidepressant.

Are NDRIs and SSRIs used to treat the same conditions?

There is an overlap in what conditions NDRIs and SSRIs are prescribed to treat, with depression and anxiety topping the list. (Only one NDRI ― bupropion, like the brand-name Wellbutrin® ― is approved by the U.S. Food and Drug Administration, FDA, for depression treatment.)

But NDRIs tend to be more stimulating given the chemicals they target, making them ideal for treating conditions such as:

• Attention-deficit/hyperactivity disorder (ADHD)
• Narcolepsy
• Seasonal affective disorder
• Tobacco use disorder

“If someone is struggling with low energy or lack of motivation, certain NDRIs may be a good option to give them more pep in their step to get through the day,” notes Dr. Maline.

SSRIs, on the other hand, tend to be more calming. They are often prescribed to treat:

• Bulimia nervosa
• Obsessive-compulsive disorder (OCD)
• Panic disorder
• Premenstrual dysphoric disorder (PMDD)
• Post-traumatic stress disorder (PTSD)
• Social anxiety disorder (social phobia)

It’s not unusual for NDRIs and SSRIs to be prescribed in tandem to increase all three neurotransmitters to address multiple needs.

Common antidepressants by class

NDRIs and SSRIs are both first-line treatment options for various mood disorders. You’ll probably recognize some of the medications and brand names that fall under both classes of antidepressants.

Examples of NDRIs include, again, Wellbutrin, as well as dexmethylphenidate (Focalin®) and methylphenidate (Ritalin®). Commonly prescribed SSRIs include fluoxetine (Prozac®), citalopram (Celexa®) and Sertraline (Zoloft®).

Potential side effects of NDRIs and SSRIs

People respond differently to certain medications, but NDRIs and SSRIs can both commonly lead to issues like:

• Headache
• Difficulty sleeping
• Dizziness
• Dry mouth

More serious concerns include a risk of suicidal thoughts or behavior.

NDRIs may also increase the risk of seizure and aren’t recommended for anyone with a history of seizures. “They can lower the seizure threshold, making it more likely a seizure may happen,” cautions Dr. Maline.

But in general, both NDRIs and SSRIs are well tolerated by most people.

So, which is more effective?

The answer to this question depends on you and what medication your body responds to best.

“In the overall sense, NDRIs and SSRIs are both effective medications,” states Dr. Maline. “But every individual is different, and given that, some medications might work better for you than others.”

It’s not unusual to try a few antidepressant prescriptions before finding the right medication or combination of medications. (Providers may even consider another class of antidepressant known as SNRIs, or serotonin and norepinephrine reuptake inhibitors.)

It typically takes a few weeks to two months to determine whether medications are working.

“There’s usually an assessment at the four-week mark to see how medications are working,” shares Dr. Maline. “Has your mood improved? Has your energy level gone up? These are some of the things we’re looking at to see if the medication is making a difference.”

Dr. Maline also emphasizes the importance of not relying solely on antidepressants to get results. Outcomes often improve when medications are combined with therapy and lifestyle adjustments focused on diet, exercise, sleep and stress management.