Finding the right antidepressant can be a frustrating process of trial and error. Researchers are starting to tease out how antidepressants work – and why they don't work for everyone.

If you’ve ever taken an antidepressant for depression, you are in good company. According to one study, about 13% of adults in the United States said they had taken an antidepressant in the last 30 days.

While it’s common to take and possibly switch antidepressants, it can still be quite frustrating. Taking a new antidepressant means slowly increasing the dose of the medication and waiting for weeks to see its effects. It may not work. Or side effects might just be too much for you.

If you’ve done this dance between different classes and types of antidepressants, you may wonder: Just how effective are antidepressants, anyway? And why don’t they work for me?

The truth is researchers and doctors don’t actually know how effective antidepressants are or why certain types work only for certain people. But recent advances in genomics and personalized medicine are bringing us closer to a better understanding.

Depression is a common problem. Antidepressants are a common solution.

Antidepressants are commonly used to treat anxiety and major depressive disorder (MDD). Depression is a mood disorder that is persistent and can last weeks, months or years. The World Health Organization ranks it as one of the most common illnesses. It’s also the main cause of disability worldwide.

Not only that, but depression is twice as common in women as in men. According to the Centers for Disease Control and Prevention, more women than men report feeling anxious or irritable, experiencing low energy or mood swings, and getting stuck on negative thoughts, also called ruminating.

Fortunately, depression can be treated with counseling, called psychotherapy, or with drugs, called pharmacotherapy. A combination of both is typically more effective than either treatment alone. However, psychotherapy is not accessible to everyone due to limitations in the number of providers and insurance coverage.

In addition, lifestyle changes can play an important role in feeling better. However, eating healthy foods and working out is challenging when you don’t feel energized.

Therefore, antidepressants have been a first treatment option for many Americans with MDD due to easy access and affordability.

Antidepressants work by acting on neurotransmitters — but it’s not clear how that helps.

Several classes of antidepressants are available based on the chemicals in the brain that they affect, such as serotonin, norepinephrine and dopamine. These chemicals are called neurotransmitters and are associated with mood. Some people may feel better by increasing one or more of these chemicals. It is common to try an antidepressant from one class and if that’s not helpful, either switch classes or add another class.

For example, fluoxetine (Prozac) is a selective serotonin reuptake inhibitor (SSRI) that boosts serotonin but does not boost dopamine and norepinephrine. This increases satisfaction, but not necessarily energy or drive. Increased satisfaction can help with both depressed mood and anxiety. This is one of the reasons SSRIs are typically prescribed first. Other classes of antidepressants include:

• Selective serotonin and norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor XR) and duloxetine (Cymbalta).
• Dopamine inhibitors such as bupropion (Wellbutrin XL, Wellbutrin SR, Aplenzin, Forfivo XL).
• Atypical antidepressants such as mirtazapine (Remeron).

Do antidepressants really work? For whom?

The question of whether antidepressants are effective has been debated for years. The best designed studies — where neither patients nor providers know who gets a drug or placebo and patients are randomly assigned to a drug or placebo —found antidepressants to have statistical advantage over placebo. But statistical significance is not the same as clinical significance. Statistical significance shows the findings are very unlikely to be due to chance. Clinical significance shows whether people’s lives were actually improved. Clinically speaking, some people find no improvement in their depression and experience bothersome side effects, while others say they have great symptom relief without side effects.

Science is getting closer to answers about antidepressants.

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Research is beginning to help tease out how antidepressants work and why they don’t work for everyone. The University of Helsinki recently led a multinational study that points to cholesterol as a possibly important factor.

The study looked at a brain-derived neurotrophic factor (BDNF), which regulates the growth of nerves in the brain and its receptor tyrosine kinase receptor-2 (TrkB). BDNF is important for regulating mood, among other things. TrkB senses cholesterol levels, and it also serves as a binding site for antidepressants. What does cholesterol have to do with mood and antidepressants?

Though cholesterol has gotten a bad rap over the years due to its role in coating arteries associated with heart disease, it’s a crucial building block of every cell in the body, including the brain. There is no life without it. And interestingly, the brain handles cholesterol independently from the rest of the body.

This new study identified a way cholesterol binds to the TrkB receptor, creating a place where antidepressants can attach and go to work. This is different from how antidepressants had been thought to work.

Does this mean you should be increasing or decreasing your cholesterol intake? Researchers don’t know yet, and you definitely shouldn’t stop taking any prescribed cholesterol-lowering drug. But if cholesterol turns out to be an essential part of the way antidepressants work, that could help scientists create drugs that target this mechanism.

Science is also getting better at predicting who will develop bad side effects to certain antidepressants.

Some people stop taking an antidepressant because they can’t tolerate side effects. Pharmacogenomic testing can now help predict how a person will metabolize a drug before the person takes it.

Some people experience side effects or lack of efficacy with antidepressants because their genetic makeup affects their drug metabolizing enzymes. I see this every day in my practice. As a pharmacogenomics pharmacist, I interpret how genetics and other factors affect the drugs a person takes or needs to take. People who are poor metabolizers are not able to break down a drug that needs to be cleared out of the body. This increases both the amount of the drug in their system and their risk of side effects. People who are rapid metabolizers may break down a drug so fast that not enough stays in their system to do the job. Such individuals often report that their antidepressants just don’t help with their symptoms.

Plus, advances in genetic medicine and technology led by artificial intelligence may help us better predict who is likely to experience benefit with antidepressants such as SSRIs or SNRIs. One such algorithm developed by doctors from the Mayo Clinic Center for Individualized Medicine is currently tested in our clinical practice.

What if my antidepressants aren’t working for me?

First, it’s important to give an antidepressant a fair shot to work, unless you’re experiencing bad side effects.

Most antidepressants take 4 to 6 weeks to work. Unfortunately, you are likely to experience some side effects, such as nausea, irritability or insomnia, before you feel better. I tell my patients to be patient: You may experience side effects in the first week or two, some improvement of symptoms in the first month, and full benefits by the end of the second month. Still, some people experience disruptive side effects, such as vomiting or drowsiness, very early, and have a hard time continuing with the treatment.

If you still want to stop your antidepressant, talk to your health care team first. Don’t discontinue your antidepressant abruptly, as this may cause unfavorable psychological and physical symptoms, even symptoms of withdrawal.