Biological Causes of Treatment-Resistant Depression

It is understandable to feel frustrated if the symptoms of depression that you're experiencing haven't responded to medication or counseling. However, it's not uncommon to have depression that doesn't respond to first-line treatments like medication. In fact, about one in three people with depression experience symptoms that do not respond to medication.

There are several potential causes of treatment-resistant depression, and one is genetic makeup. The good news is that there are constructive ways to find your own path toward effective symptom treatment—DNA does not define destiny.

You may be familiar with the idea that everyone's responses to medications are different. Imagine that you and a friend are taking the same painkiller after an injury. The resulting levels of that drug and its effect on receptors in your body can vary substantially compared to those in your friend's system, even if you are the same age and weight.

Many factors can account for this variability, such as your unique biology, diet, hormonal status, other medications, and liver or kidney issues. Crucially, genetic factors can strongly influence how your body reacts to a given medication. This is because our bodies' enzymes process the medications we take, and our genes influence how these enzymes function. That means our unique genetic blueprint directs how our enzymes break down and process medications.

There's an important set of enzymes called the cytochrome P450 enzymes that breaks down (metabolizes) many commonly used antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. If someone has a genetic variation in these enzymes, these drugs could build up quickly without being broken down, which could lead to side effects. The drugs could also leave the patient's system prematurely before they have a chance to work fully. Both of these situations can contribute to treatment-resistant depression. 

In addition, some people have genetic variations in the receptors targeted by common depression medications, which can make these medications less effective.

The extent to which genetic diversity affects response to depression medications for most patients is still under debate , and the FDA has advised caution around commercial tests that claim to predict a person's response to medications. Even if a genetic test confirms your susceptibility to developing lower or higher concentrations of a given medication in your blood, that laboratory test cannot forecast how it will function in your brain, and it cannot predict your clinical response in real life. You are more than your DNA.

However, this evolving science does suggest that some people with depression may have a genetic variation that could explain why they have not responded well to medications.

Despite the causes of treatment-resistant depression, if you have it you are not alone. Roughly one -third of patients continue to experience symptoms of depression even after trying two medications, and many don't respond to medication at all.

However, there are meaningful steps you can take toward a better quality of life, even if genes are affecting your response to medications. Non-drug treatments exist that are entirely unaffected by any genetic variations that may be governing your body's reaction to medications.

Transcranial magnetic stimulation (TMS) is one non-drug, non-invasive therapy option. TMS applies gentle magnetic pulses to brain regions that are crucial to mood regulation. TMS is FDA-cleared for use when one medication has not been effective (but covered by most insurance after two).

Even if genes are interfering with the effectiveness of medications, those genes do not decide your future. Whichever treatment avenue you choose, there are empowering ways to manage the depression you're experiencing and find relief from your symptoms.