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Biological Causes of Treatment-Resistant Depression
Jules Washington
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.
We All Respond Differently to Medications
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.
Genes Can Influence the Effectiveness of Depression 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.
- In one meta analysis of people taking SSRIs, symptom improvement was associated with people who had particular variations of a serotonin transporter gene.
- Similarly, a study of 706 patients found that variations in a gene called UST influenced the response to tricyclic antidepressants, including nortriptyline.
- Around 70 percent of people with depression have a genetic variation in an enzyme called MTHFR that causes a deficiency of a substance called L-methylfolate. L-methylfolate is important for synthesizing important chemical messengers (neurotransmitters), including dopamine, norepinephrine, and serotonin. Most antidepressants operate on these neurotransmitters, so if they aren't present in high enough quantities, antidepressants won't work as well. Research suggests that treatment with 15 mg a day of L-methylfolate can enhance the synthesis of neurotransmitters and boost the effectiveness of depression treatments.
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.
What Are the Options for Treatment-Resistant Depression?
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.
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You may feel isolated and alone when you have clinical depression, and depression also affects your relationships with family and friends. While the primary focus of your treatment is to improve your mental health, it’s also essential to understand your loved ones may experience their own issues as they try to support you. An understanding of how depression affects relationships can help everyone maintain healthy connections and navigate problems. Here are some of the ways depression may affect the people in your support network.
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Starting any medical treatment for the first time can leave you with questions, especially if you’re looking forward to the benefits it may bring. It’s no different when you’re preparing for your nasal esketamine treatment. Your previous mental health treatments may have consisted solely of taking antidepressants at home or visiting a therapist’s office for cognitive behavioral therapy (CBT), so nasal esketamine is probably a new treatment experience for you. If you're wondering what it's like to start nasal esketamine and get ready for your first session, keep reading. Getting Started with the Nasal Esketamine Treatment As with any new treatment, you’ll first talk to your primary care provider or psychiatrist about whether nasal esketamine is a good fit for you. Alternatively, you can schedule your esketamine nasal spray consultation with a treatment center (such as Greenbrook) that has certification by the FDA’s Risk Evaluation and Mitigation Strategy (REMS). At Greenbrook's REMS-certified nasal esketamine treatment centers, our Greenbrook-affiliated psychiatrists and psychiatric nurse practitioners will review your medical history and also conduct our own assessment to help determine whether nasal esketamine treatment is right for you. Certain conditions, including blood vessel disease and a history of psychosis, may make treatment a risk for you. Make sure you discuss all previous and present conditions with your doctor or nasal esketamine provider before beginning treatment. If the medication is deemed a good fit, you’ll receive your prescription from the Greenbrook-affiliated provider. Your Greenbrook Care Team will put together a personalized care plan for the weeks and months to follow. Keep in mind that you will need to take a standard (oral) antidepressant along with your nasal esketamine treatment. There are two important regulations to note when it comes to preparing for treatment: Each treatment is followed by a mandatory two-hour observation period. This means you will need to plan to stay at the center for at least two hours following your self-administration of the esketamine nasal spray. You cannot drive during the rest of the day after treatment and must arrange for transportation. These regulations are mandatory. It may be helpful to sit down and plan out several weeks’ worth of transportation once you know your treatment schedule. In addition, if you’re wondering what to bring for the treatment, we recommend entertainment such as an audiobook or playlist of favorite songs and a pair of headphones. You may want them during the two-hour observation period. What to Expect During Nasal Esketamine Treatment On the day of treatment, you’ll need to stop eating any food two hours before your appointment and stop drinking all fluids 30 minutes before you come in. Your Greenbrook Care Team will confirm that you are prepared for the two-hour observation period and that you have a ride home. You’ll get the opportunity to practice using a “trainer sprayer” that mimics the real nasal esketamine sprayer but does not release any medication. The Care Team will encourage you to use the restroom and set up your preferred environment in your private treatment bay or room. Some patients like reduced lighting, for example, while others don’t request light adjustments. You’ll complete a depression scale before each treatment session. Your Greenbrook provider will confirm that the dose kit is yours, show you how to administer it, and then hand it to you. Each sprayer contained 28mg of Spravato esketamine nasal spray. Patients usually start with two sprayers (56mg) and soon increase to 84mg (three sprayers) per treatment. But, your dosage maybe vary. Should you be left with a metallic taste by the spray, the Care Team will offer suckers to help make the flavor dissipate. After your dose, you’ll be encouraged to lie back in your comfortable recliner. While most patients enjoy a quiet setting, Greenbrook is prepared to accommodate patients with a more animated reaction to the medication. You may feel sleepy, dizzy, mildly dissociated, and/or nauseated during treatment. Greenbrook's Care Team is readily available if you need assistance. How to Prepare for after your Nasal Esketamine Treatment Most side effects begin to wane in the second hour of observation, but if you’re wondering, “Is it safe to drive immediately after nasal esketamine treatment?” the answer is a resounding no. In addition to the mandatory ride home, you will need to block off time to rest and let side effects fully dissipate. This extended rest period is especially important in the first weeks of treatment when you’ll have treatment twice a week. Do not drive or operate machinery of any kind until the day after treatment. Just take it easy, relax, and take care of yourself. If you’re unsure what activities you can do or should avoid during this time, talk to your Care Team for more information. While side effects tend to dissipate completely after a good night’s sleep, many nasal esketamine patients begin feeling relief from depression symptoms within hours of their treatment. Other Tips in Preparing for Your Nasal Esketamine Treatment At Greenbrook, we make every effort to schedule your treatment in the afternoons or whenever it is most convenient for you. We encourage you to see each treatment session as an opportunity to relax and take care of your mental health. If you have any questions or concerns, talk to your doctor or the Greenbrook Care Team. At Greenbrook, we’ll help you feel at ease when preparing for each treatment session. Schedule A Free Consultation To get started with nasal esketamine, schedule your free consultation today.
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