Why Don’t Some Common Antidepressants Work for Patients?

Finding an antidepressant that works well for your patient can feel as challenging as finding a needle in a haystack.

As a clinician who prescribes medication, you take into consideration many elements from a patient’s clinical profile when determining what medication to prescribe, including the patient’s symptoms, possible comorbidities, family history, potential side effects, and many other factors.

However, what happens when you’ve taken all those factors into consideration and your patient still fails an antidepressant? And then the next one? And the next one?

As you may have experienced, this can happen in a number of cases. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project has shown that the response rate for antidepressants for treatment-naïve patients is around 50%. This means that for every ten patients treated for depression, five will respond.

The numbers get worse the more treatment attempts that are made. According to the STAR*D study, remission rates were:

• 6% for the second treatment
• 7% for the third treatment
• and 13.0% for the fourth acute treatment steps.

Additionally, the study found that “those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase.”

Treatment-resistant depression can cause frustration for you – and your patients.

When Antidepressants Fail

Your patients may be unclear if their antidepressant is working or if it is failing. It’s important to note that antidepressant medications usually take two to 12 weeks to start working, with an apex around six to eight weeks. If your patients have tried their medication for that amount of time, you then may need to evaluate whether their antidepressant treatment is failing them. We provide a list of 5 signs a patient’s antidepressant may not be working in this blog post.

A 2016 book called Still Down: What to Do When Antidepressants Fail by Dr. Dean F. MacKinnon, a psychiatrist at The Johns Hopkins University School of Medicine, suggests that scientists are still trying to pinpoint why antidepressants work for some, but not other patients.

“The brain is a complex organ, and what transpires within it often is mysterious,” suggests Dr. MacKinnon.

When patients relapse, Dr. McKinnon writes that one of the things that he has found in his more than two-decade career in treating patients is that too few people ask the question “Why did the standard treatment not work for this person?”

Promising Depression Research

Researchers today are asking that question.

In a study, a team of scientists from the Salk Institute and Mayo Clinic may have found that there are common biological reasons behind why patients fail common antidepressants, such as SSRIs (Selective Serotonin Reuptake Inhibitors). The researchers took an innovative approach to their investigation – taking skin cells from more than 800 people with major depression and turning them into stem cells.

According to Medical News Today, the scientists found structural differences in nerve cells between SSRI responders and non-responders. Patients with longer neurites (which transmit signals to and from nerve cells) can experience “disrupt(ed) communication in serotonin brain circuits with some regions having too much traffic and others not enough.” The researchers say this disruption can cause SSRIs to be ineffective.

Senior Study Author Fred H. Gage, president of the Salk Institute, and professor at its Laboratory of Genetics, said that this study “suggests that other drugs, such as serotonergic antagonists, could be additional options for some patients.”

Using Genetics to Fight Depression

As researchers look for new antidepressants by investigating the underlying cause of depression, pharmacogenomics is providing genetic insights that may inform a healthcare providers’ medication decisions.

Pharmacogenomic tests (like the GeneSight Psychotropic test) use an integrated approach that accounts for multiple pharmacokinetic and pharmacodynamic pathways.

Experts at Myriad Neuroscience have integrated results from more than 750 published clinical studies, detailed pharmacology, and manufacturers’ FDA-approved medication labels to analyze and weight the importance of multiple pharmacokinetic and pharmacodynamic genes for the GeneSight Psychotropic test. The factors taken into consideration include:

• All known CYP450 and non-CYP450 metabolic pathways of each medication and medication metabolite, weighted for their relative importance
• The pharmacodynamic activity levels of the parent compound and any active metabolites and genetic variation that may impact pharmacodynamic activity, incorporating known clinical considerations
• Validated research regarding all known functionally significant alleles in all relevant weighted genes
• FDA labeling information related to genetically mediated efficacy or tolerability of a medication

This weighted multi-gene pharmacogenomic approach uses knowledge of each medication’s unique set of pharmacokinetic and pharmacodynamic characteristics to incorporate and appropriately weight genetic variation at multiple loci to produce more accurate predictions of patient response than testing solely for the primary metabolic pathway of a medication.

If you are interested in learning more about pharmacogenomics and clinical trials supporting the GeneSight Psychotropic test, you can read more at https://genesight.com/for-clinicians.