Sometimes people do everything right for their mental health, and things still don’t get better. They show up to therapy, take their medications as prescribed, and work hard at making lifestyle changes.
But when treatment isn’t working despite genuine effort, it’s worth asking whether it’s down to biology. Not every depression is driven by the same mechanisms, and not every brain responds to the same approach.
The neurobiology of depression and anxiety is extremely complex. Serotonin levels are a part of the story, but genetics, inflammation, hormonal function, and the brain’s capacity for change can all shape how someone responds to treatment.
This article will cover:
Mental health conditions like depression and anxiety tend to run in families, but what’s actually inherited are collections of biological tendencies.
How the brain regulates stress hormones, how sensitive certain systems are, and how quickly the nervous system returns to baseline can all influence whether someone develops a mental health disorder — and how their brain responds when treatment begins.
Beyond heritability, mental health genetics and treatment research have found that specific genetic variations predict which treatment approaches are more likely to work and which ones may not.[1]
The hormonal pathway connecting the brain’s stress response to the adrenal glands, known as the HPA axis, is one of the most genetically variable systems in the human body. For adults with treatment-resistant neurobiology, the system can often be dysregulated, producing too much cortisol (and for too long), keeping the brain in a low-grade state of threat response.[2]
Variations in the genes overseeing HPA axis function can also help to explain why two people with depression diagnoses can have completely different responses to medication. One person’s depression might be serotonergic (driven by serotonin) while the other’s depression is rooted in the stress response system.[3]
One of the biggest developments in researching the biological causes of treatment-resistant depression is understanding how much inflammation can influence mood regulation.
Adults with elevated inflammatory markers respond poorly to selective serotonin reuptake inhibitors (SSRIs) at much higher rates than the general population. This is likely due to their depression being driven by immune system activity instead of neurotransmitter deficits, which SSRIs primarily target.[4]
For decades, the explanation around depression was relatively straightforward: low serotonin levels cause it, and SSRIs raise serotonin for treatment. However, a comprehensive research review published in 2022 in the U.K. found no clear evidence that serotonin levels or serotonin activity are actually responsible for depression.[5]
The field had been researching this for years, with studies on the most commonly investigated serotonin receptor in the brain suggesting no difference between people with depression and those without it. They also found that serotonin activity was actually increased in those with depression – the opposite of what the dominant theory predicted.[6]
That doesn’t necessarily mean that serotonin isn’t or can’t be part of the picture. But it does mean that more research is needed into why treatments targeting only serotonin and dopamine leave so many people without improvement.
Neurotransmitters such as serotonin, dopamine, and norepinephrine make up less than 10% of total central nervous system activity. The brain’s two primary neurotransmitters are glutamate and GABA, and an imbalance between these two systems may play a key role in the biology of treatment-resistant depression.[7]
GABA works to calm neurons in the brain, while glutamate activates them. Research has increasingly linked disruptions in this balance to depression and nonresponse to SSRIs and SNRIs.[8]
Research has pointed to inflammation as a potential direct contributor to depression for many adults. Chronic inflammation can interfere with your brain’s ability to produce and regulate neurotransmitters, and adults with high levels of inflammation respond poorly to SSRIs at a rate much higher than the general population.[9]
This is one reason why treating depression without assessing inflammatory status can leave people going through medication after medication without finding one that works.
Over two decades’ worth of recent research into brain-based mental illness has found that conditions like depression and anxiety aren’t singular conditions with just one biological cause.
Instead, they’re categories that contain many different subtypes, each with its own underlying mechanisms.
Therefore, a treatment approach that works for one subtype might do nothing for another, because the underlying biology doesn’t match the treatment. In these cases, nonresponse isn’t a sign that nothing will work, but that the right biological target hasn’t been identified yet.
Neuroplasticity, or the brain’s ability to form new neural connections and reorganize itself, may help explain why some people have an easier time recovering from depression and anxiety.
Mental health disorders physically reshape the brain over time. Experiencing ongoing stress and mental health symptoms reduces the size of the hippocampus, the region most involved in:
It also weakens connections between the prefrontal cortex and the areas governing fear and stress response.[10]
However, these changes aren’t permanent. Neuroplasticity in mental health works in both directions, as your brain can also adapt to new treatments and ways of functioning. For example, exercise can increase a protein known as BDNF that supports the growth of new neurons. Sleep also helps the brain to consolidate new patterns.[11]
AMFM is here to help you or your loved one take the next steps towards an improved mental well-being.
If you haven’t made the progress you’d expected, you may want to consider a thorough biological workup to measure things like:
Basic bloodwork can sometimes reveal biological factors that have been working against treatment without anyone knowing.
Pharmacogenomic testing is worth asking about, especially if medications have failed without any clear cause. It examines how your body metabolizes specific drugs, which can explain why certain medications haven’t worked and which categories might be more likely to.
Beyond testing, talk with your prescriber about potential causes that haven’t been addressed or ruled out yet. A comprehensive assessment can often identify overlooked factors and help guide a more personalized, effective treatment plan.
A Mission For Michael (AMFM) provides treatment for adults experiencing various conditions. Mental Health support is a phone call away – call 866-478-4383 to learn about our current treatment options.
See our residences in Southern California’s Orange County & San Diego County.
Take a look at our homes on the east side of the Metro area in Washington County.
View our facilities in Fairfax County, VA within the DC metro area.
At AMFM (A Mission For Michael) Mental Health Treatment, we understand that biology might be one of the primary causes of treatment non-response. Our teams work with adults whose psychiatric presentations haven’t responded to conventional approaches, individualizing every aspect of your treatment to account for the fullest picture possible of your experience. We believe in treatment persistence so you can achieve lasting, life-changing outcomes.
We offer an intimate, focused mental health treatment experience for adults in home-like settings that are carefully maintained to be peaceful, comfortable spaces. AMFM Mental Health Treatment provides the full spectrum of care, including residential and outpatient treatment programs.
Our locations in California, Minnesota, and Virginia accept insurance and are in-network with most major providers. To check your insurance coverage for mental health care, simply complete our confidential online verification form or call us at 866-478-4383.
Reach out to us if you would like to start the admissions process or learn more about how we can support your mental well-being. Our compassionate team is available 24/7 to answer your questions and provide guidance with no obligation. If previous treatment hasn’t worked and you’re not sure why, that’s exactly what our team is here to help you figure out.
100% Confidential
No Commitment
Instant Results
Yes, although most standard psychiatric appointments don’t typically include this automatically.
A thorough biological workup for someone who hasn’t responded to previous treatment can include:
None of these tests is likely to provide a singular, definitive answer, but they can help to shed light on potential biological factors that are actively working against treatment.
No, and this is largely due to neuroplasticity. The brain retains the capacity to change throughout life. Treatments and lifestyle changes that support neuroplasticity can produce meaningful results even for people who have spent years without relief.
Treatment resistance describes a pattern of non-response to specific approaches and isn’t an unchangeable state. It means the right combination hasn’t been found yet, or that previous treatments were targeting the wrong biological systems.
The brain tends to adapt to medications over time, with receptor sensitivity changing and the initial response reducing as the brain adjusts to the drug’s presence. Separate from that, life stressors, hormonal shifts, and changes in inflammation can all alter the conditions that made a medication effective to begin with.
This can be an incredibly frustrating experience, and it isn’t always well-explained. If it happens, it could be an opportune time to revisit your biological picture with your prescriber. The goal is to understand what has changed, not just to switch medications.
Depression isn’t one condition; it’s a category that contains many different subtypes that each carry their own potential biological profile.
For example, depression with psychotic features can involve dopamine system disruptions that front-line SSRIs are rarely effective for. Likewise, seasonal depression has a circadian rhythm and light-exposure component that likely requires entirely different interventions for effectiveness.
Treating someone with an approach not indicated for that kind of depression will likely result in non-response, but it’s actually more indicative of a mismatch.
At AMFM, we strive to provide the most up-to-date and accurate medical information based on current best practices, evolving information, and our team’s approach to care. Our aim is that our readers can make informed decisions about their healthcare.
Our reviewers are credentialed medical providers specializing and practicing behavioral healthcare. We follow strict guidelines when fact-checking information and only use credible sources when citing statistics and medical information. Look for the medically reviewed badge on our articles for the most up-to-date and accurate information.
If you feel that any of our content is inaccurate or out of date, please let us know at info@amfmhealthcare.com
