Treatment-Resistant Depression: When Antidepressants Aren’t Working
Are you struggling with depression but not finding relief from antidepressants? You’re not alone. Nearly half of individuals diagnosed with the mood disorder may fall into the category of treatment-resistant depression, according to findings in a 2025 study.
The research—published in the British Journal of Psychiatry—revealed that 48% of patients with a depression diagnosis had been prescribed at least two different antidepressants. More alarming is the fact that 37% had tried four or more types of antidepressants without getting better.
This highlights the significant number of people who aren’t finding relief through conventional treatments. If you or someone you love is struggling with depression that won’t go away, here’s what to do when antidepressants don’t work.
At least 30% of individuals with depression meet the criteria for treatment-resistant depression but that number could be as high as 55%, according to research.
WHAT IS TREATMENT-RESISTANT DEPRESSION?
Treatment-resistant depression (TRD) is when someone doesn’t get better after trying at least two different antidepressants, even when taking them as prescribed.
When symptoms of depression persist, it can have a major negative impact on your life. It increases the risk of substance abuse, makes you more vulnerable to certain medical issues, destroys relationships, and interferes with the ability to excel at work, to name a few.
In the 2025 study mentioned above, the researchers characterize treatment-resistant depression as “one of the most challenging yet neglected conditions in psychiatry.”
Thankfully, researchers are now recognizing the severe negative effects of TRD and looking for effective alternative treatments for depression. The study above recommends access to diverse treatment options and adoption of a more holistic treatment approach when it comes to TRD.
WHY ARE ANTIDEPRESSANTS NOT WORKING?
There are several reasons why antidepressants don’t work for everybody who’s been diagnosed with major depressive disorder (MDD). If you’re resistant to pharmaceutical treatment, understanding what additional factors are at play can open up new alternatives to try.
Related: 6 Biological Causes of Depression
Here are a few significant reasons why antidepressants don’t work:
Low Blood Flow
Innovative research conducted using brain SPECT imaging found that people who didn’t respond to depression treatment had lower overall blood flow in the brain. Brain scans showed reduced blood flow particularly in key brain regions:
- Frontal lobes
- Temporal lobes
- Parietal lobes
- Parts of the hippocampus
For patients with low blood flow, antidepressants that enhance serotonin, known as selective serotonin reuptake inhibitors (SSRIs), may not be helpful since they tend to lower brain activity.
Ignoring the Seven Types of Depression
Most people don’t realize that depression isn’t a simple or single disorder. Brain imaging and depression have shown that depression is more complex.
In fact, the brain-imaging work at Amen Clinics reveals that there are seven types of depression and anxiety (anxiety often accompanies depression). Each type requires individualized treatment.
A tailored approach often involves lifestyle changes that support greater or lesser activity in certain areas of the brain helping to improve mood and calm anxiety.
The best way to determine your type of depression is with brain imaging like SPECT. Obtaining a SPECT scan for depression can help unlock what therapies are best for you. However, most psychiatrists fail to look at the organ they treat.
Related: Treating the Brain for Anxiety and Depression
Disregarding Biological Factors that Drive Depression
Did you know that the feelings of sadness, lack of motivation, irritability, and trouble concentrating associated with depression may actually be caused by biological issues?
Here are some common biological causes of depression:
- Neurohormonal problems such as thyroid abnormalities, estrogen-progesterone imbalances, or testosterone issues can cause some of the same symptoms.
- Past head trauma and concussions can lead to symptoms of depression.
- Infections, such as Lyme disease, are often associated with the condition.
If antidepressants aren’t working for you, it’s a good idea to see your healthcare professional to investigate these possibilities and treat them if necessary.
Press Play to Learn How One Woman Overcame Depression
One woman had been struggling with depression that had gotten so severe it was hard to leave her bed. In this video, she describes how her life transformed after visiting Amen Clinics for help.
ALTERNATIVE TREATMENTS FOR DEPRESSION
When antidepressants aren’t working, consider the following natural treatments:
1.Diet and Supplementation
There are many ways to enhance your mood through diet and supplementation. Here are some well-studied ways to help:
- Eat a healthy diet designed to keep blood sugar levels stable can help to reduce anxiety.
- Greatly reduce ultra-processed foods—such as foods with high levels of refined sugars, carbohydrates, unhealthy fats, and artificial sweeteners. This may help your mood as these foods are all associated with increased depressive symptoms, according to
- Alcohol consumption increases your risk of depression and makes depressed people more depressed, reports the American Addiction Centers. Reducing or eliminating alcohol may improve your mood.
- Staying away from consuming too many vegetable oils (rich in omega-6 fatty acids) and increasing consumption of omega-3 fatty acids may reduce symptoms of depression. Take omega-3 supplements or eat more omega-3-rich fatty fish, green leafy vegetables, and nuts and seeds like walnuts and flaxseed.
While more definitive research is needed, a 2025 review of existing clinical research found that the anti-inflammatory properties and neurotransmission and membrane benefits of omega-3 supplementation can reduce symptoms of depression significantly.
Additionally, the same review study found that supplementing with vitamin D may boost cognitive function and mood regulation. The researchers suggest this may be due to vitamin D’s neuroinflammatory benefits and modulation of neurotransmitter activity.
- Consider taking saffron supplements. A 2022 study on the medicinal herb saffron, published in Nutrients, noted its beneficial effects on anxiety, depression, and other common neuropsychiatric conditions.
Physical Exercise
Physical exercise releases feel-good neurotransmitters to boost your mood.
Other Natural Treatments
Other innovative natural treatment options that can help reduce depression include neurofeedback, hypnotherapy, IV nutrient therapy, and psychotherapy.
In particular, cognitive behavioral therapy (CBT) has been found to be as effective as antidepressants in the short-term, when they work, and more effective in the long-term in helping to reduce depressive symptoms, research has found.
SEEK HELP FOR TREATMENT-RESISTANT DEPRESSION
If you or a loved one is struggling with treatment-resistant depression, be reassured that antidepressants are not the only treatment pathway. Reach out to a qualified mental health professional to explore your options.
Depression and other mental health conditions can’t wait. At Amen Clinics, we provide personalized, science-backed treatment plans designed to target the root causes of your symptoms. Our 360-approach includes brain SPECT imaging, clinical evaluations, innovative therapeutic techniques, medications (when necessary), and holistic lifestyle recommendations to promote the health of your brain, body, and mind. Speak to a specialist today at 888-288-9834 or visit our contact page here.
Amen Clinics
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