Treatment-Resistant Depression: When Antidepressants Aren’t Working

Treatment-Resistant Depression When Antidepressants Aren’t Working

Are you struggling with depression but not finding relief from antidepressants? You’re not alone. Treatment-resistant depression is common. In fact, one large study found that more than half of depressed patients did not experience full remission of their symptoms after taking antidepressants. And one-third still didn’t achieve remission after four courses of treatment with antidepressants.

What can you do if medication isn’t working for you?

1. Why Do Antidepressants Make Some People Better but not Others?

A 2018 study, which was conducted using brain SPECT imaging, found that people who didn’t respond to depression treatment had lower overall blood flow in the brain and particularly in key brain regions: frontal lobes, temporal lobes, parietal lobes, and parts of the hippocampus. For patients with low blood flow, antidepressants that enhance serotonin, known as SSRIs, may not be helpful since they tend to lower brain activity.

2. Know your Depression Type

Depression isn’t a simple or single disorder. In fact, brain imaging studies reveal that there are 7 types of depression and anxiety (anxiety often accompanies depression). Each type requires individualized treatment. The best way to know your type is with brain imaging, but most psychiatrists never look at the organ they treat.

3. Look for Biological Causes of Depression Symptoms

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? For example, 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. And 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.

4. Consider Trying Natural Treatments

When antidepressants aren’t working, natural treatments may help. A healthy diet helps keep blood sugar levels stable to reduce anxiety, physical exercise releases feel-good neurotransmitters to boost your moods, and supplements provide your body with the micronutrients it needs to handle stress. Other natural treatment options include neurofeedback, hypnotherapy, IV nutrient therapy, and psychotherapy.

If you or a loved one is struggling with treatment-resistant depression, be reassured that antidepressants are not the only treatment option.

At Amen Clinics, we use brain SPECT imaging, as well as a comprehensive 4-circle approach that looks at biological, psychological, social, and spiritual elements to diagnose and treat depression symptoms. To learn more or to schedule your comprehensive evaluation, please visit us online or call 888-288-9834.


  1. There is no mention of TMS, which I have recently learned about. Why not suggest this to depressed people?

    Comment by Sue Pate — April 9, 2019 @ 7:23 PM

  2. Hello Sue, TMS is one of our treatments that we use and recommend at Amen Clinics. For more information.

    Comment by Amen Clinics — April 10, 2019 @ 7:04 AM

  3. I discovered that most medications for depression do not work for me because I am short in an enzyme utilized by most psychiatric medications.

    Comment by Amy B — April 12, 2019 @ 2:45 AM

  4. I’ve sent a couple of emails recently and have not received a reply to my question. What does dr. Amen know and think about Electric Convulsive Therapy? This has been offered to me here in Canada. Thank you Valerie

    Comment by Valerie palmer — April 12, 2019 @ 3:26 AM

  5. For 15 year old currently going through puberty and history of TBI with recent escalation on rage, aggression and verbal abuse what neurohormonal tests would you recommend ordering?

    Comment by Cathie — April 12, 2019 @ 3:46 AM

  6. NO! Please don’t do ECT !

    Comment by Jill — April 12, 2019 @ 3:51 AM

  7. I hope you get a response Valerie! I also desire to know their thoughts. There seems to be a divide on ECT in the world of Psychiatry. The possible side effects are of great concern.

    Great question!!! Looking for answers myself!

    Comment by Nate — April 12, 2019 @ 3:53 AM

  8. I have been diagnosed with inattentive ADD. The first medicine I was prescribed I had bad experience so then I was prescribed with an antidepressant. I don’t think I have a depression problem but it is supposed help with my focusing and ADD symptoms. Sometimes I think it helps and other times not. I have recently had the dosage increased.

    Comment by Chuck — April 12, 2019 @ 4:09 AM

  9. ECT was life-saving for my husband & I am so grateful!

    Comment by Kim — April 12, 2019 @ 5:18 AM

  10. Anti-depressants have only helped me to a certain degree. A micronutrient supplement formulated especially for moods has done the rest. In fact, I’ve been able to cut way down on my medication and am in hopes of getting completely off of it, thanks to the mood supplement. It is being used with great success in some mental health clinics. Studies show that 97% of the patients feel that the mood supplements help them more than medication! The supplement is called Daily Essential Nutrients.

    Comment by Christy Ray — April 12, 2019 @ 5:56 AM

  11. Is there a difference in what type if antidepressant an elderly person would take, as opposed to what someone younger than them would take? Even if diagnosis was the same for both?

    Comment by marg — April 12, 2019 @ 6:38 AM

  12. Who makes the Daily Essential Nutients and where can one purchase that?

    Comment by Nancy — April 12, 2019 @ 7:21 AM

  13. Hello Cathie, thank you for reaching out. We’d be happy to contact you via email and recommend treatment options that are possible for a 15-year-old with these symptoms. Amen Clinics does have Integrative/Functional Medicine physicians that provide neurohormone testing.

    Comment by Amen Clinics — April 12, 2019 @ 10:40 AM

  14. Panic attacks have been a part of my life since I was small. At 65 yrs. Young now, many medications have been given to me. Not going into rem sleep most of my life. Sleeping pills to help with mood or panic attack because sleep would help all of it ….They Said.
    When I turned 60 a deadly car crash almost took my life. Weeks in the hospital and months in nursing home and 2 months in a specialty hospital left me unable to walk, compromised adrenal gland, thyroid compromised, head trauma etc. We find out the my adrenal gland had been compromised since childhood. It supplies the hormone that gives you your fight or flight experience. It also supplies the melatonin for the body to be able to sleep, it provides and cross supplies with the thyroid. No more antidepressants, no more clonazapam, no more sleeping pills, no more lyrica, etc. Low dose of steroids, estratest, melatonin that works wonders. So much of our symptoms comes from the brain reacting to a message.

    Comment by Rebecca — April 12, 2019 @ 10:45 AM

  15. Who is the Integrative/Functional Medicine physician you work with?

    Comment by Roseann Funicelli — April 12, 2019 @ 4:19 PM

  16. Acupuncture! NADA protocol can be tremendously beneficial.

    Comment by Ruth Ackerman — April 12, 2019 @ 7:59 PM

  17. My son did ketamine infusions instead and it worked.

    Comment by Tricia — April 13, 2019 @ 6:44 AM

  18. What are your thoughts on low dose Ketamine therapy for Major Depressive Disorder that has responded somewhat to Antidepressants? I still suffer from depression, anxiety as well as trouble sleeping… not nearly what had been the case but still frustrating nonetheless!

    Comment by Steven — April 13, 2019 @ 7:21 AM

  19. Could you share what enzyme you are short of? Also, how did you find this out?
    Thank you for sharing.

    Comment by Dee — April 13, 2019 @ 8:54 AM

  20. I had two bouts with depression after being hospitalized for a month the doctor said that they had never seen someone that had a severe clinical depression as Bad as I had. I had a back operation which cost osteomyelitis which is severe bone deterioration I received a Ect approximately seven times they could do no more because of the Severe spasms in my back. I did get better very soon from ECT treatments it saved my life

    Comment by Lorie Corriveau — April 13, 2019 @ 9:06 AM

  21. I got zapped 7 times by choice. I had zero side effects. It changed the way i thought in regards to myself. I was shocked of who i was associating with and how i was behaving.

    Comment by Lisa handley — April 13, 2019 @ 6:15 PM

  22. That sounds odd to me. I think that maybe when you didn’t respond to the stimulant, your Dr realized your symptoms could be depression have to be on the highest mg of ssris

    Comment by Lisa handley — April 13, 2019 @ 6:19 PM

  23. Ok i have a adhd and i tried a stimulant and hated it. I got on a high dose of ssri and then the stimulant worked well. I had to use the ssri to control my anxiety and once i had that under control i could benefit from the stimulant.

    Comment by Lisa handley — April 13, 2019 @ 6:24 PM

  24. Wow! Very very interesting. Sorry for your pain. What you just said jumped out at me. I had a man tell me one time that 80% of bipolar individuals just needed thyroid meds.

    Comment by Lisa handley — April 13, 2019 @ 6:32 PM

  25. Interesting. How did you find that out?

    Comment by Bridget — April 14, 2019 @ 1:06 PM

  26. I think ECT is used as a last resort in the U.S. please do your research and get multiple opinions. I realize that you might have to pay out of pocket with Canada’s health system, but it could potentially change your entire personality, behavior. Just think about it, it’s frying key areas of your brain that can’t regenerate itself.

    Comment by Becky — April 14, 2019 @ 2:52 PM

  27. The time after treatment that it continues to help us very limited. It actually leaned me toward the anxiety spectrum, not bad, but noticeable. This was in 2014. Then in 2016, I developed anxiety & panic attacks like I have never experienced. I keep wondering if there is a connection w/the TMS treatments. Don’t know.

    Comment by Dee — April 14, 2019 @ 3:29 PM

  28. This is a case of a physical illness causing psychological symptoms. This is sometimes the case, but not always. I have ‘full blown’ Addison’s Disease (adrenal failure). I will have to take low dose steroids for the rest of my life, however, my Mother & Grandfather has mental breakdowns. I have suffered w/depression/anxiety during times of unrelenting stress since high school. The Addison’s DX wasn’t until age 34. I wished that fixed everything, but it didn’t. I believe that I have two different, but co-existing medical conditions. Each one can affect the other.

    Comment by Dee — April 14, 2019 @ 3:43 PM

  29. I do honestly enjoy reading Dr. Daniel Amen ‘s newsletter. Being from CANADA , and in need of SPECT evaluation , I wish to go to USA for observation. There is none like yours in CANADA.

    Comment by Wayne Lozo — April 14, 2019 @ 8:42 PM

  30. I appreciate the research-based material I receive rom you. I am wondering about your viewpoint on TMS: Transcranial Magnetic Stimulation. I thought maybe I’d see a remark about such a treatment in this article because it is especially for people who have not been helped by the medicines, or who have side effects that preclude them taking those meds. If you have posted on TMS, I’d love to be sent your article, because I have not been subscribing to your emails for long. Thanks, Terry Powell on April 15

    I am a long time depression sufferer, and do a blog myself on issues related to Christian faith and depression. But I am one who believes in what I call “common grace,” as well as special divine intervention, because God works through the natural world and its findings, and thru medication sometimes, etc.

    Comment by Terry Powell — April 15, 2019 @ 6:22 AM

  31. What about people who was a “breach-birth” and the problems it may cause and how ‘it’ mimics other disorders?

    Comment by Karen Criner — April 15, 2019 @ 11:33 AM

  32. We work with many Integrative/Functional Medicine physicians in the community and have physicians specialized in this area within our clinics. Dr. Mark Filidei is our Director of Integrative/Functional Medicine: We also have a specialist in our Bellevue, WA Clinic ( and our Washington D.C. Clinic (

    Comment by Amen Clinics — April 16, 2019 @ 1:07 PM

  33. Hello Steven, we’d be happy to contact you via email directly to discuss your particular needs. We do offer Ketamine Injection Therapy at one of our clinics and have seen success in patients with treatment-resistant depression.

    Comment by Amen Clinics — April 16, 2019 @ 1:04 PM

  34. Is there such a thing as believing you are born depressive? reason I ask because my mother always told me I played in a corner with all my toys I also didn’t visit my friends. Then we came to the USA I was 8 my brother 10. I was very popular in school very friendly went out a lot you know dancing everything great except I had days I wouldn’t go out just sleep a lot. Ok I got married had 5 children and now 10 grandchildren I’m 64 , well was always on the go raised my children, and as part of life they left the nest. And that’s when it hit me, in 2001 started with Zoloft it was great but after a year it stopped working and since then I’ve tried all anti depressent as of today, my despair only God knows, I’m taking Bupropion 300 mg a day, Clonazepam 2mg morning and night and Mirtazipene 15 mg well I think my depression is worst now anxiety, and my primary physician thinks I might have bipolar because no matter what I go to sleep at 7 or 8 in the morning he says that’s when my mania hits me. Last year I went out twice I get nervous and confused around people, I stop driving in 2013, I felt I just was no focusing enough to drive, I don’t miss it I’ve been driving since I was 18 good driver well I wasn’t going to cause an accident were people would be kill, well I stopped. I feel there is nothing out there that interest me I’ve become a recluse and as if you would turn the corner while walking and threw you a block of ice, well my husband of 32 years decided he was not happy, I told him to do what he had to do Oh! and to let me know if he finds it, cause happiness does not exist, we have a lot of good moments but nobody is laughing every day, and he said we could stay together haha, really I said he’ll no put the divorce. Sad to say but depressed people are always left alone, nobody cares. As for me I no longer try new meds they don’t work and sadly it gets worst as the years go by. Sorry for so much writing but just like any other kind of disease it gets worst and more resistant to meds.

    Comment by Nancy Dotel — April 16, 2019 @ 8:37 PM

  35. For me meds aren’t working anymore. I have mdd, anxiety, and problems sleeping. Have been hospitalized more times than I can count, and had more than 60 ECT’S. Nothing seems to be working for me. I just want to end it all. What do i do now.

    Comment by Roberta — April 17, 2019 @ 6:59 PM

  36. Hi, Valerie. I have had major depressive disorder/clinical depression for as far back as i can remember. After trying several antidepressants without any relief, my doctor at the time (this was appx 15 yrs ago) suggested ect treatments, otherwise known as electoshock therapy. I was excited and hopeful and thought that this was going to be my miracle cure. In order to proceed with the treatments, i had to sign a form that protected all medical personnel who would be involved in performing the treatments, including my psychiatrist, from any and all liability should i suffer brain damage, death etc., from these treatments. I signed immediately without much thought about anything except that i just wanted to feel better already. I didnt take the time to research or ask questions. Hindsight is 20/20. Those 6 treatments did nothing for my depression. What they did do was take about 85% of my long term memory. My kids, now 24 and 22 yrs old, talk about this or that memory from their childhood that i was there for but either dont remember at all or will occassionally vaguely recall it as theyre talking about it. Also my short term memory is horrible because of those ects. I can have a conversation with someone and see them again 4 hours later and start telling them the same thing and they will gently tell me that we already had this discussion and ill sometimes remember, sometimes i dont…I used to be somewhat articulate. Now, ill be talking and then blank on a word that i want to say. Simple words that just wont come to me. During one of the treatments, i woke up too early and it was one of the scariest experiences of my life so far. They administer a paralytic so that u dont flop around and hurt yourself as theyre shocking u. They also administer a short acting anesthesia so that u arent awake during it. The anesthesia wore off faster than the paralytic. All i could do was lay there, drooling. I saw the nurse by my bedside but she wasnt looking at me. She was putting stuff into her computer. I was confused and couldn’t move and felt like i couldn’t breathe but couldn’t speak. I did tell them about it later and the anesthesiologist came to talk to me and assured me that he would stay the entirety of the next and any subsequent treatments so that he could ensure i stayed under for the whole thing. And it didnt happen again thank God but once was enough.As long as this reply is, i could go on but u get the idea. I cannot speak for anyone else. Other people may say they had great outcomes from doing this. No matter what u decide to do, DO YOUR RESEARCH first. Know ur options. There are so many more choices and treatment options out there than what was available to me at the time. Utilize the safer ones first, if possible. And ultimately, whatever u decide to go with, i will pray that u have complete success with it and get relief from whatever u r struggling with. Research! Best of luck to u.

    Comment by Lisa — April 26, 2019 @ 1:01 PM

  37. I’m curious, how did they find this out about your adrenal glands? I’m trying to help someone…

    Comment by Ariel Balter — April 27, 2019 @ 2:44 PM

  38. Nancy Dotel. You need to find a medical practitioner who understands how to withdraw from Clonazepm. Get in touch with Benzobuddies who are a US support group for people coming off of Benzodiazepines who can help you get off Clonazepam SLOWLY. These drugs are soul destroying, when taken for longer than 4 weeks they actually cause REBOUND anxiety and depression. Also check out “The Ashton Protocol”, and Benzosupport.UK. All information on how to safely withdraw from Benzodiazapines. You will need support on this withdrawal as symptoms when you do a cut can be very hard, but it is being done my thousands the world over, and the only way to get your life back. Love and best wishes on your journey.

    Comment by Maureen — April 28, 2019 @ 2:52 PM

  39. Hi Valerie, I would also like Dr Amen’s opinion of ECT and the impact it has on the brain. After years of chronic, untreatable depression I agreed to ECT for the sake of my wife and children. My wife and I researched it thoroughly (we are both nurses) and the stats indicated very high success rates. After 11 rounds of ECT my depression worsened, as did my short term memory. Both my wife and I very much regretted our decision. I cannot speak for anyone else as some people clearly seem to improve with ECT but my experience and my resulting opinion is not positive.

    Comment by Edan — May 18, 2020 @ 1:11 AM

RSS feed for comments on this post.

Leave a comment

Contact Us