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Treatment-Resistant Depression: When What Should Work Doesn’t

options for treatment-resistant depression, e.g. augmentation, ketamine, somatic treatments

Wouldn’t it be nice if the treatment of depression was simple? Unfortunately, there’s nothing simple about depression treatment in the real world. Treatment-resistant depression (TRD) refers to depression that hasn’t responded to trials of adequate duration and dosage of at least two antidepressants. It’s important that previous medication trials be long enough that you’re actually seeing the therapeutic effect (or lack thereof) and not just side effects. For people who do experience treatment resistance, it may be that treatments that were trialled didn’t work in the first place, or it may be a matter of what worked before has stopped working.

STAR*D (Sequenced Treatment Alternatives to Relieve Depression), a large study conducted under real-world conditions, found that only about 1/3 of people get well with one anti-depressant trial, a further 1/4 get well with a second trial, and only 67% get well after a fourth medication trial. That’s a whole lot of people not getting well. So if you fall into that category of TRD, what are your options?

Clarify the diagnosis

If depression isn’t responding to treatment, it’s important to reevaluate the diagnosis. Has there been a history of mania/hypomania and could this be bipolar depression? In that case, the treatment strategy may need to be quite different, and antidepressants alone are seldom effective for bipolar depression.

Is there a medication, medical condition (e.g. hypothyroidism), or substance use that could be contributing to the problem that needs to be addressed in order to properly treat the depression? Is there unaddressed trauma that needs to be worked on?

Switch up the treatment

Let’s say the diagnosis is major depressive disorder and no complicating factors have been identified. Have you tried psychotherapy?  If not, that’s always a great place to start. Other first steps might be to increase the dose, switch antidepressants, or try antidepressant combos.

Augmentation is another strategy. It involves adding medications to an antidepressant regimen to achieve a greater therapeutic effect. Options include the mood stabilizer lithium, thyroid hormone, atypical antipsychotics, and stimulants.

Novel medications

Ok, so what if you’ve tried, maxed out, and failed on these various treatment strategies? Ketamine, a dissociative anesthetic, has a novel mechanism of action, affecting the glutamate system in the brain. It’s a relatively new treatment and availability can be limited, but there’s some good research supporting its effectiveness.

Botox has demonstrated effectiveness in some small research trials. I’ve had a couple of rounds of it, and I feel like I’ve had some positive results from it, although it’s hard to say for sure.

Targeting inflammation

There are a number of other drugs that have been studied that are potential options although there isn’t a large body of research evidence to support them. D-cycloserine is an antibiotic that at high doses acts on the same NDMA receptors that ketamine works on. Minocycline is another antibiotic that has shown some benefit, as it calms inflammatory microglia in the brain.

Infliximab, normally used for autoimmune diseases, has shown some antidepressant effect in depressed people with elevated levels of inflammation. As a biological agent, it is quite expensive.

Targeting the cholinergic system

Scopolamine, also used for nausea, appears to have an antidepressant effect via its action on muscarinic receptors in the brain. Studies have primarily involved 3 doses via IV infusion, with a rapid but not sustained effect. This is something I’ve considered trying in the form of an intramuscular injection, as the oral version of scopolamine that’s available in Canada doesn’t cross the blood-brain barrier to enter the brain.

Kappa opioid blockers

Blocking kappa-type opioid receptors has been associated with an antidepressant effect. This is different from the µ-type opioid receptors which are associated with effects like analgesia and respiratory depression. Buprenorphine, which is found in Suboxone, is a kappa antagonist, but it also has effects on µ receptors, and research is being done to develop drugs that are selective for kappa receptors with no activity at µ receptors.


There are a number of over-the-counter supplements that have shown some effectiveness in depression. These include L-methylfolate, which may be most useful in those with elevated inflammation or impaired methylation cycles, S-adenosyl methionine (SAMe), omega-3 fatty acids, creatine, and n-acetyl cysteine, which decreases oxidative stress.

I take L-methylfolate along with vitamin B12 by injection every 2 weeks, and I’ve noticed that if I go longer than 2 weeks between shots, my thinking and my energy start to slow down. I also take omega-3’s, although I’m not sure if it’s actually helping me or not.

Somatic treatments

Other options for treatment-resistant depression involve the application of energy to the brain; these are referred to as somatic treatments. Probably the best known is electroconvulsive therapy (ECT). ECT has been helpful for me in the past, but it’s difficult to manage on an outpatient basis, both because of the effects on memory and because you’re required to essentially have a babysitter on ECT days.

Diagram of patient receiving electroconvulsive therapy
Adapted from Gouvernement du Québec, Ministère de la Santé et des Services Sociaux

Another option is transcranial magnetic stimulation (TMS), which stimulates the brain through the creation of a magnetic field. It has demonstrated good results in research studies, and because there’s no anesthesia involved, that decreases the pain-in-the-butt factor compared to ECT. It brings about its own pain-in-the-butt factor, though, as it’s more frequent, and at least where I live, public health insurance doesn’t cover it.

transcranial magnetic stimulation patient setup

Deep brain stimulation (DBS) is another option that I have very limited familiarity with. This involves the surgical implantation of a neurostimulator device that sends electrical impulses to target areas in the brain. DBS is also used to treat other conditions, including Parkinson’s disease. The potential complications sound a bit frightening, but a quick Google search shows it’s the most common operation performed for Parkinson’s disease at the major local hospital in my area.

Living with treatment-resistant depression

I used to have periods of full remission between episodes of illness, but recently, my depression has become increasingly resistant, despite taking two antidepressants with multiple medications for augmentation. My med cocktail still works for some symptoms, but no longer does much at all for others. Some of the treatments that I would like to try, like ketamine, just aren’t accessible at this point in time. It’s frustrating to know that there are options out there that could help, but they’re not available to me.

It’s definitely been a process to wrap my head around the idea that remission no longer seems like a possibility. Hope becomes harder to find when the treatments that are supposed to work just don’t.

How is your treatment working for you? If you have treatment-resistant depression, what other options have you considered?

You may also be interested in these posts:

book cover: Managing the Depression Puzzle, 2nd Edition, by Ashley L. Peterson

Managing the Depression Puzzle takes a holistic look at the different potential pieces that might fit into your unique depression puzzle.

It’s available on Amazon and Google Play.

21 thoughts on “Treatment-Resistant Depression: When What Should Work Doesn’t”

  1. I suppose I have that condition TRD. I’ve had depression since I was 13, over 45 years ago. I’ve been on most of the prescription anti-depressants, and none worked totally, but Zoloft has the best results (IMHO). I take that and a low dose of Trazadone (for insomnia) and the combination seems to keep me, if not joyful, at least not horribly depressed. I also consider therapy to be the best tool for combating the severe episodes, I see a therapist at least once a month, or more if I’m feeling down. I’ve talked about depression to other people (or blogged about it) and one thing is always consistent: No two people respond the same way to the same methods or drugs. So it takes a lot of patience to find out what is going to work, and work the best for any individual. Just my thoughts.

    I’ve recently started following your blog and find it informative and encouraging. Thanks! 🙂

  2. I have had hyperthyroidism since I was seven years old. It wasn’t diagnosed until I was ten. I have always struggled with depression but didn’t realise the two are linked? I take levothyroxine. I’m now 58. I am also autistic which throws anxiety into the mix as well.

  3. Your blog is just SO good, keep up the good work. I may try Ketamine. I have a good friend who became so depressed after her husband left her, that she was literally catatonic. Our church had a laying on of the hands, and she says she never, ever suffered one more depressive moment. Faith is healing as well. xoxo

  4. I’ll add to consider ADHD, ASD or another developmental disorder that might be co-occurring. Also, consider that there might be a global chronic illness like fibromyalgia or EDS or another disorder that messes with pain signals or stress hormones and thus is known for co-occurring anxiety and/or depression. All of the above (plus trauma, of course) ended up being it for me. Folks with ADHD are less likely to respond to SSRIs genetically – my Genesight test reinforced that for me – and it’s really hard to treat the anxiety and depression that stem from ADHD until its underlying chaos and overwhelm is at least partially managed with appropriate medications. I couldn’t make any headway in therapy or with treating my depression or anxiety until I started stimulants for ADHD. They don’t fix the problem (any more than bipolar meds can truly “fix” bipolar), but they one of those medication strategies that are often so critical as a first-line treatment that nothing else really helps until you add them. ADHD is particularly likely to be missed in psychiatry in women and in those with the inattentive subtype.

  5. Wow…Ashley…looks like you are answering my questions today. I have had a lot of them for a long long time…n I am thrilled to know that answers exist!! Hugs

  6. Oy. I’ve probably been depressed fairly consistently (bar occasional gaps of no more than six months, maybe one longer gap early on) for about twenty years, although I wasn’t diagnosed until 2003. I’ve been on LOTS of combinations of medications. I take omega-3 and zinc. I’ve tried various talking therapies (CBT, psychodynamic, I think others). At times I’ve been tempted to try ECT, but that hasn’t happened for various reasons.

    I’ve just been referred to a psychiatrist again because of another relapse and this time I want to talk about alternative diagnoses. This has been done a bit in the past, but I’ve always been told I have straightforward unipolar depression, not bipolar disorder, autism, or anything else. I’m less and less convinced. So many of my friends and the people who read my blog who have experience of depression say that what I experience is so much worse than what they experience. I’m fairly sure I’m somewhere on the autistic spectrum (which wouldn’t directly cause depressive symptoms, but it would explain a lot about why I can’t get my life together and particularly why I’m socially anxious), but after two assessments, and despite a psychiatrist who insisted I was on the spectrum even though she never did a formal assessment, I’m sort of resigned to the fact that the psychiatrists won’t give me a piece of paper that says that I’m autistic. Bipolar doesn’t seem to fit, but I’m currently reading a book on complex PTSD which surprisingly seems to describe me well, but I’m worried that I’m reading too much into it. I periodically find something (an illness or syndrome) that seems to explain a lot and I get excited that I might finally have a breakthrough and then the mental health professionals shoot it down, despite the fact that they don’t have much of a clue about what could help me.

    1. I suspect that C-PTSD is often overlooked as a cause of depressive symptoms, and I’d say the fact that it’s not even recognized yet in the DSM speaks to that.

  7. Wow, I didn’t know that it’s not recognised in the DSM. I know the author of the book I’m reading thinks that most depressive and obsessive disorders have their origins in C-PTSD and even if that’s hyperbole, I can believe that it accounts for a lot of depression. I don’t think it has ever been raised as an issue for me before though, because my childhood traumas weren’t obvious ones. I only thought about it because I got talking to someone at my autism group who thinks that many autistic people have C-PTSD from the way they were treated as children. What she said seemed to describe me, although I still feel I was not traumatised ‘enough’.

      1. Yes, I’m beginning to realise that. I was in a situation that would probably have been upsetting for anyone, but as a young, sensitive and possibly autistic child it was just too much for me, especially as it went on for years.

  8. Very interesting post. My friends and I were just talking about the botox being a means to help with migraines, never thought it would help with depression before.
    I’ll have to check out the ketamine for when my depression gangs up on me again. Right now, it’s kept at bay. Thank goodness.

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