Treatment resistant depression: When what’s supposed to work doesn’t

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 illness that hasn’t respond to trials of adequate duration and dosage of at least two antidepressants.  The STAR*D research study 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 trail.  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 that the diagnosis be re-evaluated.  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 targeted?

Switch up the treatment

Let’s say the diagnosis is major depressive disorder and no complicating factors can be identified.  Has psychotherapy been tried?  If not, that’s always a great place to start.  Other first steps might be to increase dose, switch antidepressants, or try antidepressant combos.  Another strategy is augmentation, which refers to medications that are added onto an antidepressant regimen to achieve a greater therapeutic effect.  Options include lithium, thyroid hormone, antipsychotics, and stimulants.

Novel medications that aren’t commonly used

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

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 shows some benefit, as it calms inflammatory microglia in the brain.  I wouldn’t be all that keen to use an antibiotic for a prolonged period, particularly when there’s not much evidence to back it up.  Infliximab, which is 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.  Botox has also been shown to be helpful, and I feel like I’ve had some positive results from it.

Scopolamine, which is 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 can’t cross the blood-brain barrier to enter the brain.

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 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.

Over-the counter supplements

There are a number of over-the-counter supplements which 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 have noticed that if I go longer than 2 weeks my thinking and my energy start to slow down.  I also take omega-3’s, although I’m nor sure if it’s actually helping me or not.

ECT, TMS, deep brain stimulation

Other options involve the application of energy to the brain.  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.  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 anaesthesia 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 it’s not covered by insurance.  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 for 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.

How is your treatment working for you?  If it’s not working, what other options have you considered?

 

You can find out more about these medications in my book Psych Meds Made Simple: How & Why They Do What They Do, available on Amazon.

23 thoughts on “Treatment resistant depression: When what’s supposed to work doesn’t

  1. Melanie B Cee says:

    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! 🙂

    Liked by 1 person

  2. yarnandpencil says:

    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.

    Liked by 1 person

  3. Michele Elkins-Hoffman says:

    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

    Liked by 2 people

  4. lavenderandlevity says:

    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.

    Liked by 2 people

  5. Luftmentsch says:

    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.

    Liked by 2 people

  6. Luftmentsch says:

    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’.

    Liked by 1 person

  7. Meg says:

    I’m sad to think of someone having hard-to-treat depression. Just brainstorming–don’t overlook Provigil and/or Nuvigil, which are alertness aids. Hmm…… comedies. I know this sounds weird, but a heavy dose, even a binge-style approach, to comedies could get it done. It won’t work if you’re thinking, “Ha, ha, whatever.” It has to be really freakin’ funny! (I guess what’s funny is different for everyone.) I have a theory that overexposure to hilarity can have a long-term cognitive effect. I swear, I’m not making this up, it worked with me. I spent years watching comedies, and now I see the humor in everything. Something dismal will happen, and I’ll start laughing. (This works more for day-to-day stuff than seriously bad events, but seriously bad stuff will upset anyone.) Also, there’s laughing at yourself. There’s cognitive therapy, where you look in the mirror and try to change your outlook to, “I’m not butt-ugly. I’m reasonably attractive,” and then there’s humor therapy, where you look in the mirror and think, “Hot damn, I’m a fine sexy woman,” and trust me, you’ll burst into laughter. Comedy always helps with this cognitive reprogramming, more than I think most people realize.

    Liked by 2 people

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