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 the 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 anesthetic, 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. 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.
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 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 not sure if it’s actually helping me or not.
ECT, TMS, deep brain stimulation
Other options for treatment-resistant depression 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 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 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 you have treatment-resistant depression, what other options have you considered?
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