What Works Best in Treatment Resistant Depression Part 1

What works best when the first antidepressant fails? And the second? Today, we bring you part one of our special series on treatment resistant depression.

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KELLIE NEWSOME: I’m going to start with two surprising facts about treatment resistant depression. First, you don’t have to be very treatment resistant to have this problem. In depression, treatment resistant means the patient failed to have a meaningful recovery on at least two antidepressants. What is a meaningful recovery? A meaningful recovery does not mean 100% remission – 70-80% is often used as the cut off here – but it’s the patient’s life that we are treating, not the rating scale, so what we really mean by a meaningful recovery is that they are once again functioning in their work and relationships and no longer in significant distress.

How good are antidepressants at bringing about this kind of meaningful recovery? Not as much as we’d like. Only 1 in 3 people reach full recovery on their first antidepressant trial, and – here’s a tip – it takes longer than the usual 4-week trial for them to reach full recovery. So, as long they seeing some improvement after 4 weeks on an antidepressant, the best step is to continue it and allow those gains to build. How much longer? Another 1-2 months. If we look at all the remitters in the STAR-D trial, 50% required more 6 weeks to remit, and 40% required more than 8 weeks. 

But what if they don’t respond at all, and you need to switch to antidepressant #2? Here the chance of recovery is between 20-25%. And if that fails and you have to switch again, the chances are around 12%.  When you add all these numbers up, a little over half of patients are able to achieve full remission after 2 antidepressant trials. And this is all based on the STAR-D trial, which did not have a placebo, so a good chunk of those recovery rates were probably not due to the antidepressant at all. So when we’re talking about treatment resistant depression, we’re talking about nearly half of the patients with depression.

CHRIS AIKEN: The other surprise is that most of the studies that get cited on “treatment resistant depression” were not actually done on treatment resistant depression. Most of the studies that get cited actually enrolled people who failed only one – not two – antidepressants. For example, in 2015 Dr. Zhou’s group did a meta-analysis of treatment resistant depression in 2015 that often gets cited because it was the largest to date. If you read the title and the abstract, you’d think it was about treatment resistant depression, but buried in the methods you’ll see that three quarters of the studies included patients who had only failed one antidepressant, and half focused exclusively on that population.

KELLIE NEWSOME: So that’s a looser definition of treatment resistance, sometimes called the broad definition. It may not help us with the really tough cases, but it’s still informative. What did they find worked best after one failed trial?

CHRIS AIKEN: This was a meta-analysis of pharmacologic augmentation. Only 4 treatments were clearly effective here: lithium augmentation, thyroid augmentation, or augmentation with aripiprazole or quetiapine. A few others were possibly effective – they passed on the secondary measure of remission but not the primary measure of response – olanzapine, risperidone, and buspirone. Missing from this list is bupropion (Wellbutrin) because it actually failed in a large industry-sponsored trial of antidepressant augmentation. Also missing are esketamine and the newer atypicals brexpiprazole (Rexulti), cariprazine (Vraylar), and lurasidone (Latuda). All of those are FDA-approved for antidepressant augmentation, but their data was not available when this 2015 analysis was done.

KELLIE NEWSOME: And that analysis only looked at augmentation, so it didn’t consider other strategies like switching antidepressants, psychotherapy, or devices like lightbox, ECT, or TMS. In this month’s Carlat Report we feature an updated review of TMS, and I learned something from it. When TMS was first approved in 2008 it was only indicated in patients who had failed to respond to 1 antidepressant trial. But since then, it has gathered data in true treatment resistance – failure of 2 antidepressant trials – and one of the devices – Deep TMS from Brainsway – got FDA approved for this in 2013.  TMS is also indicated in treatment-resistant OCD, and in nicotine cessation, and they are attempting to get it approved in bipolar depression. In the online article we detail when to consider TMS, ECT, or further medication trials. If you’re interested in starting a TMS service, we go over billing issues and compare the costs and benefits of the 7 different devices that are available. But a lot of the times you won’t be using TMS, so in this podcast we’re covering the other options for treatment resistant depression.

CHRIS AIKEN: And since the title is “What works best in treatment resistant depression” we may as well start with ECT. Nothing has beaten ECT in treatment resistant depression, not even TMS, and ECT works particularly well if that depression has psychotic features. ECT also works better than medication in bipolar depression. The main drawback to ECT though is how to keep the benefits going – it doesn’t always have a lasting effect. There’s some evidence that combining an antidepressant with lithium – particularly a tricyclic antidepressant – can work to keep them in remission for non-bipolar depression.

KELLIE NEWSOME: But what about ketamine – how does that compare to ECT?

CHRIS AIKEN: There has been a lot of interest in this because ECT requires anesthesia, and ketamine is an anesthetic. But surprisingly, ECT works no better when ketamine is used as the anesthetic; the ketamine seems to just add in more psychiatric and cardiovascular side effects. But as far as ketamine vs. ECT… I’m only aware of one study that compared the two. It was a small randomized controlled trial, and ketamine worked just as well as ECT, but ECT had more side effects – particularly memory problems. This is just one study, but it challenges two myths: one – that ECT is the most effective therapy for depression – and two that ketamine is uniquely effective for suicidality. After 3 weeks, both treatments had similar benefits in reducing suicidality, although ketamine did work faster on that.

KELLIE NEWSOME: But we should emphasize that this is about ketamine, not esketamine. We have reason to believe – both from animal studies and the effect size in its clinical studies – that esketamine is not as effective as ketamine.

CHRIS AIKEN: That is true, but at least esketamine did work in true treatment resistant depression – so it’s one of the treatments that can work after two antidepressants have failed. In my own practice I have an esketamine clinic, a TMS clinic, and I refer to the local hospital for ECT. So I use all three, and here’s what I’ve seen. ECT works very well, especially in severe or psychotic depression – the kind where the depression is visible – you can see it clearly on the mental status exam with psychomotor slowing or agitation; their voice is a monotone and their affect painful and unmoving; their emotions are disconnected from their real lives because their mood doesn’t react to events whether good or bad. And they have lots of physical or neurovegetative symptoms along with the depression. These are the cases where ECT works great. I also see very good responses with TMS and esketamine in all kinds of depressions. Both of them are very effective, but esketamine works faster – within a few days. However, I prefer TMS because when it works the effects tend to last. What troubles me about esketamine is that – on average – it worked no better than placebo after 4 weeks – so I try to reserve it for patients who need rapid relief to keep them out of the hospital, or I may use it to jump start treatment and then switch to TMS.

KELLIE NEWSOME: Another thing I’ve noticed with TMS that’s unique is that get better without any side effects – they don’t have the cognitive clouding or memory problems of ECT, and they aren’t drowsy, tremulous, or emotionally blunted from medication. It’s hard to describe, but there’s something refreshing about seeing people in full recovery who don’t have that other stuff going on.

CHRIS AIKEN: So there’s pros and cons to each of these, but there are also lots of hurdles to getting patients into these higher-level treatments, from insurance coverage to the hassle of coming into the clinic 5 days a week for TMS. Now, you’d think that if someone is severely depressed that driving in for treatment 5 days a week would not be a hurdle – but paradoxically it often is. It’s one more reminder that depression is not an emotional illness – if it were just about suffering than people would be motivated to find relief – it’s really an illness of motivation and judgment. Take the animal model of depression – learned helplessness. They start with an animal in a cage who is getting random shocks from the floor of the cage. That animal is suffering, but it’s not depressed – it’s mustering all its might to get out of the cage. It’s when this set up for failure goes on too long that depression sets in.

KELLIE NEWSOME: Well how do they tell the difference – I mean either way the animal is miserable from all the random shocks. How do they know when that misery has turned into depression?

CHRIS AIKEN: Simple – it no longer tries to escape. Even if they take the walls down, the animal just hunkers down, refusing to move as if glued to the floor, and doesn’t try to get out. It has learned to be helpless and it’s not going to unlearn that just because the walls are taken down. So keep that in mind when you talk about the benefits of TMS or ECT, or psychotherapy, and the patient offers up reasons for not doing it that seem rational on the surface, but really aren’t when you consider how much they are suffering.

KELLIE NEWSOME: I actually see that with something as simple as medication. A lot of times I’ll see a patient who is in great distress over their depression and I prescribe an augmentation agent. But when they come back a few weeks later they haven’t started it. The reason is usually something minor like, “I read that it can cause insomnia,” or a hurdle that could have been easily overcome, like “I lost the script,” or just “I forgot.”

KELLIE NEWSOME: So we have a lot of options after one antidepressant failure, and the best way to choose among them is collaboratively. Treatment works best when the patient chooses them – we know this because a lot of randomized controlled trials actually ask the patient which treatment they’d prefer before randomizing them, and indeed the ones who are lucky enough to get the treatment of their choice usually have the best outcomes. So I’ll start by dividing these options into four camps: Adding a medication, adding psychotherapy, making a lifestyle change like exercise or Mediterranean diet, or adding something natural like SAMe, lightbox, or methylfolate. Oh, and of course switching antidepressants. And if the depression is severe, I might point them toward ECT or TMS. We don’t have much evidence that one of those strategies is much better than the other – except ECT – so I’ll let the patient choose. And if they haven’t started on it when they return for their next visit, I just greet them with an accepting smile and remind them that inertia is part of the illness, and troubleshoot any obstacles that got in the way.

Hyperthymic Temperament

CHRIS AIKEN: And now for the word of the day….hyperthymic

Hyperthymic comes from the Greek word for “Over spirited,” and in psychiatry it refers to a group of temperamental traits that we see more often in the relatives of bipolar patients, and more often in patients with classic, bipolar I disorder. Temperament refers to the long-standing, biologically based personality traits that we are – to some degree – born with. You can think of hyperthymic as having a low-grade, functional hypomania all the time. These people are natural leaders, extraverted, charismatic, confident, lovers of life, thick-skinned, action oriented. They have high energy and tend to need less sleep than us average people. And while all this sounds like a good thing, this temperament does have its drawbacks. They may overindulge in life’s pleasures – food, drink, and extramarital affairs. They can be impatient, hot-tempered, distracted, and impulsive – so keep this type in mind the next time you see an adult who presents with ADHD. People with this trait also tend to be very independent and may not seek or stick with psychiatric care. Hyperthymic is not in the DSM because it’s not a disorder, but it’s considered a soft sign of bipolarity, and it partly explains why people with classic bipolar I – those that have the classic euphoric manias that fully resolve when treated – have more personality strengths on average. Hyperthymic was first described by Emil Kraepelin, and later formalized by the late Hagop Akiskal, who is the subject of our next podcast.