Saturday, June 10, 2023
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Editor's Note:
What is the current state of research on treatments for chronic depression and what directions should new research take? To
find out, Elizabeth Saenger, PhD, Program Director of Medscape Psychiatry & Mental Health, interviewed Alan Schatzberg, MD,
the Kenneth T. Norris, Jr., Professor and Chair of the Department of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Stanford, California.
Medscape: What pharmacologic treatments for major depression now appear to be best supported by data? Are there any that are better than others or that would be better used with particular subsets of the population?
Dr. Schatzberg: There is a perception that the dual serotonin-norepinephrine reuptake inhibitors (SNRIs), like venlafaxine and duloxetine, are a bit more effective than the selective serotonin reuptake inhibitors (SSRIs). When you look at the meta-analyses or pooled analyses, the SNRIs tend to be a little better. Whether they're significantly better than all the SSRIs, including paroxetine, is not really clear. Frequently, their efficacy results don't differ significantly from paroxetine's. So there's a debate in the field. Certainly, compared with fluoxetine, the venlafaxine data look better. And the pooled duloxetine data look a little better compared with SSRIs too, but again, there's some debate about it, for a couple of reasons. For one thing, many studies really aren't set up to make that comparison properly, because they don't push the dose to achieve the maximum effect. So they're not necessarily treating people to remission or full response. And unless you try to achieve that level of response, by optimizing the dosing, you may in fact be underdosing.
Medscape: So you're not really giving the medication a fair chance?
Dr. Schatzberg: Correct. The other problem is that, in many duloxetine trials, the comparator drug is paroxetine at 20 mg daily. Well, that's not a full dose of paroxetine, which can be prescribed up to 50 mg daily for depression. So already you've got a discrepancy in terms of dosing. And you may not be able to fully judge relative efficacy just by reading the top-line results.
Medscape: Why are clinical trials conducted without giving what might be considered the optimal dose of a medication?
Dr. Schatzberg: Because often a trial is set up primarily to examine a drug's efficacy compared with placebo. They'll add an arm for a comparator drug, but they're less interested in adjusting the comparator dose; they just want to see whether there is a signal with the comparator. For example, the duloxetine trials are not set up to really compare full-dose duloxetine with full-dose paroxetine.
Medscape: What research would you like to see that would bring things down to earth a little more?
Dr. Schatzberg: You need to have full-dose trials, and you need to treat patients through to remission. I'd also like to see research that looks at other kinds of measures, such as imaging changes, and at genetic predictors that might help determine which groups of patients are more likely to be helped by particular drugs. It's possible that the dual reuptake inhibitors are better than SSRIs for a particular subpopulation of patients. It could be, for example, that they're better for 30% of the patients and about equally effective for the rest. If you do a study that's too small, you won't see that. That's the most likely explanation for why they've been found significantly more effective in some studies and not in others. But if you could characterize the patients from a genetic perspective, then you might be able to say, "This is the group where venlafaxine or duloxetine is really much, much better." Another argument has been in favor of looking at comorbid pain; that's the duloxetine argument. But it's not entirely clear if in fact that's going to be a significant predictor.
Medscape: Can you tell me a little bit more about that argument?
Dr. Schatzberg: Duloxetine is effective for both reduction of depression and reduction of chronic pain. A lot of depressed people have chronic pain, and so one argument is that drugs like duloxetine may be more effective against depression in people who have such pain. I think that that's one factor that can be looked at. Another is looking at genetics, and to me that makes the most sense.
Medscape: Can you tell me a little bit more about what you would do in terms of research, and also, what might you expect to find in terms of different subpopulations responding differently to different medications?
Dr. Schatzberg: It's possible, for example, that a slight genetic variation predicts a differential response to a serotonin-norepinephrine drug. It may have no additional predictive value for SSRIs. Say this variant is found in 20% of the population. That would suggest that 20% of the population would do better with a drug like venlafaxine or duloxetine.
Medscape: So it might boil down to genes having a major effect on how psychopharmacologists prescribe.
Dr. Schatzberg: Genetic research could affect both how they prescribe drugs and how they interpret data. I think that's likely to happen. Pharmacogenetic studies are likely to come up with data that will tell us who may benefit most from a particular drug. It's going to be an exciting time.
Medscape: What are the major considerations in the long-term as opposed to short-term treatment of depression?
Dr. Schatzberg: I think your question is how long we should treat people, and we don't really know for sure. We're treating people for longer and longer, and we don't really know whether that is needed. We do know that depression has long-term physiological consequences; it may have damaging effects on the hippocampal system, for example. So we may want to treat people forever, but we don't have the evidence for that yet; that's something that we need to study. Depression may also have consequences in terms of heart disease; there seems to be higher risk of heart disease in depressed patients. But we have to consider whether the best means of prevention is to keep patients on antidepressants or to take other measures. Depression has significant metabolic, endocrine, and cardiac effects, and they all need to be better studied. For example, one type of depression, psychotic depression, has very high rates of mortality from causes other than suicide. It may be that patients with psychotic depression have high cortisol levels and high rates of heart disease. If that's true, we need to know it but so far we don't have the data.
Medscape: What are the most interesting things you are doing in terms of research on the long-term treatment of depression?
Dr. Schatzberg: To begin with, we're looking at combining medications with psychotherapy, to see if that helps long-term outcome.[1] Another study we're doing involves a comparison of venlafaxine and fluoxetine; it's a blinded, multicenter trial of about 1,000 patients.[2] We're particularly interested in the question of whether there is a so-called poop-out, where people lose their response to a drug, and whether they lose it more with fluoxetine than with venlafaxine. We're also continuing to look at whether there may be some pharmacogenetic predictors that could help with anticipating patients' responses to particular medications.[3] And our group, along with the very company I'm involved with, is also studying mifepristone, which is a glucocorticoid receptor antagonist, in the treatment of psychotic depression. That's in phase 3 trials.[4]
Medscape: Can you tell me a little bit about the study combining medications and psychotherapy?
Dr. Schatzberg: We're doing a National Institutes of Health (NIH)-funded study called REVAMP, which stands for Research Evaluating the Value of Augmenting Medication with Psychotherapy.[1] The study population is chronically depressed patients who don't fully respond to an antidepressant; we're including people who are on any of several different drugs. The purpose is to see whether adding 1 of 2 forms of psychotherapy affects short-term or long-term outcomes, because we still don't know when we can use medication alone and when we need to use medication with psychotherapy to maximize results. We're particularly interested in a manualized psychotherapy called the Cognitive Behavioral Analysis System of Psychotherapy, or CBASP.[5,6] The name is somewhat misleading; it's really more an interpersonal psychotherapy than cognitive behavioral therapy. It has been designed for patients with chronic depression. And it is very effective in helping patients master certain situations in their lives. In the REVAMP study, we're looking at how it stacks up against medication changes, but we're also comparing it with supportive psychotherapy, because one of the issues is whether CBASP is more effective than less focused supportive psychotherapy. We are in the process of completing the first stage of the study, and then we're going into a maintenance study to see whether longer term outcomes are improved by using one or the other strategy.
Medscape: What are you doing to investigate pharmacogenetic factors?
Dr. Schatzberg: We have a pharmacogenetic add-on to the REVAMP trial. Several of the sites are collecting DNA, and we're going to see what implications the genetic data hold for long-term outcome. We don't have any results yet.
Medscape: What is your impression of advances in the treatment of depression, based on what was presented at the American Psychiatric Association 2005 Annual Meeting?
Dr. Schatzberg: We don't have many new drugs coming very shortly. We do have a selegiline patch, which looks close on the horizon and which I think will be useful. But most of the other medication strategies that were close, or thought to be close, have dropped off. Gepirone has been judged nonapprovable by the US Food and Drug Administration (FDA). The substance-P antagonist MK-869 has been dropped by Merck because it didn't show efficacy in depression. There are some other treatments coming, such as vagal nerve stimulation for refractory patients, or being studied, such as rapid transmagnetic stimulation (rTMS) for refractory depression and mifepristone for people with psychotic depression, which I mentioned earlier. There are also some very interesting, alternative approaches to therapy being studied. For example, Madhukar Trivedi, at The University of Texas [Dallas], has a federal grant to study exercise in patients who are partial responders to an SSRI.[7] He's randomized them to high-intensity or low-intensity exercise as an augmentation to the SSRI. It may well be that what we need to be doing with our patients is something very, very different, such as exercising them. Another example is Rachel Manber's work at Stanford. She's doing a study on the use of acupuncture to avoid medications in depressed pregnant women.[8] She has done a small trial, as has Trivedi, and now they're moving on to bigger controlled trials. There are a lot of alternative therapies that are already being used and that have evidence to support them.
