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What's the Best Way to Treat a First Bout of Depression?

An expert in depression treatment research shares his knowledge.

Master Cowley/Shutterstock
Source: Master Cowley/Shutterstock

Every year, millions of individuals come to know the pain of major depression for the first time. It can be a bewildering experience, with many people not even realizing their struggles are related to depression (as I've written about before in "Can You Be Depressed Without Knowing It? I Was").

In the midst of these difficulties, a person faces an important decision: What is the best way to treat my depression? Options include talking with close friends and family members, self-help books and apps, over-the-counter remedies, psychotherapy, and prescription medication, among others. Many people find these choices overwhelming and are not sure where to begin, especially because it's their first time dealing with depression.

Thankfully many people have thought really carefully about this decision, and none more so than psychologist Robert J. DeRubeis of the University of Pennsylvania. I recently interviewed Rob to discuss the current state of the science in depression treatment research.

Do I Have a Chemical Imbalance?

First, let's think about what causes depression, which may affect the choice of treatment. An explanation that seems to have saturated popular culture is that depression is caused by a "chemical imbalance." Most often, the imbalance is said to involve too little serotonin — with the understanding that a drug is needed to fix it. I asked Rob for his perspective on this theory:

Seth J. Gillihan: What causes depression? Is it a chemical imbalance?

Robert J. DeRubeis: The chemical imbalance theories that came around in the 1950s were quite intriguing, and they captured the imagination of the profession. There's no doubt that whenever we are in a particular mood, or when we come out of that mood, there are associated events in the brain. That's a given, and we all understand that.

But the theories that led some to talk about a "chemical imbalance" as a rather simple matter have not panned out. There's nothing simple about the neurotransmitters and their relation to depression. The brain's a very complicated organ, and current thinking is more focused on the regulatory systems in the brain, which are more active in some people than in others.

SJG: And yet that simple account of a chemical imbalance has been surprisingly persistent, given how little data there have been to support it.

RJD: Yes, and of course it's connected to the predominant treatments in the U.S. and many other Western countries for people with mood difficulties — that is, the antidepressant medications. And so there are some kind of interesting links between what we think the antidepressant medications are doing and what we know about what happens at the synapses in certain areas of the brain, but the connections are not very tight, strong, or well understood. And, indeed, as I've read these literatures and contributed a bit to them, it's common enough that what we find about a given neurotransmitter system is the opposite of what was first proposed.

Importantly, our thoughts and behaviors affect our brains, so we are not merely passive recipients of our brain states. See also this post on the limited evidence for a chemical imbalance in depression: "Do You Need Drugs for Your 'Chemical Imbalance'?"

Can Psychotherapy Really Help With Severe Depression?

The lack of evidence for a chemical imbalance in depression might call into question whether the condition requires a chemical solution. I asked Rob about existing research comparing the effectiveness of meds and psychotherapy, particularly for severe cases of depression.

SJG: When I started in my doctoral program at Penn in 2001, the idea was that medication was like a key that fit in the lock of your chemical imbalance, which fed the idea that the real treatment for depression was medication. Someone I interviewed with at Penn actually predicted that in a study you were doing at the time, "the meds were going to beat up on the therapy" in the head-to-head comparison of CBT and an SSRI. So I wanted to get your perspective on why it was widely assumed that medication was better than the best therapy for treating severe depression.

RJD: In the 1970s and '80s, the possibility that we could correct a simple imbalance was very exciting, and the medications that were being used were more effective than placebo pills, on average, for people with substantial depression. So the idea was that "Here we have a real and serious treatment for depression."

Then along came a relatively small study — but an intriguing one — which found that cognitive therapy outperformed medication in that randomized trial. This was surprising to many who believed that "real" depression needs a "real," physical treatment, and there were many skeptics, as there should have been. But then a couple of other studies showed very similar kinds of effects that were encouraging about the benefits of cognitive therapy in comparison to medication.

And then in what was thought to be a large study comparing medications with cognitive behavioral therapy, there were reports that medications outperformed CBT for those with the most severe symptoms (Elkin et al., 1989 — a study that's been cited over 3,200 times). This finding confirmed preexisting notions among the psychiatric community, and also spread to the public. The belief was that "now that we've done the real study, and we've looked at more severe depression, we can see that we were too optimistic to think that CBT could work as well as meds."

This 1989 study did indeed seem to have a lot of sway over the depression treatment field; it was frequently cited as evidence for the superiority of medication over psychotherapy. But as Rob explains, the implications of that study's findings appear to have been overblown.

RJD: It turns out that in that study, the comparison that everyone was excited about and took very seriously was a comparison of 27 patients in each group. Now, that's not nothing, and it certainly is data that one needs to take into account. In the 1999 paper we wrote, those 27 patients who got medication in that trial did significantly better than those in cognitive therapy, but it turned out that study was unusual in that regard. Clinical science is a larger enterprise than one study, and when we were able to look across several studies, there was no advantage of the medications at all in the short run. Cognitive therapy and medications, on average, performed essentially exactly the same.

Rob and his colleagues completed a subsequent study of 240 patients that again found that cognitive behavioral therapy and medication were equally effective in the short term — and that CBT was better in the long run — at preventing a return of depression.

Does Medication Work Faster Than Psychotherapy?

While CBT and medication appear to be equivalent in their short-term effectiveness, some have suggested that medication works faster, and thus can lead to quicker relief.

SJG: One of the other common arguments for giving antidepressant medications right away is that they work faster than psychotherapy. Is that the case?

RJD: They don't. And this belief again somehow meets up with preconceptions, but in the analyses we've done, there really isn't a difference in speed of the effects, and if there are any, they're really slight. Of course, it's going to depend a bit on what the medication is and how active and directive and potent the psychotherapy is. But if you're talking about an effective antidepressant and an effective cognitive behavioral therapy, the rates of change are pretty much on top of each other, on average.

Should I Get Medication Plus Psychotherapy for Best Results?

SJG: Many people say that the head-to-head comparison of CBT versus medication isn't really important, because "we all know the best approach is to combine medication and therapy" — that the meds do one thing, the therapy does something else, and they work together. And it's true, on average, that depression responds better to a combined treatment in the acute treatment phase. How much better is that combination as opposed to having just one treatment?

RJD: If we think in terms of the percentage of patients that get better over a period of time, a representative finding is that 60 percent get better if they have one of the two treatments, and 70 percent get better if they get both.

SJG: In your recent writing, you've suggested caution about combining meds and therapy for everyone at the outset of treatment. Why is that?

RJD: We recognize that there is this, on average, say a 10 percent benefit of having the two treatments together. But we've thought about some other things that make it not so simple. For example, let's say I've been given both treatments, and now I'm feeling better, but I wonder — what got me better? Was it the medications? Maybe it was, and maybe that means I should stay on the medications. And I might also wonder: Did the cognitive behavioral therapy really help? And I'd better be really convinced that the CBT helped if I'm going to do the kind of work that it requires, especially using the kinds of skills that I learned in therapy. But if I think it was the medications that did it, the best thing is for me to just stay on the medications.

But let's imagine we go back a couple months, and I'm beginning treatment, and I'm being given the psychotherapy and the medication, and I'm really hoping the medication works, because doing treatment is difficult. It requires effort, it requires looking at things that are a bit painful, looking at some behavior patterns, changing things . . . If I'm hoping the medications do the trick, I might not be so motivated to engage the therapy in the way that I would if the medication weren't around. We have some evidence to suggest that this is what can happen to individuals who are getting both treatments.

Now think of me as someone who's only getting the psychotherapy. Well now if I'm feeling better after a few months, I have a pretty good idea that this cognitive behavioral therapy treatment was a good thing, and that maybe I'd better keep it up. Maybe I'd better practice the kinds of things I've been working on with my therapist. And if I run into a bit more trouble than I can handle, maybe I check in with my therapist a few months down the road to get a bit of a boost. So it really does affect how treatment proceeds depending on whether you're getting a combined treatment or CBT alone.

The most common thing in the U.S. is that I talk with my doctor about my depressive symptoms, and they're going to start me on a medication. And then maybe if I'm struggling with the medication, then I'm given a referral for therapy. Again, we've got a mixed message about what is really going to be helpful to me if I end up getting both treatments.

Less common would be when someone starts with therapy alone, maybe because they don't want to take medication, or their doctor isn't very keen to prescribe it. In that case, they can start medication after a few weeks or a couple months if they're struggling a bit to make progress — that can always happen. And I think as practitioners we need to be supportive of that kind of sequence where if someone is really taking on a therapy, and we're not making as much progress as we'd like, then medication is still an option. But if we start those medications right away, and we get benefit from them, we're going to learn that it's the medication that we need. If we don't get better from them, then we're going to need to add the therapy. But if we start them at the same time, we're going to be left in that position of wondering what it is that helped, and what will help me in the future.

Does This Mean I'll Deal With Depression the Rest of My Life?

Depression is usually thought of as a recurring condition, meaning if you've had it once, you're bound to get it again. Based on that understanding, I was surprised to learn from Rob's work that is not necessarily the case.

SJG: It also seems like we've come to believe that depression is a recurrent condition, and it's true that if you've had an episode of depression, then you're at increased odds of having future episodes. Is it a guarantee? How likely is it that the depression will recur for people who have had a single episode.

RJD: It does seem to have become accepted wisdom that depression is a recurrent problem. If you take individuals who have their first episode of depression, the question is then, how many will have a second one? And the answer is, only about half. What that suggests is that many of us go through a period in our life when we're struggling. And I like to use the word "struggling," because I think there's a positive connotation to it as well as the painful one. We're trying to reconfigure things in our life, or at least are made to by disappointments and setbacks.

And about half of individuals who go through one of these rather rough patches are going to have to deal with another rough patch, and perhaps another rough patch, of major depression. So it really has been surprising when careful research is done to see how recurrent depression actually is when we make sure we include individuals who don't go on to have more and more depressions. So having only a single episode of depression is a rather common experience.

This fact has particular relevance to the discussion above about whether to start with therapy, medication, or a combination. Among those who take a medication, many will continue to take it indefinitely as a preventative measure, and because there are often withdrawal effects from stopping the medication. Many of these individuals would have recovered had they received psychotherapy alone. Thus it is likely that a substantial percentage of people may be taking long-term medication, even though they would in fact never experience another episode of depression.

The Bottom Line

To summarize, medication and psychotherapy can both be quite effective in treating depression. The treatments tend to provide relief equally quickly, with psychotherapy being better at preventing future depression once treatment ends. And while a combination of meds and therapy can provide somewhat better results, there are other factors to consider when deciding whether to start both treatments at once versus one at a time.

Keep in mind that all of these findings are based on average effects. In reality, some individuals will fare better with psychotherapy, while others will get more relief from medication. Similarly, some people will need a combined treatment to recover, whereas others will do quite well with a single treatment.

Rob's latest work is aimed at figuring out in advance which treatment is better for a given individual to maximize each person's chance of recovering from depression. Bringing precision medicine to psychiatry could prevent people from wasting time on treatments that are unnecessary or unlikely to work, thereby saving time and money and avoiding needless suffering.

The full conversation is available here.

Note: This post is provided for informational purposes only. Follow your doctor's or other mental health professional's guidance for your treatment decisions.


Cohen, Z. D., & DeRubeis, R. J. (2018). Treatment selection in depression. Annual Review of Clinical Psychology, 14, 209-236.

DeRubeis, R. J., Gelfand, L. A., Tang, T. Z., & Simons, A. D. (1999). Medications versus cognitive behavior therapy for severely depressed outpatients: Mega-analysis of four randomized comparisons. American Journal of Psychiatry, 156, 1007-1013.

DeRubeis, R. J., Hollon, S. D., Amsterdam, J. D., Shelton, R. C., Young, P. R., Salomon, R. M., ... & Gallop, R. (2005). Cognitive therapy vs medications in the treatment of moderate to severe depression. Archives of General Psychiatry, 62, 409-416.

Elkin, I., Shea, M. T., Watkins, J. T., Imber, S. D., Sotsky, S. M., Collins, J. F., ... & Fiester, S. J. (1989). National Institute of Mental Health Treatment of Depression Collaborative Research Program: General effectiveness of treatments. Archives of General Psychiatry, 46, 971-982.

Hollon, S. D., DeRubeis, R. J., Shelton, R. C., Amsterdam, J. D., Salomon, R. M., O’Reardon, J. P., ... & Gallop, R. (2005). Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Archives of General Psychiatry, 62, 417-422.

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