Have Antidepressants Lived Up to Their Promise?

The research literature on the effectiveness of antidepressants is filled with contradictions and controversy. Few have the scientific know-how and patience to wade into the Great SSRI Debate and make sense of it. An exception is neuropsychologist John Preston, author of Clinical Psychopharmacology Made Ridiculously Easy. While he’s a critic of the role of Big Pharma in the mental health field, in the interview below, he tells us how SSRIs may have unfairly gotten a bad rep.


Depression is probably the number-one condition for which people receive psychiatric medication. What’s the overall incidence of depression in the general population and, from a psychopharmacology viewpoint, what are the main distinctions among different kinds of depression?

John Preston: At any moment in the United States, 10 percent of people are in the midst of some kind of severe mood disorder. The lifetime prevalence for unipolar major depression is judged to be about 15 percent, and then about 5 percent of some people have some version of bipolar disorder. So we’re looking at somewhere between 15 and 20 percent of people.

Bipolar disorder, of course, presents with both depressions and either manias or hypomanias. But this isn’t just an academic question about the right diagnosis. It’s been clearly shown that if people who have bipolar disorder are treated with some of the standard antidepressant medications, the outcomes are not good. Unfortunately, a great number of these people are misdiagnosed as having more garden-variety unipolar depressions and given antidepressants, which not only don’t work, but can make a bipolar disorder worse, either increasing the frequency of episodes or causing mania. The current estimate is that the lifetime prevalence for bipolar II is about 4 percent, which is four times the incidence of the traditional manic-depressive bipolar I disorder we learned about in grad school.

Antidepressants have gotten terrible press in recent years. Studies show that they’re not much more effective than placebos, and many studies with negative outcomes were financed by the drug companies and never saw the light of day. As therapists, what conclusions should we draw from these findings?

Preston: From the get-go we should acknowledge the obvious: drug companies want to make money, and it’s been estimated that 75 percent of the outcome studies on antidepressants have been funded by drug companies. So that’s a good reason to be skeptical about this research. The most comprehensive meta-analytic that first came out in 2002 found that the outcome with antidepressants was only slightly better than with placebos. The results were statistically significant enough to meet the standards for approval required by the FDA, but just barely. In those studies, somewhere between 25 to 30 percent of people who take antidepressants have a positive placebo response, whereas somewhere between 30 to 40 percent of people who take antidepressants have a positive response. So while the separation between placebo and drug is tiny, it’s good enough for the FDA. But there’s more to the story.

To meet the FDA requirements in that research, all that was needed to get a drug licensed was two or three studies with large enough sample sizes showing superiority over placebo. At weeks 1 and 2, as you might expect, the placebo and drug typically looked very similar, but by weeks 3 or 4, the drug usually looked a little bit better. And by the time there was enough difference between the placebo and the drug to be statistically significantly different, they stopped the study. In more than 90 percent of the studies, the data were based on only four- to six-week trials, at which point the studies were stopped because they cost a lot of money to keep running, and—from the viewpoint of the drug companies—they’d achieved their aim of showing the drug was just little bit better than placebo and therefore could be approved.

But here’s where it gets interesting. If you study just a four- to six-week period, it looks like antidepressants are hardly better at all than placebos. Yet in studies that follow a longer term, the antidepressants work better. And then there’s another factor that can lead us to underestimate the effect of drug treatment. In every field of medicine—cardiology or gastroenterology or what have you—if you have a disorder that’s treated with medications and the first drug doesn’t work, you don’t just say, “Well, too bad.” You change the drug to a different class, or you add the drugs together or something like that. That’s called sequential treatment. The most rigorous studies on antidepressants by the National Institute of Mental Health show that with very aggressive treatment and sequential treatment—meaning, if there’s not a response after a while, you change the medicine or you add drugs together—you can get remission rates for depression of up to 65 percent.

Here’s the point. Drugs are certainly not a panacea, but when you take into account sequential treatment, antidepressants have shown a lot of efficacy not apparent in many of the studies that have been scrutinized and criticized, at least in people who have really severe depressions. Of course, it’s a good idea to be clear about the limitations of medications. My concern is that if you just read the article in Newsweek, or something like that, and you happen to be a person suffering from depression, or your husband’s suffering from depression, and you see that the conclusion reported in the press is that drugs are no better than placebo, you may not seek treatment. And that’s not right.

Severity of depression seems like a crucial variable in the studies I’ve heard about. What does the research say about the effect of drugs with people suffering from mild to moderate depression?

Preston: Every study shows striking differences in response to medications at the severe end of the continuum. I’m talking about people who are in the hospital or close to being there because they’re so severely impaired. There’s no debate about the fact that the drugs work in that group. But with people who are mild to moderately depressed, a lot of nonmedical approaches are equally or more effective than antidepressants—and they don’t have the side effects that a lot of drugs do.

Some studies show that even people who’ve responded well to an antidepressant will eventually have higher rates of recurrence or relapse unless they’ve been treated with psychotherapy. So it’s one thing to get people back on their feet in a current episode with medications, but it’s yet another to try to prevent recurrences down the road. A lot of psychological treatments have been shown to be more effective than drugs in that regard.

Nevertheless, many people are afraid to go to a psychotherapist or live in small communities where there are no psychotherapists. So clearly medications will continue to be a treatment of choice for those people.

Amid all the different evidence and treatment options for depression, how should we therapists think about our role?

Preston: It’s important to keep in mind the notion of informed consent. As clinicians, our job is to evaluate the problems other people bring to us and, once we have some sense about what’s going on, talk with them about what their treatment options are. So if somebody has mild to moderate depression, at the appropriate time in our assessment we should say something like, “I want to explain to you in some detail what your treatment options are.” Those options should include any kind of empirically validated treatment, including several forms of psychotherapy that have a clear track record of efficacy in treating depression. Also available are exercise treatment, high-intensity light therapy, and other effective options, along with antidepressants. People have a right to understand what their options are, and they’re the final judge about what makes the most sense to them. That means we can offer our own opinions, but we need to present them with the options in a balanced way.

When a medication isn’t working, what are the most common reasons for that?

Preston: One of the most common reasons that a drug isn’t working is that the person is simply not taking it. That may sound like I’m stating the obvious, but this is an incredibly pervasive issue in drug treatment. People have so many worries and fears about meds. They’re often afraid that their medication is addictive, or they’ve heard reports on TV about antidepressants potentially increasing suicide risk. Too often in a 15-minute session with a primary-care physician—and primary-care physicians do most of the prescribing of psychopharmaceuticals—there’s not enough time to talk about those kinds of issues. And quite often, patients don’t even tell their doctor they’re not taking the medicine; after all, they don’t want to be a bad patient.

So it’s important for psychotherapists to say, “Let’s talk about your thoughts and feelings about medication, your experiences with them, if you have side effects.” Make sure to open the door and not rush things. We need to hear what our patients’ concerns are.

Of course, there are many other issues with medications. Sometimes people are just on the wrong medicine, or they’re on doses that are way too small, below the therapeutic range. And this, again, then becomes an important issue for us, talking with them about this, as well as developing professionally tactful ways to talk with primary-care doctors about medication problems.

As a rule of thumb here, what’s the range of time in which you can expect a psychiatric medication to take effect?

Preston: That’s a key question, and a couple of factors play into it. As I said, often when people are depressed, they don’t take their meds. And sometimes it’s not just their concern about the medicine—it’s that they forget to take it. But assuming that they’re taking the medicine at a high enough dosage to be effective, and they’ve been taking it for four or five weeks and nothing is happening, something needs to take place. Still, every therapist should know what the general therapeutic dosage ranges are for the various medications. This doesn’t mean we have to be medical experts, but anybody can look at the standard published guidelines to see if, in fact, the dosage is in what’s generally considered to be a therapeutic range.

How can the research guide us in recommending alternatives to medications when they don’t seem to be helping our clients?

Preston: I often say something like, “A number of treatments have been shown to work. I think our best shot at this is doing an integrative approach: get your family involved, combat social withdrawal, exercise, enhance your sleep, get rid of alcohol if possible, psychotherapy, maybe medications.” Also, if I conclude that the person is entrenched in a highly toxic interpersonal relationship, I would be emphatic about saying, “I think what’s at the heart of your depression is not just a chemical imbalance, but your life situation. Now it’s going to be your choice about whether you want to pursue that or not, but I need to be honest with you about what I’m seeing.”

Let’s talk a little bit about the state of research for the other interventions, including psychotherapy, both in combination with meds and separately from them.

Preston: Three forms of psychotherapy have a huge amount of empirical support for efficacy in treating depression and longer-term relapse prevention. Of course, cognitive therapy for depression is well established. Next is interpersonal psychotherapy or couples counseling for situations where the marriage seems to be a major contributor to long-term depression. And then there’s behavioral activation therapy. If you look at the actual outcome data, behavior therapy has the highest success rate of all these so-called empirically validated psychotherapies, and here’s why. When people get depressed, they stop going out to eat dinner. They don’t answer the phone; they stop going to church. And we’ve known since the 1970s how important it is therapeutically to force depressed people to stay engaged with life. Of course, that’s the last thing that people who are depressed want to do, but it’s one of the highest-yielding interventions of all.

If you did a meta-analysis of these three different versions of psychotherapy, you’d find the remission rates are somewhere in the ballpark of 50 to 60 percent for patients that actually engage in and complete therapy—meaning that they’re not depressed anymore. Beyond that, many people benefit from psychotherapy but clearly haven’t crossed the finish line in terms of complete recovery.

Really good studies that look at combining medication and psychotherapy are few and far between, but the few that were done by the National Institute of Mental Health showed that the combination of the two is clearly superior to either one alone. The real benefit of psychotherapy has to do with its longer-term effects. The largest study on medication alone for treating severe depression, called the Star D study, showed relatively high remission rates with aggressive treatment. But after people recovered, at the follow-up a year later, a significant number of people had recurrences or relapses, even though they continued to take the medication. And so it’s been well established that psychotherapies, when they work, have a greater likelihood of helping people sustain recovery. People in therapy learn coping skills, so when they begin to get depressed again, they can employ some of these strategies and prevent themselves from going back into severe depressions.

Finally, it seems that while you remain skeptical about the effectiveness of meds in treating depression, you think that in many ways they’ve been given a bad rap.

Preston: It’s important for our profession not to be drawn in by sensationalized or distorted report­ing of research findings. Without the appropriate critical discernment and appreciation for the nuances of clinically applying research, empirical findings can often cause harm.

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