CCPR: Based on your experience treating kids with depression, how do you determine when a patient has the type of depression that is likely going to respond to medication?

Dr. Walkup: There are a few key things that I look for. One is a clearly defined episode onset that includes a change from prior functioning. Second, I look for diurnal variation in mood, which is a worse mood in the morning with an improved mood later in the day. Sometimes what this looks like is kids staying up late in an attempt to stay awake during the time the mood is good, or at least better. They recognize they are going to be tired and grumpy in the morning, and so they make the most of those late evening hours when their mood is slightly better than it is in the morning and they phase shift themselves. Some kids even do partial sleep deprivation, which may actually bump their mood the next day. The third thing that I look for is pervasive anhedonia.

CCPR: Why is pervasive anhedonia so important?

Dr. Walkup: Many children may meet criteria for depression but are demoralized by life circumstances rather than being clinically depressed.

CCPR: How do I sort out whether a child meeting criteria for depression is demoralized or clinically depressed?

Dr. Walkup: I might ask my patient to tell me about some upcoming fun plans. The demoralized teen might brighten in anticipation of a future fun event. The clinically depressed teen might say something like, “Ah, I don’t think I’m gonna be doing anything fun. There’s supposed to be a trip with my family, but I don’t know. They tell me it will cheer me up, but nothing is going to cheer me up.” I could then follow up with a question about a past fun event. Again, the demoralized teen would brighten with remembering a fun event, but the clinically depressed child would not. I might say, “Tell me about something you did that was fun. Your parents told me you really enjoyed yourself a couple of years ago at Disneyland.” A kid with anhedonia might say something like, “Yeah, but I don’t know why they said that. They are trying to cheer me up, but the fact that they can’t makes me even more depressed.” Whereas if you posed that follow-up question to a typically developing kid, the response would be different: “Oh, man, that was so much fun I can hardly wait to go back.” It is very common clinically to see a demoralized young person unhappy and even suicidal in the ER, but look much better after admission in a structured, secure, and predictable environment.

CCPR: So you differentiate between “depressed” and “demoralized”?

Dr. Walkup: Yes, we see many, many kids who meet the diagnostic criteria for major depression, but largely their unhappiness and disturbed mood are related to life experiences: bad schools, troublesome families, poor peer relationships, poverty, and other kinds of adversity. And we preferentially call those kids “demoralized” rather than “clinically depressed.” I have much more confidence that medication is likely to be effective for kids with pervasive anhedonia and syndromic depression that appears “to have a life of its own.” With this sorting, the number of kids who actually suffer from clinical depression with anhedonia is pretty small compared to the numbers of kids who are demoralized. 

CCPR: What kinds of treatments will the demoralized kids respond to? 

Dr. Walkup: They are most likely going to respond to good problem-solving techniques since medication treatment is oriented towards a biological condition of depression. If teens are aware that their low mood is related to their life circumstances, a med trial might actually demoralize them further.

CCPR: In what way?

Dr. Walkup: Because it leads to an attitude of, “My life is tough, but they give me this stupid medicine that is supposed to help.” What these kids really want or need is somebody to talk to and help manage situations that cause specific distress, such as at school or home. So I think there are complications to medicating that demoralized state. You could also say that the children who met criteria for MDD that was caused by demoralization might be the reason our clinical trials of antidepressants have such high placebo response rates.

CCPR: I can see how that could happen. Getting back to determining medication-responsive depression, can you tell us a little bit more about defined onset and changes in functioning?

Dr. Walkup: Sure. As far as change in functioning, I look for psychomotor slowing—parents will tell you that the child is moving slowly and just sitting in one place for long periods of time. I also look for attention and concentration problems that had a pretty clear onset to everyone involved. I also make the determination by age. I more often see depressed kids in their teens, usually at ages 15–18 years—maybe an early episode at 14. These kids have been humming along doing pretty well, and then at age 14 or 15 suddenly they really slump. I have seen young patients with serious melancholia as early as 10–12 years of age, but that is very rare. If I see an unhappy 6- or 7-year-old, I don’t necessarily think depression but rather demoralization or anxiety—a child with an anxiety disorder whose life has gotten complicated, because of all the things he or she avoids, leads to unhappiness and demoralization rather than depression. Such kids are usually not anhedonic. 

CCPR: From what you say, it sounds like we may be over-diagnosing depression in kids.

Dr. Walkup: Yes, one thing that’s happened in terms of our diagnostic criteria is that we’ve moved away from a concept of melancholia as a classic form of depression. We’ve broadened diagnostic boundaries to now include most forms of unhappiness. What’s interesting, though, is that most kids who are experiencing depression will not describe it as unhappiness. Instead, they’ll describe their mood as miserable, and say it’s harder for them to think and concentrate, that they can’t read stuff. They may report problems with focus and concentration more so than a disturbance of mood, much like what we tend to see in elderly people. Whereas the demoralized kids will really talk about how unhappy and difficult their lives are.

CCPR: Let’s say we diagnose a kid with something that we believe is a legitimate sort of melancholic depression or biologic depression with anhedonia and the other features we just discussed. We consider a medication, and many of us automatically think of either fluoxetine or escitalopram, because those are FDA-approved. Is there something particularly effective about these specific drugs with kids?

Dr. Walkup: I think when most people talk about evidence-based practice, they get kind of stuck on the idea of double-blind placebo-controlled trials. And in that sense, you really have the 2 drugs you mentioned: fluoxetine (approved for kids 8 and older) and escitalopram (approved for kids 12 and older). But keep in mind that FDA indication is really an artifact of government and pharmaceutical interaction; it doesn’t necessarily tell you much about what the true evidence base is.

CCPR: Could you tell us a little bit more about that?

Dr. Walkup: Well, I would suggest that pharmaceutical companies have never really wanted to do studies in kids, and it took the Food and Drug Administration Modernization Act (FDAMA) in 1997 to get them to do that. This law encouraged companies to do studies on kids by awarding them an extra 6 months of marketing exclusivity if they did such studies. For companies, the upside is clear—they can make quite a bit more money over those 6 months. But they also incur some legal risks if their studies actually lead to a pediatric indication.

CCPR: How would that lead to a legal risk?

Dr. Walkup: A company is marketing an antidepressant that has an indication for kids 12 and older. If someone uses it properly within that indication and there’s an adverse event or problem, the company could be liable in a lawsuit. Whereas if there is no pediatric indication, then doctors prescribe them off-label and use them at their own risk. If there’s a bad outcome, the company may have less legal exposure without the labeling, but the clinician who prescribes off-label might. It’s important for prescribers to understand what this means—namely, that there may well be other antidepressants that are effective in kids, but that because of financial and regulatory factors (or high placebo response rates), these potentially effective meds do not have official FDAapproval. So in deciding which medication to use, I would not rely on FDA approval alone, but rather the evidence base—including efficacy data, of course, but drug-drug interactions, half-life, the activity of the primary metabolites and other metabolites, etc. 

CCPR: Let’s discuss some of the factors you consider in making medication decisions, such as side effects.

Dr. Walkup: If I’m treating a kid with a history of side effects, I will choose a short acting drug and one that doesn’t have drug-drug interactions. The reason for a short-acting drug is that I want it to leave the system quickly if there are side effects. And the absence of drug-drug interactions helps avoid unpredictability in case I want to switch or cross-taper.

CCPR: Do you have different drug preferences depending on the ages of the kids that you treat?

Dr. Walkup: Somewhat. Younger kids are often anxious and have problems falling asleep, so I tend to like the quieting or sedating SSRIs more. For teenagers that are lying on the couch, so to speak, I use the SSRIs that are more activating. And if I’m working with a depressed teen who is likely to be non-adherent a good percent of the time, I might use a longer half-life medication that would maintain more consistent blood levels despite missed doses. Keep in mind that these differences, however, can be quite subtle, and I think that as a class the SSRIs all work. They just don’t all work for every patient. So sometimes you can pick one and it won’t work very well for that child, and you move them to another and it works much better. 

CCPR: Thank you, Dr. Walkup.