Landmark depression trials: STAR*D and TADS

Transcript

RyanHere's a question a client might ask you, maybe through tears. I've been on an antidepressant for three months, and I'm still not better. Does that mean nothing will work for me?

SoheeAnd it's a fair question. It's also exactly the question a huge federally funded trial was built to answer.

RyanWelcome to EPPP Prep, the podcast. I'm Ryan.

SoheeI'm Sohee. Today, two landmark trials in depression. STAR*D for adults, and TADS for adolescents. Plus a quick look at brain stimulation for depression that hasn't responded to other treatment.

RyanSTAR*D stands for Sequenced Treatment Alternatives to Relieve Depression. It was funded by the National Institute of Mental Health, and in 2006 NIMH called it the largest and longest study ever conducted to evaluate depression treatment.

SoheeIts goal was to assess the effectiveness of depression treatments in people with major depressive disorder, in both primary care and specialty care settings.

RyanAnd the sample was deliberately real-world. Over seven years, it enrolled 4,041 outpatients, ages 18 to 75, at 41 clinical sites. No media ads. People were referred by their own doctors, and most adults with depression were eligible.

SoheeThe design is what makes it memorable. Four levels. If you didn't become symptom-free at one level, you could move to the next.

RyanLevel one: everyone got citalopram, a selective serotonin reuptake inhibitor, or SSRI, for 12 to 14 weeks. NIMH said it was chosen partly because it generally isn't associated with troublesome withdrawal symptoms, it's taken once a day, and it's been shown safe for older adults and medically fragile patients.

SoheeLevel two offered two strategies. Switch, to sertraline, bupropion or venlafaxine. Or add on, with bupropion or buspirone added to the citalopram. Cognitive psychotherapy was also available as a switch or add-on.

RyanLevel three: switch to mirtazapine or the tricyclic nortriptyline, or add lithium or the thyroid hormone T3. And level four, for the most treatment-resistant: the monoamine oxidase inhibitor tranylcypromine, or venlafaxine combined with mirtazapine.

SoheeOne more design feature worth knowing. Participants could choose the strategies that were acceptable to them, and they were randomized only within those. NIMH said that reflected real clinical practice.

RyanAnd they used measurement-based care. Symptoms and side effects were measured consistently at every visit, with a manual guiding dose adjustments.

SoheeNow an exam vocabulary point. NIMH noted that most depression trials measured response, which means symptoms dropped to at least half of where they started. STAR*D used remission, meaning becoming symptom-free.

RyanWhy? NIMH explained that people who reach remission generally function better socially and at work, and have a better chance of staying well, than people who only respond.

SoheePause and think. A client's depression scores dropped by 60 percent, but she still has several symptoms. Response or remission?

RyanResponse. Her symptoms fell by at least half, but she isn't symptom-free, so she hasn't reached remission. And STAR*D's lesson is that remission matters, because people who reach it are more likely to stay well.

SoheeOkay, results. Level one: about one-third reached remission, and another 10 to 15 percent responded without remitting. It took an average of about six weeks to respond and nearly seven weeks to remit.

RyanLevel two: in the switch group, about 25 percent became symptom-free, and the three switch medications performed about the same. In the add-on group, about one-third did.

SoheeBut careful. NIMH said switching and adding on can't be directly compared, because most people wouldn't agree to be randomized between the two strategies, and the groups differed.

RyanLevel three: 12 to 20 percent in the switch group, about 20 percent with add-on, and T3 had fewer troublesome side effects than lithium. Level four: 7 to 10 percent became symptom-free.

SoheeOverall, NIMH reported that about half became symptom-free after two levels, and almost 70 percent of those who didn't withdraw became symptom-free over all four levels.

RyanWith an important caveat right there in NIMH's summary. Dropout was meaningful and rose with each level: 21 percent after level one, 30 percent after level two, 42 percent after level three.

SoheeAnd the lessons NIMH drew at the time. The odds of beating depression diminish with every additional treatment step. People who reach remission have a better chance of staying well. And people who need more steps are more likely to relapse.

RyanThere's also a later critique worth knowing about. A 2023 reanalysis published in BMJ Open argued that, using the outcome measure and inclusion rules the protocol specified, the cumulative remission rate was 35 percent, roughly half of what had been reported.

SoheeWhich is a good reminder to read even landmark findings with care. For the exam, know the design, the remission focus, and the diminishing odds with each step.

RyanAnd for our tearful client? NIMH's 2006 summary of the trial said people with depression shouldn't give up if their first treatments don't bring full benefit, and that patience is required. Full benefits may not appear until 10 or 12 weeks.

SoheeNow TADS, the Treatment for Adolescents with Depression Study. It enrolled 439 adolescents ages 12 to 17 with major depression, at thirteen sites.

RyanFour groups for the first 12 weeks: fluoxetine alone, cognitive-behavior therapy, or CBT, alone, the combination of fluoxetine and CBT, or placebo with clinical management.

SoheeAt 12 weeks, 71 percent in the combination group were much or very much improved. Fluoxetine alone, 61 percent. CBT alone, 44 percent. Placebo, 35 percent.

RyanAt 18 weeks, combination still led, 85 percent, versus 69 for fluoxetine and 65 for CBT. But at 36 weeks, combination was 86 percent, and fluoxetine and CBT had essentially caught up, at 81 percent each.

SoheeThen the safety finding the exam loves. Suicidal thinking decreased substantially in all active treatment groups. But new suicidal thinking or behavior during treatment occurred in 15 percent of the fluoxetine-alone group, versus 8 percent with combination and 6 percent with CBT alone. There were no suicides in TADS.

RyanSo NIMH's summary of the trial said the results suggest combination treatment is the safest and most effective treatment overall for adolescents with depression.

SoheeFluoxetine, alone or combined, speeds recovery compared with CBT alone. CBT catches up later. And adding CBT appears to lessen the risk of suicidal thinking and behavior in teens given fluoxetine.

RyanPause and think. Which TADS group had the highest rate of new suicidal thinking or behavior during treatment, and which approach does NIMH call safest overall?

SoheeFluoxetine alone had the highest rate, 15 percent. Combination treatment is described as safest and most effective. A tempting wrong answer is that CBT alone was most effective at 12 weeks. It had the lowest suicidal-event rate, but at 12 weeks, it trailed fluoxetine and the combination.

RyanNow, what about depression that hasn't responded to medication or therapy? NIMH describes brain stimulation therapies. Electroconvulsive therapy, ECT, uses an electric current to induce seizure activity in the brain, under anesthesia with a muscle relaxant.

SoheeThe U.S. Food and Drug Administration, the FDA, has cleared ECT for severe depressive episodes in people 13 and older with depression or bipolar disorder. It's usually considered when other treatments haven't worked, or when a rapid response is needed, for example if a person is catatonic, suicidal or malnourished.

RyanAnd it works faster than antidepressants, usually taking effect within the first week. The common side effects include headache, upset stomach, muscle aches, memory loss and confusion.

SoheeThe memory piece has a testable detail. Memory problems are more common with the older bilateral ECT. Unilateral ECT, typically on the right side, has a lower risk of memory loss.

RyanAnd after ECT, follow-up treatment, antidepressants, maintenance ECT or both, is usually needed to sustain the improvement.

SoheeThen repetitive transcranial magnetic stimulation, rTMS. It uses an electromagnet to deliver repeated low-intensity pulses. The FDA cleared the first device in 2008 for depression in people who hadn't responded to at least one antidepressant.

RyanNIMH says strong evidence supports rTMS for reducing depressive symptoms, but it doesn't match the effects of ECT, which is still considered the gold standard for treatment-resistant depression.

SoheeRecap. STAR*D: 4,041 real-world adults, up to four sequenced levels, remission as the goal. About a third remitted at level one, and the odds fell with each added step, while dropout rose. A 2023 reanalysis argued the overall remission rate was lower than reported.

RyanTADS: in adolescents, the results suggested that combining fluoxetine and CBT was safest and most effective overall. Fluoxetine works faster than CBT alone, CBT catches up, and fluoxetine alone had the most suicidal events.

SoheeECT: works faster than antidepressants and is still considered the gold standard for treatment-resistant depression, with less memory loss in unilateral treatment. rTMS: first cleared in 2008, supported by strong evidence, though its effects don't match ECT's.

RyanHere's something STAR*D shows that I think applies to you too. Not succeeding at the first step doesn't mean you won't succeed. People in that study got well at level two, three and four. Persistence was part of the treatment.

SoheeKeep going. Thanks for listening to EPPP Prep.

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