CATIE, STEP-BD and MTA: what big trials taught us

Transcript

SoheeA mother is sitting in your office. Her son has schizophrenia, and she's been reading online. She asks: shouldn't he be on the newest antipsychotic? Newer has to be better, right?

RyanAnd it's such a reasonable assumption. It's also one a major trial put to the test.

SoheeWelcome to EPPP Prep, the podcast. I'm Sohee.

RyanI'm Ryan. Last time, depression trials. Today, three more landmark trials from the National Institute of Mental Health, NIMH: CATIE for schizophrenia, STEP-BD for bipolar disorder, and MTA for attention-deficit/hyperactivity disorder, ADHD. And we'll close with what all of them suggest about combining treatments.

SoheeCATIE stands for Clinical Antipsychotic Trials of Intervention Effectiveness. It compared older antipsychotics, first available in the 1950s, with newer ones available since the 1990s. At the time, in 2005, NIMH noted the newer atypicals cost roughly ten times as much.

RyanIt enrolled 1,460 people with chronic schizophrenia at 57 sites in 24 states, and followed them for 18 months. NIMH called it the largest, longest and most comprehensive independent trial of existing therapies for the disease.

SoheeThe design: double-blind and randomized. People were assigned to one of four atypicals, olanzapine, quetiapine, risperidone or ziprasidone, or to the older drug perphenazine.

RyanWhy perphenazine and not haloperidol, the classic older drug? Because haloperidol causes high rates of movement side effects, called extrapyramidal side effects. Perphenazine is an effective older drug that's less likely to cause them.

SoheeNow the outcome measure, which is a classic exam detail. Success was measured by how long a patient stayed on a medication before they or their doctor decided it had to be changed. Because for schizophrenia, staying on medication is critical to controlling symptoms and preventing relapse.

RyanAnd the results. Overall, the medications were comparably effective, but all had high rates of discontinuation, due to intolerable side effects or symptoms not being controlled. Almost three-quarters of patients switched from their first medication.

SoheeOlanzapine did slightly better. People on it were less likely to be hospitalized for a psychotic relapse and tended to stay on it longer. But it came with substantially more weight gain and metabolic changes linked to diabetes risk.

RyanAnd the surprise: the older, cheaper perphenazine generally performed as well as the other three newer drugs, and was as well tolerated. Movement side effects weren't seen more often with perphenazine than with the newer drugs.

SoheeNIMH's summary: taken as a whole, the newer medications had no substantial advantage over the older one used in the study. With individual differences in response still an important issue.

RyanSo for the mother in your office, CATIE's answer was that newer isn't automatically better. NIMH said patients and doctors must weigh the trade-offs among effectiveness, side effects and cost.

SoheePause and think. In CATIE, which drug had the edge on staying on treatment and avoiding hospitalization, and what was its cost?

RyanOlanzapine. Its cost was substantially more weight gain and metabolic changes. And the tempting wrong answer is that the newer drugs clearly outperformed the older one. They didn't. Perphenazine held its own.

SoheeOn to STEP-BD, the Systematic Treatment Enhancement Program for Bipolar Disorder. NIMH called it the largest federally funded treatment trial ever conducted for bipolar disorder. Two pieces matter for us.

RyanFirst, the acute depression medication trial. The question: when someone with bipolar disorder is depressed, does adding an antidepressant to a mood stabilizer help more than the mood stabilizer alone? And does it trigger a switch into mania?

Sohee366 people, all on an adequate dose of a mood stabilizer, were randomized to add either an antidepressant, paroxetine or bupropion, or a placebo, for up to 26 weeks.

RyanThe outcome was durable recovery: at least eight consecutive weeks with no more than two depressive or two manic symptoms.

SoheeResults: 24 percent durable recovery with the antidepressant, 27 percent with placebo. So adding the antidepressant didn't improve recovery beyond the mood stabilizer. And it also didn't increase the risk of switching to mania or hypomania.

RyanNIMH's 2007 summary of the trial concluded that properly administered mood-stabilizing medication is an acceptable first-line treatment for outpatients with bipolar depression.

SoheeSecond, the psychosocial trial. 293 people with bipolar depression, all on medication, were randomized to either a brief collaborative care intervention, three sessions over six weeks, or one of three intensive therapies with up to 30 sessions over nine months.

RyanThose intensive therapies were cognitive-behavioral therapy, interpersonal and social rhythm therapy, and family-focused treatment.

SoheeQuick sketch of the less familiar two. Interpersonal and social rhythm therapy focuses on regular daily routines and sleep-wake cycles, and on interpersonal problems. Family-focused treatment teaches relatives about the illness and how to recognize early warning signs of an episode.

RyanResults: 64 percent recovered with intensive therapy versus 52 percent with collaborative care. Those in intensive therapy recovered faster, about 113 days versus 146, and were one and a half times more likely to be well in any given month.

SoheeFamily-focused treatment had the highest recovery rate, 77 percent, versus 65 for social rhythm therapy and 60 for CBT. But those differences weren't statistically significant. The three intensive therapies had comparable benefits.

RyanPause and think. Based on STEP-BD, a client with bipolar depression asks whether adding an antidepressant to her mood stabilizer will speed recovery. What does the trial suggest?

SoheeThe antidepressants tested, paroxetine and bupropion, didn't improve durable recovery beyond a mood stabilizer plus placebo. What did help, alongside medication, was intensive psychotherapy. That's a 2007 trial result, not a prescription, and her actual plan belongs to her and her prescriber.

RyanFinally, the MTA, the Multimodal Treatment of Attention Deficit Hyperactivity Disorder study. Nearly 600 children, ages 7 to 9, randomized to one of four groups for 14 months.

SoheeIntensive medication management alone. Intensive behavioral treatment alone. A combination of both. Or routine community care as the control group.

RyanThe main findings, published in 1999. Combination treatment and medication management alone were both significantly better than behavioral treatment alone and community care at reducing ADHD symptoms.

SoheeBut in other areas, anxiety symptoms, academic performance, parent-child relations and social skills, combination was consistently superior to community care, while medication alone or behavioral treatment alone were not.

RyanAnd here's a detail that's easy to miss. Children in the combination group ended up on lower doses of medication than those on medication alone.

SoheeAnother favorite. Why did the MTA's medication arm beat community care, when most community kids were also on medication? NIMH points to quality and intensity. Careful dose-finding in the first month, monthly visits, monthly consultation with teachers, and generally higher doses.

RyanVersus community doctors who typically saw the children face-to-face only once or twice a year.

SoheeOn safety, 4 percent of children on medication had side effects severe enough to stop, including loss of appetite, sleep problems, crying spells and repetitive movements. And medication slowed physical growth during the 14 months.

RyanAnd a limitation. Treatment was controlled only for 14 months. After that, children went back to community care, so the study can't tell us about the effectiveness of these treatments beyond 14 months.

SoheePause and think. In the MTA, was combination treatment better than medication alone for core ADHD symptoms?

RyanNot significantly. Both beat behavioral treatment and community care on core symptoms. Combination's advantages showed up in broader functioning, compared with community care, and at lower medication doses. The tempting wrong answer is that combination was clearly best on core symptoms.

SoheeNow let's zoom out to general treatment guidelines. The OpenStax psychology textbook says research suggests psychotropic medications are most effective when combined with psychotherapy, especially for the most common disorders, depression and anxiety.

RyanFor substance use, the textbook says treatment usually includes behavioral therapy and may include medication. And when someone has a substance-related disorder plus another psychiatric diagnosis, the best treatment addresses both problems at the same time.

SoheeSAMHSA, the Substance Abuse and Mental Health Services Administration, calls medication combined with counseling and behavioral therapies a whole-patient approach, and says research shows that combination can successfully treat substance use disorders.

RyanAnd the frame that ties it together is evidence-based practice. The textbook quotes the American Psychological Association's definition: the integration of the best available research with clinical expertise in the context of patient characteristics, culture and preferences.

SoheeRecap. CATIE: older perphenazine performed about as well as most newer antipsychotics. Olanzapine lasted longest but caused the most weight gain. Discontinuation was high across the board.

RyanSTEP-BD: adding paroxetine or bupropion to a mood stabilizer didn't improve recovery from bipolar depression, and didn't increase switching. Intensive psychotherapy alongside medication did improve recovery.

SoheeMTA: medication management and combination beat behavioral treatment and community care on core symptoms. Combination helped broader functioning at lower doses. NIMH credits the study's careful, frequent monitoring.

RyanAnd across the board, combined treatment and evidence-based practice. Notice how often the best answer in these trials wasn't a single magic bullet. It was careful, persistent, combined care.

SoheeWhich is not a bad model for exam prep, either. Steady, varied, and patient with yourself. Thanks for listening to EPPP Prep.

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