John March: Clinical trials show the benefit of combination therapy for adolescent depression, ADHD, and anxiety

 John S. March, MD, MPH - Brain and behavior expert on anxiety
John S. March, MD, MPH

One day it will be possible to look back and say: “The era of trial-and-error treatment of mental illness is a thing of the past.” That day has not yet arrived, but the current state of research suggests it is not far distant. When it does come, society will owe a debt to scientists like John March, M.D., M.P.H., a NARSAD Distinguished Investigator.

From his earliest years, March says he had the ambition of “helping to make the world a better place by doing medical research.” He has done that, under a spotlight that at times has cast a blinding light. March’s life’s work, which seeks to determine how best to treat young people with a range of serious mental illnesses, has intersected with and made a major impact upon several very public controversies. One has been about the question of suicide risk for young people taking a class of antidepressants called SSRIs (selective serotonin reuptake inhibitors). Another concerns risks associated with medications for children diagnosed with attention deficit-hyperactivity disorder (ADHD).

“I’ve had the privilege of being part of a group of people who have essentially built the current interventions evidence base over the last 20 years,” March says. “Before that, we really didn’t have very much evidence.” That seems an incredible statement, but it is true. The work of March and others is of “breakthrough” impact because it has forged solid links between the clinical care of children who are ill and the collection and interpretation of objective data assessing the effectiveness of that care.

Many of the tangible benefits deriving from March’s work are the product of large-scale, multi- year randomized clinical trials he has either led or contributed to as a co-principal investigator. Those studies — MTA (Multimodal Treatment of ADHD), POTS (Pediatric OCD Treatment Study), CAMS (Child/Adolescent Anxiety Multimodal Study), and TADS (Treatment for Adolescents with Depression Study) — to name only a few, constitute a body of hard evidence showing the impact of different treatments and treatment combinations upon young people with, respectively, ADHD, obsessive-compulsive disorder (OCD), anxiety, and adolescent depression.

MTA was the first large “multimodal” trial March took part in. It measured different ways of treating 579 hyperactive children, aged 7 to 10. Some received only drug therapy; another group received only intensive behavioral therapy; a third group received both; a fourth received community-based outpatient treatment. Results were measured after 14 and 24 months. Two findings were especially significant, particularly in view of then-growing debates over the appropriateness of medicating young children. “The MTA showed that you needed drug therapy — a stimulant — to normalize ADHD symptoms; and that you needed to do it three times a day, 365 days a year,” March says. The trial pointed to the utility of a long-acting stimulant, and this spurred development of drugs like Adderall XR ® , which remain bioactive for an extended period.

MTA also showed that children with ADHD and other problems, such as anxiety or parent- child conflict, did better with the combination of a psychostimulant and behavioral therapy (BT) whereas those with uncomplicated ADHD did just as well on medication alone — which was superior to BT in these children. Take home message: combined treatment in psychiatry, like other areas of medicine, is generally the best treatment for most children, but the picture varies with condition and patient.

The clinical value of cognitive behavioral therapy (CBT) has particularly impressed March over the many years that he has developed protocols for its use. In the POTS study, in which CBT adapted for OCD was compared with and offered in conjunction with the antidepressant sertraline (Zoloft), its unique worth came to the fore. “Unlike ADHD and depression, where meds are needed, acutely, whether alongside CBT or alone, we showed that with OCD you don’t need meds, only CBT — it’s the psychological intervention that proves most powerful.”

In OCD and anxiety disorders like post-traumatic stress disorder (PTSD), the main principle in CBT is exposure — you move into a situation you would otherwise avoid, and learn gradually to overcome the anxiety. But exposure is not relevant for those who suffer major depression. CBT for depression involves mood monitoring, cognitive restructuring, pleasant activities, stress management and other components. Yet while CBT must be adapted for each illness, it helps in all of those March treats. “The glory of CBT,” he says, “is that it’s just like physical therapy for mental health. CBT is not nearly as available in the U.S. as it needs to be. But when done properly it can help even with schizophrenia and autism.”

As a principal investigator of the TADS trial, which examined multimodal treatment for depressed adolescents, March was close to the database of evidence that helped influence the Food and Drug Administration in its decision to post a “black-box warning” on SSRI drugs. As March recently has written, “suicidal events seem more common in patients receiving an antidepressant for depression than for anxiety disorders or OCD.” But, he adds, “ medication-associated suicidal events may be eliminated or reduced substantially by combining the antidepressant with CBT. ” The FDA’s warning and attendant public controversy had the unfortunate effect of causing a 25 percent reduction in prescriptions and a commensurate 25 percent increase in completed teen suicides. “Withholding medication is clearly not the answer,” March declares.

His current NARSAD grant anticipates breakthroughs of the future. Advances in neuroscience and genetics point to a time when treatment will be matched to the individual patient. Genetics, genomics and related technologies make possible the matching of individual biological signatures with illnesses; these variants are called biomarkers. “And if you assemble a set of biomarkers, you have a biosignature,” March explains. “In breast cancer, your biosignature determines which treatment you get, and if you’re at the point where your tumor becomes refractory, the molecular signature of the tumor at that time becomes the determinant. We aren’t at this point in psychiatry, but that is where the science is taking us.”

He adds: “We are just now beginning to develop intervention-related biomarkers and biosignatures that we can use at baseline to tell us who should get a treatment and who shouldn’t. Today’s neuroscience medicine is so beautiful and so promising!”