In Mental Health Therapy, Cautious Steps Toward the Pharmacodigital

Xconomy National — 

[Corrected 3/17/15, 7:55 pm. See below.] The phrase “better living through chemistry,” derived from an old DuPont corporate slogan, has accumulated all kinds of ironic and wink-wink connotations over the decades. But there’s a fascinating revival and upgrade underway.

For people with debilitating mental health problems, many researchers, doctors, and businesspeople think the new phrase should be “better living through chemistry and digital technology.” OK, it’s clunky, but it helps describe a range of new digital therapies—delivered via mobile apps, desktop or TV-based games, and even immersive virtual reality—under development for mental health and addiction disorders that thousands of patients have already used.

As I wrote last fall, digital solutions to health problems have a lot of promise—and a lot of hype—but only a few have produced evidence that they improve patients’ outcomes.

In mental health, most digital therapy—and most of the evidence in its favor—has been found in research labs, not in traditional rigorous clinical trials, at least not the kind that new drugs generally have to go through for approval.

“We are taking some things developed in university clinics and test driving them in large HMOs, but we’re still grappling with the problem of when something has enough evidence,” says Farris Tuma of the National Institute of Mental Health’s division of translation research and a specialist in post traumatic stress disorder. “A lot of entrepreneurs don’t like this process, they say it stymies creativity.”

But some developers of experimental digital therapies welcome clinical rigor behind their products. “We’ve seen positive signals in the academic literature. We wouldn’t be here if we didn’t,” says Eddie Martucci, the chief operating officer of Akili Interactive Labs, a Boston startup founded by PureTech that is building video games to treat autism, attention-deficit hyperactivity disorder, depression, and traumatic brain injury. “But at this point we want to take those positive signals to the next level in large controlled clinical studies.”

Those clinical studies, says Martucci, will ultimately point Akili toward the best uses for its video game platform, called Project: Evo. (The startup Sync Project, also founded by PureTech, wants to build a clinical backbone into claims that music is good therapy.)

Claims that apps, games, and other digital products improve brain and mental health will be scrutinized intensely. Online brain-training games, for example, are under fire for making claims without scientific backing, with a long roster of scientists signing an open letter last fall to protest the way the products are promoted.

But for digital therapies aiming to stand alone or to augment pharmaceutical treatments, what will the standards be? Patrick Kennedy, a former U.S. Congressman from Rhode Island and now a mental health advocate, says regulators are lagging behind the facts on the ground. Combat veterans with the “invisible wounds” of PTSD, people with addictions, and others can’t wait for the bureaucracy to set new evaluation standards.

“We need regulatory agencies, the federal government and the Congress to respond to an urgent need,” says Kennedy, who sees a parallel to the 1980s, when activists forced the conservative FDA to allow trials of drug cocktails to treat HIV.

Kennedy, the son of former U.S. Senator Ted Kennedy, knows the regulatory and political system, has battled his own substance abuse and bipolar disorder, and is a cofounder and director of the mental health advocacy group One Mind for Research. “Multimodal therapies,” combining drugs, digital programs, and other services, are “the new end points” that the FDA needs to develop, which is why Kennedy is putting his weight behind Pear Therapeutics, a startup based in Boston and San Francisco. (Kennedy is chair of the advisory board, and another Kennedy, Stephen Kennedy-Smith, is the company’s EVP of corporate development.)

McCann: Drugs + apps.

McCann: Drugs + apps.

Pear’s business plan shows how a company that doesn’t want to wait for regulatory enlightenment has to proceed with drug-software combinations. Pear initially wants to marry academic work on digital therapies with old, generic pharmaceutical warhorses— a selective serotonin reuptake inhibitor for depression, benzodiazepine for anxiety, and zolpidem (a.k.a. Ambien) for sleep disorders, for example—and create new combination products that Pear is calling ‘eFormulations.’

[Correction: This paragraph has been changed to clarify the ownership of the addiction program and the number of trials the addiction program has been through.] CEO Corey McCann says Pear is farthest along with an addiction product and one for combat-related PTSD, where the bodies of evidence for the “drug-software synergy” are most promising. The digital therapy program for addiction, for example, has been through about half a dozen randomized controlled trials across groups of people struggling with various addictions. Pear is licensing the program—known by its acronym TES—from a small business affiliated with Lisa Marsch, director of the Center for Technology and Behavioral Health at Dartmouth College. (Dartmouth has no financial connections to TES.)

“The academics have done the heavy lifting,” says McCann.

“Pear’s model is to push [the addiction therapy program] in an entirely new direction we hadn’t planned to pursue,” says Marsch. “They’re packaging this empirically supported behavioral health tool with medication.”

Marsch: "New directions we hadn't planned."

Marsch: “A new direction we hadn’t planned.”

Some anti-addiction medicines work well, too. Buprenorphine, for abuse of opioids such as heroin or prescription pills, “is very safe and effective,” says Marsch. “It stabilizes the brain chemistry and controls cravings, but using it alone, you don’t learn anything.”

The idea for all of Pear’s products is to put an access code right on the pill bottle or package. A patient would use the code to get software or an app, and the digital therapy would complement the chemical treatment. The digital part of the equation would also allow doctors to follow patient progress and know more quickly when adjustments are needed.

Once Pear proves it can make that model work, it wants to work with pharma companies to pair their new drugs (yes, the pun is intended) with Pear’s customized digital therapies—with the drug companies paying the clinical trial costs.

What will these multimodal therapies look like, and how will they work? For anxiety and panic attacks, the pharmaceutical standard is benzodiazepine. But when an attack comes on, popping a pill doesn’t work right away. In the 30 minutes of waiting, or more, McCann imagines the patient using digital content on a smart phone as “a bridge to the [drug’s] onset,” with deep breathing and meditation exercises that are clinically validated. “These are coping skills derived from cognitive behavioral therapy,” he says.

The app could have a virtual coach—an avatar who guides the patient—and it could measure the patient’s breathing (from blowing into the microphone) and heart rate (through a plug-in monitor or by having the camera measure pulse through a finger). Many of these components, as well as the feedback loops that let doctors track patient progress, will be additions Pear builds itself or licenses from software developers.

A person struggling with addiction might consult his or her phone app in a moment of crisis—out at night with friends, say, and faced with a tempting offer of drugs or alcohol. “It needs to be sufficiently engaging so that consumers want to come back and use the software,” McCann says. (Here’s one small piece of the academic version of the addiction intervention program.)

Just as Pear is building the digital apps upon a body of work, it will move through the regulatory process step by step. The strategy is to first ask FDA for approval for its software under what’s known as the 510(k) pathway, which governs medical devices. (Note that a 510(k) clearance doesn’t require clinical evidence. It’s also cheap to attain, probably less than $1 million, according to Pear’s lead investor Andy Schwab, a managing partner at 5am Ventures.)

Eventually, however, Pear expects its “eFormulations” will be greater than the sum of their parts. Past a certain point, they’ll need permission to make medical claims about the benefits of the combination, through what’s known as a 505(b)(2) approval. That means spending some money on clinical trials, although not necessarily what a company with a brand new drug would spend, because Pear, using generics, can lean partially on studies by previous researchers. (McCann says he’ll be out raising a new round of financing this year.)

The PTSD product will be based on a virtual reality immersion called Bravemind, developed at the University of Southern California’s Institute for Creative Technologies. “Without any combat experience, you might say it’s a low-rent version of Call of Duty,” says Albert “Skip” Rizzo, a psychologist and the institute’s associate director for medical virtual reality. “Someone who was [in Iraq or Afghanistan] but doesn’t have PTSD would probably say, ‘Oh, this is interesting.’ Someone with PTSD would have a more engaged reaction to it. We try to hit enough high notes that when the person goes in there, their jaw drops.”

Rizzo and Weill Cornell Medical College psychologist JoAnn Difede, who has developed virtual-reality PTSD treatments based on the World Trade Center attack, have tested their VR programs in combination with an old antibiotic, D-cycloserine, that has been revived as a cognitive enhancer. The hypothesis is that retraining traumatized people not to fear their memories, or the triggers that cause PTSD—what’s known as “extinction learning”—is more likely to take hold when the D-cycloserine is altering the brain’s chemistry.

Difede and Rizzo are expanding that investigation with a multimillion dollar multisite trial. Pear’s McCann is confident of bringing an “eFormulation” version to the FDA next year.

A scene from Bravemind.

An image from Bravemind.

He hopes the PTSD and addiction products could get 510(k) clearance and be ready for launch by end of 2016, but both he and Schwab, who has invested in Pear alongside undisclosed angel investors and family offices, acknowledge that they’re treading new ground. “We don’t know what the FDA wants yet,” Schwab says.

That uncertainty speaks to the pioneering nature of all digital therapies, whether combined with drugs or not. For example, Akili is planning an autism trial with more than 100 children who will participate in a four-week “regimen” at home. No drugs exist to treat the disorder itself. How do you compare the therapy to a control group? What’s the digital equivalent of a placebo? “No one has done this before,” says Akili COO Eddie Martucci. “It’s kind of crazy.”

It’s not entirely unlike a drug maker trying to evaluate an experimental drug in a disease with still-mysterious biology, as Biogen Idec (NASDAQ: BIIB) R&D chief Doug Williams described to Xconomy earlier this year when talking about a drug meant to reverse the course of multiple sclerosis.

Another question revolves around safety. Biology is complicated; even well-tested drugs can sometimes show pernicious unintended effects years later. What about noninvasive games or apps?

None of the researchers and practitioners I spoke with reported ever seeing any problems. Rizzo says no adverse reactions to VR have been reported.

Kamal Jethwani, who evaluates technology for healthcare delivery at the Center for Connected Health, part of Partners Healthcare in Boston, says he’s followed game-based therapies for autism and hasn’t seen anything to set off an episode or worsen a patient’s condition. However, he did say that getting schizophrenics, who are already paranoid about being tracked and monitored, to comply with app-based regimens, was “a whole can of worms,” and a tiny pilot trial didn’t work.

There’s another paranoia circling around digital apps, that those aiming to replicate face to face therapy, will end up replacing therapists and other mental health professionals.

“We’re not positioning ourselves in any way as competitive with mental health professionals, full stop,” says McCann.

But some digital apps do aim to relieve part of the patient burden. Jethwani says Partners just began a 100-patient study of a tablet-based app that delivers cognitive behavioral therapy, or CBT, to people with moderate to severe depression. “We know that once patients have their meds in place, the CBT is successful.”

Will a digital version be as successful? Partners has 60,000 patients in its system eligible for depression medication, says Jethwani. “Therapists are hammered every day to take more patients on. They know the waiting lists”—four or five months is common in Boston—“and they’re eager to get this going.”

They’ll still need to evaluate patients, prescribe the digital CBT, and follow up, and they’ll still handle “the most complicated patients” who won’t benefit from the app. But if it works, “they won’t as much spend time on people who can watch videos and get better,” he says.

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One response to “In Mental Health Therapy, Cautious Steps Toward the Pharmacodigital”

  1. rob says:

    Whenever I see the phrase, as on page 2 of the article….with drug companies paying the cost of clinical trials….I immediately doubt the veracity of the study outcomes. There is inherently a conflict of interest.

    Having said that, I do think the idea of digital therapy, or virtual reality therapy sounds fascinating. Any treatment that helps unburden a person dealing with mental illness is worth a try. Thanks for the article.