A drug targeting dopamine receptors might be able to "kick-start" an injured brain, enabling certain kinds of vegetative and minimally conscious patients to recover faster.



Esteban Fridman of the FLENI hospital in Buenos Aires thinks the crux of the problem for such patients lies in their neuron-connecting axons. They are so badly damaged that they have a difficult time carrying chemical signals, or neurotransmitters, from neuron to neuron. Axons get disrupted when they are subject to stresses such as cranial impact—as when a fighter gets hit in the head or a driver smacks into the steering wheel in a car accident.



As a possible treatment for such damage, Fridman has focused on apomorphine, which binds to the brain's dopamine receptors. Dopamine, a neurotransmitter well known for its role in Parkinson's disease, is part of the mechanism controlling arousal and motivated behavior; it also plays a role in consciousness disorders.



Why apomorphine?

Fridman hypothesizes that apomorphine might work by acting in place of dopamine. Flooding the injured brain with the chemical might stimulate it enough to repair the connections, enabling the patients to reach full consciousness. He notes the drug wouldn't work in cases where the brain has been deprived of oxygen or blood, because the damage is more widespread. Terri Schiavo, a Florida woman whose care sparked a nationwide controversy that peaked in 2005, was in a vegetative state caused by that kind of injury.



One reason Fridman chose apomorphine was that it reaches dopamine receptors directly, even if the body's own ability to make the neurotransmitter is damaged. Apomorphine also binds to many types of dopamine receptors. Some other drugs, such as levodopa (L-dopa), are actually precursors—they are converted into dopamine by the body rather than acting directly on the receptors, so if that conversion mechanism were impaired they would be less helpful. Other drugs, such as amantadine, boost cellular production of dopamine, but if those cells are damaged or less active then they can only be boosted so far. Yet others only bind to certain dopamine receptors.



Fridman first tried apomorphine on a patient in 2004. The man had been in a minimally conscious state for 104 days. After he was given the drug the patient's mother called Fridman to tell him her son had awakened after only 24 hours.



Over the next few years, Fridman and a colleague, Ben Zion Krimchansky at the Loewenstein Hospital Rehabilitation Center in Israel tried the drug on a total of eight patients. Seven recovered consciousness. (One subsequently died of an unrelated problem.) One welcome effect, Fridman says, was that patients did not regress even after the treatment was discontinued. Five improved to where they could walk, and one can now drive by himself. Fridman published some of these results in Neurotherapeutics in 2007 as well as one of his single patient observations in Brain Injury in 2009.



But because these clinical observations were not double-blind studies—in which neither the physicians nor the patients know if subjects get a placebo or the drug—Fridman currently is starting a formal clinical study with a total of 76 patients. The apomorphine will be given between one and four months after a traumatic brain injury, and the dosages will be spread over several weeks, given over 12-hour periods. Some patients will get the drug and some will be controls.



The study is being sponsored by Boston-based Neurohealing Pharmaceuticals with initial funding from a U.S. Food and Drug Administration "orphan drug" (a pharmaceutical developed for a rare condition) grant. It is scheduled for completion later this year, although it will more likely be finished in 2011, according to Neurohealing president Daniel Katzman.



Finding what works

Apomorphine fell out of favor as a treatment for Parkinson's because the drug needs to be injected, and that made it less practical for people with tremors. On top of that, it can cause nausea. But Fridman says those problems are less of a concern with vegetative and minimally conscious patients. It is also easier to give them controlled doses over many hours.



Apomorphine isn't the only drug being researched in this way. There are current studies of amantadine, which was originally developed for treating influenza. Fridman chose apomorphine, however, because his initial group of patients did not respond to amantadine, levodopa or other drugs that act on the dopamine system.



Ross Zafonte, chairman of the Department of Physical Medicine and Rehabilitation at Harvard, is leading the investigation in the U.S. He says he is cautious but enthusiastic about the prospects of apomorphine. He notes it isn't clear whether the dopamine pathways are the only driver for consciousness or if it is some combination with others. He also wants to find the optimal neurotransmitter pathways to target. But this study will help show what factors lead to faster recovery from vegetative and minimally conscious states, even if it only works in a minority of patients. In addition, even if the treatment only changes the rate of recovery, it still would be a step in the right direction.



Mary McMahon, associate professor of Pediatric Rehabilitation at Cincinnati Children's Hospital Medical Center, has done small-scale work with amantadine, and is not involved with Fridman and Zafonte's work. She says their trial is important to establish what drug therapies may be effective as well as to find out how much of the effect is caused by the drug and how much is through natural healing.