National Alliance on Mental Illness
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Examining brain disease in a new light

By Peggy Thompson

“There is ample reason to believe that with this concerted effort—and the partnership of industry, academic, and government scientists, as well as our patients and their families—we will make significant breakthroughs.”

Understanding psychiatric disorders at the molecular and cellular level is what will ultimately lead scientists to target the underlying causes of the diseases, rather than focusing solely on treating symptoms.

That is the belief of Husseini K. Manji, MD, GlobalTherapeutic Head of Neuroscience for Johnson & Johnson Pharmaceutical Research and Development and the former director of the largest mood and anxiety disorders program in the world.

Manji, who previously held the position of chief in the Laboratory of Molecular Pathophysiology and Experimental Therapeutics at the National Institute of Mental Health (NIMH) and was director of NIMH’s Mood and Anxiety Disorders Program, says that although much progress has been made in terms of understanding mental illness, there is plenty more that remains to be done.

Fortunately, he sees 2010 as a year that will bring much promise for those living with a mental illness.

“There is really good reason to be optimistic,” he says. “The magazine Nature, in its first issue of 2010, had an editorial declaring this as ‘A Decade for Psychiatric Disorders.’ Lots of excellent researchers are taking this effort seriously and doing very good work. Breakthroughs in our understanding of the causes of these diseases are occurring daily. There is ample reason to believe that with this concerted effort—and the partnership of industry, academic, and government scientists, as well as our patients and their families—we will make significant breakthroughs.”

Manji’s scientific background is both varied and impressive; he received his BS (biochemistry) and MD from the University of British Columbia and, following residency training, he completed fellowship training at NIMH and obtained extensive additional training in cellular and molecular biology at the National Institute of Diabetes, Digestive and Kidney Diseases.

The major focus of his research has been the investigation of disease- and treatment-induced changes in gene and protein networks that regulate synaptic and neural plasticity in neuropsychiatric disorders. His research has earned him recognition numerous times over, including the NIMH Director’s Career Award for Significant Scientific Achievement, the A.E. Bennett Award for Neuropsychiatric Research, the Ziskind-Somerfeld Award for Neuropsychiatric Research, and the Brown University School of Medicine Distinguished Researcher Award. In 2008, he was inducted into the National Academy of Sciences’ Institute of Medicine. Working through discovery, he came in on the ground floor and continues to work diligently to unearth the origins of psychiatric disorders.

“During medical school, I was always interested in how the mind and brain work, particularly at the molecular and cellular level, but I wasn’t aware that psychiatry was heading in that direction,” he recalls. “During an oral exam, some of my examiners told me that psychiatry was really heading towards trying to understand things at the molecular and cellular level. They captured my interest and that was what got me hooked into choosing psychiatry.”

He says he has always been fascinated by psychiatric disorders—“especially bipolar disorder; a big part of that is recognizing how devastating an illness it is. From a scientific standpoint, it fascinated me that this one illness could present with a clinical picture that was so different in the same person. Few illnesses present so dramatically differently.”

And there it was in front of him: The core problem with bipolar disorder, indeed, with all psychiatric disorders.

“It can’t be just too much of a single neurotransmitter; it must be something much more fundamental inside the cell that is involved in regulating multiple neurotransmitters, and that’s why you see these dramatic differences in presentation,” Manji says. “The study of bipolar disorder is really what got me hooked on this sense of wanting to make a difference and developing new treatments.”

The time is right
Manji is adamant that now “is the right time” to be working in the area of psychiatric discovery, simply because the world is now at a place—technologically—where significant advancements are possible. “Many of the things that we are doing are things that others before us wanted to do, but the technological advances were not there.”

He says it’s become apparent that almost every field of medicine is looking at the same pathways inside the cell, whether to learn about the pancreas (to understand diabetes), the breast (to understand breast cancer), or the brain. “We quickly trade information, so we can make use of the advances others make. The recognition that these are all illnesses that originate with problems at the cellular level means that advances from one field of medicine can really—and quickly—lead to advances and breakthroughs in ours as well.”

Manji has a long-standing passion about neuroscience disorders, which are among the most destructive, chronic, and progressively disabling illnesses afflicting humanity. Despite this devastation, neuroscience research has been limited compared to other disease areas because the brain is so complex and challenging. Yet these diseases take a significant toll on society.

“For example, in the United States, it costs about $100 billion a year to treat serious mental illness, in addition to $200 billion lost in productivity and other indirect costs.” Manji says. “My desire is to understand the workings of the brain and mind, not just as an academic pursuit, but in order to provide our patients with more reliable and successful treatments. Finding effective treatments would move us on the path toward destigmatization, specifically because it would become increasingly apparent that these devastating disorders are medical in nature rather than part of an individual’s personality.”

Common, yet misunderstood
Disorders of the central nervous system—loosely known as neuropsychiatric and neurodegenerative disorders— continue to be among mankind’s most devastating illnesses.

Worldwide, they cause enormous suffering for those affected, impeding the ability of children to grow and learn, of adults to work and live productively, and of the elderly to age with dignity. These disorders are fairly common worldwide and are characterized by many facets that make them particularly challenging to treat, including early onset (for example, autism in childhood or schizophrenia in young adulthood), a relapsing-remitting course (as with mood and anxiety disorders and obsessive compulsive disorder), and often disabling symptoms. These disorders affect individuals at every stage of development and include Parkinson’s disease, Alzheimer’s disease, schizophrenia, mood disorders, addiction and autism. These illnesses exert a disproportionate burden on public health; their major impact is the disability they create.

Manji, who has dedicated his career to understanding psychiatric diseases, says part of the problem in developing effective treatment lies in the ongoing difficulties associated with truly understanding the central nervous system.

The complicated processes underlying human cognition and behavior are still poorly understood, in part because these diseases are so substantially complex. Further complicating the treatment of these diseases is the lack of full understanding of their many various causes, as well as difficulties in understanding the exact way in which existing therapies work.

With regard to bipolar disorder in particular, the fact that the clinical picture can be so different in one person has made researchers think that bipolar disorder cannot be as simplistic as “too much of one chemical or too little of another,” Manji says. “It has got to be more complex than that. A lot of the previous research had looked at specific chemicals, like serotonin, norepinephrine, and dopamine. Now investigators are looking at the machinery that regulates neural and synaptic plasticity.”

Neural plasticity refers to the processes that affect the ability of a nerve cell to perceive, respond, and adapt to various environmental stimuli. Synaptic plasticity refers to the processes by which the strength of information flow between synapses [the connections between nerve cells] is regulated. “For example, readers may remember some aspects of this article after several weeks or months,” says Manji. “Somehow this information has been stored long term—and perhaps permanently. We strongly believe that changes in neural and synaptic plasticity underlie the brain’s—and therefore the individual’s—ability to learn and remember. But we think that the very same mechanisms are involved in regulating changes in mood, drive, psychosis, energy, etc.”

Changing directions
Placing an emphasis on trying to understand diseases at the molecular and cellular level allows scientists to target the underlying root of disease. Equipped with that understanding, researchers can then start to think about prevention and modifying disease progression. “Alzheimer’s disease is a great example,” Manji says. “By the time someone is diagnosed with Alzheimer’s, it’s possible the disease has been brewing for many years. What if we could identify the disease much earlier, intervene, prevent things from happening in the brain, and enhance wellness? Studies are currently underway involving the removal of amyloid from the brain in Alzheimer’s disease.” Amyloid is suspected to play an important role in the pathology of Alzheimer’s disease; therefore, enhancing its clearance may provide a new treatment approach for Alzheimer’s disease.

This modification lends itself to the debate over how plastic—or capable of change—the brain is, and how different functions are related to brain structures.

“In its early days, the neuroscientific community strongly believed that the modularity of the brain was established during childhood, and that little, if any, structural brain change could occur later (all the later changes were chemical),” Manji says. “We now know that this isn’t the case and [that] changes in neural and synaptic plasticity underlie most aspects of brain function and very likely play a critical role in our major psychiatric illnesses.”

Manji points out that research in the area of neuroplasticity has really taken off in the past decade. “In the search to clarify the biological underpinnings of mood disorders, the new focus on brain plasticity is a major departure from the study of absolute changes in neurochemicals such as monoamines and neuropeptides, which was the prime focus of research in the field for the past 40 years.”

“My desire is to understand the workings of the brain and mind,
 not just as an academic pursuit, but in order to provide our patients with more reliable and successful treatments.”

Studies conducted in the past 10 years have “illuminated” the normal functioning of nerve-cell signalling pathways that allow the brain to adapt to its ever-changing environment, he says. “They also highlight negative consequences for overall health of breakdowns in this process.”

New treatments
This new direction in research results from an “accumulating body of data,” Manji says. “A major impetus was the real appreciation that our treatments (for example antidepressants) alter neurotransmitter levels within hours, and yet it takes much longer for patients to get well (often weeks). This suggested that the changes in the neurotransmitters were just an initiating event that brought about a series of changes in synaptic and neural plasticity, and it was these changes that were perhaps more responsible for the clinical benefits.”

This discovery led researchers to question whether these changes in synaptic plasticity could be targeted more directly—that is, not going through serotonin, norepinephrine, etc.—thereby paving the way for new treatments that work faster and better because they would be bypassing many steps at which different patients might have an impairment.

“The possibility of coming up with novel treatments that target synaptic and neural plasticity processes has been exciting for the field,” Manji says.

Advances in the understanding of the mechanisms underlying neural plasticity is indeed being explored in humans, he adds. “For example, based on its ability to regulate information flow in specific synapses, a drug used for many years as an anesthetic was tried in treatment resistant depression. Although the sample sizes are small, in these studies an antidepressant effect was seen within hours in a highly treatment-resistant population. These results were remarkable, and there is therefore considerable interest in developing new treatments that might work in a similar manner, but not have many of [the] side effects. There are similar novel treatments being tried in schizophrenia.”

He says researchers need to constantly look at innovative ways of discovering and developing medicines so that consumers can benefit from novel approaches t treatment. Of course, one of the major objectives is to be able to treat brain disorders much more rapidly.

The evolving knowledge of neuroplasticity is revolutionizing science’s understanding of what causes brain diseases and creates the possibility of new medications and behavioral therapies, Manji says. The key to such work, however, is a global scientific approach that draws from all of the new medical technologies currently being created and explored.

“We can work with biomarkers, integrative informatics, genetics, and brain imaging. Collaborations between researchers at many different types of institutions and all over the world are key. With complex neuroscience disorders, we cannot work in isolation. Collaborations and partnerships must play a crucial role in arriving at breakthroughs. We consider the world to be our laboratory.”

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