Wednesday, May 05, 2010

Dr. John H. Krystal - Neuroplasticity and Experimental Treatment Paradigms

File:Brain 2.jpg
Neuroplasticity challenges the idea that brain
functions are fixed in certain locations.

Dr. John H. Krystal stands to make a huge chunk of change should ketamine's potential as a treatment for depression be confirmed (he's named as an "inventor" for its use in treating depression). Still, this is an interesting article that looks at other issues around neuroplasticity and creating new treatments for common disorders.

From Psychiatry Weekly.

Neuroplasticity and Experimental Treatment Paradigms

April 19, 2010

John H. Krystal, MD

Robert L. McNeil, Jr. Professor of Translational Research; Chair, Department of Psychiatry, Yale University School of Medicine; Chief of Psychiatry, Yale-New Haven Hospital; Director, Clinical Neuroscience Division, VA National Center for PTSD

First published in Psychiatry Weekly, Volume 5, Issue 10, on April 19, 2010.

This interview was conducted on March 23, 2010 by Lonnie Stoltzfoos


Advances in our understanding of the brain’s ability to adapt and evolve are creating new avenues for research into the treatment of psychiatric disorders. Broadly conceptualized and broadly defined as neuroplasticity, it is “really any way that the brain adapts to input and changes with development,” according to Dr. John H. Krystal. “Neuroplasticity is a very important idea, because it is central to our understanding of the neurobiology and treatment of psychiatric disorders. It is through neuroplasticity that psychiatric disorders develop, and it is through neuroplasticity that we can treat them.”

Anxiety Disorders

While many treatments aim to suppress symptoms, it is suggested that neuroplasticity may be targeted as a strategy for enhancing the treatment of anxiety disorders.

“Behavioral therapies promote the extinction of fearful responses to a variety of environmental stimuli,” explains Dr. Krystal. “But some people do not benefit as completely or as rapidly from these treatments as one might hope. This is where D-cycloserine might play a role. Extinction is a type of learning that depends on the stimulation of the NMDA glutamate receptor. D-cycloserine enhances the function of the NMDA receptor. A group at Emory University showed that by administering D-cycloserine prior to extinction learning, they could increase the rapidity of the extinction of fearful responses, in this case reducing the fear of heights in their research subjects. In this study and subsequent research, D-cycloserine administered during extinction also reduced the recurrence of the fearful responses following the exinction sessions.

“D-cycloserine has hardly any effect on the symptoms of anxiety disorders, such as simple phobia, panic disorder, or OCD, but, by stimulating NMDA glutamate function, it appears to enhance the capacity of patients to learn new associations to stimuli that were previously anxiogenic—in other words, to extinguish fear,” continues Dr. Krystal. “In other words, the medication alone is not effective for treating symptoms. But combining proven behavioral therapies with a drug that increases neuroplasticity may increase the rapidity of treatment, perhaps reducing the number of sessions needed to produce clinical effect.”

Cognitive Deficits

By building a focus on neuroplasticity into the treatment of cognitive impairments associated with schizophrenia, new treatment approaches are emerging.

“Clinicians interested in treating cognitive deficits in schizophrenia have long been interested in stimulating the dopamine 1 receptor, but there is concern that dopamine agonists might cause tolerance that would reduce their efficacy in the long run,” says Dr. Krystal. “Drs. Stacy Castner and her mentor, Dr. Patricia Goldman-Rakic, administered very low doses of D1 receptor agonist, ABT-431, to non-human primates. The doses were so low that they produced minimal effects with acute administration. As a result, some would say that these initial doses were essentially homeopathic. Dr. Castner and her colleagues persisted, however, in administering these very low doses of the D1 receptor agonist on an intermittent basis for several months before something very interesting occurred: the monkeys began to show improved cognitive function when the drug was administered, and the improvements lasted increasingly longer periods of time. Instead of becoming tolerant to the D1 receptor agonist, they showed that one could produce a lasting benefit by sensitizing the monkeys to the effects of this drug.

“This approach is conceptually elegant,” noted Dr. Krystal. “Sensitization to dopamine effects is most often thought of as a problem contributing to psychosis in schizophrenia. Yet, in this case, sensitization to the effects D1 receptor agonists may constitute a useful approach for treating cognitive deficits associated with schizophrenia.”


All current antidepressant medications require several weeks of treatment to produce clinical benefit. This delay in the onset of clinical efficacy contributes to the need for hospitalization for patients dealing with severe depression symptoms. Because all current antidepressant medications work via manipulations of monoamine systems, there have not been, until now, any medications to challenge the assumption that several weeks of antidepressant treatment are needed to produce clinical benefit.

“As we’ve begun to understand the effects of antidepressants on neurocircuitry, and the neurobiology of depression, we are drawn to focus on new aspects of the biology of depression,” says Dr. Krystal. “Our group at Yale focused on the glutamate system. We found that a single dose of the NMDA glutamate receptor antagonist, ketamine, alleviated depression in many patients within hours, with clinical benefit lingering for up to a week or more. Several groups have now replicated this finding, showing that ketamine effects can be extended with repeated dosing, that suicidal ideation is among the symptoms to rapidly improve, and that other NMDA receptor antagonists also produce this effect.

“The idea of an antidepressant that would work in many people within a few hours is very attractive,” continues Dr. Krystal. “A drug that rapidly reduces severe depression symptoms might be useful in alleviating suffering and mitigating hospitalization. This is the dream that we have for this type of research, but the extent to which ketamine or other NMDA receptor antagonists will be able to realize this dream remains to be seen.”


“In each of the examples that we discussed, a focus on neuroplasticity challenged some common assumptions and drew our focus to a new perspective on the development and treatment of psychiatric disorders,” concludes Dr. Krystal. “In some cases, a focus on neuroplasticity increased the rapidity of effective treatment, and, in others, this focus drew attention to approaches that might produce enduring benefits. It is an exciting time for psychiatry as we discover that many of our preconceptions grow from our own limited knowledge base. Advances in this neuroscience foundation will undoubtedly lead to more new types of treatments.”

Disclosure: Dr. Krystal has served as consultant to Aisling Capital, AstraZeneca, Brintnall & Nicolini, Forest Laboratories, GlaxoSmithKline, Janssen, Merz, Pfizer, F. Hoffman-La Roche, SK Holdings Co., and Teva; has served on the advisory board of Abbott, Bristol-Myers Squibb, Eli Lilly, Lohocla Research Corporation, Takeda, and Transcept. Dr. Krystal has been named as an inventor on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the FDA for this indication, Dr. Krystal could benefit financially.

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