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Interview with Dr. Javitt on Glycine and Schizophrenia Research
Dr. Dan Javitt, M.D. PhD, is a leading researcher in the field of schizophrenia today. He is the head of the Program in Cognitive Neuroscience and Schizophrenia at Nathan Kline Institute for Psychiatric Research in New York. His current research interests include Schizophrenia, Cognitive dysfunction, Event-related potentials, Psychophysiology, PCP/NMDA receptors. As someone who is conducting clinical trials concerning the effectiveness of glycine or glycine-like substances as a possible supplementary treatment for schizophrenia, Dr. Javitt kindly agreed to share some words about his research and the future of glycine treatments in an interview with Schizophrenia.com.
Dr. Javitt has significant financial interests in Medifoods and Glytech, two companies attempting to develop glycine and D-serine as treatments for schizophrenia.
Editor's note: Click on hyperlinked text throughout the interview to see a definition of the term or more information on the subject
Concerning Dr. Javitt's research background, and his interest in glycine:
SZ.com: Where and when did you get your start in schizophrenia research?
Javitt: As far as I remember, I have been interested in how people think. I started high school right around the time the first computers became widely available for research. Back then, artificial intelligence was all the rage. People were sure that it would only be a short time until computers could be programmed to think like people. By the time I was in college I realized that artificial intelligence was not going anywhere fast, but I became more and more interested in natural intelligence and in the ways thought processes can break down. In college, I switched from bioengineering to straight biology and ultimately applied to medical school. I think I made the right decision in studying natural, rather than artificial, intelligence. To date, the best artificial intelligence has been able to come up with is a vacuum cleaner that drives itself around your living room. Meanwhile, we are making tremendous progress in understanding the brain changes associated with mental disorders such as schizophrenia.
SZ.com: What made you decide to focus your schizophrenia research on NMDA-receptors, and then on glycine modulatory sites as a therapeutic target?
Javitt: The focus on NMDA receptors was a fortuitous choice. In 1983, when I was a first year resident, the number one drug of abuse in the country was phencyclidine, also known as "angel dust" or PCP. People who took PCP were known to develop symptoms that closely resembled schizophrenia, but which (fortunately) resolved over time. (Most of the time PCP was not taken intentionally, but was used by drug dealers to boost the effects of other drugs such as marijuana). One of the main researchers at Albert Einstein, where I did my residency, Stephen Zukin, was working on trying to understand how PCP worked in the brain. He had discovered a receptor called the PCP receptor and was trying to figure out how it worked in the brain. At that time, NMDA receptors had not been discovered. Most people assumed that the effects of PCP had something to do with dopamine. I was fortunate that NMDA receptors were discovered while I was doing my research studies in Dr. Zukin's laboratory. We were one of the first groups to demonstrate that PCP receptors were, in fact, simply one part of the larger NMDA receptor complex, and that PCP produces its behavioral effects by blocking NMDA receptors. Later we demonstrated that glycine reverses the behavioral effects of PCP in rodents, leading us to believe that it might be an effective treatment for schizophrenia.
SZ.com: What kind of research are you involved in today (concerning schizophrenia, glycine treatment, or otherwise)?
Javitt: I am fortunate now to be heading a research group of about 30 individuals at the Nathan Kline Institute for Psychiatric Research, which is a New York State-supported research institute affiliated academically with the New York University School of Medicine. Most states have gotten out of the research business, and New York State is to be commended for its continuing commitment to research. New York University has also been very supportive of the clinical focus of our research programs. We have an integrated division that includes both basic and clinical laboratories. Our motto is essentially "NMDA is us." In our basic laboratories we investigate how NMDA receptors work, and what novel approaches can be taken to stimulate NMDA function. For example, we have shown that effects of PCP can be reversed not only by glycine, but also by several other types of agents, such as glycine transport inhibitors, that affect glycine levels in brain indirectly.
In our clinical programs, we investigate the exact processes that are disturbed in schizophrenia. For example, there is a major focus in schizophrenia on what is called "executive processing" - essentially the ability to solve problems. It is undeniable that many patients have problems in this area. What we have been able to show, however, is that problems are not limited only to complex types of problem solving. For example, we have shown that patients have problems even in very simple operations, such as the ability to hear differences between two tones that are similar in pitch, or to recognize objects that are partially hidden (e.g, "the cat behind the Venetian blind"). These deficits arise not because patients are not trying, but because the parts of their brains that are supposed to do these operations automatically - in this case the auditory and visual cortices - are not functioning properly. Patients with schizophrenia therefore have to work much harder to detect features of objects that most people would detect automatically. When compensation is made for these "bottom up" deficits, patients ability to solve problems or make other use of the information is markedly improved.
The deficits in sensory processing, like those in executive processing, are probably the result of poor NMDA functioning. NMDA receptors are spread relatively evenly throughout the brain. If there were a deficit in NMDA functioning it would be expected to affect the whole brain, not just specific regions.
Javitt: The main studies with glycine were done either at Albert Einstein, when I was still there, or more recently by Uriel Heresco-Levy, a colleague of mine in Israel. At present, there are not a lot of new studies being started with glycine. The main issue with glycine is that most people find it hard to tolerate. It gets into the brain poorly, so that individuals have to take relatively large dosages - about 2 tablespoons twice a day. Glycine powder has a sacchariny-sweet taste that is OK initially, but that most individuals get tired of over time. It also changes stomach pH (it is also an antacid), which makes some people nauseous. Some people do take it long term and report good results. Others, however, have trouble reaching the doses needed for full effect. The main research right now is on ways to coat the glycine to prevent both the taste issues and GI upset. One approach is to microencapsulate the glycine so that it does not dissolve in the stomach. It gives the glycine a crunchy texture, but does seem to avoid some of the tolerability issues.
Concerning the evidence for NMDA disfunction and glycine treatment for schizophrenia:
SZ.com: What evidence (specifically concerning the neuropathology of schizophrenia symptoms) indicates that glycine might be an effective treatment or co-treatment?
Javitt: The main findings in support of the use of glycine come from its ability to reverse the effects of PCP in animals. Interestingly, these effects were first reported even before NMDA receptors had been discovered. Abel Lajtha, who is now head of Neurochemistry at Nathan Kline Institute, simply ran down a long list of amino acids to see if any were effective. Glycine was the only one that stood out. It was not until the discovery of the glycine site of the NMDA receptor that anyone was able to make sense of the finding. Since then, there have been numerous studies showing that glycine (and related drugs) can stimulate NMDA receptor functioning in a variety of brain regions, making it an ideal candidate for clinical trials.
SZ.com: Some researchers are calling schizophrenia a "disease of the synapse": how can just one cofactor for one neurotransmitter receptor help to correct the organizational/signalling problems of synapses in the brains of people with schizophrenia? Moreover, recent studies (see Chergui et al, Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2191-6) speak about many different factors other than just the availability of glycine (i.e. certain proteins in the neurons themselves) that can increase/decrease the sensitivy of post-synaptic glutamate receptors. What evidence is there that schizophrenia symptoms are caused by a breakdown in NMDA signaling activity due to unavailability of the glycine cofactor, and not by abnormal activity/regulation of protein targets inside the post-synaptic synapse itself?
Javitt: There are really two questions. One is how specific NMDA dysfunction is in schizophrenia, and the other is what to do about it. Regarding the specificity, it is true that there are complex brain changes in schizophrenia. However, it should also be kept in mind that scientists emphasize what is wrong in the brains of individuals with schizophrenia, not what is right. It is true, for example, that patients with schizophrenia have larger ventricles, on average, than others of the same age and sex, and decreased volumes of some brain regions. On the other hand, unlike Alzheimers disease, Parkinsons disease or other neuropsychiatric disorders, one cannot diagnose schizophrenia based simply on brain structure. In contrast to Alzheimers disease, a pathologist looking at a postmortem brain would not know if it came from someone with schizophrenia or from an unaffected individual. The structural brain changes in schizophrenia are actually quite subtle, often averaging only 5-10%. The same can be said of many of the postmortem changes in gene expression. It is hard to attribute the major changes in thought and behavior simply to small changes in brain volume.
Calling schizophrenia a "disease of the synapse" also does not capture the subtleties of the disorder. Although individuals with schizophrenia have difficulties in many areas, there are also many areas of preserved function. For example, they may have trouble learning new information. Unlike individuals with Alzheimers disease, however, once they learn the information they tend to remember it. They are able to walk, talk, and feed themselves, unlike individuals, for example, with Parkinsons disease. Their gross hearing and vision are normal although, as mentioned above, their ability to decode what they see and hear may be impaired. Hearing, seeing, walking, talking, eating, remembering are all processes that require synapses just as much as complex thinking does. They are all processes that may be impaired in other neuropsychiatric conditions, but are not impaired in schizophrenia. So obviously schizophrenia is not a disorder of all synapses, but only of some synapses, or of some processes within synapses.
The main tie of NMDA receptors to schizophrenia is that drugs, such as PCP, which block only NMDA receptors nevertheless produce the full range of symptoms and cognitive deficits that one would see in schizophrenia. Moreover, these agents produce few symptoms or cognitive abnormalities that would not be seen in schizophrenia. So, NMDA dysfunction is certainly sufficient in and of itself to account for all the symptoms that one would see in schizophrenia. The question is what is causing NMDA dysfunction. As noted, there are very many brain processes that regulate NMDA receptors, including presynaptic release of glutamate, postsynaptic modification of the NMDA receptors, and factors such as glycine that modulate the NMDA activity. To date, there is no strong evidence that NMDA receptors themselves are dysfunctional in schizophrenia, although they may be somewhat reduced in density. It is likely that for any individual to develop schizophrenia, multiple regulatory processes would have to fail including both pre- and post-synaptic processes. The epidemiological evidence in schizophrenia suggests that it is not a disease of one or even two "hits," but rather of many, even up to 10 or 20 hits, all of which combine to push someone over the edge of normal brain function. These could include genetic predispositions, environmental factors, subclinical infections, birth complications, poor diet or other factors that have yet to be identified. These probably contribute in different ways to NMDA dysfunction - some, for example, leading to fewer synapses, others to changes in postsynaptic regulation, still others to abnormalities at the glycine site.
SZ.com: What is the evidence indicating that the glycine site specifically might be a major factor in schizophrenia NMDA receptor disfunction?
Javitt: To date, the most direct evidence for involvement of the glycine site (which also binds d-serine in the brain) comes from two main sources. First, the enzyme that breaks down d-serine in the brain, called d-amino acid oxidase, has consistently been linked to schizophrenia. Further, the most active form of this enzyme, which would be expected to produce the lowest levels of brain d-serine, is the form most associated with schizophrenia. Second, clinical studies in schizophrenia have shown reductions in plasma levels of both d-serine and glycine. Interestingly, glycine levels were reduced in patients taking either typical antipsychotics or newer atypicals, but not in individuals taking clozapine. We have also shown that clozapine appears to directly affect glycine reuptake, suggesting that it may produce its clinical effects in part by modulating the glycine system.
There are also two other intriguing recent findings that may relate to glycine dysfunction. One is that patients with schizophrenia, as a group, have elevated levels of the amino acid homocysteine, possibly related to impaired ability to use the vitamin folic acid. The elevation is observed particularly in young males. In the brain, homocysteine acts as a glycine-site antagonist. Researchers in Israel have found that simply supplementing folate can produce a significant improvement for many patients. Whether this is relevant in the US, where folate is added to bread, remains to be determined. Similarly, researchers in Sweden have demonstrated increased levels of an amino acid derivative called kynurenic acid in CSF of patients with schizophrenia. Like homocysteine, this compound may cross react with the glycine binding site. Ultimately, if ways can be found to correct such abnormalities, one would want to do that first. For now, one must try to overcome such disturbances by boosting levels of amino acids, such as glycine or d-serine that stimulate NMDA receptors.
SZ.com: Schizophrenia has many different types of clinical profiles - that is, symptoms appear in different combinations, and with different intensity, in various individuals. Moreover, the course of schizophrenia is not the same for everyone. How does the NMDA theory of etiology account for these varying presentations of schizophrenia?
Javitt: In trying to conceptualize what is happening in schizophrenia, it might be most useful to turn the arrow around the other way, and to suggest that the brain has characteristic ways of "failing." When the dopamine system fails, one gets symptoms that look like Parkinsons disease. When the acetylcholine system fails, one gets a dementia-like picture. When the glutamate system as a whole fails, one gets a syndrome marked by mental retardation or gross changes in mental state. When the NMDA system fails, the changes are those seen in schizophrenia. Some types of pathologies may affect one system specifically. Others may cut across multiple systems. The exact clinical presentation may depend upon what systems are involved and what parts of the brain are affected.
Concerning current research into glycine treatments for schizophrenia:
SZ.com: What have been the results of recent clinical studies that you have completed for glycine treatment?
Javitt: Evidence for and against effectiveness of glycine has been summarized very well recently in an article in Schizophrenia Research by a Finnish researcher named Tuominen. Across studies, the effects of glycine on negative symptoms were quite significant (p=.0004). They were moderate in terms of statistical strength, which is similar to the usual degree of benefit produced on positive symptoms by antipsychotic agents. Benefits were seen in combination with both typical and newer atypical antipsychotics, but not with clozapine. It should be pointed out that most of these studies were conducted at inpatient settings.
The most recent trial that has been conduced with glycine is a multicenter NIMH funded study called CONSIST. This study was carried out at 4 sites in the US and was headed by Will Carpenter from Maryland Psychiatric Research Center. Results of this study are still being analyzed. Overall, however, it did not find a significant benefit for either glycine or d-cycloserine. Nevertheless, there was a significant variability of the effects across site. Patients at inpatients sites benefited significantly from glycine. However, those at outpatient sites actually did worse on glycine than on placebo although they nevertheless improved in absolute terms. Overall, patients had difficulty in remaining on glycine for the full 16 weeks of the study, so that blood levels of glycine were not as high as seen in prior studies. The main issue from this study therefore is whether a better-tolerated form of glycine might have led to better clinical effectiveness.
SZ.com: What is the therapeutic difference between full glycine-modulatory site agonists (glycine and d-serine) and partial agonists (d-cycloserine)? What are the benefits/detriments (in terms of clinical usefulness, dosage, duration of effects, side effects, price, etc) of each?
Javitt: All the agents mentioned - glycine, d-serine, and d-cycloserine - bind to the same site in the brain, namely, the glycine site of the NMDA receptor. The differences are how well they get there and what they do at the site. The best analogy for understanding the mechanism of action of glycine agonists is that of a dimmer wall switch. In such a switch, glycine-like agents do not turn the switch on or off (this is the job of glutamate), but rather turn the knob to determine how bright the lights will be when the switch is pressed. Normally, the knob is turned about half way up because of glycine and d-serine already present in the brain. Glycine and d-serine, as full agonists, both have the ability to turn the knob all the way up when added at sufficient dose. D-cycloserine, in contrast, as a partial agonist, can only turn the knob partially to the right. Moreover, at high doses it can have adverse effects. Across studies, d-cycloserine has not been found to have significant beneficial effects.
The main differences between glycine and d-serine are how well they enter the brain, and how much is known about their safety. Glycine has many uses in both the food and medical industry and has been found to be without appreciable toxicity even at quite high dose. Nevertheless, it enters the brain very poorly so must be given in tablespoon amounts to overcome the blood brain barrier. It is also used in normal metabolism and treated like any other amino acid. Patients who take 60 grams of glycine per day (the most widely used dose) are essentially doubling their amino acid intake. Glycine is available as a dietary supplement at most health food stores or online. For the most part, however, over-the-counter preparations are not convenient and one must purchase bulk powder. Further, glycine comes in various grades which have different levels of supervision by the FDA. [In my opinion], It would be important for anyone taking glycine to make sure that they use prescription grade [also called pharmaceutical grade - ed] glycine since other formulations are not adequately regulated. Treatment should also be coordinated with a physician. In clinical trials, doses have been started at 15 gm per day (approximately 1 tablespoon) and increased by 15 gm every three days until a dose of 60 gm is reached. These doses are based upon a "typical" 70 kg (about 150 lb) person and may need to be adjusted based upon actual body weight. Again, a physician should be consulted. The main side effect that has been observed with glycine is poor tolerability of the GI side effects, especially nausea. These may reduced by microencapsulated, enteric coated formulations although these are relatively new. As expected, encapsulation may increase the price. Even the cost of encapsulated glycine, however, is only a few dollars per day.
D-serine gets into the brain much more readily than glycine. It has been found to be effective at doses as low as 2 grams per day, although whether this is the most effective dose remains to be determined. Ultimately, d-serine would be expected to replace glycine as a treatment for schizophrenia. However, d-serine causes kidney damage in rats, although not as far as can be determined in other species. For this reason, FDA has not yet approved d-serine for clinical use in this country. At present, therefore, it is not an option, although it is hoped that this will change soon.
Many thanks to Dr. Javitt for taking the time to speak with us about
his work, and for his numerous contributions to schizophrenia research
and future schizophrenia treatments. This interview took place via email
in May 2005.