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September 28, 2005
Collection of Articles about Glycine
Read more... Complementary Schizophrenia Treatments
I present these articles as a collection. There are many articles written exploring the use of glycine, or similar associated compounds, for the treatment of negative symptoms in schizophrenia. These are just a few of them. We still have much to learn about the mechanism of glycine and how it helps treat negative symptoms, but it remains a very promising molecule and one worthy of such exploration!
1. Effect of Clozapine and Adjunctive High-Dose Glycine in Treatment-Resistant Schizophrenia
Am J Psychiatry. 1999 Jan;156(1):145-7
This article was the first study to evaluate the efficacy of glycine when used in conjunction with clozapine (Clozaril). Studies up to this point primarily looked at the older or “conventional” or “first-generation” antipsychotic medications. Clozapine has a more complex mechanism of action compared to those and the authors wanted to investigate if there was a different response.
In a small study, Potkin and others added glycine to the medication regimen of patients already taking clozapine. They randomly assigned people (12 in each group) to either receive glycine or a placebo and neither the subject nor the researchers knew what any person was taking until after the study concluded. Patients were followed for 12 weeks and assessed with symptoms scales and cognitive tests.
Surprisingly, the authors found that people taking clozapine showed no benefit when taking glycine in addition. This was an interesting finding because people on first generation antipsychotics had generally showed a benefit, particularly in negative (blunt affect, decreased emotions, lack of energy and initiative, poor grooming, social isolation, etc.) symptoms compared to those who did not receive the supplement. In addition, those who received a less potent form of glycine, d-cycloserine, actually did worse on some measures than those who received a placebo. On some measures of positive (delusions, hallucinations, paranoia, etc) the patients who received glycine in addition to their clozapine had less relief than those who received a placebo with their clozapine.
As an aside, the word agonist is used frequently with respect to medication mechanisms. Most medications are some sort of agonist or antagonist, meaning that they either potentiate or attenuate direct activity at the receptor they target. Some agents are called partial agonist (could also be called partial antagonist.) A partial agonist differs from a full agonist in the way it works at the receptor it targets. While an agonist always will block a receptor, regardless of concentration, a partial agonist is only able to act on a portion of receptors regardless of how much of the partial agonist you add to the system. As a result, it can often work to balance a system that is either over or under the amount of needed molecules to work effectively. D-cycloserine is a partial agonist at the glycine receptor and therefore no matter how much glycine or clozapine is available, some d-cycloserine if added to the system also, will be there to turn on the receptor but some will also block glycine from achieving a full response. Glycine is considered a co-agonist of the NMDA receptor meaning that it acts to modulate activity at the receptor, but does not directly turn it on or off by itself. It is required for the NMDA receptor to open in conjunction with glutamate. Glycine also acts on a separate binding site to change the length of time that the NMDA receptor’s channels stays open but it does not independently open the channel itself.
The authors postulate that the effects of clozapine at the receptor where glycine acts is more potent than the d-cycloserine and that there is a negative competition at that site which turns down the effect of the clozapine when d-cycloserine is involved. When glycine is added to clozapine, it appears that there is no effect because glycine and clozapine work in similar ways at the glycine receptor. Therefore, the possible benefit is already saturated by the clozapine and adding glycine is unable to increase that benefit because all of the receptors are already occupied. Overall, it appears that adding glycine is ineffective in patients taking clozapine and in fact could actually worsen symptoms somewhat.
Placebo-controlled trial of glycine added to clozapine in schizophrenia.
Am J Psychiatry. 2000 May;157(5):826-8.
In this study, the patients continued taking clozapine as they had before the study began. Once enrolled, they received 2 weeks of placebo in addition that was either changed to glycine powder mixed in lemonade or continued placebo in a “double blind” fashion meaning that neither the subject nor the investigator knew who was getting what until the study was over. They took the glycine for 8 weeks and various tests of cognitive ability and of symptoms were performed. Overall, the authors were able to evaluate data from 27 subjects in total.
This paper found similar findings to another similar study conducted previously. Glycine, when added to clozapine, does not produce the same effects as when glycine is added to a drug regimen that does not include clozapine. The reason for this has to do with the mechanism of action for clozapine in the body. Glycine works at a receptor called the NMDA receptor. In doing so, it helps to facilitate the role of glutamate in the brain, particularly in places that are affected by schizophrenia. The receptor that glycine acts upon also is acted upon by clozapine. Therefore, adding glycine does not have any added benefit because the location on which it might have a benefit is already saturated by clozapine. In addition, molecules like d-cycloserine, which a molecule that is less potent and is able to only partially enhance the NMDA receptor can have a negative effect because it can out compete clozapine and turn down the receptor to its less potent activity level therefore causing an increase in symptoms. In this study, the authors found that there was no worsening of symptoms which is different than what was found in the previous study (see above).
Shai Shoham, Daniel C. Javitt, and Uriel Heresco-Levy
Biol Psychiatry. 2001 May 15;49(10):876-85
The glutamate system has recently become of greater importance in the study of schizophrenia. Through using the drug PCP as a model (an NMDA antagonist) researchers can create a schizophrenia-like state in healthy controls including negative and positive symptoms. As a result, medications that target this system, and could theoretically block the effects of PCP in healthy controls, are thought might block some of the symptoms of schizophrenia in people with the disorder. However, directly acting on the glutamate site of the NMDA receptor has shown severe neurotoxic (kills the cells in the brain) effects in rats. Glycine and other similar compounds have been proposed because they work at a different site in the receptor. The researchers in this paper wanted to know if using the agents that work on the glycine receptor portion of the NMDA receptor would have similar neurotoxic effects as full glutamate agonists. When the glycine portion of the NMDA receptor is triggered, it keeps the NMDA channel open longer than it would open otherwise. Glycine, a full agonist at that receptor, has poor blood-brain barrier penetrance, but at higher doses can get into the brain and cause changes in the glutamate system.
These same researchers have noted improvements in people with schizophrenia who take glycine agonists. As this represents a new type of pharmacotherapy, it is vital that they find out if these treatments have similar risks to the drugs that directly act on the NMDA receptor through modulation of glutamate levels. Glycine and glutamate play many excitatory roles within the nervous system and have far reaching impacts when in abnormal levels. Glutamate, glycine and G-aminobutyric acid (GABA) have been shown to have neurotoxic effects when in elevated levels in vitro. Additionally, all these neurotransmitters are involved in multiple pathways and feedback systems that can be altered with artificial perturbation of the system. Lastly, glutamate and glycine play a critical role in the pruning of neurons and there is concern that that process could be negatively impacted with an increased amount of glycine in the system. This study looks at long term effects on rat brain cells when the rats are given large doses of glycine.
The authors found that after 5 months, there was no neuron degeneration, even in the group of rats given the highest dose of glycine. There was some change in body weight, but it evened out among the control group and glycine groups by the end of the study. Through the use of several stains that look for neurodegeneration and by looking for other markers of neuron death, they did not find that there were any prominent areas that showed concerning uptake of their markers. While at one month, there is some abnormal astrocyte (a type of brain cell) development, it resolves after a month and goes back to normal. The authors theorize that the body is able to adapt to the new levels of glycine in a way that is not possible when brain tissue is merely looked at in vitro.
Ultimately, this study gives good evidence that glycine is not going to cause excitatory neurotoxicity in prolonged exposures. They used doses that are generally about 5 times higher than would be used for treatment and for a long time in the proportional life span of the rat. Based on these data, the further development of glycine and glycine-related pharmaceuticals can proceed without major concern for neuron damage as a side effect of long-term use.
4. Adjunctive high-dose glycine in the treatment of Schizophrenia
Daniel C. Javitt, Gail Silipo, Angel Cienfuegos, Anne-Marie Shelley, Nigel Bark, Mohan Park, Jean-Pierre Lindenmayer, Ray Suckow, and Stephen R. Zukin
International Journal of Neuropsychopharmacology (2001), 4, 385±391.
In this study, the authors look at using glycine in patients who have continued to have symptoms after taking courses of first and second generation antipsychotics. Since all the antipsychotics on the market work by blocking dopamine in some form, using glycine to potentiate the glycine portion of the NMDA receptor utilizes a different mechanism entirely to try and achieve results in people who might not respond to the current forms of treatment. As was mentioned above, clozapine has some action at the NMDA receptor and therefore was not included in this study because it has been seen that adding glycine in the presence of clozapine actually has a paradoxical effect and can worsen symptoms. In addition to measuring symptoms, the authors also measured the amounts of glycine and antipsychotic medication in the blood and around the brain to make sure that glycine does not work by merely increasing the availability of antipsychotics to the brain. In order to use each patient as his/her own control, the authors used a “cross-over” mechanism meaning that half of the patient started on placebo and the other on glycine, but then crossed over at the halfway point to the other treatment.
What the authors found, was that the most pronounced effects were on negative symptoms with some effect seen in positive symptoms and excitatory symptoms and a minor impact seen on cognitive symptoms. Interestingly, the authors noticed that those who received glycine in the first half of the study maintained much of the improvements in negative symptoms and cognitive symptoms for the next several weeks. Towards the end of the study there was a trend back towards the baseline levels, but it never evened out during the remaining half of the trial. Even though the symptoms continued to be improved after switching from glycine to placebo, the levels of glycine in the blood went back to the baseline levels within 2 weeks. Side effects were no different for those on glycine than when on placebo. This was a small study however, only 12 patients, and thusly the findings need to be seen in a larger scale before the data can be applied to a whole population of people. However, as these were all very sick patients studied, it is promising data nonetheless.
Donald C. Goff, Lawrence Herz, Thomas Posever, Vivian Shih, Guochuan Tsai, David C. Henderson, Oliver Freudenreich, A. Eden Evins, Iftah Yovel, Hui Zhang, David Schoenfeld
Psychopharmacology (2005) 179: 144–150
In this paper, the authors conducted a double blind, placebo controlled trial of using d-cycloserine in people taking conventional antipsychotics. Earlier, it was stated that adding glycine (d-cycloserine is a similar molecule that has virtually the same properties, but more easily gets in to the brain) to clozapine treatment does not have any benefit and might even make negative symptoms worse. However, that was thought to be because of properties specific to clozapine, so the authors wanted to see if adding glycine to conventional antipsychotics might have a better outcome. Conventional antipsychotics are generally considered to be very ineffective at treating negative symptoms, but often are quite useful for positive symptoms so if this were to work, it would be potentially very helpful. The authors used 50 milligrams of d-cycloserine because of previous studies that showed that to be the most effective dose. Higher doses have been shown to sometimes actually have a worse effect, presumably because they are unable to exert any more effect, but are able to cause more side effects.
55 subjects started the study and 26 completed all 12 weeks. Many dropped out because of noncompliance (12) or because or a withdrawal of consent (11) for participation. However, more patients in the placebo group (6) left because of side effects than the glycine group (2). They were followed every two weeks and given either 50 mg d-cycloserine pills or a placebo pill that looked identical. They received a battery of tests including evaluations of symptoms and cognitive function. The study lasted six months.
At the end of the 6-month trial, the results between the two groups were virtually indistinguishable. On none of the outcome measures, including the PANSS (Positive and Negative Symptoms of Schizophrenia) or SANS (Schedule for Assessment of Negative Symptoms) or any of the sub-scores of these tests were there any substantial or significant differences between the groups. There were some benefits in negative symptoms noticed prior to the study completion, but they were most strongly seen in the week 12 measurements and did not seem to hold for long-term.
While these results are not as spectacular as others, it is important to note some limitations of this study. It was first a small study, only 55 patients initially, but a high level of dropouts, for various reasons, makes it harder to see any benefit. Nearly half of the study population left the study early, though generally for reasons that had less to do with the d-cycloserine (like side effects) and more for personal reasons or an inability to comply with study procedures. Also, since they needed to find patients on conventional antipsychotics, generally less common than the atypical antipsychotics, they needed to look in more places than they might have otherwise and were unable to have as much control over their procedures as such. Also, the population that takes conventional antipsychotics may differ from the general schizophrenia population. They may be more likely to have less access to care or to be more socially isolated at baseline than people with access to newer medications and therefore may not necessarily represent an accurate depiction of those with the illness. However, it may be that despite these limitations, that glycine may only have short term benefits that wear off over the long term. People may develop a tolerance to its benefits or may just respond less over time. Also, it is possible that since d-cycloserine is a partial agonist compared to glycine which is a full agonist at the receptor, it just is not strong enough at the receptor to produce the effects desired in the same way that glycine is able to. However, none of this is known definitively and therefore more research will need to be done to replicate or refute these findings.
Posted by Jacob at September 28, 2005 03:25 PM
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