A simple amino acid called glycine, when given in conjunction with antipsychotics, may help improve the negative symptoms associated with schizophrenia. While the research to date is sparse and preliminary, it is growing and it does show considerable promise.

Traditionally, schizophrenia has been thought to be a disease involving the neurotransmitter dopamine. In the early 1950s, it was found that chlorpromazine which was originally developed as an anti-nausea treatment also helped improve psychotic symptoms. It helped relieve the positive symptoms of psychosis by blocking dopamine in the brain. Neurons in the brain are not connected to each other but are separated by gaps called synapses. Chemical messengers are released by one neuron and are received by specialized receptors on the ends of the opposite neuron. The messages they convey are then transmitted down the neuron.

Dopamine is one such chemical messenger or neurotransmitter. Chlorpromazine acts as an antagonist to dopamine and blocks the dopamine receptors on the ends of neurons. This prevents dopamine from binding to the receptor and sending its message down the neuron. As chlorpromazine helped reduce psychotic symptoms, it was thus believed that schizophrenia was a disease of either too much dopamine or too many dopamine receptors. This theory was further supported by the observations that amphetamines and LSD produce hallucinations similar to schizophrenia. These drugs are dopamine agonists which mean that they mimic the action of dopamine in the brain. Their presence has the same effect as increasing the amount of dopamine.

Blocking dopamine helped to relieve psychotic symptoms while increasing dopamine produced psychotic like symptoms.

These early antipsychotics that only influenced the dopamine system tend to be only effective for the treatment of the positive symptoms of schizophrenia and are not effective for the negative ones. This led to the consideration that other neurotransmitters might also be involved with the disease. The newer atypical antipsychotics that have been developed in recent years, therefore, influence not only the dopaminergic systems but also effect serotonin - another of the neurotransmitters in the brain. These newer drugs reduce dopamine activity in some parts of the brain and increase serotonin activity in other parts.

Over the past few years, attention has been focused on another neurotransmitter system in the brain involving agents that block N-methyl-d-aspartate or NMDA. Two street drugs, PCP (angel dust) and ketamine are known to cause behavior that closely resembles that of schizophrenia. These drugs block the N MDA receptors. In addition, post mortem evaluations of the brains of people with schizophrenia have shown that people with schizophrenia have fewer NMDA receptors than people who do not have the disease.

This has led to the hypothesis that people with schizophrenia have too little NMDA and that is one cause of some of the symptoms of the disease. Glycine is known to act as an agonist for NMDA. That is it mimics NMDA. Glycine is a protein amino acid that is found in the protein of all living things. The normal human diet results in an intake of about 2 grams of glycine daily. It is believed that supplementing with glycine may not only have antispastic activity but it may also have antipsychotic activity along with anti-oxidant and anti-inflammatory properties.

A number of small, randomized control trials have been done looking at the effect of adding glycine to atypical antipsychotics and the impact that would have on symptoms. In January 2005, a team of Finnish researchers published a meta-analysis in Schizophrenia Research (Vol 72, Issues 2-3, pages 225-234). A meta-analysis combines the results from all studies and re-analyzes the data. This has the advantage of increasing the sample size by combining studies.

In this case, there were 18 short-term trials included in the meta-analysis involving 343 patients who were given various NMDA agonist compounds in addition to their antipsychotics. The study found that both glycine and D-serine (another amino acid synthesized in the body from glycine) were effective in reducing negative symptoms but that the magnitude of the effect was small.

The two most recent trials were published in Biological Psychiatry in 2004 and 2005. The first by Uriel Heresco-Levy and colleagues is entitled “High dose Glycine Added to Olanzapine and Risperidone for the Treatment of Schizophrenia” (vol 55 pages 165-171) Seventeen patients on either olanzapine or risperidone were given 8 gm/day of glycine in addition to their regular medications for a 6-week period. Patients were then switched. If they were getting placebo during the first six weeks, they received glycine in the second phase and vice versa. The trial was blind so that neither the researchers nor the patients knew what was being taken.

It was found that glycine was well tolerated by the patients and that there was a significant reduction in negative symptoms. The size of the sample, however, was small and the length of the study was short but the researchers did conclude that the efficacy of risperdone and olanzapine might be augmented using high dose adjuvant glycine treatment.

The second study was also conducted by Dr. Heresco-Levy and involved the use of D-serine as an add-on with the same two drugs as the previous research (“D-serine efficacy as add-on pharmacotherapy to risperdone and olanzapine for treatment refractory schizophrenia”, Biological Psychiatry, 2005, Mar 15; 57 (6), 577-585). The sample size was larger at 39 and patients were given 30 mg/Kg/day of D-serine added to their regular medications.

The researchers found that there were significant improvements in negative, positive, cognitive and depression symptoms. While gylycine and D-serine both act as NMDA agonists, there are differences between them. Glycine passes the blood brain barrier with greater difficulty and thus more of it must be taken in order for it to reach the brain than D-serine. However, D-serine has been found to cause kidney damage in rats and, until its safety has been determined, it is not approved for clinical use in the U.S.

If anyone does wish to try glycine, it is highly recommended that it only be done in consultation with the doctor and that the glycine used is made to either prescription or pharmaceutical grade standards. Clinical trials have begun with 15 gm per day and the dose is then increased by 15 gm per day every 3 days until a total dose of 60 gm/day has been achieved. This dose is based upon an average weight for the individual of about 150 pounds.

Another interesting factor about glycine is that it has not been demonstrated to be effective when given with clozapine. It is hypothesized that clozapine may also be acting as an NMDA agonist.

This approach supplementing antipsychotics with glycine does show promise and is pointing researchers in a new and potentially beneficial direction.

Author: Marvin Ross

More information on Glycine:

Glycine Therapy - A New Direction for Schizophrenia Treatment? (a more in-depth report on the science, with links to suppliers, etc.)