SOCIALIZATION FACTOR (PART 2)

IMPROVED TREATMENT OF SOCIALIZATION INHIBITION WITH THE GLYCINE/ SERINE RECEPTOR MEDICATIONS.

2-A1) A NEW TYPE OF TREATMENT FOR NEGATIVE SYMPTOMS. Around the year 2000, a new class of medications was publicized as having the ability to treat the negative symptoms of schizophrenia—even beyond that of the Atypical Antipsychotics. These medications were stimulants of the Glycine-Serine receptor mechanism, a unique receptor that functions in tandem with a strongly activating receptor called the MNDA receptor site. Because the MNDA receptor is one of the main glutamate sensitive receptors, and because there has been little attention to this receptor until recently, there will be extra detail given. Below are quotes from scientific writings on NMDA and D-Serine.

2-A2) THE GLUTAMATE/ GLYCINE NMDA RECEPTOR MECHANISM.
” Glutamate is the main excitatory neurotransmitter in the mammalian CNS and mediates neurotransmission across most excitatory synapses. Three classes of glutamate-gated ion channels (AMPA, kainate and NMDA receptors) transduce the postsynaptic signal. NMDA receptors are abundant, ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission and critical for normal CNS function. Activation of the NMDA receptor is complex; both glutamate and glycine binding are required to open the ion channel and permit calcium entry. Glutamate has the neurotransmitter role, as it is released from presynaptic terminals in an activity-dependent manner, whereas glycine acts as a modulator, which is present in the extracellular fluid at more constant levels. The ion-channel integral to the NMDA receptor is voltage-dependently blocked by magnesium, and depolarization removes this block. Thus the NMDA receptor acts as a coincidence detector, linking neurotransmitter activation with the electrical state of the neuron.
® John A. Kemp1 & Ruth M. McKernan2Nature Neuroscience doi:10.1038/nn936
November 2002 Volume 5 Supplement pp 1039 - 1042

2A-3) Understanding D-Serine.
D-serine is a D-amino acid found in mammalian tissues that can act as a potent ligand for the glycine site on NMDA receptors. D-serine is made by the enzyme serine racemase, which is a member of the pyridoxal-5’ phosphate (PLP)-dependent enzyme family. Serine racemase mRNA is expressed in brain and liver, and serine racemase protein is expressed in glial cells. Degradation of D-serine by D-amino acid oxidase attenuates NMDA receptor-mediated calcium influx, and implicates D-serine as an endogenous modulator of NMDA receptor function. Thus, glial cell production of D-serine via serine racemase activity may be an important system for modulation of synaptic transmission.
® Wolosker, H., et al. 1999 PNAS 96:13409-13414
® Mothet, J.P., et al. 2000 PNAS 97:4926-4931

2-B1) THE GLYCINE/SERINE AGONIST TREATMENT OF NEGATIVE SYMPTOMS OF SCHIZOPHRENIA.
The use of Glycine in schizophrenia has been talked about since 1988. (®: Waziri R. Glycine therapy of schizophrenia. Biol Psychiatry 1988:23:210-11. ) There had been demonstrated a diminished activity of the NMDA receptor function in chronic schizophrenia, (hypofunction of NMDA receptor) and it was believed that the excess glycine gave this hypofunctioning receptor capacity to function more normally.

2-B2) THE GLYCINE AGONISTS. These drugs, L-glycine, D-serine, and D-cyclosporine have a common property – they stimulate a receptor that acts in tandem with the very active stimulant receptor NMDA. Nearly all the trials using these medications to treat negative symptoms produced positive results. However, there is no current standardized protocol for the use of these agents in treating chronic schizophrenia. None of them have proven ideal for regular use. L-glycine has poor penetration into the brain requiring high doses to produce positive effects, D-cycloserine is a partial agonist and in some situations is less effective. D-serine is not easily available in the USA and is apparently expensive.

2-B3) RECENT STUDIES USING GLYCINE RECEPTOR AGONISTS IN SCHIZOPHRENIA
In 1999-2000, there were a number of studies published about the effect of several related drugs on the negative symptoms of schizophrenia.
® Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC.
Placebo-controlled trial of glycine added to clozapine in schizophrenia.
Am J Psychiatry. 2000 May;157(5):826-8.

® Goff DC, Tsai G, Manoach DS, Coyle JT.Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia Am J Psychiatry. 1995 Aug;152(8):1213-5.

® Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden DL, McCarley R, Coyle JT.
A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry. 1999 Jan;56(1):21-7.
® Goff DC, Henderson DC, Evins AE, Amico E. A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia.
Biol Psychiatry. 1999 Feb 15;45(4):512-4.

® Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, and Liechtenstein M. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56: 29-36, 1999.
® Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D.
Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia.
Br J Psychiatry. 1996 Nov;169(5):610-7.

® Heresco-Levy U, Ermilov M, Shimoni J, Shapira B, Silipo G, Javitt DC.
Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzepine, or risperidone in schizophrenia.
Am J Psychiatry. 2002 Mar;159(3):480-2.

® Tsai, G., Yang, P., Chung, L.C., Lange, N. & Coyle, J.T. D-serine added to antipsychotics for the treatment of schizophrenia. Biol. Psychiatry 44, 1081-1089 (1998).

2-B4) NATURE OF IMPROVEMENT USING GLYCINE-SERINE AGONISTS. An example of the improvement seen is quoted from one of the researchers, Don Goff.

Case Eight
" I knew we were onto something with the first patient, who had been mute for the five years that I had known him and had really only sort of nodded or shook his head in all our meetings, We were walking from the waiting room to my office, and he slapped me on the back and said, 'How's it going, Dr. G. ?'"

2-B5) MEASUREMENT OF THE IMPROVEMENT. One author demonstrated this difference by testing. He showed that the benefit to socialization when adding a glycine receptor agonist is greater than that of switching from a typical to an atypical antipsychotic. His figures showed nearly twice as much improvement when adding a glycine agonist to a typical antipsychotic medication regime than when changing to the atypical risperidone /Risperdal.
“ The effect size of the difference in negative symptom PANSS scale scores between adding d-cycloserine and placebo to antipsychotics was 0.47.” “ the effect size of the change –with risperidone from haloperidol was 0.26,” ® Goff, Donald C et al.
A Placebo-controlled Trial of D-Cycloserine Added to Conventional Neuroleptics in Patients With Schizophrenia. Archives of General Psychiatry. Jan 1999

2-B6) PERSISTENCE OF IMPROVEMENT. Interestingly the improvement seen can be quite persistent. In one trial 87 % of those who received L-glycine showed improvement. They were then switched off L-glycine—but they maintained their improvement for three weeks.
® Heresco-Levy U. Double-blind, placebo-controlled, crossover trial of glycine adjunctive therapy for treatment –resistant schizophrenia. British Journal of Psychiatry 1996:169 (Nov); 610-617

Studies involving seen the treatment of schizophrenia by glycine-serine agonists demonstrate.
[11] That a significant percentage of chronic schizophrenics respond to glycine agents with increased socializing activities.
[12] That all of the glycine agents can improve negative symptoms when added in patients receiving typical antipsychotics.
[13] That most of the time the glycine agents provided improved benefits in treating negative symptoms when added to atypical antipsychotics.
[14] That D-cycloserine, a partial glycine agonist, apparently reverses some of the benefit of the atypical antipsychotic clozapine/ Clozaril – suggesting that clozapine has some effect on the glycine/MNDA receptor complex.
[15] That improvement in socialization which occurred during treatment of negative symptoms of schizophrenia with glycine agents sometimes persisted AFTER THE MEDICATION WAS STOPPED.

2-B6.b) THIS IS A VERY IMPORTANT FINDING – PERSISTENCE OF IMPROVEMENT AFTER MEDICATION IS STOPPED MARKS THIS AS A DIFFERENT TYPE OF REACTION FROM THOSE COMMONLY SEEN IN PSYCHIATRY.

2-C) THE GLYCINE-SERINE AGONIST TREATMENT OF SOCIAL WITHDRAWAL SYMPTOMS OF AUTISM. Since atypical anti-psychotics produced improved socialization in schizophrenia, and since the glycine-serine drugs were seemingly more effective, it was logical to test their effects in autism.

2-C1) L-glycine is available as a nutritional supplement. It was given to over autistic thirty individuals, but is not currently being used because the high doses required caused considerable gastrointestinal side effects. Observations revealed L-Glycine as being helpful in treating symptoms of autism. The following benefits were reported by their caregivers.

2-C1.a) They seem more attentive to the spoken word. b). They more readily follow directions. c). They seem more interested in trying to communicate. d). They make better eye contact. e) They have improved participation in group activities.
Examples of reports of response to L-Glycine:

Case Nine
Seven-year old male. “ I told my autistic son to go get his coat so we could go outside. He disappeared, got his coat, and came back – something I had not expected. He also looked at me when I was talking to him.”

Case Ten
Twenty-three-year-old male. “My autistic son starting looking at me when conversing. In the morning, he voluntarily made his own lunch for the first time in his life.”
These cases illustrate the following principle.
[16] Glycine agonist agents produce improved socialization in autistic individuals beyond the effect of atypical antipsychotics
2-C2) D-Cycloserine is a partial stimulant and partial blocker of the glycine/ serine receptor. It is available in 250 mg capsules, which are generally too large for psychiatric use, (The dosage for schizophrenia is up to 50 mg a day.) We obtain a 6 mg capsule from a compounding pharmacist. D-Cycloserine also can improve the verbal communication of autistic individuals.

Case Eleven
“ When my 23 year old autistic son was placed on 6 mg/day of D-cycloserine, we noticed an increase in nervous finger tapping. We were about to stop it when it was shown that he was making 200% more attempts at verbal communication in his day programming.”
This case illustrates the following point.
[17]- There is sometimes an increase in impulsive undesirable behavior occurring at the same time as there is increased socialization activity.

2-D) THE GLYCINE-SERINE AGONISTS IN PHOBIA.
There is an interesting report by Dr. Michael Davis from Emory University in 2003 that the use of D-Cycloserine in doses of 50 or 500 mg a day allowed for success in treatment of various phobias using only two sessions of desensitization therapy instead of using eight sessions, which is the standard number required with no medicine.
These cases demonstrate the following point.
[18] That the glycine-serine receptor mechanism has effects in non-schizophrenic and non-autistic individuals, and those effects increase tolerance to outside stimulation. This is similar to a prosocialization effect.

® (see also "Facilitation of Fear Extinction in Rats via Activation of NMDA Receptors: Relevance to Exposure Therapy for the Treatment of PTSD or Phobia."
Michael Davis, Ph.D.Department of Psychiatry, Emory University School of Medicine,)