L-Theanine for Schizophrenia?

Background:

According to this study, (A Revised Excitotoxic Hypothesis of Schizophrenia: Therapeutic Implications) schizophrenia could be caused by glutamate excitotoxicity.

The study (roughly) proposes that diminished activity on the NMDA glutamate receptors causes diminished release of GABA. The result of these hypothesized mechanisms is excessive stimulation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate class (KA) of glutamate receptor complexes which causes glutamate excitotoxicity and eventually cell death.

Further, the study proposes that AMPA/KA receptor antagonists could theoretically be a novel approach to treat schizophrenia.

On the other hand , there is some evidence that schizophrenics have significantly more nitrite oxide (NO) in their brain. (Increased Nitric Oxide Radicals in Postmortem Brain From Patients With Schizophrenia). Also, an agents which reduce neuronal NO attenuate the negative effects of PCP on the behaviour of mice and thus agents that reduce NO or downregulate neuronal NO synthase could possibly be helpful in the treatment of schizophrenia. (Nitric Oxide Synthase Inhibitors Attenuate Phencyclidine-Induced Disruption of Prepulse Inhibition)

Why L-Theanine?

1. L-Theanine reduces Glutamate excitotoxicity in rats. (Theanine prevents memory impairment induced by repeated cerebral ischemia in rats)

2. L-Theanine is a AMPA/KA antagonist. (although the binding concentration of L-Theanine to the AMPA/KA receptors is 80 fold less than glutamate itself, the effect can still be considered pharmacologically effective.) (Neuroprotective Effects of Green Tea components Thanine and Catechins.)

3. L-Theanine increases Glycine release (ffects of theanine, r-glutamylethylamide, on neurotransmitter release and its relationship with glutamic acid neurotransmission.)

4. L-Theanine might be a group I metabotropic glutamate receptors (mGluR1/mGlur5) agonist. Group I mGluRs agonists are thought to have neuroprotective properties. On the other hand, mGluR5 Antagonists seem to have negative impact on the behavior of rats which resemble some of the symptoms of schizophrenia.(Possible involvement of group I mGluRs in neuroprotective effect of theanine) (mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition )

Update: The following study proposes that mGlur5 agonists could reverse NMDA hypofunktion. NMDA hypofunktion is a theory about the underlaying cause of schizophrenia.( study includes mice, rats, mGluR5 knockout mice , PCP, Amphetamine and an mGluR5 agonist and an mGluR5 antagonist. this paper is great fun! but its slightly confusing)  Metabotropic Glutamate Subtype 5 Receptors (mGluR5) Modulate Locomotor Activity and Sensorimotor Gating in Rodents.

Update: Addex Pharmaceuticals has come up with an mGluR5 "activator" and thinks it's potentially an antipsychotic. it's not exactly an agonist of mGluR5 but rather an mGluR5 "positive allosteric modulator". frankly, i dont know the difference but it is supposed to do (almost) the same thing as an mGluR5 agonist.Link

5. L-Theanine increases GABA which could help with Schizophrenia according to the study at the beginning of the article.(The Neuropharmacology of L-Theanine(N-Ethyl-L-Glutamine)

6. L-Theanine increases the gene expression level of „PLC-ß1“ (Possible involvement of group I mGluRs in neuroprotective effect of theanine) which is also done by administration of Clozapine. In fact, „PLC-ß1“ knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenia-like symptoms in rodents. Clozapine administration counteracts these deficits in rats. Phospholipase C-ß1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration This data shows that increasing the expression of „PLC-ß1“ may be a way to treatment of schizophrenia and that could theoretically achieved with L-Theanine.

7. L-Theanine decreases the production of nitric oxide resulting from the down-regulated of neuronal nitric oxide synthase (nNOS) at least in vitro which could be helpful in the treatment of Schizophrenia according to the findings mentioned above. (L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway.)

On the other hand, it has been shown that the new antipsychotics olanzapine, risperidone, and quetiapine dont have any long term effect on neuronal nitric oxide synthase (nNOS) in mice. therefore, using L-Theanine or other agents that down regulate nNOS as an adjunct treatment to these agents could be helpful. (Long-term effects of newer antipsychotic drugs on neuronal nitric oxide synthase in rat brain.)

8. In 2008, a trial have taken place in Israel founded by Ritsner on using L-Theanine as an adjunct treatment to ongoing Antipsychotic treatment (duration 8 weeks). Patients taking an L-Theanine along with an Antipsychotic had a significant reduction in anxiety, positive symptoms and general psychopathology symptoms. Double-blind, randomized, placebo-controlled trial

Drawbacks of L-Theanine:

1. L-Theanine may increase the Dopamine in various regions of the brain. (The Neuropharmacology of L-Theanine(N-Ethyl-L-Glutamine).but according to this article, (Cyclic AMP in the CSF of patients with schizophrenia) schizophrenics may actually not suffer from dopamine excess as dopamine excess would cause high levels of Cyclic AMP in Cerebrospinal fluid. The cAMP level of the schizophrenics in this study was comparable with the control group.

2. L-Theanine is in fact also a weak NMDA receptor antagonist. Which according to the study mentioned at the beginning of the paper could be counterproductive. But the binding activity of L-Theanine to NMDA receptors is 3000fold less than the binding of Glutamic acid so this might be negligible. (Neuroprotective Effects of Green Tea components Thanine and Catechins)

K. M.

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