Supplementation of antipsychotic treatment with sarcosine-G1yT1 inhibitor-causes changes of glutamatergic 1NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia. (2015)

Supplementation of antipsychotic treatment with sarcosine-G1yT1 inhibitor-causes changes of glutamatergic 1NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia.

Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission. The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance (1H NMR) spectroscopy (1.5T). Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n=25) or placebo (n=25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS). In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups. This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.

“Sarcosine – an exogenous amino acid – is serving in the brain as a glycine transporter type 1 (GlyT-1) inhibitor and as a source of glycine (natural coagonist of the NMDA receptor, metabolized from sarcosine by sarcosine dehydrogenase). It was reported to be effective in treating negative and cognitive symptoms .

Supplementation of sarcosine at a 2 grams daily dose is supposed to increase glycine concentration and normalize hypofunction of the NMDA receptors, which are present in high density in the the prefrontal cortex and hippocampus – areas associated with development of cognitive and negative symptomatology”

table 3
Study results

“We conclude that augmentation of the antypsychotic treatment with sarcosine may reverse the increase in glutamatergic transmission in the left hippocampus in schizophrenia along with improvement of mental state, assessed with the PANSS. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus.”

See more:

Sarcosine Therapy – A New Complementary Direction for Schizophrenia Treatment?

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study. (2015)

Glycinergic, NMDA and AMPA augmentation – a review

GlyT1 inhibitors

Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex.

GlyT1 inhibitors

GlyT1 inhibitors may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects [1]. Similarly, GlyT1 inhibition is a potential therapeutic strategy in addressing the symptom domains of autism spectrum conditions [2].

Based on an animal model (reduced Sp4 expression in mice), GlyT1 inhibition may have promise in treating attentional deficits in neuropsychiatric patients but not learning or motivational deficits [3]:

“…by using this model relevant to schizophrenia, we demonstrated that GlyT-1 inhibition (Org 24598) significantly reversed the attentional but not learning or motivational deficits of these mice. Interestingly, GlyT-1 inhibition impaired the attention of WT littermate mice without affecting their learning or motivation. These data support GlyT-1 inhibition as a potential treatment for attentional but not positive valence deficiencies (negative symptoms) related to schizophrenia as well as a U-shape dose response of optimal synaptic glycine levels for attentional performance.”

That said:

“…the inability of GlyT1-inhibition to remediate behaviors relevant to negative symptoms is surprising given that: (1) lower plasma and cerebrospinal fluid glycine level of patients with schizophrenia is linked to negative symptoms (Hashimoto et al, 2003); and (2) glycine treatment (although chronic) modestly lowers negative symptom ratings (Heresco-Levy et al, 1999; Javitt et al, 1994). However, such positive findings have not always been reproduced (Buchanan et al, 2007). In fact, Roche recently stopped trials testing a GlyT-1 inhibitor for the improvement of negative symptoms in schizophrenia, perhaps due in part to the sole reliance on clinical rating scales rather than objective translational laboratory tests as primary outcome measures. Testing negative symptoms using laboratory-based measures with relevance to those presented here may provide more relevant cross-species findings (Barnes et al, 2014; Der-Avakian et al, 2013; Young et al, 2013b) and greater sensitivity to the effects of GlyT-1 inhibitors. Constitutively reducing Sp4 expression in mice resulted in impaired attention that was remediated by GlyT-1 inhibition. The finding that this treatment did not remediate motivational deficits suggests that the attentional deficits of Sp4 mice are unlikely a result of altered motivation or learning. The lack of effect on motivation could be because of a requirement of longer treatment duration, although it improved attention acutely. Alternatively, more direct NMDAR1 activation may be required. Furthermore, the mechanism(s) underlying impaired motivation and learning resulting from reduced Sp4 expression have yet to be delineated. As SP4 regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B (Priya et al, 2014; Priya et al, 2013), further investigation of other mechanisms using these mice is warranted.

In conclusion, reduced Sp4 expression in mice largely recreates the attentional deficits observed in patients with schizophrenia as measured by the 5C-CPT (Young et al, 2013a). These data support pairing attentional assessment with evidence of reduced SP4 levels in peripheral blood mononuclear cells, as seen in first-episode patients with schizophrenia (Fuste et al, 2013). Such an approach might provide a useful personalized biomarker for predicting whether GlyT-1 inhibition may remediate attentional deficits in individual patients. However, such treatment would unlikely treat impaired positive valence related to reward anticipation. SP4 rare copy number variations and reduced protein levels are linked to several psychiatric disorders that exhibit attentional deficits including schizophrenia, bipolar disorder, and major depressive disorder (Pinacho et al, 2011; Shi et al, 2011; Tam et al, 2010; Zhou et al, 2009). Hence, identifying the mechanism(s) of how reducing Sp4 levels negatively affect attention and the neurobiology underlying GlyT-1 inhibition-induced reversal of these effects will prove vital. Importantly though, the present work using this model organism provides opportunities for personalized medicine for the treatment of attentional deficits in neuropsychiatric patients having low SP4 levels (McMahon and Insel, 2012).”

Sarcosine, a simple GlyT-1 inhibitor, has demonstrated some promising potential [4, 5]. Some worsening of symptoms has been noted at doses in excess of 2000mg [6] and a case of hypomania has been reported [7]. Antidepressant effects have also been reported [8].

Regulation of GlyTs:

BDNF, acting on TrkB receptors, inhibits glycine uptake in astrocytes by promoting GlyT internalization through a Rho-GTPase activity dependent mechanism [9]. GSK3β is important for stabilising and/or controlling the expression of functional GlyTs on the neural cell surface [10].

A soon to be published article may be of interest:

Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there are no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation [link out]

See more:

Sarcosine Therapy – A New Complementary Direction for Schizophrenia Treatment?

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study. (2015)

Glycinergic, NMDA and AMPA augmentation – a review

Riluzole and Memantine: Attenuating early-life stress-induced disturbances to the reward system by modulating glutamatergic transmission during adolescence ?

Memantine and riluzole have recently been found (in male rats) to partially attenuate early-life stress-induced disturbances to the reward system when administered during adolescence [link].


Riluzole inhibits glutamate release via sodium channel inactivation, while blocking NMDA-receptor activation and enhancing AMPA expression. It also acts as a EAAT2 (GLT-1) activator and may exert its neuroprotective effects through an astrocyte-dependent mechanism, elevating EAAT2 activity and levels in astrocytes [1].

Riluzole may be a safe and effective medication for the treatment of negative symptoms in patients with chronic schizophrenia [2]. Case studies have indicated that riluzole may have clinical use in treating both mood and anxiety disorders [3] and in particular, may have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders [4].

Riluzole may also have therapeutic potential in the treatment of autism spectrum conditions: “A case series of the use of riluzole as an adjunctive treatment in children with ASD (n = 3; age range 15–20 years) has shown improvement in CGI scores” [5] and has been suggested as a potential therapeutic for treatment-resistant major depressive disorder: “riluzole augmentation to antidepressant therapy has resulted in significant improvements in both depression and anxiety symptoms.” [6].

Riluzole may “compensate for harmful glutamate levels and promote dendritic spine clustering in hippocampal circuits implicated in memory and emotion. Therefore, the drug may act as an effective treatment for age-related memory loss and other forms of cognitive decline” [7].

Enhancing Glutamatergic Transmission During Adolescence Reverses Early-Life Stress-induced Deficits in the Rewarding Effects of Cocaine in Rats

Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet also uniquely amenable to therapeutic intervention. It is during adolescence that the onset of the majority of psychiatric disorders, including substance use disorder (SUDs), occurs. It has been well established that stress, particularly during early development, can contribute to the pathological changes which contribute to the development of SUDs. Glutamate as the main excitatory neurotransmitter in the mammalian CNS plays a key role in various physiological process including reward function and in mediating the effects of psychological stress. We hypothesised impairing glutamatergic signalling during the key adolescent period would attenuate early-life stress induced impaired reward function. To test this, we induced early-life stress in male rats using the maternal-separation procedure. During the critical adolescent period (PND25–46) animals were treated with the glutamate transporter activator, riluzole, or the NMDA receptor antagonist, memantine. Adult reward function was assessed using voluntary cocaine intake measured via intravenous self-administration. We found that early-life stress in the form of maternal-separation impaired reward function, reducing the number of successful cocaine-infusions achieved during the intravenous self-administration procedure as well impairing drug-induced reinstatement of cocaine-taking behaviour. Interestingly, riluzole and memantine treatment reversed this stress-induced impairment. These data suggest that reducing glutamatergic signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing SUDs including certain adolescent populations, particularly those which may have experienced trauma during early-life.

“Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a key role in the induction of goal-directed behaviour as well as mediating drug-induced plasticity (Mameli et al., 2007; Sun et al., 2005; You et al., 2007). Glutamatergic and dopaminergic signalling converges at the level of the nucleus accumbens, coupling glutamate encoded environmental stimuli with dopaminergic reinforcement signals allowing drug-related cues to increase in salience increasing sensitivity to drug-related stimuli (Brown et al., 2011; Day et al., 2007; Stuber et al., 2008). Furthermore, the fronto-striatal circuits implicated in regulating compulsive and impulsive behaviours, key features of SUDS (Fineberg et al., 2010) are densely populated by glutamate receptors (Monaghan et al., 1985). Thus, the glutamatergic system is key to the regulation of reward systems and goal-directed behaviour.

Interestingly, early-life stress can disturb the glutamatergic signalling machinery (O’ Connor et al., 2012) and moreover can perturb normal glutamatergic function potentially inducing a hyperglutamatergic state (Musazzi et al., 2011; O’ Connor et al., 2012). As such, disruptions to the glutamatergic machinery may contribute to altered reward function induced by early-life psychological stress. We hypothesise that reducing glutamatergic signalling during the key adolescent development stage may serve to attenuate early-life stress-induced perturbations to brain reward systems.

To test this hypothesis we employed the well validated maternal-separation procedure to induce early-life stress (O’Mahony et al., 2011; O’Mahony et al., 2009). Following this glutamatergic signalling was reduced during adolescence using the EAAT2 activator riluzole or the NMDA receptor antagonist memantine. Both of these glutamatergic agents are clinically approved for use in humans and can reverse stress-induced deficits in preclinical behavioural models (Gosselin et al., 2010; Reus et al., 2012). Cocaine reinforcement and intake was assessed using the intravenous self-administration procedure.”

  • Early-life stress in the form of maternal-separation reduced cocaine intake in adulthood.
  • Maternal-separation impaired cocaine-induced reinstatement in adulthood.
  • The authors concluded “that the stress-induced alteration to hedonic behaviour in adulthood is a result of early-life stress alone”
  • Riluzole or memantine partially attenuated these stress-induced disturbances to reward function.
  • The subjects in this study who underwent early-life maternal separation may possess pathological disruptions to the neuronal signalling cascades or potentially impaired neural activity in discrete brain regions that mediate the effects of rewarding stimuli. Thus, they do not receive the same level of reinforcement from cocaine infusions as their non-separated counterparts resulting in lower levels of infusions.

“…reducing glutamatergic signalling during the key adolescent period can attenuate the stress-induced disturbances to reward system. This was achieved via the EAAT2 activator riluzole and the NMDA receptor antagonist memantine chosen, in part, due to their status as clinically approved drugs. Furthermore, we have previously demonstrated the effectiveness of riluzole in attenuating maternal-separation induced increases to visceral hypersensitivity (Gosselin et al., 2010) whereas memantine has been shown to reverse behavioural deficits induces by chronic mild-stress (Reus et al., 2012). Adolescence marks a key developmental stage where the glutamate-directed formation of neuronal signalling cascades is essential to correct functioning (Selemon, 2013). It is well established that psychological stress increases the release of glutamate (Gilad et al., 1990; Musazzi et al., 2010; Popoli et al., 2011; Treccani et al., 2014). Thus, early-life stress can impact greatly on the development of neuronal signalling systems via glutamatergic mechanisms. Previous studies have shown that inhibiting glutamatergic neurotransmission through AMPA or NMDA receptor blockade (Bisaga et al., 2000; Gass and Olive, 2008) or through inhibiting signalling via mGlu receptor manipulation (Heilig and Egli, 2006; Lea and Faden, 2006; Li et al., 2010; Li et al., 2013; Liechti and Markou, 2007; Moussawi and Kalivas, 2010) can block the reinforcing effects of cocaine. Furthermore, one mechanism put forward to explain the therapeutic mechanism of antidepressant drugs is the inhibition of stress-induced glutamate release (Musazzi et al., 2013). Employing memantine and riluzole directly targets the glutamatergic system aiming to reverse any excess glutamate signalling which may contribute to stress-induced phenotypes. We found that chronic adolescent riluzole and memantine had a significant dose-dependent effect on cocaine-taking behaviour in adult animals which underwent maternal-separation early in life. Furthermore, riluzole or memantine treatment had no effect on general operant responding as measured during the food-training component of the experiment. Interestingly, excessive disruption of glutamatergic signalling via pharmacological means may even result in increased cocaine intake with riluzole at a dose of 10 mg/kg/day increasing cocaine intake when 0.25 mg/kg was delivered per infusion. Interestingly, memantine, but not riluzole, treatment during adolescence was able to reverse the early-life stress induced deficit to drug-induced reinstatement of the cocaine-conditioned response. An interesting finding; possibly directly targeting the NMDA receptor, key to the induction of plasticity, results in more pronounced attenuations of stress-induced perturbations to the signalling cascades mediating reward. Further studies investigating other more selective NMDA receptor ligands, as well as strategies focused on manipulating the glutamatergic system by other means (e.g. metabotropic receptors) in adolescence, are now warranted. It is worth noting that in addition to their effects on glutamatergic signalling both riluzole and memantine have additional pharmacological effects; riluzole inhibits various Na+ channels (Bellingham, 2011) while memantine acts on 5-HT3 receptors and nicotinic acetylcholine receptors (Chen and Lipton, 2006; Rammes et al., 2001). The contribution of these mechanisms to the results seen in the present study cannot be ruled out. A further caveat worth noting is the fact that our experimental design did not include drug-treated animals free of early-life separation stress. Thus, we cannot categorically rule out that any observed drug-induced effects would have manifested independent of early-life stress. Future studies are warranted to rule this out and to show that the reversal shown in the present studies by both pharmacological agents isn’t due to disruptive effects on normal behaviour per se.”

Additionally, anhedonia, reduced cocaine reward, and dopamine dysfunction has been reported in a rat model of PTSD [link].

A neuroimmune network hypothesis of reward system dysfunction has also been proposed: “…early-life adversity amplifies crosstalk between peripheral inflammation and neural circuitries subserving threat-related, reward-related, and executive control-related processes. This crosstalk results in chronic low-grade inflammation, thereby contributing to adiposity, insulin resistance, and other predisease states. In the brain, inflammatory mediators act on cortico-amygdala threat and cortico-basal ganglia reward, circuitries in a manner that predisposes individuals to self-medicating behaviors like smoking, drug use, and consumption of high-fat diets. Acting in concert with inflammation, these behaviors accelerate the pathogenesis of emotional and physical health problems.” [link]

Covered by the above article:

  • Early Adversity Sensitizes Threat Vigilance and Response Systems
  • Early Adversity Sensitizes Cells that Propagate Inflammation
  • Early Adversity Potentiates Crosstalk Between Threat Circuitry and Immune System
  • Early Adversity Potentiates Crosstalk Between Reward Circuitry and Immune System
  • Reduced Prefrontal Regulation Maintains Neuroimmune Network

More on NMDARs

My posts are all over the place (just like my thoughts) so in the hope I can restore some order, here is a review of NMDA related posts.

The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia

While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl-d-aspartate receptor (NMDAR) function. By highlighting postmortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics.

Targeting NMDARs and interneurons as a potential therapeutic strategy

“While current pharmacologic management of schizophrenia is dependent on D2 blockers, the evolving understanding of NMDAR and GABA interactions in schizophrenia holds promise for future therapeutics. As subunit-specific positive and negative allosteric modulators become available, this approach will increasingly be guided by selective targeting of subpopulations of NMDARs in an approach consistent with their neurodevelopmental expression.

Several drugs acting at the glycine binding site of NMDARs have been tested with mixed results over the past 20 years (Tuominen et al., 2005). Increasing glycine via dietary supplementation (Rosse et al., 1989, Costa et al., 1990, Javitt et al., 1994 and Heresco-Levy et al., 1999) or by inhibiting glycine reuptake with the competitive inhibitors sarcosine (Tsai et al., 2004) or bitopertin (Umbricht et al., 2014) has been shown to ameliorate negative symptoms of schizophrenia, although results have been inconsistent (Buchanan et al., 2007 and Goff, 2014). Other trials have supported the efficacy of high dose d-serine (Tsai et al., 1998, Heresco-Levy et al., 2005 and Kantrowitz et al., 2010) and low dose d-cycloserine (Goff et al., 1999b) but again, negative results have also been reported (Goff et al., 2005, Buchanan et al., 2007 and Weiser et al., 2012). The difficulty in replicating early positive findings may reflect the larger problem of heterogeneity in schizophrenia and the unreliability of clinical trials in this population. In addition, clozapine and possibly other second generation antipsychotics may enhance glutamatergic transmission, thereby complicating pharmacologic add-on strategies (Goff et al., 1999a, Goff et al., 2002, Wittmann et al., 2005 and Fumagalli et al., 2008). Repeated dosing with glycine site agonists may produce tachyphylaxis via endocytosis of NMDARs (Nong et al., 2003 and Parnas et al., 2005) which has led to intermittent dosing strategies (Goff et al., 2008 and Cain et al., 2014).

Intracellular pathways downstream of NMDARs may also present targets for pharmacologic intervention, as exemplified by nitric oxide augmentation by nitroprusside infusion (Hallak et al., 2013).

Of note, clozapine reverses the loss of PV in interneurons produced by repeated administration of NMDAR antagonists in adult mice (Cochran et al., 2003) and differs from other antipsychotics in showing efficacy for the glycine site of the NMDAR (Schwieler et al., 2008).

Another promising new pharmacologic approach targets the Kv3.1 channel which is primarily localized on PV + interneurons (Yanagi et al., 2014).

It remains to be established whether newer strategies, such as interneuron precursor transplants (Gilani et al., 2014) and transcranial electrical stimulation (Filmer et al., 2014) will prove effective in correcting interneuron functional deficits.

Given the many genetic links between schizophrenia and NMDAR pathways, a personalized medicine approach may produce larger and more consistent therapeutic benefits which could fundamentally advance our understanding of the illness and expand our available therapeutic options.”

A recent study by found “for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.” [1]

A 2013 article reviews the following NMDAR-based therapeutics (direct and indirect) which have also been somewhat covered on this site:

Glycine transporter-1 (GlyT-1) inhibitors [sarcosine]
d-Serine and d-amino acid oxidase (DAAO) inhibitors [Treatment of negative symptoms]
AMPA receptor positive allosteric modulators (PAMs)
mGlu2/3 receptor agonists and mGlu2 PAMs

M1 receptor allosteric agonists and PAMs [Review]

The evidence for the use of adjunctive glutamate modulators in schizophrenia is reviewed here and in a meta-analysis here.

Also reviewed in the article are:

mGlu5 receptor PAMs

“Numerous mGlu5 PAMs have been reported to be efficacious in various preclinical antipsychotic and cognition models. However, despite the mounting evidence that mGlu5 PAMs show promise as potential novel antipsychotics, drug discovery efforts face various challenges. In addition to ‘flat’ SAR and challenging activity landscapes, multiple series have exhibited ‘molecular switches’, whereby minor structural changes dramatically alter the pharmacological profile of a series. ‘Molecular switches’ may also apply to metabolites generated, rendering the development of potential candidates considerably more difficult. In addition, despite the potential therapeutic advantages of allosteric modulation, mechanism-based neurotoxic effects were recently observed in rats orally dosed with mGlu5 PAMs. The study was conducted with a small set of four structurally similar modulators, and the effects observed include convulsion-like behaviors, abnormal mouth movements, decreased activity, and neuronal cell death; similar behaviors elicited by i.c.v. administration of (S)-3,5-DHPG. Additional studies are required to ascertain what factors contributed to these adverse effects and to ensure that other structural classes of mGlu5 PAM scaffolds do not share these liabilities. These questions will likely need to be addressed prior to clinical evaluation of mGlu5 PAMs.”

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including autism spectrum disorders, drug addiction, schizophrenia, and Fragile X syndrome. There is strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder [2]. mGluR5 PAMs may have therapeutic utility in targeting specific aspects of impulsivity and executive dysfunction [3], resilience to chronic stress [4, 5]  and in treating disorders of sociability [6, 7]. A mGluR5 potentiator induces a pro-vigilant profile that is distinct from that of amphetamine, caffeine and modafinil [8]. mGluR5 signalling is important for synapse formation, neuroplasticity and long term potentiation as well as neuroprotection and has been shown to have a regulatory role in neuroinflammation [9].  mGluR5 PAMs and NAMs differentially affect mPFC dendritic spine structural plasticity [10].

mGlu5-GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia has been investigated and may open up new avenues for therapeutics [11]:

“Both mGlu5 and GABAB receptor modulators [GABAB (GS39783 and CGP7930), mGlu5 (CDPPB)] effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783, induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches.”

GABAB agonism has been proposed to be a novel strategy for modifying the regulatory role of prefrontal and striatal glutamate on striatal dopamine levels [12]:

“There has been substantial progress in translating animal models to human research focusing on schizophrenia (Modinos et al., 2015). It was shown that hippocampal electrophysiological activity enhances phasic firing of midbrain dopamine neurons (Grace et al., 2007), indicating a potential excitatory effect of glutamatergic input on midbrain dopamine firing via the hippocampus. Such glutamatergic input was shown to act locally at striatal presynaptic dopamine terminals via ionotropic (e.g., NMDA) receptors to facilitate tonic and impulse-independent phasic dopamine release (Borland and Michael, 2004), but glutamate may also indirectly enhance striatal dopamine via reuptake inhibition (Whitton, 1997). Regarding prefrontal glutamate, there is support that glutamatergic projections from the PFC influence dopaminergic projections to the striatum via GABA interneurons (Mora et al., 2002). Interestingly, infusion of the GABA(B) receptor agonists C4H12NO2P and baclofen into the PFC and striatum reduced dopamine levels, and this effect was reversed by a GABA antagonist (Balla et al., 2009). However, more research regarding specific receptor interactions potentially mediating the presented findings is needed.”

To conclude “mGlu5 receptor PAMs are effective in several animal models predictive of antipsychotic activity, and are currently tested in phase2 clinical trials” [13]

Kynurenine aminotransferase II (KATII) inhibitors

“Kynurenine aminotransferase II (KAT II) is involved in the KYNA biosynthetic pathway, and it is speculated that inhibition of KAT II would lower endogenous central KYNA levels and enhance NMDA receptor function. In fact, KAT II knockout mice showed reduced hippocampal KYNA levels (up to 70% reduction) and enhanced performance in cognition models relative to wild-type controls. The early KAT II inhibitor tool compounds (S)-ESBA and BFF-122 were poorly CNS penetrant and required central administration to assess antipsychotic activity.  However, recent KAT II inhibitors with improved oral bioavailability and CNS penetration are in various stages of pre-clinical development.  Pfizer’s pre-clinical candidate PF-04859989 was reported to produce a dose-dependent reduction in brain KYNA levels in rats (up to 80% reduction in the prefrontal cortex), and it demonstrated in vivo efficacy in rodent and nonhuman primate cognition models. The inhibitor also rapidly reversed anhedonia in a rodent chronic mild stress model, suggesting it may also improve negative symptoms.”

GluN2 subtype selective NMDA receptor modulators

“…the NMDA receptor is a heterotetrameric complex composed of two GluN1 and two GluN2 (GluN2A–D) sub-units. NMDA receptors may be comprised of the same or two different GluN2 sub-units, and the GluN2 sub-unit composition influences the expression and biophysical characteristics (e.g., open probability and channel gating kinetics) of the receptor. The GluN2A/B sub-units are found extensively throughout the forebrain, whereas GluN2C/D subunits are largely expressed in the cerebellum, basal ganglia, and on hippocampal and cortical interneurons.

Sub-unit selective GluN2B negative allosteric modulators (NAMs), such as ifenprodil, have been studied to assess therapeutic potential for various CNS disorders (e.g., depression, neuropathic pain, cerebral ischemia, Alzheimer’s disease, and Parkinson’s disease) and they have been used extensively as pharmacological tools to elucidate the role GluN2B NMDA receptors play in synaptic plasticity and cognition. Mutagenesis, molecular modeling, and X-ray crystallographic studies have shown that ifenprodil and similar analogues bind to a distinct allosteric site located on the GluN2B ATD.The GluN2B NAM traxoprodil (CP-101,606)  was reported to induce a dose-dependent impairment of cognitive function and memory as well as cause psychomimetic effects in Phase II clinical trials for traumatic brain injury and major depressive disorder.These data lend further support to the glutamate hypothesis and suggest subtype selective GluN2B PAMs may offer an approach to treat schizophrenia.

Despite considerable efforts in the area of GluN2B NAMs, drug-like and selective GluN2B PAMs have yet to be reported. The endogenous polyamine spermine was found to potentiate NMDA receptor-mediated responses at GluN2B by increasing glycine affinity and reducing proton-induced inhibition of the receptor. However, the compound is weakly potent (163 μM) and does not possess drug-like characteristics for further development. The neurosteroid pregnenolone sulfate (PS) was also found to potentiate GluN2B NMDA receptors, but it does not exhibit GluN2 subtype selectivity.

With the exception of GluN2B NAMs, GluN2 subtype selective modulation is a relatively nascent field. Selective modulation of NMDA receptor subtypes holds considerable promise for the treatment of various CNS disorders, including schizophrenia, and a better understanding of the distinct pharmacological roles of the GluN2 subtypes is to be gained as additional tool compounds exhibiting good selectivity and improved drug-like characteristics are identified.”

An approach not mentioned in the article is α5 GABAA receptor modulation. Recently it was found that negative modulation of α5 GABAA receptors may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion [14]:

“Reportedly, negative modulation of α5 GABAA receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of α5 GABAA receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-d-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of α5 GABAA receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia.”

See also:

Novel Treatments of Psychosis (2015)

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. (2015)

Effect of l-theanine on glutamatergic function in patients with schizophrenia (2015)

A focus on memantine

Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia – an opportunity to target NO?

A focus on memantine

A focus on memantine Memantine.svgMemantine may offer clinical improvement in positive and/or negative psychopathology when combined with antipsychotics, as well as improvements in cognitive and/or functional domains. It may also allow for reduction of antipsychotic doses [1]. Memantine is an uncompetitive NMDA antagonist (showing rapid on-and-off kinetics) and is hypothesised to be capable of reducing cortical and prefrontal signal-to-noise patterns, thus improving symptoms [see review]. Research concludes that there is a “low but significant block of NMDA receptors [~ 30% NMDAR occupancy] by memantine at nontoxic therapeutic doses (~20mg/day)” and at clinically relevant concentrations memantine can promote synaptic plasticity, protect against excitotoxicity and preserve or enhance memory whilst lacking cognition impairing and psychotomimetic properties [2,3].

“…memantine  preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission”

Memantine also antagonises α7 nAChRs (more potently than the NMDAR) [4] and acts as a non-competitive antagonist at the 5-HT3 receptor.

Changes in astrocytic glutamate uptake due to chronic administration of memantine have been reported [5].

A Cochrane Review Intervention Protocol [6] concludes:

“Schizophrenia’s traditional models of the causative pathology have focused mainly on the dopamine hypothesis (Olney 1995). It has been suggested that there could be a possible role for other neurotransmitters such as serotonin, acetylcholine and glutamate in treating schizophrenia. This is based on the fact that currently available antipsychotics, both conventional and second generation, leave many symptoms untreated and cause undue side effects (Stone 2007).

Lately, the focus has been on the role of the excitatory neurotransmitter glutamate acting via NMDARs (Bondi 2012). It is therefore imperative to undertake a systematic review of the current studies with a view to establish if memantine with an uncompetitive antagonist action at NMDA receptors could be added to the armoury of drugs for treating schizophrenia.”

A recent study found evidence of possible enhanced cognition and function in patients with chronic psychosis treated with acute doses of memantine:

Memantine Effects on Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis.

Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), NMDA antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here, we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: 1) placebo vs. 10 mg of memantine, or 2) placebo vs. 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age-dependent and most evident in older CPD patients, while those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.

Memantine in the Treatment of Negative and Cognitive Symptoms” reviews several meta-analyses and finds that current evidence is limited by the lack of consistent results. Memantine is well-tolerated with minimal adverse effects (auditory hallucinations were reported by Lieberman et 4/69 patients). Memantine appears to be safe for use in patients with schizophrenia but cannot be routinely recommended as an adjunctive treatment for negative or cognitive symptoms. Large, adequately powered studies with well-defined, clinically meaningful outcome measures are desired to determine the role of memantine in the treatment of negative and cognitive symptoms of schizophrenia

“Memantine holds great promise as adjunctive therapy for treatment of schizophrenia. Randomized controlled trials, wherein memantine is administered at adequate doses for an adequate period of time to ongoing antipsychotic treatment are required to confirm its efficacy in alleviating symptoms of schizophrenia.”


The effect of add-on memantine on global function and quality of life in schizophrenia: A randomized, double-blind, controlled, clinical trial.


Schizophrenia severely influences function and quality of life. The benefit of newer antipsychotics in improving the quality of life in schizophrenia still remains controversial. The aim of the present study is to evaluate the effect of memantine on global function and quality of life in patients with schizophrenia.


This was a randomized controlled trial on inpatient cases of schizophrenia in Noor University Hospital, Isfahan, Iran. A number of 64 patients were selected through sequential sampling; patients were randomly allocated in intervention and placebo groups. The intervention group was treated with memantine plus previously administered, stabled-dose, atypical antipsychotic, while the control group received placebo plus previously administered, stabled-dose, atypical antipsychotic. Memantine administration was initiated at 5 mg daily; the dosage was increased at weekly intervals by 5 mg and finally up-titrated to 20 mg daily within 4 weeks. All patients were assessed by means of Global Assessment of Functioning (GAF) and quality of life scale (QLS) initially and every four weeks to the end of the 12th week.


Analysis of baseline GAF and QLS scores showed no significant differences between the two groups (P = 0.081 and P = 0.225, respectively). GAF and QLS scores increased in both groups; but it was higher in the intervention group. The difference between the two groups was statistically significant. (P < 0.001 and P < 0.001, respectively) memantine was well tolerated, with no significant side effects.


Add-on memantine was significantly effective in improving the global function of patients as well as their quality of life.

See also:

Memantine augmentation in clozapine-refractory schizophrenia: a randomized, double-blind, placebo-controlled crossover study.

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. (2015)

Unfortunately, a recent systematic review and meta-analysis has found no pro-cognitive benefits from glutamate modulators in schizophrenia:

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials.

Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

” …this is the first comprehensive meta-analysis to examine the effects of glutamate positive modulators on cognitive deficits in patients with schizophrenia. As a whole, glutamate positive modulators were not found to be superior to placebo as an adjunctive therapy to antipsychotics although 5 out of 17 individual studies have demonstrated their procognitive effects”

cognition glu
Effects of glutamate positive modulators on overall cognitive function. There were no significant differences in effects on overall cognitive function between glutamate positive modulators and placebo in patients with schizophrenia. CI, confidence interval; DCS, D-cycloserine; IV, inverse variance; SE, standard error; Std, standard.

“As a whole, glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, CI=−0.06 to 0.23, P=0.57) and each of eight cognitive domains in patients with schizophrenia.”

  • Minocycline was effective for attention/vigilance (SMD=0.42, CIs=0.02 to 0.82, P=0.04)*
  • DCS had negative effects on visual learning (SMD=−0.48, CIs=−0.86 to −0.09, P=0.01)*
    *These results, however, did not survive after adjusting for multiple comparison testing (the significance level was set at a Bonferroni corrected P-value of<0.05/(10 × 8) (10 compounds and 8 cognitive domains).
  • Glycine allosteric site of NMDA receptors: “There were no differences between the drugs (benzoate, DCS, d-serine, glycine, and Org25935) and placebo in terms of overall cognitive function.”
  • AMPA receptors: “Beneficial effects of the drugs (CX516 and minocycline) on attention/vigilance were found compared to placebo (four studies, n=205, SMD=0.32, CIs=0.01 to 0.64, P=0.05); the statistical significance did not survive after adjusting for multiple comparison testing in two subgroups and eight cognitive domains (a significance level of P<0.05/2 × 8)”
  • By concomitant antipsychotics: “No difference was found in subjects on non-clozapine antipsychotics between the drugs and placebo with respect to overall cognitive function (no data for overall cognition available for those on clozapine).”
  • By diagnosis of schizophrenia: “Among the studies that included subjects with schizophrenia only, we found beneficial effects of glutamate positive modulators on attention/vigilance (seven studies, n=460, SMD=0.20, CIs=0.01 to 0.39, P=0.04), which, however, was not confirmed after adjusting for multiple comparisons in 8 cognitive domains (significance level of P<0.05/8)”
  • Meta-regression analyses: “It was found that the higher the proportion of males in studies, the lower the SMDs of effects of glutamate modulators on overall cognitive function (11 studies, n=858, slope=−0.01, 95% CI: −0.03 to −0.002, P=0.03). There were no associations between the SMDs and age, duration of illness, concomitant antipsychotic dose, baseline PANSS total score, and baseline Clinical Global Impression score”

Some of the research is in its infancy:

“Notably, in the past several years, a number of compounds have been identified to enhance glutamatergic signaling. Minocycline, a tetracycline with broad-spectrum antimicrobial activity, has been suggested to increase GluR1 subunit phosphorylation and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiation. l-carnosine, a co-localized dipeptide with glutamate,and N-acetylcysteine, a precursor of glutathione, may enhance NMDA signaling via the redox site of the NMDA receptor. Pregnenolone, a neurosteroid, elevates serum pregnenolone sulfate, which in turn positively modulates NMDA receptors via a non-canonical G protein, phospholipase C, and a Ca2+ dependent mechanism. These promising compounds were not included in the previous studies. Therefore, it is critically important to include those new drugs and conduct a more comprehensive meta-analysis in order to provide robust evidence on the effects of glutamate positive modulators on cognitive functions in patients with schizophrenia.”

The limitations of the above study provide some hope and guidance for future research:

“The present report must be considered in light of various limitations. First, the number of included subjects and individual studies was still small. Second, we did not examine the long-term effects of glutamate positive modulators since duration of individual studies did not exceed 36 weeks. Third, the total number of subjects and studies varied across cognitive domains, as not all studies examined all cognitive domains. The results for specific cognitive domains that are based on a small number of studies or subjects need to be considered as preliminary. Fourth, it is worth noting that many of the drugs included in this study have different mechanisms of action even though each involves the glutamatergic system. As such, combining compounds with different glutamate-influencing mechanisms represents a limitation of our study. To somewhat address this limitation, we conducted subgroup analyses by the pathway of drugs to enhance the glutamatergic neurotransmission in which drugs were divided into the glycine allosteric site of NMDA receptor and AMPA receptor groups. However, the aforementioned limitation still exists for this subgroup analysis. Further research is necessitated to examine the relationships between procognitive effects and specific glutamate-influencing mechanisms of action. Fifth, some of the included compounds have been reported to have other mechanisms of action such as glutamatergic signal enhancers, anti-inflammation, or neuroprotection. Sixth, 15 out of 17 studies enrolled subjects within the chronic stage of the illness. It remains unclear whether these compounds have effects on subjects in the early stage of the illness (for example, FEP). Seventh, influences of concomitant antipsychotics are not clear. For example, 5 out of 17 studies did not discriminate between those taking clozapine, which has been reported to modulate glutamatergic signaling, and those taking non-clozapine antipsychotics. Eighth, although we included only double-blind randomized placebo-controlled trials, only 24% of the studies had a ‘low risk’ of bias, which should be carefully taken into account. Ninth, a possibility of publication bias should not be dismissed. Finally, we did not examine adverse events, which clearly hinders us from making a balanced risk-and-benefit decision.”

Some direction towards future research avenues is provided:

“…further research is needed to elucidate optimal dose ranges and route of administration of the drugs acting on glycine allosteric site in an effort to derive procognitive effects in schizophrenia.”

“Given that attention/vigilance has a crucial role in predicting favorable outcomes in patents with schizophrenia, AMPA positive modulators in particular, which may have beneficial effects on attention/vigilance, might have a role in improving functional outcome. …future studies are necessitated to investigate this relationship, given that there was a tendency that AMPA positive modulators might improve attention/vigilance.”

To conclude:

“The findings from this meta-analysis indicate that glutamate positive modulators were not effective for overall cognitive deficits in patients with schizophrenia. Further research is required to elucidate the role of the glutamatergic system on the cognitive dysfunction observed in schizophrenia. Going forward, it is necessary to characterize a subgroup of patients for which glutamate modulators are specifically procognitive within this heterogeneous population.”

Effect of l-theanine on glutamatergic function in patients with schizophrenia (2015)

Effect of l-theanine on glutamatergic function in patients with schizophrenia


Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. Previous studies suggested that l-theanine affects the glutamatergic neurotransmission and ameliorates symptoms in patients with schizophrenia. The aims of the present study were twofold: to examine the possible effects of l-theanine on symptoms in chronic schizophrenia patients and to evaluate the changes in chemical mediators, including glutamate + glutamine (Glx), in the brain by using 1H magnetic resonance spectroscopy (MRS).


The subjects were 17 patients with schizophrenia and 22 age- and sex-matched healthy subjects. l-Theanine (250 mg/day) was added to the patients‘ ongoing antipsychotic treatment for 8 weeks. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index scores and MRS results.


There were significant improvements in the PANSS positive scale and sleep quality after the l-theanine treatment. As for MRS, we found no significant differences in Glx levels before and after the 8 week l-theanine treatment. However, significant correlations were observed between baseline density of Glx and change in Glx density by l-theanine.


Our results suggest that l-theanine is effective in ameliorating positive symptoms and sleep quality in schizophrenia. The MRS findings suggest that l-theanine stabilises the glutamatergic concentration in the brain, which is a possible mechanism underlying the therapeutic effect.

  • l-theanine attenuates MK-801-induced deficits in prepulse inhibition (PPI) in rats and displays antipsychotic and antidepressant-like activity [1]
  • l-theanine improves PPI in healthy humans: “The administration of 200 mg of l-theanine and that of 400 mg, but not 600 mg, significantly increased the % PPI compared to the baseline”  [2]
  • Several studies show that l-theanine has an influence on mood
  • l-theanine increases sleep quality and satisfaction without increasing sleep duration or causing wake-up grogginess [3]
  • an 8-week, randomized, double-blind, placebo-controlled, 2-center study showed that l-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder [4]
  • Circulating BDNF levels and cortisol-to-DHEAS*100 molar ratio may be involved in the beneficial clinical effects of l-theanine as an augmentation strategy with antipsychotic therapy in schizophrenia and schizoaffective disorder patients [5]

“8-week add-on l-theanine treatment significantly reduced the PANSS scores in schizophrenia patients who were under treatment with antipsychotic medication. MRS revealed that l-theanine affected the concentration of Glx in the frontal and inferior parietal regions. Interestingly, there were significant negative correlations between Glx at baseline and the % ratio in Glx at the frontal and inferior parietal regions. To our knowledge, this is the first study that obtained evidence of the effect of l-theanine on Glx, which is related to glutamatergic neurotransmission in humans.

The therapeutic effects of l-theanine against the schizophrenic symptoms observed in the present study are consistent with those of previous studies. In addition, our finding of a positive effect of l-theanine on sleep supports the results of preceding studies.

l-Theanine, which has a chemical structure that is similar to that of glutamate, affects glutamatergic neurotransmission. The effects of l-theanine on schizophrenia symptoms and Glx concentrations in the brain observed in the present study might be attributable to its chemical structure. It is known that l-theanine has weak affinities for kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and NMDA receptors. On the other hand, l-theanine was reported to be able to suppress the excitotoxic release of glutamate derived from the Gln/glutamate cycle through the inhibition of Gln incorporation in glutamatergic neurons in a particular situation.

In a previous study, we focused on the effect of l-theanine on PPI, a measure of sensorimotor gating that is known to be impaired in schizophrenia , and we observed the enhancement of PPI at particular doses of l-theanine. It is possible that l-theanine exerts its effects, at least in part, through a partial agonistic-like action on the glutamatergic system. …l-theanine may have a stabilising effect on the glutamatergic neurotransmission.

Several studies examined glutamatergic changes in first-episode schizophrenia, chronic schizophrenia, and individuals at high risk for schizophrenia. The results obtained at each clinical stage and the clinical severity indicate that the glutamatergic metabolites of schizophrenia change in a course-dependent manner. l-Theanine was shown to be a safe and well-tolerated medication, and the stabilising effect of l-theanine on glutamatergic neurotransmission could be of significant benefit in clinical practice.”