Glycine, NMDA and AMPA augmentation – a review

The NMDA receptor ‘glycine modulatory site’ in schizophrenia: d-serine, glycine, and beyond. [Review]

Targeting of NMDA receptors in new treatments for schizophrenia

Sarcosine, [1, 2] via inhibiting the uptake of glycine through GLYT1 inhibition, is a novel strategy. Easily administrated doses of sarcosine make it a potentially preferable option to glycine and D-serine. Some worsening of symptoms has been noted at doses in excess of 2000mg and a case of hypomania has been reported

“…sarcosine may reduce negative symptoms in acutely ill schizophrenia patients receiving atypical antipsychotics, being more effective than the NMDA/glycine site agonist d-serine”

Skeletal formula of sarcosineSee: ‘Sarcosine Therapy – A New Complementary Direction for Schizophrenia Treatment?

“There have been more than 70 placebo-controlled clinical trials of glycine modulatory site (GMS) agonists in schizophrenia, including d-serine, glycine, d-cycloserine (DCS), and d-alanine. The results have been mixed; many studies reported significant improvements over multiple symptom domains while others did not. Other than intrinsic differences in efficacy among these GMS agonists, methodological factors likely contributed to the variability in results among these trials, most notably small sample sizes, differences in concomitant typical and atypical antipsychotic use, and subject compliance.”

Glycine has poor efficacy and requires high doses (at least 60 g/day).

The more CNS penetrant co-agonist at the glycine site of the NMDAR, D-Serine, has also shown benefit. When analysed alone, d-serine improved total psychopathology, negative symptoms, and cognitive symptoms. In healthy adults, D-serine (2.1g/day orally) “reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists.” [3]  It may aid cognitive remediation in schizophrenia [4]

“Although d-serine is substantially metabolized, daily doses of 30–120 mg/kg were effective.”

“…there is concern about nephrotoxicity at higher doses, although no significant adverse events have yet been observed at doses of ≤4 g/day”

“The use of DSR as NMDAR-GLY site probe has several cardinal advantages. DSR penetrates better the blood-brain-barrier and has a stronger affinity versus GLY at the NMDAR-GLY site at which, unlike DCS, acts as a specific and potent full agonist. DSR is thought to represent the primary forebrain NMDR co-agonist and unlike GLY is known to act exclusively at the NMDAR-GLY site. Moreover, in contrast to GLY, DSR may preferentially act at synaptic NMDARs which are involved in signal transduction of cell survival pathways. In animal models, DSR was shown to have procognitive and antidepressant/anxiolytic effects and reduced DSR serum and cerebrospinal fluid levels were documented in schizophrenia”

“DSR may induce improvements in cognitive parameters and reduction of subjective feelings of sadness and anxiety. Although the effects were overall modest and did not extend to all the measurements employed, the findings are remarkable given that the study: 1) used a single dose paradigm and 2) included a young population composed mainly of university students.”

“…an apparently contradictory body of data advocates in favor of NMDAR agonists efficacy as antidepressants. NMDAR-GLY site agonists improve depressive symptoms in schizophrenia patients and DSR is efficient in depression and anxiety animal models. Moreover, the GLYT1 inhibitor sarcosine and the d-amino acid oxidase inhibitor sodium benzoate were recently reported to be beneficial in depressed patients who were drug naïve for at least 3 months and had no history of treatment-resistance.”

“Depression feelings are improved in both schizophrenia and normal subjects by DSR; and in schizophrenia and non-refractory depression by sarcosine.”

D-serine has shown benefits in treating a patient positive for anti-NMDA receptor antibodies: Clinical and Electrophysiological Effects of D-Serine in a Schizophrenia Patient Positive for Anti-N-Methyl-D-Aspartate Receptor Antibodies

D-cycloserine, a glycine site partial agonist may be effective, particularly in combination with cognitive remediation. Research is conflicting:

“Glycine, d-serine, and sarcosine significantly improved multiple symptom domains, whereas no symptom domain was improved by d-cycloserine. Furthermore, glycine, d-serine, and sarcosine were found to be superior to d-cycloserine in improving overall psychopathology”

NOTE: Chronic d-serine promotes NMDAR internalization; chronic d-cycloserine results in desensitization; exogenous glycine may preferentially act at extra-synaptic NMDARs

Sodium benzoate, a DAAO inhibitor, offered a significant improvement in a single study with 500mg b.i.d [5] Attempts to replicate these findings in a single patient (1000mg mane, patient stabilised on clozapine) led to some worsening of positive symptoms.

“…sodium benzoate (SB), a prototype competitive d-amino acid oxidase inhibitor, was effective in the treatment of several symptoms, such as positive and negative symptoms, and cognitive impairment in medicated patients with schizophrenia.”

Sodium benzoate Sodium benzoate administration has been studied in a NMDA antagonist animal model of schizophrenia.

Meta-analysis of double-blind, placebo-controlled studies of small-molecule NMDA receptor enhancers in patients with schizophrenia. Sample size: 26 studies comprising about 800 patients. Effect size (ES) for glycine, d-serine, d-cycloserine, sarcosine, and all in different symptom domains of schizophrenia. See other results here

These findings may not extend to use with clozapine:

“Relative to effects in combination with typical or newer atypical antipsychotics, glycine site agonists have proved less effective when combined with clozapine. In double blind, placebo-controlled studies in which glycine (Evins et al., 2000) or D-serine (Tsai et al., 1999) has been added to clozapine, no significant beneficial response has been observed, while D-cycloserine is reported to lead to the worsening of symptoms when used in combination with clozapine (Goff et al., 1996).”

Other findings and different routes of administration:

“…intravenous administration of 100 and 200 mg/kg (D’Souza et al., 2000), and 200 mg/kg (Neumeister et al., 2006) GLY did not result in significant behavioral or neuropsychological effects. Significant cognitive effects were neither observed following acute oral administration of 0.8 g/kg GLY (Palmer et al., 2008) or 50 mg d-cycloserine DCS (D’Souza et al., 2000) which acts as a partial NMDAR agonist. In contrast, 100 mg GLY sublingually (File et al., 1999) and oral administration of 1.2 g of the GLY precursor milacemide (Schwartz et al., 1991) were reported to improve performance of memory tasks in healthy subjects. Moreover, Onur et al. (2010) and Kuriyama et al. (2011) have recently shown that DCS (250 mg and 100 mg single doses) improve declarative and procedural learning, respectively. Feld et al. (2013) demonstrated that DCS (175 mg) can enhance sleep-dependent declarative memory consolidation.”

Trials have been conducted with allosteric AMPA receptor modulators (‘‘AMPAkines’’), as well as metabotropic receptor agonists and antagonists, including a recent trial of the mGluR2/3 agonist LY-2140023.

“Piracetam augmentation of haloperidol was capable of improving psychotic symptoms in schizophrenia, but had no effect on PANSS. Because only 30 patients (all receiving haloperidol) completed the placebo-controlled trial, more scientific evidence is needed to support such an effect.

Trials with CX156 led to controversial results. In a small study, CX156 improved cognitive functions and negative symptoms in schizophrenic patients when compared to patients treated with clozapine. However, a larger study was unable to show any effect of CX516 on cognition or negative symptoms when compared to controls. Taken together, there is only little evidence about these molecules and their therapeutic effect.”

Some trials of mGluR2/3 agonists have been ceased due to lack of efficacy.

Metabotropic glutamate receptors as drug targets:what’s new?

“Metanalysis of clinical studies showed that pomeglumetad was effective in schizophrenic patients that were early-in-disease and had not been treated with atypical antipsychotics inhibiting 5-HT2A receptors (S. Stauffer, presented at the 8th international meeting on mGlu receptors, Taormina, Italy; September 28–October 3, 2014). This is in line with the evidence that treatment with atypical antipsychotics causes an epigenetic down-regulation of mGlu2 receptors in the prefrontal cortex. Thus, there is still optimism for the use of mGlu2/3 agonists or mGlu2 PAMs in the treatment of schizophrenia in targeted subpopulations of patients.

mGlu5 receptor PAMs are the other major candidate drugs in the treatment of schizophrenia. mGlu5 receptors are functional partners of NMDA receptors at many synapses of the CNS. mGlu5 receptor PAMs are effective in several animal models predictive of antipsychotic activity, and are currently tested in phase2 clinical trials”

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end? concludes:

“Despite the progress that has been made, many questions still exist, including the effective and safe window of mGluR2/3 agonists in different developmental periods, the difference between mGluR2/3 agonists and more selective mGluR2 agonists and PAMs, as well as the comparison between mGluR2/3 agonists and other antipsychotic drugs. More specifically, it is unknown whether the opposite effects of mGluR2/3 on pre-and postsynaptic sites could explain the failed action in improving SZ symptoms in clinical trials. Are the effects of mGluR2/3 agonist cell-type (excitatory pyramidal neurons versus inhibitory GABAergic interneurons) and brain region (PFC, hippocampus, ventral tegmental area, and other limbic areas) specific? Are the effects of mGluR2/3 agonist age- and/or SZ stage-dependent? Answering these questions in the future will certainly not only enhance our understanding of the mGluR2/3 effects in brain function but also provide better insights into the development of novel compounds targeting mGluR2/3 for clinical intervention of SZ. Only by solving these mechanistic puzzles can we put mGluR2/3 agonists into clinical trials and provide the optimal therapeutic benefit for individuals afflicted with SZ or other related psychiatric disorders.”

“In summary, as a potential non-dopaminergic “antipsychotic” drug, pharmacological activation of mGluR2 or mGluR3 still holds promise in alleviating symptoms of SZ. Especially, given the low side effects and high tolerability profile, selective mGluR2 agonist and mGluR2 PAM are still considered promising candidates for pharmacogenomic treatment or as an adjunct to current antipsychotic drugs in the treatment of SZ, particularly for cognitive and negative symptoms. The failure of current clinical trials should not be interpreted as a default termination of all potential studies on group II mGluRs because as discussed above, the precise manner of the execution of a clinical trial can have profound consequences for the ultimate outcome of the trial. Based on the literature review, we argue that until the mechanisms associated with mGluR2 or mGluR3, individually or jointly as mGluR2/3, are clearly elucidated, it is important to continue the study of mGluR2/3 as a therapeutic target for SZ.”

N-Acetylcysteine (NAC) enhances the endogenous activation of mGlu2/3 receptors by activating the glial glutamate:cystine membrane exchanger.

Sunifiram, via modulation of the glycine site of NMDAR (although less efficacious as an agonist than glycine) alongside AMPA receptor mediated effects, is anecdotally effective for both cognitive and positive symptoms. Further studies are required to evaluate its effectiveness but estimated human doses are low: 5-15mg orally. Sunifiram.png

  • For a hypothetical review of the promise of novel nootropics in the treatment of schizophrenia, see here

Memantine, an uncompetitive NMDA antagonist, 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. A combination of galantamine and memantine has been proposed as an intervention to improve cognition in schizophrenia. Memantine.svg

“…memantine [is] a weak noncompetitive NMDAR partial antagonist of low affinity (Gardoni and Di Luca, 2006) which at therapeutically relevant plasma concentrations produces only 30% NMDAR occupancy (Mor’e et al., 2008).”

Low-dose lamotrigine augmentation therapy seems to improve residual symptoms in some cases of treatment resistant schizophrenia.

The weak uncompetitive NMDA antagonist and putative immunomodulator dextromethorphan is yet another readily available augmentative strategy [6]. Dextromethorphan binds to several neurotransmitter receptors, notably and in rank order, to the serotonin transporter > sigma-1 receptor = norepinephrine transporter > NMDA receptor = mu opiate receptor [7]. Very high doses, leading to significant NMDA antagonism and related psychotomimetic effects, are likely to exacerbate positive symptoms. The study found that 60mg/day (doses low enough for insignificant NMDA antagonism via the parent compound, the potential role of the active metabolite is discussed later) improved immunological parameters such as TNF-α, IL-6 and IL-1β and inflammation in risperidone treated patients and lead to greater reductions in positive and negative symptoms, along with a faster treatment response over risperidone alone. Memantine has been proposed as another uncompetitive NMDA antagonist with therapeutic potential (mentioned earlier) and paradoxically, 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 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 [8]. Whether higher doses of other low-affinity uncompetitive NMDA antagonists such as dextromethorphan (or the more potent O-desmethyl metabolite, which would begin to antagonise the NMDA receptor more so than the parent compound) can also achieve similar outcomes needs to be verified. Potential interactions with other serotonergics and metabolism to the more potent NMDA antagonist by CYP2D6 necessitate caution with regard to potential drug-drug interactions. Nonetheless, a combination of dextromethorphan and quinidine (which inhibits CYP2D6, leading to higher serum levels) has been proposed as a potential treatment for bipolar disorder and MDD Dextromethorphan.svg Is there any evidence for glutamate modulators as an adjunctive treatment in schizophrenia?

High quality evidence suggests a medium effect of adjunctive glycine, D-cycloserine, D–serine or CX516 for improving overall and negative symptoms, but no benefit for cognitive function.

D-serine is most effective for overall symptoms when added to non-clozapine antipsychotics, and CX516 when added to clozapine.

For glycine, there is also moderate to low quality evidence of a small benefit for improved positive and depressive symptoms when compared to placebo.

For D-serine, there is moderate to low quality evidence for a small benefit for total psychopathology, negative, cognitive and depressive symptoms when compared to placebo.

For sarcosine, there is moderate to low quality evidence for small improvements in total symptoms, general psychopathology and negative symptoms when compared to placebo.

For memantine, there is moderate to low quality evidence for improving negative symptoms.

There is limited (low quality) evidence for the use of D-alanine or N-acetyl cysteine for improving outcomes in schizophrenia.

For patients with insufficient response to clozapine, moderate quality evidence suggests no improvements with glycine augmentation and low quality evidence is unable to determine any benefits of CX516, D-cycloserine, D-serine or sarcosine augmentation.

targeting nmda
From: Targeting of NMDA receptors in new treatments for schizophrenia

The Glutamate Hypothesis: A Pathogenic Pathway from which Pharmacological Interventions have Emerged  goes into more detail on this topic.

See also: Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system.
Glutamatergic synaptic transmission and treatment targets. In the central nervous system, glutamate (Glu) is released from presynaptic neurons and acts with postsynaptic glutamate receptors, including N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors. These ionotropic glutamate receptors are responsible primarily for fast synaptic transmission. Released glutamate is taken up by the excitatory amino-acid transporter (EAAT) on astrocytes, where it is converted to glutamine (Gln) and transported back to the presynaptic neurons. Glutamine is reconverted to glutamate and packaged into vesicles via the vesicular glutamate transporter (VGluT). Glycine is an inhibitory amino acid and obligatory co-agonist at the NMDA receptor (NMDA-R) complex. Positive allosteric modulators (PAM) on the glycine site potentiate the effect of NMDA-R-mediated transmission. Glycine is taken up by glycine transporters (GlyT). GlyT1 inhibitors increase NMDA-R-mediated transmission. Ampakines allosterically enhance AMPA receptors and facilitate synaptic plasticity. Glutamate signaling also occurs through metabotropic glutamate receptors (mGluRs). Group I mGluRs (mGluR1/5) induce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These excitatory Ca2+ flows activate cAMP-response element-binding protein (CREB), and neurotrophins such as brain-derived neurotrophic factor (BDNF), to regulate synaptic plasticity. mGluR5 PAMs can enhance such excitatory transmission. Group II mGluRs (mGluR2/3) regulate glutamate on presynaptic neurons and mGluR2/3 agonists inhibit glutamate release. Low extrasynaptic concentrations of glutamate are maintained in part by a transport system that mediates the exchange of glutamate for cystine. This cystine-glutamate antiporter produces glutathione, the primary endogenous antioxidant, for which N-acetylcysteine (NAC) is a precursor.

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