# Glutamate involvement in psychiatric conditions



## crayzyMed (Nov 2, 2006)

I'm still working on this, if anyone has any contributions please post.

A collection of the evidence and possible treatments.

Anxiety

The role of glutamate in anxiety and related disorders.
Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.

High-field MRS study of GABA, glutamate and glutamine in social anxiety disorder: response to treatment with levetiracetam.
Our findings provide preliminary support for impaired GABAergic and overactive glutamatergic function in social anxiety disorder and the potential relevance of changes in these systems for the anxiolytic response to levetiracetam.

Advances in the Treatment of Anxiety: Targeting Glutamate
Recently, however, the neurobiological literature has shown a convergence of findings focusing on the glutamatergic system in anxiety disorders, and the growth of pharmacological tools targeting these receptors has led to the development of novel treatments having anxiolytic effects in humans and animals alike. Additionally, as this system is showing promise as a final common pathway in the pathogenesis of anxiety disorders, we may be able to employ glutamate-specific neuroimaging techniques (e.g., N-acetyl-aspartate, GLX) to both guide treatment decisions and present reliable objective biomarkers for treatment efficacy.

Depression

Emerging role of glutamate in the pathophysiology of major depressive disorder.
Accumulating evidence suggests that the glutamatergic system plays an important role in the neurobiology and treatment of this disease. Some clinical studies have demonstrated that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant patients with MDD.

Glutamate and depression: clinical and preclinical studies.
Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR1,5 receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms.

The NMDA receptor as a therapeutic target in major depressive disorder.
Drugs that target the NMDA receptor have shown antidepressant properties in both clinical and preclinical studies.

The involvement of glutamate in the pathophysiology of depression.
Converging lines of evidence indicate that the glutamatergic system might be a promising target for a novel antidepressant therapy. Both ionotropic glutamate receptor ligands (functional NMDA receptor antagonists and AMPA receptor potentiators) and compounds acting at metabotropic glutamate receptors (mGluRs; group I mGluR antagonists, group II antagonists and group III agonists) produce antidepressant-like activity in several preclinical and some clinical studies.

Glutamate-based antidepressants: 20 years on.
This announcement closely follows a report that another NR2B antagonist, traxoprodil (CP 101 606), has antidepressant effects in patients unresponsive to a serotonin selective reuptake inhibitor, as well as reports of rapid and sustained antidepressant effects following a single injection of the NMDA antagonist ketamine. Here we describe evidence that glutamate-based therapies might represent an effective alternative to biogenic-amine-based agents for depression and provide perspectives on the development of these agents.

Obsessive-Compulsive Disorder

Glutamatergic Synaptic Dysfunction and Obsessive-Compulsive Disorder
In recent years, multiple lines of evidence have implicated glutamatergic synaptic dysfunction within the cortico-striatal-thalamo-cortical (CSTC) brain circuit in the etiology of OCD and related disorders, thereby prompting intensified effort in the development and evaluation of agents that modulate glutamatergic neurotransmission for the treatment of OCD. With this in mind, here we review the following topics with respect to synaptic dysfunction and the neural circuitry underlying OCD: (1) evidence supporting the critical involvement of the CSTC circuit, (2) genetic studies supporting the involvement of glutamatergic dysfunction, (3) insights from genetic animal models of OCD, and (4) preliminary findings with glutamatergic neurotransmission-modulating agents in the treatment of OCD.

Glutamatergic dysfunction--newer targets for anti-obsessional drugs.
Multiple lines of evidence point toward glutamatergic dysfunction being related to the pathophysiology of OCD, with glutamate modulating drugs being an alternative pharmacological strategy for treating OCD.

Glutamate and psychiatric disorders
Although the glutamatergic system is highly complex, there is increasing evidence for its involvement in a wide variety of symptoms seen in neuropsychiatric disorders and for the clinical potential of glutamatergic agents. It would appear from the available evidence that there are three main strands emerging. First, that hypofunction of the NMDA receptor system might be involved in the core symptoms of schizophrenia, perhaps by increasing activity in some non-NMDA systems and/or by a direct effect on dopaminergic neurotransmission. Second, that hyperfuntion in non-NMDA systems might underlie some of the more florid positive symptoms in psychotic disorders. And third, that metabotropic glutamatergic receptors might play an important role in anxiety disorders.


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## crayzyMed (Nov 2, 2006)

*Memantine*

Rat studies

Cognition-enhancing and anxiolytic effects of memantine.
These data indicate that high, stable doses of memantine improved cognition and exhibited a potential anxiolytic response in normal mice.

The combined effects of memantine and fluoxetine on an animal model of obsessive compulsive disorder.
The present study investigates the effect of fluoxetine and memantine alone and in combination in a mouse model of compulsive behavior. In this model, compulsive scratching is induced by a subcutaneous injection of serotonin or a serotonin releasing agent, compound 48-80, in the back of the neck. The effects of the memantine and fluoxetine combination were found to synergistic, specifically as defined by an isobologram.

Effects of glutamate-related drugs on marble-burying behavior in mice: implications for obsessive-compulsive disorder.
We examined the effects of glutamate-related drugs on marble-burying behavior, which is an animal model of OCD. The uncompetitive N-methyl-d-aspartate (NMDA) antagonists memantine (10 mg/kg, i.p.) and amantadine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity in mice.

Obsessive compulsive disorder

A Single-Blinded Case-Control Study of Memantine in Severe Obsessive-Compulsive Disorder
Conclusions: This study provides preliminary supportive evidence for the effectiveness of memantine as a glutamatergic augmenting agent in severe OCD. Future randomized double-blind placebo-controlled trials are warranted.

Differential Efficacy of Memantine for Obsessive-Compulsive Disorder vs. Generalized Anxiety Disorder: An Open-Label Trial.
Conclusions: These results suggest that memantine may have preferential efficacy in the treatment of OCD versus GAD. These preliminary findings warrant larger, placebo-controlled studies in OCD.

Memantine augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial.
SUMMARY: In this open-label augmentation trial of memantine in treatment-resistant OCD, almost half the subjects had a meaningful improvement in symptoms. Our study was limited by its small size, presence of comorbidities, and lack of control. Large double-blind placebo-controlled trials are needed to further test our findings.

Memantine augmentation for refractory obsessive-compulsive disorder. 
We report two cases of refractory obsessive-compulsive disorder treated with an augmentation of memantine at 15 mg/day. The first case did not benefit from such treatment, while the second showed immediate and substantial improvement.

Major depression

A double-blind, placebo-controlled study of memantine in the treatment of major depression.
CONCLUSIONS: In an 8-week trial, the low-to-moderate-affinity NMDA antagonist memantine in doses of 5-20 mg/day was not effective in the treatment of major depressive disorder.

Note that in trials where higher doses were used it was effective for major depression, the minimum dose for depression is 30 or 40mg.

An open-label, flexible-dose study of memantine in major depressive disorder.
Memantine demonstrated early-onset efficacy in patients with MDD. The treatment was well tolerated. This study suggests that double-blind, placebo-controlled studies of memantine in depression are merited.

Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence.
CONCLUSIONS: These data provide new evidence for the safety and potential efficacy of memantine and escitalopram for major depressive disorder in patients with comorbid alcohol dependence.

Post traumatic stress disorder

Pilot trial of memantine in the treatment of posttraumatic stress disorder.
These data suggest potential positive treatment outcomes, both cognitively and psychiatrically, and provide rationale for future double-blind, placebo-controlled studies of memantine in PTSD.

ADHD

A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type.
CONCLUSIONS: This pilot study suggests that a memantine dose of 20 mg/day may be a safe and possibly effective treatment for pediatric ADHD. Further investigations of memantine in ADHD appear to be warranted.


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## crayzyMed (Nov 2, 2006)

*Amantadine*

Amantadine has a few promosing animal studies, however it isnt investigated as much as memantine, it may be a good option for those that cannot afford memantine or cannot get it prescribed.

*Amantadine is structurally and functionally related to memantine and has recently been shown to inhibit marble burying in mice [152]. The overall effectiveness of amantadine in this model was more favorable than memantine and riluzole. *This result led the authors to propose the use of amantadine in the treatment of OCD. Amantadine has not been tested in OCD but has been approved by the FDA as an antiviral medication and is used in the treatment of Parkinson's disease (PD). Curiously, an in vitro study comparing amantadine and memantine action in neurons from different brain regions suggested that at therapeutically relevant doses amantadine is more active in the striatum, whereas memantine is more active in other brain structures [153]. *The basis for this functional dichotomy is unknown, but nonetheless may hint at greater potential for amantadine over memantine in treating OCD.*
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746669/

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular 5-HT in the frontal cortex of freely moving rats
Acute administration of amantadine (40 mg kg-1), budipine (10 mg kg-1), REB (10 mg kg-1), PAROX (10 mg kg-1) or CLOM (10 mg kg-1) all failed to significantly alter extracellular 5-HT in the cortex. However, when either amantadine or budipine was administered 30 min prior to any of the three antidepressants, a significant rise in 5-HT was observed. 4 For chronic studies, the effects of the drugs were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular 5-HT at any time point. The three antidepressant drugs all elicited a gradual increase in 5-HT, which became significant after 14 days and tended to plateau thereafter. When either amantadine (20 mg kg-1) or budipine (5 mg kg-1) was coadministered with any of the three antidepressants, two differences were seen compared with the effects of the antidepressants alone. Firstly, the time required for significant increases in cortical 5-HT was reduced with elevated levels now being observed by 7 days. Secondly, the absolute magnitude of the increase in extracellular 5-HT was markedly greater in these rats from day 7 until the end of the experiment. 5 If, as is widely considered, an increase in extracellular 5-HT represents a critical step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants as well as possibly enhance their efficacy.

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular dopamine in the frontal cortex of freely moving rats
When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.

Effect of repeated co-treatment with fluoxetine and amantadine on the behavioral reactivity of the central dopamine and serotonin system in rats.
The obtained results support the hypothesis that repeated co-treatment with fluoxetine and amantadine may evoke more effective antidepressant activity than treatment with fluoxetine alone.

Repeated co-treatment with fluoxetine and amantadine induces brain-derived neurotrophic factor gene expression in rats.
The obtained results suggest that the enhancement of BDNF gene expression may be essential for the therapeutic effect of the co-administration of FLU and AMA in drug-resistant depressed patients, and that among other mechanisms, 5-HT(1A) and 5-HT(2) receptors may play some role in this effect.

Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression
The obtained results indicate that joint therapy with an antidepressant and amantadine may be effective in treatment-resistant unipolar depression.


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## crayzyMed (Nov 2, 2006)

Riluzole

An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder.
CONCLUSIONS: Riluzole may be beneficial for treatment-resistant OCD in young subjects and seems well tolerated. A placebo-controlled trial of the drug is planned.

Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial.
CONCLUSIONS: Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties. The addition of this agent may be of practical clinical benefit in patients with OCD.

Riluzole in the treatment of mood and anxiety disorders.
Riluzole may hold promise for the treatment of several psychiatric conditions, possibly through its ability to modulate pathologically dysregulated glutamate levels, and merits further investigation.

Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms.
CONCLUSIONS: These data suggest that riluzole augmentation produces antidepressant and anxiolytic effects in patients with treatment-resistant depression.

An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression.
CONCLUSIONS: Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.

An open-label trial of riluzole in patients with treatment-resistant major depression.
CONCLUSIONS: Although preliminary, these results indicate that riluzole may have antidepressant properties in some patients.


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## crayzyMed (Nov 2, 2006)

Ketamine

Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels.
In conclusion, our findings demonstrate for the first time that chronic administration of acute inactive doses of ketamine (5 mg/kg) becomes active after chronic treatment, while no signs of tolerance to the behavioural effects of ketamine were observed after chronic administration of acute active doses (10 and 15 mg/kg). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of mood disorders.

Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.
Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days-45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months. CONCLUSIONS: These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD.

Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.
CONCLUSIONS: These preliminary findings support the premise that ketamine has rapid beneficial effects on suicidal cognition and warrants further study.

Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats.
In conclusion, these findings support the idea of a putative role of NMDA receptors in mood-related symptoms, and rapid and robust effects of ketamine in reverting mainly physiological alterations induced by chronic mild stressful situations in rats.

Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models.
Interestingly, ketamine also produced anxiolytic-like effects in the elevated-plus-maze. Importantly, the effective dose of ketamine in the plus-maze did not affect general locomotion measures, in either the plus-maze or in the open field test. While the selective N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 also produced antidepressant-like and anxiolytic-like effects, these were mostly confounded by changes in general activity. Finally, in a neurophysiological model of anxiolytic drug action, ketamine reduced the frequency of reticularly-activated theta oscillations in the hippocampus, similar to the proven anxiolytic drug diazepam. This particular neurophysiological signature is common to all known classes of anxiolytic drugs (i.e. benzodiazepines, 5-HT1A agonists, antidepressants) and provides strong converging evidence for the anxiolytic-like effects of ketamine. Further studies are needed to understand the underlying pharmacological mechanisms of ketamine's effects in these experiments, since it is not clear they were mimicked by the selective NMDA antagonist MK-801.

Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial.
Riluzole did not prevent relapse in the first month following ketamine. Further investigation of relapse prevention strategies post-ketamine is necessary.


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## crayzyMed (Nov 2, 2006)

Other treatments

Topiramate

An open trial of topiramate in the treatment of generalized social phobia.
This study suggests that topiramate may be effective in the treatment of generalized social phobia. These results also suggest the possibility that the neurotransmitters glutamate and GABA may be involved in the neurobiology of generalized social phobia.

Acamprosate

Open-Label Trial of Acamprosate as a Treatment for Anxiety
In this open-label study, acamprosate demonstrated a significant positive effect in decreasing anxiety for most patients. The side effect profile was substantially similar to that reported in the clinical trials. However, these data must be interpreted with caution as preliminary. Limitations to this study include the fact that only 1 clinician was involved in all aspects of the treatment. Although the clinician and the patients rated anxiety separately, the clinician based ratings on interviews with the patients. Thus, there were no truly "blind" raters. In addition, the sample size was modest; however, the effect sizes were substantial.

NAC

Glutamatergic Synaptic Dysfunction and Obsessive-Compulsive Disorder
N-acetylcysteine (NAC) is an amino acid derivative that stimulates the glial cystine/glutamate exchanger and leads to elevated extracellular glutamate levels. This rise in glutamate levels in the extrasynaptic space activates inhibitory mGluR2 receptors that dampen synaptic release of glutamate from neurons [145]. This mechanism of action prompted a case study of NAC in combination with the SSRI fluvoxamine in treatment-refractory OCD that yielded evidence for significant improvement in OCD symptoms [146]. Larger, well controlled studies are needed to further explore the potential of NAC in treating OCD symptoms. Since elevating extracellular/extrasynaptic glutamate by stimulating cystine exchange could also activate NMDA receptors similar to spillover effects of synaptically released glutamate [147], this aspect should not be overlooked in searching for the appropriate therapeutic dose of NAC.

N -acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder
Conclusions NAC augmentation was effective in treating SRI-refractory OCD in this single case. Further research is warranted to investigate the use of NAC and other glutamate modulating agents in the treatment of OCD.

N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial.
CONCLUSIONS: NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar disorder.

Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting.
We describe three cases in which its actions specifically on nail-biting and associated anxiety may offer a potential treatment. The spontaneous findings are reported as part of an ongoing treatment trial examining the utility of NAC in bipolar disorder. Its actions, if robustly replicated, also point to potential treatment targets in glutathione or glutamate pathways in the brain.

N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study.
This study, the first to our knowledge that examines the efficacy of a glutamatergic agent in the treatment of trichotillomania, found that N-acetylcysteine demonstrated statistically significant reductions in trichotillomania [obsessive hair pulling] symptoms. No adverse events occurred in the N-acetylcysteine group, and N-acetylcysteine was well tolerated.


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## euphoria (Jan 21, 2009)

Isn't amantadine significantly anticholinergic? Also, I read topiramate has bad cognitive side effects. Quite a lot of anticonvulsants do actually.


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## crayzyMed (Nov 2, 2006)

euphoria said:


> Isn't amantadine significantly anticholinergic? Also, I read topiramate has bad cognitive side effects. Quite a lot of anticonvulsants do actually.


I doubt thats very significant as its been anecdotally succesfully used to threat ADHD.
I know topiramate has bad cognitive side effects, anyway memantine is the gold standard, its the only antiglutaminergic that improves cognition and there is alot of science supporting the use of it for psychiatric conditions.

I'm not gonna dismiss other treatments tough, want to make an overview of all possible options.


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## euphoria (Jan 21, 2009)

Memantine is awesome.

L-theanine is also a glutamate blocker that's been used for anxiety.


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## crayzyMed (Nov 2, 2006)

euphoria said:


> Memantine is awesome.
> 
> L-theanine is also a glutamate blocker that's been used for anxiety.


Yeah, i could add in supplements with anti glutaminergic activity too, thx for the suggestion.


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