# Glutamate elevated in brains of mood disorder patients



## David Baxter PhD (Nov 27, 2007)

Glutamate elevated in brains of mood disorder patients
By Andrew Czyzewski
27 November 2007
_Biol Psychiatry_ 2007; 62: 1310-1316

Patients with bipolar disorder and major depression have elevated glutamate levels in the frontal cortex compared with mentally healthy controls, say the results of a postmortem study.

Glutamate is the major excitatory neurotransmitter in the cerebral cortex and is thought to play a role in major mental disorders, explain Kenji Hashimoto (Chiba University Center for Forensic Mental Health, Japan) and colleagues in the journal _Biological Psychiatry_.

Glutamate antagonists such as phencyclidine (PCP) and ketamine produce a psychotic state that mimics schizophrenia, leading some scientists to suggest that glutamate plays a role in the disease.

On the other hand it remains unclear whether glutamatergic neurotransmission plays a role in mood disorders such as bipolar disorder and major depression.

Post mortem brains are critical for examining molecular changes associated with the pathophysiology of mental disorders, but studies have so far provided conflicting results, say Hashimoto and colleagues.

This may be partly due to wide variations in the time between death and the extraction of tissue - known as the post mortem interval (PMI) - which can have a pronounced effect on glutamate levels. Unfortunately, such variations are often unavoidable when using biological samples.

To model variations in the PMI of human tissue, the researchers first examined glutamate levels in the frontal cortex of mouse brains taken at 6, 12, 24, 36, 48, 60, and 72 hours after death.

Hashimoto and colleagues then analyzed glutamate levels in human post mortem frontal cortex adjusting for PMI based on the mouse data.

Tissue samples were taken from 15 patients with schizophrenia, 15 patients with bipolar disorder, 15 patients with major depression, and 15 mentally healthy controls.

The frontal cortex of bipolar patients had, on average, 15.33 nmol of glutamate per mg of brain tissue - significantly higher than the 10.68 nmol/mg found in the brains of mentally healthy controls.

This finding is consistent with the observation that mood-stabilizing drugs used in the treatment of bipolar disorder exert neuroprotective effects against glutamate-induced excitotoxicity in neuron cultures, say the researchers.

They found that patients with major depression also had elevated levels of glutamate in the frontal cortex at 14.09 nmol/mg. Contrary to their predictions, glutamate was not, however, elevated in the brains of patients with schizophrenia.

Based on these findings, the team concludes that increased glutamate may lead to an increase in neuronal cell death contributing to the pathophysiology of mood disorders.

Abstract


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## Jan (Dec 1, 2007)

Was this the brains of people BEFORE or AFTER they'd been given psychiatric drugs? 

If you're diagnosed with BPD and are in a medical study, you are almost certain to have been on neuroleptics, and while the brain scan is ongoing you are almost certainly on neuroleptics.  A true control group would be never-medicated BPD, and this study gives no indication that the control group is a REAL control group.

Brain scans are touted to "prove" that depression/mania/bipolar disorder/you name it is caused by flawed physiology of the brain.  This is not supported by careful reading of the studies; however, it makes for excellent marketing to the unlettered and gullible (Look! Look! It's right there in front of your eyes! See? Different brain! Handicapped brain!).

Once you put psychiatric drugs into a brain, however, the brain IS changed.  So I strongly question whether the differences seen are at least in part due to the changes that neurotropic medications like Lithobid, benzodiazepines, SSRIs, Neurontin, etc., cause.  Once you introduce those medications into the brain, you have changed the brain. There's also down-regulation to consider, which leads to more drugs, which leads to more brain changes.

I don't think this study is saying what you want it to say.  I think you want it to say that by tinkering with glutamate levels (like we recklessly tinker with serotonin and norepi levels) we can someday control bipolar disorder with a (yet another miracle) pill.


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## David Baxter PhD (Dec 1, 2007)

Your comments may apply to this specific study, and I think even in this study it is acknowledged that the evidence on the role of glutamate isn't entirely clear. 

However, I think you're confusing at least two things: 

1. The first is whether there are physiological-anatomical (or at a more microscopic level chromosomal) differences in the brain that might explain various types of mental illness. 

2. The second is whether various types of mental illness are associated with alterations (excesses or deficiencies) in neurotransmitter levels.

The evidence regarding question #1 is accumulating but the issue is complex and there have been many blind alleys in such research before, as long as I have been paying attention (which goes back to the 60s now).

The evidence relevant to question #2 is not unclear at all. While we don't know whether the changes in neurotransmitter levels is cause or effect of specific mental disorders, there is no doubt whatsoever that the two are correlated. This is true in never medicated and previously medicated as well as medicated patients. It is also true that medication-induced changes in those neurotransmitter levels is associated with reduction in symptoms of mental disorders such as depression, anxiety, bipolar disorder, schizophrenia, etc. Thus, I think it would be difficult to argue that medications for these disorders are not effective. Indeed, I would argue that you would have to have your head buried quite throughly in the sand to be able to make such an argument.


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## Jan (Dec 1, 2007)

Psychiatric medications, even the newer ones, are not more effective than placebo and not more effective than talk therapy, especially in the long term.  The studies show that pretty clearly.

And please don't insult me by suggesting I have my head in the sand.  That's not being very therapeutically helpful, or even friendly.  I never said that you personally were gullible, only that this brain-scan scam is an effective marketing tool on those who aren't going to be reading and evaluating the studies themselves.


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## David Baxter PhD (Dec 1, 2007)

Jan said:


> Psychiatric medications, even the newer ones, are not more effective than placebo and not more effective than talk therapy, especially in the long term.  The studies show that pretty clearly.



That is simply not true. The majority of studies show very clearly that medication plus psychotherapy is more effective than either alone. And as for medications being no more effective than placebo, that is nonsense. And making such statement is absolutely not "therapeutically helpful".



Jan said:


> And please don't insult me by suggesting I have my head in the sand.  That's not being very therapeutically helpful, or even friendly.  I never said that you personally were gullible, only that this brain-scan scam is an effective marketing tool on those who aren't going to be reading and evaluating the studies themselves.



A marketing tool for whom exactly?


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## Into The Light (Dec 1, 2007)

> Once you put psychiatric drugs into a brain, however, the brain IS changed.


the brain is _already_  changed _before_ you start medication. the change is due to the illness the person is suffering from. yes the medication changes tbe brain, but it's supposed to! it's there to help restore the brain to a more functional physiology.



Jan said:


> Psychiatric medications, even the newer ones, are not more effective than placebo and not more effective than talk therapy, especially in the long term.  The studies show that pretty clearly.



which studies exactly would those be?

there is clear evidence that people are HELPED with medication. i personally have been helped by medication, it has saved my life and improved my quality of life. you are misinformed and are misinforming people with your above statement.


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## Jan (Dec 1, 2007)

http://www.oregoncounseling.org/ArticlesPapers/Documents/TherapyVsRx.htm

From this article, which is one of many collections and analyses of peer-reviewed research that you can find with a simple Google search on "antidepressants better than placebo":

 In 2004 Kirsch and Antonuccio (14) testified before the Food and Drug Administration stating there are a total of 12 published randomized clinical trials (RCT) in the entire world literature of treating children with antidepressants. *Eight of these 12 trials failed to find any significant benefit of medication over inert placebo.* Only 4 of the RCTs claimed significant differences between drug and placebo, and those did so only on clinician rated measures, not patient rated measures. Three of the clinical trials did not report means and/or standard deviations, leaving 9 for a meta-analysis. When these nine studies are combined the improvement attributed to placebo was 87%. Overall, this means that no more than 13% of people who improved actually benefited from antidepressants. No more that 25 % of people who improved responded to SSRIs like Prozac. This meta-analysis indicates that Tricyclic Antidepressants (TCAs) have no significant pharmacological effect on depression in children. In effect, 75% of the SSRI response and 97% of the TCA response is placebo or consequences that are associated with the passage of time. *While the effects of Selective Serotonin Reuptake Inhibiters (SSRIs) like Prozac are statistically significant, there was no evidence in these studies that the use of these drugs was clinically significant.*

And as "for whom"--the makers of psychiatric pharmaceuticals, of course. Perhaps they aren't marketed quite as aggressively in Canada as they are in the United States.

As for CBT plus medication being the _ne plus ultra_ of therapeutic approaches, when the insurance runs out, or family dynamics risk being disrupted, which treatment do you think will be maintained, and which discarded?  Talk therapy or a steady regimen of medication that insurance will subsidize pretty much indefinitely?


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## Into The Light (Dec 1, 2007)

that's a study on the effects of anti-depressants on children. that's a whole different category, and i know there is a lot unknown in that area. children's brains are still growing, changing and developing, and for many drugs we do not know the effects on children. we do know they may have different results than for adults. it may very well be that anti-depressants do not work for children. i do not know.

i do know that anti-depressants work for adults. anti-depressants alone aren't going to fix you. if you are depressed enough to need anti-depressants, you need therapy to go along with them if you want to return back to a normal feeling life. if you just take the medication and don't do the therapy, you may feel somewhat better, but you will still be feeling the effects of depression, just in a lesser amount than before. pills on their own are not enough.


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## David Baxter PhD (Dec 1, 2007)

ladybug said:


> that's a study on the effects of anti-depressants on children. that's a whole different category, and i know there is a lot unknown in that area. children's brains are still growing, changing and developing, and for many drugs we do not know the effects on children. we do know they may have different results than for adults. it may very well be that anti-depressants do not work for children. i do not know.



Exactly. Well said.


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## David Baxter PhD (Dec 2, 2007)

I didn't have time to reply fully to this thread yesterday, so let me remedy that now.

For more information bearing on the "medication vs. placebo" claim (and about age and other factors in the treatment of depression), see Age, diet, eating, exercise all affect antidepressant effectiveness - Psychlinks Psychology and Self-Help Forum 

See also Recognizing Depression in Children - Psychlinks Psychology and Self-Help Forum 

Severity of depression is also a critical factor in whether treatment without medication may be effective. I am not trying to argue that some people with mild to moderate depression, especially where there is a clear psychosocial trigger for the depression, cannot overcome the depression using psychotherapy, exercise, nutrition, and improved coping and problemn-solving skills. However, I do take issue with any claim that antidepressant medications are not an important component in the treatment of depression, and particularly I take issue with the claim that "they are no better than placebo".

A sampling of studies and reports providing evidence for the efficacy of anti-depressant medications and the role of neurotransmitters in mood and anxiety disorders (each of these links to the original reports and many contain Adobe Acrobat versions of the report as well as complete reference lists for studies, reviews, and meta analyses in scientific journals):


Combining Drug Therapy and Psychotherapy for Depression - Psychlinks Psychology and Self-Help Forum

Depressed Teens Benefit From Fluoxetine And Psychotherapy Combination - Psychlinks Psychology and Self-Help Forum

What Kind Of Treatment Is Available? - Psychlinks Psychology and Self-Help Forum

Depression Treatment Guide: Mayo Clinic - Psychlinks Psychology and Self-Help Forum

Treatment of SSRI-Resistant Depression: Use of non-SSRI medications - Psychlinks Psychology and Self-Help Forum

Need for Long-Term Treatment of Major Depression - Psychlinks Psychology and Self-Help Forum

The Role of Dopamine and Norepinephrine in Depression - Psychlinks Psychology and Self-Help Forum 

Bacteria, Serotonin, and Depression - Psychlinks Psychology and Self-Help Forum

How antidepressants create new brain cells - Psychlinks Psychology and Self-Help Forum

Double Depression Treatment Cuts Remission Rate - Psychlinks Psychology and Self-Help Forum

Antidepressant benefit may be apparent sooner - Psychlinks Psychology and Self-Help Forum 

NIMH STAR*D - Further Findings on Depression Treatment Options - Psychlinks Psychology and Self-Help Forum

Researchers Lift A Corner Of The Veil Of Depression - Psychlinks Psychology and Self-Help Forum

Pilots safer on anti-depressants - Psychlinks Psychology and Self-Help Forum

Newer antidepressants equally effective but side effects differ - Psychlinks Psychology and Self-Help Forum

SSRIs Begin Working as Early as the First Week: Study - Psychlinks Psychology and Self-Help Forum

Antidepressants May Work More Quickly Than Thought - Psychlinks Psychology and Self-Help Forum

Antidepressant effectiveness influenced by individual gene variations - Psychlinks Psychology and Self-Help Forum

SSRI antidepressants actions studied - Psychlinks Psychology and Self-Help Forum
I would also strongly recommend that you read the papers in the Suicide and SSRIs forum here, showing increases in suicide rates among young people associated with restrictions on prescribing SSRIs to young people.


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## David Baxter PhD (Dec 3, 2007)

See also Increased Brain MAO-A Levels in Major Depressive Disorder - Psychlinks Psychology and Self-Help Forum


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