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Online Discussions

Updated 5 February 2013
Printable version

Live Discussion: Taking Stock of Glutamate in Schizophrenia

Dan Javitt

Bita Moghaddam

Joseph Coyle

Adrienne Lahti

Handan Gunduz-Bruce

Lawrence Kegeles

Daniel Javitt, Bita Moghaddam, and Joseph Coyle, along with discussants Adrienne Lahti of the University of Alabama at Birmingham, Lawrence Kegeles of Columbia University, and Handan Gunduz-Bruce of Yale University, weighed in on the state of the idea that disturbed glutamate signaling contributes to the positive, negative, and cognitive symptoms of schizophrenia, and that retuning this system may offer some relief.

Many thanks to the Maryland Psychiatric Research Center and Oxford University Press, publishers of Schizophrenia Bulletin, for providing open access to the introductory article for this Webinar.

Javitt DC. Twenty-five years of glutamate in schizophrenia: Are we there yet? Schizophr Bull 2012 Sept; 38(5): 911-913. Abstract

0:57—Joe Coyle
17:00—Bita Moghaddam
30:56—Dan Javitt
46:50—Larry Kegeles
54:20—Adrienne Lahti
1:03:52—Handan Gundun-Bruce
1:13:00—Panel Discussion/Q&A

View Comments By:
Philip Seeman — Posted 17 January 2013
Philip Seeman — Posted 23 January 2013
— Posted 4 February 2013
Sergey Serdyuk — Posted 8 February 2013
Philip Seeman — Posted 8 February 2013
Paul Morrison — Posted 14 May 2013

It’s been 25 years since glutamate emerged as a potential therapeutic strategy for schizophrenia, but how is the “great glutamate hope” faring these days? In the past year, some findings have strengthened the link between upended glutamate signaling involving N-methyl-D-aspartate (NMDA) receptors (see SRF related news story and SRF news story), but disappointing clinical trials (see SRF related news story and SRF news story) have emphasized the difficulties of translating preclinical findings to helping people with schizophrenia.

Based on a series of themed articles published in the September 2012 issue of Schizophrenia Bulletin, our discussion surveyed the history of the glutamate hypothesis of schizophrenia, including the initial observation of psychomimetic effects of the drug phencyclidine (PCP); the involvement of glutamate signaling in these, with NMDA receptor antagonists mimicking a constellation of schizophrenia-like symptoms; and the current standing of various glutamate-based therapies (see also SRF Current Hypotheses papers on the topic by Moghaddam and Javitt.

To prime the discussion, the following questions were considered. Please add a comment about them, or some other ideas related to glutamate in schizophrenia:

1. How to reconcile the preclinical evidence for glutamate in psychosis and other schizophrenia-like symptoms with the recent failed clinical trials of glutamate drugs?

2. Is there a way to firm up the relationship between NMDA receptor antagonism and schizophrenia symptoms in humans?

3. With recent studies associating cannabis or methamphetamine with psychosis in humans, does this warrant rethinking the usefulness of tracking down psychomimetic effects of any drug? Is psychosis too general a symptom?

4. What can be said for circuit specificity? Are all glutamate-using circuits affected in schizophrenia, or is there a subset involved?

5. How does NMDA receptor blockade lead to the schizophrenia-like symptoms? Ideas include underactive NMDA receptors, compensatory hyperactive glutamate release, or disrupted GABA signaling. How do these models fit together?

Comments on Online Discussion
Comment by:  Philip Seeman (Disclosure)
Submitted 16 January 2013 Posted 17 January 2013

While it is important to pursue several basic approaches...  Read more

View all comments by Philip Seeman

Comment by:  Philip Seeman (Disclosure)
Submitted 23 January 2013 Posted 23 January 2013

This is in reply to the excellent preliminary...  Read more

View all comments by Philip Seeman

Comment by:  Sergey Serdyuk
Submitted 6 February 2013 Posted 8 February 2013

As is known, all NMDA antagonists produce hyperactivity,...  Read more

View all comments by Sergey Serdyuk

Comment by:  Philip Seeman (Disclosure)
Submitted 5 February 2013 Posted 8 February 2013

The dopamine-like action of phencyclidine inhibits the...  Read more

View all comments by Philip Seeman

Comment by:  Paul Morrison
Submitted 11 May 2013 Posted 14 May 2013

Ketamine, a drug that has attracted the attention of...  Read more

View all comments by Paul Morrison
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