Schizophrenia Research Forum - A Catalyst for Creative Thinking

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
Charles Stromeyer Jr. — 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 in treating psychosis, it is a fact that phencyclidine is more potent at stimulating dopamine D2 receptors than at glutamate receptors (Seeman and Guan, 2008; Seeman et al., 2009). This suggests that phencyclidine elicits psychosis via stimulation of D2 receptors, an action that is clinically inhibited by the selective block of D2 receptors with haloperidol (Giannini et al., 1984; Giannini et al., 1984-85).

References:

Giannini AJ, Eighan MS, Loiselle RH, Giannini MC. (1984) Comparison of haloperidol and chlorpromazine in the treatment of phencyclidine psychosis. J Clin Pharmacol 24:202-204. Abstract

Giannini AJ, Nageotte C, Loiselle RH, Malone DA, Price WA. (1984-85) Comparison of chlorpromazine, haloperidol and pimozide in the treatment of phencyclidine psychosis: DA-2 receptor specificity. Clin Tox 22(6):573-579. Abstract

Seeman P, Guan H-C. (2008) Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia. Synapse 62: 819-828. Abstract

Seeman P, Guan H-C, Hirbec H. (2009) Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Synapse 63(8): 698-704. Abstract

View all comments by Philip SeemanComment by:  Philip Seeman (Disclosure)
Submitted 23 January 2013
Posted 23 January 2013

This is in reply to the excellent preliminary questions:

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

A: Preclinical evidence showed that the Lilly glutamate agonist (LY404039; used in the failed clinical study) caused 50 percent stimulation of dopamine D2 receptors at 80 nM (Seeman and Guan, 2009; Seeman, 2013). This indicated that this glutamate agonist was actually more potent at dopamine D2 receptors than at the metabotropic glutamate receptors, where the drug had a dissociation constant of between 92 nM and 149 nM (Seeman and Guan, 2009; Seeman, 2013). However, this partial agonist potency of the LY drug at the D2 receptor was still very much lower than that for aripiprazole, indicating that little or no clinical antipsychotic effect would have been expected.

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

A: Phencyclidine stimulates dopamine D2 receptors by 50 percent at about 50 nM, but stimulates ionotrophic glutamate receptors between 97 nM and 2,000 nM (Seeman and Guan, 2008). This indicates that phencyclidine is more potent on dopamine D2 receptors than at the ionotrophic glutamate receptors. It follows that the psychotic action of phencyclidine may well be driven by its effect on D2 receptors. The clinical action of haloperidol in stopping phencyclidine psychosis in the emergency room (Giannini et al., 1984; Giannini et al., 1984-1985) corroborates this view, because haloperidol primarily has an anti-D2 action rather than an anti-glutamate effect.

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

A: The majority of psychotomimetics and hallucinogens stimulate the dopamine D2High receptor (Seeman et al., 2009). This includes cannabis and methamphetamine (Refs. in Fig. 4 of Seeman, 2011).

References:

Giannini AJ, Eighan MS, Loiselle RH, Giannini MC. (1984) Comparison of haloperidol and chlorpromazine in the treatment of phencyclidine psychosis. J Clin Pharmacol 24:202-204. Abstract

Giannini AJ, Nageotte C, Loiselle RH, Malone DA, Price WA. (1984-85) Comparison of chlorpromazine, haloperidol and pimozide in the treatment of phencyclidine psychosis: DA-2 receptor specificity. Clin Tox 22(6):573-579. Abstract

Seeman P. (2011) All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2High receptors. CNS Neuroscience and therapeutics. 17(2): 118-132. Abstract

Seeman P. (2013) An agonist at glutamate and dopamine D2 receptors, LY404039. Neuropharmacology 66: 87-88. Abstract

Seeman P, Guan H-C. (2008) Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia. Synapse 62: 819-828. Abstract

Seeman P, Guan HC. (2009) Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2High receptor. Synapse. 63(10): 935-939. Abstract

Seeman P, Guan H-C, Hirbec H. (2009) Dopamine D2High receptors stimulated by phencyclidines, LSD, salvinorin A, and modafinil. Synapse 63(8): 698-704. Abstract

View all comments by Philip SeemanComment by:  Charles Stromeyer Jr.
Submitted 30 January 2013
Posted 4 February 2013

This new paper (Steiner et al., 2013) published online in JAMA Psychiatry shows that there are multiple NMDA receptor antibodies present in those individuals with an initial diagnosis of schizophrenia.

What do you suppose might be the possible therapeutic implications of this new discovery?

Thank you.

References:

Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, Kästner A, Skalej M, Jordan W, Schiltz K, Klingbeil C, Wandinger KP, Bogerts B, Stoecker W. Increased Prevalence of Diverse N -Methyl-D-Aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia: Specific Relevance of IgG NR1a Antibodies for Distinction From N -Methyl-D-Aspartate Glutamate Receptor Encephalitis. JAMA Psychiatry. 2013 Jan 23:1-8. Abstract

View all comments by Charles Stromeyer Jr.Comment by:  Sergey Serdyuk
Submitted 6 February 2013
Posted 8 February 2013

As is known, all NMDA antagonists produce hyperactivity, stereotypia, and ataxia in rats as a result of compensatory stimulation of AMPA receptors by endogenous glutamate. The best option for treating behavioral toxicity in animals and schizophrenia in patients may be the use of combined NMDA+AMPA antagonists. We proposed a new AMPA+NMDA antagonist (IEM1913) for treatment of epilepsy without the side effects typical of classical NMDA antagonists.

References:

Gmiro VE, Serdyuk SE. Combined blockade of AMPA and NMDA receptors in the brain of rats prevents pentylenetetrazole-induced clonic and tonic-clonic seizures without ataxia. Bull Exp Biol Med. 2008 Jun;145(6):728-30. Abstract

View all comments by Sergey SerdyukComment by:  Philip Seeman (Disclosure)
Submitted 5 February 2013
Posted 8 February 2013

The dopamine-like action of phencyclidine inhibits the release of prolactin from primary culture of the anterior pituitary between 0.1 and 10 nM, with an IC50 percent of 4 nM (Seeman and Lasaga, 2005), far more potent than at glutamate receptors, supporting the view that the psychotic action of this drug is associated with the stimulation of dopamine receptors. The serum phencyclidine concentration that elicits psychotomimetic action is of the order of 10 nM (Javitt and Zukin, 1991).

References:

Javitt DC, Zukin SR. (1991). Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148: 1301–1308. Abstract

Seeman P, Lasaga M. (2005). Dopamine agonist action of phencyclidine. Synapse 58: 275-277. Abstract

View all comments by Philip SeemanComment by:  Paul Morrison
Submitted 11 May 2013
Posted 14 May 2013

Ketamine, a drug that has attracted the attention of psychiatrists in the past few decades, "blocks" the NMDA channel. It has been used as a model psychosis, and latterly has been demonstrated to have acute anti-depressant properties. (It certainly impairs new learning, as would be expected).

Downstream of NMDA blockade, there is no clear consensus as to how ketamine produces a psychosis. Counterintuitively (for a glutamate antagonist), ketamine increases the excitability (spiking) of pyramidal neurons. Ketamine also increases the power of γ band (~40 Hz oscillations), and some have proposed that "kernels" of "abnormal" γ underlie the psychotic-like effect.

But the behavioral pharmacology of ketamine is far from straightforward. Rating scales used in schizophrenia research are probably not ideal for capturing the nuances of the drug. Those who have taken a more phenomenological approach, in the sense of "bracketing out" existing assumptions whilst focusing on clear descriptions, have identified a much richer and more complex behavioral psychopharmacology, which includes euphoria, near-death experiences, the cessation of time, the dissolution of the ego, and the experience of being immersed in fractal geometries or boundless oneness (Jansen K, Ketamine: Dreams and Realities 2000).

Close observation reveals the dose-dependent emergence of an oneiroid (dreamlike) state and other catatonic features (ambitendency, posturing) but not a classic paranoid psychosis. Researchers have also tended to assume that ketamine can "cause" negative symptoms, but reports of euphoria, terror, and awe are inconsistent with this categorization. Motor output (which includes speech, of course) is certainly restricted following ketamine, but because the concurrent inner world is a kaleidoscope of strange, mystical, and fantastic experiences with extremes of emotion, the overall picture is far removed from the negative syndrome.

Nevertheless, ketamine is frequently championed as the most convincing drug model of schizophrenia because it can induce negative symptoms on a rating scale. The irony perhaps is that the ketamine experience might actually be more schizophrenia-like than many of its proponents have suggested. Ketamine elicits phenomena, which are now very rarely encountered in psychiatric clinics, given the modern-day domination of the softer, paranoid form of the illness.

Therapeutics... Paul Janssen's genius was in predicting that a drug which blocked the effects of amphetamine in animals would be an effective treatment for those cases of schizophrenia that resembled an amphetamine psychosis (characterized by agitation, hallucinations, and delusions). That drug was haloperidol, and that class of drug (D2 dopamine receptor antagonists) changed the landscape of psychiatry.

Janssen's logic would also suggest that a drug which inhibited the effects of ketamine in animals would be an effective treatment for those cases of schizophrenia which resemble ketamine-elicited psychopathology (characterized by bizarre, inaccessible dreamlike states and psychotic motor phenomena, i.e., cases where ECT becomes a sensible option). A pharmacological antagonist of ketamine (in animals) proved to be ineffective against human paranoid schizophrenia (see SRF related news story). Perhaps this could have been predicted by closer attention to the phenomenology of ketamine. The question now is whether "The Lilly compound" has efficacy against endogenous psychoses which resemble ketamine (at proper, not homoeopathic, doses).

References:

Jansen K, Ketamine: Dreams and Realities. 2000.

View all comments by Paul Morrison